JPH0211568A - 2-pyridylacetic acid derivative - Google Patents

Abstract

NEW MATERIAL:A 2-pyridylacetic acid derivative shown by formula I [R<1> is 8-15C aralkyl or -(CH2)n-A (n is 0-3; A is benzocyclobutyl, indanyl or tetrahydronaphthyl); R<2> is H or 1-5C alkyl] and an acid addition salt thereof. EXAMPLE:Phenethyl 2-methylthiocarbamoyl-2-(2-pyridyl)acetate. USE:Useful as a remedy for peptic ulcer having inhibitory action on secretion of acid in the stomach and protecting action on gastric mucosa and low toxicity free from side effects. PREPARATION:A 2-pyridylacetic ester shown by formula II is treated with carbon dioxide in an organic solvent in the presence of a base at -78 deg.C-0 deg.C. Then the resultant compound is reacted with methyl iodide to give a compound shown by formula III. Successively the compound shown by formula III is reacted with a compound shown by formula IV in water or organic solvent or a mixture thereof to give a compound shown by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound of the general formula H) NH-R'' [wherein R' is an aralkyl group having 8 to 15 carbon atoms or a group -(cHt), -A (In the formula, n is an integer of O to 3,
A represents a benzocyclobutyl group, an indanyl group or a tetrahydronaphthyl group, and RZ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
This invention relates to pyridylacetic acid derivatives.

The 2-pyridylacetic acid derivative having the general formula (1) and its pharmacologically acceptable acid addition salt have the effect of suppressing the aggressive factors and the enhancing effect of the protective factor of peptic ulcers, and have low 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 defensive factors, but there are still many unknowns about the factors that increase tissue abrasion resistance. Therefore, the saying ``There is no ulcer where there is no 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 not very effective in preventing ulcer worsening and recurrence.

As mentioned above, drugs that suppress attacking factors (gastric acid secretion) alone cannot be expected to be sufficiently effective in treating ulcers. Therefore, currently, measures to suppress the aggressive factors and gastric mucosal protective drugs to prevent recurrence are selected as ulcer treatment drugs depending on the symptoms. Several compounds that are said to have both of these effects have been proposed, but none have yet shown sufficient curative effects in the clinical setting, and their main effect is to protect the gastric mucosa. .

[Problem 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 suppressing aggressive 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 found that the 2-rubilidyl compound of the present invention is a novel compound with well-balanced activities and low toxicity. They succeeded in obtaining acid derivatives and completed the present invention.

[Means to solve the problem]

The novel compound 2-pyridyl acetic acid derivative represented by the general formula (I) and its pharmacologically acceptable acid addition salt according to the present invention have a gastric acid secretion suppressing effect and a gastric mucosal protective effect, and are weakly toxic. It is a useful substance that can be used to treat peptic ulcers.

The compound represented by the general formula (1) of the present invention can be synthesized, for example, as follows.

That is, a 2-pyridyl acetate represented by the general formula (It) (wherein R1 is as defined above) is dioxidized in an organic solvent at a temperature of -78°C to 0°C in the presence of a base. Apply carbon sulfide. The reaction is completed in a few minutes to several tens of minutes.

After the reaction is complete, by adding methyl iodide and stirring for several hours, an adduct having the general formula (III) -CH5 (wherein R1 is as defined above) can be obtained.

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 base used in the reaction is not particularly limited, and for example, 1 to 1.2 equivalents to the compound (n) 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 (lI[) is mixed with water, water and an organic solvent, or the general formula (■) R'' -NHz (IV) (in the formula, R2
The compound of the present invention can be obtained by reacting ammonia or amines represented by (represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) for 10 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, alcohol-based solvents, chlorine-based solvents, aromatic hydrocarbon-based solvents, ether-based solvents, or acetate-based solvents are used. is preferable.

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 general formula (II).

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

Next, the general formula (V) S=C=N-R' (V) (in the formula, R3 represents a lower alkyl group having 1 to 5 carbon atoms) is added to the above reaction solution.
By adding an isothiocyanate represented by the formula (Ia), the compound of the present invention represented by the general formula (Ia) (wherein R1 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 the general formula (I) according to the present invention
- The pyridylacetic acid derivative may be administered as such, but
It can be made into various dosage forms using known formulation techniques. For example, when administered orally, tablets,
It is formulated into powders, granules, capsules, syrups, etc., and in the case of parenteral administration, it is formulated as injections, insect bites, 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, sorbitol, 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 general formula (1) 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. Daily drug 50-2.000 mg, preferably 10
A range of 0 to 1.000 square meters can be exemplified.

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

The compound having the general formula (1) of the present invention is shown below.
It was synthesized using the same method. A method via the general formula (I[[) was designated as method B, and a method for obtaining the compound (Ia) of the present invention by directly reacting general formula (II) with an isothiocyanate was designated as method A.

1. Person ■ Person Intermediate compounds 1 to 3 represented by formula (If) shown in Table 1
was synthesized as follows. Table 1 shows the physical properties of the obtained compound.

13.26 g (69.12 mmol) of hydrochloride was added and stirred at room temperature for 3 hours.

Next, after concentrating the reaction mixture, water was added and extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent is subjected to distillation, column chromatography, recrystallization, etc.
Purification was performed to obtain 11.40 g of the title compound.

The following intermediate compounds No. 2 and No. 3 were also obtained in the same manner as above.

2: Phenylpropyl 2-pyridyl acetate Arashi 3: 2-indanyl 2-pyridyl acetate 2-pyridyl acetic acid hydrochloride 10.00 g (57,60
mill), phenethyl alcohol 7.04 g (57,
60 mil) was dissolved in a mixed solvent of 20 units of pyridine and 8 units of methylene chloride, and 1-ethyl-(3-dimethylaminopropyl)carbodiirimolymide was dissolved in the mixture. Compounds 1 to 3 shown in were synthesized as follows. Table 2 shows the physical properties of the obtained compound.

3.00 g (12.43 mmol) of phenethyl 2-pyridyl acetate was dissolved in 30% of dry tetrahydrofuran, and at -78°C under a nitrogen stream, 1.1 g of n-phyllithium hexane was added to the solution or , sodium amide was added. After stirring at the same temperature for 15 to 30 minutes, 1.00 g of methyl isothiocyanate (1
3,0 mmol) was added. After stirring at room temperature for 2 hours, water was added to the reaction solution, extracted with chloroform,
The extract was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was recrystallized from chloroform:n-hexane to obtain 3.68 g of the title compound.

3.00 g (11.75 mmol) of 3-phenylpropyl 2-pyridyl acetate was dissolved in 30% of dry tetrahydrofuran, and 1.1 equivalents of 3-phenylpropyl 2-pyridyl acetate was dissolved at -78°C under a nitrogen stream. A hexane solution of n-phytyllithium was added. After stirring at the same temperature for 15 minutes, 0.90 g (12.34 mmol) of carbon disulfide was added, and after another 5 minutes, 1.75 g (1.75 g) of methyl iodide was added. 12,34
mmol) was added. After stirring for 2 hours, the reaction temperature was raised to room temperature, diluted with saturated ammonium chloride aqueous solution, and the reaction mixture was extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 3-phenylpropyl 2-(methylthio)thiocarbonyl-2-(2-pyridyl)acetate.

Change this to dioxane 30-? It was allowed to dissolve and ammonia gas was injected for about 20 minutes. After stirring at room temperature for 5 hours, the solvent was distilled off, water was added to the obtained residue, and the mixture was extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate.

The residue obtained by distilling off the solvent was converted into a hydrochloride salt, which was recrystallized from chloroform:n-hexane to obtain the title compound 1.73.
I got g.

Below is the margin MJElq doctor's example 95 lactose
25 Crystalline cellulose 10 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 of the gastric mucosal damage per animal was calculated as the ulcer index (Iesion 1ndex).
(Dragon) and compared with the control group, the inhibition rate was calculated by the following formula, and then this inhibition rate was plotted on a semi-log graph against the dose (■/kg), and ED.

I found the value. All test drugs were prepared in a 0.5% carboxymethyl cellulose (CMC) solution or a small amount of Tween.
80 and physiological saline, 0.5 ml/100
g · Body weight was administered orally 30 minutes before administration of the hydrochloric acid ethanol solution.

Sprague-Dourii (Spr
Male Ague-Dawley rats were used after being fasted for 24 hours. A 60% ethanol solution containing 150 mmol hydrochloric acid was orally administered to the rat in a volume of 0.5 aZ/100 g body weight, and - hours later, the stomach was removed under ether anesthesia. 1 Qml of 2% formalin solution was injected into the stomach, and the mice were further immersed in the 2% formalin solution for about 15 minutes to fix the inner and outer walls of the stomach. An incision was made along the tenryu, and under a stereomicroscope with a magnification of 10 times, the Sprague-Dourii (Spr.
ague-Dawley) male rats (200-25
0g) after 24 hours of fasting (however, water intake is ad libitum), urethane 1.25g/k+rl! ! It was used after being anesthetized by intracavitary administration. During the experiment, the body temperature was maintained at 37° C. using a 100 watt light bulb and a hot 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 (1yd/win)
Shita.

Gastric acid secretion is 50ml of perfusate flowing out from the stomach! 100 mM NaOH was automatically dropped into the beaker to maintain the pH in the beaker at 7.0, and continuous measurement was performed using the pH-stat method (Teibyou Sangyo, Comtite-8).

The physiological saline in the beaker was kept at 37°C with aeration of 100% 0□.

Histamine dihydrochloride dissolved in physiological saline (5■/k
g/hr) was continuously injected at an injection rate of 2.2 d/hr through a catheter previously inserted into the tail vein. After the stimulated acid secretion stabilizes (90-120 minutes), 30#/kg of the test drug suspended in 0.5% CMC or a small amount of Tween 80 and physiological saline was injected into the duodenum in a volume of 0.2 ml/100 g. Administered intravenously. The inhibition rate of gastric acid secretion was calculated using the following method.

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. Sprague-Douley weighing 240-260g under stress.
Ague-Dowley) strain rats were fasted for 24 hours and used.

After 3 Qmin of oral administration of the test drug, the rats were placed in a restraint cage and immersed vertically up to the xiphoid process in a water tank maintained at 23°C to undergo stress. After Shr, the stomach was removed under ether anesthesia, 10 ml of 2% formalin solution was injected into the stomach, and the stomach was immersed in 2% formalin solution for about 15 minutes. Measure the length of the injured mucosal area under a stereomicroscope (xlO), - the total length per animal (,) is Le
sion 1ndex compared with the control group7, and the inhibition rate was calculated using the same formula as the effect on hydrochloric acid ethanol ulcers.

Tama-Koichi blood toxicity was determined by orally administering the test compound as a 0.5% CMC suspension using 5 to 6-week-old ddY male mice per group, and measuring its toxicity (minimum lethal i (MLD)). I asked for it.

】L-Wheat 0.2 2.0 11.7

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R' is an aralkyl group having 8 to 15 carbon atoms or a group -(CH_2)_n- A (where n is an integer of 0 to 3,
A represents a benzocyclobutyl group, an indanyl group, or a tetrahydronaphthyl group, and R^2 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms.
Pyridylacetic acid derivatives and pharmacologically acceptable acid addition salts thereof.