JPS6350328B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to N-ethyl-N-[6-(3,4-dimethoxybenzoyloxy)hexyl]-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine (hereinafter referred to as the subject compound of the present invention) or The present invention relates to an anti-peptic ulcer agent containing the salt thereof as an active ingredient. Although it is believed that many factors are involved in the etiology of peptic ulcers, it is thought that the main cause is a loss of balance between the aggressive factors represented by gastric juice and the protective factors of the gastric mucosa. There is. Conventionally, there are various therapeutic agents for peptic ulcers, but many of these agents act on one of the above-mentioned ulcerogenic factors. That is, antacids, antipepsin agents, anticholinergic agents, and antigastrin agents are used to suppress aggressive factors, while mucosal protectants and mucosal repair promoters are used to enhance protective factors. exists. In the treatment of peptic ulcers, it is desirable to have a drug that simultaneously acts on the two major factors, attack and defense, but there are few drugs that are satisfactory as a single drug. Although sucrose sulfate/aluminum is an excellent anti-peptic ulcer agent, some problems remain in terms of synthesis and dosage. Therefore, it is desired to develop a peptic ulcer agent that simultaneously acts on the two major factors, attack and defense, and is as effective as sucrose sulfate/aluminum. Based on this viewpoint, the present inventors attempted to investigate useful agents for treating peptic ulcers, and as a result, they discovered that the compound targeted by the present invention or a salt thereof is an excellent compound useful for treating peptic ulcers. In order to explain in more detail the utility of the present invention as an anti-peptic ulcer agent, the hydrochloride salt of the compound targeted by the present invention (hereinafter referred to as Compound D) will be explained as a representative example. That is, Compound D exhibited an inhibitory effect on gastric juice secretion, which is an attack factor, and exhibited significant inhibition against stress ulcers and aspirin ulcers by both oral and intraperitoneal administration methods. Furthermore, it was confirmed that this compound suppresses excessive secretion of gastric acid and exhibits local anesthetic action, which is said to improve symptoms, and antispasmodic action, which relieves abdominal pain caused by gastric spasms. More specifically, as an experiment to investigate the effect on attack factors, Compound D was investigated for its effect on gastric secretion using pylorus-ligated rats. As a result, intraperitoneal administration of Compound D at 30 mg/Kg decreased gastric juice volume, acidity, and total acidity, as well as pH. Both of these effects were significant compared to the control group. Furthermore, although the relationship between stress and ulcer etiology is already known, a water immersion restraint stress method was used as a stress ulcer model. A significant suppressive effect on this stress ulcer was observed in both oral administration of 100 mg/Kg and intraperitoneal administration of 10 mg/Kg. It also showed a significant inhibitory effect on aspirin ulcers in rats, which are commonly used as a drug-induced gastric ulcer model, both when administered orally at 30 mg/Kg and intraperitoneally at 3 mg/Kg. The comparison results between Compound D and representative known peptic ulcer agents are summarized in the table below.

[Table] Furthermore, in an experiment on corneal reflexes in guinea pigs, Compound D exhibited a long-lasting local anesthetic effect when a 1% solution was instilled into the eyes. In addition, it was confirmed that the required dose for 50% inhibition of gastric contraction due to vagus nerve stimulation in dogs is as strong as 0.61 mg/Kg (iv). As a result of examining the acute toxicity of Compound D using rats, the LD ₅₀ was extremely low at 2830 mg/Kg when administered orally, and 35.3 when administered intravenously.
It was mg/Kg. The compound of the present invention or a salt thereof is usually administered orally, and the dosage for adults is usually 30 to 400 mg.
It is thought to be about mg/day based on the results of animal experiments. When administering this drug, it can be processed into any dosage form, such as capsules, tablets, powders, granules, syrups, etc., using known formulation methods. Experimental Example 1 Effect on gastric juice secretion Experimental method The pylorus ligation method was used for investigation. i.e. weight about 160
Male Wistar rats of 1.5 g were used and fasted for 24 hours before surgery (water provided ad libitum). Pylorus ligation was performed under ether anesthesia according to the method of Shay et al. Compound D was dissolved and suspended in physiological saline and injected intraperitoneally immediately after pyloric ligation. 5
After a period of time, the stomach was removed under ether anesthesia, and the amount, acidity, PH, and total acidity of gastric juice were measured. Experimental results

[Table] 2. Effect on experimental ulcers Experimental method (1) Stress ulcer The experiment was conducted according to the method of Takagi et al. Namely, male rats weighing 280 to 350 g were placed in a stress cage, fixed, and immersed in a water tank at a water temperature of 21+1°C. After 7 hours, the stomach was removed, fixed with 10% formalin, and then incised along the greater curvature and visually observed. Compound D was dissolved or suspended in physiological saline and ion-exchanged water, and administered intraperitoneally and orally, respectively. The degree of ulceration was scored as an ulcer index according to the description below.

【table】

【table】 Experimental results

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[Table] Experimental Method (2) Aspirin Ulcer Male rats weighing 220 to 240 g were used. Rats were fasted for 18 hours before the experiment. Aspirin is suspended in 0.5% CMC solution, 300mg/Kg
was administered orally. After 5 hours, the rats were sacrificed, their stomachs were removed, and they were soaked with approximately 10% of a 5% formalin solution.
ml, which was immersed in a 10% formalin solution for 20 minutes. Drug efficacy was determined by ulcer index (total length of injury). In the case of intraperitoneal administration, Compound D was dissolved or suspended in physiological saline and administered 30 minutes before aspirin administration, and in the case of oral administration, it was dissolved or suspended in ion-exchanged water and administered 1 hour before aspirin administration. Experimental results

[Table] 3 Local anesthetic effect experimental method The eyebrows of male Hartley guinea pigs weighing around 800 g were cut, and the cornea was stimulated with a 1/4 mandoline twice at 5-minute intervals, 5 times each, and only animals with normal eyeblink response were tested. were used as a group of 3 animals. For the surface anesthetic effect, 3 drops of the drug solution were dropped on the right palpebral conjunctiva and right corneal surface using a 1/4 injection needle, water was applied to the contralateral side as a control, and each eye was stimulated 5 times on each side at each hour after instillation. Judgment was made by measuring the number of blink reactions. Compound D was applied at 1 w/v%. Experimental results

[Table] 4 Experimental method for inhibitory effect on gastric contraction Mongrel dogs weighing 8 to 15 kg were used, regardless of gender.
After being anesthetized with 30 mg/Kg of pentobarbital intravenously, the patient was fixed in the dorsal position, an incision was made along the midline of the upper abdomen, and a rubber bulb filled with water was inserted through the incision on the greater curvature side of the body of the stomach. , changes in internal pressure were recorded by polygraph via a low-pressure transducer. Frequency as vagus nerve stimulation conditions:
Electric stimulation was performed for 10 seconds with a square wave of 20 cps, duration: 1 msec, and voltage of 8 V, and this was repeated every 3 minutes. The suppression rate (%) is calculated using the following formula, s.ID ₅₀
The dose was set as the dose at which the inhibition rate was 50%. Inhibition rate (%) = 100 - average contraction height for 30 minutes after drug administration/average contraction height before drug administration x 100 Compound D was dissolved in physiological saline and injected into the femoral vein. Experimental results

[Table] 5 Acute toxicity experimental method STD-Wistar male rats weighing 180 to 240 g were used. In the case of oral administration, it was suspended in ion-exchanged water, and in the case of intravenous administration, it was dissolved in physiological saline and administered (0.5 ml/100 g). The Litchfield-Wilcoxon method was used to determine the mortality rate 72 hours after administration.
Asked for _LD50 .

[Table] Next, the manufacturing method of the new compound used in the present invention is shown as a reference example. Reference Example 1 (Compound D) (a) Mix 4.7 g of lithium aluminum hydride and 200 ml of anhydrous tetrahydrofuran, and add N-
A mixture of 10 g of acetyl-6-methoxy-1,2,3,4-tetrahydro-2-naphthylamine and 100 ml of anhydrous tetrahydrofuran is extracted.
After stirring at room temperature for 0.5 hours, heat under reflux for 4 hours, and add 4.7 ml of water and 50 mL of tetrahydrofuran under ice cooling.
Add ml of the mixture dropwise. Next, 4.7 ml of 15% sodium hydroxide and then 14 ml of water were added dropwise. The precipitated insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue was extracted with chloroform, the chloroform layer was washed with water, and dried over anhydrous sodium sulfate.
Concentrate under reduced pressure and add hydrogen chloride to the remaining oil.
Add ethanol solution and concentrate under reduced pressure. Add acetone, collect the precipitated crystals by filtration, add alcohol,
Recrystallization from ether gave 8.9 g of colorless needles of N-ethyl-6-methoxy 1,2,3,4-tetrahydro-2-naphthylamine hydrochloride. Melting point 231-232℃. The various physical data such as the melting point and infrared absorption spectrum match those obtained in Reference Example 2(a). (b) N-ethyl-6-methoxy-1,2,3,4
-tetrahydro-2-naphthylamine hydrochloride
3, to the free base obtained from 2.0g by a conventional method.
3.1 g of 4-dimethoxybenzoic acid 6-chloro-hexyl ester, 1.4 g of sodium iodide, 2.0 g of sodium carbonate and 80 g of methyl ethyl ketone.
ml and heated under reflux for 90 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform.
The chloroform layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting oil was purified using silica gel column chromatography to obtain N-ethyl-N-[6-(3,4-dimethoxybenzoyloxyhexyl]-). 6-methoxy-1,2,3,
A pale oil of 4-tetrahydro-2-naphthylamine is obtained. Dissolve this in a hydrogen chloride/ethanol solution and concentrate under reduced pressure. The residue was dissolved in acetone, ether was added, the mixture was left at a low temperature, the precipitated crystals were collected by filtration, and recrystallized from a mixture of acetone and ether to give N-ethyl-[6-(3,4-
dimethoxybenzoyloxy)hexyl]-6
-methoxy-1,2,3,4-tetrahydro-
1.3 g of colorless crystals of 2-naphthylamine hydrochloride (compound D) are obtained. Melting point 119-120℃. Elemental analysis value C ₂₈ H ₃₉ NO ₅・HCl Calculated value C66.45, H7.97, N2.77 Actual value C66.63, H8.04, N2.73

Claims (1)

[Claims] 1 N-ethyl-N-[6-(3,4-dimethoxybenzoyloxy)hexyl]-6-methoxy-
An anti-peptic ulcer agent containing 1,2,3,4-tetrahydro-2-naphthylamine or a salt thereof as an active ingredient.