Note: Descriptions are shown in the official language in which they were submitted.
WO93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
,
SP~C~FIC EATABLE TASTE ~ODIFIERS
B~CKGROUND OF T~E INVENTION
This application i~ a continuation-in-part of
application serial n~mber 07/799,207 filed November 27,
l99l which in turn is a continuation-in-part of application
serial number 07/531,388 filed June l, l990.
This invention relates in general to taste modifying
compoun~s. More particularly it relates to tastands, as
such term is used hereinbelow, to reduce or eliminate
undesirable tastes~, as such term is used hereinbelow.
There are numerous compounds that are known to be
salty but have problems associated with their use as salt
substitutes. Potassium chloride has a pronounced strong
bitter undesirable taste, as such term is used hereinbelow,
and ammonium chloride has, at least as sensed in some
people, a fishy taste a~sociated with it. Lithium chloride,
although a somewhat better tasting salt, is highly toxic.
To date there is no universally ~atisfactory salty tasting
substitute for the sodium ion.
The desirability of reducing the sodium ion intake of
humans is well do~umented. An excessive intake of sodium
ion has been linked to high blood pressure and premature
heart attack.: This problem has been addressed by numerou~
researc~ers in:~a variety of ways ~er the pas~ tWQ decades.
At the current time, reduction of sodium ion intake is
achieved via a:combination of ab~tinence a~d/or ~he
substi~ution of potas~ium chloride for sodium chloride
and/or mixing sodium chloride with fillers so that less
sodium chloride i9 used on the eatable, as defined
hereinbelow, although the volume of material added to the
eatable is the sameO In addition, for materials that are
coated with a surface salt such as for example potato
chips, it is known that smaller particle size for the
sodium chloride results in a saltier taste per~eption, and
therefore less salt need be added to obtain an equal level
of salt perception.
WO93/10677 CA 2 11 7284 pcr/usg2/lo179
There are a variety of products on the market today
utilizing potassium chloride as a saltening agent. All of
these salt substitutes rely on other ingredients which are
mixed with the potassium chloride to mask the bitter
undesirable taste, as such term is used hereinbelow, of
potassium chloride. These highly flavorful ingredients
consist of items such as onion, garlic, paprika, red
pepper, chili powder and many other spices. None of these
mixtures or potassium chloride itself has found wide-spread
acceptance, probably because the bitter taste of potassium
ion is still detectable.
In addition to reducing sodium ion intake by the
substitution of sodium chloride by potassium chloride,
there are numerous other examples of-compounds containing
sodium ions used in the food industry which could benefit
by the substitution of potassium ion for sodium ion if the
bitter taste associated with potassium ion were eliminated.
For example, sodium baking soda or baking powder could be
substituted with potassium baking soda and potassium baking
powder, respectiYely, in products requiring leavening
agents. A few more examples of substitutions which could be
made are:
A. monopotass~ium glutamate for monosodium glutamate in
the case of flavoring, and,
B. potassium~nitrate or nitrite for the corre~ponding
sodiu~ nitrate or nitrite in the case of
preservatives,~and,
C. potassium;~benzoate, potassium sulfate or sulfite in
place of oorresponding sodium salts in the case of
~-~ preservatives would also be highly desirable.
~;~ In addition, numerous eatables, as defined
hereinbelow,;on the market today have a naturally bitter
taste and/or undesirable taste, as such terms are used
hereinbelow.-Many of these materials, as currently used,
have the bitter tas~e or aftertaste partially masked by
additives, such as flavorings similar to those stated
~; above. Many of these materials are still bitter and/or
still have an aftertaste and could benefit by having a
tastand, as such term is used hereinbelow, mixed or
W0~3~10677 C A 2 1 1 7 2 8 4 3 PCT~US92J10179
ingested along with them to eliminate or substantially
reduce the undesirable taste(s), as such term is used
hereinbelow. Such eatables as for example, pharmaceuticals,
antibiotics, pain killers, aspirin, codeine, ibuprofen,
acetaminophen, caffeine, and unsweetened chocolate, and
~weeteners, as such term is used hereinbelow, can have
their undesirable tastes, as such term i8 used héreinbelow,
`reduced and/or eliminated as well as having their
palatability enhanced by the use of a tastand, as such term
is used hereinbelow. In general, any eatable which has a
naturally undesirable taste, as such term is used
hereinbelow, should be able to be rendered more palatable
by the addition of an appropriate tastand, as such term is
used hereinbelow.
.
SUMMARY OF THE INVENTION
Differences in taste perception between individuals
seem to be common. m ere are more than just the basic or
"true" tastes of sweet, sour, bitter, umami, and salty. A
few examples of these other tastes a~e alkaline,
astringent, tanl~y, dry,~sharp, cool, hot, burning, acidic,
spicy, pungent, and/or~metallic.
As used herei~and in the appended claims,
undesirable taste(s)" shall mean any taste which is sweet,
bitter, sour,;alkaline, astringent, tangy, dry, sharp,
cool, hot, burning, acidic, spicy, pungent, woody, smokey,
umami and/or metallic. Such undesirable taste shall include
any and all tastes, if such taste(s) is unwanted and
include any and~all aftertaste(s), if such aftertaste is
unwanted.
There can be more than one perception of a single
taste, whether such taste is a "true" taste or another
taste. There are;a number of different "bitter" tastes that
can be noted by some individuals. This can be demonstrated
by the following-
Some tastands which reduce or substantially eliminate
the off-taste of:
l. For example, caffeine, may have little or no
WO93/10677 PCT/US92/10179
~`C~211;7~ 4
effect on a pharmaceutical and/or the off-taste
of KCl, or,
2. For example, L aspartyl-~-phenylalanine methyl
ester (Aspartamee) may have little or no effect
on the off-taste of another high intensity
swe~tener such as saccharin.
Some specific examples of these effects are:
A. L-Aspartyl-L-phenylalanine will have a substantial
effect on the off-taste aæsociated with L-aspartyl-L-
phenylalanine me~hyl ester (Aspartame ), while it has
less effect on the off-taste associated with
&accharin,
B. Taurine has a substantial effect on the off taste
of saccharin while it has little or no effect on the
of~-taste associated with L-aspartyl-L-phenylalanine
methyl ester (Aspartame~).
C. The burning after-taste associated with some
liquors can be substantially ~liminated with the use
of potaæsium 2,4-dihydroxybenzoate while ~-a~partyl-L
phenylalanin~ and taurine have considerably less of an
:~
effect.
More specific examples of this effect are set forth in
the following table. The concentrations ~ecessary to obtain
these effects are~dependent upon the specific tastand and
~atarial and vary widely from example to exa~ple in the
table. The effects ~mmarized in the table pr~vide a
further indication of the existence of different bittsr
taste6. Ihu5~ a6 illustrated, L-aspartyl-L-phenylalanine
blocks t~e bitter~tas~e of KCl but has little effect on the
bitterness a~so~iated with caffeine. In contra-~t, N-(p-
cyanophenylcarbamoyl)-aminomethanesulfonic acid reduces the
bitter taste of caffeine but is not effective against the
: `
bitter taste of KCl. A plausible conclusion is that
eparate receptors and/or independent sites on one or more
~: '
::
WO93/lOG77 ~ A ~ 1 1 7 2 ~ 4 PCT/US92/10179
receptor are involved in the bitter taste sensation.
. . ~
REDUCTION OF THE TASTE ASSOCIATED
WITH
_ ;
SPECIFIC MATERIAL XCl SUCROSE CAFFEINE
. .
YES NO NO
I - . .
TAURINE YES NO NO l
l ~
K-2,4-DHB YES NO NO l
: - I
N-CN-$-ASP-PHE YES NO YES
N-NO2-$-ASP-PHE ~ ~ YES NO YES l
I
LAC~ISOLE YES YES YES
N-CN-$-U-So3 NO YES YES
_
~here: ~
L-aspartyl-L-phenylalanine
potassium 2,4-dihydroxybenzoate
;~ N-(p-cya~nophenylcarbamoyl)-L-aspartyl-L-
phenylalanine
N-tp-nitrophenylcarbamoyl)-L-aspartyl-L-
phenylalanine
2-~4-methoxyphenoxy)propionic acid
N-(p-cyanophenylcarbamoyl)-aminomethanesulfonic
acid.
It will be clear to anyone skilled in the art that the
above table is not alI inclusive as to tastands and/or
tastes.
As used herein and in the appended claims, a "taste"
~; shall mean any taste which is salty, bitter, sweet, sour,
alkaline, uma~i,;astringent, tangy, dry, sharp, cool, hot,
burning, acidic, spicy~ pungent and/or metallic. Such taste
shall include any and all taste(s) as well as any and all
aftertaste~s). Once again this list is not all inclusive as
one skilled in the art would recognize.
As used herein an "eatable(s)" shall mean any material
ingested. Eatables shall include, but not be limited, to
materials ingested by humans, other mammals, fish, birds,
'
`CA21 ~ ~28~
W O 93/10677 PC~r/US92/10179
and other an.i~mals.
By the term "substantially tasteless" as used herein
and the appended claims is meant a compound that has
substantially no taste upon initial ingestion at the levels
that are appropriate to be a tastand. qShe
aftertaste, if any, is not included in this definition.
By the term "~weetener" as used herein and the
appended claims is meant any material which gives a sweet
perception, including but not limited to:
~: A. monosaccharides, including but not limited to
aldoses and ketoses beginning with trioses, including
but not limited to glucose, galactose, and fructose,
B. compounds gene~~cally known as sugars, which
include but are not limited to mono-, di- and
oligosaccharides including but not limited to sucrose,
maltose, lactose, etc,
: C. sugar alcohols which include but are not limited to
:~: sorbitol, mannitol, glycerol,
D. carbohydrates and polysaccharides whic~ inc}ude but
are not limited to polydextrose and maltodex~-in,
E. high intensity sweeteners.
As used herein and the appended claims "high intensity
sweeteners" shall include but are not limited to:
L-aspartyl-L-phenylalanine methyl ester (As~artame~3
and other related dipeptide sweeteners, saccharin, L-
aspartyl-D-alanine-N-(2,2,4,4-tetramethyl thiatan-3-
yl)amide (Alita~e^), 1,6-dichloro-1,6-dideo~y-~-D-
; fructofuranoysl-4-chloro-4-deoxy-~-D-galactopyranoside
(Sucralose ), 6-methyl-1,2,3-oxathiazin-4(3H~-one 2,2-
dioxide (Acesulfame ~, 6-methyl-1,2,3-oxathiazin-
4(3H)-one 2,2-dioxide potassium salt (Acesulfame-K~),
cyclohexylsulfamic acid ~Cycl~mate ), N-(L-aspartyl)-
N ~2,2,5,5,tetramethylcycl~pentanoyl)1,1-diaminoethane
~:~ and its related compounds, guanidinium class
sweeteners, dihydrochalcone class sweeteners,
stevioside, miraculin and thaumatin, and their
phys~ological~y acceptable salts. Many more sweeteners
are described in the following publications, which are
: hereby incorpor~ted by reference:
Wo93/10677 C A 2 1 1 7 2 84 7 PCr/US92J10179
1. Walkers, D.E., Orthoefer, F.T!, and DuBois,
G.E. J (Ed.), "Sweeteners Discovery, and Molecular
D~cign, and Chemoreception," ACS Sy~posium Series
450, American Chemical Society, Washington, DC~
1991, and
2. Grenby~ T.H., "Progress in Sweeteners,"
Elsevier Applied Science Series, Elsevier Science
Publishing, L~ndon and New York, l9B9.
The authors racognize that this list, or any zther list, is
not and cannot be all inclusive.
By the term "low intensity sweet~ner" as used herein
and the appended claims is meant.any sweetener ~xcept a
high intensity sweeteners.
By *he term "masker" as used herein and the appended
claims is m~an~ any flavorful eatable which is u~ed to
cover and/or dis~ui~e and/or obscure an undesirable taste.
Two examples ~f .atables which are commonly used as ma~kers
are ~w~teners and spices such as onion, garli , paprika,
r~d pepp~r, chili powderS etc.
By the term "low calorie eatable" or "low caloxie
formulationl' as used he~ein and the appended claims i~
meant any eatabl~ in which the eatable has been ~urposely
formulated for the reduced caloriP market. Typically ~hi~
has resulted in greater than twenty-five percent ~>25~) of
th~ calori~s having been removed from said eatable that
would~have been present in the r~gular non-low calorie
:formulation.
The ter~ "tastand" as used herein and the appended
claims means an eatable, except for:
1. he class of compounds s~own in the following
W(~93/10677 GA2~ ~ 7~ PCr/U~92/10179
. 8
figure:
,, , ,,
X ~ C-- --C H 2--5 0 3 H
W h e r e i n X r e p r e s e n t s H C H 0 ,
CN, C02Cl-C3al3cyl, COCl-C3alkyl,
CO~H2 Br, Cl, F, I . or N02 or
physiologically acceptable salts
thereof .
, , ~
and then as appl ied only to the c:ase of organic:
bitter, axld,
2 . L-glutamyl~L glutamic acid ( or ~;alt thereof )
which when mixed with or when ingested along with another
eatable saia~ eatable ha~ring an undesirable taste(s), will
eliminat~ or sub tantially reduce said und~sirable taste (s)
wil:hout introducing a taæl:e of its own at ~aid level of
usage .
Tastands can also be salt ta~tands ., Tastands . lave the
propert:y that they will block one unde~irable taste for
exa~nple, bitter,: and/or in some ca~e~ at the saJne ime
anoth~r undesirable t~ste. A speciiEic tastand may have its
own particular ~aste but its ability to block an
undesirable tast~ occur~ at a concentration belc~w that at
which ilts own par~icular taste is p@rceptibl~ Ta~tandæ may
uncover tast~s and~or off-taste~ that w~re present in the
ealt~ble before ~e addition of the tastand. A tastand will
not in~roduce a~y ~ubstantial tas1:e and/or of ~-taste of its
own. This property differerltiates tastands from masking
materials. For example to determine if a tastand is a
bitter blocker it could be added to a solution of a bitter
mak~rial such as KCl. If the material is a tastand it will
block or substantially reduce the undesiæabl~ taste of KCl
before it imparts any significant taste of its o~,m. It is
understood that a tastand may have th~3 ability to blo ::k one
undesirable taste more effectively than another undesirable
taste. Some tastands may block on y one undesirable taste
W093~10677 C A 2 1 1 7 2 ~ 4 PCT/US92/10179
effectively. A given tastand may, for example, blo~k the
perception of bitter at a level of 10-20 ppm but require
lO00-lO,000 ppm in order to effectively block another
undesirable taste and/or tastes or it may not block the
perception of another undesirable taste or tastes at any
concentration. This relative effectiveness or inability to
block certain tastes at all will vary from tastand-to
tastand and/or with concentration of ths same tastand. Some
specific tastands may block tastes that are not undesirable
in certain specific applications such as sweet. Some
tastands when added to an eatable may increase the
perception of another taste for example the level of
saltiness of the eatable. The blocking of an undesirable
taste may allow in some cases an increased sensation of
another taste. In this particular instance the increased
salt sensation that is perceived by the addition of a
tastand is allowing the tastand to act as if it were a salt
enhancer.
A "salt tastand~ as used h~rein and in the appended
claims means a tastand which, is itself salty or is
combined with another salty eatable, and when mixed with or
when ingested along with an eatable possessing an
undesirable r.aste will reduce or eliminate the perceived
undesirable taste(sj of saî-d ea~able. Examples of such
salty eatables that could be used with a tastand to make a
salt tastand would be NaCl, KCl, or NH4Cl.
As used herein and the appended claim~ many of the
tastands and ~atables are molecules ~amed ~ariously as
alts and/or acids. It is obvious to one skilled in the art
that these terms are arbitrary and virtually any acid can
be a salt and vice versa depending upon the
macroenvironment and/or microenvironment that the molecule
is in. This environment can, in some instances, change the
efficacy of a particular tastand. For example, 2,4-
dihydroxyben~oic acid is not nearly as potent a tastand of
the off-taste of KCl as is potassium 2,4-dihydroxybenzoate.
(In some specific acid environments the potassium 2,4-
dihydroxybenzoate may lose some of its effectiveness.)
Consequently, throughout the body of this patent and the
W0 93/10677 C A ~ PCT/US92/10179
appended claims, it should be understood the recitation of
acid and/or base refers also to the physiologically
acceptable salts and the recitation of a salt refers to its
corresponding acid and/or base.
The solubility of the tastand in water may not be
suf f icient to demonstrate the blocking ability. In this
case the tastand's solubility could be increased-by the use
of other substances to help this lack of solubility. Ethyl
alcohol is one example of a material which can be used to
increase the solubility of potential tastands to be used in
the above referenced tastand test.
Surfactants can affect the tastand by either
increasing or decreasing the effectiveness of the tastand.
As used herein and~in the appended claims, a "surfactant"
shall mean an amphi ~ic molecule. Such surface acti e
agents shall includ- lt not be l mited to soaps, and/_r
detergents, whether ~.nic or non-ionic, and/or ~.mbrane
lipids. Some surfactants can increase the effectivenes~ of
ome tas~ands while the same surfactant may lessen the
effectiveness of other tastands or not affect that
particular tastand at all. Surfactants may affect each
tastand differently. The surfactant that affects one
particular ta~tand;in~a positive, negative or neutral æense
may affect another~tastand differently (i.e. a positive,
negative or neutral sense and not necessarily in the same
way).
Different transformations, as such term is used
~ ~ .
hereinbelow,~ of a material may al~o have a profound effect
on its tastand~char w ter.
Many of the above tastand principles can be
demonstrated with potassium 2,4-dihi~roxybenzoate
(potassium ~-resorcylate). This material in about one to
two percent (1-2~)~w/v solution is sweet. When potassium
,~
2,4-dihydroxybenzoate is combined with KCl at, for example,
0.25% to 0.50% by weight relative to the KCl (depending
upon the individual's sensitivity to bitter) it will
virtually eliminate the bitterness associated with the
potassium chloride. (This means that in an eatable
containing one percent (1~) KCl the amount of potassium
~:
W093/10677 C A 2 1 1 7 2 8 4 PCT/US92/~0179
11 "~c~
2,4-dihydroxybenzoate that would be needed would be only 2S
to 50 ppm.) Potassium 2,4-dihydroxybenzoate is also a
tastand for the metallic taste associated with saccharin.
If 25 to 5Q milIigrams of potassium 2,4-dihydroxybenzoate
is added to a can of soda sweetened with saccharin (69 to
138 ppm of potassium 2,4-dihydroxybenzoate relative to the
soda) the metallic taste is substantially reduced or
eliminated allowing other flavors in the soda to come
through. In the above examples (25-138 ppm) potassium 2,4-
dihydroxybenzoate is a tastand because of its ability to
block bitter taste at concentrations where it by itself is
substantially tasteless. Potassium 2,4-dihydroxybenzoate is
sweet only at significantly higher concentrations. In
contrast, sucrose is not a tastand in that a 2~ solution is
sweet but even at this level the bitterness of KCl is not
substantially diminished. Sucrose would be a masking
material under~the current definitions.
The use of additives to debitter eatables has been
attempted by others. Recently, a fairly comprehensive
approach to this goal was reported in "Practical
Debittering Using Model Peptides and Related Compounds" by
Tamura M, Mori;N, Miyoshi T, Koyama, et al in Agric. Biol.
Chem. 54, (1)~41-51 (1990). The authors examined the
following classes of compounds and strategies to debitter
solutions of amino acids, amino acyl sugars and peptides:
A. Chemical modification.
B. Masking~agents~ such as cyclodextrins and starch.
C. Proteins and peptides such as skim milk, soybean
casein, whey protein concentrate or casein
hydrolysates. ~
D. Fatty sùbstances.
E. Acidic amino acids.
Chemical modification of bitter tasting materials led to
,
reduced bitterness but the materials were not tastands
because the chemical modifications generally led to
derivatives with~their own characteristic undesirable
taste. Case studies 2-4 were based on a strategy of the
direct interaction of the additive with the undesirable
taste component of an eatable in order to prevent said
CA2 1 1 728~
W093/10677 PCT/US92/tO179
12
undesirable taste component from reaching the bitter taste
receptor. In case study 5, the authors used molar
equivalents of "acidic amino acids" or taurine (the authors
state that, "taurine, of course, is not an acidic amino
acid although it has a sulfonyl group and shifts to the
acidic region") to reduce bitterness.
The paper reports that under the conditions tested,
the acidic amino acids removed some of the bitter taste but
conferred their own sour taste to the test solution.
Taurine, according to figures 4 and 5 of the paper was
ineffective at debittering solutions of Arg, Phe,
methyl,2,3-di-0-(l-phenylalanyl)-~-D-glycopyranoside, Phe-
Phe, or Arg-Pro-Phe-Phe at from 0.33 to 1.5 molar
equivalents. The results from figures 4 and 5 are
internally inconsistent with respect to valine tested in a
solution at the 300 mM level. While figure 4 shows a less
than fifty percent (<.SO%) reduction of bitterness when
:
O.333 equivalents of taurine was added to the test
solution, figure 5 shows >60% reduction when 0.22
equivalents of taurine`(67 mM) was added to the solution.
The inconsistent result of the taste tests indicate that
Tamura did not contemplate an important teaching of the
present invention~and~led us to repeat the taste test. It
is also clear that~Tamura did not understand or contemplate
the effect that a tastand can have on a taste test. This
application teaches this effect hereinbelow.
As stated~above, we have repeated the taste test for
valine. This was~dnne in a 300 mM solution of valine
~; ~
(conditions of~Tamura et al.) at various levels of taurine
reported in the Ta w ra paper. The results we obtained were
confirmed by an independent testing laboratory. The
independent test laboratory's re~ults are summarized in the
.
~ . ~
WO93/10677 CA21 172~4 PCT/US92/10~79
13
following table:
CONCENTRATIC~t OF TAURINE lIEAN VALUE OF THE BITTERNESS OF A
3 OO m~I SOLUTION OF VA~INE
___ . _ . _ _ _. _
CONTROL (O TAURINE) 9.6
66 ~M 9.5 -
_ . _
200 mM 13.3
3~0 mM ~ 11.4
I _ . ~
he data show that taurlne has virtually no effect on the
bittern~ss of valine. When the tasting was repeated with
taurine on an equal molar basis with the valine (three
times the amount shown in Figure 4 of Tamura and sixteen
times that amount shown in Figure 5), there was still >~0%
of the bitterness remaining in the valine test solution. We
did not repeat the aspartic acid and glutamic acid taste
tests as they, under the conditions of Tamura, et al., are
not tastands. EYen at 300 mM level the paper shows that
taurine was ineffective at "masking of the bitterness" of
almost all solutions tested. The high concentrations uced
in these investigations~ suggest that the authors intended
to mask the bitter taste. The authors did not understand or
even contemplate the concept of tastands.
The underlying assumption of any experiment that has a
con~rol built into the methodology, is that the controls
are accurate and repeatable. If blockers are used randomly,
the controls are neither accurate nor repeatable. If a so
called control is ingested followed by a food with a
blocker, the subsequent tasting of the previously ingested
control will be different. If the authors of the Tamura
study had realized this they probably could have designed
the protocols to avoid these problems and the reported
results would have been accurate and repeatable.
In contrast to the above it is the teaching of the
present application that a tastand, as defined hereinabove,
can prevent bitter components from interacting with the
taste receptor at concentratio~s where the tastand is
tasteless or substantially tasteless. Prevention is by a
WOg3~10677 C A 2 1 1 7 2 8 4 PrT/~S92/10179
14
direct interaction with the receptor site, as such term is
used herein, to prevent or substantially eliminate:
A. the interaction of the undesirable tasting
molecule(s) with the taste receptor and/or
B. the recognition of the undesirable taste.
Glenn Roy, Chris Culberson, George Muller and
Srinivasan Nagarjan in US patent number 4,944,990 dated
February 19, 1991, described the use of N-(sulfomethyl)-N'-
arylureas to inhibit or suppress sweet taste and organic
bitter when mixed with sweet and/or organic bitter. ~The
authors specifically state that their material does not
affect the off-taste of inorganic bitter.) The example that
these authors used to show that there was a perceived
bitterness reduction was a 0.11% (1.1 mg/mL) caffeine
solution to which 4 mg/mL of N-~sulfomethyl)-N -arylurea
was added. Even while adding a four hundred percent (400%)
excess of the bitter reducing ~aterial compared to the
bitter eatable, the Roy et al resulted in only fifty
percent (50%) reduction of perceived bitterness.
We ha~e demonstrated that low concentrations (0.05~)
of potassium 2,4-dihydroxybenzoate can eliminate the bitter
aftertaste o~ KCl and the bitter aftertaste of saccharin.
Only at much higher concentrations is potassium 2,4-
dihydroxybenzoate sweet tasting. Similarly, according to
our thesis, taurine should be a tastand and we have found,
in contrast to the teaching of Tamura, et al., that taurine
at five percant (5%j (3% on a ~olar basis) relative to KCl
will eli~:nate or substantially reduce the off-taste of
KCl. This ~ould mean that in a one percent ~1%) solution of
,
KCl (10 mg/mL~ only 0.5 mg/mL of taurine would be needed
and if the blocker were potassium 2,4-dihydroxybenzo~te
only 0.05 mg/mL of blocker would be need~d.
Similarly if ten ~10) mg of taurine is added to a can
of soda (354 mL of soda per can; 28 ppm taurine) sweetened
only with saccharin the off-taste of the saccharin is
substantially reduced or eliminated, while the sweet taste
is relatively unaltered.
The present teaching is analogous to a competitive
inhibition with a hinding site of the receptor~s) and/or a
w093/10677 C A 2 1 1 7 2 ~ 4 PCT/US92/10179
non-competitive inhibition with the site(s) that influences
the receptor. As such, one of our teachings is that the
tastand can be effective at a low tastand concentration
when compare~ to the eatable with the undesir~ble tasté.
This distinction is not a minor teaching as in practical
terms it would be impossible to add more of the debittering
material tha~ the bitter materials. If the Tamura paper's
lower level of proposed use for taurine (O.5 equivalents of
taurine) is added to a one percent (l~) KCl solution, the
resultant solution has a pronounced off-taste which was not
present when only O~03 equivalents ~O.5% by weight relative
to the KCl) was used. (If even the lowest level of taurine
which was proposed in the Tamura paper is added to water,
the water has an off-taste.) The off-taste of the taurine
when added to the KCl solution is even more pronounced at
the l.0 and l.5 equivalent levels reported in the paper.
~aurine is not a tastand at the usage l~vels proposed in
t.le Tamura article. The Tamura article gives no indication
that reducing the levels to l/5 to l/lOO of their proposed
levels will gi~e better and more desirable taste test
results.
According to the authors of the above referenced
Tamura article the "debittering of peptides did not seem to
work." The authors there concluded "However, even 1.5
equivalent of acidic amino acids did not work. Probably, we
have to discuss elsewhere the order of attachment of taste
functional groups to taste recaptors sites."
The teachings in this appli~ation alearly ~how that
the debittering of peptides does work. If five (5) to seven
and one half (7~) mg of L-aspartyl-L-phenylalanine is added
to a soda sweetened only with L-aspartyl-L-phenylalanine
methyl ester ~Aspartame) (354 mL of soda per can (14 to 21
.
ppm)) the off-taste of the L-aspartyl-L-phenylalanine
methyl ester (Aspartame) is reduced or substantially
eliminated. The L-aspartyl-L-phenylalanine that is added as
a tastand to the material sweetened with the L-aspartyl-L-
phenylalanine methyl ester (Aspartame~) is in addition to
the amount of L~aspartyl-L-phenylalanine that may or may
not be present from the breakdown product of the L-
W093/10677 ~ A 2 1 1 7 2 8 4 PCT/US92/10179
16
aspartyl-L-phenylalanine methyl ester (Aspartame ) or as a
manufacturing impurity. The use of L-aspartyl-L-
phenylalanine as a tastand is an unanticipated result that
was not previously known or contemplated. In fact while L-
aspartyl-L-phenylalanine is one of the breakdown products
of L-aspartyl-L-phenylalanine methyl ester (Asparta~e ),
the breakdown of the L-aspartyl-L-phenylalanine methyl
ester (Aspartame ) has not been considered a desirable
occurrence. Both the manufacturers and users of the L-
aspartyl-L-phenylalanine methyl ester (Aspartame ) go to
great lengths to prevent this degradation. They attempt to
do this by adjusting the formulations of the products in
which the material i8 used. In addition, in the case of the
manufacturer the undesirable breakdown of the product can
be slowed down by~selling the material in a dry state, as
well as by the purifica~tion of the material. (When L-
aspartyl-L-phenylalanine is present as a manufacturing
impurity it is typically present in an amount less than one
percent (<1%) ~of~the L-aspartyl-L-phenylalanine methyl
ester.) The~above~example of the addition of five (5) to
seven and one half~(7~) mg of L-aspartyl-L-phenylalanine
would be about four percent (4%) of the L-aspartyl-L-
. ~
phenylalanine methy;l ester that has been used to sweetenthe soda. Example~s~of the products that could be found from
the~breakdown~o~the ~raspartyl-L-phenylalanine methyl
ester in the~soda~ are~-L-aspartyl-~-phenylalanine, ~-L-
;aspartyl-L-phenylalanine, methanol, L-aspartyl-L-
phenylalanine~diketopiperazine, L-phenylalanine, L-aspartic
acid, L-phenylalanine~methyl ester and ~-L-aspartyl-L-
phenylalanine methyl ester. The ratio of these and other
possible breakdown products will vary according to th~
conditions~of storage (time and temperature) as well as the
soda's specific composition its pH, etc.) The present
invention teaches~the use of the breakdown products,
whether such;breakdown occurs deliberately or accidently,
o~ the L-aspartyl-L-phenylalanine methyl ester (Aspartame~)
into one or more tastand(s). Another example of a breakdown
product of the L-aspartyl-L-phenylalanine methyl ester
(Aspartame~) that is a tastand is ~-L-aspartyl-L-
W093/10677 C A 2 1 1 7 2 ~ 4 PCT/US92/10179
17 ~
` 3
phenylalanine.
If the soda is sweetened with both L-aspartyl-L-
phenylalanine methyl ester (Aspartame ) and saccharin then
two tastands may be needed to reduce or substantially
eliminate the off-taste of the two high intensity
sweeteners. For example both taurine and ~-aspartyl-L-
phenylalanine could be used. The levels of the tastands
that would be needed would depend on the relative levels of
the high intensity sweeteners that were used in the soda.
Combination of tastands are sometimes preferred. On
potato chips, a salt consisting of a ratio of eighty
percent (80%) KCl and twenty percent ~20%) NaCl with
taurine at five percent (5%) relative to the KCl and three
percent (3%) L-aspartyl-L-phenylalanine is sometimes
preferred to a single tastand. Such single tastand could be
for example taurine, L-aspartyl-L-phenylalanine or
potassium 2,4-dihydroxybenzoate.
The results of our tastings have confirmed that any
methodology that employs a random presentation of eatables
both with and without blockers is flawed because the random
presentation of eatables with and without blockers causes
the "controls" to move. The taste evaluation of the
controls will be altered by the use of the blockers in the
same randomized tasting. This "moving" of the controls will
occur because~the blockers are consumed before the eatables
that do not contain the blocker~. (If an eatable that was
found to be bitter~in a previously conducted taste test
were presented~to the panelist at or near the end of the
tasting that contained a tastand, the typical result would
be that the previous~ly bitter food is no longer nearly as
bitter.) In~ome;tests conducted in a randomized manner,
pure KCl foods,~for exampIe, which were earlier determined
to be very bad,~ bitter and metallic, during the first round
of testing, were then determined to be almost as good
tasting as NaCl fo ds when tasted at or near the end of the
tasting.
The qualities of tastands described throughout this
document are in sharp contrast to those of gymnemic acid as
reported in The Merck ndex (Eleventh Edition, 1989)
WO93f10677 C~ 2 1 1 ~ 2 ;~ ~ PCT/US92/10179
18
(hereinafter "Index") where it is stated that gymnemic acid
~Completely obtunds taste for several hours for bitter or
sweet, ..." (This description of the properties of gy~nemic
acid is not entirely consistent with the articles that were
quoted for this information in the Index, one of which
states, "After chewing one or two leaves one is unable to
detect the sweet taste, and the bitter taste is also
suppressed to some extent.") (emphasis added) The Index
also states that gymnemic acid is a bitter tasting
compound. More recent publications that have used purified
gymnemic acid A1 and A2 have shown that there is a profsund
effect on the sweet response that is still present after
more than fi~teen minutes. These reports state that there
is no effect on the bitter response. The reports do not
comment on the taste of gymnemic acid A1 and A2~
nevertheless gymnemic acid is not a tastand under the
definition contained herèin.
~ ~,
An abundance of literature exists on the study of the
perception of taste, particularly in the area of sweet
taste. Over the past two decades, numerous researchers have
attempted to deyelop new non-caloric sweeteners. This work
began in earnest following the introduction of Aspartame
(L-aspartyl-L-phenylalanine methyl ester) several years
ago. As a result of this work, a large variety of sweet
molecules are now known.
There has been a substantial amount of work on the
perception of ~sweet~taste, as well as on the interaction of
lecules with~;the receptor for sweet taste. All of this
work points to the fact that the sweet receptor and the
bitter receptor as well as the other taste receptors may be
in close proximity andJor related to one another and/or
possibly one~and the same. It is now known, for example,
that if sweet molecules are altered slightly, particularly
in their spatial arrangements and/or orien~ation and~or
configuration of their chiral centers and/or their
stereochemistry and/or by the addition or substitution
and/or elimination~in the molecule of various groups, that
such molecules may become bitter or tasteless. Throughout
this document the alteration of a molecule in its spatial
WO93/10677 CA2t 1 7284 PCT/US92/1~179
19 "
arrangements and/or orientation and/or configuration of its
chiral centers and/or its stereochemistry and/or by the
addition or substitu~ion and/or elimination in the molecule
of various groups, will hereinafter be referred to as
"transformation(s) Il. Sometimes the transformation of a
molecule that:
A. is a tastand will change said molecule in~o a
molecul~ that is a more active tastand or less active
tastand or not a tastand at all, or
B. is not a tastand will change it to a tastand.
Such transformations in a molecule may change the mol~cule
from any one of these (sweet, bitter ox tasteless) to any
: of the following: sweet, bitter or tasteless.
Consequently, it occurred to us that:
A. the perception of sweet and the perception of
bitter may be associated with the same receptor, part
of the same~receptor, very closely spatially related
receptors or separate receptors which act together tG
give the associated sweet or bitter taste response,
and
B. that the:perception of undesirable tastes ~ay be
associated~with this sams r ceptor, part of this same
receptor or very closely spatially related receptors
~: or separate~receptors which act together to gi~e the
:~ aæsociated undesirable taste.
::
(all concepts relating to the receptor~s) are herein
referred to~as "reoeptor site(s)" or ~receptor(s~U).
This transformation feature is well illustrated in the
case of the:dipeptide-like sweeteners. For instance, L-
:~ aspartyl-L-phenylalanine methyl ester (Aspartame~) is
: inten~ely sweet. Whereas, L-aspartyl-L-phenylalanine
.
:
WO93/10677 CA 21 1 7284 PCT/USg2/10179
methylamide is intensely bit~er and L-aspart~l-L-
phenylalanine free acid is ~astele,s.
_, ,, , . . ~
~ ' ~ '
L-AS-L-PHE METHYL ESTER L-ASP~L-PHE METH~L AMIDE
ASPARTAME SlIEET E~ITTER
L- ASP- L- PHE
TASTELESS
Th-.se transformations extend to almost all of the known
dipeptide classes of sweeteners, including the aspartyl-~-
alanine amides where many of the aspartyl-D-alanine
alkylamides ~re sweet and many of the coxresponding L-
amides are bitter. A similar set o~ examples exist for the
mino malonic acid derivatives, the aspartyl alanine esters
and most other cla~ses of peptide-like ~weetener compounds.
.
Trans~ormations also extend to many other classes of
compounds. For example, in the saccharin type molecules the
presence or a~sence of nitration or alkylation can lead to
a molecule that is tasteless or sweet or bitter. This is
CA21 1 728~
WO 93/10677 PCI`/VS92/10179
21 "
illustrated in the following examp~ e:
o o
~C\ a ~C\ .
S~rE E T ~ E R
¦ ~ ~N N - C H
Another~example of a transformation can be seen in the
substituted propoxybenzenes where the position, the
locat.ion ~nd the m~mber of the NH2 and the N02 substituents
determine if the molecule is tasteless or sweet andJor
bitter~ This is illus~.rated in the following example:
OCH21 H2C~ OCHaCH
2 ~2
No2 ~a
:: : ~ I ^
~: ~ASTELESS
~: ~ :
Another example of a transformatiorl can be seerl in the
;~:
~; ~
.
WO 93/10677 i C A 2 1 1 7 2 8 4 Pcr/VS92/10179
. 22
substitllted ethoxybenzenes.
IlH-c-l~H2 ~ ~1U-C-NH2
S~ E~ ~ a I TTER .
Another example of a transformation can be seen in the
following:
. _ ~ _
rut Ino~- ~3 H
l~tT~ER OH O 14A~IIICIN
: 011 ' ,-
~ }C~I
~AStElESS OH HESPEI~ I D I ~I
'
Such transformations can be extended to most classes
of swe~t or bitter tasting substances. Consequently it is
likely that a non-sweet analogue of thaumatin ~a large
peptide) exi~ts which would be a ta~tarld. In general most
sweet or bitt-r eata~le ~hould be able to be transformed
into a tastand regardless of the ~ize or chemical
struc~ureO Irl additionO polymeric substances, as well as
di-, oligo-, and poly-peptide substances would also he
anticipated by the present di~closure.
These facts lead us to the conclusion:
Pl,. 1. if a molec:ule pO55 ssed simiiar spatial
arr~ngeraents to known sweeteners; and
2. with slight alt~rations the molecule could be
made substantially tasteless
W093/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
23 ~`
B. l. if a molecule possessed similar spatial
arrangements to a known bitter substance; and
2. with slight alterations the molecule could be
made substantially tasteless
that such molecules should interact with the receptor in
the same way a sweet or bitter tasting molecule would
interact but without the associated taste. If this occurs,
then this substantially ta~teless molecule ~hould inhibit
the entrance of other molecules into the receptor.
Consequentlyr we concluded and discovered the following:
A. If the molecule is a tastand, it may inhibit or
reduce the sweetness of substances, and in some
instances it will also inhibit or reduce undesirable
tastes; and/or
B. If the molecule is a tastand, it may inhibit or
reduce the bitterness of substances, and in some
instances it will also inhibit or reduce other
undesirable tastes; and/or
C. If a sweet molecule can be spatially altered to
become substantially tasteless, this molecule will
likely be a tastand; and/or
D. If a bitter molecule can be spatially altered to
become substantially tasteless, this molecu~e will
likely be a tastand.
In addition, it has been found that when an eatable
possesses desirable characteristics, for exa~ple, a salty
taste, these desirable characteristics may not be inhibited
or adversely a~fected by the tastand inhibitors of the
invention.
In addition, in order to achieve a desired degree of
reduction and/or elimination of undesirable taste(s), it
has been found that more than one tastand might be needed
in some cases. If more than one tastand is necessary, then
it would be obvious to one skilled in the art to either
have each one of the tastands ingested in a temporally
appropriate manner and/or to chemically link the tastands.
In the case of chemically linked tastands the basic
molecule could be linked with one or more similar or
dissimilar tastand molecule(s).
,
WO93/10677 CA2~ 172B4 PCT/VS92/10179
24
In addition, synergism of molecules in some cases may
allow two or more molecules, that in and of themselves do
not appear to be tastands, to act as a tastand when said
molecules are used in a temporally appropriate manner.
It has further been found that many of the tastands
will block or inhibit the undesirable taste(s) of, to
mention a few examples, potassium chloride, potassium
glutamate, potassium benzoate, potassium nitrate, pota~sium
nitrite, potassium sulfate, potassium sulfite, potassium
baking powder and potassium baking ~oda (which probably
become potassium chloride or other potassium salts after
baking), aspirin, acetaminophen, antibiotics, codeine,
caffeine, unsweetened chocolat~, other medicaments or other
undesirable taste(s) of the eatable.
Some tastands h~ve also been found to enhance alt
taste. Thus tastands can be used in conjunction with
~ixtures of æubstances with undesirable tastes such as, for
example, potassium chloride and/or sodium chloride and/or
aDonium chloride to both reduce the undesirable taste(s)
and to enhance the salt taste of the sodium and/or
potassium and/or ammonium chloride.
Eatables which are not generally considered to have an
undesirable taste cou1d also benefit from the addition of
an appropriate tastand as a taste modifier. For example:
A. Sodium chloride, which is normally not considered
bitter, is substantially smoothed in its aftertaste
~ ~ with the addition of the appropriate tastand.
; ~ B. A smoothing effect can be achieved when a ta~tand
is added to plain unflavor~d, unsweetened yogurt which
is normally considered tangy or acidic tasting.
C. The bitter taste of coffee can be substantially
reduced or eliminated with the addition of the
appropriate tastand.
D. The burning sensation of hard liquors can be
reduced or eliminated with the addition of the
appropriate tastand.
In the case of sour materials such as lemon juice when
the appropriate tastand and/or salt tastand is added there
is a substantial change in the undesirable taste. This is
.
WOg3/10677 CA~ 17~4 PCT/U~92/10179
especially true if a salt, such as potassium or sodium
chloride, is added to the tastand. If a salt tastand is
added, the undesirable taste can be reduced or even
eliminated.
As used herein a~d the appended cl~ims the singular
and the plural of a defined term shall be one and the same.
As used ~erein and the appended claims defined terms with :~
a~d without initial capitalization shall mean one and the
same.
':
DETAILED DESCRIPTION OF THE INVENTION
Tastands Molecules as Taste Modifiers
-~ The tastands useful in the present invention are those
compounds of the prior art which are tastand s that are
substantially tasteless. In many instances, substances of
th~ prior art which could be tastands which are not :
tasteless can be rendered substantially tasteless by
transformation(s).
~: As used herein~and the appended claims, "Group l"
~:: substituents may be represented by:
H, alkyl, substituted alkyl, a}koxy, s~bstituted
alkoxy, aryl, substituted aryl, alkylene, substituted
alkylane, amînoacyl, substituted aminoacyl, aryloxy, ~:.
substituted aryloxy, hydroxy, nitro, amino,
substituted amino, cyano, halogen, aralkoxy,
substituted:araIkoxy, acyl, substituted acyl,
aryl~yl, substituted arylacyl, trifluoroacetyl,
benzoyl, substituted benzoyl, alkylamino, substituted
alkylamino,~dialkylamino, substituted dialkylamino,
trialkyla~ino, substituted trialkylamino, carbonates,
substituted carbonat~s, alkylcarbonate~, substituted
alkylcarbonates, arylcarbonates, substituted
arylcarbonates, acylamino, substituted acylaminQ,
guanidino, substituted guanidino, alkylguanidino,
substituted alkylguanidino, acylguanidino, substituted
acylgua~idino, arylguanidino, substituted
arylguanidino, alkyurethanes, substituted
alkyurethanes, arylurethanes, substituted
WO93/10~77 CA ~ 1 ~ 7~;8~ PCr/US92/10179
` 26
arylurethanes, ureas, substituted ureas, mono- or di-
or tri- substituted ureas, alkylureas, substituted
alkylureas, an O, S or N glycoside, or a
phosphorylated glycoside ~where the glycoside is a
monosaccharide, a disaccharide, a trisaccharide, an
oligosaccharide, a ~ubstituted mono-, di-, tri-, or
oligosaccharide3, CHO, substituted C~O, COCH3,
substituted COCH3, CH2CHO, substituted CH2CHO, COOH,
CH2COOH, substituked CH2COOH, COOCH3, ~ubstituted
COOCH3, OCOCH3, substituted OCOCH3, CONHz, substituted
CONH2, NHCHO, substituted NHCHO, SCH3, substituted
SCX3, SCH2CH3, substituted SCH2CH3, CH2SCH3, substituted
CH2SCH3, SO3H, S02NH~, substitutéd 502NH2, ~02CH3,
substituted SO2CH3, CH2SO3H, substituted CH2SO3H,
cycloalkyl, substituted cycloalkyl, heterocyclic,
substituted heterocyclic, polycyclic; s~bstituted
polycyclic,and CH2SO~NHz, arylureas, substituted
arylureas, D ltiple substit~ted arylureas, an acid
group o~. the structure Z~r ~herein Z i.-, an element
sel~cted from the group consisting of carbon, sulfur~
boron or p~o~phorus, q is an int~ger from 2 to 3 and r
i~ an integer from 1 to 3; carboxylic acid ester,
ubstituted carboxylic acid ester, carboxamide,
: ~ substituted carboxamids, N-alkyl carboxamide,
substitu~ed M-a~lkyl carboxamide, di-alk~
carboxamides, ~ubstituted di-alkyl carboxamides~
: and~or two ub~tituents together represent an
aliphatic chain linked to a phenyl ring at two
positions, eith~r directly or via a an oxygenl
nitrogen or sul~ur group, any H on N, S, or O, may be
substituted with one of the substituents of Group 2,
:and combinations of any and/or all of the foregoing, and
physlologically acceptable salts of any and/or all of the
~oregoing.
: As used her in and the appended claims "Group 2~'
s~b tituents may be represented by:
H, alkyl, substituted alkyl, dialkyl, substituted
dialkyl, aralkyl, substituted aralkyl, aryl,
substituted aryl, diaryl, substituted diaryl, acyl,
WO93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
27 ~
~ ;~
sub~tituted acyl, cycloalkyl, substituted cycloalkyl, ~-~
benzoyl, substituted benzoyl, trifluoroacetyl,
alkyloxycarbonyl, substituted alkyloxycarbonyl, :~
aryloxycarbonyl, substituted aryloxycarbonyl, :~
alkylaminocarbonyl, substituted alkylaminoca~bonyl,
arylaminocarbonyl, substituted arylaminocarbonyl, ~i;
amidines, substitut~d amidines, alkylamidines~
substituted alkylamidines, arylamidines, substituted
arylamidines, a monosaccharide, substituted a .
~onosaccharide, a disaccharide, substituted
disaccharide, a trisaccharide, substituted
trisaccharide, an oligosaccharide, substituted
oligosaccharide, phosphorylated saccharides,
substituted phosphorylated saccharides, arylacyl,
substituted arylacyl, alkylene, substituted alkylene,
heterocyclic, s~bstituted heterocyclic, polycyclic,
substituted polycyclic, cyano, nitro, any H on N, S, .
or O, may be substituted with one of the above
substituents,
and combinations of any and/or all of the foregoing and
physiologically acceptable salts of any and/or all of the
foregoing. ~ ::
As used herein and the appended claims "Group 3"
~: substltuents may be~represented by::
~: H, alkyl, substituted alkyl, alkyIene, substituted
: : alkylene, branched alkyl, substituted branched alkyl,
branched alkyien~, substituted branched alk~lene,
aryl, substituted a ~ l, aralkyl, ~ubstitut~d aralkyl,
cycloalkyl,~substituted cycloalkyl, acyl, substituted `:
acyl, benzoyl,: substituted benzoyl~ alkoxy,
substituted alkoxy, aryloxy, substituted aryloxy,
trifluoromethyl, halogen, cyano, heterooyclic,
substituted heterocyclic, poly~yclic, substituted
p~lycyclic,
and combinations of any and/or all of the foregoing.
As used herein and the appended claims 9'substituted"
indicates that the molecule may have any hydrogen atom
replaced or "substituted" by any of the substituents of
Groups 1, 2 c~ 3, in any combination.
WO93/10677 ~ A 2 1 1 7 2 8 4 PCT/US92/10179
28
As used herein and the appended claims specific
tastands containing acidic or basic groups shall include
all physiologically acceptable salts thereof as well as the
free acid and/or base as is appropriate.
As use~ herein and the appended claims any aromatic
mol~cule in Groups l, 2 or 3 above may be substituted with
one of the substituents of Group l.
It would be understood by ~ne skilled in the art that
any substituent not specifically defined is H.
It is understood by those skilled in the art that only
the substitutions, replacements, and descriptions above,
allowed by the laws of chemistry, physics and nature are
contemplated for use as tastands as described in the
classes of compounds below.
:: ~
Ill~strative of suitable classes of molecules
contemplated for use as tastands are the following:
A. As used here~in and the appended claims the
following molecule shall be referred to as A-l and said
molecul.e represents the general class of compounds having
the structure:~
:: : _ _ ':
A-l ~ L11 - 0~~
, -~
wherein m represents 0 or l, n represents 0, l, 2 or
3, p represents~l, 2, 3, 4 or 5, q represents 0 or l;
R represents H or a lower alkyl (e.g. of C1-C3 alkyl);
the substituents R', which may be the same or
different, are each represented by one of the
substituents of Group 1, in any combination. X~
represen's H or a physiologically acceptable cation,
and physiologicàlly acceptable salts of any and~or all of
the foregoing.
Some specific compo~nds within this class of tastands
and their preparation are described in U.S. Patent No.
4,567,053 and are hereby incorporated by reference.
:
WO93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
29 ..
Examples of compounds of particular interest wi~hin ;~
this class are:
~ 2-(4-methoxyphenoxy)propionic acid,
2. (+)-2-(4-methoxyphenoxy~propionic acid,
3. (~)-2-(4-methoxyphenoxy)propionic acid,
4~ 4-methoxypheno~yacetic acid,
5. 2-(4-methoxyphenyl)propionic acid,
6. 2-(4-ethoxyphenoxy)propionic acid,
7. 3-(3,4-dimethoxyphenoxy)propionic acid,
8. 3-~3,4-dimethoxyphenyl)propionic acid,
9. 3~2,3,4-trimethoxyphenoxy)propionic acid,
10~ 3-(2-methoxyphenyl)propionic acid,
11. 1,4-benzodioxan-6-acetic acid,
12. 3-(2,3,4-~rimethoxyphenyl)propionic acid,
13. 3-(3,4,5-trimethoxyphenyl)propionic acid,
14. 3~ methoxyphenyl)propionic acid,
15. 4-(4-methoxyphenyl)butyric acid,
16. 2-methoxyphenylacetic acid,
17. 3-methoxyphenylacetic acid,
18. 4-methylphenylace~ic acid,
19. 4-tri~luoromethylphenyla~etiG acid,
20. phenylpyruvic acid,
21. 2,3-dihydroxybenzoic acid,
22. 2-hydroxy-4-aminobenzoic acid,
23. 3-hydroxy-4-aminobenzoic acid,
: 24. phenoxyacetic acid,
25. gallic acid,
26. 2,4-dihydroxybenzoic acid,
27. 2j4 dihydroxyphenyla etic acid,
28. 2-(2,4-dihydroxyph~nyl)propionic acid,
29. 2-(2,4-dihydroxyph no~y)propionic acid,
30. 2 (~,4-dihydroxyphenoxy)acetic acid,
and the physiologically acceptable salts of any and/or all
of the foregoing.
B. As used herein and the appended claims the
following molecule shall be referred to as B-1 and said
molecule represents the general class of compounds having
W093/10~77 ~ A 2 1 1 7 2 8 ~ PCT/US92/10179
30
the structure:
~~C~O O :~
wherein R7 may be ~elected from the 3roup consisting
of hydrogen and C~-~ alkyl, R~ may be selected from
: the group consi ting of hydrogen and Cl-C3 alkyl and
wherein R1, is the group, (as used herein and the
appended claims the structure shall be referred to as
B 2):
EJ-2
wher~in R2, R3? R4, R~ and R6 are independently elected
from the ~ubstituenks of Group 1, in any combination, --
and physiologically acceptable salts of any and/or all of
the for~goin~
~ Some specific compounds within t~is clas~ of tastands
:`~ are:describ~d in U~S. Patent No. 4,544,56S and are hereby
incorpor~ted by ~reference.
~:~ Illustrativ:~member of particular interest in this
clas~ include: ~ :
: l. 3-(3'-4'dimethylbenzoyl)prop~onic acid, :;
. 3-(2',4'-dimethylbenzoyl)propionic acid,
3. 3-~2'-methyl-4'-ethylbenzoyl)propionic acid,
4. 3-(2',4',6~'-trimethylbenzoyl)propionic acid, ~-
5. 3~ carboxybenzoyl)propionic acid,
6. 3-(4'-hydroxybenzoyl)propionic acid,
7. 3-(3'-methyl-4'-hydroxybenzoyl)propionic acid,
8. 3-(2',4'-dihydroxybenozoyl)propionic acid,
9. 3-(2,4'-dihydroxy-6'-methylbenzoyl)propionic
acid,
10. 3-(3'-methyl-4'-ethoxybenzoyl)propionic acid,
'
WO93/10677 C~ 2 ~ 4 PCT/US92/10179
3l
11. 3-(3'-ethyl 4'-eth~xybenzoyl)propionic acid,
12. 3-(4'-methoxybenzoyl)propionic acid,
l3. 3'-(4'-ethoxybenzoyl)propionic aeid,
1~. 3-(3',4'-dimethoxybenzoyl)propionic acid -`
15. 3-(4'-methoxybenzoyl)propionic acid
16. 3 t4'-methoxybenzoyl)-2-methylpropionic acid
17. 3-(4'-methoxybenzoyl)-3-methylpropionic acid,
18. 3',4'-dimethoxybenzoyl-2,3 dimethylpropionic
acid,
and physiologically acceptable salt~ of any and/or all of i-
the foregoing. -~
C. As used herein and the appended claims the
following molecule shall be referred to as C-l and said
molecule represents the general class of compounds having
the structure:
C~
wher~in R1, R2, R3, R~, Rs a~d R6 are i~dividually
represented by one of the sub:stituents of Group 1, in
any combination,
and physiologica}ly accep~ed salts of any and/or all of the
:fo~egoing.
~Some specific me~bers of this class of tastands are
::~partially described in U.S. Patent No. 4,871,570 and ~re
hereby incorporated by reference.
Illustrative members of particular interest in this
class include:
1~ R2=R3=R5eR6=H ~ R1=OC~H5, ~4=NH--
2 1~ R1--OCHzCH2CH3 t R2=N02 r R4=NH2 ~ ~R3=Rs=R6=H
3. Rl=CH3, R2=NH2, R6-N02, R3=R4=R5=H,
4. R1-CH3, R2=N02, R4=NH2, R3=R5--R6--~H,
: 5. 3,4-dihydroxybenzoic acid (protocateGhuic acid),
6. 2,4-dihydroxybenzoic acid~
Wo93/10677 CA 2 1 1 7 2 84 32 PCTlUS92/10179
7. 3-hydroxy-4-methoxybenzoic acid,
. 3,5-dihydroxybenzoic acid,
9. 2,3-dihydroxybenzoic acid,
10. 2-hydroxy 4-aminobenzoic acid,
11. 3-hydroxy-4-aminobenzoic acid,
12. 2,4,6-trihydroxybenzoic acid,
13. 2,6-dihydroxybenzoic aci~
14. 2-amino tere-phthalic acid
and physiologically acceptable salts of any and/or all of ~-~
the foregoing. ~ ~
D. As used herein and the appended clai~s the `.
following mo~ecu}e shall be referred to as D-l and said -.:
molecule represents the general class of compounds having ,
the structure~
. -_ .
D-l ¦ ( R ) p Y C ( C ~H 2 ) k C Y ( R ) q
( I ~ H 2 ) n -
O~C ~ O - X ~ ' ' '"', '.,
wherein n and k independently may be 0, 1 or 2; Y ~`
(which may be~the same or different): may be N i;
(nitrogen)~ O:~oxyg~n), or S ~sulfur~; Q may be
represented~:by one of the substituents of Group 3; p -.
and~q are~l:when;~ is O and p and q may be
independently~l;;or 2 when Y is S and p and q may be
independently~2 or 3 when Y is N; R (which may be the :~
same or dif~erent when p~l) and R' (which ~ay be the
same or different;when q>l) are represented by one of
the substituents of Group 2 or one of the following
three structures (as used h rein and the appended
claims the stxuctures shall be referred to as D 2) in ~-
any com~ination and the appropriate stereochemi~try:
~.
:
W093/10677 CA2 117284 PCT~US92/10179
33
. . ~
7 ~ H o
e c o z ~ c- z ~ N C
I 1.. ~ \..............
"~,
COZ R R R
:-
:~'
D-2
wherein Z and Z' are the same or different and are
represented by OH, -0~~, ORN, NH~, NHR~, N(R~)2,; R~
may be alkyI, branched alkyl, aryl, aralkyl, alkaryl,
cycloalky~, substituted alkyl, substituted cycloalkyl
substituted aryl, substituted aralkyl, substituted
alkaryl, and R~' may be alkyl, branched alkyl, aryl, .~
- aralkyl, alkaryl, cycloalkyl, substituted alkyl, ~
substituted cycloalkyl, substituted aryl, substituted
aralkyl, substituted alkaryl, or an amino acid side
~: chain (e.g. one of the 20 common amino acids~, X~ may
: be H~ or a physiologirally acceptable cation,
preferably an alkali metal, alkaline earth metal or
~: a~monium cation,
~: and ph~sioloqically acceptable salts of any and/or all of
the~for~going.~
IllustratiYe of compounds of particular interest in
this class are~
L-aspartyl-L-phenylalanine,
2. aminomalonyl-L-phenylalanine,
3. L-aspartyl-D-alanine,
4. L-aspartyl-D-serine,
5. L-glutamyl-L-phenylalanine,
~6r N-(L-aspartyl;)-p-aminobenzoic acid,
7. N-(L-aspzrtyl)-o-aminobenzoic acid,
: ~ 8. L-aspartyl;-L-tyrosine,
9. N-(p-cyanophenylcarbamoyl~-L-aspartyl-L-
phenylalanine,
lO. N-(p-nitrophenylcarbamoyl)-L-aspartyl-L
~ phenylal~nine,
: ll. L-~-aspartyl-L-phenylalanine methyl ester,
12. L-aspartyl-p-hydroxyanilide,
13. L-~-aspartyl-L-phenylalanine
:
WO93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
34
l4. L-aspartyl-~L-serine methyl ester
1~. L-a~partyl-D-tyrosine methyl ester
16. L-aspartyl-L-threonine methyl est~r
17. L-a~partyl-L-aspartic acid
and physiologically acceptable salts of any and/or all of
the foregoing. ;
E. As used h~rein and the appended claims the ;
~ollowing molecule shall be referred ~o as E-l and said
molecule represents the general class of compounds having -~
the structure:
. . . .
E-l \ N~
R - N - C - N ~ ~ Z
. .
wherein R , R~, R"', R6 are each independently
represented by on~ of the substituents of Group 2, in
;~ any combination; R4's and R5's which may be the same
or different are each independently represented by one .
of the substituents of Group 3; n may be 0, l, 2, 3, :
; ~ 4, 5, 6, 7, 8, 9~or lO; Z may be C, S, P or B, q is an :~. integer from 2 to 3 and r is an integer from l to 3,
when Z is C, q is 2; when Z is S, P or B, q may be 2
;~ or 3; when~Z is~C or S, r is l; when Z is P or B, r is
: 2,
and physio}ogically acceptable salts of any and/or all of
; the foregoing. :~
: Illustrative of: compounds of particular interest in
this class are: .
l~ R~-CH3,~R~'-4-cyanophenyl, R =R4=R5=H, n=l, Z=C, q=2,
r=l,
: ~ 2. R"=CH3, R"'=4-nitrophenyl, R =R4=R5eH, n=l, Z=C, q=2,
: 3. R"=CH3, R~'=4-methoxyphenyl, R =R4=R5-H, n=l, Z=C,
,
W09~/10~77 CA2~ 17284 PCT/V~92/lOi79
35 ,,~
~. RN=CH3, R"'=ph~nyl, R =R4-R5=H, n=l, Z=C, q=2, r=1,
SO R"=H, R~'-4-cyanophenyl, R =R4=R5=H, n=1, Z=C, q-2,
~--1 , ,.
6. R~H, R~'=4-ni rophenyl, R =R4=R5--H, n-1, Z=C, ~=2,
7. Rn=H, R~'=4-m~thoxyphenyl, R =R4=R5=R, n-l, Z=C, q=2, ~`
r=1,
~. R~=H, R~' =ph~nyl, R aR4=R5=H, n=l, Z=C, q=2, r=1, -~
9~ R~CH3, R~'=4-cyanophenyl, R =R4=Rs~H, n=l, Z=S, q=3,
r-l,
10. R~=CH3, R'N=4-nitrophenyl, R =R4=R5~H~ n=l, Z=S,
q--3, r=l, -~
11. R"=CH3, R~-4-methoxyphenyl, R =R4=R5=H, n=1, Z=S,
q=3, r=1,
12. ~"=C~3~ R"'=phenyl, R -R4=R5=H, n=l, Z~S, q=3, r=l,
13. R~/=H, R"'=4-cyanophenyl, R -R4-R5-H, n=l, Z-S, q=3,
14. R"=H, R~'=4-nitrophenyl, R =R4=R5--H, n=l, Z-S, q=3,
r=l, ,
15. R~=H, R~'=4-m~tho~yphenyl, R --~4=Rs=~, n-1, Z=S, `~
~--3, r=l,
: ~ 16. R~=H, R~' =phenyl, R =R4- R5=H~ n=1, Z=S, q=3t r=l,
and physiologically accep able salts of any and/or all of
: the foregoing.
F. As used hex~in and the appended claims the
follo~ing molecule shall be referred to as F 1 and said
mole~ule rep~esents the general class of compounds ha~ing :~
~he structure:
~ , . . .
Q O
F~l I 1 1 ,
( R ) p~ ( CP 2 ) n C ( ~ q
.
wherein n may be 0, 1 or 2; Y (which may be the same
or dif~erent) may be N (nitrogen), O (oxygen~, or S
(sulfur); Q may be represented by one of the
substituents of Group 3: p and q are l when Y is O and
p and q may be independently 1 or 2 when Y is S and p
and q may be independently 2 or 3 when Y is N; R
WO93/10677 C A 2 1 1 72 8 4 PCTJUS92/10179
: 36 :-
. ;
(which may be the same or di~ rent when p>l) a~d ~' ~;
(which may be the same or d. rent when q~l) are
represented by one of the s~_ ituents of &roup 2 or
one of the ~ollowing three structures ~as used herein
and the app~nded claims the structures ~hall be
referred to as F-2) in any combination and the ~
appropr~ate stereochemistry: . -
~ . .
I I R I I ,
--C--C O Z C C--Z --C--N--C
: COZ R' ' I'" R ' ~`
F-2 .
wherein Z and Z' are the same or different and are
represented by OH, -O X~, ORN, NH2, NHR~, N(R")2,; R~ is
alkyl, branched alkyl, a~yl, aralkyl, alkaryl,
cycloalkyl, substituted alkyl, ~ubstituted cycloalkyl
sub~tituted aryl, substituted aralkyl, substituted
alkaryl, and~R~ is alkyl, branchéd alkyl, aryl,
aralk~l, alkaryl~,~ cycloalkyl, substituted alkyl,
substituted cycloalkyl, substituted aryl, substituted
aralkyl, substituted alkaryl, or an amino acid side
chain te.g. one~of the 20 common amino acids). X~may
be H~ or a::physio}ogically acceptable cation,
preferably an~ alkali metal, alkaline earth metal or
ammonium cation, ~
and physiologically acceptable salts of any and/or all of
the foregoing.~
Illustrative of compounds of particular interest in
this olass are:
l. L-methionyl-L-phenylalanine methyl ester,
2. L-leucyl-~-phenylalanine methyl ester,
3. L-seryl-L-phenylalanine methyl ester,
4. L-me~hionyl-D-alanyl-tetramethylcyclopentylamide,
5. L-seryl-D-alanyl-tetrame~hylcyclopentylamide,
6. L-leucyl-D-alanyl-tetramethylcyclopentylamide,
7. L-ornithyl-~-alanine
8. L-diaminobutyryl-~-alanine
W093/10677 PCT/USg2/10179
C ~l 2 1 1 7 2 8 4 ~ ` ~
9. L-diaminopropionyl-~-alanine
10. L-lysyl-~-alanine
and physiologically acceptable salts of any and/or all of ;~
the foregoing. ~-
G. As used herein and the appended claims the -
following moiecule shall be referred to as G-1 and said
molecule represents the general class of compounds having ..
the structure:~
G~
. .
: .
~wherein p may:be 1, 2, 3, 4, or 5; the substituents
may each be represented by one of the substituents of
Group 1, in~any~co~bination, and R2 may be represented
by one of the substituents of Group 2,
and~physiolog~cally acceptable salts of any and/or all of i~
the foregoing.
: ~ -
Illustrative of compounds of particular interest in `
this~class are:~compounds where R2=H and R1 is: !
1. 3-COOM,~
2. 3-COOCH
3. 3-COOC~Hs,::
4. 3-CH30,~
5. 4-CH30,~
6. 2-Cl,
7. 3-Cl, :
8. 4-Cl, ~
9. 4-CC~C~Hs, ..
10. 3-C6HsCH20~,
11. 4-C6HsCN20,
12. 2-t-butyl,:
13. 4-t-butyl, ~ :
14. 2-CH3,
15. 3-CH3,
16. 4-CH3,
17. 3-CZHs~
..
;,J 7 ~
WO93/10677 PCT/US92/10179 -
38
1~. 4-~2H~,
l9. 3,5-di CH3,
and physiologically acceptable salts of any and/or ~ll of
the foregoin~.
H. As used herein and the appended claims the ~ :
following molecule shall be referred to as H-l and said
molecule represents the general class of compounds having `~
the structure: .
R~ ~:
: I ,~
:.
wherein R1 is 5-tetrazol, p may be l, 2, 3, or 4; and
~: the substituents: RZ, which may be the same or- ;
different, may~each be represented by one of the
; substituents of:~Group l~ in any combination; and R3 is
: : represented by one:of the substituents of Group 2,
and~ physiologically~acceptable salts of any and/or all of
the foregoing.
Illustrative ~of compounds ~of parttcular interest in
th:is class are ~
5-t~etrazolyl-6-chlorotrypta~ine,
; 2. 1-~-5-tetrazolyl-S-fluorotryptamine,
3. 1-a-~-tetrazolyl-6-methoxytrypta~ine,
and physiolog:ically~acceptable salts of any and/or all of
the foregoing.
- ~ I. As used~herein and the appehded claims the
~ : following molecule shall be referred to as I-l and said
: ~
: ' ,,.
`:
W093/10677 CA21 17284 PCl`/US92/10179
3 9 ~ '.
molecule represents the general class of compounds having
the structure:
.. . . r . . . . --
C--C--C
( R 1~ ~ R 2 ~
wherein p and q may be independently lt 2, 3, 4, or 5;
and the ~ubstituent R1 and R2, which may be the same
or dif f erent, each may be represented by one of the
substituents of Group l, in any combination ~
and physiolos~ically acceptable salts of any and/or all of
the f or~going .
An illu~trative of c:ompound of particular interest in
this class is, which hereinafter shall be referred to as:
I-2 ~ 3~ c~CI1 ¦
J. As used herein and the appended claims the
follcwing molec~le shall be referred to as J-l and said
mol~cule repxesents the general class of compounds having
the struc:~ure:
, .
: ~ , ~ '`5_o ~:
J-l ¦R2~ ~RI¦
,,
wherein, R1 is repres~nted by one of the substitu~nts
oP Group 2, and R2 and R3, which may be the same or
different, may be represented by on~ of the
substituents of Group 3, in any combination,
and physiolo~ically acceptable salts of any and/or all oiE
the f oregoing .
Wo93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
`; '' 40 "
Illustrative of compounds of particuiar interest i~ ~;
this class are: ~
1. R3=CH3, R2=H, ~1=isopropyl, ` :
2. R3=benzyl, R2=H, R~=H, :;`
3. R1=R3=H, R2=COOH,
4. R2=R3-H, R2=p-cyanophenylcarbamoyl
and physiologically acceptable salts of any and/o~ all of
the foregoing.
K. As used herein and the appended claims the
following molecule shall be referred to as K-l and said
molecule represents the general class of compounds having :~
the structure:
~-1 L~3
: :wherein p may be l, 2, 3 or 4; the substituents R2,
which may be the: same or~different, are each
~ : represented by one of the substituents of Group l, in
:: any combination,~and R1 is represented by one of the
substituents of~Group 2, wherein R1 and R2 may be
present, in;~any combination,
and:physiologi~ y~acceptable salts of any and/or all of
the foregoing.~
An illustratlve~of compound of particular interest in
this class is~
l. R1=E, R2=benzyl:, p=l, ~:
~: 2. R1=H, R2=NOz:,~ p=1, ..
3. R1=H, R2=CN, p=l, ~`
4. R2=H, R1=cyanophenylcarbamoyl . -.
and physiologically~acceptable salts of any and/or all of
the foregoing.:
:,
CA2~ 1 72~3~
W~93/10677 PCT/U~92/10179
4 1 ~. r
L. As used herein and the appended claims the
following molecul~ shall be refexred to as L-l and said
molecule represents the general class of compounds having
the structure:
. . . . ~ ~
R
~ C R ~ p N 1 C ~1 7 q 1~ 1
wherein R, R1 and R2, which may be the same or
different, may each be represented by one of the
substituents of Group 2, p may be 0 or l; each R3 and
~4 may be independently represented by one of the
subs~ituents of Group 3; n may be 0, 1, 2, 3, 4, 5, 6,
7, 8, 9, lO, ll, 12, 13, 14, 15, 16, 17, 18, l9, or
20; Z is an element selected from the group consisting
of carbon, sul~ur, boron, or phosphorus; q is an
integer from 2 to 3 and r is an integer from l to 3,
when Z .is C, q is 2; when Z is S, P or B, q may be 2
or 3; whQn Z is C or S, r is l; when Z is P or B, r is
2; R1 or R2 can be eliminated with OH to give a cyclic
amide;
and physiologically acceptable salts of any andJor all of
the foregoing.
Illustra~ive of oompounds of particular interest in
this class are:
l. R1~H, R2=t-butyl, Z=S, q-3, rGl ~ ~o ~ p=
2O Rl=H, n=0, R2=l,2,3-trimethylcyclohex~l, Z=S, q=3,
3. R1-R2=R3-R4=H, ~=2, Z=S, q=3, r=l ~This compound is
also referred to as taurine.)
4O R1=R2=R3=R4~H, n=2, Z=C, q=2, r=l, p=0 (This
compound is also referred to as ~-alanine.)
5. R1=p-cyanophenylcarbamoyl, R2=R3=R4=H, Z=C, q=~,
r=l, n=l, p-0
l`A21 1 7284
W~93/10677 PCT/US92/10179
42
6. R3=R4=R2=R1-H, n=2, Z=P, q--3, r=2, p=0
and physiologically acceptable sal~s of any and/or all of
the foregoing.
M. As used herein and the appende~ claims the
~ollowing molecule shall be referred to as M-l and said
molecule represents the general class of compounds having -~
the structure:
,
N~
~E-l I N`
~ ~ ~ ~ / N~ 3
¦~ R )p 0=5=0
wherein p may be 1, 2, 3 or 4, substituents R, R1 and
R2, which may be the same or different, are each ~~
represented by one of the substituents of Group 1, in -~
: a~y combination and R3 i5 represen~ed by one of the
~- ; sub~tituants of Group 2, wherein R, R1, R2 and R3 may
: be present in any combination,
and physiolo~ically acceptable salts of any and/or all of
~: the foregoing.
~ n illustrative of compound of particular interest in
this class is:
: 1. R1z~3-p~enyl, R2~H,.
and phy~iologicalIy acceptable salts of any and/or all of
~ the foregoing.
: N. A~ u~ed herein and the appended claims the
following ~olecule shall be re~erred to as N-l and said
molecule represents the general class of com~ounds havin~
WO 93/10677 C A 2 ~ ~ 7 2 8 4 P~/US92/10179
4 3 "`'?"~
the structure:
. ~ .
N-l ~ r 7~ ~ ~ ~
wherein p may be l, 2, 3, or 4; g may be l, 2, 3, 4,
or 5; the substituents R1 and R2, which may be the ~-
same or dif f erent are each represented }: y one OI the
sub~;ltituents of Group 1, in any combin~tion,
and physiologically ac ::eptable salts of any and/or all of
the f or~going .
Illus~rati~re of compounds OI particular interest in ~-
this class is the follo~ring molec:ule which as used herein
and the appended claims shall be referr~d to as N-2:
. . . _
N-2
O. The general class of compour~ds compris- ng amino
acids and poly amino acids.
This class includ~s but is not limited to:
~ . naturally occurring ~, ,B f y ~ ~ arld/or ~ ~
2. in general ~ amino acids ~nd~or :~.
3., unnatur~l amino acids and/or
4. peptides and poly amillo ac:id;s
The nitrogen atoms OI these compounds may be
substituted with one, two or t~ree substituents of
Group 2,; as appropriate. If oxygen (O) or sulfur (S)
atoms exist in these molecu~ es they may be substituted
with an appropriat~ number of substituents from Group
2. Any aromatic groups in these compounds may be
substituted with one or more of the substituents of
W093/~677 C A 2 1 1 7 2 8 4 PCT/US92/10179
44
&roup 1 in any combination,
and physiologically acceptable salts o~ any and/or all of
the foregoing.
Illustrative of compounds of particular interest in
this class are- -
1. D-glutami~ acid,
2. D-aspart.~_ acid,
3. aminomalonic acid,
4. ~aminoethanesulfonic acid,
S. ~-alanine,
~ 3,4-dihydroxyphenylalanine,
7. L-as~artyl-L-aspartic acid
and physiologically acceptable salts of any and/or all of
the foregoing. ; -
P. As used herein and the appended claims the
following molecule shall be referred to as P-l and said
molecule representæ the general class of ~ompo~nds having
the generalized structure: :-
One ~killed in~the art will recogniza that this general
structure twhich~would ~ot~likely exist) is a
representation of several tautomers ~everal of which are
repre~ented~by the follo~ing:
. .~ . .
¦ RlN \ 2 1 ~ \R2 ¦
WO 93~10677 C ~l 2 1 1 7 2 ~ 4 Pcr~usg2/1ol7g
1~ 5 ';
N Rl~ )J3CN
I I R2 R
L
. _- ~ V .
.
wherein the substituents R and R3, which may be the
~a~e or differe~, are each repr~sent~d by ona of the
substituents of Group 1, in any combination; pC1 and
~, which may be the same or different, may each be
represented by one of the substituents of Group 2, in
ar!y combination~ and A may be C, S, N, or O and when A
i~; C 1 substitution on this carbon may be made with one
or more of th~ tituent~ of Grs:~up lt in any
cs~mbination, when A is S or N substitution on this S
or N may be made with one of the sub~;tituants of Group
2, ~.
and physiologi ally acceptable salts of any and~or all of
the ~or~going.
Illustrative of compounds of particular interest in
this class are:
1. Xanthosine-5 mol~ophosphate
2. Inosine
W093/10677 CA 2 1 1 7~ 84 PCTlUS92/10179
46
3. Guanosine
and physiologically acceptable salts of any and/or all of
the foregoing.
Q. As used herein and the appended claims the
following mo~ecule shall be referred to as Q-l and said
molecule represents the general class of compounds having
the generalized structure~
One skilled in the art will recognize that this general
structure (which would not likely exist) is a
representation of several tautomers several of which are
represented by the following: -
~ :~
~:~ ~ 1 ~ A .
¦ N~ : R~ ~R2 ! ~:
¦ R5 N 3 - -- R5J~N R~ ¦
: :~
~ . .
~2 R6~ J~R2 ¦
¦ ~N R, ~ R~
~: ~ _ :R~ ~ _ R4
,: ~ '
wherein Rl, R2, R3, and R~, which may be the same or
different, are~each represented by one of the
~ substituents of Grsup 1, in any combination; R4 and
R6, which may be the same or different, are
represented by one of the substituents of Group 2, in
C~ 2 1 1 72~4
WO93/10677 PCT/US92~10179
47 ~ ~i
any combination, and A may be C, S, N, or O and when A
is C, ubstitution on thi~ carbon may be made with one
or more of the substituents of Group l, in any
combination, when A is S or N substitution on this S
or N may be made with one of the substituent~ of Group
2,
and physiologically acceptable salts of any and/or all of
the foregoing. ;;~
It will be recognized by one skilled in the art that :~
this class is intended to include any oxidation state of
the ring system, as for example, hydrogenation of one or ..
more o f the do~ble bonds.
Illustrative of compounds of particular interest in
this class are:
l. Orotic Acid
2. Dihydroorotic acid
and physiologically acceptable salts of any and/or all of ~:
the foregoing. ::
R. Th~ class of c~mpounds commonly known as natural
products. This class includPs but is not limited to:
alkaloids, terpines, monoterpines, diterpines,
triterpines, sesqueterpines, fl~vanoides, chalcones,.
dihydrochalcon~s, humulones, lemonoids, saponins,
: coumarins, isocoumarins, sinapines, steroids,
flavinon.es,
and physiologîca}ly acceptable salts o~ any and~or all of
: the foregoing.
; : As used~h~rein:and the append d claims ~he following
: ~ ~olecule shall be referred to as R-l, and said molecule
exemplifies the general class of compounds having, but not
WO93/1~677 C A 2 1 1 7 2 8 4 PCT/US9~/10179
. , ,. . -:
limited to the following stru~ture:
: .
' '
and physiologically acceptable salts of any and/or all of
the foregoin~.
~s u~ed herein and the appended claims the ~ollowing -~
molecule shall be referred to as R-2 and said molecule
represents the gen ral ala~s of compound~ having, but not
limit~d to the following ~tructure: -
~ ..
,
and physiologically acceptable salt~ of any and/or all of
the foregoing.
As used her~in and th~ appended claims the following ~-
molecule shall be referred o as R 3 and ~aid molecule
represe~ts the general cla~s of eompounds haYing, but not
WO 93/110677 C A 2 1 1 7 2 ~ 4 PCI/US92/10179
49
limited to the following structure:
~ , ~'
.."~
;~:
and physiologic:ally acceptable salts of any and/or all of
the f oregoing .
As used herein arld the appended c:laims the following
molecule shall be reerred to as R-4 arld said mol~c:ule
repre ents the general class of compounds havi.llg, but not
limited to the iEollowing structure: :
o 1~ .,.
: _
and physiologiczllly acceptable salts of any and/or all of
the Poregoing.
As used herein and the appended claims the îollowing
molecule shall be referred to as R-5 and said molecule
W093/10677 CA2~ 172~4 PCr/US92/10179
- 50
represents the general class of c:ompounds ~aving, but not
limited to the following structure:
and physiologically ac:c:eptable salts of any.. and/or all of `the f oregoing .
A~ used herein and the appended claims the following
molecule shall be referred to as R-6 and said molecule
represents the general class of compounds having, but not
limited to the follc:~wi~g structure:
>~ ,.
H~ /~ :~
and physiologically ac:ceptable salts of any and/or all of
the f oregoin~ .
As used herein arld the appended claims the following
molecule shall be referred to as ~-7 ~nd said molecule
''
CA2~ ~ 7284
WO93/10677 Pcr/l~592/10179 :~
5 1 ?;
represents the general class of compounds having, but not
limited to the ~ollowing structure:
I - ~0 ~ ~
~ :
and phy~i ologically as~ eptable salts of any and/or all of
the foreg~ing r
A used herein and the appended rlaims the following
: ~ : molecule shall be re~Eerxed to as R-8 and aid molecule ~:
represents the general ~ lass of compounds having, but not
limited to the following structure:
~ o ~-
~ : ..H ~
; ~ ~ .............. O H
and physiologically~ aaceptable salts of any and/or all of
~: the foregoing.
As used herein ~nd the appended claims the following
molecule shall be referred to as R-9 and said molecule
W~93/10677 C A 2 1 1 7 2 8 4 PCT/U~92/10179
52 :
represents the general class of compounds having, but not
limited to the following structure:
,,.",
;
and physiolo~ically acceptable salts of any and/or all of
the foregoing. .
~ As u~-d herein and t~ appended clai~s the following
molecule s.all be referr~ - to as ~ .O and said molecz~ : :
represents the ~eneral cl~ss of c ..~ounds havin~, bu r.~t
~:: limited to the ~ollowing structur.
,
~ i(~ ~
~ ,
and physiologically acceptable ~alts of any and~or all of
the foregoing.
, :
: ~s u d herein and the app~nded claims the following
molecule shall be referred to as~R-l~ and said molecule
represents the ge~eral class of co~pounds having, bu not
: limited to the:follo~ing structure:
. .:
: ~ CH ~ ~ C=~ ::
X `1/ C~ C--C--N--(CH~)2 ¦
~: ~ ' :~
and physiologically acceptable salts of any and/or all of
.
CA2 1 1 72~4
W093/10677 PCT/US92/10~79 53 .
the foregoing.
A~ used herein and the appended claims the ~ollowing
molecule shall be referred to as R-12 and said molecule
repre~ents the general class of compounds ha~ing, but ~ot
limited to the following structure:
_ __ _ _ _. _ ~.
and physiologically acceptable salts of any and/or all of
: the for~going.
As u ed herein and the appended claims ~he following
molecule shall be referred to as R-13 and said molecule
represents the g~neral class of compounds having, but not
limited to the following structure:
_
COOCH3
~0 ~ N 2
1~' o~c~o I ~`,
and physiologically acceptable salts of any and/or all of
the foregoins.
-.
,
WO 93/10677 C ~ 7 2 8 4 PCl~US92/10179
54
~s used herein and the appended clailus the following
molecule shall be referred to as R-14 and said molecule ~:
represents the general class of compounds having ~ but not ~:
limited to the following ;tructure:
. .................. . . .
. ~
and physiologically acc:eptable salts of any and/or a}l of -:
the foregoing~
As used herein and the appended claims the following
molecule shall be referred to as R-lS and said molecule
represents the general c:lass of compounds having, but ~ot
~: limited to the Pollow~ing structure:
. , _ _.
~ ~ ~ .
and physiologically acceptable salts of any and/or all of . ~:
the foregoing.
P,s used herein and the appended claims the f ollowing
molecule shall be referred to as P~ 16 and said mo~ ecule
WO93/10677 C ~ ~ 1 1 7 ~ ~ 4 PCT/US92/10179
5 5 ,1~"
represents the general class of compounds having, bu~ not
limited to the following structure:
~c~ """~ ~0~3 .,~
and physiologically acceptable salts of any and/or all of
the foregoing~
As used herein and the appended claims the following
molecule shall be referred to as R-17 and said molecul~
repreæents the general class of compounds having, but not
li~ited to the following structure: ~
. . . . _ .,
R~
:
:~and physiologically acceptable salt of any and/or all of
the foregoing~
As used herein and the appended claims the following
molecule sha.l be referred to as R-18 and said molecule
represents the general class of compounds having, but not
~,
W093/10677 PCT/US92/10179
-~ C~21 1 7284 56 :
; ~ i
limited to the following structure: ~
_ _ _
' [~
_ ,~
_ '~,',.
.
and physiologically acceptable salts of any and~or all of
: the foregoing.
As used herein:and:~the appended claims the following ~:
~, molecule shall be~referred to as R-l9 and said molec~.le
represents the:general;class of compounds ha~ing, b~l~ not
limited~to:the fol~lowing structure~
~ i , ,
and physiologically~acceptable salts of any and/or all of -~
the foregoing. .
As used herein and the appended claims the following
molecule shall~be referred to as R-20 and said molecule
,; ~ ' ' ~
W~ 93/1~677 C A 2 1 ~ 7 2 1~ 4 PCr/US~2/10179
57 .~,
r~preæents the general class of coJnpounds having, but rlot
limited to the following struc:ture:
and physiologically accsptable salts of any ancl/or all of
the foregoing. ;
As used herein and the appended claims the followiIlg
molecule shall be referred to as R-21 and said molecule
rep:res~nts th~ general cl ass of csmpounds having, but not
limited to the following structure:
~b ~
;: :
and physiologically accepta~le salts of any and/or all of
the f oregoing .
As used herein and the appended claims the following
.
molecule shall be referred to as R-22 and said molecule
W093/tO677 PCT/US92/10179
: CA21 17284 58
repre ents the general cla~s of compounds haYing, but not
limited to t~e following structure: `
. . . . ,. ................. .. ~
~ . ~
and physiologically acceptable salts of any and/or all of
th foregoing.
As used hereîn and the appended claims the following ~-
molecule shall be referred to as R-23 and said molecule
repre~ents the general class of compounds having, but not
limited to the following structure: ~.
and physiologically acceptable salts of any and~or all of
the f oregoing.
As used herein and the appended claims the following .
molecule shall be referred to as R-24 and said molecule
WO93/10677 C A 2 1 1 ~ ~ 8 4 PCT/US9~/10179
59 : .
r~presents the general class of compounds ha~ing, but not
limited to the following structure:
and physiologically acceptable s~l~s of any and/or all of
the foregoing,
As u~ed herein and the app nded claims the foilowing
molecule shall be referred to as R-25 and said molecule
represents the general class of compounds having, but not
limited to the following structure: -
and physiologically acceptable salts of any and/sr all of
the foregoing.
As used herein and the appended claims the following
molecule shall be referred to as R-26 and said molecule
W093/10677 ~ A 2 1 1 7 2 ~ 4 ~CT/US92/10179
represents the general class of compounds haYing, but not
limited to the following structure:
and physiologically acceptable salts of any and/or all of
the foregoing.
As used herein and the app~nded claims the following
molecule shall be raferred to as R-27 and said molecule ~:
repr~sents the general class of compounds having, but not
limited to the following ~tructure:
... . . . - . . . .
0~
and physiologically acceptable salts of any and~or all of
~he foregoi~g. :
As used herein and the appended claims the following
molecule ~hall be referred to as R-28 and said molecule
WO93/10677 C~ 8 4 PCT/USg2/aol79
61
- represents the general class of compounds having, but not
lîmited to the following tructure:
,~
~ 3~ o-~lu~O~ j
and physiologically accep able salts of any and/or all of ::
the *oregoing.
As used hereîn and the appended claims the following
molecule shall be referred to as R-29 and said molecule .
represents the general class of comp~unds having, but not
limited to the following structure:
_ _ . . ................... . ... ~:
~- ~ ,L
.
'
and physiologically acceptable salts of any and/or all of ~:
: ~he foregoing.
As use~ herein and the appended claims the following
molecule ~hall be referred to as R 30 and said molecule
: , .
.
WO93/106~ ~ 2 1 1 7 2 ~ 4 PCT/U~9~/10179
. 62
represents thP general class of compounds haYing~ but not
limited to the following structure~
.. _ . ,'
0~011~ ' ~
¦H0 ~ ~
"~'
and physiologically acceptable salts of any and/or all of
the foregoing.
As used herein and the appended c:laims the f ol~owing
molecule shall be referred to as R-31 ancl said molecule
represents the general class of compounds having, but not
limited to the foIlQwing stnlcture ~
: : . ~ ~_ _ ,:'
~ U~ 81~
~/ ,.. _ __ _
and phyiiologically ac::c:eptable salts of any and/or all s:~f
the f oregoing, :
As us~id herein and the appanded claims the following
molecule shall be ref~irred to as R-32 and said molecule
.
w0 93/io677 ~ 7 ~ 84 PCT/US92/10179 ~
63 ,
represents the general class of compound~ having, but not -`.
limited to the following structure~
and physiologically acceptable salts of any and/or all of
~he foregoing.
As used herein and the appended claims the following :`
molecule shall be referred to as R-33 and said molecule
represents the general class of compounds having, but not ``
limited to the following structure:
.
~:
. . / .,_ : ~
~,
and physiologically accPptable salts of any andJor all of
: the foregoing,
~ s u~ed herein and the appended claims the following
molecule shall be referred to as R-34 and said molecule
;~
- :
WO93/10677 CA~l 17~ PCI/U~92/101~9 : --
. ~4 ~:
repre~entC the general class of s~ompounds having, but not
limited to the ~oll~wing structure:
_ ,.
~ '
, .:
and physiologically acceptable salts of any and/or all of
the f oregoing .
As used herein and the appended claims the following
molecule shall be referred to as R-35 and said molecule `~
represent~ the general class of compounds having, but not
limited to tike follc)wing structure:
_ _ .
~1
and physiological1y acceptable~ ~alts of any and/or all of
the f oregoing ~ : :
As used h~rein and the appended claims the following
ms:lec:uIe shall be~ ref~rred to as R-36 and said molecule
represents t~e general ` class of compounds having, but rlot ~ -
: :.
~'~
;:
-
,
WO93~10~77 ;~ 7~ 8~ PCI/l~S92/~179
,..~
limited to the following structure: : -
and physiologicaIly acceptable salts of any and/or all of
the foxegoing.
The above examples and other natural lproducts of this
la~3s may be tra~s~c)~med (as per the usage OI this term
de~ined above) to additional tastands by a variety of
ch~mical modifications. Thus, we envi~age additional
tastands in which the above examples s:an be ~odif ied b~ -
variation of 'che ~alency or oxidation state of any carbon
atomf in which; epoxides may ~e opened by oxidation or
nucleophilic ~ubs~itution or may be reduced to alcohols, in
which lactones may be Gonverted tc~ hydroxy acids or hydrc3xy
acids may be cyc:lized to lactones, or in which enol
tautomers ~re converted ts:~ the appropriate keto tautomer.
~urth~rmore, the rlng systems depicted in the abvve ::
~xa~pIes may be substituted with a variety of aliphatic, ~
alicy~:lic, aroma~ic gr~ups, hydroxy, amino, or other ~ ;:
substituents of group 1 or 3, as def ined above, and
hydroxyl, amino or thio groups may be substituted with one
of ~he substituents of group 2, as def ined above ~ The ~ `
stereochemical relationships of the iubstituents laay be is
or trans, and chiral centers may be of R or S
conf iguration . In all exampl~s nitrogerl or oxyg n atoms may
be substituted with group 2, substituents or mono or
polysaccharic~es including but no~ restricted to those
WO 93/10677 CA 2 1 1 72~4 PCl`/US92/10179
66
indicated in the above examples.
Illustrative of compounds of particular intere~t in
this c:lass are the following:
As used her~in and the appended claims the following
molecules shall ~e referred to as R-37 ~
J J, I .
~ 0 0R~
where:
1- R~ D glc:, R2=a-L-rha 3-Me,
2. Pc1~1-D-glcZ~-L-rha, R2=H
and physiologically acceptable salts of any and/or all
of the foregoing.
As used herein and the appended claims *he following
,:
7 ~ 8 ~
W093~10677 PCT/US92/10179
67 ~ -
molecule shall be referred to as R-38: -~
. _ . .
.
. `'.~ ;~
and physiologically acceptable salts of any and/or all
o~ the foregoing.
~ ~ As used herein and~the appended~claims the following
: molecule~ shall be`;referred to as ~-39:
~: ~ ~,X
- , ; .
:~
: H
~ 2 ~H - X ~ \ ~ ';
: ~ ~1-R2-H. X~O g~ .`
R1~)H. R2~H. X~H2
_ R1~0H, R2~0Ac, X~H2
and physiologically acceptable salts of any and/or all
C~ 2 1 1 7284
WO 93/10677 PCr/US92/10179
68
of l:he oregoing.
As used herein ~nd the appended claims the following
molecules shall be referred to as R-40:
R1 ~R2YH . X- \
OH
R~ OAC, R2~H ~ X~H2
R, ~ R2~OAC ~ X ~ H2
and physiologica~ ly ac:ceptable salts of any and/or all
of the foregoing7
As used herein and the appended claims the following
molecules shall be re~exred to as R-4 1: ..
J ~ :
~..
R ~H
and physiolc)gic:ally acceptable salts of any and/or all
of ~he foregoing.
As used herein and the appended claims the following
W093/10677 ~ 4 pCT/~9~/10179
69 ,~
molecule ~hall be referred to as R-42:
L~ ~
,~
and physiologically acceptable salts of any and/or all
of the foregoin~
As used herein and the appended claims the following
mo~ecule shall be referred to as R-43:
,:
' ,'.
and physiologically acceptable salt~ of any and/or all
o~ the foregoing.
~: As used herein and the appended clai~s the following `~-
: molecule shall be referred to as R-44~
:: ~,
.
~ .
~ and physiologically acceptable salts of any and/or all
:: of the ~oregoing.
As used herein and the appended claims the following
_ _ _,,, _,, ~, _, . _ .. _ .. _ . T-- _ .-- -- ' -- ' '
WO93/10S77 C A 2 ~ 1 7 2 8 4 P~T/U~92/~179
molecule shall be referred to a~ R-45:
.. -- ~
O . I
/~
and physlologically acceptable salts of any and/or all
of the foregoing.
As us d herein and the appended claims the following
molecule shall be referred to as R-46: ,-
, . ._ _
~: : .. ,,,'
i ~i
¦ COOH
and physiologically acceptable salts of any and/or all
of the foregoing.
As used herein and the appended claims the following
. ~,.
8 ~
W~93/1~677 P~/US92/10179
71
- molecules shall be referred to as R-47:
.. . .. - _ .
~ ~C O O H j
R~DH
~ 'I
R2 R3
R~ RR5~0 ~ R2-R3~H ,R"~ OH :~
Rl~R~-,8 OH, R2R,~H, RS~O
R~ ~R5~0 P~2~R3~H, R~-c3H
R~O. R2~0H. ~3~ H~ RS~ O~H
R ~ n - O H, R 2 - R " ~ H, R 3 ~ S ' O
'~"
and physiologically acceptable salts of any and~or all
o f the~i foregoing O - .
As used herein and the appanded claims the following
molecule hall be re~erred to as R;48:
~'~
.-~
and phy~iolosically acceptable salt~ of any and/or all
of the foregoing.
As used herein and the appended claims the following
~.~
WO93J10677 CA 2 1 1 72 8 4 PCT/USg2/}0179
72
molecule shall be referred to as R-4~:
. . ~ _
~ r~
and physiologically acceptable salts of any and/or all ;;.
of the foragoing.
As used herein and the appended claims the following ..
molecule shall be referred to as R-50:
. . ...................... _ _ ,, .
; ~ and physialogically acceptable salts of any and/~- all
of the ~or~oing~.
~ As used herein;and the appended claims the follo~.ng :~
:~ molecule shall:b~ referred to as:~-51:
I
and physiologically acceptable salts of any and/or all
wo 93/10677 CA ~ 1 1 i 2 ~ 4 PCI/US92/10179
7 3 ;~
of the f oregoing .
As used hersin and the appended claims the following
molecules shall be referred to as R-52: :
._, . . . ,
/~\ ! I /~='\
~C C ~0 C H ~ ..
OH :~
R
R ~ 3-OH `~;
R ~ 3-OCH3 ~:~
R ~ O C H 3 :~
R 3, 4-d i -OCH3 ::
~3-CO0~2~s :;~
R~ 4-GOOC2H~, :
R 3 C11~50H
R 4 ~ tl 2 H
R ~ 4 ~ C I :
-.-
and phy iologic:ally ~cceptable salts of any and~or all
:: of the f oregoing .
As u~ed hexein and the appended claim~ the following :
molecule sha}l be referred to as R-53:
H H H 7
c--c ~ o ~ . .
H I / I H ~ H ~:
~ \N ~
and physiologic:ally acceptable salts of any and/or all
of the ~oregoing.
As used herein and the appended c:laims the following
,,
W093/10677 CA2] ~ 7284 P(~/US92/1û179
~: 74
molecule shall be referred to as R-54: -
1 ~2~H
~ ,'':'
~ O-G I U-0 2'~
, `-
and physiologically accepta~le salts of any and/or all
of the f oregoing . . .
As used herein and ~he appended claims the following
molec:ules shall be referred to as R-55: 1:
, _ :
~~-OH, R2~11, 2~CH~O~I, iR~,.CHa
IR~.~ OH, R2~H, R~CU20-Clc--Clc, IR~CNy
1~1 ~a-OH, R2~H, R3~CH20-G I c, R~CH,
Rl~O, R2~H, R~OH, R~CH~
~ O, R2~14, R3~CH20-Clc-CI:~, R~CH
R~ 2D~o, ~ H20--GIo. ~~H3~
~ p-OH,' ~2~Hf ~C~ 4'~ H2~
R 1 - O , R 2 W ~ I c , R3 ~ C H ~ , R 4 ~ C ~2 - - ~ l e
~ ~ ~ ~2~N, R~CH~, R6~CH2-O-~ I e~ ~^~
~ l c ~ g l t~ c o p ~ n ~
~ - -
and physic:~logically acceptable ~alt~ of any and/or all
of the foregoing.
S. The c:lass OI compounds having the struc:ture, or
structures clo~ely related to the following molecule which
~1 1 12`~4
WO93~10677 PCr/USs2/10179
~
as used herein and th~ appended claims shall be refarred to
as S-l:
.. . . - ~ ~ ~.
~ ~ R5 ~
5~
''.:.`
wherein R1, R2 ~ R3, and R4 which may be the same or :~
different are each designated by one of the
substituents of Group 1. ~ is represented by one of
the substituents of Group 2, and R6 is represented by
one of the substituents o~ Group 3, wherein Rl, R2, R3,
R4, ~, and R6, may be present in any ~ombination,
and physiologically acceptable salts of any and/or all of
~he foregoingO ~ ~
Of parti ular interest is the compound ha~ing the ~ :
structure (commonly known as epihernandulcin~: :
.__ . . ~ , ~
~ ~ ~\~ ~
~ T. Th~ clasæ of compounds having the structure (or
: ~ .
:
W~93/10677 ~4 PCT/US92/10179
: i 76
structures closely related to) which as used herein and the
appended claims shall be referred to 2s T-l:
. ~
~-1
wherein p may ba l, 2, 3, 4 or 5; R1, which may be the
same or different, are each represented by one of the
substituents o~ Group 1 in any combination; R2 and R3,
which may be the same or different, are each
repre~ented by one of the substituents of Group 2;
each R4 and Rs may be independently represented ~y one ~:
of the substituents of Group 3 and wherein R1, R2 g~ -
R4, and R5 may be present in any combination; n may be
0, l, 2, 3, 4, 5, 6, 7, B~ 9, lO, ll, 12, 13, 14, 15,
16~ 17, 18, 19, or 20; Z may be an element selected
: from the group c~nsisting of carbon, sul~ur, boron, or
phosphorus; q is ~n integer from X to 3 and r is an
integer from 1 to 3, when 2 is C, q i~ 2; when Z is S,
:P or B, q may be 2 or 3: when Z is C or S, r is l; ~:
when Z is F or B, r is 2;a
nd phy iologically acceptable salts of any and/or all of
the foregoing.
Illustrative of compounds of particular interest in
this class are:
l. R2-R~=*=R5-H, n=2, R1=p-cyano t Z=C ~ q=2 r=l, p=l
2. R2=R3=R4zR5=H, n=2, Rl-p-nitro, Z=C, q=2, r=l, p=l
3. R~=p-cyano; R2=~=R4=R5=H, n=l, Z-P, q=3, r--2, p=l
4 R1=p-nitr~; ~2=R3=R4=R5=H, nol, Z=P, q--~, r=2, p=l
R1=p-cyano; R2=R3=R4=~.5=~, n 1, Z-S, q=3, r=l, p=l
6 R1=p-nitro; R2=R3=~4-R5=H, n=l, Z=S~ q=3, r=l, pcl
and physiologically acceptable salts of any and/or all of
the foregoin~.
U. The class of compounds having the structure (or
:
WO93/10677 C ~ 2 1 1 7 2 ~ 4 PCT/VS92/1017~
77 , 5c,,,
structures c105ely related to) which as used herein and the :~
appended claims shall be referred to as U~
. . ~ ......... . . . ...... .. . '
U-l ~ R~ I .
~"~ ~
~.
wherein A may be O(oxygen), S(sulfur), or C(carbon~, :
and when A is C, n is l and wh n A may be O or S, n is
zero; ~ , R2, R3, R4, R5, R6, ~7, R8 R9 ~10 R11 a d R12
which may be the ~ame or differ~nt, and which may be
pre ent in any combination, may each be repr sented by
one of the following: one of the substituents of
~Gr~up l~ o~R13,~ NH-R13, N-(R13)2, or S-R13, where Rl3 is
represented by one of the substituents of "Group 2"; -~
~r two R substituents may be dehydrated to form an
: anhydride linkage;:or two R s~bstituents ~ay form a
cyclic structure,
and phy~iologically a¢eeptable salts of any and/or all of
the for~going. ~-~
o~e skilled in the art would recogniæe the six
msmbered (pyranose) rings of this class may isomerize to
five membered (furanose3 rings as is w~ll known for many
sugars.
Illustrative o~ compounds of particular interest in
this class are:
1. 6-chloro-6-deoxytrehalose, -~
2~ 61,6-dichloro-6',6-dideoxytrehalose,
3. 6-chloro-6-deoxy-D-galactose,
4. 6-chloro-6-d.eoxy-D-mannose,
W093/l0677 CA21 1 72~4 PCI/US92/10179
78 ~:~
S. 6-chloro-6 deoxy-~-mannitol,
6. methyl-2,3-di-(glycyl-glycyl)-~-D-glucopyanoside,
7~ methyl-2-0-methyl-~-D-glucopyranoside,
8. methyl-3-0-~ethyl ~-D-glucopyranoside, -~
9. methyl-4-0-methyl-~-D-glucopyranoside,
10. met~yl-6-0-methyl-~-D-glucopyranoside,
11. 2,2'-di-0-methyl-~ trehalose,
12. 3,3'-di-0-methyl~ trehalose,
13. 4,4'-di-0-methyl~ -trehalose,
14. 6,6'-di O-methyl~ -trehalose,
15. 6'-0-methylsucrose,
16. 4'~ methylsucrose,
17. 6,6l-di-0-methylsucrose,
18. 4,6'-di-0-methylsucrosP, -~
19. 1,6'-di-0-methylsucrose,
20. cyclohexane 1,2/4,5 tetrol,
21. (~)-cyclohexane 1,3,4/2,5 pentol~(~)-proto .~;
quercitol],
22. (-)-cyclohexane 1,3,4/3,5 pentolt(-)-vibo
~uercitol]~
23. cycl~hexane 1,2,3/4,5,6 hexol ~neo Inosit~
24. cyclohexane 1,2,3,5/4,6 hexol tmyo Inositol~,
25. cyclohexane 1,2,4,5~3,6 hexol [muco Inositol],
26. methyl-~ D-arabinopyranoside,
27. met~yl-3-deoxy~ D-arabinohexopyranoside,
2~.~ 3-deoxy-~-D-arabinohexopyranosyl-3-deoxy-~-D
arabinohexopyx~nose,
29. 2-d~o~y~ D-ribo hexopyranosyl-2-deo~y-~D
ribohexopy~a~ose,
30. 3-deoxy-a D--ribo-hexopyrano yl-3-deoxyf-~-D-
ribohexopyranose,
31~ 1,6-anhydro-3 dimethylamino-3-deoxy-~-D- .
glucopyranose, ..
32. 1,6-anhydro-3-dimethylamino-3-deoxy ~-D~ , ~
al~ropyranose, ~:
33. 1,6-anhydro-3-acetamido-3-deoxy~-D- . -
glucopyranose,
34. 1,6-anhydro-3-acetamido-3-deoxy-~-D-gulopyranose,
35. 1,6-anhydro-3-amino-3-deoxy-~-D-gulopyranose,
WO93/10677 CA ~ 1 ~ 72~4 79 PCT/US92~10~79
36. methyl-3,6-anhydro-~-D-glucopyranoside,
37O 3,6-anhydro-~-D-glucopyransyl-3,6-anhydro-~-D- ~
glucopyranoside, :
38. 3,6-anhydro-~-D-glucopyransyl-3,6-anhydro-~-D- ..
fructofuranoside, ~
39. 3,6-anhydro-~-D-glucopyransyl-l,4:3,6-dianhydro- .
~ -D-fructofuranoside,
and physiologically acceptable salts of any and/or all of
the foregoing. ~:
V. The class of compounds having the structure (or .:
structures closely related to) which as used herein and the
appended claims shall be referred to as V~
, . . .
. ~:
( R ) p ( y ) ~ ( A ) 1--( Y ) ~--( R ' ) q
. ( A ) a
: l ~,
~:~ : : :
- :"
V~
wherein a, r,:~l, and m may be O or l; n, j, and k are
O, 1, 2, or 3~;~ea~h R2 and R3 which may be the same or
different independently may each be represented by one .~:.
: ~ of the sub~tituents of group 3; Y tWhich may be the ;:
same or different) may be N (nitrogen), O (o~ygen), or
; 5 ~sulfur); when r. or m is 1 and Y is N, p or q may be
2 or 3, when r or~m is 1 and Y is O, p or q is l; when
~: r or m is 1 and Y is S, p may be 1 or 2; A may be H,
C=O, O-S=O, S=O, O=P~H~OH, O=P(OH)2, or O=B(H)OH; Q is
represen~ed by one of the substituents of Group 3; R
which may be ~he same or d}ff rent when p>l) and R'
(which may be the same or different when ~1) are ~-~
~,
wo g3,l0677 C A 2 ~ 1 7 ~ 8i4 PCr/l~S92/10179
! 80
represented by one of the substituents of Group 2 or
one of the following three structures (as used herein
and the appended cl aims the structures shall be
referred to as V-2 ) in any combination and th~ :
appropriate stereoc~emistry:
Q-
--C CR2R3) f--C~ C A) b--Z
V-2 ~)c
... Z .~
2R3~f C-- -~ A~ b--Z
R
:~
Q
¦_ ~ C R ~ ( Y ~ d- ~ A ~ b--~ R ~ e l
wher~in Y (which may be the same or different) may be
N tnitrogen), O (~oxygen), or S (sulfur3; when d is 1
and b i~; 0 ànd Y is N " e may be 2 or 3, when d is
and b is 0 and Y is O, e is l; f may be 0, 1, 2, 3, 4,
5, 6, 7 ;, 8, ~9, 10; when d is 1 and b is 0 and Y is S, -
e may be 1 or 2; A may be H, CoO, O--S=O, S=O, O=P~H)OH -;
or O=P(OH)2, O=B(~OH; Q is repre~ented by one of the
substit~aent of Group 3; R~ and Q together may f orm a
cyelic structure; any of the R3 ' s and Q together may
form a cyclic structure; any of the R3 ' s and R"~ s
together may form a cyclic structure; b may be 0, 1,
or 2 and c may be 0 or 1; Z and Z ' are the same or : .
different and ~are represented by ~H, -O~X~, OPc", NH~
NHR", N (R~ ) zj; Rl' may be alkyl, branched alkyl, aryl, - -
aralkyl, alkaryl, cycloal3cyl, substituted alkyl, :~
substituted cycloalkyl substituted aryl, substituted
aralkyl, su~s ituted alkaryl, and R"' may be alkyl,
wo 93/10677 C A 2 1 1 7 2 ~ 4 PCT/VS92/10179 ;;
81
branched alkyl, aryl, aralkyl, alkaryl, cycloalkyl,
substituted alkyl, substituted cycloalkyl, substituted
aryl, substituted aralkyl, substituted alkaryl, or an
amino acid side chain ~e.g. one of thP 20 common amino
acids), X~ may be H~ or a physiologically acceptable
cation, preferably an alkali metal, alkaline earth
metal or ammonium cation,
and physiologically acceptable salts of any and/or all of
the foregoing.
Illustrative of compounds of particular interest in
this class are:
1. N-(L-aspartyl)-p-aminobenzenesulfonic acid,
2. N-(aminomalonyl)-p-aminobenzenesulfonic acid,
3. amino ethane phosphoric acid,
4. N-~N-(p-cyanophenylcarbamoyl)-L-aspartyl]-p-
aminobenzenesulfonic acid,
5. N~-L-aspartyl)-l-aminocyclopentane-l-carboxylic
acid, , ,
6. N(-L-aspartyl)-1-aminocyclopropane-1-carboxylic
acid,
7. N~-L-aspartyl)-1-aminocyclooctane-1-carboxylic
acid,
8. N(-L-aspartyl)-l-aminocyclohexane-l-carboxylic
acid,
9. N(-L-aspartyl)-2-aminocyclopentane-1-carboxylic
acid,
and physiologically~acceptable salts of any and/or all of
the foregoing.
W. The class of compounds having the structure (or
'
'
~.
WO 93/10677 ~ 7 ~$~ PCr/US92/10179
82
stnlcture~; elosely related to3 which as used herein and the
appended daims ~;hall be referred to as ~-1:
W~ 1
wherein r, l, and m may be O or 1; ~, and k ~ay be 0,
1, 2, or 3; each R2 and R3 whicb may be the ~ame or
slif ferent ind pendently may each be represented by one
o~ lth~ subsl:ituents of group 3; Y (which may be the
~;ame or different~ may be N (nitrogell), O (oxygen) ~ or ~.
S ~sulfur); when r or m is 1 and Y is N, p or q may be
2 or 3, . when r or m is l and Y is O, p or q is l; when ;~
r or ~ is 1 and Y is S, p may be 1 or 2: A ~aay be H,
C-O, O=SzO, S=O, O=PIH)OH, O=P~I)2, or O=B~H)OH; Q is
represented by one of the ~;ubstituents of Group 3; R~
and Q toge~her may form a ~y~lic E;tructure; any of the
R3's and Q together ~ay form a cyclic structure; any ~.
of the R3 ' s and R"' together may form a cyclic
ctructure; R (which may be the same or different when
p>l) and R' (which may be the same or different wher
q>l ) are represented by one of the substituents of
Group 2 or one of the following three structures ~as
used herain and the appended claims the structures
shall be re~erred to as W-2 ) in any combination and
W093/10677 CA~l 17~84 PCI`/US92/10179
~ 3 ~s~,~
the appropriate stereochemistry ~
. . ~:
- ( C R 2 R 3) f--C C A ~ b Z
W-2 z/ .
''``''''
Q
C C R 2 R 3 ) f C--- C A ) b--
R :
.
Q
l ~ CR2~3~ CY)d-cA~b--cR~el ~ ~
: ~.
- ~,
wherein Y (which may be ~he same or dif ferent) may be ~ ~ ~
~ ~ N !nitrog~n), (oxygen), or s (sulfur); when d is 1 .~
and b is 0 and Y is N, e may be 2 or 3, when d is 1 :~
and b is O and Y is O, e i~; l; f may be O, 1, 2, 3, 4, - ~;
5, 6, 7, 8, 9, }0; when d is 1 and b is O and Y is S, ~-
e may be 1 or 2; A may be H, C=O, O-S=O, S=O, O=P(H~O~ ~-
or O-P(OH)2, O=B(H):OH; Q is repr~sented by one of the
substituents of Group 3; b may be O, 1, or 2 and c may . :~
be O or l; Z and Z': are the same or di~ferent and are ~:
represented by~ OH, -0~~, ORN, NH2, N~V ~ N(R" ~2~
may be alkyl, branched alkyl, aryl, aralkyl, alkaryl t
cycl~3alkyl, substituted alkyl, substituted cycloalkyl
substituted~ aryl~ substituted aralkyl, substitut d
alkaryl, and R"' may be alkyl, branched alkyl, aryl,
aralkyl, alkaryl, cycloalkyl, substituted alkyl,
substituted cyaloalkyl, s~stituted aryl, substituted ;~
aralkyl, substituted alkaryl, or an amino acid ~ide
chain (e.g. one of the 20 common amino acid ), X~ may
be H~ or a physiologically ~cceptable cation,
preferably an alkali metal, alkaline earth metal or
ammonium cati on,
WO93~10677 ~ 3 ~7 PCI`~US92/1017g
8 4 `;
and physiologically acceptable salts of any and/or all of
the foregoing.
Illustrative of compounds of particular interest in
thi~ class are: :
1. L-ornithyl-taurine
2. L-ornithyl-~-alanine .-
3. L-lysyl-taurine
4. ~-diaminobu~yryl-taurine
5. L-diaminobutyryl-~-ala~ine
6. L-diaminopropionyl-~ alanine
7. L-diaminopropionyl-taurine
8. L-ly~yl-~-alanine
9. L-methionyl-taurine
10. L-methionyl-~-alanine
11. N-tL-ornithyl-)-p-aminobenzenesulfonic acid
anld physioloa~cally acceptable salts of any and/or all of
the foregoin~ :
~. The general class of compounds commonly referred to
as chelators. These are molecules capable of chelating ~:
with, binding with, co~plexing with or ~oGrdinating with
me~al ions. Included in this class are the physiologically
: accept ble ~alts of any and~or all of the for~going~
Illustrative of compounds of particular interest in
this class a~e:
1. E~hylenediaminetetraacetic acid (EDTA) and
physiologically acceptable salts thereof~
2~ Ta ~ aric acid and physiologically acceptable salts `-
th~reof. ~ ; -
3. Lactic acid and physiologically aeceptable salts
th~reof.
4. Ascorbic~acid and physiologically acceptable salts
thereof. :
It should be understood that the present invention
con~emplates the use of chelating agents that have varying
degrees of affinity ~or met~l ions relative to the above
listed compounds. Many of these more or le~s effective
compounds are listed in A through W hereinabove. ~ few ~;
illustrative examples are:
1. 2,4-Dihydroxybenzoic acid,
W093/10677 CQ21 1 7284 PCT/US92/10179
. .i
2. 3,4-Dihydroxybenzoic acid,
3. ~-Amino acids,
4. ~-Hydroxy acids,
5. peptides,
6. sulfonamides,
7. ~-Amino acids,
and physiologically acceptable salts thereof.
Y. Tastand Enhancers: The ef~ectiveness of any ~;
individual tastand as described in Classes A-X may be
enhanced by one surfactant while the same surfactant may
lessen the effectiveness of other tastands or not affect
that particular tastand at al}.
Illustrative examples of surfactants: .
l. tergitols
2. pluronics
3. poloxamars . ~
4. quaternary a~moni~m salts ..
5. sorbit~ns
6~ trit~ns :~
7. polyoxyethene ethers
8. sulfonic acid salts
Surfactants can increase the effectiveness of some tastands r~
while the same:surfactant may lessen the effectiveness of
other tastands or not~affect that particular tastand at
:all. Surfactants~may: affect each tastand differently. The
surfactant that affects~one particular tastand in a
positive, negative or~neutral sense may affect another
:tastand differently~ (i.e. a positive, negative or neutral
sense and not necessari}y in the same way).
Z~ Tastand:Model: In l967, Sha}lenberger and Acree
(Nature (London) 1967,;216, 480-4B2; which is hereby
inco~porated by referènce) proposed that all compounds that
elicit a sweet taste::response possess an AH, B system (AH
being a hydrogen bond donor and B being a hydrogen bond
acceptor3 separated ~y about 0.28 to 0.40 nm. In this
theory, AH was OH or NH and B an oxygen atom in groups such
as CO2H, SO2H, SO2, CO, NO2, ~he nitrogen atom of CN, or
even a halogen. For instance, in L-aspartyl-L-phenylalanine
methyl ester the NH3~ is the AH and the COO~ is the B. They
.
CA21 l ~2~
WO93/10677 PCT/USg2/10179
86
suggested that such compounds interacted with a sweet
receptor by a pair of reciprocal hydrogen bonds ~a
complementary AH, B system). This theory was widely
accepted by most of the researchers in the field.
In 1972, Kier tJ. Pharm. Sci. 1972, 61, 1394; which is
hereby incorporated by reference) expanded on the model of
Shallenberger and Acree and proposed the existence of a
third binding site which involved a hydrophobic
interaction, which he designated as X. A molecule which
would interact with all three (AH, B, and X) would be a --
higher potency sweetener than one which only interacted
with the AH, B site. Ariyoshi (Bull. Chem. Soc. Japan,
1974, 47, 326-330: which is hereby incorporated by
reference) alid van~der Heijden ~Feed Chem. 1978, 3, 207;
which is hereby incorporated by reference) added ;
configurational restraints for the X group, that resulted -
in assigning a 5.~5 nm spacing for the B and X sites and a
3.5 hm separation for the AH and X sites. This model has -
become widely accepted~and~has been studied extensively by
a number of researchers including Goodman and co-workers,
Temussi and co-workers, Tinti and Nofre and co-workers, and
Belitz who has also ~tudied the requirements for bitter ~-
response in his modeling systems.
Goodman (Sweeteners, ACS Symposium Series 450, Chapt. `
10, 128-142; which~is~hereby incorporated by reference) has
further refined the requirements necessary for a molecule
to elicit a swe-t~respon6e by developing three dimensional
requirements for thé~AH, ;B, X system. ~inti and Nofre
~Sweeteners, AC~S symposium Series 450, Chapter 7 and 15:
which are hereby incorporated by reference) have identified
a fourth primary binding site which they call "D" (they
refer to the "xn site as "G") and four secondary binding
sites (Figure 1). The D site in a sweetener is a hydrogen
bond accepter group and appears to be particularly
effective when this group is a -CN or a -N02 group. Using
this 8 centered model, they have developed extremely potent
sweeteners which interact with all four primary sites and
several secondary sites.
Goodman (J. Am. Chem. Soc. 1987, 101, 4712-4714; which
WO93/1~77 C A 2 1 1 7 2 8 4 PCT/US92/10179
87 ~
is hereby incorporated by refe~ence) reports that the four
stereoisomeric tetramethylcyclopentane compounds; L-
aspartyl-L-alanyl-2,2,5,5-tetramethylcyclopentyl amide, L-
aspartyl-D-alanyl-2,2,5,5-tetramethylcyclopentyl amide, N-
(L-aspartyl)-N'-~tetramethylcyclopentanoyl)-(S)-l,l-
diaminoethane and N-(L-aspartyl)-N'-(2,205,5-
tetramethylcyclopentanoyl)-(R)-l,l-diaminoethane, present a
unique opportunity to study structure-taste relationships.
Small changes in the overall topology affect the taste of
these analogs (the ~,L amide is bitter while the L,D amide
and the retro-inverso analogs are intensely sweet). In -
~ddition, the bulky tetramethylcyclopentane group greatly
decreases the conformational mobility of the peptide,
allowing for a more complete analysis by NMR. With the
assumption of a trans peptide bond and a nearly planar
zwitterionic ring for the aspartyl moiety, the structure of -
the compounds can be determined from an extensive
conformational analysis by NMR. The coupling constants, NOE
values, and temperature coefficients used in defining the
conformations of the four molecules were reported. The
preferred mi~imum energy conformations are shown in Figure
2. Based on the results of this conformational study,
Goodman proposed a model for sweet tasting analogs which
contains elements of the models proposed by Kier, Temussi,
van der ~eijden, Tinti and Nofre,~ and Shallenberger and
Acree. The conformation of a sweet molecule can be
described as possessing an "L shape", with the A-H and B
zwitterionic ring of the aspartyl moiety forming the stem,
and the hydrophobic X (G in the Tinti-Nofre model) group
forming the base of the L (Figure 3). Planarity of the
molecule in the x and y dimensions is critical for sweet
taste, substantial deviation from this plane into the z
dimension is correlated with tasteless (~z) or bitter (-z)
molecules. The existence of the aspartyl zwitterionic ring
cannot be proven conclusively but can be assumed a priori
on the basis of evidence obtained from NMR experiments. The
Ca-C~ bond of the a6partyl residue pos~es~es a staggered
conformation with the carboxyl moiety and the amino group
in the gauche position and the sp2 plane of the terminal
WO93/10677 r ~ 1 1 7 ~ ~/US92/10179
88
aspartyl carboxylate carbon atom and the Ca-C~ bond
coplanar. These conditions are conformationally favorable
for the formation of the zwitterionic aspartyl ring.
The X-ray structure of L-aspartyl-L-phenylalanine
methyl ester has been solved by Kim (J. Am. Chem. Soc.
1985, 107, 4279; which is hereby incorporated by
reference~. Crystallization was achieved in the tetragonal
space group P41 with four L-aspartyl-L-phenylalanine methyl
ester ~olecules and one water molecule per unit cell. The
molecule shows an extended conformation with trans peptide
bonds. However, the~phenyl ring is perpendicular to the
peptide backbone and not coplanar with the zwitterionic
ring of aspartic acid as would be predicted for a sweet
dipeptide. This twis~ing of the phenyl ring is due to ~-
packing fcrces within the crystal structure which result in
stacking of ~djacent L-ospartyl-L-phenylalanine methyl
ester molecules into stable columnar structures. The
isolated molecule fro~the crystal structure can be rotated
40 about the ~" bond, to achieve an isoenergetic
conformation in which~the rings are coplanar. This
~conformation correlates~ closely to our proposed model for
~; the structure of~sweet~dipeptides in solution (Figure 3).
Of coUrse, in solution the L-aspartyl-L-phenylalanine
methyl ester moleoule ;is solvated and devoid of packing
forces. Thus, the ~inherent flexibility of this linear
peptide will easily accommodate the "L-shape" conformation
required by the model~. Figure 4 depicts L-aspartyl-L-
phenylalanin~ methyl ester in the L "shape" required for
sweet taste in the~Goodman model superimposed in the 8-
centered Tinti and Nofre model. In this configuration the ~`~
NH3~, C00~,-and `phenyl ring fit well into the AH, B and G
sites required for~a sweet taste in the Tinti and Nofre
model as well as the AH, B and X sites of the Goodman
model.
Belitz (ACS, Food Taste Chemistry, 1979, 93-131; which
is hereby incorporated by reference) describes minimum
requirements for bitter taste perception as a molecule
possessing an A~I group~and a hydrophobic moiety. Using the
model ascribed to Goodman above the hydrophobic moiety of
Wog3/1067Ç A 2 1 1 7 2 8 4 PCT/Usg2/l0l79
89 ! ~
~ t
Belitz would be in the -z (or bitter taste) region
described by Goodman.
It is a plau ible aonsequence of the aboYe models that
mol~cules c~pable of binding to one or more of the taste
r~ceptor l'sites" as d~scribed by these researchers, and
their models, and which do not allow a hy~rophobic group
into the "X" (or G, sweet taste~ region or into the (-z) :
(bitter taste~ area, is likely to be tasteless (or nearly
tasteless). Such a mo}ecule (a tastand as described herein ---
abo~e) would be predicted to competitively bind to the -::
receptor and cause inhibition of one or more of the tastes ~:.
(sweet, bitter, organic bitter) produced by such a
receptor.
~ hat we have found is that if a molecule is bitter or
sweet and interacts with the receptor site as describ~d by
the above models and such a molecule can be transformed in
such a manner as to displace the hydrophobic portion of the
molecule from th~ X ~G, sweet taste) zone, ~nd in such a
manner that the hydrophobic portion does not interact with
the ~itter taste (-z) zone, that such a molecule will t~nd
to be tasteless. ~urthermore, the transformation of the
hydFophobic zone:substituent to a hydrophilic substituent,
and/or the increasing or decreasing of the size of the
hydrophobic substituent, and/or the increasing or
decreasing of the distance between the various hydrogen
bonding and hy~rophobic interaction sites, may result in a
change in binding conformation and/or structure in a manner
which prevents substantial interaction with the sweet taste
(G or X3 zone or substantial interaction with the bitter
taste (-zj zone, thus, generating a substantially tasteless
molecule.
We have found that an inhibitor of sweet taste or
bitter taste may interact in various ways with the receptor
site. Consequentlyl depending on the nature of the
interaction of a tastand with the receptor, saîd tastand
may be capable of competing favorably against one class of
compounds, say for instance sweeteners, and unfavorably
against other classes of compounds such as bitter
compounds.
WO~3/10677 rA21 I 72~T/llS92/10179
Another consequence of our finding is that a model
explaining both sweet and bitter taste might include the
possibility that there are saparate receptors or receptor
sites for sweet and bitter taste perception. Thus, if a ~;
tastand were to interact with only one of these receptors
or receptor sites it could completely eliminate one
sensation without affecting the other.
It ~as also been reported and we have found that there
are at least two types of bitter taste. One is organic
bitter t~ste which is elicited by compounds such as
caffeine and the other is the bitter taste elicited by
inorgani~ molecules like potassium ion. Consequently, a
tastand may compete favorable against organic bitter taste,
perhaps even favorably against sweet taste as well, and
unfavorably against potassium ion, depending on the sites
of interaction. Conversely the tastand may compete
favorably against potassium ion and unfavorably against
organic bitt~r or sweet tastes.
As an example of the transformations which are capable
of eliciting the;re~ponses just described, L-aspartyl-L-
phenylalanine methyl ester is approximately 200 times
sweeter than sucrose. L-Aspartyl-L-phenylalanine ~ethyl
ester can be transformed to a bitter compound by changing
the L-phenylalanine methyl ester to D-phenylalanine methyl
ester (which places the phenyl ring in the -z (bitter
taste) zone. L-Aspartyl-L-phenylalanine methyl ester can
also be tr~nsformed to a tasteless compound by changing the
methyl ester to a~carboxylic acid. L-Aspartyl-L-
phenylalanine (L-aspartyl-L-phenylalanine methyl ester
minus the me~hyl ester) is tasteless and has been shown to
effectively block the bitter taste of potassium ion~ L-
Aspartyl-L-phenylalanine has minimal effect on the sw~et
taste of L-aspartyl-L-phenylalanine methyl ester but does
block the sweet taste of sucrose at very high
concentrations (relative to the sucrose). L-Aspartyl-L
phenylalanine has very little effect on the bitter taste of
caffeine but doe~ block the off-taste associated with L-
aspartyl-L~phenylalanine methyl ester. N-(p
Cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine methyl
WO 93/10677 CA 2 1 1 72~4 PCT/US92/10179
91 ,
ester as described by Tinti and Nofre is-14,000 times -~
sweeter than sucrose. When this compound is transformed
into N-(p-cyanophenylcarbamoyl)-L-aspartyl-L-phenylalanine, -
i.e. the super sweetener minus the methyl ester, the
compound becomes essentially tasteless. This compound can -
now interact with the AH, B and D, but not with the X(G),
portions of the receptor site and we have found thàt this
compound effectiveIy blocks the bitter taste of potassium
ion and the bitter taste of caffeine while having only a
very small effect on the sweet taste of sucrose. N-(p-
Cyanophenylcarbamoyl)-aminomethanesulfonate which possesses
a D and B site, and is essentially tasteless inhibits
organic bitter taste (caffeine) and sweet taste, but not
the bitter taste associated with potassium chloride.
Taurine and ~-alanine which both possess an AH, B array are
both example of tastands.
Consequently, it is possible to tailor c~mpounds by
transforming known sweeteners or known bitter compounds
into essentially tasteless molecules capable of either
blocking the sweet taste response, the organic bitter ta~te
response, the inorganic bitter taste response or various
combinations of each. Thus, a new and previously-
unanticipated teaching of this invention is that the models
of Goodman and coworkers and others can be used to predict
tasteless collpounds which can be used as tastands as
described herein. Such tastands are predicted to be
,
tasteless or nearly tasteless compounds which can be
generated by transformation of a sweet or bitter compound
in a manner that eliminates hydrophobic interactions in the
-z or X~G) areas (as defined by Goodman or Tinti and Nofre)
of the taste receptor(s). Such tastands are capable of
blocking or inhibiting any one or any combination of the
three tastes; sweet, organic bitter or inorganic bitter.
A molecule need only interact with one of the hydrogen
bonding sites described above and have little or no
hydropho~ic interaction in the X~G) zone or -z zone to be a
tastand. Fre~uently molecules capable of interacting with
onIy one hydrogen bonding site and having a hydrophobic
moiety will po88e~8 sufficient flexibility (depending on
W093/lQ677 92 C A 2 1 1 7 2 8P~/US92 1
size) to enter the -z zone and will consequently be bitter
tasting. Molecules with the ability to hydrogen bond with ;~
more than one complementary site on a receptor will have a
better chance of keeping hydrophobic groups out of the X(G)
and -z zone, and consequently should have a high
probability of being a tastand.
According to the above logic, molecules which can
interact with the reciprocal AH and/or B hydrogen bonding
sites on a receptor as described by Goodman (Figure 3) and
whose conformation~and/or structure prevents any -
hydrophobic interactions in the X (sweet taste) region and
which also do not allow hydrophobic interactions in the -z
(bitter taste)~zone are tastands as defined herein.
Also, according to the above logic, molecu}es which
can interact with the reciprocal AH and/or B and/or D ~or
secondary sites~) hya ~gen bonding sites on a receptor as
described by Tinti and Nofre (Figure 1) and whose
conformation and/or structure prevents any hydrophobic
interactions with the G (sweet taste) region and which also
do not allow`hydr~ophobic`interactions in the -z (bitter
taste) zone which~is developed when the AH, B, D, G system
of Tinti and Nofre is superimposed into the AH, B, X system
of~Goodman ~Fig~ure 4), are tastands.
.
As used herein and the appended c}aims AH, B, D, El,
E2, XH, Y, X, G,~ shapeN, and the coordinates of x, y, z
are defined hereinabove.
~ : -
'
~;
WC~ ~3~10~77 ~ A 2 1 1 7 2 8 4 PCr/US92/10179
93
~)
~igure 1.
AH - Hydrogen Bond Donor Group
E~ Hydrogen Bond Acceptor &roup
G - Hydrophobic Group
D - Hydrogsn Bond Ac:ceptor Group
X~I Weak Hydrogen Bond Donor Group
y D Weak Hydrogen Bond Acceptor Group
E1 ~ Waak Hydrogen Bond ~cceptor ~rs~up
E2 - Weak Hydrogen Bond Acceptor Group
.... .. . _ _ _
,...
Figur@ 2 a ~
.~
CA21 l 7284
WO 93~10677 PCI/US92/1017g
;. . ..
. ; _ , . . , , , , , . , .
~S
Figure 2b .
1~ ~,
~1 ~
Figure 2c
.
'~
WO93~10677 CA 2 1 1 72~4 PCT/VS92/10179
95 ; .~ :
,, ,~
Figure 2d~
: ~Figure 2~a-d. Preferred minimum ener~y eonformations of ~A)
N-(L-aspartyl3-N'-(tetra~et~yl¢yclopenta~oyl3 (R)-191-
~: dia~inoethane, (B) N-(L-aspartyl)-N~-
(tetramethylcyclopentanoyl) (S)~ diaminoethane, (C) L- ~
aæpar~yl-D-alanyl-~etram~thylcycl~pen~ylamide and (D~ L- .
a~partyl-L-alanyl-tetramethylcyclop~ntyl~mide.
WO93/10677 C~ 2 1 ~ 7284 96 PCT/US92/10179
, ,,, . ,,,, , , _ . ;~:
Figure 3. The Goodman model ~r the sweet taste with L-
asp~rtyl-L-phenylalan~ e methyl ester sup~ri~posed. The
bond, shown by the arrow, has been rotated 40 from the X-
ray diffraation structure. In addition, th~ hydrogen atoms
have b~ n added, with the ~tandard bond lengths and angl~s.
The ~H-B and X groups o~ the molecule are illu~trated
according to the Shallenberger-Xi~r suggestions. ~:
. -
` ~
: ~ .
~ ' .
- ..
W093/10677~ A 2 1 1 7 2 8 4 PCT/US92/10179
97 ~
., --- ,
D
~ ~:
I
. .
. '::
. , , , ", ., ".
, . `.
Figure 4. L-aspartyl-~-ph~nylalanine methyl ester in the
R'~-shape" proposed by Goodman for the sweet taste receptor
~uperimposed into th~ 8-centered ~odel propo~ed by Tinti
and Nofre. .
~ ~any of the ab~ve t~stands exist ~ race~ic :~
: mix~ures~), minus (-3, plus (~), or dia~tere~meric optical
isomers~ It hould be understood that the present invention
contemplates use of the tastands in either the rac~mate or
as the individual optical isomer~. It is likely that one or
the other of the optical isomers of the racemic tastands
possess the greater, if not all, of the blocking or tastand
activity. For example, it has been found that the ~
isomer of 2-(4-methoxyphenoxy)propionic acid possesses the
majority of the activity that reduces undesirable tastes.
~he use of the most active isomer alone is advantageous in
that far less tastand is needed to gain th~ desired
reduction in undesirable taste(s).
WO 93J10677 C A 2 1 1 7 2 8 4 Pcr/usg2/l0l7~
.. , 98
It has further been found that tastands described
above and in particular (-)-2-(4-methoxyphenoxy)propionic
acid, in addition to inhibiting bitter taste also enhances
the salty taste of sodium containing compounds, if employed
in sufficient concentration~s. Thus, the present invention
contemplates the preparation of eatables containing, for
example, low sodium chloride and the tastands in an amount
sufficient to enhance the salty taste of sodium chloride.
Moreover, the present invention contemplates the
preparation of eatables comprised of a mixture of
substances havinq an undesirable taste such as potassium
chloride, magnesium chloride with sodium chloride and/or
ammonium chlcride in conjunction with the tastands referred
to herein in an amount that both reduces the undesirable
taste(s) and enhances the salty taste of the sodium
chloride. Preferred eatable admixture products of the
invention comprise from slightly more than 0 up to about
300% by weiqht of substances with undesirable tastes such
as, for example, potassium chloride and magnesium chloride
and 0 to 50% by weight sodium chloride in combination with
. .
effective concentrations of a tastand(s), typically 0.001%
to about 50% preferable 0.1% to about 5%.
Moreover, the present invention contemplates the
preparation of eatables such aæ ~reads, biscuits, pancakes,
.
cakes, pretzels, snack foods, baked goods etc. prepared `
using for example potassium bicarbonate or potassium
carbonate in place of the sodium salt& as leavening agents `~
in conjunction with a tastand in an amount sufficient to
eliminate the undesirable taste associated with potassium
ion or other tastes. The tastand is typically present in an
amount ranging from about 0.001% to about 50% by weight,
preferably about 0.1% to about 10% by weight, of the
material with the undesirable taste. The present invention
also contemplates the preparation of preservatives for -
eatables comprised of the potassium salts of benzoate,
nitrate, nitrite, sulfate and sulfite and so on, in
conjunction with~an appropriate concentration of a
tastand(s) to eliminate undesirable tastes in foodstuffs.
Ideally the tastand is usually about 0.00~ to about 10%,
W093/t0677 CA21 17284 PCl`/US92/10179
. . .
preferably about 0.1~ to about 5%, by weight of the
material with the undesirable taste.
The present invention also contemplates the use of
potassium salts of flavoring agents (such as for example
glutamate~ in place of sodium salts. Consequently
monopotassium glutamate and/or guanalate and/or inosinate
in conjunction with~an appropriate amount of tastand to
eliminate most if not all of the undesirable tastes, thus
rendering monopotassium glutamate essentia}ly equivalent to
monosodium glutamate. m e tastand can be present from about
0.0000001% to about 300%, preferably from about 0.1% to
about 5%, by weight of the material with the undesirable
taste.
The present invention also contemplates the
preparation of medicaments such as aspirin, acetaminophen,
ibuprofen, codeine, antibiotics, etc. in conjunction with a
tastand~s) in sufficient concentration to remove or reduce
.
the undesirable taste(s) of these ma~erials. The tastand is ~-
usually 0.001% to about 50% by weight, preferably from
..
about 0.5% to about 5% by weight of the material with the
undesirable taste. The present invention also contemplates
the preparation of~eatables w~ich have inherently
undesirable tastes,~such as unsweetened chocolate, in
conjunction with a~ tastand in sufficient concentration to
eliminate or reduce the bitterness of these products. The
tasta~nd is usually~;a~out 0~.001% to about 50% by weight,
preferably about 0.2%~to about 5~, by weight of the
material with the undesirable taste.
~ As one skill;ed in the art would recognize, this
reduction in the undèsirable taste(s) could result in a
reformulation of the product now that the undesirable
taste(s) is ~educed. A few specific examples of this would
be:
1. The preparation of lower calorie chocolate
products,
.~", .
2. The preparation of lower calorie beverages,
3. The preparation of an eatable with a reduced
quantity of high intensity sweeteners, or
4. The preparation of an eatable with a reduced
W093/10677 CA21 17284 loo PCT/~S92/10179
quantity of low intensity sweeteners.
5. The preparation of an eatable with a reduced
quantity of high intensity sweeteners.
By the use of at least one tastand in an eatable with an
undesirable taste; a reformulation could be made which
would result a reduction in calories and/or masking agents
such as l~w intensity sweeteners, high intensity
~weeteners, spices, and/or other flavorings.
The concentration of tastand employed to reduce the
undesirable taste~s) in any given instance will vary
depending principally on the particular tastand selected,
the particular substance or substances with the undesir~ble
taste(s?, the extent of the reduction of the undesirable
taste(s) desired as well as the other tastes and Clavors
present in the mixture. In most instances, concentrations
of about O.OOl to 300% by weight, preferably about 0.05 to
5% o~ tastand to the material with the undesirable taste
are satisfactory.
As an illustrative specific example, when tL tastand
is selected for use with an admixture of sodium chloride
and an undesirable tasting substance such as potassium
chloride and~or magnesium chloride, it will generally be
necessary to employ at least 0.2% by weight up to 10% by
weight of the tastand based on the weight of the salt(s) to
obtain both the reduction of the undesirable taste(s) and
salty taste enhancement.
~ The eatables to which the tastands of the invention
can be added are wi hout limitation and include both
foodstuff and eatables having essentially no food value
such as pharmaceuticals, medicament~ and other eatables.
Therefore, the tastands of the present invention are
effective for use with all substances which have an
undesirable taste(s). Illustrative of substances with
undesirable taste(s) with which the taste modifiers of the
invention can be used are potassium chloride, ammonium
chloride, sodium chloride, magnesium chloride, halide
salts, naringin, ~affeine, urea, magnesium ~ulfate,
saccharin, acetosulfames, aspirin, potassium benzoate,
potassium bicarbonate, potassium carbonate, potassium
W093/10677 ~ A 2 1 1 7 2 ~ 4 PCT/US92tlOt79
101 '~
nitrate, potassium nitrite, potassium sult`ate, potassium
sulfite, potassium glutamate, food preservatives in their
physiologically acceptable salts, ibuprofen, acetaminophen,
antibiotics, codeine, cognac, unsweetened chocolate, cocoa
beans, yogurt, pxeservatives, flavor enhancers, dietary
supplements, gelling agents, Ph control agents, nutrients,
processing aids, bodying agents, dispersing agents,
stabilizers, colorings, coloring diluents, anticaki~g ~.
agents, antimicrobial agents, formulation aids, leavening
agents, surface active agents, anticaking agents, nutrient
supplements, alkali, acids, sequestrants, denuding agent
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, ~alts, animal glue adjuvant, cheese, nuts, meat
and meat products,~poultry a~d poultry product, pork and
pork products, fish~and fish produ~ts, 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 strengthene~s, 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-
al~oholic 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
undesirabl~ tastes and the like.
While the above listing is extensive it is by no means
all inclusive. Clearly one skilled in the art would
recognize that many if not all of the:
WV93/1~677 C A ~ 1 1 7 ~ a 4 PCT/US~2/10179
102
A. sodium based salts or compounds, and~or,
B. sodium based salts or compounds made into their
non-~odium based counterparts, and/or,
C. pota.~sium based salts or compounds, and/or,
D. acid~ or acids made into their corr~sponding salts
(sodium and/or non sodium based compounds), and/or,
E. alkalis or alkalis made into their corresponding ~-
salts, and/or,
substances that are approved, at any time, as eatable~ by
the Food and Dru~ Administration and/or that are ~RAS as
defined by the Flavor Extract Manufacturers' Association
could then be made more palatable by the use of th~
taætands taught herein (h reinafter and in the appended
claims referred to as "material~s)"). These materials would
or could be made more palatable by the reduction or
elimination of any undesirable ta~tets) associated with ~:
them. ~Generally, sodiu~ based salts are better tasting -~
than the corresponding non-sodium salts.) The use of
tastands with all o~ the~e materials as well as all of
their anticipa~ed uses is hereby anticipated by the
teachings set forth herein.
.
: Despite the breadth of this disclosure, one skilled in
the art and the~teaching taught herein shall be able to
: envision other examples.
~: E~AMPLE 1.
An aqueous solution (1 L) containing 20 grams of a
mixture compris~d of 95~ potassium chloxide and 5% ::
odium chloride, and~0.05 grams (-)-2-(4-
methoxy~henoxy)propionic acid sodium salt, gave a
sodium chloride-like taste with virtually none of the
; ~ bitterness normally associated with potassium
chloride.
:~ EXAMPLE 2.
An aque~us solution (100 mL) containing 2 gram~ of
potassium chloride and 0.06 grams of L-aspartyl-L~
phenylalanine monopotassium salt, gave a clean, salty
taste virtually free of the bitter taste normally
asssciated with potassium chloride.
WO93/10677 C Q 2 1 1 7 2 8 4 P ~/US92/10179
103 i; !: `
EXAMPLE 3.
An aqueous ~olution (1 L~ containin~ 10 grams of
sodium chloride and 1 gram of (-)-2-(4-
methoxyph~noxy~propionic acid sodium salt had a
substantially saltier taste than a 1% solution of
sodium chloride alone.
EX~MPLE 4~
An agueous solution ~1 L) containing 22.5 gra~ of
potassium chloride and 0.79 grams of 3-methoxyphenyl
acetic acid sodium alt gave a substantially bitter~
free salty taste~
EXAMPLE 5.
An aqueous solut}on ~1 L) containing 20 grams of
potassium chloride and 0.~ grams of 2,6-
dihydroxybenzoic acid potassium salt was nearly devoid
of the characteristic potassium chloride bitter taste.
~XAMP~E 6. t
A solid preparation containing a mixture of potassium
chloride (90 grams~, sodium chloride (10 grams) and (
: )-2-(4-methoxyphenoxy)propionic acid sodium salt (0.25
grams) gave a ~clean salty sodium chloride-lîke taste.
~: EXA~PLE 7
A solid preparation containing potassium chloride (80
grams), sodium :ohloride (10 grams), magnesium chloride
(10 grams) and ( -~ -2-(4-metho ~ henoxy)-
propionic~:acid sodiu~ salt ~0.25 gram) ga~e a well-
rounded, ~alty taste with virtually no bitterness.
X~NPLE 8. ~
The taste:of~lithium chloride was greatly improved by
the addition of 1% by weight (-)-20(4-
msthox~phenoxy)propionic acid sodium salt . The
saltine s was substantially increased.
EXAMPLE 9.
Addition of 0.5% by weight of (-~-2-(4-
methoxypheno~y)propionic acid sodium salt to
monopotassium glutamate produced a flavor almost
: identical to monosodium glutamateO Virtually no bikter
taste was detectable.
W093/10677 P~T/US92J10179
`"~ CA211 72~4 104
EXAMPLE 10.
Addition of 6~ by weight of (-)-2-14-
methoxyphenoxy)propionic acid sodium salt to aspirin
gave a formulation that was slightly ~our, with almost
no bitter taste or characteristic "aspirin"-like
bitter aftertast~.
EXAMPLE 11.
Addition of 3% by weight of (-)-2-(4- ::
methoxyphenoxy)propionic acid ~odium salt to aspirin
gave a formulation substantially lacking the bitter
taste o~ aspirin. ~.
EXAMPLE 12.
A solut~on containing 100 ppm caffeins and 10 ppm by
weight ~relative to caffeinP) of (-)-2-(4-
methoxyphenoxy)propionic acid sodium salt was almost
tasteless, and virtually all of the bitterne~s was
removed.
~; EXAMPLE 13.
:~ The strong bitter taste of unsweetened chocolate was
nearly eliminated by the addition of 0.25% by weight
of (-)-2-(4-methoxyphenoxy)propionic acid sodium ~alt. ~:
EXAMPLE 14. .
~ Potassium benzoate containing 0.5~ by weight (-) o2- (4- -
:~ ~etho~yphenoxy)propionic acid sodium salt was added to
foodstuffs in place of sodium benzoate. There was no
: : detectable difference in the taste of the foodstuffs.
EXA~PLE 15. :
Potassium nitrate and potassi~m nitrite containing
:: 0.5% ( )-2-(4-methoxyphenoxy)propionic acid sodium
salt were added to foodstuffs in place of the sodium
salts. There was no detectable difference in the
taste.
EXAMPLE 16.
: Po~assium bicarbonate containi~g 0.5% by weight (-)-2-
~4-methoxyphenoxy)propionic acid sodium salt was used
in place of baking soda for the baking of biscuits.
There was essentially no bitterness detected.
WO93/10677 CA 2 1 1 7 2 84 PCTtUS92/10179
105
EXAMPLE 17.
Potassium bicarbonate/carbona~e mixture containing
~.5% by weight (-)-2-(4-methoxyphenoxy)propionic acid
sodium salt was used in place of baking powder for the
preparation of pancakes. Essentially no bitterness was
detected.
EXAMPLE 18.
When 10-20 ppm of (-)-2-(4-methoxypheno~y)propionic
acid sodium ~alt was added to black coffee, the strong
bitter taste of the coffee was almost completely
eliminated.
EXA~PLE 19~
An aqueous solution (1 L) containing 20 grams of
potassium chloride and 0.6 grams of monosodium D-
glutamate had substantially less bitterness than a 2%
solution of potassium chloride.
EXAMP$E 20.
An a~ueous olution (1 L) containing 20 grams of
: potassium chloride and 1.2 gra~s of monopotassium D-
glutamate had virtually none of the bitterness
normally associate~ with potassium chlorid~
EXAMPLE 21.
Whe~ O.2S~ by~weight of hesp~ridin methyl chalcone
(relative to RCl) was add~d to a 2% solution of KCl
th2 bitterness of th~ KCl was reduced.
22
EXAMPLE
Wh2n 0.25~ by w~i~ht (relative to th~ so~ium nitrite)
f ~ 2-(4~m~tho ~ henoxy)propionic acid sodium salt
~:~ was added to 1% solution of sodium nitrite, the
saltiness of the sodium nitrite was enhanced.
EXAMPTE 23 .
When 5% by weight o~ hesperidin (relative to potassium
chloride3 was added to a 2% solution of potassium
chloride and the mixture heated to 4 0 C the bitterne s
of the XCl was almost completely eliminated.
EXAMPLE 2 4 .
When 6.696 by weight of sodium D-aspartate (relative to
potassium chloride~ was added to a 296 solution of
potassium chloride the bitter taste of the potassium
wo 93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
~`~ 106
chlorid~3 was reduced and there was virtually no :~
aftertaste.
EXANPLE 25.
When 0.06 grams of phenoxyacetic acid sodium salt was
added to an aqueous ~olution containing 18 grams of
potassium chloride and two grams of sodium chloride,
the bitter taste of the potassium chloride was
substantially eliminated.
~XAMPLE 26.
When 5% by weight (relative to potassium chloride) of
2-methyl-3-nitroaniline was added to a 2~ solution of
potassium chloride~the bitter taste was virtually
eliminated.
EXAMPLE 27.
The bitter compon¢nt of a l~ by weight aqueous calcium :~
chloride solution (lO0 mL) was substantially
eliminated by the addition of 0.2 grams of (-)-2-(4-
metl1oxyphenoxy)propionic acid sodium salt.
EXRMPLE 28.~ ;
The bitter component of a 1% by weight aqueous
magnesium chloride soIution (lO0 mL) was reduced by
the addition of 0.2 grams of (-)-2-(4- ;
~ethoxyphenoxy)propionic acid sodium salt.
~: : EXAMPLE 29.
The bitter~component of a 2% aqueous magnesîum sulfate
:~ :
solutio~ oO mL3 was greatly reduced by the addition
of 0.04 grams of ~ 2-(4-methoxyphenoxy)propionic
: acid: sodium sal~.
EXANPLE 30
When lO0 ppm:of (-)-2-~4-methoxyphenoxy)propionic acid
sodium salt was added to whiskey, the strong burning
~;~ sensation of the w~iskey was substantially reduced.
;~: :EXAMPLE 31.
::~: When lO0 ppm of ~ 2-(4-m~thoxyphenoxy)propionic acid
:~ sodium salt was added to cognac, the strong burning
~: sensation of the cognac was substantially reduced.
.
WO93/10677 C A 2 1 1 7 2 84 PCT/US92/10179
107
EX~MPLE 32.
When lO0 ppm of (-)-2-(4-methoxyphenoxy~propionic acid
sodium salt was mixed with commercially prepared ~alsa
sauce there was a substantial reduction in the hotness .
of the sauce. -~
EXAMPLE 33.
When lO~ (w/w relative to the saccharin) of racemic 2~
(4-metho~yphenoxy)propionic acid sodium salt was added
to a O.l~ solution of sodium saccharin r vir~ually all
of the bitterness was removed. There was no aftertaste
noted.
~XAMPLE 34.
When 1% (w/w, relative to the potassium nitrate3 of ~-
)-2-(4-methoxyphenoxy)propionic acid sodium salt was :~
added to a 3% aqueous potas~ium nitrate solution there
was almost a complete elimination of the bitterne~s of :
the potassium nitrate '.~!i
.
EXAMPLE 35.
When 0.25% (~ 4-methoxyphenoxy)propionic acid
sodium salt w/w~was added to lO grams La Victoria Hot
Salsa t~e salsa sauce was significantly less harsh.
EXAMPLE 36.
When a solution containing 25 ppm of a mixture having
: a ratio of 90 parts ~+)-2-(4-methoxyphenoxy)propionic ^:
acid sodium~salt~to lO parts [-)-2-(4-
: methoxyphenoxy)propionic:acid sodium ~alt and lO0 ppm
sodium saccharin there was no noticeable diminution of
sweetness~of the sodium saccharin and at the same time ~`
~:~ ; there was significantly Iess a~tertaste.
: EXAMPLE 37.
-. When 0.5% b~ weight of potassium 2,4-dihydroxybenzoate
(relative to potassium chloride) was added to 1%
SOlUtiOIl of potassium chloride virtually all of the ~-
~: bitterness of the potassium chloride was eliminated. ~;.
: EXAMPLE 38. :
When 0.5%:by weight potassium 2,4-dihydroxybenzoate
~: (relative to~the potassium chloride~ was added to a 1%
potassium chloride solution which also contains 2%
sucrose, virtually all of the bitterness of the
W093~10677 PCT/US92/10179
~ CA2117284 108
potassium chloride was eliminated and the sucrose
taste was not suhstantial...~ affected.
EX~MPLE 390
When 25 mg of potassium 2,4-dihydroxybenzoate (69 ppm
relative to the total volume of the cola~ was added to
a cola sweetened with saccharin, virtually all of he
metallic aftertaste of the saccharin was eliminat~d. -
EXAMPLE 40.
When 25 ppm of potassium 2,4-dihydroxybenzoate was
added to a solution containing 100 ppm sodium
saccharin there wa~ no noticeable diminution of
sweetness o~ the ~accharin and at the ~ame time there
wa~ significantly less aftertaste.
EXAMPL~ 41.
Addition of 5% by weight (relative to the potassium
chloride) of disodium ethylenediaminetetraacetic acid
(EDTA) to an aqueous solution of 2% potassium chloride
: greatly reduced the bitterness of potassium chloride.
E~A~PLE 42.
he bitterness o$ a 100 mL ~olution containing 0.11
caffeine was reduced to the bitterness of a 0.08%
solution of caffeine by the addition af 100 mg
potassi ~ 2,4Ddihydroxybenzoate.
E ~ PLE 43.
A taste panel consisting of six tasters unanimously
prsferred ~otato chips salted ~ith 1~6% w/w pota~ium
chloride/codium chloride/L-aspartyl-~-phenylalanin~
~ ; pot~ssium ~alt (90/10/3) over potato chip~ salted with
;: 1. 696 w/w pot~s i~am chloride/~odium chloride (90/10)
due to substantially reduced bitterness.
EXP~PIE 44.
An aqueous 50lution containi~g l~ sodium chloride and
O.005% potassium 2,4-dihydroxybenzoate was salti~r
than an a~ueous solution containing only 1% sodiu7.i
chloride.
EXAMPLE 45.
The bitter taste of 200 mL of freshly bre~ed Sarks
brand Espresso was greatly reduced by the addition of
20 mg of potassium 2,4-dihydroxybenzoate.
W093/10677 ~ A 2 1 1 7 2 8 4 PCT/VS92/10179
10~
EXAMPLE 46. "
The bitter and sour tastes of sodium acetylsalicylate
was essentially absent from an agueous su~pension
comprised of sodium acetylsalicylate tO.5 gram), water
(2 m~) and potassium 2,4-dihydroxybenzoate ~0.375 ~:
gram) ~
EXAMPLE 47.
The bitterness of a 2% aqueous potassium chloride
solution was nearly liminated by the addition of 1%
by weigh~ (relative to the potassium chloride) of
3,4-dihydroxyphenylalanine, (DL-DOPA).
EXAMPLE 48.
A sample of refried beans (100 gm) salted with
potassium chloride (0.98 gm), sodium chloride (0.42
gm) and sodium:tartrate (O.15 gm) gave a clean, salty
taste, almost completely devoid of bitterness, when
compared with a sample of 100 grams of refried beans
salted only with p~tassium chloride (0.38 gm~ and
sodium chloride (O.42 gm).
EXAMPLE 49.
~ Addition of:~5%~by weight of sodium tartrate (relative
: to t~e potass~ium chloride) t9 a 2% aqueous solution of
potassiu~ chloride significantly reduced the
bitterness~associated wi:th potassium chloride.
E ~ PLE 50.
A sample of:~refried~beans (100 gm) salted with
potassium chloride:~(0.98 gm), sodium chloride (0.42
: gm) t: a 70/30 ratio) and disodium
: ethylenediaminetetraacetic acid (0.7 gm) gave a clean,
salty taste, virtually devoid of bitterness when
compared with a~6ample of 100 gm of refried beans
salted only with potassium chloride (0.98 gm) and
sodium chloride (:0.4~ gm).
EXAMPLE 51.
The add~tion of 5 mg of sodium 2,4-dihydroxybenzoate
to a cup of Tetley tea (200 mL) which had been
sweetened with 40 mg of sodium saccharin almost
completely eliminated the bitter, metallic aftertaste
of the saccharin.
W093~1067/ PCT/U~92/10179
"",~ CA21~72~4 110
EXAMPLE 52.
A solid, lyophilized salt preparation composed of 70
~arts pvtassium chloride, 30 part~ sodium chloride and :-
O.35 parts potassium 2,4-dihydroxybenzoate had a ::
~harper initial salty taste, but was otherwise
virtually indistinguishable from lyophilized sodium
chloride. - :~
EXAMPLE 53. :
Addition of S% by weight (relati~e to the pota~sium
chlorid~) of odium (+)-lactate to a 2% aqueous
solution of potassium chloride significantly reduced
the bitterness associated with potassium chloride.
EXAMPLE 54.
Addition of 5% by weight (relative to the potassium
chloride) of sodium ascorbate to a 2% aqueous solution
of potassium chloride ~ignificantly reduced the
bitterness associated with potassium chloride.
EXAMP~E 55.
Addi~ion of 1% by weight (relative to the potassium
~ chloride) of sodium p-anisate to a 2~ aqueous solution
: of potassium chloride reduced the bitterness
associated with potassium chloride.
EXAMP~E 56.
Addition of 7:0 mg of sodium 2,4-dihydroxybenzoate to 1
liter of~a~0.04% solution of caffeine (400 mg) reduced ~:
: : the bitternes~s a~sociat~d with ca~feine.
.
EXANPLE 57.
Addition~of 0.5% by;weight ~relative to the potassium ;~
: chloride) of~DL-methionine-methyl sulfonium chloride :~
to a 2% aqueous solution of potassium chloride reduced
the bi~terne~s associated with potassium chloride.
EXAMPLE 58.
: Addition of 6 grams of maltose to 100 mL of a 2%
aqueous solution of potassium chloride reduced the
bitterness of the potassium chloride.
EXAMP1E 59.
To 50 grams of mashed potatoes was added 1.2 mL of a
100 mL solution containing potassium chloride (17.3
gm~, sodium chloride (1.9 gm) and (+)-2-(4
W093/10677 C A 2 1 1 7 2 ~ 4 PCT/US92/10179
111 ~'~
methoxyphenoxy)propionic acid sodium salt (O.8 ~m).
The mashed potatoes had a clean, salty taste with
almost no bitter taste associated with potassium
chloride.
EXAMPLE 60.
Addition of 8 mg of xanthosine 5' monophosphate to ~Oo
mL of a 2% aqueous solution of potassium chloride
reduced the bitterness sf potassium chloride and
enhanced the saltiness.
EXAMPLE 61.
: Addition of 5% by weight (relative to the potassium
chloride) of sodium 2-hydroxyphenylacetate to a ~%
agueous solution of potassium chloride significantly
reduced the bitterness associated with potassium
chloride.
EXAMPLE 62.
Addition of 0.5% by weight (relative to the potassium
:~ chloride) of sodium l-hydroxy-2-naphthoate to a 2%
aqueous solution~of potassium chloride significantly
reduced the bitt~En~ss associated wi h potassium
~: chloride.
~; EXAMPLE 63.
Addition of 1%:by weight (relative to the potassium
chloride) of~sodi~m 3-hydroxy-2-naphthoate to a 2~
aqueous ~olution of potassium chloride significantly
reduced the bitterness associated with potassi~m
chloride.
: ~ :EXAMPLE 64. ~
ddition of 5%~by weight (relative to the potassium
;~ chl~ride) of sodium 2,4,6-trihydroxybenzoate to a 2%
aqueous solution of potassium chloride significantly
reduced the bitterness associated with potassium
: chloride.
~: EXAMPLE 65.
Addition of 0.5% by weight (relative to the potassium
chloride) of sodium 4-aminosalicylate to a 2% a~ueous
solutioll of potassium chloride reduced the bitterness
associated with potassium chloride.
Wo93J1o677 CA21 17284 PCT/U~g2/1017~ ~
112
ExAMpLæ 66.
Addition of 1% by weight (relative to the potassium
ch~oride) of sodium anthranilate to a 2~ aqueous ~:
~olution of potassium chloride reduced the bitterness
a~sociated with potassium chloride.
EXAMP~E 67.
Addition of 0~5~ by weight ~relative to the potassium
chloride) of sodium aniline-2 sulfonate to a 2%
aqueous ~olution of potas-~ium chloride reduced the ~-
bitterness associatsd with potassium chloride.
~XA~PLE 68.
Addition of 3.5% by weight (relative to ~he potassium
chloride) of 3-methoxyphenylacetic acid to a 2.25%
agueous solution of potassium chloride, reduced the
bitterness associated with potassium chloride.
EXAMPLE 69.
Addition of 0.65% by wei~ht (relative to the potassium
;~ chloride) of neodiosmin to a 2~ a~ueous solution of
potassium chloride reduced the bitterness associated
with potassium chlorîde.
EXAMPLE 70.
Health Valley Chicken Broth (unsalted, 200 mL) salted
with potassium chloride (0~8 gm), sodium chloride (0.2
gm) and sodium (+)-2-(4-m~thoxyph~noxy)propionate
(Q.03 gm) (a ~0/20/3 ratio), gave a well salted flavor
virtually free of any bitter.taste.
EXAMPLE 71.
Addition of 25 mg sodium 2,4-dihydro~ybenzoate to one
:~ can of C&C Diet Cola (354 mL) containing 126 mg sodium sacch~rin reduced the aftertaste associated with
sodium saccharin.
EX~MPLE 72.
Addition of 6.6% by weight (relative to the potassium
chloride) of sodium syringate to a 2% aqueous solution
of potassium chloride reduced the bitterness
associated with potassium chloride.
WO93/10677 ~ $~ 113 P~T/USg2/10~79
EX~MPLE 73.-
Additior. of 0.1 gram of guanosine to a 100 mL agueous
solution containing 0.1 gram of a~pirin signi~icantly
reduced the bitterness associated with the aspirin.
EXAMPLE 74.
Campbell's Chicken Broth ~unsalted, 100 mL) was salted
with potassium hloride (1.8 gm), sodium chloride (0.2
gm) and potassium 2,4-dihydroxybenzoate (0.01 $m) (a
ratio of 90/10/0.5), gave a good, salty tasting broth
essentially de~oid of bitterness.
EX~MPLE 75.
Addi~ion of 5% by weight (relative to the potassium ^~
chloride) of 3,4-dihydroxyphenylacetic acid sodium
salt to a 2~ aqueous solution of potasslum chloride
reduced the bitterness associated with potassium
chloride. ~
EXAMPLE 76. ~ -
~: The bitternes~ associated with potas~ium chloride was
reduced when a 2% aqueous solution of potassium :;
chloride was saturated with uric acid.
EXAMPLE 77.
: Addition of:3.7~ by weight ~relative to the potassium
chloride) of ~uanosine to a ~% aqueous solution of
~potassium chloride reduced the bitterness associated
~ ~ with potassium~chloride.
: ~: EXAMPLE 78.
The bitt2rness~associated with potassium chloride was
reduced when~a 2% aqueous solution of potassium
:~ chloride was saturated with uracil.
;~ EXAMPLE 79.
: The bitterness associated with potassium chloride was
~ reduced when a::2% aqueous solution of potassium
:~ chloride was saturated with d-biotin. :~:
EXAMPLE 80.
: The bitterness associated with potassium chloride was
reduced when a 2% agueous solution of potassium
~hloride was ~aturated with DL-dihydroorotic acid.
EXAMPLE 81~
A sample of 100 gm of unsalted refried beans salted
WO93~10677 C A 2 1 1 7 2 ~ 4 PCT/US92/10t79
114
with potassium chloride (0.98 gm), sodium chloride
(0.42 gm), potassium 2,4-dihydroxybenzoate (5~0 mg),
and disodium ethylenediaminetetraacetic acid (0.7
gram, 5 mL of a 14% solution, adjusted to pH 6.8) gave
~ clean, salty taste essentially devoid of bitterness.
EXAMPLE 82u ~
The bitter taste of a 2% aqueous solution of potassium - :
chloride was reduced by the addition of 20% by weight
(relati~ve to the potassium chloride) of L-threonine.
EXAMPLE 83.
The bitter taste of a 2% aqueous solution of potassium
chloride was nearly eliminated by the addition of 20%
by weight (relative to the potassium chloride~ of
~: sodium malate.
EXAMPLE 84.
Hains No Salt Vegetable Soup (100 gm) salted with
potassium chloride (0.9 gm), sodium chloride (0~1 gm)
~ and potassium 2,4-dihydroxybenzoate (0.005 gm) ~a
: ~: ratio of 90/10/.5), gave a salty, good tasting soup
basically devoid of bitterne~s.
EXA~PLE 85.
Hains No Salt Vegekable Soup (100 gm) salted with
potasæium chloride (0.9 gm), sodium chloride (0.1 ~m)
and sodium::2,4,6-trihydroxybenzoate (0~005 gm) (a
: ratio of 9~0/10/0.5), gave a salty, good tastin~ soup
practically~devoid of bitterness.
EXAMPLE 86.
Hains No Salt Vegetable Soup (100 gm) sal~ed with
potassium chloride (O.9 gm), so~ium chloride (0.1 gm),
~-aspartyl-L-phenyla}anine potassium salt (O.015 gm)
and potasæiu~ 2,4-dihydroxybenzoate (0.0025 gm) (a
ratio of 90/10/1.5/0.25~, gave a taste essentially
without bitterness. It was more salty than soup salted
with potassium chloride (0.9 gm), sodium chloride ~0.1
gm~ and L-aspartyl-L-phenylalanine potassium salt
(0.03 gm) (a ratio of 90/10/3t or potassi~m chloride
~: (O.9 gm~, sodium chloride tO.1 gm) and potassium 2,4
:~ dihydroxybenzoate (0.005 gm) (a ratio of 90/10/0.5).
wo93tl0677 C A 2 1 1 7 2 ~ 4 11~ PCT/US92/l0l7g
EXANP~E 87.
Charles brand unsalted potato chips (100 gm) salted -~
with potassium chloride (1.6 gm) and potassiu~ 2,4~
dihydro~ybenzoate tO.008 gm3 gave a good salty taste
that was essentially free of any bitt~r ~aste.
E~fPI;E 88. -
Charle~ brand unsalted potato chips (100 gm) ~alted
with potassium chloride (0.98 gm), ~odi~m chloride
(O.42 gm) and potassium 2,4-dihydroxybenzoate (0~005
gm) ~a ratio of 70/30/0.35~ gave a good salty taste
devoid of bitterne~s. These chips were essentially
indistinguishable from chips salted with sodium
chIoride.
EXAMPLE 89.
Charles brand unsalted potato chips (100 ~m) salted
with potassium :chloride (0.67 gm~, sodium chloride
~ 0.67 gm):and potassi~m 2,4-dihydroxybenzoate (0.0034
: gm) (a ratio of 50/50/0.25) gave a good salty taste as
if the ¢hips~were prepared with pure sodiu~ chloride.
EXAMPLE gO ~ ~
A sampl~:of unsalt~d r~fried beans (100 gm) salted
with pota~sium chloride (O.98 gm), sodium chlorîde
(0.42 gm) (a ratio of 70/30~ and sodium (~)-lactate
0.1 gm) gave;~a clean, salty tas~e l~ke that of sodium
chloride. ~:
~PLE ~ 9 1 .
A sample of;unsalted refrie~ beans (IOO gm) salted
; with potass~ium chloride (1.12 gm), sodium chloride
(0:.48 ~)~, potassium~2,4-dihydroxybenzoate (0.0056 gm~
~ ~ .
(a ratio of:70/39/0.35) and 0.3 gm ~odlum (+)-lactate
gave a tas~e eS~entially devoid of bitterness. It was
also ~ore~salty then: refried beans salted wi~h
potassium chloride (1.2 gm), sodium chloride (0.4 gm)
ta ratio of 70/30) and sodium (t)-lactate (0.~1 gm).
EXAMPLE 92.
A sample of~unsalted refried beans (100 gm) salted
with potassium chloride (1.2 gm~, sodium chloride (0.4
gm) (a ratio of 70~30) and sodium ~?-lactate (0.3 gm) :
gave a sodium chloride like taste. It was ~lso more ~`
W093/10677 ~A ~ 2 8~ 116 PCTIUS9~/10179
salty than refried beans salted with potassium
chloride (1.2 gm~, sodium chloride (0.4 gm) (a ratio
of 70/30) and sodium ~+)-lactate (0.1 gm).
~XAMPLE 93.
The bitter taste of a 1000 ppm solution (100 mL~ of
caffeine was s~ stantially reduced by the addition of
guanosine (20 mg)~ -
EXAMPLE 94.
The bitter taste of a 1000 ppm solution (100 mL~ of
c~affeine was almost completely eliminated by the
addition of inosine (20 mg).
E ~ PLE 95. :
An aqueous solution (100 mL~ containing potassium
chloride (2.0 g) and N-(L-aspartyl)-p-aminobenzoic
acid monopotassium salt (0.1 g) gave a salty taste
~ without the bitterness ~ormally associated with
;~ pot~ssium chloride.
~ EXAMPLE 96.
::: An aqueous 801ution (100 mL) containing potassium
chloride (2.0 g)~and N-(L-aspartyl)-p-aminobenzoic
acid monopotassIum salt (0.02 g) gave a salty taste,
with a substantially decrease of bitterness from
potassium chloride. ~ '.
:EXaMP~E ~7~
:A~solid preparation containing a mixture of potassium
chloride (1~.8 g), sodium chloride (0.2 g) and N-(L-
aspartyl)-p-aminobenzoic acid ~onopotassium salt (0.02
g) gave a clean salty sodium chloride-like taste.
EXAMPLE 98.~
:
A solid lyophilized from a aqueous solution containing
potassium chloride (1.8 g), sodium chloride (0.2 g)
and N-(L-aspartyl)-o-aminobenzoic acid monopotassium
salt (0.1 g~ gave a clean sodium chloride-like taste
with virtually none of the bitterness normally
associated with potassium chloride.
~ :
: :
,
WO93/10677 ~ PCT/U~92/10179
~ 117 j<~
EXAMpLE 99 ~ !
A solid obtained from a aqueous solution containing
potassium chloride (l.B g), sodium chloride (0.02 g)
and N~ aspartyl)~o-aminobenzoic acid monopota~sium
salt gaye a bitterness-free salty taste.
~AMPLE lOC.
When 5% by weight of potassium L-aspartyl-L-tyrosine
(relative to potassium chloride3 was added to a 2%
solution of potassium chloride the bitter taste of -
potassium chloride was completely eliminated.
EXAMPLE 101.
When 1% by weight of potassium L-aspartyl-L-tyrosine
(relative to potassium chloride) was added to a 2%
solution of pctassium chloride the bitter taste of
potassium chloride was virtually eliminated.
EXAMPLE 102.
Addition of 0.5% by weight of potassium N-(p- ~
cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine ;
(relative to potassium chloride~ to a 2% of potassium
chloride olution~ave a salty taste with free of the
bitter taste.
EXAMPLE 103.
Addition of 0.1% by w~ight of potassium N-(p-
cyanophenyl-carbamoyl)-L-aspartyl-L-phenylalanine
(relative to;pota~sium chloride) to an aqueous
solution of 2~%~potassium chloride substantially
eliminated~the bitter taste of potas~ium chloride.
EXAMPLE 104.
: ~:
When 0.5% by wei:ght of potassium N-(p-nitroph~nyl-
carbamo~ L-aspartyl-L-phenylalanine (relative to
~ potassium chloride) was added to a 2~ potassium
- ~ chloride solution, the bitter taste of potassium
chloride ~as virtually eliminated.
E~AMPLE 105.
When 0.1% by weight of potassium N-~p-nitrophenyl-
~ carbamoyl)-L-aspartyl-L-phenylalanine ~relative to
- potassium chloride) was added to a 2~ solution of
potassium chloride, no bitterness was essentially
detected .
W093/10677 `~ A 2 1 ;1 7 2 ~ 4 118 PCT/US92/10179
EXAMPLE 106.
An aqueous solution (100 mL) containing potassium
ahloride (2.0 g) and potas~ium L-~-a~partyl-L-
phenylalanine (0.1 g) gave a salty taste with no
bitter taste associated with potassium chloride.
EXAMPTE 107.
An aqueous solution (100 mL) containing pota~sium
chloride (2.0 g) and potassium L-~-aspartyl-L-
phenylalanine (0.02 g) gave a salty taste with a
substantial reduction of bitter taste.
EXAMPLE 108.
Addition of potassium (-)-2-(4-methoxyphenoxy)
propiona~e (500 mg, 10 times relative to caffeine) to
a 0.05% of caffeine (100 mL) completely eliminated the
bitter taste, with a lingering sweet after taste only.
EXAMPLE 109.
Addition of potassium (-)-2-(4-methoxyphenoxy)
~:~ propionate (250 mg, 5 times re~ative to caffeine) to a
: ~ 0.05% of caffeine (100 mL) significantly reduced the
bitter taste of~caffeine with a~sweet after taste.
EXAMPLE 110.
:~ A solid lyophilized from a solution containing
potassium chloride (1.8 g), sodium chloride (0.2 g)
: and;potassium N-(p-cyanophenyl~carbamoyl)-L-aspartyl- :
L-phenylalanine ;~0.010 g) gave a sodium chloride-like
taste with vi ~ ually none of the:bitterness normally
; associated~with potassium chloride.
EXAMPLE 111.
A strong bitter~taste was completely eliminated when
potassium N-(p-oyanophenyl-carbamoyl)-~-aspartyl-L-
phenylalanine (500 mg, 10 ~ime relative to caffeine) ~:
:: wa~ added to a 0.05% solution of caffeine tlO0 mL).
: ~,
EX~MPLE 112.
: A strong bitter taste was nearly eliminated when
potassium N-(p-cyanophenyl-carbamoyl)-L-aspartyl-L-
phenylalanine 1250 mg, 5 times relative to caffeine)
~: was added to a 0.05% caffeine solution (100 mL).
W093/10677 CA 2 1 ~ 7284 PCT/US92/10179
119 ,~
EXAMPLE 113.
An aqueous solution (100 mL) containing caffeine (50
mg) and potassium N-(p-nitr~phenyl-carbamoyl)-L-
aspartyl-L-phenylalanine (500 mg) was slightly sweet
and completely devoid of the bitter taste.
EXAMPLE 114.
An aqueouæ solution (100 mL) containing caffeine (S0
mg) and potassium N-(p-nitrophenyl-carbamoyl)-L-
aspartyl-L-phenylalanine ~250 mg) gave almost no
bitter taste with a slightly sweet taste.
EXAMPLE llS.
When 1% by weight of potassium 2,4,6-
trihydroxybenzoaèe (relative to potassium chloride)
was added to a 2% solution of potassium chloride the
bitterness of potassium chloride was completed -
eliminated. - --
EXAMPLE 116.
When 0.5%~by~weight of potassium 2,4,6-
trihydroxybènzoate (relative to potassium chloride)
was added to a 2% solution of potassium chloride a
salty taste;~was~obtained with no bitterness associated
with potassium chl~oride.
EXAMP~E~ 117.~
When~0.25S~by weight of;potassium 2,4,6-
trihydro ~ enzoate (relative to potassium chloride)
;was~:added~a~potas~sium chloride solution (2%), a salty
and~free~of~bitterness taste were given.
EXAMPLE 118.~
A solid lyophilized from a aqueous solution of
potassium chloride (1.6 g), sodium chloride (0.4 g)
and potassium 2,4,6-trihydroxybenzoate (0.01 g) gave a
sodium chloride-like taste with none of the bitterness
associated~with~potassium chloride.
EXAMPLE 119.~ ~
A solid lyophilized from a solution containing
potassium chloride (1.6 g), sodium chloride (0.4 g~
and potassium;~2,4,6-t~ihydroxybenzoate (0.005 g) gave
a salty taste~virtually free of bitter taste
associated~with potassium chloride.
:: :
WO93/10677 C A 2 1 1 7 2 8 4 PCT/US92~10179
! 120
- EXAMPLE 120.
When 5% by weight of potassium taurine (relative ~o
potassium chloride) wa~ added to a 2% solution of
potassium chloride the bitter taste of potassium
chloride was completely eliminated.
EXAMPLE 121.
The sweetness of a 4% solution of sugar (100 mL~ was
significantly reduced by th addition of N-(L-
aspartyl)-o-aminobenzoic acid monopota~sium salt ~40
mg)-
r ~AMpLE 12 :2 .
The sweetness was completely eliminated when N-(L-
aspartyl~-o-aminobenzoic acid monopotassium salt (200
mg) was added to or 4% solution of sugar (100 mL~. .
EXAMPLE 12_.
The sweetness of a 4% solution of sugar (100 mL) was
reduced to the sweetness of a 2% solution of sugar by .~.
addition o~ L-aspartyl-L-phenylalanine monopotassium ,
salt (1.2 g, 30% relative to sugar). i-
: : :
EXAMPLE 124.
The sweetnesc; of~a 0.04% solution of Aspartame~ (100
mL) was slig~-ly~reduced and the lingeri~g taste of
Aspartamee eliminated ~ addition of L-asparts~-l-L-
pheny.?.alanine monopot~ssium salt (400 mg, 10 times
relatSve to Aspartame ).
EXAMPLE 125.
An aqueous solution (75 mL) containing glycerol (12
grams) and taurine~(0.37 grams):wherein the burning
a`ftertaste of:the glycerol is substantially decreased
or eliminated.
EXA~PLE 126.
An aqueous solution (?5 mL) adjusted to a pH=6
containing glycero} (12 grams~ and L-aspartyl-L
phenylalanine ~0.62 grams) wherein the burning
aftertaste of the glycerol is substantially decreased
or eliminated and the mixture tasted somewhat sweeter.
WO93/10677 -CA~ 8~ PCT/US92/10179
121
EXAMPLE 127.
An aqueous solution (75 mL) containing glycerol (12
grams) and potassium 2,4-dihydroxybenzoate (0.12
grams) wherein the burning aftertaste of the glycerol
is decreased.
EXAMPLE 128.
An aqueous solution (75 mL) containing glycerol (12 ;
grams) and ~-alanine (0.60 grams) wherein the burning
aftertaste of the glycerol is decreased.
EXAMPLE 129.
The aftertaste~of L-aspartyl-L-phenylalanine methyl
~; ester (Aspartame ) used to sweetened a Diet Coke (354
mL can) was substantially eliminated by the addition
of 7.5 mg of L-aspar yl-L-phenylalanine.
EXAMPLE 130.
- The aftertaste of the L-aspartyl-L-phenylalanine
methyl ester ~Aspartame) used to sweetened a Diet
Pepsi (354~mL~c~an) was substantially eliminated by
the addition of 7.5 mg of L-aspartyl-L-phenylalanine.
EXAMPLE 131. ; ~ ~
~: The aftertaste~of the saccharin used to ~weeten C&C
Diet Cola ~(354~mL can) was substantially eliminated
by the addition of~10 mg;of taurine.
EXANPLE 132.
When 5% by weight of ~-a}anine (relative to potassium
chloride)~was added to a 2% solution of potassium
chloride the~bitter taste of potassium chloride was
completely~el~iminated.
EXAMPLE 133. ~
An aqueous~solution (100 mL) containing potassium
chloride~(2.0 g) and N-(L-aspartyl)-a-amino-
cycIopentanecarboxylic acid mono-potassium salt (0.1
g) eliminated~almost all of the bitterness associated
with potassium chloride.
W093/10677 C A 2 1 1 7 2 8 ~ PCT/USg2/10179
122
EXAMPLE 134.
A solid lyophilized from an a~ueous solution
containing potassium ch~oride (1.8 g), sodium chloride
(O.2 g)L~nd N-(L-aspartyl)-~-amino-
cyclopentanecarboxylic acid mono-potassium salt (0.1
g) gave a salty sodium chloride-like taste which was
. free of bitterness associated with potassium chloride.
EXAMPLE 135.
A solid lyophilized from a solution containing
potassium chloride (1.8 g), sodium chloride (0.2 g)
and N-(L-aspartyl)-a-amino-cyclopentanecarboxylic acid
mono-potassium ~alt (0.02 g) ~ave a clean salty tast~,
virtually free of the bitterness from potassium
chloride.
EX~MPLE 136.
A solid lyophilized from a solution containing
potassium chloride (1.8 g), sodium chloride (0.2 g)
and N-(L-aspartyl)-~-amino-cyclooctanecarboxylic acid
mono-potassium ~alt ~0~1 g) gave a ~alty taste. The
bitter ta te of potassium chloride was essentially ~:
~:~ eliminated.
EXAMPLE 137.
Addition of 5% ~y~weight of ~-alanine (relative to
potassium:chloride) to a 2% solution of potassium
~: ~ chloride eliminated the bitter taste of potassium
~;: : chloride.
: E ~ PLE 138.
A powder ;.yophilized from an aqueous mixt~re of
~ ,
: potassium:chloride ~1.8 g), sodium chloride ~0.2 g)
and ~-alanine :(;0,1 g) gave a clean sodium chloride-
: like taste~.
EXAMPLE 139.
A powder lyophilized from a mix~ure of potassium
chloride ~1.8:g), sodium chloride (0.2 g) an~
alanine (0.02 g) gave a salty taste without the
bitterness normally associated with potassium
chloride.
EX~PLE 140.
When 5% by weight of potassium N-~phenylcarbamoyl~-L-
WO93/10677 CA 21 1 7 2~4 PCT/US92/10179
123 ~.
aspartyl-L-phenylalanine (relative to potassium
chloride) was added to a 2% solution of pota sium
chloride, t~e bitterness associated with potassium
chloride wa~ eliminated.
EXAMPLE 141.
An aqueous ~olution (100 mL~ containing L-ornithine-
~alanine dihydrochloride (0.1 g) and potassium chloride
g2.0 g~ at pH 6.1 gave a salty taste without ~.
bitterness.
EXAMPLE 142.
A powder lyophilized from an aqueous solution
containi~ po~assium chloride (1.8 g), sodium chloride
(0.2 g) and L-ornithine-~-alanine dihydrochloride at :
pH 6.1 gave a salty taste with free of bitterness.
EXAMPLE 143. .
A powder lyophilized from an aqueous solution -~
containing potassium chloride (1.8 g), sodium chloride ':
(0.2 g) and L-ornithine-~-alanine dihydrochloride :~
(0.02 g) at;pH 6.1 ~irtually elimi~ated the bitterness -~
associated~with potassium chlorid~ and gave a salty .
~ taste.
; EXAMPLE 144. ;~
Addition of 1~ by weight of ~-aminoethyl phosphonic
acvid (relative to potassium chloride) to a 2%
: potassium ~hloride solution gave a salty taste free of -~
the bitter taste~a sociated with potassium chloride.
EXAMPLE 14~.
Addition of 5S by weight of ~-aminoethyl phosphonic
:~ acid ~relative to potassi~m chloride) to a 2~ solution
of potassium chloride gave a sa~ty taste free o~ the
bitter taste~ associated with potassium chloride.
EXAMPLE 146.
A solid lyophilized from the mixture of potassium
chloride (1.8 g), sodium chloride (0.2 g) and ~-
aminoethyl phosphonic acid (0.02 g) gave a clean salty
taste without the bitter taste associated with
potassium chloride.
EXAMPLE 147. -~
A solid made f~om a solution of potassium chloride
W093/10677 C A 2 1 1 7 2 8 4 PCTtVS92/10179
124
~1.8 g), sodium chloride (0.2 g) and ~-aminoethyl
phosphonic acid (O.l g) was completely free of the
bitterness from potassium chloride.
~XA~PLE 148.
The bitterness associated with potassium chlorid~ was
complet~ly eliminated when 2-amino tere-phthalic acid
potassium ~alt (O.02 g, 1% relative to the potassium
~hloride) was added to a 2% solution of potassium
chloride ~lO0 mL).
EXAMPLE 149. ~ ;-
The bitterness associated with potassium chloride was
completely eliminated when 2-amino tere-phthalic acid
potass~um salt (~0.1 g, 5% relative to the potassium :~
chloride) was:added to a 2% solution of potassium
chloride (lO0 mL). ~.
EXAMPLE l50.
~;~ When taurine (0.05 g, 50% relative to Acesulfame X)
was added to a 0.l% solution of Acesulfame K (lO0 mL)
:: the aftertaste~associated with Aeesulfame K was L
substantially decreased.
: EXAMPLE lSl.
j::
~ When taurine~(O.lO g) was added to an aqueous solution
; j
: containing~Acesulfame K ~O.lO g), the sweetness was
decreased and ~the aftertaste was completely
: eliminated.
~: :
: EXAMPLE 152. :~ ~
: Addition~of ~-alanine (O.Ol g, 10% relative to
: Acesulfame K:) :i~ a 0.1% solution of Acesulfame K (lO0
mL) fully eliminated:the off-taste associated with
AcesuIfa~e:K and gave a clean sweet taste.
,
EXP~lPLE }53.
Addition of ~-alanine ~0.05 g, 50% relative to
Acesu1fame K):in a 0.1% solution of Acesulfame K fully
:
~; eliminated the aftertaste of Acesulfame K and
decreased the sweet potency by about 70%.
~:
WO93/10677 C A 2 1 1 7 2 8 4 PCT/US92/10179
; 125
EXAMPLE 15~.
When ~-alanine (0.025 g) was added to a can of Shasta
diet cola (354 mL), the off-taste asso~iated with
sodium ~accharin a~d/or Aspartame was ~ubstantially
decreased.
EX~MPLE 155.
When ~-alanine (O.02 g) was added to a can of VONS
sugar-free cola (355 mL) containing sodium saccharin
(C,107 g),: the aftertaste associated with saccharin
wa- cmpletely eliminated.
EXANPLE 156~
Ad~ ion of ~-alanine (0O02 g) to a can of aiet Pepsi
(355 mL) reduced significantly the aftertaste
: associated with Aspar;~me.
: EXAMPLE 157~ ;
Addition of 50% by weight of potassium L-aspartyl-L-
~: phenylalanine (relative t ~cesulfame K) to a 0.1%
solution of Acesulfame K r uced both the sweetness
and aftertaste associated with Acesulfame K.
E~AMP~E 158.
`~ When 5% by weight of L-aspartyl-L-aspartic acid was
added ~relative~to KCl) to a 2% solution of KCl
adjusted to a p~=6, the bitterness of the KCl was
virtually eliminated.
~:
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: ~ .
