JPS6151568B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a therapeutic agent for peptic ulcers containing a benzothiazepine derivative or a physiologically acceptable acid addition salt thereof as an active ingredient. BACKGROUND OF THE INVENTION The following formula: Benzothiazepine derivative (chemical name: cis-(+)-3-(acetyloxy)-5-[2
-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one) and physiologically acceptable acid addition salts thereof is known to have a coronary vasodilatory effect [French patent no.
No. 8199M] and is marketed as a vasodilator under the generic name Diltiazem. Surprisingly, the inventors have demonstrated that diluteiazem (including its physiologically acceptable acid addition salts) has activity as a histamine _H2 -receptor antagonist; Therefore, they found that it is useful as a therapeutic agent for peptic ulcers and completed the present invention. Cimetidine, represented by the following formula, is conventionally well-known as a histamine H ₂ -receptor antagonist: Although diluteiazem, which is used as an active ingredient in the present invention, has a chemically completely different structural formula from cimetidine, it has the same histamine H ₂ -receptor antagonistic effect as cimetidine, and is far more effective than cimetidine. It shows activity that surpasses that of
This knowledge must be said to be a completely unpredictable new discovery. Deilteazem histamine H ₂ as above
-The fact that it has receptor antagonistic effects is proven by, for example, the following animal experiments. The necks of male and female guinea pigs (Hartley, 350-450 g) were broken and fractured, the whole heart was removed from the thoracic cavity, and the whole heart was removed from the thoracic cavity and placed in a salt solution (NaCl120, KCl5.6, CaCl) saturated with oxygen (95% _O2 , ₅ % CO2). ₂ 2.2, MgCl ₂ 2.1,
_{NaH2PO4 1.2} , _NaHCO3 25.0, glucose
10.0mM). The left and right atria were dissected separately from all attached tissue. The base of the right atrial appendage was mounted on a tissue support and a thread was threaded through the apex of each atrium. The specimen was transferred to a tissue bath containing 30 ml of the above oxygen-saturated salt solution (31°C) and placed in a force dis-placement transducer.
Connected to Grass FT.03 with thread. The average tension in this state was 0.5g. The right atrium was allowed to beat spontaneously. After 60 minutes of equilibration, the experiment was started. Histamine (1.0μM) in the right atrium of guinea pigs
When challenged, they showed a sustained positive chronotropic response. Using this preparation, the effects of diluteiazem (0.04 μM), cimetidine (0.3 μM) or their solvents (salt solutions) on histamine were tested. In three sets of guinea pig atria used to test diluteiazem (0.04 μM), cimetidine (0.3 μM), or their vehicle (salt solution), the initial spontaneous beat rates were 123 ± 10, 119 ± 8, and 119 ± 8, respectively. 95±beats/min.Histamine (1.0μ
M), the atrial beat rate was 53±
3, 48±9 and 87±9 beats/min increased. Under conditioned conditions, this maximal response lasted for 45 minutes. Deilteazem (0.04 μM) and cimetidine (0.3 μM) reduced this positive chronotropic effect of histamine to a similar extent. As a result of the above pharmacological studies, diluteazem (including its physiologically acceptable acid addition salts) has shown to be an excellent histamine _H2-
It was found to have activity as a receptor antagonist. In particular, it is noteworthy that diluteiazem has higher activity than cimetidine. Therefore,
This compound was expected to have a strong therapeutic activity against peptic ulcers, and therefore the gastric secretion suppressing effect, which is the main indicator of anti-ulcer activity, was evaluated using the method of MNGhosh and HOShild. British Journal of Pharmacology
Pharmacology, 1958, vol. 13, p. 54] using rats. The results are shown in Tables 1 and 2 below.

【table】

[Table] As is clear from Tables 1 and 2, diluteiazem has a gastric acid secretion suppressing effect equal to or greater than that of cimetidine, and is found to be extremely useful as a therapeutic agent for peptic ulcers. As mentioned above, diluteazem is already used as a medicine (coronary vasodilator), and it is clear that its toxicity to humans is within an acceptable range. The toxicity values are as follows:

[Table] As is clear from the above, diluteiazem can be used in the form of a pharmaceutical composition for the prevention and treatment of peptic ulcers in humans. The pharmaceutical composition of the present invention can be prepared by mixing diluteiazem with a suitable carrier such as water, ethanol, syrup, olive oil, starch, sucrose, talc, or gelatin, granulating it, or compressing it into tablets in a conventional manner. It can be manufactured by making it into a liquid or a solution, and can be administered orally or parenterally depending on the dosage form. The amount of active ingredient in the pharmaceutical composition may be sufficient to block histamine _H2 -receptors and preferably contains about 5 to 250 mg of diluteazem per dosage unit. 1
Preferably, the active substance is administered 1 to 6 times per day. The daily dosage of deltiazem varies depending on various conditions, but it is usually about 10 to
1000 mg, and the preferred dosage is 180-360 mg/day. Examples of the present invention are shown below. Example 1 Dilteiazem 50mg, sucrose 80mg, starch 50mg
After sieving and mixing 15 mg of talc and 15 mg of talc, the mixture is filled into hard gelatin capsules. Example 2 A formulation suitable for parenteral administration is prepared by dissolving 50 mg of diluteiazem hydrochloride in 2 ml of sterile water or buffered saline.

Claims (1)

[Claims] 1 Formula: A therapeutic agent for peptic ulcers containing a benzothiazepine derivative or a physiologically acceptable acid addition salt thereof as an active ingredient.