JPH0211567A - 2-pyridylacetic acid derivative - Google Patents

Abstract

NEW MATERIAL:A 2-pyridylacetic acid derivative shown by formula I (R<1> is group shown by formula II; n is 1-5 integer; X-Z is H, 1-5C alkyl, 1-5C alkoxy, 2-10C alkenyloxy, halogen, group shown by the formula III with the proviso that X, Y and Z are not H at the same time; m is 0-5 integer: A is nitrogen- containing heterocyclic; R<2> is H or 1-5C alkyl) and a pharmaceutically acceptable acid addition salt thereof. EXAMPLE:4-Methylphenethyl 2-(2-pyridine)-2-thiocarbamoylacetate hydrochloride. USE:A remedy for peptic ulcer having both inhibitory effects on peptic ulcer attack factor and enhancing effects on preventing factor. PREPARATION:A compound shown by formula IV is reacted with carbon disulfide in an organic solvent in the presence of a base at -78-0 deg.C and treated with methyl iodide to give a compound shown by formula V. This compound is reacted with a compound shown by formula R<2>-NH<2> in water and/or organic solvent to give a compound shown by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (I) [wherein R1 is the formula NH-R] [wherein R1 is the formula (wherein n is 1 to 5 integer, X, Y and Z are hydrogen atoms,
An alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an alkenyloxy group having 2 to 10 carbon atoms, a halogen atom, or a group ÷CH2÷, A (where m is an integer of 0 to 5, A represents a nitrogen-containing heterocycle), but X, Y and Z
is simultaneously a hydrogen source (wherein n is an integer of 1. to 5, X, Y and Z are hydrogen atoms, alkyl groups having 1 to 5 carbon atoms, 1 carbon number
~5 alkoxy group, alkenyloxy group having 2 to 10 carbon atoms, halogen atom, or group 10CH, +, A (wherein m is an integer of O to 5, A represents a nitrogen-containing heterocycle) However, X, Y and Z are never hydrogen atoms at the same time), and R2 is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms].

The 2-pyridylacetic acid derivative having the general formula (I) 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 protective factors, but there are still many unknowns about the factors that increase tissue 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 atrobin, 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, 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 weak inhibitory effects on aggressive factors (mainly gastric mucosal protective effects), and are of limited clinical use. It does not show sufficient healing effects in the field.

[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 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 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 (I) of the present invention can be synthesized, for example, as follows.

That is, a 2-pyridyl acetate represented by general formula (II) (wherein R' is as defined above) is heated in an organic solvent at a temperature of -78°C to 0°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, by adding methyl iodide and stirring for several hours, an adduct having the general formula (I[[)%formula%, where R' 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, it is preferable to use an alkyllithium reagent, sodium amide, potassium amide, sodium hydride, potassium hydride, potassium t-butoxide, sodium alcoholate, potassium alcoholade, sodium metal, etc. .

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

Next, the compound (Ill) is mixed with general formula (IV) 1? in water, water and an organic solvent, or in an organic solvent. The compound of the present invention is obtained by reacting ammonia or amines represented by ``-NH, (IV) (wherein R2 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, and examples include water, alcohol-based solvents, chlorine-based solvents, aromatic hydrocarbon-based solvents, ether-based solvents, and acetate-based solvents. It is preferable to use a solvent - After the reaction, the desired compound can be purified by recrystallization, column chromatography, etc., or treated with a pharmacologically acceptable acid and recrystallized or converted into an acid addition salt. Purification can also be achieved by 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 (If) 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. Further, 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 the general formula (rl).

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-R3(V) (in the formula, R3 represents an alkyl group having 1 to 5 carbon atoms) to the above reaction solution, the general formula (Ia ) NH-R' (wherein R' and R3 are as defined above) can be obtained. The compound (Ia) thus obtained can also be purified using the purification method described above, or it can be treated with a pharmaceutically suitable acid to form an acid addition salt as described above. I can do it.

The novel 2 represented by the general formula (I) according to the present invention
- The pyridylacetic acid derivative 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, 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 (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. Approximately 50~2,000■ per day, preferably 100~
A range of 1,000 square meters can be exemplified.

〔Example〕

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.

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

1 day Person ■A Intermediate compounds 1 to 10 represented by formula (n) shown in Table 1
was synthesized as follows. Table 1 shows the physical properties of the obtained compound.

2-pyridyl acetate 10.00 g (57.60 mmol), 4-methylphenethyl alcohol 7.84 g
(57.60 mmol) was dissolved in a mixed solvent of pyridine 20- and methylene chloride 801111, and 1
13.26 g (69.12 mmol) of -ethyl-3-(3-dimethylaminopropyl)carposiimide hydrochloride was added, and the mixture was 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 was purified by distillation or silica gel column chromatography to obtain 12.06 g of the title compound.

The following intermediate compounds Nα2 to Nα2 (I10) were also synthesized in the same manner as above.

Nα2: 4-isopropylphenethyl 2-pyridyl acetate Nα3: 2.3.6-,) dimethylphenethyl 2-pyridyl acetate Nα4: 4-fluorophenethyl 2-pyridyl acetate Nα5: 4-methoxyphenethyl 2-pyridyl acetate 6:2 , 4.6-1-dimethoxyphenethyl 2-pyridyl acetate Nα7: 4-prenyloxyphenethyl 2-pyridyl acetate Nα8: 3-(piperidinomethyl)phenethyl 2-pyridyl acetate Nα9: 3-(4-methylphenyl)propyl 2
-Pyridyl acetate Nl1IO: '3-(4-Methoxyphenyl)propyl 2-biridyl acetate ■ -Him Compounds Nos. 1 to 12 of general formula (I) shown in Table 2 were synthesized as follows. Table 2 shows the physical properties of the obtained compound.

3.00 g of 4-methylphenethyl 2-pyridyl acetate (I1,7
5 mmol) and heated to -78° under a nitrogen stream.
At C, 1.1 equivalents of n-butyllithium in hexane were added. After stirring for 15 minutes at the same temperature, 0.98 g (I2,92 mmol) of carbon disulfide was added, and after another 15 minutes, 1.84 g (I2,9 mmol) of methyl iodide was added.
2 mmol) was added. After stirring for 2 hours, the reaction temperature was raised to room temperature and 0.0% diluted with saturated ammonium chloride aqueous solution
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 recrystallization or silica gel column chromatography to obtain 4-methylphenethyl
2-(methylthio)thiocarbonyl-2-(2-pyridyl)acetate was obtained. This was dissolved in dioxane 30Id, ammonia gas was injected for about 20 minutes, and the mixture was further stirred at room temperature for 5 hours. Add water to the reaction mixture,
Extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel chromatography as necessary to further give a hydrochloride.

This was recrystallized from chloroform:n-hexane to obtain 3.68 g of the title compound.

The following compounds were synthesized according to method B similar to compound Nα1.

2 to the compound: 4-isopropylphenethyl 2-(
2-pyridyl)-2-thiocarbamoylacetate hydrochloride compound Na4:2.4.6-)limethylphenethyl 2
-(2-pyridyl)-2-thiocarbamoyl acetate hydrochloride compound Nα6: 4-fluorophenethyl 2-(2-pyridyl)-2-thiocarbamoyl acetate hydrochloride compound No. 7: 4-methoxyphenethyl 2-(2-pyridyl )-2-thiocarbamoyl acetate hydrochloride compound 8:2,4.6-)rimethoxyphenethyl 2
- (2-pyridyl)-2-thiocarbamoylacetate hydrochloride compound Nα11:3-(4-methoxyphenyl)propyl 2-(2-pyridyl)-2-thiocarbamoylacetate hydrochloride compound Nα12:3-(4-methoxyphenyl) Phenyl)propyl 2-(2-pyridyl)-2-thiocarbamoyl acetate hydrochloride 4-isopropylphenethyl 2-pyridyl acetate) 0.87 g (3,07
mmol) and heated to -78°C under a nitrogen stream.
1.1 equivalents of n-phthyllithium hexane solution or sodium amide was added.

After stirring for 15-30 minutes at the same temperature, 0.27 g (3.07 mmol) of methyl isothiocyanate was added.

Subsequently, the mixture was stirred at room temperature for 2 hours, and the reaction solution was diluted with water and extracted with chloroform. The extract was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography, converted into a hydrochloride, and recrystallized from acetic acid ethyl acetate:ether to obtain 0.87 g of the title compound.

The following compounds were synthesized according to method A similar to compound Nα3.

Compound Na5j2.4.6-)limethylphenethyl 2
-Methylthiocarbamoyl-2-(-2-pyridyl)acetate compound Nα9:4-prenyloxyphenethyl 2-methylthiocarbamoyl-2-(2-pyridyl)acetate compound Nα10:3-(piperidinomethyl)phenethyl 2-methylthiocarbamoyl-2- (2-pyridyl)
Compound 95 Lactose of the example below the acetate margin November
25 Crystalline cellulose 10 Corn starch 100 The above components were split 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.

Sprague-Dourii (Sp) weighing 200-240 g
(Rague-Dawley) male rats were used after being fasted for 24 hours. This rat was treated with 0.5 rrdl/lo of a 60% ethanol solution containing 150 mmol hydrochloric acid.
The mice were orally administered at a volume of 0.4 oz/kg body weight, and after - hours, the stomach was removed under ether anesthesia. 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. Make an incision along Tenryu, 10
Measure the length of the damage occurring on the dorsal part of the gland under a stereoscopic microscope, and compare the total length of gastric mucosal damage per animal with the control group as ulcer index (ms). The inhibition rate is calculated by the following formula, and then this inhibition rate is plotted on a semi-logarithmic graph against the dose (■/kg) to obtain E D s.

I found the value. All test drugs were prepared in 0.5% carboxymethyl cellulose (CMC) solution or a small amount of Tween.
80 and suspended in physiological saline, 0.5rIt1/100g
-Administered orally at a volume equal to body weight 30 minutes before administration of the hydrochloric acid ethanol solution.

Sprague-Dawley
) strain male rats (200-250 g) were fasted for 24 hours (however, water intake was ad libitum), urethane 1.25 g/k
g It was used after being anesthetized by intraperitoneal administration. Furthermore, during the experiment, 1
Reduce body temperature to 3-7°C using a 00 watt light bulb and a heat plate.
was held at

After making a midline neck incision and inserting a tracheal tube 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/win)
Shita.

For gastric acid secretion, the perfusate flowing out from the stomach is placed in a 50-mm beaker, and the pH inside the beaker is maintained at 7.0.
0mM Mail was automatically dropped, and the pH was continuously measured by the pH stat method (Teibyou Sangyo, Comtite-8). In addition, the physiological saline in the beaker is aerated with 100% Ot.
The temperature was kept at 37°C.

Histamine dihydrochloride dissolved in physiological saline (5■/k
g/hr) was continuously infused at an injection rate of 2.2 rd/hr through a catheter previously inserted into the tail vein. After the stimulated acid secretion stabilizes (90-120 minutes), 30 μ/kg of the test drug suspended in 065% CMC or a small amount of Tween 80 and physiological saline was administered into the duodenum at a volume of 0.2 d/100 g. did. The inhibition rate of gastric acid secretion was calculated using the following formula.

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-Dawley (Spragweed) weighing 240-260 g under stress
Male rats of the Rague-Dawley strain were fasted for 24 hours and used.

After 30111 inches of oral administration of the test drug, the rats were placed in a stress cage and immersed 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 d 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 tenryu region, and the length of the mucosal injury occurring in the glandular stomach region was measured under a stereomicroscope (xlO), and the total sum per animal (ff1m) was taken as Region 1ndex and compared with the control group. The inhibition rate was calculated using the same formula as the effect on hydrochloric acid ethanol ulcers.

Tama-1-Schitotoxicity uses 5-6 week old ddY mice (5 to 6 weeks old) to orally administer the test compound as a 0.5% CMC suspension to determine its toxicity (minimum lethality (MLD)). Ta.

Margin below 0.03 3.7 1.0 6.6 <10 Me'L-table 51 (I0mg/kg) 72 (I0■/kg) >2197 >2197 >1300 >1300 96 (30■/kg)

Claims (1)

[Claims] 1. General formula (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, n is an integer of 1 to 5, X, Y and Z are hydrogen atoms,
Alkyl group with 1 to 5 carbon atoms, alkoxy group with 1 to 5 carbon atoms, alkenyloxy group with 2 to 10 carbon atoms, halogen atom, or group ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, m is 0 -5 integer, A represents a nitrogen-containing heterocycle), but X, Y and Z are not hydrogen atoms at the same time), and R^2 is a hydrogen atom or a carbon number of 1 to 5
A 2-pyridyl acetic acid derivative represented by the following and a pharmacologically acceptable acid addition salt thereof.