JPS591685B2 - antihypertensive drugs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antihypertensive agent containing aminobenzoic acid N-D-mannoside or a salt thereof represented by the following general formula 1) as an active ingredient.

O suitable hit bottom ``(Ma) (1) Hereinafter, the configuration of the present invention will be explained in detail.

Aminobenzoic acid -N-D monomannoside or its salt (hereinafter referred to as the present substance) shown by the above formula (1) Zt Although the position of the group -COOH in the formula is not limited, -NH-
Particularly preferred are those in the para position. In addition, the salt refers to the hydrogen atom of the above -COOH group being converted to Na,...
It refers to a salt substituted with a metal atom selected from the group consisting of lV1g, , Ca) and Al, but it may be any salt that is pharmaceutically acceptable. Note that sodium salt is particularly preferred. An example of the method for preparing this substance is as follows. Aminobenzoic acid and D-mannose are heated and condensed under reflux of ethyl alcohol in the presence of ammonium chloride.

In this case, when crystals precipitate after a while after heating,
The reaction solution is thoroughly filtered, and the resulting crystals are thoroughly washed with water, alcohol, etc., and then recrystallized with methanol water. However, those that are difficult to crystallize are passed through a silica gel column to separate the crystals, which are then freeze-dried to obtain the substance.

Note that the hydrogen of the carboxyl group is Na. K. Mg,. C
For substitution with a or Al, a well-known substitution method may be used, for example, by dissolving the present substance in an alcohol-monohydric solvent and adding thereto an inorganic salt corresponding to each of the above-mentioned atoms for substitution. Next, the melting point, elemental analysis value, and ultraviolet absorption of the substance obtained as described above are shown in Table 1 below.

The infrared absorption spectrum of this substance is shown in Part 1 of the attached drawing.
As shown in FIGS. Next, the toxicological and pharmacological properties of this substance will be explained in order.

Toxicological properties: (1) Acute toxicity The acute toxicity of this substance was investigated by various administration routes using ICR-JCL mice.

For oral and transdermal administration, the substance was dissolved in distilled water, and for other administrations, the substance was dissolved in physiological saline, which was adjusted to a predetermined amount using a stomach probe or syringe. Post-administration observation of toxicosis was continued, and the mortality rate over time was determined for up to 7 days. Then, the LD and O values were determined, and findings were obtained through autopsy in both surviving and dead cases.

The LD5O value is determined by the Li
tchfield-WilcOxOn) graphic calculation method. The results are shown in Table 2 below. As can be seen from the above table, all of the present substances exhibit high LD5O values, and therefore can be safely applied as medicines.

Furthermore, sodium p-aminobenzoate-N-D-mannoside shows a particularly high LD5O value. (2) Antibacterial activity Dissolve this substance in a 10% dimethyl sulfoxide (DMSO) aqueous solution, prepare a 2-fold dilution series,
This diluted solution was mixed with 9 times the amount of heated and dissolved agar medium, and then poured into a Petri dish to form a flat plate.

Bacteria were cultured in TS broth overnight at 37°C, one platinum loop was streaked onto the plate, and cultured at 37°C for 20 to 24 hours. The fungus was cultured on a Sabouraud agar slant at 25°C for 2 to 3 days, and its suspension in physiological saline 1
Platinum loops were streaked and cultured at 25°C for 3 to 5 days to examine their growth. The following test bacteria and culture medium were used. Bacteria: Pseudomonas aeruginosa
l5l4) Escherichia coli
2734) Staphylococcus aureus (Stapl!YlOcOc
cusauI′Eus2O9p) Bacillus subtilis (BaCill
ussubtilislO69) baker's yeast (Sacch
arOmyces cerevisiae 42O7) Candida albicans 752 medium: Hartin's Hygiene Agar (PH7) Sabouraud Agar (PH6) This substance did not exhibit antibacterial activity against any bacteria at a concentration of 1η/ml.

This shows that this substance has almost no effect on bacteria existing in the body. Therefore, since this substance has no antibacterial effect, it can be used continuously for a long period of time without worrying about disturbance of intestinal flora. 3) Mutagenicity Mutagenicity was investigated as follows.

Recombinant repair-deficient strain (Bacillus subtilis M
45) and a recombinant repair carrier strain (Bacillus subti
Using a small pipette, the mixture was streaked onto a B-agar medium (107 meat scratches, 107 polypeptone, 5 y of salt, 15 V of agar, 1000 ml of distilled water, pH 7.0) so that the starting point did not touch. Dissolve this substance in sterile water, stain 0.04 ml of it on a circular piece of paper with a diameter of 8 mm, and place it so as to cover the starting point of the streak.
After culturing overnight at °C, the length of the zone of growth inhibition was measured. Kanamycin was used as a negative control, and mitomycin was used as a positive control. The results are shown in Table 3 below.

These results show that although this substance does not exhibit mutagenicity even at high concentrations, sodium p-aminobenzoate-N-D-mannoside is the most excellent. Pharmacological properties: This substance exhibits excellent antihypertensive effects as described below.

(1) Blood pressure lowering effect Using a spontaneously hypertensive rat (SHR), which most closely approximates human essential hypertension and is known to be an excellent hypertension model animal, a blood pressure measuring device (USM-105R) was used.
Tail artery pressure was measured non-invasively as blood pressure using a model (manufactured by Ueda Seisakusho).

The rats used in this experiment were 20 to 25 weeks old and had a systolic blood pressure of 200 to 210 Hg.

This substance was dissolved in distilled water and orally administered to 5 rats per group at a concentration of 75 mg/Kg. The results of the average values are shown in Figure 4 of the attached drawings. In the figure, C is the control group, M is potassium m-aminobenzoate-N-D-mannoside, 0 is sodium o-aminobenzoate-N-D-mannoside, and P is sodium p-aminobenzoate-N -D-mannoside administration groups are shown respectively. According to FIG. 4, it is clear that the administration of this substance lowers blood pressure, indicating that this substance is useful as an antihypertensive agent. It turns out that sodium p-aminobenzoate-N-D-mannoside is particularly preferred. As mentioned above, the proboscis of the present invention exhibits an excellent antihypertensive effect, and on the other hand, the LD5O
This substance has high medicinal suitability because it has a high value, has no antibacterial activity, and does not exhibit mutagenicity, so it can be said that this substance is useful as an antihypertensive agent.

Next, formulation for applying this substance as a drug as described above will be explained. When used as a hypotensive agent, this substance can be used in any convenient form to obtain medicinal effects against diseases, and can be used alone or in mixtures with pharmaceutically acceptable diluents and/or other drugs. It can also be used as

The substance may also be applied orally or parenterally. Therefore, it can take any form for oral or parenteral administration. Additionally, the substances can be provided in dosage unit form. In this case, the form of the product containing an effective amount of the active ingredient may be a powder, granule, tablet, sugar-coated tablet, capsule, suppository, suspension, solution, emulsion, ampoule, injection solution, etc. As a diluent, solid, liquid, semi-solid,
Alternatively, it may be in the form of an ingestible capsule, e.g.
These include excipients, fillers, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, fragrances, preservatives, solubilizing agents, and solvents. Furthermore, these may be used alone or in combination of two or more. Such formulations of the present substances may be manufactured by any known method. The preparation generally contains from 0.01 to 100% by weight of this substance as an active ingredient. Such preparations may be administered to humans and animals orally or parenterally, with oral administration being preferred. Oral administration in this case also includes sublingual administration. Parenteral administration includes injection, eg, subcutaneous, intramuscular, intravenous, infusion, and the like. The dosage of the above preparation is determined depending on whether it is an animal or a human, and is influenced by age, individual differences, medical conditions, etc.; however, when it is administered to humans, it is generally administered orally. Weight 1kg, 0.1-800 per day
η, preferably 1 to 400η, parenterally at a body weight of 1k9 and 0.01 to 200TV1 per day, preferably 0
．． Administer 1 to 100 mg in 1 to 4 divided doses. The preparation method and formulation of this substance will be illustrated below as an example of the present invention. Example 1 Preparation of p-aminobenzoic acid-N-D-mannoside 27 p-aminobenzoic acid, 37 D-mannose and 0.2y of ammonium chloride are condensed in 10ml of ethyl alcohol by heating under reflux for about 1 hour. Let the reaction take place.

After the reaction, the product is left at room temperature to precipitate crystals. The crystals are then separated, washed with water, dilute ethyl alcohol, and a small amount of ether, and then recrystallized using 50% methanol to obtain colorless needle-like crystals of p-aminobenzoic acid-N-D-mannoside. . Yield 56.1%, melting point 1
82℃! α12B+35.7 (94% ethyl alcohol). Preparation of sodium p-aminobenzoic acid N-D-mannoside 0.27 g of the hydrate of p-aminobenzoic acid N-D-mannoside obtained as described above was dissolved in NaOH2
5.2TIV7 was dissolved in 2.5 ml of water and gradually added to the solution, concentrated under reduced pressure, and excess ethyl alcohol was added to form a precipitate.

This precipitate is collected, dehydrated, and then dried to obtain colorless crystals. These crystals are further recrystallized using an aqueous solution consisting of 5 parts of water and 1 part of acetone to obtain colorless Q crystals of sodium p-aminobenzoate-N-D-mannoside. Yield: 95% o The physical properties of sodium p-aminobenzoate-N-D-mannoside thus obtained are as follows.

Decomposition point: 196°C (begins to turn yellow at 185°C)
Becomes brown at ℃) Optical rotation 1aI sweet-10 (H2O) Example 2 Potassium 0-aminobenzoate 10 parts (weight) N-D
-Mannoside heavy magnesium oxide 15 parts (
〃) 75 parts (by weight) of lactose are mixed uniformly and made into a powder or fine granules.

Further, this powder is put into a capsule container to form a capsule. Example 3 p-Aminobenzoic acid-N-D- 45 parts (by weight) Mannoside starch 15 parts (〃) Lactose 16 parts (〃) Crystalline cellulose 21 parts (〃) Polyvinyl alcohol 3 parts (〃) Water
After homogeneously mixing and kneading 30 parts (30 parts), crush and granulate, dry and sieve to obtain granules.

Example 4 4 parts by weight of calcium stearate were added to 96 parts by weight of the granules obtained in Example 3, and the mixture was compressed to form tablets with a diameter of 10 mm.

Example 5 Sodium m-aminobenzoate 94 parts (weight) -N-
D-Mannoside polyvinyl alcohol 6 parts (〃) Water 30 parts (
) to prepare granules according to the same procedure as in Example 3.

10 parts by weight of crystalline cellulose was added to 90 parts by weight of the obtained granules and compression molded to obtain a diameter of 8W! 1 tablet, and add syrup gelatin and precipitated calcium carbonate to make sugar-coated tablets. Example 6 Sodium p-aminobenzoate 0.6 part (weight) N-
D-mannoside nonionic surfactant 2.4
Part (″) 97 parts of physiological saline ( 〃
), mix under heating, and sterilize to make an injection.

[Brief explanation of drawings]

FIG. 1 shows p-aminobenzoic acid-N-D-mannoside,
Figure 2 shows sodium p-aminobenzoate N-D-mannoside and Figure 3 shows sodium m-aminobenzoate-N
FIG. 4 is a graph showing the infrared absorption spectra of each -D-mannoside, and FIG. 4 is a graph showing the blood pressure lowering effect of this substance. In Figure 4, C~control group, M-m-potassium aminobenzoate-N-D-mannoside, O~0-sodium aminobenzoate-N-D-mannoside, P~p-sodium aminobenzoate-N -D-mannoside.

Claims (1)

[Claims] 1. A hypotensive agent containing aminobenzoic acid N-D-mannoside or a salt thereof represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼. 2 Aminobenzoic acid-N-D-mannoside has the formula ▲mathematical formula,
The antihypertensive agent according to claim 1, which is a compound represented by ▼, which has a chemical formula, table, etc. 3 Claims 1 or 2 in oral dosage form
Antihypertensive agents listed in Section 1.