JPH0655737B2 - Imidazole derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel imidazole derivative or a salt thereof.

[0002]

2. Description of the Related Art A large amount of gastric acid secretion is mentioned as one of the factors causing the formation of digestive ulcers. This gastric acid is histamine,
It is known that it is secreted from gastric parietal cells upon stimulation with acetylcholine, gastrin, etc., and as a drug that suppresses gastric acid secretion by antagonizing these stimulants, cholinergic receptor blockers (eg, atropine), histamine H ₂ receptor Body antagonists (eg, cimetidine) and the like are clinically used. [Medicina, No. 23
Vol. 4, No. 4, 560-565 (1986)]
Recently, benzimidazole compounds (for example, omeprazole), which inhibit the gastric acid secretion by inhibiting the enzymatic activity of H ⁺ / K ⁺ ATPase involved in the concentration and secretion of gastric acid, have been found (JP-A-54-54). 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.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel imidazole derivative or a salt thereof which is useful as a synthetic intermediate for a pharmaceutical compound having an excellent gastric acid secretion inhibitory action.

[0005]

The present invention has the general formula (II)

[0006]

[Chemical 2]

(However, ring A is a halogen atom, a lower alkyl group, a lower alkoxy group, a phenyl lower alkoxy group,
Nitro group, amino group, lower alkanoylamino group, N-
Lower alkyl-N-lower alkanoylamino group, mono-
Alternatively, it may be substituted with one or two groups selected from a di-lower alkylamino group, a lower alkanoyloxy group, a cyanide group, a trihalogeno lower alkyl group, a trihalogeno lower alkoxy group, a lower alkenyloxy group and a hydroxyl group. , 3- or 4-pyridyl group; ring B is nitro group, amino group, mono- or di-lower alkylamino group, lower alkanoylamino group, phenylamino group, cycloalkylamino group, N- (tri-lower alkylphenyl) Sulfonylamino group, N-lower alkyl-N
-(Tri-lower alkylphenyl) sulfonylamino group,
N-lower alkyl-N-phenylamino group, di (lower alkyl) amino lower alkylideneamino group, di-lower alkylamino lower alkyl group, N-lower alkyl-N-lower alkanoylamino group, lower alkoxy group, arylcarbonylamino group Represents a phenyl group substituted with a group selected from a lower alkylsulfonylamino group, a formylamino group, a lower alkoxycarbonylamino group, a phthalimido group and a nitrogen-containing 5- to 6-membered heteromonocyclic group,
R ¹ and R ² are both hydrogen atoms or are bonded to each other at the ends to form a group represented by the formula — (CH ₂ ) _q —, n is 0, 1 or 2, and q is 3 or 4. . ) Relating to an imidazole derivative or a salt thereof.

Specific examples of the object compound of the present invention include, for example, in the general formula (II), ring A is a halogen atom (eg chlorine atom, bromine atom), a lower alkyl group (eg methyl group, ethyl group). ), Lower alkoxy group (eg, methoxy group, ethoxy group, isopropoxy group), phenyl lower alkoxy group (eg, benzyloxy group), nitro group, amino group, lower alkanoylamino group (eg, acetylamino group, propionylamino) Group), N-lower alkyl-N-lower alkanoylamino group (eg, N-methyl-N-acetylamino group), mono- or di-lower alkylamino group (eg, methylamino group, ethylamino group, dimethylamino) Group, diethylamino group), lower alkanoyloxy group (for example, acetyloxy group), cyanide group, One selected from a rehalogeno lower alkyl group (for example, trifluoromethyl group), a trihalogeno lower alkoxy group (for example, 2,2,2-trifluoroethoxy group), a lower alkenyloxy group (for example, allyloxy group) and a hydroxyl group; 2-, 3- or 4-pyridyl group optionally substituted with two groups; ring B is a nitro group, an amino group, a mono- or di-lower alkylamino group (for example, a methylamino group, an ethylamino group, Dimethylamino group, diethylamino group, dipropylamino group), lower alkanoylamino group (eg, acetylamino group, propionylamino group), phenylamino group, cycloalkylamino group (eg, cyclohexylamino group), N- (tri-lower group) Alkylphenyl) sulfonylamino groups (eg (2,4,6- Limethylphenyl) sulfonylamino group), N-lower alkyl-N- (tri-lower alkylphenyl) sulfonylamino group (for example, N-methyl-N- (2,4,6-trimethylphenyl) sulfonylamino group), N A lower alkyl-N-phenylamino group (eg N-methyl-N-
Phenylamino group, N-ethyl-N-phenylamino group), di (lower alkyl) amino lower alkylideneamino group (for example, dimethylaminomethylideneamino group),
Di-lower alkylamino-lower alkyl group (for example, dimethylaminomethyl group, diethylaminomethyl group), N-lower alkyl-N-lower alkanoylamino group (for example,
N-methyl-N-acetylamino group), lower alkoxy group (eg, methoxy group, ethoxy group), arylcarbonylamino group (eg, benzoylamino group), lower alkylsulfonylamino group (eg, methanesulfonylamino group), Formylamino group, lower alkoxycarbonylamino group (for example, methoxycarbonylamino group, ethoxycarbonylamino group), phthalimido group, and nitrogen-containing 5- or 6-membered heteromonocyclic group (for example, morpholino group, imidazolyl group, pyrrolyl group, A pyrrolidinyl group and a piperidyl group), a phenyl group substituted with a group selected from the group consisting of R ¹ and R ² are both hydrogen atoms or a lower alkylene group which is bonded to each other at the terminals (eg,
A compound which forms a trimethylene group or a tetramethylene group and n is 0, 1 or 2.

Of these, preferred compounds are those represented by the general formula (II) in which 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. Group, a cyanide group, a trihalogeno lower alkyl group, a trihalogeno lower alkoxy group, a lower alkenyloxy group, and a 2-, 3- or 4-pyridyl group optionally substituted with one or two groups selected from a hydroxyl group; ring B Is an amino group, a mono- or di-lower alkylamino group, a lower alkanoylamino group, a cycloalkylamino group, an N-lower alkyl-N-phenylamino group,
Di-lower alkylamino-lower alkyl group, N-lower alkyl-N-lower alkanoylamino group, lower alkoxy group, arylcarbonylamino group, lower alkylsulfonylamino group, formylamino group, lower alkoxycarbonylamino group and nitrogen-containing 5 to 6 A phenyl group substituted with a group selected from a membered ring heteromonocyclic group, wherein R ¹ and R ² are both hydrogen atoms or are bonded to each other at the terminals to form a lower alkylene group, and n is 0 The compound which is 1 or 2 is mentioned.

More preferred compounds are represented by the general formula (I
Ring A in I) is C ₁ - ₄ alkyl group, C ₁ - ₄ alkoxy group and a phenyl group substituted C ₁ - ₂ one selected from alkoxy or optionally substituted by two groups 2- or 4- a pyridyl group; ring B is di C ₁ - ₄ alkyl-substituted amino group, C ₁ - ₄ alkanoylamino group, morpholino group, a phenyl group substituted by a group selected from piperidino group, and a pyrrolyl group, R ¹ and There is a compound in which both R ^{2 s} are hydrogen atoms or bonded to each other at the terminals to form a trimethylene group, and n is 0, 1 or 2.

The compound (II) of the present invention can form a salt, and examples of such a salt include inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and nitrate. And organic acid addition salts such as formate, oxalate, methanesulfonate, and glucuronate.

The compound (II) of the present invention has the general formula (III)

[0013]

[Chemical 3]

(Wherein ring A, R ¹ , R ² and n have the same meanings as described above) and a mercaptoimidazole compound or a salt thereof and the general formula (IV)

[0015]

[Chemical 4]

(Wherein, X represents a reactive residue and ring B has the same meaning as described above), and it can be produced by reacting with a toluene compound or a salt thereof.

Alternatively, in the imidazole derivative (II), a compound in which R ¹ and R ² form a group represented by the formula — (CH ₂ ) _q — (q has the same meaning as above) is represented by the general formula ( V)

[0018]

[Chemical 5]

(Wherein R ¹¹ and R ²¹ are bonded to each other at the terminals to form a group represented by the formula — (CH ₂ ) _q —
Rings B, q and n have the same meanings as above. It is also possible to produce the imidazole derivative represented by the formula (1) or a salt thereof by subjecting it to a dehydration reaction.

Mercaptoimidazole compound (III)
Alternatively, the reaction of the salt with the toluene compound (IV) or the salt can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As the reactive residue X of the toluene compound (IV), any group can be used as long as it can react with a mercapto group to form a C—S bond. Halogen atom,
Alkylsulfonyloxy group (for example, methylsulfonyloxy group), arylsulfonyloxy group (for example,
A toluenesulfonyloxy group and a benzenesulfonyloxy group) can be preferably used. When the toluene compound (IV) has an amino group, a substituted amino group or the like on the benzene ring, it serves as an addition salt with an organic acid or an inorganic acid, and the mercaptoimidazole compound (III) serves as an inorganic acid addition salt, an organic acid addition salt, It can also be used in the reaction as a salt such as an alkali metal salt, an alkaline earth metal salt or a quaternary ammonium salt. As the reaction solvent, any conventional solvent such as lower alkanol, dimethylformamide, dimethylsulfoxide, water and a mixed solvent thereof can be preferably used. As the deoxidizing agent, an inorganic base such as an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkali metal alkoxide, an alkali metal amide, an alkali metal fluoride or an alkali metal hydride; Organic bases such as pyridine, tri-lower alkylamine, lower alkyllithium, and quaternary ammonium hydroxide (tetra-n-butylammonium hydroxide, etc.) can be used. The reaction is preferably carried out at room temperature or under heating.

On the other hand, the dehydration reaction of the imidazole derivative (V) can be carried out in a suitable solvent in the presence of a dehydrating agent. Examples of the dehydrating agent include organic acids such as formic acid, trifluoroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid and camphorsulfonic acid, inorganic acids such as hydrochloric acid and sulfuric acid, phosphorus tribromide, phosphorus trichloride and phosphorus oxychloride. A combination of a halogenating agent and a base such as pyridine or triethylamine can be used. As the salt of the imidazole derivative (V), an inorganic acid addition salt, an organic acid addition salt or the like can be appropriately used. This reaction is preferably carried out at room temperature to under heating.

The substituents on the ring A and ring B of the object (II) of the present invention can be appropriately interconverted with each other, for example, having an amino group on the ring A and / or ring B. Compound (II) is a corresponding nitro group-substituted compound (II)
Can also be produced by a conventional method or by hydrolyzing the corresponding N-phthalimide or N-tri-lower alkylphenylsulfonylamide group-substituted product (II).
Further, the amino group on ring A and / or ring B is a lower alkanoyl group, a lower alkylsulfonyl group, a formyl group, a lower alkyl group, an arylcarbonyl group, a lower alkoxycarbonyl group, a (substituted phenyl) sulfonyl group, etc. 1 to 2
The compound (II) substituted with one group can also be produced by further acylating or alkylating the corresponding amino group, N-alkylamino group or N-acylamino group-substituted compound (II) by a conventional means. .

The compound (II) thus obtained (including the dehydrated product of the imidazole derivative (V)) is oxidized to give the compound of the general formula (I)

[0024]

[Chemical 6]

(Wherein m represents 1 or 2 and the other symbols have the same meanings as described above) can be produced.

The above compound (I) and salts thereof have excellent gastric acid secretion inhibitory action and / or excellent H ⁺ / K ⁺ A.
A drug useful as an anti-ulcer agent (for example, treatment / prevention of gastrointestinal ulcer such as gastric ulcer, duodenal ulcer, etc.) that does not have side effects as seen in histamine H ₂ receptor antagonists because it has an enzyme activity inhibitory action against TPase It is a compound.

For example, when the inhibitory effect on gastrin-stimulated gastric acid secretion in rats was examined, 1- (2-pyridyl)
-2- [2- (1-pyrrolyl) benzylsulfinyl]
Imidazole, 1- (3-methyl-2-pyridyl) -2
-[2- (Dimethylamino) benzylsulfinyl] imidazole and 1,4,5,6-tetrahydro-1-
(2-pyridyl) -2- (2-diethylaminobenzylsulfinyl) cyclopenta [d] imidazole is 30
Oral administration of mg / kg caused gastric acid secretion to be 7 compared to non-administered group
It can be suppressed by 0% or more. In addition, when the enzyme activity inhibitory effect on H ⁺ / K ⁺ ATPase prepared from the fundus mucosa of pig was examined, 1,4,5,6-tetrahydro-1- (2-pyridyl) -2- (2 -Diethylaminobenzylsulfinyl) cyclopenta [d] imidazole has an IC ₅₀ (50% inhibitory concentration) of about 10 μM.
(2-pyridyl) -2- [2- (cyclohexylamino) benzylsulfinyl] imidazole, 1- (4-
Methoxy-6-methyl-2-pyridyl) -2- [2-
The IC ₅₀ of (diethylamino) benzylsulfinyl] imidazole was 10 μM or less.

Further, the compound (I) and salts thereof include those exhibiting an excellent gastric acid secretion inhibitory action not necessarily depending on the enzyme activity inhibiting action on H ⁺ / K ⁺ ATPase, and existing compounds such as omeprazole. It exhibits excellent properties as an anti-ulcer agent with a mechanism of action different from that of the H ⁺ / K ⁺ ATPase inhibitor.

The oxidation reaction of compound (II) can be carried out by treating with an oxidizing agent.

Examples of the oxidizing agent include peracids such as metachloroperbenzoic acid, perbenzoic acid and peracetic acid; alkali metal hypochlorite, alkali metal chlorite, alkali metal periodate, periodate. Conventional oxidizing agents such as tetra-n-butylammonium, t-butylhydroperoxide and iodooxybenzene can be preferably used. Examples of the reaction solvent include lower alkanol, methylene chloride, chloroform, tetrahydrofuran, dioxane,
Water and mixtures of these can be used as appropriate. The reaction is preferably carried out at room temperature or with cooling, and the compound (I
The imidazole derivative (I) of sulfinyl type (m = 1) can be obtained by using 1 equivalent or a small excess of the oxidizing agent with respect to I), and the sulfonyl type (m = 2) can be obtained by using 2 equivalents or more of the oxidizing agent.

In the starting compound (III) of the present invention, the compound in which R ¹ and R ² are both hydrogen atoms has the general formula (VI)

[0032]

[Chemical 7]

(Wherein rings A and n have the same meanings as described above) and a pyridine compound represented by the general formula (VII)

[0034]

[Chemical 8]

(Wherein R ³ is an alkyl group and Z is an oxygen atom or a sulfur atom) is reacted with an iso (thio) cyanate compound in a suitable solvent to obtain a (thio) urea compound. It can be produced by treating the compound with an organic or inorganic acid to cause ring closure, and when Z is an oxygen atom, further treating with a sulfiding agent.

Of the starting compound (III), R ¹
And R ² are bonded to each other at the terminals, and the formula-(CH ₂ ) _q- (q
Has the same meaning as above. ), A compound forming a group represented by the formula (2) is a compound of the general formula (VIII) with 2-aminocyclohexanone or 2-aminocyclopentanone.

[0037]

[Chemical 9]

(Wherein ring A and n have the same meanings as described above) and condensed in the presence of triethylamine, and then reacted in the same manner as the dehydration reaction of compound (V). You can

The starting compound (V) is prepared by condensing 2-aminocyclohexanone or 2-aminocyclopentanone and compound (VIII) in the presence of triethylamine, and then reacting with toluene compound (IV). You can

[0040]

【Example】

Example 1 1- (2-pyridyl) -2-mercaptoimidazole (3.0 g) was dissolved in ethanol (50 ml), and the mixture was cooled with ice to 2N.
-Add 16.9 ml of aqueous sodium hydroxide solution. 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 to 80 ° C. Examples 2 to 25 The corresponding starting material compounds are treated in the same manner as in Example 1 to obtain the compounds shown in Tables 1 to 4 below.

[0042]

[Table 1]

[0043]

[Table 2]

[0044]

[Table 3]

[0045]

[Table 4]

Examples 26 to 31 The corresponding starting compounds are treated in the same manner as in Example 1 to obtain the compounds shown in Table 5 below.

[0047]

[Table 5]

Examples 32 to 50 By treating corresponding raw material compounds in the same manner as in Example 1, compounds shown in Tables 6 to 8 below are obtained.

[0049]

[Table 6]

[0050]

[Table 7]

[0051]

[Table 8]

Examples 51 to 58 The corresponding starting compounds are treated in the same manner as in Example 1 to obtain the compounds shown in Tables 9 to 10 below.

[0053]

[Table 9]

[0054]

[Table 10]

Examples 59 to 63 The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Table 11 below.

[0056]

[Table 11]

Examples 64 to 65 The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds shown in Table 12 below.

[0058]

[Table 12]

Example 66 2- (2-Dimethylaminobenzylthio) -1,3a,
4,5,6,6a-hexahydro-6a-hydroxy-
7.53 g of 1- (2-pyridyl) cyclopenta [d] imidazole is heated under reflux in 200 ml of toluene for 1 hour together 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 the extract was dried, the solvent was distilled off to give 1,4,5,6-tetrahydro-2.
3.94 g of-(2-dimethylaminobenzylthio) -1- (2-pyridyl) -cyclopenta [d] imidazole
To get

Yield 55% p. 115 to 117 ° C. (recrystallized from ethyl acetate-n-hexane) Examples 67 to 69 The corresponding starting compounds were treated in the same manner as in Example 66 to give compounds shown in Table 13 below.

[0061]

[Table 13]

Example 70 (1) By treating 1- (2-pyridyl) -2-mercaptoimidazole and 2- (2,4,6-trimethylphenyl) sulfonylaminobenzyl chloride in the same manner as in Example 1, , 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 give 1- (2-pyridyl) -2-.
1.1 g of (2-aminobenzylthio) imidazole are 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 ) Example 71 A mixture of 4.8 g of 1- (2-pyridyl) -2- (2-aminobenzylthio) imidazole, 5 ml of acetic anhydride and 50 ml of pyridine is stirred at room temperature for 16 hours.

The solvent was distilled off, and the residue was crystallized from toluene and collected by filtration to give 1- (2-pyridyl) -2-
(2-Acetylaminobenzylthio) imidazole 4.
31 g are obtained.

Yield 78% M. p. 150 to 151 ° C. (recrystallized from isopropyl alcohol) Example 72 (1) 60 mg of sodium hydride (100 mg) was suspended in dimethylformamide (2 ml), and the suspension was cooled with ice to give 1-.
A solution of 1 g of (2-pyridyl) -2- [2- (2,4,6-trimethylphenyl) sulfonylaminobenzylthio] imidazole in 2 ml of dimethylformamide is added.
After stirring for 30 minutes at room temperature, 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 purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 3: 2) to give 1- (2-pyridyl) -2- {2- [N- Methyl-N- (2,4,6
0.76 g of -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 Example 70- (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) Example 73 1- (2-pyridyl) -2- (2-acetylaminobenzylthio) imidazole was treated in the same manner as in Example 72- (1) to give 1 -(2-pyridyl) -2- [2-
(N-Methyl-N-acetylamino) benzylthio] imidazole is obtained as an oil.

Yield 78% Mass (m / e): 338 (M ⁺ ), 120 ¹ H-NMR (CDCl ₃ , δ): 1.76 (s, 3H, COCH ₃ ) 3.20 (s.3H, NCH ₃ ). ,
4.39 (s, 2H, SCH ₂₎ Example 74 (1) 2- (2-phthalimidomethyl-benzyl thio) -1,
By treating 3a, 4,5,6,6a-hexahydro-6a-hydroxy-1- (2-pyridyl) cyclopenta [d] imidazole as in Example 66, 1,3
4,5,6-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-pyridyl) -2- (2-aminobenzylthio)
1.06 g of cyclopenta [d] imidazole is obtained as pale yellow plate crystals.

Yield 83% p. 121 ~ 123 ℃ (3) 1.0g of this product and 0.35g of triethylamine
A solution of 0.27 g of acetyl chloride in 5 ml of methylene chloride is added dropwise to a solution of 20 ml of methylene chloride in ice. 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 mixed solution of chloroform-ethyl acetate to give 1,4,5,6-tetrahydro-1- (2-pyridyl).
0.83 g of 2- (2-acetylaminobenzylthio) cyclopenta [d] imidazole is obtained.

Yield 74% M. p. 214-217 ° C (decomposition) Example 75 (1) 1- (4-pyridyl) by treating 1- (4-pyridyl) -2-mercaptoimidazole and 2-phthalimidobenzyl chloride in the same manner as in Example 1 −
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 Example 74- (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) This product is treated in the same manner as in Example 74- (3) to give 1- (4-pyridyl) -2- (2-acetylaminobenzylthio) imidazole.

M. p. 153-155 ° C (ethyl acetate-
Recrystallization from n-hexane) Example 76 (1) 1- (2-pyridyl) was prepared by treating 1- (2-pyridylmethyl) -2-mercaptoimidazole and 2-phthalimidobenzyl chloride in the same manner as in Example 1. Methyl) -2- (2-phthalimidobenzylthio) imidazole is obtained.

M. p. 80 to 83 ° C. (recrystallized from ethanol) (2) This product is treated in the same manner as in Example 74- (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 ) Example 77 A solution of 4.33 g of o- (N-methyl-N-phenylamino) benzyl alcohol in 50 ml of tetrahydrofuran was added at 60 ° C. to n-hexane solution of n-butyllithium (1.
5%) 14.3 ml is added. After reacting for 20 minutes, 2.67 g of triethylamine was added, and a solution of 5.03 g of p-toluenesulfonyl chloride in 20 ml of tetrahydrofuran was added dropwise. After reacting at -20 ° C for 1 hour, 5.0 g of triethylamine was further added, and then 1- (2-pyridyl)
Add 3.59 g of 2-mercaptoimidazole. After reacting for 2 hours at room temperature, ethyl acetate was added, washed with water and dried,
The solvent is distilled off. The residue was purified by silica gel column chromatography (solvent; ethyl acetate: chloroform = 1: 9) to give 1- (2-pyridyl) -2- [2- (N-methyl-N-phenylamino) benzylthio] imidazole. 4.55 g are obtained.

Yield 60% M. p. 90-92 ° C. (recrystallized from ethyl acetate-n-hexane) Examples 78 to 83 The corresponding starting material compounds were treated in the same manner as in Example 77 to give the compounds shown in Table 14 below.

[0079]

[Table 14]

Example 84 19.6 g of 1- (5-nitro-2-pyridyl) -2- [2- (dimethylamino) benzylthio] imidazole was mixed with 400 ml of concentrated hydrochloric acid-70% ethanol (1: 5).
Dissolve in. A solution of 82.7 g of stannous chloride dihydrate in 100 ml of water was added dropwise to the solution at 80 ° C.
After stirring for an hour, the mixture is made alkaline with an aqueous sodium hydroxide solution and the insoluble matter is 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 Example 85 (1) 1- (5-Nitro-2-pyridyl) -2-mercaptoimidazole and 2-morpholinobenzyl chloride were treated in the same manner as in Example 1 to give 1- (5-
Nitro-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole is obtained.

M. p. 199 to 202 ° C. (recrystallized from chloroform-n-hexane) (2) Dissolve 7.95 g of this product in 120 ml of acetic acid to prepare 1
2.5 g of 0% 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. Water was added to the residue, and the precipitated crystals were neutralized with a saturated aqueous solution of sodium hydrogen carbonate, collected by filtration, and recrystallized from a mixed solution of chloroform-n-hexane to give 1- (5-amino-2-).
5.92 g of pyridyl) -2- (2-morpholinobenzylthio) imidazole are obtained.

Yield 81% M. p. 178-181 [deg.] C. Example 86 1- (5-amino-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole Example 74- (3)
The same treatment as in 1- (5-acetylamino-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole is obtained.

Yield 78% M. p. 164-167 ° C. (recrystallized from chloroform-n-hexane) Examples 87-90 (1) The corresponding starting material compounds are treated in the same manner as in Example 1 to obtain the compounds shown in Table 15 below.

[0084]

[Table 15]

(2) The product of the above (1) was used in Example 85.
-By treating in the same manner as in (2), compounds shown in Table 16 below are obtained.

[0086]

[Table 16]

(3) The product of the above (2) was used in Example 74-
By treating in the same manner as in (3), compounds shown in Table 17 below are obtained.

[0088]

[Table 17]

Example 91 1- (2-pyridylmethyl) -2- (2-aminobenzylthio) imidazole was treated in the same manner as in Example 74- (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, SC
_{H 2), 5.10 (s,} 2H, NCH 2) Example 92 1- (5-amino-2-pyridyl) -2- [2- (dimethylamino) benzylthio] imidazole 0.98 g,
0.26 ml of acetyl chloride is added dropwise to a mixture of 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 Example 93 1.4 g of acetic anhydride was added to 2.5 ml of formic acid, and the mixture was mixed at 60 ° C for 3
Warm for 0 minutes. This solution was ice-cooled, and a solution of 1- (4,6-dimethyl-2-pyridyl) -2- (2-aminobenzylthio) imidazole (1.07 g) in formic acid (4 ml) was added,
Stir 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 is purified by silica gel column chromatography (solvent; ethyl acetate: n-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 Example 94 To a solution of 1.2 g of 1- (2-pyridyl) -2- (2-aminobenzylthio) imidazole in 10 ml of methylene chloride was added 10 ml of an aqueous solution of 1.7 g of potassium carbonate, and the mixture was vigorously stirred. While adding 0.65 g of benzoyl chloride dropwise.
After reacting for 1 hour at room temperature, the organic layer is separated, washed with water, dried and the solvent is distilled off. The obtained crude crystals are recrystallized from an isopropyl alcohol-isopropyl ether mixed solution to obtain 1- (2-pyridyl) -2- (2-benzoylaminobenzylthio) imidazole (1.55 g).

Yield 95% M. p. 132 to 133 ° C. Examples 95 to 96 The corresponding starting compounds were treated in the same manner as in Example 94 to give compounds as shown in Table 18 below.

[0094]

[Table 18]

Example 97 1- (3-Hydroxy-2-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole 2.94 g and triethylamine 3.76 ml methylene chloride 100
0.96 ml of acetyl chloride is added dropwise to the ml solution 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-n-
Recrystallization from a hexane mixture gives 2.08 g of 1- (3-acetoxy-2-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole as colorless needle crystals.

Yield 63% M. p. 85-87 ° C Example 98 1- (3-Hydroxy-2-pyridyl) -2- (2-morpholinobenzylthio) imidazole was treated as in Example 97 to give 1- (3-acetoxy-2-pyridyl). −
2- (2-morpholinobenzylthio) imidazole is obtained.

Yield 73% M. p. 89-91 ° C (recrystallized from ethyl acetate-n-hexane mixed solution) Example 99 1- (4,6-dimethyl-2-pyridyl) -2- (2-
To a solution of 1.09 g of aminobenzylthio) imidazole and 0.5 ml of triethylamine in 10 ml of methylene chloride, 0.48 g of methanesulfonyl chloride is added under ice cooling. After 1 hour, 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: ethyl acetate = 10: 1) and then ethyl acetate-n.
1- (4,6 by recrystallizing from -hexane mixture
1.0 g of -dimethyl-2-pyridyl) -2- (2-methanesulfonylaminobenzylthio) imidazole are obtained as colorless needles.

Yield 73% M. p. 121 to 123 ° C Example 100 3.26 g of 1- (3-hydroxy-2-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole was dissolved in 100 ml of dimethylformamide, and 60% thereof was added thereto.
% Sodium hydride 0.48 g is added. After stirring for 20 minutes at room temperature, 1.3 ml of isopropyl bromide is added dropwise and stirred for 17 hours at room temperature. 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 was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 1- (3-isopropoxy-2-pyridyl) -2-.
(2-Dimethylaminobenzylthio) imidazole 2.
47 g are obtained.

Yield 67% M.P. p. 85 to 87 ° C. Examples 101 to 102 The corresponding starting material compounds are treated in the same manner as in Example 100 to give compounds as shown in Table 19 below.

[0100]

[Table 19]

Example 103 1- (3-Methyl-2-pyridyl) -2-mercaptoimidazole and 2-phthalimidobenzyl bromide were treated in the same manner as in Example 1 to give 1- (3-methyl-2- Pyridyl) -2- (2-phthalimidobenzylthio) imidazole is obtained.

M. p. 135-138 ° C Example 104 1,4,5,6-tetrahydro-2-mercapto-1-
By treating (3-methyl-2-pyridyl) cyclopenta [d] imidazole and 2-phthalimidobenzyl bromide in the same manner as in Example 1, 1,4,5,6-tetrahydro-2- (2-phthalimidobenzyl) was treated. Thio)-
1- (3-methyl-2-pyridyl) cyclopenta [d]
Get imidazole.

M. p. 137-139 ° C. Reference Example 1 (1) 2-aminopyridine (3.76 g) and 2,2-diethoxyethyl isothiocyanate (7 g) are refluxed in toluene. 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. 126-128 ° C (2) 8.94 g of the product of (1) above and a solution of concentrated hydrochloric acid in a small amount of acetic acid are refluxed and the solvent is distilled off. Dissolve the residue in water,
Sodium hydrogen carbonate was added, and the precipitated crystals were collected by filtration and 1- (2
-Pyridyl) -2-mercaptoimidazole 4.91 g
To get

M. p. 159 to 161 ° C. (recrystallized from isopropyl alcohol-isopropyl ether-n-hexane) Reference Examples 2 to 25 By treating corresponding raw material compounds in the same manner as in Reference Examples 1- (1) and (2), the following No. 20- 23 The compounds listed in Table are obtained.

[0106]

[Table 20]

[0107]

[Table 21]

[0108]

[Table 22]

[0109]

[Table 23]

Reference Example 26 (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 reacting at room temperature, boron trifluoride etherate 170.3
g, and reflux. After cooling, 54 g of oxalic acid in a water-methanol mixture 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 2.9 g methylene chloride solution of this product. 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 to 147 ° C Reference Example 27 (1) To a tetrahydrofuran solution of 5.12 g of N-phenylanthranilic acid at -60 ° C, 32.2 ml of an n-hexane solution of n-butyllithium, and then a tetrahydrofuran solution of 4.42 g of methyl iodide was added. In addition, the reaction is carried out at room temperature. After the reaction, water was added and the mixture was extracted with ethyl acetate under hydrochloric acid, and the solvent was distilled off from the extract to obtain 5.06 g of N-methyl-N-phenylanthranilic acid.

Yield 93%, oil IR (liquid, cm ^-1 ): 1690 Mass (m / e) 227 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ): 3.22 (s, 3H, NCH ₃ (2) To a tetrahydrofuran suspension of 1.7 g of lithium aluminum hydride, a tetrahydrofuran solution of 5.06 g of N-methyl-N-phenylanthranilic acid is added dropwise under ice cooling. After reaction at room temperature, the mixture is ice-cooled, water and saturated aqueous sodium sulfate solution are added, and the insoluble matter is filtered off. The solvent was distilled off from the filtrate, the residue was purified with a silica gel column, and o-
4.33 g of N-methyl-N-phenylaminobenzyl alcohol are obtained.

Colorless oil IR (liquid, cm ^-1 ): 3360 Mass (m / e) 213 (M ⁺ ) ¹ H-NMR (CDCl ₃ , δ): 2.10 (t, 1H, J = 6Hz, OH) , 3.21 (s, 3H, NC
H ₃ ), 4.56 (d, 2H, J = 6Hz, CH ₂ O) Reference Example 28 In an ether suspension of 2.4 g of lithium aluminum hydride under ice cooling, 9 g of ethyl o- (1-pyrrolyl) benzoate was added. The ether solution is added dropwise and reacted. Water and an aqueous sodium sulfate solution were added under ice-cooling to remove insolubles, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain the compounds shown in Table 24 below.

[0115]

[Table 24]

Reference Example 29 A mixture of 6.82 g of 2-aminocyclohexanone hydrochloride, 6.21 g of 2-pyridylisothiocyanate dimer and 100 ml of toluene is heated and stirred. The internal temperature was lowered to 50 ° C., 4.61 g of triethylamine was added dropwise, and the reaction was further continued. Water is added to the reaction solution and the mixture is extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was evaporated to give N- (2-pyridyl) -N '-(2-oxocyclohexyl) thiourea (8.2 g).

Yield 72% M. p. 149-151 ° C. Reference Example 30 2-Mercapto-1,3a, 4 was prepared by treating 2-aminocyclopentanone hydrochloride in the same manner as in Reference Example 29.
5,6,6a-Hexahydro-6a-hydroxy-1-
(2-Pyridyl) cyclopenta [d] imidazole is obtained.

Yield 55% p. 126-127 ° C. Reference Example 31 2-Mercapto-1- (2-pyridyl) -4, by treating N- (2-pyridyl) -N ′-(2-oxocyclohexyl) thiourea in the same manner as in Example 66. 5,
6,7-Tetrahydrobenzimidazole is obtained.

Yield 94% M.P. p. 203-204 ° C (recrystallized from ethyl acetate-n-hexane) Reference Examples 32-36 2-mercapto-1,3a, 4,5,6,6a-hexahydro-6a-hydroxy-1- (2-pyridyl) cyclopenta [D] The imidazole and the corresponding starting material compound are treated in the same manner as in Example 1 to obtain the compounds shown in Table 25 below.

[0120]

[Table 25]

Reference Example 37 (1) 24.2 g of ethyl o-fluorobenzoate and 9.8 g of imidazole were heated in the presence of sodium hydride to obtain 23 g of ethyl o-imidazolylbenzoate.

B. p. 165 to 167 ° C. (2 mmHg) (2) This product (5 g) is treated in the same manner as in Reference Example 28 to obtain o-imidazolylbenzyl alcohol (3.4 g).

(3) 3.4 g of this product was used in Reference Example 26-
Treatment in the same manner as (2) gives 3.3 g of o-imidazolylbenzyl chloride hydrochloride.

M. p. 160-161 ° C (Ethanol-
Recrystallization from ether) Reference Example 38 1- (2-pyridyl) -2- (3-dimethylaminobenzylthio) imidazole 3.73 g of methylene chloride 10
The 0 ml solution 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. By recrystallizing the residue from methanol, 1-
1.48 g of (2-pyridyl) -2- (3-dimethylaminobenzylsulfinyl) imidazole are obtained.

Yield 55% p. 177 to 179 [deg.] C. Reference Examples 39 to 62 By treating the products obtained in Examples 2 to 25 in the same manner as in Reference Example 38, compounds shown in Tables 26 to 29 below are obtained.

[0126]

[Table 26]

[0127]

[Table 27]

[0128]

[Table 28]

[0129]

[Table 29]

Reference Examples 63 to 68 By treating the products obtained in Examples 26 to 31 in the same manner as in Reference Example 38, compounds shown in Table 30 below are obtained.

[0131]

[Table 30]

Reference Examples 69 to 87 By treating the products obtained in Examples 32 to 50 in the same manner as in Reference Example 38, compounds shown in Tables 31 to 33 below are obtained.

[0133]

[Table 31]

[0134]

[Table 32]

[0135]

[Table 33]

Reference Examples 88 to 95 By treating the products obtained in Examples 51 to 58 in the same manner as in Reference Example 38, compounds shown in Tables 34 to 35 below are obtained.

[0137]

[Table 34]

[0138]

[Table 35]

Reference Examples 96 to 100 By treating the products obtained in Examples 59 to 63 in the same manner as in Reference Example 38, compounds shown in Table 36 below are obtained.

[0140]

[Table 36]

Reference Examples 101 to 102 By treating the products obtained in Examples 64 to 65 in the same manner as in Example 38, the compounds shown in Table 37 below are obtained.

[0142]

[Table 37]

Reference Example 103 1,4,5,6-Tetrahydro-2- (2-dimethylaminobenzylthio) -1- (2-pyridyl) -cyclopenta [d] imidazole is treated in the same manner as in Reference Example 38. Therefore, 1,4,5,6-tetrahydro-2-
(2-Dimethylaminobenzylsulfinyl) -1-
(2-Pyridyl) -cyclopenta [d] imidazole is obtained.

Yield 74% M. p. 139.5 to 141 ° C. (recrystallized from ethyl acetate-n-hexane) Reference Examples 104 to 106 By treating the products obtained in Examples 67 to 69 in the same manner as in Reference Example 38, the compounds shown in Table 38 below. To get

[0145]

[Table 38]

Reference Example 107 1- (2-Pyridyl) -2- (2-aminobenzylthio) imidazole was treated in the same manner as in Reference Example 38 to give 1- (2-pyridyl) -2- (2-amino). Benzylsulfinyl) imidazole is obtained.

M. p. 145 to 146 ° C. (recrystallized from isopropyl alcohol) Reference Example 108 1- (2-pyridyl) -2- (2-acetylaminobenzylthio) imidazole was treated in the same manner as in Reference Example 38 to give 1- (2- Pyridyl) -2- (2-acetylaminobenzylsulfinyl) imidazole is obtained.

M. p. 172 to 173 ° C. (recrystallized from isopropyl alcohol) Reference Example 109 1- (2-pyridyl) -2- (2-methylaminobenzylthio) imidazole was treated in the same manner as in Reference Example 38 to give 1- (2- Pyridyl) -2- (2-methylaminobenzylsulfinyl) imidazole is obtained.

M. p. 135-137 ° C (recrystallized from ethyl acetate) Reference Example 110 1- (2-pyridyl) -2- [2- (N-methyl-N-
Acetylamino) benzylthio] imidazole was treated as in Reference Example 38 to give 1- (2-pyridyl) -2- [2- (N-methyl-N-acetylamino).
Benzylsulfinyl] imidazole is obtained.

M. p. 188-189 ° C (recrystallized from chloroform-isopropyl ether) Reference Example 111 1,4,5,6-tetrahydro-1- (2-pyridyl)
By treating 2- (2-acetylaminobenzylthio) cyclopenta [d] imidazole in the same manner as in Reference Example 38, 1,4,5,6-tetrahydro-1- (2-pyridyl) -2- (2- Acetylaminobenzylsulfinyl) cyclopenta [d] imidazole is obtained.

M. p. 188-191 ° C. (decomposition, recrystallization from ethyl acetate-n-hexane) Reference Example 112 By treating 1- (4-pyridyl) -2- (2-acetylaminobenzylthio) imidazole in the same manner as in Reference Example 38. 1- (4-Pyridyl) -2- (2-acetylaminobenzylsulfinyl) imidazole is obtained.

M. p. 147 to 149 ° C. (recrystallized from isopropyl alcohol-isopropyl ether) Reference Example 113 1- (2-pyridylmethyl) -2- (2-aminobenzylthio) imidazole was treated in the same manner as in Reference Example 38 to give 1-. (2-Pyridylmethyl) -2- (2-aminobenzylsulfinyl) imidazole is obtained.

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 ) Reference Example 114 By treating 1- (2-pyridyl) -2- (N-methyl-N-phenylaminobenzylthio) imidazole in the same manner as in Reference Example 38, , 1- (2-pyridyl) -2-
[2- (N-methyl-N-phenylamino) benzylsulfinyl] imidazole is obtained.

M. p. 137 to 139 ° C. (recrystallized from isopropyl alcohol-n-hexane) Reference Examples 115 to 120 By treating the products obtained in Examples 78 to 83 in the same manner as in Reference Example 38, the following compounds shown in Table 39 are obtained. .

[0155]

[Table 39]

Reference Example 121 1- (5-amino-2-pyridyl) -2- [2- (dimethylamino) benzylthio] imidazole was used as Reference Example 38.
By treating in the same manner as in 1- (5-amino-2-
Pyridyl) -2- [2- (dimethylamino) benzylsulfinyl] imidazole is obtained.

M. p. 140 to 143 ° C. (recrystallized from ethanol-ether) Reference Example 122 1- (5-amino-2-pyridyl) -2- [2- (dimethylamino) benzylthio] imidazole was used as Reference Example 38.
By treating in the same manner as in 1- (5-amino-2-
Pyridyl) -2- (2-morpholinobenzylsulfinyl) imidazole is obtained.

M. p. 190-192 ° C. (decomposition, recrystallization from chloroform-n-hexane) Reference Example 123 1- (5-acetylamino-2-pyridyl) -2- (2
-Moliphorinobenzylthio) imidazole in Reference Example 38
By the same treatment as described above, 1- (5-acetylamino-2-pyridyl) -2- (2-morpholinobenzylsulfinyl) imidazole is obtained.

M. p. 207 to 209 ° C (decomposition, recrystallization from chloroform-n-hexane) Reference Examples 124 to 127 By treating the products obtained in Examples 87 to 90 in the same manner as in Reference Example 38, the compounds shown in Table 40 below were obtained. obtain.

[0160]

[Table 40]

Reference Example 128 1- (2-Pyridylmethyl) -2- (2-acetylaminobenzylthio) imidazole was treated in the same manner as in Reference Example 38 to give 1- (2-pyridylmethyl) -2.
-(2-Acetylaminobenzylsulfinyl) imidazole is obtained.

M. p. 146-148 ° C (ethyl acetate-
Recrystallized from n-hexane) Reference Example 129 1- (5-acetylamino-2-pyridyl) -2- [2
By treating-(dimethylamino) benzylthio] imidazole in the same manner as in Reference Example 38, 1- (5-acetylamino-2-pyridyl) -2- [2- (dimethylamino) benzylsulfinyl] imidazole is obtained.

M. p. 168 to 170 ° C. (recrystallized from ethanol-ether) Reference Example 130 1- (4,6-dimethyl-2-pyridyl) -2- (2-
Formylaminobenzylthio) imidazole Reference Example 3
By treating in the same manner as in 8, 1- (4,6-dimethyl-2-pyridyl) -2- (2-formylaminobenzylsulfinyl) imidazole is obtained.

M. p. 160 to 162 ° C. (decomposition, recrystallization from methylene chloride-n-hexane) Reference Example 131 By treating 1- (2-pyridyl) -2- (2-benzoylaminobenzylthio) imidazole in the same manner as in Reference Example 38. , 1- (2-pyridyl) -2- (2-benzoylaminobenzylsulfinyl) imidazole is obtained.

M. p. 109 to 111 ° C. (recrystallized from ethyl acetate) Reference Examples 132 to 133 The products obtained in Examples 95 to 96 are treated in the same manner as in Reference Example 38 to give the compounds shown in Table 41 below.

[0166]

[Table 41]

Reference Example 134 1- (3-acetoxy-2-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole was used as Reference Example 38.
1- (3-acetoxy-
2-Pyridyl) -2- (2-dimethylaminobenzylsulfinyl) imidazole is obtained as an oil.

Mass (m / e): 385 (M ⁺ +1), 134 ¹ H-NMR (CDCl ₃ , δ): 2.19 (s, 3H, COCH ₃ ), 2.57 (s, 6H, N (C
_{H 3) 2), 4.77 (} ABq, 2H, SCH 2) IR (Nujol, cm -1): 1770,1045 Reference Example 135 1- (3-acetoxy-2-pyridyl) -2- (2-morpholino-benzyl thio ) By treating imidazole in the same manner as in Reference Example 38, 1- (3-acetoxy-2-
Pyridyl) -2- (2-morpholinobenzylsulfinyl) imidazole is obtained.

M. p. 104-107 ° C (ethyl acetate-
Recrystallization from n-hexane mixture) Reference Example 136 1- (4,6-dimethyl-2-pyridyl) -2- (2-
By treating methanesulfonylaminobenzylthio) imidazole in the same manner as in Reference Example 38, 1- (4,
6-Dimethyl-2-pyridyl) -2- (2-methanesulfonylaminobenzylsulfinyl) imidazole is obtained.

M. p. 138-142 ° C (recrystallized from methylene chloride-n-hexane mixed solution) Reference Example 137 1- (3-isopropoxy-2-pyridyl) -2- (2
By treating -dimethylaminobenzylthio) imidazole in the same manner as in Reference Example 38, 1- (3-isopropoxy-2-pyridyl) -2- (2-dimethylaminobenzylsulfinyl) imidazole is obtained.

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, 6H, N (CH 3) 2), 4.81 (ABq, 2H, SCH 2) was treated in the same manner as in Reference Example 38 The product obtained in Reference Example 138-139 Examples 101-102, the following The compounds listed in Table 42 are obtained.

[0172]

[Table 42]

Reference Example 140 1- (4-pyridyl) -2- (2-dimethylaminobenzylthio) imidazole 1.5 g of chloroform 100
80% metachloroperbenzoic acid 3.4 ml under ice cooling
Add 2 g. After stirring the mixture for 1 hour, 8.36 g of sodium dithionite is added and left at room temperature. After 2 hours, the reaction solution is washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (40: 1)] and then recrystallized from a mixed solution of chloroform and isopropyl ether to give 1- (4
0.91 g of -pyridyl) -2- [2- (dimethylamino) benzylsulfonyl] imidazole is obtained.

M. p. 132-135 ° C. Reference Example 141 (1) 1- (3-methyl-2-pyridyl) -2- (2-
Phthalimidobenzylthio) imidazole Reference Example 38
By treating in the same manner as in 1- (3-methyl-2-
Pyridyl) -2- (2-phthalimidobenzylsulfinyl) imidazole is obtained.

M. p. 187 to 192 ° C (recrystallized from ethyl acetate) (2) This product was treated in the same manner as in Example 74- (2), to give 1- (3-methyl-2-pyridyl) -2- (2).
-Aminobenzylsulfinyl) imidazole is obtained.

M. p. 112.5-113.5 ° C. (recrystallized from ethyl acetate) Reference Example 142 (1) 2-amino-3-methylpyridine 2.16 g, sodium bicarbonate 4.40 g, ether 100 ml, water 5
While stirring 0 ml of the mixture under ice cooling with vigorous stirring, a solution of 2.60 g of thiophosgene in 10 ml of ether is added dropwise.
After reacting for 30 minutes, the organic layer is separated, washed with water and dried, and then the solvent is distilled off. The obtained residue is dissolved in chloroform, and 2.84 g of 2-aminocyclopentanone hydrochloride is added thereto. After adding 4 ml of triethylamine to the reaction solution, the mixture is stirred at room temperature for 3 hours. After the reaction, the reaction solution is washed with water and dried, and then the solvent is distilled off. By recrystallizing the obtained residue from isopropanol, 2-mercapto-1, 3a, 4,
5,6,6a-hexahydro-6a-hydroxy-1-
3.88 g of (3-methyl-2-pyridyl) cyclopenta [d] imidazole are obtained.

M. p. 171 to 174 ° C. (2) By treating this product in the same manner as in Example 66,
1,4,5,6-tetrahydro-2-mercapto-1-
(3-Methyl-2-pyridyl) cyclopenta [d] imidazole is obtained.

M. p. 230-234 ° C. (recrystallized from ethanol) Reference Example 143 (1) 1,4,5,6-tetrahydro-2- (2-phthalimidobenzylthio) -1- (3-methyl-2-pyridyl) cyclopenta [d By treating imidazole in the same manner as in Reference Example 38, 1,4,5,6-tetrahydro-2- (2-phthalimidobenzylsulfinyl)
-1- (3-Methyl-2-pyridyl) cyclopenta [d] imidazole is obtained.

M. p. 170-172 ° C (2) This product was treated in the same manner as in Example 74- (2) to give 1,4,5,6-tetrahydro-2- (2-aminobenzylsulfinyl) -1- (3-. Methyl-2-
Pyridyl) cyclopenta [d] imidazole is obtained.

M. p. 141.5 ° C

[0181]

INDUSTRIAL APPLICABILITY According to the present invention, when compound (II) is used as a synthetic intermediate in the production of pharmaceutical compound (I) having an excellent gastric acid secretion inhibitory effect, compound (I) can be efficiently produced. Obtainable.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location A61K 31/445 7431-4C 31/535 7431-4C

Claims (1)

[Claims] 1. A compound represented by the general formula (II): (However, ring A is a halogen atom, lower alkyl group, lower alkoxy group, phenyl lower alkoxy group, nitro group, amino group, lower alkanoylamino group, N-lower alkyl-N-lower alkanoylamino group, mono- or di- Lower alkylamino group, lower alkanoyloxy group, cyanide group, trihalogeno lower alkyl group, trihalogeno lower alkoxy group, lower alkenyloxy group and optionally substituted with one or two groups selected from 2-, 3- Or 4-pyridyl group; Ring B is nitro group, amino group, mono- or di-lower alkylamino group, lower alkanoylamino group, phenylamino group, cycloalkylamino group, N- (tri-lower alkylphenyl) sulfonylamino group , N-lower alkyl-N- (tri-lower alkylphenyl) Rufonylamino group, N-lower alkyl-N-phenylamino group, di (lower alkyl) amino lower alkylideneamino group, dilower alkylamino lower alkyl group, N-lower alkyl-N-lower alkanoylamino group, lower alkoxy group, aryl Represents a phenyl group substituted with a group selected from a carbonylamino group, a lower alkylsulfonylamino group, a formylamino group, a lower alkoxycarbonylamino group, a phthalimido group and a nitrogen-containing 5- to 6-membered heteromonocyclic group, R ¹ and R ² are both hydrogen atoms or are bonded to each other at the terminals to form a compound represented by the formula-
(CH _{2) q} - group represented by the formation, n represents 0, 1 or 2, q represents 3 or 4. ) The imidazole derivative or its salt shown by these.