JPS5924965B2 - Antipyretic analgesic containing an aminobenzoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a central nervous system depressant containing a compound represented by the following general formula (C) as an active ingredient.

In particular, it relates to antipyretics or analgesics. R1-NH
Q...(1) (In the formula, R1 is arabinose, xylose, glucose,
Indicates galactose, rhamnose or mannose residues.

) Conventionally, synthetic compounds and antibiotics have been used as anticancer agents, but although these have excellent cancer killing effects, they have the disadvantage 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, and while researching the structure and activity of this anticancer agent, the compound represented by the general formula (1) above was found to have a remarkable analgesic and antipyretic effect. They discovered this and completed the present invention. The compound represented by the above general formula (1) (hereinafter,
Although the substance has a simple structure, it has extremely low toxicity and no antibacterial activity, so there is no concern about disturbance of intestinal flora, and it can be administered over a long period of time.

Furthermore, it is an extremely safe drug that does not have mutagenicity or affect cellular or nocturnal immunity, and therefore poses no risk of teratogenicity or allergic reactions in healthy people. In addition, both of these substances have analgesic and antipyretic effects, and are useful as central nervous system depressants. There are three types of carboxyl group positions in this substance: P-, m-, and 0-.
Although there may be some differences in activity, all are essentially useful.

Pharmaceutically acceptable salts of aminobenzoic acid refer to salts of alkali metals, and the alkali metals usually include Na, K, M
g, Ca, Al, etc. are preferable, and Na is particularly preferable.
The sugar moiety has a 6-membered ring (pyranose) structure. The manufacturing method of this substance is exemplified as follows.
D-xylose, D-glucose, D-galactose or L-rhamnose) 2.0-6.4f1 ammonium chloride 0.05-0.5g at 95-100? Heat condensation is carried out under reflux of 10 to 90 ml of ethanol or pure methanol.

If crystals precipitate after being left at room temperature or in a cool place for a while, the reaction solution is thoroughly filtered, the crystals are thoroughly washed with water, alcohol, ether, etc., and then recrystallized from methanol water or ethanol water. A well-known method was used to replace the hydrogen of the carboxyl group 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 obtained by the above production method are shown in Table 1 below. Further, infrared absorption spectra are shown in FIGS. 1 to 24. 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 a UV Hitachi EPS-3T self-recording spectrophotometer, -H was measured using an alcohol monoaqueous system, and -Na was measured using water as a solvent.

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

Note that the drawing numbers correspond to the sample numbers in Table 1.

Next, the toxicological properties of this substance are shown.

1) Acute toxicity Acute toxicity was investigated by intraperitoneal and forced oral administration using ICR-JCL mice.

This substance was dissolved in physiological saline for intraperitoneal administration, and in distilled water for oral administration, and the solution was adjusted to a predetermined amount using a syringe or a stomach tube and administered. After administration, poisoning symptoms 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-Wil-COxOn) graphic calculation method. The results are shown in Table 2. Both are LD5 regardless of intraperitoneal or oral administration.
With an O value of 6g/Kg or more, it is a low-toxic substance that falls well within the category of so-called "ordinary drugs," and 6 out of 10 compounds, more than half, have an LD5O value of 10f/Kg or more, making it extremely safe. It can be said that it is an expensive drug. 2) Antibacterial activity This substance was dissolved in distilled water to prepare a 2-fold dilution series, and this dilution was mixed with 9 times the amount of heated and dissolved agar medium, poured into a Petri dish, and plated.

Heart infusion agar (bacteria) and Sabouraud agar (fungi) were used as the culture medium, and after smearing and inoculating the pre-cultured test bacteria, the bacteria were incubated at C20 for 37 to 24 hours. Fungi are 25th grade C3~
The cells were cultured for 7 days and the presence or absence of growth was examined. The following bacterial species were used as test bacteria. Pseudomonas aeruginosa
OrlasaeruginOsaI, AIVl5l4)
Escherichia coli (EscherichiacOlllFOl27
34) Staphylococcus aureus
aureus2O9P) Bacillus subtilis
btilis IAMlO69) baker's yeast (Saccha
rOmycescerevisiaeIAM42O7)
Candida albicans ATO
O752) TrichOphytOnment
agrOphytesIFO6l24) Black mold (Asp
As a result, this substance did not inhibit the growth of any bacteria at a concentration of 1 mg/MlO.

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

That is, a recombinant repair-deficient strain (Bacillus subt.
i-11sM45) and the recombinant repair carrier strain (B. subti
lisHl7) on B-agar medium (10f
1 polypeptone 10fsNaC15f11 agar 15f1
A streak was drawn on 1000 ml of distilled water (pH 7.0) so that the starting points did not touch each other.

Dissolve this substance in sterilized water, absorb 0.05 ml of the solution onto a circular paper with a diameter of 8 squares, and immediately leave it standing so as to cover the starting point of the streak, and culture it overnight at 37°C to grow. The length of the inhibition zone was measured. Kanamycin was used as a negative control, and mitomycin C was used as a positive control. Next, perform the reverse mutation test with S
almOnellatyphi-MuriumTA98
and TAlOO (both were performed using histidine-requiring O).

0.5mM biotin-0.5mM histidine solution 1/1
0 volumes of soft agar solution (NaCl 6ql agar 6y1 distilled water 1000ml) 2ml 1C bacterial solution 0.1ml 11 drug solution 0.
177! / was added, mixed well, and layered on a minimal agar medium.

The cells were cultured at 37°C for 2 days and the number of revertant colonies was counted.

Furilfuramide (AF2) was used as a positive control.

The results of the Rec-Assay are shown in Table 3, and the results of the reverse mutation test are shown in Table 4.

In the Rec-Assay, this substance did not show mutagenicity even at high concentrations, but the sodium P-aminobenzoate derivative was particularly excellent. In addition, in the reverse mutation test, no change was observed in the mutation incidence rate due to this substance compared to the non-additive control even when a high concentration was applied, proving that it is a highly safe drug. 4) Delayed intradermal reaction ICR-JC to understand the effect of this substance on cell-mediated immunity
Foot reaction using sheep red blood cells as an antigen using L mice (
FOOtpadrectiOn) was performed.

10 sheep red blood cells in saline? This FS. O. Primary sensitization was performed by injecting 2 ml through the tail vein, and 7 days later, 0.0 ml of a 40% suspension of sheep red blood cells was injected.
Secondary sensitization was performed by injecting 05ml into the paw, and the thickness of the paw was measured the next day. This substance is used for 25 days mainly on the day of primary sensitization.
0η/K9 was administered intraperitoneally 5 times daily. 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-administered) group.

]) Antibody production ability In order to understand the effect of this substance on humoral immunity, 1CR-J
CL mice were given 0.0% suspension of sheep red blood cells.
2ml was injected into the tail vein for sensitization, and on the 7th day after sensitization, blood was collected and antibody production ability was measured by hemagglutination reaction.

The substance was intraperitoneally administered at 250η/K9 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.

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 animal was a 6-week-old ICR mouse (purchased from CLEA Japan Co., Ltd., male), and pressure was applied to the ridge of the mouse.
Select those with a pain threshold of 50 to 80 mmHg, group 1
It was set as 0. After oral administration of a sample of 10~/Kg or 1000η/Kg, measurements were performed over time, and the analgesic effect was determined from the pressure and time required until the test animal showed a pseudo-escape response (8).

The results are shown in Table 5.

In all of the groups administered with this substance, the pressure at which the pseudo-escape response appeared was higher than in the control group, and the time at which it appeared also tended to be longer than in the control group, confirming its analgesic effect. This effect was particularly pronounced for sodium P-aminobenzoate-N-D-xyloside and sodium P-aminobenzoate-N-L-arabinoside. In addition, P-aminobenzoic acid-N-
About D-xylod, P-aminobenzoic acid-N-L-rhamnoside, P-aminobenzoic acid-N-D-mannoside
! In the same manner, the pressure and time required until the onset of the pseudoescape reaction were measured, and the results were 98, 82, and 84 m71 LHg, respectively.
134, 31, and 24 seconds were obtained.

Chemical stimulation method ICR mice, 5-6 weeks old (female, purchased from Nippon Clea Co., Ltd.), 10 mice per group, KOs
1 sample according to the method of Teretal (1959).
0~/1<g, 500~/Kg or 1000W9/K9
0.6 after 30 days after oral administration? Acetic acid solution 0.1ml/
After intraperitoneal injection per 10 f mice body weight, the number of writings that occurred in the mice for 101 Lm after 10 pilgrimages was counted, and the inhibition rate (maximum) compared to the control group was determined using the following formula.

(1-T/c)XlOO=1. R. (%) T: Average number of writings in administration group C: Control group The results are shown in Table 6.

All of the sample compounds had some degree of analgesic effect, but especially sodium P-aminobenzoate-N-L-rhamnoside and sodium P-aminobenzoate-N-D-mannoside had an analgesic effect of 70% when administered at 1000η/Kg. It is noteworthy that the above suppression rate was achieved. Antipyretic effect According to the method of Winteretal (1961), a 20% brewer's yeast suspension was administered subcutaneously to 6-week-old Oryu rats (purchased from Tokyo Experimental Animals (4)), and the animals were fasted for 19 hours. After that, the sample was 10m9/Kg5OOT! 19/Kg
Alternatively, 1000 ~/Kg was orally administered, the rectal temperature was measured, and the fever suppression rate relative to the control fever rat body temperature at the time of the maximum effect of the sample was determined from the following formula.

T: Average body temperature of administration group C1: Average body temperature of control fever rats (38.7°C) C2
: The average body temperature (37.2 CC) of control untreated rats is shown in Table 7.

Among the compounds tested, sodium P-aminobenzoate-N-L-rhamnoside and sodium P-aminobenzoate-N-L-arabinoside had excellent antipyretic effects, and the body temperature of fever rats was almost as low as that of untreated rats. showed the effect of lowering the level of In addition, P-aminobenzoic acid-N-D-xyloside, P-aminobenzoic acid-N-L-
For rhamnoside and P-aminobenzoic acid-N-D-mannoside, the fever suppression rate was similarly determined by oral administration of 10η/K9, and 62.8%, 80.2%, and 10.3% were obtained, respectively (
However, C1 was 38.5℃ and C2 was 37.1℃)
.

Next, we will discuss the formulation of this substance.

When used as an analgesic and antipyretic, this substance can be used in any form convenient for obtaining medicinal efficacy depending on the type and symptoms of the disease, and can be used alone or in mixtures with acceptable diluents and other drugs. Can be used as

The substance is applied orally or parenterally.

Therefore, it may take any form for oral or parenteral administration. The substances can be provided in dosage unit form.

They contain an effective amount of the active ingredient and can take the form of powders, granules, tablets, dragees, capsules, suppositories, suspensions, solutions, ampoules, injections, and the like. The diluent may be solid, liquid, semi-solid, or in an ingestible capsule, such as the following: That is, excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, fragrances, preservatives, solubilizing agents, solvents, and the like. -Furthermore, one or more of these may be used in combination. The central nervous system depressant 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. %included. The pharmaceutical 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 injections such as subcutaneous, intramuscular, intravenous, infusion, and the like. The dosage of the pharmaceutical agent of the present invention depends on whether it is an animal or a human being, and is influenced by age, individual differences, medical conditions, etc., so in some cases, doses outside the range shown below may be administered, but in general, it is not intended for humans. In this case, the oral dosage of this substance is 0.1 to 1000 mg/day, preferably 1 to 500 mg per kg body weight, and the parenteral dosage is 0.01 to 200 η, preferably 0.1 to 100 mg/day. ~ is administered in 1 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.

Formulation example 1 Mix them uniformly to make a powder or fine granules.

Further, this powder was put into a capsule container to form a capsule. Formulation Example 2 After uniformly mixing and blending the substance (4)-aminobenzoic acid, the mixture is crushed and granulated, dried, and sieved to form granules.

Manufacturing Example 3 Sodium O-aminobenzoate in Example 2
Sodium O-aminobenzoate instead of xyloside
Granules are prepared in the same manner using N-D-glucoside, 4 parts of calcium stearate are added to 96 parts of the granules, and the mixture is compression molded to form tablets with a diameter of 10 mm.

Formulation example 4 ~ Granules are prepared in the same manner as in Example 2 using

10 parts of crystalline cellulose is added to 90 parts of the obtained granules and compressed to form tablets with a diameter of 8 mm, and syrup gelatin and precipitated calcium carbonate are added to the tablets to form sugar-coated tablets.
Formulation Example 5 is heated and mixed and then sterilized to prepare an injection.

Production Example 1 Method for producing P-aminobenzoic acid-N-L-arabinoside monosodium salt: P-aminobenzoic acid 4.6ys L-arabisose 5f1 ammonium chloride 0.5f was heated under reflux in 40ml of 194% ethyl alcohol. Condense.

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 recrystallized several times from 50% methyl alcohol to obtain colorless needle-shaped crystals. The yield was 45.8%.

The thus obtained P-aminobenzoic acid monoN-L
- Gradually dissolve the arabinoside 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 form colorless crystals. Obtained.

The yield was 100%, and the total yield was 45.8%.

Production example 20-Aminobenzoic acid-N-L-arabinoside monosodium salt production method: Anthranilic acid 2.3fsL-arabinose 2.59, ammonium chloride 0.2q in 30m
1. Heat condensation in methyl alcohol under reflux.

After the reaction, if left at room temperature, crystals will precipitate.

After the reaction, the filtered crystals were washed with water, methyl alcohol, and ether to obtain colorless needle-like or disk-like crystals. Yield 61
．． It was 3%.

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

The yield was 100%, and the total yield was 61.3%.

Production example 3Production method of P-aminobenzoic acid-N-D-xyloside monosodium salt: P-aminobenzoic acid 2.3fsD-xylose 2.5f1 ammonium chloride 0.05f 25
Heat condensation in m1 ethyl alcohol under reflux.

Although crystals precipitate during the reaction, add more solvent and continue heating to complete the reaction.

After standing in a cold place, the reaction solution was sifted, the crystals were washed with water, dilute methyl alcohol, and a small amount of ether, and recrystallized from 94% ethyl alcohol to obtain colorless needle-shaped crystals. The yield was 73.7% S. The thus obtained P-aminobenzoic acid mono-N-D-xyloside 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 amount of Add excess acetone,
After dehydration and drying, colorless crystals were obtained.

The yield was 100%, and the TOtal yield was 73.7%.

Production example 40-Aminobenzoic acid-N-D-xylodide monosodium salt production method: Anthranilic acid 2,3y1D-xylose 2.5' and ammonium chloride 0.2' are heated and condensed in 35 ml of ethyl alcohol under reflux. .

After the reaction, the mixture was concentrated to about 1/2 under reduced pressure, and when left at room temperature, crystals were observed to precipitate.

After the reaction, the crystals were washed with water, methyl alcohol, and ether, and recrystallized from ethyl alcohol to obtain colorless needle-like crystals. The yield was 74.6%.

The anthranilic acid-N-D-xyloside thus obtained was gradually dissolved in a 1% aqueous solution containing NaOH as shown in the calculation sheet, the insoluble material was filtered off, the oral solution was concentrated under reduced pressure, and a large excess of acetone was added. was added, dehydrated and dried to obtain colorless crystals.

The yield was 100%, and the TOtal yield was 76.4%.

Production example 5P-aminobenzoic acid-N-D-glucoside-
Production method of Na salt: 50ml of P-aminobenzoic acid 5fsD-glucose 6.4y1 ammonium chloride 0.5f
Heat condensation in 4% ethyl alcohol under reflux.

After the reaction, the solution was concentrated to about 1/3 under reduced pressure and left in a cool place, and the entire solution became gel-like.

Add a small amount of water, warm again to dissolve, and then leave it in the refrigerator to see crystals precipitate. Pass the reaction solution and remove the crystals.
Wash with water, dilute methyl alcohol and a small amount of ether;
Recrystallization from 50% methyl alcohol gave colorless needle-like crystals.

The yield was 33.7%.

P-aminobenzoic acid-N-1 thus obtained
)-glucoside was gradually dissolved in a 1% aqueous solution containing the calculated amount of NaOH, the insoluble matter was filtered through the mouth, the oral fluid was concentrated under reduced pressure, a large excess of acetone was added, and the mixture was dehydrated and dried to obtain colorless crystals. Ta.

The yield was 100%, and the TOtal yield was 33.7%.

Production Example 6 Production method of 0-aminobenzoic acid-N-D-glucoside-Na salt: Anthranilic acid 4.6fsD-glucose 6.0
f11 0.5f of ammonium chloride is heated and condensed in 40ml of 195% ethyl alcohol under reflux.

After the reaction, concentrate to about 1/2 under reduced pressure and leave it in the refrigerator overnight to see crystal precipitation.

The reaction solution was passed through the mouth, the crystals were washed with water, methyl alcohol, and ether, and recrystallized twice from methyl alcohol to obtain colorless needle-like crystals.

The yield was 4.6%.

The anthranilic acid-N-D-glucoside thus obtained was gradually dissolved in a 1% aqueous solution containing a calculated amount of NaOH, the insoluble material was filtered through the mouth, the oral liquid was concentrated under reduced pressure, and a large excess of acetone was removed. In addition, the mixture was dehydrated and dried to obtain colorless crystals.

The yield was 100%, and the TOtal yield was 4.6%.

Production example 7Production method of P-aminobenzoic acid-N-D-galactoside-Na salt: P-aminobenzoic acid 1.5fsD-
Galactose 2y1 ammonium chloride 0.1y 30m
Heat condensation in 194% ethyl alcohol under reflux.

After the reaction, concentrate under reduced pressure and leave in a cool place to observe crystal precipitation. The reaction solution was passed through the mouth, the crystals were washed with water, dilute methyl alcohol, and a small amount of ether, and recrystallized from methyl alcohol to obtain colorless needle-like crystals.

The yield was 18.1%. Obtained in this way, P
-Aminobenzoic acid mono-N-D-galactoside in the calculated amount of N
The mixture was gradually dissolved in a 1% aqueous solution containing aOH, filtered to remove insoluble matter, and the oral liquid was concentrated under reduced pressure. A large excess of acetone was added, dehydrated, and then dried to obtain colorless crystals.

The yield was 100%, and the TOtal yield was 18.1%.

Production example 80-Aminobenzoic acid-N-D-galactoside-Na salt production method: anthranilic acid 2.4fs D-galactose 3.0ys ammonium chloride 0.2f 307
! 11! Heat condensation in 95% ethyl alcohol under reflux.

After the reaction, the mixture was concentrated to about 1/2 under reduced pressure, and when left at room temperature, crystals were observed to precipitate.

The reaction solution was passed through the mouth, the crystals were washed with water, methyl alcohol, and ether, and recrystallized from 95% ethyl alcohol to obtain colorless needle-like crystals.

The yield was 16.4%.

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

The yield was 100%, and the TOtal yield was 16.4%.

Production Example 9 Method for producing P-aminobenzoic acid-N-L-rhamnoside mono-Na salt: 3fs of P-aminobenzoic acid, 4 g of L-rhamnose, and 0.1 f of ammonium chloride are heated and condensed in 94% ethyl alcohol under reflux cooling.

After the reaction, if left at room temperature, crystals will precipitate.

After the reaction, the crystals are washed with water and diluted methyl alcohol, and then recrystallized from 50% methyl alcohol to obtain colorless needle-shaped crystals.

The yield was 30.9%.

The thus obtained P-aminebenzoic acid monoN-L
- Gradually dissolve rhamnoside 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. Ta.

The yield was 100%, and the TOtal yield was 30.9%.

Production example 100-Aminobenzoic acid-N-L-rhamnoside monosodium salt production method: anthranilic acid 2.3f1L-rhamnose 2.8f1 ammonium chloride 0.2f 257n
1. Heat condensation in methyl alcohol under reflux.

After the reaction, if left at room temperature, crystals will precipitate.

After the reaction, the crystals are washed with water and methyl alcohol, and then recrystallized from 50% methyl alcohol to obtain colorless needle-like crystals. With a yield of 9.8%, the anthranilic acid-N-L-rhamnoside thus obtained was gradually dissolved in a 1% aqueous solution containing a calculated amount of 5:1 NaOH, and the insoluble matter was filtered out. The oral fluid was concentrated under reduced pressure, a large excess of acetone was added, dehydrated, and then dried to obtain colorless crystals.

The yield was 100%, and the TOtal yield was 9.8%. Production Example 11 Method for producing P-aminobenzoic acid-N-D-mannoside mono-Na salt: P-aminobenzoic acid 2ysD-mannose 3f and ammonium chloride 0.2y were mixed with ethyl alcohol 10
The condensation reaction is carried out by heating under reflux in a mj for about 1 hour.

After the reaction, the product is left at room temperature to precipitate crystals. The crystals were then separated and washed with water, dilute ethyl alcohol and a small amount of ether, and then recrystallized from 50% methyl alcohol to give P-aminobenzoic acid -N-D-
Colorless needle-like crystals of mannoside were obtained. The yield was 56.1%. The hydrate of P-aminobenzoic acid mono-D-mannoside obtained as described above was gradually added and dissolved in a 1% aqueous solution containing a calculated amount of NaOH, and concentrated under reduced pressure. Add ethyl alcohol to form a precipitate.

This precipitate is collected, dehydrated, and then dried to obtain colorless crystals. These crystals were further recrystallized using an aqueous solution consisting of 5 parts of water and 1 part of acetone to obtain colorless crystals of sodium P-aminobenzoate mono-N-D-mannoside. Yield: 95%, TOtal yield 53.3%. Production example 12m-aminobenzoic acid-N-D-mannoside-N
Method for producing a salt: m-aminobenzoic acid 2fsD-mannose 3f1 ammonium chloride 0.2f1 is heated and condensed in 10 ml of ethyl alcohol under reflux in a water bath at 95-96°C.

A thick crystal mass precipitated shortly after heating. The reaction solution was passed through the mouth, the crystals were thoroughly washed with water and methyl alcohol, and then recrystallized from methyl alcohol to obtain colorless needle-like crystals. The yield was 33.0%.

The thus obtained m-aminobenzoic acid monoN-D
- Mannoside with calculated amount of NaOH 1? It was gradually dissolved in the aqueous solution, and if there was any insoluble matter, the mouth liquid was concentrated under reduced pressure, a large excess of ethanol was added, and after dehydration, it was dried to obtain colorless crystals.

The yield was 100%, and the TOtal yield was 33%.

[Brief explanation of drawings]

Figures 1 to 24 of the attached drawings represent waterfalls 1 to 24 shown in Table 1.
The infrared absorption spectra of each compound are shown.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 represents arabinose, xylose, glucose, galactose, rhamnose, or mannose residue. ] An antipyretic analgesic agent containing at least one aminobenzoic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 2. Aminobenzoic acid derivatives have the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R represents arabinose, xylose, glucose, galactose, rhamnose or mannose residue] Antipyretic analgesic as described in section. 3. The antipyretic analgesic agent according to claim 1 or 2, which is in an oral dosage form. 4. The antipyretic analgesic agent according to claim 1 or 2, which is in a parenteral administration form.