JPS5939406B2 - Antipyretic analgesic containing ortho- or meta-aminobenzoic acid derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the following general formula (I) □COOH(I) (excluding galactose, mannose and rhamnose),
An antipyretic agent containing 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 the formula R1-NH represents the ortho or meta position. It concerns painkillers.

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 polysaccharide derived from Wakomycetes, but during research on the structure and activity of this anticancer agent, aminobenzoic acid-ND-mannoside, aminobenzoic acid-N-L -arabinoside, aminobenzoic acid-N-D-glucoside, aminobenzoic acid-N-D-
It has been found that galactoside, aminobenzoic acid-N-L-rhamnoside, has 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 antipyretic and analgesic effects,
It is useful as an antipyretic analgesic. 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 is preferable, and Na is particularly preferable.

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
The reaction is carried out in 2 to 200 ml of MSO) in the presence or absence of a catalyst at 2'C to 200°C, preferably 50 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 is added in an amount of 0.05 to 57% relative 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, lower alkyl esters)
1.4-67, acetic acid 1-2 for solvent 2-200111
The most preferable results were obtained when the ratio of m1 was used.

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) Melting point Measured using a Yanagimoto micro melting point measuring device.

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

(3) Using UV Hitachi EPS-3T self-recording spectrophotometer,
It was measured.

(4) Measured by the KBr method using IR Japan Spectroscopy DS-701G model.

The drawing numbers correspond to the sample waterfalls in Table 1. Next, the 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. LD5O value is determined by Litchfield-Wilcoxon (Litchfi
eld-WilcOxOn) was calculated using the graphic calculation method.

The results are shown in Table 2. Both have large LD and O 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. .

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
TAMl5l4) Escherichia coli
liIFOl2734) Staphylococcus aureus
lOcOccusaureuS2O9P) Bacillus subtilis (Ba
cillusSUbtillSIAMIO69) Baker's Yeast (SaccharOmycescerevisiae)
AM42O7) Candida albi
cansATCC752) TrichOphy
tOnmentagrOphytesFO6l24) Black mold (Aspergillus nigerIAM3OO
l) As a result, this substance was effective against any bacteria at 1/m
No growth inhibition was observed at a concentration of 1.

3) Mutagenicity First, we conducted a study using Rec-Assay.

That is, a recombinant repair-deficient strain (Bacillus sl) B
tillsM45) and recombinant repair carrier strain (B. subti
llsHl7) on B-agar medium (Meatworks Scratch 107).
, polypeptone 107, NaCl 57, agar 157, distilled water 1000ml, pH 7.0) The soil was streaked so that the starting points did not touch each other.

Dissolve or suspend this substance in sterile water, absorb 0.05 ml of it onto a circular ▲ paper with a diameter of 8 mm, immediately leave it to cover the starting point of the streak, and culture it overnight at 37°C. 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 footprint 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 jumping area, and the foot thickness was measured the next day.

This substance was intraperitoneally administered at a dose of 250 ~/Kg 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.
2 ml was injected into the tail vein for sensitization, and on the 7th day after sensitization, blood was collected and antibody production performance was measured by hemagglutination reaction.

The substance was intraperitoneally administered at a dose of 250 kg/kg five times on consecutive days, mainly 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 antipyretic and analgesic effects.

1) Analgesic effect Mechanical stimulation method (pressure stimulation method) A pressure stimulation device (manufactured by Natsume Seisakusho) by Takagi and Kameyama et al. was used.

The test animals used were 6-week-old ICR mice (purchased from CLEA Japan Co., Ltd.). Pressure was applied to the ridge of the mouse, and mice with a pain threshold of 50 to 80 Hg were selected and 10 mice were selected per group. did.

After oral administration of a sample of 100~/K9 or 1000/Kg, measurements were taken over time, and the analgesic effect was determined based on the pressure and time required (seconds) until the test animal showed a pseudo-escape response.

Chemical stimulation method ICR mice, 5-6 week old (female, purchased from Nippon Clea Co., Ltd.), 10 mice per group, were placed on KOsteret.
al. (1959), a sample of 100~/Kg or 1000η/K9 was orally administered and 30 days later, 0,
A 6% acetic acid solution was intraperitoneally injected per 0.1 d/107 mice body weight, and the number of Writhimgs occurring in the mice was counted for 10 m and thereafter, and the inhibition rate (%) relative to the control group was determined using the following formula.

(1-T/C)XlOO-. R. (%) T: Average WrithiIlg number of administration group C: Control group The results are shown in Table 4.

(2) Antipyretic effect Winter et. al. (1961), a 20% brewer's yeast suspension was administered subcutaneously to 6-week-old Donryu rats (female, purchased from Tokyo Experimental Animals Co., Ltd.), 6 in each group.
After fasting for 19 hours, 100~/Kg or 1000Tn9/
A kg sample was orally administered, the rectal temperature was measured, and the fever suppression rate relative to the control fever rat body temperature at the peak of the sample's effect was determined from the following equation.

T: Average body temperature of the administration group C1: Average body temperature of control fever rats (39.2°C) C2: Average body temperature of control untreated rats (
37.6°C) The results are shown in Table 5.

The above results indicate that this substance is useful as an antipyretic analgesic. Since this substance has little acute toxicity and few other side effects, it is useful as a medicine for animals and humans.

As a medicine, it is used for humans as an antipyretic analgesic. Next, we will discuss the formulation of this substance. When used as an antipyretic analgesic, the substance can be used in any convenient form to obtain its medicinal effect depending on the type and symptoms of the disease, and may be used alone or in mixtures 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, solvents, etc. Specific examples include lactose, sucrose, solpit, mannitrate, starch,
Precipitated calcium carbonate, heavy magnesium oxide, talc, calcium stearate, magnesium stearate, cellulose or its derivatives, amylopectin, polyvinyl alcohol, gelatin, surfactant, water, saline, ethanol, glycerin, propylene glycol,
These include cocoa butter, lauric fat, petrolatum, paraffin, and higher alcohols.

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 Wt. % 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 (eg, subcutaneous, intramuscular, intravenous injection, infusion), rectal administration, and the like. The dose of the bioactive agent of the present invention depends on whether it is an animal or a human, and is influenced by age, individual differences, medical conditions, etc., so in some cases, doses outside the ranges listed below may be administered, but in general, humans are administered. In this case, the oral dosage of this substance is 0.1 to 500 per kg body weight per day,
Preferably from 1 to 250, the parenteral dosage is also 0.
．． 01~200m9, preferably 0.1~100~1
Administer in 4 to 4 divided 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. The formulation example is uniformly mixed to form a powder or fine granules with a 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, 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
- 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 and 3 parts of calcium stearate are added and compression molded to form tablets with a diameter of 8 mm, and a mixed suspension of syrup gelatin and precipitated calcium carbonate is added to form sugar-coated tablets.

Formulation example 5 After heating and mixing, place in an ampoule and sterilize it to make an injection.

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

Production example 1 0-aminobenzoic acid-N! Production method of D-riboside Na salt 0-aminobenzoic acid 2.77, D-ribose 3.07,
0.37 ammonium chloride was added to 30 m 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 5.5%.

Thus obtained o-aminobenzoic acid-N-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 5.5%.

Production Example 2 Production method of 0-aminobenzoic acid-N-2-deoxy-D-riboside monosodium salt 0-aminobenzoic acid 2.77, 2-
Deoxy-D-ribose 2.57, ammonium chloride 0
．． 257 was added to 30R 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 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 Na salt 0-aminobenzoic acid 2.77, D-flag dose 3.67, ammonium chloride 0.37 in 30ml 194%
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 recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 4.5%.

The o-aminobenzoic acid monoN-D thus obtained
- 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.
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 3.7%.

Thus obtained, o-aminobenzoic acid monoN-L
- Gradually dissolve sorbocide 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 soil 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
- 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 40.2%.

Production Example 60-Aminobenzoic acid-N-D-glucuronolactonide monosodium salt production method 0-Aminobenzoic acid 2.57
, D-glucuronolactone 32y, ammonium chloride 0
．． 3y was added to 25ml 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 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 2.01
, 3,07 ml of 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, N-acetyl-D-glucosamine (3.07 g) and ammonium chloride (0.057 g) 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 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 of 0-aminobenzoic acid-N-maltoside monosodium salt 0-aminobenzoic acid 1,47, maltose 3.67, glacial acetic acid 1.4 ml, water 2 ml, . 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-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 1.4y, cellobiose 3.47y,
1.4Tf111 of glacial acetic acid and 13ml of water were added with 5mj 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 acicular Z/ 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-satucarose sodium salt production method 0-aminobenzoic acid 1.47, sutucarose 3.67,
Add 51111 water, 1.4 ml of 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 50% methyl alcohol to obtain colorless needle-like 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 1.4y1 lactose 3.67,
101 LI1 of water and 1.41 n1 of glacial acetic acid are added to 4.2111 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 material was 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 15.2%.

Production Example 130-Aminobenzoic acid-N-maltotrioside monosodium salt production method 1.4 y of 0-aminobenzoic acid, 5.07 ml of maltotriose, 2.8 ml of water, 11 ml of acetic acid.

4 ml was added to 8.5 ml of 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 ethyl alcohol to obtain colorless needle-like 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 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 1.2y,.
L-fucose 1.3V1 ammonium chloride 0.2f 1
Add 5ml to 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 21.3%. Production Example 16 Method for producing 0-aminobenzoic acid methyl ester-N-N-acetyl-D-glucosaminide 0-aminobenzoic acid methyl ester 2.0y,. 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 1.57,
Maltose 3.

67. Add 2 ml of water and 1.5 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 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
, 3.41 g of cellobiose, 13 d of water, 1.4 ml of 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. 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,
3.6 y of lactose, 10 T of water, 1.4 ml 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 was passed through the mouth, the crystals were washed with ether, and recrystallization was repeated several times from 50% methyl alcohol to obtain colorless needle-like crystals with a yield of 10.5%.

Production Example 20 Production method of 0-aminobenzoic acid methyl ester-N-maltotrioside 0-aminobenzoic acid methyl ester 1.
5y1 Maltotriose 5.0y1 Water 2.8ml 11 Acetic acid 1.4111 are added to 4.2ml 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 4.7%.

Production Example 21 Production method of 0-aminobenzoic acid ethyl ester-N-D-riboside 0-aminobenzoic acid ethyl ester 2.8y
．． D-ribose 2,57, ammonium chloride 0.257
was added to 3011194% 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 50% methyl alcohol to obtain colorless needle-shaped 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
、． L-fucose 1.37, ammonium chloride 0.27
was added to 15 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 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 1.71
, cellobiose 3.4f, water 13711j, 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 Method for producing 0-aminobenzoic acid propyl ester-N-D-riboside 0-aminobenzoic acid propyl ester 3.
07, D-ribose 3.07, ammonium chloride 0.3
7 was added to 3007r1994% 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 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 3.07, 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 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.
0f7, cellobiose 3.4y1 water 13ml11 acetic acid 1.
4 ml of the solution was 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 g), and ammonium chloride (0.37 g.) were 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 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 1
5TILI 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 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 13ml11 acetic acid 1.4ml
was added to 11Tn1 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 m-Aminobenzoic acid - Production method of N-D-riboside monosodium salt m-Aminobenzoic acid 2.

7y,. D-ribose 3.0v, ammonium chloride 0,
3 was added to 30 m 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 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 of m-aminobenzoic acid-N-2-deoxy-D-riboside monosodium salt m-aminobenzoic acid 2.7y, 2-deoxy-D-ribose 2.57y, ammonium chloride 0.
3V 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. 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%.

The thus obtained m-aminobenzoic acid N-2-
Deoxy-D-riboside containing calculated amount of NaOH 1
% 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 3.2%.

Production example 32 Production method of m-aminobenzoic acid-N-D-fructoside Na salt m-aminobenzoic acid 2.77, D-flag dose 3.67, ammonium chloride 0.3V 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 ammonium chloride 0.37 3011194%
Add to 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 monoN-L
- Gradually dissolve sorbocide 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 1.8%.

Production Example 34 Production method of m-aminobenzoic acid-N-L-fucoside Na salt m-aminobenzoic acid 1.2y,. L-fucose 1,47
, 0.27 ammonium chloride was added to 15 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 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 0.37 g 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 monoN-D
- 1% glucuronolactonide with 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 7.0%.

Production Example 36 Production method of m-aminobenzoic acid-N-methyl-D-glucuronide monosodium salt m-aminobenzoic acid 1.07, methyl-
D-glucuronic acid 1.5 grams, ammonium chloride 0.27 grams
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-shaped 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 solution under reduced pressure, add a large excess of acetone, dehydrate, and then dry to obtain colorless crystals. Yield: 100%, total yield: 8.2 It was %.

Production Example 37 Method for producing m-aminobenzoic acid-N-N-acetyl-D-glucosaminide monosodium salt m-aminobenzoic acid 1.97,
3.0 y of N-acetyl-D-glucosamine and 0.05 y 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 mono-N-N-acetyl-D-glucosaminide 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 depressurized. Concentrate, add a large excess of acetone, dehydrate, and dry to obtain colorless crystals.

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

Production Example 38 Production method of monosodium salt of m-aminobenzoic acid-N-maltoside Add 1.4f1 m-aminobenzoic acid, 3.6y maltose, and 1.4111 y of glacial acetic acid to 157!11 ethyl alcohol and heat condensation under reflux. .

When the reaction solution is left in the refrigerator, no crystals are observed to 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 m-aminobenzoic acid 1.41, cellobiose 3.40υ7, water 137T111 glacial acetic acid 1.4m
Add i 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 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 matter was sifted through the mouth, 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 40 Method for producing m-aminobenzoic acid-N-satucaroside monosodium salt Add m-aminobenzoic acid 1.4y1 sutucarose 3,67, water 7ml, and acetic acid 1.4ml to 7ml of 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 ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 0.8%.

The thus obtained m-aminobenzoic acid mono-N-saccharoside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was sifted through the mouth, 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 0.8%.

Production Example 41 Production method of m-aminobenzoic acid-N-lactoside monosodium salt m-aminobenzoic acid 1.4y, lactose 3.67y,
10 ml of water and 1.4 ml of glacial acetic acid are heated and condensed in 4.2111 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%.

The thus obtained m-aminobenzoic acid monoN-lactoside was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble matter was sifted through the mouth, the oral liquid 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 21.7%.

Production example 42 Production method of m-aminobenzoic acid-N-maltotriosydide Na salt m-aminobenzoic acid 1,41, maltotriose 5.0y, water 2,8T1111 glacial acetic acid 1
．． 4 ml of the solution was added to 8.5 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. 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 ml of ammonium chloride are added to 20771194% 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 15.0%. Production Example 44 Production method of m-aminobenzoic acid ethyl ester-N-L-fucoside m-aminobenzoic acid ethyl ester 1.37,
L-fus 1.37, ammonium chloride 0.2y 1
511194% 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 50% methyl alcohol to obtain colorless needle-shaped 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 3.47, water 13m11 glacial acetic acid 1.4m
1 was added to 7d 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-shaped 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 1571111 acetic acid 1
．． 4 ml of the solution was added to 157!11 ethyl alcohol and heated under reflux for condensation.

When the reaction solution is left in the refrigerator, crystals are observed to 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 Production method of m-aminobenzoic acid butyl ester-N-D riboside m-aminobenzoic acid butyl ester 1.9y,
．． 1.57 ml of D-ribose and 0.27 ml of ammonium chloride were added to 20 m'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 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 R_1-NH- An antipyretic analgesic agent containing an ortho- or meta-aminobenzoic acid derivative, or a pharmaceutically acceptable salt or alkyl ester thereof, as an active ingredient. 2. The antipyretic analgesic 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 antipyretic analgesic agent according to claim 1, wherein the salt is a Na salt. 4. The antipyretic analgesic agent according to claim 1, wherein the ester is a methyl, ethyl or butyl ester.