Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-04-01
2003-11-18
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C544S322000, C558S413000, C560S038000
Reexamination Certificate
active
06649784
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of PCT/JP00/06627, filed Sep. 26, 2000. This application is also related to and claims priority to JP 11/281920, filed Oct. 1, 1999.
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to novel aspartyl dipeptide ester derivatives that are safe, have a taste similar to that of sugar and a high degree of sweetness, for instance, to compounds which are at least 10,000-times sweeter than sugar. The invention also encompasses sweeteners comprising these aspartyl dipeptide ester derivatives, as well as products, such as foods and drinks, containing such sweeteners. Methods for making and using the sweeteners of the present invention are also described.
2. Description of the Related Art
In recent years, the development of low-calorie sweeteners has been demanded due to changes in eating habits, such as increased fatness caused by excessive intake of sugar, as well as due to the prevalence of various diseases associated with fatness.
Aspartame is a sweetener that is presently widely used and is excellent in terms of safety and for its sweetening qualities. However, the stability of aspartame is problematic.
Slight improvements in stability as well as improvements in sweetening potency have been reported for aspartame derivatives obtained by introducing an alkyl group into a nitrogen atom of aspartic acid in aspartame, see Kokai Publication of the International Patent WO 94/11391. Most excellent among compounds described in this Publication is N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester having a 3,3-dimethylbutyl group as an alkyl group, and the sweetening potency (degree of sweetness) is 10,000 times that of sucrose (compared with 2, 5 and 10% sucrose solutions).
Other aspartame derivatives having introduced therein 20 types of substituents other than the 3,3-dimethylbutyl group are also described. However, the sweetening potencies (degrees of sweetness) of all these derivatives has been reported to be not more than 2,500 times.
Derivatives having a 3-(substituted phenyl)propyl group as an alkyl group are also described. With respect to derivatives having a relatively high sweetening potency among them, it is reported that a sweetening potency of N-[N-(3-phenylpropyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is 1,500 times and a sweetening potency of N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is 2,500 times. However, the sweetening potencies of these derivatives do not reach the potency (10,000 times that of sugar) of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
Further, it is reported that the sweetening potency of N-[N-[(RS)-3-phenylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester having a substituent of a structure that a methyl group is further introduced in the 3-position of a 3-phenylpropyl group, namely a 3-phenylbutyl group as an alkyl group is only 1,200 times. Thus, by introducing the methyl group in the 3-position, the sweetening potency is decreased in comparison with N-[N-(3-phenylpropyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester.
Thus, the development of sweeteners that solve the aforementioned problems and which are safe, taste like sugar, have greater stability, and/or have a much higher sweetening potency has been in demand.
BRIEF SUMMARY OF THE INVENTION
The present invention solves the problems of prior art sweeteners mentioned above, such as low sweetening potency, by providing a novel aspartyl dipeptide ester derivative excellent in safety, having a sweet taste similar to sugar and a sweetening potency which is equal to or higher than that of the N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl-L-phenylalanine 1-methyl ester described above. The invention also encompasses sweeteners, such as low-calorie sweeteners, and foods and drinks containing these more potent sweeteners.
DETAILED DESCRIPTION OF THE INVENTION
To solve the foregoing problems, the present inventors have synthesized various compounds in which various 3-(substituted phenyl)propyl groups, for example, a 3,3-dialkyl-3-(substituted phenyl)propyl group, are introduced into nitrogen of aspartic acid constituting aspartame by a reductive alkylation reaction using 3-phenylpropionaldehyde derivatives or cinnamaldehyde derivatives (including derivatives having an alkyl substituent in a main chain) having various substituents, especially two or more hydroxyl groups in a phenyl group, and have examined a sweetening potency thereof.
As a result, compounds have been discovered that have a sweetening potency which is by far higher than that of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, which has been reported to have a sweetening potency of 10,000 times in the foregoing Kokai Publication of the International Patent WO 94/11391, not to mention N-[N-[(RS)-3-phenylbutyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester reported therein to have a sweetening potency of 1,200 times, N-[N-3-(3-methoxy-4-hydroxyphenyl)propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester reported therein to have a sweetening potency of 2,500 times, and the like.
In particular it has been found that compounds represented by the following general formula (1) are especially excellent as sweeteners and the present invention has been completed on the basis of this finding. That is, the present invention lies in aspartyl dipeptide ester derivatives represented by the following general formula (1) (including those in the form of salts), sweeteners and products, such as foods and drinks, and the like comprising the same, and in a method for imparting sweetness to various products.
Formula (1)
wherein R
1
, R
2
, R
3
, R
4
and R
5
independently from each other, represent a hydrogen atom (H) or a hydroxyl group (OH), at least any two selected from R
1
, R
2
, R
3
, R
4
and R
5
are hydroxyl groups, and R
6
and R
7
, independently from each other, represent a hydrogen atom (H) or an alkyl group having 1 to 3 carbon atoms (CH
3
, CH
2
CH
3
, CH(CH
3
)
2
or the like).
When R
6
and R
7
represent different substituents, a steric configuration of a carbon atom to which these substituents are bound is not particularly limited, and it may be any of (R), (S) and (RS), or a mixed form of these plural forms. Incidentally, in the general formula (1) described above, the binding site (linkage) between R
6
or R
7
and the carbon atom is indicated by a wavy line, meaning that there are no limitations on the direction of linkage.
MODE FOR CARRYING OUT THE INVENTION
The compounds represented by the general formula (1) described above and those in the form of salts are both included in the novel aspartyl dipeptide ester derivatives of the present invention.
When they are incorporated in sweeteners and the like, it is advisable that at least one compound or at least one compound in the form of a salt is incorporated. Accordingly, one of the compounds or a mixture of more than one thereof, one of the salts of the compounds or a mixture of more than one thereof, a mixture of the compound(s) and the salt(s) of the compound(s), and the like can all be incorporated in sweetener(s), foods and drinks and the like of the present invention.
Amino acids (aspartic acid and phenylalanine) constituting the derivatives described above are both preferably L-isomers because they are present in nature.
With respect to the preferable forms of the compounds, the following inventions are included in the compounds of the present invention.
[1] Compounds represented by the general formula (1) described above.
In the general formula (1), R
1
, R
2
, R
3
, R
4
and R
5
, independently from each other, represent a hydrogen atom (H) or a hydroxyl group (OH), and at least any two selected from R
1
, R
2
, R
3
, R
4
and R
5
are hydroxyl groups, and
R
6
and R
7
, independently from ea
Amino Yusuke
Nakamura Ryoichiro
Takemoto Tadashi
Yuzawa Kazuko
Ajinomoto Co. Inc.
Reyes Hector M.
Rotman Alan L.
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