JPS63230670A - Substituted pyridiylacetic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is 1-5C alkyl or formula II (n is 1-5); R<2> is H, 1-5C alkyl or phenyl; X<1> and X<2> are H, 1-5C alkyl, 1-5C alkoxy or 1-5C halogen-substituted alkoxy (except when both X<1> and R<2> are H)]. EXAMPLE:Geranyl 2-(4-methoxy-6-methyl-2-pyridyl)-2-(methylthiocarbamoyl)ace tate. USE:A remedy for peptic tumor having both inhibitory action on gastric acid secretion and protecting action on gastric mucosae and low toxicity. PREPARATION:A substituted pyridylacetic acid ester expressed by formula III is reacted with carbon disulfide in the presence of a base in an organic solvent at -78-0 deg.C to provide a compound expressed by formula IV, which is then reacted with ammonia or amines expressed by the formula R<2>-NH2 for 10-30hr to afford the aimed compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (I) [wherein R1 is an alkyl group or group having 1 to 5 carbon atoms (in the formula, η is an integer of 1 to 5] ), R2 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a phenyl group;
~5 lower alkyl group, a lower alkoxy group having 1 to 5 carbon atoms, or a halogen-substituted lower alkoxy group having 1 to 5 carbon atoms (excluding cases where both Xl and x2 are hydrogen atoms)] The present invention relates to a substituted pyridyl acetic acid derivative represented by the above formula or a pharmacologically acceptable acid addition salt thereof, and a pharmaceutical containing the same as an active ingredient.

The substituted pyridyl acetic acid derivatives having the general formula (R) and pharmacologically acceptable acid addition salts thereof according to the present invention have the effect of suppressing the aggressive factors and the effect of enhancing the protective factors of peptic ulcers, and have low toxicity. Therefore, it is a new compound useful as a therapeutic agent for peptic ulcers.

[Prior art]

The pathogenesis of peptic ulcer disease has been discussed in terms of an imbalance between offensive and protective factors, but the factors that increase tissue resistance are still unclear. Therefore, “there is no ulcer where there is no acid.”
The word "°" still lives on as a saying, and the current treatment goal for peptic ulcer disease is still aimed at controlling gastric acid.

Anticholinergic drugs, such as atrobin, 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 new ulcers from occurring, that is, drugs that suppress aggressive factors alone cannot be expected to be sufficiently effective in treating ulcers. Mucosal protective drugs 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 suppressive effect on attacking factors, and their main effect is to protect the gastric mucosa.

[Problem that the invention seeks to solve]

As mentioned above, there is a strong desire to develop a powerful anti-peptic ulcer drug that has a balanced effect of 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 discussed the development of a drug focusing on these active and toxic aspects, and as a result, the substituted pyridyl of the present invention 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 problems]

The novel compound-substituted 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 and therefore difficult to digest. It is a useful substance that can be used to treat ulcers.

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

That is, a substituted pyridyl acetate represented by general formula (II) (wherein R', Carbon disulfide is applied at a temperature of . The reaction is completed in minutes to tens of minutes. After completion of the reaction, methyl iodide is added and stirred for several hours to obtain the general formula (I[) (where RI, Xl and X2 are as defined above). ) can be obtained.

Examples of solvents that can be used in the reaction include ethers such as tetrahydrofuran, ether, dimethane)xyethane or dioxane, aromatic hydrocarbons such as benzene, toluene or xylene, and dimethyl sulfoxide. On the other hand, the bases used in the reaction include alkyl lithium reagents, sodium amide, potassium amide, sodium hydride,
Preference is given to using potassium hydride, potassium tert-butoxide, sodium alcoholade, potassium alcoholade, metallic sodium, and the like.

The amount of 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 (I[[) thus obtained can be purified by commonly used purification methods, such as chromatography, recrystallization or distillation.

Next, the compound (IN) is added with water, water and an organic solvent, or ammonia or an amine represented by the general formula (IV) R2-Nl2(IV) (wherein R2 is as defined above). The compound of the present invention can be obtained by reacting these compounds 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 solvents, chlorine solvents, aromatic hydrocarbon solvents, ether solvents, or acetate solvents are used. It is preferable to do so.

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 substituted pyridyl acetic 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, citric acid, lactic acid, maleic acid, succinic acid,
Organic acids such as fumaric acid, tartaric acid, gluconic acid, mandelic acid, and methanesulfonic acid can be mentioned.

Another method for synthesizing substituted pyridyl acetic acid derivatives according to the invention is to dissolve the compound having the general formula (II) 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, and although there is no particular limitation on the amount of the base used in the reaction, it is preferable to use the compound of general formula (II) above. It is used in an amount of 1.0 to 1.2 equivalents.

As such a base, it is preferable to use an alkyl lithium reagent such as sodium hydride, sodium alkoxide, potassium alkoxide, sodium amide or metallic sodium.

Then, by adding an isothiocyanate represented by the general formula (V) S=C=N-R3(V) (in the formula, R3 represents an alkyl group having 1 to 5 carbon atoms or a phenyl group) to the above reaction solution. A compound of the present invention represented by the general formula (Im)C:SNH-R'' (wherein R1 and R3 are as defined above) can be obtained.The compound thus obtained (Im ) 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 substituted pyridyl acetic acid derivative represented by the general formula (I) according to the present invention may be administered as such, but
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, suppositories, 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 a compound represented by the general formula (R) 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. Approximately 50-2,000 mg per day, preferably 100 mg
A range of 1,000 mg to 1,000 mg can be exemplified.

〔Example〕

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

Yutaka 1 Tsuma 1 Ni Ni Topuri 1 Water 20 companies Concentrated sulfuric acid 16-1 and (3-methyl-2-pyridyl) acetonitrile 17.00. (I28.6 mmol 0 was added and heated under reflux for 3 hours. After cooling, water was distilled off under reduced pressure. Next, 10 Dst' of ethanol was added to the residue and heated under reflux for an additional hour. After ethanol was distilled off,
The residue was poured into ice water, the reaction mixture was neutralized with sodium hydroxide, and then extracted with chloroform. After drying the extract, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain the title compound 12.
91. I got it.

In the above method, instead of (3-methyl-2-pyridyl)acetonitrile, (4-methyl-2-pyridyl)acetonitrile (Reference Example 2), (5-methyl-2-pyridyl)acetonitrile (Reference Example 3), ( 6-Methyl-2-pyridyl)acetonitrile (Reference Example 4), (4,6-cymethyl-2-pyridyl)acetonitrile (
Reference Example 5), (4-methoxy-3-methyl-2-pyridyl)acetonitrile (Reference Example 6), (4-methoxy-6-methyl-2-pyridyl)acetonitrile (Reference Example 7), or (6-methyl -4-(2,2,2-)lifluoroethoxy)-2-pyridyl)acetonitrile (Reference Example 8), and ethyl (4-methyl-2-pyridyl)acetate (Reference Example 2), respectively. ), Ethyl (5-methyl-2-pyridyl) acetate (Reference example 3), Ethyl (6-methyl-2-pyridyl) acetate (Reference example 4), Ethyl (4,6-dimethyl-2-pyridyl) acetate (Reference example) Example 5), ethyl (4-methoxy-3-methyl-2-pyridyl)
Acetate (Reference 15i16), Ethyl (4-methoxy-6-methyl-2-pyridyl) acetate (Reference Example 7)
), or ethyl [6-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl coacetate (Reference Example 8)
, got .

Moreover, amyl (3-methyl-2-pyridyl) acetate (Reference Example 9) was obtained by using amyl alcohol instead of ethanol in the above method.

The physical property data and yield of each of the above compounds are shown in Table 1.
.

T! JLu East Zul Futami! 8 WAl of concentrated sulfuric acid and 8.5 g (64.3 mmol) of (5-methyl-2-pyridyl)acetonitrile were added to 10 pieces of water and heated under reflux for 3 hours. After cooling, the mixture was neutralized with an aqueous sodium hydroxide solution, and water was distilled off. After completely removing water by azeotroping the residue with benzene, 25 g of pyridine, 50 g of methylene chloride, and 9.9 g of geraniol (64,3 g) were added.
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 18.49 g (98,5
mmol) and stirred at room temperature for 3 hours. After evaporating the solvent, it was diluted with water and extracted with chloroform. After drying the extract, the solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain the title compound 17.8. I got it.

In the above method, instead of (5-methyl-2-pyridyl)acetonitrile, (6-methyl-2-pyridyl)acetonitrile (Reference Example 11) (4,6-cymethyl-2-pyridyl)acetonitrile (Reference Example 12) (4 -Methoxy-3-methyl-2-pyridyl)acetonitrile (Reference Example 13) (4-Methoxy-6-methyl-2-pyridyl)acetonitrile (Reference Example 14) or (6-methyl-4-(2,2, 2-trifluoroethoxy)-2-pyridyl)acetonitrile (by using the reference example, geranyl (6-methyl-2-pyridyl)acetate (
Reference example 11) Geranyl (4,6-cymethyl-2-)pyridyl) acetate (Reference example 12) Geranyl (4-methoxy-3-methyl-2-pyridyl) acetate (Reference example 13) Geranyl (4-methoxy-6- Methyl-2-pyridyl) acetate (Reference Example 14) or geranyl [6-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl coacetate (Reference Example 1)
5) Obtained.

Further, in the method of Reference Example 14 above, prenyl (4-methoxy-6-methyl-2-pyridyl) acetate was obtained by using prenyl alcohol instead of geraniol (Reference Example 16), and further by the method of the above (Reference Example 10). Farnesyl (3-methyl-2-pyridyl) acetate was obtained by using farnesol instead of geraniol and using 3-methyl-2-pyridylacetonitrile instead of 5-methyl-2-pyridylacetonitrile (Reference Example 17).

Table 1 shows the physical property data and yield of each of the above compounds.

1.5 fish belly ethyl (4-methyl-2-pyridyl) acetate 2.
20 g (I2.4 mmol) in 2% NaOR aqueous solution 5
0 and stirred at room temperature for 12 hours. After neutralizing the reaction solution with an aqueous hydrochloric acid solution, the solvent was distilled off. After azeotropically distilling the residue with benzene to completely remove water, pyridine 1
0mf, methylene chloride 100 companies, then geraniol 1.
91 g (I2.4 mmol), 1-ethyl-3-(3
-dimethylamino 10 pyru) carbodiimide hydrochloride 4.
F5. (24.8 mmol) was added and stirred at room temperature for 3 hours. Diluted with water and extracted with methylene chloride. After drying the extract, the solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain 2.50 g of the above compound.

Table 1 shows the physical property data and yield of the obtained compound.

5.0 Og (I5.8 mmol) of geranyl 2-(4-methoxy-6-methyl)pyridyl acetate was added to 50% of anhydrous tetrahydrofuran at -78°C under a nitrogen stream.
15% n-butyllithium hexane solution 10.4
mt' was added dropwise. After stirring for 15 minutes, 1.27 g (I7.3 mmol) of mezal isothiocyanate was added,
Furthermore, the reaction mixture 3, which had been stirred at room temperature for 1.5 hours, was diluted with an aqueous ammonium chloride solution and extracted with chloroform. After drying the extract, the solvent was distilled off, and the residue was subjected to silica gel chromatography. Obtain 4.67 g of the compound.
Table 2 shows the physical property data and yield of the obtained compound.

The target compounds shown in Table 2 were synthesized by reacting with the following compounds.

Table 2 shows the physical property data and yield of the obtained compound.

2- Rubamoyl acetate song.

Geranyl (5-methyl-2-pyridyl)acetate)2
．． 60 g (9.05 mmol) was added to 25 ml of anhydrous tetrahydrofuran and heated to 15% η at -78°C under a nitrogen stream.
-Butyllithium hexane solution 6.2-jF was added.

After stirring for 15 minutes, 0.76 g (9.95 mmol) of carbon disulfide was added, and the mixture was stirred for an additional 15 minutes at the same temperature.

Next, 1.35 g (9.50 mmol) of methyl iodide was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with chloroform. After drying the extract, the solvent was distilled off and the residue was subjected to silica gel chromatography to obtain 2.80 g (5.45 mmol) of geranyl 2-dithiomethoxycarbonyl-2-(2-pyridyl) acetate as a yellow oil. .

This was dissolved in 3 ml of ethanol, 0.68-ffi (5.45 mmol) of 28% aqueous ammonia was added thereto, and the extract was dried at room temperature, the solvent was distilled off, and the residue was subjected to silica gel chromatography. The target compound 1.35. I got it. Table 2 shows the physical property data and yield of the obtained compound.

According to the method of Example 5, appropriate starting compounds were reacted to synthesize the target compounds shown in Table 2.

Table 2 shows the physical property data and yield of the obtained compound.

Lactose 25 Crystalline cellulose 10 Corn starch 100 The above ingredients were prepared 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 effect of suppressing gastric acid secretion and protecting the gastric mucosa was confirmed. In addition, the toxicity (LDso) was determined by orally administering the test compound to a group of 6 mice.

Weight 200-240. Sprague Dowry 4 (Spr.
Male rats of the agu6-Dawley strain were used and fed 24 hours a day (water was provided ad libitum). The abdomen was opened under ether anesthesia, the pylorus was ligated, the abdomen was closed, and the animal was left without food for 4 hours. The stomach was removed under ether anesthesia and gastric juice was collected. The collected gastric juice was centrifuged at 30 GO rpm for 10 minutes,
After measuring the volume of the supernatant, 1 m& of gastric juice was
．． The pH was titrated to 0 with a 1N sodium hydroxide solution to determine acidity (μEg/sf). Furthermore, the acid excretion amount (μEg/4 h) is calculated from the product of the gastric juice volume and the acidity; the suppression rate is calculated from the formula below, and then the suppression rate is expressed as the dose (sg/k).
g) was plotted on a semi-log graph to determine the ED5° value. All test drugs were suspended in physiological saline and
．． It was administered into the duodenum immediately after pyloric ligation at a ratio of 2 companies/100 g body weight.

The results are shown in Table 3.

2. Sprague-Dawley (Spr.
Ague-D@wley) male rats were used and fed 24 hours a day. A 60% ethanol solution containing 150 mmol hydrochloric acid was orally administered to the rat in a volume of 0.5 ml/100 g/body weight, and one hour later, the stomach was injected under ether anesthesia.
Extracted. 10 days 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 greater curvature, and the length of the damage occurring in the glandular stomach was measured under a stereomicroscope at 10x magnification.
The sum of the lengths of gastric mucosal damage per 6 points is the ulcer index (Ies
ion 1 index) (brass ring), the inhibition rate was calculated using the following formula, and this inhibition rate was then plotted on a semi-logarithmic graph against the dose (mg/kg) to determine the ED. I found the value. 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 the hydrochloric acid ethanol solution.

The results are shown in Table 3.

Table 3

Claims (1)

[Claims] 1. General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 is an alkyl group having 1 to 5 carbon atoms, or a group ▲ Numerical formula, chemical formula, There are tables etc. ▼ (In the formula, n represents an integer from 1 to 5), R^2 represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a phenyl group, and X^1 and X^ 2 is independently a hydrogen atom,
Indicates either a lower alkyl group having 1 to 5 carbon atoms, a lower alkoxy group having 1 to 5 carbon atoms, or a halogen-substituted lower alkoxy group having 1 to 5 carbon atoms (however, X^1 and X^
2 is a hydrogen atom)] A substituted pyridyl acetic acid derivative or a pharmacologically acceptable acid addition salt thereof. 2. General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is an alkyl group or group having 1 to 5 carbon atoms▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, n represents an integer from 1 to 5), R^2
represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or a phenyl group, and X^1 and X^2 are independently a hydrogen atom,
Represents either a lower alkyl group having 1 to 5 carbon atoms, a lower alkoxy group having 1 to 5 carbon atoms, or a halogen-substituted lower alkoxy group having 1 to 5 carbon atoms (however, X^1 and X^2
are both hydrogen atoms)] A therapeutic agent for peptic ulcer disease containing a substituted pyridyl acetic acid derivative represented by the following or a pharmacologically acceptable acid addition salt thereof as an active ingredient.