JP2000026430A - 2,5,6-substituted benzimidazole compound derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having a production inhibiting action of a specific interleukin and useful as an anti-inflammatory agent, a treating agent against autoimmune disease, etc., to chronic rheumatism, etc. SOLUTION: This compound derivative is expressed by formula I [R1 is H, a 1-8C alkyl or the like; R2 is a lower alkyl or the like; R3 is H, a 1-10C alkyl or the like; R4 is H, a lower alkyl or the like; X is O or the like], e.g. 6-methoxy-2-phenyl-5-(4-pyridylsulfenyl)benzimidazole. The compound of formula I is obtained by adopting, e.g. a compound (e.g. 3,4-difluoronitrobenzene or the like) of formula II (Y1 and Y2 are each fluorine or the like) as a starting material and performing a reaction with a compound of the formula: R1-OH, reduction of a nitro group and acetylation, then subjecting the resultant compound to nitration, a reaction with a compound of the formula: R2-SH and hydrolysis of an acetamide group, then subjecting the resultant compound to amidation, reduction of a nitro group and a cyclization reaction. The resultant compound exhibits a production inhibitory activity of interleukin-1, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a therapeutic agent for a disease caused by these cytokines, which has an inhibitory effect on the production of cytokines such as interleukin (IL) -1, IL-5 and IL-6. , A 2-aryl-5-arylthiobenzimidazole compound useful as a therapeutic agent for autoimmune diseases against rheumatoid arthritis and the like, a therapeutic agent for bone diseases against osteoporosis and the like, and a therapeutic agent for allergic diseases, and a pharmaceutical composition containing an effective amount of the compound About things.

[0002]

2. Description of the Related Art Conventionally, nonsteroidal anti-inflammatory drugs (NSA)
ID) has an action of inhibiting prostaglandin (PG) biosynthesis by inhibiting cyclooxygenase, and is widely used in various inflammatory and painful diseases as its main pharmacological action including antipyretic, analgesic and anti-inflammatory actions. It has been. NSAI for rheumatoid arthritis
D. Immunomodulators (DMARDs) are used for causal purposes. Osteoporosis is classified into postmenopausal osteoporosis and senile osteoporosis, and the cause of postmenopausal osteoporosis is that postmenopausal estrogen loss excessively promotes bone resorption. As a first-line treatment for postmenopausal osteoporosis, bone resorption inhibitors such as calcitonin and estrogen have been used. For bronchial asthma, steroids, β2 stimulants, xanthine preparations, antiallergic agents (production of chemical mediators such as histamine, thromboxane A2, leukotriene, release inhibitors or antagonists), etc. are used for the treatment of allergic diseases. For allergic rhinitis, antihistamines, antiallergic agents (release inhibitors of chemical mediators such as leukotrienes), steroids, anticholinergics, etc. are used. For atopic dermatitis, steroids and nonsteroidal anti-inflammatory agents are used. And antiallergic agents (histamine, thromboxane A2, leukotrienes, etc., generation inhibitors, release inhibitors or antagonists) and the like.

[0003]

The conventional NSAIDs cause gastrointestinal disorders such as gastric ulcers due to their mechanism of action, and have problems in long-term continuous use. Also, DMAR
D has not yet sufficiently separated the efficacy and side effects. Furthermore, calcitonin used as a therapeutic agent for postmenopausal osteoporosis is limited to administration by intramuscular injection and has a problem that it tends to become resistant. On the other hand, estrogen has a problem of increasing the incidence of breast cancer and endometrial cancer.
In recent years, active substances collectively called cytokines produced by immunocompetent cells have been found. IL-
1, IL-6, tumor necrosis factor, etc. are called inflammatory cytokines, and act as inflammatory mediators, such as activation of arachidonic acid metabolism, which is a metabolic production system of PG, migration of leukocytes, induction of acute phase proteins, etc. These inflammatory cytokine production inhibitors are expected to be used as a new-generation anti-inflammatory agent having a different mechanism of action from the past, and as a therapeutic agent for autoimmune diseases against rheumatoid arthritis and the like. Furthermore, IL-1 and IL-6 are also known as osteoclast formation promoting factors, and their production inhibitors are expected as therapeutic agents for postmenopausal osteoporosis. However, IL-1, I
No useful anti-inflammatory agent having a L-6 production inhibitory effect, a therapeutic agent for an autoimmune disease against rheumatoid arthritis and the like, and a therapeutic agent for a bone disease against osteoporosis and the like have not been found. Among allergic diseases, LAR (late-onset allergic reaction) has recently gained importance. The main body of LAR is eosinophilic inflammation, and I lymphocyte-produced I
Cytokines such as L-5 play an important role.
It is known that steroids and immunosuppressants have an inhibitory effect on the production of these cytokines, but both drugs have other physiological effects, and steroids cause adrenal atrophy, edema, stomach ulcer, full moon face etc. The occurrence of side effects and the occurrence of side effects such as infectious diseases, hepatic / renal disorders, and blood disorders have been problematic for immunosuppressants. Therefore, providing a substance that selectively suppresses the production of cytokines such as IL-5 produced from T lymphocytes can be a useful antiallergic agent with reduced side effects seen in steroids and immunosuppressants. .

[0004]

Means for Solving the Problems The present inventors have proposed IL-
1. To provide useful anti-inflammatory agents having an inhibitory effect on IL-5 or IL-6 production, therapeutic agents for autoimmune diseases against rheumatoid arthritis, etc., therapeutic agents for bone diseases against osteoporosis and the like, and antiallergic agents. As a result of the study, they have found that the following 2,5,6-substituted-benzimidazole compounds can achieve the object, and have completed the present invention. That is, the present invention relates to formula (1)

Embedded image (Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms which may be substituted, a phenyl group, or 1 to 3 halogen atoms. A substituted phenyl group; R ² represents an alkyl group substituted with a lower alkyl group, a carboxy group or a lower alkoxycarbonyl group, a cycloalkyl group having 4 to 8 carbon atoms which may be substituted, Phenyl group or pyridyl group, lower alkylphenyl group, carboxyalkylphenyl group, alkylaminocarbonylalkylphenyl group, cyclic aminocarbonylalkylphenyl group, 1 or 2 nitrogen atoms and / or Or a heterocyclic ring containing an oxygen atom and / or a sulfur atom as a hetero atom, wherein R ³ is a hydrogen atom,
Alkyl group having 1 to 10 carbon atoms, 4 to 8 carbon atoms
Cycloalkyl group, lower alkoxy group, hydroxyl group, alkoxycarbonyl group having 2 to 6 carbon atoms, 1 or 2
A cycloalkyl group having 3 to 7 carbon atoms or a phenylalkyl group, a carboxy group, an aralkyl group, or a 2 to 6 carbon atom which may be substituted with 1 or 2 hydroxyl groups. An alkylaminocarbonyl group, a carbamoyl group, a nitrile group, an amino group, an acetylamino group, a halogen atom, a phenyl group, a lower acetoxyalkyl group, a lower hydroxyalkyl group, a lower haloalkyl group, and a lower alkyl group having one or two nitrogen atoms. The optionally substituted lower aminoalkyl group or cyclic aminoalkyl group represents a phenyl group, a pyridyl group, a furyl group or a thienyl group which may be substituted by 1 or 2 groups, and R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkyl group. Alkoxy group, formula (2)
Or (3)-(CH ₂ ) _n -A (2)-(CH ₂ ) _n -YA (3) (in the formula (2) or the formula (3), n is an integer of 1 to 5) A represents an alkyl group, an alkoxy group, an acyl group, a carboxy group, an alkoxycarbonyl group, or an alkenyl group, a cycloalkyl group which may be substituted,
A phenyl group or a monocyclic or bicyclic heterocyclic group having O and / or N and / or S as a hetero atom, wherein Y is 0,
S, SO, SO ₂ , a carbonyl group, an ester group, an amide group or an amino group), and X represents O, S, S
O, a group represented by SO _2. ), 2, 5,
A 6-substituted-benzimidazole compound derivative is provided.

Further, according to the present invention, in the above formula (1),
R ¹ is an alkyl group having 1 to 8 carbon atoms, 4 carbon atoms
Represents a cycloalkyl group, a phenyl group or a phenyl group substituted with one or two halogen atoms,
² represents an aromatic heterocyclic ring containing one or two nitrogen atoms; R ³ represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, a carboxy group, 1 or 2 Alkylaminocarbonyl, carbamoyl, nitrile, amino, acetylamino, halogen, phenyl, lower acetoxyalkyl, lower hydroxyalkyl groups which may be substituted with two hydroxyl groups A lower haloalkyl group, a lower aminoalkyl group in which a nitrogen atom may be substituted with one or two lower alkyl groups or a phenyl group, a pyridyl group, a furyl group, in which one or two cyclic aminoalkyl groups may be substituted. X represents S, S
O or a group represented by SO ₂ 2, 5, 6-substituted - providing benzimidazole compound derivatives.

Further, the present invention provides a compound of the formula (1) wherein R ¹ is a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group or a phenyl substituted with 1 to 3 halogen atoms. R ² represents a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group, a phenyl group substituted with one or two halogen atoms, a lower alkylphenyl group, a carboxyalkylphenyl group, An alkylaminocarbonylalkylphenyl group or a cyclic aminocarbonylalkylphenyl group represented by R
³ represents a phenyl group, X is S, is a group represented by SO or SO ₂ 2,5,6-substituted - providing benzimidazole compound derivatives.

The present invention further relates to a compound of the formula (1) wherein R ¹ is a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group or a phenyl substituted with one or two halogen atoms. R ² represents a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms, an alkyl group substituted with a carboxy group or a lower alkoxycarbonyl group, a phenyl group, or a substituent substituted with 1 or 2 halogen atoms. Represents a phenyl group or a pyridyl group;
³ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms substituted by 1 or 2 nitrogen atoms Alternatively, there is provided a 2,5,6-substituted-benzimidazole compound derivative in which R ⁴ represents a hydrogen atom and X represents a group represented by S, SO or SO ₂ .

In the present invention, further, in the compound of the formula (1), R ¹ represents a hydrogen atom, a lower alkyl group or an optionally substituted cycloalkyl group, and R ² represents an optionally substituted O, N Or a monocyclic or bicyclic heterocyclic group having S as a hetero atom, and R ³ represents an aralkyl group;
R ⁴ is a lower alkyl group, an alkoxy group, or-(CH ₂ ) n-A (2) or-(CH ₂ ) n-Y-A (3) 2) and formula (3)), wherein X represents O, S, SO or SO ₂ , and a 2,5,6-substituted-benzimidazole compound derivative is provided. The present invention further provides pharmaceutically acceptable salts of the above compound derivatives. Further, the present invention provides a pharmaceutical composition containing an effective amount of the above compound derivative or a pharmaceutically acceptable salt thereof.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. R
The 1-8 ¹ carbon atoms, alkyl groups, e.g., linear or branched methyl group, ethyl group, normal propyl group, an isopropyl group, normal butyl group, isobutyl group, normal pentyl group, n Examples include a peptyl group and a normal octyl group. In the present invention, when a lower alkyl group is referred to, it has 1 to 6 carbon atoms.
Means a straight or branched carbon chain. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2
-Methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-
Methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-
Dimethylbutyl group, 1,3-dimethylbutyl group, 2,3
-Dimethylbutyl group, 3,3-dimethylbutyl group, 1-
Ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-
Examples include a 2-methylpropyl group. Examples of the cycloalkyl group having 3 to 8 carbon atoms of R ¹ and R ² include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

As the aromatic heterocycle containing one or two nitrogen atoms, oxygen atoms and / or sulfur atoms as hetero atoms of R ² , a single atom having a nitrogen atom and / or sulfur atom as a hetero atom is preferable. A cyclic or bicyclic heterocyclic group,
Examples include a monocyclic or bicyclic heterocyclic group having a substituted nitrogen atom and / or sulfur atom as a hetero atom. Among these, as the monocyclic or bicyclic heterocyclic group having a nitrogen atom and / or a sulfur atom as a hetero atom, a pyrrolyl group, a pyrrolinyl group, an imidazolyl group, an imidazolinyl group, a pyrazolyl group, a pyrazolinyl group, a triazolyl group, a tetrazolyl group Group, pyridyl group, dihydropyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, triazinyl group, etc. 5- to 6-membered monocyclic heterocyclic group containing 1 to 4 nitrogen atoms only, thiazolyl group, isothiazolyl group, Only a sulfur atom such as a thiadiazinyl group, a dithiazinyl group and the like, a 5- to 6-membered monocyclic heterocyclic group containing 1 to 4 nitrogen atoms and 1 to 4 sulfur atoms, a thienyl group, a dithiolyl group, a thiopyranyl group, a dithienyl group and a trithienyl group 5 to 6 membered monocyclic heterocyclic group containing 1 to 4 Ndoriru group, an imidazolyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, phthalazinyl group, cinnolinyl group, quinazolyl group, a nitrogen-Motoni heterocycle such quinoxalinyl group as preferred. More specifically, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a pyrrol-2-yl group, a pyrrol-3-yl group, a 2-pyrimidyl group, a 4-pyrimidyl group, a 5-pyrimidyl group , An imidazol-2-yl group,
Examples thereof include an imidazol-4-yl group, a 2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group, an indol-2-yl group, an indol-3-yl group, and a benzimidazol-2-yl group. In the present invention, a lower alkyl group means a straight-chain or branched alkyl group having 1 to 5 carbon atoms. Examples of the alkyl group having 1 to 10 carbon atoms containing 1 to 5 carbon atoms include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a normal pentyl group, a normal octyl group, and a normal octyl group. A nonyl group;

In the present invention, the lower alkoxy group represented by R ³ means a straight-chain or branched alkoxy group having 1 to 5 carbon atoms. Examples include a methoxy group, an ethoxy group, a normal propyloxy group, an isopropyloxy group, a normal butyloxy group, an isobutyloxy group, a normal pentyloxy group, and the like. R ³ having 2 carbon atoms
Examples of the six alkoxycarbonyl groups include a methoxycarbonyl group, an ethoxycarbonyl group, a normal propyloxycarbonyl group, an isopropyloxycarbonyl group, a normal butyloxycarbonyl group, an isobutyloxycarbonyl group, a normal pentyloxycarbonyl group, and the like. . As the alkylaminocarbonyl group for R ³ , an alkylaminocarbonyl group having 2 to 6 carbon atoms is preferable, and these may be substituted with one or two hydroxyl groups. Examples of the alkylaminocarbonyl group having 2 to 6 carbon atoms include a methylaminocarbonyl group, an ethylaminocarbonyl group, a normal propylaminocarbonyl group, an isopropylaminocarbonyl group, a normal butylaminocarbonyl group, an isobutylaminocarbonyl group, and a normal A pentylaminocarbonyl group, a hydroxymethylaminocarbonyl group, a 2-hydroxyethylaminocarbonyl group, a 3-hydroxypropylaminocarbonyl group, a 5-hydroxypentylaminocarbonyl group, and a 1,3-dihydroxy-2-propylaminocarbonyl group. .

The lower acetoxyalkyl group for R ³ is a straight-chain or branched alkyl group having 1 to 5 carbon atoms which may be substituted by one or two acetoxy groups. Acetoxymethyl group, 2-acetoxyethyl group, 3-acetoxypropyl group, 2-acetoxybutyl group, 3-acetoxybutyl group, 4-acetoxybutyl group, 3-acetoxypentyl group, 4-acetoxypentyl group, 5-acetoxypentyl And a 1,3-diacetoxy-2-propyl group. The lower hydroxyalkyl group for R ³ is a linear or branched alkyl group having 1 to 5 carbon atoms which may be substituted with one or two hydroxyl groups, such as a hydroxymethyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 3-hydroxypentyl group, 4-hydroxypentyl group, 5-hydroxypentyl group, 1, Examples thereof include a 3-dihydroxy-2-propyl group.

The lower haloalkyl group for R ³ is a straight-chain or branched alkyl group having 1 to 5 carbon atoms and substituted by 1 to 3 halogen atoms, such as a fluoromethyl group, Chloromethyl group, bromomethyl group, difluoromethyl group, trifluoromethyl group, 2-chloroethyl group, 3-chloropropyl group, 5-chloropentyl group and the like. The lower aminoalkyl group in which the nitrogen atom of R ³ may be substituted by one or two lower alkyl groups is the number of carbon atoms substituted by an amino group or an amino group substituted by one or two lower alkyl groups. 1 to 5 straight-chain and branched alkyl groups. For example, an aminomethyl group,
2-aminoethyl group, 3-aminopropyl group, 5-aminopentyl group, N-methylaminomethyl group, 2- (N-
A methylamino) ethyl group, a 3- (N-methylamino) propyl group, a 5- (N-methylamino) pentyl group,
N-dimethylaminomethyl group, 2- (N, N-dimethylamino) pentyl group, N, N-diethylaminomethyl group, N, N-diethylaminopentyl group and the like.

Examples of the cyclic aminoalkyl group for R ³ include a pyrrolidinomethyl group, a 2-pyrrolidinoethyl group,
3-pyrrolidinopropyl group, 5-pyrrolidinopentyl group, piperidinomethyl group, 2-piperidinoethyl group, 3
-Piperidinopropyl group, 5-piperidinopentyl group,
Morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl, 5-morpholinopentyl, piperazinomethyl, 2-piperazinoethyl, 3-piperazinopropyl, 5-piperazinopentyl, 4-methylpipe A radinomethyl group and a 4-diphenylmethylpiperazinomethyl group. Examples of the furyl group for R ³ include a 2-furyl group and a 3-furyl group. Examples of the thienyl group for R ³ include a 2-thienyl group and a 3-thienyl group. The aralkyl group for R ³ is a group formed by replacing a terminal hydrogen atom of a lower alkyl group with an aromatic ring, and includes, for example, a benzyl group, a phenethyl group, a phenylpropyl group,
Phenylbutyl, phenylpentyl, naphthylmethyl, picolyl, furfuryl, thenoyl, imidazolylmethyl, thiazolylmethyl, oxazolylmethyl, indolylmethyl, benzimidazolylmethyl, quinolylmethyl, isoquinolyl Examples thereof include a methyl group and a quinoxalinylmethyl group.

Examples of the alkoxy group represented by R ⁴ include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec
-Butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, t
ert-pentyloxy group, 1-methylbutoxy group, 2
-Methylbutoxy group, 1,2-dimethylpropoxy group,
Hexyloxy group, isohexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-
Methylpentyloxy group, 1,1-dimethylbutyloxy group, 1,2-dimethylbutyloxy group, 2,2-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 3,3-dimethylbutyloxy group, 1-ethylbutyloxy group, 2-ethylbutyloxy group, 1,1,2-trimethylpropyloxy group, 1,2,2-trimethylpropoxy group, 1-
Examples thereof include an ethyl-1-methylpropoxy group and a 1-ethyl-2-methylpropoxy group.

Examples of the alkyl represented by A include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 -Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,
1-ethyl-1-methylpropyl group, 1-ethyl-2-
Examples include a methylpropyl group, a heptyl group, an octyl group, a nonyl group, a decanyl group undecanyl group, a dodecanyl group, a tridecanyl group, a tetradecanyl group, and a pentadecanyl group. Examples of the acyl group include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, and a pivaloyl group. As the carboxy group, a carboxymethyl group, 1-
Carboxyethyl group, 2-carboxyethyl group, 1-carboxypropyl group, 2-carboxypropyl group, 3-
Carboxypropyl group, 1-carboxybutyl group, 2-
Carboxybutyl group, 3-carboxybutyl group, 4-carboxybutyl group, 1-carboxypentyl group, 2-carboxypentyl group, 3-carboxypentyl group, 4-
Examples include a carboxypentyl group and a 5-carboxypentyl group. The alkoxycarbonyl group means a group in which these alkoxy groups are replaced with OH of the carboxy group to form an ester (for example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.).

The compounds of the present invention form salts with acids.
Further, depending on the type of the substituent, a salt with a base may be formed. The present invention also includes pharmaceutically acceptable salts of the compounds. Examples of such salts include inorganic salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and formic acid and acetic acid. Propionic acid, butyric acid, valeric acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid,
Acid addition salts with organic acids such as ethanesulfonic acid, glutamic acid and aspartic acid; inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; and methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, and monoethanol Examples thereof include salts with organic bases such as amine, diethanolamine, triethanolamine, cyclohexylamine, lysine, and ornithine, and ammonium salts.
In addition, the compound of the present invention may be isolated as various solvates such as hydrates and ethanolates and polymorphic substances, and the present invention includes all of these substances.

The compound represented by the formula (1) of the present invention can be produced by the following method. (1) In the compound of the formula (1), the compound in which X is a group represented by -S- can be obtained, for example, by a method represented by the following reaction formula.

[Reaction formula]

Embedded image

(In the reaction formula, R ¹ and R ² are as defined above, and R ⁵ is a lower alkyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms, a nitrile group, an acetyl group. An amino group, a halogen atom, a phenyl group, a phenyl group, a pyridyl group, a furyl group or a thienyl group in which one or two lower acetoxyalkyl groups or lower haloalkyl groups may be substituted, Y ¹ and Y ² are a fluorine atom, Chlorine, bromine and iodine; Z
Represents a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, and a p-toluenesulfonyloxy group. )

The following is a detailed description of the above reaction formulas in the order of reaction. (A) By reacting an alcohol compound (III) in the presence of a base with 3,4-dihalonitrobenzene (II) as a starting material, a 4-nitrophenyl ether compound (IV) can be obtained. The base used in this reaction is
Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; hydrogen Sodium hydroxide, alkali metal hydrides such as potassium hydride, metal sodium, metal potassium, an inorganic base such as sodium amide or triethylamine, diisopropylethylamine, trinormal butylamine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine and N, N-dimethylaminopyridine are exemplified. This reaction can be performed in a solvent. Solvents used are methanol, ethanol, normal propanol, isopropanol, normal butanol, tertiary butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, normal hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N , N-
Examples include dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water and the like. In this reaction, copper, copper oxide, copper halide, potassium iodide, tris @ 2- (2-methoxyethoxy)
Quaternary ammonium salts such as ethyldiamine, tetranormalbutylammonium chloride, tetranormalbutylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide and tricaptylmethylammonium chloride; crown ethers such as 18-crown-6 ether The reaction can also be accelerated by arbitrarily adding or the like.

(B) The 4-nitrophenyl ether compound (V) can be obtained by reducing the nitro group of the 4-nitrophenyl ether compound (IV) to an amino group. Subsequently, the 4-aminophenyl ether compound (V) can be acetylated at the amino group without isolation and purification to obtain the acetanilide compound (VI). The reduction used in this reaction may be a normal reduction method for reducing a nitro group to an amino group, for example, palladium-carbon, Raney nickel, catalytic reduction using platinum or the like as a catalyst, reduction using iron or tin, Reduction using sodium sulfide-ammonium chloride, reduction using an alkali metal hydride such as sodium borohydride, lithium aluminum hydride and the like can be mentioned. The solvent used for the reduction in this reaction is preferably arbitrarily selected according to the reduction method, for example, methanol, ethanol, normal propanol, isopropanol, normal butanol, tertiary butanol, water, acetic acid, ethyl acetate, dioxane, Examples include tetrahydrofuran and acetonitrile. Acetylation in this reaction may be a conventional method for acetylating aniline, and examples of the acetylating agent include acetic acid, acetyl chloride, acetyl bromide, and acetic anhydride. Acetylation in this reaction can be performed in a solvent. The solvent used is the solvent used for the reduction reaction, or
For example, ethyl ether, petroleum ether, normal hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, carbon tetrachloride, water, acetic acid, sulfuric acid, and the like. .

(C) By nitrating the acetoanilide compound (VI), a 2-nitroacetanilide compound (VII) can be obtained. Examples of the nitrating agent used in this reaction include fuming nitric acid, sodium nitrate, potassium nitrate, iron nitrate, and urea nitrate. The solvent used in this reaction is preferably arbitrarily selected according to the nitrating agent, for example, acetic acid, acetic anhydride, trifluoroacetic acid, sulfuric acid, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane, ethanol , Normal propanol, isopropanol and the like.

(D) The 2-nitroacetanilide compound (VII) is reacted with a mercaptan compound (VIII) in the presence of a base, and the acetamido group is hydrolyzed in the reaction system, or is hydrolyzed after isolation and purification. Thereby, the nitroaniline compound (IX) can be obtained. Bases used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. Alkali metal hydrides, such as alkali metal hydrides, sodium hydride, potassium hydride, etc .; inorganic bases such as metal sodium, metal potassium, and sodium amide; or triethylamine, diisopropylethylamine, trinormal butylamine, 1,5-diazabicyclo [4 .3.0] -5-Nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, N, N
Organic bases such as -dimethylaminopyridine. This reaction can be performed in a solvent. Solvents used are methanol, ethanol, normal propanol,
Isopropanol, normal butanol, tertiary butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, normal hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform , Carbon tetrachloride, water and the like. In this reaction, copper, copper oxide, copper halide, potassium iodide, tris {2- (2-methoxyethoxy) ethyl} amine,
Optionally, quaternary ammonium salts such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, and tricaptylmethylammonium chloride; crown ethers such as 18-crown-6 ether; The addition can also accelerate the reaction. The hydrolysis used in this reaction may be a conventional hydrolysis method in which an amide is hydrolyzed under basic or acidic conditions to give an amine, and when the hydrolysis is continued in the reaction system, the basic conditions are preferable. Examples of the base used under the conditions include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and potassium tert-butyloxy. Acids used under acidic conditions include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The solvent used for the hydrolysis in this reaction is preferably arbitrarily selected according to the hydrolysis method, for example, water, methanol, ethanol, propanol, tertiary butanol, tetrahydrofuran,
Examples include dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like.

(E) Starting from 5-arylthio-4-alkoxy-2-nitroaniline (IX) as a starting material and reacting with a carboxylic acid derivative (X) in the presence of a base,
2-Nitrobenzamide compound (XI) can be obtained. Subsequently, the nitro group of the 2-nitrobenzamide compound (XI) is reduced to an amino group, and the obtained aniline compound is cyclized to obtain the 5-arylthiobenzimidazole compound (1a) of the present invention. be able to. The amidation used in this reaction may be a conventional amidation method in which the carboxylic acid derivative (X) is activated and reacted. For example, the carboxylic acid derivative (X) may be chlorinated with thionyl chloride, oxalyl chloride, phosphorus oxychloride, or the like. A method of using a condensing agent such as 1,3-dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, a method of forming a mixed acid anhydride, and the like. Can be The amidation of this reaction can be performed in a solvent. The solvent to be used is preferably arbitrarily selected according to the amidation method, for example, methanol, ethanol, normal propanol, isopropanol, normal butanol, tertiary butanol, dioxane, tetrahydrofuran, diethyl ether, petroleum ether, benzene, toluene , Xylene, chlorobenzene, pyridine, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, dichloromethane, carbon tetrachloride, water and the like. In this reaction, an alkali metal carbonate such as lithium carbonate, sodium carbonate and potassium carbonate, an alkali metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, triethylamine, diisopropylethylamine, trinormal butylamine, 1,5-diazabicyclo [ The reaction is carried out by optionally adding an organic base such as 4,3,0] -5-nonene, 1,8-diazabicyclo [5,4,0] -7-undecene, pyridine, N, N-dimethylaminopyridine and the like. You can also accelerate. The reduction of the nitro group used in this reaction may be a conventional reduction method of reducing the nitro group to an amino group,
For example, catalytic reduction using palladium-carbon, Raney nickel, platinum or the like as a catalyst, reduction using iron or tin,
Reduction using sodium sulfide-ammonium chloride, reduction using an alkali metal hydride such as sodium borohydride, lithium aluminum hydride and the like can be mentioned. The solvent used for the reduction in this reaction is preferably arbitrarily selected according to the reduction method, for example, methanol, ethanol, normal propanol, isopropanol,
Normal butanol, tertiary butanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile and the like can be mentioned. The cyclization reaction used in this reaction may be a commonly used condensation method in which N-acyl orthodianiline is intramolecularly condensed to benzimidazole, for example, a method of heating in the presence of an acid such as acetic acid, hydrochloric acid, and a sulfonic acid derivative. And the like. The cyclization of this reaction can be performed in a solvent. The solvent used is dioxane, tetrahydrofuran, diethyl ether, petroleum ether,
Examples include benzene, toluene, xylene, chlorobenzene, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, dichloromethane, carbon tetrachloride and the like.

(2) The compound of the present invention represented by the formula (1) wherein X is a group represented by -S- and R ³ is a phenyl group substituted by one or two lower hydroxyalkyl groups. Is a compound (1a) of the present invention obtained in (1)
Can be obtained by hydrolyzing the acetoxy group of a compound in which R ⁵ is a phenyl group substituted with one or two lower acetoxyalkyl groups. The hydrolysis used in this reaction may be a conventional hydrolysis method in which an acetoxy group is hydrolyzed under basic or acidic conditions to form a hydroxyl group. Examples of the base used under basic conditions include lithium hydroxide and water. Examples include sodium oxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and potassium tert-butyloxy. Acids used under acidic conditions include hydrochloric acid, hydrobromic acid, sulfuric acid and the like.
The solvent used in this reaction is preferably arbitrarily selected depending on the hydrolysis method. For example, water, methanol, ethanol, propanol, tert-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like can be mentioned. In the compound of the present invention represented by the formula (1), X is -S-
Wherein R ³ is a phenyl group substituted with one or two hydroxymethyl groups,
The compound (1a) of the present invention obtained in (1), wherein R ⁵ is a phenyl group substituted by one or two alkoxycarbonyl groups, may be reduced to a hydroxymethyl group by reducing the alkoxycarbonyl group. Obtainable. The reducing agent used in this reaction may be a commonly used reducing agent that reduces an ester to an alcohol, and examples thereof include sodium borohydride and lithium aluminum hydride. The solvent used in this reaction is preferably arbitrarily selected depending on the reduction method.Examples include methanol, ethanol, normal propanol, isopropanol, dichloromethane, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, acetonitrile, ethyl ether, and petroleum. Ether, normal hexane, cyclohexane, benzene, toluene, xylene,
Chlorobenzene, pyridine, N, N-dimethylformamide, water and the like can be mentioned.

(3) The compound of the present invention represented by the formula (1) wherein X is a group represented by --SO-- or --SO _2- is a group wherein X of the compound of the present invention is represented by --S-- Can be obtained by oxidizing a compound. The oxidation used in this reaction may be an ordinary oxidation reaction of oxidizing sulfide to sulfoxide or sulfone or an ordinary oxidation method of oxidizing sulfoxide to sulfone, for example, hydrogen peroxide, tertiary butyl hydroperoxide, metachloro Examples include a method using perbenzoic acid, peracetic acid, sodium metaperiodate, sodium bromite, periodic benzene, and the like. The solvent used in the present reaction is preferably arbitrarily selected according to the oxidation method, for example, methanol, ethanol, normal propanol, isopropanol, dichloromethane, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, dimethoxyethane, acetone, acetonitrile , Ethyl acetate, ethyl ether, petroleum ether, normal hexane, cyclohexane, benzene, toluene, xylene,
Chlorobenzene, pyridine, N, N-dimethylformamide, water and the like can be mentioned.

(4) The compound of the present invention represented by the formula (1) wherein X is a group represented by --SO-- and R ³ is a phenyl group substituted with an amino group or a carboxy group is a compound of the present invention. Can be obtained by hydrolyzing a compound in which R ³ is a phenyl group substituted with an acetylamino group or an alkoxycarbonyl group. The hydrolysis used in this reaction may be a conventional hydrolysis method in which an ester or amide is hydrolyzed under basic or acidic conditions to form a carboxylic acid or an amine. Examples of the base used under basic conditions include water. Examples include lithium oxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, and potassium tert-butyloxy. Acids used under acidic conditions include hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The solvent used in this reaction is preferably arbitrarily selected depending on the hydrolysis method. For example, water, methanol, ethanol, propanol, tert-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like can be mentioned.

(5) In the compound of the present invention represented by the formula (1), X is a group represented by —SO—, and R ³ is a group having one nitrogen atom.
Or a compound in which X of the compound of the present invention is a lower aminoalkyl group which may be substituted with two lower alkyl groups or a phenyl group substituted with a cyclic aminoalkyl group,
It can be obtained by aminating a hydroxyl group of a compound represented by SO-, wherein R ³ is a phenyl group substituted by a lower hydroxyalkyl group. The amination used in this reaction includes a method of converting a hydroxyl group to a leaving group and then aminating. Examples of the leaving group include halogen, sulfonate, and the like.
Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphorus oxychloride, carbon tetrabromide, and hydrogen bromide.Examples of the sulfonating agent include mesyl chloride, tosyl chloride, and methanesulfonyl chloride. No. This reaction can be performed in a solvent. The solvent to be used is preferably arbitrarily selected depending on the amination method, for example, dichloromethane, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, dimethoxyethane, acetone, acetonitrile, ethyl acetate, ethyl ether, petroleum ether, normal Hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, N, N-dimethylformamide and the like can be mentioned. In this reaction, triethylamine, diisopropylethylamine, trinormal butylamine,
1,5-diazabicyclo [4,3,0] -5-nonene,
The reaction can be accelerated by optionally adding an organic base such as 1,8-diazabicyclo [5,4,0] -7-undecene, pyridine, N, N-dimethylaminopyridine and the like.

(6) In the compound of the present invention represented by the formula (1), X is a group represented by -SO-, and R ³ has 2 to 6 carbon atoms which may be substituted by one or two hydroxyl groups. Are phenyl groups substituted with an alkylaminocarbonyl group or a carbamoyl group, wherein X in the compound of the present invention is a group represented by —SO—, and R ³ is a phenyl group substituted with a methoxycarbonyl group. It can be obtained by reacting a compound with an amine. The amidation used in this reaction may be a conventional method of converting an ester to an amide, for example, a method of heating a mixture of an ester and an amine, or a method in which an amine is activated with a base such as sodium methoxide, sodium hydride, and normal butyllithium. And then reacting with an ester. The solvent used in this reaction is preferably arbitrarily selected according to the amidation method, for example, methanol, ethanol,
Dioxane, tetrahydrofuran, diethyl ether,
Petroleum ether, benzene, toluene, xylene, chlorobenzene, pyridine, N, N-dimethylformamide,
Examples include dimethyl sulfoxide, dichloroethane, chloroform, dichloromethane, carbon tetrachloride, water and the like.

(7) A method for producing a compound of the present invention represented by the formula (1) wherein R ⁴ is other than a hydrogen atom is shown below.

[0032]

Embedded image

(Wherein, R ¹ , R ² , R ³ , R ⁴ and X have the above-mentioned meanings, and Z represents a halogen atom.) The compound of the present invention comprises a reaction-corresponding amount of a benzimidazole compound. And a halide compound in a solvent such as diethyl ether, tetrahydrofuran, dioxane, dimethoxy ether, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, chlorobenzene, pyridine, etc., while stirring under basic conditions. Can be performed. Examples of the base used in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate. Alkali metal hydrides such as alkali metal hydrides, sodium hydride, potassium hydride and the like; inorganic bases such as metal sodium, metal potassium and sodium amide; or organic such as triethylamine, pyridine, N, N, -dimethylaminopyridine Bases. The compound of the present invention can also be produced by various conventional methods, particularly the methods described in Reference Examples and modifications thereof, in consideration of the structural features, in addition to the above-mentioned production methods. The compound of the present invention thus produced is isolated and purified as a free compound, a salt, a hydrate, various solvates, and the like. It can be produced by subjecting to the salt formation reaction of the method. Isolation and purification are performed by applying ordinary scientific operations such as extraction, fractional crystallization, and various types of fractional chromatography.

Pharmaceutical compositions containing one or more of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient can be prepared by using a commonly used pharmaceutical carrier or excipient. Tablets, powders, fine granules, granules, capsules, pills, liquids, injections, suppositories, etc. are prepared using forms and other additives, and are orally or parenterally administered. . The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, body weight, etc. of the administration subject, and is usually 1 to 1000 mg, preferably 50 to 200 mg per day for an adult. It is orally administered once or several times a day, or in the range of 1 mg to 500 mg per adult per day, is administered intravenously once to several times a day, or 1 hour to 24 hours a day It is continuously administered intravenously within the range. Of course, as described above, the dosage varies under various conditions, so that an amount smaller than the above dosage range may be sufficient. As a solid composition for oral administration with the compound of the present invention,
Tablets, powders, granules and the like are used. In such solid products, the one or more active substances comprise at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolodone, metasilicate. , Mixed with magnesium aluminate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, and glutamic acid. Or it may contain a solubilizing and / or solubilizing agent such as aspartic acid. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and commonly used inert diluents such as purified Contains water and ethanol. The composition may contain, in addition to the inert diluent, solubilizing and / or solubilizing agents, adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, flavoring agents, and preservatives. . Injections for parenteral administration include sterile aqueous or non-aqueous emulsions, solutions and suspensions. Diluents for aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and alcohols such as ethanol. Such compositions may further include isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers,
Additives such as (eg, lactose), solubilizing and / or solubilizing agents may be included. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used to produce a sterile solid composition which is dissolved in sterile water or a sterile injectable solvent before use.

[0035]

EFFECT OF THE INVENTION The compound (1) of the present invention is IL-1
It is useful as a therapeutic agent for diseases caused by L-5 and IL-6, for example, an anti-inflammatory agent, a therapeutic agent for autoimmune diseases against rheumatoid arthritis and the like, a therapeutic agent for bone diseases against osteoporosis and the like, and an antiallergic agent. Hereinafter, the present invention will be described more specifically with reference to test examples.

Test Example 1 IL-5 Production Inhibitory Effect [Test Method] The mouse Th2 clone was D10. G4.
One cell (ATCC) was prepared by fetal bovine serum 10%, penicillin 100 U / ml, streptomycin 100 μg / m
1, Sodium hepyruvate 1 mM, L-glutamine 2
The cells were suspended in an RPMI-1640 medium (Gibco) supplemented with 0.05 mM mM and β-mercaptoethanol to adjust the cell number to 2 × 10 ⁵ cells / ml. The antigen-presenting cells were obtained by suspending spleen cells of C3 / Hen mouse (8-week-old, female) in RPMI-1640 medium (Gibco),
After incubating with 30 μg / ml of mitomycin C at 37 ° C. for 30 minutes, the cells were washed three times with the above-mentioned medium solution to adjust the cell number to 1 × 10 6 cells / ml. The sample was prepared by dissolving the sample in ethanol and diluting the sample with the above-mentioned medium solution so that the final concentration of ethanol was 0.03%. D10. 100 μl each of cell suspensions of G4.1 cells and antigen-presenting cells, ConA
(Sigma) 10 μl of each of the above medium solutions of 400 μg / ml and the test compound (the compound of the present invention) was added to a V-bottom 96-well plate (manufactured by Nippon Intermed), and 5% C
The cells were cultured in an O ₂ incubator at 37 ° C. for 48 hours. After the culture, IL-5 (pg / ml) was added to the cell supernatant by ELI.
Measurement was performed using an SA kit (ENDOGEN), and the production inhibition rate (%) was calculated (a control in which the concentration of the test compound was adjusted to 0 was used as a control). Table 1 shows the results. [Production inhibition rate (%) = (1−T / C) × 100: T is the amount of IL-5 produced at each concentration of the test compound, and C is the amount of IL-5 produced by the control] Table 2 shows the production inhibition rate ( %) To obtain the IC ₅₀ value (M). The concentration of the test compound was 3 μg / ml, 1 μg
It was calculated as three concentrations of g / ml and 0.3 μg / ml. (A control in which the concentration of the test compound was adjusted to 0 was used as a control. [Results] Test results are shown in Tables 1 and 2.

Table 1 IL-5 Production Inhibitory Activity Test Compound Concentration IL-5 (Production Example No.) (μg / ml) (Production Inhibition Rate:%) 34 0.3 73 35 0.3 55 37 37 0.3 53 38 0.1 58 40 0.3 76 41 0.3 71 46 0.35 75 52 0.1 52 53 0.3 61 61 60 170 63 1 82 72 0.3 76 81 81 68 (M-24) 1071 57 (M-23)

Table 2 IC ₅₀ (μM) Production Example D10 Production Example D10 116 4.9 117 1.0 118 118 2.3 119 0.7 120 3.4 121 121 2.6 122 2.3 123 3.4 124 N . E 125 4.2 126 N.E. E 127 2.1 128 N.E. E 129 1.9 130 4.1 131 2.5 133 133 1.6 133 1.8 135 135 3.0 135 2.5 137 6.0 Note: N.E. E: not effect

Test Example 2 Inhibitory effect of IL-1β and IL-6 production [Test method and results] Human peripheral blood mononuclear cells produce IL-1β and IL-6 by stimulating ConA.
By adding a test compound (compound of the present invention) simultaneously with ConA, IL-1β in the produced cell supernatant was
And IL-6 were measured with an ELISA kit, and the production inhibition rate (%) of the test compound was calculated (when the concentration of the test compound was 0%).
Was prepared as a control). As a result, the compound of the present invention produced by the methods of Production Examples 35, 36, 40 and 45 showed that the compound of 36 to 6 at a concentration of 0.3 μg / ml.
A 4% IL-1β production inhibitory effect was exhibited. Further, the compound of the present invention produced by the method of Production Examples 34, 36, 40 and 45 has a concentration of 55 to 93% at a concentration of 0.3 μg / ml.
Showed an inhibitory effect on IL-6 production. [Production inhibition rate (%) = (1−T / C) × 100: T is the amount of IL-1β and IL-6 produced at each concentration of the test compound, and C is the amount of control IL-1β and IL-6 produced]

Hereinafter, the present invention will be described more specifically with reference to production examples. Production Example 1 6-methoxy-2-phenyl-5- (4-pyridylsulfenyl) benzimidazole 1) 5-fluoro-4-methoxy-2-nitroacetanilide 60% sodium hydride 32.0 g (0.801 mol)
l) was added to 530 ml of methanol to form a solution, and 85.0 g (0.5%) of 3,4-difluoronitrobenzene was added under ice cooling.
34 mol) over 0.5 hours, and further added at room temperature for 2 hours.
Stirred for hours. Thereafter, 500 ml of water was added to the reaction solution,
The precipitate was collected by filtration. This was washed with water and dried to obtain yellow crystals. 237.0 g of iron powder was added to the obtained yellow crystals (4.2
4 mol) to obtain a mixture, 160 ml (0.16 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated at 85 ° C.
For 50 minutes. After the reaction solution was cooled to 50 ° C., 500 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. Triethylamine 5 was added to the obtained filtrate at room temperature.
3.6 g (0.53 mol) were added, and acetic anhydride 54.1 was added.
g (0.53 mol) is added over 20 minutes, and another 20
Stirred for minutes. Thereafter, the reaction solution was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain colorless crystals. The obtained colorless crystals were treated with acetic acid (530 m).
to 33.4 g of fuming nitric acid at 60 ° C.
(0.53 mol) was added over 20 minutes, and the mixture was further stirred for 20 minutes. Thereafter, the reaction solution is returned to room temperature, and water 750 is added.
Then, the precipitate was collected by filtration. This was washed with water and dried to obtain 104 g (85%) of 5-fluoro-4-methoxy-2-nitroacetanilide as yellow crystals. m. p. 166-168 ° C.

2) 4-methoxy-2-nitro-5- (4
-Pyridylsulfenyl) aniline 53.5 g (0.181 mol) of 5-fluoro-4-methoxy-2-nitroacetanilide and 24.1 g (0.217 mol) of 4-mercaptopyridine were added to 360 ml of isopropanol to form a suspension, 100 ml (0.682 mol) of a 6.8 N aqueous sodium hydroxide solution was added, and the mixture was heated and stirred at 60 ° C. for 3 hours. Thereafter, the reaction solution was returned to room temperature, 500 ml of water was added, and the precipitate was collected by filtration. This was washed with water and dried to obtain 44.8 g (72%) of 4-methoxy-2-nitro-5- (4-pyridylsulfenyl) aniline as orange crystals. m. p. 199-201 ° C.

3) 6-methoxy-2-phenyl-5-
(4-Pyridylsulfenyl) benzimidazole (compound of the present invention: Production Example 1) 4 g (0.0144 mol) of 4-methoxy-2-nitro-5- (4-pyridylsulfenyl) aniline and 1.22 ml of pyridine were added to chloroform. A solution was added to 47 ml, and benzoyl chloride (2.13 g) was added at 60 ° C. with stirring.
(0.0151 mol), and the mixture was further stirred at 60 ° C. for 4 hours. Thereafter, the reaction solution was returned to room temperature, and washed sequentially with water and saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the origin component was removed with a silica gel column to obtain 0.500 g of a yellow oily substance. The obtained yellow oil was dissolved in 2.6 ml of acetic acid, and
40 g (0.00786 mol) was added to make a suspension,
Stirred at 85 ° C. for 30 minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 2 hours. Thereafter, the reaction solution was returned to room temperature, acetic acid (20 ml) was added, the mixture was filtered through celite, and concentrated under reduced pressure. Ethyl acetate (20 ml) was added to the obtained residue, and the residue was added to give 0.1 ml.
The extract was washed with a 5N aqueous solution of sodium hydroxide, a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride in that order. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to give 6-methoxy-colorless crystals.
0.260 g (6%) of 2-phenyl-5- (4-pyridylsulphenyl) benzimidazole was obtained. m. p. 219-220 ° C

Production Examples 2 to 6 2-Aryl-6-methoxy-5- (4-pyridylsulfenyl) benzimidazole compound Instead of the benzoyl chloride used in Production Example 1-3), 4-methoxybenzoyl chloride and 4-methoxybenzoyl chloride were used. Hydroxybenzoyl chloride, 4-chlorobenzoyl chloride, 4-
Using methoxycarbonylbenzoyl chloride or 4-pyridinecarbonyl chloride, acylation, reduction and cyclization were carried out in accordance with the method of Production Example 1-3), whereby Table 2 was obtained.
The 2-aryl-5- (4-pyridylsulfenyl) -6-methoxybenzimidazole compounds shown in Production Examples 2 to 6 were obtained.

Production Example 7 6-Cyclohexyloxy-2-phenyl-5- (4-
Pyridylsulfenyl) benzimidazole 1) 4-cyclohexyloxy-3-fluoronitrobenzene 60% sodium hydride 37.7 g (0.943 mo
l) was added to 1600 ml of tetrahydrofuran to make a suspension, and 94.4 g (0.9%) of cyclohexanol was added at room temperature.
43 mol) and stirred for 1 hour. Next, 100 g (0.629 mol) of 3,4-difluoronitrobenzene
Was added over 1.5 hours, and the mixture was further stirred for 2.5 hours. Thereafter, the reaction solution was extracted with normal hexane, and the organic layer was washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: normal hexane: ethyl acetate = 50: 1) to give 4-cyclohexyloxy-3 as yellow crystals. -125.8 g (84%) of fluoronitrobenzene were obtained. m. p. 44-45 ° C.

2) 4-Cyclohexyloxy-3-fluoroacetanilide 72.9 g (0.330 mol) of 4-cyclohexyloxy-3-fluoronitrobenzene and 82.9 g of iron powder
(1.484 mol) was added to form a mixture, 140 ml (0.099 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated with stirring at 85 ° C. for 3.5 hours. Thereafter, the reaction solution was returned to room temperature, 200 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. The obtained filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 330 ml of isopropanol was added to the obtained residue to form a solution, 40.4 g (0.396 mol) of acetic anhydride was added under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. Thereafter, 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration.
The crystal was recrystallized from normal hexane to give colorless crystalline 4-cyclohexyloxy-3-fluoroacetanilide 61.8.
g (74.5%). m. p. 123.5-124.5 ° C.

3) 4-Cyclohexyloxy-5-fluoro-2-nitroacetanilide 54.5 g (0.217 mol) of 4-cyclohexyloxy-3-fluoroacetanilide was added to 220 ml of acetic acid to form a solution. 14.3 g (0.
(227 mol) was added over 15 minutes, and the mixture was further stirred for 5 minutes. Thereafter, the reaction solution was returned to room temperature, 300 ml of water was added, the precipitate was collected by filtration, and the obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give 4-cyclohexyloxy-5-fluoro- yellow crystals. 58.7 g (92%) of 2-nitroacetanilide were obtained. m. p. 120-121.5 ° C.

4) 4-Cyclohexyloxy-2-nitro-5- (4-pyridylsulphenyl) aniline 53.5 g (0.181 mol) of 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide and 4
-24.1 g (0.217 mol) of mercaptopyridine
Was added to 360 ml of isopropyl alcohol to form a suspension, and 73 ml of a 6N aqueous sodium hydroxide solution (0.43
3 mol), and the mixture was heated and stirred at 60 ° C. for 1 hour. Thereafter, the reaction solution was returned to room temperature, 500 ml of water was added, and the precipitate was collected by filtration. This is washed with water, dried and dried as orange crystals.
44.8 g (72%) of -cyclohexyloxy-2-nitro-5- (4-pyridylsulphenyl) aniline were obtained. m. p. 87-89 ° C.

5) 6-Cyclohexyloxy-2-phenyl-5- (4-pyridylsulfenyl) benzimidazole (compound of the present invention: Production Example 7) 4-cyclohexyloxy-2-nitro-5- (4-pyridyl) 1.66 g (0.004 of sulfenyl) aniline
80mol) and 0.00790 g of triethylamine
(0.00720 mol) was added to 15 ml of chloroform to form a solution, and benzoyl chloride 1.
01 g (0.00720 mol) was added, and the mixture was stirred for 2 hours. Thereafter, the reaction solution was washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the origin component was removed with a silica gel column to obtain 3.97 g of a yellow oily substance. Acetic acid 1
0 ml, and iron powder 1.61 g (0.0288mo)
l) was added to form a suspension, and the mixture was stirred at 85 ° C for 30 minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 2 hours.
Thereafter, the reaction solution was returned to room temperature, 80 ml of acetic acid was added, the mixture was filtered through celite, and concentrated under reduced pressure. Ethyl acetate (80 ml) was added to the obtained residue, and the mixture was washed successively with a 0.5 N aqueous solution of sodium hydroxide, a saturated aqueous solution of ammonium chloride, and a saturated saline solution. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give colorless crystals of 6-cyclohexyloxy-2-phenyl-5- (4-pyridylsulfenyl) benz. 0.20 g (2%) of imidazole was obtained. m. p. 138-139 ° C.

Production Examples 8-26 2-Aryl-6-cyclohexyloxy-5- (4-
Pyridylsulfenyl) benzimidazole compound Instead of benzoyl chloride used in Production Example 7-5), 4-methoxybenzoyl chloride, 3-methoxybenzoyl chloride, 2-methoxybenzoyl chloride, 3,
4-dimethoxybenzoyl chloride, 3-cyclohexyloxy-4-methoxybenzoyl chloride, 4-chlorobenzoyl chloride, 2,4-dichlorobenzoyl chloride, 4-fluorobenzoyl chloride, 4-methylbenzoyl chloride, 4-trifluoromethylbenzoyl chloride , 4-phenylbenzoyl chloride, 4-cyanobenzoyl chloride, 4-methoxycarbonylbenzoyl chloride, 3- (acetoxymethyl) benzoyl chloride, 3,4-di (acetoxymethyl) benzoyl chloride, 4-acetamidobenzoyl chloride, 4-
By acylating, reducing and cyclizing pyridinecarbonyl chloride, 2-furoyl chloride or 2-thenoyl chloride in accordance with the method of Production Example 7-5), Tables 3, 4 and 5 were obtained. The 2-aryl-6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole compounds shown in Production Examples 8 to 26 were obtained.

Production Example 27 2- (4-chlorophenyl) -6- (2,4-difluorophenoxy) -5- (4-pyridylsulfenyl) benzimidazole 1) 4- (2,4-difluorophenoxy) -3 -Fluoronitrobenzene 42 g of 2,4-difluorophenol (0.396 mol
1) and 15.8 g of sodium hydroxide (0.396 mol
l) was added to 775 ml of water to form a solution, 51.5 g (0.264 mol) of 3,4-difluoronitrobenzene was added, and the mixture was heated under reflux for 2 hours. Thereafter, the reaction solution was returned to room temperature and extracted with toluene. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- (2,4-difluorophenoxy) -3- as yellow crystals.
56.2 g (83%) of fluoronitrobenzene were obtained. m. p. 40.5-41.5 ° C.

2) 4- (2,4-difluorophenoxy) -3-fluoroacetanilide 4- (2,4-difluorophenoxy) -3-fluoronitrobenzene 64 g (0.239 mol) of iron powder 60
g (1.07 mol) was added to make a mixture, 71 ml (0.0717 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was stirred at 85 ° C. for 1 hour. Thereafter, the reaction solution was returned to room temperature, 360 ml of isopropanol was added, and insolubles were removed by filtration through celite. Acetic anhydride 29.7m was added to the obtained filtrate.
was added and stirred at room temperature for 10 minutes. Thereafter, 1000 ml of water was added to the reaction solution, and the precipitate was collected by filtration. This was washed with water and normal hexane, dried and dried to give colorless crystals of 4-.
65.5 g (98%) of (2,4-difluorophenoxy) -3-fluoroacetanilide were obtained. m. p. 117-118 ° C.

3) 4- (2,4-difluorophenoxy) -5-fluoro-2-nitroacetanilide 4- (2,4-difluorophenoxy) -3-fluoroacetanilide 65 g (0.231 mol) of acetic acid 23
0 g, and 16 g of fuming nitric acid (0.
(254 mol) was added slowly and stirred for 1 hour. Thereafter, the reaction solution was returned to room temperature, 800 ml of water was added, and the precipitate was collected by filtration. This is washed with water and dried to obtain 4 yellow crystals.
-(2,4-difluorophenoxy) -5-fluoro-
66.0 g (88%) of 2-nitroacetanilide were obtained. m. p. 130.5-132 ° C.

4) 4- (2,4-difluorophenoxy) -5- (4-pyridylsulfenyl) -2-nitroaniline 4- (2,4-difluorophenoxy) -5-fluoro-2-nitroacetanilide 8 0.7g (0.0267m
ol) and 3.3 g of 4-mercaptopyridine (0.02
97 mol) in 90 ml of isopropanol to form a suspension, and 12 ml of a 6.25 N aqueous sodium hydroxide solution.
Was added and stirred at 60 ° C. for 4 hours. Thereafter, the reaction solution was returned to room temperature, 90 ml of water was added, and the precipitate was collected by filtration. This was washed with water and dried to obtain 9.1 g (99%) of 4- (2,4-difluorophenoxy) -2-nitro-5- (4-pyridylsulfenyl) aniline as yellow crystals. m. p. 224-226 ° C.

5) 2- (4-chlorophenyl) -6
(2,4-difluorophenoxy) -5- (4-pyridylsulfenyl) benzimidazole (compound of the present invention: Production Example 27) 4- (2,4-difluorophenoxy) -2-nitro-
9.0 g of 5- (4-pyridylsulfenyl) aniline
(0.0240 mol) and 40 ml of pyridine were added to 80 ml of chloroform to form a solution.
4.61 g of chlorobenzoyl chloride (0.0264
mol), and the mixture was stirred at room temperature for 15 hours. Thereafter, the reaction solution was returned to room temperature, and washed with water and saturated saline in this order.
This is dried over anhydrous magnesium sulfate, concentrated under reduced pressure,
The origin component was removed with a silica gel column to obtain 9.07 g of a yellow oily substance. Acetic acid 50m
Then, 5.90 g (0.105 mol) of iron powder was added to form a suspension, and the mixture was stirred at 85 ° C. for 30 minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 3 hours. afterwards,
The reaction solution was returned to room temperature, 400 ml of acetic acid was added, the mixture was filtered through celite, and concentrated under reduced pressure. Ethyl acetate 4 was added to the obtained residue.
00 ml, 0.5N aqueous sodium hydroxide solution,
The extract was washed successively with a saturated aqueous solution of ammonium chloride and a saturated saline solution. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to give colorless crystals of 2- (4-chlorophenyl) -6- (2,4-difluorophenoxy)- 5.12 g (47%) of 5- (4-pyridylsulphenyl) benzimidazole were obtained. m. p. 204-205 ° C.

Production Example 28 6- (2,4-Difluorophenoxy) -2- (4-methoxycarbonylphenyl) -5- (4-pyridylsulfenyl) benzimidazole 4-chloro used in Production Example 27-5) By using 4-methoxycarbonylbenzoyl chloride instead of benzoyl chloride and acylating, reducing and cyclizing according to the method of Production Example 27-5), 6- (2,4-difluorophenoxy) -2- (4-Methoxycarbonylphenyl) -5- (4-pyridylsulfenyl) benzimidazole was obtained. m. p. 223-225 ° C (recrystallized from ethyl acetate).

Production Example 29 6-Normalhexyloxy-2-phenyl-5- (4
-Pyridylsulfenyl) benzimidazole 1) 7.6 g (0.188 mol) of 60% sodium hydride 3-fluoro-4-normalhexyloxyacetanilide
Was added to 180 ml of dimethylformamide to form a suspension, and 19.2 g of normal hexanol (0.1
(88 mol) and stirred for 3 hours. Next, 25 g (0.157 mol) of 3,4-difluoronitrobenzene was gradually added, and the mixture was further stirred for 4 hours. Thereafter, the reaction solution was extracted with normal hexane, and the organic layer was washed with water and saturated saline in this order. This is dried over anhydrous magnesium sulfate,
After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solvent: normal hexane: ethyl acetate = 15: 1) to obtain yellow crystals. 88 g (1.570 mol) of iron powder was added to the obtained yellow crystals to form a mixture, and 47.1 ml of a 1 N aqueous ammonium chloride solution was added.
(0.047 mol), and the mixture was heated and stirred at 85 ° C. for 1.5 hours. Thereafter, the reaction solution was returned to room temperature, 100 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. The filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 157 ml of isopropanol was added to the obtained residue to form a solution, and 17.6 g (0.173 mol) of acetic anhydride was added under ice cooling, followed by stirring at room temperature for 0.5 hour. Thereafter, 250 ml of water was added to the reaction solution, the precipitate was collected by filtration, and the obtained crude crystals were recrystallized from dichloromethane-normal hexane to give 44.3 g of colorless crystals of 3-fluoro-4-normalhexyloxyacetanilide ( 93%). m. p. 105.5-107.5 ° C.

2) 5-Fluoro-4-normalhexyloxy-2-nitroacetanilide 4-cyclohexyloxy-3 used in Production Example 7-3)
3-fluoro-4 instead of fluoroacetanilide
-Normal hexyloxyacetanilide was used for nitration according to the method of Production Example 7-2), whereby
5-Fluoro-4-normalhexyloxy-2-nitroacetanilide was obtained. m. p. 88.5-89 ° C (recrystallized from dichloromethane-normal hexane).

3) 4-Normalhexyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline 4-Cyclohexyloxy-5 used in Production Example 7-4)
-Instead of fluoro-2-nitroacetanilide, 5-
By performing thioetherification according to the method of Production Example 7-3) using fluoro-4-normalhexyloxy-2-nitroacetanilide, 4-normalhexyloxy-2-nitro-5- (4-pyridylsulfur) was obtained. Phenyl) aniline was obtained. m. p. 144.5 to 145.5 ° C (recrystallized from isopropyl alcohol-normal hexane).

4) 6-Normalhexyloxy-2-phenyl-5- (4-pyridylsulfenyl) benzimidazole (compound of the present invention: Production Example 29) 4-Normalhexyloxy-2-nitro-5- (4 −
Pyridylsulfenyl) aniline 2.0 g (0.005
76 mol) and 0.0014 g of triethylamine
(0.0126 mol) was added to 18 ml of chloroform to form a solution, and benzoyl chloride 0.8 was added at room temperature under stirring.
9 g (0.00633 mol) was added, and the mixture was stirred for 24 hours. Thereafter, the reaction solution was washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the origin component was removed with a silica gel column to obtain 0.830 g of a yellow oily substance. The obtained yellow oily substance was dissolved in 4 ml of acetic acid, and 0.670 g (0.0120 m
l) was added to form a suspension, and the mixture was stirred at 85 ° C for 20 minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 4 hours.
Thereafter, the reaction solution was returned to room temperature, acetic acid (30 ml) was added, the mixture was filtered through celite, and concentrated under reduced pressure. Ethyl acetate (30 ml) was added to the obtained residue, and the mixture was washed sequentially with a 0.5 N aqueous solution of sodium hydroxide, a saturated aqueous solution of ammonium chloride, and a saturated saline solution. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to give colorless crystals of 6-normalhexyloxy-2-phenyl-5- (4-pyridylsulfenyl). 0.184 g (8%) of benzimidazole was obtained. m. p. 152-153 ° C.

Production Example 30 0.3 g (0.00780) of lithium aluminum hydride 6-cyclohexyloxy-2- (4-hydroxymethylphenyl) -5- (4-pyridylsulfenyl) benzimidazole
mol) was added to 30 ml of tetrahydrofuran to form a suspension, and the suspension was stirred at 0 ° C. at 0 ° C. to obtain 6-cyclohexyloxy-2- (4-methoxycarbonylphenyl) -5- (4-pyridylsulfenyl). ) 3.0 g (0.00650 mol) of benzimidazole was added, and 2
Stirred for hours. Then, saturated sodium sulfate aqueous solution 20
Then, the obtained filtrate was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to give 6-cyclohexyloxy-2-colorless crystals.
2.2 g of (4-hydroxymethylphenyl) -5- (4-pyridylsulfenyl) benzimidazole
%). m. p. 248-250 ° C.

Production Example 31 6-Cyclohexyloxy-2- (3-hydroxymethylphenyl) -5- (4-pyridylsulfenyl) benzimidazole 2- (3-acetoxymethylphenyl)-obtained by the method of Production Example 21 0.43 g of 6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole
(0.00900 mol) was added to 2 ml of ethanol to form a solution, and 0.5 ml (0.00135 mol) of a 3N aqueous potassium hydroxide solution was added at room temperature with stirring, followed by stirring for 1 hour. Thereafter, 5 ml of water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give 6-cyclohexyloxy-2- (3-hydroxyl) as a colorless oily substance. Methylphenyl) -5-
(4-pyridylsulfenyl) benzimidazole 0.
18 g (46%) were obtained. NMR (200 MHz, CDCl3) [delta]: 1.10
1.82 (m, 10H), 4.18 (m, 1H), 4.
76 (s, 2H), 6.94 (br.d, 2H), 7.
10 (br.s, 1H), 7.37 (br.s, 2
H), 7.64 (br.s, 1H), 7.88 (br.
s, 1H), 8.10 (br.s, 1H), 8.21
(Br.s, 2H).

Production Example 32 6-Cyclohexyloxy-2- {3,4-di (hydroxymethyl) phenyl} -5- (4-pyridylsulfenyl) benzimidazole 2- (3-acetoxymethyl) used in Production Example 31 Preparation Example 2 instead of phenyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole
6-cyclohexyloxy-2- (3,
By using 4-di (acetoxymethyl) phenyl) -5- (4-pyridylsulfenyl) benzimidazole and hydrolyzing according to the method of Production Example 31, 6-
Cyclohexyloxy-2- {3,4-di (hydroxymethyl) phenyl} -5- (4-pyridylsulfenyl) benzimidazole was obtained. m. p. 256-258 ° C (recrystallized from methanol-ethyl acetate).

Production Example 33 6- (2,4-Difluorophenoxy) -2- (4-hydroxymethylphenyl) -5- (4-pyridylsulfenyl) benzimidazole 6-cyclohexyloxy-2 used in Production Example 30 −
6- (2,4-Difluorophenoxy) -2- (4-methoxycarbonylphenyl) obtained by the method of Preparation Example 28 instead of (4-methoxycarbonylphenyl) -5- (4-pyridylsulfenyl) benzimidazole −5-
By using (4-pyridylsulfenyl) benzimidazole and reducing according to the method of Production Example 30,
6- (2,4-Difluorophenoxy) -2- (4-hydroxymethylphenyl) -5- (4-pyridylsulfenyl) benzimidazole was obtained. m. p. 253-255 ° C (recrystallized from methanol-ethyl acetate).

Production Example 34 6-Methoxy-2-phenyl-5- (4-pyridylsulfinyl) benzimidazole 6-methoxy-2-phenyl-5- (4-pyridylsulfur) obtained by the method of Production Example 1-3) Phenyl) benzimidazole (0.05 g, 0.000150 mol) was added to chloroform (1.5 ml) to form a solution, and the mixture was stirred at 0 ° C. at 0 ° C. to give metachloroperbenzoic acid (0.028 g (0.000160 mol)).
l) was added slowly and stirred for 30 minutes. Thereafter, 3 ml of a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, extracted with chloroform, and washed with saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to give colorless crystals of 6-methoxy-2-phenyl-.
0.028 g (53%) of 5- (4-pyridylsulfinyl) benzimidazole was obtained. m. p. 233-235 ° C.

Preparation Examples 35 to 63 2-Aryl-5- (4-pyridylsulfinyl) benzimidazole Compound Instead of 6-methoxy-2-phenyl-5- (4-pyridylsulfenyl) benzimidazole used in Preparation Example 34 6-methoxy-2- (4-methoxyphenyl) -5 obtained by the method of Production Examples 2 to 20
(4-pyridylsulfenyl) benzimidazole, 2
-(4-acetoxyphenyl) -6-methoxy-5-
(4-pyridylsulfenyl) benzimidazole, 2
-(4-chlorophenyl) -6-methoxy-5- (4-
Pyridylsulfenyl) benzimidazole, 6-methoxy-2- (4-methoxycarbonylphenyl) -5
(4-pyridylsulfenyl) benzimidazole, 6
-Methoxy-2- (4-pyridyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2-phenyl-5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2 -(4-methoxyphenyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (3-methoxyphenyl) -5- (4
-Pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (2-methoxyphenyl)-
5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (3,4-dimethoxyphenyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2-
(3-cyclopentyloxy-4-methoxyphenyl)
-5- (4-pyridylsulfenyl) benzimidazole, 2- (4-chlorophenyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (2,4-
Dichlorophenyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-
2- (4-fluorophenyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (4-toluyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy -2- (4-trifluoromethylphenyl) -5
-(4-pyridylsulfenyl) benzimidazole,
2- (4-biphenyl) -6-cyclohexyloxy-
5- (4-pyridylsulfenyl) benzimidazole, 2- (4-cyanophenyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (4-methoxycarbonyl) Phenyl) -5- (4-pyridylsulfenyl) benzimidazole, 2- (4-acetylaminophenyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) obtained by the method of Production Examples 23 to 27
Benzimidazole, 6-cyclohexyloxy-2-
(4-pyridyl) -5- (4-pyridylsulfenyl)
Benzimidazole, 6-cyclohexyloxy-2-
(2-furyl) -5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2-
(2-thienyl) -5- (4-pyridylsulfenyl)
Benzimidazole, 2- (4-chlorophenyl) -6
-(2,4-difluorophenoxy) -5- (4-pyridylsulfenyl) benzimidazole, Production Examples 29 to
6-Normalhexyloxy-2-phenyl-5- (4-pyridylsulfenyl) benzimidazole obtained by the method of Example 33, 6-cyclohexyloxy-2- (4-hydroxymethylphenyl) -5- (4-pyridylsulfur Phenyl) benzimidazole, 6-cyclohexyloxy-2- (3-hydroxymethylphenyl) -5- (4-
Pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2- (3,4-dihydroxymethylphenyl) -5- (4-pyridylsulfenyl) benzimidazole, 6- (2,4-difluorophenoxy)
-2- (4-hydroxymethylphenyl) -5- (4-
Using pyridylsulfenyl) benzimidazole, oxidized according to the method of Production Example 34, Tables 5, 6 and 7
The 2-aryl-5- (4-pyridylsulfinyl) benzimidazole compounds shown in Production Examples 35 to 63 of the above were obtained.

Production Example 64 6-Methoxy-2-phenyl-5- (4-pyridylsulfonyl) benzimidazole 6-methoxy-2-phenyl-5- (4-pyridylsulfur) obtained by the method of Production Example 1-3). 0.15 g (0.000450 mol) of phenyl) benzimidazole was added to 2 ml of chloroform to form a solution.
Was slowly added and stirred for 30 minutes. Thereafter, 5 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and washed with saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to give 6-methoxy-2-phenyl-5-colorless crystals.
(4-pyridylsulfonyl) benzimidazole 0.1
09 g (66%) were obtained. m. p. 262-264 ° C.

Production Example 65 2- (4-carboxyphenyl) -6-methoxy-5
(4-pyridylsulfinyl) benzimidazole 0.11 g (0.00027) of 6-methoxy-2- (4-methoxycarbonylphenyl) -5- (4-pyridylsulfinyl) benzimidazole obtained in Production Example 38
0 mol) was dissolved in 5 ml of tetrahydrofuran, and 0.1 ml of a 6.25 N aqueous sodium hydroxide solution was added with stirring, followed by stirring for 1 hour. Thereafter, 5 ml of water was added to the reaction solution, which was washed with diethyl ether. The obtained aqueous solution was neutralized by adding 1.3 ml of a 0.5 N hydrochloric acid aqueous solution, extracted with ethyl acetate, and washed with saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to give colorless crystals of 2- (4-carboxyphenyl) -6-methoxy-5- (4-pyridylsulfinyl) benzimidazole. 055 g (52%) were obtained. m. p. 300 ° C or higher. NMR (200 MHz, DMSO-d6) [delta]: 3.93
(S, 3H), 7.65 to 7.78 (m, 3H), 8.
02 to 8.18 (m, 3H), 8.18 to 8.32
(M, 2H), 8.69 to 8.76 (m, 2H), 9.
79 (br.s, 1H), 13.32 (br.s, 1H)
H).

Production Example 66 2- (4-aminophenyl) -6-cyclohexyloxy-5- (4-pyridylsulfinyl) benzimidazole 2- (4-N-acetylaminophenyl) -6 obtained in Production Example 54 -Cyclohexyloxy-5- (4-pyridylsulfinyl) benzimidazole 0.34 g
(0.00720 mol) in 10 m of 3N hydrochloric acid aqueous solution
and stirred at 80 ° C. for 30 minutes. Thereafter, the reaction solution was neutralized by adding 5 ml of a 6.25 N aqueous sodium hydroxide solution, extracted with ethyl acetate, and washed sequentially with a saturated aqueous ammonium chloride solution and a saturated saline solution. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give 2- (4-aminophenyl) -6-cyclohexyl as a colorless oil. Oxy-5- (4-pyridylsulfinyl) benzimidazole 0.3 g (96
%). NMR (200 MHz, CDCl3) [delta]: 1.20
2.10 (m, 10H), 3.80 to 4.05 (m, 2
H) 4.28-4.40 (m, 1H), 6.73
(D, 2H, J = 8.5 Hz), 7.20 (s, 1
H), 7.68 (d, 2H, J = 5.5 Hz), 7.9
0 (d, 2H, J = 8.5 Hz), 8.11 (s, 1
H), 8.65 (d, 2H, J = 5.5 Hz).

Production Example 67 6-Cyclohexyloxy-2- (4-N-methylaminomethylphenyl) -5- (4-pyridylsulfinyl) benzimidazole 6-cyclohexyloxy-2- obtained in Production Example 60
0.5 g of (4-hydroxymethylphenyl) -5- (4-pyridylsulfinyl) benzimidazole (0.0
0112 mol) was added to 12 ml of dimethylformamide to form a solution.
ml (0.00118 mol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Thereafter, 5 ml of toluene was added to the reaction solution, and toluene and unreacted thionyl chloride were removed under reduced pressure. Dioxane (12 ml) was added to the obtained residue, and methylamine gas (50 ml) was blown into the mixture with stirring, followed by stirring at room temperature for 1 hour. Thereafter, 20 ml of water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 9: 1) to give a colorless oil 6
-Cyclohexyloxy-2- (4-N-methylaminomethylphenyl) -5- (4-pyridylsulfinyl)
0.36 g (70%) of benzimidazole was obtained. NMR (200 MHz, CDCl3) [delta]: 1.10
2.19 (m, 10H), 2.49 (s, 3H),
83 (s, 2H), 4.37 (br.s, 1H), 7.
41 to 7.50 (m, 2H), 7.70 (br.d, 2
H), 7.88 to 8.17 (m, 2H), 8.67 (b
r. d, 2H).

Production Examples 68-72 2- (4-Aminomethylphenyl) -6-cyclohexyloxy-5- (4-pyridylsulfinyl) benzimidazole Compound Instead of the methylamine gas used in Production Example 67, dimethylamine gas was used. By amination using piperidine, morpholine, N-methylpiperazine or N- (diphenylmethyl) piperazine according to the method of Production Example 67, 2- (4-amino) shown in Production Examples 68 to 72 of Table 7 was obtained. Methylphenyl) -6-cyclohexyloxy-5-
(4-Pyridylsulfinyl) benzimidazole compound was obtained.

Production Example 73 6-Cyclohexyloxy-2- [4- {N- (2-hydroxyethyl) aminocarbonyl} phenyl] -5
(4-Pyridylsulfinyl) benzimidazole 6-cyclohexyloxy-2- obtained in Production Example 53
0.3 g of (4-methoxycarbonylphenyl) -5- (4-pyridylsulfinyl) benzimidazole (0.
[000630 mol) and 3 m of 2-ethanolamine were added to 3 ml of methanol to form a solution, and the mixture was stirred under reflux for 5 hours. Thereafter, the reaction solution was returned to room temperature, 10 ml of water was added, extracted with ethyl acetate, and washed with saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate to give colorless crystals of 6-cyclohexyloxy-2- [4- {N- (2-hydroxyethyl) aminocarbonyl} phenyl]-. 0.210 g (66%) of 5- (4-pyridylsulfinyl) benzimidazole was obtained. m. p. 188-191 ° C.

Production Example 74 6-Cyclohexyloxy-2- {4-N-di (hydroxymethyl) methylaminocarbonylphenyl} -5-
(4-Pyridylsulfinyl) benzimidazole By using 1,3-dihydro-2-propylamine in place of 2-ethanolamine used in Production Example 73 and aminating according to the method of Production Example 73, 6 -Cyclohexyloxy-2- {4-N-di (hydroxymethyl) methylaminocarbonylphenyl) -5- (4-
Pyridyl sulfinyl dibenzimidazole was obtained. m. p. 249-250 ° C (recrystallized from ethyl acetate). Structure, melting point and N of the compounds obtained in Production Examples 1 to 74
Tables 3 to 8 show the MR measurement values.

[0073]

[Table 3]

[0074]

[Table 4]

[0075]

[Table 5]

[0076]

[Table 6]

[0077]

[Table 7]

[0078]

[Table 8]

Production Example 75 6-Cyclohexyloxy-2-phenyl-5-methylsulphenylbenzimidazole 1) 4-Cyclohexyloxy-3-fluoronitrobenzene 60% sodium hydride 37.7 g (0.943 mol)
l) was added to 1600 ml of tetrahydrofuran to make a suspension, and 94.4 g (0.9%) of cyclohexanol was added at room temperature.
43 mol) and stirred for 1 hour. Next, 100 g (0.629 mol) of 3,4-difluoronitrobenzene
Was added over 1.5 hours, and the mixture was further stirred for 2.5 hours. Thereafter, the reaction solution was extracted with normal hexane, and the organic layer was washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: normal hexane: ethyl acetate = 50: 1) to give 4-cyclohexyloxy-3 as yellow crystals. -125.8 g (84%) of fluoronitrobenzene were obtained. m. p. 44-45 ° C.

2) 4-Cyclohexyloxy-3-fluoroacetanilide 72.9 g (0.330 mol) of 4-cyclohexyloxy-3-fluoronitrobenzene and 82.9 g of iron powder
(1.484 mol) was added to form a mixture, 140 ml (0.099 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated with stirring at 85 ° C. for 3.5 hours. Thereafter, the reaction solution was returned to room temperature, 200 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. The obtained filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 330 ml of isopropanol was added to the obtained residue to form a solution, 40.4 g (0.396 mol) of acetic anhydride was added under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. Thereafter, 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration.
The crystal was recrystallized from normal hexane to give colorless crystalline 4-cyclohexyloxy-3-fluoroacetanilide 61.8.
g (74.5%). m. p. 123.5-124.5 ° C.

3) 4-Cyclohexyloxy-5-fluoro-2-nitroacetanilide 54.5 g (0.217 mol) of 4-cyclohexyloxy-3-fluoroacetanilide was added to 220 ml of acetic acid to form a solution. 14.3 g (0.
(227 mol) was added over 15 minutes, and the mixture was further stirred for 5 minutes. Thereafter, the reaction solution was returned to room temperature, 300 ml of water was added, the precipitate was collected by filtration, and the obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give 4-cyclohexyloxy-5-fluoro- yellow crystals. 58.7 g (92%) of 2-nitroacetanilide were obtained. m. p. 120-121.5 ° C.

4) 4-Cyclohexyloxy-5-methylsulfenyl-2-nitroaniline 8.7 g (0.0295 mol) of 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide and 1
5% aqueous solution of 5% methyl mercaptan sodium
(0.0439 mol) in isopropyl alcohol 80
The resulting suspension was added to 8.8 ml (0.0152 mol) of a 6.25 N aqueous sodium hydroxide solution, and the suspension was added.
The mixture was heated and stirred at 0 ° C. for 3 hours. Thereafter, the reaction solution was returned to room temperature, 100 ml of water was added, and the precipitate was collected by filtration. This was washed with water and dried, and the obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give orange crystals of 4-cyclohexyloxy-5-methylsulfenyl-2-nitroaniline (8.1 g, 98%). ) Got. m. p. 134-135 ° C.

5) 6-Cyclohexyloxy-5-methylsulfenyl-2-phenylbenzimidazole (Compound of the present invention: Production Example 75) 4-Cyclohexyloxy-5-methylsulfenyl-
1 g (0.00400 mol) of 2-nitroaniline is added to 12 ml of pyridine to form a solution, and 0.646 g (0.00460 mol) of benzoyl chloride is stirred at room temperature.
Was added and stirred for 2 hours. Then, add 12 ml of water to the reaction solution.
And extracted with chloroform. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and a 3N aqueous solution of hydrochloric acid. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.780 g of yellow crystals. The obtained yellow crystals were dissolved in 3.6 ml of acetic acid, and 0.607 g (0.0109 g) of iron powder was dissolved.
mol) was added to form a suspension, and the mixture was stirred at 85 ° C for 15 minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 1.5 hours. Thereafter, the reaction solution was returned to room temperature, 10 ml of water and ethyl acetate were added, and the mixture was filtered through celite and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals. This was purified by silica gel column chromatography (developing solvent: normal hexane: ethyl acetate = 3: 1), and recrystallized from ethanol-normal hexane to give 6-cyclohexyloxy-5-methylsulfenyl-2-colorless crystal. 0.371 g (31%) of phenylbenzimidazole was obtained. m. p. 215.5-216.5 ° C.

Production Example 76 5- (3-chlorophenylsulfenyl) -6-cyclohexyloxy-2-phenylbenzimidazole 1) 5- (3-chlorophenylsulfenyl) -4-cyclohexyloxy-2-nitroaniline Production Example 75 35.1) 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide obtained by the method of 3).
g (0.119 mol) and 18 g (0.124 mol) of 3-chlorothiophenol were added to 350 ml of isopropyl alcohol to form a suspension.
The mixture was heated and stirred at 60 ° C. for 3.5 hours. Thereafter, the reaction solution was returned to room temperature, 300 ml of water was added, and the precipitate was collected by filtration.
This was washed with water, dried, and the obtained crude crystals were recrystallized from isopropanol to give orange-colored 5- (3-chlorophenylsulfenyl) -4-cyclohexyloxy-2-.
43.4 g (97%) of nitroaniline were obtained. m. p. 120-120.5 ° C.

2) 5- (3-Chlorophenylsulfenyl) -6-cyclohexyloxy-2-phenylbenzimidazole (compound of the present invention: Production Example 76) 4-Cyclohexyloxy- used in Production Example 75-5)
Production Example 75-Using 5- (3-chlorophenylsulfenyl) -4-cyclohexyloxy-2-nitroaniline obtained by the method of Production Example 2-1) in place of 5-methylsulfenyl-2-nitroaniline. By acylation, reduction and cyclization according to the method 5), 5- (3-chlorophenylsulfenyl) -6-cyclohexyloxy-2-phenylbenzimidazole was obtained. m. p. 179-181 ° C (recrystallized at).

Production Example 77 5- (3-chlorophenylsulfenyl) -6- (2
4-Difluorophenoxy) -2-phenylbenzimidazole 1) 4- (2,4-difluorophenoxy) -3-fluoronitrobenzene 42 g of 2,4-difluorophenol (0.396 mo
1) and 15.8 g of sodium hydroxide (0.396 mol
l) was added to 775 ml of water to form a solution, 51.5 g (0.264 mol) of 3,4-difluoronitrobenzene was added, and the mixture was heated under reflux for 2 hours. Thereafter, the reaction solution was returned to room temperature and extracted with toluene. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4- (2,4-difluorophenoxy) -3- as yellow crystals.
56.2 g (83%) of fluoronitrobenzene were obtained. m. p. 40.5-41.5 ° C.

2) 4- (2,4-Difluorophenoxy) -3-fluoroacetanilide Iron powder 60 was added to 64 g (0.239 mol) of 4- (2,4-difluorophenoxy) -3-fluoronitrobenzene.
g (1.07 mol) was added to make a mixture, 71 ml (0.0717 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was stirred at 85 ° C. for 1 hour. Thereafter, the reaction solution was returned to room temperature, 360 ml of isopropanol was added, and insolubles were removed by filtration through celite. Acetic anhydride 29.7m was added to the obtained filtrate.
was added and stirred at room temperature for 10 minutes. Thereafter, 1000 ml of water was added to the reaction solution, and the precipitate was collected by filtration. This was washed with water and normal hexane, dried and dried to give colorless crystals of 4-.
65.5 g (98%) of (2,4-difluorophenoxy) -3-fluoroacetanilide were obtained. m. p. 117-118 ° C.

3) 4- (2,4-Difluorophenoxy) -5-fluoro-2-nitroacetanilide 65 g (0.231 mol) of 4- (2,4-difluorophenoxy) -3-fluoroacetanilide was added to acetic acid 23.
0 g, and 16 g of fuming nitric acid (0.
(254 mol) was added slowly and stirred for 1 hour. Thereafter, the reaction solution was returned to room temperature, 800 ml of water was added, and the precipitate was collected by filtration. This is washed with water and dried to obtain 4 yellow crystals.
-(2,4-difluorophenoxy) -5-fluoro-
66.0 g (88%) of 2-nitroacetanilide were obtained. m. p. 130.5-132 ° C.

4) 5- (3-chlorophenylsulfenyl) -4- (2,4-difluorophenoxy) -2-nitroaniline 3 g of 4- (2,4-difluorophenoxy) -5-fluoro-2-nitroacetanilide (0.0114mo
l) and 1.8 g (0.01 g) of 3-chlorothiophenol
25 mol) was added to 37 ml of isopropanol to form a suspension, and 4.1 m of a 6.25 N aqueous sodium hydroxide solution was added.
1 (0.023 mol) was added, and the mixture was stirred at 60 ° C. for 1 hour. Thereafter, the reaction solution was returned to room temperature, and 20 ml of water was added.
The precipitate was collected by filtration. This was washed with water, and the resulting crude crystals were recrystallized from ethyl acetate-normal hexane to give orange-colored 5- (3-chlorophenylsulfenyl) -4-.
4.03 g (86%) of (2,4-difluorophenoxy) -2-nitroaniline were obtained. m. p. 107-108 ° C.

5) 5- (3-chlorophenylsulfenyl) -6- (2,4-difluorophenoxy) -2-phenylbenzimidazole (compound of the present invention: Production Example 7)
7) 5- (3-chlorophenylsulfenyl) -4- (2,
4-Difluorophenoxy) -2-nitroaniline
5 g (0.00122 mol) and pyridine 0.25 m
of benzoyl chloride 0.182 g (0.00128 mol) with stirring.
Was added and stirred at room temperature for 6 hours. Thereafter, the reaction solution was returned to room temperature, and washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.539 g of yellow crystals. The obtained yellow crystals were dissolved in 2 ml of acetic acid, and 0.349 g (0.00624 mol) of iron powder was added to form a suspension, followed by stirring at 85 ° C. for 10 minutes. Thereafter, ethanol was added, the mixture was filtered through celite, and the solvent was removed under reduced pressure. 10 ml of toluene was added to the obtained residue to form a solution, and 0.06 g of paratoluenesulfonic acid monohydrate was added.
(0.000312 mol), and the mixture was stirred under reflux for 6 hours using a Gene Stark apparatus. Thereafter, the reaction solution was returned to room temperature, 10 ml of water was added, and the mixture was extracted with ethyl acetate. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give colorless crystals of 5- (3-chlorophenylsulfenyl) -6- (2,4 0.243 g (48%) of (-difluorophenoxy) -2-phenylbenzimidazole were obtained. m. p. 161-162 ° C.

Production Example 78 3- {4- (2-carboxyethylphenyl) sulfenyl} -6-methoxy-2-phenylbenzimidazole 60% sodium hydride 32.0 g (0.801 mol
l) was added to 530 ml of methanol to form a solution, and 85.0 g (0.5%) of 3,4-difluoronitrobenzene was added under ice cooling.
34 mol) over 0.5 hours, and further added at room temperature for 2 hours.
Stirred for hours. Thereafter, 500 ml of water was added to the reaction solution,
The precipitate was collected by filtration. This was washed with water and dried to obtain yellow crystals. 237.0 g of iron powder was added to the obtained yellow crystals (4.2
4 mol) to obtain a mixture, 160 ml (0.16 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated at 85 ° C.
For 50 minutes. After the reaction solution was cooled to 50 ° C., 500 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. Triethylamine 5 was added to the obtained filtrate at room temperature.
3.6 g (0.53 mol) were added, and acetic anhydride 54.1 was added.
g (0.53 mol) is added over 20 minutes, and another 20
Stirred for minutes. Thereafter, the reaction solution was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain colorless crystals. The obtained colorless crystals were treated with acetic acid (530 m).
to 33.4 g of fuming nitric acid at 60 ° C.
(0.53 mol) was added over 20 minutes, and the mixture was further stirred for 20 minutes. Thereafter, the reaction solution is returned to room temperature, and water 750 is added.
Then, the precipitate was collected by filtration. This was washed with water and dried to obtain 37.9 g of yellow crystals. 4 g of the obtained yellow crystals
And 4-mercaptohydrocinamic acid 2.7
7 g (0.0152 mol) of isopropanol 40 m
5.8 ml (0.0289 mol) of a 6.25 N aqueous sodium hydroxide solution,
The mixture was heated and stirred at ℃ for 3 hours. Thereafter, the reaction solution was returned to room temperature, 20 ml of water was added, and the precipitate was collected by filtration. This was washed with water and dried to obtain 7.11 g of yellow crystals. The obtained yellow crystals were dissolved in 70 ml of acetic acid, and 5.1 g of iron powder (0.1 g) was dissolved.
0928 mol) to give a suspension,
Stirred for minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 2 hours. Thereafter, the reaction solution was returned to room temperature, 10 ml of water and ethyl acetate were added thereto, and the mixture was filtered through celite, extracted with ethyl acetate, and washed with water. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from dimethylsulfoxide-water to give 5- {4-
(2-carboxyethylphenyl) sulfenyl} -6
-Methoxy-2-phenylbenzimidazole 4.30
g (77%). m. p. Measurement not possible. NMR (200 MHz, DMSO-d6) δ: 2.55
(T, 3H, J = 7 Hz), 2.85 (t, 2H, J =
7 Hz), 3.90 (s, 3H), 7.22 to 7.40
(M, 4H), 7.06 (s, 1H), 7.25 (s,
1H), 7.47 to 7.72 (m, 3H), 8.09 to
8.25 (m, 2H).

Production Example 79 5- [4- {2- (4-diphenylmethylpiperazinocarbonyl) ethyl} phenylsulfenyl] -6-methoxy-2-phenylbenzimidazole 5- {obtained in Production Example 78 4- (2-carboxyethylphenyl) sulfenyl {-6-methoxy-2-phenylbenzimidazole 1 g (0.00247 mol)
And 1-diphenylmethylpiperazine 0.623 g
(0.00247 mol) was added to 30 ml of chloroform to form a solution.
507 g (0.00264 mol) was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, 10 ml of water and 0.5 ml of a 6.25 N aqueous sodium hydroxide solution were added, extracted with chloroform, and washed with water. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (chloroform: methanol 10: 1).
To give 1.05 g (67%) of 5- [4- {2- (4-diphenylmethylpiperazinocarbonyl) ethyl} phenylsulfenyl] -6-methoxy-2-phenylbenzimidazole as a brown oil. Obtained. NMR (200 MHz, CDCl3) [delta]: 2.58
(T, 2H, J = 7 Hz), 2.93 (t, 2H, J =
7 Hz), 3.35 to 3.50 (m, 4H), 3.52
-3.68 (m, 4H), 3.90 (s, 3H), 7.
05 to 7.55 (m, 21H), 7.92 to 8.03
(M, 2H).

Production Example 80 6-Cyclohexyloxy-2-phenyl-5-methylsulfinylbenzimidazole 6-Cyclohexyloxy-5-methylsulfenyl-2-phenylbenzimidazole obtained by the method of Production Example 75-5). 2 g (0.00591 mol) was added to 2 ml of chloroform to form a solution, and 0.107 g (0.00621 mol) of metachloroperbenzoic acid was gradually added at 0 ° C. with stirring, followed by stirring for 30 minutes. Thereafter, 4 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and washed with saturated saline. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform: methanol 10: 1) to give a brown oily substance, 6-cyclohexyloxy-2-phenyl-5-methyl. 0.210 g (93%) of sulfinylbenzimidazole was obtained. NMR (200 MHz, CDCl3) [delta]: 1.25-1.25
2.15 (m, 10H), 2.87 (s, 3H), 4.
32 to 4.48 (m, 1H), 7.31 (br.s, 1
H), 7.51 (s, 1H), 7.42 to 7.62.
(M, 2H), 8.20 to 8.31 (m, 2H), 8.
42 (s, 1H), 12.32 (br.s, 1H).

Preparation Examples 81 to 84 2-Phenyl-5-sulfinylbenzimidazole compound The method of Preparation Examples 76 to 79 in place of 6-cyclohexyloxy-5-methylsulfenyl-2-phenylbenzimidazole used in Preparation Example 80 5- (3-chlorophenylsulfenyl) -6-cyclohexyloxy-2-phenylbenzimidazole, 5- (3-chlorophenylsulfenyl) -6- (2,4-difluorophenoxy) -2-phenylbenzimidazole obtained in , 5-
{4- (2-carboxyethylphenyl) sulfenyl} -6-methoxy-2-phenylbenzimidazole or 5- [4- {2- (4-diphenylmethylpiperazinocarbonyl) ethyl} phenylsulfenyl] -6
Using -methoxy-2-phenylbenzimidazole,
Oxidation was carried out according to the method of Production Example 80, and Production Example 81 of Table 1 was produced.
The 2-phenyl-5-sulfinylbenzimidazole compounds shown in Nos. To 84 were obtained.

Production Example 85 5- [4- {2- (4-diphenylmethylpiperazinocarbonyl) ethyl} phenylsulfenyl] -6-methoxy-2-phenylbenzimidazole dihydrochloride obtained by the method of Production Example 79. 0.31 g (0.000473 mol) of 5- [4- {2- (4-diphenylmethylpiperazinocarbonyl) ethyl} phenylsulfenyl] -6-methoxy-2-phenylbenzimidazole was added to 6 ml of ethyl acetate. The solution was slowly added with 0.26 ml (0.00104 mol) of a 4N hydrochloric acid ethyl acetate solution,
Stir for 30 minutes. Thereafter, the precipitated crystals were collected by filtration and washed sequentially with ethyl acetate and normal hexane to give colorless crystals of 5- [4- {2- (4-diphenylmethylpiperazinocarbonyl) ethyl} phenylsulfenyl] -6-. Methoxy-2-phenylbenzimidazole dihydrochloride
31 g (95%) were obtained. m. p. Measurement not possible. NMR (200 MHz, DMSO-d6) δ: 2.55
~ 4.40 (m, 12H), 3.90 (s, 3H),
5.50 (s, 1H), 7.20 to 7.50 (m, 10
H), 7.58 to 7.65 (m, 2H), 7.65 to
7.72 (m, 3H), 7.90 (br.d, 3H, J
= 7 Hz), 8.10 (s, 1H), 8.26 to 8.3
5 (m, 2H), 12.48 (br.s, 1H).

Preparation Example 86 6-Cyclohexyloxy-2-phenyl-5-methylsulfonylbenzimidazole 6-Cyclohexyloxy-5 obtained by the method of Preparation Example 80
0.15 g (0.000330 mol) of -methylsulfinyl-2-phenylbenzimidazole was added to 10 ml of chloroform to form a solution, and 0.17 g (0.0099090 mol) of metachloroperbenzoic acid was added at 0 ° C with stirring, followed by stirring for 30 minutes. did. Thereafter, 10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, extracted with chloroform, and washed with saturated saline. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give colorless crystals of 6-cyclohexyloxy-2-phenyl-5-methylsulfonylbenzimidazole. 094 g (61%) were obtained. m. p. Unmeasurable NMR (200 MHz, CDCl3) δ: 1.18-
1.93 (m, 10H), 4.19 (m, 1H), 7.
11 (s, 1H), 7.33 to 8.12 (m, 9H),
8.42 (s, 1H) Structural formula, melting point, N of the compounds obtained in Production Examples 81 to 84
Table 9 shows the MR measurement values.

[0097]

[Table 9]

Production Example 87 2-benzyl-6-methoxy-5-methylsulphenylbenzimidazole 1) 5-fluoro-4-methoxy-2-nitroacetanilide 60% sodium hydride 32.0 g (0.801 mol)
l) was added to 530 ml of methanol to form a solution, and 85.0 g (0.5%) of 3,4-difluoronitrobenzene was added under ice cooling.
34 mol) over 0.5 hours, and further added at room temperature for 2 hours.
Stirred for hours. Thereafter, 500 ml of water was added to the reaction solution,
The precipitate was collected by filtration. This was washed with water and dried to obtain yellow crystals. 237.0 g of iron powder was added to the obtained yellow crystals (4.2
4 mol) to obtain a mixture, 160 ml (0.16 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated at 85 ° C.
For 50 minutes. After the reaction solution was cooled to 50 ° C., 500 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. Triethylamine 5 was added to the obtained filtrate at room temperature.
3.6 g (0.53 mol) were added, and acetic anhydride 54.1 was added.
g (0.53 mol) is added over 20 minutes, and another 20
Stirred for minutes. Thereafter, the reaction solution was washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain colorless crystals. The obtained colorless crystals were treated with acetic acid (530 m).
to 33.4 g of fuming nitric acid at 60 ° C.
(0.53 mol) was added over 20 minutes, and the mixture was further stirred for 20 minutes. Thereafter, the reaction solution is returned to room temperature, and water 750 is added.
Then, the precipitate was collected by filtration. This was washed with water and dried to obtain 104 g (85%) of 5-fluoro-4-methoxy-2-nitroacetanilide as yellow crystals. m. p. 166-168 ° C.

2) 4-methoxy-5-methylsulfenyl-2-nitroaniline 3.0 g (0.013 mol) of 5-fluoro-4-methoxy-2-nitroacetanilide was added to isopropanol 5
The solution was added to 0 ml to make a solution, 7.5 ml (0.016 mol) of a 15% aqueous solution of methyl mercaptan and 3.2 ml of a 6.25 N aqueous solution of sodium hydroxide were added, and the mixture was heated with stirring at 60 ° C. for 2 hours. Thereafter, the reaction solution was returned to room temperature, and the precipitate was collected by filtration, washed with water, and dried to give 4-methoxy-5-methylsulfenyl-2-methyl orange.
2.9 g (98%) of nitroaniline were obtained. m. p. 174-176 ° C.

3) 2-benzyl-6-methoxy-5-methylsulfenylbenzimidazole (compound of the present invention: Production Example 87) 1 g (0.00470 mol) of 4-methoxy-5-methylsulfenyl-2-nitroaniline And pyridine 0.
6 ml (0.00700 mol) of chloroform 20 m
and phenylacetyl chloride (0.00105 g, 0.00700 mol) was added thereto at room temperature with stirring, and the mixture was stirred for 10 hours. Then, add 20 ml of water to the reaction solution.
And extracted with chloroform. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and a 3N aqueous solution of hydrochloric acid. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 0.950 g of yellow crystals. Acetic acid 3
Dissolve in 0ml, iron powder 0.880g (0.0157mo
l) was added to form a suspension, and the mixture was stirred at 85 ° C for 15 minutes. Thereafter, the temperature was raised to 110 ° C., and the mixture was further stirred for 3 hours.
Thereafter, the reaction solution was returned to room temperature, water and chloroform were added in 30 ml portions, and the mixture was filtered through celite and extracted with chloroform. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude crystals. This was recrystallized from acetone to give colorless crystals of 2-benzyl-6-methoxy-5-methylsulfenylbenzimidazole 0.240 g (19%).
I got m. p. 142-143 ° C.

Production Example 88 2-Benzyl-6-methoxy-5- (4-pyridylsulfenyl) benzimidazole 1) 4-Methoxy-2-nitro-5- (4-pyridylsulfenyl) aniline Production Example 87-1 53.5 g (0.18 g) of 5-fluoro-4-methoxy-2-nitroacetanilide obtained by the method of (1).
1 mol) and 24.1 g of 4-mercaptopyridine
(0.217 mol) was added to 360 ml of isopropanol to form a suspension, and 100 ml (0.682 mol) of a 6.8 N aqueous sodium hydroxide solution was added.
The mixture was heated and stirred for an hour. Thereafter, the reaction solution was returned to room temperature, 500 ml of water was added, and the precipitate was collected by filtration. This was washed with water and dried to give 4-methoxy-2-nitro-5 as orange crystals.
-(4-pyridylsulfenyl) aniline 44.8 g
(72%). m. p. 199-201 ° C

2) 2-benzyl-6-methoxy-5
(4-pyridylsulfenyl) benzimidazole (compound of the present invention: Production Example 88) 4-methoxy-2 is used instead of 4-methoxy-5-methylsulfenyl-2-nitroaniline used in Production Example 87-3). The acylation, reduction and cyclization of -nitro-5- (4-pyridylsulfenyl) aniline according to the method of Production Example 87-3) to give 2-benzyl-6-
Methoxy-5- (4-pyridylsulfenyl) benzimidazole was obtained. m. p. 176-178 ° C (recrystallized with ethyl acetate-normal hexane).

Production Example 89 2-Benzyl-6-isopropyloxy-5- (4-pyridylsulfenyl) benzimidazole 1) 5-Fluoro-4-isopropyloxy-2-nitroacetanilide Used in Production Example 87-1) Etherification, reduction, acetylation, and nitration were performed according to the method of Production Example 87-1) using isopropanol instead of methanol to obtain 5-fluoro-4-isopropyloxy-2-nitroacetanilide. . m. p. 69-70 ° C.

2) 4-Isopropyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline Instead of 5-fluoro-4-methoxy-2-nitroacetanilide used in Production Example 88-1), 5- Fluoro-
4-isopropyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline was converted into thioether using 4-isopropyloxy-2-nitroacetanilide according to the method of Production Example 88-1). Obtained. m. p. 134.5-136 ° C.

3) 2-Benzyl-6-isopropyloxy-5- (4-pyridylsulfenyl) benzimidazole (compound of the present invention: Production Example 89) 4-methoxy-5 used in Production Example 87-3) Using 4-isopropyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline instead of methylsulfenyl-2-nitroaniline, acylation / reduction / By cyclization, 2-benzyl-6-isopropyloxy-5- (4-pyridylsulfenyl) benzimidazole was obtained. NMR (200 MHz, CDCl3) [delta]: 1.17
(D, 6H, J = 6 Hz), 4.29 (s, 2H),
4.46 (m, 1H), 6.90 (m, 2H), 7.2
0 to 7.45 (m, 5H), 7.50 (br.s, 1 /
2H), 7.92 (br.s, 1 / 2H), 8.26
(M, 2H).

Production Example 90 2-Benzyl-6-cyclohexyloxy-5-cyclohexylsulfenylbenzimidazole 1) 4-Cyclohexyloxy-3-fluoronitrobenzene 60% sodium hydride 37.7 g (0.943 mo)
l) was added to 1600 ml of tetrahydrofuran to make a suspension, and 94.4 g (0.9%) of cyclohexanol was added at room temperature.
43 mol) and stirred for 1 hour. Next, 100 g (0.629 mol) of 3,4-difluoronitrobenzene
Was added over 1.5 hours, and the mixture was further stirred for 2.5 hours. Thereafter, the reaction solution was extracted with normal hexane, and the organic layer was washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: normal hexane: ethyl acetate = 50: 1) to give 4-cyclohexyloxy-3 as yellow crystals. -125.8 g (84%) of fluoronitrobenzene were obtained. m. p. 44-45 ° C.

2) 4-Cyclohexyloxy-3-fluoroacetanilide 72.9 g (0.330 mol) of 4-cyclohexyloxy-3-fluoronitrobenzene and 82.9 g of iron powder
(1.484 mol) was added to form a mixture, 140 ml (0.099 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated with stirring at 85 ° C. for 3.5 hours. Thereafter, the reaction solution was returned to room temperature, 200 ml of ethyl acetate was added, and insolubles were removed by filtration through celite. The obtained filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 330 ml of isopropanol was added to the obtained residue to form a solution, 40.4 g (0.396 mol) of acetic anhydride was added under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. Thereafter, 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration.
The crystal was recrystallized from normal hexane to give colorless crystalline 4-cyclohexyloxy-3-fluoroacetanilide 61.8.
g (74.5%). m. p. 123.5-124.5 ° C.

3) 4-Cyclohexyloxy-5-fluoro-2-nitroacetanilide 54.5 g (0.217 mol) of 4-cyclohexyloxy-3-fluoroacetanilide was added to 220 ml of acetic acid to form a solution. 14.3 g (0.
(227 mol) was added over 15 minutes, and the mixture was further stirred for 5 minutes. Thereafter, the reaction solution was returned to room temperature, 300 ml of water was added, the precipitate was collected by filtration, and the obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give 4-cyclohexyloxy-5-fluoro- yellow crystals. 58.7 g (92%) of 2-nitroacetanilide were obtained. m. p. 120-121.5 ° C.

4) 4-Cyclohexyloxy-5-cyclohexylsulfenyl-2-nitroaniline Instead of 5-fluoro-4-methoxy-2-nitroacetanilide used in Production Example 88-1), 4-cyclohexyloxy-5 was used. -Fluoro-2-nitroacetanilide was thioetherified according to the method of Production Example 88-1) using cyclohexylmercaptan instead of 4-mercaptopyridine to give 4-cyclohexyloxy-5-cyclohexylsulfenyl. -2
-Nitroaniline was obtained. m. p. 123.5-124 ° C (recrystallized from isopropanol).

5) 2-Benzyl-6-cyclohexyloxy-5-cyclohexylsulfenylbenzimidazole (Compound of the present invention: Production Example 90) 4-methoxy-5-methylsulfenyl- used in Production Example 87-3) 4-cyclohexyloxy-5-cyclohexylsulfenyl-2 instead of 2-nitroaniline
-Nitroaniline was used for acylation, reduction and cyclization according to the method of Production Example 87-3) to give 2-benzyl-6-cyclohexyloxy-5-cyclohexylsulfenylbenzimidazole. NMR (200 MHz, CDCl3) [delta]: 1.20
2.18 (m, 20H), 3.20 (m, 1H), 4.
22 (s, 2H), 4.22 (m, 1H), 7.00
(Br.s, 1H), 7.26 to 7.41 (m, 5
H), 7.52 (br.s, 1H).

Production Example 91 5- (3-chlorophenylsulfenyl) -6-cyclohexyloxy-2-normalhexylbenzimidazole 1) Production Example of 5- (3-chlorophenylsulfenyl) -4-cyclohexyloxy-2-nitroaniline 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide in place of 5-fluoro-4-methoxy-2-nitroacetanilide used in 88-1), and 3-chlorothiophenol in place of 4-mercaptopyridine Each was used and thioetherified according to the method of Production Example 2-1) to give 5- (3-chlorophenylsulfenyl) -4-cyclohexyloxy-2-nitroaniline. m. p. 120-120.5 ° C (recrystallized with isopropanol).

2) 5- (3-chlorophenylsulfenyl) -6-cyclohexyloxy-2-normalhexylbenzimidazole (compound of the present invention: Production Example 91) 4-methoxy-5 used in Production Example 87-3) 5- (3-) instead of -methylsulfenyl-2-nitroaniline
By using chlorophenylsulfenyl) -4-cyclohexyloxy-2-nitroaniline for acylation, reduction and cyclization according to the method of Production Example 87-3),
5- (3-Chlorophenylsulfenyl) -6-cyclohexyloxy-2-normalhexylbenzimidazole was obtained. m. p. 74-75 ° C (recrystallized from diethyl ether-normal hexane).

Production Example 92 6-Cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole 1) 4-Cyclohexyloxy-2-nitro-5- (4
-Pyridylsulfenyl) aniline Instead of 5-fluoro-4-methoxy-2-nitroacetanilide used in Production Example 88-1), 5-fluoro-
4-cyclohexyloxy-2-nitroacetanilide was thioetherified according to the method of Production Example 88-1) to give 4-cyclohexyloxy-2-nitroacetanilide.
Nitro-5- (4-pyridylsulphenyl) aniline was obtained. m. p. 87-89 ° C

2) 6-cyclohexyloxy-5- (4
-Pyridylsulfenyl) benzimidazole (Compound of the present invention: Production Example 92) 1 g of 4-cyclohexyloxy-2-nitro-5- (4-pyridylsulfenyl) aniline (0.00289 m
ol) and 1.94 g (0.0347 mol) of iron powder were added to form a mixture, and 0.8N aqueous 1N ammonium chloride solution was added.
ml (0.00870 mol) and a small amount of isopropanol were added, and the mixture was heated and stirred at 85 ° C. for 30 minutes. Thereafter, the reaction solution was returned to room temperature, and 10 ml of ethyl acetate was added.
After filtration through celite, the solvent was removed under reduced pressure to obtain an oily substance.
0.158 g (0.001 g) of triethyl orthoformate
07 mol), and the mixture was heated and stirred at 100 ° C. for 3 hours. Thereafter, the reaction solution was returned to room temperature, 5 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order. This was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) to give a yellow oily substance, 6-cyclohexyloxy-5- (4-pyridylsulfur). 0.433 g of phenyl) benzimidazole (46
%). NMR (200 MHz, CDCl3) [delta]: 1.12
1.80 (m, 10H), 4.41 (br.s, 1
H), 6.93 (br.d, 2H, J = 4.5 Hz),
7.32 (br.s, 1H), 7.81 (br.s, 1H)
H), 8.23 (s, 1H), 8.28 (br.d, 2
H, J = 4.5 Hz).

Production Example 93 6-Cyclohexyloxy-2-methyl-5- (4-pyridylsulfenyl) benzimidazole Preparation of 4-methoxy-5-methylsulfenyl-2-nitroaniline used in Production Example 87-3) Production Example 92 instead
4-cyclohexyloxy-2-nitro- obtained in -1)
5- (4-pyridylsulfenyl) aniline is acylated, reduced, and cyclized according to the method of Production Example 87-3) using acetyl chloride instead of phenylacetyl chloride to give 6-cyclohexyl. Oxy-2-methyl-5- (4-pyridylsulfenyl) benzimidazole was obtained. NMR (200 MHz, CDCl3) [delta]: 1.08-
1.87 (m, 10H), 2.60 (s, 3H), 4.
22 (br.s, 1H), 6.92 (br.d, 2H,
J = 5.5 Hz), 7.11 (br.s, 1H), 7.
72 (br.s, 1H), 8.27 (br.d, 2H,
J = 5.5 Hz).

Production Example 94 2-benzyl-6-cyclohexyloxy-5- (4-
Pyridylsulfenyl) benzimidazole Preparation Example 92 in place of 4-methoxy-5-methylsulfenyl-2-nitroaniline used in Preparation Example 87-3)
4-cyclohexyloxy-2-nitro- obtained in -1)
By using 5- (4-pyridylsulfenyl) aniline for acylation, reduction and cyclization according to the method of Production Example 87-3), 2-benzyl-6-cyclohexyloxy-5- (4- Pyridylsulfenyl) benzimidazole was obtained. m. p. 157 to 159 ° C (recrystallized from ethyl acetate-normal hexane).

Production Example 95 6-Cyclohexyloxy-2-phenethyl-5- (4
-Pyridylsulfenyl) benzimidazole Production Example 92 in place of 4-methoxy-5-methylsulfenyl-2-nitroaniline used in Production Example 87-3)
4-cyclohexyloxy-2-nitro- obtained in -1)
5- (4-pyridylsulfenyl) aniline is acylated, reduced and cyclized using 2-phenylpropionyl chloride in place of phenylacetyl chloride according to the method of Production Example 1-3) to give 6 -Cyclohexyloxy-2-phenethyl-5- (4-pyridylsulphenyl) benzimidazole was obtained. m. p. 131.5-132 ° C (recrystallized with ethyl acetate-normal hexane).

Production Example 96 2- (4-N-acetylpiperidinyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole 4-methoxy-5 used in Production Example 87-3) Production Example 92 instead of methylsulfenyl-2-nitroaniline
4-cyclohexyloxy-2-nitro- obtained in -1)
Acylation, reduction and cyclization of 5- (4-pyridylsulfenyl) aniline using 4-N-acetylpiperidinecarbonyl chloride instead of phenylacetyl chloride according to the method of Production Example 87-3). Thereby 2
-(4-N-Acetylpiperidinyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole was obtained. NMR (200 MHz, CDCl3) [delta]: 1.20
2.20 (m, 10H), 2.18 (s, 3H),
27 (t, 2H, J = 12 Hz), 3.82 (t, 2
H, J = 12 Hz), 3.98 (d, 2H, J = 12H)
z), 4.22 (m, 1H), 4.66 (d, 2H, J
= 12 Hz), 6.94 (d, 2H, J = 6 Hz),
7.20 (br.s, 1H), 7.70 (br.s, 1H)
H), 8.26 (d, 2H, J = 6 Hz).

Production Example 97 2-Benzyl-6-cyclohexyloxy-5-ethoxycarbonylmethylsulfenylbenzimidazole 1) 4-Cyclohexyloxy-5-ethoxycarbonylmethylsulfenyl-2-nitroaniline Production Example 88-1) Instead of the 5-fluoro-4-methoxy-2-nitroacetanilide used, 5-fluoro-
4-cyclohexyloxy-2-nitroacetanilide was thioetherified according to the method of Production Example 88-1) using ethyl thioglycolate instead of 4-mercaptopyridine to give 4-cyclohexyloxy-5. -Ethoxycarbonylmethylsulfenyl-2-nitroaniline was obtained. m. p. 106.5 to 109 ° C (recrystallized from ethyl acetate-normal hexane).

2) 2-benzyl-6-cyclohexyloxy-5-ethoxycarbonylmethylsulfenylbenzimidazole (compound of the present invention: Production Example 97) 4-methoxy-5-methylsulfur used in Production Example 87-3) Production Example 87-3) using 4-cyclohexyloxy-5-ethoxycarbonylmethylsulfenyl-2-nitroaniline instead of phenyl-2-nitroaniline.
Acylation, reduction and cyclization were performed according to the method described above to give 2-benzyl-6-cyclohexyloxy-5-ethoxycarbonylmethylsulfenylbenzimidazole. NMR (200 MHz, CDCl3) [delta]: 1.16
(T, 3H, J = 7 Hz), 1.25 to 2.05 (m,
10H), 3.64 (s, 3H), 4.10 (q, 2
H, J = 7 Hz), 4.19 (s, 2H), 4.28
(M, 1H), 7.02 (s, 1H), 7.20-7.
40 (m, 5H), 7.53 (s, 1H).

Production Example 98 2-benzyl-6-cyclohexyloxy-5-carboxymethylsulfenylbenzimidazole 2-benzyl-6-cyclohexyloxy-5-ethoxycarbonyl which is the compound of the present invention obtained by the method of Production Example 97 Methylsulfenylbenzimidazole 1.1 g
(0.00260 mol) in 6 ml of tetrahydrofuran
The solution was dissolved in 3 ml of ethanol to give a solution, and 3 ml (0.003 mol) of a 1 N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 5 minutes. Thereafter, 2 ml of a 3N hydrochloric acid aqueous solution was added to neutralize the mixture, 10 ml of water was added, and the aqueous layer was removed by decantation to obtain a precipitated oily substance. Ethyl acetate (10 ml) was added thereto, and the mixture was gently heated to form a solution, cooled to room temperature, and the precipitated crystals were filtered to obtain colorless crystals. This was washed with ethyl acetate, and 0.62 g of 2-benzyl-6-cyclohexyloxy-5-carboxymethylsulfenylbenzimidazole as colorless crystals was obtained.
(60%). m. p. 204-205 ° C (washed with ethyl acetate).

Production Example 99 2-benzyl-5-cyclohexylsulfenyl-6-
(3-Fluorophenoxy) benzimidazole 1) 25 g (0.223 mol) of 4- (3-fluorophenoxy) -2-nitroacetanilide 3-fluorophenol and 8.9 g (0.223 mol) of sodium hydroxide were added to 450 ml of water. Then, 23.7 g (0.149 mol) of 3,4-difluoronitrobenzene was added, and the mixture was heated and refluxed for 2 hours with stirring. Thereafter, the reaction solution was returned to room temperature and extracted with toluene. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain yellow crystals. 68.1 g of iron powder was added to the obtained yellow crystals.
(1.218 mol) was added to form a mixture, 38 ml (0.038 mol) of a 1 N aqueous ammonium chloride solution was added, and the mixture was heated with stirring at 85 ° C. for 45 minutes. Reaction solution at 50 ° C
After cooling to room temperature, 130 ml of isopropanol was added, and insolubles were removed by filtration through Celite. 260 ml of isopropanol was further added to the obtained filtrate, and acetic anhydride 14.3 was added at room temperature.
g (0.140 mol) was added over 3 minutes, and the mixture was further stirred for 7 minutes. Thereafter, 650 ml of water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated saline. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain colorless crystals. The obtained colorless crystals were added to 100 ml of acetic acid to form a solution, and 6.5 g of fuming nitric acid was added at 60 ° C. (0.104 mol).
l) was added over 20 minutes and stirred for a further 45 minutes. Thereafter, the reaction solution was returned to room temperature, 200 ml of water was added, and the precipitate was collected by filtration. This was washed with water and dried to give 5-fluoro-4- (3-fluorophenoxy) -2-yellow crystals.
25.7 g (84%) of nitroacetanilide were obtained. m. p. 116-118 ° C (recrystallized from dichloromethane-normal hexane).

2) 5-Cyclohexylsulfenyl-4
-(3-Fluorophenoxy) -2-nitroaniline Instead of 5-fluoro-4-methoxy-2-nitroacetanilide used in Production Example 88-1), 5-fluoro-
Production Example 88-1) using 4- (3-fluorophenoxy) -2-nitroacetanilide and cyclohexylmercaptan instead of 4-mercaptopyridine.
By thioetherification according to the method of 5-
Cyclohexylsulfenyl-4- (3-fluorophenoxy) -2-nitroaniline was obtained. m. p. 159.5-160.5 ° C (recrystallized from isopropanol-water).

3) 2-Benzyl-5-cyclohexylsulfenyl-6- (3-fluorophenoxy) benzimidazole (compound of the present invention: Production Example 99) 4-methoxy-5 used in Production Example 87-3) According to the method of Production Example 87-3), 5-cyclohexylsulfenyl-4- (3-fluorophenoxy) -2-nitroaniline was used in place of methylsulfenyl-2-nitroaniline, and acylation, reduction, By cyclizing,
2-benzyl-5-cyclohexylsulphenyl-6-
(3-Fluorophenoxy) benzimidazole was obtained. m. p. 157 to 159 ° C (recrystallized from ethyl acetate).

Production Example 100 2-benzyl-6-methoxy-5-methylsulfinylbenzimidazole 2-benzyl-6-methoxy-5-methylsulfenylbenzimidazole obtained by the method of Production Example 88-2).
175 g (0.00600 mol) of chloroform 10
Then, 0.12 g (0.000680 mol) of metachloroperbenzoic acid was gradually added at 0 ° C. with stirring, and the mixture was stirred for 1 hour. Thereafter, 10 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction solution, extracted with chloroform, and washed with saturated saline. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate-normal hexane to give colorless crystals of 2-benzyl-6-methoxy-5-methylsulfinylbenzimidazole 0.1%. 100 g (49%) were obtained. m. p. 115-117 ° C.

Production Examples 101 to 112 5-Methylsulfinylbenzimidazole compound 2-benzyl-6-methoxy-5 used in Production Example 100
2-benzyl-6-methoxy-5- (4-pyridylsulfenyl) benzimidazole, 2-benzyl-6-isopropyloxy-5-, obtained by the method of Preparation Examples 88-99, instead of -methylsulfenylbenzimidazole
(4-pyridylsulfenyl) benzimidazole, 2
-Benzyl-6-cyclohexyloxy-5-cyclohexylsulfenylbenzimidazole, 5- (3-chlorophenylsulfenyl) -6-cyclohexyloxy-2-normalhexylbenzimidazole, 6-cyclohexyloxy-5- (4-pyridylsulfur Phenyl) benzimidazole, 6-cyclohexyloxy-
2-methyl-5- (4-pyridylsulfenyl) benzimidazole, 2-benzyl-6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole, 6-cyclohexyloxy-2-phenethyl-5
-(4-pyridylsulfenyl) benzimidazole,
2- (4-N-acetylpiperidinyl) -6-cyclohexyloxy-5- (4-pyridylsulfenyl) benzimidazole, 2-benzyl-6-cyclohexyloxy-5-ethoxycarbonylmethylsulfenylbenzimidazole, 2 Oxidation using -benzyl-6-cyclohexyloxy-5-carboxymethylsulfenylbenzimidazole or 2-benzyl-6- (3-fluorophenoxy) -5-cyclohexylsulfenylbenzimidazole according to the method of Production Example 100 And
The 5-methylsulfinylbenzimidazole compounds shown in Production Examples 101 to 112 in Table 10 were obtained.

Production Example 113 6-Cyclohexyloxy-2- (4-piperidinyl)
-5- (4-Pyridylsulfinyl) benzimidazole hydrochloride 2- (4-N-acetylpiperidinyl) -6-cyclohexyloxy-5- (4-pyridylsulfinyl) benzimidazole 0 obtained by the method of Production Example 109 .300g
(0.000640 mol) was dissolved in a 6 N aqueous hydrochloric acid solution, and the mixture was heated under reflux with stirring for 6 hours. Thereafter, the reaction solution was returned to room temperature, the solvent was removed under reduced pressure, and the obtained crude crystals were recrystallized from methanol-isopropanol to give 6-colorless crystals.
Cyclohexyloxy-2- (4-piperidinyl) -5
0.23 g (78%) of-(4-pyridylsulfinyl) benzimidazole hydrochloride was obtained. m. p. Decomposed at 234 ° C. (recrystallized from methanol-isopropanol) Table 10 shows the structures, melting points, and NMR values of the compounds obtained in Production Examples 101 to 112.

[0128]

[Table 10]

Production Example 114 2-benzyl-6-cyclohexyloxy-5- (4-
Pyridylsulfinyl) benzimidazole a) 94 g of cyclohexanol was added to 1.3 L of tetrahydrofuran suspension containing 37 g of 60% 4-cyclohexyloxy-3-fluoronitrobenzene 60% sodium hydride and stirred at room temperature for 1 hour. Then, 100 g of 3,4-difluoronitrobenzene was added over 3 hours under ice cooling, and the mixture was stirred at the same temperature for 3.5 hours and at room temperature for 12 hours. 3N hydrochloric acid was added to the reaction solution, and extracted with n-hexane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the extract was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50: 1) to obtain 79 g (52%) of 4-cyclohexyloxy-3-fluoronitrobenzene as yellow crystals. . Melting point: 44-45 [deg.] C.

B) 4-Cyclohexyloxy-3-fluoroacetanilide 79 g of 4-cyclohexyloxy-3-fluoronitrobenzene, 83 g of iron powder and 5.3 ammonium chloride
A mixture of 100 ml of an aqueous solution containing
The mixture was heated and stirred for hours. After the temperature of the reaction solution was returned to room temperature, the insoluble matter to which 200 ml of ethyl acetate was added was filtered off through celite. The filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The obtained residue was dissolved in 330 ml of isopropyl alcohol, 40 g of acetic anhydride was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 62 g (75 g) of colorless crystals of 4-cyclohexyloxy-3-fluoroacetanilide.
%). Melting point: 123.5-124.5 ° C.

C) 4-Cyclohexyloxy-5-fluoro-2-nitroacetanilide In a 220 ml solution of acetic acid containing 54.5 g of 4-cyclohexyloxy-3-fluoroacetanilide was added 14 g of fuming nitric acid with stirring at 60 ° C. for 15 minutes. The mixture was stirred for 5 minutes. The reaction solution was returned to room temperature, 300 ml of water was added, and the precipitate was collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give colorless crystals of 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide 59.
g (92%). Melting point: 120-121.5 ° C.

D) 4-Cyclohexyloxy-2-nitro-5- (4-pyridylthio) aniline 59 g of 4-cyclohexyloxy-5-fluoro-2-nitroacetanilide, 4-mercaptopyridine 1
2 g, 42 ml of a 20% aqueous sodium hydroxide solution and 300 ml of isopropanol were stirred at 60 ° C. for 3 hours. After adding 200 ml of water, the resulting precipitate was left overnight, and the precipitate formed was removed and washed with water. The obtained crude product was recrystallized from acetone to give red crystalline 4-cyclohexyloxy-2-.
Nitro-5- (4-pyridylthio) aniline 21 g
(61%). Melting point: 171-171.5 ° C.

E) 50 g (145 mmol) of 2-benzyl-5-cyclohexyloxy-6- (4-pyridylthio) benzimidazole 4-cyclohexyloxy-2-nitro-5- (4-pyridylthio) aniline were added to 100 ml of chloroform. The solution was stirred and stirred at room temperature at room temperature for 34 g of phenylacetyl chloride (217 mmol).
l) and then 30 ml of triethylamine (217 mm
ol) and stirred for 1 hour. Thereafter, water was added to the reaction solution, extracted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 90 g of 4-cyclohexyloxy-2-nitro-5-pyridylthio and N-phenethylamide. The resulting amide is converted to acetic acid 5
The mixture was dissolved in 00 ml, and iron powder (49 g, 870 mmol) was added to form a suspension. Thereafter, the temperature was raised to 130 ° C., and the mixture was further stirred for 2 hours. afterwards,
The mixture was filtered through celite, washed with ethyl acetate, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 5). )
To obtain 45 g (75%) of white crystals of 2-benzyl-5-cyclohexyloxy-6- (4-pyridylthio) benzimidazole. Melting point: 147-148 [deg.] C.

Production Example 115 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylthio) benzimidazole 10 g (24 mm
ol) and 6 g of m-chloroperbenzoic acid (36 mm
ol) was dissolved in 40 ml of chloroform and stirred under ice cooling. After 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. And recrystallize
9 g of benzyl-5-cyclohexyloxy-6- (4-pyridylsulfinyl) benzimidazole (94
%)Obtained. Melting point: 157-159 [deg.] C.

Production Example 116 and Production Example 117 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol) and 35 mg (0.25 mmol) of potassium carbonate are suspended in 5 ml of acetone, and propyl bromide 2
3 μl (0.25 mmol) was added at room temperature, and the mixture was stirred overnight. After adding water, the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained crude mixture is subjected to silica gel column chromatography (elution solvent: chloroform: methanol = 10:
Separated and purified in 1), yellow amorphous 2-benzyl-5-cyclohexyloxy-1-methoxymethyl-6
-(4-pyridylsulfinyl) benzimidazole
44 mg (40%) (Production Example 116) and yellow amorphous 2-benzyl-6-cyclohexyloxy-
31 mg (28%) of 1-methoxymethyl-5- (4-pyridylsulfinyl) benzimidazole (Production Example 117) was obtained. Production Example 116 mass spectrometry value (m / z): 474 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 0.90 (3H, t, J = 8 Hz), 1.00-2.10 (10H, m), 3.98 (2H, t, J = 8)
Hz), 4.20-4.42 (1H, m), 4.25 (2H, s), 7.20-7.40 (6H, m), 7.
70 (2H, d, J = 5 Hz), 7.80 (1 H, s), 8.65 (2H, d, J = 5 Hz) Production Example 117 Mass spectrometry (m / z): 474 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 0.93 (3H, t, J = 8 Hz), 1.20-2.20 (10H, m), 3.90 (2H, t, J = 8)
Hz), 4.20-4.45 (1H, m), 4.230 (2H, s), 7.18-7.40 (6H, m),
7.70 (2H, d, J = 5Hz), 8.20 (1H, s), 8.50-8.80 (2H, br)

Production Example 118 and Production Example 119 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) sulfinylbenzimidazole 1.0 g (2.3 mmol) and sodium hydride 100 m
g (2.5 mmol) was suspended in 10 ml of tetrahydrofuran, and 192 μl of methoxymethyl chloride (2.5 mm
l) was added at room temperature and stirred overnight. After adding water, the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude mixture is subjected to silica gel column chromatography (elution solvent
Chloroform: methanol = 10: 1), purified and brown amorphous 2-benzyl-5-cyclohexyloxy-1-propyl-6- (4-pyridylsulfinyl) benzimidazole 600 mg (55%) (Production Example 118) And brown amorphous 2-benzyl-6-cyclohexyloxy-1-propyl-5- (4
-Pyridylsulfinyl) benzimidazole 480
mg (44%) (Production Example 119). Production Example 118 Mass spectrometry value (m / z): 476 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.00-2.25 (10H, m), 3.20 (3H, s), 4.25-4.45 (1H, m), 4.3
5 (2H, s), 5.20-5.40 (2H, m), 7.20-7.35 (6H, m), 7.60 (2H, m
d, J = 5 Hz), 7.92 (1 H, s), 8.68 (2 H, d, J = 5 Hz) Production Example 119 Mass spectrum (m / z): 476 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.10 (10H, m), 3.10 (3H, s), 4.30-4.45 (1H, m), 4.3
5 (2H, s), 5.25 (2H, s), 6.88 (1H, s), 7.20-7.35 (5H, m), 7.6
5-7.75 (2H, br), 8.22 (1H, s), 8.60-8.80 (2H, br)

Production Example 120 and Production Example 121 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol) and 63 mg (0.46 mmol) of potassium carbonate were suspended in 5 ml of dimethylformamide, and 54 mg (0.25 mmol) of 2-chloromethylquinoline hydrochloride was added at room temperature, followed by stirring overnight. After adding water, the mixture was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude mixture was separated and purified by silica gel column chromatography (elution solvent: chloroform: methanol = 10: 1) to give colorless amorphous 2-benzyl-5-cyclohexyloxy-
6- (4-pyridylsulfinyl) -1- (2-quinolinomethyl) benzimidazole 30 mg (23%)
(Production Example 120) and 60 mg (45%) of colorless amorphous 2-benzyl-6-cyclohexyloxy-5- (4-pyridylsulfinyl) -1- (2-quinolinomethyl) benzimidazole (Production Example 121). Was. Production Example 120 Mass spectrometry value (m / z): 574 (MH +) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.10 (10H, m), 4.30-4.45 (1H, m), 4.55 (2H, s), 5.5
5 (2H, s), 6.70 (1H, d, J = 5Hz), 7.10-7.25 (5H, m), 7.30 (1H,
s), 7.52-7.62 (3H, m), 7.70-7.80 (2H, m), 7.88 (1H, s), 7.95
(1H, d, J = 5Hz), 8.00-8.10 (1H, m), 8.60 (2H, d, J = 5Hz) Production Example 121 Mass spectrometry (m / z): 574 (MH +) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.10-2.10 (10H, m), 4.10-4.20 (1H, m), 4.35 (2H, s), 5.4
5 (2H, s), 6.48 (1H, d, J = 5Hz), 7.10-7.30 (5H, m), 7.50-7.6
0 (3H, m), 7.65 (2H, d, J = 4Hz), 7.70-7.80 (2H, m), 7.85-7.95
(1H, m), 8.00-8.07 (1H, m), 8.22 (1H, s), 8.65 (2H, d, J = 4H
z).

Production Example 122 and Production Example 123 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), potassium carbonate 39 mg (0.25 mmol),
38 μl of methyl 4-bromomethylbenzoate (0.25 mmo
l) and yellow amorphous 2-benzyl-5 using the same method as in Examples 1 and 2 using 5 ml of acetone.
Cyclohexyloxy-1- (4-carbomethoxybenzyl) -6- (4-pyridylsulfinyl) benzimidazole 40 mg (30%) (Production Example 122) and yellow amorphous 2-benzyl-6-cyclohexyloxy-1- (4-carbomethoxybenzyl) -5
-(4-pyridylsulfinyl) benzimidazole
73 mg (55%) (Preparation Example 123) were obtained. Production Example 122 Mass spectrometry value (m / z): 580 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.15 (10H, m), 3.90 (3H, s), 4.05-4.30 (2H, m), 4.3
0-4.50 (1H, m), 5.18-5.40 (2H, m), 5.18-5.40 (2H, m), 6.95
(2H, d, J = 8Hz), 7.10-7.30 (6H, m), 7.60 (2H, d, J = 5Hz), 7.70
(1H, s), 7.95 (2H, d, J = 8 Hz), 8.62 (2H, d, J = 5 Hz) Production Example 123 Mass spectrometry (m / z): 580 (MH +) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-1.90 (10H, m), 3.90 (3H, s), 4.10-4.25 (1H, m), 4.2
1 (2H, s), 5.18 (2H, s), 6.45 (1H, s), 6.85 (1H, s), 7.15-7.3
0 (5H, m), 7.65 (2H, d, J = 5Hz), 7.90 (2H, d, J = 8Hz), 8.25 (1H,
s), 8.62 (2H, d, J = 5Hz).

Production Example 124 and Production Example 125 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 35 mg (0.25 mmol) of potassium carbonate,
39 μl of 4-methoxybenzyl chloride (0.25 mmo
l) and Production Examples 116 and 11 using 5 ml of acetone
Using the same method as in Example 7, yellow amorphous 2-benzyl-5-cyclohexyloxy-1- (4-methoxybenzyl) -6- (4-pyridylsulfinyl) benzimidazole 12 mg (9%) (Production Example 124) And yellow amorphous 2-benzyl-6-cyclohexyloxy-1- (4-methoxybenzyl) -5- (4
-Pyridylsulfinyl) benzimidazole 10 m
g (8%) (Example 125). Production Example 124 Mass spectrometry value (m / z): 552 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.10 (10H, m), 3.78 (3H, s), 4.10-4.30 (2H, m), 4.3
0-4.45 (1H, m), 5.05-5.25 (2H, m), 6.75-6.90 (4H, m), 7.15
-7.35 (6H, m), 7.60 (2H, d, J = 5Hz), 7.75 (1H, s), 8.62 (2H, d,
J = 5Hz). Production Example 125 Mass spectrometry value (m / z): 552 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.05 (10H, m), 3.75 (3H, s), 4.10-4.40 (1H, m), 4.2
2 (2H, s), 5.05 (2H, s), 6.55 (1H, s), 6.75-6.85 (4H, m), 7.1
0-7.35 (5H, m), 7.63 (2H, d, J = 5Hz), 8.20 (1H, s), 8.6 (2H, d,
J = 5Hz).

Production Examples 126 and 127 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 35 mg (0.25 mmol) of potassium carbonate, 30 μl (0.25 mmol) of benzyl bromide, and 5 ml of acetone, and in the same manner as in Examples 1 and 2, colorless amorphous 5-cyclohexyloxy-1,2-
46 mg (38%) of dibenzyl-6- (4-pyridylsulfinyl) benzimidazole (Example 11) and colorless amorphous 6-cyclohexyloxy-
73 mg (60%) of 1,2-dibenzyl-5- (4-pyridylsulfinyl) benzimidazole (Example 12) were obtained. Production Example 126 Mass Spec (m / z): 522 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.12 (10H, m), 4.18 (2H, d, J = 5 Hz), 4.36 (1H, sp, J =
4Hz), 5.21 (2H, d, J = 5Hz), 6.86-6.94 (2H, m), 7.12-7.32 (9
H, m), 7.60 (2H, d, J = 8Hz), 7.74 (1H, s), 8.62 (2H, d, J = 8H
z). Production Example 127 Mass Spectrometry Value (m / z): (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-1.82 (10H, m), 4.36 (1H, sp, J = 4 Hz), 4.22 (2H, s),
5.12 (2H, s), 6.52 (1H, s), 6.82-6.97 (8H, m), 7.15-7.34 (6
H, m), 7.66 (2H, d, J = 8Hz), 8.22 (1H, s), 8.62 (2H, d, J = 8H
z).

Production Example 128, Production Example 129 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 10 mg of sodium hydride (0.25 mmol)
l) and 21 μl of methylthiomethyl chloride
(0.25 mmol) and 55 mg (52) of 2-benzyl-5-cyclohexyloxy-1-methylthiomethyl-6- (4-pyridylsulfinyl) benzimidazole as a brown oil in the same manner as in Production Examples 118 and 119.
%) (Production Example 118) and 35 mg (33%) of 2-benzyl-6-cyclohexyloxy-1-methylthiomethyl-5- (4-pyridylsulfinyl) benzimidazole as a brown oil (Production Example 119). . Production Example 118 Mass spectrometry value (m / z): 460 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.05 (10H, m), 1.95 (3H, s), 4.30-4.42 (1H, m), 4.3
8 (2H, m), 5.00 (2H, s), 7.20-7.40 (6H, m), 7.65 (2H, d, J = 5H
z), 7.90 (1H, s), 8.65 (2H, d, J = 5Hz). Production Example 119 Mass spectrometry value (m / z): 460 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.20 (10H, m), 1.85 (3H, s), 4.30-4.43 (1H, m), 4.3
8 (2H, m), 4.90 (2H, s), 6.85 (1H, s), 7.20-7.40 (5H, m), 7.7
0 (2H, d, J = 5Hz), 8.20 (1H, s), 8.65 (2H, d, J = 5Hz).

Production Example 130 and Production Example 131 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 10 mg of sodium hydride (0.25 mmol)
l) and 2-bromoethyl ethyl ether 28μ
1 (0.25 mmol) and 2-benzyl-5-cyclohexyloxy-1- (2-ethoxyethyl) -6- (4-yellow) as a yellow oil using the same method as in Production Examples 118 and 119.
Pyridylsulfinyl) benzimidazole 27mg
(23%) (Production Example 130) and 2- of yellow oil
Benzyl-6-cyclohexyloxy-1- (2-ethoxyethyl) -5- (4-pyridylsulfinyl) benzimidazole 43 mg (37%) (Production Example 131)
I got Production Example 130 Mass Spec (m / z): 504 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.05 (3H, t, J = 6 Hz), 1.20-2.10 (10H, m), 3.20-3.40 (2H,
m), 3.40-3.60 (2H, m), 4.00-4.30 (2H, m), 4.30-4.43 (1H,
m), 4.35 (2H, m), 7.10-7.40 (6H, m), 7.65 (2H, d, J = 5Hz), 7.
80 (1H, s), 8.65 (2H, d, J = 5Hz). Production Example 131 Mass Spec (m / z): 504 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.05 (3H, t, J = 6 Hz), 1.20-2.10 (10H, m), 3.30 (2H, q, J = 6)
Hz),), 3.35-3.40 (2H, m), 4.10 (2H, t, J = 5Hz), 4.25-4.42
(1H, m), 4.35 (2H, s), 6.82 (1H, s), 7.18-7.40 (5H, m), 7.70
(2H, d, J = 5Hz), 8.20 (1H, s), 8.65 (2H, d, J = 5Hz).

Production Example 132 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.2 mmol), 10 mg of sodium hydride (0.25 mmo
l) and prenyl bromide 29 μl (0.25 mmo
l) Using a method similar to that of Production Examples 118 and 119, 2-benzyl-6-cyclohexyloxy-1-prenyl-5- (4-pyridylsulfinyl) benzimidazole as a yellow oil 35 mg (31%) (Production Example) 13
2) was obtained. Production Example 132 Mass spectrometry value (m / z): 500 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.10 (10H, m), 1.63 (3H, s), 1.75 (3H, s), 4.20-4.4
0 (1H, m), 4.30 (2H, s), 4.50 (2H, d, J = 5Hz), 4.80-4.95 (1H,
m), 7.15-7.40 (5H, m), 7.70 (2H, d, J = 6Hz), 8.26 (1H, s), 8.6
5 (2H, d, J = 5Hz).

Production Example 133 and Production Example 134 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.2 mmol), 10 mg of sodium hydride (0.25 mmo
l) and 2-phenoxyethyl chloride 39m
g (0.25 mmol) as a solvent in dimethylformamide 1
After adding ml, 27 mg of 2-benzyl-5-cyclohexyloxy-1- (2-phenoxyethyl) -6- (4-pyridylsulfinyl) benzimidazole as a colorless oil was prepared in the same manner as in Production Examples 118 and 119.
(21%) (Production Example 133) and colorless amorphous 2-benzyl-6-cyclohexyloxy-1- (2
-Phenoxyethyl) -5- (4-pyridylsulfinyl) benzimidazole 42 mg (33%) (Production Example 134) was obtained. Production Example 133 Mass spectrometry value (m / z): 552 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.20 (10H, m), 3.98-4.05 (2H, m), 4.30-4.60 (3H,
m), 4.43 (2H, s), 6.65-6.75 (2H, m), 6.90-7.00 (1H, m), 7.1
5-7.40 (8H, m), 7.70 (2H, d, J = 5Hz), 7.97 (1H, s), 8.60-8.75
(2H, br). Production Example 134 Mass spectrometry value (m / z): 552 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.05 (10H, m), 3.80-3.95 (2H, m), 4.25-4.45 (3H,
m), 4.40 (2H, s), 6.60-6.65 (2H, m), 6.85 (1H, s), 7.15-7.4
0 (7H, m), 7.65 (2H, d, J = 5Hz), 8.20 (1H, s), 8.55-8.80 (2H, b
r).

Production Example 135, Production Example 136 2-Benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 1 g (2.
3 mmol), 100 mg (2.5 mmol) of sodium hydride,
And 410 mg of 2-picolyl chloride hydrochloride (2.
After adding dimethylformamide as a solvent to 5 mmol), brown oil 2-benzyl-5-cyclohexyloxy-1- was obtained in the same manner as in Production Examples 118 and 119.
(2-picolyl) -6- (4-pyridylsulfinyl)
Benzimidazole 300 mg (25%) (Production Example 1)
35) and 810 mg of 2-benzyl-6-cyclohexyloxy-1- (2-picolyl) -5- (4-pyridylsulfinyl) benzimidazole as a brown oil
(68%) (Production Example 136) was obtained. Production Example 135 Mass Spec (m / z): 523 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.00-2.15 (10H, m), 4.20-4.50 (1H, m), 4.30 (2H, s), 5.3
8 (2H, s), 6.58-6.65 (1H, m), 7.10-7.30 (7H, m), 7.40-7.55
(1H, m), 7.65 (2H, d, J = 5Hz), 7.78 (1H, s), 8.50-8.60 (1H,
m), 8.65 (2H, d, J = 5Hz). Production Example 136 Mass Spec (m / z): 523 (MH +). Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard): δ: 1.20-2.50 (10H, m), 4.15-4.35 (1H, m), 4.30 (2H, s), 5.2
5 (2H, s), 6.40-6.45 (1H, m), 6.70 (1H, s), 7.10-7.30 (6H,
m), 7.40-7.50 (1H, m), 7.65 (2H, d, J = 5Hz), 8.25 (1H, s), 8.5
0-8.60 (1H, m), 8.65 (2H, d, J = 5Hz).

Production Example 137, Production Example 138 2-Benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 10 mg of sodium hydride (0.25 mmol)
l) and tetrahydrofurfuryl bromide 5
Using 7 mg (0.25 mmol) of 2-benzyl-5-cyclohexyloxy-6- (4-pyridylsulfinyl)-as a brown oil using the same method as in Production Examples 118 and 119.
1-tetrahydrofurfurylbenzimidazole 5
0 mg (42%) (Production Example 137) and 2-benzyl-6-cyclohexyloxy-5- (4
-Pyridylsulfinyl) -1-tetrahydrofurfurylbenzimidazole 20 mg (17%) (Production Example 138) was obtained. Production Example 137 Mass Spectrum (m / z): 516 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.05-2.40 (10H, m), 3.60-4.50 (6H, m), 4.35 (2H, s), 6.8
5-6.95 (1H, m), 7.15-7.35 (5H, m), 7.70 (2H, d, J = 5Hz), 8.1
8 (1H, s), 8.65 (2H, d, J = 5Hz). Production Example 138 Mass Spectrometry Value (m / z): 516 (MH +). Nuclear magnetic resonance spectrum (CDCl3, TMS internal standard): δ: 1.20-2.00 (10H, m), 3.90 (3H, s), 4.20 (2H, s), 4.20-4.3
5 (1H, m), 5.20 (2H, s), 7.00 (2H, d, J = 8Hz), 7.10-7.20 (5H,
m), 7.70 (2H, d, J = 5Hz), 7.82 (2H, d, J = 8Hz), 8.25 (1H, s), 8.
65 (2H, d, J = 5Hz).

Production Example 139, Production Example 140 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 1.0 g
(2.3 mmol), sodium hydride 100 mg (2.5 mmo
l) and 4-methoxyphenacyl bromide 57
Using 3 mg (2.5 mmol) and the same method as in Production Examples 118 and 119, red powder of 2-benzyl-5-cyclohexyloxy-1- (4-methoxyphenacyl) -6- was used.
(4-pyridylsulfinyl) benzimidazole 4
10 mg (31%) (Production Example 139) and red powder of 2-benzyl-6-cyclohexyloxy-1- (4
-Methoxyphenacyl) -5- (4-pyridylsulfinyl) benzimidazole (320 mg, 24%) (Preparation Example 140) was obtained. Production Example 139 Melting Point: 138-143 ° C (CHCl ₃ -IPE). Mass spec (m / z): 580 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.15 (10H, m), 3.90 (3H, s), 4.20 (2H, s), 4.30-4.5
0 (1H, m), 5.35 (2H, s), 7.00 (2H, d, J = 8Hz), 7.10-7.30 (6H,
m), 7.62 (2H, d, J = 5Hz), 7.65 (1H, s), 7.90 (2H, d, J = 8Hz), 8.
65 (2H, d, J = 5Hz). Production Example 140 Melting Point: 201.5-210.5 ° C (CHCl ₃ -IP
E). Mass spec (m / z): (580 MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.00 (10H, m), 3.92 (3H, s), 4.22 (2H, s), 4.22-4.3
5 (1H, m), 5.21 (2H, s), 6.53 (1H, s), 7.00 (2H, d, J = 8Hz), 7.
10-7.38 (5H, m), 7.68 (2H, d, J = 5Hz), 7.82 (2H, d, J = 8Hz), 8.
26 (1H, s), 8.65 (2H, d, J = 5Hz).

Production Examples 141 and 142 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 10 mg of sodium hydride (0.25 mmol)
l) and Production Example 1 using μl (mmol) of chloride
A colorless amorphous 2-benzyl-5-cyclohexyloxy-1- (2-
Morifolinoethyl) -6- (4-pyridylsulfinyl) benzimidazole 50 mg (13%) (Production Example 141) and colorless amorphous 2-benzyl-6
-Cyclohexyloxy-1- (2-morpholinoethyl) -5- (4-pyridylsulfinyl) benzimidazole 20 mg (5%) (Production Example 142) was obtained. Production Example 141 Mass spectrometry value (m / z): 545 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.20 (10H, m), 2.20-2.50 (6H, m), 3.60-3.80 (4H,
m), 4.00-4.20 (2H, m), 4.30-4.50 (1H, m), 4.35 (2H, s), 7.2
0-7.40 (6H, m), 7.70 (2H, d, J = 5Hz), 7.82 (1H, s), 8.65 (2H,
d, J = 5Hz). Production Example 142 Mass spectrometry value (m / z): 545 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.20-2.20 (10H, m), 2.10-2.50 (6H, m), 3.60-3.80 (4H,
m), 3.95-4.20 (2H, m), 4.20-4.45 (1H, m), 4.35 (2H, s), 6.7
5 (1H, s), 7.20-7.40 (6H, m), 7.70 (2H, d, J = 5Hz), 7.82 (1H,
s), 8.65 (2H, d, J = 5Hz).

Production Example 143, Production Example 144 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 1.0 g
(2.3 mmol), 110 mg (2.8 mmo) sodium hydride
l) and 0.2 ml (2.8 mmol) of methyl iodide in the same manner as in Production Examples 118 and 119 to give 2-benzyl-5-cyclohexyloxy-1-methyl-6- (4- Pyridylsulfinyl) benzimidazole 197 mg (19%) (Production Example 143), and
White powder of 2-benzyl-6-cyclohexyloxy-
430 mg (41%) of 1-methyl-5- (4-pyridylsulfinyl) benzimidazole (Production Example 144)
I got Production Example 143 Melting point: 87-89 ° C (AcOEt-n-Hexan)
e). Mass spec (m / z): 446 (MH @ +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.28-2.12 (10H, m), 3.64 (3H, s), 4.28 (2H, s), 4.39 (1H,
m), 7.23 (6H, m), 7.72 (2H, br), 7.81 (1H, s), 8.7 (2H, br). Production Example 144 Mass spectrometry value (m / z): 446 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 1.28-2.08 (10H, m), 3.52 (3H, s), 4.27 (2H, s), 4.39 (1H,
m), 6.73 (1H, s), 7.17-7.36 (5H, m), 7.66 (2H, m), 8.20 (1H,
s), 8.63 (2H, br).

Production Examples 145 and 146 2-benzyl-5-cyclohexyloxy-6- (4-
Pyridylsulfinyl) benzimidazole 0.1 g
(0.23 mmol), 10 mg of sodium hydride (0.25 mmol)
l) and 27 μl of isopropyl bromide (0.25 m
mol)) and brown amorphous 2-benzyl-5-cyclohexyloxy-1-isopropyl-6- (4-pyridylsulfinyl) -1-isopropylbenzimidazole 5 using the same method as in Production Examples 118 and 119.
0 mg (44%) (Production Example 1450) and brown amorphous 2-benzyl-6-cyclohexyloxy-
1-isopropyl-5- (4-pyridylsulfinyl)
20 mg (18%) of benzimidazole (Production Example 14)
6) was obtained. Production Example 145 Mass spectrometry value (m / z): 488 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 0.70-1.00 (6H, m), 1.00-2.40 (11H, m), 3.85 (2H, d, J = 8H)
z), 4.25-4.45 (1H, m), 4.30 (2H, s), 7.20-7.40 (6H, m), 7.7
0 (2H, d, J = 5Hz), 7.80 (1H, s), 8.65 (2H, d, J = 5Hz). Production Example 146 Mass spectrometry value (m / z): 488 (MH +). Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard): δ: 0.80-1.00 (6H, m), 1.20-2.40 (11H, m), 3.70 (2H, d, J = 8H)
z), 4.20-4.45 (1H, m), 4.25 (2H, s), 6.70 (1H, s), 7.18-7.4
0 (5H, m), 7.70 (2H, d, J = 5Hz), 8.20 (1H, s), 8.60-8.80 (2H, b
r).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/44 ADT A61K 31/44 ADT 31/495 ABG 31/495 ABG 31/535 ABA 31/535 ABA C07D 401/12 235 C07D 401/12 235 401/14 235 401/14 235 405/14 213 405/14 213 409/14 213 409/14 213 (72) Inventor Toshio Nakamura 3-24 Takada, Toshima-ku, Tokyo No. 1 Taisho Seiyaku Co., Ltd. F term (reference) 4C063 AA01 AA03 BB01 BB08 CC75 CC92 DD12 DD26 EE01 4C086 AA01 AA02 AA03 BC39 GA02 GA04 GA07 GA08 MA01 MA04 NA14 ZA97 ZB11 ZB13 ZB15 ZC41

Claims (7)

[Claims] (1) Formula (1) (Wherein, R ¹ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms which may be substituted, a phenyl group, or 1 to 3 halogen atoms. A substituted phenyl group; R ² represents an alkyl group substituted with a lower alkyl group, a carboxy group or a lower alkoxycarbonyl group, a cycloalkyl group having 4 to 8 carbon atoms which may be substituted, Phenyl group or pyridyl group, lower alkylphenyl group, carboxyalkylphenyl group, alkylaminocarbonylalkylphenyl group, cyclic aminocarbonylalkylphenyl group, 1 or 2 nitrogen atoms and / or Or a heterocyclic ring containing an oxygen atom and / or a sulfur atom as a hetero atom, wherein R ³ is a hydrogen atom,
Alkyl group having 1 to 10 carbon atoms, 4 to 8 carbon atoms
Cycloalkyl group, lower alkoxy group, hydroxyl group, alkoxycarbonyl group having 2 to 6 carbon atoms, 1 or 2
A cycloalkyl group having 3 to 7 carbon atoms or a phenylalkyl group, a carboxy group, an aralkyl group, or a 2 to 6 carbon atom which may be substituted with 1 or 2 hydroxyl groups. An alkylaminocarbonyl group, a carbamoyl group, a nitrile group, an amino group, an acetylamino group, a halogen atom, a phenyl group, a lower acetoxyalkyl group, a lower hydroxyalkyl group, a lower haloalkyl group, and a lower alkyl group having one or two nitrogen atoms. The optionally substituted lower aminoalkyl group or cyclic aminoalkyl group represents a phenyl group, a pyridyl group, a furyl group or a thienyl group which may be substituted by 1 or 2 groups, and R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkyl group. Alkoxy group, formula (2)
Or (3)-(CH ₂ ) _n -A (2)-(CH ₂ ) _n -YA (3) (in the formula (2) or the formula (3), n is an integer of 1 to 5) A represents an alkyl group, an alkoxy group, an acyl group, a carboxy group, an alkoxycarbonyl group, or an alkenyl group, a cycloalkyl group which may be substituted,
A phenyl group or a monocyclic or bicyclic heterocyclic group having O and / or N and / or S as a heteroatom, Y is O,
S, SO, SO ₂ , a carbonyl group, an ester group, an amide group, or an amino group), and X is O, S, S
O and SO ₂ are shown. 2,5,6-substituted benzimidazole compound derivatives represented by the formula: 2. In the compound of the formula (1), R ¹ is an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group or one or two halogen atoms. A substituted phenyl group; R ² represents an aromatic heterocyclic ring containing one or two nitrogen atoms; R ³ represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, an alkoxy group having 2 to 6 carbon atoms; Carbonyl group, carboxy group,
2 carbon atoms which may be substituted by 1 or 2 hydroxyl groups
Up to 6 alkylaminocarbonyl groups, carbamoyl groups, nitrile groups, amino groups, acetylamino groups, halogen atoms, phenyl groups, lower acetoxyalkyl groups, lower hydroxyalkyl groups, lower haloalkyl groups, and one or two nitrogen atoms X represents a phenyl group, a pyridyl group, a furyl group or a thienyl group which may be substituted with one or two lower aminoalkyl groups or one or two cyclic aminoalkyl groups which may be substituted with a lower alkyl group; R ⁴ represents a hydrogen atom; 2,5,6-substituted benzimidazole compound derivative of claim 1, wherein a group represented by S, SO or SO ₂ in. 3. In the compound of the formula (1), R ¹ is a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms,
R ² represents a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group, a phenyl group or a phenyl group substituted with 1 to 3 halogen atoms;
A halogen atom-substituted phenyl group, lower alkylphenyl group, carboxyalkylphenyl group, alkylaminocarbonylalkylphenyl group or cyclic aminocarbonylalkylphenyl group, R ³ represents a phenyl group, and R ⁴ represents a hydrogen atom. , X is 2,5,6-substituted according to claim 1, wherein a group represented by S, SO or SO ₂ - benzimidazole compound derivatives. 4. In the compound of the formula (1), R ¹ is a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms,
R ² represents a phenyl group or a phenyl group substituted with one or two halogen atoms, and R ² represents a lower alkyl group, a cycloalkyl group having 4 to 8 carbon atoms, an alkyl substituted with a carboxy group or a lower alkoxycarbonyl group. Group,
A phenyl group, a phenyl group or a pyridyl group substituted with one or two halogen atoms, R ³ represents a hydrogen atom,
Alkyl group having 1 to 10 carbon atoms, 4 to 8 carbon atoms
Cycloalkyl groups or phenylalkyl groups having 3 to 7 carbon atoms substituted with 1 or 2 nitrogen atoms, R ⁴ represents a hydrogen atom, X represents S,
2,5,6-substituted according to claim 1, wherein a group represented by SO or SO ₂ - benzimidazole compound derivatives. 5. In the compound of the formula (1), R ¹ represents a hydrogen atom, a lower alkyl group or an optionally substituted cycloalkyl group, and R ² represents an optionally substituted O and / or N And / or a monocyclic or bicyclic heterocyclic group having S as a hetero atom, and R ³ represents an aralkyl group;
R ⁴ is a lower alkyl group, an alkoxy group, or-(CH ₂ ) n-A (2) or-(CH ₂ ) n-Y-A (3) (wherein, n, Y and A are claim 1) Wherein X represents O, S, SO or SO _2, and the 2,5,6, -substituted-benzimidazole compound derivative according to claim 1, wherein X is O, S, SO or SO ₂ . 6. A pharmaceutically acceptable salt of the compound according to claim 1. 7. A pharmaceutical composition comprising the compound according to claim 1 in an effective amount.