U.S. patent application number 12/702921 was filed with the patent office on 2010-08-05 for heterocyclic compounds as sweetener enhancers.
This patent application is currently assigned to Redpoint Bio Corporation. Invention is credited to Anita B. Atwal, Karnail S. ATWAL, Ivona Bakaj, Robert W. Bryant, Rok Cerne, Roy Kyle Palmer.
Application Number | 20100197813 12/702921 |
Document ID | / |
Family ID | 39107364 |
Filed Date | 2010-08-05 |
United States Patent
Application |
20100197813 |
Kind Code |
A1 |
ATWAL; Karnail S. ; et
al. |
August 5, 2010 |
Heterocyclic Compounds as Sweetener Enhancers
Abstract
The present invention is directed to the use of a compound of
Formula I ##STR00001## and physiologically acceptable salts thereof
wherein G.sup.1, G.sup.2, G.sup.3, R.sup.1, R.sup.2, R.sup.7,
R.sup.3, R.sup.4, and R.sup.5 are defined herein. Compounds
according to Formula I can be used to enhance a sweet taste
produced by a tastant. The invention is also directed to
compositions comprising a compound according to the above formula.
Other aspects of the invention provide methods, compounds, and
compositions for improved food products wherein the food product
comprises a compound according to Formula I and a reduced amount of
a sweet tastant.
Inventors: |
ATWAL; Karnail S.;
(Pennington, NJ) ; Atwal; Anita B.; (Pennington,
NJ) ; Bryant; Robert W.; (Princeton, NJ) ;
Bakaj; Ivona; (Cranbury, NJ) ; Palmer; Roy Kyle;
(Cranbury, NJ) ; Cerne; Rok; (Lawrenceville,
NJ) |
Correspondence
Address: |
STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C.
1100 NEW YORK AVENUE, N.W.
WASHINGTON
DC
20005
US
|
Assignee: |
Redpoint Bio Corporation
Ewing
NJ
|
Family ID: |
39107364 |
Appl. No.: |
12/702921 |
Filed: |
February 9, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11843411 |
Aug 22, 2007 |
7674831 |
|
|
12702921 |
|
|
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|
60839118 |
Aug 22, 2006 |
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Current U.S.
Class: |
514/784 ;
426/534; 426/535; 514/785; 514/788 |
Current CPC
Class: |
A23L 27/205 20160801;
A23L 27/204 20160801; A61K 47/22 20130101; A61P 43/00 20180101;
A23L 27/88 20160801 |
Class at
Publication: |
514/784 ;
426/534; 426/535; 514/785; 514/788 |
International
Class: |
A61K 47/12 20060101
A61K047/12; A23L 1/22 20060101 A23L001/22; A61K 47/14 20060101
A61K047/14; A61K 47/18 20060101 A61K047/18; A61K 47/22 20060101
A61K047/22; A61P 43/00 20060101 A61P043/00 |
Claims
1-19. (canceled)
20. A composition comprising (a) a sweet tastant; and (b) a
compound of Formula I: ##STR00082## or a physiologically acceptable
salt thereof, wherein G.sup.1, G.sup.2, and G.sup.3 are
independently selected from N, S, and C; R.sup.1 and R.sup.2 are
independently absent or selected from the group consisting of
C.sub.1-6 alkoxycarbonyl, hydrogen, C.sub.1-6 alkyl, halogen,
nitro, optionally substituted C.sub.6-14 aryl, optionally
substituted 5-14 membered heteroaryl, Ar-Q, optionally substituted
(CH.sub.2).sub.nC(.dbd.O)--O--R.sup.2a, and optionally substituted
(CH.sub.2).sub.nC(.dbd.O)aryl, or R.sup.1 and R.sup.2, together
with the G.sup.3 and the carbon atom to which R.sup.1 is attached,
form a C.sub.6-14 aryl or 5- to 14-membered heterocycle, each of
which is optionally substituted with 1-3 substituents independently
selected from the group consisting of amino, hydroxy, nitro,
halogen, cyano, thiol, oxo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkenyloxy,
optionally substituted C.sub.6-14 aryl; or if the bond to R.sup.1
and/or R.sup.2 is a double bond, then R.sup.1 and R.sup.2 are
independently selected from .dbd.NH and .dbd.O; R.sup.3 is selected
from the group consisting of H, C.sub.1-6 haloalkyl, C.sub.1-6
alkyl, oxo, .dbd.NH, optionally substituted C.sub.6-14 aryl,
optionally substituted 5-14 membered heterocycle, and
L.sup.1-R.sup.31; R.sup.4 is absent or is selected from the group
consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6
alkoxy, C.sub.1-6 hydroxyalkyl, optionally substituted C.sub.6-14
aryl, and optionally substituted (CH.sub.2).sub.nC(.dbd.O)aryl, or
when the bond to R.sup.4 is a double bond, R.sup.4 is .dbd.O;
R.sup.5 is either absent or is selected from the group consisting
of hydrogen, C.sub.1-6 alkyl, and optionally substituted phenyl
amide; R.sup.7 is either absent or selected from the group
consisting of H and C.sub.1-6 alkyl; R.sup.2a is C.sub.1-6 alkyl;
R.sup.31 is H, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, optionally
substituted phenyl, amino, C.sub.1-6 alkylamino, or C.sub.1-6
dialkylamino; L.sup.1 is a linker selected from the group
consisting of .dbd.Z.sup.1--(CH.sub.2).sub.n--Z.sup.2--,
-(Het)-C(O)--NH--,
.dbd.N--(CH.sub.2).sub.n--C(.dbd.Z.sup.3)--Z.sup.4--,
--NH--C(.dbd.O)--(CH.sub.2).sub.n--, ##STR00083## Z.sup.1 is
selected from the group consisting of .dbd.N, --NH, O, and S;
Z.sup.2 is absent, O, S, C(.dbd.O), C(.dbd.S), --C(.dbd.O)--O,
C(.dbd.S)--O, --C(.dbd.O)--NH-- or --C(.dbd.S)--NH; Z.sup.3 is O or
S; Z.sup.4 is O, S, or NH; Het is a 5- to 7-membered
nitrogen-containing heterocycle; Q is CH.sub.2, O, NH, or S; Ar is
optionally substituted aryl or optionally substituted heteroaryl;
and n is 0 to 10.
21. The composition according to claim 20, wherein the compound of
Formula I is ##STR00084## or a physiologically acceptable salt
thereof, wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.4 is absent, H,
C.sub.1-6 alkyl, or C.sub.1-6 hydroxyalkyl; R.sup.5 is absent, H,
or C.sub.1-6 alkyl; R.sup.a is H or C.sub.1-6 alkyl; and G.sup.1
and G.sup.2 are independently C, N, or S.
22. The composition according to claim 20, wherein the compound of
Formula I is ##STR00085## or a physiologically acceptable salt
thereof, wherein R.sup.4 is H, C.sub.1-6 alkyl, or C.sub.1-6
hydroxyalkyl; R.sup.a is H or C.sub.1-6 alkyl; R.sup.31 is selected
from the group consisting of H, C.sub.1-6 alkyl, and C.sub.1-6
alkenyl; Z.sup.3 is O or S; Z.sup.4 is O, S, or NH; and n is 0 to
3.
23. The composition according to claim 20, wherein the compound of
Formula I is ##STR00086## or a physiologically acceptable salt
thereof, wherein R.sup.4 is selected from the group consisting of
H, C.sub.1-6 alkyl, and C.sub.1-6 hydroxyalkyl; R.sup.a is H or
C.sub.1-6 alkyl; R.sup.b is C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, or
hydroxy; n is 0 to 3; and p is 0 to 5.
24. The composition according to claim 20, wherein the compound of
Formula I is ##STR00087## or a physiologically acceptable salt
thereof, wherein G.sup.1 is N or S; Q is N or C; R.sup.3 is H or
optionally substituted phenyl; R.sup.5 is H when G.sup.1 is N, or
otherwise is absent; R.sup.6 is selected from the group consisting
of H and C.sub.1-6 alkyl; and R.sup.7 is selected from the group
consisting of H, C.sub.1-6 alkyl, and optionally substituted
phenyl, or, when Q is N, R.sup.7 is absent.
25. The composition according to claim 20, wherein the compound of
Formula I is ##STR00088## or a physiologically acceptable salt
thereof, wherein R.sup.1 and R.sup.2 are independently selected
from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6
alkoxycarbonyl, and Ar-Q, wherein Q is O, NH, S, or CH.sub.2, and
Ar is an optionally substituted aryl or optionally substituted
heteroaryl; R.sup.3 is H or C.sub.1-6 alkyl; R.sup.4 is absent, H,
or C.sub.1-6 alkyl; R.sup.5 is absent, H, or C.sub.1-6 alkyl;
G.sup.1 is C or N; and G.sup.2 is N or S.
26. The composition according to claim 20, wherein Ar-Q is an
optionally substituted 5-14 membered heteroaryloxy or optionally
substituted 5-14 membered heteroarylthio.
27. The composition according to claim 21, wherein the compound is
##STR00089## or a physiologically acceptable salt thereof, wherein
R.sup.3 is L.sup.1-R.sup.31; R.sup.5 is H or C.sub.1-6 alkyl;
G.sup.2 is N or S; and R.sup.a is H or C.sub.1-6 alkyl.
28. The composition according to claim 21, wherein the compound of
Formula I is: ##STR00090## or a physiologically acceptable salt
thereof, wherein G.sup.1 is S or N; R.sup.4 is H, C.sub.1-6 alkyl,
or C.sub.1-6 hydroxyalkyl; R.sup.31 is H, C.sub.1-6 alkyl,
C.sub.1-6 alkenyl, or optionally substituted phenyl; R.sup.a is H
or C.sub.1-6 alkyl; Z.sup.1 is S or N; Z.sup.2 is --C(.dbd.O)--O--,
--C(.dbd.S)--O, --O--, --S--, --C(.dbd.O)--NH--, or
--C(.dbd.S)--NH--; and n is 0 to 4.
29. The composition according to claim 24, wherein the compound is
##STR00091## or a physiologically acceptable salt thereof, wherein
R.sup.3 is H, C.sub.1-6 alkyl, or optionally substituted phenyl;
and R.sup.7 is selected from the group consisting of H, C.sub.1-6
alkyl, and optionally substituted phenyl.
30. The composition according to claim 20, wherein the compound is
##STR00092## or a physiologically acceptable salt thereof, wherein
R.sup.3 is H or C.sub.1-6 alkyl; R.sup.5 is H or C.sub.1-6 alkyl;
Ar is a 5- to 10-membered aryl or heteroaryl group optionally
substituted with one or more groups independently selected from the
group consisting of NO.sub.2, halogen, C.sub.1-6 alkyl, and
C.sub.1-6 hydroxyalkyl; Q is O or NH; R.sup.b is H or C.sub.1-6
alkyl; and n is 0 to 3.
31. The composition according to claim 30, wherein the compound is
##STR00093## or a physiologically acceptable salt thereof, wherein
R.sup.3 is H or C.sub.1-6 alkyl; each occurrence of R.sup.a is
independently selected from the group consisting of NO.sub.2,
halogen, C.sub.1-6 alkyl, or C.sub.1-6 hydroxyalkyl; R.sup.b is H
or C.sub.1-6 alkyl; and n is 0 to 3.
32. The composition according to claim 20, wherein the compound is:
##STR00094## or a physiologically acceptable salt thereof, wherein
R.sup.1 is H, C.sub.1-6 alkyl, halogen, or NO.sub.2; R.sup.3 and
R.sup.4 are independently H or C.sub.1-6 alkyl; Q is S, N, or O;
and Ar is a 5- to 6-membered heteroaryl optionally substituted with
one or more substituents independently selected from the group
consisting of nitro and halogen.
33. The composition according to claim 20, wherein the compound of
Formula I is: ##STR00095## or a physiologically acceptable salt
thereof, wherein R.sup.1 and R.sup.3 are independently optionally
substituted phenyl; R.sup.4 is absent or C.sub.1-6 alkyl; and
R.sup.2 and R.sup.7 are independently C.sub.1-6 alkyl.
34. The composition according to claim 20, wherein the compound is
##STR00096## or a physiologically acceptable salt thereof, wherein
R.sup.1 is H or C.sub.1-6 alkyl; R.sup.2 is H; R.sup.3 is C.sub.1-6
alkyl, H, oxo, or .dbd.NH; R.sup.31 is optionally substituted
phenyl; and n is 0 to 3.
35. The composition according to claim 20, wherein the compound is:
##STR00097## or a physiologically acceptable salt thereof, wherein
R.sup.1 is H or C.sub.1-6 alkyl; R.sup.2 is H or C.sub.1-6 alkyl;
R.sup.33 is optionally substituted phenyl; R.sup.34 is H or
C.sub.1-6 alkyl; and m is 1.
36. The composition according to claim 20, wherein the compound is
selected from the group consisting of ethyl
2-(3-methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate;
2-(2-(2-methoxyphenoxy)ethylthio)-1H-benzo[d]imidazole; methyl
3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate;
6-(4-chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazo-
le; 6-p-tolylimidazo[2,1-b][1,3,4]thiadiazole;
N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide;
2-(2-(2-(2,6-dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)ethanol;
1-ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole;
2,4-diphenyl-5,5-dimethylimidazole-1-oxide;
1-allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea;
2-(2-iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone;
3-benzyl-1-isopropyl-5-(4-methylthiazol-2-yl)pyrimidine-2,4(1H,3H)-dione;
2-(3-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine;
N-(4-(4-ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide;
1-phenylthiochromeno[4,3-d]imidazol-4(1H)-one;
N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;
5-chloro-1-methyl-3-(trifluoromethyl)-N-(4-trifluoromethyl)phenyl)-1H-pyr-
azole-4-carboxamide; and physiologically acceptable salts
thereof.
37. The composition according to claim 20, wherein the sweet
tastant is selected from the group consisting of sucrose, fructose,
and mixtures thereof.
38. The composition according to claim 37, wherein the compound
according to Formula I and the sweet tastant are in a ratio from
about 1:10.sup.6 to about 1:10.sup.3.
39. The composition according to claim 20, wherein said composition
further comprising an active agent and optionally one or more
pharmaceutically acceptable carriers.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. application Ser.
No. 11/843,411, filed Aug. 22, 2007, which claims the benefit of
U.S. Provisional Application No. 60/839,118, filed Aug. 22, 2006,
which is herein incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to the use of compounds of
Formula I for enhancing a sweet taste, masking an unpleasant taste
by creating a sweet taste, and related uses. The invention is also
directed to, among other things, compositions comprising a compound
of Formula I that can be used in pharmaceutical, food, and other
products as a sweetener enhancer or as a taste masking agent. In
certain aspects, the invention provides methods and compositions
for enabling one to prepare consumable products, such as food and
pharmaceutical products, which retain a desired sweetness but
contain lower amounts of sweetener, such as sugar, and in some
cases fewer calories.
[0004] 2. Background Art
[0005] Taste perception plays a critical role in the nutritional
status and survival of both lower and higher animals (Margolskee,
R. F., J. Biol. Chem. 277:1-4 (2002); Avenet, P. and Lindemann, B.,
J. Membrane Biol. 112:1-8 (1989)). The ability to taste has
significance beyond providing people with pleasurable culinary
experiences. For example, the ability to taste allows us to
identify tainted or spoiled foods, and provides satisfying
responses that may be proportionate to caloric or nutritive
value.
[0006] There are generally considered to be only four or five
categories of basic taste: sweet, sour, bitter, acid, and "umami"
(the Japanese word describing the taste of monosodium glutamate;
Hemess, M. S. & Gilbertson, T. A., 1999, Annu. Rev. Physiol.
61:873-900). These can be sub-classified as the appetitive tastes,
such as salty, sweet and umami, which are associated with
nutrient-containing foods, and the bitter and sour tastes elicited
by toxic compounds.
[0007] The anatomic basis for the initial events of taste is the
taste receptor cell ("TRC"), located in clusters referred to as
"taste buds" (Lindemann, supra). Taste buds are distributed
throughout the oral cavity, including the tongue as well as
extra-lingual locations (see Hemess and Gilbertson). In the human
tongue, taste buds are organized into three specialized types of
specialized structures, namely fungiform, foliate, and
circumvallate papillae. Each taste bud comprises between about 50
and 100 individual cells grouped into a cluster that is between 20
and 40 microns in diameter. Nerve fibers enter from the base of the
taste bud and synapse onto some of the taste receptor cells.
Typically, a single TRC contacts several sensory nerve fibers, and
each sensory fiber innervates several TRCs in the same taste bud
(Lindemann, supra).
[0008] When a subject ingests a tastant, and that tastant
encounters a taste receptor cell in the appropriate concentration,
an action potential is produced which, via synapses with primary
sensory neurons, communicates the signal registered by the
receptor, via afferent nerves, to the appropriate region of the
sensory cortex of the brain, resulting in the perception of a
particular taste by the subject.
[0009] Although taste perception is a vital function, sometimes it
is useful to modify certain tastes. For example, many active
pharmaceutical ingredients of medicines produce undesirable tastes,
such as a bitter taste. Masking the bitter taste produced by the
medicine by adding a sweetener enhancer may lead to improved
acceptance by the patient.
[0010] Traditionally, sweeteners and flavorants have been used to
mask the bitter taste of pharmaceuticals. The sweetener or
flavorant is known to activate other taste pathways and at
sufficiently high concentration this serves to mask the bitter
taste of the pharmaceutical. Using large concentrations of
sweeteners such as table sugar (sucrose) is undesirable because of
the high number of calories and because it cannot be administered
to diabetics. Artificial sweeteners such as aspartame and saccharin
do not have these drawbacks but can have an undesirable aftertaste
or present safety concerns if used in large quantities.
[0011] A number of other methods have been suggested to inhibit,
alter, or mask unwanted tastes. However, the presently available
compounds are lacking in desirable characteristics.
[0012] Another area in which enhancing sweet taste would be useful
is in encouraging food intake in subjects who have an impaired
ability to taste or in patients who have lost their appetites.
Studies have shown increased food intake as palatability increased.
Sorensen, et al., Int. J. Obes. Relat. Metab. Disord.
27(10):1152-66 (2003). For instance, certain drugs, such as
antihypertensives and antihyperlipidemics, have been reported to
produce untoward alterations in taste and may result in decreased
food intake. Doty, et al., J Hypertens. 21(10):1805-13 (2003).
Taste impairment has also been associated with radiation treatments
for head and neck cancer and this taste impairment has been
considered to be one of the factors associated with reduces
appetite and altered patterns of food intake. Vissink, et al.,
Crit. Rev. Oral Biol. Med. 14(3):213-25 (2003). Decreased food
consumption has also been correlated with loss of taste sensations
in the elderly. Shiffman, S. S., J. Am. Med. Ass'n
278(16):1357-1362 (1997). Enhancing the sweet taste of food could
lead to increased consumption of foods containing these
enhancers.
[0013] Therefore, there exists a need for compounds that can
effectively enhance a sweet taste, preferably without exhibiting
one or more of the limitations of the prior art sweetening
agents.
BRIEF SUMMARY OF THE INVENTION
[0014] A first aspect of the present invention is directed to a
method of enhancing a sweet taste, comprising administering to a
subject a sweet tastant and one or more compounds of Formula I, or
a physiologically acceptable salt thereof.
[0015] In certain aspects of the invention, as described further
below, the methods and compositions of the present invention allow
one to create food products with sufficient sweetness but with
reduced levels of known sweet tastants, such as sugar. These
methods also enable one to prepare an improved food product with
the same level of sweetness as the original food product but with
reduced calories from the caloric sweetness.
[0016] An additional aspect of the present invention is directed to
a method of enhancing a sweet taste of a food product, comprising
administering to a subject a food product comprising a sweet
tastant and one or more compounds of Formula I, or a
physiologically acceptable salt thereof.
[0017] An additional aspect of the present invention is directed to
a method of enhancing a sweet taste of a pharmaceutical, comprising
administering to a subject a pharmaceutical comprising a sweet
tastant and one or more compounds of Formula I, or a
physiologically acceptable salt thereof.
[0018] An additional aspect of the present invention is directed to
a method of increasing the palatability of food and its intake
comprising administering to a subject a food product comprising a
sweet tastant and one or more compounds of Formula Ito a subject in
need of such treatment.
[0019] An additional aspect of the present invention is directed to
a method of masking an undesirable taste of a food product,
comprising administering to a subject a food product comprising a
sweet tastant and one or more compounds of Formula I, or a
physiologically acceptable salt thereof.
[0020] An additional aspect of the present invention is directed to
a method of masking an undesirable taste of a pharmaceutical,
comprising administering to a subject a pharmaceutical comprising a
sweet tastant, one or more compounds of Formula I, or a
physiologically acceptable salt thereof.
[0021] An additional aspect of the present invention is directed to
a food product comprising a sweet tastant and one or more compounds
according to Formula I or a physiologically acceptable salt
thereof.
[0022] An additional aspect of the present invention is directed to
a pharmaceutical composition comprising an active agent, optionally
one or more pharmaceutically acceptable carriers, a sweet tastant,
and one or more compounds of Formula I or a physiologically
acceptable salt thereof.
[0023] These and additional aspects of the present invention are
described in detail below.
BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES
[0024] The accompanying drawings, which are incorporated herein and
form a part of the specification, serve to explain the principles
of the invention and to enable a person skilled in the pertinent
art to make and use the invention.
[0025] FIG. 1 illustrates the generation of the TRPM5 membrane
potential dye fluorescent response in transfected HEK 293 cells. It
utilizes a fluorescence Intentsity Plate Reader (FLIPR) and
carbachol to cause a Ca++ response and trigger TRPM5.
[0026] FIG. 2 illustrates a cell-based assay utilizing cloned
mTRPM5 for detecting active compounds. FIG. 2 demonstrates that
only TRPM5-transfected cells generate a membrane potential response
while all cells, both sham and transfected, generate Ca.sup.2+
signals.
[0027] FIG. 3 illustrates the selective enhancement of TRPM5
activity by three different concentrations of the compound of
Example 8. The upper left graph of FIG. 3 shows the effect of 1, 3,
10, and 30 micromolar (.mu.M) of the compound of Example 8 on TRPM5
activity in hTRPM5-HEK293 cells, as measured in the fluorescent
assays described herein. The upper right graph of FIG. 3 shows the
effect of 1, 3, 10, and 30 .mu.M of the compound of Example 8 at on
TRPM5 activity in CHO cells as measured in the fluorescent assays
described herein. The lower left graph of FIG. 3 illustrates a
calcium counterscreen assay, in which the hTRPM5-HEK293 cells were
loaded with a calcium sensitive dye and stimulated by ATP to check
to see if the compound of Example 8 blocks the GPCR-mediated
calcium activated step. The lower right graph of FIG. 3 illustrates
a KCl counterscreen, in which 1, 3, 10, and 30 .mu.M of the
compound of Example 8 is added to hTRPM5-hTRPM5-HEK293 cells,
stimulated by KCl instead of ATP to determine whether the compound
was a specific ion channel enhancer. In these experiments TRPM5 was
stimulated by another GPCR present in HEK and CHO cells using ATP
as agonist.
[0028] FIG. 4 illustrates the enhancement of TRPM5 activity
(membrane potential response) as a function of ATP concentration
with several different compounds. The compounds had little effect
on calcium dye response to increasing ATP agonist levels. The
results show selective enhancement of TRPM5 activity by the
compounds of the invention at low concentrations of GPCR agonist
ATP (a surrogate tastant). The left graph of FIG. 4 shows the
effect of the addition of 30 micromolar of the compounds of
Examples 1-3,5,10 and 18 on the ATP concentration-effect function
for membrane potential in hTRPMS-HEK293 cells, as measured by the
fluorescent assay described herein. The right graph shows the
effect of the addition of a compound of the invention at 30
micromolar on ATP concentration-effect function for intracellular
calcium in hTRPM5-HEK293 cells, as measured in the fluorescent
assays described herein.
[0029] FIG. 5 illustrates the results of the selective enhancement
of TRPM5 activity by the compounds of Examples 1-3, 5, 10, and 18.
The results indicate a dramatic increase (>10.times.) of TRPM5
activity at sub-optimal ATP agonist concentrations (0.1 .mu.M). At
low ATP concentration, i.e. 0.1 uM, the ratio of ATP signal alone
vs. the signal in the presence of the compounds in some cases is
greater than 10 fold.
[0030] FIG. 6 illustrates stimulation of TRPM5 current when TRPM5
transfected HEK 393 cell are exposed to 10 .mu.M boluses (red bars)
of the compound (Example 10) in a flow-through electrophysiological
apparatus. The left graph of FIG. 6 shows no activation by compound
in the absence of calcium. The central graph of FIG. 6 show a large
>5 nA current (+80 mV) pulses in response to boluses of the
compound at a calcium concentration of 300 nm. Note that the
current drops off when the exposure of compound is stopped, i.e.
the compound is washed away. The far right graph shows a
stimulation of current by compound at 30 .mu.m calcium. While there
is further stimulation of the TRPMS current by compound at 30 uM,
it is not as dramatic as at 300 nn Ca++. Note that no significant
current was seen in non-transfected, sham HEK cells (not
shown).
[0031] FIG. 7 shows dose-response curve for enhancing the activity
of TRPMS protein in hTRPMS-HEK293 cells. The graphs show the
effects of the compounds of Examples 1, 2, 3, and 10.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The present invention provides compounds and compositions
that are useful, for example, for enhancing sweet tastes. The
methods of the present invention enable one to use a known
sweetening agents, or sweet tastants, in a reduced amount combined
with a compound according to Formula I, or any of the specific
subgroups or specific compounds described herein, in order to
achieve the same level of sweetness when the known sweet tastant is
used alone in the traditional amount. By way of brief example, a
common carbonated cola beverage may contain about 20 to 30 grams of
sugar (e.g., fructose) and about 100 calories per 8 ounce serving.
The present invention enables one to prepare a similar cola
beverage with substantially reduced sugar and caloric content but
with the same level of sweetness. The compounds identified in here,
e.g., according to Formula I, enhance the sweet taste produced by
the reduce sugar content, thereby creating an enhanced sweet taste
based on the reduced level of sweet tastant, e.g., table sugar.
[0033] Other aspects of the present invention are described in
detail herein.
Methods of Use
[0034] A first aspect of the present invention is directed to a
method of enhancing a sweet taste, said method comprising
administering to a subject a sweet tastant and a compound of
Formula I or a physiologically acceptable salt thereof,
##STR00002##
wherein
[0035] G.sup.1, G.sup.2, and G.sup.3 are independently selected
from N, S, and C;
[0036] R.sup.1 and R.sup.2 are independently absent or selected
from hydrogen, C.sub.1-6 alkyl, halogen, nitro, optionally
substituted C.sub.6-14 aryl, optionally substituted 5-14 membered
heteroaryl, optionally substituted 5- to 14-membered heteroaryloxy,
optionally substituted 5-14 membered heteroarylthio, Ar-Q,
optionally substituted (CH.sub.2).sub.nC(.dbd.O)--O--R.sup.2a, and
optionally substituted (CH.sub.2).sub.nC(.dbd.O)aryl, or R.sup.1
and R.sup.2, together with the G.sup.3 and the carbon atom to which
R.sup.1 is attached, form a C.sub.6-14 aryl or 5- to 14-membered
heterocycle, each of which is optionally substituted; or if the
bond to R.sup.1 and/or R.sup.2 is a double bond, then R.sup.1 and
R.sup.2 are independently selected from .dbd.NH and .dbd.O;
[0037] R.sup.3 is selected from H, C.sub.1-6 haloalkyl, C.sub.1-6
alkyl, oxo, .dbd.NH, optionally substituted C.sub.6-14 aryl, and
optionally substituted 5-14 membered heterocycle, or R.sup.3 is
L.sup.1-R.sup.31, such as
.dbd.Z.sup.1-(CH.sub.2).sub.n--Z.sup.2--R.sup.31 or;
[0038] R.sup.4 is absent or is selected from the group consisting
of H, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkoxy,
C.sub.1-6hydroxyalkyl, optionally substituted C.sub.6-14 aryl, and
optionally substituted (CH.sub.2).sub.nC(.dbd.O)aryl, or when the
bond to R.sup.4 is a double bond, R.sup.4 is .dbd.O; and
[0039] R.sup.5 is either absent or is selected from hydrogen,
C.sub.1-6 alkyl, and optionally substituted phenyl amide;
[0040] R.sup.7 is either absent or selected from H and C.sub.1-6
alkyl;
[0041] R.sup.2a is C.sub.1-6 alkyl;
[0042] R.sup.31 is H, C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
optionally substituted phenyl, amino, C.sub.1-6 alkylamino, or
C.sub.1-6 dialkylamino;
[0043] Z.sup.1 is selected from .dbd.N, --NH, O, and S;
[0044] Z.sup.2 is O, S, C(.dbd.O), C(.dbd.S), --C(.dbd.O)--O,
C(.dbd.S)--O, --C(.dbd.O)--NH-- or --C(.dbd.S)--NH;
[0045] L.sup.1 is linker containing 1 to 30 carbon and/or
heteroatoms;
[0046] Q is CH.sub.2, O, NH, or S;
[0047] Ar is optionally substituted aryl or optionally substituted
heteroaryl; and
[0048] n is 0 to 10.
[0049] Preferred groups of compounds within Formula I to be used in
the methods of the present invention include
##STR00003##
wherein R.sup.1R.sup.5 are defined as above.
[0050] Each of the bonds in the five-membered ring of Formula I may
be a single or double bond. In one embodiment, the ring formed from
G.sup.1, G.sup.2, and G.sup.3 contains only single bonds. In
another embodiment, the ring formed from G.sup.1, G.sup.2, and
G.sup.3 contains one or two double bonds.
[0051] In one embodiment, one of G.sup.1, G.sup.2, and G.sup.3 is
carbon, and the others are selected from N or S. In a further
embodiment, G.sup.3 is carbon, and G.sup.1 and G.sup.2 are selected
from N or S. In a further embodiment, G.sup.3 is carbon, one of
G.sup.1 and G.sup.2 is N, and the other is S. In a further
embodiment, G.sup.3 is carbon, and both G.sup.1 and G.sup.2 are N.
In a further embodiment G.sup.2 is carbon, and G.sup.1 and G.sup.3
are selected from N or S
[0052] In another embodiment, one of G.sup.1, G.sup.2, and G.sup.3
is S, and the others are N. In another, G.sup.1, G.sup.2, and
G.sup.3 are N. In another, G.sup.1 is S, and G.sup.2 and G.sup.3
are carbon.
[0053] In another embodiment, G.sup.1, G.sup.2, and G.sup.3 are
selected to form one of the following groups:
##STR00004##
[0054] In one embodiment, R.sup.1 and R.sup.2 are independently
optionally substituted C.sub.6-10 aryl, such as phenyl or naphthyl.
In another embodiment, R.sup.1 and/or R.sup.2 are an optionally
substituted 5-10 membered, preferably 5-7 membered, heteroaryloxy
or heteroarylthio. The heteroaryl includes but is not limited to
pyridyl, pyrimindinyl, imidazolyl, tetrazolyl, furanyl, thienyl,
indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl, and
benzothiazolyl, each of which is optionally substituted. In other
instances, the heteroaryl group is a 5-10 membered, preferably 5-7
membered, nitrogen-containing heteroaryl.
[0055] Another subset of R.sup.1 and R.sup.2 includes a substituted
aryl or heteroaryl group having 1-3 substituents independently
selected from the group consisting of amino, hydroxy, nitro,
halogen, cyano, thiol, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy,
C.sub.1-6 alkylenedioxy, C.sub.1-6 alkoxy(C.sub.1-6)alkyl,
C.sub.1-6 aminoalkyl, C.sub.1-6 hydroxyalkyl, C.sub.2-6
hydroxyalkoxy, mono(C.sub.1-4)alkylamino, di(C.sub.1-4)alkylamino,
C.sub.2-6 alkylcarbonylamino, C.sub.2-6 alkoxycarbonylamino,
C.sub.2-6alkoxycarbonyl, carboxy, C.sub.2-6 carboxyalkoxy, and
C.sub.2-6 carboxyalkyl.
[0056] In another embodiment, R.sup.1 and R.sup.2 are independently
a C.sub.3-10 ester or C.sub.1-6 alkyl-C(.dbd.O)--Ar, wherein Ar is
an optionally substituted phenyl. In a further embodiment, Ar is
optionally substituted by 1-3 substituent selected from the group
consisting of amino, hydroxy, nitro, halogen, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, and C.sub.1-6 alkoxy.
[0057] In another embodiment, the bond to R.sup.1 and/or R.sup.2 is
a double bond, and R.sup.1 and R.sup.2 are independently selected
from .dbd.NH and .dbd.O. More specifically, both the bond from the
ring to R.sup.1 or R.sup.2 can be either a single bond or a double
bond. When the bond to R.sup.1 is a single bond, R.sup.1 is
selected from hydrogen, C.sub.1-6 alkyl, halogen, nitro, optionally
substituted C.sub.6-14 aryl, optionally substituted 5- to
14-membered heteroaryloxy, optionally substituted 5-14 membered
heteroarylthio, optionally substituted
CH.sub.3(CH.sub.2).sub.nC(.dbd.O)--O--R, and optionally substituted
CH.sub.3(CH.sub.2).sub.nC(.dbd.O)aryl. When the bond to R.sup.1 is
a double bond, R.sup.1 is either NH or O. R.sup.2 is defined
likewise.
[0058] In another embodiment, R.sup.1 and R.sup.2, together with
the G.sup.3 and the carbon atom to which R.sup.1 is attached, form
an optionally substituted C.sub.6-14 aryl, such as phenyl or
naphthyl, or an optionally substituted 5-14 membered heterocycle,
such as but not limited to pyridyl, pyrimindinyl, imidazolyl,
tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl,
pyrrolyl, benzimidazolyl, diazole, triazole, thiazole, thiadiazole,
thiatriazole, benzothiophene, benzothiopyran, and benzopyran. In
other instances, the heterocycle group is a nitrogen-containing
and/or sulfur-containing heterocycle.
[0059] In another subset of R.sup.1 and R.sup.2, R.sup.1 and
R.sup.2, together with the G.sup.3 and the carbon atom to which
R.sup.1 is attached, form a C.sub.6-14 aryl or a 5-14 membered
heterocycle having 1-3 substituents independently selected from the
group consisting of amino, hydroxy, nitro, halogen, cyano, thiol,
oxo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkenyloxy, and optionally substituted
C.sub.6-14 aryl. In a further embodiment, the ring formed from
R.sup.1 and R.sup.2 together with the G.sup.3 and the carbon atom
to which R.sup.1 is attached is substituted by a C.sub.6-14 aryl,
optionally containing one or more C.sub.1-6 alkyl, halo, C.sub.1-6
haloalkyl or nitro groups.
[0060] Alternatively, R.sup.1 and R.sup.2 may be independently
Ar-Q, wherein Q is CH.sub.2, O, NH, or S, and Ar is optionally
substituted aryl or optionally substituted heteroaryl. Preferably,
Ar is optionally substituted C.sub.6-14 aryl or optionally
substituted 5-14 membered heteroaryl. Suitable Ar-Q groups include
optionally substituted 5- to 14-membered heteroaryloxy and
optionally substituted 5-14 membered heteroarylthio.
[0061] In another embodiment, G.sup.1, G.sup.2, and G.sup.3 along
with R.sup.1, R.sup.2, form a heterocycle ring system selected
from:
##STR00005##
[0062] In one embodiment, R.sup.3 is optionally substituted
C.sub.6-10 aryl, such as phenyl or naphthyl. In another embodiment,
R.sup.3 is optionally substituted 5-10 membered, or preferably 5-7
membered, heterocycle, such as, but not limited to pyrrolidyl,
piperidyl, diazacyclopentyl, triazacyclopentyl, azacyclohexyl,
diazacyclohexyl, triazacyclohexyl, azacycloheptyl,
diaazacycloheptyl, triazacyclohepyl, azacyclopentenyl,
diazacyclopentenyl, triazacyclopentenyl, azacyclohexenyl,
diazacyclohexenyl, triazacyclohexenyl, azacycloheptenyl,
diazacycloheptenyl, and triazacycloheptenyl. In a further
embodiment, R.sup.3 is selected from a diazacycheptyl and a
diazacyclohexenyl. In a further embodiment, R.sup.3 is either
1,4-diazacycloheptyl or 1,5-diazacyclohex-2-en-3-yl.
[0063] Another subset of R.sup.3 includes a substituted aryl group
having 1-3 substituents independently selected from the group
consisting of amino, hydroxy, nitro, halogen, cyano, thiol,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6 haloalkyl, C.sub.1-6
alkoxy, and C.sub.3-6 alkenyloxy. In a further embodiment R.sup.3
is substituted by one or more of nitro, halogen, C.sub.1-6 alkyl,
and C.sub.1-6 alkoxy.
[0064] Another subset of R.sup.3 includes a substituted heterocycle
group having 1-4 substituents independently selected from the group
consisting of amino, hydroxy, nitro, oxo (i.e. .dbd.O), halogen,
cyano, thiol, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy, C.sub.1-6
alkyl-Ar, Ar, and --C(.dbd.O)--NH--Ar, wherein Ar is an optionally
substituted phenyl. In a further embodiment, Ar is optionally
substituted by 1 to 3 substituents selected from the group
consisting of nitro, halogen, C.sub.1-6 alkyl, and C.sub.1-6
alkyloxy.
[0065] In another embodiment, R.sup.3 is L.sup.1-R.sup.31, wherein
L.sup.1 is a linker containing 1 to 30 carbon atoms and/or
heteroatoms and R.sup.31 is selected from the group consisting of
H, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, optionally substituted
phenyl, amino, C.sub.1-6 alkylamino, or C.sub.1-6 dialkylamino.
[0066] The linker L.sup.1 can comprise various carbon- and/or
heteroatom-containing moieties. The size of the linker can be from
1 (e.g., CH.sub.2, O, NH, etc.) to 30 carbon atoms and/or
heteroatoms. The number of carbon atoms and/or heteroatoms does
not, of course, include hydrogen atoms. In certain instances, the
linker is an alkylene linker containing only carbon and hydrogen
atoms. In other instances, the linker is a heteroalkylene linker
containing carbon and hydrogen atoms and also one or more
heteroatoms, such as nitrogen, oxygen, and sulfur. The linker can
be straight-chained or branched. The linker may comprise one or
more cyclic groups, either as the whole linker or as part of the
linker group. The cyclic group may be carbocyclic or heterocyclic.
The linker may be optionally substituted.
[0067] The linker group of L.sup.1 may saturated or unsaturated.
Certain linker groups may contain one or more double bonds.
In a preferred embodiment, the linker contains at least one
heteroatom, and contains 2-15, preferably 2-10, carbon atoms and
heteroatoms. Other suitable linker groups for L.sup.1 include
.dbd.N--CH.sub.2C(O)OCH.sub.2--, --SCH.sub.2CH.sub.2O--,
.dbd.NC(S)NHCH.sub.2CH.dbd., --C(O)NH--, and --NHC(O)CH.sub.2--.
Alternatively, L.sup.1 may be -Het-C(O)--NH-- wherein Het is a 5-
to 7-membered nitrogen-containing heterocycle
[0068] In other instances, the linker group comprises a 5-7
membered cyclic, preferably heterocyclic moiety. The linker group
may contain 1-4, preferably 1-2 heteroatoms.
[0069] In another instance. L.sup.1 is one of the following linker
groups:
##STR00006##
[0070] In another embodiment, L.sup.1-R.sup.31 is
.dbd.Z.sup.1--(CH.sub.2).sub.n--Z.sup.2--R.sup.31 wherein:
[0071] Z.sup.1 is N, NH, O, or S;
[0072] n is 0 to 4, preferably 1 or 2;
[0073] Z.sup.2 is O, S, C(.dbd.O), C(.dbd.S), --C(.dbd.O)--O,
C(.dbd.S)--O, --C(.dbd.O)--NH-- or --C(.dbd.S)--NH; and
[0074] R.sup.31 is selected from C.sub.1-6 alkyl, C.sub.1-6
alkenyl, optionally substituted phenyl, and
[0075] --(CH.sub.2)--NR'R'' wherein R' and R'' are selected from H
and C.sub.1-6 alkyl.
[0076] In a further embodiment, R.sup.31 is a substituted aryl,
such as substituted phenyl containing 1 to 3 substituents
independently selected from the group consisting of nitro, halogen,
hydroxy, C.sub.1-6 haloalkyl, C.sub.1-6 alkyl, and C.sub.1-6
alkyloxy.
[0077] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00007##
wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.4 is absent, H,
C.sub.1-6 alkyl, or C.sub.1-6 hydroxyalkyl; R.sup.5 is absent, H,
or C.sub.1-6 alkyl; R.sup.a is H or C.sub.1-6 alkyl; and G.sup.1
and G.sup.2 are independently C, N, or S.
[0078] A preferred compound of Formula I for use in the methods of
the present invention is a compound according to the formula:
##STR00008##
wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.5 is H or C.sub.1-6
alkyl; G is N or S; and R.sup.a represents H or C.sub.1-6
alkyl.
[0079] Another preferred compound for use in the methods of the
present invention is a compound according to the formula:
##STR00009##
wherein G.sup.2 is N or S; R.sup.5 is H or C.sub.1-6 alkyl; G.sup.4
is N, S, or O; L.sup.2 is a linker containing 1-10 carbon and/or
heteroatoms; and R.sup.31 is H or optionally substituted
phenyl.
[0080] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00010##
wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.4 is H, C.sub.1-6
hydroxyalkyl; R.sup.5 is absent; and R.sup.a is H or C.sub.1-6
alkyl.
[0081] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00011##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
and Ar-Q, wherein Q is O, NH, S, or CH.sub.2, and Ar is an
optionally substituted aryl or optionally substituted heteroaryl;
R.sup.3 is H or C.sub.1-6 alkyl; R.sup.4 is absent, H, or C.sub.1-6
alkyl; R.sup.5 is absent, H, or C.sub.1-6 alkyl; and G.sup.1 is C
or N; and G.sup.2 is N or S.
[0082] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00012##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
and Ar-Q, wherein Q is O, NH, S, or CH.sub.2, and Ar is an
optionally substituted aryl or optionally substituted heteroaryl;
R.sup.3 is H or C.sub.1-6 alkyl; R.sup.4 is H or C.sub.1-6 alkyl;
and R.sup.5 is absent.
[0083] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00013##
wherein R.sup.1 and R.sup.2 are independently selected from the
group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 alkoxycarbonyl,
and Ar-Q, wherein Q is O, NH, S, or CH.sub.2, and Ar is an
optionally substituted aryl or optionally substituted heteroaryl;
R.sup.3 is H or C.sub.1-6 alkyl; R.sup.4 is absent; and R.sup.5H or
C.sub.1-6 alkyl.
[0084] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00014##
wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.5 is H or C.sub.1-6
alkyl; G.sup.2 is C, N, or S; and Cy represents an optionally
substituted fused ring comprising 5-10, preferably 5-7, carbon
atoms and/or heteroatoms.
[0085] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00015##
wherein R.sup.3 is L.sup.1-R.sup.31; and Cy represents an
optionally substituted fused ring comprising 5-10, preferably 5-7,
carbon atoms and/or heteroatoms. Alternatively, R.sup.3 represents
optionally substituted aryl, such as phenyl, and the Cy group
contains one or more nitrogen and/or sulfur atoms.
[0086] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00016##
wherein R.sup.3 is L.sup.1-R.sup.31; and Cy represents an
optionally substituted fused ring comprising 5-10, preferably 5-7,
carbon atoms and/or heteroatoms.
[0087] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00017##
wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.5 is H or C.sub.1-6
alkyl; G.sup.2 is C, N, or S; G.sup.3 is C or N; R.sup.4 is H or
absent; and Cy represents an optionally substituted fused ring
comprising 5-10, preferably 5-7, carbon atoms and/or
heteroatoms.
[0088] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00018##
wherein R.sup.3 is L.sup.1-R.sup.31; R.sup.4 is H or absent;
R.sup.5 is H or C.sub.1-6 alkyl; G.sup.2 is C or N; and Cy
represents an optionally substituted fused ring comprising 5-10,
preferably 5-7, carbon atoms and/or heteroatoms.
[0089] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to the
formula:
##STR00019##
wherein R.sup.1 is C.sub.1-6 alkyl or optionally substituted
C.sub.6-10 aryl; R.sup.2 is H or absent; R.sup.3 is
L.sup.1-R.sup.31; R.sup.4 is H or absent; R.sup.5 is H or absent;
R.sup.31 is a linker, preferably comprising 2 to 20 carbon atoms
and/or heteroatoms; G.sup.1 is N or C; G.sup.2 is N or S; and
G.sup.3 is N or C.
[0090] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to
formula:
##STR00020##
wherein R.sup.1 is C.sub.1-6 alkyl or optionally substituted
C.sub.6-10 aryl; R.sup.3 is L.sup.1-R.sup.31; R.sup.4 is H or
absent; R.sup.5 is H or absent; G.sup.1 is N or C; and G.sup.2 is N
or S.
[0091] Another preferred compound of Formula I for use in the
methods of the present invention is a compound according to
formula:
##STR00021##
wherein R.sup.1 is C.sub.1-6 alkyl or optionally substituted
C.sub.6-10 aryl; R.sup.4 is H or absent; R.sup.5 is H or absent;
G.sup.1 is N or C; G.sup.2 is N or S; G.sup.4 is NH, S, or O;
L.sup.1 is a linker containing 1-10 carbon atoms and/or
heteroatoms; and R.sup.31 is H, NR.sup.aR.sup.b or optionally
substituted phenyl, wherein R.sup.a and R.sup.b are independently H
or C.sub.1-6 alkyl.
[0092] In a first subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula II
##STR00022##
wherein:
[0093] R.sup.4 is H, C.sub.1-6 alkyl, or C.sub.1-6
hydroxyalkyl;
[0094] R.sup.31 is H, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, or
optionally substituted phenyl, preferably optionally substituted by
one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy and hydroxyl;
[0095] R.sup.a is H or C.sub.1-6 alkyl, preferably H;
[0096] G.sup.1 is S or N;
[0097] Z.sup.1 is S or N;
[0098] Z.sup.2 is --C(.dbd.O)--O, --C(.dbd.S)--O--, --O--, --S--,
--C(.dbd.O)--NH--, or --C(.dbd.S)--NH--; and
[0099] n is 0 to 4, preferably 1 or 2.
[0100] In one embodiment within the first subclass, the compound of
Formula II is selected from a compound of Formula III:
##STR00023##
wherein R.sup.4 is H, C.sub.1-6 alkyl, or C.sub.1-6
hydroxyalkyl;
[0101] R.sup.31 is selected from H, C.sub.1-6 alkyl, and C.sub.1-6
alkenyl;
[0102] R.sup.a is H or C.sub.1-6 alkyl, preferably H;
[0103] Z.sup.3 is O or S;
[0104] Z.sup.4 is O, S, or NH; and
[0105] n is 0 to 3.
[0106] In a further embodiment within the first subclass, the
compound of Formula III is selected from a compound of Formula
IV:
##STR00024##
wherein R.sup.4 is selected from H and C.sub.1-6 alkyl;
[0107] R.sup.31 is H or C.sub.1-6 alkyl;
[0108] R.sup.a is H or C.sub.1-6 alkyl; and
[0109] n is 0 to 3.
[0110] In a further example of this embodiment, R.sup.31 is alkyl,
preferably ethyl. In another example, R.sup.4 is alkyl, preferably
methyl. In another, n is 1. In another, R.sup.a is hydrogen
[0111] In a further embodiment within the first subclass, the
compound of Formula III is selected from a compound of Formula
V:
##STR00025##
wherein R.sup.2 is H or C.sub.1-6 alkyl;
[0112] R.sup.3 is H, C.sub.1-6 alkyl, or C.sub.1-6 alkenyl;
[0113] R.sup.4 is selected from H and C.sub.1-6 alkyl; and
[0114] n is 0, 1, 2, or 3.
[0115] In one example of this embodiment, R.sup.4 is alkyl,
preferably methyl. In another example, R.sup.a is hydrogen. In
another, n is zero. In another, R.sup.31 is alkenyl, preferably
2-propenyl.
[0116] In a further embodiment within the first subclass, the
compound of Formula II is selected from a compound of Formula
VI
##STR00026##
wherein R.sup.4 is selected from H, C.sub.1-6 alkyl, and C.sub.1-6
hydroxyalkyl;
[0117] R.sup.a is H or C.sub.1-6 alkyl;
[0118] R.sup.b is C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, or
hydroxy;
[0119] n is 0 to 3; and
[0120] p is 0 to 5.
[0121] In one example of this embodiment within the first subclass,
R.sup.a is hydrogen. In another, R.sup.4 is hydroxyalkyl,
preferably 2-hydroxyethyl. In another, R.sup.4 is hydrogen. In
another, n is 2 or 3. In another embodiment, R.sup.b is alkyloxy,
preferably methoxy. In another, the phenyl ring containing
(R.sup.b).sub.p is 2,6-dimethoxyphenyl or 2-methoxyphenyl.
[0122] In a second subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula VIII:
##STR00027##
wherein G.sup.1 is N or S;
[0123] Q is N or C;
[0124] R.sup.3 is H or optionally substituted phenyl, preferably
optionally substituted by one or more selected from the group
consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, hydroxyl, halogen,
and nitro;
[0125] R.sup.5 is H when G.sup.1 is N, or otherwise is absent;
[0126] R.sup.6 is selected from H and C.sub.1-6 alkyl; and
[0127] R.sup.7 is selected from H, C.sub.1-6 alkyl, and optionally
substituted phenyl, preferably optionally substituted by one or
more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl or
nitro, or, when Q is N, R.sup.7 is absent.
[0128] In one embodiment within this second subclass, R.sup.3 is
hydrogen. In another embodiment, R.sup.3 is an optionally
substituted phenyl, preferably optionally substituted by one or
more of halogen or nitro. In another, R.sup.7 is hydrogen or
tolyl.
[0129] In another embodiment within this second subclass, the
compound of Formula VIII is selected from a compound of Formula
IX,
##STR00028##
wherein R.sup.3 is H, C.sub.1-6 alkyl, or optionally substituted
phenyl, preferably optionally substituted by one or more of
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, or nitro; and
R.sup.7 is selected from H, C.sub.1-6 alkyl, and optionally
substituted phenyl, preferably optionally substituted by one or
more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl or
nitro.
[0130] In a further example of this embodiment, R.sup.3 is
hydrogen. In another, R.sup.7 is an optionally substituted phenyl,
preferably optionally substituted by one or more of C.sub.1-6
alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl or nitro; or R.sup.7 is
a tolyl group.
[0131] A further embodiment within this second subclass is a
compound of Formula IX, wherein: R.sup.3 is H or C.sub.1-6 alkyl,
preferably H; and R.sup.7 is selected from H, C.sub.1-6 alkyl, and
optionally substituted phenyl, preferably optionally substituted by
one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl
or nitro, or preferably R.sup.7 is an optionally substituted
phenyl. In one embodiment, R.sup.7 is a tolyl group.
[0132] In a further embodiment within this second subclass, the
compound of Formula VIII is selected from a compound of Formula
X:
##STR00029##
wherein R.sup.3 is selected from H, C.sub.1-6 alkyl, and C.sub.6-10
aryl, preferably optionally substituted phenyl, preferably
optionally substituted with one or more of C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, halogen, hydroxyl, or nitro; R.sup.5 is H; and
R.sup.6 is selected from H and C.sub.1-6 alkyl.
[0133] In a further embodiment within this second subclass, the
compound of Formula VIII is selected from a compound of Formula X,
wherein R.sup.3 is C.sub.6-10 aryl, preferably phenyl, optionally
substituted with one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
halogen, or nitro; and R.sup.6 is H or C.sub.1-6 alkyl. In one
embodiment, R.sup.3 is substituted by one or more halogen and/or a
nitro groups. In another embodiment, R.sup.3 is
3-nitro-4-chlorophenyl or C.sub.1-6 alkyl, preferably ethyl.
[0134] In a third subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula XI:
##STR00030##
wherein R.sup.3 is H or C.sub.1-6 alkyl, preferably hydrogen;
[0135] R.sup.5 is H or C.sub.1-6 alkyl, preferably hydrogen;
[0136] Ar is a 5- to 10-membered aryl or heteroaryl group,
preferably a 5- or 6-membered nitrogen containing heteroaryl group,
optionally substituted with one or more groups independently
selected from the group consisting of NO.sub.2, halogen, C.sub.1-6
alkyl, and C.sub.1-6 hydroxyalkyl;
[0137] Q is O or NH;
[0138] R.sup.b is H or C.sub.1-6 alkyl; and
[0139] n is 0 to 3.
[0140] In one embodiment of this third subclass, R.sup.1 is a
C.sub.1-6 alkyl, preferably methyl. In another embodiment Q is
oxygen. In another, Ar is a 5- or 6-membered nitrogen containing
heteroaryl group, preferably pyridyl. In another, R.sup.2 is nitro.
In another, n is one.
[0141] In another embodiment within this third subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula
XII:
##STR00031##
wherein R.sup.3 is H or C.sub.1-6 alkyl;
[0142] each occurrence of R.sup.a is independently selected from
the group consisting of NO.sub.2, halogen, C.sub.1-6 alkyl, or
C.sub.1-6 hydroxyalkyl;
[0143] R.sup.b is H or C.sub.1-6 alkyl; and
[0144] n is 0 to 3.
[0145] In one example of this embodiment, R.sup.1 is C.sub.1-6
alkyl, preferably methyl. In another, R.sup.3 is hydrogen. In
another, n is 1. In another, R.sup.2 is nitro. In another, the
pyridine ring is attached to the oxygen atom at the 2-position.
[0146] In a fourth subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula XIII
##STR00032##
wherein R.sup.1 is an optionally substituted phenyl, preferably
optionally substituted by one or more substituents independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6
alkyloxy, halogen, hydroxyl and nitro;
[0147] R.sup.3 is Het-C(O)--NH--R.sup.31;
[0148] Het is a 5- to 7-membered nitrogen-containing heterocycle;
and
[0149] R.sup.31 is an optionally substituted phenyl, preferably
optionally substituted by one or more substituents independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6
alkyloxy, halogen, and NO.sub.2.
[0150] In one embodiment of this fourth subclass, R.sup.1 is
unsubstituted phenyl.
[0151] The Het group can be any 5- to 7-membered
nitrogen-containing heterocycle, including heteroaryl groups. The
Het group, in certain embodiments, contains 1 to 4, preferably 1 or
2 nitrogen atoms in the ring. Suitable Het groups include, but are
not necessarily limited to, piperidine, piperizine, pyrrolidine,
azepine, and morpholine.
[0152] By way of example, a suitable group of compounds for use
within this fourth subclass is a compound of Formula XIII
##STR00033##
wherein R.sup.1 is phenyl optionally substituted, for example, by
one or more of C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, halogen, and/or
NO.sub.2, preferably R.sup.1 is phenyl; and R.sup.31 is phenyl
optionally substituted, for example, by one or more of C.sub.1-6
alkyl, C.sub.1-6 alkyloxy, halogen, hydroxyl and/or NO.sub.2,
preferably R.sup.31 is unsubstituted phenyl.
[0153] In a fifth subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula XIV:
##STR00034##
wherein R.sup.1 is H, C.sub.1-6 alkyl, halogen, or NO.sub.2;
[0154] R.sup.3 and R.sup.4 are independently H or C.sub.1-6
alkyl;
[0155] Q is S, N, or O, preferably S; and
[0156] Het is a 5- to 6-membered heteroaryl, preferably a
nitrogen-containing heteroaryl, optionally substituted with one or
more substituents selected from the group consisting of nitro and
halogen.
[0157] Suitable Het groups include pyridinyl, pyrrolyl, and
pyrimindyl. For example, Het can be a pyridyl group and, in
particular, wherein the pyridyl group is attached to Q at the
2-position. In one embodiment, the Het group is substituted with a
halogen, preferably chlorine. In one embodiment, n is 1. In another
embodiment, Het is a 5-chloropyridyl group attached to Q at the
2-position. In another embodiment, R.sup.1 is nitro. In another
embodiment, R.sup.3 is alkyl, preferably methyl. In another
embodiment, R.sup.4 is alkyl, preferably ethyl.
[0158] In a sixth subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula XV:
##STR00035##
wherein R.sup.1 and R.sup.3 are independently optionally
substituted phenyl, preferably optionally substituted by one or
more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, or
nitro;
[0159] R.sup.4 is absent, O, or C.sub.1-6 alkyl; and
[0160] R.sup.2 and R.sup.7 are independently C.sub.1-6 alkyl.
[0161] In a further embodiment within the sixth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula
XVI:
##STR00036##
wherein R.sup.1 and R.sup.3 are independently optionally
substituted phenyl, preferably optionally substituted by one or
more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, or
nitro; and R.sup.2 and R.sup.7 are independently is H or C.sub.1-6
alkyl.
[0162] In a further embodiment within the sixth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula XVI
wherein: R.sup.1 and R.sup.3 are phenyl; and R.sup.2 and R.sup.7
are independently H or C.sub.1-6 alkyl.
[0163] In a seventh subclass, the present invention is directed to
a method of enhancing a sweet taste, said method comprising
utilizing a compound of Formula XVII:
##STR00037##
wherein R.sup.1 is H or C.sub.1-6 alkyl;
[0164] R.sup.2 is H;
[0165] R.sup.3 is C.sub.1-6 alkyl, H, oxo, or .dbd.NH;
[0166] R.sup.31 is optionally substituted phenyl, preferably
optionally substituted by one or more of C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, hydroxyl, and nitro; and
[0167] n is 0 to 3.
[0168] In one embodiment, R.sup.31 is a phenyl substituted by a
nitro group, preferably R.sup.31 is 3-nitrophenyl. The bond between
R.sup.3 and the ring can be either a single or double bond, as
indicated by the dashed line. In certain embodiments, the bond must
be double bond, e.g., when R.sup.3 is .dbd.NH. In other instances,
the bond must be a single bond, e.g., when R.sup.3 is H.
[0169] In a further embodiment within this seventh subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula
XVI:
##STR00038##
wherein R.sup.1 is H or C.sub.1-6 alkyl; R.sup.2 is H; R.sup.31 is
optionally substituted phenyl, preferably optionally substituted by
one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen,
hydroxyl, or nitro; and n is 0 to 3. In one example within this
embodiment, R.sup.1 is hydrogen. In another, n is 1. In another,
R.sup.31 is phenyl substituted by a nitro group, and preferably
R.sup.31 is 3-nitrophenyl.
[0170] In an eighth subclass, the present invention is directed to
a method of enhancing a sweet taste, said method comprising
utilizing a compound of Formula XVIII:
##STR00039##
wherein R.sup.1 is H or C.sub.1-6 alkyl;
[0171] R.sup.2 is H, C.sub.1-6 alkyl, or optionally substituted
phenyl, preferably optionally substituted by one or more
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, and nitro;
and
[0172] R.sup.3 is NH--C(.dbd.O)--(CH.sub.2).sub.n--R.sup.a,
wherein, n is 0 to 3 and R.sup.a is selected from (a) optionally
substituted phenyl, preferably optionally substituted by one or
more substituents independently selected from the group consisting
of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, and nitro,
and (b) NR.sup.31R.sup.32, wherein R.sup.31 and R.sup.32 are
independently selected from H or C.sub.1-6 alkyl and n is 0 to 3,
or R.sup.3 is
##STR00040##
wherein R.sup.33 is optionally substituted phenyl, preferably
optionally substituted by one or more of C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, hydroxyl, or nitro; R.sup.34 is H or C.sub.1-6
alkyl; and m is 0 to 3.
[0173] In one embodiment within this eighth subclass, R.sup.2 is
phenyl substituted by a halogen, preferably chlorine. In another
embodiment, R.sup.2 is 4-chlorophenyl. In another, R.sup.2 is
C.sub.1-6 alkyl, preferably methyl.
[0174] In a further embodiment within the eighth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula
XIX:
##STR00041##
wherein R.sup.1 is H or C.sub.1-6 alkyl;
[0175] R.sup.2 is H or C.sub.1-6 alkyl;
[0176] R.sup.33 is optionally substituted phenyl, preferably
optionally substituted by one or more of C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, hydroxyl, or nitro;
[0177] R.sup.34 is H or C.sub.1-6 alkyl; and
[0178] m is 0 to 3.
[0179] In one embodiment within this eighth subclass, R.sup.1 is
hydrogen. In another embodiment, R.sup.2 is C.sub.1-6 alkyl,
preferably methyl. In another, R.sup.34 is an isopropyl group. In
another, R.sup.33 is phenyl.
[0180] In a further embodiment within the eighth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula XIX
wherein:
[0181] R.sup.1 is H or C.sub.1-6 alkyl;
[0182] R.sup.2 is H or C.sub.1-6 alkyl;
[0183] R.sup.33 is optionally substituted phenyl, preferably
optionally substituted by one or more of C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, hydroxyl, or nitro;
[0184] R.sup.34 is H or C.sub.1-6 alkyl; and
[0185] m is 1.
[0186] In one example within this embodiment, R.sup.1 is hydrogen.
In another example, R.sup.2 is C.sub.1-6 alkyl, preferably methyl.
In one, R.sup.34 is an isopropyl group. In another, R.sup.33 is
phenyl.
[0187] In further embodiment within the eighth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula
XX:
##STR00042##
wherein:
[0188] R.sup.1 is H, C.sub.1-6 alkyl, or optionally substituted
phenyl, preferably optionally substituted by one or more
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, and
nitro;
[0189] R.sup.2 is H, C.sub.1-6 alkyl, or optionally substituted
phenyl, preferably optionally substituted by one or more
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, and
nitro;
[0190] R.sup.31 is either an optionally substituted phenyl,
preferably optionally substituted by one or more substituents
independently selected from the group consisting of C.sub.1-6
alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, and nitro, or is
NR.sup.5aR.sup.6a, wherein R.sup.5a and R.sup.6a are independently
selected from H or C.sub.1-6 alkyl; and
[0191] n is 0 to 3.
[0192] In further embodiment within the eighth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula XX
wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.2 is an
optionally substituted phenyl, preferably optionally substituted by
one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen,
hydroxyl, or nitro; R.sup.31 is NR.sup.5aR.sup.6a; and n is 0 to 3.
In a further embodiment, R.sup.2 is substituted by a halogen,
preferably chlorine. In another embodiment, R.sup.2 is
3-chlorophenyl. In another embodiment, R.sup.1 is hydrogen. In
another embodiment, R.sup.5a and R.sup.6a are both alkyl groups,
preferably methyl.
[0193] In further embodiment within the eighth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula XX
wherein R.sup.1 is hydrogen or C.sub.1-6 alkyl; R.sup.2 is H,
C.sub.1-6 alkyl, optionally substituted phenyl, preferably
optionally substituted by one or more of C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, hydroxyl, or nitro; n is 0 to 3; R.sup.31 is
optionally substituted phenyl, preferably optionally substituted by
one or more of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen,
hydroxyl, or nitro; and n is 0 to 3. In one embodiment, R.sup.2 is
an optionally substituted phenyl, preferably R.sup.2 is substituted
by one or more alkyl groups. In a further embodiment, R.sup.2 is a
ethyl-substituted phenyl, preferably 3-ethylphenyl. In one
embodiment, R.sup.3 is substituted by one or more methyl groups,
preferably R.sup.31 is 3,5-dimethyoxyphenyl. In one embodiment, n
is zero.
[0194] In a ninth subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula XXI:
##STR00043##
wherein R.sup.3 is optionally substituted phenyl, preferably
optionally substituted by one or more substituents independently
selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halogen, hydroxyl, and nitro; R.sup.4 is H; and R.sup.a is
H or C.sub.1-6 alkyl. In an embodiment of this ninth subclass, the
present invention is directed to a method of enhancing a sweet
taste, said method comprising utilizing a compound of Formula XXI
wherein R.sup.a is H or C.sub.1-6 alkyl; and R.sup.3 is a
disubstituted phenyl containing C.sub.1-6 alkyl, halogen, or
NO.sub.2, or preferably is a disubstituted phenyl containing a
C.sub.1-6 alkoxy substituent and a halogen substituent.
[0195] In a further embodiment of the ninth subclass, the present
invention is directed to a method of enhancing a sweet taste, said
method comprising utilizing a compound of Formula XXI wherein
R.sup.a is H or C.sub.1-6 alkyl; and R.sup.3 optionally substituted
phenyl, preferably optionally substituted by one or more of
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halogen, hydroxyl, or nitro. In
one embodiment, R.sup.3 is a phenyl substituted with a halogen and
a C.sub.1-6 alkyloxy group, preferably R.sup.3 is
2-methoxy-3-chlorophenyl.
[0196] In a tenth subclass, the present invention is directed to a
method of enhancing a sweet taste, said method comprising utilizing
a compound of Formula XXII wherein:
##STR00044##
wherein R.sup.3 is H or C.sub.1-6 alkyl; R.sup.a is H or C.sub.1-6
alkyl; and R.sup.4 is optionally substituted phenyl, preferably
optionally substituted by one or more substituents independently
selected from the group consisting of C.sub.1-6 alkyl, halogen, and
nitro. In an embodiment of this tenth subclass, the present
invention is directed to a method of enhancing a sweet taste, said
method comprising utilizing a compound of Formula XXII wherein
R.sup.3 is H or C.sub.1-6 alkyl; R.sup.4 is phenyl; and R.sup.a is
H or C.sub.1-6 alkyl.
[0197] In a eleventh subclass, the present invention is directed to
a method of enhancing a sweet taste, said method comprising
utilizing a compound of Formula XXIII:
##STR00045##
wherein R.sup.1 is H, C.sub.1-6 alkyl, or halogen;
[0198] R.sup.2 is H or C.sub.1-6 alkyl;
[0199] R.sup.3 is H, halogen, C.sub.1-6 haloalkyl, preferably
trifluoromethyl, or C.sub.1-6 alkyl;
[0200] R.sup.5 is phenylamide (i.e., C(O)NH-Ph) optionally
substituted with one or more substituents selected from the group
consisting of H, halogen, C.sub.1-6 haloalkyl, preferably
trifluoromethyl, nitro, C.sub.1-6 alkyl, and C.sub.1-6
alkyloxy.
[0201] In one embodiment within this eleventh subclass, the
invention comprises the use of a compound of the following
formula:
##STR00046##
wherein R.sup.1, R.sup.2, and R.sup.3 are defined as above. In
another embodiment of this eleventh subclass, the present invention
is directed to a method of enhancing a sweet taste, said method
comprising utilizing a compound of Formula XXIII wherein R.sup.1 is
halogen; R.sup.2 is H or C.sub.1-6 alkyl; R.sup.3 is C.sub.1-6
haloalkyl, preferably CF.sub.3; and the phenylamide group is
substituted with one or two groups independently selected from the
group consisting of halogen, C.sub.1-6 haloalkyl, NO.sub.2,
C.sub.1-6 alkyl, and C.sub.1-6 alkyloxy.
[0202] In certain embodiments of this eleventh subclass, R.sup.1 is
halogen and R.sup.3 is CF.sub.3.
[0203] Examples of suitable compounds for use in the method of the
present invention include: ethyl
2-(3-methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate; [0204]
2-(2-(2-methoxyphenoxy)ethylthio)-1H-benzo[d ]imidazole; [0205]
methyl 3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate; [0206]
6-(4-chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazo-
le; [0207] 6-p-tolylimidazo[2,1-b][1,3,4]thiadiazole; [0208]
N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide;
[0209]
2-(2-(2-(2,6-dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)etha-
nol; [0210]
1-ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole;
[0211] 2,4-diphenyl-5,5-dimethylimidazole-1-oxide; [0212]
1-allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea; [0213]
2-(2-iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone; [0214]
3-benzyl-1-isopropyl-5-(4-methylthiazol-2-yl)pyrimidine-2,4(1H,3H)-dione;
[0215] 2-(3-chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine; [0216]
N-(4-(4-ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide; [0217]
1-phenylthiochromeno[4,3-d]imidazol-4(1H)-one; [0218]
N-(4-(4-chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide;
[0219]
5-chloro-1-methyl-3-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)-1H-py-
razole-4-carboxamide; and physiologically acceptable salts
thereof.
[0220] Further examples of suitable compounds for use in the method
of the present invention include:
N-(4-(((2,6-dimethoxypyrimidin-4-yl)amino)sulfonyl)phenyl)-4-nitrobenzami-
de; [0221] 4-phenyl-2-(pyrrolidin-1-ylmethyl)phthalazin-1(2H)-one;
[0222] 5-(perfluorophenoxy)isophthalic acid; [0223]
2-(dibenzylamino)acetic acid; [0224] ethyl
2-cyano-2-(phenyldiazenyl)acetate; and
[0225] physiologically acceptable salts thereof.
[0226] The methods of the present invention also include the use of
a physiologically acceptable salt of a compound according to
Formula I. The term physiologically acceptable salt refers to an
acid- and/or base-addition salt of a compound according to Formula
I. Acid-addition salts can be formed by adding an appropriate acid
to the compound according to Formula I. Base-addition salts can be
formed by adding an appropriate base to the compound according to
Formula I. Said acid or base does not substantially degrade,
decompose, or destroy said compound according to Formula I.
Examples of suitable physiologically acceptable salts include
hydrochloride, hydrobromide, acetate, furmate, maleate, oxalate,
and succinate salts. Other suitable salts include sodium,
potassium, carbonate, and tromethamine salts.
[0227] All stereoisomers of the compounds of the instant invention
are contemplated, either in admixture or in pure or substantially
pure form. The compounds of the present invention can have
asymmetric centers at any of the carbon atoms including any one or
the R substituents. Consequently, compounds of Formula I can exist
in enantiomeric or diastereomeric forms or in mixtures thereof. The
processes for preparation can utilize racemates, enantiomers or
diastereomers as starting materials. When diastereomeric or
enantiomeric products are prepared, they can be separated by
conventional methods for example, chromatographic or fractional
crystallization.
[0228] The compounds of the present invention can have asymmetric
centers at certain of the nitrogen or sulfur atoms. Consequently,
these isomers or mixtures thereof are part of the present
invention.
[0229] The compounds of the present invention may also display
other instances of chirality, such as atropoisomerism. Thus, these
isomers or mixtures thereof are part of the invention. It is
further understood that the present invention encompasses the use
of tautomers of a compound of Formula I. Tautomers are well-known
in the art and include keto-enol tautomers.
[0230] The compounds of the present invention may also contain
varying amounts of isotopes of carbon, hydrogen, nitrogen, oxygen,
sulfur, halogen, etc.; such as .sup.13C, .sup.14C, deuterium,
tritium, .sup.15N, .sup.18O, .sup.128I, etc. Some of the isotopic
content is naturally occurring, but the compounds of the present
invention may be enriched or depleted in one or more of these.
Thus, these isotopes or mixtures thereof are part of the
invention.
[0231] The compounds of Formula I may also be solvated, including
hydrated. Hydration may occur during manufacturing of the compounds
or compositions comprising the compounds, or the hydration may
occur over time due to the hygroscopic nature of the compounds.
[0232] Certain compounds within the scope of Formula I may be
derivatives referred to as "prodrugs." The expression "prodrug"
denotes a derivative of a known direct acting agent, wherein the
derivative has therapeutic value that may be similar to, greater
than, or less than that of the agent. Generally, the prodrug is
transformed into the active agent by an enzymatic or chemical
process when delivered to the subject, cell, or test media. In
certain instances, prodrugs are derivatives of the compounds of the
invention which have metabolically cleavable groups and become by
solvolysis or under physiological conditions the compounds of the
invention which are pharmaceutically active in vivo. For example,
ester derivatives of compounds of this invention are often active
in vivo, but not in vitro. Other derivatives of the compounds of
this invention have activity in both their acid and acid derivative
forms, but the acid derivative form often offers advantages of
solubility, tissue compatibility, or delayed release in the
mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9,
21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives
well known to practitioners of the art, such as, for example,
esters prepared by reaction of the parent acid with a suitable
alcohol, or amides prepared by reaction of the parent acid compound
with an amine. Simple aliphatic or aromatic esters derived from
acidic groups pendent on the compounds of this invention are
preferred prodrugs.
[0233] When any variable occurs more than one time in any
constituent or in Formula I, its definition on each occurrence is
independent of its definition at every other occurrence, unless
otherwise indicated. Also, combinations of substituents and/or
variables are permissible only if such combinations result in
stable compounds.
[0234] The term "alkyl," as used herein by itself or as part of
another group, refers to both straight and branched chain radicals
of up to 10 carbons, unless the chain length is limited thereto,
such as methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl,
2-methylpropyl, pentyl, 1-methylbutyl, isobutyl, pentyl, t-amyl
(CH.sub.3CH.sub.2(CH.sub.3).sub.2C--), hexyl, isohexyl, heptyl,
octyl, or decyl.
[0235] The term "alkenyl," as used herein by itself or as part of
another group, refers to a straight or branched chain radical of
2-10 carbon atoms, unless the chain length is limited thereto,
including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl,
1-hexenyl, and 2-hexenyl.
[0236] The term "alkylene," as used herein by itself or as a part
of another group, refers to a diradical of an unbranched saturated
hydrocarbon chain, having, unless otherwise indicated, from 1 to 15
carbon atoms, preferably 1 to 10 carbon atoms and more preferably 1
to 6 carbon atoms. This term is exemplified by groups such as
methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
propylene (--CH.sub.2CH.sub.2CH.sub.2--), butylene, and the
like.
[0237] The term "alkenylene," as used herein by itself or part of
another group, refers to a diradical of an unbranched, unsaturated
hydrocarbon chain, having, unless otherwise indicated, from 2 to 15
carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to
6 carbon atoms, and having at least 1 and preferably from 1 to 6
sites of vinyl unsaturation. This term is exemplified by groups
such as ethenylene (--CH.dbd.CH--), propenylene
(--CH.sub.2CH.dbd.CH--, --CH.dbd.CHCH.sub.2--), and the like.
[0238] The term "alkoxy," as used herein by itself or as part of
another group, refers to any of the above alkyl groups linked to an
oxygen atom. Typical examples are methoxy, ethoxy, isopropyloxy,
sec-butyloxy, and t-butyloxy.
[0239] The term "alkenyloxy," as used herein by itself or as part
of another group, refers to any of the above alkenyl groups linked
to an oxygen atom. Typical examples include ethenyloxy,
propenyloxy, butenyloxy, pentenyloxy, and hexenyloxy.
[0240] The term "aryl," as used herein by itself or as part of
another group, refers to monocyclic or bicyclic aromatic groups
containing from 6 to 14 carbons in the ring portion, preferably
6-10 carbons in the ring portion. Typical examples include phenyl,
naphthyl, anthracenyl, or fluorenyl.
[0241] The term "heteroaryl," as used herein by itself or as part
of another group, refers to groups having 5 to 14 ring atoms; 6,
10, or 14 .pi. electrons shared in a cyclic array; and containing
carbon atoms and 1, 2, 3, or 4 oxygen, nitrogen, or sulfur atoms.
Examples of heteroaryl groups are: thienyl, benzo[b]thienyl,
naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,
isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathinyl,
2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,
indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl,
quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl,
pteridinyl, 4.alpha.H-carbazolyl, carbazolyl, .beta.-carbolinyl,
phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl,
phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl,
phenoxazinyl, and tetrazolyl groups. Further heteroaryls are
described in A. R. Katritzky and C. W. Rees, eds., Comprehensive
Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use
of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, NY (1984).
[0242] The term "halogen" or "halo," as used herein by itself or as
part of another group, refers to chlorine, bromine, fluorine or
iodine.
[0243] The term "monoalkylamine" or "monoalkylamino," as used
herein by itself or as part of another group, refers to the group
NH.sub.2 wherein one hydrogen has been replaced by an alkyl group,
as defined above.
[0244] The term "dialkylamine" or "dialkylamino," as used herein by
itself or as part of another group refers to the group, NH.sub.2
wherein both hydrogens have been replaced by alkyl groups, as
defined above.
[0245] The term "hydroxyalkyl," as used herein by itself or as part
of another group, refers to any of the above alkyl groups wherein
one or more hydrogens thereof are substituted by one or more
hydroxyl moieties.
[0246] The term "haloalkyl," as used herein by itself or as part of
another group, refers to any of the above alkyl groups wherein one
or more hydrogens thereof are substituted by one or more halo
moieties. Typical examples include fluoromethyl, trifluoromethyl,
trichloroethyl, and trifluoroethyl.
[0247] The term "carboxyalkyl," as used herein by itself or as part
of another group, refers to any of the above alkyl groups wherein
one or more hydrogens thereof are substituted by one or more
carboxylic acid moieties.
[0248] The term "heteroatom" is used herein to mean an oxygen atom
("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It will be
recognized that when the heteroatom is nitrogen, it may form an
NR.sup.aR.sup.b moiety, wherein R.sup.a and R.sup.b are,
independently from one another, hydrogen or alkyl, or together with
the nitrogen to which they are bound, form a saturated or
unsaturated 5-, 6-, or 7-membered ring.
[0249] The term "oxy" means an oxygen (O) atom.
[0250] The term "thio" means a sulfur (S) atom.
[0251] As used herein, unless otherwise indicated, Cy represents a
cyclo group fused to another ring in the chemical structure of
which the Cy is a part. Suitable cyclo groups include cycloalkyl,
cycloheteroalkyl, aryl, and heteroaryl. The cyclo group can be a
monocyclic group or polycyclic group, such as a bicyclic group.
Thus, if the Cy group is a bicyclic ring system, the entire
molecule will comprise a tricyclic ring system including the core
ring show in Formula I. The cyclo group may contain 5-10 carbon
atoms and/or heteroatoms as part of its ring, excluding the shared
ring atoms of the other ring system. Suitable cyclo groups include
any aryl and heteroaryl rings described herein.
[0252] For instance, in the following structure,
##STR00047##
Cy represents a cyclo group fused to the five-membered
nitrogen-containing heterocycle. Thus, the above structure covers,
among other possibilities, a benzimidazole compound. Further, and
by way of example, a Cy containing 5-10, preferably 5-7, carbon
atoms and/or heteroatoms in the above structure would indicate that
the Cy group contains 5-10, preferably 5-7, carbon atoms and/or
heteroatoms including the 2 carbon atoms shared between the cyclo
ring and the imidazole ring.
[0253] Generally and unless defined otherwise, the phrase
`optionally substituted` used herein refers to a group or groups
being optionally substituted with one or more substituents
independently selected from the group consisting of: halogen,
nitro, cyano, OR.sub.22, alkyl which may be substituted with one or
more occurrences of R.sub.23, alkenyl which may be substituted with
one or more occurrences of R.sub.23, alkynyl which may be
substituted with one or more occurrences of R.sub.23, cycloalkyl
which may be substituted with one or more occurrences of R.sub.23,
aryl which may be substituted with one or more occurrences of
R.sub.23, heterocyclo which may be substituted with one or more
occurrences of R.sub.23, SR.sub.22, SO.sub.2R.sub.22, COOR.sub.22,
C(O)R.sub.22, CONR.sub.24R.sub.25, SO.sub.2NR.sub.24R.sub.25,
SO.sub.2N(H)C(O)R.sub.22, SO.sub.2N(H)CO.sub.2R.sub.22 wherein
R.sub.22 is not H, NR.sub.24R.sub.25, N(R.sub.24)SO.sub.2R.sub.25,
N(R.sub.24)C(O).sub.mR.sub.25 (wherein m is 1 or 2),
N(R.sub.24)C(O)NR.sub.25R.sub.26,
N(R.sub.24)SO.sub.2NR.sub.25R.sub.26, OC(O)R.sub.22,
OC(O)OR.sub.22, OC(O)NR.sub.25R.sub.26,
C(O)N(H)SO.sub.2NR.sub.25R.sub.26, C(O)N(H)SO.sub.2R.sub.25, oxo
(or keto, i.e., .dbd.O), thioxo (i.e., .dbd.S), imino (i.e.,
.dbd.NR.sub.27), NR.sub.27--C(.dbd.NR.sub.28)R.sub.29,
NR.sub.27--C(.dbd.NR.sub.28)NR.sub.29R.sub.30,
C(.dbd.NR.sub.27)NR.sub.28R.sub.29,
OC(.dbd.NR.sub.27)NR.sub.28R.sub.29, OC(.dbd.NR.sub.27)R.sub.28,
C(.dbd.NR.sub.27)R.sub.28, and C(.dbd.NR.sub.27)OR.sub.22; wherein
R.sub.22 is selected from H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.6-C.sub.10 aryl, or C.sub.1-C.sub.9 heterocyclo each of which
may be substituted with 1 to 3 independent occurrences of R.sub.23;
wherein R.sub.24, R.sub.25, and R.sub.26 are selected from
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.6-C.sub.10 aryl, or
C.sub.1-C.sub.9 heterocyclo each of which may be substituted with 1
to 3 independent occurrences of R.sub.23; or R.sub.24 and R.sub.25,
or R.sub.24 and R.sub.26, or R.sub.25 and R.sub.26 may be joined by
an alkylene or an alkenylene chain to form a 5- to 8-membered
heterocyclo ring which is defined as for heterocyclo wherein the
substituents may be one or more occurrences of R.sub.23; wherein
R.sub.27, R.sub.28, R.sub.29, and R.sub.30 are independently
selected from the group consisting of H, nitro, cyano, OH,
O(C.sub.1-C.sub.6 alkyl), C(O)R.sub.22, C(O)NR.sub.24R.sub.25,
CO.sub.2R.sub.22 (with the proviso that R.sub.22 is not H),
SO.sub.2R.sub.22, SO.sub.2NR.sub.24R.sub.25, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.6-C.sub.10 aryl, and C.sub.1-C.sub.9 heterocyclo;
or R.sub.27 and R.sub.28, or R.sub.27 and R.sub.29, or R.sub.27 and
R.sub.30, or R.sub.28 and R.sub.29, or R.sub.28 and R.sub.30, or
R.sub.29 and R.sub.30 are joined by an alkylene or alkenylene chain
to form a 5-8 membered ring that may be optionally substituted with
one or more occurrences of R.sub.23; wherein each occurrence of
R.sub.23 is independently selected from the group consisting of
halogen, nitro, cyano, OR.sub.31, alkyl optionally substituted with
halogen, cycloalkyl optionally substituted with halogen, aryl
optionally substituted with halogen, hydroxy, nitro, methoxy,
trifluoromethyl, cyano, carbomethoxy, CONH.sub.2, or CHO,
heterocyclo optionally substituted with halogen, hydroxy, nitro,
methoxy, trifluoromethyl, cyano, carbomethoxy, CONH.sub.2, or CHO,
SR.sub.31, CO.sub.2R.sub.31, C(O)R.sub.31, CONR.sub.32R.sub.33,
SO.sub.2NR.sub.32R.sub.33, NR.sub.32R.sub.33,
N(R.sub.32)SO.sub.2R.sub.33, N(R.sub.32)C(O).sub.mR.sub.33 (m is 1
or 2), N(R.sub.32)C(O)NR.sub.33R.sub.34,
N(R.sub.32)SO.sub.2NR.sub.33R.sub.34, OC(O)R.sub.31,
OC(O)OR.sub.31, SO.sub.2R.sub.31, SO.sub.2N(H)C(O)R.sub.31,
SO.sub.2N(H)CO.sub.2R.sub.31 wherein R.sub.31 is not H,
C(O)N(H)SO.sub.2NR.sub.32R.sub.33, C(O)N(H)SO.sub.2R.sub.31,
OC(O)NR.sub.32R.sub.33, NR.sub.35--C(.dbd.NR.sub.36)R.sub.37,
NR.sub.35--C(.dbd.NR.sub.36)OR.sub.31,
NR.sub.35--C(.dbd.NR.sub.36)NR.sub.37R.sub.38,
C(.dbd.NR.sub.35)NR.sub.36R.sub.37, OC(.dbd.NR.sub.35)R.sub.36,
OC(.dbd.NR.sub.35)NR.sub.36R.sub.37, and
C(.dbd.NR.sub.35)OR.sub.31, R.sub.31 is selected from unsubstituted
alkyl, alkenyl, unsubstituted alkynyl, unsubstituted cycloalkyl,
unsubstituted aryl, and unsubstituted heterocyclo; wherein each
occurrence of R.sub.32, R.sub.33 and R.sub.34 is independently
selected from the group consisting of unsubstituted alkyl,
unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted
cycloalkyl, unsubstituted aryl, unsubstituted heterocyclo; or
R.sub.32 and R.sub.33, or R.sub.32 and R.sub.34, or R.sub.33 and
R.sub.34, are joined by an unsubstituted alkylene or unsubstituted
alkenylene chain to form a 5-8 membered unsubstituted heterocyclo
ring; and wherein R.sub.35, R.sub.36, R.sub.37, are R.sub.38
independently selected from the group consisting of nitro, cyano,
unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl,
unsubstituted cycloalkyl, unsubstituted aryl, unsubstituted
heterocyclo; or R.sub.35 and R.sub.36, or R.sub.35 and R.sub.37, or
R.sub.35 and R.sub.38, or R.sub.36 and R.sub.37, or R.sub.36 and
R.sub.38, or R.sub.37 and R.sub.38 is joined by an unsubstituted
alkylene chain or unsubstituted alkenylene chain to form a 5- to
8-membered unsubstituted heterocyclo ring.
[0254] Where alkyl groups as defined above have single bonds for
attachment to other groups at two different carbon atoms, they are
termed "alkylene" groups and may optionally be substituted as
defined above for "alkyl." Where alkenyl groups as defined above
and alkynyl groups as defined above, respectively, have single
bonds for attachment at two different carbon atoms, they are termed
"alkenylene groups" and "alkynylene groups", respectively, and may
optionally be substituted as defined above for "alkenyl" and
"alkynyl".
[0255] In a subgroup of the invention, the phrase "optionally
substituted" refers to a group or groups being optionally
substituted with one or more substituents independently selected
from the group consisting of amino, hydroxyl, nitro, halogen,
cyano, thiol, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.3-6
cycloheteralkyl, C.sub.3-6 cycloheteroalkenyl, C.sub.6-10 aryl,
5-10 membered heteroaryl, C.sub.1-6 alkoxy, C.sub.3-6 alkenyloxy,
C.sub.1-6 alkylthio, C.sub.1-6 alkylenedioxy, C.sub.1-6
alkoxy(C.sub.1-6)alkyl, C.sub.6-10 aryl(C.sub.1-6)alkyl, C.sub.6-10
aryl(C.sub.2-6)alkenyl, C.sub.6-10 aryl(C.sub.1-6)alkoxy, C.sub.1-6
aminoalkyl, C.sub.1-6 aminoalkoxy, C.sub.1-6 hydroxyalkyl,
C.sub.2-6 hydroxyalkoxy, mono(C.sub.1-4)alkylamino,
di(C.sub.1-4)alkylamino, C.sub.2-6 alkylcarbonylamino, C.sub.2-6
alkoxycarbonylamino, C.sub.2-6 alkoxycarbonyl, carboxy,
(C.sub.1-6)alkoxy(C.sub.2-6)alkoxy,
mono(C.sub.1-4)alkylamino(C.sub.2-6)alkoxy,
di(C.sub.1-4)alkylamino(C.sub.2-6)alkoxy C.sub.2-10
mono(carboxyalkyl)amino, bis(C.sub.2-10 carboxyalkyl)amino,
aminocarbonyl, C.sub.6-14 aryl(C.sub.1-6)alkoxycarbonyl, C.sub.2-6
alkynylcarbonyl, C.sub.1-6 alkylsulfonyl, C.sub.2-6
alkynylsulfonyl, C.sub.6-10 arylsulfonyl, C.sub.6-10
aryl(C.sub.1-6)alkylsulfonyl, C.sub.1-6 alkylsulfinyl, C.sub.1-6
alkylsulfonamido, C.sub.6-10 arylsulfonamido, C.sub.6-10
aryl(C.sub.1-6) alkylsulfonamido, C.sub.1-6 alkyliminoamino,
formyliminoamino, C.sub.2-6 carboxyalkoxy, C.sub.2-6 carboxyalkyl,
and carboxy(C.sub.1-6)alkylamino.
[0256] A "tastant" is any substance capable of eliciting gustatory
excitation, i.e., stimulation the sense of taste. When a subject
ingests a tastant, and that tastant encounters a taste receptor
cell in the appropriate concentration, an action potential is
produced which, via synapses with primary sensory neurons,
communicates the signal registered by the receptor, via afferent
nerves, to the appropriate region of the sensory cortex of the
brain, resulting in the perception of a particular taste by the
subject. Examples of sweet tastants include, but are not limited
to, sugar, (sucrose), dextrose, maltose, dextrin, dried invert
sugar, fructose, levulose, lactose, galactose, corn syrup,
malodextrin, honey, sugar alcohols such as sorbitol, mannitol,
xylitol, lactitol, malitol, hydrogenated starch hydrolysates,
maltitol and the like, thaumatin, aspartame, acesulfame K,
saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,
dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt,
spray dried licorice root, glycyrrhizin, sodium gluconate,
glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA.RTM.,
EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
[0257] The phrase "a sweet tastant" as used herein means "one or
more sweet tastants." Thus, the methods of this invention may
comprise administering one sweet tastant or multiple sweet tastants
and the compositions of this invention may comprise one sweet
tastant or multiple sweet tastants. For example, the food products
of this invention can comprise both sucrose and corn syrup as sweet
tastants, or sucrose and aspartame as sweet tastants, or saccharin
and sucralose as sweet tastants. In some cases a sweet tastant(s)
may be present at a suboptimal amount where its sweetness is
enhanced or intensified by use of this invention.
[0258] Although detailed definitions have not been provided for
every term used above, each term is understood by one of ordinary
skill in the art.
[0259] As explained above, the present invention provides methods,
compounds, and compositions that are useful, for example, for
enhancing sweet tastes. The methods of the present invention enable
one to use a known sweetening agents, or sweet tastants, in a
reduced amount combined with a compound according to Formula I, or
any of the specific subgroups or specific compounds described
herein, in order to achieve the same level of sweetness when the
known sweet tastant is used alone in the traditional amount. By way
of brief example, a common carbonated cola beverage may contain
about 20 to 30 grams of sugar (e.g., fructose) and about 100
calories per 8 ounce serving. The present invention enables one to
prepare a similar cola beverage with substantially reduced sugar
and caloric content but with the same level of sweetness. The
compounds identified in here, e.g., according to Formula I, enhance
the sweet taste produced by the reduce sugar content, thereby
creating an enhanced sweet taste based on the reduced level of
sweet tastant, e.g., table sugar.
[0260] As mentioned above, the above described compounds may be
used to enhance a sweet taste. Such enhancement may be in vitro or
in vivo. The amount of the compound of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, used to enhance the sweet taste may not necessarily be the
same when used in vivo compared to in vitro. Factors such as
pharmacokinetics and pharmacodynamics of the particular compound
may require that a larger or smaller amount of the compound of
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, be used when enhancing a taste
modulating protein in vivo. Accordingly, one aspect of the present
invention is a method of enhancing a sweet taste by utilizing a
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above.
[0261] The compounds of the present invention can be used to
enhance the sweet taste of a food product exhibiting a sweet taste
comprising administering to a subject a food product comprising a
sweet tastant and one or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above. Furthermore, in a preferred embodiment, the food
product comprises a compound of Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above in an
amount sufficient to enhance the sweet taste.
[0262] The compounds of this invention may be used to enhance the
desirable properties of sweetness in any food product. The phrase
"food product" as used herein includes but is not limited to
fruits, vegetables, juices, meat products such as ham, bacon and
sausage; egg products, fruit concentrates, gelatins and
gelatin-like products such as jams, jellies, preserves, and the
like; milk products such as ice cream, sour cream and sherbet;
icings, syrups including molasses; corn, wheat, rye, soybean, oat,
rice and barley products, nut meats and nut products, cakes,
cookies, confectionaries such as candies, gums, fruit flavored
drops, and chocolates, chewing gum, mints, creams, icing, ice
cream, pies and breads, beverages such as coffee, tea, carbonated
soft drinks, such as COKE.RTM. and PEPSI.RTM., non-carbonated soft
drinks, juices and other fruit drinks, sports drinks such as
GATORADE.RTM., coffee, teas, iced teas, coca, alcoholic beverages,
such as beers, wines and liquors, and KOOL-AID..RTM. Preferably,
the food products in which the sweetness is enhanced with the
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, will contain a
decreased level of known sweet tastant(s). For example, an improved
carbonated soft drink can be produced with the same sweetness as
the known carbonated soft drink but with a lower sugar content by
adding a compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above. In
some cases a sweet tastant(s) may be present at a suboptimal amount
where its sweetness is enhanced or intensified by use of this
invention.
[0263] Food products also include condiments such as herbs, spices
and seasonings, flavor enhancers such as monosodium glutamate. A
food product also includes prepared packaged products such as
dietetic sweeteners, liquid sweeteners, granulated flavor mixes
which upon reconstitution with water provide non-carbonated drinks,
instant pudding mixes, instant coffee and tea, coffee whiteners,
malted milk mixes, pet foods, livestock feed, tobacco and materials
for baking applications such as powdered baking mixes for the
preparation of breads, cookies, cakes, pancakes, donuts and the
like. Food products also include sugar-free foods or beverages
designed for diabetics and others that cannot consume products
containing sucrose and diet or low-calorie food and beverages
containing little or no sucrose. Especially preferred food products
are carbonated beverages containing one or more of the subject
enhancers. Other examples of food products envisioned in accordance
with the present invention are described below and throughout the
specification.
[0264] In one embodiment, the present invention is directed to a
method of enhancing the sweet taste of a food product comprising a
administering to a subject a food product comprising a sweet
tastant and one or more compounds according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above. Furthermore, in a preferred embodiment, the food product
comprises a compound of Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above in an
amount sufficient to enhance the sweet taste. Specific sweet
tastants to which one of more compounds of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, can be added to enhance its sweet taste include but are not
necessarily limited to sugar, (sucrose), dextrose, maltose,
dextrin, dried invert sugar, fructose, levulose, lactose,
galactose, corn syrup, malodextrin, honey, sugar alcohols such as
sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
Specific food products in which an enchanted sweet taste is desired
include but are not limited to cakes, cookies, confectionaries such
as candies, gums and chocolates, creams, icing, ice cream, pies and
breads. Specific food products which are beverages include soft
drinks such as COKE.RTM., and PEPSI.RTM., juices and other fruit
drinks, sports drinks such as GATORADE.RTM., coffee, teas, iced
teas, coca, alcoholic beverages and KOOL-AID.RTM.. In one
embodiment, the food product comprises one sweet tastant. In
another embodiment, the food product comprises more than one sweet
tastant. In certain embodiments, the food product comprises sucrose
and corn syrup; sucrose and aspartame; or saccharin and sucralose
as sweet tastants.
[0265] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a food product selected
from fruits, vegetables, juices, meat products such as ham, bacon
and sausage; egg products, fruit concentrates, gelatins and
gelatin-like products such as jams, jellies, preserves, and the
like; milk products such as ice cream, sour cream and sherbet;
icings, syrups including molasses; corn, wheat, rye, soybean, oat,
rice and barley products, nut meats and nut products, cakes,
cookies, confectionaries such as candies, gums, fruit flavored
drops, and chocolates, creams, icing, ice cream, pies and breads,
comprising administering to a subject a sweet tastant and a
compound of Formula I.
[0266] In a preferred embodiment, the invention is directed to a
method of decreasing the amount of sweet tastant, such as sucrose,
fructose, or sucralose, needed in a consumable product, such as a
food product or pharmaceutical product, to exhibit a given level of
sweetness.
[0267] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a food product comprising
administering to a subject a sweetener and one or more compounds
according to Formula I. Sweeteners are well known in the art, and
include compounds such as sugar, (sucrose), dextrose, maltose,
dextrin, dried invert sugar, fructose, levulose, lactose,
galactose, corn syrup, malodextrin, honey, sugar alcohols such as
sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
Especially useful are the blends of the compounds of Formula I of
this invention and saccharin or physiologically acceptable salts
thereof. Examples of saccharin salts include the sodium, potassium,
calcium and ammonium salts. In blends with saccharin, the compounds
of this invention may reduce or completely mask the recognized
undesirable bitter aftertaste of the saccharin.
[0268] Any of the food products described herein may comprise one
or more sweet tastants. In one embodiment, the food products
comprise one sweet tastant. In a further embodiment, the food
product comprises more than one sweet tastant. In certain
embodiments, the food product comprises sucrose and corn syrup as
sweet tastants, or sucrose and aspartame, or saccharin and
sucralose.
[0269] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the food product.
[0270] In each of the embodiments of the methods described herein,
a compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, may be used in
varying ratios to the tastant, i.e. the agent that is believed to
cause the sweet taste. For example, a composition of the invention
may comprise a compound of Formula I in a molar ratio of about
1:10.sup.6 to about 10:1, or alternatively administered in a molar
ratio of about 1:10.sup.5, about 1:10.sup.4, about 10:10.sup.3,
about 1:10.sup.2, relative to the tastant. As will be appreciated,
the various ranges and amounts of the compound of Formula I can be
used, with modifications if preferred, in each of the embodiments
described herein. The composition may also comprise 10.sup.-4% to
10.sup.-1% of the compound of Formula I relative to the sweet
tastant, by weight.
[0271] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in the food product in an amount ranging from
about 0.001 mg to about 10 g per serving, preferably about 0.01 mg
to about 5 g per serving, or alternatively, from 0.05 mg to about 1
g per serving. The present invention also contemplates food
products with amounts of the compound of Formula I of about 0.05
mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 500
mg, 1 g, 2 g, 5 g and 8 g per serving.
[0272] The method may be performed such that the sweet taste of the
food product or food ingredient being enhanced by the compound of
Formula I is enhanced by at least about 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, or
alternatively from about 20% to about 50%. Thus, in a more specific
embodiment, the method comprises administering a food product or
food ingredient comprising a sweet tastant and one or more
compounds according to Formula I, wherein the one or more compounds
according to Formula I are present in an amount sufficient to
enhance a sweet taste, produced by the food product, by at least
about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from
about 60% to about 99%, or alternatively from about 30% to about
70%. Of course, in other embodiments, the sweetness may be enhanced
to differing extents.
[0273] Any amount of the compound of Formula I that provides the
desired degree of sweetness enhancement can be used. For example, a
compound of Formula I may be used at a concentration of about 30
.mu.g/L to about 1.5 g/L to enhance a sweet taste. Alternatively,
concentrations of about 0.1 to 100 mg/L of a compound of Formula I
may be used to enhance a sweet taste. It is contemplated that
between 0.1 mg/L and 100 mg/L of the compound of Formula I is
present and between 10 g/L and 100 g/L of sweet tastant is present.
For example, a composition could contain 0.1 mg/L, 1 mg/L, or 10/L
mg of the compound of Formula I for 10 mg/L of the tastant.
Alternatively, the composition could contain 0.5 mg/L, 5 mg/L or 50
mg/L of the compound of Formula I for 50 mg/L of the tastant. In
other embodiments, the composition contains 1 mg/L, 10 mg/L or 100
mg/L of the compound of Formula I for 100 g/L of the tastant.
[0274] In one embodiment, the present invention is directed to a
method of enhancing the sweet taste of a food product selected from
a beverage or drink comprising administering to a subject a
beverage or drink comprising a sweet tastant and one or more
compounds according to Formula I. Examples of suitable beverages in
which having a sweet taste is desired include, but are not limited
to coffee, teas, such as black tea, green tea, fermented tea,
semi-fermented tea, carbonated soft drinks, such as COKE.RTM. and
PEPSI.RTM., non-carbonated soft drinks, lemonade, juices and other
fruit drinks, sports drinks, such as GATORADE.RTM., iced teas,
coca, alcoholic beverages, such as beers, wines and liquors, and
KOOL-AID..RTM. In certain embodiments, the sweetness enhancing
amount of a compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, has a
range of from about 0.01 milligrams to about 5.0 grams per 100 mL.
In other embodiments, the sweetness enhancing effective amount of a
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, has a range of
from about 0.1 mg to about 2 grams per 1 L. Alternatively, a
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, is administered
in an amount of about 1 gram per 100 mL. In one embodiment, the
beverage or drink comprises one sweet tastant. In another
embodiment, it comprises more than one sweet tastant. In certain
embodiments, the beverage or drink comprises sucrose and corn
syrup, or it comprises sucrose and aspartame, or it comprises
saccharin and sucralose as sweet tastants.
[0275] One embodiment of the invention is directed to a method of
enhancing the sweet taste of a cola beverage, such as COKE.RTM. or
PEPSI.RTM. comprising administering to a subject a cola drink
comprising a sweet tastant and one or more compounds according to
Formula I. In a preferred embodiment, the cola beverage will
contain a reduced amount of sugar but maintain substantially the
original level of sweet taste.
[0276] Cola beverages are prepared by mixing cola concentrate with
carbonated water. Typically about 50 mL of cola concentrate is
added per 250 mL of carbonated water. Cola concentrate can be
prepared by mixing cola flavor, caramel color, and optionally
caffeine with water, one or more sweet tastants, one or more
compounds of Formula I, and one or more acid components.
[0277] A cola flavor refers to either a natural or artificial
flavor. Such cola flavors are commercially available. Commercial
cola flavors are available, for example, from International Flavor
and Fragrances, Dayton, N.J.; Artificial--#13573011 and Natural
#K3559549. Commercial cola flavors are also available from
Tastemaker, Cincinnati, Ohio, and Givaudan Roure, Clifton, N.J.
[0278] The acid component refers to an ingredient that contributes
sourness to the beverage and is added to balance the flavor profile
by reducing chemical or sweetener side tastes. Acids may include
malic acid, citric acid, phosphoric acid or combinations
thereof.
[0279] Examples of sweet tastants include but are not limited to
the group consisting of sugar, (sucrose), dextrose, maltose,
dextrin, dried invert sugar, fructose, levulose, lactose,
galactose, corn syrup, malodextrin, honey, sugar alcohols such as
sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
Sucrose, saccharin, sucralose, and aspartame are preferred. As
discussed supra, the compositions of the invention can comprise
more than one sweet tastant. For example, the food products of this
invention can comprise both sucrose and corn syrup as sweet
tastants, or sucrose and aspartame as sweet tastants, or saccharin
and sucralose as sweet tastants.
[0280] For example, the cola concentrate can prepared by mixing
phosphoric acid (75% Rhone-Poulenc), citric acid (anhydrous, ADM,
Decatur, Ill.), caffeine (Mallinckrodt, Paris, Ky.), caramel Color
(DS400, Sethness, Chicago, Ill.), cola Flavor (SN018976,
International Flavors and Fragrances, Dayton, N.J.), sucrose, one
or more compounds of Formula I, and water. The concentrate is
blended until all ingredients are dissolved (30-40 minutes) using a
magnetic stirring plate. Fifty milliliters of the concentrate are
added to 250 mL of carbonated water to complete the preparation of
the cola beverage. Fifty milliliters of cola concentrate typically
contains from 0.01 to 5 mL of phosphoric acid, preferably about
0.01-1 mL, 0.1 to 100 g of sucrose, preferably about 1-10 g, about
1.times.10.sup.-6 g to 10 g of a compound of Formula I, preferably
about 1.times.10.sup.-3 g to 1 g, about 0.001 g to 0.1 g of citric
acid, preferably about 0.005-0.1 g, 0.001 to 1 g of caffeine,
preferably about 0.01 to 0.1 g of caffeine, 0.01 to 5 g of caramel
flavor, preferably about 0.05 to 1 g, 0.001 to about 10 mL of cola
flavor, preferably about 0.01 to about 2 mL.
[0281] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the cola beverage.
[0282] In each of the embodiments of the methods described herein,
a compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, may be used in
varying ratios to the tastant, i.e. the agent that is believed to
cause the sweet taste. For example, a composition of the invention
may comprise a compound of Formula I in a molar ratio of about
1:10.sup.6 to about 10:1, or alternatively administered in a molar
ratio of about 1:10.sup.5, about 1:10.sup.4, about 1:10.sup.3,
about 1:10.sup.2, relative to the tastant. As will be appreciated,
the various ranges and amounts of the compound of Formula I can be
used, with modifications if preferred, in each of the embodiments
described herein. The composition may also comprise 10.sup.-4% to
10.sup.-1% of the compound of Formula I relative to the sweet
tastant, by weight.
[0283] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in the cola beverage in an amount ranging from
about 0.001 mg to about 10 g per serving, preferably about 0.01 mg
to about 5 g per serving, or alternatively, from 0.05 mg to about 1
g per serving. The present invention also contemplates cola
beverages with amounts of the compound of Formula I of about 0.05
mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 500
mg, 1 g, 2 g, 5 g and 8 g per serving.
[0284] Any amount of the compound of Formula I that provides the
desired degree of sweetness enhancement can be used. For example, a
compound of Formula I may be used at a concentration of about 30
.mu.g/L to about 1.5 g/L to enhance a sweet taste. Alternatively,
concentrations of about 0.1 to 100 mg/L of a compound of Formula I
may be used to enhance a sweet taste. It is contemplated that
between 0.1 mg/L and 100 mg/L of the compound of Formula I is
present and between 10 g/L and 100 g/L of sweet tastant is present.
For example, a composition could contain 0.1 mg/L, 1 mg/L, or 10/L
mg of the compound of Formula I for 10 mg/L of the tastant.
Alternatively, the composition could contain 0.5 mg/L, 5 mg/L or 50
mg/L of the compound of Formula I for 50 mg/L of the tastant. In
other embodiments, the composition contains 1 mg/L, 10 mg/L or 100
mg/L of the compound of Formula I for 100 g/L of the tastant.
[0285] In certain embodiments, the improved food product, such as
the cola beverage, e.g., COKE.RTM. or PEPSI.RTM., will contain a
reduced amount of sugar compared to the prior art cola beverage.
The method may be performed such that the amount of sugar required
to maintain the desired sweetness of the cola beverage is reduced
by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
95%, or from about 60% to about 99%, or alternatively from about
20% to about 50%. Thus, in a more specific embodiment, the cola
beverage comprising a sweet tastant and one or more compounds
according to Formula I, contains one or more compounds according to
Formula I in an amount sufficient to reduce the amount of sugar
required to maintain the desired sweetness of the beverage is
reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or
from about 60% to about 99%, or alternatively from about 30% to
about 70%. Of course, in other embodiments, the amount of sugar
required may be decreased to differing extents.
[0286] Additionally, the invention is directed to a process of
preparing an improved food product, wherein the improvement
comprises adding one or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, to a food product. In certain embodiments, the one
or more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, are
added to the food product in an amount of about 1% to about 25%,
about 1% to about 10%, or about 5%, 10%, or 15%, by weight.
[0287] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of an animal food product
comprising administering to a subject an animal food product
comprising a sweet tastant and one or more compounds according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. The one or more compounds are
preferably in an amount sufficient to enhance one or more sweet
tastes associated with the animal food product. Animal food
products are well known in the art, see, e.g., U.S. Pat. No.
6,403,142, and include dog food, cat food, rabbit food, and the
like. The animal food product may also be food products useful for
feeding livestock, such as cattle, bison, pigs, chicken, and the
like. In another embodiment, the animal food composition of the
present invention is a solid hypoallergenic pet food comprising a
component that contains protein or protein fragments wherein all of
said component is partially hydrolyzed and further comprises one or
more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above. In
certain embodiments, the one or more compounds according to Formula
I, or any of the specific subgroups, subclasses, or specific
compounds described above, are added to an animal food product in
an amount as described above for food products.
[0288] Any of the animal food products described herein comprise
one or more sweet tastants and one or more of compounds according
to Formula I. In one embodiment, the animal food products comprises
one sweet tastant. In a further embodiment, the food product
comprises more than one sweet tastant. In certain embodiments, the
food product comprises sucrose and corn syrup as sweet tastants, or
sucrose and aspartame, or saccharin and sucralose. In another
embodiment, the animal food product contains a sweet tastant
selected from sugar (sucrose), dextrose, maltose, dextrin, dried
invert sugar, fructose, levulose, lactose, galactose, corn syrup,
malodextrin, honey, sugar alcohols such as sorbitol, mannitol,
xylitol, lactitol, malitol, hydrogenated starch hydrolysates,
maltitol and the like, thaumatin, aspartame, acesulfame K,
saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,
dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt,
spray dried licorice root, glycyrrhizin, sodium gluconate,
glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA.RTM.,
EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
[0289] In another aspect, the present invention is directed to
method of enhancing the sweet taste of a pharmaceutical composition
comprising administering a subject a pharmaceutical composition
comprising a sweet tastant and a compound of Formula I, as defined
above, including any of the specific embodiments, subclasses, or
species described above, and one or more pharmaceutically
acceptable carriers. Preferred compositions are pharmaceutical
compositions comprising a compound selected from one or more
embodiments listed above, and one or more pharmaceutically
acceptable excipients. Pharmaceutical compositions that comprise
one or more compounds of Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, may
be used to formulate pharmaceutical drugs containing one or more
active agents that exert a biological effect other than sweetness
enhancement.
[0290] The pharmaceutical composition preferably further comprises
one or more active agents that exert a biological effect. Such
active agents includes pharmaceutical and biological agents that
have an activity other than taste enhancement. Such active agents
are well known in the art. See, e.g., The Physician's Desk
Reference. Such compositions can be prepared according to
procedures known in the art, for example, as described in
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa., USA. In one embodiment, such an active agent includes
bronchodilators, anorexiants, antihistamines, nutritional
supplements, laxatives, analgesics, anesthetics, antacids,
H.sub.2-receptor antagonists, anticholinergics, antidiarrheals,
demulcents, antitussives, antinauseants, antimicrobials,
antibacterials, antifungals, antivirals, expectorants,
anti-inflammatory agents, antipyretics, and mixtures thereof.
[0291] In another embodiment, the method of enhancing the sweet
taste of a pharmaceutical composition comprises administering a
pharmaceutical composition containing an active agent is selected
from the group consisting of antipyretics and analgesics, e.g.,
ibuprofen, acetaminophen, or aspirin; laxatives, e.g.,
phenolphthalein dioctyl sodium sulfosuccinate; appetite
depressants, e.g., amphetamines, phenylpropanolamine,
phenylpropanolamine hydrochloride, or caffeine; antacidics, e.g.,
calcium carbonate; antiasthmatics, e.g., theophylline;
antidiuretics, e.g., diphenoxylate hydrochloride; agents active
against flatulence, e.g., simethecon; migraine agents, e.g.,
ergotaminetartrate; psychopharmacological agents, e.g.,
haloperidol; spasmolytics or sedatives, e.g., phenobarbitol;
antihyperkinetics, e.g., methyldopa or methylphenidate;
tranquilizers, e.g., benzodiazepines, hydroxinmeprobramates or
phenothiazines; antihistaminics, e.g., astemizol, chloropheniramine
maleate, pyridamine maleate, doxlamine succinate, bromopheniramine
maleate, phenyltoloxamine citrate, chlorocyclizine hydrochloride,
pheniramine maleate, and phenindamine tartrate; decongestants,
e.g., phenylpropanolamine hydrochloride, phenylephrine
hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine
sulfate, phenylpropanolamine bitartrate, and ephedrine;
beta-receptor blockers, e.g., propanolol; agents for alcohol
withdrawal, e.g., disulfuram; antitussives, e.g., benzocaine,
dextromethorphan, dextromethorphan hydrobromide, noscapine,
carbetapentane citrate, and chlophedianol hydrochloride; fluorine
supplements, e.g., sodium fluoride; local antibiotics, e.g.,
tetracycline or cleocine; corticosteroid supplements, e.g.,
prednisone or prednisolone; agents against goiter formation, e.g.,
colchicine or allopurinol; antiepileptics, e.g., phenyloine sodium;
agents against dehydration, e.g., electrolyte supplements;
antiseptics, e.g., cetylpyridinium chloride; NSAIDs, e.g.,
acetaminophen, ibuprofen, naproxen, or salts thereof;
gastrointestinal active agents, e.g., loperamide and famotidine;
various alkaloids, e.g., codeine phosphate, codeine sulfate, or
morphine; supplements for trace elements, e.g., sodium chloride,
zinc chloride, calcium carbonate, magnesium oxide, and other alkali
metal salts and alkali earth metal salts; vitamins; ion-exchange
resins, e.g., cholestyramine; cholesterol-depressant and
lipid-lowering substances; antiarrhythmics, e.g.,
N-acetylprocainamide; and expectorants, e.g., guaifenesin.
[0292] Active substances which have a particularly unpleasant taste
include antibacterial agents such as ciprofloxacin, ofloxacin, and
pefloxacin; antiepileptics such as zonisamide; macrolide
antibiotics such as erythromycin; beta-lactam antibiotics such as
penicillins and cephalosporins; psychotropic active substances such
as chlorpromazine; active substances such as sulpyrine; and agents
active against ulcers, such as cimetidine.
[0293] In another embodiment, the method of enhancing the sweet
taste of a pharmaceutical composition comprises administering a
pharmaceutical composition comprising a sweet tastant, one or more
compounds according to Formula I and at least one amino acid
selected from the group consisting of glycine, L-alanine,
L-arginine, L-aspartic acid, L-cystine, L-glutamic acid,
L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine,
L-methionine, L-ornithine, L-phenylalanine, L-proline, L-serine,
L-threonine, L-tryptophan, L-tyrosine, L-valine, creatine, and
mixtures thereof.
[0294] In a further embodiment of the present invention, the
pharmaceutical product comprises one sweet tastant. In another
embodiment, the pharmaceutical product comprises more than one
sweet tastant. In another embodiment, the pharmaceutical product
comprises sucrose and corn syrup as sweet tastants, or sucrose and
aspartame, or saccharin and sucralose. In one embodiment, the food
product comprises one sweet tastant. In another embodiment, the
food product comprises more than one sweet tastant. In certain
embodiments, the food product comprises sucrose and corn syrup, or
sucrose and aspartame, or saccharin and sucralose as sweet
tastants. In another embodiment, the pharmaceutical composition
contains a sweet tastant selected from sugar, (sucrose), dextrose,
maltose, dextrin, dried invert sugar, fructose, levulose, lactose,
galactose, corn syrup, malodextrin, honey, sugar alcohols such as
sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., and
NUTRASWEET.RTM..
[0295] The method of enhancing the sweet taste of a pharmaceutical
composition comprises administering pharmaceutical compositions in
any form suitable to achieve their intended purpose. Preferably,
however, the composition is one which can be administered buccally
or orally. Alternatively, the pharmaceutical composition may be an
oral or nasal spray.
[0296] The method of enhancing the sweet taste of a pharmaceutical
composition comprises administering a pharmaceutical composition in
any form suitable for administration to any animal that can
experience the beneficial effects of one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. Foremost among
such animals are humans, although the invention is not intended to
be so limited. Other suitable animals include canines, felines,
dogs, cats, livestock, horses, cattle, sheep, and the like. A
veterinary composition, as used herein, refers to a pharmaceutical
composition that suitable for non-human animals. Such veterinary
compositions are known in the art.
[0297] In another embodiment, the pharmaceutical composition in
which the taste is enhanced is selected from a liquid dosage forms
for oral administration, including pharmaceutically acceptable
emulsions, solutions, suspensions, syrups, and elixirs. In addition
to the active compounds, the liquid dosage forms may contain inert
diluents commonly used in the art such as, for example, water or
other solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethyl formamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof.
[0298] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, and tragacanth, and mixtures thereof.
[0299] In a further embodiment, the invention is directed to method
of enhancing the sweet taste of a chewable tablet comprising
administering to a subject a chewable tablet comprising a sweet
tastant, one or more compounds according to Formula I, and one or
more biologically active agents. Chewable tablets are known in the
art. See, e.g., U.S. Pat. Nos. 4,684,534 and 6,060,078, each of
which is incorporated by reference in its entirety. Any kind of
medicament may be contained in the chewable tablet, preferably a
medicament of bitter taste, natural plant extracts or other organic
compounds. More preferably, vitamins such as vitamin A, vitamin B,
vitamin B.sub.1, vitamin B.sub.2, vitamin B.sub.6, vitamin C,
vitamin E and vitamin K; natural plant extracts such as
Sohgunjung-tang extracts, Sipchundaebo-tang extracts and
Eleutherococcus senticosus extracts; organic compounds such as
dimenhydrinate, meclazine, acetaminophen, aspirin,
phenylpropanolamine, and cetylpyridinium chloride; or
gastrointestinal agents such as dried aluminum hydroxide gel,
domperidone, soluble azulene, L-glutamine and hydrotalcite may be
contained in the core.
[0300] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of an orally disintegrating
composition comprising administering to a subject an orally
disintegrating composition wherein said orally disintegrating
composition comprises a sweet tastant and one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. Orally
disintegrating tablets are known in the art. See, e.g., U.S. Pat.
Nos. 6,368,625 and 6,316,029, each of which is hereby incorporated
by reference in its entirety.
[0301] In another embodiment, the present invention is further
directed to a method of enhancing the sweet taste of a nasal
composition comprising administering to a subject a nasal
composition comprising a sweet tastant and one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. Nasal sprays are
known in the art. See, e.g., U.S. Pat. No. 6,187,332. Addition of
one or more compounds according to Formula I to a nasal spray can
reduce the experience of an unpleasant taste associated with the
composition of the nasal spray. By way of a nonlimiting example, a
nasal spray composition according to the present invention
comprises water (such as 95-98 weight percent), a citrate (such as
0.02 M citrate anion to 0.06 M citrate anion), a compound according
to Formula I, and optionally phosphate (such as 0.03 M phosphate to
0.09 M phosphate).
[0302] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a solid dosage form,
comprising administering to a subject a solid dosage form
comprising a water and/or saliva activated effervescent granule,
such as one having a controllable rate of effervescence, a sweet
tastant, and a compound according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above. The effervescent composition may further comprise a
pharmaceutically active compound. Effervescent pharmaceutical
compositions are known in the art. See, e.g., U.S. Pat. No.
6,649,186, which is incorporated by reference in its entirety. The
effervescent composition can be used in pharmaceutical, veterinary,
horticultural, household, food, culinary, pesticidal, agricultural,
cosmetic, herbicidal, industrial, cleansing, confectionery and
flavoring applications. Formulations incorporating the effervescent
composition comprising a compound according to Formula I can
further include one or more additional adjuvants and/or active
ingredients which can be chosen from those known in the art
including flavors, diluents, colors, binders, filler, surfactant,
disintegrant, stabilizer, compaction vehicles, and non-effervescent
disintegrants.
[0303] In another embodiment, the present invention is directed a
method of enhancing the sweet taste of a film-shaped or
wafer-shaped pharmaceutical composition, comprising administering
to a subject a film-shaped or wafer-shaped pharmaceutical
composition that comprises a sweet tastant and a compound according
to Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, and is capable of
disintegrating. Such a film-shaped or wafer-shaped pharmaceutical
composition can be configured, for example, as quickly
disintegrating administration forms, e.g., administration forms
disintegrating within a period of 1 second up to 3 minutes, or as
slowly disintegrating administration forms, e.g., administration
forms disintegrating within a period of 3 to 15 minutes.
[0304] The indicated disintegration times can be set to the
above-mentioned ranges by using, for example, matrix-forming
polymers which have different disintegrating, or solubility,
characteristics. Thus, by mixing the corresponding polymer
components, the disintegration time can be adjusted. In addition,
disintegrants are known which "draw" water into the matrix and
cause the matrix to burst open from within. As a consequence,
certain embodiments of the invention include such disintegrants for
the purpose of adjusting the disintegration time.
[0305] Suitable are polymers for use in the film-shaped or
wafer-shaped pharmaceutical composition include cellulose
derivatives, polyvinyl alcohol (e.g. MOWIOL.TM.) polyacrylates,
polyvinyl pyrrolidone, cellulose ethers, such as ethyl cellulose,
as well as polyvinyl alcohol, polyurethane, polymethacrylates,
polymethyl methacrylates and derivatives and copolymerisates of the
aforementioned polymers.
[0306] In certain embodiments, the total thickness of the
film-shaped or wafer-shaped pharmaceutical composition according to
the invention is preferably 5 .mu.M up to 10 mm, preferably 30
.mu.m to 2 mm, and with particular preference 0.1 mm to 1 mm. The
pharmaceutical preparations may round, oval, elliptic, triangular,
quadrangular or polygonal shape, but they may also have any rounded
shape.
[0307] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a composition comprising a
medicament or agent contained in a coating that surrounds a gum
base formulation comprising administering the composition, a sweet
tastant and a sweetness-enhancing amount of a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. Preferably, the coating
comprises at least 50% by weight of the entire product. As the
center is chewed, the medicament or agent is released into the
saliva. For example, U.S. Pat. No. 6,773,716, which is incorporated
herein by reference in its entirety, discloses a suitable
medicament or agent contained in a coating that surrounds a gum
base formulation. One or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, can be used in preparing the coating. Optionally,
the composition may further comprise high-intensity sweeteners and
appropriate flavors. It has been found that with respect to certain
medicaments or agents that may have an astringent or bitter taste
that by adding a sweetener enhancing agent to the formulation, that
a much more palatable formulation, including the medicament, can be
provided. In this regard, even though the medicament in, for
example, its powder form may be bitter or have an offensive taste,
the matrix used as the coating of the present invention, including
the inhibiting agent, will afford a product having acceptable
medicinal properties.
[0308] In a further embodiment, the invention is directed to a
method of enhancing the sweet taste of a pharmaceutical composition
suitable for aerosol administration, comprising administering to a
subject, a pharmaceutical composition suitable for aerosol
administration comprising a sweet tastant and a compound according
to Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, and a suitable carrier. The
aerosol composition may further comprises pharmaceutically active
agent. Aerosol compositions are known in the art. See, e.g., U.S.
Pat. No. 5,011,678, which is hereby incorporated by reference in
its entirety. As a nonlimiting example, an aerosol composition
according to the present invention may comprise a medically
effective amount of a pharmaceutically active substance, one or
more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, and a
biocompatible propellant, such as a (hydro/fluoro)carbon
propellant.
[0309] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a nutritional composition
comprising administering a nutritional composition comprising a
sweet tastant and one or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, and optionally one or more carriers. Examples of
nutritional compositions having an undesirable taste include, but
are not necessarily limited to, enteral nutrition products for
treatment of nutritional deficit, trauma, surgery, Crohn's disease,
renal disease, hypertension, obesity and the like, to promote
athletic performance, muscle enhancement or general well being or
inborn errors of metabolism such as phenylketonuria. In particular,
such nutritional formulations may contain one or more amino acids
which have a bitter or metallic taste or aftertaste. Such amino
acids include, but are not limited to, an essential amino acids
selected from the group consisting of L isomers of leucine,
isoleucine, histidine, lysine, methionine, phenylalanine,
threonine, tryptophan, tyrosine, and valine.
[0310] In certain embodiments, the administered pharmaceutical or
comprises the compound according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, in an amount ranging from about 0.001% to about 50% by
weight, preferably about 0.1% to about 10% by weight, or
alternatively, from 0.1% to about 1% by weight. The present
invention also contemplates an amount of about 1% to about 20%,
preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of
the pharmaceutical or nutritional composition.
[0311] In various embodiments, the method comprises administering
the compound according to Formula I in an amount from about 0.01 mg
to about 100 mg per 100 mL of the composition, or in an amount from
about 0.01 mg to about 10 mg per 100 mL of the composition.
Alternatively, the compound is administered an amount of about 0.1
mg/L to about 100 mg/L and the sweet tastant is administered in an
amount of 10 g/L to 100 g/L, or in an amount ranging from
10.sup.-4% to 10.sup.-1% of the sweet tastant by weight, or the
compound according to Formula I and the sweet tastant are
administered in a ratio ranging from 1:10.sup.6 to 1:10.sup.3.
[0312] In each of the embodiments of the methods described herein,
a compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, may be used in
varying ratios to the tastant, i.e. the agent that is believed to
cause the sweet taste. For example, a pharmaceutical or nutritional
composition of the invention may comprise a compound of Formula I
in a molar ratio of about 1:10.sup.6 to, or alternatively
administered in a molar ratio of about 1:10.sup.5, about
1:10.sup.4, about 1:10.sup.3, about 1:10.sup.2, relative to the
tastant. As will be appreciated, the various ranges and amounts of
the compound of Formula I can be used, with modifications if
preferred, in each of the embodiments described herein. The
composition may also comprise 10.sup.-4% to 10.sup.-1% of the
compound of Formula I relative to the sweet tastant, by weight.
[0313] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in the pharmaceutical composition or
nutritional composition in an amount ranging from about 0.001 mg to
about 10 g per serving, preferably about 0.01 mg to about 5 g per
serving, or alternatively, from 0.05 mg to about 1 g per serving.
The present invention also contemplates compositions with amounts
of the compound of Formula I of about 0.05 mg, 0.1 mg, 0.5 mg, 1
mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 500 mg, 1 g, 2 g, 5 g and 8
g per serving.
[0314] The method may be performed such that the sweet taste of the
pharmaceutical composition or nutritional composition being
enhanced by the compound of Formula I is enhanced by at least about
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about
60% to about 99%, or alternatively from about 20% to about 50%.
Thus, in a more specific embodiment, the method comprises
administering a pharmaceutical composition or nutritional
composition comprising one or more food ingredients and one or more
compounds according to Formula I, wherein the one or more compounds
according to Formula I are present in an amount sufficient to
enhance a sweet taste, produced by the tastant in pharmaceutical
composition or nutritional composition by at least about 10%, 20%,
30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to
about 99%, or alternatively from about 30% to about 70%. Of course,
in other embodiments, the sweetness may be enhanced to differing
extents.
[0315] Any amount of the compound of Formula I that provides the
desired degree of sweetness enhancement can be used. For example, a
compound of Formula I may be used at a concentration of about 30
.mu.g/L to about 1.5 g/L to enhance a sweet taste. Alternatively,
concentrations of about 0.1 mg/L to 100 mg/L of a compound of
Formula I may be used to enhance a sweet taste.
[0316] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a dental hygienic
composition comprising administering a dental hygienic composition
comprising a sweet tastant and one or more compounds according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. Dental hygienic compositions
are known in the art and include but are not necessarily limited to
toothpaste, mouthwash, plaque rinse, dental floss, dental pain
relievers (such as ANBESOL.TM.), and the like. In certain
embodiments, the one or more compounds according to Formula I are
present in the dental hygienic composition in an amount of about 1%
to about 20%, preferably about 1% to about 5%, or about 5%, 10%, or
15%, by weight. In one embodiment, the dental hygienic composition
comprises more than one sweet tastant. In certain embodiments, the
hygienic composition comprises sucrose and corn syrup, or it
comprises sucrose and aspartame, or it comprises saccharin and
sucralose as sweet tastants.
[0317] In another embodiment, the present invention is directed to
a method of enhancing the sweet taste of a cosmetic product
comprising administering to a subject a cosmetic product comprising
a sweet tastant and one or more compounds according to Formula I,
or any of the specific subgroups, subclasses, or specific compounds
described above. For example, but not by way of limitation, the
cosmetic product comprising a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, may be a face cream, lipstick, lip gloss, and the
like. In certain embodiments, the one or more compounds according
to Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, are added to a cosmetic product
in an amount of about 1% to about 20%, preferably about 1% to about
5%, or about 1%, 2%, or 3%, by weight. Other suitable compositions
of the invention include lip balm, such as CHAPSTICK.RTM. or BURT'S
BEESWAX.RTM. Lip Balm, further comprising one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above.
[0318] The method of the present invention in its various
embodiments may also be used to mask one or more tastes selected
from the group consisting of bitter, sour, salty, or umami.
Preferably, the method of the present invention inhibits a bitter
taste.
[0319] As used herein, the phrase "mask a taste" and grammatical
variants thereof, such as "masking," refers to interfering with the
perception of a taste. The taste may be sensed to a lesser degree
or not sensed at all by application of the present invention.
[0320] In another embodiment, a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, is useful for masking a taste, such as an
undesirable taste of a food product by creating a sweet taste.
Examples of food products having an undesirable taste include, but
are not necessarily limited to, citrus fruits such as grapefruit,
orange, and lemon; vegetables such as tomato, pimento, celery,
melon, carrot, potato and asparagus; seasoning or flavoring
materials, such as soy sauce and red pepper; soybean products; fish
products; meats and processed meats; dairy products such as cheese;
breads and cakes; and confectioneries such as candies, chewing gum
and chocolate. Other examples of food products envisioned in
accordance with the present invention are described below and
throughout the specification.
[0321] In another embodiment, the present invention is directed to
a method of masking an undesirable taste of food product comprising
administering to a subject a food product comprising a sweet
tastant and one or more compounds according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above. Preferably, the food product is one which exhibits an
desirable taste, which can be masked by a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. Furthermore, in a preferred
embodiment, the food product comprises a compound of Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above in an amount sufficient to mask an undesirable
taste.
[0322] Specific food products to which one of more compounds of
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, can be added include but are
not necessarily limited to, potassium chloride, ammonium chloride,
sodium chloride (e.g., table salt), magnesium chloride, halide
salts, naringin, caffeine, urea, magnesium sulfate, acetosulfames,
aspirin, potassium benzoate, potassium bicarbonate, potassium
carbonate, potassium nitrate, potassium nitrite, potassium sulfate,
potassium sulfite, potassium glutamate, food preservatives in their
physiologically acceptable salts, antibiotics, unsweetened
chocolate, cocoa beans, yogurt, preservatives, flavor enhancers,
dietary supplements, gelling agents, pH control agents, nutrients,
processing aids, bodying agents, dispersing agents, stabilizers,
colorings, coloring diluents, anticaking agents, antimicrobial
agents, formulation aids, leavening agents, surface active agents,
anticaking agents, nutrient supplements, alkali, acids,
sequestrants, denuding agents, general purpose buffers, thickeners,
cooked out juice retention agents, color fixatives in meat and meat
products, color fixatives in poultry and poultry products, dough
conditioners, maturing agents, yeast foods, mold retardants,
emulsifiers, texturizers, binders, water correctives, miscellaneous
and general purpose food additives, tableting aids, lye peeling
agents, washing water agents, oxidizers, antioxidants, enzymes,
extenders, fungicides, cake mixes, coffee, tea, dry mixes,
non-dairy creamers, salts, animal glue adjuvant, cheese, nuts, meat
and meat products, poultry and poultry product, pork and pork
products, fish and fish products, vegetable and vegetable products,
fruit and fruit products, smoked products such as meat, cheese
fish, poultry, and vegetables, whipping agents, masticatory
substances in chewing gums, dough strengtheners, animal feed,
poultry feed, fish feed, pork feed, defoaming agents, juices,
liquors, substances or drinks containing alcohol, beverages
including but not limited to alcoholic beverages and non-alcoholic
carbonated and/or non-carbonated soft drinks, whipped toppings,
bulking agents used in eatables including but not limited to
starches, corn solids, polysaccharides and other polymeric
carbohydrates, icings, as well as potassium-containing or
metal-containing substances with undesirable tastes and the like.
The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.001% to
about 50% by weight, preferably about 0.1% to about 10% by weight,
or alternatively, from 0.1% to about 1% by weight. The present
invention also contemplates an amount of about 1% to about 20%,
preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of
the composition
[0323] The method may be performed such that the taste of the food
product being masked by the compound of Formula I is reduced by at
least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or
from about 60% to about 99%, or alternatively from about 20% to
about 50%. Thus, in a more specific embodiment, the method
comprises administering a food product comprising one or more food
ingredients and one or more compounds according to Formula I,
wherein the one or more compounds according to Formula I are
present in an amount sufficient to mask a bitter taste, produced by
the food product, by at least about 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or 95%, or from about 60% to about 99%, or
alternatively from about 30% to about 70%. Of course, in other
embodiments, a taste may be masked to differing extents.
[0324] Any amount of the compound of Formula I that provides the
desired degree of taste masking can be used. For example, a
compound of Formula I may be used at a concentration of about 30
.mu.g/L to about 1.5 g/L to mask a bitter taste. Alternatively,
concentrations of about 0.1 mg/L to 100 mg/L of a compound of
Formula I may be used to mask an undesirable taste.
[0325] A food product may also include beverages and drinks.
Examples of suitable beverages include, but are not limited to
coffee, teas, such as black tea, green tea, fermented tea,
semi-fermented tea, carbonated soft drinks, such as COKE.RTM. and
PEPSI.RTM., non-carbonated soft drinks, lemonade, juices and other
fruit drinks, sports drinks, such as GATORADE.RTM., iced teas,
coca, alcoholic beverages, such as beers, wines and liquors, and
KOOL-AID..RTM. In certain embodiments, the taste masking effective
amount of a compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, has a
range of from about 0.001 to about 5.0 grams per 100 mL. In other
embodiments, the taste masking effective amount of a compound
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, has a range of
from about 0.5 to about 2 grams per 100 mL. Alternatively, a
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, is administered
in an amount of about 1 gram per 100 mL. It is contemplated that
between 0.1 mg/L and 100 mg/L of the compound of Formula I is
present and between 10 g/L and 100 g/L of sweet tastant is present.
For example, a composition could contain 0.1 mg/L, 1 mg/L, or 10
mg/L of the compound of Formula I and 10 mg/L of the tastant.
Alternatively, the composition could contain 0.5 mg/L, 5 mg/L, or
50 mg/L of the compound of Formula I and 50 mg/L of the tastant. In
other embodiments, the composition contains 1 mg/L, 10 mg/L or 100
mg/L of the compound of Formula I and 100 g/L of the tastant.
[0326] In another embodiment, the present invention is directed to
a method of increasing the palatability and/or intake of food,
comprising administering to a subject in need of such treatment a
food product comprising a sweet tastant and one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, in an amount
sufficient to increase the palatability and/or intake of food.
Thus, according to the present invention, a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, may be administered to a
subject so that the palatability of food, as experienced by said
subject, is increased. Without being bound by theory, it is
believed that a higher palatability of food can lead to a greater
intake of food by the subject. Thus, in certain embodiments, by
administering a compound according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, to a subject, the subject will consume an increased amount
of food compared to the subject's food intake when not being
administered a compound of Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above. In
other embodiments, by administering a compound according to Formula
I, or any of the specific subgroups, subclasses, or specific
compounds described above, to a subject, the subject will have a
higher caloric intake compared to the subject's caloric intake when
not being administered a compound of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above. In other embodiments, administering a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, to a subject can be means to
overcome taste impairment associated with radiation treatments for
cancer, with certain drugs and loss of taste sensations in the
elderly.
[0327] In each of the embodiments of methods described above, the
subject of the method, unless otherwise limited to, may be any
animal which is need of the particular treatment or effect of the
method. Such animals include but are not limited to a cow, horse,
sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit,
monkey, or guinea pig taste modulating protein. In other
embodiments, the animal is a livestock animal, a domesticated
animal, or an animal kept as a pet. In particular embodiments, the
subject of the claimed method is a human.
[0328] Furthermore, in each of the embodiments of the methods
described herein, a compound of Formula I may be used in varying
ratios to the agent that is believed to cause the unwanted taste,
such as a bitter taste. For example, a composition of the invention
may comprise a compound of Formula I in a molar ratio of about
0.001:1 to about 10:1, or alternatively administered in a molar
ratio of about 0.01:1, about 0.02:1, about 0.05:1, about 0.1:1, or
about 0.5:1, relative to the agent causing the unwanted taste. As
will be appreciated, the various ranges and amounts of the compound
of Formula I can be used, with modifications if preferred, in each
of the embodiments described herein.
[0329] In another example, the present invention is directed to a
method of masking the bitter taste of a pharmaceutical composition,
comprising administering to a subject in need of such method a
pharmaceutical composition comprising a sweet tastant and a
compound according to Formula I, wherein the pharmaceutical
composition comprises a pharmaceutically active agent and
optionally one or more excipients, and wherein the compound
according to Formula I is administered as either a component of the
pharmaceutical composition or as a separate dosage form, and
wherein the molar ratio of the compound of Formula I to the
pharmaceutically active agent is about 1:10.sup.6 to about 10:1, or
alternatively administered in a molar ratio of about 1:10.sup.5,
about 1:10.sup.4, about 1:10.sup.3, or about 1:10.sup.2, relative
to the tastant. As will be appreciated, the various ranges and
amounts of the compound of Formula I can be used, with
modifications if preferred, in each of the embodiments described
herein.
[0330] In certain embodiments, a single dose or two to four divided
daily doses, provided on a basis of about 0.001 to 100 mg per
kilogram of body weight per day, preferably about 0.01 to about 25
mg/kg of body weight per day is appropriate. When enhancing a taste
receptor cell in vivo, the compound of Formula I is preferably
administered orally.
[0331] An additional aspect of the present invention is a method of
masking the undesirable of a pharmaceutical composition, comprising
administering pharmaceutical composition comprising a sweet tastant
and a compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, to a
subject receiving the pharmaceutical composition. The compound of
Formula I may be administered together with the pharmaceutical
composition as separate compositions, for example either
concurrently or sequentially. The compound of Formula I may
administered, or caused to be administered, prior to the
pharmaceutical agent producing the taste to be enhanced or masked.
Alternatively, the compound for Formula I may be administered as a
component of the pharmaceutical composition.
[0332] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in the composition in an amount ranging from
about 0.0001 mg to about 500 mg per dose, preferably about 0.001 mg
to about 100 mg, or alternatively, from 0.05 mg to about 10 mg per
dose. The present invention also contemplates compositions with
amounts of the compound of Formula I of about 0.0001 mg, 0.0005 mg,
0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg,
10 mg, 25 mg, 50 mg, 100 mg, 500 mg per dose.
[0333] By way of additional examples, the method of masking the
taste of a pharmaceutical composition may comprise masking a taste
produced by one or more agents selected from the group consisting
of antipyretics, analgesics, laxatives, appetite depressants,
antacidics, antiasthmatics, antidiuretics, agents active against
flatulence, antimigraine agents, psychopharmacological agents,
spasmolytics, sedatives, antihyperkinetics, tranquilizers,
antihistaminics, decongestants, beta-receptor blockers, agents for
alcohol withdrawal, antitussives, fluorine supplements, local
antibiotics, corticosteroid supplements, agents against goiter
formation, antiepileptics, agents against dehydration, antiseptics,
NSAIDs, gastrointestinal active agents, alkaloids, supplements for
trace elements, ion-exchange resins, cholesterol-depressant agents,
lipid-lowering agents, antiarrhythmics, and expectorants. Further
specific examples of pharmaceutical compositions in accordance with
the method of the invention are described below.
[0334] Additionally, the method of masking the taste of a
pharmaceutical composition may comprise masking a taste produced by
a counterterrorism pharmaceutical. Because of the increased risk of
terrorist attacks, such as chemical, nuclear, or biological
attacks, the use of counterterrorism pharmaceutical agents is
expected to increase in the future. A counterterrorism
pharmaceutical agent includes those pharmaceutical agents that are
useful in counteracting agents that can be used in a terrorist
attack. Agents that have been used in terrorist acts, or considered
as useful for carrying out future terrorist acts, include ricin,
sarin, radioactive agents and materials, and anthrax.
Pharmaceutical agents that counteract these agents are useful as a
counterterrorism pharmaceutical. Such counterterrorism
pharmaceuticals include, but are not limited to, antibiotics such
as ciprofloxacin and doxycycline; potassium iodide; and antiviral
agents. Thus, in one embodiment of the present invention, the
method may be performed such that the taste of a counterterrorism
pharmaceutical, such as an antibiotic such as ciprofloxacin and
doxycycline; potassium iodide; or an antiviral agent, is masked by
the compound of Formula I by at least about 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, or
alternatively from about 25% to about 50%. In another embodiment,
the compound of Formula I is administered in a ratio of from about
10:1 to about 1:10 in relation to the counterterrorism agent.
[0335] In another embodiment, a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, is useful for masking an undesirable taste of a
nutritional composition. Examples of nutritional compositions
having an undesirable taste include, but are not necessarily
limited to, enteral nutrition products for treatment of nutritional
deficit, trauma, surgery, Crohn's disease, renal disease,
hypertension, obesity and the like, to promote athletic
performance, muscle enhancement or general well being or inborn
errors of metabolism such as phenylketonuria. In particular, such
nutritional formulations may contain one or more amino acids which
have a bitter or metallic taste or aftertaste. Such amino acids
include, but are not limited to, an essential amino acids selected
from the group consisting of L isomers of leucine, isoleucine,
histidine, lysine, methionine, phenylalanine, threonine,
tryptophan, tyrosine, and valine. Further specific examples of
nutritional compositions in accordance with the method of the
invention are described below.
[0336] In one embodiment, the nutritional composition comprises one
sweet tastant. In another embodiment, the nutritional composition
comprises more than one sweet tastant. In certain embodiments, the
nutritional composition comprises sucrose and corn syrup, or
sucrose and aspartame, or saccharin and sucralose as sweet
tastants. In another embodiment, the nutritional composition
contains a sweet tastant selected from sugar, (sucrose), dextrose,
maltose, dextrin, dried invert sugar, fructose, levulose, lactose,
galactose, corn syrup, malodextrin, honey, sugar alcohols such as
sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., and
NUTRASWEET.RTM..
[0337] By way of example, the method may be performed such that the
taste being masked by the compound of Formula I is masked by at
least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or
from about 60% to about 99%, or alternatively from about 20% to
about 50% Thus, in a more specific embodiment, the method comprises
administering a nutritional composition comprising a sweet tastant,
a nutritional agent, optionally one or more excipients, and one or
more compounds according to Formula I, wherein the one or more
compounds according to Formula I are present in an amount
sufficient to mask a undesired taste, produced by the nutritional
agent, by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,
90%, or 95%, or from about 60% to about 99%, or alternatively from
about 10% to about 50%.
[0338] A compound according to Formula I may be incorporated into
medical and/or dental compositions. Certain compositions used in
diagnostic procedures have an unpleasant taste, such as contrast
materials and local oral anesthetics. The enhancers of the
invention may be used to improve the comfort of subjects undergoing
such procedures by improving the taste of compositions. In
addition, the enhancers of the invention may be incorporated into
pharmaceutical compositions, including tablets and liquids, to
improve their flavor and improve patient compliance particularly
where the patient is a child or a non-human animal).
[0339] In another embodiment, a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, is used to enhance the taste of a cosmetic
product. For example, but not by way of limitation, a compound
according to Formula I may be incorporated into face creams,
lipsticks, lip gloss, and the like. Also, a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, can be used to mask an
unpleasant taste of lip balm, such as CHAPSTICK.RTM. or BURT'S
BEESWAX.RTM. Lip Balm.
[0340] In addition, a compound according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above, may be incorporated into compositions that are not
traditional foods, pharmaceuticals, or cosmetics, but which may
contact taste membranes. Examples include, but are not limited to,
soaps, shampoos, toothpaste, denture adhesive, and glue on the
surfaces of stamps and envelopes. Thus, the present invention also
covers a process of preparing a composition that is not a
traditional food, pharmaceutical, or cosmetic, but which may
contact taste membranes, according to conventional methods, wherein
the improvement comprises adding a compound of Formula I to said
composition.
[0341] In another embodiment, a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, is used to mask the taste associated with one or
more the following: bitter pharmaceutical alkaloids such as
acetaminophen, ampicillin, chlorpheniramine, chlarithromycin,
doxylamine, guaifenesin, ibuprofen, pseudoephedrine hydrochloride,
and ranitidine, bitter pharmaceutical metallic salts such as zinc
containing bioadhesives (denture adhesive), bitter vitamins, bitter
components of foods such as creatine, limonin, naringin,
quinizolate, and bitter components of beverages such as caffeine,
and humulone. In one embodiment, the concentration of the compound
according to Formula I used is in the range of 0.01 mM to 20 mM and
may vary depending on the amount of bitter compound used and its
bitterness.
[0342] In another embodiment, the present invention is directed to
a method of masking the taste of a veterinary product, such as
veterinary medicines, veterinary food products, veterinary
supplements, and the like, that are administered to domesticated
animals. In a preferred embodiment, a compound according to Formula
I, or any of the specific subgroups, subclasses, or specific
compounds described above, is used to mask a taste of a veterinary
product administered to a cat or dog.
[0343] In one embodiment, in each of the methods of masking a taste
described herein, a compound according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, is administered in an amount effective to mask said taste.
As a nonlimiting example, the taste masking effective amount of a
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, administered in
one embodiment is from about 0.01 to about 5.0 grams per 100
mL.
[0344] In one embodiment, the present invention is directed to a
method of masking the taste of a pharmaceutical product, comprising
administering to a subject a pharmaceutical product comprising a
sweet tastant and a compound according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, is administered in an amount that is sufficient, in
combination with the administration of one or more additional
sweetening agents, to enhance said taste. For example, in a method
enhancing the sweet taste in a liquid pharmaceutical composition,
the composition comprises a sweet tastant and a compound according
to Formula I and another sweetening agent, wherein the amount of
the compound of Formula I is about 25% to about 75% of the amount
required to inhibit the bitter taste in the absence of the other
taste inhibiting agent. Suitable sweetening agents include but are
not limited to sugar, (sucrose), dextrose, maltose, dextrin, dried
invert sugar, fructose, levulose, lactose, galactose, corn syrup,
malodextrin, honey, sugar alcohols such as sorbitol, mannitol,
xylitol, lactitol, malitol, hydrogenated starch hydrolysates,
maltitol and the like, thaumatin, aspartame, acesulfame K,
saccharin, sucralose, glycyrrhizin, alitame, cyclamate, stevioside,
dihydrochalcones, zinc gluconate, ethyl maltol, glycine, isomalt,
spray dried licorice root, glycyrrhizin, sodium gluconate,
glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA.RTM.,
EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
[0345] In another embodiment the above described compounds may be
used to enhance a taste modulating protein. Such inhibition may be
in vitro or in vivo. The amount of the compound of Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, used to inhibit the taste modulating protein may
not necessarily be the same when used in vivo compared to in vitro.
Factors such as pharmacokinetics and pharmacodynamics of the
particular compound may require that a larger or smaller amount of
the compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, be used when
inhibiting a taste modulating protein in vivo. Accordingly, one
aspect of the present invention is a method of enhancing a taste
modulating protein, comprising contacting the taste modulating
protein with a compound according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above.
[0346] In one embodiment of this aspect of the present invention,
the method comprises contacting a cell with a compound of Formula
I, or any of the specific subgroups, subclasses, or specific
compounds described above, wherein said cell expresses said taste
modulating protein.
[0347] In another embodiment of the present invention, the method
comprises administering a compound of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, to a subject in an amount sufficient to inhibit a taste
modulating protein, wherein said subject has or expresses said
taste modulating protein. Furthermore, when administered orally,
the compound may be dispersed or diluted by saliva.
[0348] The present invention is directed to a method of enhancing a
taste modulating protein, comprising contacting said protein with a
compound of Formula I, or any of the specific subclasses and
specific compounds listed above, and enhancing the protein by at
least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or
from about 50% to about 99%. In another embodiment, the method
comprises contacting said protein with a compound of Formula I, or
any of the specific subclasses and specific compounds listed above,
and enhancing the protein by about 10% to about 50%. In another
embodiment, the present invention is directed to a method of
enhancing a taste modulating protein, comprising contacting said
protein with a compound of Formula I, or any of the specific
subclasses and specific compounds listed above, and enhancing the
protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,
90%, or 95%, or from about 50% to about 99%, or alternatively from
about 10% to about 50%, and wherein said taste modulating protein
is a naturally occurring taste modulating protein. In another
embodiment, the present invention is directed to a method of
enhancing a taste modulating protein, comprising contacting said
protein with a compound of Formula I, or any of the specific
subclasses or specific compounds listed above, and enhancing the
protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%,
90%, or 95%, or from about 50% to about 99%, or alternatively from
about 10% to about 50%, and wherein said protein is a naturally
occurring human taste modulating protein.
[0349] Any amount of the compound of Formula I that provides the
desired degree of enhancement can be used. For example, a compound
of Formula I may be used at a concentration of about 0.1 .mu.M to
about 1,000 .mu.M to enhance a taste modulating protein.
Alternatively, concentrations of about 1, 10 or 100 .mu.M of a
compound of Formula I may be used to enhance a taste modulating
protein. In certain embodiments, a single dose or two to four
divided daily doses, provided on a basis of about 0.001 to 100 mg
per kilogram of body weight per day, preferably about 0.01 to about
25 mg/kg of body weight per day is appropriate. The substance is
preferably administered orally, but parenteral routes such as the
subcutaneous, intramuscular, intravenous or intraperitoneal routes
or any other suitable delivery system, such as intranasal or
transdermal routes can also be employed.
[0350] As used herein, the term "enhancing" and grammatical
variants thereof refers to interfering with the normal activity of.
For example, enhancing a taste modulating protein means interfering
with the normal activity of a taste modulating protein. Enhancing
includes but is not necessarily limited to modulating, modifying,
activating, and the like.
[0351] As used herein, the phrase "taste modulating protein" refers
to a TRPM5 protein, and includes naturally and recombinantly
produced TRPM5 proteins; natural, synthetic, and recombinant
biologically active polypeptide fragments of said protein;
biologically active polypeptide variants of said protein or
fragments thereof, including hybrid fusion proteins and dimers;
biologically active polypeptide analogs of said protein or
fragments or variants thereof, including cysteine substituted
analogs. The taste modulating protein may be a nonhuman protein,
for example a nonhuman mammalian protein, or in other embodiments a
nonhuman protein such as but not limited to a cow, horse, sheep,
pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, monkey,
or guinea pig taste modulating protein. The taste modulating
protein may be generated and/or isolated by any means known in the
art. An example of the taste modulating protein and methods of
producing the protein are disclosed in, for example, Liu and Liman,
Proc. Nat'l Acad. Sci. USA 100: 15160-15165 (2003); D. Prawitt, et
al., Proc. Nat'l Acad. Sci. USA 100: 15166-71 (2003); and Ulrich,
N. D., et al., Cell Calcium 37: 267-278 (2005); each of which is
fully incorporated by reference herein.
[0352] A homologue is a protein that may include one or more amino
acid substitutions, deletions, or additions, either from natural
mutations of human manipulation. Thus, by way of example, a taste
modulating protein may include one or more amino acid
substitutions, deletions or additions, either from natural
mutations or human manipulation. As indicated, changes are
preferably of a minor nature, such as conservative amino acid
substitutions that do not significantly affect the folding or
activity of the protein.
[0353] The variant taste modulating proteins which may be enhanced
in accordance with the present invention comprise non-conservative
modifications (e.g., substitutions). By "nonconservative"
modification herein is meant a modification in which the wild-type
residue and the mutant residue differ significantly in one or more
physical properties, including hydrophobicity, charge, size, and
shape. For example, modifications from a polar residue to a
nonpolar residue or vice-versa, modifications from positively
charged residues to negatively charged residues or vice versa, and
modifications from large residues to small residues or vice versa
are nonconservative modifications. For example, substitutions may
be made which more significantly affect: the structure of the
polypeptide backbone in the area of the alteration, for example the
alpha-helical or beta-sheet structure; the charge or hydrophobicity
of the molecule at the target site; or the bulk of the side chain.
The substitutions which in general are expected to produce the
greatest changes in the polypeptide's properties are those in which
(a) a hydrophilic residue, e.g., seryl or threonyl, is substituted
for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl,
phenylalanyl, valyl or alanyl; (b) a cysteine or proline is
substituted for (or by) any other residue; (c) a residue having an
electropositive side chain, e.g., lysyl, arginyl, or histidyl, is
substituted for (or by) an electronegative residue, e.g., glutamyl
or aspartyl; or (d) a residue having a bulky side chain, e.g.,
phenylalanine, is substituted for (or by) one not having a side
chain, e.g., glycine. In one embodiment, the variant taste
modulating proteins used in accordance with the present invention
have at least one nonconservative modification.
[0354] In other embodiments, the method of the invention comprises
enhancing a taste modulating protein that is a nonhuman protein,
such as but not limited to a cow, horse, sheep, pig, chicken,
turkey, quail, cat, dog, mouse, rat, rabbit, monkey, or guinea pig
taste modulating protein.
[0355] In other instances, the method comprises administering the
compound according to Formula I as a food composition, a
pharmaceutical composition, or a veterinary composition, e.g.,
wherein the compound is in a concentration from about 1% to about
10% on a weight percentage basis, or in an amount of about 0.01 mg
to about 10 mg per mL.
[0356] An additional aspect of the present invention is a method of
enhancing the depolarization of a taste receptor cell, comprising
contacting the taste receptor cell with a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. For example, a compound of
Formula I may enhance the depolarization of a taste receptor cell
by a mechanism other than, or in addition to, the mechanism of
enhancing a taste receptor protein. In one embodiment of this
aspect of the present invention, the method comprises contacting a
taste receptor cell with a compound of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, wherein said taste receptor cell can detect a sweet taste.
In another embodiment of the present invention, the method
comprises administering a compound of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, to a subject in an amount sufficient to enhance the
depolarization of a taste receptor cell. Furthermore, when
administered orally, the compound may be dispersed or diluted by
saliva.
[0357] By way of example, the present invention is directed to a
method of enhancing the depolarization of a taste receptor cell,
comprising contacting said taste receptor cell with a compound of
Formula I, or any of the specific subclasses and specific compounds
listed above, and enhancing the depolarization of the taste
receptor cell by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, or 95%, or from about 60% to about 99%, or alternatively
from about 30% to about 75%. In another embodiment, the present
invention is directed to a method of enhancing the depolarization
of a taste receptor cell, comprising contacting said protein with a
compound of Formula I, or any of the specific subclasses and
specific compounds listed above, and enhancing the depolarization
of the taste receptor cell by at least about 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%, or
alternatively from about 20% to about 60%, and wherein said taste
receptor cell is a naturally occurring taste modulating protein. In
another embodiment, the present invention is directed to a method
of enhancing a taste receptor cell, comprising contacting said
protein with a compound of Formula I, or any of the specific
subclasses or specific compounds listed above, and enhancing the
taste receptor cell by at least about 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90%, or 95%, or from about 50% to about 99%, or
alternatively from about 40% to about 80%, and wherein said taste
receptor cell is a human taste receptor cell.
[0358] Any amount of the compound of Formula I that provides the
desired degree of enhancement can be used. For example, a compound
of Formula I may be used at a concentration of about 0.1 .mu.M to
about 1,000 .mu.M to enhance a taste receptor cell. Alternatively,
concentrations of about 1 .mu.M, 50 .mu.M, or 100 .mu.M of a
compound of Formula I may be used to enhance the depolarization of
a taste receptor cell.
[0359] In certain embodiments, a single dose or two to four divided
daily doses, provided on a basis of about 0.001 to 100 mg per
kilogram of body weight per day, preferably about 0.01 to about 25
mg/kg of body weight per day is appropriate. When enhancing a taste
receptor cell in vivo, the compound of Formula I is preferably
administered orally.
[0360] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight.
[0361] In one embodiment of this aspect of the present invention,
the method comprises contacting a taste receptor cell with a
compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, wherein said
taste receptor cell can detect a sweet, bitter, sour, salty, or
umami taste. In another embodiment of the present invention, the
method comprises administering a compound of Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above, to a subject in an amount sufficient to enhance the
depolarization of a taste receptor cell. Furthermore, when
administered orally, the compound may be dispersed or diluted by
saliva.
Compositions
[0362] The present invention is also directed to various, useful
compositions comprising a compound of Formula I or a
physiologically acceptable salt thereof.
[0363] In another embodiment, the present invention is directed to
a food product comprising a sweet tastant and one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. Preferably, the
food product is one which exhibits a sweet taste and/or contains a
sweetening agent which can be enhanced by a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. Furthermore, in a preferred
embodiment, the food product comprises a compound of Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above in an amount sufficient to enhance the sweet taste.
Specific sweetening agents to which one of more compounds of
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, can be added to enhance its
sweet taste include but are not necessarily limited to sugar,
(sucrose), dextrose, maltose, dextrin, dried invert sugar,
fructose, levulose, lactose, galactose, corn syrup, malodextrin,
honey, sugar alcohols such as sorbitol, mannitol, xylitol,
lactitol, malitol, hydrogenated starch hydrolysates, maltitol and
the like, thaumatin, aspartame, acesulfame K, saccharin, sucralose,
glycyrrhizin, alitame, cyclamate, stevioside, dihydrochalcones,
zinc gluconate, ethyl maltol, glycine, isomalt, spray dried
licorice root, glycyrrhizin, sodium gluconate,
glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA.RTM.,
EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM.. Specific food
products in which an enchanted sweet taste is desired include but
are not limited to cakes, cookies, confectionaries such as candies,
gums and chocolates, creams, icing, ice cream, pies and breads.
Specific food products which are beverages include soft drinks,
juices and other fruit drinks, sports drinks such as GATORADE.RTM.,
coffee, teas, iced teas, coca, alcoholic beverages and
KOOL-AID.RTM..
[0364] Specific food products to which one of more compounds of
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, can be added include but are
not necessarily limited to, potassium chloride, ammonium chloride,
sodium chloride (e.g., table salt), magnesium chloride, halide
salts, naringin, caffeine, urea, magnesium sulfate, acetosulfames,
aspirin, potassium benzoate, potassium bicarbonate, potassium
carbonate, potassium nitrate, potassium nitrite, potassium sulfate,
potassium sulfite, potassium glutamate, food preservatives in their
physiologically acceptable salts, antibiotics, unsweetened
chocolate, cocoa beans, yogurt, preservatives, flavor enhancers,
dietary supplements, gelling agents, pH control agents, nutrients,
processing aids, bodying agents, dispersing agents, stabilizers,
colorings, coloring diluents, anticaking agents, antimicrobial
agents, formulation aids, leavening agents, surface active agents,
anticaking agents, nutrient supplements, alkali, acids,
sequestrants, denuding agents, general purpose buffers, thickeners,
cooked out juice retention agents, color fixatives in meat and meat
products, color fixatives in poultry and poultry products, dough
conditioners, maturing agents, yeast foods, mold retardants,
emulsifiers, texturizers, binders, water correctives, miscellaneous
and general purpose food additives, tableting aids, lye peeling
agents, washing water agents, oxidizers, antioxidants, enzymes,
extenders, fungicides, cake mixes, coffee, tea, dry mixes,
non-dairy creamers, salts, animal glue adjuvant, cheese, nuts, meat
and meat products, poultry and poultry product, pork and pork
products, fish and fish products, vegetable and vegetable products,
fruit and fruit products, smoked products such as meat, cheese
fish, poultry, and vegetables, whipping agents, masticatory
substances in chewing gums, dough strengtheners, animal feed,
poultry feed, fish feed, pork feed, defoaming agents, juices,
liquors, substances or drinks containing alcohol, beverages
including but not limited to alcoholic beverages and non-alcoholic
carbonated and/or non-carbonated soft drinks, whipped toppings,
bulking agents used in eatables including but not limited to
starches, corn solids, polysaccharides and other polymeric
carbohydrates, icings, as well as potassium-containing or
metal-containing substances and the like. The compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, can be typically present in an
amount ranging from about 0.001% to about 50% by weight, preferably
about 0.1% to about 10% by weight, or alternatively, from 0.1% to
about 1% by weight, of the sweet tastant. The present invention
also contemplates the preparation of amount of about 1% to about
20%, preferably about 1% to about 5%, about 1%, 3%, or 4%, by
weight.
[0365] In other embodiments, the food product is a liquid food
product, e.g., a carbonated beverage, or a solid food product,
e.g., citrus fruits; vegetables; seasoning or flavoring materials;
soybean products; fish products; meats and processed meats; dairy
products; breads and cakes; and confectioneries. A
[0366] The food product may contain the compound according to
Formula I in a concentration from about 1% to about 10% on a weight
percentage basis, or in an amount from about 0.01 mg to about 100
mg per mL of food product, or in an amount from about 0.01 mg to
about 100 mg per gram of food product, or in an amount of about 0.1
mg/L to about 100 mg/L and the sweet tastant is administered in an
amount of 10 g/L to 100 g/L. Alternatively, the food product
comprises the compound according to Formula I and the sweet tastant
are administered in a ratio ranging from 1:106 to 1:103, or
comprises the compound according to Formula I is administered in an
amount ranging from 10.sup.-4% to 10.sup.-1% of the sweet tastant
by weight.
[0367] In other instances, the method is such that the sweet
tastant is selected from the group consisting of sugar, (sucrose),
dextrose, maltose, dextrin, dried invert sugar, fructose, levulose,
lactose, galactose, corn syrup, malodextrin, honey, sugar alcohols
such as sorbitol, mannitol, xylitol, lactitol, malitol,
hydrogenated starch hydrolysates, maltitol and the like, thaumatin,
aspartame, acesulfame K, saccharin, sucralose, glycyrrhizin,
alitame, cyclamate, stevioside, dihydrochalcones, zinc gluconate,
ethyl maltol, glycine, isomalt, spray dried licorice root,
glycyrrhizin, sodium gluconate, glucono-delta-lactone, ethyl
vanillin, vanillin, SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM.,
NUTRASWEET.RTM., and mixtures thereof.
[0368] In other instances, the food product comprises, consists of,
or consists essentially of a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, and one or more sweet tastants. Such sweet
tastants include sugar, (sucrose), dextrose, maltose, dextrin,
dried invert sugar, fructose, levulose, lactose, galactose, corn
syrup, malodextrin, honey, sugar alcohols such as sorbitol,
mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., NUTRASWEET.RTM., and
mixtures thereof.
[0369] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the food product.
[0370] For example, an embodiment of the invention includes an
improved cola beverage, such as COKE.RTM. or PEPSI.RTM. wherein the
improvement comprises one or more s of Formula I. Cola beverages of
the invention can be prepared by mixing cola concentrate with
carbonated water. Typically about 50 mL of cola concentrate is
added per 250 mL of carbonated water. Cola concentrate can be
prepared by mixing cola flavor, caramel color, and optionally
caffeine with water, one or more sweet tastants, one or more
compounds of Formula I, and one or more acid components.
[0371] A cola flavor refers to either a natural or artificial
flavor. Such cola flavors are commercially available. Commercial
cola flavors are available, for example, from International Flavor
and Fragrances, Dayton, N.J.; Artificial--#13573011 and Natural
#K3559549. Commercial cola flavors are also available from
Tastemaker, Cincinnati, Ohio, and Givaudan Roure, Clifton, N.J.
[0372] The acid component refers an ingredient that contributes
sourness to the beverage and is added to balance the flavor profile
by reducing chemical or sweetener side tastes. Acids may include
malic acid, citric acid, phosphoric acid or combinations
thereof.
[0373] Examples of sweet tastants include but are not limited to
the group consisting of sugar, (sucrose), dextrose, maltose,
dextrin, dried invert sugar, fructose, levulose, lactose,
galactose, corn syrup, malodextrin, honey, sugar alcohols such as
sorbitol, mannitol, xylitol, lactitol, malitol, hydrogenated starch
hydrolysates, maltitol and the like, thaumatin, aspartame,
acesulfame K, saccharin, sucralose, glycyrrhizin, alitame,
cyclamate, stevioside, dihydrochalcones, zinc gluconate, ethyl
maltol, glycine, isomalt, spray dried licorice root, glycyrrhizin,
sodium gluconate, glucono-delta-lactone, ethyl vanillin, vanillin,
SPLENDA.RTM., EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
Sucrose, saccharin, sucralose, and aspartame or preferred. As
discussed supra, the compositions of the invention can comprise
more than one sweet tastant. For example, the food products of this
invention can comprise both sucrose and corn syrup as sweet
tastants, or sucrose and aspartame as sweet tastants, or saccharin
and sucralose as sweet tastants.
[0374] For example, the cola concentrate can prepared by mixing
phosphoric acid (75% Rhone-Poulenc), citric acid (anhydrous, ADM,
Decatur, Ill.), caffeine (Mallinckrodt, Paris, Ky.), caramel Color
(DS400, Sethness, Chicago, Ill.), cola Flavor (SN018976,
International Flavors and Fragrances, Dayton, N.J.), sucrose, one
or more compounds of Formula I, and water. The concentrate is
blended until all ingredients are dissolved (30-40 minutes) using a
magnetic stirring plate. Fifty milliliters of the concentrate are
added to 250 mL of carbonated water to complete the preparation of
the cola beverage. Fifty milliliters of cola concentrate typically
contains from 0.01 to 5 mL of phosphoric acid, preferably about
0.01-1 mL, 0.1 to 100 g of sucrose, preferably about 1-10 g, about
1.times.10.sup.-6 g to 10 g of a compound of Formula I, preferably
about 1.times.10.sup.-3 g to 1 g, about 0.001 g to 0.1 g of citric
acid, preferably about 0.005-0.1 g, 0.001 to 1 g of caffeine,
preferably about 0.01 to 0.1 g of caffeine, 0.01 to 5 g of caramel
flavor, preferably about 0.05 to 1 g, 0.001 to about 10 mL of cola
flavor, preferably about 0.01 to about 2 mL.
[0375] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the cola beverage.
[0376] In each of the embodiments of the methods described herein,
a compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, may be used in
varying ratios to the tastant, i.e. the agent that is believed to
cause the sweet taste. For example, a composition of the invention
may comprise a compound of Formula I in a molar ratio of about
1:10.sup.6 to about 10:1, or alternatively administered in a molar
ratio of about 1:10.sup.5, about 1:10.sup.4, about 10:10.sup.3,
about 1:10.sup.2, relative to the tastant. As will be appreciated,
the various ranges and amounts of the compound of Formula I can be
used, with modifications if preferred, in each of the embodiments
described herein. The composition may also comprise 10.sup.-4% to
10.sup.-1% of the compound of Formula I relative to the sweet
tastant, by weight.
[0377] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in the cola beverage in an amount ranging from
about 0.001 mg to about 10 g per serving, preferably about 0.01 mg
to about 5 g per serving, or alternatively, from 0.05 mg to about 1
g per serving. The present invention also contemplates cola
beverages with amounts of the compound of Formula I of about 0.05
mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 500
mg, 1 g, 2 g, 5 g and 8 g per serving.
[0378] Any amount of the compound of Formula I that provides the
desired degree of sweetness enhancement can be used. For example, a
compound of Formula I may be used at a concentration of about 30
.mu.g/L to about 1.5 g/L to enhance a sweet taste. Alternatively,
concentrations of about 0.1 to 100 mg/L of a compound of Formula I
may be used to enhance a sweet taste. It is contemplated that
between 0.1 mg/L and 100 mg/L of the compound of Formula I is
present and between 10 g/L and 100 g/L of sweet tastant is present.
For example, a composition could contain 0.1 mg/L, 1 mg/L, or 10/L
mg of the compound of Formula I for 10 mg/L of the tastant.
Alternatively, the composition could contain 0.5 mg/L, 5 mg/L or 50
mg/L of the compound of Formula I for 50 mg/L of the tastant. In
other embodiments, the composition contains 1 mg/L, 10 mg/L or 100
mg/L of the compound of Formula I for 100 g/L of the tastant.
[0379] In certain embodiments, the improved food product such as
the cola beverage, e.g., COKE.RTM. or PEPSI,.RTM. will contain a
reduced amount of sugar compared to the prior art cola beverage.
The method may be performed such that the amount of sugar required
to maintain the desired sweetness of the cola beverage is reduced
by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
95%, or from about 60% to about 99%, or alternatively from about
20% to about 50%. Thus, in a more specific embodiment, the cola
beverage comprising a sweet tastant and one or more compounds
according to Formula I, contains one or more compounds according to
Formula I in an amount sufficient to reduce the amount of sugar
required to maintain the desired sweetness of the beverage is
reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or
from about 60% to about 99%, or alternatively from about 30% to
about 70%. Of course, in other embodiments, the amount of sugar
required may be decreased to differing extents.
[0380] Additionally, the invention is directed to a process of
preparing an improved food product, wherein the improvement
comprises adding one or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, to a food product. In certain embodiments, the one
or more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, are
added to the food product in an amount of about 1% to about 25%,
about 1% to about 10%, or about 5%, 10%, or 15%, by weight. In
other embodiments, the improved food product will contain a reduced
amount of sweet tastant, e.g., sucrose.
[0381] In another embodiment, the present invention is directed to
an animal food product comprising one or more compounds according
to Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. The one or more compounds are
preferably in an amount sufficient to enhance one or more sweet
tastes associated with the animal food product. Animal food
products are well known in the art, see, e.g., U.S. Pat. No.
6,403,142, and include dog food, cat food, rabbit food, and the
like. The animal food product may also be food products useful for
feeding livestock, such as cattle, bison, pigs, chicken, and the
like. In another embodiment, the animal food composition of the
present invention is a solid hypoallergenic pet food comprising a
component that contains protein or protein fragments wherein all of
said component is partially hydrolyzed and further comprises one or
more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above.
[0382] Additionally, the invention is directed to a process of
preparing an improved animal food product, wherein the improvement
comprises adding one or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, to an animal food product. In certain embodiments,
the one or more compounds according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, are added to an animal food product in an amount of about 1%
to about 25%, about 1% to about 10%, or about 5%, 10%, or 15%, by
weight.
[0383] In one embodiment, the pharmaceutical composition comprises
one sweet tastant. In another embodiment, the pharmaceutical
composition comprises more than one sweet tastant. In certain
embodiments, the pharmaceutical composition comprises sucrose and
corn syrup, or sucrose and aspartame, or saccharin and sucralose as
sweet tastants. In another embodiment, the pharmaceutical
composition contains a sweet tastant selected from sugar,
(sucrose), dextrose, maltose, dextrin, dried invert sugar,
fructose, levulose, lactose, galactose, corn syrup, malodextrin,
honey, sugar alcohols such as sorbitol, mannitol, xylitol,
lactitol, malitol, hydrogenated starch hydrolysates, maltitol and
the like, thaumatin, aspartame, acesulfame K, saccharin, sucralose,
glycyrrhizin, alitame, cyclamate, stevioside, dihydrochalcones,
zinc gluconate, ethyl maltol, glycine, isomalt, spray dried
licorice root, glycyrrhizin, sodium gluconate,
glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA.RTM.,
EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
[0384] In each of the embodiments of the compositions described
herein, a compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, may be used in
varying ratios to the agent that is believed to cause the sweet
taste. The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.001% to
about 50% by weight, preferably about 0.1% to about 10% by weight,
or alternatively, from 0.1% to about 1% by weight. The present
invention also contemplates an amount of about 1% to about 20%,
preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of
the food product.
[0385] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the food product.
[0386] In each of the embodiments of the methods described herein,
a compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, may be used in
varying ratios to the tastant, i.e. the agent that is believed to
cause the sweet taste. For example, a composition of the invention
may comprise a compound of Formula I in a molar ratio of about
0.001:1 to about 10:1, or alternatively administered in a molar
ratio of about 0.01:1, about 0.02:1, about 0.05:1, about 0.1:1, or
about 0.5:1, relative to the tastant. As will be appreciated, the
various ranges and amounts of the compound of Formula I can be
used, with modifications if preferred, in each of the embodiments
described herein.
[0387] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in the food product in an amount ranging from
about 0.001 mg to about 10 g per serving, preferably about 0.01 mg
to about 5 g per serving, or alternatively, from 0.05 mg to about 1
g per serving. The present invention also contemplates food
products with amounts of the compound of Formula I of about 0.05
mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 500
mg, 1 g, 2 g, 5 g and 8 g per serving.
[0388] The sweet taste of the food product may be enhanced by the
compound of Formula I is enhanced by at least about 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about
99%, or alternatively from about 20% to about 50%. Thus, in a more
specific embodiment, composition comprising a food product
comprising a sweet tastant, one or more food ingredients, and one
or more compounds according to Formula I, wherein the one or more
compounds according to Formula I are present in an amount
sufficient to enhance a sweet taste, produced by the food product,
by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or
95%, or from about 60% to about 99%, or alternatively from about
30% to about 70%. Of course, in other embodiments, the sweetness
may be enhanced to differing extents.
[0389] Any amount of the compound of Formula I that provides the
desired degree of sweetness enhancement can be used. For example, a
compound of Formula I may be used at a concentration of about 0.1
.mu.M to about 5,000 .mu.M to enhance a sweet taste. Alternatively,
concentrations of about 1 .mu.M, 100 .mu.M, or 500 .mu.M of a
compound of Formula I may be used to enhance a sweet taste.
[0390] In one aspect, the present invention is directed to a
pharmaceutical composition comprising a compound of Formula I, as
defined above, including any of the specific embodiments,
subclasses, or species described above, and one or more
pharmaceutically acceptable carriers. Preferred compositions of the
present invention are pharmaceutical compositions comprising a
compound selected from one or more embodiments listed above, and
one or more pharmaceutically acceptable excipients. Pharmaceutical
compositions that comprise one or more compounds of Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, may be used to formulate pharmaceutical drugs
containing one or more active agents that exert a biological effect
other than sweetness enhancement.
[0391] In one embodiment, the pharmaceutical composition comprises
one sweet tastant. In another embodiment, the pharmaceutical
composition comprises more than one sweet tastant. In certain
embodiments, the pharmaceutical composition comprises sucrose and
corn syrup, or sucrose and aspartame, or saccharin and sucralose as
sweet tastants. In another embodiment, the pharmaceutical
composition contains a sweet tastant selected from sugar,
(sucrose), dextrose, maltose, dextrin, dried invert sugar,
fructose, levulose, lactose, galactose, corn syrup, malodextrin,
honey, sugar alcohols such as sorbitol, mannitol, xylitol,
lactitol, malitol, hydrogenated starch hydrolysates, maltitol and
the like, thaumatin, aspartame, acesulfame K, saccharin, sucralose,
glycyrrhizin, alitame, cyclamate, stevioside, dihydrochalcones,
zinc gluconate, ethyl maltol, glycine, isomalt, spray dried
licorice root, glycyrrhizin, sodium gluconate,
glucono-delta-lactone, ethyl vanillin, vanillin, SPLENDA.RTM.,
EQUAL.RTM., SWEET 'N LOW.RTM., and NUTRASWEET.RTM..
[0392] The pharmaceutical composition preferably further comprises
one or more active agents that exert a biological effect. Such
active agents includes pharmaceutical and biological agents that
have an activity other than taste enhancement. Such active agents
are well known in the art. See, e.g., The Physician's Desk
Reference. Such compositions can be prepared according to
procedures known in the art, for example, as described in
Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,
Pa., USA. In one embodiment, such an active agent includes
bronchodilators, anorexiants, antihistamines, nutritional
supplements, laxatives, analgesics, anesthetics, antacids,
H.sub.2-receptor antagonists, anticholinergics, antidiarrheals,
demulcents, antitussives, antinauseants, antimicrobials,
antibacterials, antifungals, antivirals, expectorants,
anti-inflammatory agents, antipyretics, and mixtures thereof. The
pharmaceutical composition according to the present invention may
comprise one or more compounds according to Formula I, as described
above, or any of the specific subgroups, subclasses, or specific
compounds described above; an active agent that has a bitter taste;
and optionally one or more pharmaceutically acceptable
carriers.
[0393] In another embodiment, the active agent is selected from the
group consisting of antipyretics and analgesics, e.g., ibuprofen,
acetaminophen, or aspirin; laxatives, e.g., phenolphthalein dioctyl
sodium sulfosuccinate; appetite depressants, e.g., amphetamines,
phenylpropanolamine, phenylpropanolamine hydrochloride, or
caffeine; antacidics, e.g., calcium carbonate; antiasthmatics,
e.g., theophylline; antidiuretics, e.g., diphenoxylate
hydrochloride; agents active against flatulence, e.g., simethecon;
migraine agents, e.g., ergotaminetartrate; psychopharmacological
agents, e.g., haloperidol; spasmolytics or sedatives, e.g.,
phenobarbitol; antihyperkinetics, e.g., methyldopa or
methylphenidate; tranquilizers, e.g., benzodiazepines,
hydroxinmeprobramates or phenothiazines; antihistaminics, e.g.,
astemizol, chloropheniramine maleate, pyridamine maleate, doxlamine
succinate, bromopheniramine maleate, phenyltoloxamine citrate,
chlorocyclizine hydrochloride, pheniramine maleate, and
phenindamine tartrate; decongestants, e.g., phenylpropanolamine
hydrochloride, phenylephrine hydrochloride, pseudoephedrine
hydrochloride, pseudoephedrine sulfate, phenylpropanolamine
bitartrate, and ephedrine; beta-receptor blockers, e.g.,
propanolol; agents for alcohol withdrawal, e.g., disulfuram;
antitussives, e.g., benzocaine, dextromethorphan, dextromethorphan
hydrobromide, noscapine, carbetapentane citrate, and chlophedianol
hydrochloride; fluorine supplements, e.g., sodium fluoride; local
antibiotics, e.g., tetracycline or cleocine; corticosteroid
supplements, e.g., prednisone or prednisolone; agents against
goiter formation, e.g., colchicine or allopurinol; antiepileptics,
e.g., phenyloine sodium; agents against dehydration, e.g.,
electrolyte supplements; antiseptics, e.g., cetylpyridinium
chloride; NSAIDs, e.g., acetaminophen, ibuprofen, naproxen, or
salts thereof; gastrointestinal active agents, e.g., loperamide and
famotidine; various alkaloids, e.g., codeine phosphate, codeine
sulfate, or morphine; supplements for trace elements, e.g., sodium
chloride, zinc chloride, calcium carbonate, magnesium oxide, and
other alkali metal salts and alkali earth metal salts; vitamins;
ion-exchange resins, e.g., cholestyramine; cholesterol-depressant
and lipid-lowering substances; antiarrhythmics, e.g.,
N-acetylprocainamide; and expectorants, e.g., guaifenesin.
[0394] Active substances which have a particularly unpleasant taste
include antibacterial agents such as ciprofloxacin, ofloxacin, and
pefloxacin; antiepileptics such as zonisamide; macrolide
antibiotics such as erythromycin; beta-lactam antibiotics such as
penicillins and cephalosporins; psychotropic active substances such
as chlorpromazine; active substances such as sulpyrine; and agents
active against ulcers, such as cimetidine.
[0395] In another embodiment, the pharmaceutical composition
comprises one or more compounds according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above, and at least one amino acid selected from the group
consisting of glycine, L-alanine, L-arginine, L-aspartic acid,
L-cystine, L-glutamic acid, L-glutamine, L-histidine, L-isoleucine,
L-leucine, L-lysine, L-methionine, L-ornithine, L-phenylalanine,
L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine,
L-valine, creatine, and mixtures thereof.
[0396] In another embodiment, the pharmaceutical composition
comprises one or more compounds according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above; a biologically active agent that exhibits an activity other
than sweetness enhancement; and at least one amino acid, such as
one selected from the group consisting of glycine, L-alanine,
L-arginine, L-aspartic acid, L-cystine, L-glutamic acid,
L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine,
L-methionine, L-ornithine, L-phenylalanine, L-proline, L-serine,
L-threonine, L-tryptophan, L-tyrosine, L-valine, creatine, and
mixtures thereof.
[0397] The pharmaceutical compositions of the present invention can
be in any form suitable to achieve their intended purpose.
Preferably, however, the composition is one which can be
administered buccally or orally. Alternatively, the pharmaceutical
composition may be an oral or nasal spray.
[0398] The pharmaceutical compositions of the invention can be in
any form suitable for administration to any animal that can
experience the beneficial effects of one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. Foremost among
such animals are humans, although the invention is not intended to
be so limited. Other suitable animals include canines, felines,
dogs, cats, livestock, horses, cattle, sheep, and the like. A
veterinary composition, as used herein, refers to a pharmaceutical
composition that suitable for non-human animals. Such veterinary
compositions are known in the art.
[0399] The pharmaceutical preparations of the present invention can
be manufactured using known methods, for example, by means of
conventional mixing, granulating, dragee-making, dissolving, or
lyophilizing processes. Thus, pharmaceutical preparations for oral
use can be obtained by combining the active compounds with solid
excipients, optionally grinding the resulting mixture and
processing the mixture of granules, after adding suitable
auxiliaries, if desired or necessary, to obtain tablets or dragee
cores.
[0400] Pharmaceutical excipients are well known in the art.
Suitable excipients include fillers such as saccharides, for
example, lactose or sucrose, mannitol or sorbitol, cellulose
preparations and/or calcium phosphates, for example, tricalcium
phosphate or calcium hydrogen phosphate, as well as binders, such
as, starch paste, using, for example, maize starch, wheat starch,
rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or
polyvinyl pyrrolidone. If desired, disintegrating agents can be
added, such as, the above-mentioned starches and also
carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof, such as, sodium alginate.
Auxiliaries are, above all, flow-regulating agents and lubricants,
for example, silica, talc, stearic acid or salts thereof, such as,
magnesium stearate or calcium stearate, and/or polyethylene glycol.
Dragee cores are provided with suitable coatings that, if desired,
are resistant to gastric juices. For this purpose, concentrated
saccharide solutions can be used, which may optionally contain gum
arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or
titanium dioxide, lacquer solutions and suitable organic solvents
or solvent mixtures. In order to produce coatings resistant to
gastric juices, solutions of suitable cellulose preparations, such
as, acetylcellulose phthalate or hydroxypropylmethyl-cellulose
phthalate, are used. Dye stuffs or pigments can be added to the
tablets or dragee coatings, for example, for identification or in
order to characterize combinations of active compound doses.
[0401] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage forms may contain inert diluents commonly used in the
art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
[0402] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, and tragacanth, and mixtures thereof.
[0403] In a further embodiment, the invention is directed to a
chewable tablet comprising a sweet tastant and one or more
compounds according to Formula I and one or more biologically
active agents. Chewable tablets are known in the art. See, e.g.,
U.S. Pat. Nos. 4,684,534 and 6,060,078, each of which is
incorporated by reference in its entirety. Any kind of medicament
may be contained in the chewable tablet, preferably a medicament of
bitter taste, natural plant extracts or other organic compounds.
More preferably, vitamins such as vitamin A, vitamin B, vitamin
B.sub.1, vitamin B.sub.2, vitamin B.sub.6, vitamin C, vitamin E and
vitamin K; natural plant extracts such as Sohgunjung-tang extracts,
Sipchundaebo-tang extracts and Eleutherococcus senticosus extracts;
organic compounds such as dimenhydrinate, meclizine, acetaminophen,
aspirin, phenylpropanolamine, and cetylpyridinium chloride; or
gastrointestinal agents such as dried aluminum hydroxide gel,
domperidone, soluble azulene, L-glutamine and hydrotalcite may be
contained in the core.
[0404] In another embodiment, the present invention is directed to
an orally disintegrating composition wherein said orally
disintegrating composition comprises a sweet tastant and one or
more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above.
Orally disintegrating tablets are known in the art. See, e.g., U.S.
Pat. Nos. 6,368,625 and 6,316,029, each of which is hereby
incorporated by reference in its entirety.
[0405] In another embodiment, the present invention is further
directed to a nasal composition comprising a sweet tastant and one
or more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above. Nasal
sprays are known in the art. See, e.g., U.S. Pat. No. 6,187,332.
Addition of one or more compounds according to Formula I to a nasal
spray can reduce the experience of an unpleasant taste associated
with the composition of the nasal spray. By way of a nonlimiting
example, a nasal spray composition according to the present
invention comprises water (such as 95-98 weight percent), a citrate
(such as 0.02 M citrate anion to 0.06 M citrate anion), a compound
according to Formula I, and optionally phosphate (such as 0.03 M
phosphate to 0.09 M phosphate).
[0406] In another embodiment, the present invention is directed to
a solid dosage form comprising a sweet tastant and a water and/or
saliva activated effervescent granule, such as one having a
controllable rate of effervescence, and a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. The effervescent composition
may further comprise a pharmaceutically active compound.
Effervescent pharmaceutical compositions are known in the art. See,
e.g., U.S. Pat. No. 6,649,186, which is incorporated by reference
in its entirety. The effervescent composition can be used in
pharmaceutical, veterinary, horticultural, household, food,
culinary, pesticidal, agricultural, cosmetic, herbicidal,
industrial, cleansing, confectionery and flavoring applications.
Formulations incorporating the effervescent composition comprising
a compound according to Formula I can further include one or more
additional adjuvants and/or active ingredients which can be chosen
from those known in the art including flavors, diluents, colors,
binders, filler, surfactant, disintegrant, stabilizer, compaction
vehicles, and non-effervescent disintegrants.
[0407] In another embodiment, the present invention is directed to
a film-shaped or wafer-shaped pharmaceutical composition that
comprises a sweet tastant and a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, and is capable of disintegrating. Such a
film-shaped or wafer-shaped pharmaceutical composition can be
configured, for example, as quickly disintegrating administration
forms, e.g., administration forms disintegrating within a period of
1 second up to 3 minutes, or as slowly disintegrating
administration forms, e.g., administration forms disintegrating
within a period of 3 to 15 minutes.
[0408] The indicated disintegration times can be set to the
above-mentioned ranges by using, for example, matrix-forming
polymers which have different disintegrating, or solubility,
characteristics. Thus, by mixing the corresponding polymer
components, the disintegration time can be adjusted. In addition,
disintegrants are known which "draw" water into the matrix and
cause the matrix to burst open from within. As a consequence,
certain embodiments of the invention include such disintegrants for
the purpose of adjusting the disintegration time.
[0409] Suitable are polymers for use in the film-shaped or
wafer-shaped pharmaceutical composition include cellulose
derivatives, polyvinyl alcohol (e.g. MOWIOL.TM.) polyacrylates,
polyvinyl pyrrolidone, cellulose ethers, such as ethyl cellulose,
as well as polyvinyl alcohol, polyurethane, polymethacrylates,
polymethyl methacrylates and derivatives and copolymerisates of the
aforementioned polymers.
[0410] In certain embodiments, the total thickness of the
film-shaped or wafer-shaped pharmaceutical composition according to
the invention is preferably 5 mm up to 10 mm, preferably 30 .mu.m
to 2 mm, and with particular preference 0.1 mm to 1 mm. The
pharmaceutical preparations may round, oval, elliptic, triangular,
quadrangular or polygonal shape, but they may also have any rounded
shape.
[0411] In another embodiment, the present invention is directed to
a composition comprising a sweet tastant, a medicament or agent
contained in a coating that surrounds a gum base formulation and a
sweetness-enhancing amount of a compound according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above. Preferably, the coating comprises at least 50% by
weight of the entire product. As the center is chewed, the
medicament or agent is released into the saliva. For example, U.S.
Pat. No. 6,773,716, which is incorporated herein by reference in
its entirety, discloses a suitable medicament or agent contained in
a coating that surrounds a gum base formulation. One or more
compounds according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, can be used in
preparing the coating. Optionally, the composition may further
comprise high-intensity sweeteners and appropriate flavors. It has
been found that with respect to certain medicaments or agents that
may have an astringent or bitter taste that by adding a sweetener
enhancing agent to the formulation, that a much more palatable
formulation, including the medicament, can be provided. In this
regard, even though the medicament in, for example, its powder form
may be bitter or have an offensive taste, the matrix used as the
coating of the present invention, including the enhancing agent,
will afford a product having acceptable medicinal properties. The
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, can be typically
present in an amount ranging from about 0.001% to about 50% by
weight, preferably about 0.1% to about 10% by weight, or
alternatively, from 0.1% to about 1% by weight. The present
invention also contemplates an amount of about 1% to about 20%,
preferably about 1% to about 5%, about 1%, 3%, or 4%, by weight, of
the pharmaceutical composition.
[0412] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the pharmaceutical
composition.
[0413] In yet another embodiment, the present invention is directed
to a process of preparing an improved composition comprising a
medicament or agent contained in a coating that surrounds a gum
base formulation, wherein the improvement comprises adding a
compound according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, to the coating
that surrounds the gum base formulation. The compound according to
Formula I may be added in varying amounts, such as about 30% 50%,
75%, 80%, or 90%, or from about 10% to about 90%. In other
embodiments, the compound according to Formula I is present in
about 1% to about 30%.
[0414] In a further embodiment, the invention is directed to a
pharmaceutical composition suitable for aerosol administration,
comprising a sweet tastant and a compound according to Formula I,
or any of the specific subgroups, subclasses, or specific compounds
described above, and a suitable carrier. The aerosol composition
may further comprises pharmaceutically active agent. Aerosol
compositions are known in the art. See, e.g., U.S. Pat. No.
5,011,678, which is hereby incorporated by reference in its
entirety. As a nonlimiting example, an aerosol composition
according to the present invention may comprise a medically
effective amount of a pharmaceutically active substance, one or
more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, and a
biocompatible propellant, such as a (hydro/fluoro)carbon
propellant.
[0415] In certain embodiments, the pharmaceutical compositions of
the invention comprise from about 0.001 mg to about 1000 mg of a
compound of Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. In another
embodiment, the compositions of the invention comprise from about
0.01 mg to about 10 mg of a compound of Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above.
[0416] In another embodiment, the composition of the invention
comprises a compound of Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, in an
amount sufficient to enhance the sweet taste of a modulating
protein. By way of example, the present invention is pharmaceutical
or veterinary composition, comprising a compound of Formula I, or
any of the specific subclasses and specific compounds listed above,
in an amount sufficient to enhance the taste modulating protein by
at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%,
or from about 50% to about 99%, or alternatively from about 10% to
about 40%. In another embodiment, the present invention is directed
to a method of enhancing a sweet taste modulating protein,
comprising contacting said taste modulating protein with a compound
of Formula I, or any of the specific subclasses and specific
compounds listed above, and inhibiting the protein by at least
about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from
about 50% to about 99%, or alternatively from about 20% to about
60%, and wherein said taste modulating protein is a naturally
occurring taste modulating protein. In another embodiment, the
present invention is directed to a method of enhancing a taste
modulating protein, comprising contacting said protein with a
compound of Formula I, or any of the specific subclasses and
specific compounds listed above, and inhibiting the protein by at
least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or
from about 50% to about 99%, or alternatively from about 20% to
about 40%, and wherein said protein is a naturally occurring human
taste modulating protein.
[0417] In another embodiment, the present invention is directed to
a nutritional composition comprising one or more nutritional, one
or more compounds according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, and
optionally one or more carriers. Examples of nutritional
compositions having an undesirable taste include, but are not
necessarily limited to, enteral nutrition products for treatment of
nutritional deficit, trauma, surgery, Crohn's disease, renal
disease, hypertension, obesity and the like, to promote athletic
performance, muscle enhancement or general well being or inborn
errors of metabolism such as phenylketonuria. In particular, such
nutritional formulations may contain one or more amino acids which
have a bitter or metallic taste or aftertaste. Such amino acids
include, but are not limited to, an essential amino acids selected
from the group consisting of L isomers of leucine, isoleucine,
histidine, lysine, methionine, phenylalanine, threonine,
tryptophan, tyrosine, and valine. Additionally, the invention is
directed to a process of preparing an improved nutritional
composition, wherein the improvement comprises adding one or more
compounds according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, to a nutritional
composition. In certain embodiments, the one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above, are added to a
nutritional composition in an amount of about 1% to about 50%, or
about 5%, 10%, or 15%, by weight.
[0418] In another embodiment, the present invention is directed to
a dental hygienic composition comprising one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above. Dental hygienic
compositions are known in the art and include but are not
necessarily limited to toothpaste, mouthwash, plaque rinse, dental
floss, dental pain relievers (such as Anbesol.TM.), and the
like.
[0419] Additionally, the invention is directed to a process of
preparing an improved dental hygienic composition, wherein the
improvement comprises adding one or more compounds according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, to a dental bleaching
composition. In certain embodiments, the one or more compounds
according to Formula I are added to a dental hygienic composition
in an amount of about 0.001% to about 50% by weight, preferably
about 0.1% to about 10% by weight, or preferably, from 0.1% to
about 1% by weight.
[0420] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the dental hygienic
composition.
[0421] In another embodiment, the present invention is directed to
a cosmetic product comprising one or more compounds according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above. For example, but not by way of
limitation, the cosmetic product comprising a compound according to
Formula I, or any of the specific subgroups, subclasses, or
specific compounds described above, may be a face cream, lipstick,
lip gloss, and the like. Other suitable compositions of the
invention include lip balm, such as CHAPSTICK.RTM. or BURT'S
BEESWAX.RTM. Lip Balm, further comprising one or more compounds
according to Formula I, or any of the specific subgroups,
subclasses, or specific compounds described above.
[0422] Additionally, the invention is directed to a process of
preparing an improved cosmetic product, wherein the improvement
comprises adding one or more compounds according to Formula I, or
any of the specific subgroups, subclasses, or specific compounds
described above, to a cosmetic product. In certain embodiments, the
one or more compounds according to Formula I, or any of the
specific subgroups, subclasses, or specific compounds described
above, are added to a cosmetic product in an amount of about 1% to
about 20%, preferably about 1% to about 5%, or about 1%, 2%, or 3%,
by weight.
[0423] The compound according to Formula I, or any of the specific
subgroups, subclasses, or specific compounds described above, can
be typically present in an amount ranging from about 0.00001% to
about 50% by weight, preferably about 0.0001% to about 2% by
weight, or alternatively, from 0.0001% to about 0.1% by weight. The
present invention also contemplates an amount of about 0.0001% to
about 1%, preferably about, 0.0005%, 0.001%, 0.002%, 0.005%, 0.01%,
0.05%, 0.1%, 0.3%, 0.8%, 1.5%, by weight, of the cosmetic
product.
[0424] The activity of a compound according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above can be determined by testing said compound using a number of
methods known in the art. For example, one can evaluate the ability
of a compound to enhance a sweet taste by using an in vivo taste
assay.
[0425] The activity of a compound according to Formula I, or any of
the specific subgroups, subclasses, or specific compounds described
above, can also be determined by means of the assay described
below.
Methods of Preparation of Compounds
[0426] A compound according to Formula I can be synthesized
according to methods outlined in the following descriptions. The
compounds for use in the present invention can be synthesized using
procedures known in the art.
[0427] The following general schemes illustrate synthetic methods
that can be used to prepare compounds of the present invention. In
one process, a compound of Formula I can be prepared by condensing
a suitable optionally substituted thiophene, pyrrole, imidazole or
thiazole halide with a suitable hydroxypyridine or thiopyridine in
a suitable organic solvent, as shown in Scheme 1 (wherein G.sup.1
is N or S; X is halogen, such as a bromo group; A is S or O; n is
between 0 and 4; R.sup.4 is selected from NO.sub.2, halogen,
C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl; and G.sup.3, R.sup.1,
R.sup.2, and R.sup.3 are defined as above).
##STR00048##
[0428] For instance, this reaction can be used to prepare the
compound of Example 3 by reacting methyl
3-bromothiophene-2-carboxylate with 2-hydroxy-5-nitropyridine
according to Scheme 2.
##STR00049##
[0429] The compound of Example 8 can be prepared by reacting
1-ethyl-2-methyl, 4-nitro-5-bromoimidazole and
2-thio-5-chloropyridine according to Scheme 3.
##STR00050##
[0430] As a further example, compounds of Formula I, wherein
R.sup.1 and R.sup.2 together with G.sub.3 and the carbon atom to
which R.sup.1 is attached form a heterocycle, can be prepared by a
direct condensation of an alpha-halo aldehyde or ketone with an
amino heterocycle in a reaction medium containing a suitable
solvent according to Scheme 4 (wherein G.sub.1, G.sub.2, G.sub.3,
R.sup.2, R.sup.3, R.sup.4 are as defined above; R.sup.5 is selected
from H, C.sub.1-6 alkyl, and optionally substituted phenyl; R.sup.6
is selected from H and C.sub.1-6 alkyl; and X is a halogen,
preferably bromine).
##STR00051##
[0431] For example, the compound of Example 5 can be prepared by
reacting 2-aminothiadiazole with bromo-benzaldehyde according to
Scheme 5.
##STR00052##
[0432] As a further example, the Compounds of Formula I wherein
R.sup.3 is an ether or thioether can be prepared by reacting
suitable optionally substituted thiophene, pyrrole, imidazole or
thiazole with an appropriate alkyl halide in a suitable organic
solvent according to Scheme 6 (wherein G.sub.1, G.sub.2, G.sub.3,
R.sup.1, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are as defined
above; and X is a halogen, preferably bromine; Q.sub.1 and Q.sub.2
are independently selected from S or O; n is 0 to 4; R.sup.7 is H,
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, or optionally substituted
phenyl). The reaction mixture is heated and filtered to give the
desired product.
##STR00053##
[0433] For example, the compound of Example 2 can be prepared by
according to Scheme 7 in one step by a direct condensation of
2-thiol-aminobenzodithione in a 1:1 reaction medium.
##STR00054##
[0434] The compound of Example 7 can also be prepared by this
method as Scheme 8 illustrates.
##STR00055##
[0435] Compounds of Formula I wherein R.sup.3 is
.dbd.N--CH.sub.2--(C=Q)-R.sup.7, wherein Q is selected from S or O;
and R.sup.7 is H, C.sub.1-6 alkyl or C.sub.1-6 alkenyl, can be
prepared by reacting an isothiocyanate or isocyanate with an imine
in a suitable organic solvent, according to Scheme 9. The mixture
is kept under reduced pressure, and the desired product is
precipitated out of the reaction mixture. It is then filtered off
and dried to give an off-white solid.
##STR00056##
[0436] In particular, the compound of Example 10 is prepared from
allyisothiocyanate and 1-imino-compound according to Scheme 10.
##STR00057##
[0437] The compounds of Formula I, wherein R.sup.3 is
.dbd.N--(CH.sub.2)--(C.dbd.O)--OR.sup.7 (wherein n is 0 to 4; and
R.sup.7 is C.sub.1-6 alkyl, or C.sub.1-6 alkenyl) can be prepared
according to Scheme 11.
##STR00058##
[0438] The iminio compound and haloalkyl ester are heated together
in a suitable organic solvent for a brief period of time. The
contents are then allowed to cool down, and the material is allowed
to settle down. The cooled down material is then filtered.
[0439] This method can be used to prepare the Compound of Example 1
by reacting ethyl 2-bromoacetate with an iminiothiomethyl compound
according to Scheme 12.
##STR00059##
[0440] Similarly other compounds of this invention can be obtained
from commercial sources and prepared by those skilled in the art.
Starting materials are commercially available or they can be
prepared by ordinary persons trained in the art.
[0441] The following examples are illustrative, but not limiting,
of the method, compounds, and compositions of the present
invention. Each of the compounds listed below was obtained from
commercially available catalog companies, such as Aldrich
RarechemLib, Aldrich Sigma, AsInEx, Bionet, Biotech Corp.,
Brandon/Berlex, Calbiochem, ChemBridge, Comgenex West, Foks H, G.
& J. Research, IBS, ICN Biochemicals, Institute for
Chemotherapy, IF Ltd., Kodak, Lederle Labs, Ligand-CGX, Maybridge
PRI, Menai Organics, Menai/Neurocrine, MicroSource, MPA Chemists,
Mybrgd/ONYX, PRI-Peakdale, RADIAN, Receptor Research, RGI,
Rhone-Poulenc, SPECS/BioSPECS/SYNTHESIA, T. Glinka, Tripos Modem,
VWR, Zaleska, Zelinksy/Berlex, Aeros, and Chemica. The compounds
were purified using conventional purification procedures, such as
HPLC. The identity of the compound was confirmed using HPLC and
mass spectrometry. Other suitable modifications and adaptations of
the variety of conditions and parameters normally encountered and
obvious to those skilled in the art are within the spirit and scope
of the invention.
EXAMPLES
Example 1
Ethyl 2-(3-Methylbenzo[d]thiazol-2(3H)-ylideneamino)acetate
##STR00060##
[0443] Molecular Formula: C.sub.12H.sub.14N.sub.2O.sub.2S; m/z: 251
(M+H, found), 250 (calculated).
Example 2
2-(2-(2-Methoxyphenoxy)ethylthio)-1H-benzimidazole
##STR00061##
[0445] Molecular Formula: C.sub.16H.sub.15N.sub.2O.sub.2S; m/z:
301, (M+H, found), 300 (calculated).
Example 3
Methyl 3-(5-nitropyridin-2-yloxy)thiophene-2-carboxylate)
##STR00062##
[0447] Molecular Formula: C.sub.11H.sub.8O.sub.5N.sub.2S; m/z: 281
(M+H, found), 280 (calculated).
Example 4
6-(4-Chloro-3-nitrophenyl)-3-ethyl-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-
e
##STR00063##
[0449] Molecular Formula: C.sub.11H.sub.9N.sub.6O.sub.2Cl; m/z: 292
(calculated).
Example 5
6-p-Tolylimidazo[2,1-b][1,3,4]thiadiazole
##STR00064##
[0451] Molecular Formula: C.sub.11H.sub.9N.sub.3S; m/z: 216 (M+H,
found), 215 (calculated).
Example 6
N-Phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl)-1,4-diazepane-1-carboxamide
##STR00065##
[0453] Molecular Formula: C.sub.20H.sub.21ON.sub.5S; m/z: 379
(calculated).
Example 7
2-(2-(2-(2,6-Dimethoxyphenoxy)ethylthio)-1H-benzimidazol-1-yl)ethanol
##STR00066##
[0455] Molecular Formula: C.sub.19H.sub.22O.sub.2N.sub.4S; m/z: 374
(calculated).
Example 8
1-Ethyl-2-methyl-4-nitro-5-(5-chloropyridin-2-ylthio)imidazole
##STR00067##
[0457] Molecular Formula: C.sub.11H.sub.11O.sub.2ClS; m/z: 298
(calculated), 299 (M+H, found).
Example 9
2,4-Diphenyl-5,5-dimethylimidazole-1-oxide
##STR00068##
[0459] Molecular Formula: C.sub.17H.sub.16N.sub.2O; m/z: 264
(calculated).
Example 10
1-Allyl-3-(3-methylbenzo[d]thiazol-2-(3H)-ylidene)thiourea
##STR00069##
[0461] Molecular Formula: C.sub.12H.sub.13N.sub.3S.sub.2; m/z: 264
(M+H, found), 263 (calculated).
Example 11
2-(2-Iminothiazol-3(2H)-yl)-1-(3-nitrophenyl)ethanone
##STR00070##
[0463] Molecular Formula: C.sub.11H.sub.9N.sub.3O.sub.3; m/z: 263
(calculated).
Example 12
4-Phenyl-2-(pyrrolidin-1-ylmethyl)phthalazin-1(2H)-one
##STR00071##
[0465] Molecular Formula: C.sub.18H.sub.19N.sub.3O.sub.2S; m/z: 341
(calculated).
Example 13
2-(3-Chloro-2-methoxyphenyl)imidazo[1,2-a]pyridine
##STR00072##
[0467] Molecular Formula: C.sub.14H.sub.11N.sub.2OCl; m/z: 258
(calculated).
Example 14
N-(4-(4-Ethylphenyl)thiazol-2-yl)-3,5-dimethoxybenzamide
##STR00073##
[0469] Molecular Formula: C.sub.20H.sub.20N.sub.2O.sub.3S; m/z: 368
(calculated).
Example 15
1-Phenylthiochromeno[4,3-d]imidazol-4(1H)-one
##STR00074##
[0471] Molecular Formula: C.sub.16H.sub.10N.sub.2OS; m/z: 278
(calculated).
Example 16
N-(4-(4-Chlorophenyl)thiazol-2-yl)-2-(dimethylamino)acetamide
##STR00075##
[0473] Molecular Formula: C.sub.13H.sub.14N.sub.3OSCl; m/z: 295
(calculated).
Example 17
5-Chloro-1-methyl-3-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)-1H-pyr-
azole-4-carboxamide
##STR00076##
[0475] Molecular Formula: C.sub.13H.sub.8F.sub.6N.sub.3OCl; m/z:
371 (calculated).
Example 18
N-(4-(((2,6-Dimethoxypyrimidin-4-yl)amino)sulfonyl)phenyl)-4-nitrobenzamid-
e
##STR00077##
[0477] Molecular Formula: C.sub.19H.sub.17N.sub.5O.sub.7S; m/z: 461
(found), 459 (calculated).
Example 19
4-Phenyl-2-(pyrrolidin-1-ylmethyl)phthalazin-1(2H)-one
##STR00078##
[0479] Molecular Formula: C.sub.19H.sub.19N.sub.3O; m/z: 305
(calculated).
Example 20
5-(Perfluorophenoxy)isophthalic acid
##STR00079##
[0481] Molecular Formula: C.sub.14H.sub.5F.sub.5O.sub.5; m/z: 348
(calculated).
Example 21
2-(Dibenzylamino)acetic acid
##STR00080##
[0483] Molecular Formula: C.sub.15H.sub.17O.sub.2N; m/z: 255
(calculated).
Example 22
Ethyl 2-cyano-2-(phenyldiazenyl)acetate
##STR00081##
[0485] Molecular Formula: C.sub.11H.sub.11N.sub.3O.sub.2; m/z: 217
(calculated).
Activity of Selected Compounds
[0486] TRPM5 is an ion channel that is a part of the
taste-perception machinery. This ion channel has been shown to be
essential for taste transduction. Perez et al., Nature Neuroscience
5:1169-1176 (2002); Zhang et al., Cell 112:293-301 (2003). Because
TRPM5 is a necessary part of the taste-perception machinery,
enhancement of its activity could enhance the sensation of
particular tastes.
[0487] Taste is the ability to respond to dissolved molecules and
ions called tastants. Humans detect taste with taste receptor
cells, which are clustered in taste buds. (Kinnamon, S. C. TINS
11:491-496 (1988)). Tastants bind specific receptors on the cell
membrane of a taste receptor cell, leading to a voltage change
across the cell membrane. A change in voltage across the cell
membrane depolarizes, or changes the electric potential of the
cell. This leads to a signal being sent to a sensory neuron leading
back to the brain.
[0488] TRPM5 is a member of the transient receptor potential (TRP)
family of ion channels. Ion channels are transmembrane proteins
that form pores in a cell membrane and allow ions to pass from one
side to the other (reviewed in B. Hille (Ed), 1992, Ionic Channels
of Excitable Membranes 2nd ed., Sinauer, Sunderland, Mass.). Many
channels have "gates" that open in response to a specific stimulus.
As examples, voltage-gated channels respond to a change in the
electric potential across the membrane, mechanically-gated channels
respond to mechanical stimulation of the membrane, and ligand-gated
channels respond to the binding of specific molecules. Various
ligand-gated channels can open in response to extracellular
factors, such as a neurotransmitters (transmitter-gated channels),
or intracellular factors, such as ions (ion-gated channels), or
nucleotides (nucleotide-gated channels). Still other ion channels
are modulated by interactions with other proteins, such as
G-proteins (G-protein coupled receptors or GPCRs).
[0489] Most ion channels mediate the permeation of one predominant
ionic species. For example, sodium (Na.sup.+), potassium (K.sup.+),
chloride (CF), and calcium (Ca.sup.2+) channels have been
identified. While TRPM5 has been characterized as a non-selective
monovalent cation channel, Prawitt et al., Proc. Nat. Acad. Sci.
USA 100:15166-71 (2003), physiologically it is thought to primarily
conduct sodium, the most abundant cation in extracellular
fluids.
[0490] TRPM5 is believed to be activated by stimulation of a
receptor pathway coupled to phospholipase C and by IP3-mediated
Ca.sup.2+ release. The opening of this channel is dependent on a
rise in Ca.sup.2+ levels. Hofmann et al., Current Biol.
13:1153-1158 (2003). The activation of this channel leads to
depolarization of the TRC, which in turn leads to transmitter
release and excitation of primary gustatory nerve fibers. Huang, et
al., Proc. Nat. Acad. Sci. USA 104: 6436-6441 (2007).
[0491] The activity of human TRPM5 ion channel was measured in live
cells on a fluorescent imaging plate reader (FLIPR). The basis of
the assay (shown in FIG. 1) is the calcium-dependent activation of
the ion channel which occurs via by activation of a G-protein
coupled receptor (GPCR). GPCR activation by an appropriate agonist
causes a transient increase in intercellular Ca.sup.2+ ion
concentration which in turn causes the ion channel to open, letting
in Na.sup.+ ions. This influx causes a change in the membrane
potential of the cell which can be monitored as a change in the
fluorescent signal from voltage-dependent (membrane potential)
fluorescent dyes. A demonstration of the assay is shown in FIG. 2,
where traces of fluorescent response (Ex 530 nm/Em565 nm) versus
time are shown for cells containing the plasmid and sham plasmid
controls. While all cells gave a Ca.sup.2+ response to the
endogenous muscarinic GPCR agonist carbachol (left panel), only
cells containing the plasmid showed a sharp peak for the membrane
potential dye response (right panel).
[0492] For the screening assay, the human TRPM5 gene was cloned,
put into HEK293 cells, and a stable, high expression clone was used
for screening. Cells were grown in standard media at 37.degree. C.
The day before screening, the cells were removed from flasks and
added to 384 well clear bottom plates (8K cells in 20 .mu.L/well).
On the assay day, 20 .mu.L of membrane potential dye (Part No.
88123, Molecular Devices Corp.) was added to the cells and dye was
allowed to be taken up, i.e., load, into the cells for 1 hr at
37.degree. C. The dye-loaded cell plate was placed in the FLIPR
along with a second 384 well plate containing test compounds as
well as positive (fully inhibited) and negative (non-inhibited)
controls. The assay was started by addition of 10 .mu.L of solution
from the compound plate into the cell plate. During this process,
continuous fluorescent recordings were made simultaneously for all
wells. After addition of the compound solution, the tips were
automatically washed and a stimulation solution of 3 .mu.M ATP to
activate TRPM5 (an agonist for an endogenous purinurgic GPCR), was
added to all wells of the cell plate. The height of the response
was calculated and percent inhibition or enhancement values, versus
negative control wells, was calculated for the test samples.
Exemplary results are shown in the upper left graph of FIG. 3.
[0493] Two counterscreen assays were run on separate cell plates
utilizing the same cells as described above. In the calcium
counterscreen, the cells were loaded with a calcium sensitive dye
(Calcium3 Dye, Part no. 8090, Molecular Devices Corp.) and
stimulated by ATP to check for compounds that block the
GPCR-mediated calcium activation step. Exemplary results of this
assay are shown in the lower left graph of FIG. 3. In the KCl
counterscreen, cells are stimulated with 10 mM KCl instead of ATP
to check for compounds that inhibit the membrane potential response
by virtue of being non-specific ion channel blockers or enhancers.
Exemplary results are shown in FIGS. 3-5. The selective enhancement
TRPM5 activity by the compounds of Examples 1-3,5,10 and 18 at low
concentration of ATP, the G-protein coupled receptor ligand is
illustrated in FIG. 4. The left graph of FIG. 4 shows the
enhancement effect of the addition of a compound of the invention
at 30 micromolar on the ATP concentration-effect function for
membrane potential in hTRPM5-HEK293 cells, as measured by the
fluorescent assay described herein. The right graph shows the lack
of effect of the addition of a compound of the invention at 30
micromolar on ATP concentration-effect function for intracellular
calcium in hTRPM5-HEK293 cells, as measured in the fluorescent
assays described herein.
[0494] FIG. 5 illustrates the selective enhancement of TRPM5
activity by the compounds of Examples 1-3, 5, 10, and 18. In
particular, enhancement is most pronounced at low ATP
concentrations.
[0495] Unless otherwise indicated, the data in the table below were
determined using the three assays described above, providing
percent inhibition data at 10 Stimulation or enhancement is seen as
negative inhibition.
TABLE-US-00001 TRPM5 Calcium KCl Example No. Activity Counterscreen
Counterscreen 1 -139 -18 10 2 -136 19 -3 3 -113 11 17 4 -101 13 -32
5 -100 23 7 6 -98 -69 16 7 -95 -15 -4 8 -76 -22 7 9 -73 -15 17 10
-73 0 1 11 -68 -12 21 12 -62 -5 3 13 -57 9 -10 14 -55 10 -101 15
-48 -22 -9 16 -23 -25 -9 17 -16 4 -25
Example 23
Electrophysiological Results
[0496] Standard whole-cell recordings were obtained from HEK 393
cells stably transfected with human TRPM5. Internal solution
contained 135 mM CsGlutamate, 10 mM HEPES, 2 mM MgATP, 5 mM
CaCl.sub.2 and 10 mM EGTA. External solution was HBSS (Gibco)
buffered with 20 mM HEPES to pH 7.2. Currents were recorded with
Multiclamp 700B amplifier using PClamp software; filtered at 1 kHz,
sampled at 5 kHz. Holding potential was -80 mV. TRPM5 current in a
single was activated by intracellular calcium dialysis (free
calcium) and sampled with 200 ms ramps from -80 to 80 mV at 1 Hz.
Current amplitudes were measured at -80 and 80 mV and plotted
versus time. FIG. 6 shows stimulation of TRPM5 current when TRPM5
transfected cells are treated with 10 .mu.M of the compound of
Example 10 applied in a flow-through chamber such that exposure of
the cell to the compound can be quickly turned on and off. The left
graph of FIG. 6 shows no current activation by compound application
in the absence of calcium. The central graph of FIG. 6 shows a
large >5 nA current (+80 mV) in response to compound at an
otherwise suboptimal calcium concentration of 300 nm. The far right
graph shows a current activated by compound exposures at 30 .mu.m
calcium. While there is further stimulation of the TRPM5 current by
compound at 30 uM, it is not as dramatic as at 300 nn Ca++. In
essence, it appears that the compound makes the TRPM5 responsive
lower or weaker Ca++ signals than is normally the case. Note that
no significant current was seen in non-transfected, sham HEK cells
(not shown).
[0497] Having now fully described this invention, it will be
understood by those of ordinary skill in the art that the same can
be performed within a wide and equivalent range of conditions,
formulations and other parameters without affecting the scope of
the invention or any embodiment thereof. All patents and
publications cited herein are fully incorporated by reference
herein in their entirety.
* * * * *