JPH0959233A - Ortho-hydroxynaphthylalkylamine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel O-hydroxynaphthylamine derivative which is useful as a preventive for diseases associating with Maillard reaction suck as diabetic complication because it has the action to inhibit the Maillard reaction. SOLUTION: This compound is represented by formula I [R is formula (R<1> , R<2> , R<3> , R<4> , R<5> , and R<6> are independent1y of one another H, a lower alkyl); R is H, a lower alkyl; A is a single bond, a lower alkylene; Y is a single bond, a lower alkylene; Z is carboxy], typically, 2-amino-2-(2-hydroxy-1-naphthyl)acetic acid. A compound of formula I (Z is COOH) is obtained by hydrolysis of the corresponding hydantoin derivative under alkaline conditions.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an o-hydroxynaphthylalkylamine derivative useful as a medicine and a pharmaceutically acceptable salt thereof.

More specifically, the present invention provides a compound of general formula useful as a prophylactic and therapeutic agent for diseases associated with Maillard reaction and in cosmetics and foods.

[0003]

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(E in the formula is a general formula

[0005]

[Chemical 6]

The group represented by the general formula

[0007]

[Chemical 7]

A group represented by or a general formula

[0009]

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Is a group represented by R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ and R ^{6, which} may be the same or different, each represent a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a mercapto group, a halogen atom, a nitro group,
Is an amino group, an acylamino group, an acyl group or a hydroxy lower alkyl group, R is a hydrogen atom or a lower alkyl group, and A is a lower bond which may have a hydroxyl group as a single bond or a substituent, or a lower alkenylene group. And Y is a single bond or lower alkylene,
Z is a carboxy group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a mono- or diarylaminocarbonyl group, a mono- or dialalkylaminocarbonyl group,
Cyano group, sulfo group, lower alkylsulfinyl group, lower alkylsulfonyl group, arylsulfinyl group, arylsulfonyl group, alalkylsulfinyl group, alalkylsulfonyl group, sulfamoyl group, lower alkylsulfamoyl group, arylsulfamoyl group or An alkylalkylsulfamoyl group)
-A hydroxynaphthylalkylamine derivative and a pharmaceutically acceptable salt thereof.

[0011]

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. In the living Maillard reaction, reducing sugars such as glucose, fructose and pentose, their phosphoric acid esters or carbonyl compounds such as ascorbic acid liberate in vivo proteins. 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).

AG formed 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.

From these facts, examples of proteins in the living body that undergo the Maillard reaction include, for example, ocular lens crystallin, serum albumin, collagen and elastin of connective tissues such as skin and blood vessel wall, nerve myelin protein, hemoglobin, kidney thread. 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 new compounds that inhibit the Maillard reaction.

[0015]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel o-hydroxynaphthylalkylamine derivative having a Maillard reaction inhibitory action and useful as a Maillard reaction inhibitor.

[0016]

Means for Solving the Problems As a result of intensive studies to find a compound useful as a Maillard reaction inhibitor, the present inventors have found that a certain o-hydroxynaphthylalkylamine represented by the above general formula (I) is used. The present inventors have obtained the finding that the derivative has excellent Maillard reaction inhibitory activity, and completed the present invention.

Here, in the compound represented by the above general formula (I) of the present invention, the lower alkyl group is a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, isoptyl group, sec-butyl group, tert-butyl group,
Pentyl group, isopentyl group, neopentyl group, ter
A t-pentyl group, a hexyl group, or another linear or branched alkyl group having 1 to 6 carbon atoms, and a lower alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isoptoxy group. Base, sec-
Butoxy group, tert-butoxy group, pentyloxy group,
Isopentyloxy group, neopentyloxy group, tert-
A linear or branched alkoxy group having 1 to 6 carbon atoms such as a pentyloxy group and a hexyloxy 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 has a carbon number of 2 to 6 such as vinylene group and propenylene group.
Is a linear or branched alkenylene group.

The o-represented by the general formula (I) of the present invention
Hydroxynaphthylalkylamine derivatives are described in the literature (for example, JP-A-46-7875 and JP-A-48-
67245, JP-A-52-36644, JP-A-53-139551, J. Agric. Fo
od. Chem. , No. 4, pp965 (1977)
Etc.) and methods similar to those described above, or by combining other known methods.

For example, among the o-hydroxynaphthylalkylamine derivatives represented by the general formula (I) of the present invention, the general formula

[0020]

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(Wherein Z ¹ is a carboxy group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a mono- or diarylaminocarbonyl group, or a mono- Or a dialalkylaminocarbonyl group and E has the same meaning as described above)

[0022]

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(In the formula, R ⁷ is a hydroxyl-protecting group,
⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹³ may be the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a protected hydroxyl group, a protected mercapto group or a halogen atom. , A nitro group, a protected amino group, an acylamino group, an acyl group or a protected hydroxy lower alkyl group).

[0024]

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(In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R
¹¹ , R ¹² and R ¹³ have the same meanings as described above) or a naphthyl aldehyde derivative represented by

[0026]

[Chemical 12]

(In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R
¹¹ , R ¹² and R ¹³ have the same meanings as described above), and a naphthyl aldehyde derivative represented by the following general formula is reacted with ammonium carbonate and sodium cyanide in an inert solvent.

[0028]

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(In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R
¹¹ , R ¹² and R ¹³ have the same meanings as described above),

[0030]

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(Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R
¹¹ , R ¹² and R ¹³ have the same meanings as described above) or a hydantoin derivative represented by

[0032]

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(In the formula, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R
⁽¹¹ , R ¹² and R ¹³ have the same meanings as described above), and the resulting compound is hydrolyzed under alkaline conditions. After protection with a protecting group, an ester is prepared by an ordinary method using an alcohol compound represented by the general formula R ¹⁴ —OH (IV) (wherein R ¹⁴ is a lower alkyl group, an aryl group or an aralkyl group). And, if desired,
General formula

[0034]

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(Wherein R ¹⁵ and R ¹⁶ may be the same or different and each is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group), and Then, it can be produced by removing a protective group such as a hydroxyl group.

The compound represented by the above general formula (I) of the present invention is an in vitro compound containing lysozyme and fructose.
In the ro Maillard reaction inhibitory activity test, aminoguanidine, which is known as a substance having Maillard reaction inhibitory activity, inhibits the dimerization of lysozyme by 2.9% at a concentration of 0.2 mM and 17.2% at a concentration of 2 mM, respectively. On the other hand, for example, 2-amino-2- (2-hydroxy-1-naphthyl) acetic acid hydrochloride has an inhibitory activity of 33.5% at a concentration of 0.2 mM and 68.7% at a concentration of 2 mM. showed that.

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 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.

O-represented by the general formula (I) of the present invention
The hydroxynaphthylalkylamine 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,
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 acid addition salts, sodium salts, potassium salts, calcium salts, etc. Salt, morpholine,
Examples thereof include salts with organic amines such as piperidine and amino acids.

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.

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

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

2- represented by the above 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.

The dose is appropriately determined depending on the sex, age, body weight, degree of symptoms, etc. of the target patient, but in the case of oral administration, it 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 of the present invention represented by the general formula (I) 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 so as to be 10 parts by weight and prepared by a conventional method using a general base for external use or a base for cosmetics. Further, the compound of the present invention can be prepared for foods by a conventional method, or can be added to foods for use.

[0047]

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

[0048]

【Example】

Reference Example 1 2-Methoxymethoxy-1-naphthaldehyde 2.5 g of 2-hydroxy-1-naphthaldehyde was dissolved in 20 ml of methylene chloride, 3.79 ml of diisopropylethylamine and then 1.65 ml of chloromethyl methyl ether under ice cooling. The mixture was stirred at room temperature for 1.5 hours.
After completion of the reaction, the reaction mixture was mixed with 2N sodium hydroxide solution,
The extract was washed with saturated saline, 10% aqueous citric acid solution and saturated brine in that order, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.0 g of 2-methoxymethoxy-1-naphthaldehyde.

White solid NMR (CDCl ₃ , 270 MHz) δppm: 3.56 (3H, s), 5.40 (2H,
s), 7.39-7.49 (2H, m), 7.57-
7.68 (1H, m), 7.78 (1H, d, J = 8.
9 Hz), 8.03 (1H, d, J = 8.9 Hz),
9.22-9.30 (1H, m), 10.94 (1H,
s)

Reference Example 2 5- (2-Methoxymethoxy-1-naphthyl) hydantoin 4.71 g of ammonium carbonate and sodium cyanide 1.
03 g was dissolved in 25 ml of water, and 2-methoxymethoxy-
A solution of 3.0 g of 1-naphthaldehyde in 25 ml of ethanol was added, and the mixture was stirred at 45 ° C. for 4 hours and then at 85 ° C. for 1 hour. After the reaction was completed, about 1/2 amount of the solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration under ice cooling. After washing with water, it was dried under reduced pressure in the presence of diphosphorus pentoxide to obtain 2.4 g of 5- (2-methoxymethoxy-1-naphthyl) hydantoin.

Gray solid NMR (DMSO-d ₆ , 270 MHz) δ ppm: 3.39 (3 H, s), 5.20-5.35
(2H, m), 5.90-6.10 (1H, m), 7.
35-7.60 (3H, m), 7.90-8.10 (3
H, m), 8.10-8.30 (1H, m), 10.6
-10.7 (1H, m)

Example 2-Amino-2- (2-hydroxy-1-naphthyl) acetic acid hydrochloride 5- (2-methoxymethoxy-1-naphthyl) hydantoin 2.4 g of 3N sodium hydroxide solution 12.5 m
It was heated to reflux for 1 day. After the reaction was completed, 12.5 ml of 3N hydrochloric acid was added under ice cooling, and the solvent was distilled off under reduced pressure until no foaming occurred. Tetrahydrofuran 3 in this mixture
After adding 0 ml, 1.22 ml of triethylamine and 1.92 g of di-t-butyl dicarbonate were added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, add chloroform to the reaction mixture and
Back-extract with normal sodium hydroxide solution. 2 in this water layer
The pH of the aqueous layer was made acidic by adding normal hydrochloric acid and a 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was roughly purified by silica gel column chromatography, 4 ml of hydrogen chloride-2-propanol solution was added to the obtained brown oil, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, the solvent was distilled off under reduced pressure and recrystallized from tetrahydrofuran to obtain 67 mg of 2-amino-2- (2-hydroxy-1-naphthyl) acetic acid hydrochloride.

White solid NMR (DMSO-d ₆ , 400 MHz) δ ppm: 5.74 (1 H, s), 7.26 (1 H,
d, J = 8.9 Hz), 7.37 (1H, t, J = 7.
1 Hz), 7.50-7.58 (1 H, m), 7.85
-7.95 (2H, m), 8.05 (1H, br d,
J = 7.2 Hz), 8.2-8.8 (3H, br), 1
0.4-11.1 (1H, br)

 ─────────────────────────────────────────────────── ─── 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 (E in the formula is a general formula: A group represented by the general formula: A group represented by or a general formula: R < ¹ >, R < ² >, R < ³ >, R < ⁴ >, R < ⁵ > and R < ⁶ >, which may be the same or different, are each 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 represents 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 lower alkylene, Z is a carboxy group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-lower alkylaminocarbonyl group, a mono- or diarylaminocarbonyl group, Mono- or dialalkylaminocarbonyl group, cyano group, sulfo group, lower alkylsulfinyl group, lower alkylsulfonyl group, arylsulfinyl group, arylsulfonyl group, aralkylsulfinyl group, aralkylsulfonyl group, sulfamoyl group, lower alkylsulfamoyl group Group, an arylsulfamoyl group or an aralkylsulfamoyl group), and a pharmacologically acceptable salt thereof.