JPH0228574B2 - KOKAIYOZAI - Google Patents

Description

[Detailed description of the invention]

"Industrial Application Field" The present invention relates to an anti-ulcer agent. "Prior Art" and "Problems to be Solved by the Invention" The present inventor attempted to synthesize the components of the herbal medicine and its related compounds. An easy-to-synthesize 3-(3
-Methyl-2-butenyl)-4-hydroxy-
It was discovered that benzoitsucic acid has not only a choleretic effect but also a strong anti-ulcer effect. As an anti-ulcer agent on the market in recent years, Cervex (Eisai Co., Ltd., generic name teprenone) is Solon (Taisho Pharmaceutical Co., Ltd., generic name Sofalcon) However, the present inventor believes that the above-mentioned compound is more effective than these commercially available anti-ulcer agents, both in terms of ease of synthesis and anti-ulcer effect. As a result of further research, we have arrived at the anti-ulcer agent of the present invention. "Means for solving problems" and "action" The present invention is based on the formula 3-(3-methyl-2-butenyl) represented by
This relates to an anti-ulcer agent containing 4-hydroxybenzoic acid as an active ingredient. 3-(3-Methyl-2-butenyl)-4-hydroxy-benzoic acid (hereinafter referred to as the compound of the present invention) can be synthesized using 4-hydroxybenzoic acid as a starting material as shown in the following formula. The above compound of the present invention is a colorless needle crystal with a mp of 100 to 101°C, and is soluble in methanol, ethanol, n-butanol, acetone, ethyl acetate, ether, pyridine, etc., but is soluble in chloroform, benzene, n-hexane, etc. , insoluble in petroleum ether. Synthesis examples, pharmacological test examples, etc. of the compounds of the present invention will be shown below to clarify the present invention more specifically. "Pharmacological test examples, etc." (1) Synthesis example of the compound of the present invention 4-hydroxybenzoituccinic acid (15.0g,
0.11 mol) in 6.7% sodium hydroxide solution (130
ml, 0.22 mol) and γ, γ with stirring.
-Dimethylallyl bromide (14.0g, 0.095
mol) was added dropwise, and stirring was continued for an additional 4 hours at room temperature. The reaction solution was made acidic with 2N-HCl solution,
Extract three times with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is dissolved in methanol, a diazomethane-ether solution is added, and after 5 minutes, acetic acid is added dropwise to decompose the excess diazomethane. The solvent was distilled off under reduced pressure, and the resulting crude product (19.34 g) was subjected to silica gel column chromatography [n-hexane-
3-(3) from the n-hexane-ethyl acetate eluate.
-Methyl-2-butenyl)-4-hydroxybenzoic acid methyl ester (2.98 g) was obtained as a colorless prism crystal, and the raw material methyl ester form, 4-hydroxybenzoic acid methyl ester (10.48 g) was obtained from the acetone eluate. Collect as white powder. The compound obtained in this way (2.98
g, 0.013 mol) was added with 10% sodium hydroxide solution (100 ml) and heated under reflux at 100°C for 1 hour.
After cooling, acidify with 2N HCl solution and extract twice with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methanol to give 3-(3-methyl-2-butenyl)-4
-Hydroxybenzoic acid (2.75 g, yield: 33.7%) was obtained as colorless needles. (2) Anti-ulcer effect test example a) Water immersion restraint stress ulcer A dd-k strain male mouse (weight 18-22 g) is placed in a stress cage and immersed up to the chest in a water tank at 22±1°C to apply stress. After 5 hours, the fish was removed from the water tank, killed with ether, and the stomach was removed. 1.2ml of 10% formalin solution
was injected into the stomach, and the stomach was soaked in the same solution for 10 minutes to fix the tissue. After fixation, an incision is made along the greater curvature and the ulcer that has developed in the glandular stomach area is observed.
The degree of ulceration is determined by the ulcer index (ulcer) as follows:
index). Ulcer index 0: No ulcer 1: Mild bleeding 2: Bleeding and Elodion 3: Severe bleeding and Elodion The test drug was administered orally as a 5% gum arabic suspension just before stress load. did. The above results are shown in the table below.

[Table] b) Pylorus ligation ulcer (Shay ulcer) After fasting male Wistar rats (weight 180-200 g) for 48 hours, the abdomen was opened under ether anesthesia, and the pylorus was ligated with suture.
After 13 hours, the animals were sacrificed with ether, the stomach was removed, gastric juice was collected, and the stomach was fixed in the same manner as in a). The gastric juice was centrifuged at 3000 r.p.m for 10 minutes, and the amount and acidity of the gastric juice were measured. Acidity was measured using PH paper. The ulcer index was determined as follows. Ulcer index 1: Not ulcerated 2: 5 or more small ulcers with congestion 3: 5 or more small ulcers and 1 large ulcer 4: 2 or more large ulcers 5: Perforation was administered into the duodenum immediately after pylorus ligation. The above results are shown in the table below.

[Table] c) Indomethacin ulcer Male Wistar rat (body weight 170-210
g) after fasting for 24 hours, indometacin 20mg/
Kg body weight is administered subcutaneously. After 7 hours, the animals were sacrificed with ether and the stomachs were removed. The stomach was fixed in the same manner as in a), incised, and the length of the ulcer developed in the glandular stomach was measured, and the total length of the ulcer developed per animal was taken as the ulcer index.
The test drug was orally administered 10 minutes before administration of indomethacin. The above results are shown in the table below.

【table】

[Table] d) Hydrochloric acid-ethanol ulcer Wistar male rats (body weight 160-190
g) After fasting for 24 hours, 1 ml of 150 mM hydrochloric acid and 60% ethanol is administered orally. After 1 hour, the animals were sacrificed with ether and the stomachs were removed. Hereinafter, the ulcer index was determined in the same manner as in c).
The test drug was hydrochloric acid-ethanol administration 1.
Administered orally before 1 hour. The above results are shown in the table below.

[Table] e) NaOH ulcer Male Wistar rat (body weight 160-190
After fasting g) for 24 hours, add 1 ml of 0.2N-NaOH.
Administer orally. One hour later, the animals were sacrificed with ether and the stomachs were removed. Hereinafter, the ulcer index was determined in the same manner as in c). In addition, the tested drugs are:
It was orally administered 1 hour before NaOH administration. The above results are shown in the table below.

[Table] (3) Acute toxicity test example A group of 4 male DD-K mice weighing 20 g were used, and the test drug was administered at 500 mg/Kg, 1000 mg/Kg,
Suspensions of gum arabic powder at a rate of 2000 mg/Kg and 4000 mg/Kg were orally administered and observed. As a result, the LD ₅₀ of the compound of the present invention is 2000
It was mg/Kg. From the above results, it is considered that the compound of the present invention exhibits antiulcer activity when administered orally. For treatment of adults, it is estimated that the compound of the present invention in the form of capsules, fine granules, etc. should be administered three times at a dose of 50 mg to 100 mg. "Effects of the Invention" The compound of the present invention has been found to be effective as a gastrointestinal drug, promoting bile secretion and also against hepatitis caused by CCl ₄ , ethanol, etc., and is a new type of easily synthesized anti-ulcer drug. It is expected to be used as a drug.

Claims (1)

[Claims] 1 formula 3-(3-methyl-2-butenyl) represented by
-An anti-ulcer agent containing 4-hydroxybenzoic acid as an active ingredient.