JPS6326729B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anti-arteriosclerotic agent containing aminobenzoic acid represented by the following general formula (1) or a derivative thereof as an active ingredient. The present inventor has discovered that aminobenzoic acid or its derivatives having the following general formula (hereinafter referred to as the present substance) exhibits anti-arteriosclerotic effects, and that the present substance has low toxicity, low antibacterial activity, and does not exhibit mutagenicity. Therefore, it was discovered that it can be administered for a long period of time and has pharmaceutical suitability, leading to the present invention. (In the formula, R represents a hydrogen atom, a lower alkyl group, or a metal of a pharmaceutically acceptable inorganic salt.) Therefore, the present invention provides an antiarteriosclerosis agent that can be administered over a long period of time, especially orally. The purpose is to The present invention will be explained in detail below. The active ingredient of the present invention is an aminobenzoic acid having the general formula (1) shown above or a derivative thereof. Here R
is an alkyl group, preferably a lower alkyl group such as methyl, ethyl, propyl, butyl group in addition to a hydrogen atom, or a pharmaceutically acceptable inorganic salt of a metal such as 1/3Al, 1/2Cu, alkali metal, alkaline earth Metals (e.g. Na, K, 1/2Mg, 1/2Ca, etc.)
shows. These groups are introduced by common methods known in organic chemistry. In addition, the active ingredient of the present invention is p-aminobenzoic acid,
Includes o-aminobenzoic acid, m-aminobenzoic acid or their respective ester derivatives. However, among these substances, inorganic salts of aminobenzoic acid, particularly Na salt, are preferred from the viewpoint of medicinal efficacy and safety. Next, the toxicological and pharmacological properties of this substance will be explained in order. (1) Acute toxicity Acute toxicity was investigated using ICR-JCL mice using various routes of administration. For oral 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. After administration, the symptoms of toxicity were continued to be observed, the mortality rate over time was determined for up to 7 days, and the LD ₅₀ value was determined. The findings were obtained through autopsy in both surviving and dead cases. LD ₅₀ values were calculated using the Litchfield-Wilcoxon graph calculation method. The results are shown in Table 1. From the above results, high LD ₅₀ in both cases
Therefore, it can be seen that this substance can be safely applied as a medicine.

[Table] (2) Mutagenicity Mutagenicity was investigated using the following method. Using a recombinant repair-defective strain (Bacillus subtilis M45) and a recombinant repair-carrying strain (Bacillus subtilis H17), use a small pipette to prepare a B-agar medium (10 g of meat extract,
The mixture was streaked onto 10 g of polypeptone, 5 g of NaCl, 15 g of agar, and 1000 ml of distilled water (PH7.0) so that the starting points did not touch. Dissolve this substance in sterile water, dye a circular paper with a diameter of 8 mm with 0.04 ml of the solution, place it so as to cover the starting point of the streak, and store it at 37℃ for 1 hour.
After late cultivation, the length of the growth inhibition zone was measured. Kanamycin was used as a negative control, and mitomycin was used as a positive control. The results are shown in Table 2. It can be seen from Table 2 below that this substance does not exhibit mutagenicity. This shows that this substance is not carcinogenic even when used continuously over a long period of time, and can be said to be extremely safe.

[Table] (3) Blood lipid lowering effect: 1% cholesterol in Japanese white male rabbits
Containing solid feed (CR-1) was given orally ad libitum,
Approximately 3 months later, an increase in serum lipid components was confirmed, and this animal was used as an experimental arteriosclerosis model animal.
This substance was dissolved or dispersed in distilled water and 300 mg/Kg was orally administered to these arteriosclerosis model animals. Blood was collected from the ear vein over time after administration, and serum lipid analysis was performed.Changes in total cholesterol in the blood were measured by an enzymatic method, and β-lipoprotein was measured by a turbidimetric method. The results are shown in Table 3. In view of the above-mentioned toxicological and pharmaceutical properties of this substance, it is understood that this substance can be put to practical use as an anti-arteriosclerotic agent.

[Table] Next, formulation for applying this substance as a therapeutic agent for arteriosclerosis will be described. This substance can be applied in various forms when used as an anti-arteriosclerotic agent. The substances can also be used alone or in admixture with pharmaceutically acceptable diluents and other agents. The substances can also be applied orally or parenterally and may take any form suitable for their administration. Additionally, the substance can be presented in dosage unit form, such as powders, granules, tablets, dragees, capsules, suppositories, suspensions, solutions, emulsions, ampoules, injection solutions, etc., provided they contain an effective dosage. It can take various forms. It should therefore be understood that the medicament of the present invention can be prepared by applying any conventionally known formulation means. The content of the substance (active ingredient) in the drug of the present invention can be adjusted within a wide range of 0.01 to 100%, preferably 0.1 to 70% (by weight). As mentioned above, the drug of the present invention is administered orally or parenterally to humans and animals, with oral administration being particularly preferred. In this case, oral administration also includes sublingual administration, and parenteral administration includes subcutaneous, intramuscular, intravenous, etc. injections and infusions. The dosage of the drug of the present invention depends on whether the subject is an animal or a human, and is influenced by age, individual differences, medical conditions, etc. In some cases, doses outside the range shown below may be administered, but in general, humans When targeted, the oral dosage of this substance is 1 kg body weight, 0.1 to 500 doses per day.
mg, preferably 1 to 250 mg, and the parenteral dosage is 0.01 to 30 mg per day, preferably 1 kg body weight.
Administer 0.1 to 10 mg in 1 to 4 divided doses. Specific examples of formulation of the drug of the present invention are shown below as examples. Parts in the examples indicate weight unless otherwise specified. Example 1 10 parts of sodium p-aminobenzoate, 15 parts of heavy magnesium oxide, and 75 parts of lactose are uniformly mixed to make a powder or fine granules. Also, this powder is put into a capsule container to form a capsule. Example 2 45 parts of o-aminobenzoic acid, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol, 30 parts of water were uniformly mixed and kneaded, then crushed and granulated, dried,
It is sieved and made into granules. Example 3 4 parts of calcium stearate was added to 96 parts of the granules obtained in Example 2, and the mixture was compressed to form tablets with a diameter of 10 mm. Example 4 Granules were prepared in the same manner as in Example 2 using 94 parts of para-aminobenzoic acid, 6 parts of polyvinyl alcohol, and 30 parts of water. 10 parts of crystalline cellulose is added to 90 parts of the obtained granules and compressed to form tablets with a diameter of 8 mm, and syrup gelatin precipitated calcium carbonate is added to the tablets to form sugar-coated tablets. Example 5 Add 0.6 parts of sodium p-aminobenzoate, 2.4 parts of nonionic surfactant, and 97 parts of physiological saline, heat and mix, and sterilize to prepare an injection. Example 6 This example shows a method for preparing ethyl p-aminobenzoate as an example of this substance. Add 27.4 g of p-aminobenzoic acid to 140 g of ethanol (which is saturated with dry hydrochloric acid) and add 1
Boiled for a day. adding the resulting reaction product to water;
It was neutralized with carbonated soda. This neutralization product
Heat until dissolved in 50% ethanol aqueous solution,
The mixture was then cooled, recrystallized, and the resulting crystals were collected. The yield was 74% based on p-aminobenzoic acid. The infrared absorption spectrum of the obtained ethyl p-aminobenzoate is shown in FIG. 1 of the accompanying drawings. The melting point of this substance was 90-92°C, and the maximum absorption was observed at 266 mμ of ultraviolet absorption. Note that methyl and butyl p-aminobenzoate were obtained in yields of 78% and 70% in the same manner as above, using methanol and butanol in place of ethanol, respectively. The melting points of these substances were as follows. Methyl p-aminobenzoate 110-112°C Butyl p-aminobenzoate 56-57°C Further, o-aminobenzoic acid can be obtained in the same manner by replacing p-aminobenzoic acid with o- and m-aminobenzoic acid in the above method. Methyl (melting point 25-26
°C) and methyl m-aminobenzoate (melting point
3536℃) was obtained. Example 7 This example shows a method for preparing sodium p-aminobenzoate as an example of this substance. 1 containing p-aminobenzoic acid and an equivalent amount of NaOH
% aqueous solution, the solution was filtered, and the resulting solution was concentrated under reduced pressure, rapidly washed with excess ether, and further dried under reduced pressure. The yield was 95%. The ultraviolet absorption of the obtained aqueous solution of sodium P-aminobenzoate was measured and an absorption maximum was obtained at 288 mμ. An infrared absorbing spectroscopy is shown in FIG. 2 of the accompanying drawings.

[Brief explanation of the drawing]

Figure 1 of the accompanying drawings shows the infrared absorption spectrum of ethyl p-aminobenzoate, and Figure 2 shows the infrared absorption spectrum of sodium p-aminobenzoate.

Claims (1)

[Claims] 1. General formula An anti-arteriosclerotic agent characterized by containing aminobenzoic acid, its salts, or its esters as an active ingredient. 2. The antiarteriosclerosis agent according to claim 1, wherein the salt is a sodium salt. 3. The antiarteriosclerosis agent according to claim 1, wherein the ester is a _C1 - _C4 alkyl ester.