DE3348149C2 - Use of aminobenzoic acid derivatives for the treatment of kidney disorders - Google Patents

Abstract

Published without abstract.

Description

The present invention relates to the use of aminobenzoic acid Derivatives in the treatment of kidney disease, in particular glomerulonephritis, in which an aminobenzoic acid Derivative of the following general formula (I)

is used, in which R is a radical from the group of radicals, by removing an OH group in the 1 (alpha) or 1 (beta) position of arabinose, xylose, Glucose, galactose, rhamnose and mannose are, or a pharmaceutically acceptable salt such a derivative in addition to a pharmaceutical suitable carrier or diluent for this Active ingredient.

The above-defined aminobenzoic acid derivatives, those according to the present invention as active ingredient are used in terms of their chemical and physical properties known compounds. Inoue et al. have chemical synthesis (See J. Agr. Chem. Soc., Japan, Vol. 25, page 59 to 63 and 291 to 293 (1951); as well as chemical abstracts Vol. 48, 2001d and 2001i (1954) as well as certain physical Properties (J. Agr. Chem. Soc. Vol. 26, pages 329 to 331 (1952) and Chemical Abstracts Vol. 48, 2003a (1954) of the above-mentioned Compounds described.

It is also known that pharmaceutical compositions with the above aminobenzoic acid Derivatives as an active ingredient for the treatment of hyperglycemia, Hyperlipemia, hypertension, inflamatory Diseases, pain and pyrexia due to arousal of the central nervous system as well as of tumors  can be set (DE-OS 29 14 005).

From DE-OS 30 30 892 it is also known certain ischemic diseases with pharmaceutical To treat compositions that the above aminobenzoic acid derivatives contain.

The object of the invention is a means extreme low toxicity for the treatment of kidney disease provide.

This is inventively by the use achieved a pharmaceutical composition, which the above-mentioned aminobenzoic acid Contains derivatives as an active ingredient.

The invention will be explained in more detail below.  

Here, FIGS. 1 to 24 show infrared absorption spectra of the compounds according to the invention Nos. 1 to no. 24, as defined in Table 1.

As can be seen from the general formula (I) are the compounds used in the invention (hereinafter simply referred to as the present substance (s)) Compounds with a simple chemical structure.

Since each of the substances present an extremely low Toxicity for mammals and also no shows antimicrobial activity, it can be sent to a patient be administered over a long period of time without there being any danger that it would disturb the bacterial intestinal flora is coming. In addition, such a Substance has no mutagenic activity and impaired neither the cellular nor the humoral immunity of the patients, so that the present substances as active ingredients of pharmaceutical compositions as very be sure to apply, so that they are safe from the risk of Malformations or allergic reactions to one Patients can be administered. In addition, each works the present substances in the sense of an increase the flow rate of the blood through the coronary artery, an increase in the deformability of the erythrocytes, Suppression of agglutination of platelets and the prevention of thrombogenesis in a living Body.

Although each of the present substances has three isomers in the Regarding the position of the -NH-R group on the benzene ring has, d. H. every substance in the form of o-, p- and m-isomers, and although the activity of the  corresponding isomers depending on the position the -NH-R group may be slightly different all three isomers of each of the present substances pharmaceutically useful.

The beneficial effect of the present substances shows also in the case, if you put the substance in shape a salt used so that each salt of the present Substances of the present invention is included, as long as it is pharmaceutically acceptable. As salts are in particular, alkali metal salts, alkaline earth metal salts and aluminum salts. These are sodium, potassium, Magnesium, calcium and aluminum salts are preferred, the sodium salt being most preferred.

As the saccharide for forming the glycoside unit of present substance, arabinose, xylose, Glucose, galactose, mannose and rhamnose.

The saccharide may be in the form of its L-isomer or its D isomers are present, and it may be the alpha-anomer, beta anomers or a mixture of these two anomers his. Accordingly, the present invention can be alpha anomeres, beta anomeres or a mixture of be both anomers.

The present substances, for example, after the following general procedure.

In 40 to 50 ml of absolute ethanol, pure methanol or an aqueous ethanolic or methanolic solution 4.5 to 5.0 g of an aminobenzoic acid, 5.0 to 6.0 g a monosaccharide such as L-arabinose, D-xylose, D-glucose, D-galactose, L-rhamnose or D-mannose  and 0.1 to 0.5 g of ammonium chloride heated to reflux, whereby a condensation reaction is effected.

After cooling the reaction mixture to room temperature or after allowing the reaction mixture to stand alone on room temperature let it cool down, the thereby excreted Crystals filtered off, well with water, ethanol and ether washed and then from an aqueous methanolic Solution or an aqueous ethanolic solution recrystallized to obtain the present substances become. Metal salts of the produced in this way present substances are prepared by known methods generated. For example, a present substance dissolved in an aqueous ethanolic solution, and to this solution is added a metal hydroxide.

The physical properties of some of the present Substances (i.e., some agents of the invention pharmaceutical compositions) according to those mentioned above Processes are prepared in Table 1 summarized.  

Table 1

Physicochemical properties of the substances used according to the invention and their salts

(1) melting point

Determined using the micro-melting point Determination device manufactured by Yanagimoto Works, Japan.

(2) Specific rotation

Determined using the polarimeter model OR-50 with direct reading, manufactured by Yanagimoto Works, Japan, at a thickness of 50 mm of an aqueous ethanolic Solution of the acidic substance and an aqueous Solution of the sodium salt of this acidic agent.

(3) Molecular composition

Elemental analysis was performed using the CHN Encoder Model MT-2, manufactured by Yanagimoto Works, Japan, performed.

(4) Ultraviolet absorption spectrum

Determined using the self-recording spectro Photometers model PS-3T, manufactured by Hitachi Works, Japan, from an acidic aqueous ethanolic solution Active ingredient or an aqueous solution of the sodium salt of the acidic agent.

Below are the physiological properties of present substances and their determination described.

1. Acute toxicity to mammals

The acute toxicological properties of the present Compounds and their salts expressed by the LD₅₀- Value, were as follows on the two described below  Determined routes of administration, and the obtained Results are shown in Table 2.

(i) Acute mammalian toxicity (oral administration)

A solution of each of the present substances and their Salts in distilled water were taken through a gastric tube administered to each of a group of ICR-JCL mice, and the mortality of the mice was 7 days after of administration. After the determination of mortality The mice were killed so they under autopsy could be further investigated. From the accumulated Mortality became the LD₅₀ value after the graphic Procedures of Litchfield-Wilcoxon calculated, and the results obtained are shown in Table 2.

(ii) Acute mammalian toxicity (intraperitoneal administration

Another solution of each of the present substances and their salts in an aqueous physiological saline solution was in the abdominal cavity of each mouse another Group of ICR-JCL mice introduced, and mortality of the mice was determined 7 days after the administration. From the accumulated mortality became the LD₅₀ value determined by the same method as in (i), and the results are also shown in Table 2.

As can be seen in Table 2, the LD₅₀ values are of all substances tested and their salts greater than 6 g / kg body weight of the mice, and 6 compounds out of 10 compounds an LD₅₀ of more than 10 g / kg body weight in both cases, d. H. in oral and intraperitoneal administration.  

This means that at least 6 representative compounds the present substances and their salts an extreme low mammalian toxicity. Considering the chemical structure of the representative 10 Compounds can be said that the present Substances and their salts for mammals extraordinarily safe materials are.  

Table 2

Acute mammalian toxicity of the salts of the present substances (LD₅₀ g / kg body weight)

2. Antimicrobial activity

The antimicrobial activity of those shown in Table 2 Compounds were examined as follows.

A series of double-diluted solutions was used by each the compounds shown in Table 2 and their salts prepared by adding distilled water as a diluent used, and 1 part by weight of a dilute Solutions and 9 parts by weight of an agar culture medium were mixed, and the resulting mixture was given in petri dishes, being used for cultivation bacterial species as agar culture medium the heart Infusion agar culture medium and for the cultivation of eumycetic Species the Sabouraud agar culture medium were used. After the strikeout of each of the subsequent pre-cultured microorganisms each culture medium in a petri dish became the bacterial species cultured at 37 ° C for 20 to 24 hours, and the eumycetic species became 3 to 7 at 25 ° C Days cultivated to the growth state of microorganisms in the respective culture medium. The following microorganisms were used:

Pseudomonas aeruginosa, IAM 1514,
Escherichia coli, IFO 12735,
Bacillus subtilis, IAM 1069,
Staphylococcus aureus, 209 P,
Saccharomyces cerevisiae, IAM 4207,
Candida albicans, ATCC 752,
Trichophyton mentagrophytes, IFO 6124 and
Aspergillus niger, IAM 3001.

The investigation showed that none of the in Table 2 shown compounds in a concentration of 1 mg / ml compared to the above microorganisms wash hindering seemed.

3. Mutagenicity

The mutagenicity of the compounds shown in Table 3 was determined by the following rec assay and the reverse mutation Test examined.

(i) Rec assay assay

After inoculation of Bacillis subtilis, M45 (strain without recombination repair) and Bacillus subtilis H 17 (Strain with preserved recombination repair) on a B-II agar culture medium consisting of 10 g meat broth, 10 g Polypeptone, 5 g sodium chloride, 15 g agar and 1000 ml distilled water at a pH of 7.0, so that the corresponding lines did not cross each other, was a circular sheet of filter paper with a diameter of 8 mm, to each 0.05 ml of a solution each of the compounds shown in Table 3 in sterilized Water were impregnated, so on the culture medium given that the starting points of the two linear Vaccines were covered, and the inoculated culture medium was kept in an incubator at 37 ° C for one night. Thereafter, the length of the growth inhibition was measured Kanamycin being a negative control and Mitomycin were used as a positive control. The Results are shown in Table 3.

As can be seen in Table 3, none of the examined Compounds a mutagenicity to the Microorganisms at a concentration of even 500 μg / disk Culture medium, and especially the sodium salts  p-aminobenzoic acid did not show any mutagenicity a concentration of even 5,000 μg / disk Culture medium.

(ii) Lapel mutation test

Two histidine-dependent strains of Salmonella typhimurium, TA 98 and TA 100 were used as test bacteria used.

After mixing 0.1 ml of an aqueous suspension of the test bacterial strain and 0.1 ml of an aqueous Solution of each of the compounds shown in Table 4 with 2 ml of an aqueous mixture obtained by adding 0.2 ml an aqueous solution of 0.5 mM biotin and 0.5 mM histidine to 1.8 ml of an aqueous solution of agar (with a Content of 6 g sodium chloride and 6 g agar in 1000 ml distilled water) had been prepared, the in this way prepared mix on the minimum culture medium painted. After cultivating the vaccinated Medium at 37 ° C for 2 days was the number of revertant colonies (reverse mutants) determined numerically, using furylfuramide, AF₂, as a positive control. The results are shown in Table 4.  

Table 3

Rec assay

Table 4

Reverse mutation test

As can be seen in Table 4, the frequency was a mutagenesis based on the compounds shown in Table 4 even at concentrations of 5000 μg / plate Culture medium for both strains of S. typhimurium extraordinarily low, given the numbers obtained compares to the comparative figures.

4. Effect on the immunity of the host

The effect of the present compounds on the Immunity of a patient was following the following Immunity tests examined.

(i) Delayed Type Intracutaneous Response

Effect of the compounds shown in Table 2 on the cellular immunity was detected in the "Foot Pad Reaction" (Footpad reaction), using ICR-JCL mice used as host and sheep erythocytes as antigens were.

From the tail vein of a mouse 0.2 ml of a 10% suspension of sheep erythrocytes in an aqueous injected physiological saline into the mouse, to bring about a first sensitization, and 7 days after the first sensitization, 0.05 ml a 40% suspension of the same sheep erythrocytes in an aqueous physiological saline solution injected in the balls of the mouse to the second Sensitization. The day after the second Sensitization was the thickness of vaccinated football measured.

Each of the compounds shown in Table 2 became intraperitoneally for 5 days to the sensitized Mouse administered, the day of the first sensitization  was taken as a middle day. The dose was 2500 mg / kg / day.

The increase in the thickness of the football was treated Mouse compared with that of the control mouse, the the compounds according to Table 2 have not been administered were not significant.

(ii) activity of producing antibodies

The effect of the compounds shown in Table 2 on the humoral immunity of the host was used of ICR-JCL mice as host and sheep erythrocytes as Antigens determined as follows.

After sensitization of a mouse by injection of 0.2 ml of a 10% suspension of sheep erythrocytes in an aqueous physiological saline solution Injection into the mouse from the tail vein, was on the 7th. Day after sensitization collected the blood of the mouse, and the blood became the erythrocyte agglutination test subjected.

Each of the compounds shown in Table 2 was intraperitoneally Administered for 5 days, with the sensitization day was taken as a central day.

As a result of the investigation, no significant Difference between the agglutination value of the blood, taken from the thus treated mice and blood from the control mice detected.

The results of the above 4 types of tests for Determination of physiological properties of the present Substances and their salts confirm the safety  the present substances and their salts as active ingredients for a pharmaceutical composition.

Because the substances present both orally and can be administered parenterally, can be a pharmaceutical Composition any desired shape for oral or parenteral administration. Moreover, the present substances can also be found in Form of medicines of the unit dose type supplied which are an effective amount of the invention Contain substances, and they can be in the form of a powder, Granules, in the form of tablets, capsules, Suppositories, suspensions, solutions, emulsions, ampoules, Injection solutions, etc. are present. As a carrier or diluents may be vehicles, binders, Wetting agents, disintegrants, surfactants, demulcenzien, Dispersants, buffers, fragrances, preservatives, Solution aids and solvents in the form of solids, liquids and semi-solids be mentioned. The carriers or excipients will be alone or in combination of one or more such Used substances. The invention Pharmaceutical compositions may after each  be made of any method, so that they from 0.01 to 100 wt .-% of the present substances as Active ingredient included.

As stated above, the pharmaceutical compositions orally or parenterally including oral administration sublingual administration is. Parenteral administration may take the form of a Injection, for example a subcutaneous injection, muscular injection and intravenous injection, or occur as instillation.

The pharmaceutical compositions are effective for the treatment of kidney diseases such as a glomerulonephritis.

The dosage of the pharmaceutical compositions according to the invention depends on the age, personal characteristics, the symptoms of the patient, and indeed Human or other animal, but in the case of a Administration to human patients in general from 0.1 to 1000 mg of the active ingredient as daily oral Dose per kg of body weight, preferably 1 to 500 mg / day / kg and 0.01 to 200 mg of the active ingredient as daily parenteral dose per kg of body weight, preferably 0.1 to 100 mg / day / kg. The daily Dose is divided into 1 to 4 parts, with the split Quantity is given at once.

Hereinafter, the present invention will be referred to to the following examples in more detail explained.  

It is understood that the present Invention is not limited to the following examples is. From the above description, it will be apparent to those skilled in the art easily possible, the essential features of the present Invention and without departing from the scope thereof, make numerous changes and modifications, around them to the different applications and to different ones To adapt conditions.

example 1 Preparation of p-aminobenzoic acid N-L-arabinoside and its sodium salt

In 40 ml of an aqueous 94 wt .-% solution of ethanol were 4.6 g of p-aminobenzoic acid, 5 g of L-arabinose and 0.5 g of ammonium chloride heated to reflux to a condensation to reach. After the storage of Reaction mixture in a refrigerator had Crystals from the reaction mixture deposited. These Crystals were filtered off and washed with ether and repeated from an aqueous, 50 vol .-% methanolic Recrystallized solution, giving colorless crystals were obtained in a yield of 45.8%.  

The thus obtained p-aminobenzoic acid N-L-arabinoside was slowly added in a quantity of an aqueous, 1 wt .-% solution of sodium hydroxide dissolved, the the calculated amount of acid, and after Filtration of insoluble constituents became the filtrate concentrated at reduced pressure. After drainage of the condensate by adding a large excess Acetone, the residue was dried and it became colorless Crystals in a yield of 100% and in one Overall yield of 45.8%. The product obtained was sodium p-aminobenzoate-N-L-arabinoside.

Example 2 Preparation of o-aminobenzoic acid N-L-arabinoside and its sodium salt

In 30 ml of methanol, 2.3 g of anthranilic acid, 2.5 g Refluxing L-arabinose and 0.2 g of ammonium chloride, to effect a condensation. After graduation The reaction separated from that at room temperature left standing reaction mixture from crystals. The obtained by filtering the reaction mixture crystals were washed with water, methanol and then ether, and it became colorless needle-shaped or plate-like Crystals obtained in a yield of 61.3%.

The thus obtained anthanilic acid N-L-arabinoside was slowly in a calculated amount of one aqueous 1% by weight solution of sodium hydroxide dissolved, and after filtering off insoluble constituents The filtrate was concentrated under reduced pressure, after which a large excess of acetone was added to to dehydrate the condensate. By drying the In this way dehydrated product became colorless Crystals of the sodium salt in a yield of 100% and obtained in a total yield of 61.3%.  

Example 3 Preparation of p-aminobenzoic acid N-D-xyloside and its sodium salt

In 25 ml of ethanol was added 2.3 g of p-aminobenzoic acid, 2.5 g Refluxing D-xylose and 0.05 g of ammonium chloride, to effect a condensation. As during the Precipitated reaction crystals, ethanol was added, and the condensation was continued under heating. After the reaction was over, divorced the in a cool place allowed reaction mixture Crystals off. These crystals were filtered of the cooled condensate collected, and the obtained Crystals were washed with water, methanol and then Ether washed and from a 94% ethanolic solution recrystallized, wherein the acid glycoside in a Yield of 73.7% was obtained.

The thus obtained p-aminobenzoic acid N-D- xyloside was slowly in a calculated amount of one dissolved 1 wt .-% aqueous sodium hydroxide solution, and after filtering off insoluble constituents from the Reaction mixture was the filtrate obtained at reduced Pressure concentrated, after which a large excess Acetone was added to drain the condensate, and the condensate obtained in this way was dried, and it became a colorless product in one Yield of 100% and a total yield of 73.7% receive.  

Example 4 Preparation of o-aminobenzoic acid N-D-xyloside and its sodium salt

In 35 ml of ethanol, 2.3 g of anthranilic acid, 2.5 g Refluxing D-xylose and 0.2 g of ammonium chloride, to effect a condensation. After completion of the reaction The reaction mixture became under reduced pressure concentrated to half its volume, and the condensate was allowed to stand at room temperature. The on This deposited crystals were filtered through of the cooled condensate collected, and the obtained Crystals were washed with water, methanol and then Ether and recrystallized from ethanol, and the acid glycoside was in a yield gained by 74.6%.

The anthranilic acid N-D-xyloside thus obtained was slowly in a calculated amount of one Dissolved 1% aqueous sodium hydroxide solution, and after filtering off the insoluble constituents from the Reaction mixture was the filtrate obtained at reduced Pressure narrowed, and it became a big surplus Acetone added to the condensate to drain it. The condensate obtained in this way was to give a colorless product in a yield of 100% and a total yield of 76.4% dried.

Example 5 Preparation of p-aminobenzoic acid N-D-glucoside and its sodium salt

In 50 ml of a 94% aqueous ethanol solution were 5 g of p-aminobenzoic acid, 6.4 g of D-glucose and 0.5 g Ammonium chloride heated to reflux to a condensation  to effect. After completion of the reaction was the reaction mixture at reduced pressure to 1/3 Concentrated their volume, and allowed to drain the condensate standing in a cool place where it gelled. After Add a small amount of water to the gel-like material and heating the mixture to its renewed Liquefaction was the liquid in a refrigerator let stand, where crystals separated. The crystals were collected by filtration and water, a diluted aqueous methanol solution and a small Washed amount of ether. The washed crystals were then recrystallized from a 50% aqueous methanol solution, and it became colorless needle-shaped Obtained crystals in a yield of 33.7%.

The thus obtained p-aminobenzoic acid N-D- Glucoside was slow in a calculated amount of one Dissolved 1% aqueous sodium hydroxide solution, and after filtering off the insoluble constituents concentrated filtrate at reduced pressure, after which a large excess of acetone is added to the condensate was to drain it. The mixture was then dried and it was in a yield of 100% and in an overall yield of 33.7% colorless crystals receive.

Example 6 Preparation of o-aminobenzoic acid N-D-glucoside and its sodium salt

In 40 ml of a 95% aqueous ethanol solution 4.6 g of anthranilic acid, 6.0 g of D-glucose and 0.5 g of ammonium chloride heated to a condensation reaction between the reactants. after the Reaction was over, the reaction mixture was added reduced pressure to 1/3 of its volume,  after which you put the condensate in a refrigerator overnight left, with crystals separated. The crystals were collected by filtering the reaction mixture, then with water, methanol and finally ether washed and recrystallized twice from methanol. It were colorless needle-like crystals in a yield of 4.6%.

The anthranilic acid N-D-glucoside thus obtained was slow in a calculated amount of 1% dissolved aqueous solution of sodium hydroxide, and after the Filtration of insoluble constituents became the filtrate concentrated under reduced pressure, after which a large excess Acetone was added to the condensate. The case separated crystals were dried, and in a Yield of 100% and a total yield of 4.6% colorless crystals were obtained.

Example 7 Preparation of p-aminobenzoic acid N-D-galactoside and its sodium salt

In 30 ml of a 94% aqueous ethanol solution, 1.5 g p-aminobenzoic acid, 2 g of D-galactose and 0.1 g of ammonium chloride heated to a degree of condensation effect. After completion of the reaction, the Reaction mixture at reduced pressure to half Concentrated their volume, and the condensate was at Room temperature gel, with crystals separated. By filtering the reaction mixture were The crystals are collected with water, methanol and water finally ether were washed and then off Methanol were recrystallized. There were colorless needle-like crystals in a yield of 18.1% receive.  

The p-aminobenzoic acid N-D-galactoside thus obtained was slowly in a calculated amount of one Dissolved 1% aqueous sodium hydroxide solution, and after removal of insoluble materials by filtration the solution was the filtrate at reduced Pressure condensed and it became a large excess Acetone added to the condensate to drain it. By drying the condensate were in a yield obtained from 100% colorless crystals. The total yield was 18.1%.

Example 8 Preparation of o-aminobenzoic acid N-D-galactoside and its sodium salt

In 30 ml of a 95% aqueous ethanol solution were 2.4 g of anthranilic acid, 3.0 g of galactose and 0.2 g of ammonium refluxed to a condensation reaction to effect.

After completion of the reaction, the reaction mixture became at reduced pressure to about half its volume concentrated and allowed to stand at room temperature, where crystals separated. The crystals were collected by filtering the reaction mixture, with Washed water, methanol and ether and then recrystallized from a 95% aqueous ethanolic solution, being colorless needle-like crystals in a yield of 16.4% were obtained.

The anthranilic acid N-D-galactoside thus obtained was slowly in a calculated amount of one Dissolved 1% aqueous sodium hydroxide solution, and after removal of insoluble constituents by filtration the filtrate was concentrated at reduced pressure, after which a large excess of acetone to the condensate  was added to drain it. The dewatered condensate was dried, giving colorless crystals in one Yield of 100% and a total yield of 16.4% were.

Example 9 Preparation of p-aminobenzoic acid N-L-rhamnoside and its sodium salt

In 30 ml of a 94% aqueous ethanol solution were 3 g of p-aminobenzoic acid, 4 g of L-rhamnose and 0.1 g of ammonium chloride heated to a condensation reaction to effect.

After completion of the reaction, the reaction mixture became allowed to stand at room temperature, with crystals separated out. The crystals were filtered by filtration Reaction mixture collected, and after washing the Crystals with water and a dilute aqueous methanolic Solution, the washed crystals were recrystallized from a 50% aqueous methanol solution, whereby colorless needle-like crystals in a yield of 30.9% were obtained.

The p-aminobenzoic acid N-L-rhamnoside thus obtained was slowly in a calculated amount of one Dissolved 1% aqueous solution of sodium hydroxide, and after removal of insoluble matter by filtration the solution was the filtrate at reduced Concentrated pressure. After adding a large excess from acetone to the condensate to drain it dried the dewatered condensate, and there were colorless crystals in 100% yield and one Overall yield of 30.9%.  

Example 10 Preparation of o-aminobenzoic acid N-L-rhamnoside and its sodium salt

In 25 ml of methanol, 2.3 g of anthanilic acid, 2.8 g L-rhamnose and 0.2 g of ammonium chloride heated to reflux, to effect a condensation. After completion of the reaction The reaction mixture became at room temperature let stand, and it separated crystals. To Filtration of the crystals from the reaction mixture were the crystals became from the reaction mixture the crystals are washed with water and methanol and then from a 50% aqueous methanol solution recrystallized. In a yield of 9.8% were colorless Needle-like crystals obtained.

The anthranilic acid N-L-rhamnoside thus obtained was slow in a calculated amount of 1% dissolved aqueous sodium hydroxide solution, and after filtering insoluble constituents became the filtrate concentrated under reduced pressure, after which a large Excess acetone was added to the condensate to to drain it. By drying the dewatered condensate were colorless crystals in a yield of 100% and a total yield of 9.8%.

Example 11 Preparation of p-aminobenzoic acid N-D-mannoside and its sodium salt

In 10 ml of ethanol was added 2 g of p-aminobenzoic acid, 3 g D-mannose and 0.2 g of ammonium chloride at reflux for about 1 hour heated to effect condensation.

After completion of the reaction, the reaction mixture became allowed to stand at room temperature, with crystals separated out. After filtering off the crystals from the  Reaction mixture, these were diluted with water, a dilute aqueous ethanol solution and a small amount Ether washed and finally from a 50% aqueous Recrystallized methanol solution. There were colorless needle-like Crystals of p-aminobenzoic acid N-D-mannoside obtained in a yield of 56.1%.

The glycoside (hydrate) thus obtained became slow in a calculated amount of 1% aqueous sodium hydroxide. Solution dissolved, and after concentration of the solution at reduced pressure became an excess amount Ethanol is added to the condensate, leaving a precipitate formed. By filtering off the precipitate, Draining and drying the collected precipitate colorless crystals were obtained. By recrystallization of the precipitate from a mixture of 5 parts by weight Water and 1 part by weight of acetone was sodium p aminobenzoate-N-D-mannoside in the form of colorless crystals in a yield of 95% and a total yield of 53.3% received.

Example 12 Preparation of m-aminobenzoic acid N-D-mannoside and its sodium salt

In 10 ml of ethanol, 2 g of m-aminobenzoic acid, 3 g D-mannose and 0.2 g of ammonium chloride in a water bath heated at 95 to 96 ° C to cause condensation of the constituents to effect. After heating the reaction mixture separated from this crystal lumps. The recovered by filtering off the reaction mixture Crystals were sufficiently washed with water and methanol and recrystallized from methanol, giving colorless needle-like crystals of m-aminobenzoic acid N-D- mannoside were obtained in a yield of 33%.  

The glucoside thus obtained became slow in a calculated amount of 1% aqueous sodium hydroxide Dissolved solution, and after filtering insoluble Components from the solution became the filtrate concentrated under reduced pressure, and after addition of a large excess of ethanol to the condensate to its Drainage was dried this, and in a yield of 100% and a total yield of 33% obtained colorless crystals.

Example 13 Formulation of a pharmaceutical composition

The following ingredients became uniform with each other mixed and in a powder mixture of ultrafine granules processed, and the mixture was encapsulated in capsules:

10 parts by weight of sodium p-aminobenzoate NL-arabinoside (one of the active substances used according to the invention),
15 parts by weight heavy magnesium oxide and
75 parts by weight lactose.

Example 14 Formulation of a pharmaceutical composition

The following ingredients became uniform with each other mixed, and the mixture was pulverized and added processed granules. By drying and sieving of the granules was a granular composition receive:

45 parts by weight of sodium o-aminobenzoate ND-xyloside (one of the active ingredients used in the invention),
15 parts by weight of starch,
16 parts by weight lactose,
21 parts by weight of crystalline cellulose,
3 parts by weight of polyvinyl alcohol and
30 parts by weight of water.

Example 15 Formulation of a pharmaceutical composition

After the production of a very fine granulate mixture according to the same procedure as in Example 14, except that the same amount by weight of sodium o-aminobenzoate-N-D- glucoside in place of sodium o-aminobenzoate-N-D-xyloside was used according to Example 14, 96 parts by weight the finest granules mixture produced in this way mixed with 4 parts by weight of calcium stearate, and the Mixture was subjected to compression molding, wherein Obtained pellets with a diameter of 10 mm were.

Example 16 Formulation of a pharmaceutical composition

The following ingredients were as in Example 14 formulated to obtain a very fine granule mixture has been:

94 parts by weight of sodium p-aminobenzoate-NL-rhamnoside (one of the active ingredients used in the invention)
6 parts by weight of polyvinyl alcohol and
30 parts by weight of water.

To 90 parts by weight of the microfinished Granules mixture were 10 parts by weight of crystalline cellulose added, and the prepared in this way  Mixture was press-formed into tablets with one Subjected to a diameter of 8 mm. By coating the tablets prepared in this way with a mixture from syrup, gelatin and precipitated calcium carbonate obtained sugar-coated tablets.

Example 17 Formulation of a pharmaceutical composition

The following ingredients were mixed with heating, and after the sterilization of the uniform in this way It was sterilized in mixed material Container injected:

0.6 part by weight of sodium p-aminobenzoate-ND-galactoside (one of the active ingredients used in the invention),
2.4 parts by weight of a nonionic surfactant and
97 parts by weight of a physiological saline solution.

Example 18

Wistar rats were puromycin every day for 10 days at a dose of 1.5 mg / 100 g rat body weight injected subcutaneously to experimental rats with kidney disease to obtain. The experimental rats became the present substance orally in one dose of 100 mg / kg body weight of the rat per day for 10 days administered long every day. As a control, the same amount of a physiological saline solution in the same way as described above Administered to experimental rats.

Seven days after cessation of administration were Urine samples from each group of experimental animals within collected from 24 hours and the protein content was measured. Then, due to the amount of Urine and its protein content the whole protein  amount of each group containing urine within 24 hours was calculated, calculated. The results are in Tab. 5 played.

Each substance tested showed a suppressive Effect on the amount of protein associated with the urine was eliminated within 24 hours. The rats were further dissected and were pathological and histological kidney examinations carried out. The results showed that each tested substance a certain oppressive Effect on the hypertrophy of the glomerulus Had basic membrane.  

substance Amount of protein excreted within 24 hours with urine (mg) Sodium-p-aminobenzoate-N-L-arabinoside 12003 Sodium-o-aminobenzoate-N-L-arabinoside 13222 Sodium-p-aminobenzoate-N-L-rhamnoside 9015 Sodium-o-aminobenzoate-N-L-rhamnoside 9005 Sodium o-aminobenzoate-N-D-galactoside 12020 Sodium o-aminobenzoate-N-D-galactoside 13240 Sodium-p-aminobenzoate-N-D-xyloside 9250 Sodium o-aminobenzoate-N-D-xyloside 12760 Sodium-p-aminobenzoate-N-D-glucoside 12444 Sodium o-aminobenzoate-N-D-glucoside 11382 Sodium-p-aminobenzoate-N-D-mannoside 8812 Sodium o-aminobenzoate-N-D-mannoside 10025 control 20 110

Claims (2)

1. Use of an aminobenzoic acid derivative of the formula (I): in which R is a radical from the group of radicals formed by removal of an OH group in the 1 (alpha) or 1 (beta) position of arabinose, xylose, glucose, glactose, rhamnose and mannose, or one pharmaceutically acceptable salt of such a derivative, for the treatment of kidney disease. 2. Use according to claim 2, wherein the kidneys disease is glomerulonephritis.