JPS6232725B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides 7-diethylamino-5-methyl-s
The present invention relates to a therapeutic agent for renal diseases containing -triazolo-[1,5-a]-pyrimidine (generic name: Trapidil) as an active ingredient. Conventionally, there is no fundamental treatment for nephritis, and steroids, immunosuppressants, non-steroidal anti-inflammatory drugs, etc. have been used to treat nephrotic syndrome, but these drugs have many drawbacks. There is.
For example, steroids have mild side effects such as moon-like facial appearance, acne, transient increase in blood pressure, and steroid diabetes, while serious side effects include gastrointestinal ulcers, bleeding, infections, mental disorders, and suppression of pituitary and adrenocortical functions. can be given. Immunosuppressants are used to treat bone marrow hematopoietic dysfunction, digestive disorders, reproductive function suppression,
Side effects include induction of malignant tumors, susceptibility to infection, skin rash, and hair loss. In addition, non-steroidal anti-inflammatory drugs may have side effects such as gastrointestinal disorders, headaches, and anemia. In view of the above circumstances, the present inventors conducted various studies and found that the formula: It was newly discovered that 7-diethylamino-5-methyl-s-triazolo-[1,5-a]-pyrimidine (Trapidil), which has the structure: completed. Trapidil is a white to slightly yellow crystalline powder with a bitter taste that is easily soluble in organic solvents, and has coronary vasodilatory effects, so it has already been used as a treatment for ischemic heart disease [Toroku Hashimoto et al., Applied Pharmacology ,8,
33 (1974)]. However, it has not been previously known that trapidil has a urinary protein-reducing effect, and this fact was first revealed by the present inventors. Next, the effect of trapidil on nephritis will be explained in more detail using experimental examples. Experimental example 1 Effect on aminonucleoside nephritis Method of K. Kimura et al. [K. Kimura et al.: Journal of Toxicological Science (K. Kimura et al., J. Toxicol. Sci.) 4 , 1
(1978)] showed that aminonucleoside 80 was found in rats.
mg/Kg was injected subcutaneously to produce experimental nephritis.
Trapidil was administered 30 minutes before administration of the aminonucleoside, and thereafter was administered orally every day for 10 days. Tests are done every other day for urine and every other day for serum.
I did it on the 10th day. The results are shown in FIG. 1, FIG. 2, and Table 1. Trapidil administration reduced both urinary protein and urinary albumin, and the effect was particularly marked when administered at 30 mg/Kg. In serum, significant effects were shown on total protein, albumin, and cholesterol, and the effects were particularly remarkable in the 30 mg/Kg administration group.

[Table] Experimental Example 2 Effect on Umasugi Nephritis Umasugi nephritis was induced by intravenously administering 20 ml/Kg of rabbit anti-rat renal serum to rats in a conventional manner. Trapidil was orally administered daily from 2 days before serum administration until 20 days after administration. Urine tests were conducted daily before and after administration until the 21st day, and serum tests were conducted on the 21st day. The results are shown in Figures 3 and 4 and Table 2. As is clear from these results, urinary protein and albumin tended to decrease with the administration of trapidil. In addition, serum tests showed a therapeutic effect on nephritis, such as suppressing the decrease in total protein and albumin, and suppressing the increase in total cholesterol. Furthermore, on the 21st day, kidney specimens for light microscopy and electron microscopy were collected and subjected to histopathological examination. When observed using a light microscope, control kidneys showed thickening of the glomerular loops and the appearance of urinary casts in the renal tubules.
Electron microscopic observation revealed partial thickening of the glomerular basement membrane and loss of fusion of the foot processes, but these changes were suppressed by trapidil administration.

【table】

[Table] Experimental example 3: Chronic nephritis patients were treated with 300 doses of trapidil per day.
mg of each drug was administered orally, and the healing status due to administration was observed based on the degree of proteinuria and hematuria. Proteinuria was measured by the dipstick method, and hematuria was measured by collecting the number of red blood cells in a certain amount of urine by centrifugation and observing it under a microscope. The results are shown in Table 3. As is clear from Table 3, the symptoms of proteinuria and hematuria were significantly improved by the administration of trapidil, and trapidil also showed clear therapeutic effects on actual human nephritis.

[Table] Experimental Example 4 Acute Toxicity Experiment Mice and rats were raised in groups of 10 each with free access to solid food and tap water, and trapidil was administered orally, intravenously, and subcutaneously. The acute toxicity was investigated. Calculation of LD ₅₀ is based on the mortality rate for 7 days after administration for oral administration, and from the mortality rate for 3 days after administration for intravenous injection and subcutaneous injection, respectively.
Wilcoxon) law. The results are shown in Table 4.

[Table] As is clear from the above experimental examples, trapidil is effective against renal diseases and has no side effects, making it a useful drug as a therapeutic agent for renal diseases. When Trapidil is administered to humans, usually 1
The daily dose is 100 to 500 mg orally, but the dose may be increased or decreased as appropriate depending on the medical condition. Advantageously, the dosage form is a tablet or capsule according to a conventional method. That is, excipients such as lactose, starch, and mannitrate, disintegrants such as carboxymethylcellulose and potato starch, binders such as potato starch and gum arabic, magnesium stearate,
Tablets or capsules can be manufactured using lubricants such as talc and silica. Furthermore, the tablets may be coated with sugar if necessary. Tablets are shown below as examples, but the formulation is not limited thereto. Example 1 Tablet (i) Trapidil 50g (ii) Lactose appropriate amount (iii) Crystalline cellulose 60g (iv) Potato starch 54g (v) Magnesium stearate 2g Among the above, (i) to (iv) were mixed and separated in advance. Add a portion of (iv) as 10% glue to make granules and dry. Next, (v) is added to this and mixed to form a 200 mg tablet. The tablets may be coated with sugar by a conventional method, if necessary. Example 2 Capsule (i) Trapidil 50g (ii) Calcium hydrogen phosphate 50g (iii) Aluminum silicate appropriate amount (iv) Crystalline cellulose 60g (v) Magnesium stearate 2g Mix the above (i) to (v) After passing through a sieve and mixing thoroughly, the mixture is made into capsules of 200 mg each according to a conventional method. Example 3 Injection Take 100 g of trapidil crystals, dissolve it in distilled water for injection in step 2, and prepare an injection of 100 mg/2 ml per ampoule using a conventional method.

[Brief explanation of the drawing]

1 and 2 are graphs showing the results of Experimental Example 1, and FIGS. 3 and 4 are graphs showing the results of Experimental Example 2.

Claims (1)

[Scope of Claims] A therapeutic agent for renal diseases containing 17-diethylamino-5-methyl-s-triazolo-[1,5-a]-pyrimidine as an active ingredient.