JPS6045614B2 - Diyne polyprenyl alcohol and antihypertensive agents containing it - Google Patents

Description

[Detailed description of the invention] The present invention relates to the following general formula (I) [In the formula, A is .

, , , , upper , , , chain, and n represents an integer 3 or 4. The present invention relates to a diyne polyprenyl alcohol represented by the following formula and an antihypertensive agent containing the diyne polyprenyl alcohol.

Compound (1) used to achieve the object of the present invention
) is a new compound, and there are various methods for synthesizing it due to its chemical structure, one of which is the method described below.

That is, 1,4 dichlorobetin-2 and the following general formula (■)
[In the formula, A and n represent the above meanings.

It can be obtained by reacting polyprenylacetone represented by [Armita? , J. B et al. J. Chem. SOC. 4
4 (1951)].

Conventionally, various antihypertensive agents have been used for the purpose of treating hypertension, but these drugs 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 drugs such as reserpine and methyldopa preparations cause dry mouth and Vasodilators such as apresolin often have side effects such as headache, tachycardia, and angina pectoris, while vasodilators such as apresoline often have side effects such as disturbance of consciousness and orthostatic hypotension. We searched for a safer antihypertensive agent that does not have these drawbacks, and found the compound (1) 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 O Blood Pressure Lowering Effect of Okamoto and Aoki on Spontaneous Hypertensive Rats (hereinafter abbreviated as 1SHR) [Method] The blood pressure lowering effect of the test compound on SHR of Okamoto and Aoki was measured.

Is SHR chronic hyperemia at about 40 weeks old? HR was used. The systolic blood pressure was around 0,240 mHy. 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, and five experimental animals were divided into 50m91k9 administration groups depending on the dose of the test compound, and a control group was also administered with only an aqueous solution of gum arabic.

Four experimental animals were used in each group. Administration: once a day for 3
It was orally administered continuously for 1 day. Blood pressure was measured before administration and at the first
Changes in blood pressure were observed at 6 hours, 24 hours (second administration), 7 hours (third administration), and 7 hours after each administration.

[Test compound]

2,6,10.14,19,23,27,31-octamethyl-2,6,10,22,26,30-dotriacontahexene-15,17-diyne-14,19-diol (hereinafter referred to as compound A) [Results] In Okamoto and Aoki's SHR, compound A5O7yl9l
kg was administered orally for 3 consecutive days to a group of experimental animals.
As shown in the figure, a clear blood pressure lowering effect was observed.

That is, the control group (blood pressure at the start of the test 240Tn!
NHg), 246,717 even after 3 days of the experimental period.
7! In contrast, in the administration group (blood pressure at the start of the test 239?Hy), the blood pressure was 210 TIr!6 hours after the first administration. NHyl same 2
After 4 hours (at the time of the second administration), the blood pressure was 223 wunHy, and after the same 3 hours (at the time of the third administration), the blood pressure was 210 wunHy, indicating that it had a sustained blood pressure lowering effect. As is clear from the results of the above pharmacological and toxicity tests,
The compound (1) of the present invention, represented by Compound A, has an excellent antihypertensive effect and exhibits almost no toxicity, so it is extremely safe.

Therefore, the compound (1) 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. Compound (1) of the present invention
The administration method and dosage depend on the symptoms to be treated.
Although it can be selected and adjusted as appropriate, for oral administration in adults,
10 to 200 m9 per day, preferably 50 to 100 m9. Compound (1) of the invention can be prepared for administration using conventional formulation techniques. Therefore, the present invention also includes a pharmaceutical composition containing at least one compound represented by formula (1), which is suitable as a human medicine. 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 single-position dosage forms, with binders such as syrup, acacia, gelatin, sorbitol, tongacanth, or polyvinylpyrrolidone, excipients such as lactose, sugar, corn starch, calcium phosphate, sorbitol, 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. 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 a dry product 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, glucose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated Edible fats, emulsifiers such as lecithin, zorbitan moqualate 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, propyl p-hydroxybenzoate. Alternatively, it may contain 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 formulating agents such as suspending, stabilizing, and/or dispersing agents. good. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use. Next, the present invention will be explained with reference to examples.

Example 1] 2, 6, 10, 14, 19, 23, 27, 3
1-octamethyl-2,6,10,22,26,30-
dotriacontahexene-15,17-diyne-14,
19-Dionole 250ml of liquid ammonia at -50℃
While cooling, add 4.6y of sodium metal and stir for 1 hour.

Next, 6.2y of 1,4-dichlorobutin-2 was added dropwise in 3 powders, and stirring was continued for 1 powder under the same conditions. 27g of phalnesyl acetone and 33g of dry ethyl ether
Dissolve in 0ml and drop into the solution prepared earlier. After the addition was complete, the reaction mixture was kept overnight at -50°C, and then the ammonia was distilled off. The residue is dissolved in 200 mL of n-hexane and then washed with water. The organic solvent layer is separated and concentrated under reduced pressure to obtain an orange-yellow oily substance, which is purified by silica gel chromatography using a mixed solvent of ether/n-hexane as an eluent to obtain the desired product as a pale yellow oily substance. Yield 9
f elemental analysis value: C4OH62O2MAS spectrum measurement value: M+574 IR spectrum measurement value: (Crn-1) 3350 (0
H), 2950, 2200, 1640, 1450, ″1
378,1128,1030,900 NMR spectrum measurement value: (CDCl3, ppm) Example 2] 2,6,1
0,14,18,23,27,31,35,39-decamethyl-2,6,10,14,26,30,34,38
-tetracontaoctaene-19,21-diyne-18
, 23-diol 1,4-dichlororubutin-2 and geranylgeranylacetone are reacted according to Example 1].

The desired product is obtained as a pale yellow oil. Elemental analysis value: C5O
H76O2'~Vl4lU=◆~Rv'ν甐? VA 蕃v●●t'M
AS spectrum measurement value: M+708IR spectrum measurement value; (C77!-1) 3350 (0H), 2950,
2200, 1640, 1450, 1378, 1128,
1030,900 NMR spectrum measurements: (CDCl
3, ppm) Next, 2, 6, 10, 14, 1S23, 2
7,31-octamethyl-2,6,10,22,26,
A formulation using 30-dotriacontahexaene-15,17-diyne-14,19-diol (hereinafter referred to as the main drug) is provided as an example.

Example 3 Capsules The above ingredients were granulated by method I, and then filled into 1000 hard capsules.

One capsule contains 5mg of the main drug.

Example 4 Powder The main ingredient was dissolved in acetone, then adsorbed onto microcrystalline cellulose, and then dried.

This was mixed with corn starch and a powder was prepared as the main drug, 2 Kosan, by a conventional method. Example 5 Tablet
The main agent of the agent was dissolved in acetate, and then adsorbed onto microcrystalline cellulose, followed by drying.

Corn starch, lactose, and carboxymethylcellulose calcium were mixed therein, and then an aqueous solution of polyvinyl-7-lpyrrolidone was added as a binder and granulated by a conventional method. After adding talc as a lubricant and mixing, the mixture was compressed into tablets of 100 m9 each. One tablet contains 5mg of the main drug.

Example 6 The main drug for injection, NikkOlHCO-60, sesame oil, and half the amount of propylene glycol were mixed and dissolved by heating at about 80°C. To this was added distilled water in which phosphate buffer, sodium chloride, and propylene glycol had been dissolved in advance. The mixture was heated to 80'C and added to make an aqueous solution with a total volume of 1000ml.

This aqueous solution was dispensed into 2 nt ampoules, which were melted and sterilized by heating. One tube contains 20m9 of the active ingredient.

[Brief explanation of the drawing]

Figure 1) Compound 2 of the present invention was administered to spontaneously hypertensive rats.
6,10,1.4,19,23,27,31-octamethyl-2,6,10,22,26,30-dotriacontahexene-15,17-diyne-14,19-diol (hereinafter referred to as compound A) This shows the blood pressure lowering effect when administered.

Claims (1)

[Claims] 1 The following general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is ▲There are mathematical formulas, chemical formulas, tables, etc.▼The chain is n
represents an integer 3 or 4. Diyne polyprenyl alcohol 2 2,
6,10,14,19,23,27,31-octamethyl-2,6,10,22,26,30-dotriacontahexene-15,17-diyne-14,19-diol Diyne polyprenyl alcohol according to item 1. 3 2, 6, 10, 14, 18, 23, 27, 31, 3
5,39-decamethyl-2,6,10,14,26,3
0,34,38-tetracontaoctaene-19,21
The diyne-based polyprenyl alcohol according to claim 1, which is -diyne-18,23-diol. 4 The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ The chain is n
represents an integer 3 or 4. A hypotensive agent containing diyne polyprenyl alcohol represented by: