JP2517009B2 - Lysine derivative and sweetener containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a lysine derivative and a salt thereof and a sweetener containing the same as an active ingredient.

[Prior Art] In recent years, obesity due to excessive intake of sugar and various diseases associated therewith have become problems, and development of low-calorie or non-caloric sweeteners to replace sugar has been desired. Currently, saccharin, stevia, aspartame, etc. are used to meet these demands, but saccharin is considered to be a safety issue such as carcinogenicity when continuously ingested, and saccharine, etc. Currently, many natural sweeteners leave problems in terms of quality, sugar technology, price, and the like. Aspartame is said to be quite similar to sugar in terms of taste quality, but also bitterness is mixed in the aftertaste, and further development of high-quality sweeteners is desired. Although the safety of aspartame has been confirmed, the C-terminal methyl ester contained in aspartame may be decomposed in the body and accumulated as methanol.

The mechanism of sweetness of aspartame is the H.S.C. proposed by Shallenberger et al.
Explained by the Bee (AH, B) system (Shallenberger and Acree, Nature (London) 216, 480
Page (1967)), and then synthetic research on many aspartames revealed the necessity of a hydrophobic group (X) in addition to an amino group (AH) and a carboxyl group (B). It was concluded that the sweetness is expressed by the three-dimensional positional relationship of (Fujimaki et al., Chemical & Pharmaceutical Bulletin (Chem.Pharm.Bul.
l.) 24, page 2112 (1976)).

On the other hand, Ariyoshi is also examining the involvement of methyl esters. As a result, we conclude that the methyl ester corresponds to the hydrophobic group (X) and is essential for enhancing sweetness (Ariyoshi Wai).
Y.), Agricultural and Biological
Chemistry (Agric. Biol. Chem.) 40, 983 (197
See 6)).

[Problems to be Solved by the Invention] An object of the present invention is to provide a novel lysine derivative and a salt thereof, which have a refreshing sweetness and do not have a methyl ester which may accumulate methanol in the body, and It is intended to provide a low-calorie sweetener containing these as active ingredients.

[Means for Solving Problems] The inventors of the present invention considered that three components AH, B, and X are three-dimensionally arranged in a certain specific positional relationship to develop sweetness,
As a result of synthesizing a large number of lysine derivatives having salts AH, B, and X and having no methyl ester and salts thereof, and conducting intensive studies on their taste behavior, a lysine derivative having a good sweetness without bitterness was obtained. The invention was completed based on the findings and the findings. That is, the present invention has the general formula (I): (In the formula, R is a phenylacetyl group, phenylpropionyl group, benzoyl group, L-phenylalanine residue, D-
Phenylalanine residue, general formula (II): (Wherein R ¹ represents a benzoyl group, a phenylacetyl group or a phenylpropionyl group, and R ² represents a methyl group, an ethyl group or a hydroxymethyl group),
Or general formula (III): (In the formula, m represents 1 or 2, and n represents 1, 2 or 3) and a salt thereof and a sweetener containing the same as an active ingredient.

[Examples] The lysine derivative of the present invention is synthesized according to a general peptide synthesis method. For example, lysine having the N ^α nitrogen atom protected by a protecting group such as a benzyloxycarbonyl group can be used in the formula (I). The amino acid residue, acyl group or acylamino acid derivative residue corresponding to R of is subjected to the active ester method in a solvent such as tetrahydrofuran (hereinafter referred to as THF), N, N-dimethylformamide (hereinafter referred to as DMF) or chloroform. The compound of the present invention or a salt thereof can be obtained by introducing the compound by condensation used and then removing the protecting group by catalytic reduction or the like. The protecting group, the condensation method, and the method for removing the protecting group used at this time are not limited to the above methods, and other known methods may be used.

The compound of the present invention can be obtained in a free or salt form, and these can be easily converted into a salt and a salt can be converted into a free salt by a known method such as passing an ion exchange resin in a suitable solvent. can do. For example, by treating with a solvent such as methanol-hydrochloric acid, the free one can be converted into a hydrochloride or the like.

The lysine derivative of the present invention and its salt can be isolated and purified by a conventional method, and the object can be achieved by recrystallization, reprecipitation, chromatography or the like using an appropriate solvent.

Examples of the salt of the lysine derivative of the present invention include, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, acetic acid, formic acid, propionic acid, sulfamic acid, ascorbic acid, cinnamic acid, Shu plan, citric acid, tartaric acid, Salts with organic acids such as lactic acid, malic acid, malonic acid, maleic acid, succinic acid, as well as alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and amines such as monoethanolamine. I can give you some salt.

When the lysine derivative of the present invention or a salt thereof is used as a sweetener, it may be used alone or in combination of two or more kinds, or may be used in combination with other sweeteners.

Other sweeteners include dultin, saccharin, aspartame, glycyrrhizin, stevioside, neohesperidin dihydrochalcone, monerin and the like. Further, as a method of preparation, for example, by mixing stevioside as the sweetener in a ratio of 2: 1 and using it, a mellow sweetness that does not feel bitterness lasts, and the like, and adjust according to each characteristic and usage. You can In addition, it is possible to improve solubility and stability by including the obtained sweetener in cyclodextrin.

The lysine derivative of the present invention is a lysine ε-amino group (A
H), the carboxyl group (B) and the hydrophobic group (X) contained in R are α of aspartic acid in aspartame.
-Amino group (AH), γ-carboxyl group (B) and Ph
Sweetness develops when there is a steric relationship similar to the spatial arrangement of the hydrophobic group (X) contained in e.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples. The abbreviations used in the examples are as follows.

Bz-: benzoyl group Z-: benzyloxycarbonyl group DCC: dicyclohexylcarbodiimide DCUrea: dicyclohexylurea TLC: thin layer chromatography Rf ₁ : n-butanol: acetic acid: pyridine: water = 4: 1: 1: 2 (volume ratio) Rf value with developing solvent Rf ₂ : Chloroform: Methanol = 5: 1 (volume ratio) Rf value with developing solvent HONSu: N-hydroxysuccinimide-ONSu: N-hydroxysuccinimide ester group DMF: N, N-dimethylformamide Ph-ac -: Phenylacetyl group Ph-pr-: Phenylpropionyl group Phe: Phenylalanine Ala: Alanine Lys: Lysine Gly: Glycine α-Abu: α-Aminobutyric acid Ser: Serine Example 1 Synthesis of Bz-Lys (1) Lys (Z ) Lys.HCl 11 g (60 mmol) was dissolved in hot water 150 ml, and CuCO ₃
· Cu and _{(OH) 2 · H 2 O12g} (50mmol) was added, after boiling for 10 minutes, which was filtered and allowed to cool the filtrate. Then, the filtrate was ice-cooled with NaHCO ₃ 10.1 g (120 mmol) and Z-Cl 12 ml.
(75 mmol) was added in several portions with stirring. 3-4
Lys (Z) ・ 1 / 2Cu which precipitates after stirring under ice cooling for 1 hour
Was collected by filtration, washed with cold water, ethanol, acetone and ether, suspended in 250 ml of water, added with 400 ml of 6NUHCl, and added with H ₂
I passed S for 2 hours. Except CuS in high flow super cell,
After washing with 1N HCl and passing air through, the solution was filtered,
The filtrate was adjusted to pH 6.5 with aqueous ammonia under ice cooling. Crystals were precipitated in a refrigerator, washed with water, ethanol and ether, and dried to obtain Lys (Z) crystals.

Lys (Z) yield (yield), melting point, TLC obtained below
₂ shows Rf ₁ and Rf ₂ and elemental analysis values by.

Yield (Yield): 10.1g (60%) mp : 253~254 ℃ Rf 1: 0.81, Rf 2: 0.06 Elemental analysis _{(C 12 H 20 O 4 N} 2) theory (%): C60.0 H7. 2 N10.0 Actual value (%): C59.9 H7.3 N9.8 (2) Synthesis of Bz-Lys (Z) 1.40 g (5 mmol) of Lys (Z) obtained in (1) was added to 10 ml of water.
Dissolve in a mixture of 2.5 ml (5 mmol) of 2N NaOH and 0.69 ml (6 mmol) of Bz-Cl and 3 ml of 2N NaOH while stirring under ice cooling.
(6 mmol) was dispensed 5 times and then stirred for 2 hours. Excess Bz-Cl was extracted with ether and the aqueous layer was adjusted to pH 1--6 with 6N HCl.
After adjusting to 2, the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After this solution was filtered, the filtrate was concentrated under reduced pressure, crystallized with ether, and left to cool to grow crystals.
After that, the supernatant was filtered off, the crystals were dried, and Bz-Lys
A crystal of (Z) was obtained.

The yield (yield) of Bz-Lys (Z), melting point, Rf ₁ and Rf ₂ by TLC, specific optical rotation and elemental analysis values obtained below are shown below.

Yield (Yield): 1.42g (74.7%) mp: 102-105 ℃ Rf ₁ : 0.81, Rf ₂ : 0.39 ▲ [α] ²³ _D ▼ ＝ ＋ 0.99 (c = 1, DMF) Elemental analysis (C ₂₁ H ₂₄ O ₅ N ₂ ) Theoretical value (%): C64.1 H6.2 N7.1 Actual value (%): C63.7 H6.1 N7.0 (3) Synthesis of Bz-Lys (2) 0.76 g (2 mmol) of the obtained Bz-Lys (Z) was dissolved in 5 ml of acetic acid, 300 mg of palladium black was added, and the mixture was stirred at room temperature for 3 hours for catalytic reduction. After confirming the completion of the reaction by TLC, the reaction mixture was filtered to remove palladium black, and the filtrate was concentrated under reduced pressure, crystallized with ether, and left to cool to grow crystals.
After that, the supernatant was filtered off and the crystals were dried to obtain Bz-Lys crystals. The obtained Bz-Lys was hygroscopic.

The yield (yield), Rf ₁ and Rf ₂ by TLC, and elemental analysis values are shown below.

Yield (yield): 0.50 g (80.7%) Rf ₁ : 0.46, Rf ₂ : 0.00 Example 2 Synthesis of Ph-ac-Lys (1) Synthesis of Ph-ac-Lys (Z) (1 of Example 1 ) Was obtained according to the same method as
Lys (Z) 1.40 g (5 mmol) 10 ml of water and 2.5 ml of 2N NaOH
Dissolve in a mixture of (5mmol), Ph
-Ac-Cl 1.11 ml (6 mmol) and 2N NaOH 2.5 ml (5 mmol) 5
It was dispensed in batches and then stirred overnight. Excess Ph-ac-Cl was removed from the reaction solution with ether, and 6N HCl was added to pH 1-2.
After that, extract with ethyl acetate and extract the ethyl acetate layer with 0.5N.
It was washed with HCl and then dried over anhydrous sodium sulfate.
After filtering this solution, the filtrate was concentrated under reduced pressure, crystallized with ether, allowed to cool and allowed to grow crystals, and recrystallized with a mixed solvent of ethyl acetate-ether to obtain Ph-ac-Lys (Z).
I got a crystal.

The yield (yield) of Ph-ac-Lys (Z) obtained below,
The melting point, Rf ₁ and Rf ₂ by TLC, specific rotation and elemental analysis values are shown.

Yield (Yield): 1.20 g (60.3%) mp: 101-102 ° C Rf ₁ : 0.85, Rf ₂ : 0.30 ▲ [α] ²³ _D ▼ ＝ －3.97 (c = 1, DMF) Elemental analysis (C ₂₂ H ₂₆ O ₅ N ₂ ) Theoretical value (%): C66.3 H6.6 N7.0 Actual value (%): C66.2 H6.5 N7.1 (2) Synthesis of Ph-ac-Lys (1) The obtained Ph-ac-Lys (Z) 0.40 g (1 mmol)
Was treated in the same manner as in (3) of Example 1 to obtain crystals of the target compound Ph-ac-Lys.

The yield of Ph-ac-Lys (yield), melting point, T
Rf ₁ and Rf ₂ by LC, specific rotation and elemental analysis values are shown.

Yield (yield): 0.24 g (75.0%) mp: 227-230 ° C Rf ₁ : 0.51, Rf ₂ : 0.00 ▲ [α] ²³ _D ▼ ＝ －14.97 (c = 1, DMF) Elemental analysis (C ₁₄ H ₂₀ O ₃ N ₂ · CH ₃ COOH) Theoretical value (%): C59.2 H7.5 N8.6 Actual value (%): C59.5 H7.6 N8.4 Example 3 Synthesis of L-Phe-Lys (1) Synthesis of ZL-Phe L-Phe (1.65 g, 10 mmol) was dissolved in 4N NaOH (2.5 ml, 10 mmol), and 4N NaOH (3 ml, 12 mm) was vigorously stirred under ice cooling.
ol) and 1.87 g (11 mmol) of Z-Cl were simultaneously added dropwise over 20 to 30 minutes. The reaction solution was always kept alkaline. After completion of dropping, the mixture was further stirred for 20 minutes, and after completion of the reaction, the reaction solution was washed with ether to remove unreacted Z-Cl. While cooling with ice, 5N HCl was added dropwise to the aqueous layer to adjust the pH to 2.5-3. This aqueous solution was put in a refrigerator to grow crystals, which was collected by filtration, washed with cold water, and then dried with a desiccator to obtain ZL-Phe crystals.

Yield (yield), melting point, T of ZL-Phe obtained below
Rf ₁ and Rf ₂ by LC, specific rotation and elemental analysis values are shown.

Yield (Yield): 2.70 g (90.3%) mp: 81-84 ° C Rf ₁ : 0.67, Rf ₂ : 0.35 ▲ [α] ²³ _D ▼ ＝ ＋ 3.99 (c = 1, EtOH) Elemental analysis (C ₁₇ H ₁₇ O ₄ N) Theoretical value (%): C68.2 H5.7 N4.7 Actual value (%): C68.0 H5.7 N4.6 (2) Synthesis of ZL-Phe-ONSu (1 ) Obtained ZL-Phe 1.50g (5mmol) and HONSu
Dissolve 0.58 g (5 mmol) in 20 ml of acetonitol, and under ice cooling
After stirring for 10 minutes, DCC (1.03 g, 5 mmol) was added and the mixture was stirred overnight. The precipitated DC Urea was filtered off, the filtrate was concentrated under reduced pressure, and decanted with ether 2 to 3 times to obtain oily ZL-Phe-ONSu.

The yield (yield) of ZL-Phe-ONSu and Rf ₁ and Rf ₂ by TLC are shown below.

Yield (yield): 1.95 g (98.2%) Rf ₁ : 0.81, Rf ₂ : 0.33 (3) Synthesis of Z-L-Phe-Lys (Z) Z-L-Phe-ONSu1 obtained in (2) .59 g (4 mmol)
Was dissolved in 10 ml of DMF, and 1.12 g (4 mmol) of Lys (Z) obtained according to the method of (1) of Example 1 was added to DMF10.
It was added to the solution dissolved in ml and stirred overnight. 2% after completion of reaction
The reaction solution was adjusted to pH 1-2 with HCl, extracted with ethyl acetate, the ethyl acetate layer was washed with 2% HCl, and dried over anhydrous sodium sulfate. After this solution was filtered, the filtrate was concentrated under reduced pressure, crystallized using petroleum ether as a poor solvent, and recrystallized from ether to give ZL-Phe-Lys- (Z) crystals.

The yield (yield) of Z-L-Phe-Lys (Z) obtained below, melting point, Rf ₁ and Rf ₂ by TLC, specific optical rotation and elemental analysis values are shown below.

Yield (Yield): 0.71 g (31.6%) mp: 117-121 ° C Rf ₁ : 0.85, Rf ₂ : 0.49 ▲ [α] ²³ _D ▼ ＝ －6.90 (c = 1, DMF) Elemental analysis (C ₃₁ H ₃₅ O ₇ N ₃ ) Theoretical value (%): C66.3 H6.3 N7.5 Actual value (%): C66.4 H6.1 N7.7 (4) Synthesis of L-Phe-Lys.HCl (3 ) Obtained Z-L-Phe-Lys (Z) 0.56g (1mm
ol) was treated in the same manner as in (3) of Example 1 to obtain the target acetate, L-Phe-Lys.CH ₃ COOH. The oil was washed several times with methanol, and 8 mL of 0.5N MeOH-HCl (2 mm
ol) was added, and the mixture was concentrated and further washed several times with methanol. The target hydrochloric acid salt L-Phe-Lys.HCl thus obtained was an oily hydrochloride. The yield (yield) and Rf ₁ and Rf ₂ by TLC are shown.

Yield (yield): 0.33 g (100%) Rf ₁ : 0.33, Rf ₂ : 0.00 Example 4 Synthesis of D-Phe-Lys In Example 3, except that D-Phe was used instead of L-Phe. Following the same procedure as in Example 3, D-Phe
-Lys was synthesized.

The yield (yield) of the intermediates obtained in each step in synthesizing D-Phe-Lys from D-Phe and the TLC are shown below.
The physical properties such as Rf ₁ and Rf ₂ are shown.

(1) Z-D-Phe (Crystalline) Yield (Yield): 2.55 g (85.2%) mp: 92-95 ° C Rf ₁ : 0.63, Rf ₂ : 0.19 ▲ [α] ²³ _D ▼ = -5.20 ( C = 1, EtOH) Elemental analysis (C ₁₇ H ₁₇ O ₄ N) Theoretical value (%): C68.2 H5.7 N4.7 Actual value (%): C68.5 H5.5 N4.5 (2) Z-D-Phe-ONSu (oil) Yield (Yield): 1.89 g (95.2%) Rf ₁ : 0.77, Rf ₂ : 0.35 (3) Z-D-Phe-Lys (Z) (Crystalline) Yield ( Yield): 0.79 g (35.2%) mp: 136-139 ° C Rf ₁ : 0.89, Rf ₂ : 0.51 ▲ [α] ²³ _D ▼ ＝ ＋ 2.98 (C = 1, DMF) Elemental analysis (C ₃₁ H ₃₅ O ₇ N ₃ ) Theoretical value (%): C66.3 H6.3 N7.5 Actual value (%): C66.2 H6.3 N7.6 (4) D-Phe-Lys.HCl (oil) Yield ( Yield): 0.33 g (100%) Rf ₁ : 0.35, Rf ₂ : 0.00 Example 5 Synthesis of Ph-ac-Gly-Lys (1) Synthesis of Ph-ac-Gly 0.38 g (5 mmol) of Gly in 10 ml of water. And 2.5 ml of 2N NaOH (5 mm
ol) mixed solution and stirred under ice cooling with stirring Ph-ac-
Cl1.11 ml (6 mmol) and 2N NaOH 2.5 ml (5 mmol) were dispensed 5 times and then stirred overnight. After completion of the reaction, 6N HCl was added to the reaction solution to adjust the pH to 1-2, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N HCl and then dried over anhydrous sodium sulfate. After filtering this solution, the filtrate was concentrated under reduced pressure,
Crystallize with ether, leave to cool to crystallize, and recrystallize this in ethyl acetate-ether mixed solvent, Ph
A crystal of -ac-Gly was obtained.

The yield of Ph-ac-Gly (yield), melting point, T
The Rf ₁ , Rf ₂ and elemental analysis values by LC are shown.

Yield (Yield): 0.60 g (62%) mp: 138-143 ° C Rf ₁ : 0.63, Rf ₂ : 0.30 Elemental analysis (C ₁₀ H ₁₁ O ₃ N) Theoretical value (%): C62.2 H5.7 N7.2 measured value (%): C62.1 H5.5 N7.3 (2) Synthesis of Ph-ac-Gly-ONSu Ph-ac-Gly1.35 g (7 mmol) and HONSu 0.81 g (7 mmol)
Dissolve in 10 ml of DMF and keep it at 0 ℃, DCC 1.59g (7.7mmo
l) was added, and the mixture was stirred at 0 to 5 ° C for 20 hours. After completion of the reaction, DC Urea was filtered off, the filtrate was concentrated under reduced pressure, and 1.15 g of the obtained residue was diluted with isopropanol and allowed to cool and recrystallized to obtain Ph-ac-Gly-ONSu crystals.

The yield (yield) of Ph-ac-Gly-ONSu obtained below, T
The Rf ₁ and Rf ₂ and elemental analysis values by LC are shown.

Yield (Yield): 0.87 g (43%) Rf ₁ : 0.81, Rf ₂ : 0.62 Elemental analysis (C ₁₄ H ₁₄ O ₅ N ₂ ) Theoretical value (%): C57.9 H4.9 N9.7 Measured value (%): C57.7 H5.1 N9.8 (3) Synthesis of Ph-ac-Gly-Lys (Z) Ph-ac-Gly-ONSu 1.45 g (5 mmol) and the same as (1) of Example 1. Lys (Z) 1.4 obtained according to the method of
The target Ph-ac-Gly-Lys (Z) was obtained by treating with 0 g (5 mmol) in the same manner as in (3) of Example 3.

The yield (yield) of Ph-ac-Gly-Lys (Z), Rf ₁ and Rf ₂ by TLC, and elemental analysis values obtained below are shown.

Yield (Yield): 1.37 g (60%) Rf ₁ : 0.76, Rf ₂ : 0.32 Elemental analysis (C ₂₄ H ₂₉ O ₆ N ₃ ) Theoretical value (%): C63.3 H6.4 N9.2 Measured value (%): C63.2 H6.5 N9.0 (4) Synthesis of Ph-ac-Gly-Lys Ph-ac-Gly-Lys (Z) 0.46 g (1 mmol), (3) of Example 1 Aim by performing the same processing as
Ph-ac-Gly-Lys was obtained. The obtained Ph-ac-Gly-Lys was a hygroscopic crystal. Its yield (yield), R by TLC
f ₁ and Rf ₂ and elemental analysis values are shown.

Yield (yield): 0.31 g (82%) Rf ₁ : 0.45, Rf ₂ : 0.00 Example 6 Predetermined concentration of the prescribed amount of Ph-ac-Gly-Lys obtained in Example 5 Was added to the cyclodextrin aqueous solution of Example 1, dissolved, homogenized at 10,000 rpm for 30 minutes, and then freeze-dried to obtain a Ph-ac-Gly-Lys inclusion complex powder.

(Taste test) The taste of each of the compounds shown in Table 1 was evaluated by a sensory test method using a multiple dilution of 50 panelists of 18 to 55 years old. The results are shown in Table 1. The sweetness intensity indicates a taste threshold value measured by tasting a sample adjusted to a multiple dilution series from a low concentration, and is an average value of 50 persons. Regarding the taste quality, the mixture of other tastes and the quality of sweetness were evaluated at a concentration at which the taste was sufficiently felt, and ⊚ indicates pure sweetness, and ∘ indicates that there is a mixture of other tastes.

As shown in Table 1, Bz-introduced into lysine exhibits sweetness, but its intensity is low, and Ph-ac- and
Regarding those into which Ph-pr- was introduced, there was a mixture of bitterness although it had sweetness.

Similarly, bitterness was also mixed in the lysine in which L-Phe and D-Phe were introduced. Further, R in the general formula (I) is Bz-Ala-, Bz-α-Abu-, Bz-Ser-, P
h-ac-Ala-, Ph-ac-α-Abu-, Ph-ac-Ser-, Ph
There was a mixture of bitterness in the case of introducing -pr-Ala-, Ph-pr-α-Abu-, and Ph-pr-Ser-, but Bz-α-
Abu-Lys had a slight astringency, but exhibited a relatively good sweetness, which was about 10 times that of sugar.

Next, a Ph-ac-
When the tastes of Gly-Lys and Ph-pr-Gly-Lys were examined, it was found that each had a good quality sweetness that did not contain bitterness. In particular, Ph-ac-Gly-Lys was found to be 50 times as sweet as sugar. However, compounds with further extended chain lengths Ph-ac-β-Ala-Lys, Ph-pr-β-Ala-L
Regarding ys and the like, bitterness was found again in addition to sweetness.

These are dipeptide derivatives, which have almost the same number of calories as sugar (4 kcal / g), but especially Ph-ac-Gly-Ly.
Since s has 50 times the sweetness intensity, it requires only 1/50 calories, so it is particularly useful as a low-calorie sweetener.

[Effects of the Invention] The lysine derivative and its salt of the present invention have an effect of expressing a refreshing sweetness, and a sweetener containing the same is useful as a low-calorie sweetener.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07K 5/06 C07K 5/06

Claims (3)

(57) [Claims] 1. General formula (I): (In the formula, R is a phenylacetyl group, phenylpropionyl group, benzoyl group, L-phenylalanine residue, D-
Phenylalanine residue, general formula (II): (Wherein R ¹ represents a benzoyl group, a phenylacetyl group or a phenylpropionyl group, and R ² represents a methyl group, an ethyl group or a hydroxymethyl group),
Or general formula (III): (In the formula, m represents 1 or 2, and n represents 1, 2 or 3) and a salt thereof. 2. General formula (I): (In the formula, R is a phenylacetyl group, phenylpropionyl group, benzoyl group, L-phenylalanine residue, D-
Phenylalanine residue, general formula (II): (Wherein R ¹ represents a benzoyl group, a phenylacetyl group or a phenylpropionyl group, and R ² represents a methyl group, an ethyl group or a hydroxymethyl group),
Or general formula (III): (In the formula, m represents 1 or 2, and n represents 1, 2 or 3) A lysine derivative represented by the formula and a salt thereof as an active ingredient. 3. The sweetener according to claim 2, wherein the active ingredient is the sweetener clathrated with cyclodextrin.