JPH03148262A - Imidazole derivative, production thereof and antiulcer agent containing the same - Google Patents

Abstract

NEW MATERIAL:An imidazole derivative expressed by formula I (R<1> is H, 1-8C straight-chain or branched alkyl or 3-9C alkenyl or alkynyl; R<2> is 3-9C alkenyl or aklynyl; R<3> to R<6> are H, halogen, lower alkoxy, aralkyloxy, lower alkyl, lower alkoxycarbonyl, nitro, amino or acyl group; R<7> and R<8>, are H, halogen lower alkoxy, lower alkyl, etc., or R<7> and R<8>, together with C to which both are linked, may form a ring). EXAMPLE:2-[2-(2-Propynylamino)benzylsulfinyl]imidazole. USE:Useful as an antiulcer agent having inhibitory action on gastric acid section. PREPARATION:A compound expressed by formula II (X is leaving group) is reacted with a compound expressed by formula III to provide a product, which is then oxidized to afford the compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to novel imidazole derivatives, more specifically to compounds of the following general formula (I): [wherein R1 is hydrogen atoms, 1 to 8] a straight-chain or branched alkyl group having 3 to 9 carbon atoms, or a straight-chain, branched or ring-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms, and R2 is 3 to 9 carbon atoms.
a straight chain, branched or ring moiety-containing alkenyl group or alkynyl group having R3R4) carbon atoms;
j 6 and R6 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 It is a fluorine-substituted alkoxy group, and R7 and R6 are the same or different and are 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, a lower alkyl group, a lower alkoxy group, or an aryl group optionally substituted with a halogen atom as a substituent, or R7
and Rδ may combine to form a ring together with the carbon atoms to which R7 and R8 are bonded], a method for producing the same, and an antiulcer agent containing the same as an active ingredient.

[Prior Art] Conventionally, - Formula (A): (wherein R'' and R1 represent a hydrogen atom or a lower alkyl group, and at least one of R'' and R13 represents a halogen atom, a trifluoromethyl group, a lower alkyl group, a lower (representing an alkoxy group, lower alkoxycarbonyl group or amino group) is a benzimidazole derivative represented by
It is known to be useful as an anti-ulcer agent having an ATPase inhibitory effect (Japanese Patent Application Laid-Open No. 61-221175).

Furthermore, - Formula (B): (wherein R'' and R1' are an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms having a hydroxyl group, and R1 and At least one of RI6 is an alkyl group having 1 to 6 carbon atoms having a hydroxyl group, and RI6 R'?RI8 R19 and R'' are
The same or different groups are selected from the group consisting of a hydrogen atom, a halogen atom, a lower alkoxy group, a lower alkyl group, a trifluoromethyl group, a lower alkoxycarbonyl group, a nitro group, an amino group, an acyl group, and a fluorine-substituted alkyl group. The benzimidazole derivative represented by
It is also known to have a gastric acid secretion suppressing effect based on the ATPase inhibitory effect (Japanese Patent Application Laid-open No. 1-230560).

[Problems to be Solved by the Invention] It is desired to provide a novel compound that has an excellent anti-ulcer effect and is also safer.

[Means for Solving the Problems] Under these circumstances, the present inventors conducted intensive research and found that the novel imidazole derivative represented by the above-mentioned formula (I) has an excellent effect of suppressing gastric acid secretion. The present invention has been completed.

The novel imidazole derivative represented by the general formula (1) of the present invention is different from the above-mentioned known imidazole derivatives in that at least one of R1 and R2 in the formula (I) is a group having a carbon-carbon unsaturated bond. This is a compound whose structure is completely different from that of the compound .

Therefore, the present invention provides a novel imidazole derivative represented by the general formula (1) which is useful as an anti-ulcer agent.

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

Furthermore, the present invention provides an anti-calcium agent containing a novel imidazole derivative represented by general formula (1).

In the general formula (I), R1 is a hydrogen atom, a straight chain or branched alkyl group having 1 to 8 carbon atoms, or a straight chain, branched or ring moiety-containing group having 3 to 9 carbon atoms. It is an alkenyl group or an alkynyl group. 1
Examples of straight-chain or branched alkyl groups having ~8 carbon atoms include, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, Mention may be made of heptyl, octyl, 2-ethylhexyl, and the like.

In addition, a linear, branched, or ring moiety-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms has a carbon-carbon double bond or a carbon-carbon double bond in at least one of the straight chain, branched, or ring moiety. A group having a triple bond, examples of which include allyl group, 2-propynyl group, 2-butenyl group, 3-butenyl group, 2. -butynyl group, 3-butynyl group, 3-methyl-2-butenyl group, 3-
Examples include methyl-3-butenyl group, cyclohex-1-dylmethyl group, and 2-cyclopropylideneethyl group.

In general formula (I), R2 is a linear, branched or ring-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms, as described above for R1. When R1 and R2 are both alkenyl or alkynyl groups as described above, R1 and R2 may be the same or different.

In the general formula (I), one of the lower alkoxy groups represented by R3R4R5 R6R7 or R8 is
Preferably, it is a straight-chain or branched alkoxy group having ~5 carbon atoms, such as methoxy, ethoxy, isopropoxy, etc., and the aralkyloxy group has a substituent such as a halogen atom or lower alkyl on the aromatic ring. The alkylene moiety may be an aralkyloxy group having 1 to 3 carbon atoms, such as a benzyloxy group, and the lower alkyl group is a straight-chain or branched alkyl group having 1 to 6 carbon atoms. groups, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-
Butyl, t-butyl, pentyl, hexyl, etc. are preferred, and lower alkoxycarbonyl groups are linear or branched alkoxycarbonyl groups having 2 to 5 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, isopropoxy carbonyl etc., and the acyl group is preferably an aliphatic acyl group having 2 to 5 carbon atoms or an aromatic acyl group having 7 to 9 carbon atoms, such as acetyl, benzoyl, etc., and fluorine-substituted The alkyl group is 1 to 3 hydrogen atoms of the above lower alkyl group.
is preferably a group in which each is substituted with a fluorine atom,
Further, the fluorine-substituted alkoxy group is preferably a group in which 1 to 3 of the hydrogen atoms of the above lower alkoxy group are substituted with fluorine atoms. In addition, R7 and R8 are combined,
Aromatic rings such as benzene rings and benzoquinone rings which may form alkylene having 3 to 5 carbon atoms, and which may have substituents together with the carbon atoms to which R7 and R8 are bonded. A ring or a heterocycle such as a furan ring, pyrrole ring, thiophene ring, or pyridine ring may be formed.

In particular, R5 is a lower alkyl group (particularly preferably methyl and ethyl), a lower alkoxy group (particularly,
methoxy and ethoxy are preferred) or fluorine-substituted alkyl groups (particularly preferred is trifluoromethyl group)
A compound in which R3R4R6R7 and Ra are hydrogen atoms is preferred.

The imidazole derivative (1) of the present invention can be prepared, for example, by the general formula (
■): [In the formula, RI R2R3R4RS and R6 are the same as those shown for the general formula (I), or are leaving groups] and a compound represented by the general formula (■): [In the formula, R7 and R8 are the same as those shown for general formula (I)] to form the following general formula (): (where RI R2R3, R4) jsR6R? and R
8 is the same as above) It can be produced by producing a compound represented by the following formula and then oxidizing this compound.

Representative compounds of the imidazole derivatives of the present invention include:
The following compounds can be exemplified.

That is, representative compounds of the imidazole derivatives of the present invention are
General formula (I): When represented by, RI, R2R3)j 4 in the formula
R! i R6R? and R8 are each a group shown in Table 1.

Margin below Table 1 N.

B+ R lazy 1 H-cn*co-cooh HHHHHH2
H-CH, Cmi CHHHHHHR 3H-CH, CI straw C (CH,)ffi HHHH
HHa lie −CH, CH<Ha7
H-CHtCH<R 8H-CH, CH-CH.

9 H-CHtCH<Ht l 0 H-CIIICI-CHHI31 H
-C1,CH-CHH I32 H-CHtCH<IIcHsl 3
H-CHtCfCCHs 14 H-CH, CIl, C in the formula 15 H-C1, CIl, C or C11t16-CH
, CH, CH Snow CH2 17H-CIl, CH, C Tomi CH3 r141 Table (continued) 2 ff 4 R% 6 7 8 -CH*CH=CHt -Cl1. Cl-CH.

−[H, CIl<Jl* -CH, Cl-CH.

-C) ItCH<Ha -CH, CH-CI.

-CHoCH-CH.

-CH, CmiCH -CH,C formula H CHtCIl, CH*CH* C) I*CH*C11tCHt C1-C11-CIl-CH C1l-CltoCH-CII C) I-CH-CI-CH C1 to C-C11 stolen CH Me CltoC11-CIl<H Cl1. CIl, CIl, CH1l C1toCH-CIl-CH In Table 1, the abbreviations mean the following.

H: Hydrogen atom 1Me: Methyl group The results of pharmacological effects of the representative compound (1) of the present invention thus obtained are as follows.

(1) H"+K"ATPase inhibitory effect The method of porcine gastric mucosa Forte et al. [Journal of
Applied Physiology (J, AppliedP)
hysiol, ) 32, 714-717 (1972)
], gastric acid-secreting cells were isolated from pig gastric mucosa, and H4
Vesicles containing "10K" ATPase were prepared by centrifugation in a Ficoll discontinuous density gradient.

2mM Bis-Tris-acetate buffer (pH 5,5)
After incubating the enzyme and test substance for 30 minutes at 37°C, 37.5mM bis-tris-acetate buffer (
pH 7,4), 2mM magnesium chloride, 2mM ATP
After further reaction at 37°C for 10 minutes in the presence or absence of 5mM potassium chloride, 5% trichloroacetic acid was added to stop the reaction, and the liberated inorganic phosphorus was removed using Fiske-5
It was quantified by the ubbarow method. K1-dependent ATPase activity was determined by subtracting the value in the absence of potassium chloride from the value in the presence of potassium chloride.

Table 2 (2) Effect on suppressing gastric acid secretion (Created using male pegle dogs)
After fasting to the npouch dogs, histamine hydrochloride was continuously administered intravenously at a dose of 160 μs/kg/hr as a drug for gastric acid secreting cells. Gastric juice was collected at 15 minute intervals, the amount and acidity of the gastric juice were measured, and the amount of acid excreted (mEq/15ml n) was calculated.

As drugs, the compounds obtained in the examples shown in Table 3 and the comparative compounds were administered at 1 m 1 hour after the start of histamine administration.
It was administered intravenously at a dose of g/kg, and gastric fluid was collected over time.

The amount of 1a acid excreted when the above compound was administered at 3 mg/kg12 was determined, and the suppression rate of gastric acid secretion was determined as a percentage of the total acid excreted amount in the case of a control to which the above compound was not administered.

Table 3 shows the doses and inhibition rates for the compounds of the present invention and comparative compounds obtained in each Example.

(Oral administration test method) He1denhain created using corded beagle dogs
After fasting the pouch dog, a polyethylene cannula was inserted into the lower leg artery, and histamine hydrochloride was administered at 160 μg/kg.
1nfusion pu intravenously at a dose of /hr
Continuous infusion was given by mp. Gastric juice was collected at 15 minute intervals to measure gastric juice volume and acidity, and acid excretion amount (mEq/15 minutes)
was calculated and used as a control. The drug is 15mJ! 0.5%CM
The suspension was suspended in C and was orally administered at a dose of tomg/kg using Okawa's oral sonde 2 hours before histamine stimulation, and the gastric juice was collected at 15-minute intervals by flushing with approximately 60 mL of water, which was 4 times the volume, to determine gastric fluid volume and acidity. and acid excretion 11 (mE
q/15 minutes) was calculated. The gastric acid secretion suppressing effect was determined as the ratio of the amount of acid excreted 1 hour after the start of histamine stimulation to the amount of acid excreted in a control to which no drug was administered.

Table 3 The compounds of the invention also have gastrointestinal cytoprotective effects (see US Pat. No. 4,359,465).

The compounds of the present invention can be administered either orally or parenterally. Examples of dosage forms for oral administration include tablets, capsules, powders, granules, and syrups, and examples of dosage forms for parenteral administration include injections.

For their preparation, conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used. Excipients include glucose, lactose, etc.; disintegrants include starch,
Calcium carboxymethyl cellulose, etc., as lubricants, magnesium stearate, talc, etc.
As the binder, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, etc. are used.

The dosage is usually about 1 mg per day for adults as an injection.
50mg, or about 10mg to 500mg per day when administered orally, but the dose can be increased or decreased depending on age, symptoms, etc.

Margin below Next, the present invention will be explained 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 It was dissolved in 50 mJl of methanol and heated under reflux for 40 hours. Methanol was distilled off under reduced pressure, 500 mR of ether was added, and the precipitated solid was filtered off.

The filtrate was washed with IN-HCfl, IN-NaOH and saturated brine, and then dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and 160 mj2 of hexane was added to the residue, followed by cooling. The precipitated crystals were collected by filtration and washed with cold hexane to give 20.4 g (yield 35.0%) of the title compound.
was obtained as yellow crystals.

'H-NMR (CDC data) δ = 2.21 (t, IH, J-2Hz) 3.
85 (s, 3H) 4.02 (dd, 2H, JII2Hz, 6Hz
)6.5-8.0 (m, 4H) (2) 2-(2-propynylamino)benzyl alcohol: 1.0 g (26° 4 mmol) of lithium aluminum hydride in 50 ml of dry tetrahydrofuran (T)IF)
5.0 g (26.4 mmol) of methyl N-propargylanthranilate obtained in (1) was suspended in 20 mj of dry THF under water cooling. The solution was added dropwise over 30 minutes and stirred for an additional 30 minutes. After decomposition by adding saturated sodium sulfate water under water cooling, insoluble materials were filtered off, the solvent was distilled off, and the resulting oil was purified using a silica gel column to obtain 1.73 g of the title compound (yield: 40.7 %) was obtained as white crystals.

'H-NMR (CDCj!s) δ = 1.84 (bs, IH) 2.19
(t, IH, J-3Hz) 3.93 (
d, 2H, J-13Hz) 4.60 (S, 2
M) 10 (bs, IH) 6.7-7.4 (m, 41()(3)2- [
2-(2-propynylamino)benzylthiokoimidazole: 2-(2-propynylamino)benzyl alcohol1.
Dissolve 61 g (10 mmol) in 16 ml of dichloromethane, and add 0.87 mJ2 (12 mmol) of thionyl chloride to 4 ml of dichloromethane under water cooling. The solution was added dropwise over 10 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 m of dichloromethane, and this solution was added little by little to a solution of 1.5 g (15 mmol) of 2-mercaptoimidazole in 15 mfi of ethanol, and the mixture was stirred at room temperature for 1 hour. After removing the solvent from the resulting solution under reduced pressure and adding water and saturated sodium hydrogen carbonate water to the residue,
Extracted with ether. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue for crystallization, and the crystals were collected by filtration to obtain 1.73 g (yield: 71.2%) of the title compound as a pale yellow crystalline powder.

'H-N M R (CDCl, /CD, 00-3/l)
δ= 2.30 (t, IH, J-12Hz)
:1.99 (d, 2)1. J-2H
z) 4.13 (s, 28) 6.5-7.3 (m, 4) 1) 7.01 (s, 2H) (4) 2-[2-(2-propynylamino)benzylsulfinylcoimidazole : 1.0 g (4.12 mmol) of 2-(2-(2-propynylamino)benzylthiokoimidazole) was dissolved in 15 mj! of chloroform and 1 ml of methanol, and 880 mg (purity 80) of m-chloroperbenzoic acid was dissolved under ice cooling. %,
4.12 mmol) was added over about 10 minutes. After the reaction is complete, add saturated sodium bicarbonate water to the reaction product solution, and add 30ml of chloroform! Extracted with. The chloroform layer was reduced to 0.
INlN-NaOH1O! After washing with 0.3N-NaO
Extracted with H7mIL. This alkaline solution was extracted twice with 30 mL of chloroform, and the resulting chloroform layer was combined with the first chloroform layer and washed with saturated saline.
It was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue for crystallization, and the crystals were collected by filtration to obtain 380 mg (yield 35.6%) of the title compound as a pale yellow crystalline powder.

Melting point: 158-159°C (decomposition) 'H-NMR (CDCl3/(:D, 0D-2/l
) δ = 2.32 (t, IH, J-3Hz)
3.99 (d, 2H, J-3Hz) 4.29
, 4.53 (each d, 2) 1. Ji311z
)6.5-7.3 (m, 4H) 7.22 (s, 2) 1) IRν(niBr)am-': 3370.3260,1600,1580°1515.
1300,1100,1025゜960.940,89
0,780,740° [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 allylpromide were dissolved in 75 ml of methanol.
It was dissolved in IL and heated under reflux for 40 hours. Methanol was distilled off under reduced pressure, 5.0 m square of ether was added, and the precipitated solid was filtered off. The filtrate was washed with IN7HCIt, IN-NaOH and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 3.85 g of the title compound (yield: 40°3%).
I got it.

(2) 2-(Alylamino)benzyl alcohol: Dry 0.76 g (20.0 mmol) of lithium aluminum hydride with 50 mj of THF! Suspended in water and cooled in water (1
) methyl N-allylanthranilate 3.82
A dry THF 20 mR solution of g (20.0 mmol) was added dropwise over 30 minutes and stirred for an additional 30 minutes. After decomposing excess lithium aluminum hydride with saturated aqueous sodium sulfate under water cooling, insoluble materials were filtered off, the solvent was distilled off, and the resulting oil was purified using a silica gel column to obtain 2.44 g of the title compound ( Yield: 75.1%) was obtained as a colorless oil.

'H-N M R (CD C113) δ= 1.7 (bs, IH) 3.80
(dt, 28.J-12Hz, 5) 1z) 4.64
(s, 2B) 5.0-5.4 (m, 2H) 5.7-6.2 (m, 1fl) 6.7-7.3 (m, 4H) (3) 2- [2-( allylamino)benzylthiokoimidazole: 2-(allylamino)benzyl alcohol 2°8g (1
7.2 mmol) was dissolved in 28 ml of dichloromethane, and 1.5 m of thionyl chloride (20.6 mmol) was added under water cooling.
A 10rnJZ solution of dichloromethane 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 mixed with 2.58 g of 2-mercaptoimidazole (25,
The mixture was added little by little to a solution of 8 mmol) in 25 ml of ethanol and stirred at room temperature for 1 hour. Ethanol was distilled off under reduced pressure from the resulting solution, and water and saturated sodium bicarbonate water were added to the residue, followed by extraction with ether. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, ether was added to the residue to crystallize it, and the crystals were collected by filtration to obtain the title compound 3.
34 g (yield 79.3%) was obtained as white crystals.

'HN M R (CD Cl 3) δ= 3.76 (dt, 2LJ-2+lz,
51 (z) 4.19 (s, 2H) 5.0-5.4 (m, 28) 5.6-6.1 (fll, l) 6.4-7.2
(m, 4H) 7.04 (s, 2H) (4) 2-[2-(allylamino)benzylsulfinylcoimidazole: 2-(2-(allylamino)benzylthiocoimidazole 1.5 g (6.1 mmol) Chloroform 15
Dissolve in mIL and add 1.1 m-chloroperbenzoic acid under ice-cooling.
8 g (80% purity, 5.5 mmol) was added over about 10 minutes. After the reaction was completed, saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with 30 mM chloroform. The chloroform layer was washed with 0.3N-NaOHlomffi. The alkaline layer was extracted twice with 30 ml of chloroform, and then 2 drops of saturated NH,O)I solution were added and extracted with 30 ml of chloroform.
Extracted with L. On the other hand, from the first chloroform layer, IN-l
The mixture was extracted with 10 N-NaOH, made ammonia alkaline with saturated NH4OH solution, and extracted with 20 mL of chloroform. The chloroform layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, acetonitrile/ether was added to the residue to crystallize it, and the crystals were collected by filtration to give 730 mg of the title compound (yield: 45
．． 9%) was obtained as white crystals.

Melting point = 139°C (decomposition) 'H-N M R (CDCl: +/CD*0Da2/l
) δ= 3.72 (d, 211.JI16
Hz) 4.31, 4.53 (each d, 2H,
J=14Hz) 4.9-5.4 (m, 2H) 5.7-6.2 (m, IH) 6.4-7.4 (m, 4B) 7.21 (s, 2H) IRν ( Br) cm-': 3390, 1605. 1585. 1520°13
15, 1100. 1000,895°750, 5
00° [Example 3] 2- [2-(3-methyl-2-butenylamino benzylsulfinyl imidazole: (1) Methyl 2-
(3-Methyl-2-butenylamino)benzoate: 16.1 g (0.10 mol) of methyl anthranilate was dissolved in 75 ml of methanol, and 1-bromo-3-benzoate was dissolved in 75 ml of methanol.
7.5 g (50 mmol) of methyl-2-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, and 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 obtain 6.51 g (yield 59.5%) of the title compound as a pale yellow oil.

'H-N M R (CD CIt 3) δ-1,73 (
s, 6H) 3.72 (d, 2LJ-6) 1z) 3.84
(s, 3H) 5.32 (bt, l1l) 6.4-7.9 (m, 4H) 7.57 (bs, IH) (2) 2-(3-methyl-2-butenylamino>benzyl alcohol: Lithium aluminum hydride 2.263 m THF65m
The methyl 2- obtained in (1) was suspended in water and cooled with water.
(3-Methyl-2-butenylamino) benzoate 6.
51 g of THF15mJZ solution was added dropwise over 15 minutes, and the mixture was further stirred at room temperature for 30 minutes. After decomposition with saturated sodium sulfate water under water cooling, the organic layer was obtained by decantation and concentrated under reduced pressure.

The residue was dissolved in chloroform, washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 5.48 g (yield: 95.6%) of the title compound as a residual yellow oil.

'H-NMR (CDCl2) δ = 1.72 (s, 6H)3
．． 71 (d, 2H, J-7Hz) 4.62
(S, 2H) 6.28 (bt, l11) 6.4-7.3 (m, 411) (3) 2-[2-(3-methyl-2-butenylamino)hensylthiokoimidazole: 2-( 5.48 g (29 mmol) of 3-methyl-2-butenylamino)benzyl alcohol was dissolved in 55 ml of dichloromethane. Dissolved in 3.1 ml of thionyl chloride under water cooling.
20 mj of dichloromethane! Add the solution dropwise over 15 minutes,
The mixture was stirred for an additional 30 minutes. The residue obtained by distilling off the solvent was dissolved in 20 m square of dichloromethane, and this solution was mixed with 144 g of 2-mercaptoimidazole in 35 ml of ethanol.
It was added to the solution over 10 minutes and stirred for an additional 30 minutes at room temperature. Ethanol was distilled off from the resulting solution, chloroform and 5% sodium carbonate water 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 3.82 g of the title compound was obtained as a white crystalline powder.
(Yield 48.9%) was obtained.

'H-NMR (CDCfi3) δ = 1.70 (s, 3H) 1.74 (s, 3H) 3.70 (d, 28.J-6Hz) 4.17
(s, 211) 5,:13 (m, IH) 6.4-7.3 (a, 48) 7.02 (s, 211) (4) 2-[2-(3-methyl-2-butenylamino) ) benzylsulfinylcoimidazole = 2- [2-
1.62 g (5.9 mmol) of (3-methyl-2-butenylamino)benzylthiokoimidazole was dissolved in a mixed solvent of 16 mJ2 of chloroform and 1.6 ml of methanol, and 1.10 g (1.10 g) of m-chloroperbenzoic acid ( (purity 85%) was added over 30 minutes. After the reaction was completed, chloroform and 5% aqueous sodium carbonate were added to the reaction product solution, and the organic layer was separated. Furthermore, after washing twice with 0.05N-sodium hydroxide solution, 1 portion of 2N-sodium hydroxide solution was added to this.
0ml1. was added to extract the aqueous layer. IN-ammonium chloride water (30 rnJZ) was added little by little to the aqueous layer, and the precipitated oil was extracted with chloroform and dried over anhydrous sodium sulfate. The chloroform was distilled off, the residue was crystallized from ether-hexane, and the crystals were collected by filtration to obtain 0.52 g of the title compound as a white crystalline powder (yield 30%).
I got it.

Melting point: 135-136°C (decomposition) 'H-NMR (CD(:13/CD30D-1/I
) δ = 1.75 (s, 6+ mouth) 3.68 (d, 2H, J=6Hz) 4.
32 (d, IH, J-13Hz) 4.53
(d, IH, J=1:1)lz)5.3
1 (bt, IH) 6.4-7.3 (m, 4H) 7.23 (s, 2H) IRu(niBr)am-': 3380.2900. 1600. fsso.

1520, 1310. 1105. 1090°10
00, 890. 740. 500° [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 mf of methanol, and 3.03 g (25 mmol) of allylpromide was added thereto.
After heating under reflux for a minute, an additional 1.52 g (1
3 mmol) was added thereto, and the mixture was heated under reflux for 30 minutes. Methanol was distilled off under reduced pressure, chloroform and 5% aqueous sodium carbonate were added to the residue, and 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 obtain 4.68 g of the title compound as a pale yellow oil (yield 60.7%).
I got it.

'H-NMR (CDCffi3) δ = 2.22 (s, 3H) 3.85 (s, 3H) 3.85 (a, 2H) 5.0-6.1 (m, 3H) 6.4-7 .7 (m, 38) (2) (2-allylamino-5-methyl)benzyl alcohol: 1.30 g of lithium aluminum hydride was dissolved in 40 m of THF.
The methyl obtained in (1) was suspended in IL and cooled with water.
2-allylamino-5-methyl)benzoate 4.68
g of THF10mJ! The solution was added dropwise over 15 minutes, and the mixture was further stirred at room temperature for 30 minutes. After decomposition with saturated sodium sulfate water under water cooling, the organic layer was obtained by decantation and concentrated under reduced pressure. The residue was dissolved in chloroform, washed with water, and then dried over anhydrous sodium sulfate. The light brown oil that remains after distilling off the solvent! 3.59 g (yield 88.8%) of the M title compound was obtained.

'H-NMR (CDCfi,) δ = 2.22 (s, :IH) 3.77
(m, 2H) 4.60 (m, 211) 4.9-6.2 (m, 3H) 6.4-7.1 (m, 3H) (3) 2-[(2-allylamino-5- Methyl)benzylthiokoimidazole: 3.59 g (20 mmol) of (2-allylamino-5-methyl)benzyl alcohol was dissolved in 36 ml of dichloromethane.
A solution of 2.2 mfl of thionyl chloride in 10 m square of dichloromethane was added dropwise over 15 minutes under cooling with water, and
Stir for a minute. The residue obtained by distilling off the solvent was dissolved in 20 ml of dichloromethane, and this solution was added to a solution of 2.44 g of 2-mercaptoimidazole in 25 mft of ethanol over 10 minutes, followed by further stirring for 30 minutes at room temperature.

Ethanol was distilled off from the resulting solution, chloroform and 5% sodium carbonate water 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 obtain 4.06 g (yield 77.3%) of the title compound as a white crystalline powder.

Seal H-N MR (CD Cl 3 ) δ= 2
．． 16 (s, 3H) 3.75 (m, 2H) 4.17 (s, 2N) 4.9-6.1 (m, 311) 6.3-7.1 (@l, :IH)7. 04
(s, 2H) (4) 2-[(2-allylamino-5-methyl)benzylsulfinylcoimidazole: 2- ((2-allylamino-5-methyl)benzylthiocoimidazole 2.OOg (7,7 mmol) was dissolved in a mixed solvent of 20 mj2 of chloroform and 2 ml of methanol, and 1.57 g of m-chloroperbenzoic acid was added under ice cooling.
(85% purity) was added over 30 minutes. After the reaction was completed, chloroform and 5% aqueous sodium carbonate were added to the reaction product solution, and the organic layer was separated. Furthermore, after washing three times with 0.05N sodium hydroxide water, 20 mL of IN-sodium hydroxide water was added thereto to extract the aqueous layer. IN-ammonium chloride water 60snj2 was added little by little to the aqueous layer, and the precipitated oil was extracted with chloroform and dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was evaporated into ether.
By crystallizing from hexane and filtering the crystals,
0.91 g of the title compound as a white crystalline powder (yield: 43
%) was obtained.

Melting point: 135-137°C (decomposition) IH-N MR (CDC137C030D-1/l)
δ= 2.15 (s, 3H) 3.72 (m, 2) 1) 4.32 (d, IH, J=1411z) 4
．． 52 (d, ILJ-14112) 5.0
-6.2 (m, 3H) 6.4-7.0 (m, 38) 7.24 (s, 211) IRν (Br)am-': 3350, 3080. 3000. 2920162
0, 1520. 1430. 13201 100,
1025. 905. 800°745° [Formulation Example 1] Formulation example (tablet) 1 M (220 mg) contains the following ingredients.

Active ingredient 50mg lactose
103 starch
5° Magnesium Stearate 2 Hydroxypropylcellulose 15 [Formulation Example 2] Formulation Example (Capsule) One hard gelatin capsule contains the following ingredients (350 mg).

Active ingredient 40mg lactose
200 Starch 70 Polyvinylpyrrolidone 5 Crystalline Cellulose 35 [Formulation Example 3] Formulation Example (Granules) 1 g of granules contains the middle and lower symbols.

active ingredient lactose corn starch hydroxypropyl cellulose 00mg 50 00 0

Claims (1)

[Claims] 1. The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, Or, it is a linear, branched, or ring moiety-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms, and R^2 is 3 to
A straight chain, branched or ring moiety-containing alkenyl group or alkynyl group having 9 carbon atoms, 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 R^7 and R
^8 are the same or different, hydrogen atom, halogen atom,
Lower alkoxy group, lower alkyl group, lower alkoxycarbonyl group, nitro group, amino group, acyl group, fluorine-substituted alkyl group, fluorine-substituted alkoxy group, or substituted with a lower alkyl group, lower alkoxy group, or halogen atom as a substituent is an aryl group which may be
Or, R^7 and R^8 combine to form R^7 and R^
8 may form a ring together with the carbon atom to which it is bonded]
An imidazole derivative represented by 2. The following general formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formula, R^1 is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, Or, it is a linear, branched, or ring moiety-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms, and R^2 is 3 to
A straight chain, branched or ring moiety-containing alkenyl group or alkynyl group having 9 carbon atoms, 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, is a fluorine-substituted alkyl group or a fluorine-substituted alkoxy group, and X is a leaving group] and the following general formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [Formula R^7 and R^8 are the same or different and are 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 It is a substituted alkoxy group, or an aryl group which may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom as a substituent, 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] to form the following general formula (IV).
: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, R^1, R^2, R^3, R^4, R^5, R
The following general formula (I) characterized by producing a compound represented by (^6, R^7 and R^8 are the same as above) and then oxidizing this compound: ▲Mathematical formula, chemical formula, table, etc. There is ▼(V) (in the formula, R^1, R^2, R^3, R^4, R^5, R
^6, R^7 and R^8 are the same as above). 3. The following general formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, Or, it is a linear, branched, or ring moiety-containing alkenyl group or alkynyl group having 3 to 9 carbon atoms, and R^2 is 3 to
A straight chain, branched or ring moiety-containing alkenyl group or alkynyl group having 9 carbon atoms, 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 R^7 and R
^8 are the same or different, hydrogen atom, halogen atom,
Lower alkoxy group, lower alkyl group, lower alkoxycarbonyl group, nitro group, amino group, acyl group, fluorine-substituted alkyl group, fluorine-substituted alkoxy group, or substituted with a lower alkyl group, lower alkoxy group, or halogen atom as a substituent is an aryl group which may be
Or, R^7 and R^8 combine to form R^7 and R^
8 may form a ring together with the carbon atom to which it is bonded]
An anti-ulcer agent containing an imidazole derivative represented by the following as an active ingredient.