JP2794637B2 - Imidazole derivative, method for producing the same, and anti-ulcer agent containing the same - Google Patents

Description

The present invention relates to a novel imidazole derivative, and more particularly to the following general formula (I): [Wherein, R ¹ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear, branched or cyclic moiety-containing alkenyl group having 3 to 9 carbon atoms. Or an alkynyl group, R ² is a straight-chain, branched or cyclic moiety-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms, and R ³ , R ⁴ , R ⁵ and
R ⁶ is the same or different and is a hydrogen atom, a halogen atom, a lower alkoxy group, an aralkyloxy group, a lower alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, or a fluorine-substituted alkoxy group R ⁷ and R ⁸ are the same or different,
A hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, a fluorine-substituted alkoxy group, or a lower alkyl group or lower alkoxy group as a substituent or substituted with a halogen atom is also substituted aryl group, or by R ⁷ and may be and R ⁸ combine to form a ring with the carbon atom to which R ⁷ and R ⁸ are attached] The present invention relates to an imidazole derivative represented by the formula, a method for producing the same, and an anti-ulcer agent containing the same as an active ingredient.

[Prior art] Conventionally, general formula (A): (Wherein, R ¹⁰ and R ¹¹ are a hydrogen atom or a lower alkyl group, and at least one of R ¹² and R ¹³ is a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower alkoxy group,
Benzimidazole derivative represented by the formula: H ⁺ + K ⁺ ATP
It is known that it is useful as an anti-ulcer agent having an ase inhibitory action (JP-A-61-221175).

Furthermore, the general formula (B): (Wherein, R ¹⁴ and R ¹⁵ are an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms having a hydroxyl group, wherein at least one of R ¹⁴ and R ¹⁵ is a hydroxyl group Wherein R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are the same or different and are a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, fluoromethyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, and benzimidazole derivatives represented by fluorine-substituted alkyl is a substituent selected from the group consisting of group), H ^{+ +} K ⁺ ATP
It is also known to have a gastric acid secretion inhibitory action based on an enzyme inhibitory action (JP-A-1-230560).

[Problems to be Solved by the Invention] It is desired to provide a novel compound having an excellent anti-ulcer effect and further having a higher safety and the like.

[Means for Solving the Problems] Under these circumstances, the present inventors have conducted intensive studies and as a result, have found that the novel imidazole derivative represented by the general formula (I) has an excellent gastric acid secretion inhibitory action. Heading, the present invention has been completed.

The novel imidazole derivative of the present invention represented by the general formula (I) is characterized in that at least one of R ¹ and R ² in the general formula (I) is a group having a carbon-carbon unsaturated bond as described above. These compounds have completely different structures from known compounds.

Accordingly, the present invention provides a compound of the general formula (I) useful as an anti-ulcer agent
And a novel imidazole derivative represented by the formula:

The present invention also provides a novel method for producing a novel imidazole derivative represented by the general formula (I).

Furthermore, the present invention provides an anti-ulcer agent containing the novel imidazole derivative represented by the general formula (I).

In the general formula (I), R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear, branched or cyclic moiety having 3 to 9 carbon atoms. Is an alkenyl group or an alkynyl group.
Examples of linear or branched alkyl groups having 1 to 8 carbon atoms include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl , Heptyl, octyl, 2-
Ethylhexyl and the like. Also, 3 ~
A straight-chain, branched or cyclic moiety-containing alkenyl group or alkyl group having 9 carbon atoms has a carbon-carbon double bond or a carbon-carbon triple bond at least in any of its straight-chain, branched or cyclic moieties. And examples thereof include an allyl group, a 2-propynyl group, a 2-butenyl group, a 3-butenyl group, a 2-butynyl group, a 3-butynyl group, a 3-methyl-2-butenyl group, and a 3-methyl- Examples thereof include a 3-butenyl group, a cyclohex-1-ynylmethyl group, and a 2-cyclopropylideneethyl group.

In the general formula (I), R ² is a straight-chain, branched or cyclic moiety-containing alkenyl or alkynyl group having 3 to 9 carbon atoms as described above for R ¹ . When R ¹ and R ² are both an alkenyl group or an alkynyl group as described above, R ¹ and R ² may be the same or different.

In the general formula (I), among the groups represented by R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ , the lower alkoxy group is a linear or branched alkoxy group having 1 to 5 carbon atoms. For example, methoxy, ethoxy, isopropoxy and the like are preferable, and the aralkyloxy group may have a substituent such as a halogen atom or lower alkyl on the aromatic ring, and the alkylene moiety has 1 to 3 carbon atoms. Having an aralkyloxy group,
For example, a benzyloxy group is preferable, and a lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, Preferred are i-butyl, t-butyl, pentyl, hexyl and the like, and the lower alkoxycarbonyl group is a straight-chain or branched alkoxycarbonyl group having 2 to 5 carbon atoms, for example,
Preferred are methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like.
An aliphatic acyl group having from 5 to 5 carbon atoms or an aromatic acyl group having from 7 to 9 carbon atoms, for example, acetyl, benzoyl and the like are preferable, and the fluorine-substituted alkyl group is a hydrogen atom of the above lower alkyl group. It is preferable that 1 to 3 have a value substituted with a fluorine atom, and the fluorine-substituted alkoxy group is a group in which 1 to 3 of the hydrogen atoms of the above lower alkoxy group have been substituted with a fluorine atom. preferable. Further, by bonding the R ⁷ and R ^8, may form an alkylene having 3 to 5 carbon atoms and, R ⁷ and
Together with the carbon atom to which R ⁸ is bonded, a benzene ring which may have a substituent, an aromatic ring such as a benzoquinone ring or a furan ring, a pyrrole ring, a thiophene ring, a heterocyclic ring such as a pyridine ring are formed. May be.

In particular, R ⁵ is a lower alkyl group as described above (particularly, preferably methyl and ethyl), a lower alkoxy group (particularly,
Methoxy and ethoxy are preferred) or a fluorine-substituted alkyl group (particularly a trifluoromethyl group is preferred)
Wherein R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ are hydrogen atoms.

The imidazole derivative (I) of the present invention has, for example, the general formula (II): [Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are represented by the general formula (I)
And X is a leaving group], and a compound represented by the general formula (III): [Wherein, R ⁷ and R ⁸ are the same as those described for the general formula (I)].
V): (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as described above), and then oxidizing the compound can do.

As typical compounds of the imidazole derivative of the present invention, the following compounds can be exemplified.

That is, a representative compound of the imidazole derivative of the present invention is represented by the general formula (I): Where R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷
And R ⁸ are compounds in which each is a group shown in Table 1.

The results of tests on the pharmacological effects of the thus obtained representative compounds of the present compound (I) are as follows.

(1) H ⁺ + K ⁺ ATPase inhibitory activity Porcine gastric mucosa The method of Forte et al. [Journal of Applied Physiol.
14-717 (1972)], gastric acid-secreting cells were separated from porcine gastric mucosa, and vesicles containing H ⁺ + K ⁺ ATPase were prepared by centrifugation in a discontinuous density gradient of Ficoll. After incubating the enzyme and the test substance with 2 mM bis-tris-acetate buffer (pH 5.5) at 37 ° C. for 30 minutes, 37.5 mM bis-tris-acetate buffer (pH 7.4), 2 mM magnesium chloride and 2 mM ATP were added. After further reacting at 37 ° C. for 10 minutes in the presence or absence of 5 mM potassium chloride, the reaction was stopped by adding 5% trichloroacetic acid, and the released inorganic phosphorus was removed by Fiske.
-Quantified by the Subbarow method. K ⁺ -dependent ATPase activity
It was determined by subtracting the value in the absence of potassium chloride from the value in the presence of potassium chloride.

(2) Gastric acid secretion inhibitory action After fasting Heidenhain pouch dogs prepared using male beagle dogs, histamine hydrochloride was used as a gastric acid secretion stimulant for 160 days.
It was continuously administered intravenously at a dose of μg / kg / hr. Gastric fluid was collected at 15 minute intervals, and the gastric fluid volume and acidity were measured, and the acid excretion (mEq /
15min).

One hour after the start of histamine administration, the compound obtained in the example shown in Table 3 and the comparative compound were intravenously administered at a dose of 1 mg / kg as a drug, and gastric juice was collected over time.

The total acid excretion when the above compound was administered at 3 mg / kg was determined, and the gastric acid secretion inhibition rate was determined as a ratio to the total acid excretion when a control was not administered with the compound. Table 3 shows the dose and inhibition rate of the compound of the present invention and the comparative compound obtained in each Example.

(Method of Oral Administration Test) After fasting a Heidenhain pouch dog prepared using a male beagle dog, a polyethylene cannula was inserted into the lower limb artery, and histamine hydrochloride was injected intravenously at a dose of 16 μg / kg / hr in histamine hydrochloride.
Continuous infusion with a usion pump. Gastric juice was collected at 15-minute intervals, the gastric juice volume and acidity were measured, and the acid excretion (mEq / 15 min) was calculated and used as a control. The drug was suspended in 15 ml of 0.5% CMC and administered 10 hours before histamine stimulation by an oral sonde for dogs.
The dose was administered at a dose of mg / kg, and the gastric juice was poured at a time interval of 15 minutes with 4 times the volume of about 60 ml of water. The gastric juice and acidity were measured, and the acid excretion (mEq / 15 minutes) was calculated. . The gastric secretion inhibitory effect was determined by taking the acid excretion one hour after the start of histamine stimulation as a ratio to the acid excretion in the case of a control to which no drug was administered.

The compounds of the present invention also have a gastrointestinal cytoprotective effect (see US Pat. No. 4,359,465).

The compound of the present invention can be administered orally or parenterally. As the dosage form of the oral administration agent, for example, tablets,
Capsules, powders, granules, syrups and the like can be mentioned, and parenteral dosage forms include injections and the like. For these preparations, ordinary excipients, disintegrants, binders, lubricants, pigments, diluents and the like are used. As excipients, glucose, lactose, etc., as disintegrants, starch, carboxymethylcellulose calcium, etc.,
As a lubricant, magnesium stearate, talc or the like is used, and as a binder, hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone or the like is used.

The dose is usually about 1 mg to 5 mg / day for an adult.
0 mg, orally about 10 mg to 500 mg daily, but it can be increased or decreased depending on age, symptoms and the like.

 Next, the present invention will be described with reference to examples.

Example 1 2- [2- (2-propynylamino) benzylsulfinyl] imidazole: (1) Methyl N-propargylanthranilate: 45.6 g (303 mmol) of methyl anthranilate and 18 g (151 mmol) of propargyl bromide in methanol 50ml
And heated to reflux for 40 hours. The methanol was distilled off under reduced pressure, and 500 ml of ether was added, and the precipitated solid was separated by filtration. The filtrate was washed with 1N-HCl, 1N-NaOH and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and 160 ml of hexane was added to the residue, followed by cooling. The precipitated crystals were collected by filtration and washed with cold hexane to give the title compound (20.4 g, yield 35.0%) as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ = 2.21 (t, 1H, J = 2 Hz) 3.85 (s, 3H) 4.02 (dd, 2H, J = 2 Hz, 6 Hz) 6.5-8.0 (m, 4H) (2) 2 -(2-propynylamino) benzyl alcohol: 1.0 g (26.4 mmol) of lithium aluminum hydride was suspended in 50 ml of dry tetrahydrofuran (THF), and 5.0 ml of the methyl N-propargylanthranilate obtained in (1) was suspended under ice-cooling. g (26.4 mmol) in 20 ml of dry THF was added dropwise over 30 minutes and stirred for a further 30 minutes. Under ice-cooling, a saturated sodium sulfate aqueous solution was added to decompose the mixture. After insoluble matter was removed by filtration, the solvent was distilled off, and the obtained oil was purified by a silica gel column to give 1.73 g of the title compound (yield 40.7%). Was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ = 1.84 (bs, 1H) 2.19 (t, 1H, J = 3 Hz) 3.93 (d, 2H, J = 3 Hz) 4.60 (s, 2H) 5.0 (bs, 1H) 6.7− 7.4 (m, 4H) (3) 2- [2- (2-propynylamino) benzylthio] imidazole: 2- (2-propynylamino) benzyl alcohol 1.
61 g (10 mmol) was dissolved in 16 ml of dichloromethane, and a solution of 0.87 ml (12 mmol) of thionyl chloride in 4 ml of dichloromethane was added dropwise over 10 minutes under ice cooling. After stirring at room temperature for 15 minutes, the solvent was distilled off at room temperature. The resulting oil is treated with dichloromethane
5 ml, and dissolve this solution in 2-mercaptoimidazole
A solution of 1.5 g (15 mmol) in 15 ml of ethanol was added little by little and stirred at room temperature for 1 hour. The solvent was distilled off from the obtained solution under reduced pressure, water and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was crystallized by adding ether, and the crystals were collected by filtration to obtain 1.73 g (yield: 71.2%) of the title compound as pale yellow crystalline powder. ¹ H-NMR (CDCl ₃ / CD ₃ OD = 3/1) δ = 2.30 (t, 1H, J = 2 Hz) 3.99 (d, 2H, J = 2 Hz) 4.13 (s, 2H) 6.5-7.3 (m, 4H) 7.01 (s, 2H) (4) 2- [2- (2-propynylamino) benzylsulfinyl] imidazole: 2- [2- (2-propynylamino) benzylthio]
1.0 g (4.12 mmol) of imidazole in 15 ml of chloroform
And 880 mg (purity 80%, 4.12 mmol) of m-chloroperbenzoic acid was added over about 10 minutes under ice-cooling. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction product, and the mixture was extracted with 30 ml of chloroform. The chloroform layer was washed with 10 ml of 0.1 N-NaOH and then extracted with 7 ml of 0.3 N-NaOH. This alkali solution was extracted twice with 30 ml of chloroform, and the obtained chloroform layer was combined with the first chloroform layer, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized by adding ether, and the crystals were collected by filtration to give the title compound (380 m).
g (yield 35.6%) was obtained as pale yellow crystalline powder.

Melting point: 158-159 ° C (decomposition) ¹ H-NMR (CDCl ₃ / CD ₃ OD = 2/1) δ = 2.32 (t, 1H, J = 3 Hz) 3.99 (d, 2H, J = 3 Hz) 4.29, 4.53 (Each d, 2H, J = 13Hz) 6.5−7.3 (m, 4H) 7.22 (s, 2H) IRν (KBr) cm ^-1 : 3370,3260,1600,1580,1515,1300,1100,1025,960,940,
890,780,740. [Example 2] 2- [2- (allylamino) benzylsulfinyl] imidazole: (1) Methyl N-allylanthranilate: 15.1 g (0.10 mol) of methyl anthranilate and 6.05 g (50 mmol) of allyl bromide in methanol It was dissolved in 75 ml and heated under reflux for 40 hours. The methanol was distilled off under reduced pressure, and 500 ml of ether was added, and the precipitated solid was separated by filtration. The filtrate is 1N-H
After washing with Cl, 1N-NaOH and saturated saline, it was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give 3.85 g of the title compound (yield 4
0.3%).

(2) 2- (allylamino) benzyl alcohol: 0.76 g (20.0 mmol) of lithium aluminum hydride
Was suspended in 50 ml of dry THF, and a solution of 3.82 g (20.0 mmol) of methyl N-allylanthranilate obtained in (1) in 20 ml of dry THF was added dropwise over 30 minutes under ice cooling, followed by stirring for 30 minutes. Under ice-cooling, the excess lithium aluminum hydride was partitioned with saturated aqueous sodium sulfate, the insolubles were filtered off, the solvent was distilled off, and the resulting oil was purified on a silica gel column to give the title compound (2.44 g, Yield 75.1%) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ = 1.7 (bs, 1H) 3.80 (dt, 2H, J = 2 Hz, 5 Hz) 4.64 (s, 2H) 5.0-5.4 (m, 2H) 5.7-6.2 (m, 1H) 6.7-7.3 (m, 4H) (3) 2- [2- (allylamino) benzylthio] imidazole: 2.8 g of 2- (allylamino) benzyl alcohol (17.2)
Mmol) in 28 ml of dichloromethane, and 1.5 ml (20.6 mmol) of thionyl chloride in 10 ml of dichloromethane under ice-cooling.
The solution was added dropwise over 15 minutes, and after stirring at room temperature for 15 minutes, the solvent was distilled off at room temperature. The obtained oil was dissolved in 5 ml of dichloromethane, and this solution was treated with 2.58 g of 2-mercaptoimidazole.
(25.8 mmol) in 25 ml of ethanol was added little by little, and the mixture was stirred at room temperature for 1 hour. Ethanol was distilled off from the resulting solution under reduced pressure, water and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized by adding ether. The crystals were collected by filtration to give 3.34 g (yield 79.3%) of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ = 3.76 (dt, 2H, J = 2 Hz, 5 Hz) 4.19 (s, 2H) 5.0-5.4 (m, 2H) 5.6-6.1 (m, 1H) 6.4-7.2 (m, 4H) 7.04 (s, 2H) (4) 2- [2- (allylamino) benzylsulfinyl] imidazole: 1.5 g (6.1 mmol) of 2- [2- (allylamino) benzylthio] imidazole was dissolved in 15 ml of chloroform and cooled with ice. Below, 1.18 g of m-chloroperbenzoic acid (purity 80%,
5.5 mmol) was added in about 10 minutes. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and chloroform 30
Extracted with ml. The chloroform layer was washed with 10 ml of 0.3N-NaOH. The alkaline layer was extracted twice with 30 ml of chloroform, and 2 drops of a saturated NH ₄ OH solution were added, followed by extraction with 30 ml of chloroform. On the other hand, the first chloroform layer was extracted with 10 ml of 1N-NaOH, made alkaline with a saturated NH ₄ OH solution, and extracted with 20 ml of chloroform. The chloroform layers were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, acetonitrile / ether was added to the residue for crystallization, and the crystals were collected by filtration to give the title compound 73.
0 mg (45.9% yield) was obtained as white crystals.

Melting point: 139 ° C (decomposition) ¹ H-NMR (CDCl ₃ / CD ₃ OD = 2/1) δ = 3.72 (d, 2H, J = 6 Hz) 4.31, 4.53 (each d, 2H, J = 14 Hz) 4.9- 5.4 (m, 2H) 5.7-6.2 (m, 1H) 6.4-7.4 (m, 4H) 7.21 (s, 2H) IRν (KBr) cm ^-1 : 3390,1605,1585,1520,1315,1100,1000, 895,750,500. Example 3 2- [2- (3-methyl-2-butenylamino) benzylsulfinyl) imidazole: (1) Methyl 2- (3-methyl-2-butenylamino)
Benzoate: 15.1 g (0.10 mol) of methyl anthranilate was dissolved in 75 ml of methanol, and 1-bromo-3-methyl-2- was added.
7.5 g (50 mmol) of butene was added, and the mixture was heated under reflux overnight.
Methanol was distilled off under reduced pressure, chloroform and 3N-hydrochloric acid were added to the residue, the chloroform layer was separated, washed with 5% aqueous sodium carbonate, and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified by silica gel column chromatography to give the title compound 6.51 as a pale yellow oil.
g (59.5% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ = 1.73 (s, 6H) 3.72 (d, 2H, J = 6 Hz) 3.84 (s, 3H) 5.32 (bt, 1H) 6.4-7.9 (m, 4H) 7.57 (bs, 1H) (2) 2- (3-methyl-2-butenylamino) benzyl alcohol: 2.26 g of lithium aluminum hydride is suspended in 65 ml of THF, and the methyl 2- (3-methyl) obtained in (1) is cooled under ice-cooling. A solution of 6.51 g of (-2-butenylamino) benzoate in 15 ml of THF was added dropwise over 15 minutes, and the mixture was further stirred at room temperature for 30 minutes. After decomposing with saturated aqueous sodium sulfate under ice-cooling, the organic layer was obtained by decantation and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the title compound (yield: 5.48 g, yellow oil) was obtained in a yield of 95.
6%). ¹ H-NMR (CDCl ₃ ) δ = 1.72 (s, 6H) 3.71 (d, 2H, J = 7 Hz) 4.62 (s, 2H) 6.28 (bt, 1H) 6.4-7.3 (m, 4H) (3) 2 -[2- (3-methyl-2-butenylamino)
Benzylthio] imidazole: Dissolve 5.48 g (29 mmol) of 2- (3-methyl-2-butenylamino) benzyl alcohol in 55 ml of dichloromethane and dichloromethane in 10 ml of 3.1 ml of thionyl chloride under ice cooling.
The solution was added dropwise over 15 minutes and stirred for another 30 minutes. The residue obtained by distilling off the solvent was dissolved in 20 ml of dichloromethane, and this solution was added to a solution of 3.44 g of 2-mercaptoimidazole in 35 ml of ethanol over 10 minutes, followed by stirring at room temperature for another 30 minutes. Ethanol was distilled off from the resulting solution, chloroform and 5% aqueous sodium carbonate were added to the residue, and the organic layer was separated and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography and crystallized from ether-hexane. This was collected by filtration to give the title compound as a white crystalline powder 3.
82 g (48.9% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ = 1.70 (s, 3H) 1.74 (s, 3H) 3.70 (d, 2H, J = 6 Hz) 4.17 (s, 2H) 5.33 (m, 1H) 6.4-7.3 (m, 4H) 7.02 (s, 2H) (4) 2- [2- (3-methyl-2-butenylamino)
Benzylsulfinyl] imidazole: 1.62 g (5.9 mmol) of 2- [2- (3-methyl-2-butenylamino) benzylthio] imidazole is dissolved in a mixed solvent of 16 ml of chloroform and 1.6 ml of methanol,
Under ice-cooling, 1.10 g of m-chloroperbenzoic acid (purity 85%) was added to 30
Minutes. After completion of the reaction, chloroform and 5% aqueous sodium carbonate were added to the reaction solution, and the organic layer was separated.
Furthermore, after washing twice with 0.05N-sodium hydroxide aqueous solution,
To this was added 10 ml of 2N aqueous sodium hydroxide to extract an aqueous layer. To the aqueous layer, 30 ml of 1N aqueous ammonium chloride was added little by little, and the precipitated oil was extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was crystallized from ether-hexane. The crystals were collected by filtration to obtain 0.52 g (yield 30%) of the title compound as a white crystalline powder.

Melting point: 135-136 ° C (decomposition) ¹ H-NMR (CDCl ₃ / CD ₃ OD = 1/1) δ = 1.75 (s, 6H) 3.68 (d, 2H, J = 6 Hz) 4.32 (d, 1H, J = 13Hz) 4.53 (d, 1H, J = 13Hz) 5.31 (bt, 1H) 6.4−7.3 (m, 4H) 7.23 (s, 2H) IRν (KBr) cm ^-1 : 3380,2900,1600,1580,1520 , 1310,1105,1090,1000,89
Example 4 2-[(2-allylamino-5-methyl) benzylsulfinyl] imidazole: (1) Methyl (2-allylamino-5-methyl) benzoate: 8.25 g of methyl 5-methylanthranilate ( (50 mmol) was dissolved in 40 ml of methanol, and 3.03 g (25 mmol) of allyl bromide was added thereto. After heating under reflux for 30 minutes, 1.52 g (13 mmol) of allyl bromide was further added, followed by heating under reflux for 30 minutes. Methanol was distilled off under reduced pressure, chloroform and 5% aqueous sodium carbonate were added to the residue, the chloroform layer was separated, and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography to give 4.68 g of the title compound as a pale yellow oil.
(60.7% yield). ¹ H-NMR (CDCl ₃ ) δ = 2.22 (s, 3H) 3.85 (s, 3H) 3.85 (m, 2H) 5.0-6.1 (m, 3H) 6.4-7.7 (m, 3H) (2) (2- Allylamino-5-methyl) benzyl alcohol: 1.30 g of lithium aluminum hydride is suspended in 40 ml of THF, and a solution of 4.68 g of methyl (2-allylamino-5-methyl) benzoate obtained in (1) in 10 ml of THF is added under ice-cooling. 15
After that, the mixture was stirred at room temperature for 30 minutes. After decomposing with saturated aqueous sodium sulfate under ice-cooling, the organic layer was obtained by decantation and concentrated under reduced pressure. Dissolve the residue in chloroform,
After washing with water, it was dried over anhydrous sodium sulfate. The solvent was distilled off and the title compound (3.59 g, yield 88.8) was obtained as a pale brown oily residue.
%). ¹ H-NMR (CDCl ₃ ) δ = 2.22 (s, 3H) 3.77 (m, 2H) 4.60 (m, 2H) 4.9-6.2 (m, 3H) 6.4-7.1 (m, 3H) (3) 2- [ (2-allylamino-5-methyl) benzylthio] imidazole: Dissolve 3.59 g (20 mmol) of (2-allylamino-5-methyl) benzyl alcohol in 36 ml of dichloromethane and add a solution of 2.2 ml of thionyl chloride in 10 ml of dichloromethane under ice cooling. After that, the mixture was added dropwise for 30 minutes and stirred for another 30 minutes. The residue obtained by distilling off the solvent was dissolved in 20 ml of dichloromethane, and this solution was dissolved in 2.44 g of 2-mercaptoimidazole in ethanol 2
The solution was added to the 5 ml solution over 10 minutes and stirred at room temperature for another 30 minutes. Ethanol was distilled off from the resulting solution, chloroform and 5% aqueous sodium carbonate were added to the residue, and the organic layer was separated and dried over anhydrous sodium sulfate. Chloroform was distilled off, and the residue was purified by silica gel column chromatography and crystallized from ether-hexane. This was collected by filtration, and 4.06 g of the title compound as a white crystalline powder (yield 7
7.3%). ¹ H-NMR (CDCl ₃ ) δ = 2.16 (s, 3H) 3.75 (m, 2H) 4.17 (s, 2H) 4.9-6.1 (m, 3H) 6.3-7.1 (m, 3H) 7.04 (s, 2H) (4) 2-[(2-allylamino-5-methyl) benzylsulfinyl] imidazole: 2.00 g (7.7 mmol) of 2-[(2-allylamino-5-methyl) benzylthio] imidazole in chloroform
Dissolve in a mixed solvent of 20 ml and methanol 2 ml, under ice cooling,
1.57 g (purity 85%) of m-chloroperbenzoic acid was added over 30 minutes. After completion of the reaction, chloroform and 5% aqueous sodium carbonate were added to the reaction solution, and the organic layer was separated. In addition, 0.
After washing 3 times with 05N-sodium hydroxide solution, add 1N
-20 ml of aqueous sodium hydroxide was added to extract an aqueous layer. 60 ml of 1N aqueous ammonium chloride was added little by little to the aqueous layer, and the precipitated oil was extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is ether-
By crystallizing from hexane and filtering the crystals,
0.91 g (yield 43%) of the title compound was obtained as a white crystalline powder.

Melting point: 135-137 ° C (decomposition) ¹ H-NMR (CDCl ₃ / CD ₃ OD = 1/1) δ = 2.15 (s, 3H) 3.72 (m, 2H) 4.32 (d, 1H, J = 14 Hz) 4.52 (D, 1H, J = 14Hz) 5.0−6.2 (m, 3H) 6.4−7.0 (m, 3H) 7.24 (s, 2H) IRν (KBr) cm ^-1 : 3350,3080,3000,2920,1620,1520 , 1430,1320,1100,102
5,905,800,745. [Formulation Example 1] Formulation Example (Tablet) One tablet (220 mg) contains the following components.

Active ingredient 50 mg Lactose 103 Starch 50 Magnesium stearate 2 Hydroxypropylcellulose 15 [Formulation example 2] Formulation example (capsule) One gelatin hard capsule contains the following components (350 mg).

 Active ingredient 40 mg Lactose 200 Starch 70 Polyvinylpyrrolidone 5 Crystalline cellulose 35 Formulation example (granules) The following components are contained in 1 g of granules.

 Active ingredient 200mg Lactose 450 Corn starch 300 Hydroxypropylcellulose 50

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07D 233/84 C07D 235/28 C07D 233/86 C07D 233/88 C07D 233/90 A61K 31/415 REGISTRY (STN ) CA (STN)

Claims (3)

(57) [Claims] 1. The following general formula (I): [Wherein, R ¹ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear, branched or cyclic moiety-containing alkenyl group having 3 to 9 carbon atoms. Or an alkynyl group, and R ² is an alkenyl group or an alkynyl group containing a straight-chain, branched or cyclic moiety having 3 to 9 carbon atoms, and R ³ , R ⁴ , R ⁵ and R ⁶
Are the same or different and are a hydrogen atom, a halogen atom, a lower alkoxy group, an aralkyloxy group, a lower alkyl group,
A lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, or a fluorine-substituted alkoxy group, wherein R ⁷ and R ⁸ are the same or different and are a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkoxy group; An alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, a fluorine-substituted alkoxy group, or a substituent may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. An aryl group, or R ⁷ and R ⁸ are bonded
R ⁷ and R ⁸ may form a ring together with the carbon atom to which they are attached.]. 2. The following general formula (II): [Wherein, R ¹ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear, branched or cyclic moiety-containing alkenyl group having 3 to 9 carbon atoms. Or an alkynyl group, and R ² is an alkenyl group or an alkynyl group containing a straight-chain, branched or cyclic moiety having 3 to 9 carbon atoms, and R ³ , R ⁴ , R ⁵ and R ⁶
Are the same or different and are a hydrogen atom, a halogen atom, a lower alkoxy group, an aralkyloxy group, a lower alkyl group,
A lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, or a fluorine-substituted alkoxy group, and X is a leaving group] and a compound represented by the following general formula (III): [Wherein, R ⁷ and R ⁸ are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, Substituted alkoxy group,
Or, as a substituent, a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom, or R ⁷ and R ⁸ are bonded to form R ⁷ and R ⁸
May form a ring together with the carbon atom to which it is bonded.] With a compound represented by the following general formula (I
V): Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as defined above, and then oxidizing the compound. The following general formula (I): (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as those described above). 3. The following general formula (I): [Wherein, R ¹ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear, branched or cyclic moiety-containing alkenyl group having 3 to 9 carbon atoms. Or an alkynyl group, and R ² is an alkenyl group or an alkynyl group containing a straight-chain, branched or cyclic moiety having 3 to 9 carbon atoms, and R ³ , R ⁴ , R ⁵ and R ⁶
Are the same or different and are a hydrogen atom, a halogen atom, a lower alkoxy group, an aralkyloxy group, a lower alkyl group,
A lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, or a fluorine-substituted alkoxy group, wherein R ⁷ and R ⁸ are the same or different and are a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkoxy group; An alkyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, a fluorine-substituted alkyl group, a fluorine-substituted alkoxy group, or a substituent may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom. An aryl group, or R ⁷ and R ⁸ are bonded
May form a ring together with the carbon atom to which R ⁷ and R ⁸ are bonded] as an active ingredient.