JPH0495028A - Vasodilator - Google Patents

Abstract

PURPOSE:To obtain a vasodilator containing a dihydrofuroquinolone quaternary ammonium salt and salt thereof as active ingredients, having vasodilating action and useful to treatment and prevention of a circulatory disease. CONSTITUTION:The aimed vasodilator containing a compound expressed by the formula (R is H or OH; Me is methyl) and salt thereof as active ingredients. The compound expressed by the formula is obtained by isolation from Lunasia costulata Mig., etc., of Rutaceae according to ordinary method or obtained by chemical synthesis. The compound expressed by formula is dosed at an amount of 0.1-1000mg/adult day in the case of oral administrating agent and is preferably mixed at an amount of 0.1-10wt.% in the case of ointment, cream agent, hair-restoring agent, hair tonic and bathing agent.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a vasodilator containing dihydrofloquinoline quaternary ammonium or its salt as an active ingredient. It can be used for the treatment and prevention of diseases.

[Prior Art] Dihydrofloquinoline quaternary ammoniums are alkaloids that are biosynthesized from anthranilic acid, along with floquinolines (including floquinolones), quinolines (including quinolones), acridine (including acridone) 11, etc. It is a component unique to plants of the Rutaceae family.

In addition, plants of the Rutaceae family containing the above-mentioned alkaloids are used as folk medicine for purposes such as carminative, diuretic, expectorant, and mesogenic effects.

In addition, the compound in which R is a hydrogen atom in the quaternary ammonium dihydrofloquinoline represented by Shipin (1) below is called Lunasine, and is published in the Australian Journal of Chemistry (＾us
talarian Journal of Chemi
stry).

1959.41.458, and the Journal of the American Chemistry Society.
of＾-erican Chemical 5ocie
ty), t9s9. Compounds in which R is a hydroxyl group are also called balfourodinium, and are known as phytochemistry.
, 1979 [, tSS et al.

In addition, in recent years, new vasodilators such as sympatholytic agents, prostaglandin preparations, and calcium antagonists are being developed.

[Question H to be solved by the invention] However, the reality is that little is known about the pharmacology of alkaloids having a floquinoline ring as their core. There is no mention of the quaternary ammonium dihydrofloquinoline having a vasodilatory effect.

In addition, with regard to the vasodilators that have been developed in recent years, problems such as side effects have been highlighted as the efficacy of their main action has been increased, and there is a demand for the development of safe and highly effective vasodilators. ing.

Therefore, an object of the present invention is to meet the above-mentioned needs, that is, to provide a vasodilator that is safe and has a strong vasodilatory effect.

[Means for Solving the Problems] In order to achieve the above object, the present inventors conducted intensive research on Japanese and Chinese herbal medicines, Mexican herbal medicines, Philippine herbal medicines, etc., and as a result, they discovered that Lunasia costulata (Lunsia costulata), a member of the Rutaceae family, was found.
asia costulata Mig.
ta) and Abeloa bilimbiel of the Oxalis family, blood r.
It has been found that crude extracts of plants such as rhoa Bilimbi L.) have strong vasodilatory activity.

Therefore, the present inventors isolated a specific quaternary ammonium dihydrofloquinoline from the crude extract and examined the vasodilatory activity of this isolate, and found that it had an extremely strong vasodilatory effect.

The present invention has been made based on the above findings, and provides a vasodilator characterized by containing a dihydrofloquinoline quaternary ammonium represented by the following (1) or a salt thereof as an active ingredient. It is.

Me (wherein R represents a hydrogen atom or a hydroxyl group, and Me represents a methyl group) The vasodilator of the present invention will be described in detail below.

Said-Funenin (1) which is an active ingredient of the vasodilator of the present invention
Dihydrofloquinoline quaternary ammonium represented by Lunasia cosulata 7 costu of the Rutaceae family.
Lata Mig,), Lunasia Querifolia Dan 1 Call L Punishment Study μ Engineering ■Gekimasha and Coixia Ternata (
Abeloa (Oxalis ternata) and Oxalis avelor
It can be isolated by conventional methods from plants such as Bilimbi L., 7 Bilimbi L.), etc.

In addition, the dihydrofuroquinoline quaternary ammonium is
It may be obtained by chemical synthesis, and its manufacturing method is as follows:
Tetrahedron vol, 4
0. k18. Synthesis methods disclosed in literature such as P.3431, 1984 can be used.

Further, examples of the salts of the quaternary ammonium dihydrofloquinoline, which is the active ingredient of the vasodilator of the present invention, include salts formed with counter ions such as hydroxide, halide, lower carboxylate, barchlorate, and bicrate. .

The vasodilator of the present invention containing the above-described quaternary ammonium dihydrofloquinoline or its salt can be easily produced by using conventional pharmaceutical methods.

For example, in the case of oral administration, dihydrofloquinoline quaternary ammonium represented by the above-mentioned shipman (1) or its salt (hereinafter sometimes referred to as dihydrofloquinoline quaternary ammoniums) is mixed with kaolin, talc, etc. It may also be made into tablets, powders, granules, and capsules in a conventional manner using carriers such as lactose, starch, and crystalline cellulose. It is also possible to mix the dihydrofloquinoline quaternary ammoniums with vaseline, lanolin, plastisol hese, emulsion base, etc. to form ointments and creams. Furthermore, the dihydrofloquinoline quaternary ammoniums can be made into an injection as a water-soluble preparation together with a nonionic surfactant and the like.

In addition, the vasodilator of the present invention can be used as a hair growth/hair tonic agent, bath additive, etc. based on its blood circulation promoting effect, and when used as a hair growth/hair tonic agent, it can be used externally as a tonic agent using a solvent such as alcohol. It can be used as a bath additive, and when used as a bath additive, it can be mixed with ordinary bath additive ingredients.

The content of the dihydrofloquinoline quaternary ammoniums in the vasodilator of the present invention varies depending on the dosage form and use of the vasodilator, and cannot be determined unconditionally, but usually, when administered orally, the content is 0.1~1000+ag
/Adults, 0.1 to 1 for ointments and creams
It is preferably 0% by weight, 0.1-10% by weight when used as a hair growth agent, and 0.1-10% by weight when used as a bath additive.

[Effect]

According to the vasodilator of the present invention, the vasodilatory action of the quaternary ammonium dihydrofloquinoline represented by the above-mentioned shipman (1) or its salt contained as an active ingredient lowers blood pressure, improves peripheral circulation, and promotes blood circulation. can be achieved.

〔Example〕

Next, the present invention will be specifically explained with reference to Examples showing the effects of the vasodilator of the present invention.

Example 1 SD male rats weighing 150 to 200 g were anesthetized with sodium thiobental, and thoracotomy was performed to quickly remove the median aorta. Furthermore, after removing excess connective tissue etc. with tweezers etc., the specimen was cut into a length of 1 to 2+ ma. Using this blood vessel fragment as a material, the vasodilatory activity of the test substances shown in Table 1 below was measured by the Magnus method using an isotonic transducer. That is, the blood vessel fragment was treated with a physiological nutrient solution (PSS, Hepes buffer, pH 7,
4) After stabilizing for a while under oxygen gas ventilation, KC
The inhibitory effect of the test substance on the vasoconstriction response caused by the addition of L was defined as vasodilatory activity.

(Measurement results) 50% inhibitory activity concentration (ID
,. values) were as shown in Table 1 below.

Notes to Table 1] *1 A salt formed by the compound of the above-mentioned shipman (1) in which R is a hydrogen atom and Cl2-.

*2 A salt formed by the compound in which R is a hydroxyl group in the above-mentioned -Funenin (1) and Cl-.

From the results shown in Table 1 above, it can be seen that dihydrofloquinoline quaternary ammoniums, which are the active ingredients of the vasodilator of the present invention, exhibit extremely strong vasodilatory activity against depolarizing vasoconstriction.

Example 2 - Blood pressure: 6 male rats with spontaneous hypertension were used in each group, and the test started at 7.
50 days before administration of heparin sodium under thiobental anesthesia
Insert a cannula filled with 0 U/d into the abdominal aorta,
The other end was sealed and guided to the back of the neck and fixed. On the day of the test, the cannula was connected to a blood pressure monitor (manufactured by Nihon Denki Sanei ■, 45363), and blood pressure was recorded without anesthesia. Physiological saline (vasodilator of the present invention) containing 10 d/kg of dihydrofloquinoline quaternary ammoniums shown in Table 2 below was injected intraperitoneally, and blood pressure was measured over time. A control group was injected with the same amount of physiological saline for comparison.

(Test results) The test results are shown in Table 2 below.

Notes to Table 2] *1 The salt formed by the compound in which R is a hydrogen atom and C1- in the above - Shipman (1) is 101111! /kg of physiological saline.

*2 Physiological saline containing 1Od/kg of the salt formed by the compound in which R is a hydroxyl group and Cj2- in the above-mentioned - Shipman (1).

As can be seen from the results shown in Table 2 above, the dihydrofloquinoline quaternary ammonium-containing physiological saline (vasodilator of the present invention) exhibited a significant hypotensive effect. This is thought to be due to the strong vasodilatory action of dihydrofloquinoline quaternary ammoniums, which are the active ingredients of the vasodilator of the present invention, as shown in Example 1.

Example 3 ・I. As a result of oral administration of quaternary ammonium dihydrofloquinoline, which is an active ingredient of the vasodilator of the present invention, to male IcR mice, LD was observed. The values are shown in Table 3 below, and the safety of the vasodilator of the present invention was confirmed.

Notes to Table 3] *1 A salt formed by the compound in which R is a hydrogen atom in the above-mentioned shipman (I) and C1-.

*2 A salt formed by the compound in which R is a hydroxyl group in the above-mentioned -Funenin (1) and Cl-.

[Effects of the Invention] The vasodilator of the present invention has a safe and strong vasodilatory effect, and has effects such as lowering blood pressure and improving peripheral circulation. In addition, for external use on the skin, it can also be used as a hair nourishing agent and bath additive based on its blood circulation promoting effect.

Claims (1)

[Scope of Claims] A vasodilator characterized by containing a dihydrofloquinoline quaternary ammonium represented by the following general formula (I) or a salt thereof as an active ingredient. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a hydrogen atom or a hydroxyl group, and Me represents a methyl group.)