JPS603048B2 - Digestive system disease treatment - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, R represents pyridyl or chenyl.

) or an acid addition salt thereof as a main component.

Conventionally, so-called anticholinergic drugs with antiacetylcholine effects, which have been widely used in the treatment of gastrointestinal diseases such as gastric and duodenobobito, gastric and yang irritability, and gastric hyperacidity, have the effect of increasing tumor size and mouth. Unfavorable effects such as lag were observed, and there were considerable problems in terms of side effects, and there was a strong desire to develop a drug for the digestive system that could replace anticholinergic drugs. The present inventors have discovered that although the compound of general formula [1] or its acid addition salt has extremely low anti-acetylcholine activity, it has anti-cholinergic activity, suppresses gastric secretion, etc., and is used as a drug for the digestive system. The present inventors have found that the invention is useful and have completed the present invention.

The compound of general formula [1] or its acid addition salt is
Although the manufacturing method is described in the specifications of No. 9-82676 and Mochiseki No. 50-18938, its application to gastrointestinal diseases is not yet known.

Representative compounds used in the present invention are as follows. 2
1[2-(2-tenyl)phenoxymethyl]morpholine maleate Melting point 155-156℃ E-21[2-(2-tenyl)phenoxymethyl]morpholine maleate Melting point 128-129℃[Q]20/ D-5.0
Zu (cl. 01, methanol) 21 [21 (2-pyridylmethyl) fluoride/Kishime Aki] Machine-1 Ura Fuma-Yashio De, 32-1 father.

0 2-[3-(2-pyridylmethyl)phenoxymethyl]
Morpholine maleate Melting point: 130-13 Next, we will show, along with experimental methods, that the compound of general formula [1] or its acid addition salt has anti-fouling effects, suppressing gastric juice secretion, and the like.

01 Effect on stress stress The method of Takagi et al. [Japanese Journal of Pharmacology (Jap.

After fasting female Wistar rats weighing around 160 ta for 20 hours, they were restrained in stress cages and kept at 22°C.
soaked in water. After 6 hours, the animals were sacrificed with ether and fixed by injecting 8 volumes of 1% formalin solution into their stomachs.

The stomach was incised, and the sum of the major axes of the injured part of the stomach was logarithmically transformed to obtain the thin field index. The test compound was orally administered 30 minutes before stress loading.

Incidentally, the supine rate due to the test compound was calculated by the following formula, and then this supine rate was plotted on a semi-log graph against the dose (p/k9) to calculate the ED5.

I found the value. ■ Effect on Shay hot water [Gastroenterology] Shay et al.'s method
Rolo Battle) Volume 5, pages 43-61 (1st place 5th year)] was modified.

Female Wistar rats weighing around 160 kg were placed in individual cages for 44 hours and fasted (water was provided ad libitum), then the pylorus was sacrifuged under ether anesthesia and left without food or water for 1q hours.

After ether sacrificing, the stomach contents were collected from the mice into graduated centrifuge tubes, centrifuged at 300 pm for 1 minute, and the amount of gastric juice per 100 ta body weight was determined from the amount of supernatant. After collecting the gastric contents, a 1% formalin solution was injected into the stomach to fix it. Then, the stomach was incised, and the total area of the injured area was logarithmically transformed to obtain the concentration index. Test compounds were administered subcutaneously immediately after pylorus ligation.

The supine rate due to the test compound was calculated using the following formula,
Then, plot this supine rate against the dose (secret/[9) on a semi-logarithmic graph and get E. I found the value. [3' Magnetic Wist with a weight of around 150 ta that acts on aspirin storage
After fasting ar rats for 24 hours, aspirin 100 p/
K9 was orally administered and left in fasted koji water for 5 hours.

After ether slaughter, Hevontamin sky blue in the stomach.
Add 1% formalin solution containing 0.2% of music to 8 [
Injected and fixed. After the stomach was incised, the gastric mucus was wiped off and the sum of the longitudinal lengths of the stained injured part of the stomach was logarithmically transformed to obtain the concentration index. Test compounds were administered subcutaneously 30 minutes before aspirin administration.

The rate of supineness due to the test compound is determined from the following formula, and then this rate of supineness is plotted on a semi-logarithmic graph against the dose (female/kg) to calculate ED5. I found the value. '4} Effect on histamine bonds Method of Bageton et al. [Journal.
Of Pathology and Bacteriolo
gy) No. 9 Kyogaya, pages 679-682 (1965)].

Male white guinea pigs weighing around 700 ta were placed in individual cages for 2 feeding hours and after fasting, 3/k9 of histamine phosphate 5 was added.
was administered intraperitoneally.

Two hours later, the animals were killed by buffeting, and 30 minutes of 1% formalin solution was injected into the stomach to fix it.

After 5 minutes, the stomach was incised, and the total area of the injured part of the stomach was logarithmically transformed and used as the thinning index.

The test compound was administered subcutaneously 3 minutes before histamine administration.

The supine rate due to the test compound is determined by the following formula, and then this supine rate is plotted on a semi-log graph against the dose (9/k9) to calculate ED5. I found the value. '51 Effect of Watanabe's method on gastric hyperactivity under stress [Chemical
and Pharmaceutical Bulletin (Che
mical and Pharm port-ce mountain icaIBu
lletin) Volume 14, pages 101-10 (196 Mother King)] is used for E. I found the value. '61 Shay Effect on gastric juice secretion The method of Shay et al. [Gastroenterology Vol. 5, pages 43-61 (1-5)] was also modified.

Male Wistar rats weighing around 200 ta were kept in individual cages for 48 hours, fasted (water was given ad libitum), and then the pylorus was removed under ether anesthesia.

After abdominal closure, 5 minutes of physiological saline was administered intraperitoneally, and the animals were left without food or water for 4 hours. After the ether slaughter, the esophagus was pierced and the body was extracted. The gastric contents were collected into a graduated centrifuge tube and centrifuged at 300 pm for 10 minutes, and the amount of gastric juice secreted per 100 kg of body weight was determined from the amount of supernatant. The test compound was administered subcutaneously immediately after pylorus ligation. The supine rate due to the test compound is determined by the following formula, and then this supine rate is calculated as the dose (Shiguru/
kg) on a semi-logarithmic graph. I found the value. '71 Antiacetylcholine effect J. MVanR
The method of Ossum et al.
ves ln rMtionales de Pharm
ac's like amjeet de Therapy, 14th page 240-246 and 299-0 page (1
9 adults)], and p et al.

'81 Acute Rhombic Value Litchfield-Wilco
LD-specific values (oral) were determined by Fuuss using the xon method.

The results of the above experiments are summarized in Table 1.

As is clear from the experimental results in Table 1 and above, the general formula [1
) compounds or their acid addition salts are
It is useful as a medicine for the treatment and prevention of acute or chronic gastritis, gastric hyperacidity, gastrointestinal tract upset, etc., and also for the prevention of gastric and duodenal sulcus due to stress.

The compound of general formula [1] or its acid addition salt can be prepared by itself or mixed with appropriate pharmacologically acceptable substances, excipients, and diluents to form powders, parent granules, tablets, capsules, and injections. It can be administered orally or parenterally.

The dosage for adults is, for example, 3 tablets per day with the following composition, but depending on the age,
Needless to say, the dosage may be adjusted depending on body weight, symptoms, etc. Composition example

Claims (1)

[Claims] 1. A digestive system whose main component is a morpholine derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R represents pyridyl or thienyl) or its acid addition acid. Disease treatment agent.