JPS6133802B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () [In the formula, R ₁ , R ₂ , R ₃ are hydrogen atoms or hydroxyl groups, A is -CH=CH-, -OCH ₂ CH ₂ -, -CO
(CH ₂ ) ₄ - or -C _o-1 H _2o-2 (n represents an integer from 1 to 6. However, if only one hydroxyl group is substituted at the para position, n is not 3). vinegar. ] or 5-(p-hydroxyphenethyl)
The present invention relates to a therapeutic agent for peptic ulcer characterized by containing tetrazole. Many drugs have been known and commercially available as therapeutic agents for peptic ulcers, and representative examples of these existing drugs include aluminum sulfate sulfate and glutamine. All of these are excellent therapeutic agents for peptic ulcers, but they have complex chemical structures, are difficult to manufacture, and lack sufficient chemical stability, making them difficult to manufacture or preserve. It cannot be said that it is necessarily satisfactory. Therefore, the present inventors have conducted extensive studies on stable and effective therapeutic agents for peptic ulcers with a simple structure, and have found that the compound represented by the general formula () is superior to the known representative drugs mentioned above. The present invention was completed based on the discovery that it has a therapeutic effect on ulcers. That is, the target compound of the present invention has properties such as simple structure, high stability, no deliquescent property, and easy production from a physicochemical viewpoint, and from a pharmacological viewpoint, it has the characteristics of a known representative compound as described below. It has been shown to have a main pharmacological effect that is equivalent to or better than that of anti-ulcer drugs, and furthermore, it has low toxicity and has no anticholinergic effect, so it is said that it does not have the side effects that anti-cholinergic drugs generally exhibit (dry mouth, blushing, difficulty urinating, etc.). Therefore, the anti-ulcer agent of the present invention can be said to be extremely excellent overall. The effectiveness of the target compounds of the present invention against peptic ulcers is clear from the effects on gastric juice secretion, the results of the pylorus ligation ulcer test, and the results of the aspirin ulcer test, as shown in Tables 1 and 2. 1 Experimental method for effects on gastric juice secretion The pylorus ligation method was used to investigate. That is, the weight is about 210g
Male Nodonriyu rats were used and fasted for 48 hours before surgery (water was available ad libitum). Pylorus ligation was performed under ether anesthesia according to the method of Shay et al. The target compound was suspended in a 0.5% carboxymethyl cellulose aqueous solution and injected intraperitoneally immediately after pyloric ligation. After 18 hours, the stomach was removed under ether anesthesia, and the amount, acidity, and pH of gastric juice were measured.
was measured. Acidity was determined by titrating gastric juice with 0.01N NaOH. The results are shown in Table 1.

【table】

[Table] 2 Anti-ulcer effect Table 2 lists the experimental results regarding the inhibitory effect and acute toxicity (LD ₅₀ ) on pyloric ligation ulcer (Shay ulcer) and aspirin ulcer.
The usefulness of the present invention will be clarified.

【table】

[Table] (i) Experimental method for pyloric ligation ulcer (Shay ulcer) An experimental ulcer model is used to evaluate the anti-ulcer effect of drugs. Methods for creating experimental models include surgery, administration of ulcer-inducing agents, and stress loading, but among surgical models, pyloric ligation ulcers have been the most effective method for ulcers since Shay et al. published them in 1945. It is most widely used for testing the etiology, gastric secretion mechanism, and efficacy of ulcer treatment drugs. That is, according to this method, by ligating the pyloric-duodenal junction, secreted gastric acid and pepsin are stored in the stomach, while ligation causes abnormal blood flow and Defense ability decreases and ulcers occur. On the other hand, drugs to be tested for anti-ulcer effects are generally administered intra-abdominally because the pylorus is ligated and cannot reach the absorption site. Specifically, male rats weighing approximately 210 g were used, and after fasting for 48 hours before ligation (water was freely available), the test animals underwent open surgery to ligate the pylorus and create an ulcer. Next, the compound of the present invention was added to 0.5% carboxymethyl cellulose (hereinafter referred to as
(abbreviated as CMC) was suspended in an aqueous solution and injected into the abdomen immediately after surgery. As a control, 0.5% CMC aqueous solution was injected. After 18 hours, the stomach was removed under ether anesthesia, incised along the greater curvature, and visually observed.
The effect of the compound of the present invention was investigated by examining the degree of gastric damage. The degree of gastric damage (degree of ulcer formation) was scored as described below and expressed as an ulcer index according to Adami et al., and the effect of the drug was determined as an inhibition rate based on this index. The ulcer index was determined from the sum of the scores of each individual stomach, and the average ulcer index was determined by dividing the total number of ulcer indexes in each group by the number of experimental animals. In addition, the suppression rate was determined using the following formula. (Ulcer index of drug administered group - Ulcer index of control)/Ulcer index of drug administered group 0: No damage 1: Bleeding spots 2: Small ulcers (diameter <3 mm), 1 to 5 pieces 3: Small ulcers ( >5) or large ulcers (>3 in diameter)
mm) 1 piece 4: Large ulcer > 2 pieces 5: Perforated ulcer present

[Table] (ii) Aspirin ulcer experimental method Wistar female rats weighing approximately 180 g were used.
Aspirin is suspended in 0.5% CMC solution at 300mg/Kg
was administered orally. After 5 hours, the rats were sacrificed.
The stomach was removed, injected with approximately 10 ml of 5% formalin solution, and immersed in 10% formalin solution for 20 minutes. Drug efficacy was determined by ulcer index (total length of injury). The target compound was dissolved in physiological saline and injected intravenously immediately before aspirin administration.

[Table] (iii) Acute toxicity experimental method One group of 6-week-old ddY mice (male and female)
It was used as 10 animals. The target compound was dissolved in dilute caustic soda, adjusted to pH 7 with dilute hydrochloric acid, and determined from the mouse mortality rate 3 days after oral administration.
LD ₅₀ was determined using the Wilcoxon method. In addition, when the inhibitory effect of glutamine, a known peptic anti-ulcer agent, on pyloric ligation ulcer was investigated using the above-mentioned experimental method, oral administration of 1000 mg showed an inhibition rate of 59%. The inhibitory effect on aspirin ulcers was investigated using the experimental method described above for aluminum sucrose sulfate, and it was found that oral administration of 400 mg
It showed an inhibition rate of 54%. As described above, it has been revealed that the target compound of the present invention is a safe and useful drug with extremely low toxicity that suppresses gastric juice secretion and has an antiulcer effect. When administering this drug for the treatment of peptic ulcers, for example, the dosage of 3-(2-hydroxyphenylpropionic acid) is usually about 600 to 1200 mg per day for adults and experimental animals. When administering this drug, it can be processed into any dosage form, such as capsules, tablets, powders, granules, syrups, etc., using known formulation methods.Reference Example p-Hydroxyphenylpropionitrile 38
A mixture of 33 g of benzyl chloride, 36 g of K ₂ CO ₃ and 700 ml of ethanol was heated under reflux for 15 hours with stirring in an oil bath. Filter off insoluble matter when hot and wash thoroughly with hot ethanol. The filtrate was allowed to stand at room temperature, and the precipitated crystals were collected by filtration to yield 41.5 g of colorless plate-like crystals with a melting point of 94-95°C.
get. Furthermore, the filtrate is concentrated to about 1/3, left at room temperature, and the precipitated crystals are collected by filtration.
9 g of colorless platelet crystals at 95° C. are obtained. This compound is
As a result of NMR and IR measurements, it was confirmed that it was p-benzyloxyphenylpropionitrile.
Yield 82.4%. 2.37 g of p-benzyloxyphenylpropionitrile obtained as described above, 3.25 g of NaN ₃ , LiCl
A mixture of 2.13 g and 50 ml of DMF was heated under reflux for 3 days while stirring in an oil bath. DMF was distilled off under reduced pressure, water was added to the residue, and the mixture was made alkaline with 2N-NaOH. Insoluble matter (0.8 g of raw material recovered) was removed by filtration, and the filtrate was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. By washing with water, 1.65g (58.9g) of colorless crystals with a melting point of 168-170℃
%). A portion is recrystallized from acetone-petroleum ether to obtain colorless prismatic crystals with a melting point of 171-172°C. This product was found to be 5 by NMR measurement.
-(p-benzyloxyphenethyl)tetrazole was confirmed. 30 g of 5-(p-benzyloxyphenethyl)tetrazole obtained as described above, ethanol
Using 10 g of 5% palladium on charcoal (52% moisture) in 700 ml, subject to catalytic reduction under normal pressure and irradiation with an IR lamp. After absorbing the calculated amount of hydrogen, filter off the catalyst. The filtrate is distilled off under reduced pressure, and the resulting candy is crystallized by stimulation with ether. Filter this out,
Washing with ether gives 17.7 g of colorless crystals with a melting point of 143-146°C. Recrystallization from acetone-ether gives 14.1 g (69.3%) of colorless platelets with a melting point of 146 DEG-148 DEG C. This one is IR,
As a result of NMR and mass spectrometry analysis, it was confirmed that it was 5-(p-hydroxyphenethyl)tetrazole.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ , R ₂ , R ₃ are hydrogen atoms or hydroxyl groups, A is -CH=CH-, -OCH ₂ CH ₂ -, -CO
(CH ₂ ) ₄ - or -C _o-1 H _2o-2 (n represents an integer from 1 to 6. However, if only one hydroxyl group is substituted at the para position, n is not 3). vinegar. ] or 5-(p-hydroxyphenethyl)
A therapeutic agent for peptic ulcer characterized by containing tetrazole.