JPH03130218A - Uterus-relaxing agent and bladder-relaxing agent - Google Patents

Abstract

PURPOSE:To provide a uterus-relaxing agent free from side effects, having both uterus and bladder relaxing effects, containing, as active ingredients, a benzyl alcohol derivative and its acidadded salt. CONSTITUTION:The objective agent containing, as active ingredients, a compound of the formula and its acid-added salt. Said salt is e. g. a mineral acid (e.g. HCl, H2SO4) salt or organic acid (e. g. maleic acid, fumaric acid) salt. Both the active ingredients can be prepared into pharmaceutical(s) such as tablets, capsules, powders, granules for oral administration, injections or suppositories, etc., through conventional process using additives for the preparation to be used, in general, as medicines. The dose of the present active ingredients is normally ca. 0.01-10mg/day per adult.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a uterine relaxant and a bladder relaxant, which contain as active ingredients a benzyl alcohol derivative represented by the following formula and its pharmacologically acceptable acid addition salt.

BACKGROUND ART The benzyl alcohol derivative represented by the above formula (I) is
This compound was synthesized for the first time by the applicant, and as it has an excellent bronchodilatory effect based on the adrenergic β2-receptor stimulating effect, it is expected to be used as a therapeutic agent for obstructive airway diseases such as bronchial asthma. [Special Public Service 1977-
Publication No. 6625].

However, the usefulness of the compound represented by the formula (I) as a uterine relaxant and a bladder relaxant is not described in the above-mentioned patent publication, and has been completely unknown until now.

Since threatened preterm labor is associated with risks such as premature birth and perinatal death, it is extremely important to treat and manage threatened preterm labor. Although there are still many unknowns about the causes of preterm labor, the majority of preterm labor is caused by early uterine contractions, so drugs that relax the uterus can be expected to be used to treat it.

Traditionally, for this purpose, the progestin preparation, isoxsuprine [The MerckIndex
dex), 10th edition, 5081 and Ritodrine (The Merck Index, 1
0 version, 8121) etc. have been used, but it is thought that there is room for improvement in terms of effectiveness and side effects.

In addition, urinary disorders in which urine leaks involuntarily, such as urinary incontinence and nocturnal enuresis, have been on the rise in recent years, but since all of these disorders are accompanied by an increase in intravesical pressure (contraction of the bladder), treatment is necessary. The use of bladder relaxants can be expected.

Means for Solving the Problems As a result of intensive research in view of the above circumstances, the present inventors have found that the benzyl alcohol derivative represented by the above formula (I) has not only a bronchodilatory effect but also can be used to treat conditions such as threatened premature labor. The present inventors have discovered that this drug has a uterine relaxing effect and a bladder relaxing effect useful for treating urinary incontinence, nocturnal enuresis, etc., and has fewer side effects such as cardiac stimulation, and has completed the present invention.

Examples of the pharmacologically acceptable phosphoric acid addition salts of the benzyl alcohol derivative represented by formula (I) of the present invention include mineral salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Acid acid, or acetic acid, maleic acid, fumaric acid, citric acid, oxalic acid, malic acid, methanesulfonic acid,
Examples include organic acid salts such as p=toluenesulfonic acid, mandelic acid, 10-camphorsulfonic acid, and tartaric acid.

The benzyl alcohol derivative represented by the formula (r) of the present invention and its pharmacologically acceptable acid addition salt can be prepared into tablets and capsules by conventional methods using formulation additives commonly used as pharmaceuticals.

Powders, granules, fine granules 5 It can be made into oral preparations such as syrups and dry syrups, injections, and halved preparations. Pharmaceutical additives include excipients (sucrose, sugar,

Lactose, D-mannitol, corn starch.

hydroxypropyl starch, crystalline cellulose, etc.).

Disintegrants (carboxymethylcellulose, carboxymethylcellulose calcium, etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.).

Lubricants (magnesium stearate, talc, etc.).

Pharmaceutical ingredients such as coating agents (hydroxypropyl methylcellulose, sucrose, etc.), bases (polyethylene glycol, hard fat, etc.), and in the case of injections, solubilizers or solubilizers that make up the aqueous or ready-to-dissolve injections. Solubilizing agents (distilled water for injection, physiological saline, propylene glycol, etc.).

Pharmaceutical ingredients such as pH adjusters (inorganic acids, organic acids or inorganic bases), stabilizers, tonicity agents (sodium chloride, glucose, etc.) are used.

The main dosage for treatment patients depends on the patient's symptoms, but
Normally, for adults, the daily dose is about 0.01 to 10 mg.

Effects The excellent effects found by the present invention will be explained below using test examples.

Test Example 1 Uterine relaxation effect in isolated rats The uterus was removed from a nulliparous, non-pregnant Wistar rat (weighing around 200 g), and a specimen with a length of 15 mm was prepared.

The specimen was prepared using a modified Locke-Ringer solution (composition: NaCl) through which a gas mixture of 95% 02 and 5% CO□ was aerated.
, 150; KCl, 5.4; Ca1l! , 0.3
6; MgC1z, 0.19; NaHCOs, 4.
8; KH2PO4,0,15; NatHPO4,o,
56; Glucose.

The relaxing effect of the test compound on the contraction of oxytocin (10-, "U/rn" was measured isodominantly. The test compound was suspended in a solution bath (37°C). The effect of the test compound was 50% when the relaxation response of 10-''M isoproterenol was taken as 100%.
It was expressed as the concentration required for % relaxation (EDso value).

The results are shown in Table 1.

Table 1 As is clear from Table 1, the compound of the present invention has a uterine relaxant effect approximately 14 times stronger than that of Hitodrine, and is an extremely useful compound as a uterine relaxant.

Test Example 2 Extracted Rabbit Bladder Relaxation Effect The bladder was removed from a male Japanese white rabbit (weighing approximately 2.7 kg), and a specimen measuring 10 mm in length and 3 mm in width was prepared from the bladder body. The specimen was a Krebsu-Henseleit solution (composition: NaC) through which a mixed gas of 95% 02 and 5% CO2 was aerated.
1,118; KCI, 4.7; CaC1x, 2.5
5; MgSO4゜1,18; KH*PO4,1,18;
NaHCOs, 24.88; Glucose, 11
．． A load of 0.5 g was suspended in a bath (37° C.), and the resting tension was measured isometrically.

Test compounds were applied cumulatively into the bath. The effect of the test compound was to suppress the relaxation response of 10-'M isoproterenol by 100
%, the concentration required for 50% relaxation (E
D so value).

The results are shown in Table 2.

Table 2 As is clear from Table 2, the compound of the present invention exhibits a strong bladder relaxing effect and is an extremely useful compound as a bladder relaxant.

Test Example 3 Effect on isolated guinea pig atrium (heart rate) The heart was extracted from a male Hartley guinea pig (weighing approximately 500 g), and a right atrium specimen was prepared.

The specimen was suspended in a Krebs-Henseleit solution bath (30° C.) through which a mixed gas of 95% COt and 5% COt was aerated, and the heart rate was measured. Test compounds were applied cumulatively into the bath.

The effect of the test compound is to reduce the heart rate by 50% before applying the test compound.
It is expressed as the concentration required to increase the concentration by % (E D s. value).

The results were evaluated for uterine and bladder relaxation selectivity (vs. heart rate increase).
Table 3 shows the values of .

Example 1 Capsules are manufactured according to the following formulation.

Compound of the present invention 0.25mg lactose
Mix an appropriate amount of 45 mg or more of corn starch using a conventional method.

As is clear from Table 3, the compound of the present invention, which is packed in a 30 mg hard capsule, has few side effects such as cardiac stimulation, and is an extremely useful compound as a pharmaceutical with excellent uterine or bladder relaxation selectivity.

Example 2 Tablets are manufactured according to the following formulation.

Compound of the present invention 0.25mg lactose
Appropriate amount Corn starch 30mg Examples The present invention will be explained below with reference to Examples, but the present invention is not limited to the specific details of these Examples.

Example 3 Granules are manufactured according to the following formulation.

Compound of the present invention 0.5B lactose
Appropriate amount Hydroxypropyl starch 200mg Hydroxypropylcellulose 20mg Talc
5mg appropriate amount of distilled water for injection Example 6 A half-open bottle is manufactured according to the following formulation.

Compound of the present invention 0.25 mg Hard fat 1299.75 mg Example 4 A dry syrup preparation is produced according to the following formulation.

Compound of the present invention 0.5mg white sugar Appropriate amount Example 5 An injection is manufactured according to the following formulation.

Compound of the present invention: 2.5 mg Sodium chloride: 40 mg Effects of the Invention According to the present invention, a new pharmaceutical product containing a benzyl alcohol derivative or its pharmacologically acceptable acid addition salt as an active ingredient is provided.

That is, the benzyl alcohol derivative represented by the formula (1) of the present invention or its pharmacologically acceptable acid addition salt has an excellent uterine relaxant effect and bladder relaxant effect, and is used as a uterine relaxant and a bladder relaxant. Very useful as a relaxant.

Claims (2)

[Claims] (1) A uterine relaxant containing as an active ingredient a benzyl alcohol derivative represented by the formula (numerical formula, chemical formula, table, etc.) and its pharmacologically acceptable acid addition salt. (2) A bladder relaxant containing as an active ingredient a benzyl alcohol derivative represented by the formula (numerical formula, chemical formula, table, etc.) and its pharmacologically acceptable acid addition salt.