GB2060635A - Derivative of para- aminobenzoic acid, their preparation and use in pharmaceutical compositions - Google Patents

Abstract

The invention provides derivatives of p-aminobenzoic acid of the formula: <IMAGE> wherein R<1> represents a residual group formed by the removal of -OH from the 1(alpha)- or 1(beta)- position of ribose, desoxyribose, fructose, sorbose, fucose, N-acetylglucosamine, glucuronic acid, saccharose, maltose, cellobiose, lactose or maltotriose, and R<2> represents hydrogen, alkyl of 1 to 4 carbon atoms or an equivalent amount of a pharmaceutically acceptable alkali metal, alkaline earth metal or aluminum. These compounds are useful as an active ingredient of pharmaceutical compositions for use in treating hypertension, diabetes, mellitus, arteriosclerosis, tumours, inflammatory diseases, pyrexia and pain.

Description

SPECIFICATION Derivative of para-aminobenzoic acid, their preparation and use in pharmaceutical compositions The present invention relates to novel derivatives of p-aminobenzoic acid and to pharmaceutical compositions containing at least one such derivative as an active ingredient.

The derivatives of p-aminobenzoic acid according to the present invention are of the formula (1):

wherein R' represents a residual group formed by the removal of -OH from the 1 (alpha)- or 1 (beta)position of ribose, desoxyribose, fructose, sorbose, fucose, N-acetylglucosamine, glucuronic acid, saccharose, maltose, cellobiose, lactose or maltotriose, and R2 represents hydrogen, alkyl of 1 to 4 carbon atoms or an equivalent amount of a pharmaceutically acceptable alkali metal, alkaline earth metal or aluminum.These derivatives of p-aminobenzoic acid (hereinafter referred to as the present compounds) have, as will be shown later, the activities of reducing blood sugar level, of reducing blood pressure, of reducing blood lipid level, and anti-tumour activity, anit-inflammatory activity, analgesic activity and antipyretic activity, and in addition, their toxicity is extremely low and they do not show any antimicrobial or mutagenetic activity.

Accordingly, the present compounds represented by the above-mentioned formula (I) are effectively utilizable for treating hypertension, diabetes mellitus, arteriosclerosis, tumours, inflammatory diseases, pyrexia and pains.

In the above-mentioned formula (I) representing the present compounds, the sugar shown by R1 may be D-isomer or L-isomer, or may be alpha-anomer or beta-anomer and further, it may be a mixture of both anomers. Accordingly, the present compound may be alpha-, beta- or the mixture of alpha- and beta-anomer.

In addition, the alkali metals and alkaline earth metals shown by R2 in the above-mentioned general formula (I) may be one which is pharmaceutically acceptable, preferably be Na, K, 1/2 Mg and 1/2 Ca usually, particularly Na being more preferable.

The present compound Is easily prepared by the following method: A sugar selected from the group consisting of ribose, desoxyribose, fructose, sorbose, fucose, Nacetylglucosamine, glucuronic acid, saccharose, maltose, cellobiose, lactose and maltotriose is brought into reaction with p-aminobenzoic acid or its lower alkyl ester in a solvent, for instance, water, methanol, ethanol, acetone, chloroform, dioxane or dimethylsulfoxide (DMSO) at a temperature of 20 to 2000 C, preferably 50 to 1500C for 10 min to 48 hours, preferably 0.5 to 24 hours in the presence or absence of a catalyst. The catalyst used herein is preferably acetic acid, its salt, hydrochloric acid or ammonium chloride.

After the above-mentioned reaction is over, the reaction product is cooled, and as it is, or after condensing, the thus formed compound is crystallized. After collecting the crystals by filtration, they are washed with water, methanol, acetone or ethyl ether and recrystallized from methanol to obtain the present compound.

In order to substitute the hydrogen atom of the carboxyl group of the present compound obtained by using p-aminobenzoic acid as a starting material with an alkali metal, alkaline earth metal or aluminum, a publicly known method may be applicable. That is, the above-mentioned acidic compound is brought into reaction with an inorganic salt of the corresponding metal or with the hydroxide of the metal in an aqueous solvent.

The present compounds obtained as above have the chemical and physical properties shown in Table 1: TABLE 1 Physical and Chemical Properties of the Present Compounds Specific Elementary Ultraviolet Melting rotatory power analysis (%) absorption max.

No. and Name of Present Compound point ( C) [&alpha;]D20 C : H : N (nm) 1 p-Aminobenzoic acid-N-D- 140 - 145 +2 53.4 5.5 5.1 293 riboside (c=1, 50% CH3OH) (53.5 5.3 5.2) 2 Sodium p-aminobenzoate-N- 150 descomp. +37.6 49.5 4.8 4.7 293 D-riboside (c=0.5, water) (49.5 4.8 4.8) 3 p-Aminobenzoic acid-N-D-2- 132 - 138 +10.4 56.7 6.3 5.4 293 deoxyriboside (c=0.5, 50% CH3OH) (56.9 6.2 5.5) 4 Sodium p-aminobenzoate-N- 170 decomp. +32.5 52.2 5.0 5.0 293 D-2-deoxyriboside (c=0.5, water) (52.2 5.1 5.1) 5 p-Aminobenzoic acid-N-L- 169 - 174 +50 55.0 6.1 5.0 293 fucoside (c=1, water) (55.1 6.0 4.9) 6 Sodium p-aminobenzoate-N- 185 decomp. +6.0 51.0 5.0 4.5 293 L-fucoside (c=0.5, water) (51.1 5.2 4.6) 7 p-Aminobenzoic acid-N-D- 191 - 195 +7.2 52.7 5.9 7.9 293 N-acetylglucosamide (c=1, CH3OH) (52.9 5.9 8.2) 8 Sodium p-aminobenzoate-N- 185 decomp. +20.4 51.0 5.0 7.5 293 D-N-acetylglucosamide (c=0.5, water) (51.1 5.2 7.7) 9 p-Aminobenzoate-N-maltoside 190 decomp. +22 49.4 5.7 3.0 293 (c=1, CH3OH) (49.5 5.9 3.1) TABLE 1 (Continued) Specific Elementary Ultraviolet Melting rotatory power analysis (%) absorption max.

No. and Name of Present Compound point ( C) [&alpha;]D20 C : H : N (nm) 10 Sodium p-aminobenzoate-N- 175 decomp. +93.4 47.1 5.3 2.7 293 maltoside (c=0.3, water) (47.2 5.4 2.9) 11 p-Aminobenzoic acid-N- 160 -165 -33.6 49.6 6.0 3.0 293 cellobioside (c=1, CH3OH) (49.5 5.9 3.1) 12 Sodium p-aminobenzoate-N- 165 - 170 -32.0 47.0 5.3 2.9 293 cellobioside (c=0.5, water) (47.2 5.4 2.9) 13 p-Aminobenzoic acid-N- 175 - 179 -26 49.4 5.9 3.0 293 lactoside (c=1, CH3OH) (49.5 5.9 3.1) 14 Sodium p-aminobenzoate-N- 168 decomp. -41.6 47.2 5.3 2.8 293 lactoside (c=0.5, CH3OH) (47.2 5.4 2.9) 15 p-Aminobenzoic acid-N- 171 - 177 +86.9 48.2 5.7 2.2 293 maltotrioside (c=1, CH3OH) (48.2 5.9 2.2) 16 Sodium p-aminobezoate-N- 186 decomp. +93.4 46.3 5.7 2.1 293 maltotrioside (c=0.3, water) (46.5 5.6 2.2) 17 Methyl p-aminobenzoate-N- 146 - 152 +14.9 55.0 6.1 4.8 293 D-riboside (c=1, 50% CH3OH) (55.1 6.0 4.9) 18 Methyl p-aminobenzoate-N- 172 - 176 +18.8 58.9 6.4 5.2 293 D-2-deoxyriboside (c=1, CH3OH) (59.0 6.3 5.2) 19 Methyl p-aminobenzoate-N- 102 - 104 +4.4 53.6 6.2 4.5 293 D-fructoside (c=0.5, CH3OH) (53.7 6.1 4.5) TABLE 1 (Continued) Specific Elementary Ultraviolet Melting rotatory power analysis (%) absorption max.

No. and Name of Present Compound point ( C) [&alpha;]D20 C : H : N (nm) 20 Methyl p-aminobenzoate-N- 187 - 190 +114 56.5 6.4 4.7 293 L-fucoside (c=1, 50% CH3OH) (56.6 6.4 4.7) 21 Methyl p-aminobenzoate-N- 145 - 150 +18 50.4 6.0 2.9 293 maltoside (c=1, CH3OH) (50.5 6.1 2.9) 22 Methyl p-aminobezoate-N- 180 - 196 -110 50.3 6.2 2.9 293 cellobioside (c=1, CH3OH) (50.5 6.1 2.9) 23 Methyl p-aminobenzoate-N- 155 - 160 +37.2 50.4 6.2 2.9 293 lactoside (c=1, CH3OH) (50.5 6.1 2.9) 24 Methyl p-aminobezoate-N- 180 decomp. +42 48.8 6.2 2.3 293 maltotrioside (c=1, CH3OH) (49.0 6.1 2.2) 25 Ethyl p-aminobenzoate-N- 169 - 173 +22.5 56.6 6.4 4.7 293 D-riboside (c=1, 50% CH3OH) (56.6 6.4 4.7) 26 Ethyl p-aminobenzoate-N- 171 - 176 +18.8 60.3 6.7 4.8 293 D-2-deoxyriboside (c=1, CH3OH) (60.4 6.7 4.9) 27 Ethyl p-aminobenzoate-N- 90 - 92 +1 54.8 6.5 4.2 293 D-fructose (c=0.5, C2H5OH) (55.0 6.4 4.3) 28 Ethyl p-aminobenzoate-N- 148 - 154 +88 57.7 6.9 4.4 293 L-fucoside c=1, CH3OH) (57.9 6.8 4.5) 29 Ethyl p-aminobenzoate-N- 146 - 149 -79.1 51.3 6.3 2.9 293 cellobioside (c=0.5, 50% CH3OH) (51.5 6.3 2.9) TABLE 1 (Continued) Specific Elementary Ultraviolet Melting rotatory power analysis (%) absorption max.

No. and Name of Present Compound point ( C) [&alpha;]D20 C : H : N (nm) 30 Propyl p-aminobenzoate-N- 136 - 141 +202 58.0 6.8 4.5 293 D-riboside (c=0.5, 50% CH3OH) (57.9 6.8 4.5) 31 Propyl p-aminobenzoate-N- 178 - 181 +17.6 61.0 7.1 4.8 293 D-2-deoxyriboside (c=0.5, 50% CH3OH) (61.5 7.0 4.7) 32 Propyl p-aminobenzoate-N- 168 - 172 +99.2 59.0 7.0 4.2 293 L-fucoside (c=0.5, 50% CH3OH) (59.1 7.1 4.3) 33 Propyl p-aminobenzoate-N- 145 - 149 -65.4 52.4 6.5 2.8 293 cellobioside (c=0.5, 50% CH3OH) (52.5 6.6 2.8) 34 Butyl p-aminobenzoate-N- 133 - 138 +18.5 59.3 7.1 4.3 293 D-riboside (c=0.5, 50% CH3OH) (59.1 7.1 4.3) 35 Butyl p-aminobenzoate-N- 168 - 171 +24.4 62.7 7.2 4.5 293 D-2-deoxyriboside (c=0.5, 50% CH3OH) (62.6 7.3 4.5) 36 Butyl p-aminobenzoate-N- 154 - 160 +96.8 60.1 7.4 4.1 293 L-fucoside (c=0.5, 50% CH3OH) (60.2 7.4 4.1) 37 Butyl p-aminobenzoate-N- 190 - 195 -73.1 53.3 6.9 2.6 293 cellobioside (c=0.5, 50% CH3OH) (53.4 6.8 2.7) In addition, the results of determination of infrared absorption spectra of the present compounds are illustrated in the drawing, from Figure 1 to Figure 37. The numbers of the figures correspond to the numbers of the compounds in Table 1, for example, Fig. 1 shows the infrared absorption spectrum of the compound No. 1 in Table 1.

In the following, the toxicological and pharmacological properties of the present compounds are explained in the order: (1) Acute toxicity: Acute toxicity of the present compound was examined by forced oral administration to ICR--JCL mice. The specimen was dissolved or suspended in distilled water.

The presence or absence of their symptoms are observed after administration until the 7th day of administration, and LD50 of the specimen was obtained from the mortality accumulated to the 7th day, according to the graphic method of Litchfield-Wilcoxon. The results are shown in Table 2. As is seen in Table 2, the present compounds are qualified to be highly safe.

TABLE 2 Acute Oral Toxicity of the Present Compound, LDso g/kg

No. Compound LD50 No. Compound LD,, 10.0 19 9.7 2 13.1 20 8.6 3 9.9 21 10.8 4 9.5 22 9.5 5 12.0 23 7.0 6 11.2 24 9.9 7 8.0 25 5.5 8 8.0 26 6.9 9 12.7 27 7.7 10 10.0 28 8.1 11 15.4 29 7.9 12 13.9 30 6.0 13 11.5 31 5.1 14 8.9 32 7.2 15 16.0 33 8.0 16 14.4 34 7.1 17 8.0 35 5.3 its 7.0 36 5.7 37 9.0 (2) Anti microbial activity: The present compound was dissolved in distilled water at a series of two fold dilution system.

These diluted solutions were mixed with agar culture medium in 9 times by volume and the mixture was poured into a petridish. Heart-infusion agar culture medium was used for bacteria, and Sabouraud's agar culture medium was used for fungi. After streaking with the pre-culture of a microorganism, the inoculated plates were incubated at 37 C for 20 to 24 hours for bacteria and at 25 C for 3 to 7 days for fungi, respectively, and then the growth of microorganism was examined.The following microorganisms were used for assessing the antimicrobial activity: Pseudomonas aeruginosa IAM 1 514 Escherichia coli IFO 12734 Staphylococcus aureus 209 P Bacillus subtllis IAM 1069 Saccharomyces cerevisiae IAM 4207 Candida albicans ATCC 752 Trichophyton mentagrophytes IFO 6124 Aspergillus niger IAM 3001 As the result of the above-mentioned tests, it was found that none of the tested present compounds showed growth inhibition of all the microorganisms even at a concentration of 1 mg/ml.

(3) Mutagenicity: Mutagenicity of the present compounds was tested by rec-assay as follows: A strain of Bacillus subtilis M 45, a defectant of recombination repair, and a wild strain of Bacillus subtilis H 1 7 keeping recombination-repair activity were inoculated to make their own streaks not crossed at their start points on a B-2 agar culture plate (made by dissolving 10 g of meat extract, 10 g of polypeptone, 5 g of sodium chloride and 15 g of agar in 1000 ml of distilled water at a pH of 7.0).

Then, a circular disc of filter paper 8 mm in diameter, which absorbed 0.04 ml of an aqueous solution of the present compound (using sterilized water) at a concentration of 500 ppm was put on the surface of the agar plate so as to cover the starting points of the above-mentioned streaks of bacteria culture. The inoculated B-2 agar culture was kept at 370C for a night and the length of growth-inhibited region was measured. Kanamycin was used as the negative control and Mitomycin C was used as the positive control.

As the results, although kanamycin used as the negative control at a concentration of 10 ppm showed a length of growth inhibition region of 6 mm to B. subtilis M 45, and of 5 mm to B. subtilis H 1 7, respectively, and mitomycin C used as the positive control at a concentration of 0.05 ppm showed a length of growth inhibition of 14 mm to B. subtilis M 45, and of 3 mm to B. subtilis H 17, respectively, all the tested present compounds did not show any inhibition to both M 45 and H 17 strains. These results show that all the tested present compounds did not show any mutagenicity even at a high concentration of 500 ppm.

(4) Delayed-type foot pad reaction: In order to know the effects of the present compounds on cellular immunity, the foot pad reaction test was carried out using ICR--JCL mice as experimental animals and erythrocytes of sheep as an antigen.

A mouse was primary-sensitized by injecting 0.2 ml of 10% suspension of sheep erythrocytes in physiological saline solution from the caudal vein and after 7 days of the first sensitization, 0.05 ml of 40% suspension of sheep erythrocytes in physiological saline solution was injected into the foot pad for the second sensitization. The thickness of the foot pad was determined on the next day. The administration of the present compound was carried out intraperitoneally at the dosage of 250 mg/kg/day once a day for consecutive 5 days centering around the day when the first sensitization was carried out.

As the result, the increment of the thickness of the foot pad of the mouse administered with the present compound showed no significant difference as compared to the increment in the group of mouse not administered with the present compound.

(5) Antibody-producing activity: in order to know the effects of the present compound on humoral immunity, the hemagglutination test was carried out using ICR--JCL mice sensitized with sheep erythrocytes.

A mouse was sensitized by injecting 0.2 ml of 10% suspension of sheep erythrocytes in physiological saline solution from the caudal vein and after 7 days of sensitization the mouse blood was sampled for the hemagglutination test of determination of the antibody-producing activity. The present compound was administered for consecutive 5 days centering around the day of sensitization, intraperitoneally at the dosage of 250 mg/kg/day.

As the result, there was no significant difference in agglutination titer between the group administere'd with the present compound and the control group.

The followings are the pharmacological properties of the present compound described in the order of (1) blood sugar-reducing activity, (2) antihypertensive activity, (3) anti-tumour activity, (4) blood lipid reducing activity, (5) anti-inflammatory activity and (6) analgetic- and antipyretic activity.

(1) Blood sugar reducing activity Streptozotocin was administered intraperitoneally to a group of Wistar rats at a dosage of 60 mg/kg and after confirming the positivity of urinary sugar of the animals on the 8th day, regular insulin was further administered to the rats to reduce both the urinary sugar and the blood sugar. Out of the thus treated animals, those which certainly showed a higher urinary sugar value and also a higher blood sugar value after a few days of insulin-administration were used as the model animals suffering from artificial diabetes mellitus. The present compound was administered to the model animals orally as a solution in distilled water at the dosage of 300 mg/kg.Blood specimens were collected after 3 and 6 hours of the administration, and the determination of glucose in the specimen was carried out by using a RaBA-kit (made by Chugai Pharmaceutical Co., Japan) according to the enzyme method.

The results are shown in Table 3. As is seen in Table 3, the difference between the values of the blood sugar before and after the administration of every compound of the present invention (A value) was larger than the A value of control.

TABLE 3 Activity of the Present Compound in Reducing the Level of Blood Sugar

Reduced concentra- Reduced concentrai tion of blood sugar tion of blood sugar level (mgldl) after level (mg/dl) after No. Compound 3 hours 6 hours No. Compound 3 hours 6 hours 1 125 125 19 98 157 2 137 102 20 164 181 3 152 131 21 175 184 4 143 108 22 107 115 5 137 129 23 115 157 6 105 118 24 147 154 7 147 134 25 151 161 8 138 95 26 110 139 9 151 162 27 131 164 10 168 127 28 159 171 11 151 143 29 163 ; 171 12 150 129 30 147 153 13 119 121 31 126 139 14 132 113 32 99 151 15 128 137 33 158 1 158 16 140 108 34 172 | 177 17 162 173 35 121 151 18 109 169 36 95 108 37 105 122 Control 30 40 (2) Antihypertensive activity An aqueous solution of the present compound in distilled water was orally administered to rats of spontaneous hypertension at a dosage of 300 mg/kg and their blood pressure was determined after 3 and 6 hours of administration by a sphygmomanometer (made by Ueda Works, Japan, Model USM-1 05R).The difference of blood pressures before and after the administration was used to evaluate the antihypertensive activity of the present compound. Mean value of blood pressure of the above-mentioned rats in spontaneous hypertension was 200 mmHg.

The results are shown in Table 4. As is seen in Table 4, all the tested present compounds clearly showed an antihypertensive effect.

TABLE 4 Hypertensive Activity of the Present Compound Unit: mmHg

Reduced amount of Reduced amount of blood pressure blood pressure after after No. Compound 3 hours 6 hours No. Compound 3 hours 6 hours 1 26 28 19 23 25 2 24 28 20 21 21 3 23 26 21 24 24 4 22 23 22 21 22 5 27 27 23 22 24 6 25 25 24 22 22 7 26 29 25 23 25 8 24 24 26 29 22 9 26 28 27 15 27 10 25 25 28 20 21 11 27 27 29 11 29 12 24 28 30 23 26 13 25 26 31 22 23 14 23 24 32 23 24 15 28 30 33 26 29 16 29 20 34 27 30 17 25 29 35 23 25 18 26 28 36 22 25 37 18 23 Control -2 2 (3) Antitumour activity Cells of Sarcoma 180 were transplanted subcutaneously into the right axillary part of ICR-JCL mice at the rate of 1 x 106 cells/mouse, and from after 24 hours of transplantation an aqueous solution of the present compound in sterilized physiological saline solution was orally administered every other day at a dose rate of 500 mg/kg, 10 times in all. On the 25th day of the transplantation, the nodular tumour(s) were extirpated and weighed.

The inhibition ratio (l.R.) (%) of the active ingredient was calculated by the following formula: (1T/C) x 100=I.R.(%) wherein T: mean weight of the tumour(s) in treated group of mice, C: mean weight of the tumour(s) in control group* of mice.

The results of the test are shown in Table 5. As is seen in Table 5, all the present compounds tested exhibited an antitumour activity.

Note: *Mice transplanted, but not administered.

TABLE S AntiXtumour Activity of the Present Compounds ~ ~~~~~~~~~~~

Rate of inhibiting Rate of inhibiting tumour growth tumour growth No. Compound (I.R. %) No. Compound (I.R. %) 1 63.8 19 55.4 2 61.2 20 59.6 3 59.7 21 47.7 4 57.3 22 45.4 5 64.5 23 48.9 6 65.5 24 51.0 7 60.1 25 42.0 8 58.7 26 43.0 9 57.6 27 39.9 10 55.5 28 40.1 11 54.3 29 45.4 12 59.0 30 37.2 13 59.4 31 44.3 14 60.2 32 39.4 15 60.3 33 52.3 16 58.0 34 45.3 17 51.4 35 36.5 18 53.3 36 47.0 37 39.2 (4) Blood lipid reducing activity Japanese male white rabbits were fed for about 3 months with solid feed (CR--1) containing 1 % of cholesterol and those animals in which the increase of seral lipid component was confirmed were used as the model animals having experimental arteriosclerosis.

An aqueous solution or suspension of the present compound in distilled water was administered at the dose rate of 300 mg/kg orally and after the administration, blood specimen was collected as time passes from the auricular vein and the change of total cholesterol (determined by the enzyme method) and beta-lipoprotein (determined by turbidmetry) in the serum of the blood specimen was observed.

The results are shown in Table 6. In Table 6, the values of serum cholesterol (mean value of 550 mg/dl) and of beta-lipoprotein (mean value of 2500 mg/dl) after respectively 3 and 6 hours of administration were respectively subtracted from the value before the administration, and only the differences are shown, respectively. Therefore, the value shows the decrease and the minus value shows the increase of the respective values due to the administration. As is clearly seen in Table 6, generally, all the tested present compounds exhibited the activity of reducing the lipid components as compared to control.

TABLE 6 Blood Lipid-reducing Activity of the Present Compound Unit: mg/dl

Reduced concentration of Reduced concentration of ss-liloprotein cholesterol ss-lipoprotein cholesterol after (hours) after (hours) after (hours) after (hours) No. Compound 3 6 3 6 No. Compound 3 6 3 6 1 147 152 -3 43 19 171 181 -1 77 2 151 157 2 52 20 184 190 2 82 3 134 139 -5 44 21 192 202 7 90 4 137 144 3 57 22 179 193 6 81 5 141 150 -1 50 23 193 210 0 79 6 146 160 3 60 24 185 197 3 69 7 138 142 -7 47 25 181 193 4 63 8 141 153 4 53 26 177 185 5 74 9 129 137 -8 54 27 189 201 8 82 10 133 142 1 58 28 169 183 2 66 11 145 151 -4 60 29 172 180 3 71 12 147 160 2 64 30 192 199 4 64 13 132 143 -4 49 31 179 190 10 77 14 139 152 4 54 32 168 182 2 82 15 147 160 -8 57 33 181 194 2 69 16 153 164 3 67 34 179 187 7 75 17 187 194 5 75 35 184 197 1 80 18 179 183 3 68 36 141 155 -1 60 37 162 171 3 54 Control 4 -4 -4 11 (5) Antiinflammatory activity (a) Carrageenin-edema inhibitory activity Following the method of Van Arman et al. (1963), the present compound was forcibly and orally administered to each rat of a group consisting of 10 animals at the dose rate of 1000 mg/kg, and after one hour of the administration 0.1 ml of 1% suspension of carrageenin in physiological saline solution was injected to their right foot pad.The volume of the foot pad was determined as time passes and the antiinflammatory activity was expressed by the ratio of inhibition of the swelling of the foot pad due to carrageenin by the present compound, using the determined value of 1-4 hours from the injection and calculating by the following formula: (1 - T/C) x 100 = l.R. (%) = antiinflmmatory activity wherein T: mean value of volumes of foot pad in administered animals C: mean value of volumes of foot pad of control (not administered and then injected) The results are shown in Table 7. As is seen in Table 7, all the present compounds tested showed the inhibitory activity against the edema caused by carrageenin.

(b) Antigranuloma activity Following the method of Winter et al. (1963), two cotton wool pellets were implanted into the skin of back of each rat of a group consisting of 6 rats at the symmetrical positions having the median line as the axis of symmetry, the weight of one pellet being 30 + 1 mg. Oral administration of 1000 mg/kg/day of the present compound was carried out for consecutive 7 days. On the 8th day, the granuloma formed in the rats was extirpated and weighed after drying. The antigranuloma activity expressed by the ratio of inhibition of the growth of the granuloma (I.R., %) was calculated in a manner as shown in (5) (a), and the results are shown in Table 7. As is seen in Table 7, each of the present compounds exhibited the inhibiting activity of growth of the granuloma.

(c) Antiexudation activity Following the method of Baris et al. (1965), a volume of air was injected subcutaneously in the back of each rat of a group consisting of 6 rats to make an air pouch, and then 0.5 ml of 1% croton oil solution in sesame oil was injected into the pouch. The oral administration of 1000 mg/kg/day of the present compound was then begun to continue for 5 days. On the 6th day, the amount of exudated liquid into the pouch was determined and the antiexudation activity expressed by the ratio of inhibitory activity to exudation was calculated in the same manner as shown in (5) (a). The results are shown in Table 7. As is seen in Table 7, all the present compounds tested exhibited the antiexudation activity.

TABLE 7 Anti-inflammatory Activities of the Present Compounds Unit: %

Rates of Inhibition of Edema due to Granuloma due to Exudation due to air No. Compound carrageenin cotton pellet pouch with oil 1 19.7 30.2 8.3 2 21.1 21.1 9.6 3 15.3 8.3 21.7 4 25.6 19.6 15.5 5 28.3 31.0 6.8 6 29.5 25.7 19.7 7 17.7 15.3 21.7 8 19.3 21.7 15.4 9 28.6 29.9 35.6 10 20.1 31.0 20.3 11 34.4 26.8 16.4 12 20.0 40.0 21.7 13 29.1 21.7 12.5 14 19.1 18.7 17.2 15 35.0 33.3 27.0 16 35.0 49.7 19.8 17 41.0 9.9 38.6 18 25.0 23.3 34.2 19 33.0 19.5 35.7 20 42.0 37.7 32.4 21 # 40.1 45.0 27.1 22 47.7 10.0 31.2 23 42.3 12.1 33.3 24 38.6 18.8 36.8 25 25.6 23.3 32.5 26 33.3 35.6 24.7 TABLE 7 (Continued) Antisinflammatory Activities of the Present Compounds Ubit:: %

Rates of Inhibition of Edema due to Granuloma due to Exudation due to air No. Compound carrageenin cotton pellet pouch with oil 27 19.6 20.0 39.2 28 28.8 38.8 34.5 29 31.5 39.8 26.5 30 24.3 27.7 35.8 31 36.7 35.4 27.8 32 29.7 36.6 22.4 33 47.1 35.1 36.2 34 30.0 48.1 38.4 35 40.0 25.6 36.8 36 21.5 19.5 30.6 37 31.7 12.6 23.3 (6) Analgetic- and anti-pyretic activity (i) Analgetic activity Determination by the mechanical stimulation method (by applying pressure) Female ICR mice which showed a threshold value of pain of 50 to 80 mmHg when their tale base part was pressured by a pressure stimulation apparatus (made by Natsume Works, Japan) of Takagi and Kameyama were chosen as test animals, ten animals comprising a group.

After administering the present compound, the test was carried out as the time passes and the applied pressure and the time period until the animal showed a pseudo-escaping reaction were determined to evaluate the analgetic activity of the present compound.

The results are shown in Table 8. As is seen in Table 8, the pressure applied on animals when the animal showed the pseudo-escaping reaction was higher in animals to which the present compound had been applied than in animals not administered, and the time period from the beginning to the time point when the animal showed the reaction was longer in animals administered with the present compound than in animals not administered. Thus, an analgetic activity of the present compound was confirmed.

Determination by the chemical stimulation method The present compound was orally administered to a group (10 animals) of female ICR mice of age of 5 to 6 weeks, and after 30 min of the administration an aqueous 0.6% acetic acid solution was intraperitoneally injected into the mouse at a dose rate of 0.1 my/1 0 g of body weight. The number of writhing motion which occurred in the mouse during 10 minutes after 10 minutes of intraperitoneal administration was recorded. The analgetic activity was evaluated from the writhing syndrome inhibiting ratio obtained by the following formula: (1 - T/C) x 100 = writhing syndrome - inhibiting ratio (%I, wherein T: mean number of writhing syndrome in the group administered C: mean number of writhing syndrome in the control group.

The results are shown in Table 9. As is seen in Table 9, every compound of the present invention showed analgetic activity. The above-mentioned process was carried out following the method of Kostet et al. (1959).

TABLE 8 Analgetic Activity in the Case of Mechanical Stimulation shown by the Occurrence of Pseudo-escaping Reaction under Pressure P (minHg) after the time T (sec)

No. Compound P T No. Compound P T 1 80 36 19 97 38 2 88 38 20 96 46 3 84 37 21 94 43 4 92 44 22 93 51 5 83 32 23 97 42 6 89 37 24 95 47 7 85 34 25 94 39 8 90 38 26 96 44 9 87 35 27 97 40 10 92 42 28 90 43 11 89 36 29 93 47 12 95 43 30 95 41 13 87 37 31 92 48 14 93 47 32 97 52 15 83 34 33 98 47 16 90 45 34 98 41 17 98 47 35 92 44 18 92 ~ 52 ~# 36 92 39 37 88 40 Control 75 33 TABLE 9 Analgetic Activity in the case of Chemical Stimulation shown by Syndrome-inhibiting Rate (I.R. %)

No. Compound I.R. % No. Compound I.R. % No. Compound I.R. % 1 30.5 13 34.7 25 46.2 2 35.2 14 33.4 26 50.5 3 32.5 15 27 53.1 4 33.4 16 30.5 28 50.2 5 29.7 17 53.2 29 47.7 6 38.2 18 51.2 30 46.5 7 30.4 19 47.4 31 43.2 8 41.1 20 50.5 32 49.4 9 27.8 21. 46.2 33 50.0 10 40.1 22 51.7 34 43.1 11 26.9 23 43.8 35 41.2 12 36.5 24 47.6 36 35.5 37 42.8 Control 0 (ii) Antipyretic activity Following the method of Winter et al. (1961), a 20% suspension of beer yeast was subcutaneously injected to a group (consisting of 6 animals) of rats, and after 10 hours of fasting, the present compound was orally administered to the rats at a dose rate of 1000 mg/kg and their rectal temperature was determined.

The antipyretic activity is expressed by the ratio of inhibiting pyrexia due to beer yeast (I.R.%) at the time when the antipyretic activity of the present compound is at its maximum according to the following formula: C1 -T Antipyretic activity = I.R. (%) = # x 100 C,C2 wherein T: mean rectal temperature of rats injected beer yeast to which the present compound was administered.

C,: mean rectal temperature of rats injected beer yeast, without the present compound.

C2: mean rectal temperature of untreated rats (control).

the results are shown in Table 10. As is seen in Table 10, all the present compounds exhibited a considerable antipyretic activity.

TABLE 10 Antipyretic Activity shown by the Rate of Inhibiting Pyrexia (I.R. %)

No. Compound I.R. % No. Compound l.R. % No. Compound l.R. % 1 36.9 13 38.4 25 60.8 2 43.8 14 44.6 26 56.9 3 472 15 34.7 27 58ss 4 462 16 45.2 28 57.4 5 36.4 17 62.5 29 59.5 6 43.9 18 63.3 30 58.8 7 47.8 19 58.7 31 60.7 8 44.7 20 592 32 61.1 9 36.1 21 63.4 33 56.7 10 48,2 22 59.8 34 582 11 39.6 23 602 35 56.9 12 53.1 / 24 1 57.7 | 36 i 46.2 37 53.0 From the above-mentioned results shown in Tabies 8, 9 and 10, it wili be understood that the present compounds have activity of suppressing the central nerve system.

In view of the above-illustrated toxicological and pharmacological properties of the present compounds, it will be recognized that the present compounds are possibly and effectively utilized as an active ingredient of the pharmaceutical compositions for treating hypertension, diabetes mellitus, arteriosclerosis, tumours, inflammatory diseases, pyrexia and pains.

Formulation of the present compound to be the pharmaceutical composition is carried out as shown below. The present compound may be formulated to be dose units and states which are appropriately administered according to the kinds and states of the above-mentioned diseases, singly or combined with other pharmaceuticals while using carriers and diluents pharmaceutically acceptable.

The states of the above-mentioned dose unit include powders, granules, tablets, sugar-coated tablets, capsulated ones, suppositories, suspensions, solutions, emulsions, ampouled ones and injections.

As the carriers and diluents, pharmaceutically applicable vehicles, fillers, combining agents, wetting agents, disintegrants, surfactants, lubricants, buffering agents, perfumes, preservatives, dissolution aids and solvents are mentioned. These carriers and diluents may be liquid or semi-solid, and may be used after mixing two or more kinds.

The formulation of the present compounds are possibly carried out while applying the publicly known methods, and the pharmaceutical composition may contain 0.01 to 100% of the present compound. The pharmaceutical composition according to the present invention may be administered to human and mammal orally or parenterally, however, it is preferable to administer orally. The oral administration includes sublingual administration, and the parenteral administration includes subcutaneous-, muscular- and intravenous injections as well as the administration by the drop inethod.

The dose of the present compound as a pharmaceutical depends upon the object (human or mammal) and the age, the individual difference and the state of disease, and accordingly it is not limitative, however, in the human cases, the daily dose is 0.1 to 500 mg/kg, preferably 1 to 250 mg/kg in oral administration, and 0.01 to 200 mg/kg, preferably 0.1 to 100 mg/kg in parenteral administration.

These doses are preferably divided into 1 to 4 portions and administered.

The following are more detailed explanations of the present invention while referring to the examples of production of the present compound and to the formulation examples of the pharmaceutical compositions according to the present invention.

EXAMPLE 1 Production of Sodium p-aminobenzoate-N-D-riboside.

In 30 ml of an aqueous 95% ethanolic solution, 2.75 g of p-aminobenzoic acid, 3.0 g of D-ribose and 0.3 g of ammonium chloride were brought into reaction by heating under a reflux condenser.

Crystals separated after leaving the reaction mixture in a refrigerator. After collecting the crystals by filtration, the crystals were washed with ether and then repeatedly recrystallized from an aqueous 50% methanolic solution to obtain colorless needle-like crystals with a yield of 30.2%.

The thus obtained p-aminobenzoic acid-N-D-riboside was slowly dissolved into an aqueous 1 % solution of sodium hydroxide containing an equivalent amount of sodium hydroxide to the riboside and after filterig the solution to remove the undissolved matters of the solution, the filtrate was condensed and a great excess amount of acetone was added to the condensate. The separated crystals were dried to obtained colorless crystals of the sodium salt with a yield of 100%. The overall yield was 30.2%.

EXAMPLE 2 Production of Sodium p-aminobenzoate-N-D-2-deoxyriboside.

EXAMPLE 3 Production of Sodium p-aminobenzoate-N-D-fructoside.

EXAMPLE 4 Production of Sodium p-aminobenzoate-N-L-sorboside.

EXAMPLE 5 Production of Sodium p-aminobenzoate-N-L-fucoside.

EXAMPLE 6 Production of Sodium p-aminobenzoate-N-D-glucuronolactone.

EXAMPLE 7 Production of Sodium p-a minobenzoate-N-D-glucuronide.

In these Examples 2 to 7, the same procedures as in Example 1 were taken to obtain the respective products except for using the respective derivative of sugars shown in Table 11 instead of Dribose in Example 1, the results being shown also in Table 11.

TABLE 11

Amount of p-ami noben- Yield of acid Overall zoic acid glycoside yield Example (g) Sugar derivative (g) ( fi) (YO) 1 2.75 D-ribose (3.0) 30.2 30.2 2 2.7 D-2-deoxyribose (2.75) 14.0 14.0 3 2.4 D-fructose (2.6) 26.5 26.5 4 2.7 L-sorbose (2.1) 5.0 5.0 5 2.1 L-fucose (2.6) 15.8 15.8 6 4.7* Doglucuronolactone 89,0 89.0 (5.9) 7 2.7t* Methyl-D-glucuronic 78.0 78.0 acid (4.2) Notes: *: In Example 69 300 ml (instead of 30ml) of the aqueous 94% ethanotic solution were used. The melting point and the specific rotatory power of the product were respectively 150 - 1610C and [&alpha;]D22 = =-47G (in inethanol).

**: in Example 7, 20 ml (instead of.30 ml) of the aqueous 94% ethanolic solution were used. The melting point and the specific rotatory power of the product were respectively 193 - 197 C and [&alpha;]D19 = -89 .

EXAMPLE 8 Production of Sodium p-aminobenzoate-N-D-acetylglucosaminide.

In 1 50 ml of ethanol. 1.9 g of p-aminobenzoic acid, 3.0 g of D-N-acetylglucosamine and 0.05 9 ôf ammonium chloride were brought into reaction by heating under a reflux condenser. After cooling the reaction mixture in a refrigerator, the separated crystals were collected by filtration, washed with ether and repeatedly recrystallized from an aqueous 50% methanolic solution to obtain colorless needle-like crystals of p-aminobenzoic acid-N-D-acetylglucosaminide.

The thus obtained crystals were slowly dissolved in an aqueous 1% solution of sodium hydroxide containing an equivalent amount of NaOH corresponding to the glucosaminide and then applying the same procedure as in Example 1, colorless crystals of the product, sodium p-aminobenzoate-N-Dacetylglucosaminide at a yield of 100% and an overall yield of 30.0% were obtained.

EXAMPLE 9 Production of Sodium p-a mlnobenzoate-N-maltoside.

In a solution of 3.6 g of maltose in 2 ml of water, a solution of 1.4 g of p-aminobenzoic acid in 4.2 ml of ethanol and 1.4 ml of acetic acid were added, and the mixture was brought into reaction by heating under a reflux condenser. After the reaction was over, the reaction mixture was left in a refrigerator to have p-aminobenzoic acid-N-maltoside crystallized out. The crystals were collected by filtration, washed with ether and then repeatedly recrystallized from an aqueous 50% methanolic solution to purify the crystals colorless and needle-like of a yield of 3.1%.

By carrying out the same procedure of neutralization and purification as in Example 1, the sodium salt was obtained at a yield of 100%, at an overall yield of 3.1%.

EXAMPLE 10 Production of Sodium-p-aminobenzoate-N-cellobioside.

The same procedures in Example 9 were repeated except for using 3.4 g of cellobiose dissolved in 13 ml of water instead of 3.6 g of maltose dissolved in 2 ml of water and 5 ml of ethanol instead of 4.2 ml of ethanol. The yield of p-amino-benzoic acid-N-D-cellobioside was 22.8%. Then the neutralization was carried out in the same manner as in Example 9 to obtain recrystallized colorless crystals of the product at an overall yield of 22.8%.

EXAMPLE 11 Production of Sodium p-amlnobenzoate-N-saccharnside The same procedures as in Example 10 were repeated except for using 3.6 g of saccharose dissolved in 10 ml of water (instead of 3.4 g of cellobiose dissolved in 13 ml of water) and using 4.2 ml of ethanol (instead of 5 ml). The yield of colorless minute needie-like crystals of p-aminobenzoic acid-Nsaccharoside was 2.5%. The same treatment of the thus obtained acid-saccharoside as in Example 10 was carried out to obtain colorless crystals of the product at an overall yield of 2.5%.

EXAMPLE 12 Production of Sodium p-aminobenzoate-N-lactoside.

The same procedures were repeated as in Example 11 except for using 3.6 g of lactose instead of 3.6 g of saccharose in Example 11. The yield of p-aminobenzoic acid-N-lactoside was 24.9%, and the overall yield of the product was also 24.9%.

EXAMPLE 13 Production of Sodium p-aminobenzoate-N-maltotrioside.

The same procedures were repeated as in Example 12 except for using 3.5 g of maltotriose dissolved in 2 ml of water (instead of 3.6 g of lactose dissolved in 10 ml of water) and using 1.0 g of paminobenzoic acid dissolved in 6 ml of ethanol (instead of 1.4 g of the acid dissolved in 4.2 ml of ethanol). The yield of p-aminobenzoic acid-N-maltotrioside was 6.9% and the overall yield of sodium p aminobenzoate-N-maltotrioside was also 6.9%.

EXAMPLE 14 Production of Methyl p-aminobenzoate-N-D-riboside.

By bringing 4.6 g of methyl p-aminobenzoate, 5.0 g of D-ribose and 0.2 g of ammonium chloride into reaction in 100 ml of an aqueous 94% ethanolic solution in the same manner as in Example 1, methyl p-aminobenzoate-N-D-riboside was obtained after recrystallizing the crude reaction product. It was colorless needle-like crystal obtained at a yield of 30.2%.

EXAMPLE 15 Production of Methyl p-aminobenzoate-N-D-2-deoxyriboside.

In the same manner as in Example 14, except for using 5.63 g of methyl p-aminobenzoate, 5.0 g of D-2-deoxyribose and 0.3 g of ammonium chloride in 40 ml of the aqueous 94% methanolic solution, methyl p-aminobenzoate-N-D-2-deoxyriboside was obtained as colorless needle-like crystals at a yield of 45.5%.

EXAMPLE 16 Production of Methyl p-aminobenzoate-N-D-fructoside.

In the same manner as in Example 1 5 except for using 2.5 g of methyl p-aminobenzoate, 2.6 g of D-fructose and 0.2 g of ammonium chloride, methyl p-aminobenzoate-N-D-fructoside was obtained as colorless needle-like crystals at a yield of 28.8%, melting at 102-1 040C, and of [aj20 = +4.42 (c=0.5, methanol).

The elementary composition found was 53.6% of C,6.2% of H and 4.5% of N; calculated as C,3H,7NO5,53.7% of C, 6.1% of H and 4.5% of N.

EXAMPLE 17 Production of Methyl p-aminobenzoate-N-L-fucoside.

In the same manner as in Example 1 5 except for using 1.2 g of methyl p-aminobenzoate, 1.3 g of L-fucose and 0.2 g of ammonium chloride in 1 5 ml of the aqueous 94% ethanolic solution, colorless needle-like crystals of methyl p-aminobenzoate-N-L-fucoside were obtained at a yield of 46.6%.

EXAMPLE 18 Production of Methyl p-aminobenzoate-N-maltoside.

In the same manner as in Example 9 except for bringing into reaction of 3.6 g of maltose dissolved in 2 ml of water, 1.5 g of methyl p-aminobenzoate dissolved in 4.2 ml of ethanol and 1.5 ml of acetic acid, and washing the reaction product with acetone and ether, methyl p-aminobenzoate-N-maltoside was obtained as colorless crystals at a yield of 5.4%.

EXAMPLE 19 Production of Methyl p-aminobenzoate-N-cellobioside.

In the same manner as in Example 1 8 except for using 3.4 g of cellobiose (instead of maltose) dissolved in 13 ml of water and 5.0 ml of ethanol for dissolving methyl p-aminobenzoate, methyl paminobenzoate-N-cellobioside was produced at a yield of 36.0% as colorless needle-like crystal.

EXAMPLE 20 Production of Methyl p-aminobenzoate-N-lactoside.

EXAMPLE 21 Production of Methyl p-aminobenzoate-N-maltotrioside.

EXAMPLE 22 Production of Methyl p-aminobenzoate-N-cellobioside.

EXAMPLE 23 Production of Propyl p-aminobenzoate-N-cellobioside.

EXAMPLE 24 Production of Butyl p-a minobenzoate-N-cellobioside.

In these respective Examples 20, 21, 22, 23 and 24, the synthesis of the product was respectively carried out in the same manner as in Example 19 except for bringing respective sugar derivative dissolved in the respective amount of water, the respective amount of respective ester of paminobenzoic acid dissolved in respective amount of ethanol and the respective amount of acetic acid illustrated in Table 12. The respective yields of the products are also shown in Table 12.

TABLE 12 Different Conditions in Examples 20, 21, 22, 23 and 24 from those of Example 19

Amount Ester of Amount Sugar of p-amino- of Acetic derivative water benzoic ethanol acid Yield Example (g) (ml) acid (g) (ml) (ml) (%) 19 cellobiose 13 methyl 5 1.5 36.0 (3.4) (1.5) 20 lactose 10 methyl 4.2 1.4 5.1 (3.6) (1.5) 21 maltotriose 2 methyl 6 1.4 5.8 (3.5) (1.0) 22 cellobiose 17 ethyl 6 1.5 8.5 (5.0) (2.41) 23 cellobiose 17 propyl 6 1.5 27.1 (5.0) (2.6) 24 cellobiose 17 butyl 6 1.5 7.6 (5.0) (2.8) EXAMPLE 25 Production of Ethyl p-aminobenzoate-N-D-riboside.

EXAMPLE 26 Production of Ethyl p-aminobenzoate-N-D-2-deoxyriboside.

EXAMPLE 27 Production of Ethyl p-aminobenzoate-N-D-fructoside.

EXAMPLE 28 Production of Ethyl p-aminobenzoate-N-L-fucoside.

EXAMPLE 29 Production of Propyl p-a minobenzoate-N-D-riboside.

EXAMPLE 30 Production of Propyl p-aminobenzoate-N-D-2-deoxyriboside.

EXAMPLE 31 Production of Propyl p-a minobenzoate-N-L-fucoside.

EXAMPLE 32 Production of Butyl p-aminobenzoate-N-D-riboside.

EXAMPLE 33 Production of Butyl p-aminobenzoate-N-D-2-deoxyriboside.

EXAMPLE 34 Production of Butyl p-aminobenzoate-N-L-fucoside.

In these respective Examples 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34, the synthesis was carried out in the same manner as in Example 14 except for using the respective ester (instead of methyl ester) of p-aminobenzoic acid in the respective amount, the respective amount of sugar derivatives (instead of D-ribose) in the respective amount, and the respective amount of ammonium chloride, in the respective amounts of the aqueous 94% ethanolic solution to obtain the respective products at the respective yields, the ester of p-aminobenzoic acid and its amount, the sugar derivative and its amount, the amount of ammonium chloride and the amount of the ethanolic solution being illustrated in Table 13 as well as the yield of the product.

TABLE 13 Different Conditions in Examples 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34 from those of Example 14

Ester of p-amino- Sugar Ammonium Amount og benzoic derivative chloride 94% ethanol Yield Example acid (g) (g) (g) (ml) Product (%) 14 methyl D-ribose 0.2 100 Methyl-p-aminobenzoate- 30.2 (4.6) (5.0) N-D-riboside 25 ethyl D-ribose 0.2 100 Ethyl p-aminobenzoate- 18.1 (5.05) (5.0) N-D-riboside 26 ethyl D-2-deoxy- 0.2 15 Ethyl p-aminobenzoate- 54.1 (6.16) ribose N-D-2-deoxyriboside (5.0) 27 ethyl D-fructose 0.2 15 Ethyl p-aminobenzoate- 24.5 (2.6) (2.6) N-D-fructoside* 28 ethyl L-fucose 0.2 15 Ethyl p-aminobezoate- 48.8 (1.3) (1.3) N-L-fucoside 29 propyl D-ribose 0.1 25 Propyl p-aminobenzoate- 49.1 (6.0) (5.0) N-D-riboside 30 propyl D-2-deoxy- 0.3 40 Propyl p-aminobenzoate- 58.3 (6.68) ribose N-D-2-deoxyriboside (5.0) 31 propyl L-fucose 0.2 15 Propyl p-aminobenzoate- 27.2 (1.4) (1.3) N-L-fucoside 32 butyl D-ribose 0.1 30 Butyl p-aminobenzoate- 26.4 (6.5) (6.5) N-D-riboside TABLE 13 (Continued)

Ester of p-amino- Sugar Ammonium Amount of benzoic derivative chloride 94% ethanol Yield Example acid (g) (g) (g) (ml) Product (%) 33 butyl D-2-deoxy- 0.3 50 Butyl p-aminobenzoate- 54.2 (3.6) ribose N-D-2-deoxyriboside (2.5) 34 butyl L-fucose 0.2 15 Butyl p-aminobenzoate- 41.4 (1.5) (1.3) N-L-fucoside Note: *: In Example 27, the melting point of the product, ethyl p-aminobenzoate-N-D-fructoside was 90 - 92 C, with the specific rotatory power of [&alpha;]D20 = +1 (c=0.5, ethanol).Its elementary composition was found to be 54.8% of C, 6.5% of H and 4.2% of N as compared to calculated values based on C15H21NO7 of 55.0% of C, 6.4% of H and 4.3% of N.

FORMULATION EXAMPLE 1 Formulation of powder or powder consisting of minute particles.

The following ingredients were uniformly mixed and ground to be powder or powder consisting of minute particles. In addition, the powder was put into capsule-containers to be capsulated; 10 parts by weight of butyl p-aminobenzoate-N-D-riboside, 15 parts by weight of heavy magnesium oxide and 75 parts by weight of lactose.

FORMULATION EXAMPLE 2 Formulation of granular composition.

The following materials were uniformly mixed and kneaded and after shaping to particles, the particles were dried and sifted to be granular composition: 45 parts by weight of propyl p-aminobenzoate-N-cellobioside, 1 5 parts by weight of starch, 16 parts by weight of lactose, 21 parts by weight of crystalline cellulose, 3 parts by weight of polyvinyl alcohol, and 30 parts by weight of water.

FORMULATION EXAMPLE 3 Formulation of tablet composition.

In the first place, granular composition was formulated as in Formulation Example 2 except for using methyl p-aminobenzoate-N-lactoside instead of methyl p-aminobenzoate-N-D-cellobioside and in the second place, 96 parts by weight of the thus formulated composition and 4 parts by weight of calcium stearate were mixed and the mixture was press-shaped to be tablets of 10 mm in diameter.

FORMULATION EXAMPLE 4 Formulation of sugar-coated tablet composition.

In the first place, granular composition was prepared by the same procedures of Formulation Example 2 using the following components: 94 parts by weight of ethyl p-aminobenzoate-N-L-fucoside, 6 parts by weight of polyvinyl alcohol and 30 parts by weight of water.

In the next place, 10 parts by weight of crystalline cellulose were added to 90 parts by weight of the thus prepared granules and the mixture was press-shaped to be tablets of 8 mm in diameter, and then syrup, gelatine and precipitated calcium carbonate were added to the tablets to formulate sugarcoated tablets.

FORMULATION EXAMPLE 5 Formulation of injection: The following components were mixed under heating and after sterilization, the mixture was made to be injection: 0.6 parts by weight of sodium p-aminobenzoate-N-D-N-acetylglucosa mide, 2.4 parts by weight of a nonionic surfactant and 97 parts by weight of an aqueous physiological saline solution.

FORMULATION EXAMPLE 6 Formulation of injection.

An injection was formulated according to the procedures in Formulation Example 5 except for using p-aminobenzoic acid-N-maltrotrioside instead of sodium p-aminobenzoate-N-D-Nacetylglucosamide.

Claims (11)

1. A derivative of para-aminobenzoic acid of the formula:

wherein R1 represents a residual group formed by the removal of -OH from the 1 (alpha)- or 1 (beta)position of ribose, desoxyribose, fructose, sorbose, fucose, N-acetylglucosamine, glucuronic acid, saccharose, maltose, cellobiose, lactose or maltotriose, and R2 represents hydrogen, alkyl of 1 to 4 carbon atoms or an equivalent amount of a pharmaceutically acceptable alkali metal, alkaline earth metal or aluminum.

2. A derivative of para-aminobenzoic acid according to claim 1, wherein R2 represents sodium.

3. A derivative of para-aminobenzoic acid according to claim 1 which is any one of compounds 1 to 37 identified in Table 1.

4. A process for producing a derivative of para-aminobenzoic acid as claimed in claim 1 wherein R2 is hydrogen or alkyl, which process comprises reacting a sugar selected from ribose, desoxyribose, fructose, sorbose, fucose, N-acetylglucosamine, glucuronic acid, saccharose, maltose, cellobiose, lactose and maltotriose with para-aminobenzoic acid or a lower alkyl ester thereof in the presence of a solvent.

5. A process for producing a derivative of para-aminobenzoic acid as claimed in claim 1 wherein R2 is an equivalent amount of an alkali metal, alkaline earth metal or aluminum, which process comprises reacting a sugar selected from ribose, desoxyribose, fructose, sorbose, fucose, Nacetylglucosamine, glucuronic acid, saccharose, maltose, cellobiose, lactose and maltotriose with para aminobenzoic acid in the presence of a solvent, separating out the reaction product as crystals, and reacting the separated crystals with an inorganic salt or a hydroxide of said alkali metal, alkaline earth metal or aluminum in an aqueous solvent.

6. A process according to claim 4 or 5, wherein the reaction between said sugar and paraaminobenzoic acid or a lower alkyl ester thereof is carried out in the presence of a catalyst.

7. A process according to claim 6, wherein said catalyst is acetic acid, hydrochloric acid or ammonium chloride.

8. A process according to claim 4 or 5 substantially as described with reference to any one of Examples 1 to 34.

9. A pharmaceutical composition containing as active ingredient at least one derivative of paraaminobenzoic acid as claimed in claim 1 or 2, and a pharmaceutically acceptable carrier or diluent.

1 0. A pharmaceutical composition according to claim 9 for use in the treatment of hypertension, diabetes mellitus, arteriosclerosis, tumours, inflammatory diseases, pyrexia or pains.

11. A pharmaceutical composition according to claim 9 substantially as described with reference to any one of Formulation Examples 1 to 6.