JPH0940626A - Bis(2-hydroxyphenylalkylamine) derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject derivative useful for the prevention and treatment of diseases relating to Maillard reaction e.g. diabetic complications such as retinosis and nephropathy and diseases caused by aging and useful also in the field of cosmetics and foods. SOLUTION: This bis(2-hydroxyphenylalkylamine) derivative of formula I R<1> , R<2> , R<3> and R<4> are each an alkoxy, etc.; R is an alkyl, etc.; A is an alkylene, etc.; Y is an alkylene; Z<1> and Z<2> are each O or NR<5> ; R<5> is an alkyl, etc.; X is an alkenylene, etc.}, e.g. N,N'-bis(α-amino-2-hydroxyphenylacetyl) octamethylenediamine. The compound of formula I is produced by reacting a compound of formula II [D is a protected hydroxyl group; R<6> , R<7> , R<8> and R<9> are each an alkoxy, etc.} with a benzaldehyde derivative of formula III in the presence of ammonium carbonate and Na cyanide in an inert solvent, hydrolyzing the produced hydantoin derivative under alkaline condition and protecting the amino group, etc., with protecting groups.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a bis (2-hydroxyphenylalkylamine) derivative useful as a drug or 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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(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 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 ¹ And Z ² is O or NR ⁵ , R ⁵ is a hydrogen atom or a lower alkyl group, and X is a lower alkylene group or a lower alkenylene group) or a bis (2-hydroxyphenylalkylamine) derivative or It relates to a pharmacologically acceptable salt thereof.

[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 new compounds that inhibit the Maillard reaction.

[0009]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel bis (2-hydroxyphenylalkylamine) derivative having a Maillard reaction inhibitory action and useful as a Maillard reaction inhibitor.

[0010]

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 bis (2-hydroxyphenyl) represented by the above general formula (I) is used. Alkylamine) derivative,
The present inventors have obtained the finding that it has an excellent Maillard reaction inhibitory activity, and completed the present invention.

Here, in the compound represented by the general formula (I) of the present invention, the lower alkyl group is a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group,
Pentyl group, isopentyl group, neopentyl group, ter
A linear or branched alkyl group having 1 to 6 carbon atoms, such as a t-pentyl group and a hexyl group, refers to a lower alkoxy group, and a lower alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group. Group, 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 halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and the acyl group refers to an acetyl group, a propionyl group, a butyryl group, or the like, which has a linear or branched alkyl group and has 2 to 7 carbon atoms. Refers to an alkylcarbonyl group. The lower alkylene group is a methylene group, an ethylene group,
A propylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, or a linear or branched alkylene group having 1 to 6 carbon atoms. A lower alkenylene group is a vinylene group, a propenylene group, or the like. It refers to a linear or branched alkenylene group having 2 to 6 carbon atoms.

The bis (2-hydroxyphenylalkylamine) derivative represented by the general formula (I) of the present invention is a novel compound and can be produced, for example, as follows. That is, the compound of the general formula (I) of the present invention has the general formula

[0013]

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(In the formula, D is a hydroxyl group having a protecting group, E is an amino group having a protecting group, and R ⁶ , R ⁷ ,
R ⁸ and R ⁹ may be the same or different and each represents 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 amino group, An acylamino group,
An acyl group or a protected hydroxy-lower alkyl group, A, R, and Y is a compound represented by have) the same meanings as defined above, the general formula ^{H-Z 1 -X-Z 2} -H (III) (X, Z ¹ and Z ² in the formula have the same meanings as described above)
It can be easily produced by reacting with a compound represented by the formula (1) in an inert solvent in the presence or absence of a dehydrating agent or a condensing agent, followed by deprotection by a conventional method.

The compound represented by the general formula (II) used in the above production method is described in JP-A-46-7875.
JP-A-48-67245, JP-A-52-
36644, JP-A-53-135951,
J. Agric. Food. Chem. , No. 4, p
It can also be produced by a method described in the literature such as p965 (1977) or a method similar thereto, or a combination of these methods.

For example, of the compounds of the general formula (II), the general formula

[0017]

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(Wherein D, E, R ⁶ , R ⁷ , R ⁸ and R ⁹ have the same meanings as described above)

[0019]

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(In the formula, D, R ⁶ , R ⁷ , R ⁸ and R ⁹
Has the same meaning as above), and is reacted with ammonium carbonate and sodium cyanide in an inert solvent to give a compound of the general formula

[0021]

[Chemical 6]

(In the formula, D, R ⁶ , R ⁷ , R ⁸ and R ⁹
Has the same meaning as above), and the resulting compound is hydrolyzed under alkaline conditions, and then the amino group etc. is protected by a protecting group by a conventional method. You can

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, N, N′-bis (α-amino-2-
Hydroxyphenylacetyl) octamethylenediamine dihydrochloride is 46.7% at a concentration of 0.2 mM, 2 mM
The inhibitory activity was 92.2%.

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 related to 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 bis (2-hydroxyphenylalkylamine) derivative represented by the general formula (I) of the present invention is
A pharmaceutically acceptable salt can be prepared by a conventional method. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid,
Formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid,
1 to 1 with an organic acid such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Examples thereof include salts with diacid addition salts, sodium salts, potassium salts, calcium salts and the like, and salts with amino acids.

Further, the compounds represented by the above general formula (I) of the present invention include hydrates and solvates with pharmaceutically acceptable solvents such as ethanol.

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

When the bis (2-hydroxyphenylalkylamine) derivative represented by the above general formula (I) of the present invention and a pharmacologically acceptable salt thereof are used for actual treatment, a suitable pharmaceutical composition is used. For example, it is orally or parenterally administered 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. 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 above 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.

[0034]

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.

[0035]

【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 with 2N sodium hydroxide solution, saturated saline solution, 10% aqueous citric acid solution and saturated saline solution in this order, the organic layer was dried over 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 (3 H, s), 5.31 (2 H,
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 1/2 of the solvent
The amount was evaporated under reduced pressure, and after cooling with ice, the precipitated solid was collected by filtration.
After washing with water and ether in this order, the organic layer 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 a solution of 2.02 g of sodium hydroxide in 40 ml of water for 2 days. Heated to reflux. 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 4.06 g of di-t-butyl dicarbonate were 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, and the mixture was washed with 10% aqueous citric acid solution and saturated brine in that order, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and α-tert-butyloxycarbonylamino-2-methoxymethoxyphenylacetic acid 3.65 g.
I got

Colorless amorphous NMR (CDCl ₃ , 400 MHz) δ ppm: 1.43 (9H, s), 3.46 (3H,
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 4 100 mg of N, N'-bis (α-tert-butyloxycarbonylamino-2-methoxymethoxyoxyphenylacetyl) octamethylenediamine α-tert-butyloxycarbonylamino-2-methoxymethoxyphenylacetic acid was added. Dissolve in 3 ml of acetonitrile and add octamethylenediamine 2 under ice cooling.
4 mg, diethylphosphoryl cyanide 52 mg,
The mixture was stirred for 2 hours while returning to room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, chloroform was added, and a 10% aqueous citric acid solution was added.
The organic layer was dried over magnesium sulfate and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 89 mg of N, N′-bis (α-tert-butyloxycarbonylamino-2-methoxymethoxyoxyphenylacetyl) octamethylenediamine.

White solid NMR (CDCl ₃ , 400 MHz) δ ppm: 1.1-1.5 (30 H, m), 3.11
-3.25 (4H, m), 3.52 (6H, s), 5.
24-5.30 (4H, m), 5.5-5.6 (2H,
m), 6.0-6.1 (2H, m), 6.2-6.3.
(2H, m), 6.98-7.06 (2H, m), 7.
07-7.14 (2H, m), 7.20-7.35 (4
H, m)

Example N, N'-bis (α-amino-2-hydroxyphenylacetyl) octamethylenediamine dihydrochloride N, N'-bis (α-tert-butyloxycarbonylamino-2-methoxymethoxyoxy) Phenylacetyl) octamethylenediamine 40 mg, methanol 1 m
1 ml of hydrogen chloride-methanol solution under ice cooling
Was added, and the mixture was stirred for 2 hours while returning to room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. After adding a hydrogen chloride-2-propanol solution to the obtained fraction, the solvent was distilled off under reduced pressure and N, N′-bis (α-amino-2-hydroxyphenylacetyl) octamethylenediamine dihydrochloride 2 was added.
7 mg were obtained.

Colorless amorphous NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.10-1.18 (8H, m), 1.3
0-1.40 (4H, m), 2.98-3.08 (2
H, m), 3.08-3.18 (2H, m), 5.00
(2H, br s), 6.84 (2H, t, J = 7.5
Hz), 6.95 (2H, d, J = 8.4Hz), 7.
20-7.28 (4H, m), 8.08 (2H, m),
8.34 (6H.br), 10.34 (2H, br)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/165 ACV A61K 31/165 ACV ADD ADD 31/215 AAA 31/215 AAA C07C 229/34 9450 -4H C07C 229/34 231/02 231/02 271/10 271/10 // A23L 1/29 A23L 1/29 C07C 47/575 C07C 47/575 (72) Inventor Miho Kobayashi Minamihodaka, Toyoshina-cho, Minamiazumi-gun, Nagano Prefecture 2583

Claims (1)

[Claims] 1. A 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 is a hydrogen atom or a lower alkyl group, and A is a single bond or a substituent. It is a lower alkylene group or a lower alkenylene group which may have a hydroxyl group, Y is a single bond or a lower alkylene group, Z ¹ and Z ² are O or NR ⁵ , and R ⁵ is a hydrogen atom or lower alkyl. Group, and X is a lower alkylene group or a lower alkenylene group), or a bis (2-hydroxyphenylalkylamine) derivative or a pharmaceutically acceptable salt thereof.