JPS63250322A - Remedy for alimentary disease - Google Patents

Abstract

PURPOSE:To obtain the titled remedy comprising a 5-substituted tetrazol, 3- substituted-alpha-aminopropionic acid, an ester of a salt thereof as an active ingredient. CONSTITUTION:A remedy for alimentary diseases containing a compound {e.g. 5-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl]tetrazole} shown by formula I (m is 3 or 4; n is 0 or 1; R is group shown by formula II or formula III), an ester (e.g. lower alkyl ester) or a salt (e.g. salt of base or acid) thereof as an active ingredient. A dose is 50-1,000mg/person and orally administered divided twice - three times daily. The remedy is effective for treating and remedying alimentary diseases, especially gastric ulcer and gastritis.

Description

[Detailed Description of the Invention] The active ingredient of the pharmaceutical of the present invention is 5-substituted tetrazole or 3-substituted-α- represented by the following general formula (I).
Aminopropionic acid, its esters or non-toxic salts.

(In the formula, 2m means 3 or 4, and n means 0 or 1 or 2-amino-2-calhoki) General formula (Two representative compounds among the compounds included in INK are as follows.

5-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butylcotetrazole (compound A) S-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]-L- Cysteine (Compound B) 5-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylcotetrazole 5-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthiocotetrazole The ester of S-[4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyl]-L-cysteine compound (I) is an ester of a compound having a carboxy group in the formula (I), for example Examples include lower alkyl esters (methyl ester, ethyl ester, flobyl ester, butyl ester, etc.) and alkoxyphenyl lower alkyl esters (p-ethoxybenzyl ester, p-hebutyloxybenzyl ester, etc.).

In addition, non-toxic salts include salts with bases or acids.

Examples of salts with bases include salts with inorganic bases such as sodium and potassium, ethylamine, propylamine,
Salts with organic bases such as N-ethylpiperidine, jetanolamine, and cyclohexylamine, salts with basic amino acids such as lysine and ornithine, ammonium salts, and salts with acids include hydrochloric acid and sulfuric acid.

Mineral acid salts such as phosphoric acid and hydrobromic acid.

(Prior Art) Regarding the usefulness of these compounds as medicines, the publication describes that they have leukotriene antagonistic activity and are therapeutic agents for allergic diseases.

(Problems to be Solved and Means for Solving) The present inventors have discovered that the pharmacological activity of the 5-substituted tetrazole or 3-substituted-α-aminopropionic acid represented by the above general formula (1), its ester or non-toxic salt is 2 It was found that these compounds have effects such as suppressing gastric acid secretion, suppressing ethanol ulcers, and suppressing water immersion restraint stress ulcers, and have extremely low toxicity.

Next, the pharmacological effects of the active ingredients will be explained along with experimental methods.

(1) Experimental method for effect on gastric acid secretion: Male Wistar rats (weighing around 200 g were used,
H, 5hay et al. [Gastroenterolo
After fasting for 24 hours, the abdomen was opened under light anesthesia with ether, and the pyloric region was ligated according to [Gy+ 5+ 43 (1945)]. Immediately after ligation, the abdomen was opened, and 4 hours later, the animals were sacrificed by deep anesthesia.

Gastric juice was collected.

After measuring the amount of gastric juice, the acid concentration in the gastric juice was determined using an automatic titrator (Hiranuma Sangyo, Comtite-7). −． pH7,
It was calculated from the amount of 0.05N caustic soda aqueous solution required for titration to 0. Gastric acid secretion was expressed as the product of gastric acid concentration and gastric juice volume. Test compounds were administered orally 1 hour before pylorus ligation.

Test results: Table 1 shows the effect of Compound A of the present invention on gastric acid secretion.

Table 1 Control -17318,5±39.3
-Compound A 30 10 263.8±1
7.8 17.2100 10 168.0±
40.1 47.3300 7 47.3±
6.0 85.1 Compound A of the present invention is 1101rr/k
7 g/kg or more, the secretion of gastric acid in the body was dose-dependently suppressed, and the suppression rate compared to the control group was 100,111 g/kg or more.
73% and 85.1% at 3oorr1g/kg (ED, o=103.9mg/kg).

(2) Effect of ethanol on ulcer Experimental method: Using male Wigtar rats (weighing around 200 g), after fasting for 24 hours and water for 18 hours, 1 m of absolute ethanol was administered.
It was administered orally at a ratio of t/rat. One hour later, the animals were sacrificed by deep anesthesia and the stomachs were removed.

The stomach was cut open along the major groove side, and the area of ulcers generated on the glandular gastric mucosa was measured, and the sum total was defined as the ulcer coefficient (mm2). Test compounds were administered orally 1 hour before absolute ethanol administration.

Experimental results: Effect of the compound of the present invention on ethanol ulcers (Table 2)
It was shown to.

Table 2 Funtrol - 5 55.0±6.
9-Compound A 3 5 40.8±9725
．． 810 5 25.6±4.2 53.530 5
14.0±5.8 73.5100 5 3.
0±2. ] 94.5 Compound A of the present invention is 10.30
D5G value was 9.6 mg.
It weighed 7 kg.

(3) Effect experimental method on water immersion restraint stress ulcers: Takagi et al.'s method [Takagi Keijibe et al., Jap, J., Pha.
r-macol,, 18. 9 (1968), two male ICR mice weighing approximately 40 g were placed in a restraining wire mesh cage.

The animal was immersed in water up to the lower edge of the sternum in a water tank at 23°C and left for 7 hours. The animals were then killed under deep anesthesia and the stomachs were removed. The stomach was cut open along the major groove side, and the area of ulcers occurring in the glandular stomach was measured, and the total ulcer coefficient (mrn2) was determined. Test compounds were orally administered 60 minutes before water immersion.

Experimental results: Table 3 shows the effect of the compound B of the present invention on water immersion restraint stress ulcers.

Table 3 Control - 5 90±14
-Compound B30 5Z2±1.3 75.6 Compound B of the present invention suppressed water immersion restraint stress in mice at 3011]g/kg, and the suppression rate compared to the control group was 75
．． It was 6%.

(Effect) From the results of the above pharmacological tests, it is clear that the two active ingredients of the present invention have anti-ulcer effects.

It is a therapeutic agent for digestive system diseases that is effective in treating and preventing digestive system diseases such as gastric ulcers and gastritis.

For clinical application of the pharmaceutical of the present invention, a pharmaceutical composition mixed with known pharmaceutically acceptable carriers, excipients, etc. [
Examples: tablets, capsules, powders.

It can be safely administered mainly orally as granules and gunpowder. The dosage varies depending on the subject, route of administration, symptoms, etc.2, but is usually 50 to 1,0 per adult.
OOff@, which is orally administered in 2 to 3 divided doses a day. Next, a prescription example is shown.

(Tablet) Compound of formula CI+ 39mg milk
Sugar 104mg
Corn starch 57ff1g Hydroxyglobil cellulose 4mg Carboxymethyl cellulose calcium 41T1g Magnesium stearate 1■Total
200 fl1g 30 g of the compound of formula +I+, 104 g of lactose and 57 g of corn starch were uniformly mixed, 4 mm of a 10% (w/v) hydroxyglobil cellulose aqueous solution was added to this mixture, and granules were prepared by wet granulation.

4g of carboxymethyl cellulose calcium in this granule
After adding and mixing 1 g of magnesium stearate, the mixture was compressed into tablets (200 mg per tablet).

Formulation example 2 (capsule) Compound of formula (I) 30mg crystalline cellulose 40fl1g crystalline lactose
129 rq meter
200 mg of each of the above ingredients was mixed in a conventional manner with 100 times the amount, and then filled into gelatin capsules to prepare capsules (1 capsule 200 ff1g).

Procedural amendment dated August 2, 1988; Name of the invention: Digestive system disease treatment agent 3; Relationship with the person making the amendment; Patent applicant address: 2-3-11 Nihonbashi Honmachi, Chuo-ku, Tokyo Name ( 667) Yamanouchi Pharmaceutical Co., Ltd. Representative Shigeo Morioka 4, Agent Address 1-1-8 Azukizawa, Itabashi-ku, Tokyo Yamanouchi Pharmaceutical Co., Ltd. Voluntary initiative within the Patent Department (1) "Water immersion" at the end of page 7 of the specification Correct to "water temperature".

(2) In the 5th line from the bottom of page 8 of the specification, "Suppress Ress ulcers" is corrected to "Suppress Ress ulcers."

(3) Insert the following passage in two new lines following the fourth line from the bottom of page 8 of the specification.

(4) Toxicity The acute toxicity LD,o when the active ingredient of the pharmaceutical of the present invention is administered intraperitoneally to rats is as follows.

Compound A 312.5■/kg Compound B
) 1,000 mg/kg j (4)
In the third line from the bottom of page 10 of the specification, "1,000 times the amount is taken as l'-1" is corrected to "take the 1,000 times amount."

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. ) 5-substituted tetrazole or 3-substituted -α-
A therapeutic agent for digestive system diseases containing aminopropionic acid, its ester or non-toxic salt as an active ingredient