JPS6041642B2 - Antiarteriosclerotic agent containing aminobenzoic acid derivatives as active ingredients - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antiarteriosclerotic agent containing an aminobenzoic acid derivative represented by the following general formula (1) as an active ingredient.

R, one, H0C00R2 (1) where R1 is arabinose, xylose, glucose,
Each residue of galactol or rhamnose, R2 represents H, Na, 112Mg) 112Ca) 112Cu or 1'3Al.

Compound having the above general formula (1) (hereinafter abbreviated as this substance)
The present inventors have previously discovered that this substance is useful as an anti-inflammatory agent (Japanese Patent Application No. 53-161385).
(see issue).

The present inventors further discovered that this substance has an excellent anti-arteriosclerosis effect, and have accomplished the present invention.

The present invention will be explained in detail below.

This substance is.

Since it has low toxicity and no antibacterial activity, there is no concern about disturbance of intestinal microbial industry, and therefore long-term administration is possible. Furthermore, this substance is said to be an extremely safe drug as it does not have mutagenicity or affect cellular or humoral immunity, and therefore poses no risk of teratogenicity or allergic reactions to healthy people. obtain.

Both of these substances are associated with abnormally high levels of blood cholesterol and beta.
- It has the effect of lowering riboproteins and phospholipids, so it is useful as an anti-arteriosclerotic agent.

There are three positions of the R1-NH- group in this substance represented by the above general formula (1): p-, m-, and o-positions, and there may be some differences in the activity of each. Essentially, all of them are useful as active ingredients of anti-arteriosclerosis agents. In the above formula (1), R2 may include alkali metals, alkaline earth metals, and other metals in addition to hydrogen, but these metals may be any as long as they are acceptable as pharmaceuticals, and usually are Na,,K. ．． Mg. ．． Ca.
．． A', Cu, etc. are preferred, and Na is particularly preferred. In addition, the sugar moiety has a 6-membered ring (pyranose) structure,
Either the D or L form can be used. Furthermore, the conjugate of the sugar moiety may be in the α or β form or a mixture thereof. This substance is a known substance, and its manufacturing method and physicochemical properties are disclosed in the specification of Japanese Patent Application No. 161385/1983. Next, we will discuss the toxicological and pharmacological properties of this substance.

Toxicological properties (1) Acute toxicity Acute toxicity was investigated by intraperitoneal and forced oral administration using ICR-JCL mice.

This substance was dissolved in physiological saline for intraperitoneal administration, and in distilled water for oral administration, and the predetermined amount was adjusted and administered using a syringe or stomach tube. After administration, the symptoms of toxicity were continued to be observed, and the LD5O value was determined from the mortality rate over time up to the 7th day.

The findings were obtained through autopsy in both surviving and dead cases. LD5O value is determined by Lichfield Wilcoxon (Lichfield Wilcoxon).
d-WilcOxOn) was determined by the graphic calculation method. The results are shown in Table 1.In all cases, the LD5O value was 6g/K9 or higher regardless of whether it was administered intraperitoneally or orally.
It is a low toxicity substance that falls well into the category of
types of compounds, that is, more than half have an LD5O value of 10g
/Kg or more, it can be said that it is an extremely safe drug.
(2) Antibacterial activity This substance was dissolved in distilled water to prepare a 2-fold dilution, and this dilution was mixed with 9-fold volume of heated agar medium, poured into a Petri dish, and plated.

Heart infusion agar (bacteria) and Sapro agar (fungi) were used as the culture medium, and after inoculation, the pre-cultured test bacteria were smeared and inoculated at 37°C for bacteria, and at 25°C for fungi at 3-7°C.
The cells were cultured for several days and the presence or absence of growth was examined. The following bacterial species were used as test bacteria.

Pseudomonas aeruginosa
IAMl5l4) Escherichia coli (EscharlchiacOI
iIFOl2734) Staphylococcus aureus (StaPhyl
OCOCCllSaureus2O9P) Bacillus subtilis (Ea
Baker's yeast (SaccharOmycescerevisiae)
IMA42O7) Candida yeast (Candidaalb)
icansATCC752) TrichOph
ytOnmentagr'0phytesIF0612
4) Black mold (Aspergillusni?RIAM3)
OOl) As a result, this substance has a 1 m
No growth inhibition was observed at a concentration of 9/ml.

(3) Mutagenicity First, an investigation using Rec-Assay was conducted. That is, a recombinant repair-deficient strain (Bacillus
ssubtillsM45) and recombinant repair carrier strain (B-S
ubtllllSHl7) were streaked onto a B-■ agar medium (10 g of meat scratches, 10 g of polypeptone..5 g of Nac', 15 g of agar, 1000 ml of distilled water, pH 7.0) so that the starting points did not touch each other. After dissolving this substance in sterile water and absorbing 0.04TrLt onto a circular piece of paper with a diameter of 8 Tnm, it was immediately left to stand so as to cover the starting point of the streak, and cultured overnight at 37°C to grow. The length of the inhibition zone was measured. Kanamycin was used as a negative control, and mitomycin was used as a positive control. Next, perform the reverse mutation test with Sal
mOnellatyphimuriunlTA98 and T
This was carried out using AlOO (both require histidine).

0.5n1M biothione-0.5mM histidine solution 11
To 2TrL1 of soft agar solution (6 g of Nacf, 6 g of agar, 1000 ml of distilled water) to which 10 volumes had been added, 0.1 ml of bacterial solution, 0.1 ml of drug solution was added, mixed well, and layered on a minimum agar medium.

The cells were cultured at 37°C for 2 days and the number of revertant colonies was counted.

Furilfuramide (AF'2) was used as a positive control. The measurement results by Rec-Assay are shown in Table 2, and the results of the reverse mutation test are shown in Table 3.

In the Rec-Assay, this substance did not exhibit mutagenicity even at high concentrations, but sodium p-aminobenzoate derivatives were particularly excellent. In addition, in a reverse mutation test, no change was observed in the mutation rate due to this substance compared to a control without additives, even when a high concentration was applied, proving that it is a highly safe drug. As described above, this substance does not exhibit mutagenicity and is presumed to have no possibility of carcinogenicity even when used for a long period of time, indicating that it is extremely safe. 4. Delayed intradermal reaction To learn about the effect of this substance on cell-mediated immunity, ICR-JCL
Footpad reaction (F) using hinge red blood cells as an antigen using mice
OOtpadreactiOn) was performed.

Hinge red blood cells were suspended in 10% physiological saline, and 0.2 mt of this solution was injected through the tail vein to perform primary sensitization.
After a further 7 days, suspend 0.05 m of 40% volume of hinge red blood cells.
1 was injected into the footpad for secondary sensitization, and foot thickness was measured the next day. The amount of this substance was 250m9 mainly on the day of primary sensitization.
/K9 was administered intraperitoneally 5 times daily. As a result, no significant difference was observed in the increase in footpad thickness in the group administered with this substance compared to the control (non-administered) group.

5 Antibody production ability In order to understand the effect of this substance on humoral immunity, ICR-J
For CL mice, a 10% volume suspension of hinge red blood cells was administered at 0.
211L was injected into the tail vein for sensitization, and on the 7th day after sensitization, blood was collected and antibody production ability was measured by hemagglutination reaction.

The substance was intraperitoneally administered at 250 m9/Kg for 5 consecutive days, mainly on the day of sensitization. As a result, no significant difference was observed in the agglutination value between the group administered with this substance and the control group. Pharmacological properties: 1 Blood lipid lowering effect Japanese white hybrid male rabbits (body weight approximately 2.5k9) were given orally ad libitum solid feed (CR-1) containing 1% cholesterol, and after approximately 3 months, serum lipid components decreased. was measured.

As a result, the total average of phospholipids was 600 m9/De, the total average of serum cholesterol was 1500 m9/De, and the total average of β-riboprotein was approximately 1330 mg/De, indicating a clear increase in blood lipids. It is well known that these rabbits exhibiting hyperlipidemia also develop atherosclerosis, and have been widely used as arteriosclerosis model animals for testing the efficacy of anti-arteriosclerotic agents. Five rabbits were used in each group. This substance was dissolved in distilled water and administered to these arteriosclerosis model animals at 30mg/K9 or 300m9/Kg.
was administered orally. After administration, blood was collected from the ear vein over time and serum lipid analysis was performed, and changes in total cholesterol in the blood were measured using an enzymatic method. Changes in lipoproteins (P on β) were measured by nephelometric method, and changes in phospholipids were measured by enzymatic method.

The results are shown in Table 4. Each of the above measured values in Table 4 shows the change values at 3 and 6 hours after administration with respect to the values before administration of this substance, and 1 in the table indicates a decrease.
+ indicates increase. As can be understood from the table above, this substance has the effect of substantially reducing blood phospholipids, β-riboproteins and cholesterol, and is therefore useful as an anti-arteriosclerotic agent.

Moreover, this substance has few side effects and can be effectively applied as a therapeutic agent for patients with arteriosclerosis. Next, we will describe the formulation of Yanghe using this substance as a therapeutic agent for arteriosclerosis.

When this substance is used as an anti-arteriosclerotic agent, it can be used in any convenient form to obtain the medicinal effect depending on the type and symptoms of the disease, and can be used alone or in combination with pharmaceutically acceptable diluents and other drugs. It can be used in the form of a composition.

The substance may be applied orally or parenterally.

Accordingly, the substance may optionally take a form for oral or parenteral administration. The substance can also be provided in dosage unit form, including powders, granules, tablets, dragees, capsules, suppositories, suspensions, solutions, ampoules, and injections containing an effective amount of the substance. It can take the form of liquid, etc.

The anti-arteriosclerosis agent of the present invention can be produced by any known method.

The active ingredient in the composition used as a formulation in the present invention generally ranges from 0.01% to 100 Wt. % preferably 0
．． Contains 1 to 70 wt%. The antiarteriosclerosis agent of the present invention can be administered orally or parenterally to humans and animals, but oral administration is preferred. Oral administration includes sublingual administration.
Parenteral administration includes injections, such as subcutaneous, intramuscular, intravenous, infusion, and the like. The dose of the anti-arteriosclerotic agent of the present invention depends on whether it is an animal or a human, and is influenced by age, individual differences, medical conditions, etc., and in some cases doses outside the range shown below may be administered. When targeting subjects, the oral dosage of this substance is 0.1 to 1 kg9 body weight per day. 1000mg
, preferably from 1 to 500 m9, the parenteral dosage is also from 0.01 to 200 m9, preferably from 0.1 to 100 m9
g in 1 to 4 divided doses.

Hereinafter, the present invention will be explained in more detail by showing formulation examples of substances as examples.

Parts in the examples represent parts by weight. Example 1 Sodium p-aminobenzoate-N-supra-arabinoside
1α Heavy Magnesium Oxide 15 Lactose 75 are uniformly mixed to make a powder or fine granules.

Further, this powder was put into a capsule container to form a capsule. Example 2 Sodium 0-aminobenzoate-N-D-xyloid
45 parts starch
15 Lactose 16 Crystalline cellulose 21 Polyvinyl alcohol 3 Water
After uniformly mixing and blending 30, the mixture is crushed, granulated, dried, and sieved to form granules.

Example 3 Sodium o-aminobenzoate-N- in Example 2
Granules were made in the same manner using sodium o-aminobenzoate-N-D-glucoside instead of D-xyloid, and 4 parts of calcium stearate was added to 96 parts of the granules, which were then compressed to form tablets with a diameter of 1 h. do.

Example 4 Sodium p-aminobenzoate-N supra-rhamnoside
97 parts polyvinyl alcohol 6 water
Granules were prepared in the same manner as in Example 2 using No. 30.

105 ml of crystalline cellulose is added to part (6) of the obtained granules and compressed to form tablets with a diameter of 8 Tf$L, and syrup gelatin and precipitated calcium carbonate are added to make sugar-coated tablets. Example 5 Sodium p-aminobenzoate-N-D-caraxide
0.6 parts nonionic surfactant 2.4 physiological saline
97 was heated and mixed and then sterilized to make an injection.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R_1 represents each residue of arabinose, xylose, glucose, galactol, or rhamnose. An anti-arteriosclerotic agent containing as an active ingredient at least one aminobenzoic acid derivative or a salt thereof. 2 Aminobenzoic acid derivatives have a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R_1 represents each residue of arabinose, xylose, glucose, galactol, or rhamnose. The anti-arteriosclerosis agent according to claim 1, which has the following.
3. The antiarteriosclerosis agent according to claim 1 or 2, which is in an oral administration form. 4. The antiarteriosclerosis agent according to claim 1 or 2, which is in a parenteral administration form.