JPS5939408B2 - Antidiabetic agents containing ortho- or meta-aminobenzoic acid derivatives - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the following general formula (I) □COOH(I) / R, [wherein R1 is a sugar residue of a monosaccharide to trisaccharide (However, among the monosaccharides, arabinose, xylose, (excluding glucose, galactose, mannose and rhamnose),
An ortho- or meta-aminobenzoic acid derivative or a pharmaceutically acceptable salt or alkyl ester thereof (hereinafter collectively referred to as ``the substance'') represented by R1 -NH- group represents the ortho or meta position] is used as an active ingredient. This invention relates to an antidiabetic agent.

Conventionally, synthetic compounds and antibiotics have been used as anticancer agents, but although these have excellent cancer killing effects, they have the drawback of being highly toxic and causing side effects because they also act on normal cells. Therefore, recently, polysaccharides of various origins have attracted attention because they exhibit anticancer effects by enhancing the immune capacity of the host. The present inventors have already developed and provided to society an anticancer agent made from a basidiomycete-derived polysaccharide, but while researching the structure and activity of this anticancer agent, aminobenzoic acid-N-D-
mannoside, aminobenzoic acid-N-L-arabinoside,
It has been found that aminobenzoic acid-ND-glucoside, aminobenzoic acid-ND-galactoside, and aminobenzoic acid-NL-rhamnoside have various useful physiological activities. However, these substances are not necessarily sufficient to maintain their medicinal efficacy over a long period of time.

As a result of further research, it was discovered that the compound represented by the above general formula (1), which has low toxicity and high medicinal efficacy, is effective, and the present invention has been completed. Although this substance has a simple structure, it has extremely low toxicity and has no antibacterial activity, so it can be administered for a long period of time without worrying about disturbance of intestinal flora. Furthermore, it is an extremely safe drug that does not have mutagenicity or affect cellular or humoral immunity, and therefore poses no risk of teratogenicity or allergic reactions to healthy people. In addition, all of these substances have hypoglycemic effects,
It is useful as an anti-diabetic agent. Salts of this substance include alkali metal, alkaline earth metal, and aluminum salts, and the alkali metal and alkaline earth metal salts may be any as long as they are acceptable as pharmaceuticals, and usually Na. K. Mg. Ca salts are preferred, and Na salts are particularly preferred.

Moreover, as the ester of this substance, methyl, ethyl, propyl, butyl ester, etc. are preferable. R1 in the above formula (1)
represents monosaccharides to trisaccharides excluding arabinose, xylose, glucose, galactose, mannose and rhamnose, and these sugars are in the form of D or L form, α-anomer or β-anomer, or a mixture of anomers. I can do it.

Therefore, the present substance can also be α or β or a mixed anomer thereof. This substance can be produced by the following method.

Sugar or aminobenzoic acid or its ester 1-107
solvent (e.g. water, alcohol (e.g. methanol, ethanol), acetone, chloroform, dioxane, D
MSO) in the presence or absence of a catalyst at 20°C to 200°C, preferably 50°C to 150°C, for 10 minutes to 48 hours, preferably 30 minutes to 24 hours. Here, the catalyst is preferably acetic acid or a salt thereof, hydrochloric acid, ammonium chloride, etc., and 0.1 to 5 y is added to the above amount.
In the case of condensation reactions using disaccharides or trisaccharides, ammonium chloride is not necessarily suitable, but after investigating effective catalysts, we found that acetic acid is particularly effective. In this case, aminobenzoic acid (including salts and lower alkyl esters)2
The most favorable results were obtained when acetic acid was used in a ratio of 1 to 2 me to 2 to 200 mj of ~6f1 solvent.

When the amount of acetic acid used was below this range, the yield decreased, and when it was above this range, no increase in the product was observed. After the reaction, the reaction product is cooled, either as it is or concentrated to precipitate crystals of the reaction product, separated by filtration and washed with water, methanol, acetone, ether, etc. Further recrystallization is performed to obtain this substance. A well-known method was used to replace hydrogen in the carboxyl group of this substance with a base. That is, this substance was dissolved in an alcoholic aqueous solvent and an inorganic salt was added for substitution. The physicochemical properties of this substance example obtained by the above manufacturing method are shown in Table 1 below.
Shown below.

Further, infrared absorption spectra are shown in FIGS. 1 to 41. The analysis method in Table 1 is as follows. (1) Fusion
Point Measured using a Yanagimoto micro melting point measuring device.

(2) Elemental analysis Measured using Yanagimoto CHN coater MT2 type.

(3) Measured using UV Hitachi EPS-3T self-recording spectrophotometer.

(4) R KB by JASCO DS-701G type
Measured by r method.

The drawing numbers correspond to the sample waterfalls in Table 1.

Next, the toxicological properties of this substance are shown.

(l) Acute toxicity Acute toxicity was investigated by forced oral administration using ICR-JCL mice.

This substance was dissolved or dissolved in distilled water, and the solution was adjusted to a predetermined amount using a stomach tube and administered. After administration, the symptoms of toxicity were continued to be observed, and the LD5O value was determined from the mortality rate over time up to the 7th day.

The findings were obtained through autopsy in both surviving and dead cases. The LD5O value is determined by the Litchfield-Wilcoxon (Litchfie)
ld-WilcOxOn) graphic calculation method. The results are shown in Table 2. All have high LD5O values, are low toxicity substances, and can be said to be extremely safe drugs. Prepare a 2-fold dilution series by dissolving or suspending this substance in distilled water,
This diluted solution was mixed with 9 times the volume of heated and dissolved agar medium,
It was poured into a Petri dish and made into a flat plate.

Heart infusion agar (bacteria) and Sabouraud agar (fungi) were used as the culture medium, and pre-cultured test bacteria were smeared and inoculated. Bacteria were incubated at 37℃ for 20-24 hours. Fungi were incubated at 25℃ for 3-7 hours.
The cells were cultured for several days and the presence or absence of growth was examined.

The following bacterial species were used as test bacteria.

Pseudomonas aeruginosa
IAMl5l4) Escherichia coli
liIFOl2734) Staphylococcus aureus
lOcOccusaureus2O9P) Bacillus subtilis (Ba
cillus subtilis IAMlO69) baker's yeast (SaccharOmycescerevisia)
eIAM42O7) Candidaal
bicans ATCC752) TrichOp
hytOnmentagrOphytes body IFO6l
24) Black mold (Aspergillus nigerIA)
M3OOl) As a result, this substance did not inhibit the growth of any bacteria at a concentration of 1 to 1/ml.

(3) Mutagenicity First, an investigation using Rec-Assay was conducted.

In other words, a recombinant repair-deficient strain (Bacillus sub
tilis M45) and the recombinant repair carrier strain (B. subti
lisHl7) on B-agar medium (meat processing scratch 10V).
) Polypeptone 10V,. NaC15t) Agar 15y,
Stretches were drawn on distilled water (1000 m, pH 7.0) so that the starting points did not touch each other.

Dissolve or suspend this substance in sterilized water, absorb 0.05 ml onto a round paper with a diameter of 8 mm, immediately leave it to cover the starting point of the streak, and incubate at 37°C overnight. The length of the zone of growth inhibition was measured. kanamycin as a negative control;
Mitomycin C was used as a positive control. Rec-A
The results of ssay are shown in Table 3.

None of these substances exhibits mutagenicity even when applied at high concentrations, and is known to be a highly safe drug. (4) Delayed intradermal reaction In order to determine the effect of this substance on cell-mediated immunity, a foot kick reaction (FOOtpadreactiOn) using sheep red blood cells as an antigen was performed using ICR-JCL mice.

Higgi's red blood cells were suspended in 10% physiological saline, and 0.2 m' of this solution was injected through the tail vein to perform primary sensitization.
After a further 7 days, a 40% volume suspension of sheep erythrocytes 0.05
Secondary sensitization was performed by injecting m1 into the foot, and the foot thickness was measured the next day.

This substance was administered intraperitoneally at 250η/K9 five times on consecutive days, mainly on the day of primary sensitization. As a result, no significant difference was observed in the increase in heel thickness in the group administered with this substance compared to the control (non-administered) group.

(5) Antibody production ability In order to understand the effect of this substance on humoral immunity, ICR-J
CL mice were given 0.0% suspension of sheep red blood cells.
2ml was injected into the tail vein for sensitization, and on the 7th day after sensitization, blood was collected and antibody production ability was measured by hemagglutination reaction.

This substance is 250 TI based on the day of sensitization! 9/K9
was administered intraperitoneally 5 times daily. As a result, no significant difference was observed in the agglutination value between the group administered with this substance and the control group.

Next, we will discuss the pharmacological properties of this substance, namely its hypoglycemic effect.

Streptozotocin 60m9/K9 was intraperitoneally administered to 10-week-old Wistar rats, and urinary glucose was confirmed positive one week later. Furthermore, although regular insulin administration showed a decrease in urinary sugar and blood sugar, Only animals in which hyperglycemia and hyperglycemia were confirmed again several days later were used as diabetic model animals.

Ten animals were used in each group. This substance was dissolved or suspended in distilled water and orally administered at a concentration of 30m9/Kg or 300rn9/Kg. Blood was collected 3 hours and 6 hours after administration, and glucose was measured using a RaBA kit (Chugai enzyme method).
This was done using The results of the average values are shown in Table 4.

The difference between the pre-administration blood sugar level and the post-administration blood sugar level, that is, the blood sugar level actually lowered by administration of this substance (Δ value), was greater than that of the control for all compounds, indicating a hypoglycemic effect.
However, the total average blood glucose value before administration was 521 η/dl. In general, even if drugs are highly effective, many have strong side effects and cannot be administered over a long period of time.

As mentioned above, this substance not only has low acute toxicity, but also does not exhibit mutagenicity, allergy, or adverse effects on intestinal flora, and its LD5O value is at least 250 times higher than that of 30η/K9, which shows medicinal efficacy. dosage, and the safety factor is extremely high.
From this point of view as well, this substance can be said to be a drug that can be safely administered over a long period of time. Furthermore, diabetes is a long-term disease, and once the administration of hypoglycemic agents has been started, it is impossible to stop taking them, and in this sense, the present substance is considered to be useful as a hypoglycemic agent. This substance has low acute toxicity and few other side effects, so it is useful as a medicine for both animals and humans.

As a medicine, it is used for human use as an anti-diabetic agent. Next, we will discuss the formulation of this substance. When used as an anti-diabetic agent, this substance can be used in any form convenient for obtaining medicinal efficacy depending on the type and symptoms of the disease, and may be used alone or in a mixture with pharmaceutically acceptable diluents and other drugs. Can be used.

The substances can be provided in dosage unit form.

It contains an effective amount of the active ingredient, and its forms include powders, granules, tablets, sugar-coated tablets, capsules, etc. for oral use.
syrups, pills, suspensions, solutions, emulsions, etc.
For parenteral use, it can be in the form of an ampoule or pin as an injection solution. Suppositories are also available. The diluent may be solid, liquid, or semi-solid, and examples include the following. i.e. excipients, fillers, binders, wetting agents, disintegrants,
surfactants, lubricants, dispersants, buffers, fragrances, preservatives,
These include solubilizing agents and solvents. Specific examples include lactose, sucrose, solpit, 7-unit, starch, precipitated calcium carbonate, heavy magnesium oxide, talc, calcium stearate, magnesium stearate, cellulose or its derivatives, amylopectin, polyvinyl alcohol, gelatin. , surfactant, water, saline,
These include ethanol, glycerin, propylene glycol, cacao butter, lauric fat, vaseline, paraffin, and higher alcohols.

The bioactive agent of the present invention can be produced by any known method.

The active ingredient in the compositions used in the present invention generally ranges from 0.01% to 100% by weight. % preferably from 0.05% to 80wt. %included. The bioactive agent of the present invention can be administered orally or parenterally to humans and animals, but oral administration is preferred. Oral administration includes sublingual administration. Parenteral administration includes injection administration (e.g. subcutaneous, intramuscular, intravenous injection, intravenous drip administration, etc.).The dosage of the bioactive agent of the present invention depends on the animal or human, and is influenced by age, individual differences, medical condition, etc. However, in general, when administering to humans, the oral dosage of this substance is 0.1 to 500 per kilogram of body weight per day.
Preferably from 1 to 250, the parenteral dosage is also 0
．． 01-200, preferably 0.1-100TI19
Administer in 1 to 4 doses.

Hereinafter, the present invention will be explained in more detail by showing formulation examples and manufacturing examples of the substance of the present invention. Parts in the examples below indicate weight. Formulation Example 1 is uniformly mixed to form a powder or fine granules with a particle size of 350μ or less.

Further, this powder was put into a capsule container to form a capsule. After uniformly mixing and blending Formulation Example 2, the mixture is crushed, granulated, dried, and then sieved to obtain granules having a size of 1410 μm to 177 μm.

Formulation Example 3 In place of o-aminobenzoic acid ethyl-N cellobioside in Example 2, m-aminobenzoic acid ethyl ester-N-
Granules are prepared in the same manner using L-fucoside, 4 parts of calcium stearate are added to 96 parts of the granules, and the mixture is compressed to form tablets with a diameter of 10 mm.

Formulation Example 4 One part of crystalline cellulose was added to 90 parts of the granules obtained by the method of Example 2.
0 parts, 3 parts of calcium stearate was added and compression molded to a diameter of 8m77! A sugar-coated tablet is prepared by adding syrup, gelatin, and a mixed suspension of precipitated calcium carbonate.

Formulation example After heating and mixing, place in an ampoule and sterilize it to make an injection.

Formulation Example 6 An injection was prepared in the same manner as in Example 5 except that o-aminobenzoic acid-N-maltoside was used in place of o-aminobenzoic acid sodium N-N-acetyl-D-glucosaminide.

Production Example 1 Method for producing 0-aminobenzoic acid-N-D-riboside Na salt 0-aminobenzoic acid 2.7y. ．． D-ribose 3,07
, 0.3y of ammonium chloride was added to 30ml of 194% ethyl alcohol, and the mixture was heated and condensed under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 5.5%.

Thus obtained o-aminobenzoic acid N-D-
Ribosides are gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, insoluble matter is filtered out, the oral fluid is concentrated under reduced pressure, a large excess of acetone is added, and after dehydration, colorless crystals are obtained by drying.

The yield was 100%, and the total yield was 5.5%.

Production Example 2 Production method of 0-aminobenzoic acid-N-2-deoxy-D ribose monosodium salt 0-aminobenzoic acid 2.77, 2-deoxy-D ribose 2.5y, ammonium chloride 0.2
57 was added to 30ml of 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 4.0%. The thus obtained o-aminobenzoic acid N-2-deoxy-D-riboside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was filtered off, and the oral liquid was concentrated under reduced pressure. Then, add a large excess of acetone, dehydrate, and then dry to obtain colorless crystals.

The yield was 100%, and the total yield was 4.0%.

Production Example 3 Method for producing 0-aminobenzoic acid-N-D-fructoside Na salt 0-aminobenzoic acid 2.7y,. D-flag dose 3.67, ammonium chloride 0.37 30m19
The mixture was added to 4% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 4.5%.

Thus obtained o-aminobenzoic acid N-D-
The fructosides were gradually dissolved in a 1% aqueous solution containing the calculated amount of NaOH, the insoluble materials were sifted, the oral fluid was condensed under reduced pressure, a large excess of acetone was added, and after dehydration, colorless crystals were formed when dried. can get.

The yield was 100%, and the total yield was 4.5%. Production Example 4 Method for producing 0-aminobenzoic acid-N-L-sorboside Na salt 0-aminobenzoic acid 2.

77, L-sorbose 3.67, ammonium chloride 0.
37 was added to 30m'94% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Passing the reaction mixture through the mouth, washing the crystals with ether, and recrystallizing them several times from methyl alcohol yields colorless needles. The yield was 3.7%.

The o-amino acid zoic acid N-L-
Sorboside is gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter is filtered out, the oral fluid is concentrated under reduced pressure, a large excess of acetone is added, and after dehydration, colorless crystals are obtained.

The yield was 100%, and the total yield was 3.7%.

Production Example 5 0-Aminobenzoic acid-N-L-fucoside Na salt was produced using 0-aminobenzoic acid 1.2y, . L-fucose 1.4y
, 0.27 ammonium chloride was added to 1.5 m of 194% ethyl alcohol, and the mixture was heated and condensed under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 40.2%.

Thus obtained o-aminobenzoic acid N-L-
Fucoside is gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, insoluble matter is filtered out, the oral solution is concentrated under reduced pressure, a large excess of acetone is added, and after dehydration, colorless crystals are obtained.

The yield was 100%, and the total yield was 40.2%.

Production Example 60-Aminobenzoic acid-N-D-glucuronolactonide monosodium salt production method 0-Aminobenzoic acid 2.5
7. Add 3.27 g of D-glucuronolactone and 0.3 y of ammonium chloride to 25 m of 194% ethyl alcohol, and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 25.2%.

Thus obtained o-aminobenzoic acid N-D-
Glucuronolactonide was gradually dissolved in a 1% aqueous solution containing the calculated amount of NaOH, the insoluble matter was filtered out, the oral fluid was concentrated under reduced pressure, a large excess of acetone was added, and after dehydration, colorless crystals were obtained when dried. can get.

The yield was 100%, and the total yield was 25.2%.

Production Example 7 Production method of 0-aminobenzoic acid-N-methyl-D-glucuronide monosodium salt 0-aminobenzoic acid 2.0f
7. Add 3.07 ml of methyl-D-glucuronic acid and 0.47 ml of ammonium chloride into 10 ml of 194% ethyl alcohol and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 12.0%.

The thus obtained o-aminobenzoic acid N-methyl-D-glucuronide was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was sifted through the mouth, and the oral fluid was concentrated under reduced pressure. Add a large excess of acetone, dehydrate, and then dry to obtain colorless crystals.

The yield was 100%, and the total yield was 12.0%.

Production example 80-aminobenzoic acid-N-N-acetyl-D
Production method of glucosaminide monosodium salt 0-aminobenzoic acid 1
．． 9y. 3.0 y of N-acetyl-D-glucosamine and 0.057 ml of ammonium chloride are added to 150 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 9.1%. The thus obtained o-aminobenzoic acid N-N-acetyl-D-glucosaminide was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was filtered off, and the oral liquid was concentrated under reduced pressure. Then, add a large excess of acetone, dehydrate, and then dry to obtain colorless crystals.

The yield was 100%, and the total yield was 9.1%.

Production Example 9 Production method of 0-aminobenzoic acid-N-maltoside monosodium salt 0-aminobenzoic acid 1.47, maltose 3.67,
Glacial acetic acid 1.4ml, water 2mj. The mixture was added to 5m' of Et0H and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 15.2%. The thus obtained o-aminobenzoic acid mono-N-maltoside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was filtered off, the oral liquid was concentrated under reduced pressure, and a large excess was removed. Add acetone,
After dehydration and drying, colorless crystals are obtained.

The yield was 100%, and the total yield was 15.2%.

Production example 100-Aminobenzoic acid-N-cellobioside Na salt production method 0-aminobenzoic acid 1.4y1 cellobiose 3.47,
1.4 ml of glacial acetic acid and 13 ml of water were added to 5 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 13.0%.

The thus obtained o-aminobenzoic acid N-cellobioside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was filtered off, the oral fluid was concentrated under reduced pressure, and a large excess of acetone was added. is added, dehydrated, and dried to obtain colorless crystals.

The yield was 100%, and the total yield was 13.0%.

Production example 110-Aminobenzoic acid-N-satucarose Na salt production method 0-aminobenzoic acid 1,4y, sutucarose 3.67,
5 ml of water and 1.4 ml of acetic acid were added to 5 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 1.2%.

The thus obtained o-aminobenzoic acid N-saccharoside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was filtered off, the oral fluid was concentrated under reduced pressure, and a large excess of acetone was added. is added, dehydrated, and dried to obtain colorless crystals.

The yield was 100%, and the total yield was 1.2%.

Production Example 12 Production method of 0-aminobenzoic acid-N-lactoside monosodium salt 1.4 y of 0-aminobenzoic acid, 3.6 y of lactose,
10 ml of water and 1.4 me of glacial acetic acid were added to 4.2 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 15.2%.

The thus obtained o-aminobenzoic acid N-lactoside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was filtered off, the oral fluid was concentrated under reduced pressure, and a large excess of acetone was added. is added, dehydrated, and dried to obtain colorless crystals.

The yield was 100%, and the total yield was 15.2%.

Production example 130-Aminobenzoic acid-N-maltotrioside Na salt production method 0-aminobenzoic acid 1.47, maltotriose 5.07, water 2.8 ml, acetic acid 1.4 ml
was added to 8.5 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 9.6%.

The thus obtained o-aminobenzoic acid N-maltotrioside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was filtered off, and the oral fluid was concentrated under reduced pressure to obtain a large excess. Add acetone, dehydrate, and dry to obtain colorless crystals.

The yield was 100%, and the total yield was 9.6%.

Production Example 14 Production method of 0-aminobenzoic acid methyl ester-N-D-riboside 0-aminobenzoic acid methyl ester 3.07
, D-ribose 3.07, ammonium chloride 0.37 3
The mixture was added to 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from ethyl alcohol to obtain colorless needle-shaped crystals. Yield: 45.

It was 9%.

Production Example 15 Production method of 0-aminobenzoic acid methyl ester-N-L fucoside 0-aminobenzoic acid methyl ester 1.2y,.
L-fucose 1.3y, ammonium chloride 0.2y 15
The mixture was added to 94% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 21.3%. Production Example 16 0-Aminobenzoic acid methyl ester-N-N acetyl-
Production method of D-glucosaminide 0-aminobenzoic acid methyl ester 2.07, N-acetyl-D-glucosamine 3.
07, 0.57 ammonium chloride was added to 150 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% ethyl alcohol to obtain colorless needle-like crystals. The yield was 2.1%.

Production Example 17 Production method of 0-aminobenzoic acid methyl ester-N-maltoside 0-aminobenzoic acid methyl ester 1.57,
Maltose 3.67, water 2ml11 glacial acetic acid 1.5me 5
Add to m1 ethyl alcohol and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 94% ethyl alcohol to obtain colorless needle-like crystals. The yield was 18.9%.

Production Example 18 Production method of 0-aminobenzoic acid methyl ester-N-cellobioside 0-aminobenzoic acid methyl ester 1.57
, Cellobiose 3.4f! , water 13m11 acetic acid 1.4m
1 was added to 5 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 6.3%.

Production Example 19 Production method of 0-aminobenzoic acid methyl ester-N-lactoside 0-aminobenzoic acid methyl ester 1.5y,
Lactose 3,67, water 10ml, acetic acid 1.4ml 4
．． The mixture was added to 2 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and the crystals are re-crystallized several times from 50% methyl alcohol to obtain colorless needles. The yield was 10.5%.

Production Example 20 Production method of 0-aminobenzoic acid methyl ester-N-maltotrioside 0-aminobenzoic acid methyl ester 1.
57, 5.07 g of maltotriose, 2.8 ml of water, and 1.4 mj of acetic acid were added to 4.2 ml of ethyl alcohol, and the mixture was heated and condensed under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 4.7%.

Production Example 21 Method for producing 0-aminobenzoic acid ethyl ester-N-D riboside 0-aminobenzoic acid ethyl ester 2.8y.
D-ribose 2.5f1 ammonium chloride 0.257 to 3
The mixture was added to 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 28.2%. Production Example 22 Production method of 0-aminobenzoic acid ethyl ester-N-L fucoside 0-aminobenzoic acid ethyl ester 1.37,
L fucose 1.3y1 ammonium chloride 0.2y 15
The mixture was added to 94% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and the crystals are re-crystallized several times from 50% methyl alcohol to obtain colorless needles. The yield was 28.5%. Production Example 23 Production method of 0-aminobenzoic acid ethyl ester-N-cellobioside 0-aminobenzoic acid ethyl ester 1.7y
1 cellobiose 3.47, water 13m11 glacial acetic acid 1.4m
1 was added to 11 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 12.3%.

Production Example 24 Production method of 0-aminobenzoic acid propyl ester-N-D-riboside 0-aminobenzoic acid propyl ester 3.
07, D-ribose 3.07, ammonium chloride 0.3
Add y to 300ml of 194% ethyl alcohol and heat condensation under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 90% ethyl alcohol to obtain colorless needle-like crystals. The yield was 6.5. Production Example 25 Production method of 0-aminobenzoic acid propyl ester-N-L-fucoside 0-aminobenzoic acid propyl ester 3.
07, L-fucose 3.0? , ammonium chloride 0.2
7 was added to 20 m of 194% ethyl alcohol under reflux.
Heat condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and the crystals are re-crystallized several times from 94% ethyl alcohol to obtain colorless needles. The yield was 4.7%. Production Example 26 Method for producing 0-aminobenzoic acid propyl ester-N-cellobioside 0-aminobenzoic acid propyl ester 2.
07, cellobiose 3,4y1 water 13ml11 acetic acid 1.4
m1 is heated and condensed in 11 ml of ethyl alcohol under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 94% ethyl alcohol to obtain colorless needle-like crystals. The yield was 5.5%.

Production Example 27 Method for producing 0-aminobenzoic acid butyl ester-N-D riboside 0-aminobenzoic acid butyl ester 3.87,
D-ribose 3.07, ammonium chloride 0.37 30
m' Add to 94% ethyl alcohol and heat condensate under reflux.

When the reaction solution is placed in a refrigerator, precipitation of crystals is observed. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 94% ethyl alcohol to obtain colorless needle-like crystals. The yield was 21.5%. Production Example 28 Production method of 0-aminobenzoic acid butyl ester-N-L fucoside 0-aminobenzoic acid butyl ester 1.5y,.
L fucose 1.37, ammonium chloride 0.2y 15
m1 Add to 94% ethyl alcohol and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 33.6%. Production Example 29 Production method of 0-aminobenzoic acid butyl ester-N-cellobioside 0-aminobenzoic acid butyl ester 1.9y
1 cellobiose 3.4y1 water 13m11 acetic acid 1.4m'
was added to 11m' ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 94% ethyl alcohol to obtain colorless needle-like crystals. Production Example 30 Production method of m-aminobenzoic acid-N-D-riboside Na salt m-aminobenzoic acid 2.77, D-ribose 3.0V1
Add 0.3 f of ammonium chloride to 30 m of 194% ethyl alcohol and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. Passing the reaction mixture through the mouth, washing the crystals with ether, and recrystallizing them several times from methyl alcohol yields colorless needles. The yield was 3.0%.

The thus obtained m-aminobenzoic acid monoN-D
- Gradually dissolve ribosides in a 1% aqueous solution containing a calculated amount of NaOH, filter out insoluble matter, concentrate the oral fluid under reduced pressure, add a large excess of acetone, dehydrate, and dry to obtain colorless crystals. .

The yield was 100%, and the total yield was 3.0%.

Production Example 31 Production method of monosodium salt of m-aminobenzoic acid-N-2-deoxy-D ribose m-aminobenzoic acid 2.77, 2-deoxy-D ribose 2,51, ammonium chloride 0.3
7 was added to 30me94% ethyl alcohol under reflux.
Heat condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and the crystals are re-crystallized several times from methyl alcohol to obtain colorless needle-shaped crystals.

The yield was 3.2%.

The thus obtained m-aminobenzoic acid N-2-
Deoxy-D-riboside 1 containing calculated amount of NaOH
% aqueous solution, filter out insoluble matter, concentrate the mouth liquid under reduced pressure, add a large excess of acetone, dehydrate, and dry to obtain colorless Q crystals.

The yield was 100%, and the total yield was 3.2%. Production Example 32 Production method of m-aminobenzoic acid-N-D-fructoside monosodium salt m-aminobenzoic acid 2.77, D-flag dose 3.6y, ammonium chloride 0.37 in 30m194
% ethyl alcohol and heat condensation under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 2.2%.

The thus obtained m-aminobenzoic acid N-D-
The fructosides are gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter is filtered out, the oral liquid is concentrated under reduced pressure, a large excess of acetone is added, and after dehydration, colorless crystals are obtained.

The yield was 100%, and the total yield was 2.2%.

Production Example 33 Production method of m-aminobenzoic acid-N-L-sorboside Na salt m-aminobenzoic acid 2.7y. L-sorbose 3.
6y1 0.3y of ammonium chloride is added to 30ml of 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 1.8%.

The thus obtained m-aminobenzoic acid N-L-
Sorboside is gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter is filtered out, the oral fluid is concentrated under reduced pressure, a large excess of acetone is added, and after dehydration, colorless crystals are obtained.

The yield was 100%, and the total yield was 1.8%.

Production Example 34 Production method of m-aminobenzoic acid-N-L-fucoside Na salt m-aminobenzoic acid 1.27, L-fucose 1.47,
0.2 V of ammonium chloride was added to 15 m' of 94% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 12.0%.

The thus obtained m-aminobenzoic acid-N-L
- Gradually dissolve the fucoside in a 1% aqueous solution containing the calculated amount of NaOH, filter out the insoluble matter, concentrate the oral fluid under reduced pressure, add a large excess of acetone, dehydrate, and dry to obtain colorless crystals. .

The yield was 100%, and the total yield was 12.0%.

Production Example 35Production method of m-aminobenzoic acid-N-D-glucuronolactonide monosodium salt m-aminobenzoic acid 2.5
7. D-glucuronolactone 3,27 and ammonium chloride 0.37 are added to 25m'94% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 7.0%.

The thus obtained m-aminobenzoic acid N-D-
Glucuronolactonide was gradually dissolved in a 1% aqueous solution containing the calculated amount of NaOH, the insoluble matter was filtered out, the oral fluid was concentrated under reduced pressure, a large excess of acetone was added, and after dehydration, colorless crystals were obtained when dried. can get.

Production Example 36 Production method of m-aminobenzoic acid-N-methyl-D-glucuronide monosodium salt m-aminobenzoic acid 1.07, methyl-
D-glucuronic acid 1.5y, ammonium chloride 0.27
The mixture was added to 10ml of 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 8.2%.

The thus obtained m-aminobenzoic acid N-methyl-D-glucuronide was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was sifted through the mouth, and the oral fluid was concentrated under reduced pressure. Add a large excess of acetone, dehydrate, and then dry to obtain colorless crystals.

The yield was 100%, and the total yield was 8.2%.

Production Example 37 Method for producing m-aminobenzoic acid-N-N-acetyl-D-glucosaminide mono-Na salt m-aminobenzoic acid 1.97,
3.07 ml of N-acetyl-D-glucosamine and 0.057 ml of ammonium chloride were added to 150 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 34.9%. The thus obtained m-aminobenzoic acid N-N-acetyl-D-glucosaminide was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was filtered off, and the oral liquid was concentrated under reduced pressure. Then, add a large excess of acetone, dehydrate, and then dry to obtain colorless crystals.

The yield was 100%, and the total yield was 34.9%.

Production Example 38 Production of monosodium salt of m-aminobenzoic acid-N-maltoside 1.47 ml of m-aminobenzoic acid, 3.67 ml of maltose, and 1.4 ml of glacial acetic acid are added to 15 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 45.6%. Obtained in this way,
m-aminobenzoic acid N-maltoside in a calculated amount of NaO
Gradually dissolve in a 1% aqueous solution containing H, pass through the insoluble matter,
The oral fluid was concentrated under reduced pressure, a large excess of acetone was added, and after dehydration,
When dried, colorless crystals are obtained.

The yield was 100%, and the total yield was 45.6%.

Production Example 39 Production method of m-aminobenzoic acid-N-cellopioside Na salt m-aminobenzoic acid 1.47, cellobiose 3.4y1
Add 13 ml of water and 1.4 ml of glacial acetic acid to 5 ml of ethyl alcohol and heat to condense under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 20% ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 23.9%.

The thus obtained m-aminobenzoic acid mono-N-cellobioside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble materials were filtrated, the oral fluid was concentrated under reduced pressure, and a large excess was removed. Add acetone, dehydrate, and dry to obtain colorless crystals.

The yield was 100%, and the total yield was 23.9%.

Production example 40Method for producing m-aminobenzoic acid-N-satucarose Na salt m-aminobenzoic acid 1.47, sutucarose 3,6y1
7 ml of water and 1.4 ml of acetic acid were added to 7 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from ethyl alcohol to obtain colorless needle-like crystals. The yield was 0.8%.

The thus obtained m-aminobenzoic acid N-saccharoside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble materials were sifted through the mouth, the oral fluid was concentrated under reduced pressure, and a large excess of acetone was added. is added, dehydrated, and dried to obtain colorless crystals.

The yield was 100%, and the total yield was 0.8%.

Production Example 41 Production method of m-aminobenzoic acid-N-lactoside monosodium salt m-aminobenzoic acid 1.47, lactose 3.67,
10 ml of water and 1.4 m' of glacial acetic acid are heated and condensed in 4.2 ml of ethyl alcohol under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 27.1%. Obtained in this way,
m-aminobenzoic acid N-lactoside in a calculated amount of NaO
Gradually dissolve in a 1% aqueous solution containing H, pass through the insoluble matter,
The oral fluid was concentrated under reduced pressure, a large excess of acetone was added, and after dehydration,
Drying gives colorless crystals.

The yield was 100%, and the total yield was 21.7%.

Production Example 42 Production method of m-aminobenzoic acid-N-maltotrioside Na salt m-aminobenzoic acid 1.47, maltotriose 5.0y1 water 2.8ml, glacial acetic acid 1.4m
1 was added to 8.5 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. Pass the reaction solution through the mouth, wash the crystals with ether, and repeat crystallization several times from methyl alcohol to obtain colorless needle-shaped crystals. The yield was 80.3%.

The thus obtained m-aminobenzoic acid N-maltotrioside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was filtered off, and the oral fluid was concentrated under reduced pressure to obtain a large excess. Add acetone, dehydrate, and dry to obtain colorless crystals.

The yield was 100%, and the total yield was 80.3%.

Production example 43m-aminobenzoic acid methyl ester-N-
Method for producing L-fucoside: 1.27 ml of m-aminobenzoic acid methyl ester, 1.37 ml of L-fucose, and 0.27 ammonium chloride are added to 20 m of 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 15.0%. Production Example 44 Production method of m-aminobenzoic acid ethyl ester-N-L fucoside m-aminobenzoic acid ethyl ester 1.37, L
15m of fucose 1.3y, ammonium chloride 0.2y
The mixture was added to 194% ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 56.9%. Production Example 45 Production method of m-aminobenzoic acid ethyl ester-N-zerobioside m-aminobenzoic acid ethyl ester 1.77
, cellobiose 3.47, water 13m11 glacial acetic acid 1.4m
Add j to 7 ml of ethyl alcohol and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 30% ethyl alcohol to obtain colorless needle-like crystals. The yield was 24.4%.

Production Example 46 Method for producing m-aminobenzoic acid propyl ester-N-cellobioside m-aminobenzoic acid propyl ester 1.
77, cellobiose 3.47, water 15ml11 acetic acid 1.4
ml was added to 15 ml of ethyl alcohol and heated under reflux for condensation.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 94% ethyl alcohol to obtain colorless needle-like crystals. The yield was 2.0%.

Production example 47 Method for producing m-aminobenzoic acid butyl ester-N-D riboside m-aminobenzoic acid butyl ester 1.97,
D-ribose 1.5y, ammonium chloride 0.2y 20
m1 Add to 94% ethyl alcohol and heat condensate under reflux.

If the reaction solution is left in the refrigerator, crystals will precipitate. The reaction solution is passed through the mouth, the crystals are washed with ether, and recrystallized several times from 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 3.7%.

[Brief explanation of the drawing]

1 to 41 show infrared absorption spectra of the following aminobenzoic acid derivatives according to the present invention.

Claims (1)

[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R
_1 represents a monosaccharide to trisaccharide residue (excluding arabinose, xylose, glucose, galactose and mannose among monosaccharides), an amino sugar residue or a deoxy sugar residue (excluding rhamnose), and R_1-NH- The group is in the ortho or meta position. ] An antidiabetic agent containing an ortho- or meta-aminobenzoic acid derivative represented by the following, or a pharmaceutically acceptable salt or alkyl ester thereof as an active ingredient. 2. The antidiabetic agent according to claim 1, wherein R_1 in the above formula (I) is ribose, deoxyribose, fucose, N-acetylglucosamine, maltose, cellobiose, lactose, or maltotriose. 3. The antidiabetic agent according to claim 1, wherein the salt is a Na salt. 4. The antidiabetic agent according to claim 1, wherein the ester is a methyl, ethyl or butyl ester.