GB2060636A - Esters of aminobenzoic acid, their preparation and compositions containing them - Google Patents

Abstract

The invention provides novel esters of aminobenzoic acid of formula: <IMAGE> wherein R<1> represents a residual group formed by the removal of -OH from the 1(alpha)- or 1(beta)- position of arabinose, xylose, mannose, glucose, galactose or rhamnose and R<2> represents alkyl of 1 to 4 carbon atoms, subject to the proviso that when R<1> is derived from mannose and R<2> represents methyl, the, carboxymethyl group -COOR<2> is not in an ortho-position to the R<1>-NH- group. These esters have therapeutic activities and are particularly useful in the treatment of hyperglycemia, hypertension, hyperlipemia, inflammation, pain, pyrexia and tumours. They can be incorporated into pharmaceutical compositions.

Description

SPECIFICATION Esters of aminobenzoic acid, their preparation and compositions containing them The present invention relates to novel esters of aminobenzoic acid and further relates to pharmaceutical compositions containing at least one such ester as active ingredient particulariy compositions for use intreating hyperglycemia, hypertension, hyperlipemia, inflammation, pain, pyrexia and tumours.

We have previously invented, a pharmaceutical composition containing, as active ingredient, a derivative of aminobenzoic acid represented by the general formula

wherein R' represents a residual group formed by the removal of -OH from the 1 (alpha)- or 1 (beta)position of arabinose xylose, glucose, galactose, rhamnose or mannose and R2 represents H, Na, K, 1/2 Mg, 1/2Ca, 1/3AI or methyl based on their finding that the abovementioned compounds have therapeutical activities (West German Offenlegungsschrift No. 29 14 005).

We, as a result of synthesizing various derivatives of aminobenzoic acid other than the abovementioned derivatives and examining their therapeutical activities, have found that the novel esters of aminobenzoic acid represented by the following general formula (I) have therapeutical activities together with the appropriateness as the pharmaceutical agents and have attained the present invention.

wherein R1 denotes a group formed by removing the OH group from the carbon atom at I (alpha)- position or 1 (beta)-position of arabinose, xylose, mannose, glucose, galactose or rhamnose, and R2 denotes an aikyl group of 1 to 4 carbon atoms with a proviso that in the case where R1 is formed from mannose in the above-mentioned manner and R2 is methyl group, the carboxymethyl group does not occupy the ortho position in the benzene ring with respect to the group R1-NH-.

The esters of aminobenzoic acid represented by the above-mentioned general formula (I) (hereinafter referred to as the present compounds) are remarkably low in toxicity to mammals and humans and do not show any anti-microbial activity which causes the intra-intestinal microbial disturbance and do not show mutagenicity as are described later. Furthermore, since the present compounds do not affect the cellular and humoral immunity of mammals and humans, it may be said that the present compound has a pharmaceutical aptitude of positively administering for a long time period.

The followings are the detailed explanation of the present invention.

The physical properties of the present compounds are illustrated in Table 1. The infrared absorption spectra of the respective compounds of the present invention are shown in the drawing, Figs 1 to 28 wherein the number of each Fig. corresponds to the number of each of the present compounds shown in Table 1.

The present compounds includes the isomers having the position of their carboxyalkyl group at ortho, meta and para respectiveíy, in the benzene ring with respect to the R1-NH- group, and further includes those having R' respectively formed from L-arabinose, D-xylose, D-glucose, D-galactose and Lrhamnose.

The present compound is synthesizable by condensing one of methyl-, ethyl-, propyl- and butyl aminobenzoates with one of L-arabinose, D-xylose, D-mannose, D-glucose, D-galactose and Lrhamnose in the presence of ammonium chloride while heating the mixture of the above-mentioned raw materials under a reflux condenser and using an aqueous ethanolic solution or pure methanol as a solvent.In addition, the present compound is obtainable as crystals by filtering and separating the crystals which separates when the above-mentioned reaction mixture is left as it is at room temperature or in a cool place from the reactor solution, washing the thus obtained crystals well with water, ethanol or ether and recryatallizing the thus washed crystals from an aqueous methanolic- or ethanolic solution. TABLE 1 Physical property of the present compound

Ultraviolet Melting absorption No. Name of compound point ( C) Specific rotatory Power [&alpha;]D20 max. (nm) 1 Methyl o-aminobenzoate-N-D-xyloside 169 - 171 -23.0 (c=1, methanol) 220 2 Methyl o-aminobenzoate-N-D-glucoside 160 - 164 + 5 (c=0.5, ethanol) 220 3 Methyl o-aminobenzoate-N-D-galactoside 150 - 154 -102 (c=0.5, ethanol) 220 4 Methyl o-aminobenzoate-N-L-rhamnoside 191 - 196 +51.6 (c=0.5, ethanol) 220 5 Ethyl o-aminobenzoate-N-L-arabinoside 139 - 141 -22.5 (c=0.67, 67% methanol) 220 6 Ethyl o-aminobenzoate-N-D-mannoside 141 - 143 -36.0 (c=0.5, methanol) 220 7 Ethyl o-aminobenzoate-N-D-galactoside 151 - 155 +31.5 (c=0.67, 67% methanol) 220 8 Ethyl o-aminobenzoate-N-L-rhamnoside 210 - 212 +51.6 (c=0.5, ethanol) 220 9 Butyl o-aminobenzoate-N-D-mannoside 144 - 146 +19.8 (c=1, methanol) 220 10 Butyl o-aminobenzoate-N-L-rhamnoside 156 - 158 +47.0 (c=0.5, ethanol) 220 11 Methyl p-aminobenzoate-N-L-arabinoside 182 - 184 +41.2 (c=0.5, methanol) 293 12 Methyl p-aminobenzoate-N-D-xyloside 174 - 177 -66.4 (c=0.5, methanol) 293 13 Methyl p-aminobenzoate-N-D-mannoside 186 - 187 -138.8 (c=0.5, methanol) 293 14 Methyl p-aminobenzoate-N-D-glucoside 206 - 209 -123.2 (c=0.5, methanol) 293 15 Methyl p-aminobenzoate-N-D-galactoside 150 - 168 -99.6 (c=0.5, methanol) 293 16 Methyl p-aminobenzoate-N-L-rhamnoside 202 - 204 +145.2 (c=0.5, 94% ethanol) 293 17 Ethyl p-aminobenzoate-N-L-arabinoside 180 - 181 -10.9 (c=0.5, methanol) 293 TABLE 1 continued

Ultraviolet Melting absorption No. Name of compound point ( C) Specific rotatory Power [&alpha;]D20 max. (nm) 18 Ethyl p-aminobenzoate-N-D-mannoside 179 - 180 +7.2 (c=0.5, 94% ethanol) 293 19 Ethyl p-aminobenzoate-N-D-glucoside 126 - 128 -25.0 (c=0.5, 94% ethanol) 293 20 Ethyl p-aminobenzoate-N-D-galactoside 155 - 158 +31.5 (c=0.67, 67% ethanol) 293 21 Ethyl p-aminobenzoate-N-L-mannoside 191 - 196 +13.7 (c=0.5, 94% ethanol) 293 22 Propyl p-aminobenzoate-N-L-arabinoside 179 - 182 -16.6 (c=0.5, 50% methanol) 293 23 Propyl p-aminobenzoate-N-D-mannoside 186 - 189 -10.0 (c=0.5, 50% methanol) 293 24 Propyl p-aminobenzoate-N-D-glucoside 162 - 163 -96.0 (c=0.5, ethanol) 293 25 Propyl p-aminobenzoate-N-L-rhamnoside 205 - 207 -134.0 (c=0.5, ethanol) 293 26 Butyl p-aminobenzoate-N-L-arabinoside 176 - 178 -16.0 (c=1, methanol) 293 27 Butyl p-aminobenzoate-N-D-mannoside 174 - 178 -63.2 (c=0.67, 67% methanol) 293 28 Butyl p-aminobenzoate-N-L-rhamnoside 195 - 197 +66.6 (c=1, methanol) 293 The concrete process for synthesizing the present compound is illustrated in Examples described later.

In the followings, in order to clearly show the pharmaceutical aptitude of the present compound, the results of examination carried out on the acute toxicity, anti-microbial activity, mutagenicity, delayed-type foot pad reaction and antibody producing activity of the present compound are illustrated.

(1) Acute toxicity to mammals: Acute toxicity of the present compound was examined by forced oral administeration to ICR--JCL mice. The specimen of the present compound was dissolved or suspended in distilled water and orally administrated via a stomach tube.

The presence or absence of their symptoms was 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 as the active ingredients of the medicine, since LD50 of every one of the present compounds tested was larger than 5 g/kg.

TABLE 2 Acute oral toxicity of the present compound, LD,, unit: g/kg body weight

No. Compound LD,,0 No. Compound LD50 1 8.6 15 10.4 2 9.3 16 7.9 3 6.1 17 11.2 4 6.3 18 10.9 5 9.0 19 13.5 6 10.7 20 9.5 7 7.8 21 7.3 8 6.5 22 9.1 9 7.0 23 10.6 10 5.8 24 10.5 11 9.8 25 7.0 12 8.2 26 6.4 13 12.3 27 8.8 14 11.0 28 10.9 (2) Anti microbial activity: The present compound was dissolved in warm distilled water at a series of two fold dilution system. These diluted solutions were mixed with an agar culture medium in 9 times by volume and the mixture was poured into a petri-dish. 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, the inoculated plates were incubated at 370C for 20 to 24 hours for bacteria and at 250C for 3 to 7 days for fungi, respectively, and then the growth of the microorganism was examined.The following microorganisms were used for assessing the antimicrobial activity: Pseudomonas aeruginosa IAM 1514 Escherichia coli IFO 12734 Staphylococcus aureus 209P Bacillus subtilis IAM 1069 Saccharomyces cerevisiae IAM 4207 Candida albicans ATCC 752 Trichophyton mentagrophytes IFO 6124 Aspergillus niger IAM 3001 As the result of lie above-mentioned tests, it was found that none of the tested present compounds showed growth inhibition of all the microorganisms at a concentration of 1 mg/ml.

(3) Mutagenicity: The present compounds were 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 so as to make their own streaks not crossed at their starts on a B-Il agar culture plate (made by dissolving 10 g of meat extract, 10 g of polypeptone, 5 g of sodium chloride and 1 5 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 (in sterilized water thus holding 500 micrograms of the present compound per disc) was put on the surface of the agar plate so as to cover the starting points of the above-mentioned streaks of bacterial culture. The inoculated B-ll'agar plate was kept at 37OC for a night and the length of growth-inhibited region was measured. Kanamycin was used as the negative control at a concentration of 10 micrograms per disc and Mitomycin C was used as the positive control at a concentration of 0.05 microgram per disc.As a result, although Kanamycin showed the lengths of growth inhibition of 7 mm and 5 mm, respectively to Bacillus subtilis M 45 and B.subtilis K 1 7, and Mitomycin C showed the length of growth inhibition of 1 5 mm and 2 mm, respectively to B.subtilis M 45 and H 17, every compound of the present invention tested herein did not show any growth inhibition to both strains M 45 and H 1 7 of Bacillus subtilis at the concentration of 500 micrograms per disc.

These facts show that none of the present compounds tested herein showed mutagenicity to Bacillus subtilis.

(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 a 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 a 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 sensitized, however, not administered with any of the present compounds.

(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 a 1 0% 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 dose of 250 mg/kg/day.

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

The followings are the pharmacological properties of the present compounds described in the order of (1) blood sugar-reducing activity, (2) antihypertensive activity, (3) antitumor activity, (4) blood lipid reducing activity, (5) anti-inflammation activity, and (6) analgetic- and antipyrexial activity.

(1) Blood sugar reducing activity Streptozotocin was administered intraperitoneally to a group of Wistar rats at a dose 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 dose 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 blood sugar before and after the administration of every one of the present compounds (| value) was larger than the A value of control.

TABLE 3 Blood sugar-reducing activity (by A value) Unit: mg/dl

Decrement of Decrement of concentration of | concentration of blood sugar after | blood sugar after compound 3 No. of compound 3 hours 6 1 115 138 | 15 76 2 85 119 j 16 125 127 3 80 95 | 17 90 108 4 121 173 | 18 121 130 5 101 104 | 19 107 145 6 133 145 20 80 92 7 92 96 | 21 102 103 8 133 150 | 22 105 114 9 129 147 | 23 111 138 10 118 137 24 97 104 11 108 116 25 110 129 12 98 116 26 88 99 13 113 129 27 132 149 14 84 105 28 129 140 Control 30 25 (2) Antihypertensive activity An aqueous solution of the present compound in distilled water was orally administered to rats of spontaneous hypertension at a dose of 300 mg/kg and their blood pressure was determined before and 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 abovementioned rats in spontaneous hypertension before administration was 200 mmHg.

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

TABLE 4 Antihypertensive activity.

Difference of blood pressure between the value before administration and the value after 3 and 6 hours of administration (mmHg) is shown as depression.

Depression after Depression after No. of No. of compound 3 hours | 6 hours compound 3 hours 6 hours 1 20 26 15 12 19 2 14 18 16 20 27 3 15 20 17 24 26 4 26 29 18 23 23 5 16 26 19 19 26 6 23 25 20 14 18 7 18 20 21 18 25 21 21 24 22 14 19 9 19 21 23 12 21 10 19 27 24 17 20 11 20 21 25 20 29 12 23 29 26 16 20 13 23 24 27 16 24 14 17 19 28 19 24 Control 1 -2 (increase) (3) Antftumour activity Cells of Sarcoma 1 80 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 or suspension of the present compound in sterilized physiological saline solution was orally administered every other day at a dose rate of 500 mg/kg/time,1 10 times in all. On the 25th day of the transplantation, the nodular tumour(s) was extirpated and weighed.

The inhibition ratio (I.R.) (%) of the present compound 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, and 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 5 Anti-tumour activity of inhibiting the proliferation of Sarcoma 180 cells (Inhibiting rate, I.R. /0)

No. of No. of compound I.R. (%) compound I.R. ( /0) 1 1 62.3 15 38.8 2 54.5 16 59.0 3 46.3 17 48.7 4 66.0 18 51.4 5 59.4 19 39.5 6 48.8 20 37.0 7 46.5 21 55.0 8 61.0 22 44.4 9 63.3 23 47.1 10 60.1 24 37.5 11 51.4 25 56.6 12 52.0 26 45.0 13 43.9 27 50.2 14 43.6 1 28 51.9 (4) Blood lipid reducing activity Japanese male white rabbits were fed for about 3 months with solid diet (CR-1) containing 1% of cholesterol ad lib. 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 dispersion 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 both changes of total cholesterol (determined by the enzyme method) and beta-lipoprotein (determined by turbidmetry) in the serum were observed.

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

TABLE 6 Activity of reducing the level of seral lipid components

Decrement of total Decrement of Decrement of total Decrement of cholesterol beta-lipoprotein cholesterol beta-lipoprotein (mg/dl) after (mg/dl) after (mg/dl) after (mg/dl) after Number of Number of compound 3 hours 6 hours 3 hours 6 hours compound 3 hours 6 hours 3 hours 6 hours 1 -1 49 138 150 15 0 59 130 137 2 4 60 132 139 16 0 62 184 195 3 -6 51 140 148 17 -5 64 167 173 4 0 66 182 204 18 8 66 179 188 5 3 78 175 195 19 6 50 162 170 6 2 70 166 179 20 -1 51 155 162 7 -6 42 144 160 21 -2 82 170 193 8 -4 65 181 193 22 1 77 144 161 9 -1 73 155 175 23 9 76 155 173 10 5 74 164 188 24 -5 64 165 172 11 -4 61 139 151 25 -4 73 165 176 12 3 66 128 136 26 -1 53 149 160 13 2 80 129 140 27 2 49 171 187 14 2 75 158 166 28 3 58 163 172 Control -3 9 5 -2 (5) Anti-inflammation 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 a 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 anti-inflammatory activity was expressed by the ratio of inhibition of the swelling of the foot pad due to carrageenin by the present compound, using the deterinined value of 1-4 hours from the injection and calculating by the following formula: (1 -- T/C) x 100 = I.R. (%) = anti-inflammation 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 cottonwool 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 l 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 also shown in Table 7. As is seen in Table 7, each of the present compound tested 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 a air pouch, and then 0.5 ml of a 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 a manner as shown in (5) (a). The results are also shown in Table 7.As is seen in Table 7, all the active ingredieht tested exhibited the antiexudation activity. TABLE 7 anti-inflammatory activity shown in the three kinds of experiments

Rate of Rate of Rate of Rate of Rate of Rate of inhibition inhibition inhibition inhibition inhibition inhibition Number of of Carrageenin of granuloma of exudation Number of of Carrageenin of granuloma of exudation compound edema (%) (%) (%) compound edema (%) (%) (%) 1 22.0 16.8 35.6 15 16.6 11.4 35.5 2 15.4 22.4 17.8 16 32.5 22.4 24.0 3 14.9 26.5 28.9 17 27.7 8.5 31.6 4 44.8 20.9 33.0 18 37.0 10.3 18.7 5 26.1 13.8 16.9 19 22.1 28.8 20.6 6 39.0 16.5 31.6 20 18.6 26.2 25.2 7 18.5 20.7 23.5 21 34.2 30.1 19.6 8 41.3 9.8 34.0 22 30.9 12.4 29.8 9 42.0 18.8 29.1 23 24.5 30.4 27.8 10 33.6 15.5 19.3 24 13.7 13.0 33.9 11 30.7 7.7 20.5 25 29.4 20.6 15.4 12 35.6 18.6 27.9 26 22.8 22.4 10.6 13 28.6 26.2 23.4 27 31.5 26.2 22.6 14 20.1 9.2 37.0 28 36.7 18.3 19.3 (6) Analgetic- and antipyretic activity 6-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 tail 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 orally at 1000 mg/kg, the test was carried out as the time passes, both the applied pressure and the time period until the animal showed a pseudo-escaping reaction were determined to evaluate the analgetic activity of the active ingredient.

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, the analgetic activity of the present compound was confirmed.

Determination by the chemical stimulation method The present compound was orally administered at 1000 mg/kg to a group (ten 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 ml/10g 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: (1T/C) x 100=writhingsyndrome-inhibiting ratio (%), wherein mean number of writhing syndrome in the group administered C: mean number of writhing syndrome in the control group.

The results are shown also in Table 8. As is seen in Table 8, every one of the present compounds showed analgetic activity. The above-mentioned procedures were carried out following the method of Kostet et al. (1959) TABLE 8 Analgetic activity

Occurrence of pseudo-escape Inhibiting Ratio Occurrence of pseudo-escape Inhibiting Ratio reaction after to writhing motion reaction after to writhing motion Number of Number of compounds time (sec) at pressure (mmHg) I.R. (%) compounds time (sec) at pressure (mmHg) I.R. (%) 1 46 98 45.0 16 39 88 45.5 2 40 80 33.6 17 44 96 42.4 3 35 79 37.3 18 42 99 46.2 4 45 103 54.1 19 39 86 41.1 5 42 85 49.2 20 37 80 30.6 6 41 88 32.4 21 45 101 39.8 7 36 78 38.5 22 42 91 42.2 8 46 94 40.9 23 42 93 44.8 9 39 79 49.8 24 39 89 35.0 10 43 90 52.1 25 44 93 51.2 11 38 85 43.3 26 45 90 37.7 12 45 95 46.7 27 43 96 36.1 13 41 94 47.7 28 39 89 40.2 14 42 90 33.3 Control 30 66 0 15 37 82 29.0 6-2) 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, 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 was at its maximum according to the following formula: C,T Antipyretic activity = I.R. (%) = - x 100 C1-Q wherein T: mean rectal temperature of rats 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 9. As is seen in Table 9, all the present compound exhibited a considerable antipyretic activity.

TABLE 9 Antipyretic activity

Number of Antipyretic Number of Antipyretic compound activity (IR /O) compound activity (IR O/o) 1 70.3 15 34.8 2 42.0 16 57.6 3 36.8 17 69.5 4 58.9 18 55.0 5 56.3 19 32.5 6 77.2 20 37.4 7 43.1 21 51.8 8 66.6 22 38.0 9 73.2 23 49.9 10 60.7 24 40.1 11 52.1 25 76.2 12 49.3 26 65.4 13 30.5 27 47.7 14 42.6 28 43.6 From the experimental results shown in (6) of the pharmacological properties of the present compounds, it has been recognized that the present compounds have the activity of suppressing the excitation of the central nerve system.

In the next place, the formulation of the present compounds into the pharmaceutical compositions which are administered to human and mammal is described.

In the cases where the present compound is used for treating hypertension, hyperglycemia, tumours, arteriosclerosis, inflammations and accentuation of the central nerve, the present compound may take various appropriate forms for obtaining favorable effects, and accordingly, the compositions containing the present compound as an active ingredient singly or together with the pharmaceutically acceptable diluent (s) and other pharmaceuticals are possibly administered for treating the abovementioned diseases.

In principle, the present compound is administrable orally or parenterally and accordingly, it may take various shapes and forms for the oral or parenteral administration optionally.

The composition of present compound can be offered as the dose units containing the effective amount of the present compound, taking various forms and shapes such as powders, granules, tablets, sugar-coated tablets, capsuled compositions, suppositories, suspended forms in liquid, dissolved forms in solvent, emulsified form in liquid, ampouled compositions and compositions for injection. As the diluent solids liquids and semi-solids may be utilized, for example, excipients, fillers, binding agents, wetting agents, disintegrators, surfactants, lubricants, dispersion agents, buffering agents, perfumes, preservatives, dissolution agents and solvents. They are usable singly or in combination.

The pharmaceutical compositions containing the present compound(s) as active ingredient(s)can be prepared by any known methods for formulation. The content of the present compound contained in the above-mentioned pharmaceutical composition as an active ingredient is generally from 0.01 to 100% by weight.

The pharmaceutical composition containing the present compound as an active ingredient is administered to humans and mammals orally or parenterally, however, the oral administration is preferable. The parenteral administration includes subcutaneous-, muscular- and intra-venous injections as well as those by drop method.

The dose of the pharmaceutical composition depends on the content of the active ingredient, the species and the age of the object, the individual difference and the condition of the disease, and although there are cases of administering a larger amount than that described as follows, the daily oral dose for human of the present compound itself is generally 0.1 to 500 mg/kg body weight, preferably 1 to 250 mg/kg, while the daily parenteral dose is generally 0.01 to 200 mg/kg, preferably 0.1 to 100 mg/kg, and the above-mentioned daily dose is divided into 1 to 4 portions, the portion being administered at a time.

The followings are the examples of producing the present compounds listed in Table 1 and the formulation examples of preparing the pharmaceutical composition for use in treating the above mentioned diseases to explain the present invention more in detail.

In addition, parts and percentages appearing hereinafter mean parts by weight and percentage by weight respectively.

EXAMPLE 1 Production of methylo-aminobenzoate-N-D-xyloside: In 30 ml of an aqueous 95% ethanolic solution, 3.0 g of methylo-aminobenzoate, 3.0 g of Dxylose and 0.4 g of ammonium chloride were brought in reaction by heating under a reflux condenser.

After leaving the reaction mixture in a refrigerator, crystals separated from the mixture. After collecting the crystals by filtration, the crystals were washed with ether and then repeatedly recrystallized from an aqueous 95% ethanolic solution to obtain colourless needle-like crystals at a yield of 1 2.8% as the product.

EXAMPLES 2 to 28 Production of the other twenty-seven species of the present compounds illustrated in Table 1 is described in Examples 2 to 28 in which each of the present compounds No. 2 to No. 28 was produced in the same manner as in Example 1 (Compound No. 1), however, using the same or different amount of the same or different ester of aminobenzoic acid, the same or different amount of the same or different sugar, the same or different amount of ammonium chloride and the solvent for the reaction and the same or different solvent for recrystalizing the reaction product.

Accordingly, the product, the species and the amount of each reactant and the species of solvent used in recrystallization of the reaction product as well as the yield in each Example are summarized in Table 1 0 together with those of Example 1 for reference and for brevity.

TABLE 10 Summarized presentation of the caracteristic points of Example 1 to 29.

Amount of Amount of Yield of Number of Ester of aminobenzoic ammonium 95% ethanolic Solvent of recrystallized Example Product acid (g) Sugar (g) chloride (g) solution (ml) recrystallization product (%) 1 Methyl o-aminobenzoate-N- Methyl o-aminobenzoate D-xylose 0.4 20 95% ethanol 12.8 D-xyloside 3.0g 3.0g 2 Methyl o-aminobenzoate-N- Methyl o-aminobenzoate D-glucose 0.4 20 95% ethanol 40.4 D-glucoside 3.0g 3.0g 3 Methyl o-aminobenzoate-N- Methyl o-aminobenzoate D-galactose 0.4 20 95% ethanol 78.2 D-galactoside 3.0g 3.0g 4 Methyl o-aminobenzoate-N- Methyl o-aminobenzoate L-rhamnose 0.4 20 95% ethanol 54.3 L-rhamnoside 3.0g 3.0g 5 Ethyl o-aminobenzoate-N- Ethyl o-aminobenzoate L-arabinose 0.4 20 95% ethanol 10.4 L-arabinose 3.0g 3.0g 6 Ethyl o-aminobenzoate-N- Ethyl o-aminobenzoate D-mannose 0.4 20 95% ethanol 6.5 D-mannoside 3.0g 3.0g 7 Ethyl o-aminobenzoate-N- Ethyl o-aminobenzoate D-galactose 0.4 20 95% ethanol 3.0 D-galactoside 3.0g 3.0g 8 Ethyl o-aminobenzoate-N- Ethyl o-aminobenzoate L-rhamnose 0.4 20 95% ethanol 41.4 L-rhamnoside 3.0g 3.0g 9 Butyl o-aminobenzoate-N- Butyl o-aminobenzoate D-mannose 0.4 20 95% ethanol 30.0 D-mannoside 3.0g 3.0g 10 Butyl o-aminobenzoate-N- Butyl o-aminobenzoate L-rhamnose 0.4 20 95% ethanol 22.2 L-rhamnoside 3.0g 3.0g 11 Methyl p-aminobenzoate-N- Methyl p-aminobenzoate L-arabinose 0.2 20 50% methanol 19.8 L-arabinose 1.7g 2.0g TABLE 10 in continuation Amount of Amount of Yield of Number of Ester of aminobenzoic ammonium 95% ethanolic Solvent of recrystallized Example Product acid (g) Sugar (g) chloride (g) solution (ml) recrystallization product (%) 12 Methyl p-aminobenzoate-N- Methyl p-aminobenzoate D-xylose 0.2 20 50% methanol 8.3 D-xyloside 1.7 g 2.0 g 13 Methyl p-aminobenzoate-N- Methyl p-aminobenzoate D-mannose 0.3 20 50% methanol 19.8 D-mannoside 3.0 g 3.4 g 14 Methyl p-aminobenzoate-N- Methyl p-aminobenzoate D-glucose 0.3 20 50% methanol 47.1 D-glucoside 3.0 g 3.4 g 15 Methyl p-aminobenzoate-N- Methyl p-aminobenzoate D-galactose 0.3 20 50% methanol 82.0 D-galactoside 3.0 g 3.4 g 16 Methyl p-aminobenzoate-N- Methyl p-aminobenzoate L-rhamnose 0.3 20 50% methanol 66.1 L-rhamnoside 3.0 g 3.4 g 17 Ethyl p-aminobenzoate-N- Ethyl p-aminobenzoate L-arabinose 0.3 20 50% methanol 11.0 L-arabinoside 1.7 g 2.0 g 18 Ethyl p-aminobenzoate-N- Ethyl p-aminobenzoate D-mannose 0.3 20 50% methanol 28.3 D-mannoside 3.0 g 3.4 g 19 Ethyl p-aminobenzoate-N- Ethyl p-aminobenzoate D-glucose 0.3 20 50% methanol 29.1 D-glucoside 3.0 g 3.4 g 20 Ethyl p-aminobenzoate-N- Ethyl p-aminobenzoate D-galactose 0.3 20 50% methanol 7.8 D-galactoside 3.0 g 3.4 g 21 Ethyl p-aminobenzoate-N- Ethyl p-aminobenzoate L-rhamnose 0.3 20 50% methanol 64.1 L-rhamnoside 3.0 g 3.4 g 22 Propyl p-aminobenzoate-N- Propyl p-aminobenzoate L-arabinose 0.3 20 50% methanol 41.1 L-arabinoside 3.0 g 3.0 g TABLE 10 in continuation Amount of Amount of Yield of Number of Ester of aminobenzoic ammonium 95% ethanolic Solvent of recrystallized Example Product acid (g) Sugar (g) chloride (g) solution (ml) recrystallization product (%) 23 Propyl p-aminobenzoate-N- Propyl p-aminobenzoate D-mannose 0.3 20 50% methanol 42.0 D-mannoside 3.0 g 3.0 g 24 Propyl p-aminobenzoate-N- Propyl p-aminobenzoate D-glucose 0.3 20 50% methanol 66.7 D-glucoside 3.0 g 3.0 g 25 Propyl p-aminobenzoate-N- Propyl p-aminobenzoate L-rhamnose 0.3 20 50% methanol 70.3 L-rhamnoside 3.0 g 3.0 g 26 Butyl p-aminobenzoate-N- Butyl p-aminobenzoate L-arabinose 0.3 20 50% methanol 45.4 L-arabinoside 3.0 g 3.0 g 27 Butyl p-aminobenzoate-N- Butyl p-aminobenzoate D-mannose 0.3 20 50% methanol 42.6 D-mannoside 3.0 g 3.0 g 28 Butyl p-aminobenzoate-N- Butyl p-aminobenzoate L-rhamnose 0.3 20 50% methanol 82.6 L-rhamnoside 3.0 g 3.0 g FORMULATION EXAMPLE 1: A pharmaceutical powdery composition was prepared by uniformly mixing and pulverizing the following components: 10 parts of butyl p-aminobenzoate-N-D-mannoside (one of the present compounds, Compound No. 27) 1 5 parts of heavy magnesium oxide and 75 parts of lactose.

In addition, a capsuled pharmaceutical composition could be obtained by encapsulating the thus obtained powdery composition in capsular containers.

FORMULATION EXAMPLE 2: A granular pharmaceutical composition was prepared by uniformly mixing the following components, extruding the thus obtained mixture to be filaments, cutting and drying the filaments and sifting the cut and dried material to be granular shape: 45 parts of ethyl o-aminobenzoate-N-L-rhamnoside (one of the present compounds, Compound No. 8), 1 5 parts of starch, 1 6 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of water.

FORMULATION EXAMPLE 3: In the same manner as in Formulation Example 2 except for using the same amount of propyl paminobenzoate-N-L-arabinoside (one of the present compounds, Compound No. 22) instead of ethyl oaminobenzoate-N-rhamnoside in Formulation Example 2, a granular pharmaceutical composition is prepared and by compression-shaping the mixture consisting of 96 parts of the thus prepared granular composition and 4 parts of calcium stearate, a tablet-form of pharmaceutical composition of 10 mm in diameter was prepared.

FORMULATION EXAMPLE 4: A granular composition was prepared by kneeding the mixture consisting of the following components uniformly and processing in the same manner as in Formulation 2: 94 parts of ethyl p-aminobenzoate-N-D-glucoside (one of the present compounds, Compound No.

19) 6 parts of polyvinyl alcohol and 30 parts of water.

A mixture of 90 parts of the thus obtained granular composition and 10 parts of crystalline cellulose was compression-shaped to be tablets of 8 mm in diameter, and a sugar-coated tablet form of a pharmaceutical composition was prepared by coating the tablets with syrup, gelatin and precipitated calcium carbonate.

FORMULATION EXAMPLE 5: A pharmaceutical injection-type composition was prepared by mixing the following components in warmed state, filtering and sterilizing the mixture: 0.6 part of methyl p-aminobenzoate-N-D-xyloside (one of the present compounds, Compound No. 12) 2.4 parts of a non-ionic surfactant and 97 parts of an aqueous physiological saline solution.

FORMULATION EXAMPLE 6: In the same manner as in Formulation Example 5 except for using the same amount of methyl oaminobenzoate-N-D-galactoside (one of the present compounds, Compound No. 3) instead of methyl paminobenzoate-N-D-xyloside in Formulation Example 5, a pharmaceutical injection-type composition was prepared.

Claims (9)

1. An ester of aminobenzoic acid of the formula (I)

wherein R' represents a residual group formed by the removal of -OH from the 1 (alpha)- or 1 (beta)position of arabinose, xylose, mannose, glucose, galactose or rhamnose and R2 represents alkyl of 1 to 4 carbon atoms, subject to the proviso that when R1 is derived from mannose and R2 represents methyl, the carboxymethyl groupCOOR2 is not in an ortho-position to the R1-NH group.

2. An ester of aminobenzoic acid according to claim 1 which is any one of compounds 1 to 28 identified in Table 1.

3. A process of producing an ester of aminobenzoic acid as claimed in claim 1, which process comprises reacting a C1-C4 alkyl aminobenzoate with L-arabinose, D-xylose, D-mannose, D-glucose, D-galactose or L-rhamnose in the presence of ammonium chloride.

4. A process according to claim 3 wherein said reaction is carried out under reflux using ethanol or methanol.

5. A process according to claim 3 substantially as described with reference to any one of Examples 1 to 28.

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

7. A pharmaceutical composition according to claim 6 for use in treating hyperglycemia, hypertension, hyperlipemia, inflammation, pain pyrexia or tumours.

8. A pharmaceutical composition according to claim 6 or 7, which is in a dose unit form appropriate for oral administration.

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