JPH0242059A - 2-pyridylacetic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is group of formula II (n is 1-5; X is H, 1-5C alkyl or 1-5C alkoxy); R<2> is H or 1-5C alkyl] and its acid addition salt. EXAMPLE:2-Phenoxyethyl 2-(2-pyridyl)-2-thiocarbamoylacetate hydrochloride. USE:A remedy for peptic ulcer. It is effective in suppressing the aggressive factor and potentiating the protective factor of peptic ulcer. PREPARATION:The compound of formula I can be produced by reacting a 2-pyridylacetic acid ester of formula III with carbon disulfide in an organic solvent in the presence of a base (e.g., alkyllithium reagent or sodium amide) at -78-0 deg.C, adding methyl iodide to the system after the completion of the reaction and reacting the resultant adduct of formula IV with ammonia or an amide of formula R<2>-NH2.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (I) [wherein R1 is -(CHz>,, -o -3x(in the formula,
n is an integer of 1 to 5, X is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms], R
2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms] A 2-pyridyl acetic acid derivative and a pharmacologically acceptable acid addition salt thereof.

[In the formula, R1 is -(CH2). −〇−[===]Yaw
(In the formula, n is an integer of 1 to 5, X is a hydrogen atom, and the number of carbon atoms is 1 to 5.
5 alkyl group or an alkoxy group having 1 to 5 carbon atoms], R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. The 2-pyridylacetic acid derivative having the above-mentioned form (I) and its pharmacologically acceptable acid addition salt have an effect of suppressing the aggressive factors and an enhancing effect of the protective factor of peptic ulcer, and are low in toxicity. This is a new compound useful as a therapeutic agent for peptic ulcers.

[Conventional technology]

The pathogenesis of peptic ulcer disease has been discussed in terms of the imbalance between offensive and protective factors, but the factors that increase tissue resistance are still largely unknown. Therefore, the saying "There is no ulcer without acid" still lives on as a maxim, and the current goal of treatment for peptic ulcers is still to control gastric acid.

Anticholinergic drugs, such as atropine, can make the stomach nearly acid-free, but these are also not very effective in preventing ulcer worsening and recurrence.

As mentioned above, drugs that prevent the new occurrence of ulcers, that is, suppress the aggressive factors, alone cannot be expected to be sufficiently effective in treating ulcers. Therefore, at present, drugs that suppress the attack factor and drugs that protect the gastric mucosa to prevent recurrence are selected as ulcer treatments depending on the symptoms. Several compounds have been proposed that are said to have both of these effects, but in reality, these have only a weak inhibitory effect on attacking factors, and their main effect is to protect the gastric mucosa.

[Problems to be Solved by the Invention] As mentioned above, there is a strong desire for the development of a powerful anti-peptic ulcer drug that is well-balanced in protecting against attacking factors and protecting the gastric mucosa. Furthermore, it is important that the agent has as little toxicity and side effects as possible as a peptic ulcer agent.

Therefore, the present inventors planned and studied the development of a drug focusing on these active and toxic aspects, and as a result, the present inventors developed the 2-pyridyl compound of the present invention, which is a novel compound with well-balanced activities and weak toxicity. They succeeded in obtaining an acetic acid derivative and completed the present invention.

[Means for solving the problem] Novel compound 2 represented by the above-mentioned form (I) according to the present invention
- Pyridyl acetic acid derivatives and their pharmacologically acceptable acid addition salts have the effect of suppressing gastric acid secretion and protect the gastric mucosa, and are weakly toxic, so they are useful substances that can be used for the treatment of peptic ulcers.

The compound represented by the above-mentioned form (I) of the present invention can be synthesized, for example, as follows.

That is, a 2-pyridyl acetate of the form (I[), where R1 is as defined above, is treated in an organic solvent at a temperature of -78°C-O''C in the presence of a base. to act with carbon disulfide.

The reaction is completed in a few minutes to several tens of minutes.

After the reaction is complete, methyl iodide is added and stirred for several hours to obtain an adduct having the general formula (II[)-CH5, where the sum is as defined above.

Examples of solvents that can be used in the reaction include ethers such as tetrahydrofuran, ether, dimethoxyethane or dioxane, aromatic hydrocarbons such as benzene, toluene or xylene, and dimethyl sulfoxide. On the other hand, as the base used in the reaction, alkyl lithium reagent, sodium amide, potassium amide, sodium hydride, potassium hydride, potassium t-butoxide, sodium alcoholade, potassium alcoholade, sodium metal, etc. are used. preferable.

The amount of the base used in the reaction is not particularly limited, and for example, 1 to 1.2 equivalents relative to the compound (II) is sufficient.

The adduct having the general formula (II[) thus obtained can be purified by commonly used purification methods, such as chromatography, recrystallization or distillation.

Next, the compound (III) is dissolved in water, water and an organic solvent, or in an organic solvent - format (IV) R2-NH2(rv) (wherein, R2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms. ) ammonia or amines represented by 1
The compound of the present invention can be obtained by reacting for 0 to 30 hours. The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction; for example, water,
Preferably, alcohol solvents, chlorine solvents, aromatic hydrocarbon solvents, ether solvents or acetate ester solvents are used.

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

The acids used to prepare the acid addition salts of the 2-pyridylacetic acid derivatives according to the invention include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, acetic acid, oxalic acid, etc. , citric acid, lactic acid, maleic acid, succinic acid,
Examples include organic acids such as fumaric acid, tartaric acid, gluconic acid, mandelic acid, and methanesulfonic acid.

Another method for synthesizing the 2-pyridylacetic acid derivative according to the invention is to dissolve the compound having the general formula (n) above in an organic solvent and treat it with a base at a temperature below 0°C. As such an organic solvent, it is preferable to use an ether solvent or an aromatic hydrocarbon solvent. The amount of the base used in the reaction is not particularly limited, but it is preferably used in an amount of 1.0 to 1.2 equivalents relative to the compound of form (II).

As such a base, it is preferable to use sodium hydride, sodium alkoxide, potassium alkoxide, sodium amide, sodium metal, or the like.

Next, by adding an isothiocyanate represented by the general formula (V) S=C=N-R' (V) (in the formula, R3 represents an alkyl group having 1 to 5 carbon atoms) to the above reaction solution, the general formula (
Ia) ■ A compound of the invention represented by NH-R' (wherein R' and R3 are as defined above) can be obtained.

Compound (Ia) thus obtained can also be purified using the purification method described above, or can be treated with a pharmaceutically suitable acid to form an acid addition salt as described above. .

The novel 2- represented by form (I) according to the present invention
Pyridylacetic acid derivatives may be administered as such, but they can be made into various dosage forms using known formulation techniques. For example, when administered orally, it is usually formulated as a tablet, powder, granule, capsule, syrup, etc., and when administered parenterally, it is formulated as an injection, suppository, etc. In either case, it can be mixed with a known liquid or solid diluent or carrier commonly used in pharmaceutical preparations to form preparations in various shapes.

Examples of such diluents or carriers include, for example, polyvinylpyrrolidone, gum arabic, gelatin, tulpinto, tragacanth, magnesium stearate, talc, polyethylene glycol, polyvinyl alcohol,
Examples 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 peptic ulcer therapeutic agent of the present invention can contain an effective amount of the compound represented by formula (I) or a pharmacologically acceptable acid addition salt thereof.

The effective dosage of the peptic ulcer therapeutic agent of the present invention can be changed as appropriate depending on various factors, such as the symptoms of the patient to be treated, age, route of administration, dosage form, number of administrations, etc. about 50-2,000 mg per day, preferably 10
A range of 0 to L 000 mg can be exemplified.

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

2-pyridyl acetic acid hydrochloride 5.00 g (28.80 mmol), 2-phenoxyethanol 3.98 g (28
, 80 mmol) was dissolved in a mixed solvent of 10 ml of pyridine and 40 mmol of methylene chloride.

To this, 6.63 g of 1-ethyl-3-(3-dimethylaminopropyl)carposiimide hydrochloride (34,56
mmol) and stirred at room temperature for 3 hours. Subsequently, the reaction mixture was concentrated under slight pressure, water was added, and the mixture was extracted with chloroform. After washing the extract with water, it is dried over anhydrous magnesium sulfate, the solvent is distilled off, and the residual aroma is separated and purified by distillation (or column chromatography).
5.26g of the title compound was obtained.

Entry No. 2 and 3 people The following intermediate compounds 2 and 3 were synthesized in the same manner as above.

Intermediate compound No. 2: 2-(4-methylphenoxy)ethyl 2-pyridyl acetate Intermediate compound No. 3: 2-(4-methoxyphenoxy)
Ethyl 2-pyridyl acetate The physical properties of the obtained intermediate compounds No. 1 to 3 are shown in Table 1.

12: The target compounds Nos. 1 to 4 shown in Table 2 were synthesized as follows. Table 2 shows the physical properties of the obtained compound.

3.00 g (I1, 66 mmol) of 2-phenoxyethyl nivyridyl acetate was dissolved in 30/d of dry tetrahydrofuran, and 1.1 equivalents of A-phyllithium hexane was added to the solution at -78°C under a nitrogen stream. solution was added. After stirring at the same temperature for 15 minutes, 0.98 g (I2, 83 mmol) of carbon disulfide was added, and after another 15 minutes, 1.66 g (11.66 mmol) of methyl iodide was added. After stirring for 2 hours, the reaction temperature was lowered to room temperature, diluted with saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The residual aroma obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 2-phenoxyethyl 2-(methylthio)thiocarbonyl-2-(2-pyridyl)acetate.

This was dissolved in 30 mft of dioxane, and ammonia gas was injected for about 20 minutes. After that, the mixture was stirred at room temperature for 5 hours, and then the solvent was distilled off. Water was added to the obtained residual aroma, extracted with chloroform, and the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residual aroma obtained was converted into a hydrochloride to obtain 1.36 g of the title compound.

2-phenoxyethyl acetate in 20ml of dry tetrahydrofuran2. OOg (7.77 mmol) was dissolved, and 1.1 equivalents of n-butyllithium hexane solution was added thereto at -78°C under a nitrogen stream.

After stirring at the same temperature for 30 minutes, 0.68 g (9.33 mmol) of methyl isothiocyanate was added and the reaction temperature was raised to room temperature.

After stirring for 2 hours, water was added to the reaction solution and extracted with chloroform. After washing the extract with water, it was dried with anhydrous magnesium sulfate. The residual aroma obtained by distilling off the solvent was recrystallized from chloroform:n-hexane to obtain 1.49 g of the title compound.

Compound No. 3 and Compound No. 4 were synthesized according to method B above.

Compound 95 of Seikukan Example
25 Crystalline Cellulose 1° Corn Starch 100 The above ingredients were made into a formulation according to a known method.

The following tests were conducted on the pharmacological effects of the compounds of the present invention. The results are shown in Table 3.

The length was measured, and the total length of gastric mucosal damage per animal was compared with the control group as the ulcer index (lesion 1ndex) (mm), and the inhibition rate was calculated using the following formula. EDS plotted on a semi-log graph versus dose (■/kg). I found the value. All test drugs were 0.5% carboxymethylcellulose (CM
C) Suspended in a solution or a small amount of Tween 80 and physiological saline, and administered orally in a volume of 0.5 ml/100 g body weight 30 minutes before administration of the hydrochloric acid ethanol solution.

Sprague Dawley weighing 200-240g
Male rats of the Dainley strain were fasted for 24 hours and used. A 60% ethanol solution containing 150 mmol hydrochloric acid was orally administered to the rat in a volume of 0.3rd/100 g body weight, and - hours later, the stomach was removed under ether anesthesia. Inject 10 ml of 2% formalin solution into the stomach, and immerse it in the 2% formalin solution for about 15 minutes.
The inner and outer walls of the stomach were fixed. An incision was made along the greater curvature, and a male Sprague-Dawley rat (200-250 g) with damage occurring in the glandular stomach was examined under a stereomicroscope at 10x magnification after fasting for 24 hours. (Water intake was ad libitum), and the animals were anesthetized by intraperitoneal administration of 1.25 g/kg of urethane. During the experiment, the body temperature was maintained at 37°C using a 100 watt light bulb and a heating plate.

After making a midline neck incision and inserting a tracheal cannula to secure the airway, the esophagus was ligated. Next, a midline incision is made in the abdomen,
After exposing the stomach and duodenum, a small incision was made in the forestomach, and a polyethylene catheter was inserted and ligated and fixed. On the other hand, a small incision was made at the origin of the duodenum, and another incision was made from there.
A main catheter was inserted into the stomach, avoiding blood vessels, and the pyloric ring was ligated and fixed. Constant flow perfusion of physiological saline into the stomach using these two catheters (Iml, 7 ml)
Shita.

For gastric acid secretion, the perfusate flowing out from the stomach is received in a 5M beaker, and the pI (pI) in the beaker is adjusted to 100 to maintain it at 7.0.
mM NaOH was automatically dropped, and pi (pi) was continuously measured by the stat method (Teibyou Sangyo, Comltite-8).

The physiological saline in the beaker was aerated with 100% 02 and kept at 37°C.

Histamine dihydrochloride (5mg/
kg/hr) was continuously infused at an injection rate of 2.2 rnl/hr through a catheter previously inserted into the tail vein.

After stimulation acid secretion stabilizes (90-120 minutes), 0.5%
C'pIC or a small amount of Tween 80 and 30 mg/kg of the test drug suspended in physiological saline at 0.2 d/100 g.
It was administered into the duodenum at a volume of The inhibition rate of gastric acid secretion was calculated using the following formula.

Secretion amount (u Eq/30 m1n) Statistical processing was performed using a paired 5 student test with 4 animals per group, and a risk rate of less than 5% was considered statistically significant.

3. Stress ・ Sprague-Dawley weighing 240-260g
Male rats of the Ague Dawley strain were fasted for 24 hours and used.

After 30 ml of oral administration of the test drug, the rats were placed in a restraining cage and immersed vertically up to the xiphoid process in a water tank maintained at 23°C to undergo stress loading. After 5 hours, the stomach was removed under ether anesthesia, 10 m2 of 2% formalin solution was injected into the stomach, and further immersed in 2% formalin solution for about 15 minutes, the stomach was opened along the greater curvature, and the glandular stomach was removed. Measure the length of the injured mucosal area under a stereomicroscope (XIO), and compare the total length (mm) per animal with the control group using Lesion 1ndex, and calculate the inhibition rate using the same formula as the effect on hydrochloric acid ethanol ulcers. did.

4.Toxicity was determined by oral administration of the test compound as a 0.5% suspension in 5- to 6-week-old (IclY-type neutral mice) in a group of 5 mice.
Its toxicity (minimum lethal dose (MLD)) was determined.

4.2

Claims (1)

[Claims] 1. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, n is An integer from 1 to 5, X is a hydrogen atom, and has a carbon number of 1 to 5
5 alkyl group or an alkoxy group having 1 to 5 carbon atoms], R^2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms] and its pharmacological Acceptable acid addition salts.