JP4631463B2 - Novel carnosine ester compounds - Google Patents

Description

  The present invention relates to a novel carnosine ester compound, and the compound can be suitably used as a Maillard reaction inhibitor in the fields of pharmaceuticals, quasi drugs, cosmetics, foods and the like.

  Maillard reaction is a non-enzymatic reaction of amino groups in amino acids and proteins with aldehyde groups of reducing sugars, leading to the formation of various compounds, cross-linking and denaturation of proteins via Schiff bases and Amadori rearrangement products. It is a reaction. In the food industry, it is a reaction related to the coloration and fragrance components generated during the processing and storage of food, and is regarded as a very important reaction in terms of food differentiation and quality control. Patent Document 1).

  On the other hand, it is known that the Maillard reaction also participates and proceeds in vivo and causes protein cross-linking and denaturation (Non-patent Document 2). Not only middle-aged and elderly people but also diabetics whose age has progressed in recent years, there are various complications in the patient, but the main complications of vascular disorders such as cataract and arteriosclerosis are typical diabetic complications. One of the causes is reported to be due to the progress of the Maillard reaction (Non-patent Document 3). In addition, aging phenomena such as skin wrinkles, rashes, and decreased elasticity that progress with aging are considered to be caused by cross-linking and denaturation of dermal constituent proteins such as collagen and elastin that involve the Maillard reaction (Patent Literature). 1).

  Therefore, the development of compounds and drugs that inhibit or suppress the Maillard reaction, which is the main cause of various disorders as described above, is an important research subject in the fields of medicine, dermatology, food chemistry and the like. So far, several Maillard reaction inhibitors including aminoguanidine (Patent Document 2) have been reported (Non-Patent Document 4), but the effect is not always sufficient, and the development of a new inhibitor is desired. ing.

  It has been reported that phenylpropenoic acids containing ferulic acid or derivatives thereof are useful as Maillard reaction inhibitors (Patent Documents 3 and 4). On the other hand, N-feruloylglycine, a compound present in barley, is known. In the study of N-feruloylglycine amide hydrolase, which is a related enzyme of this compound, N-feruloylalanine, N-dihydroferrule. Roylglycine and the like have been synthesized (Non-patent Document 5). In addition, it has been reported that caffeic acid amide derivatives, which are compounds similar in structure to N-feruloyl amino acids, have antioxidant activity and ability to inhibit tyrosinase activity (Patent Document 5). However, none of these documents are reports on N-feruloyl amino acids or N-dihydroferuloyl amino acids involved in the Maillard reaction and their inhibitory activity. Furthermore, it is known that an N-acyl amino acid compound obtained by chemically modifying carnosine (β-alanyl-L-histidine) has antioxidant power, emulsifying power, antibacterial power, moisturizing power, and the like (for example, Patent Documents). 6). However, in this N-acylamino acid compound, long-chain fatty acids are exclusively used as raw materials for acylating agents in order to exert emulsifying power, and ferulic acid or dihydroferulic acid was used as the raw material for acylating agents. It is not a thing.

JP-A-62-249909 (Detailed Description of the Invention) JP 62-142114 A (Claims) JP 2000-256259 A (Claims) JP 2003-221774 A (Embodiment of the Invention) JP 2003-192522 A (Claims) JP-A-5-65275 (Claims) Maillard, L.C., Compt. Rend. Soc. Biol., 72, 599 (1912) Brownlee, M. et al., Science, 232, 1629 (1986) Brownlee, M. et al., N. Engl. J. Med., 318, 1315 (1988) Ken Kato, Journal of Medicine, 38, No 4, 1259 (2002) Martens, M., et al., Phytochemistry, 27, 2465 (1988)

  An object of the present invention is to provide a novel compound suitable as an excellent Maillard reaction inhibitor in view of the above situation.

As a result of repeated studies on the Maillard reaction, the present inventors have found that a novel carnosine ester compound in which ferulic acid or dihydroferulic acid and carnosine are bound has an inhibitory activity on the Maillard reaction, thereby completing the present invention.
That is, the present invention is a carnosine ester compound represented by the following general formula (A).

However, X in the formula (A) represents —CH ₂ CH ₂ — or —CH═CH—, and n represents 2 or 3. R ¹ represents a hydrocarbon group that may have a branched or unsaturated bond having 1 to 8 carbon atoms, and R ² represents a hydrogen atom or a methyl group.

Since the novel carnosine ester compound of the present invention has an excellent inhibitory activity on the Maillard reaction, diseases involving the Maillard reaction, that is, diseases associated with aging such as various diabetic complications, atherosclerosis, and skin It is effective against aging. The compound is not only used as a Maillard reaction inhibitor, but also as a preventive / therapeutic agent for the above-mentioned diseases, etc. In addition, it can be widely applied in the fields of pharmaceuticals, quasi drugs, cosmetics and foods.

O Regarding the compound represented by the formula (A), first, the compound represented by the formula (A) (hereinafter also referred to as the compound (A), which is also abbreviated in the same manner for the following compounds represented by the general formula) will be described.

X in the formula (A) represents —CH ₂ CH ₂ — or —CH═CH—, and n represents 2 or 3. R ¹ represents a hydrocarbon group that may have a branched or unsaturated bond having 1 to 8 carbon atoms, and R ² represents a hydrogen atom or a methyl group.
Here, if specific examples of R ¹ in formula (A), a methyl group, an ethyl group, a propyl group, a butyl group, a straight-chain saturated hydrocarbon groups such as octyl group, an isopropyl group, t- butyl group , A saturated hydrocarbon group having a branch such as a cyclohexyl group and a 2-ethylhexyl group, a hydrocarbon group having an unsaturated bond such as a methallyl group, and a benzyl group, among which a methyl group and an ethyl group are preferable. .

O About the manufacturing method of the compound represented by Formula (A) Compound (A) is compound (D) by hydrolyzing an ester group, for example after condensing compound (B) and compound (C). The compound (D) and the compound (E) prepared and obtained can be produced by condensation. The condensation reaction can be carried out according to conventional methods used in the field of chemical synthesis, such as a method using a dehydrating condensing agent and an active ester method.

However, X in formula (B) represents —CH ₂ CH ₂ — or —CH═CH—.

  However, n in Formula (C) represents 2 or 3. R represents a hydrocarbon group that may have a branched or unsaturated bond having 1 to 8 carbon atoms. Specific examples of R include linear saturated hydrocarbon groups such as methyl group, ethyl group, propyl group, butyl group, octyl group, isopropyl group, t-butyl group, which are used as protecting groups for carboxyl groups in the field of synthetic chemistry. , A saturated hydrocarbon group having a branch such as a cyclohexyl group, a 2-ethylhexyl group, a hydrocarbon group having an unsaturated bond such as a methallyl group, a benzyl group, a methyl group, an ethyl group, a t-butyl group, a benzyl group. Groups can preferably be used.

X in the formula (D) represents —CH ₂ CH ₂ — or —CH═CH—, and n represents 2 or 3. Further, R ¹ in the formula (E) represents a hydrocarbon group which may have a branched or unsaturated bond having 1 to 8 carbon atoms, R ² represents a hydrogen atom or a methyl group. Specific examples of R ¹ are the same as R.

As a method for synthesizing the compound (A), the active ester method using N-hydroxysuccinimide will be described in more detail as an example. Note that the abbreviations X, n, R, R ¹ , and R ² used in the following description represent the meanings defined above.

  First, compound (F) can be prepared by reacting compound (B) with N-hydroxysuccinimide in an organic solvent using a dehydration condensing agent.

  The amount of N-hydroxysuccinimide used in this reaction is basically 1 chemical equivalent to compound (B), preferably 0.7 to 1.3 chemical equivalents, more preferably 0.9 to 1.1 chemical equivalents.

  Examples of the dehydrating condensing agent include N, N-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, N-ethyl-N ′-(3 dimethylamipropyl) carbodiimide, 4- (4,6-dimethoxy-1,3,5). -Triazin-2-yl) -4-methylmorpholinium chloride, di-2-pyridyl carbonate, di-2-pyridylthionocarbonate, etc. are exemplified, and N, N-dicyclohexylcarbodiimide is preferably used. Can do. The amount of the dehydrating condensing agent used is basically 1 chemical equivalent to the compound (B), preferably 0.7 to 1.3 chemical equivalents, and more preferably 0.9 to 1. 1 chemical equivalent.

  This reaction is preferably carried out in an organic solvent, particularly an aprotic solvent, such as tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, N, N-dimethylpropyleneurea, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, chloroform, dichloromethane, toluene, a mixed solvent thereof and the like can be preferably used.

The reaction temperature is preferably 0 to 50 ° C, more preferably 10 to 30 ° C. If this reaction temperature is too low, it is costly to maintain the temperature, and if the reaction temperature is too high, side reactions may proceed.
The reaction time varies depending on the conditions, but is usually several hours.
After completion of the reaction, the compound (F) can be used as it is without purification, and the compound (F) can be isolated and purified by a known method such as recrystallization.

  The compound (D) can be synthesized by reacting the compound (F) prepared as described above with the compound (C), followed by hydrolysis of the ester group.

The amount of the compound (C) used in the reaction between the compound (F) and the compound (C) is basically 1 chemical equivalent to the compound (F), and 0.7 to 1.3 chemical equivalents. Preferably, it is 0.9 to 1.1 chemical equivalent.
This reaction is preferably carried out under basic conditions. Preferably, sodium hydrogen carbonate and potassium hydrogen carbonate are added in an amount of 0.7 to 5 chemical equivalents, more preferably 1.0 to 3 with respect to compound (F). Use 0.0 chemical equivalents.

This reaction is preferably carried out in a solvent that dissolves the compound (C), the compound (F), and a basic substance such as sodium hydrogencarbonate. Tetrahydrofuran, 1,4-dioxane, diethyl ether, 1,2 -Combined use of an organic solvent such as dimethoxyethane, N, N-dimethylpropylene urea, N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropyl alcohol, toluene, chloroform, dichloromethane, and water Is preferred.
The reaction temperature is preferably 0 to 50 ° C, more preferably 10 to 30 ° C. If this reaction temperature is too low, it is costly to maintain the temperature, and if the reaction temperature is too high, side reactions may proceed.
This reaction time varies depending on conditions, but is usually from several hours to several tens of hours.
After completion of the reaction, it can be purified by a known method such as solvent extraction, column chromatography, recrystallization and the like.

  Next, the compound (D) can be synthesized by hydrolyzing the ester group. This hydrolysis reaction can be carried out by a conventional method used in the field of synthetic organic chemistry, that is, by performing a reaction under acidic or alkaline conditions. The obtained compound (D) can be purified by known methods such as solvent extraction, column chromatography, and recrystallization.

  The compound (D) obtained as described above can be converted into an active ester derivative of N-hydroxysuccinimide by the same method as the method for producing the compound (F). Compound (A) can be produced by reacting this active ester derivative with compound (E) in the same manner as in the reaction between compound (F) and compound (C) described above.

  The obtained compound (A) can be used after being purified by known methods such as solvent extraction, column chromatography, recrystallization and the like.

The compound represented by the formula (A) of the present invention exhibits an excellent inhibitory activity against Maillard reaction. From this, various diabetic complications (for example, coronary heart disease, peripheral circulatory disorder, cerebrovascular disorder, neuropathy, nephropathy, arteriosclerosis, joint sclerosis, cataract and conjunctiva, which are diseases involving Maillard reaction Prevention / treatment agent for atherosclerosis, etc., prevention / treatment agent for atherosclerosis, anti-aging agent for skin, and prevention / preservation agent for coloring / discoloration or alteration of foods that involve Maillard reaction, etc. It is extremely useful in a wide range of pharmaceuticals, quasi drugs, cosmetics and foods.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

<Synthesis Example 1>
A condensation reaction between dihydroferulic acid and N-hydrosuccinimide was performed to obtain Compound 1.
That is, N, N-dicyclohexylcarbodiimide (25.0 g, 121 mmol) was added to a tetrahydrofuran (250 ml) solution of dihydroferulic acid (23.6 g, 120 mmol) and N-hydroxysuccinimide (13.9 g, 121 mmol). . After stirring at room temperature for 3 hours, 5 ml of distilled water was added and left for 16 hours. Next, the produced insoluble matter was filtered off, and the filtrate was concentrated. The obtained residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain a colorless crystalline compound (25.0 g, yield 71%). ¹ H-NMR spectrum and infrared absorption spectrum analysis were performed, and it was confirmed that the obtained compound was Compound 1.

The melting point of Compound 1 was 140-142 ° C. The chemical shift value of the ¹ H-NMR spectrum measured in deuterated chloroform of Compound 1 is 2.80-2.92 (6H, m), 2.96-3.02 (2H, m), 3.89 (3H, s), 5.57 (1H, s ), 6.70-6.75 (2H, m), 6.85 (1H, d, J = 7.6Hz). Further, wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3430, 2940, 1820, 1780, 1730, 1520, 1370, 1220, 1070, 820, 650.

○ Structural formula of Compound 1

<Synthesis Example 2>
N-dihydroferuloyl-β-alanine (hereinafter referred to as compound 2) was synthesized by reacting compound 1 with β-alanine ethyl ester hydrochloride and subsequently hydrolyzing the ester group.
That is, distilled water (65 ml) was added to and dissolved in β-alanine ethyl ester hydrochloride (10.0 g, 65.1 mmol) and sodium bicarbonate (5.47 g, 65.1 mmol). A solution prepared by dissolving Compound 1 (19.1 g, 65.1 mmol) in tetrahydrofuran (200 ml) was added to this solution while stirring. After stirring at room temperature for 18 hours, 20% aqueous sodium carbonate solution (50 ml), saturated brine (100 ml) and ethyl acetate (50 ml) were added and partitioned. After collecting the organic layer, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Next, the obtained residue was dissolved in isopropyl alcohol (180 ml), 1N aqueous sodium hydroxide solution (70 ml) was added, and the mixture was stirred at room temperature. After 18 hours, 6N hydrochloric acid (12 ml) was added to the reaction solution to stop the reaction. After the solvent was concentrated under reduced pressure, the operation of adding isopropyl alcohol (30 ml) to the residue and concentrating under reduced pressure was repeated twice to remove water. Isopropyl alcohol (50 ml) was added to the resulting residue and heated, and the insoluble material was filtered off. The filtrate was allowed to stand at 4 ° C. to obtain a colorless crystalline compound (6.13 g, yield 35%). ¹ H-NMR spectrum and infrared absorption spectrum analysis were performed, and it was confirmed that the obtained compound was Compound 2.

Compound 2 had a melting point of 129-130 ° C. The chemical shift values of the ¹ H-NMR spectrum measured in deuterated dimethyl sulfide of Compound 2 are 2.26-2.40 (4H, m), 2.68 (2H, t, J = 7.8Hz), 3.22 (2H, d, J = 6.0 , 6.8Hz), 3.73 (3H, s), 6.56 (1H, d, J = 8.0Hz), 6.65 (1H, d, J = 8.0Hz), 6.74 (1H, s), 7.88 (1H, br), 8.65 (1H, br), 12.20 (1H, br). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3520, 3320, 1700, 1640, 1550, 1520, 1280, 1270, 1220, 1030, 690.

○ Structural formula of Compound 2

<Synthesis Example 3>
Compound was obtained by conducting the same operation as in Synthesis Example 2 except that 4-aminobutyric acid hydrochloride was used instead of β-alanine ethyl ester hydrochloride and the recrystallization solvent of the crude product was changed from isopropyl alcohol to ethyl acetate. 3 was synthesized.

Chemical shift values of ¹ H-NMR spectrum measured in deuterated dimethyl sulfide of compound 3 are 1.55-1.63 (2H, m), 2.19 (2H, t, J = 7.4Hz), 2.28-2.33 (2H, m), 2.69 (2H, t, J = 7.4Hz), 3.01-3.06 (2H, m), 3.73 (3H, s), 6.56 (1H, dd, J = 1.6,8.0Hz), 6.65 (1H, d, J = 8.0Hz), 6.74 (1H, d, J = 1.6Hz), 7.81 (1H, t, J = 5.6Hz), 8.66 (1H, br), 12.04 (1H, br).

○ Structural formula of Compound 3

<Example 1>
After converting Compound 2 prepared in Synthesis Example 2 into an active ester derivative of N-hydroxysuccinimide, Compound 4 of the present invention was produced by reacting with L-histidine methyl ester dihydrochloride.
That is, N, N-dicyclohexyl was added to a solution of Compound 2 (3.26 g, 12.2 mmol) prepared in Synthesis Example 2 and N-hydroxysuccinimide (1.73 g, 15.0 mmol) in tetrahydrofuran (75 ml). Carbodiimide (3.26 g, 15.8 mmol) was added. After stirring at room temperature for 3 hours, the generated insoluble material was filtered off and washed with tetrahydrofuran (75 ml). The combined filtrates were added to a solution of L-histidine methyl ester dihydrochloride (3.63 g, 15.0 mmol) and sodium bicarbonate (2.52 g, 30.0 mmol) previously dissolved in distilled water (50 ml). After stirring at room temperature for 18 hours, the reaction solution was partitioned by adding 20% aqueous sodium carbonate solution (10 ml), saturated brine (100 ml), and ethyl acetate (50 ml). The organic layer was collected and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was produced by silica gel column chromatography to obtain a colorless hygroscopic powdery compound (3.54 g, yield 70%). ¹ H-NMR spectrum and infrared absorption spectrum analysis were performed, and it was confirmed that the obtained compound was the compound 4.

The chemical shift value of ¹ H-NMR spectrum measured in deuterated dimethyl sulfide of Compound 4 is 2.23-2.32 (4H, m), 2.68 (2H, t, J = 7.2Hz), 2.81-2.94 (2H, m), 3.16-3.23 (2H, m), 3.59 (3H, s), 3.73 (3H, s), 4.45-4.50 (1H, m), 6.55 (1H, d, J = 8.0Hz), 6.65 (1H, d, J = 8.0Hz), 6.74 (1H, s), 6.80 (1H, s), 7.53 (1H, s), 7.86 (1H, t, J = 5.8Hz), 2.29 (1H, d, J = 7.2Hz) , 8.72 (1H, br), 11.85 (1H, br). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3280, 2960, 1740, 1660, 1520, 1440, 1280, 1220, 1030, 760, 620.

○ Structural formula of Compound 4

<Example 2>
Compound 5 was produced by performing the same operation as in Example 1 except that 1-methyl-L-histidine methyl ester hydrochloride was used instead of L-histidine methyl ester dihydrochloride used in Example 1. .

The chemical shift value of ¹ H-NMR spectrum measured in deuterated dimethyl sulfide of compound 5 is 2.24-2.32 (4H, m), 2.69 (2H, t, J = 7.4Hz), 2.76-2.87 (2H, m), 3.18-3.24 (2H, m), 3.56 (3H, s), 3.59 (3H, s), 3.73 (3H, s), 4.44-4.47 (1H, m), 6.54-6.57 (1H, m), 6.66 ( 1H, d, J = 7.4Hz), 6.74 (1H, s), 6.84 (1H, s), 7.45 (1H, s), 7.88 (1H, t, J = 5.6Hz), 8.27 (1H, d, J = 7.4Hz), 8.78 (1H, br). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3300, 2950, 1740, 1660, 1520, 1440, 1280, 1220, 1030, 820, 630.

○ Structural formula of Compound 5

<Example 3>
Compound 6 was produced in the same manner as in Example 1, except that Compound 3 prepared in Synthesis Example 3 was used instead of Compound 2.

The chemical shift values of ¹ H-NMR spectrum measured in deuterated dimethyl sulfide of compound 6 are 1.14-1.57 (2H, m), 2.05-2.09 (2H, m), 2.30 (2H, t, J = 7.4Hz), 2.70 (2H, t, J = 7.4Hz), 2.84-3.00 (4H, m), 3.59 (3H, s), 3.72 (3H, s), 4.43-4.49 (1H, m), 6.55-6.57 (1H, m), 6.65 (1H, d, J = 7.4Hz), 6.74 (1H, s), 6.80 (1H, s), 7.53 (1H, s), 7.79 (1H, t, J = 5.4Hz), 8.20 ( 1H, d, J = 7.2Hz), 8.70 (1H, br), 11.80 (1H, br). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3270, 2950, 1740, 1640, 1550, 1520, 1440, 1280, 1220, 1030, 760, 620.

○ Structural formula of compound 6

<Example 4>
Instead of dihydroferulic acid used in Synthesis Example 1, trans-ferulic acid was used,
Subsequently, the same operation as in Synthesis Example 2 and Example 1 was performed to produce Compound 7.

The chemical shift value of ¹ H-NMR spectrum measured in deuterated dimethyl sulfide of compound 7 is 2.32-2.35 (2H, m), 2.82-2.95 (2H, m), 3.24-3.50 (3H, brm), 3.59 (3H , s), 3.80 (3H, s), 4.47-4.52 (1H, m), 6.45 (1H, d, J = 16.0Hz), 6.78-6.81 (1H, m), 6.97-7.00 (1H, m), 7.12 (1H, s), 7.31 (1H, d, J = 16.0Hz), 7.54 (1H, s), 7.97 (1H, t, J = 5.6Hz), 8.32-8.34 (1H, m), 9.49 (1H , br), 11.82 (1H, br). The wave numbers (cm ⁻¹ ) absorbed in the infrared absorption spectrum (KBr pellet method) were 3270, 1740, 1660, 1600, 1520, 1440, 1260, 1210, 1030, 820, 760, 620.

○ Structural formula of Compound 7

<Test example>
Using the compounds 4 to 7 produced in Examples 1 to 4 and aminoguanidine hydrochloride which is a known Maillard reaction inhibitor, the furosine production inhibition rate, which is a conventional method for measuring the Maillard reaction inhibition rate, was measured ( For example, see E. Schleicher, et al., J. Clin. Chem. Clin. Biochem. 19, 81 (1981)).
The specific procedure is shown below.

[1] Preparation of phosphate buffer Potassium dihydrogen phosphate (2.04 g, 15 mmol) and sodium hydroxide (440 mg, 11.0 mmol) were dissolved in distilled water (300 ml).

[2] Preparation of test solution The following sample solution was prepared using the phosphate buffer, bovine serum albumin (Sigma No. A-8022, hereinafter abbreviated as BSA), glucose, and a test substance. DMSO represents dimethyl sulfoxide, aminoguanidine hydrochloride was added to the phosphate buffer, and the other test substances were dissolved in DMSO in advance.
(Normal group): BSA (60 mg) + phosphate buffer (2.85 ml) + DMSO (0.15 ml)
(Control group): BSA (60 mg) + glucose (27 mg) + phosphate buffer (2.85 ml) + DMSO (0.15 ml)
(Test group): BSA (60 mg) + glucose (27 mg) + phosphate buffer (2.85 ml) + DMSO (0.15 ml) + test substance (0.030 mmol)

[3] Measurement of nonenzymatic glycosylation reaction and furosine production inhibition rate Each test solution (3 lots) was stored at 37 ° C. After standing for 3 weeks, each test solution (1.2 ml) was taken, and 40% aqueous trichloroacetic acid solution (0.3 ml) was added. After collecting the produced precipitate, the precipitate was washed twice with 8% aqueous trichloroacetic acid solution (6 ml). The precipitate was dried under reduced pressure, 6N hydrochloric acid (1 ml) was added, and hydrolysis was performed at 100 ° C. for 20 hours. After distilling off hydrochloric acid under reduced pressure, distilled water (1 ml) was added to prepare a sample for high performance liquid chromatography.
The peak area ratio of tyrosine (retention time: about 9.2 minutes) and furosine (retention time: about 3.6 minutes) produced with the progress of non-enzymatic glycosylation on high performance liquid chromatography is defined as The inhibition rate of furosine production was determined by the formula. The average inhibition rate of 3 lots obtained for each test substance is shown in Table 1.

[Conditions for high performance liquid chromatography]
Column: TOSOH TSKgel Octyl-80Ts (15 cm)
Eluent: 7 mM phosphoric acid aqueous solution Detection wavelength: 280 nm, column temperature 25 ° C., flow rate 0.8 ml / min

As shown in Table 1, it has been clarified that the compounds 4 to 7 of the present invention have a higher inhibitory effect on furosine production compared to aminoguanidine hydrochloride which is a known Maillard reaction inhibitor. That is, it has been found that the production itself of the Amadori transition product, which is a direct causative substance of the protein-molecule cross-linking formation in the Maillard reaction, is inhibited.

Since the carnosine ester compound of the present invention is novel and has Maillard reaction inhibitory activity, diseases involving Maillard reaction, that is, peripheral circulation disorder, diabetic nephropathy, coronary heart disease, cerebrovascular disorder, neuropathy, retina To prevent and treat various diseases related to aging such as diabetic complications and cataracts, atherosclerosis, senile cataracts, capillary obstruction, dialysis related complications, etc. It can be expected to be applied in the field of pharmaceuticals, quasi-drugs, cosmetics, and foods, and its usefulness is very high.

Claims (1)

A carnosine ester compound represented by the following general formula (A).