Aspartyl dipeptide ester derivatives and sweeteners

Details Aspartyl dipeptide ester derivatives and sweeteners Aspartyl dipeptide ester derivatives and sweeteners

2000-12-15

2003-10-07

Wong, Leslie (Department: 1761)

Food or edible material: processes, compositions, and products

Products per se, or processes of preparing or treating...

Noncarbohydrate sweetener or composition containing same

C558S411000, C562S433000

Reexamination Certificate

active

06630191

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel aspartyl dipeptide ester derivatives, and sweeteners and products such as foods which contain the same as an active ingredient.
2. Description of the Related Art
In recent years, as eating habits and products eaten have changed, fatness caused by excessive intake of sugar and diseases caused by fatness have been of significant concern. Accordingly, the development of a low-calory sweetener that replaces sugar has been in demand. A sweetener that has been widely used is aspartame which is excellent in regarding both safety and taste properties. However, there are some problems of the aspartame with regard to its stability. WO 94/11391 states that derivatives in which an alkyl group is introduced on the amino group of aspartic acid constituting aspartame markedly improves sweetening potency and also results in a slight improvement in the stability of the compound. The best compound described in this document is N-[N-(3,3-dimethylbutyl)-L-&agr;--aspartyl]-L-phenylalanine 1-methyl ester having a 3,3-dimethylbutyl group as an alkyl group which has a sweetening potency 10,000 times that of sugar.
Aspartame derivatives having 20 different substituents other than the 3,3-dimethylbutyl group are also disclosed where the derivatives have sweetening potencies less than 2,500 times that of sugar. Derivatives having a 3-(substituted phenyl)propyl group as an alkyl group are also shown. However, it is reported that the sweetening potency of N-[N-(3-phenylpropyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is 1,500 times that of sugar and that of N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester is 2,500 times that of sugar. These sweetening potencies are far less than that of N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl)-L-phenylalanine 1-methyl ester, 10,000 times. Furthermore, N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyll-L-tyrosine 1-methyl ester is stated therein as an example of the derivatives in which L-phenylalanine methyl ester is replaced by the other amino acid ester, and it is reported that its sweetening potency is 4,000 times that of sugar.
Under these circumstances, development of a low-calory sweetener having fine sweetening potency is in demand.
A problem to be solved by the present invention is to provide novel aspartyl dipeptide ester derivatives which are excellent in the safety and which have sweetening potency equal to or higher than that of the N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester, a low-calory sweetener containing the same as an active ingredient and products, such as foods, containing the sweetener.
SUMMARY OF THE MENTION
In order to solve the problem, the present inventors have synthesized several aspartame derivatives in which various 3-(substituted phenyl) propyl group are introduced onto a nitrogen atom of aspartic acid constituting the aspartame derivatives, wherein a moiety of L-Phenylalanine methyl ester in the aspartame is replaced by another amino acid ester, through reductive alkylation by use of cinnamaldehydes having various substituent and which are readily available, or 3-phenylpropionaldehyde having various substituent that can easily derived therefrom as precursor aldehyde, and have examined the sweetening potency of them. The Inventors have discovered that with respect to the sweetening potency, the novel compounds have a far higher sweetening potency than N-[N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-tyrosine 1-methyl ester which is reported to have the sweetening potency of 4,000 times that of sugar in WO 94/11391 and N-(N-(3,3-dimethylbutyl)-L-&agr;-aspartyl]-L-phenylalanine 1-methyl ester which is reported therein to have the potency of 10,000 times that of sugar. Particularly, the compounds represented by the following formula (1) are excellent as sweeteners. These findings have led to the completion of the present invention.
The present invention is directed to novel aspartyl dipeptide ester derivatives (including the salts thereof) represented by the following formula (1):
wherein;
R
1
, R
2
, R
3
, R
4
and R
5
, independently from each other, each represents a substituent selected from a hydrogen atom (H), a hydroxyl group (OH), an alkoxy group having from 1 to 3 carbon atoms (OCH
3
,OCH
2
CH
3
, OCH
2
CH
2
CH
3
, etc.), an alkyl group having from 1 to 3 carbon atoms (CH
3
, CH
2
CH
3
, CH
2
CH
2
CH
3
, etc.) and a hydroxyalkyloxy group having 2 or 3 carbon atoms (O(CH
2
)
2
OH, OCH
2
CH(OH)CH
3
, etc.), or R
1
and R
2
, or R
2
and R
3
together form a methylenedioxy group (OCH
2
O) wherein R
4
, R
5
, and R
1
or R
3
which does not form the methylenedioxy group, independently from each other, each represents any substituent as mentioned above designated for the R
1
, R
3
, R
4
and R
5
, respectively; R
6
represents a substituent selected from a hydrogen atom, a benzyl group (CH
2
C
6
H
5
), a p-hydroxybenzyl group (CH
2
C
6
H
4
-p-OH), a cyclohexylmethyl group (CH
2
C
6
H
11
), a phenyl group (C
6
H
5
), a cyclohexyl group (C
6
H
11
), a phenylethyl group (CH
2
CH
2
C
6
H
5
) and a cyclohexylethyl group (CH
2
CH
2
C
6
H
11
); R
7
represents a substituent selected from a hydrogen atom, a methyl group (CH
3
), an ethyl group (CH
2
CH
3
), and an isopropyl group (CH(CH
3
)
2
); R
8
represents a substituent selected from a methyl group, an ethyl group, an isopropyl group, a n-propyl group (CH
2
CH
2
CH
3
) and a t-butyl group (C(CH
3
)
3
);
provided the derivatives in which R
6
represents a benzyl group and R
7
represents a hydrogen atom at the same time, and the derivatives in which R
8
represents a p-hydroxybenzyl group and R
7
represents a hydrogen atom at the same time are excluded.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The novel aspartyl dipeptide ester derivatives of the present invention include the compounds represented by the above formula (1) and the salts thereof.
Preferred in the novel aspartyl dipeptide ester derivatives is the L-isomer of aspartic acid, whereas other amino acids may be L- or D-isomer forms.
In the compounds described above of the present invention, the following inventions are included as the embodiments for the preferable compounds:
(A) The compounds of formula (1) wherein R
7
is a substituent selected from a methyl group, an ethyl group and an isopropyl group; R
1
, R
2
, R
3
, R
4
and R
5
, independently from each other, each is a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms (for example, O(CH)
2
OH, OCH
2
CH (OH)CH
3
, etc.), or R
1
and R
2
, or R
2
and R
3
together form a methylenedioxy group (OCH
2
O) wherein R
4
, R
5
and, R
1
or R
3
which does not form the methylenedioxy group, independently from each other, each is a substituent selected from any substituent as mentioned above designated or exemplified for the R
1
, R
3
, R
4
and R
5
; R
6
is a substituent selected from a hydrogen atom, a benzyl group, p-hydroxybenzyl group, a cyclohexylmethyl group, a phenyl group, a cyclohexyl group, a phenylethyl group and a cyclohexylethyl group; R
8
is a substituent selected from a methyl group, an ethyl group, an isopropyl group, a n-propyl group and a t-butyl group.
(B) The compounds of formula (1) wherein R
6
is a substituent selected from a hydrogen atom, a cyclohexylmethyl group, a phenyl group, a cyclohexyl group, a phenylethyl group and a cyclohexylethyl group; R
1
, R
2
, R
3
, R
4
and R
5
, independently from each other, each is a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms (for example, O(CH
2
)
2
OH, OCH
2
CH(OH)CH
3
, etc.), or R
1
and R
2
, or R
2
and R
3
together form a methylenedioxy group (O

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