JPH03215423A - Vasodilator - Google Patents

Abstract

PURPOSE:To obtain a vasodilator containing wortmannin as an active ingredient and useful as treating agent of hypertension and ischemic heart disease. CONSTITUTION:The objective vasodilator containing wortmannin expressed by the formula as an active ingredient and obtained by properly blending wortmannin further with vehicle for preparation, lubricant, binder, disintegrator, suspension, isotonic agent, emulsion, absorption accelerator, carrier, etc., ordinarily employed, and formulating the blend according to ordinary method. The objective vasodilator can be prepared in the form of tablet, pill, inhalant, granule, capsule, suppository, injection, dropping injection, etc. The daily dosage is 0.01-2mg/kg/adult. The agent is effective on hypertension, occlusive arteriosclerosis, ischemic heart disease, transient ischemic shock, cerebral thrombosis, cerebral embolism, etc. The wortmannin is a metabolite of microorganism and has also antiphlogistic action.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel vasodilators. The vasodilator of the present invention is useful for treating hypertension, arteriosclerosis obliterans, ischemic heart disease, transient ischemic attack, cerebral thrombosis, emboli, and the like.

PRIOR ART Wortmannin, a metabolite of microorganisms, has been known to have anti-inflammatory effects [Bxperientia, Vol. 30, 135-
136, 1973], but other pharmacological effects are unknown.

Problems to be Solved by the Invention Pavaberine dilators, calcium antagonists, and β receptor stimulants are known as vasodilators, and are used as therapeutic agents for ischemic heart disease and hypertension. However, they are not necessarily satisfactory in terms of effectiveness, sustainability, side effects, etc., and there is a need for the development of even better vasodilators.

Means for Solving Problem M The present invention provides a vasodilator containing wortmannin represented by formula (1) as an active ingredient.

Wortmannin is Penicillium wor
tmannκ16cker is cultured in a medium, produced and accumulated in the culture, and purified and isolated from the culture [Transactions British Mycological Society (Trans.
, MycoSac, ) Volume 4Q, pp. 365-368, 1
957 and Journal of the Chemical Society (J. chem, Soc.) Perkin
I. Pages 2898-2903. 1972]
.

Next, the pharmacological effects of wortmannin will be explained using experimental examples.

Experimental Example 1 Antihypertensive effect in Spontaneous Hypertension Lab (SIIR) SHR (Japan Rat Co., Ltd., male, 12 weeks old) was anesthetized with 50 IIlg/kg of bentobarbital (Nembutal, manufactured by Dynapot) by intraperitoneal administration. Then, under artificial respiration, blood pressure was measured via a pressure transducer through a cannula inserted into the femoral artery. After blood pressure stabilized, 3 μmol/kg of wortmannin was dissolved in dimethyl sulfoxide (DMSO) at 300 JdI/k.
g was administered intravenously, and its hypotensive effect was observed. In addition, DMS0300/kg administration was used as a control.

The results are shown in Table 1.

As is clear from Table 1, wortmannin sustainedly lowered the blood pressure of SHR.

Table 1? Experimental Example 2: Inhibitory effect on contraction in rabbit thoracic aorta specimen After removing the thoracic aorta of a rabbit (male, weighing 2-3 kg), a helical strip specimen with a width of approximately 3 mm was prepared, and Taleb-Suhenseleit (κrebs- Henseleit) solution (composition: Na
Cj! 118mM; κCl 4. 75mM
; CaC1 22.54mM; MgSro4
1.19mM; NaHCOa 12.5m
M: κlbP04 1.19mM: Glucose 10. It was suspended in a Magnus tube filled with 0mM) with a load of 2g. The inside of the Magnus tube is kept at 32℃, and mixed gas (9
5% RO2 + 5% CO■) was bubbled through. The generated tension is measured using an isometric transducer (FD pickup T
B-6 12T, manufactured by Nihon Kohden Co., Ltd., and was measured isometrically and recorded on an ink-type pen recorder.

After the specimens were allowed to stabilize for over 60 minutes, contractions were induced with 40 mM κCl. When the contraction stabilized, wortmannin was added to Magnus and KCI! The inhibitory effect on contraction was investigated.

The results are shown in Table 2.

As is clear from Table 2, 40mM KCj! Wortmannin showed a clear contraction-inhibiting effect at 10 6 M.

Table 2 Wortmannin can be administered orally or parenterally as it is or as various pharmaceutical compositions. Dosage forms of such pharmaceutical compositions include, for example, tablets, pills, powders, granules, capsules, suppositories, injections, and drips.

Generally known methods are applied to formulate the above dosage form,
For example, it may contain various excipients, lubricants, binders, disintegrants, suspending agents, tonicity agents, emulsifiers, absorption enhancers, and the like.

Carriers used in pharmaceutical compositions include, for example, water, distilled water for injection, physiological saline, glucose, fructose,
White sugar, mannitol, lactose, starch, corn starch, cellulose, methylcellulose, carboxymethylcellulose, hydroxybupil cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin , sorbitan fatty acid ester, glycerin fatty acid ester, etc., and these are appropriately selected depending on the type of preparation.

The dosage used for the above purpose is determined depending on the desired therapeutic effect, administration method, treatment period, age, body weight, etc.; The dose is usually 0.01 to 2 mg/kg per day for adults, depending on the administration method.

The acute toxicity of wortmannin is 3-10 mg/kg when administered orally to rats [Experien Lia, Vol. 30, 135-1].
36 pages, 1974].

The new use of wortmannin according to the present invention is clearly distinguishable from the known use as an anti-inflammatory therapeutic agent in terms of the scope of use.

Next, embodiments of the present invention will be described with reference to Examples.

Example l Tablet Wortmannin 100g Lactose
40g cornstarch
18g carboxymethylseltos calcium
10g of the above mixture was added with 1O% hydroxybutylene cellulose solution and kneaded. This kneading solution was added to l. It was granulated using an extrusion granulator equipped with an O mm basket, and magnesium stearate was added to form pellets for tabletting, which were then prepared into 1 formulation (170 mg) using a conventional method.
The tablets were made into 8 mm diameter tablets containing 100 mg of wortmannin.

Example 2 Capsule Wortmannin 50. g-lactose
80g potato starch
A 10% hydroxypropylene cellulose solution was added to a mixture consisting of 38 g and kneaded. Granules were prepared in the same manner as in Example 1, magnesium stearate was added, and 1 capsule (1) was prepared by a conventional method.
A capsule containing 5 (]+g of wortmannin in 170 mg) was prepared.

Example 3 Soft Capsules Soft capsules containing 10 mg of wortmannin per capsule were prepared by dissolving 10 g of wortmannin in 100 g of soybean oil and injecting the resulting solution into capsules in a conventional manner.

Effects of the Invention Wortmannin, the active ingredient of the present invention, has a vasodilatory effect and is useful as a therapeutic agent for hypertension and ischemic heart disease.

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A vasodilator whose active ingredient is a compound (wortmannin) shown by (I) (2) A therapeutic agent for hypertension containing the wortmannin according to claim (1) as an active ingredient (3) A therapeutic agent for ischemic heart disease containing the wortmannin according to claim (1) as an active ingredient