JPS5939407B2 - Antiarteriosclerotic 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) (excluding glucose, galactose, mannose and rhamnose),
R1-NH- group represents ortho or meta position] or a pharmaceutically acceptable salt or alkyl ester thereof (hereinafter referred to as
The present invention relates to an anti-arteriosclerotic agent containing ``this substance'' as an active ingredient.

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 cell-mediated or humoral immunity, and therefore poses no risk of teratogenicity or allergic reactions in healthy people. In addition, all of these substances have a blood lipid-lowering effect and are useful as anti-arteriosclerosis agents. Salts of this substance include alkali metal, alkaline earth metal, aluminum salts, etc. As the alkali metal and alkaline earth metal salts, any salt may be used as long as it is acceptable as a drug. ．． K. Mg,. Preferably, C or the like, and particularly preferable is Na salt. Moreover, as the ester of this substance, methyl, ethyl, propyl, butyl ester, etc. are preferable. In the above general formula (1), R1 is arabinose,
Represents monosaccharides to trisaccharides excluding xylose, glucose, galactose, mannose and rhamnose, which sugars can be in the D or L form or in the form of the α- or β-anomer or in the form of a mixture of anomers.

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
~6f7, and the use of acetic acid in a ratio of 1 to 2 ml to 2 to 200 ml of solvent showed the most favorable results. 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.
After filtering, wash 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 the example of this substance obtained by the above production method are shown in Table 1 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) Measured by the KBr method using IR Japan Spectroscopy DS-701G model.

Note that the drawing number corresponds to the black sample in Table 1. The following toxicological properties of this substance are shown.

(1) Acute toxicity Acute toxicity by forced oral administration was investigated 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.
(2) Antibacterial activity Dissolve or suspend this substance in distilled water to create a 2-fold dilution series, mix this dilution with 9-fold volume of heated and dissolved agar medium, pour it into a Petri dish, and plate it. .

For the culture medium, infusion agar (bacteria) and Sabouraud agar (fungi) were used, and the pre-cultured test bacteria was smeared and inoculated. Bacteria: 3TC20-24hr Fungi: 25℃ 3-7
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
cillusSUbtillSIAMlO69) Baker's Yeast (Sacchar Only'Cescerevisi
aeIAM42O7) Candidaa
lbicans ATCC752) TrichO
phytOnmentagrOphytesFO6l2
4) Black mold (Aspergillus nigerIAM)
3OOl) As a result, this substance has a 1% effect against any bacteria.
No growth inhibition was observed at a concentration of η/ml.

{) Mutagenicity First, a Rec-Assay study was conducted.

That is, a recombinant repair-deficient strain (Bacillus subt.
B. illsM45) and recombinant repair carrier strain (B. subtil
lsHl7) on B-agar medium (Nikukozu 107,
Polypeptone 107, NaCl5f, agar 157, distilled water 1000ml, PH7. O) A line was drawn on the top so that the starting points did not touch each other.

This substance is dissolved or suspended in sterile water, and 0.05 ml of it is absorbed into a circular F paper with a diameter of 8 mm. Immediately, it is left standing so as to cover the starting point of the streak, and the substance is incubated overnight at 37°C to grow. The length of the inhibition zone 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 reaction (FOOtpadreactiOn) using sheep red blood cells as an antigen was performed using ICR-JCL mice.

Sheep red blood cells were suspended in physiological saline at a volume of 10%, and 0.2 ml 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 heel, and the heel thickness was measured the next day.

This substance was administered intraperitoneally at 250 m9/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 foot thickness in the group administered with this substance compared to the control (non-administration) group.

(5) Antibody production ability In order to understand the effect of this substance on humoral immunity, CR-JC
For L mice, 10% suspension of sheep red blood cells 0.2
ml 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.

The substance was administered at 250η/K9 into the recovery cavity 5 days on consecutive days, centered on the day of sensitization. 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 blood lipid-lowering effect.

Japanese white male rabbits (weighing approximately 2.5k9) were given a solid feed (CR-1) containing 1% cholesterol orally ad libitum, and after about 3 months, an increase in serum lipid components was observed, and this was confirmed experimentally. It was used as an arteriosclerosis model animal.

The total average values of serum cholesterol and β-LP in this rabbit were 560 TI1 g/dl and 230 W9/dl, respectively. These rabbits exhibiting hyperlipidemia also develop atherosclerosis, and have been commonly used as arteriosclerosis model animals for testing the efficacy of anti-arteriosclerosis drugs.

This substance was dissolved or suspended in distilled water and 300W9/K9 was orally administered to these arteriosclerosis model animals. After administration, blood was collected from the ear vein over time and serum lipid analysis was performed, and changes in total cholesterol in the blood were measured using an enzymatic method and β-
Lipoproteins were measured by turbidimetry. The results are shown in Table 4. In view of the above-mentioned toxicological and pharmacological properties of this substance, it is understood that this substance can be put to practical use as an anti-arteriosclerotic agent.

Furthermore, 24 hours after administration, the liver was removed and homogenized using a Teflon homogenizer.

The homogenized liver was extracted with hexane to obtain cholesterol, and liver cholesterol was determined for each sample by a modified Zak-Henly Kitamura method. The results are shown in Table 4.
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-arteriosclerotic agent. Next, we will discuss the formulation of this substance.

When this substance is used as a therapeutic agent for arteriosclerosis, it can be used in a form convenient for obtaining medicinal effects depending on the type and symptoms of the disease, and can be used alone or in a mixture with a pharmaceutically acceptable diluent and other drugs. Can be used as

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,
Surfactant, lubricant, dispersant, buffer, fragrance, preservation 1
materials, solubilizing agents, solvents, etc. Specific examples include lactose, sucrose, solpit, mannite, starch, precipitated calcium carbonate, heavy magnesium oxide, talc, calcium stearate, magnesium stearate, cellulose or its derivatives, amylopectin, polyvinyl alcohol, gelatin, surfactant, water,
These include physiological saline, ethanol, glycerin, propylene glycol, cacao butter, lauric fat, petrolatum, paraffin, and higher alcohols.

2 The bioactive agent of the present invention can be produced by any known method. The active ingredients in the compositions used in the present invention generally range 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,
Including intramuscular, intravenous injection, infusion), rectal administration, etc. The dosage of the bioactive agent of the present invention depends on the animal or human being, and is influenced by age, individual differences, medical conditions, etc., and in some cases, doses outside the range shown below may be administered; however, in general, For humans, the oral dose of this substance is 1 kg body weight,
0.1-500η per day, preferably 1-250Tn
9. Parenteral administration 5. Dosage is also 0.01-200T
! f1 is preferably 0.1 to 100η divided into 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.
2 Formulation Example 1' is uniformly mixed to form a powder or fine granules with a particle size of 350 μm 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 and granulated, dried, and then identified to give granules having a size of 1410 μm to 177 μm.

Formulation agent 3 m-aminobenzoic acid ethyl ester-N instead of o-aminobenzoic acid ethyl-N-cellobioside in Example 2
- Making granules using L-fucoside in the same manner,
4 parts of calcium stearate are added to 96 parts of the granules and compression molded 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 5 After heating and mixing, place in an ampoule and sterilize it to make an injection.

Formulation Example 6 Sodium 0-aminobenzoate in Example 5 -N-N-
An injection is prepared in the same manner using o-aminobenzoic acid-N-maltoside in place of acetyl-D-glucosaminide.

Production Example 1 Production method of 0-aminobenzoic acid-N-D-riboside Na salt 0-aminobenzoic acid 2.77, D-ribose 3.0y1
Add 0.3y of ammonium chloride to 30ml of 94% ethyl alcohol and heat to condense 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-riboside mono-Na salt 0-aminobenzoic acid 2.77, 2-
Deoxy-D ribose 2.57, ammonium chloride 0.
257 was added to 30Tn194% 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 sifted through the mouth, and the oral fluid was depressurized. Concentrate, add a large excess of acetone, dehydrate, and dry to obtain colorless crystals.

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

Production Example 3 Production method of 0-aminobenzoic acid-N-D-fructoside monosodium salt 0-aminobenzoic acid 2.77, D-flag dose 3.6f7, ammonium chloride 0.3f7 in 30ml
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-shaped crystals. The yield was 4.5%.

Thus obtained o-aminobenzoic acid-N-D
- Gradually dissolve the fructosides in a 1% aqueous solution containing a calculated amount of NaOH, sift off the insoluble materials, and concentrate the oral fluid 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 4.5%.

Production Example 4 Production method of 0-aminobenzoic acid-N-L-sorboside Na salt 0-aminobenzoic acid 2.77, L-sorbose 3.
6V, 0.37 ammonium chloride was added to 30 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. 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 3.7%.

Thus obtained, o-aminobenzoic acid monoN-L
- Gradually dissolve sorposide 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 3.7%.

Production Example 5 Production method of 0-aminobenzoic acid-N-L-fucoside monosodium salt 0-aminobenzoic acid 1.27, L-fucose 1.4
7. Add 0.27 g of ammonium chloride to 15 m 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-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 2.5y
．． 3.27 g of D-glucuronolactone and 0.3 y of ammonium chloride were added to 25 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. 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-glucanido monosodium salt 0-aminobenzoic acid 2.0y
3.07 ml of 1-methyl-D-glucuronic acid and 0.47 ml of ammonium chloride were added to 10 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-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
．． 97. 3.0 t of N-acetyl-D glucosamine and 0.057 t of ammonium chloride are added to 150 mj 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 mono-N-N-acetyl-D-glucosaminide 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 depressurized. Concentrate, add a large excess of acetone, dehydrate, and dry to obtain colorless crystals.

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

Production Example 9 Production method of monosodium salt of 0-aminobenzoic acid-N-maltoside 1.4y of 0-aminobenzoic acid, 3.67y of maltose,
Glacial acetic acid 1.4ml, water 2ml. Add 5 ml of EtOH 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 50% methyl alcohol to obtain colorless needle-like crystals. The yield was 15.2%. The thus obtained o-aminobenzoic acid N-maltoside 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 100-Aminobenzoic acid-N-cellobioside Na salt production method 0-aminobenzoic acid 1.47, 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-like crystals. The yield was 13.0%.

The thus obtained o-aminobenzoic acid mono-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 was removed. Add acetone, dehydrate, and dry to obtain colorless crystals.

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

Production Example 110-Aminobenzoic acid-N-satucarosid monosodium salt production method Add 1.47 0-aminobenzoic acid, 3.6 y of satucarose, 5 ml of water, 1.4 ml of acetic acid to 5 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 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 0-aminobenzoic acid 1.47, lactose 3.67,
10 ml of water and 1.4 ml 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-like crystals. The yield was 15.2%.

The thus obtained o-aminobenzoic acid mono-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 was removed. Add acetone, dehydrate, and dry 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 1.4y1 maltotriose 5,07, water 2.8ml11 acetic acid 1.4ml
was added to 8.5 ml of ethyl alcohol and heated under reflux for condensation.

When the reaction solution is left in a storage room, crystals are observed to 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 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 9.6%.

Production Example 14 Method for producing 0-aminobenzoic acid methyl ester-N-D riboside 0-aminobenzoic acid methyl ester 3.07,
D-ribose 3.0y1 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-like crystals. The yield was 45.9%.

Production Example 15 Production method of 0-aminobenzoic acid methyl ester-N-L-fucoside 0-aminobenzoic acid methyl ester 1.27,
L fucose 1,37, ammonium chloride 0.27 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-like crystals. The yield was 21.3%. Production Example 16 Method for producing 0-aminobenzoic acid methyl ester-N-N-acetyl-D-glucosaminide 0-aminobenzoic acid methyl ester 2.0f. 3.07 ml of N-acetyl-D-glucosamine and 0.57 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% 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 1.5y1
Maltose 3.

67, 2 ml of water and 1.5 ml of glacial acetic acid were added to 5 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 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 3.47, water 13mel1 acetic acid 1.4ml
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 1.57,
4 lactose 3.6t1 water 10ml, acetic acid 1.4ml
．． 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 recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. 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, maltotriose 5.07, water 2.8T! F. ,
1.4 ml of acetic acid was 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-shaped crystals. The yield was 4.7%.

Production Example 21 Production method of 0-aminobenzoic acid ethyl ester-N-D riboside 0-aminobenzoic acid ethyl ester 2.87,
D-ribose 2.

0.25y of 5y1 ammonium chloride is added to 30me94% 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 1.3y
．． 1.3y1 of L-fucose and 0.27% of ammonium chloride are added to 15ml 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 28.5%. Production Example 23 Production method of 0-aminobenzoic acid ethyl ester-N-cellobioside 0-aminobenzoic acid ethyl ester 1.77
, cellobiose 3.4y1 water 13Tf111 glacial acetic acid 1.
4 ml of the solution was added to 11 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-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 3.0
7, D-ribose 3.07, ammonium chloride 0.3t
was added to 300ml 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 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 3.0
7, L-fucose 3.07, ammonium chloride 0.27
was added to 20 ml 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 94% ethyl alcohol to obtain colorless needle-like crystals. 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 3.47, 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 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 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 1.57, L
- Fucose 1.37, ammonium chloride 0.27 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-like crystals. The yield was 33.6%. Production Example 29 Production method of 0-aminobenzoic acid butyl ester-N-cellobioside 0-aminobenzoic acid butyl ester 1.97
, cellobiose 3.47, water 13m11 acetic acid 1.4m2
was added to 11ml 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 3.9%.

Production Example 30 Production method of m-aminobenzoic acid-N-D-riboside Na salt m-aminobenzoic acid 2.77, D-ribose 3.07,
Add 0.3 V 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. 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 3.0%.

The thus obtained m-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 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 2.57, ammonium chloride 0.3
7 was added to 30 m of 194% ethyl alcohol under reflux.
Heat 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 3.2%.

Obtained in this way.

m-Aminobenzoic acid N-2-deoxy-D-riboside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH;
Insoluble matter is filtered out, the oral liquid is concentrated under reduced pressure, a large excess of acetone is added, dehydrated, and dried to obtain colorless Q-packed crystals. The yield was 100%, and the total yield was 3.2%. Production example 32 Production method of m-aminobenzoic acid-N-D-fructoside Na salt m-aminobenzoic acid 2.77, D-flag dose 3.6f7, ammonium chloride 0.3y 30TI11
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. 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 2.77, L-sorbose 3.
67. Add 0.37 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. 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 monosodium salt m-aminobenzoic acid 1.2y. L-fucose 1.4
7. Add 0.27 g of ammonium chloride to 15 m 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-like crystals. The yield was 12.0%.

The thus obtained m-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 12.0%.

Production Example 35Production method of m-aminobenzoic acid-N-D-glucuronolactonide monosodium salt m-aminobenzoic acid 2.5
7. Add 3.27 g of D-glucuronolactone and 0.3 f7 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 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.

The yield was 100%, and the total yield was 7.0%. Production Example 36 Production method of m-aminobenzoic acid-N-methyl-D-glucuronide monosodium salt m-aminobenzoic acid 1.0y, methyl-
D-glucuronic acid 1.57, 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 added to a 1% solution containing a calculated amount of NaOH.
Gradually dissolve in an aqueous solution, filter out insoluble matter, concentrate the oral liquid 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 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 g of N-acetyl-D glucosamine and 0.05 v 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-like 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 m-aminobenzoic acid-N-maltoside monosodium salt 1.47 m-aminobenzoic acid, 3.6y1 maltose, 1.4 ml of glacial acetic acid were 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 monosodium salt of m-aminobenzoic acid-N-cellobioside 5 m of m-aminobenzoic acid 1,47, cellobiose 3.47, water 13 ml, glacial acetic acid 1.4 ml
1 in 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 20% ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 23.9%.

The thus obtained m-aminobenzoic acid 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 of acetone was added. is added, dehydrated, and dried to obtain colorless crystals.

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

Production example 40M-aminobenzoic acid-N-satucarose Na salt production method m-aminobenzoic acid 1.47, sutucarose 3.67,
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 ml 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 21.7%. Obtained in this way,
m-Aminobenzoic acid monoN-lactoside was added to the calculated amount of Na
Gradually dissolve in a 1% aqueous solution containing OH, pass through the mouth to remove insoluble materials, 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 21.7%.

Production example 42M-aminobenzoic acid-N-maltotrioside Na salt production method m-aminobenzoic acid 1.4f1 maltotriose 5.0y1 water 2.8mj1 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 mono-N-maltotrioside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was sifted through the mouth, and the oral fluid was concentrated under reduced pressure. Add excess 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 m-aminobenzoic acid methyl ester 1.2y,. 1.37 L fucose and 0.27 g of ammonium chloride were 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 fucose 1.37, ammonium chloride 0.27 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-like crystals. The yield was 56.9%. Production Example 45 Production method of m-aminobenzoic acid ethyl ester-N-cellobioside m-aminobenzoic acid ethyl ester 1.77
, cellobiose 3.4y, water 13ml11 glacial acetic acid 1.4m
1 was 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. 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 Production method of m-aminobenzoic acid propyl ester-N-cellobioside JO m-aminobenzoic acid propyl ester 1.77, cellobiose 3.47, water 15ml11 acetic acid 1.4ml 15ml
e Add to 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 the crystals are re-crystallized several times from 94% ethyl alcohol to obtain colorless needles. 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 1.57, and ammonium chloride 0.27 are added to 20 ml 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 the crystals are re-crystallized several times from 50% methyl alcohol to obtain colorless needles. The yield was 3.7%.

[Brief explanation of drawings]

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 R1-NH- The group is in the ortho or meta position. ] An anti-arteriosclerosis agent containing an ortho- or meta-aminobenzoic acid derivative represented by the following formula, or a pharmaceutically acceptable salt or alkyl ester thereof as an active ingredient. 2 In the above formula (I), R1 is ribose, deoxyribose, fucose, N-acetylglucosamine, maltose,
The antiarteriosclerosis agent according to claim 1, which is cellobiose, lactose, or maltotriose. 3. The antiarteriosclerosis agent according to claim 1, wherein the salt is a Na salt. 4. The antiarteriosclerosis agent according to claim 1, wherein the ester is a methyl, ether or butyl ester.