JPS6231682B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the following general formula () [In the formula, n represents an integer 7, 8, 9 or 10.

The present invention relates to a hypotensive agent containing polyprenyl alcohol as a main component.

Conventionally, various antihypertensive agents have been used for the purpose of treating hypertension, but these agents are accompanied by various side effects and pose problems in administration, particularly in large doses and long-term continuous administration. For example, diuretic antihypertensive drugs such as sulfonamides and thiazide preparations cause serious side effects such as hyperuricemia and hypokalemia, while sympatholytic suppressants such as reserpine preparations and meltidopa preparations cause dry mouth and consciousness. Vasodilators such as apresolin are often accompanied by side effects such as headache, tachycardia, and angina pectoris. We searched for a safer antihypertensive agent that does not have these drawbacks, and found the compound () of the present invention.

The pharmacological action and toxicity (acute toxicity) of the compound of the present invention revealed in animal experiments are as follows.

Pharmacological test Γ Okamoto and Aoki's spontaneously hypertensive rats (hereinafter
It is called SHR. ) [Method] The blood pressure lowering effect of the test compound on Okamoto and Aoki's SHR was measured. The SHR used was a chronically hypertensive SHR who was approximately 40 weeks old. The systolic blood pressure was around 260 mmHg. Blood pressure was measured using a Shimadzu continuous blood pressure measuring device SCS-301 (manufactured by Shimadzu Corporation), and systolic blood pressure was measured non-invasively from the rat's tail artery.

The test compound was made into a suspension with gum arabic;
Experimental animals received 50 mg/Kg depending on the dose of test compound.
In addition to the administration group, there was also a control group to which only an aqueous gum arabic solution was administered. Four experimental animals were used in each group. The drug was orally administered once a day for three consecutive days.

Blood pressure measurements were taken before administration, 6 hours after the first administration, and 24 hours after the first administration.
Changes in blood pressure were observed after 1 hour (at the time of the second administration), 48 hours later (at the time of the 3rd administration), and 72 hours later.

[Test compound]

3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctan-1-ol (hereinafter referred to as compound A) 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol (hereinafter compound ) 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,
34,38-tetracontadecaen-1-ol (hereinafter referred to as compound C) [Results] Compound A, B or C was orally administered at a dose of 50 mg/Kg for 3 consecutive days in Okamoto and Aoki's SHR. As shown in Figures 1 to 3, a clear blood pressure lowering effect was observed in the experimental animal group. For example, with Compound A, the control group (blood pressure at the start of the test, 259 ± 4 mmHg) showed a blood pressure of 258 ± 4 mmHg even after 3 days of the experimental period, showing almost no change in blood pressure, whereas the administration group (blood pressure 259 ± 4 mmHg) showed almost no change in blood pressure. The blood pressure at the start of the test was 256±5 mmHg), 6 hours after the first administration the blood pressure was 230±7 mmHg, and 24 hours after the same administration (at the time of the second administration) the blood pressure was 234±8 mmHg. These results revealed that Compound A has a marked hypotensive effect, and that this effect is long-lasting.

Toxicity test SD rats (female and male weighing approximately 200 g) were used as test animals, and 500 mg/Kg of the test compound was orally administered according to the method of the pharmacological experiment described above, but no deaths or side effects were observed.

As is clear from the results of the above pharmacological and toxicity tests, the compound of the present invention () has an excellent antihypertensive effect and has almost no toxicity, indicating that it is extremely safe. I understand. Therefore, the compound () of the present invention is an effective compound for the prevention and treatment of various types of hypertension, including renal, endocrine, cardiovascular, neurological, and essential hypertension. The administration method and dosage of the compound (2) of the present invention can be appropriately selected and adjusted depending on the symptoms to be treated, but oral administration in adults is approximately 10 to 10 minutes per day.
200 mg, preferably 50-100 mg.

The compounds of the invention () can be prepared into pharmaceutical compositions for administration using conventional formulation techniques.

Such compositions are provided for use in a conventional manner with any required pharmaceutical carriers or excipients.

Desirably, the composition is provided in a form suitable for absorption from the gastrointestinal tract. Tablets and capsules for oral administration are in unit dosage form and contain binders such as syrup, acacia, gelatin, sorbit, tragacanth, or polyvinylpyrrolidone, excipients such as lactose, sugar, corn starch, calcium phosphate, sorbitate, or It may contain conventional excipients such as glycine, lubricants such as magnesium stearate, talc, polyethylene glycol or silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by methods well known in the art. Oral liquid preparations may be aqueous or oily suspensions, solutions, syrups, elixirs, etc., or they may be dry products for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain commonly used excipients such as suspending agents such as sorbitol syrup, methylcellulose, glycose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, calcium carboxymethylcellulose, aluminum stearate gel or Hydrogenated edible fats, emulsifiers such as lecithin, sorbitan monooleate or gum arabic, non-aqueous vehicles such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl p-hydroxybenzoate, p-hydroxy It may also contain propyl benzoate or sorbic acid.

Compositions for injection may be presented in unit-dose ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, emulsions in oily or aqueous vehicles, and may contain formulation agents such as surfactants, stabilizers, and the like.

Next, 3,7, which is one of the compounds of the present invention,
11,15,19,23,27,31,35-nonamethyl-2,
A formulation containing 6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol (hereinafter referred to as the main drug) as the main ingredient will be described as an example.

Example 1 Capsule Main drug 5g Microcrystalline cellulose 80g Corn starch 20g Lactose 22g Polyvinylpyrrolidone 3g Total amount 130g The above ingredients were granulated by a conventional method and then filled into 1000 hard gelatin capsules. Each capsule contains 5mg of the active ingredient.

Example 2 Powder Main drug 50g Microcrystalline cellulose 400g Corn starch 550g Total amount 1000g The main drug was dissolved in acetone, which was then adsorbed onto microcrystalline cellulose, and then dried. This was mixed with corn starch and a 20-fold powder of the main drug was prepared as a powder using a conventional method.

Example 3 Tablet Main drug 5g Corn starch 10g Lactose 20g Carboxymethylcellulose calcium
10g Microcrystalline cellulose 40g Polyvinylpyrrolidone 5g Talc 10g Total amount 100g The main ingredient was dissolved in acetone, which was then adsorbed onto microcrystalline cellulose and then dried. Corn starch, lactose, and carboxymethyl cellulose calcium were mixed therein, and then an aqueous solution of polyvinylpyrrolidone was added as a binder to form granules in a conventional manner. After adding talc as a lubricant and mixing, the mixture was compressed into tablets each weighing 100 mg. Each tablet contains 5mg of the active ingredient.

Example 4 Injection Main drug 10g Nikkol HCO-60 (Nikkol Chemical Company product name)
37g Sesame oil 2g Sodium chloride 9g Propylene glycol 40g Phosphate buffer (0.1M, PH6.0) 100ml Distilled water Total volume 1000ml Mix the main ingredient, Nikkol HCO-60, sesame oil and half of propylene glycol and dissolve by heating at approximately 80℃. Then, a phosphate buffer solution, and distilled water in which sodium chloride and propylene glycol had been dissolved in advance were added while heating to about 80°C to make an aqueous solution with a total volume of 1000 ml. This aqueous solution was dispensed into 2 ml ampoules, which were sealed and sterilized by heating.

Each tube contains 20mg of the main drug.

[Brief explanation of the drawing]

Figure 1: Compounds of the present invention 3, 7, 11, 15, 19,
23,27,31-octamethyl-2,6,10,14,
18,22,26,30-dotriacontaoctaene-1
- This figure shows the blood pressure lowering effect when ol (compound A) was administered. Figure 2: Compounds of the present invention 3,7,11,15,19,23,27,31,35-
Nonamethyl-2, 6, 10, 14, 18, 22, 26, 30,
This figure shows the blood pressure lowering effect when 34-hexatriacontanonaen-1-ol (compound B) was administered. Figure 3: Compounds of the present invention 3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,
This figure shows the blood pressure lowering effect when 38-tetracontadecaen-1-ol (compound C) was administered.

Claims (1)

[Claims] First-order general formula [In the formula, n represents an integer 7, 8, 9 or 10. An antihypertensive agent whose main ingredient is polyprenyl alcohol. 2. The antihypertensive agent according to claim 1, wherein n=7. 3. The antihypertensive agent according to claim 1, wherein n=8. 4. The antihypertensive agent according to claim 1, wherein n=9. 5. The antihypertensive agent according to claim 1, wherein n=10.