JPH0660098B2 - Anti-ulcer agent - Google Patents

Description

TECHNICAL FIELD The present invention relates to an anti-ulcer agent.

(Prior Art) A large amount of gastric acid secretion is mentioned as one of the factors for the formation of digestive ulcers. It is known that this gastric acid is secreted from gastric parietal cells by stimulation with histamine, acetylcholine, gastrin, etc. As a drug that antagonizes these gastric acids and suppresses gastric acid secretion, a cholinergic receptor blocker (eg, atropine) , Histamine H ₂ receptor antagonists (eg, cimetidine), etc. are clinically used. [Medicina, Vol. 23, No. 4, 5
60-565 (1986)] In addition, H ⁺ / K ⁺ AT, which is recently involved in the concentration and secretion of gastric acid,
A benzimidazole compound (for example, omeprazole) that inhibits the enzyme activity of Pase and suppresses gastric acid secretion has also been found (JP-A-54-141783).

However, cholinergic receptor blockers are highly toxic such as atropine poisoning, and side effects such as antiandrogen action and prolactin release stimulating action are known for histamine H ₂ receptor antagonists such as cimetidine.

(Structure and Effect of the Invention) (However, ring A is a halogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group, a nitro group, an amino group, a lower alkanoylamino group, a lower alkanoyloxy group, a cyanide group, a trihalogeno lower alkyl group,
2- or 4-pyridyl group optionally substituted with one or two groups selected from trihalogeno lower alkoxy groups and hydroxyl groups, and ring B is an amino group, mono- or di-
A lower alkylamino group, a lower alkanoylamino group, a cycloalkylamino group, a formylamino group, a morpholino group, a pyrrolyl group, a phenyl group which may be substituted with a group selected from a piperidino group and an imidazolyl group,
R ¹ and R ² are both hydrogen atoms or are bonded to each other at the terminals to form a group represented by the formula — (CH ₂ ) q—,
n represents 0, 1 or 2, and q represents 3 or 4. The present invention relates to an anti-ulcer agent containing an imidazole derivative or a salt thereof as an active ingredient.

Compound (I) or a salt thereof which is an active ingredient of the present invention has an excellent gastric acid secretion inhibitory action and / or an excellent H ⁺ /
It is a medicinal compound useful as an anti-ulcer agent having an enzyme activity inhibitory action against K ⁺ ATPase and having no side effects as seen in histamine H ₂ receptor antagonists, and an anti-ulcer agent of the present invention comprising the compound as an active ingredient. The ulcer agent can be used for treating / preventing gastrointestinal ulcer such as gastric ulcer and duodenal ulcer. In addition, the compound (I) or a salt thereof includes those exhibiting an excellent gastric acid secretion inhibitory action without necessarily depending on the enzyme activity inhibitory action against H ⁺ / K ⁺ ATPase, and existing H ⁺ / K such as omeprazole. ⁺ Exhibits excellent properties as an anti-ulcer agent with a mechanism of action different from that of ATPase inhibitors. Furthermore, the compound (I) or a salt thereof as the active ingredient of the present invention has low toxicity and shows high safety as a medicine. For example, 1,4,5,6-tetrahydro-1- (2-pyridyl) -2- [2- (diethylamino) benzylsulfinyl] cyclopenta [d] imidazole is orally administered to mice at 1000 mg / kg and observed for 3 days. However, no deaths were observed and no weight suppression was observed.

In the compound of general formula (I), ring A is substituted with one or two groups selected from lower alkyl group, lower alkoxy group, phenyl lower alkoxy group, amino group and lower alkanoylamino group. Good 2-
Or 4-pyridyl group; ring B is substituted with a group selected from an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a formylamino group, a morpholino group, a pyrrolyl group, a piperidino group and an imidazolyl group. And R ¹ and R ² are both hydrogen atoms or are bonded to each other at the terminals to form a trimethylene group.

As a more preferable compound from the viewpoint of efficacy, in the general formula (I), ring A may be substituted with one or two groups selected from a lower alkyl group and a lower alkoxy group 2-
Or 4-pyridyl group; a compound in which ring B is a phenyl group substituted with a group selected from an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a morpholino group, a piperidino group and a pyrrolyl group. .

Another group of compounds that are preferable in terms of efficacy include compounds in which n is 0 in the general formula (I).

Further, in the above specific examples and preferred compound groups, the lower alkyl group, the lower alkoxy group and the lower alkanoyl group include an alkyl group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, an alkoxy group and an alkanoyl group, The cycloalkyl group includes a cycloalkyl group having 3 to 8 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms.

The compound (I), which is the active ingredient of the present invention, can be used for medicinal use in the form of either a free base or an acid addition salt. Examples of the pharmaceutically acceptable salt include, for example, hydrochloride,
Examples thereof include inorganic acid addition salts such as hydrobromide, hydroiodide, sulfate and nitrate; organic acid addition salts such as formate, oxalate, methanesulfonate and glucuronate.

The compound (I) or a salt thereof as the active ingredient of the present invention can be administered orally or parenterally. When administered orally, it can be administered as a solid preparation such as tablets, powders, capsules, and granules, which may contain conventional excipients, and may further contain binders and diluents. , A disintegrating agent, a wetting agent and the like. Further, it can be orally administered as a liquid preparation such as an aqueous or oily suspension, solution, syrup, and elixir, or parenterally as an injection.

The dose of the anti-ulcer agent of the present invention is the degree of disease, the age of the patient,
The dose of the compound (I) as an active ingredient or a pharmaceutically acceptable salt thereof is usually about 0.05 to 50 mg / kg, especially about 0. It is preferably used in the range of 1 to 20 mg / kg.

The compound (I), which is an active ingredient of the present invention, includes both an optical isomer based on an asymmetric sulfoxide group and a mixture thereof.

Compound (I) or a salt thereof which is an active ingredient of the present invention is
For example, the general formula (However, ring A, R ¹ , R ² and n have the same meanings as described above) and a mercaptoimidazole compound represented by (Wherein X represents a halogen atom and ring B has the same meaning as described above) and a toluene compound represented by the formula (I) or a salt thereof is used as a deoxidizing agent (for example, alkali metal hydroxide, alkaline earth metal hydroxide, pyridine, Tri-lower-alkylamine etc.) in the presence or absence of the resulting compound of the general formula (However, ring A, ring B, R ¹ , R ² and n have the same meanings as described above), for example, by treating with a conventional oxidant such as metachloroperbenzoic acid or perbenzoic acid. Can be manufactured.

Alternatively, among the imidazole derivatives (I), R ¹ and R
^The compound in which 2 forms a group represented by the _formula- (CH ₂ ) _q- (q has the same meaning as described above) is represented by the general formula (However, R ¹¹ and R ²¹ are bonded to each other at the terminal and are represented by the formula- (C
H ₂ ) _q- to form a group represented by ring A, ring B, q and n
Has the same meaning as above. The imidazole derivative represented by the formula (1) or a salt thereof may be dehydrated with an organic acid such as p-toluenesulfonic acid or an inorganic acid such as hydrochloric acid or sulfuric acid, and then the product may be oxidized in the same manner as above. it can.

The substituents on ring A and ring B of the novel intermediate (II) obtained by the above reaction can be appropriately interconverted with each other as desired, and, for example, have an amino group on ring A and / or ring B. The intermediate (II) is produced by reducing the corresponding nitro group-substituted product (II) by a conventional method or hydrolyzing the corresponding N-phthalimide or N-tri-lower alkylphenylsulfonylamide group-substituted product (II). You can also do it. Further, the intermediate (II) in which the amino group on the ring A and / or the ring B is substituted with a group such as a lower alkanoyl group, a formyl group, a lower alkyl group, etc., can be prepared by using the corresponding amino group-substituted product (II) by a conventional means. Can be further acylated and alkylated to produce.

Experimental Example 1 Suppression of gastric acid secretion SD male fasted rats (5 mice per group) were tested with the test compound (30 mg /
(kg) solution or suspension was orally administered, and pentagastrin (1 mg / kg) was subcutaneously administered 1 hour after the administration. Thirty minutes after that, the rat was slaughtered, the abdomen was opened, and the pyloric region was ligated. Then, the stomach was extracted and the total acidity of the collected gastric juice was measured and used as the gastric acid secretion amount. The results are as shown in Table 1. In the table, the gastric acid secretion inhibitory action was determined by the difference in total acidity between the control group and the administration group,
When it was suppressed by not less than%, "++" was displayed, and when it was suppressed by 40 to 70%, it was displayed as "+".

Experimental Example 2 H ⁺ / K ⁺ ATPase activity inhibitory action The method of Sigrist-Nelson et al. [Febs Letters; FEBS LETTERS 197, 1.2, p. 187 1986
The gastric acid-secreting cells were isolated from the fresh gastric mucosa of edible pigs according to the above method, and the vesicles containing H ⁺ / K ⁺ ATPase were prepared by centrifugation in a discontinuous sucrose density gradient. H ⁺ / K ⁺ AT of the same enzyme in the presence of the test compound
The measurement of Pase activity is carried out by the method of Keeling et al. [Biochemical Ph.
armacology 34, No. 16, page 2967, 1985], and the inhibition rate was calculated from the difference from the H ⁺ / K ⁺ ATPase activity measured in the absence of the test compound. Then, the IC ₅₀ value of each compound was determined from the concentration / inhibition curve prepared based on the inhibition rate for each added concentration of the test compound.

The results are shown in Table 2.

Production Example 1 (1) 3.0 g of 1- (2-pyridyl) -2-mercaptoimidazole was dissolved in 50 ml of ethanol, and 2
16.9 ml of N-sodium hydroxide aqueous solution are added. To this, m-dimethylaminobenzyl chloride hydrochloride 3.8
Add 4 g and stir at room temperature for 2 hours. After the solvent is distilled off, water is added to the residue and the mixture is extracted with ethyl acetate. The extract is washed with water and dried, and then the solvent is distilled off. By recrystallizing the residue from a mixed solution of ethyl acetate and n-hexane, 1- (2
3.95 g of -pyridyl) -2- (3-dimethylaminobenzylthio) imidazole are obtained.

Yield 75% M. p. 79-80 ° C (2) A solution of 3.73 g of this product in 100 ml of methylene chloride is cooled to -40 ° C under a stream of argon. 5.32 g of 80% metachloroperbenzoic acid is added to the solution in small portions. Stir for 1 hour at the same temperature. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution, dried and the solvent is evaporated. 1- (2-pyridyl) was obtained by recrystallizing the residue from methanol.
There are obtained 1.48 g of 2- [3- (dimethylamino) benzylsulfinyl] imidazole.

Yield 55% p. 177 to 179 ° C. Production Examples 2 to 24 The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 3 below.

Production Examples 25 to 30 The corresponding starting compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 4 below.

Production Examples 31 to 49 The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 5 below.

Production Examples 50 to 57 The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 6 below.

Production Examples 58 to 61 The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 7 below.

Production Examples 62 to 63 The corresponding starting material compounds are treated in the same manner as in Production Example 1 to obtain the compounds shown in Table 8 below.

Production Example 64 (1) 2- (2-dimethylaminobenzylthio) -1,
7.53 g of 3a, 4,5,6,6a-hexahydro-6a-hydroxy-1- (2-pyridyl) cyclopenta [d] imidazole are heated to reflux in 200 ml of toluene for 1 hour with a catalytic amount of p-toluenesulfonic acid. . The solvent is distilled off, water is added to the residue, and the mixture is neutralized with an aqueous sodium hydrogen carbonate solution and extracted with chloroform. After drying the extract,
The solvent is distilled off to obtain 3.94 g of 1,4,5,6-tetrahydro-1- (2-pyridyl) -2- [2- (dimethylamino) benzylthio] cyclopenta [d] imidazole.

Yield 55% p. 115 to 117 ° C. (recrystallized from ethyl acetate-n-hexane) (2) By treating this product in the same manner as in Production Example 1- (2), 1,4,5,6-tetrahydro-1- (2 -Pyridyl) -2- [2- (dimethylamino) benzylsulfinyl] cyclopenta [d] imidazole is obtained.

Yield 74% p. 139.5-141 ° C. (recrystallized from ethyl acetate-n-hexane) Production Examples 65-67 The corresponding starting compounds are treated in the same manner as in Production Example 64 to obtain the compounds shown in Table 9 below.

Production Example 68 (1) Treating 1- (2-pyridyl) -2-mercaptoimidazole and 2- (2,4,6-trimethylphenyl) sulfonylaminobenzyl chloride in the same manner as in Production Example 1- (1). Thus, 1- (2-pyridyl) -2-
[2- (2,4,6-Trimethylphenyl) sulfonylaminobenzylthio] imidazole is obtained.

Yield 87% M. p. 154-156 ° C (recrystallized from isopropyl alcohol) (2) A mixture of 2 g of this product, 2.5 ml of anisole and 15 ml of methanesulfonic acid is stirred at room temperature for 20 hours. After the reaction, it is poured into water and extracted with ethyl acetate. The extract was washed with saturated saline and dried, and then the solvent was distilled off to obtain 1
-(2-pyridyl) -2- (2-aminobenzylthio)
1.1 g of imidazole is obtained as an oil.

Yield 93% Mass (m / e): 282 (M ⁺ ), 106 ¹ H-NMR (CDCl ₃ , δ): 3.9 (br, 2H, NH ₂ ), 4.43 (s, 2H, SCH ₂ ) (3 ) This product is treated in the same manner as in Production Example 1- (2) to give 1- (2-pyridyl) -2- (2-aminobenzylsulfinyl) imidazole.

M. p. 145 to 146 ° C. (recrystallized from isopropyl alcohol) Production Example 69 (1) A mixture of 4.8 g of 1- (2-pyridyl) -2- (2-aminobenzylthio) imidazole, 5 ml of acetic anhydride and 50 ml of pyridine at room temperature. Stir for 16 hours. The solvent is distilled off, and the residue is crystallized from toluene and collected by filtration to obtain 1- (2-pyridyl) -2- (2-acetylaminobenzylthio) imidazole (4.31 g).

Yield 78% p. 150 to 151 ° C. (recrystallized from isopropyl alcohol) (2) By treating this product in the same manner as in Production Example 1- (2), 1- (2-pyridyl) -2- (2-acetylaminobenzylsulfinyl) Get imidazole.

M. p. 172 to 173 ° C. (recrystallized from isopropyl alcohol) Production Example 70 (1) 100 mg of 60% sodium hydride was suspended in 2 ml of dimethylformamide, and 1- (2-pyridyl) -2- [2 -(2,4,6-Trimethylphenyl) sulfonylaminobenzylthio] imidazole 1 g
2 ml solution of dimethylformamide in. 30 at room temperature
After stirring for 3 minutes, 320 mg of methyl iodide is added and stirred for 2 hours. The reaction solution is poured into water, and the released oily substance is extracted with ethyl acetate. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent; n-hexane: ethyl acetate =
1- (2-pyridyl)-by purification in 3: 2)
0.76 g of 2- {2- [N-methyl-N- (2,4,6-trimethylphenyl) sulfonylamino] benzylthio} imidazole is obtained.

M. p. 131-133 ° C. (recrystallized from ethyl acetate) (2) This product was treated in the same manner as in Production Example 68- (2) to give 1- (2-pyridyl) -2- (2-methylaminobenzylthio) imidazole. As an oil.

Yield 92% Mass (m / e): 296 (M ⁺ ), 120 ¹ H-NMR (CDCl ₃ , δ): 2.83 (d, 3H, J = 3Hz, NCH ₃ ), 4.42 (s, 2H,
SCH ₂ ), 5.20 (br, 1H, NH) (3) This product was treated in the same manner as in Production Example 1- (2) to give 1-((2-pyridyl) -2- (2-methylaminobenzyl). Sulfinyl) imidazole is obtained.

M. p. 135-137 ° C (recrystallized from ethyl acetate) Production Example 71 (1) 2- (2-phthalimidobenzylthio) -1,3
By treating a, 4,5,6,6a-hexahydro-6a-hydroxy-1- (2-pyridyl) cyclopenta [d] imidazole in the same manner as in Production Example 64- (1), 1,4,5,5 6-Tetrahydro-1- (2-pyridyl) -2- (2-phthalimidobenzylthio) cyclopenta [d] imidazole is obtained.

M. p. 196-197 ° C (recrystallized from chloroform-ethyl acetate) (2) A mixture of 1.80 g of this product, 0.22 g of hydrazine hydrate and 100 ml of methanol is heated under reflux for 5 hours. After cooling, the solvent is distilled off, methylene chloride is added to the residue, and the insoluble matter is filtered off. The filtrate is washed with water, dried and the solvent is distilled off. The residual crystals were recrystallized from a mixed solution of ethyl acetate-n-hexane to give 1,4,5,6-tetrahydro-1- (2
1.06 g of -pyridyl) -2- (2-aminobenzylthio) cyclopenta [d] imidazole is obtained as pale yellow plate crystals.

Yield 83% p. 121-123 ° C (3) A solution of 1.0 g of this product and 0.35 g of triethylamine in 20 ml of methylene chloride under ice-cooling and 0.2 acetyl chloride.
A solution of 7 g of methylene chloride in 5 ml is added dropwise. After 1 hour, the reaction solution is washed with a saturated aqueous solution of sodium hydrogencarbonate and then with water, dried and the solvent is distilled off. The residual crystals were recrystallized from a chloroform-ethyl acetate mixed solution to give 1,4.
5,6-Tetrahydro-1- (2-pyridyl) -2-
0.38 g of (2-acetylaminobenzylthio) cyclopenta [d] imidazole is obtained.

Yield 74% p. 214-217 ° C (decomposition) (4) This product is treated in the same manner as in Production Example 1- (2) to prepare 1,4,5,6-tetrahydro-1- (2-pyridyl) -2- (2-). Acetylaminobenzylsulfinyl) cyclopenta [d] imidazole is obtained.

M. p. 188 to 191 ° C. (decomposition, recrystallization from ethyl acetate-n-hexane) Production Example 72 (1) 1- (4-pyridyl) -2-mercaptoimidazole and 2-ftylimidobenzyl chloride are produced Example 1- ( By treating in the same manner as 1), 1- (4-pyridyl) -2- (2-phthalimidobenzylthio) imidazole is obtained.

M. p. 145 to 147 ° C. (recrystallized from ethanol) (2) This product was treated in the same manner as in Production Example 71- (2) to give 1- (4-pyridyl) -2- (2-aminobenzylthio) imidazole as an oil. Get as a thing.

Mass (m / e): 282 (M ⁺ ), 106 ¹ H-NMR (CDCl ₃ , δ): 4.21 (br, 2H, NH ₂ ), 4.30 (s, 2H, SCH ₂ ) (3) By treating in the same manner as in Production Example 7- (3), 1- (4-pyridyl) -2- (2-acetylaminobenzylthio) imidazole is obtained.

M. p. 153-155 ° C. (recrystallized from ethyl acetate-n-hexane) (4) This product was treated in the same manner as in Production Example 1- (2) to give 1- (4-pyridyl) -2- (2-acetylamino). Benzylsulfinyl) imidazole is obtained.

M. p. 147-149 ° C (isopropyl alcohol-
Recrystallization from isopropyl ether) Production Example 73 (1) 1- (2-pyridylmethyl) -2-mercaptoimidazole and 2-phthalimidobenzyl chloride are treated in the same manner as in Production Example 1- (1) to give 1- ( 2-
Pyridylmethyl) -2- (2-phthalimidobenzylthio) imidazole is obtained.

M. p. 80-83 ° C (recrystallized from ethanol) (2) This product was treated in the same manner as in Production Example 71- (2) to give 1- (2-pyridylmethyl) -2- (2-aminobenzylthio) imidazole. Obtained as an oil.

Mass (m / e): 296 (M ⁺ ), 106 ¹ H-NMR (CDCl ₃ , δ): 4.21 (s, 2H, SCH ₂ ), 4.31 (br, 2H, NH ₂ ),
5.10 (s.2H.NCH ₂ ) (3) This product was treated in the same manner as in Production Example 1- (2) to give 1- (2-pyridylmethyl) -2- (2-aminobenzylsulfinyl) imidazole. obtain.

Mass (m / e): 312 (M ⁺ ), 106 ¹ H-NMR (CDCl ₃ , δ): 4.26 (br, 2H, NH ₂ ), 4.59 (ABq, 2H, NC
H ₂ ), 5.29 (ABq, 2H, NCH ₂ ) Production Example 74 (1) o- (1-pyrrolyl) benzyl alcohol 2.1
7 g and 2.14 g of triethylamine are dissolved in 10 ml of tetrahydrofuran and cooled to -50 ° C under a stream of argon. To this, 10.4 ml of an n-hexane solution of n-butyllithium (15%) was added, and after reacting for 10 minutes, a solution of 3.11 g of p-toluenesulfonyl chloride in 10 ml of tetrahydrofuran was added dropwise. The temperature is raised to −20 ° C., 4.28 g of triethylamine is added, and then a tetrahydrofuran solution of 2.0 g of 1- (6-methoxy-2-pyridyl) -2-mercaptoimidazole is added. After returning to room temperature for 1 hour, adding water and extracting with ethyl acetate, and drying,
The solvent is distilled off. The residual oily substance was purified by silica gel column chromatography (solvent; ethyl acetate: n-hexane = 1: 3) to give 1- (6-methoxy-2-pyridyl) -2- [2- (1-pyrrolyl). ) Benzylthio] imidazole (3.07 g) is obtained as a colorless oil.

Yield 88% Mass (m / e): 362 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ): 3.96 (s, 3H, OCH ₃ ), 4.33 (s, 2H, SCH ₂ ),
6.27 (t, 2H, = CH-) (2) By treating this product in the same manner as in Production Example 1- (2), 1- (6-methoxy-2-pyridyl) -2- [2
-(1-Pyrrolyl) benzylsulfinyl] imidazole is obtained.

M. p. 112 to 114 ° C. (recrystallized from ethyl acetate-n-hexane) Production Examples 75 to 79 The corresponding raw material compounds are treated in the same manner as in Production Example 74 to obtain the compounds shown in Table 10 below.

Production Example 80 (1) 1- (5-nitro-2-pyridyl) -2- [2-
(Dimethylamino) benzylthio] imidazole 19.
6 g of a mixed solution of concentrated hydrochloric acid-70% ethanol (1: 5) 40
Dissolve in 0 ml. Stannous chloride-2 in the solution at 80 ° C
A solution of 82.7 g of the hydrate in 100 ml of water was added dropwise, the mixture was stirred at the same temperature for 1 hour, made alkaline with an aqueous sodium hydroxide solution, and the insoluble matter was removed by filtration. The filtrate is extracted with ethyl acetate, washed with water, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (30: 1)], crystallized with ether, and the crystals were collected by filtration to give 1- (5-amino-2-pyridyl) -2. 6.27 g of [[2- (dimethylamino) benzylthio] imidazole are obtained.

M. p. 134-138 ° C (2) This product is treated in the same manner as in Production Example 1- (2) to give 1- (5-amino-2-pyridyl) -2- [2-
(Dimethylamino) benzylsulfinyl] imidazole is obtained.

M. p. 140 to 143 ° C. (recrystallized from ethanol-ether) Production Example 81 (1) 1- (5-nitro-2-pyridyl) -2-mercaptoimidazole and 2-morpholinobenzyl chloride were produced as Production Example 1- (1). By performing the same processing, 1-
(5-Nitro-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole is obtained.

M. p. 199-202 ° C (recrystallized from chloroform-n-hexane) (2) Dissolve 7.95 g of this product in 120 ml of acetic acid to obtain 10%
2.5 g of palladium-carbon is added and catalytic reduction is performed at room temperature and atmospheric pressure. After the reaction, the catalyst is filtered off and the solvent is distilled off. 1- (5-Amino-2-pyridyl) -2 was obtained by adding water to the residue, neutralizing it with a saturated aqueous sodium hydrogen carbonate solution, and collecting the precipitated crystals by filtration and recrystallizing them from a mixed solution of chloroform-n-hexane. 5.92 g of-(2-morpholinobenzylthio) imidazole are obtained.

Yield 81% M. p. 178-181 ° C. (3) By treating this product in the same manner as in Production Example 1- (2), 1- (5-amino-2-pyridyl) -2- (2-
Morpholinobenzylsulfinyl) imidazole is obtained.

M. p. 190-192 ° C (decomposition, chloroform-n-
Recrystallization from hexane) Production Example 82 (1) 1- (5-amino-2-pyridyl) -2- (2-
Morpholinobenzylthio) imidazole Preparation Example 71-
By treating in the same manner as in (3), 1- (5-acetylamino-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole is obtained.

Yield 78% p. 164-167 ° C (recrystallized from chloroform-n-hexane) (2) This product was treated in the same manner as in Production Example 1- (2) to give 1- (5-acetylamino-2-pyridyl) -2.
-(2-morpholinobenzylsulfinyl) imidazole is obtained.

M. p. 207-209 ° C (decomposition, chloroform-n-
Recrystallization from hexane) Production Examples 83 to 86 Corresponding raw material compounds were produced in Production Examples 1- (1), 81- (2), 7
By treating in the same manner as in 1- (3) and 1- (2), the compounds shown in Table 11 below are obtained.

Production Example 87 (1) 1- (2-Pyridylmethyl) -2- (2-aminobenzylthio) imidazole was treated in the same manner as in Production Example 71- (3) to give 1- (2-pyridylmethyl).
2- (2-Acetylaminobenzylthio) imidazole is obtained.

Mass (m / e): 338 (M ⁺ ), 106 ¹ H-NMR (CDCl ₃ , δ): 2.29 (s, 3H, COCH ₃ ), 4.31 (s, 2H, SCH ₂ ),
5.10 (s, 2H, NCH ₂ ) (2) This product was treated in the same manner as in Production Example 1- (2) to give 1- (2-pyridylmethyl) -2- (2-acetylaminobenzylsulfinyl) imidazole. To get

M. p. 146-148 ° C (recrystallized from ethyl acetate-n-hexane) Production Example 88 (1) 1- (5-amino-2-pyridyl) -2- [2-
Dimethylamino) benzylthio] imidazole 0.98
0.26 ml of acetyl chloride was added dropwise to a mixture of g, 1 ml of triethylamine and 30 ml of methylene chloride under ice cooling. The mixture is stirred at the same temperature for 2 hours, washed with water and saturated aqueous sodium hydrogen carbonate solution, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (30: 1),
1- (5-Acetylamino-2-pyridyl) was obtained by crystallization from isopropyl ether and then filtering the crystals.
0.82 g of 2- [2- (dimethylamino) benzylthio] imidazole is obtained.

M. p. 137-139 ° C. (2) This product is treated in the same manner as in Production Example 1- (2) to give 1- (5-acetylamino-2-pyridyl) -2.
-[2- (Dimethylamino) benzylsulfinyl] imidazole is obtained.

M. p. 168-170 ° C (recrystallized from ethanol-ether) Production Example 89 (1) Acetic anhydride (1.4 g) was added to formic acid (2.5 ml) at 60 ° C.
Heat for 30 minutes. This solution was ice-cooled and 1- (4,6
A solution of 1.07 g of dimethyl-2-pyridyl) -2- (2-aminobenzylthio) imidazole in 4 ml of formic acid is added, and the mixture is stirred at room temperature for 1 hour. After the reaction, the solvent is distilled off, water is added to the residue, and the mixture is made alkaline with potassium carbonate. Extract with ethyl acetate, dry the extract and evaporate the solvent. The residue was subjected to silica gel column chromatography (solvent; ethyl acetate: n-
Purify with hexane = 1: 1). By recrystallizing the obtained crude crystal from a mixed solution of ethyl acetate-n-hexane, 1
0.64 g of-(4,6-dimethyl-2-pyridyl) -2- (2-formylaminobenzylthio) imidazole is obtained.

Yield 55% p. 124-126.5 ° C (2) By treating this product in the same manner as in Production Example 1- (2), 1- (4,6-dimethyl-2-pyridyl) -2-
(2-Formylaminobenzylsulfinyl) imidazole is obtained.

M. p. 160-162 ° C (decomposition, methylene chloride-n-
Recrystallization from hexane) Production Example 90 (1) 0.7 g of propionic anhydride was added to a solution of 1.1 g of 1- (2-pyridyl) -2- (2-aminobenzylthio) imidazole in 10 ml of pyridine, and the mixture was added at room temperature overnight. Stir. After the reaction, the solvent was distilled off, the obtained oily substance was purified by silica gel column chromatography (solvent; ethyl acetate: n-hexane = 2: 1), and recrystallized from an isopropyl alcohol-isopropyl ether mixed solution to give 1 -(2
1.1 g of -pyridyl) -2- (2-propionylaminobenzylthio) imidazole are obtained.

Yield 83% p. 98-100 ° C (2) This product is treated in the same manner as in Production Example 1- (2) to obtain 1- (2-pyridyl) -2- (2-propionylaminobenzylsulfinyl) imidazole.

M. p. 155 to 156 ° C. (recrystallized from chloroform-isopropyl ether) Production Example 91 (1) 1- (3-hydroxy-2-pyridyl) -2-
To a solution of 2.94 g of [2- (dimethylamino) benzylthio] imidazole and 3.76 ml of triethylamine in 100 ml of methylene chloride, 0.96 ml of acetyl chloride is added dropwise under ice cooling. After 2 hours, the reaction solution is washed with water, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; chloroform: acetone = 30: 1) and then ethyl acetate-
By recrystallizing from an n-hexane mixed solution, 1- (3-
2.08 g of acetoxy-2-pyridyl) -2- [2- (dimethylamino) benzylthio] imidazole are obtained as colorless needles.

Yield 63% M. p. 85-87 ° C. (2) By treating this product in the same manner as in Production Example 1- (2), 1- (3-acetoxy-2-pyridyl) -2-
[2- (Dimethylamino) benzylsulfinyl] imidazole is obtained as an oil.

FAB Mass (m / e): 385 (M ⁺ +1), 134 ¹ H-NMR (CDCl ₃ , δ): 2.19 (s, 3H, COCH ₃ ), 2.57 (s, 6H, N (CH ₃ )
₂ ), 4.77 (ABq, 2H, SCH ₂ ) Production Example 92 (1) 1- (3-hydroxy-2-pyridyl) -2-
The (2-morpholinobenzylthio) imidazole was treated as in Preparation Example 91 to give 1- (3-acetoxy-2-pyridyl) -2- (2-morpholinobenzylsulfinyl).
Get imidazole.

M. p. 104 to 107 ° C. (recrystallized from ethyl acetate-n-hexane mixed solution) Production Example 93 (1) 1- (3-hydroxy-2-pyridyl) -2-
3.26 g of [2- (dimethylamino) benzylthio] imidazole was dissolved in 100 ml of dimethylformamide,
To this is added 0.48 g of 60% sodium hydride.
After stirring for 20 minutes at room temperature, 1.3 ml of isopropyl bromide was added dropwise, and the mixture was stirred at room temperature for 17 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The extract solution is washed with water and dried, and then the solvent is distilled off. The residue is recrystallized from a mixed solution of ethyl acetate-n-hexane to obtain 1- (3-isopropoxy-2-pyridyl) -2- [2- (dimethylamino) benzylthio] imidazole (2.47 g).

Yield 67% M. p. 85-87 ° C. (2) This product was treated in the same manner as in Production Example 1- (2) to give 1- (3-isopropoxy-2-pyridyl) -2.
-[2- (Dimethylamino) benzylsulfinyl] imidazole is obtained as an oil.

Mass (m / e): 384 (M ⁺ ), 134 ¹ H-NMR (CDCl ₃ , δ): 1.32 and 1.34 (each d, 3H, CH ₃ ), 2.63 (s, 6
_{H, N (CH 3) 2} , 4.81 (ABq, 2H, SCH 2) Preparation 94 1- (3-hydroxy-2-pyridyl) -2- (2-morpholino-benzyl thio) imidazole in the same manner as described in Example 93 1- (3-isopropoxy-2 by treatment
-Pyridyl) -2- (2-morpholinobenzylsulfinyl) imidazole is obtained.

M. p. 120 to 122 ° C (recrystallized from ethyl acetate-n-hexane mixed solution) (Preparation of raw material compound) Reference Example 1 (1) 2-aminopyridine 3.76 g and 2,2-diethoxyethyl isothiocyanate 7 g were refluxed in toluene. To do. The solvent was distilled off, and the residue was recrystallized from a mixed solution of ethyl acetate-n-hexane to give N- (2,2-diethoxyethyl)-.
9 g of N '-(2-pyridyl) thiourea are obtained.

M. p. 126 to 128 ° C. (2) After refluxing 8.94 g of the product of (1) above and a small amount of concentrated hydrochloric acid in acetic acid, the solvent is distilled off. The residue was dissolved in water, sodium hydrogen carbonate was added, and the precipitated crystals were collected by filtration and 1- (2-
Pyridyl) -2-mercaptoimidazole (4.91 g) is obtained.

M. p. 159-161 ° C (isopropyl alcohol-
Recrystallization from isopropyl ether-n-hexane) Reference Examples 2 to 24 The corresponding raw material compounds are treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 12 below.

Reference Example 25 (1) A tetrahydrofuran solution of 57.96 g of o-dimethylcarbamoylbenzoic acid was added dropwise to a tetrahydrofuran suspension of 34.05 g of sodium borohydride. After reaction at room temperature, boron trifluoride etherate 170.3g
Is added dropwise and refluxed. After cooling, a water-methanol mixture of 54 g of acid is added and the mixture is further refluxed. The reaction solution is concentrated and extracted with ethyl acetate under alkaline conditions. The solvent was distilled off from the extract, and the residue was distilled under reduced pressure to obtain 19.04 g of o-dimethylaminomethylbenzyl alcohol.

B. p. 106-109 ° C. (4 mmHg) (2) 2.89 g of thionyl chloride is added dropwise to a solution of 2.9 g of this product in methylene chloride. After reaction at room temperature, the reaction solution is diluted with ether, and the precipitated crystals are collected by filtration to obtain 3.78 g of o-dimethylaminomethylbenzyl chloride hydrochloride.

M. p. 143-147 ° C. Reference Example 26 To an ether suspension of 2.4 g of lithium aluminum hydride, an ether solution of 9 g of ethyl o- (1-pyrrolyl) benzoate was added dropwise under ice-cooling and reacted. Water and an aqueous sodium sulfate solution were added under ice-cooling, the insoluble matter was filtered off, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain o- (1-pyrrolyl) benzyl alcohol 6.3 g.

Reference Example 27 (1) 2-aminocyclohexanone hydrochloride 6.82 g,
A mixture of 6.21 g of 2-pyridyl isothiocyanate dimer and 100 ml of toluene is heated and stirred. Internal temperature 50
The temperature is lowered to ℃, 4.61 g of triethylamine is added dropwise, and the reaction is further continued. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract was washed with saturated brine and dried, and the solvent was evaporated to give N- (2-pyridyl) -N '-(2-
8.2 g of oxocyclohexyl) thiourea are obtained.

Yield 72% M. p. 149-151 ° C (2) This product was treated in the same manner as in Production Example 64- (1) to give 2-mercapto-1- (2-pyridyl) -4,
5,6,7-Tetrahydrobenzimidazole is obtained.

Yield 94% p. 203 to 204 ° C. (recrystallized from ethyl acetate-n-hexane) Reference Example 28 2-aminocyclopentanone hydrochloride was used as Reference Example 27-
By performing the same treatment as in (1), 2-mercapto-
1,3a, 4,5,6,6a-hexahydro-6a-hydroxy-1- (2-pyridyl) cyclopenta [d] imidazole is obtained.

Yield 55% p. 126 to 127 ° C. Reference Examples 29 to 33 2-Mercapto-1,3a, 4,5,6,6a-hexahydro-6a-hydroxy-1- (2-pyridyl) cyclopenta [d] imidazole and corresponding raw material compounds were produced. By performing the same processing as in Example 1- (1), the following 13th
The compounds listed in the table are obtained.

Reference Example 34 (1) 24.2 g of ethyl o-fluorobenzoate and 9.8 g of imidazole were heated in the presence of sodium hydride to obtain o.
23 g of ethyl imidazolyl benzoate are obtained.

B. p. 165 to 167 ° C. (2 mmHg) (2) 5 g of this product is treated in the same manner as in Reference Example 26 to obtain 3.4 g of o-imidazolylbenzyl alcohol.

(3) 3.4 g of this product was treated in the same manner as in Reference Example 25- (2) to obtain 3.3 g of o-imidazolylbenzyl chloride hydrochloride.
To get

M. p. 160-161 ° C (recrystallized from ethanol-ether)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 401/14 207 7602-4C 233 7602-4C

Claims (6)

[Claims] 1. A general formula (However, ring A is a halogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group, a nitro group, an amino group, a lower alkanoylamino group, a lower alkanoyloxy group, a cyanide group, a trihalogeno lower alkyl group,
2- or 4-pyridyl group optionally substituted with one or two groups selected from trihalogeno lower alkoxy groups and hydroxyl groups, and ring B is an amino group, mono- or di-
A lower alkylamino group, a lower alkanoylamino group, a cycloalkylamino group, a formylamino group, a morpholino group, a pyrrolyl group, a phenyl group which may be substituted with a group selected from a piperidino group and an imidazolyl group,
R ¹ and R ² are both hydrogen atoms or are bonded to each other at the terminals to form a group represented by the formula — (CH ₂ ) _q —,
n represents 0, 1 or 2, and q represents 3 or 4. ) An anti-ulcer agent containing, as an active ingredient, an imidazole derivative represented by: or a pharmacologically acceptable salt thereof. 2. A ring A, which may be substituted with one or two groups selected from a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group, an amino group and a lower alkanoylamino group, 2- or 4-. Pyridyl group; Ring B
Is an amino group, a mono- or di-lower alkylamino group,
A lower alkanoylamino group, a formylamino group, a morpholino group, a pyrrolyl group, a piperidino group, and a phenyl group which may be substituted with a group selected from an imidazolyl group, wherein R ¹ and R ² are both hydrogen atoms or The anti-ulcer agent according to claim 1, wherein the anti-ulcer agent is bonded at the terminal to form a trimethylene group. 3. A 2- or 4-pyridyl group in which ring A is optionally substituted with one or two groups selected from a lower alkyl group and a lower alkoxy group; ring B is an amino group, mono- or di-group. The anti-ulcer agent according to claim 2, which is a phenyl group substituted with a group selected from a lower alkylamino group, a lower alkanoylamino group, a morpholino group, a piperidino group and a pyrrolyl group. 4. A 2-pyridyl group in which ring A may be substituted with a lower alkyl group; phenyl in which ring B is substituted with a group selected from an amino group, a mono- or di-lower alkylamino group and a pyrrolyl group. The antiulcer agent according to claim 2, which is a base. 5. The antiulcer agent according to claim 1, wherein n is 0. 6. A ring A is a 2-pyridyl group substituted with a methyl group; a ring B is a phenyl group substituted with a group selected from an amino group, a mono- or di-lower alkylamino group,
The anti-ulcer agent according to claim 1, wherein R ¹ and R ² are both hydrogen atoms and n is 0.