JPH09124471A - Inhibitor of maillard reaction - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an inhibitor of the Maillard reaction containing a 2- hydroxyphenylalkylamine derivative or its salt as an active ingredient. SOLUTION: This inhibitor of the Maillard reaction contains a 2- hydroxyphenylalkylamine derivative, represented by the formula (R<1> to R<4> are each H, an alkyl group, an alkoxy group, hydroxyl group, mercapto group, a halogen, nitro group, amino group, an acylamino group, an acyl group or a hydroxyalkyl group; R<5> is H or an alkyl group; A is a single bond, an alkylene group, etc.; Y is a single bond or an alkylene group; Z is hydroxyl group, an alkoxy group, an aryloxy group, an aralkyloxy group, a substitutable amino group, mercapto group, nitro group, etc.), having inhibiting activities against the Maillard reaction and useful as a preventing or a therapeutic agent for diseases, etc., caused by diabetic complications or aging, a cosmetic or a food as an active ingredient.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a Maillard reaction inhibitor containing a 2-hydroxyphenylalkylamine derivative or a pharmacologically acceptable salt thereof as an active ingredient.

More specifically, the present invention has the general formula

[0003]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ are
They may be the same or different, and each is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a mercapto group, a halogen atom, a nitro group, an amino group, an acylamino group, an acyl group or a hydroxy lower alkyl group,
R ⁵ is a hydrogen atom or a lower alkyl group, A is a single bond or a lower alkylene group which may have a hydroxyl group as a substituent, or a lower alkenylene group, Y is a single bond or a lower alkylene group, and Z is Is a hydroxyl group, lower alkoxy group, aryloxy group, aralkyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, arylamino group, diarylamino group, aralkylamino group, dialalkylamino group, mercapto group , A lower alkylthio group, an arylthio group, an aralkylthio group, or a nitro group), which is a 2-hydroxyphenylalkylamine derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and is related to the Maillard reaction. As a preventive and therapeutic agent for diseases, as well as cosmetics and foods In regard to the Maillard reaction inhibitor useful in.

[0005]

2. Description of the Related Art In the field of food chemistry, it has been observed that reducing sugars such as glucose react with amino compounds in foods to form brown pigments. On the other hand, in recent years, it has been confirmed that a similar reaction occurs in the living body, and is considered to be strongly involved as one of the onset factors of diseases such as diabetic complications and arteriosclerosis. I'm taking a bath.

The above-mentioned reaction is called the Maillard reaction. The Maillard reaction in the living body is such that reducing sugars such as glucose, fructose and pentose, their phosphoric acid esters or carbonyl compounds such as ascorbic acid liberate proteins in the living body. A Schiff base is non-enzymatically reacted with an amino group to form a Schiff base, which is converted to an Amadori rearrangement product by chemical rearrangement, and subsequent reactions such as oxidation, dehydration, polymerization, and cleavage cause the protein to intermolecular and A late-stage reaction product (AGE: Advan, which is denatured with formation of intramolecular crosslinks, exhibits a brown color, is poorly soluble, and is difficult to be decomposed by protease
ced Glycation End Product
The reaction proceeds by a series of reactions consisting of the later stages up to s).

[0007] AG produced in the process of the Maillard reaction
The production of E and its precursors increases with the concentration of sugar and protein and the reaction time. Therefore, renal diseases such as diabetes, where hyperglycemic conditions persist, ageing for a long period of exposure to sugar, or in vivo proteins in tissues with a long half-life of proteins, and decrease in clearance. It is known that proteins in blood and tissues of patients such as are susceptible to Maillard reaction.

[0008] From these facts, examples of the in-vivo protein which undergoes the Maillard reaction include ocular lens crystallin, serum albumin, collagen and elastin of connective tissues such as skin and blood vessel wall, nerve myelin protein, hemoglobin, and thread of kidney. There are many proteins such as the basement membrane of the sphere,
The Maillard reaction is the onset of diabetic complications such as retinopathy, nephropathy, cardiovascular system disorders, neuropathy and cataracts caused by degeneration, abnormality or functional decline of these proteins, and diseases caused by arteriosclerosis or aging. It is considered to be one of the causes. Therefore, for the prevention and treatment of these diseases, developmental research has been attempted to find compounds that inhibit the Maillard reaction.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel and safe Maillard reaction inhibitor having a chemical structure different from that of the conventional compound having a Maillard reaction inhibitory action.

[0010]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies to find a compound having a Maillard reaction inhibitory action, and as a result, found that the 2-hydroxyphenylalkylamine derivative of the present invention has an excellent Maillard reaction inhibitory activity. The findings were obtained and the present invention was accomplished.

That is, the Maillard reaction inhibitor of the present invention has the general formula

[0012]

Embedded image

(Wherein R ¹ , R ² , R ³ and R ⁴ are
They may be the same or different, and each is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a mercapto group, a hydroxyl group, a halogen atom, a nitro group, an amino group, an acylamino group, an acyl group or a hydroxy lower alkyl group,
R ⁵ is a hydrogen atom or a lower alkyl group, A is a single bond or a lower alkylene group which may have a hydroxyl group as a substituent, or a lower alkenylene group, Y is a single bond or a lower alkylene group, and Z is Is a hydroxyl group, lower alkoxy group, aryloxy group, aralkyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, arylamino group, diarylamino group, aralkylamino group, dialalkylamino group, mercapto group , A lower alkylthio group, an arylthio group, an aralkylthio group or a nitro group), or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the lower alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a te group.
An rt-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group or the like is a linear or branched alkyl group having 1 to 6 carbon atoms, and a lower alkoxy group is a methoxy group, Ethoxy group,
Propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, etc. 6 refers to a straight-chain or branched alkoxy group. The aryl group refers to an aromatic hydrocarbon group such as a phenyl group and a naphthyl group, and the aralkyl group refers to the above lower alkyl group substituted with the above aryl group.
Further, the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the acyl group is an acetyl group, a propionyl group, a butyryl group or the like having a linear or branched alkyl group having 2 to 2 carbon atoms. 7 refers to an alkylcarbonyl group. The lower alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms such as methylene group, ethylene group, propylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, etc. The alkenylene group refers to a linear or branched alkenylene group having 2 to 6 carbon atoms such as a vinylene group and a propenylene group.

2- represented by the general formula (I) of the present invention
The hydroxyphenylalkylamine derivative is described in the literature, including some known compounds, and described in the literature (for example, JP-A-5-208954 and JP-A-7-12).
6227, etc.) or a method similar thereto, or a combination of other known methods.

For example, among the compounds of the present invention, the general formula

[0017]

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(In the formula, Z ¹ is a hydroxyl group, a lower alkoxy group, an aryloxy group or an aralkyloxy group, and R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above). The compound has the general formula

[0019]

Embedded image

(In the formula, R ⁶ is a hydroxyl-protecting group, and R ^6
7 , R ⁸ , R ⁹ and R ^{10, which} may be the same or different, each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a protected hydroxyl group, a protected mercapto group, a halogen atom, a nitro group, a protected group. An amino group, an acylamino group, an acyl group or a protected hydroxy lower alkyl group) represented by formula (1) is reacted with ammonium carbonate and sodium cyanide in an inert solvent to give a compound represented by the general formula:

[0021]

[Chemical 6]

(Wherein R ⁶ , R ⁷ , R ⁸ , R ⁹ and R
¹⁰ has the same meaning as described above), and the resulting compound is hydrolyzed under alkaline conditions and, if desired, the amino group and the like are protected with an appropriate protecting group by a conventional method. , Esterified by a conventional method with a lower alcohol such as methanol, and further reduced with a reducing agent such as lithium borohydride, and then, if necessary, represented by the general formula: R ¹¹ —OH (IV) (wherein R ¹¹ is a lower alkyl group, an aryl group or an aralkyl group) and is O-alkylated by a conventional method using an alcohol compound represented by the general formula

[0023]

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(Wherein R ¹² is an amino group having a protecting group, and R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and Z ¹ have the same meanings as described above) After obtaining, it can be produced by removing protective groups such as hydroxyl group and amino group.

2- represented by the above general formula (I) of the present invention
The hydroxyphenylalkylamine derivative can be converted into a pharmacologically acceptable salt by a conventional method. Such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid,
Acid addition salts with mineral acids such as sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid,
With inorganic bases such as tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and other acid addition salts, sodium salts, potassium salts, calcium salts, etc. Can be mentioned.

Further, the compound represented by the above general formula (I) of the present invention includes a hydrate and a solvate with a pharmaceutically acceptable solvent such as ethanol.

2- represented by the general formula (I) of the present invention
Since the hydroxyphenylalkylamine derivative has one or more asymmetric carbon atoms, there are two optical isomers of R configuration and S configuration at each asymmetric carbon, and any optical isomer is used in the present invention. Alternatively, it may be a mixture of those optical isomers.

Among the compounds represented by the above general formula (I) of the present invention, compounds having an unsaturated bond have two geometric isomers. In the present invention, cis (Z) is present.
Either the body compound or the trans (E) compound may be used.

The compound of the present invention represented by the above general formula (I) is an in vitro compound containing lysozyme and fructose.
In the Maillard reaction inhibitory activity test of ro, it showed the same degree of inhibitory activity against the dimerization of lysozyme, as compared with aminoguanidine known as a substance having a Maillard reaction inhibitory activity.

As described above, the compound represented by the general formula (I) and the pharmaceutically acceptable salt thereof of the present invention have excellent Maillard reaction inhibitory activity, and diseases associated with the Maillard reaction. It is a very useful compound as a prophylactic and therapeutic agent for.

The compound represented by the above general formula (I) and the pharmaceutically acceptable salt thereof of the present invention have a Maillard reaction inhibitory activity and are effective against diseases associated with the Maillard reaction. It is valid. Such diseases include:
Coronary artery disease, peripheral circulation disorder, cerebrovascular disorder, diabetic neuropathy, nephropathy, arteriosclerosis, arteriosclerosis, cataract, retinopathy, coagulopathy, diabetic complications such as diabetic osteopenia, atheroma Diseases considered to be caused by aging such as arteriosclerosis, glomerulonephritis, senile cataract, osteoarthritis, periarticular stiffness, arteriosclerosis and senile osteoporosis can be mentioned. It is very useful as a preventive and therapeutic agent for. Also, as is well known, the Maillard reaction proceeds in cosmetics and foods containing proteins and amino acids, and protein and amino acids are degraded. Therefore, they are also useful as cosmetics and foods as compounds that inhibit the Maillard reaction.

The compound represented by the above general formula (I) of the present invention can be used, for example, in an acute toxicity test using mice.
2-amino-2- (2-hydroxyphenyl) ethanol / hydrochloride was not administered, and no death was observed after the single administration of 1000 mg / kg. Thus, the compounds of the present invention are
It is a highly safe compound and a very useful compound as a Maillard reaction inhibitor.

2- represented by the general formula (I) of the present invention
When the hydroxyphenylalkylamine derivative and a pharmacologically acceptable salt thereof are used for the actual treatment,
It is orally or parenterally administered as a suitable pharmaceutical composition such as tablets, powders, fine granules, granules, capsules, solutions, injections, external preparations, eye drops, suppositories and the like. These pharmaceutical compositions can be prepared by a pharmaceutical method performed in a general preparation, by using carriers, excipients, and other additives for pharmaceuticals that are generally used.

Of the above-mentioned pharmaceutical compositions, in tablets, powders, fine granules, granules, capsules, etc., the excipients, disintegrants, binders, lubricants etc. that are commonly used are used. As an excipient, for example, sugar or sugar alcohol D-mannitol, lactose, sucrose, starch or starch derivative wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partial α Starch, dextrin, cyclodextrin, pullulan, hydroxypropyl starch, etc., cellulose or cellulose derivative crystalline cellulose, crystalline cellulose / carmellose sodium, methyl cellulose, hydroxypropyl methylcellulose, etc. and other sodium alginate, acacia, agar, macrogol, Aluminum stearate, Aluminum non-stearate, as an inorganic excipient, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, magnesium aluminometasilicate, synthetic aluminum silicate, synthetic hydrotalcite,
Aluminum hydroxide, magnesium hydroxide, calcium phosphate, dry ammonium hydroxide gel, precipitated calcium carbonate, light anhydrous silicic acid and the like can be used, but these are not limited as excipients and are disintegrators or binders. Can also be used as

Examples of the disintegrant include carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, tragacanth, starch or starch derivatives such as wheat starch, rice starch, corn starch and potato starch. , Α-starch, partially α-starch, dextrin, pullulan, hydroxypropyl starch and the like can be used, but these are not limited as disintegrants and can be used as excipients.

Examples of the binder include hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, povidone, starch or starch derivatives such as wheat starch, rice starch, corn starch, potato starch, pregelatinized starch, partially pregelatinized starch, dextrin and pullulan. , Hydroxypropyl starch and the like can be used.

Examples of lubricants include calcium stearate, magnesium stearate, stearic acid, talc, cetanol, polyoxyl 40 stearate, leucine, lubrice wax, sodium lauryl sulfate, paraffin, polyoxyethylene glycol fatty acid ester and fatty acid ester. Although they can be used, they are not limited to lubricants and can be used as excipients.

The tablets may be coated with a film of lactose, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer or hydroxypropylmethylcellulose phthalate.

Examples of the diluent for the liquid agent include, for example,
Purified water, polyol, sucrose, invert sugar, glucose or the like can be used. In addition to the diluent, a solubilizing agent, a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, an antiseptic agent and the like may be added to the liquid agent, if desired.

As the diluent for the injection, for example, distilled water, physiological saline, alcohol, glycerol, polyol, vegetable oil and the like can be used. In addition to the diluent, a buffer, an isotonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, a solubilizing agent and the like may be added to the injection, if desired.

As the ophthalmic solution, a buffer, a tonicity agent, a stabilizer, a preservative, an antioxidant, a thickener, an antiseptic, a solubilizing agent, etc. may be added, if desired, in addition to the diluent. May be.

As the carrier for suppositories, lipids, waxes, semisolid or liquid polyols, natural oils or hydrogenated oils can be used. Further, in the suppository, in addition to the carrier, a dispersant, a dispersion aid, an absorption promoter and the like may be added.

The dose is appropriately determined according to the sex, age, weight, and degree of symptoms of the subject patient. In the case of oral administration, the dose is generally 1 to 1000 per adult per day.
mg, parenteral administration: about 0.1
It is administered within the range of 100 mg in a single dose or in divided doses.

When the compound represented by the general formula (I) of the present invention is used as an eye drop, it is 0.05 W / V% to 5%.
It is mixed in the range of W / V% and prepared by a conventional method, and the frequency of administration is appropriately determined depending on the degree of symptom of the patient.

When the compound of the present invention represented by the general formula (I) is used as an external preparation or a cosmetic, the content of the compound of the present invention is about 0.05 based on the whole preparation.
It can be produced by blending it in an amount of 10 to 10 parts by weight and preparing it by a conventional method using a general external base or cosmetic base. Further, the compound of the present invention can be prepared for foods by a conventional method, or can be added to foods for use.

[0046]

BEST MODE FOR CARRYING OUT THE INVENTION The contents of the present invention will be described in more detail with reference to Reference Examples, Examples and Prescription Examples below, but the present invention is not limited to these contents.

[0047]

【Example】

Reference Example 1 2-methoxymethoxybenzaldehyde 15 g of salicylaldehyde was dissolved in 150 ml of methylene chloride, and diisopropylethylamine 23.5 was dissolved under ice cooling.
ml, then 10.3 ml of chloromethyl methyl ether
20 ml of methylene chloride solution was added dropwise and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed successively with 2N sodium hydroxide solution, saturated saline, 10% aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 20.4 g of 2-methoxymethoxybenzaldehyde.

Colorless oil NMR (CDCl ₃ , 270 MHz) δ ppm: 3.52 (3H, s), 5.31 (2H,
s), 7.00-7.15 (1H, m), 7.22 (1
H, d, J = 7.9 Hz), 7.45-7.60 (1
H, m), 7.85 (1H, dd, J = 7.4 Hz,
2.0 Hz), 10.51 (1H, br d, J = 1.
0Hz)

Reference Example 2 5- (2-methoxymethoxyphenyl) hydantoin 20.2 g of ammonium carbonate and sodium cyanide 4.
43 g was dissolved in 75 ml of water, a solution of 10 g of 2-methoxymethoxybenzaldehyde in 75 ml of ethanol was added, and the mixture was stirred at 50 ° C. for 2 days. After completion of the reaction, about 1 of solvent
/ 2 amount was distilled off under reduced pressure, and the precipitated solid was collected by filtration under ice cooling. After washing with water and ether in this order, it was dried under reduced pressure in the presence of diphosphorus pentoxide to obtain 7.4 g of 5- (2-methoxymethoxyphenyl) hydantoin.

White powder NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.36 (3 H, s), 5.18 (2 H,
s), 5.20 (1H, s), 6.96-7.04 (1
H, m), 7.09 (1H, d, J = 8.2 Hz),
7.25 (1H, dd, J = 7.6Hz, 1.6H
z), 7.28-7.36 (1H, m), 8.06 (1
H, br s), 10.68 (1H, br s)

Reference Example 3 α-tert-Butyloxycarbonylamino-2-methoxymethoxyphenylacetic acid 4.0 g of 5- (2-methoxymethoxyphenyl) hydantoin was added to 2.02 g of sodium hydroxide in an aqueous solution of 40 m.
It was heated to reflux for 2 days. After completion of the reaction, 31.9 ml of 2N hydrochloric acid was added under ice cooling, and the solvent was distilled off under reduced pressure until foaming stopped. After adding 30 ml of dioxane to this mixture, 3.24 ml of triethylamine and dit.
-Butyl (4.06 g) was added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, chloroform and a small amount of methanol were added to the reaction mixture, which was washed with 10% aqueous citric acid solution and saturated brine in that order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and α-tert-butyloxycarbonylamino-
3.65 g of 2-methoxymethoxyphenylacetic acid was obtained.

Colorless amorphous NMR (CDCl ₃ , 400 MHz) δ ppm: 1.43 (9 H, s), 3.46 (3 H,
s), 5.21 (1H, d, J = 6.7 Hz), 5.2
5 (1H, d, J = 6.7 Hz), 5.60 (1H, b
r), 5.66 (1H, br), 7.02 (1H, t,
J = 7.5 Hz), 7.13 (1H, d, J = 8.3H)
z), 7.24-7.36 (2H, m)

Reference Example 4 Methyl α-tert-butyloxycarbonylamino-2-methoxymethoxyphenylacetic acid α-tert-butyloxycarbonylamino-2-methoxymethoxyphenylacetic acid 2.0 g of methanol 10
It was dissolved in ml and the diazomethane-ether solution was added dropwise under ice cooling. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and α
1.91 g of methyl-tert-butyloxycarbonylamino-2-methoxymethoxyphenylacetate was obtained.

White solid NMR (CDCl ₃ , 400 MHz) δ ppm: 1.43 (9H, s), 3.46 (3H,
s), 3.69 (3H, s), 5.18 (1H, d, J
= 6.7 Hz), 5.22 (1H, d, J = 6.7H)
z), 5.53 (1H, br d, J = 8.9 Hz),
5.65 (1H, br d, J = 7.9 Hz), 7.0
0 (1H, dt, J = 7.4Hz, 1.0Hz), 7.
11 (1H, d, J = 8.3 Hz), 7.23-7.3
5 (2H, m)

Reference Example 5 2-tert-butyloxycarbonylamino-2-
(2-Methoxymethoxyphenyl) ethanol 1.2 g of methyl α-tert-butyloxycarbonylamino-2-methoxymethoxyphenylacetate was dissolved in 6 ml of tetrahydrofuran, and 400 mg of lithium chloride was added.
Sodium borohydride (250 mg) was added at room temperature to suspend the mixture, and subsequently ethanol (12 ml) was added to dissolve the mixture and the mixture was stirred overnight. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride, and the solvent was distilled off under reduced pressure. Water was added to this residue and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel chromatography, 2-tert-
1.2 g of butyloxycarbonylamino-2- (2-methoxymethoxyphenyl) ethanol was obtained.

White amorphous NMR (CDCl ₃ , 400 MHz) δ ppm: 1.42 (9H, s), 3.46 (3H,
s), 3.72-3.80 (1H, m), 3.83-.
3.89 (2H, m), 5.08-5.10 (1H, b
r), 5.22 (2H, s), 5.48-5.50 (1
H, br), 6.98 (1H, dt, J = 7.2, 1.
0 Hz), 7.12 (1H, dd, J = 8.3, 1.1
Hz), 7.23-7.26 (2H, m)

Example 1 2-Amino-2- (2-hydroxyphenyl) ethanol.hydrochloride 2-tert-butyloxycarbonylamino-2-
(2-Methoxymethoxyphenyl) ethanol 7.4 g
Was dissolved in 10 ml of ethanol, 25 ml of hydrogen chloride-2-propanol solution was added, and the mixture was stirred at room temperature for one day. The solvent was distilled off under reduced pressure, and the obtained solid was purified by recrystallization from chloroform-n-hexane to give 2-amino-2-
(2-Hydroxyphenyl) ethanol / hydrochloride 3.6
5 g were obtained.

White solid NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.65 (2 H, m), 4.45 (1 H,
q, J = 4.5 Hz), 5.50 (1H, br s),
6.84 (1 H, t, J = 7.6 Hz), 6.92 (1
H, d, J = 8.3 Hz), 7.18 (1H, t, J =
7.6 Hz), 7.34 (1H, d, J = 7.6H)
z), 8.10-8.50 (3H, br), 10.00
-10.25 (1H, br)

Reference Example 6 N-tert-butyloxycarbonyl-α-methoxymethyl-2-methoxymethoxybenzylamine To 6 ml of a tetrahydrofuran suspension of 189 mg of sodium hydride (60% oily) in 2-tert-butyl under ice cooling. 6 ml of a tetrahydrofuran solution containing 1.27 g of oxycarbonylamino-2- (2-methoxymethoxyphenyl) ethanol was added, and the mixture was stirred for 30 minutes under ice cooling and 30 minutes at room temperature, then ice cooled again and 2.7 ml of dimethylsulfate was added. Three
The mixture was stirred for an hour, and stirred overnight while warming to room temperature. The reaction was stopped by adding a saturated aqueous ammonium chloride solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel chromatography and N-ter.
t-butyloxycarbonyl-α-methoxymethyl-2
1.12 g of -methoxymethoxybenzylamine was obtained.

White solid NMR (CDCl ₃ , 400 MHz) δ ppm: 1.42 (9H, s), 3.32 (3H,
s), 3.49 (3H, s), 3.52-3.65 (2
H, m), 5.20 (1H, br), 5.23 (2H,
s), 5.45 (1H, br), 6.98 (1H, t,
J = 5.5 Hz), 7.10 (1H, dd, J = 8.
3, 4.6 Hz), 7.23-7.26 (2H, m)

Example 2 α-methoxymethyl-2-hydroxybenzylamine
Hydrochloride N-tert-butyloxycarbonyl-α-methoxymethyl-2-methoxymethoxybenzylamine 1.12
g was dissolved in 10 ml of ethanol, 3 ml of hydrogen chloride-2-propanol solution was added, and the mixture was stirred at room temperature for one day. The solvent was distilled off under reduced pressure, and the obtained solid was purified by recrystallization from chloroform-n-hexane to obtain 0.55 g of α-methoxymethyl-2-hydroxybenzylamine · hydrochloride.

White solid NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.26 (3 H, s), 3.39-3.6
4 (2H, m), 4.56 (1H, dd, J = 8.4,
4.2Hz), 6.83 (1H, t, J = 7.5H
z), 6.90 (1H, d, J = 7.3 Hz), 7.1
7 (1H, dt, J = 7.3, 1.6Hz), 7.32
(1H, dd, J = 7.6, 1.4Hz), 8.32
(3H, br)

Reference Example 7 4-tert-butyloxycarbonylamino-4-
Methyl (2-methoxymethoxyphenyl) crotonate 2-tert-butyloxycarbonylamino-2-
(2-methoxymethoxyphenyl) ethanol 1.0 g
To 20 ml of methylene chloride, 2 ml of dimethyl sulfoxide and 1 ml of triethylamine were added at room temperature, and then 2 g of sulfur trioxide pyridine complex was gradually added under ice cooling and stirred for 15 minutes, and then the temperature was raised to room temperature. Stir for 1 hour. After 1N hydrochloric acid was added to stop the reaction, water was added to the reaction solution and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an aldehyde mixture. Separately, a tetrahydrofuran solution containing 0.7 ml of trimethylphosphonoacetate 2
5 ml of sodium hydride (60 ml) in an argon stream under ice cooling.
% Oily) was added and stirred for 5 minutes to prepare, and then 25 ml of a tetrahydrofuran solution of the aldehyde mixture was added dropwise. The mixture was stirred for 10 minutes as it was, and then stirred for 30 minutes while warming to room temperature. The reaction was stopped by adding saturated aqueous ammonium chloride, water was further added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were collected, washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is isolated by silica gel chromatography, 4-tert-
780 mg of methyl butyloxycarbonylamino-4- (2-methoxymethoxyphenyl) crotonate was obtained.

White solid NMR (CDCl ₃ , 400 MHz) δ ppm: 1.41 (9H, s), 3.46 (3H,
s), 3.71 (3H, s), 5.20 (1H, d, J
= 6.8 Hz), 5.24 (1H, d, J = 6.8H)
z), 5.37 (1H, br d, J = 7.6 Hz),
5.65 (1H, br d, J = 7.6 Hz), 5.9
3 (1H, dd, J = 1.8, 15.8Hz), 6.9
8 (1H, t, J = 7.6Hz), 7.06 (1H,
d, J = 4.8 Hz), 7.11 (1H, d, J = 8.
0 Hz), 7.18-7.29 (2H, m)

Reference Example 8 4-tert-butyloxycarbonylamino-4-
Methyl (2-methoxymethoxyphenyl) butyrate 4-tert-butyloxycarbonylamino-4-
Methyl (2-methoxymethoxyphenyl) crotonate 4
00 mg was dissolved in 20 ml of methanol, hydrogenated at 1 atm in the presence of 100 mg of 10% palladium-carbon powder, and stirred overnight at room temperature. After removing the palladium-carbon powder by Celite filtration, the reaction filtrate was concentrated, and then 4-ter
360 mg of methyl t-butyloxycarbonylamino-4- (2-methoxymethoxyphenyl) butyrate was obtained.

White solid NMR (CDCl ₃ , 400 MHz) δ ppm: 1.41 (9 H, s), 2.04-2.1
8 (2H, m), 2.20-2.38 (2H, m),
3.49 (3H, s), 3.63 (3H, s), 4.8
9 (1H, q, J = 7.5 Hz), 5.25 (2H,
s), 5.42 (1H, br d, J = 6.2 Hz),
6.92 (1H, dt, J = 7.5, 1.1Hz),
7.12 (1H, dd, J = 6.2, 1.1Hz),
7.15-7.24 (2H, m)

Reference Example 9 4-tert-butyloxycarbonylamino-4-
(2-Methoxymethoxyphenyl) butanol 4-tert-butyloxycarbonylamino-4-
Methyl (2-methoxymethoxyphenyl) butyrate 700 m
g was dissolved in 4 ml of tetrahydrofuran, 200 mg of lithium chloride and 125 mg of sodium borohydride were added and suspended at room temperature, 12 ml of ethanol was subsequently added and dissolved, and the mixture was stirred overnight at room temperature. After adding saturated aqueous ammonium chloride to stop the reaction, the solvent was distilled off under reduced pressure,
Further, water was added to the residue and the solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to obtain 530 mg of 4-tert-butyloxycarbonylamino-4- (2-methoxymethoxyphenyl) butanol.

White solid NMR (CDCl ₃ , 400 MHz) δ ppm: 1.41 (9H, s), 1.50-1.6
4 (2H, m), 1.83-1.91 (2H, m),
3.49 (3H, s), 3.67 (2H, t, J = 6.
3Hz), 4.89 (1H, q, J = 7.5Hz),
5.25 (2H, s), 5.37 (1H, br d, J
= 7.6 Hz), 6.92 (1H, dt, J = 7.6,
1.1 Hz), 7.12 (1H, dd, J = 6.2,
1.1 Hz), 7.18-7.22 (2H, m)

Example 3 4-Amino-4- (2-hydroxyphenyl) butanol-hydrochloride 4-tert-butyloxycarbonylamino-4-
(2-Methoxymethoxyphenyl) butanol 50 mg
Was dissolved in 3 ml of ethanol, 1 ml of hydrogen chloride-2-propanol solution was added, and the mixture was stirred at room temperature for one day. The solvent was distilled off under reduced pressure and the obtained solid was purified by recrystallization from chloroform-n-hexane to give 4-amino-4-
(2-Hydroxyphenyl) butanol / hydrochloride 85m
g was obtained.

White solid NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.21-1.59 (2H, m), 1.8
3-1.94 (2H, m), 3.45 (2H, m),
4.39-4.54 (1H, m), 6.85 (1H,
t, J = 7.5 Hz), 6.92 (1H, d, J = 7.
2Hz), 7.18 (1H, dt, J = 8.9, 1.6
Hz), 7.33 (1H, d, J = 7.2 Hz), 8.
10-8.35 (3H, br), 10.07 (1H,
s)

Example 4 Acute toxicity test Five 6-week-old male ICR mice (29.5 to 31.0 g) were used.
2-Amino-2 fasted for 0.5 hours and suspended in 0.5% CMC
-(2-hydroxyphenyl) ethanol / hydrochloride (1
(00 mg / ml) was orally administered at a dose of 1000 mg / kg body weight. The control group received only 0.5% CMC.

After 4 hours from the administration, food and drinking water were freely given, and the animals were kept for 5 days. As a result, no individual died within 5 days after administration.

Example 5 Maillard Reaction Inhibitory Activity Test Lysozyme, fructose and test compound were adjusted to 10 mg / ml, 200 mM and 20 mM, respectively.
Dissolve in 5M sodium phosphate buffer (pH 7.4),
Incubated at 37 ° C for 1 week.

Incubation samples were SDS-P
Separated by AGE, Coomassie Bril
After staining with lient Blue R-250, the dimer generation rate with respect to the total protein was measured with a densitometer.

The inhibitory activity of the test compound was determined from the dimer production rate in the presence of the test compound relative to the dimer production rate in the absence of the test compound.

[0076]

[Table 1]

Prescription Example 1 Tablet active ingredient 100 mg Corn starch 50 mg Lactose 70 mg Hydroxypropyl cellulose 7 mg Magnesium stearate 3 mg (total 230 mg)

Prescription Example 2 Fine-grain base drug 100 mg Mannitol 190 mg Corn starch 100 mg Hydroxypropyl cellulose 10 mg (total 400 mg)

Prescription Example 3 Capsule active ingredient 100 mg Lactose 18 mg Crystalline cellulose 35 mg Corn starch 25 mg Magnesium stearate 2 mg (total 180 mg)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Miho Kobayashi 2583 Minamihotaka, Toyoshina-cho, Minamiazumi-gun, Nagano Prefecture

Claims (1)

[Claims] 1. A compound of the general formula (In the formula, R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents a hydrogen atom, a lower alkyl group,
A lower alkoxy group, a hydroxyl group, a mercapto group, a halogen atom, a nitro group, an amino group, an acylamino group, an acyl group or a hydroxy lower alkyl group, R ⁵ represents a hydrogen atom or a lower alkyl group, and A represents a single bond or a substituent. Is a lower alkylene group which may have a hydroxyl group or a lower alkenylene group, Y is a single bond or a lower alkylene group, Z is a hydroxyl group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, an amino group, Lower alkylamino group, di-lower alkylamino group, arylamino group, diarylamino group, aralkylamino group, dialalkylamino group, mercapto group, lower alkylthio group, arylthio group, aralkylthio group or nitro group) Induced 2-hydroxyphenylalkylamine A Maillard reaction inhibitor containing a conductor or a pharmacologically acceptable salt thereof as an active ingredient.