JPH0688974B2 - 2-Pyridylacetamide derivative, production method and use thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is represented by the general formula (I). (In the formula, R ¹ represents a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 3 to 20 carbon atoms or an aralkyl group having 7 to 15 carbon atoms, and R ² represents a hydrogen atom, a linear alkyl group. Group, a cyclic alkyl group, an alkenyl group, an aryl group or an aralkyl group), a 2-pyridylacetamide derivative, a process for producing the same, and a medicament containing the same. More specifically, the 2-pyridylacetamide derivative having the general formula (I) and a pharmacologically acceptable acid addition salt thereof have an inhibitory effect on an attack factor of peptic ulcer and an enhancing effect on a defense factor. Since it is low in toxicity, it is a novel compound useful as a therapeutic agent for peptic ulcer.

[Conventional technology]

Although the etiology of peptic ulcer is discussed as an imbalance between attack and defense factors, the factors that increase tissue resistance are still unknown. Therefore, "there is no ulcer where there is no acid"
The word still lives as a maxim, and the therapeutic goal of peptic ulcer is still aimed at controlling gastric acid.

Although anticholinergic agents such as atropine can bring the stomach into a nearly acid-free state, they are not very effective in preventing ulcer exacerbation and recurrence.

As described above, a drug that prevents new ulcers from occurring, that is, suppresses an attack factor alone cannot be expected to have a sufficient effect for treating ulcers. Therefore, at present, a suppressive agent for an attacking factor and a gastric mucosa protective agent for preventing recurrence are each selected as a therapeutic agent for ulcer according to the symptoms. Although some compounds that are said to have both of these actions have been proposed, these compounds were actually weak in suppressing the attack factors, and were mainly gastric mucosa-protecting actions.

[Problems to be solved by the invention]

As described above, there is a strong demand for the development of a potent anti-peptic ulcer drug that balances both the defense of attacking factors and the protection of gastric mucosa. Furthermore, it is important that the peptic ulcer drug has as little toxicity and side effects as possible. Therefore, as a result of planning and studying the development of a drug focusing on these active and toxic aspects, the present inventors have found that 2-pyridyl of the present invention, which is a novel compound that balances these activities well and is weakly toxic. We succeeded in obtaining an acetic acid derivative and completed the present invention.

[Means for solving problems]

INDUSTRIAL APPLICABILITY The novel compound 2-pyridylacetamide derivative represented by the general formula (I) and the pharmacologically acceptable acid addition salt thereof according to the present invention have a gastric acid secretion inhibitory effect as well as a gastric mucosa protective effect and are weakly toxic. Therefore, it is a useful substance that can be used for the treatment of peptic ulcer.

The compound represented by the general formula (I) of the present invention can be synthesized, for example, as follows. That is, the general formula (II) (In the formula, R ² is as defined above, and R ³ represents a lower alkyl group.)
In water, a mixed solvent of water and an organic solvent or an organic solvent, for example, at a temperature of room temperature to 100 ° C, the general formula (III) H ₂ N-R ¹ (III) (in the formula, R ¹ is as defined above) The compound of the present invention represented by the general formula (I) can be obtained by reacting ammonia or amines represented by the formula for 12 to 24 hours.

The solvent used in the reaction is not particularly limited as long as it does not participate in the reaction, for example, water, alcohol solvents,
Chlorine solvent, aromatic hydrocarbon solvent, ether solvent,
It is preferable to use an amide solvent or pyridine.

After completion of the reaction, the desired compound can be purified by recrystallization, column chromatography or the like, or can be purified by recrystallization or chromatography as an acid addition salt after treatment with a pharmacologically acceptable acid. .

Examples of the acid used for producing the acid addition salt of the 2-pyridylacetamide derivative according to the present invention include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and perchloric acid, acetic acid, Oxalic acid, citric acid, lactic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, gluconic acid, mandelic acid,
An organic acid such as methanesulfonic acid may be mentioned.

According to the present invention, the novel 2 represented by the above general formula (I)
The -pyridylacetamide derivative may be administered per se, but can be made into various dosage forms by utilizing known formulation techniques. For example, when administered orally,
Tablets, powders, granules, capsules, syrups, etc.
When administered parenterally, it is formulated as an injection, suppository or the like. In any case, it can be mixed with a known liquid or solid diluent or carrier that is commonly used in the formulation to give various formulations.

Examples of such diluents or carriers include polyvinylpyrrolidone, gum arabic, gelatin, sorbit, tragacanth, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol,
Examples thereof include silica, lactose, crystalline cellulose, sugar, starch, calcium phosphate, vegetable oil, carboxymethyl cellulose calcium, sodium lauryl sulfate, water, ethanol, glycerin, mannitol, syrup and the like.

The therapeutic agent for peptic ulcer of the present invention can contain a compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof in an effective amount.

The effective dose of the therapeutic agent for peptic ulcer of the present invention is determined by various factors such as symptoms of a patient to be treated, age, administration route,
It may be appropriately changed depending on the dosage form, the number of administrations, etc., but is usually about 50 to 2,000 mg, preferably 100 per adult per day.
A range of up to 1,000 mg can be exemplified.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Example 1 2-Benzylthiocarbamoyl-2- (2-pyridyl)
Synthesis of acetamide Ethyl 2-benzylthiocarbamoyl-2- (2-pyridyl) acetate (1.00 g, 3.18 mmol) was dissolved in 20 ml of ethanol, and 10 ml of 28% aqueous ammonia solution was added thereto, followed by stirring at room temperature for 24 hours. After the ethanol was distilled off, water was added to the reaction solution and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue, which was recrystallized from chloroform: n-hexane to obtain 0.55 g (yield 64%) of the title compound.

The physical properties of the obtained compound were as shown in Table 1.

Examples 2 to 12 The following compounds were synthesized in the same manner as in Example 1.

The physical properties of the obtained compound were as shown in Table 1.

Example 2 2-Cyclohexylthiocarbamoyl-2- (2-pyridyl) acetamide Example 3 2-Methylthiocarbamoyl-2- (2-pyridyl)-
N-Methylacetamide Example 4 2-allylthiocarbamoyl-2- (2-pyridyl)-
N-Methylacetamide Example 5 2-Benzylthiocarbamoyl-2- (2-pyridyl)
-N-methylacetamide Example 6 2-cyclohexylthiocarbamoyl-2- (2-pyridyl) -N-methylacetamide Example 7 2-phenylthiocarbamoyl-2- (2-pyridyl)
-N-Methylacetamide Example 8 2-Methylthiocarbamoyl-2- (2-pyridyl)-
N-allylacetamide Example 9 2-allylthiocarbamoyl-2- (2-pyridyl)-
N-allylacetamide Example 10 2-Benzylthiocarbamoyl-2- (2-pyridyl)
-N-allylacetamide Example 11 2-Cyclohexylthiocarbamoyl-2- (2-pyridyl) -N-allylacetamide Example 12 2-phenylthiocarbamoyl-2- (2-pyridyl)
-N-allylacetamide Example 13 2-Methylthiocarbamoyl-2- (2-pyridyl)-
Synthesis of N-benzylacetamide Ethyl 2-methylthiocarbamoyl-2- (2-pyridyl) acetate (1.00 g, 4.20 mmol) was dissolved in 20 ml ethanol, and benzylamine (0.54 g, 5.04 mmol) was added to the solution for 48 hours. Heated to reflux. The residue obtained by distilling off ethanol was subjected to silica gel column chromatography to obtain 0.97 g (yield 77%) of the title compound.

The physical properties of the obtained compound were as shown in Table 1.

Examples 14 and 15 The following compounds were synthesized in the same manner as in Example 1.

The physical properties of the obtained compound were as shown in Table 1.

Example 14 2-Methylthiocarbamoyl-2- (2-pyridyl)-
N- (3-phenylpropyl) acetamide Example 15 2-Methylthiocarbamoyl-2- (2-pyridyl)-
N-geranyl acetamide The following tests were conducted for the pharmacological effects of the compounds of the present invention.
From these experiments, the inhibitory effect on gastric acid secretion and the protective effect on gastric mucosa can be obtained as the inhibitory percentage.

〔Test method〕

1. Action on gastric acid secretion (Shay rat) Body weight 200-240g
Sprague-Dawley male rats were used after fasting for 24 hours (water was given ad libitum).
Open the abdomen under ether anesthesia, ligate the pylorus, and close the abdomen.
Fasted and left under water. The stomach was removed under ether anesthesia and the gastric juice was collected. The collected gastric juice was spun down at 3000 rpm for 10 minutes, the volume (ml) of the supernatant was measured, and then 1 ml of the gastric juice was collected.
Was titrated to pH 7.0 with 0.1N sodium hydroxide solution,
The acidity (μEq / ml) was determined. Further, the acid excretion amount (μEq / 4h) was calculated from the product of gastric juice volume and acidity; the inhibition rate was calculated from the following formula. All the test drugs were suspended in physiological saline, 0.2 ml / 10
Immediately after the pylorus was ligated at a rate of 0 g / body weight, it was administered into the duodenum.

2. Effects on ethanol ulcers of hydrochloric acid Sprague-Dawl weighing 200-240 g
ey) male rats were used after fasting for 24 hours. 0.5 ml of 60% ethanol solution containing 150 mM hydrochloric acid was added to this rat.
Oral administration was performed at a volume of / 100 g / body weight, and one hour later, the stomach was extracted under ether anesthesia. The inside and outside walls of the stomach were fixed by injecting 10 ml of a 2% formalin solution into the stomach and further immersing it in the 2% formalin solution for about 15 minutes. An incision was made along the greater curvature, and the length of damage occurring in the glandular stomach was measured under a stereoscopic microscope at 10x, and the sum of the lengths of gastric mucosal damage per animal was calculated as the ulcer index (lesionindex) ( mm) was compared with the control group, and the inhibition rate was calculated by the following formula. All test drugs were suspended in physiological saline and orally administered in a volume of 0.5 ml / 100 g / body weight 30 minutes before administration of hydrochloric acid-ethanol solution.

The results are as shown in Table 2.

3. Results of Acute Toxicity Test Five-week-old male ddY mice were fasted overnight, and the results obtained in Example 8 above.
The compound was suspended in a solvent and orally administered at a rate of 0.1 ml / 10 g body weight, and the minimum lethal dose (MLD) was measured. The result was MLD> 1000 mg / Kg, po. 100
At 0 mg / Kg, po, he showed staggered gait and hypotonia. This symptom is a multidimensional observation method of Irwin (Irwin,
S. (1964): Drug screening and evaluation of new co
mpounds in animals.in “Animal and clinical pharmac
ological techniques in drugs evaluation ", ed.by Nod
ine, JHand Siegler, PE, 36-54 pages, Year Book Medic
Al Publishers, Chicago.).

Claims (7)

[Claims] 1. A general formula (I) (In the formula, R ¹ represents a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 3 to 20 carbon atoms or an aralkyl group having 7 to 15 carbon atoms, and R ² represents a hydrogen atom, a linear alkyl group. Group, a cyclic alkyl group, an alkenyl group, an aryl group or an aralkyl group), and a pharmaceutically acceptable acid addition salt thereof. 2. The compound according to claim 1, wherein R ² is a linear or cyclic alkyl group having 1 to 8 carbon atoms. 3. The compound according to claim 1, wherein R ² is an aryl group having 6 to 10 carbon atoms. 4. The compound according to claim 1, wherein R ² is an alkenyl group of 3 to 6. 5. The compound according to claim 1, wherein R ² is an aralkyl group of 7-9. 6. General formula (II) (In the formula, R ² is a hydrogen atom, a linear or cyclic alkyl group,
A 2-pyridyl acetic acid ester derivative represented by an alkenyl group, an aryl group or an aralkyl group, and R ³ represents a lower alkyl group) is represented by the general formula (III) H ₂ N—R ¹ (III) ¹ represents a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 3 to 20 carbon atoms, or an alaru group having 7 to 15 carbon atoms), and is reacted with a compound represented by the general formula (I ) A method for producing a 2-pyridylacetamide derivative represented by the formula: wherein R ¹ and R ² are as defined above, and a pharmaceutically acceptable acid addition salt thereof. 7. General formula (I) (In the formula, R ¹ represents a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 3 to 20 carbon atoms or an aral group having 7 to 15 carbon atoms, and R ² represents a hydrogen atom, a linear alkyl group. , A 2-pyridylacetamide derivative having a cyclic alkyl group, an alkenyl group, an aryl group or an aralkyl group) and / or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. .