JPS60123418A - Vasodilator - Google Patents

Abstract

PURPOSE:To provide a vasodilator containing a specific 2-(2-substituted-2-phenylethyl)-2-imidazoline, having characteristic alpha2-receptor antagonistic effect and carotid artery blood flow increasing effect, and useful especially as a cerebral and peripheral circulation improver. CONSTITUTION:The objective vasodilator contains the 2-(2-substituted-2-phenylethyl- or 2-(2-substituted-2-phenylethenyl)-2-imidazoline of formula I [R is group of formula II or formula III (X is phenyl or pyridyl)] or its acid addition salt. The compound of formula I is known as a blood sugar depressing agent and a blood platelet coagulation inhibitor, however, it has been found newly that the compound has excellent characteristic adrenergic alpha2-receptor antagonistic effect and carotid artery blood flow increasing effect compared with yohimbine, and is useful as a vasodilator. Dose: 10-500mg daily in 1-3 divided doses usually by oral administration.

Description

Detailed Description of the Invention The present invention relates to 2-(2-substituted-2-phenylethyl- or 2-substituted-2-pyridyl) represented by the general formula (1) (X is a phenyl group or a pyridyl group). The present invention relates to a vasodilator containing ethynyl)-2-imidazoline or an acid addition salt thereof.

The compound represented by the formula (I) is known as Chem, Pharm,
Bull.

Disclosed in Volume 28, Page 1894 (1980), 1511
No. 65, JP-A-52-156932.

J, Chem, Soc, 1950, p. 188 and J, Am.

If it is disclosed in Ohem, Soc, Vol. 75, p. 2968, it is a known compound disclosed in JP-A-54-79279.

However, the above literature only discloses a method for synthesizing the compound of formula 2 (1) and its hypoglycemic, antiplatelet aggregation, and antihistamine effects. Also, the description regarding the compound of formula (1) is as follows.

There are no other examples other than the above literature.

Regarding the pharmacological action of the compound of Formula 9 (1), the present inventors have
Further, as a result of intensive studies, we confirmed completely unexpected new pharmacological effects, namely, adrenergic pseudo-receptor antagonism and carotid artery blood flow increasing effect with excellent and specificity, and completed the present invention. .

That is, the compound represented by Formula 1 (1) can be said to have unprecedented characteristics as a vasodilator, especially a brain and peripheral circulation improving agent, due to the pharmacological action described above.

The excellent biological activity of the compound represented by formula (1) will be specifically explained below.

1. Adrenergic α2-receptor antagonism α2-receptors present in synaptic structures have an inhibitory effect on the release of transmitters from nerve terminals. α2-receptors also exist in the sympathetic nerves that control the mesenteric artery, and the sympathetic contraction response induced by transmural electrical stimulation is
It is partially suppressed by free leradrenaline itself. Yohimbine, which is an α2-receptor antagonist, blocks this synaptic formation of α2-receptors, so that the sympathetic contraction response is enhanced. Similarly to yohimbine, the compound represented by formula (1) also enhanced the sympathetic response evoked by transmural electrical stimulation in canine mesenteric artery specimens. About this.

This suggests that the compound of formula (1) has α2-receptor antagonistic activity. This was also supported in experiments using rat vas deferens. That is, when the rat vas deferens is electrically stimulated transmurally, a contraction response is observed, but this response is suppressed by clonidine, an α2-receptor stimulant. Clonidine inhibits synaptic formation by stimulating α2-receptors.

The compound of formula (I) and yohimbine antagonize the α2-receptor stimulating effect of noclonidine.

It showed a potentiating effect on listed i.

Based on the above facts, it was considered that the compound of Formula 1 (1), like yohimbine, has an antagonistic effect on α2-receptors in synapse formation.

On the other hand, the compound of Formula 9 (1) had no effect on α1-tibe receptors mediated in the postsynaptic membrane of the canine mesenteric artery. This was proven by the following experiment. That is,
Exogenous noradrenaline acts on α1-receptors distributed in the postsynaptic membrane of the mesenteric artery to induce contraction. This contractile response was antagonized by prazosin, a known α1-receptor antagonist. On the other hand, the compound of formula (1) had no antagonistic effect at all. Furthermore, yohimbine, which is known as an α2-receptor antagonist, is an α1-receptor antagonist.
- It was found that it acts on the receptor and inhibits noradrenaline contraction.

Based on the above facts, the compound of formula (1) was considered to be an adrenergic α2-receptor antagonist with higher specificity than yohimbine, which is conventionally known as an α2-receptor antagonist. Furthermore, this adrenergic α2-receptor antagonism.

It was confirmed in experiments on the basilar artery that α2-receptors are also present in the postsynaptic membrane. That is, noradrenaline induces a contractile response to the α2-receptor present in the postsynaptic membrane of the basilar artery, but the compound of formula (1) suppressed this contractile response in a dose-dependent manner.

■ Carotid artery blood flow increasing effect When the compound of formula (1) was intravenously administered to cats and the carotid blood flow was measured after administration, an increase in blood flow was observed.
) was confirmed to have a vasodilatory effect.

As described above, the compound of Formula 9 (1) was excellent. These compounds also have a specific vasodilatory effect, as disclosed in JP-A-52-151165,
All have low toxicity. (Table 1) Although the vasodilator of the present invention can be made into an injection, it is usually administered orally, and the dose for adults is 10 to 500 m9 administered once to a day. It is preferable to do so. In addition, the vasodilator of the present invention is orally administered (preferably made into tablets, capsules, powders, etc. by known formulation methods, and these are usually prepared using suitable binders, excipients, disintegrants, etc.). may be included.

Table 1 Acute Toxicity Rat (oral) 1.) No fatalities after administration of 300F''9/~ Next, the present invention will be explained with reference to Examples.

Example 1 Specimens of mesenteric artery and basilar artery spiral pieces removed from an adult mongrel dog and rat vas deferens (each approximately 15 mm in length,
2 mm). That is, the specimen was suspended in the cisternae.

Changes in tension were recorded isometrically. (Reaction solution Krebs
HOnseleit solution, pH 7, 4, 81°C 10-
(containing 6M propranolol) (a) A spiral specimen of the coloperiosteal artery was heated at 3 to 80 Hz (I
When transmural electrical stimulation was performed at a frequency of OV, 5 seconds), a transient sympathetic contraction response was observed. In this contraction reaction system, formula 9 (
Compounds A, B, and C as representative examples of compounds in 1) and yohimbine as a control drug were added to the reaction solution 20 minutes before transmural electrical stimulation, and their effects on the contractile response were examined. The results are shown in Table 1.2 The compound of formula <1> has the ability to enhance the contractile response caused by transmural electrical stimulation based on α2-receptor antagonistic action, similar to yohimbine, which is known as an α2-receptor antagonist. was recognized.

Table 2 Effects on mesenteric artery red wall electric ablation *Compound treatment 11″-″; Previous transmural electric ablation lI1. (:3 H2)
The height of the contraction caused by this is taken as 100%.

(b) The t+'J tube was divided into two, and the prostatic side was used for the experiment. After suspending the ring shield in the anterior tank containing the same reaction solution as in (a), transmural electrical stimulation (Single Pu1
seO-8m5ac, )4', a contraction reaction was observed. When clonidine (1-8M), a χ2-receptor stimulant, was added to this system, the electrical stimulation-induced contraction reaction was suppressed.Compounds A and B of formula (1) Pretreatment of yohimbine as a reference compound with R:C antagonizes the inhibitory effect of clonidine.

It has become clear that this is based on α2-receptor antagonism. Table 8 shows the pAz value of each compound.

Table 8: Antagonistic effect of clonidine on contraction of rat vas deferens (c) Using Peng's membrane arterial specimen, the effect of Compound A on the post-synaptic abdominal α-receptor stimulation by noradrenaline (111p) was investigated.

That is, the same experimental conditions as in (a) were used, and noradrenaline was used as the contractile agent. noradrenaline is 1
Vascular strips were contracted at concentrations of 0-8 to 10''-'M.

The compound had no effect on this noradrenaline contraction at concentrations of 10-8×10 M. Yohimbine and the α1-receptor antagonist prazosin used as a control inhibited /luadrenaline contraction in a dose-dependent manner, and the antagonistic mode was competitive. Table 4 shows the results.

Table 4 Effect of noradrenaline on contraction of canine mesenteric artery 1) No antagonistic effect on noradrenaline at concentrations of lo-7 to axto M d) Experiments were conducted using canine basilar artery specimens.

After suspending the specimen in a pre-tank containing the same reaction solution as above, 1
When noradrenaline is added to the reaction solution, 10-8 to 1
A dose-dependent contractile response was observed at a concentration of 0''M.

Add compound A to the pre-tank.

The influence on the contraction response was divided horizontally. The results are shown in Table 5. Compound A inhibited noradrenaline-induced blood clot contraction at concentrations of 10-6 and io-5M.

Table 5 Antagonistic effect on noradrenaline contraction of dog basilar artery 1) 100% contraction by noradrenaline 10””M
shall be.

Example 2 A male cat (body weight 1.6-8.6 9) was treated with α-chloralose (50 m/kgr 1 p) and urethane (250 m/kgr 1 p).
M/kgl ip) After anesthesia, compound A1r
n9/'+9 was administered intravenously, and carotid blood flow was measured using an electromagnetic flowmeter. As shown in Table 1, the carotid blood flow increased immediately after administration, and also showed an increasing tendency 20 minutes after administration.

Table 6 Effect on carotid blood flow in anesthetized cats The target compounds of the present invention used in Examples 1 and 2 are as follows.

Compound 1 A: 2-[2-phenyl-2-(2-pyridyl)ethyl)-
2-Imidacillin dihydrochloride 1.5 ice crystal compound +3: 2-(2,2-diphenylethyl)-2-imidacilline hydrochloride compound C: 2-(2,2-diphenylethynyl)-2- imidacillin hydrochloride

Claims (1)

[Scope of Claims] 2-(2-position@-2-7-nylethylumo L<ha2-
Vasodilator (2) containing 2-(2-phenyl-2-(2-pyridyl)ethyl-2-imidacillin or its acid addition salt) A vasodilator according to claim 1