JPH1077260A - 4-aryloxy-5-arylthionitroaniline compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound having inhibitory activity against the production of interleukin-1, -5 and -6 of cytokines, thus useful as an antiinflammatory agent, therapeutic agent for autoimmune diseases such as chronic arthrorheumatism or that for osteopathy such as osteoporosis or allergic diseases. SOLUTION: This compound is shown by formula I [R<1> is tetrahydronaphthyl or a (substituted) phenyl; R<2> is pyridyl, thienyl, naphthyl or a (substituted) phenyl; is S, SO or SO2 ], e.g. 5-(3-fluorophenylthio)-2-nitro-4-phenyloxyaniline. The compound of formula I (where, X is S) is obtained by reaction using a 3,4- dihalonitrobenzene of formula II (Y is a halogen) as starting material, namely, etherification, reduction, acetylation, nitration and thioetherification successively in this order to form a compound of formula III which, in turn, is hydrolyzed.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention has an inhibitory effect on the production of cytokines such as interleukin (IL) -1, IL-5, and IL-6. The present invention relates to a 4-aryloxy-5-arylthionitroaniline compound useful as an agent, a therapeutic agent for autoimmune diseases against rheumatoid arthritis and the like, a therapeutic agent for bone diseases against osteoporosis and the like, a therapeutic agent for allergic diseases and the like.

[0002]

2. Description of the Related Art Heretofore, non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used as therapeutic agents for various inflammatory and painful diseases. NSAIDs are known to have a prostaglandin (PG) biosynthesis inhibitory action by cyclooxygenase inhibitory action as a mechanism of action. For rheumatoid arthritis and the like, an NSAID is used for symptomatic treatment, and an immunomodulator (DMARD) is used for causal treatment.

[0003] In recent years, osteoporosis, which is on the increase, is classified into postmenopausal osteoporosis and senile osteoporosis. Here, postmenopausal osteoporosis is caused by the loss of estrogen after menopause excessively promotes bone resorption, and bone resorption inhibitors such as calcitonin and estrogen are used as the first-line treatment used for the treatment. ing.

[0004] Further, allergic diseases, which have been increasing in recent years, are known to have various symptoms.
In addition to steroids, antiallergic agents (suppressors or antagonists of the production or release of chemical mediators such as histamine, thromboxane A ₂ , leukotriene), for bronchial asthma, β2 stimulants and xanthine preparations are allergic rhinitis For example, antihistamines and anticholinergics are used, and for atopic dermatitis, nonsteroidal anti-inflammatory external preparations are used.

[0005]

Conventional NSAIDs cause gastrointestinal disorders such as gastric ulcers due to their mechanism of action, and have problems in long-term continuous use. Also, DMA
RD has not yet sufficiently separated the efficacy and side effects. Furthermore, calcitonin has a problem that it is limited to administration by intramuscular injection and is liable to become resistant. Estrogen has a problem of increasing the incidence of breast cancer and endometrial cancer.

In recent years, active substances collectively referred to as cytokines produced by immunocompetent cells have been found. Among them, IL-1, IL-6, tumor necrosis factor, etc. are called inflammatory cytokines, and are inflammatory mediators such as activation of arachidonic acid metabolism system, which is a metabolic production system of PG, migration of leukocytes, induction of acute phase proteins. These inflammatory cytokine production inhibitors are expected to be used as a new-generation anti-inflammatory drug with a different mechanism of action and as a therapeutic agent for autoimmune diseases against rheumatoid arthritis, etc. I have. Further, IL-1 and IL-6 are also known as osteoclast formation promoting factors, and their production inhibitors are expected as postmenopausal osteoporosis therapeutic agents.

[0007] Among allergic diseases, LAR (late-onset allergic reaction) has recently gained importance.
It is. The main body of LAR is eosinophilic inflammation, and it has been found that cytokines such as IL-5 produced from T lymphocytes play an important role.

[0008] Steroids and immunosuppressants are known to have an inhibitory effect on the production of these cytokines. However, both drugs have other physiological effects. For steroids, adrenal atrophy, edema, gastric ulcer, and full moon The occurrence of side effects such as the face, and the occurrence of side effects such as infectious diseases, hepatic / renal disorders, and blood disorders in immunosuppressants have become problems.

Therefore, I produced from T lymphocytes
Providing a substance that selectively suppresses the production of cytokines such as L-5 can be a useful antiallergic agent with reduced side effects seen in steroids and immunosuppressants.

[0010] However, no effective drug having an inhibitory action on the production of IL-1, IL-5 or IL-6 has been found.

[0011]

Means for Solving the Problems The present inventors have proposed IL-
1, having an activity of inhibiting IL-5 or IL-6 production,
As a result of intensive studies for the purpose of providing useful anti-inflammatory agents, therapeutic agents for autoimmune diseases against rheumatoid arthritis and the like, therapeutic agents for bone diseases against osteoporosis and the like, or compounds which can be antiallergic agents, certain 4-aryloxy-5 The present inventors have found that an arylthionitroaniline compound can achieve the object and completed the present invention.

That is, the present invention relates to

[0013]

Embedded image

(Wherein R ¹ is a tetrahydronaphthyl group,
A phenyl group or a phenyl group substituted by one or two of “an alkyl group having 1 to 5 carbon atoms, a halogen atom or a phenyl group”, and R ² represents a pyridyl group, a thienyl group, a naphthyl group or a “ A phenyl group substituted by a halogen atom, an amino group, an alkoxy group having 1 to 5 carbon atoms, a carboxy group or a carboxyalkyl group having 2 to 6 carbon atoms, and X represents -S-, -SO- or -SO ₂ - is a group represented by the. 4-) represented by
An aryloxy-5-arylthionitroaniline compound or a salt thereof (hereinafter abbreviated as "compound (I)").

In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The alkoxy group having 1 to 5 carbon atoms is a linear or branched one, and specifically, a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group,
-Butoxy, isobutyloxy, n-pentyloxy and the like. The alkyl group having 1 to 5 carbon atoms is a linear or branched one, and specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group,
-Butyl group, isobutyl group, n-pentyl group and the like.

The carboxyalkyl group having 2 to 6 carbon atoms includes, for example, a carboxymethyl group, a carboxyethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group and a 5-carboxypentyl group. The pyridyl group is a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group. The thienyl group is a 2-thienyl group or a 3-thienyl group. The naphthyl group is a 1-naphthyl group or a 2-naphthyl group.

In the present invention, the salt means a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, tartaric acid, methanesulfonic acid,
It includes not only salts with organic acids such as tosylic acid and aspartic acid, but also hydrates.

The compound (I) of the present invention can be produced by the following method.

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

[0020]

Embedded image

(In the reaction formula, R ¹ and R ² have the same meanings as described above, and Y is a halogen atom.) The detailed description of the reaction formula will be shown below in the order of reaction.

(A) 3,4-dihalonitrobenzene (I
Starting from phenol compound (I) in the presence of a base,
By reacting II), 4-nitrophenyl ether compound (IV) can be obtained.

The base used in this reaction includes 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 the like. Alkali metal bicarbonates such as potassium hydrogen carbonate, sodium hydride, alkali metal hydrides such as potassium hydride, metal sodium, metal potassium, inorganic bases such as sodium amide or triethylamine, diisopropylethylamine, tri-n-butylamine;
1,5-diazabicyclo [4.3.0] -5-nonene,
Organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, N, N-dimethylaminopyridine and the like can be mentioned.

This reaction can be carried out in a solvent. As the solvent to be used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-
Butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene,
Examples include 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, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide Quaternary ammonium salts such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, and tricaptylmethylammonium chloride;
The reaction can be promoted by adding a crown ether such as 8-crown-6 ether.

(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 acetoanilide compound (VI) can be obtained by acetylating the amino group of the compound (V) without isolation and purification.

The reduction may be performed by a usual reduction method of reducing a 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, sodium sulfide -Reduction using ammonium chloride, reduction using sodium borohydride, lithium aluminum hydride and the like.

The solvent used in this reaction may be arbitrarily selected depending on the reduction method.
Ethanol, n-propanol, isopropanol, n
Alcohols such as butanol, t-butanol, water,
Acetic acid, ethyl acetate, dioxane, tetrahydrofuran,
Acetonitrile and the like.

Acetylation may be a conventional method for acetylating aniline, and examples of the acetylating agent include acetic acid, acetyl chloride, acetyl bromide, acetic anhydride and the like.

The solvent used in this reaction may be the solvent used in the reduction reaction or ethyl ether, petroleum ether,
n-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 acetanilide compound (VI), a 2-nitoacetanilide compound (VII) can be obtained.

The nitrating agent used in this reaction includes acetic acid, fuming nitric acid, sodium nitrate, potassium nitrate, iron nitrate, urea nitrate and the like.

The solvent to be used may be arbitrarily selected depending on the nitrating agent. Specifically, acetic acid, acetic anhydride,
Examples thereof include trifluoroacetic acid, sulfuric acid, dichloroethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane, ethanol, n-propanol, and isopropanol.

(D) Compound (IX) can be obtained by reacting 2-nitroacetanilide compound (VII) with thiol compound (VIII) in the presence of a base. Compound (IX) of the present invention can be obtained by continuously hydrolyzing compound (IX) in the reaction system or hydrolyzing after isolation.

The base used in this reaction includes 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 the like. Alkali metal bicarbonates such as potassium hydrogen carbonate, sodium hydride, alkali metal hydrides such as potassium hydride, metal sodium, metal potassium, inorganic bases such as sodium amide or triethylamine, diisopropylethylamine, tri-n-butylamine;
1,5-diazabicyclo [4.3.0] -5-nonene,
Organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, N, N-dimethylaminopyridine and the like can be mentioned.

This reaction can be carried out in a solvent. As the solvent to be used, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-
Butanol, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene,
Examples include 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, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide Quaternary ammonium salts such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, and tricaptylmethylammonium chloride;
The reaction can be promoted by adding a crown ether such as 8-crown-6 ether.

The hydrolysis is a usual method for hydrolyzing amides under basic conditions or acidic conditions. When the hydrolysis is continued in the reaction system, the basic conditions are preferable. , Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Sodium methoxide, sodium ethoxide, potassium t-butoxide and the like can be used. In the case of acidic conditions, acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are used.

The solvent used in this reaction may be arbitrarily selected depending on the hydrolysis conditions. Specifically, water, methanol, ethanol, propanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like can be mentioned.

(2) In the present invention, X in the formula (I) is-
SO- or -SO ₂ - compound is a group represented by the
For example, it can be obtained by oxidizing the compound (Ia) of the present invention, which can be obtained by the method (1).

The oxidation is an ordinary oxidation reaction of oxidizing sulfide to sulfoxide or sulfone or an ordinary oxidation reaction of oxidizing sulfoxide to sulfone. Examples thereof include hydrogen peroxide, t-butyl hydroperoxide, and metachloro. Examples thereof include methods using perbenzoic acid, peracetic acid, sodium metaperiodate, sodium bromite, sodium hypochlorite, periodic benzene and the like.

The solvent used in this reaction is methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, carbon tetrachloride, dioxane,
Tetrahydrofuran, acetone, acetonitrile, ethyl acetate, ethyl ether, petroleum ether, n-hexane, cyclohexane, benzene, toluene, xylene,
Chlorobenzene, pyridine, N, N-dimethylformamide, water and the like can be mentioned.

The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. These include, for example, tablets, granules, powders, capsules, solutions, emulsions,
Suspensions, injections, etc., all of which can be produced by ordinary methods. When used as an anti-inflammatory agent for humans, a therapeutic agent for autoimmune diseases against rheumatoid arthritis, etc., a therapeutic agent for bone diseases against osteoporosis, etc., or an anti-allergic agent, the dosage is as follows: age, body weight, symptoms, administration route, administration Although it depends on the number of times, it is usually 1 to 1000 mg per day for adults.

[0044]

EFFECT OF THE INVENTION The compounds of the present invention are IL-1 and IL-5.
It is also useful as a therapeutic agent for a disease caused by IL-6, for example, an anti-inflammatory agent, a therapeutic agent for an autoimmune disease against rheumatoid arthritis, a therapeutic agent for a bone disease against osteoporosis, an antiallergic agent, and the like.

[0045]

The present invention will be described more specifically with reference to the following examples and test examples.

Example 1 5- (3-fluorophenylthio) -2-nitro-4-
Phenyloxyaniline 1) 3-fluoro-4-phenoxyphenyl successively added nitrobenzene phenol water 425ml solution containing sodium hydroxide 45g in 110.6g and 3,4-difluoronitrobenzene 85 g, was heated under reflux for 1.5 hours. The reaction solution was returned to room temperature, 3N hydrochloric acid was added thereto, and the mixture was neutralized and extracted with toluene. The organic layer was washed (in the order of water, 5% aqueous sodium hydroxide solution, water, and saturated saline) and dried (anhydrous magnesium sulfate), and then the organic layer was concentrated under reduced pressure to give 3-fluoro-4-phenoxynitrobenzene as yellow crystals. 118.8 g (9
5%).

M. p. 67.5-68.5 ° C.

2) 3-fluoro-4-phenoxyaceto
Anilide 3-fluoro-4-phenoxynitrobenzene 118.
7 g, iron powder 179.9 g and ammonium chloride 8.2
The mixture of 150 ml of an aqueous solution containing g was heated and stirred at 85 ° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, 500 ml of isopropanol was added, and the insoluble matter was removed by filtration through celite. After gradually adding 62.5 g of acetic anhydride to the filtrate, the mixture was stirred at room temperature for 10 minutes. 500 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed (in the order of water and n-hexane) to give 3-colorless crystals.
107.8 g of fluoro-4-phenoxyacetanilide
(86%).

M. p. 110-111 ° C (diethyl ether-n-hexane).

3) 5-Fluoro-2-nitro-4-fe
Nonoxyacetanilide 3-fluoro-4-phenoxyacetanilide 87.2
23.6 g of fuming nitric acid was gradually added to a 360 ml solution of acetic acid containing 60 g at 60 ° C. while heating and stirring, followed by stirring for 1 hour. The reaction solution was returned to room temperature, 750 ml of water was added, and the precipitate was collected by filtration and washed with water. The resulting crystals were recrystallized from ethyl acetate-n-hexane to give 5-fluoro-2-yellow crystals.
89.3 g of nitro-4-phenoxyacetanilide (8
6%).

M. p. 116.5-117.5 ° C.

4) 5- (3-fluorophenylthio)-
2-nitro-4-phenoxyaniline (the compound of the present invention)
Product) A suspension of 30 ml of isopropyl alcohol containing 3.0 g of 5-fluoro-2-nitro-4-phenoxyacetanilide, 1.5 g of 3-fluorothiophenol and 4.5 ml of a 20% aqueous sodium hydroxide solution at 60 ° C. Heated and stirred for hours. The reaction solution was returned to room temperature, water was added, and the precipitate was collected by filtration. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 3.6 g (96%) of 5- (3-fluorophenylthio) -2-nitro-4-phenoxyaniline as orange crystals.

M. p. 101-102.5 ° C.

Example 2 5- (3-chlorophenylthio) -2-nitro-4-f
Enoxyaniline 3-chlorothiophenol was used in place of 3- fluorothiophenol used in 4) of Example 1, and thioetherified according to the same method to give 5- (3-chlorophenylthio) -2-nitro. -4-phenoxyaniline was obtained.

M. p. 105.5-106.5 ° C (ethyl acetate-n-hexane).

Examples 3 to 10 1) 4- (2,4-difluorophenyloxy) -3-
Fluoronitrobenzene Instead of phenol used in 1) of Example 1, 2,4-
Etherification was performed using difluorophenol according to the same method to obtain 4- (2,4-difluorophenyloxy) -3-fluoronitrobenzene.

M. p. 40.5-41.5 ° C.

2) 4- (2,4-difluorophenylo )
Xy) -3-fluoroacetanilide 4- (2,4-difluorophenyloxy) -3-fluoronitrobenzene is reduced and acetylated by reducing the nitro group according to the method of 2) of Example 1 to give 4-
(2,4-Difluorophenyloxy) -3-fluoroacetanilide was obtained.

M. p. 117-118 ° C (dichloromethane-n-hexane).

3) 4- (2,4-difluorophenylo )
Xy) -5-fluoro-2-nitroacetanilide 4- (2,4-difluorophenyloxy) -3-fluoroacetanilide is converted to nitro group according to the method of 3) in Example 1 to give 4- ( 2,4-Difluorophenyloxy) -5-fluoro-2-nitroacetanilide was obtained.

M. p. 130.5-132 ° C (dichloromethane-n-hexane).

4) Thioether compound (compound of the present invention )
Compounds: Examples 3 to 10) 4- (2,4-difluorophenyloxy) -5-fluoro-2-nitroacetanilide, 3-fluorothiophenol, 3-chlorothiophenol, 3-aminothiophenol, 4- Thioetherification using aminothiophenol, 2-carboxythiophenol, 4- (2-carboxyethyl) thiophenol, 4-pyridylmercaptan or 1-mercaptonaphthalene, respectively, according to the method of 4) of Example 1 The nitroaniline compounds of the present invention shown in Table 1 (Examples 3 to 10)
Was obtained.

Example 11 5- (3-fluorophenylthio) -4- (4-isoprop
Ropirphenoxy) -2-nitroaniline 1) 4- (4-isopropylphenyloxy) -3-f
Phenol changed using 4-isopropyl phenol used Le Oro 1 nitrobenzene Example 1), by etherification in compliance with the method, 4- (4-isopropyl-phenyl) -3- fluoronitrobenzene Obtained.

NMR (200 MHz, CDCl ₃ ) δ: 1.26 (6H, d, J = 6H
z), 2.95 (1H, m), 6.94 (1H, t, J = 10Hz), 7.00 (2H, m), 7.28 (2
H, m), 7.95 (1H, m), 8.08 (1H, dd, J = 2,10Hz).

2) 4- (4-isopropylphenyloxy )
B) 3-Fluoroacetanilide 4- (4-isopropylphenyloxy) -3-fluoronitrobenzene is reduced and acetylated according to the method of 2) in Example 1 to give 4- (4-
(Isopropylphenyloxy) -3-fluoroacetanilide was obtained.

M. p. 124.5-126 ° C (dichloromethane-n-hexane).

3) 4- (4-isopropylphenyloxy )
B) -5-Fluoro-2-nitroacetanilide 4- (4-isopropylphenyloxy) -3-fluoroacetanilide is converted to nitro group according to the method of Example 1-3) to give 4- (4- (Isopropylphenyloxy) -5-fluoro-2-nitroacetanilide was obtained.

M. p. 79-80 ° C (ethyl acetate-n-
Hexane).

4) 5- (3-fluorophenylthio)-
4- (4-isopropylphenoxy) -2-nitroani
Phosphorus (compound of the invention ) 5-Fluoro-2-nitro-4 used in Example 1-4)
-4- (4-isopropylphenyloxy) -5-fluoro-2-nitroacetanilide was used instead of phenoxyacetanilide, and thioetherified according to the same method to give 5- (3-fluorophenylthio).
4- (4-Isopropylphenoxy) -2-nitroaniline was obtained.

M. p. 120-121 ° C (acetone).

Examples 12 and 13 1) 4- (2-isopropylphenyloxy) -3-f
Fluoronitrobenzene Using 2-isopropylphenol in place of the phenol used in Example 1-1) and performing etherification according to the same method, 4- (2-isopropylphenyloxy) -3-fluoronitrobenzene was converted. Obtained.

NMR (200 MHz, CDCl ₃ ) δ: 1.21 (6H, d, J = 6H
z), 3.15 (1H, m), 6.83 (1H, dd, J = 10,10Hz), 6.90 ~ 7.00 (1H,
m), 7.18 to 7.30 (2H, m), 7.40 (1H, m), 7.94 (1H, m), 8.10 (1H,
dd, J = 2,10Hz).

2) 4- (2-isopropylphenyloxy )
C) 3-Fluoroacetanilide 4- (2-isopropylphenyloxy) -3-fluoronitrobenzene is reduced and acetylated according to the method of Example 1-2) to give 4- (2-fluoroacetanilide).
(Isopropylphenyloxy) -3-fluoroacetanilide was obtained.

M. p. 84.5 to 86 ° C (toluene-n
-Hexane).

3) 4- (2-isopropylphenyloxy )
B) -5-Fluoro-2-nitroacetanilide 4- (2-isopropylphenyloxy) -3-fluoroacetanilide is converted to 4- (2-nitroacetanilide) by nitro groupation according to the method of Example 1-3). (Isopropylphenyloxy) -5-fluoro-2-nitroacetanilide was obtained.

NMR (200 MHz, CDCl ₃ ) δ: 1.25 (6H, d, J = 6H
z), 2.30 (3H, s), 3.26 (1H, m), 6.81 (1H, m), 7.19 (2H, m), 7.3
8 (1H, m), 7.74 (1H, d, J = 6Hz), 8.77 (1H, d, J = 12Hz).

4) Thioether compound (the compound of the present invention )
Compounds: Examples 12 and 13) Using 4- (2-isopropylphenyloxy) -5-fluoro-2-nitroacetanilide instead of 5-fluoro-2-nitro-4-phenoxyacetanilide of Example 1-4) Further, 3-chlorothiophenol or 4-mercaptopyridine was used in place of 3-fluorothiophenol, and thioetherification was carried out according to the method of Example 1-4), whereby the nitro compound of the present invention shown in Table 1 was obtained. An aniline compound (compounds of Examples 12 and 13) was obtained.

Examples 14 to 19 1) 3-Fluoro-4- (2-phenylphenyloxy )
B) Nitrobenzene 3-fluoro-4- (2-phenylphenyloxy) nitrobenzene was converted to ether by using 2-phenylphenol in place of the phenol used in Example 1-1) and performing etherification according to the same method. Obtained.

M. p. 73.5-75 ° C.

2) 3-Fluoro-4- (2-phenylf)
The nitro group is reduced and acetylated according to the method of Example 1-2) to give 3-fluoro- ( enyloxy) acetanilide 3-fluoro-4- (2-phenylphenyloxy) nitrobenzene.
4- (2-Phenylphenyloxy) acetanilide was obtained.

M. p. 174-175 ° C (ethyl acetate-
n-hexane).

3) 5-Fluoro-2-nitro-4- (2
-Phenylphenyloxy ) acetanilide Nitro- formation of 3-fluoro-4- (2-phenylphenyloxy) acetanilide according to the method of Example 1-3) gives 5-fluoro-2-nitro-4-.
(2-Phenylphenyloxy) acetanilide was obtained.

M. p. 89 to 90.5 ° C (ethyl acetate-
n-hexane).

4) Thioether compound (compound of the present invention )
Compounds: Examples 14 to 19) 5-Fluoro-2-nitro-4- (2-phenylphenyloxy) acetanilide, 3-fluorothiophenol, 3-chlorothiophenol, 3-methoxythiophenol, 4-pyridylmercaptan , 2-mercaptothiophene or 1-mercaptonaphthalene, respectively, and thioetherified according to the method of Example 1-4) to obtain the nitroaniline compound of the present invention shown in Table 1 (Examples 14 to 19). Compound) was obtained.

[0085]

[Table 1]

Example 20 5- (3-chlorophenylthio) -2-nitro-4-
(5,6,7,8-tetrahydronaphthalen-2-yl
Oxy) aniline 1) 3-fluoro-4- (5,6,7,8-tetrahydrid
(Ronaphthalen-2-yloxy) nitrobenzene Using 2-hydroxy-5,6,7,8-tetrahydronaphthalene instead of the phenol used in Example 1-1), and performing etherification according to the same method. 3-
Fluoro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) nitrobenzene was obtained.

M. p. 71-72 ° C.

2) 3-Fluoro-4- (5,6,7,8
-Tetrahydronaphthalen-2-yloxy) acetoa
Example 1 Nilide 3-fluoro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) nitrobenzene was used in Example 1.
By reducing and acetylating the nitro group according to the method of -2), 3-fluoro-4- (5,6,7,8-
Tetrahydronaphthalen-2-yloxy) acetanilide was obtained.

M. p. 164 to 166 ° C (ethyl acetate-
n-hexane).

3) 5-Fluoro-2-nitro-4-
(5,6,7,8-tetrahydronaphthalen-2-yl
Example 1 was performed using oxy) acetanilide 3-fluoro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) acetanilide.
By nitro grouping according to the method of -3), 5
-Fluoro-2-nitro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) anilide was obtained.

M. p. 105-107 ° C (diethyl ether-n-hexane).

4) 5- (3-chlorophenylthio) -2
-Nitro-4- (5,6,7,8-tetrahydronaphtha
Len-2-yloxy) aniline (compound of the present invention) using 5-fluoro-2-nitro-4- (5,6,7,8-tetrahydronaphthalen-2-yloxy) acetanilide and 3-chlorothiophenol Example 1-4)
By thioetherification according to the method of 5-
(3-chlorophenylthio) -2-nitro-4- (5,
6,7,8-Tetrahydronaphthalen-2-yloxy) aniline (the compound of the present invention) was obtained.

M. p. 128-129 ° C (ethyl acetate).

Example 21 5- (3-Fluorophenylsulfinyl) -2-nitto
B-4 -Phenyloxyaniline m-chloroperbenzoic acid in a 30 ml solution of chloroform containing 1.5 g of 5- (3-fluorophenylthio) -2-nitro-4-phenoxyaniline obtained by the method of Example 1 under ice-cooling. After adding 1.1 g of acid and stirring for 2 hours, water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed (saturated sodium bicarbonate, water, and saturated saline) and dried (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 = 1: 1 to 1: 4) and recrystallized from acetone to give 5- (3-
0.6 g (36%) of (fluorophenylsulfinyl) -2-nitro-4-phenyloxyaniline were obtained.

M. p. 208-208.5 ° C.

Examples 22 to 40 The compounds of the present invention obtained by the methods of Examples 2 to 20 were oxidized according to the method of Example 21 to give the nitro compounds of the present invention shown in Tables 2 and 3. An aniline compound was obtained.

[0097]

[Table 2]

[0098]

[Table 3]

Example 41 5- (3-fluorophenylsulfonyl) -2-nitro
-4-phenyloxyaniline 0.50 g of 5- (3-fluorophenylthio) -2-nitro-4-phenoxyaniline obtained by the method of Example 1.
Was added to 20 ml of a chloroform solution containing m-chloroperbenzoic acid under ice cooling, followed by stirring at room temperature for 1 hour. Water was added to the reaction solution, and extracted with chloroform. After washing the organic layer (saturated sodium hydrogen carbonate) and drying (anhydrous magnesium sulfate), the extract was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1: 1), and then recrystallized from ethanol to give 5- (3-fluorophenylsulfonyl) -2-nitro-. 0.3 g (48%) of 4-phenyloxyaniline was obtained.

M. p. 201-202 ° C.

Examples 42 to 48 The compounds of the present invention obtained by the methods of Examples 2, 3, 11, 13, 16, 18 and 20 were oxidized according to the method of Example 41 to give Table 4. The nitroaniline compound of the present invention shown in (1) was obtained.

[0102]

[Table 4]

Test Example 1 Inhibitory effect of IL-1β and 6 production [Test method] Heparin-treated normal human peripheral blood was overlaid on lymphoprep (Daiichi Pharmaceutical Co., Ltd.) under aseptic conditions to remove red blood cells. 10%, penicillin 100U /
RPM containing 100 ml / ml, streptomycin 100 U / ml, Hepes buffer 10 mM and L-glutamine 2 mM
The cells were suspended in I-1640 medium (Gibco) to obtain 2 cells.
It was adjusted to × 10 ⁶ cells / ml.

[0104] After the sample is dissolved in ethanol,
It was prepared by diluting with the above medium solution so that the final concentration of ethanol became 0.05%.

500 μl of the prepared cell suspension, ConA
2.0 μg (Sigma) and 250 μl of the above-described medium solution of the test compound (the compound of the present invention) were added to a flat-bottomed 24-well plate (manufactured by Iwaki Glass), and cultured in a 5% CO ₂ incubator for 48 hours. After culturing, I in the cell supernatant
ELISA for L-1β and IL-6 levels (pg / ml)
The measurement was performed using a kit (Amersham), 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).

[Production inhibition rate (%) = (1−T / C) × 1
00: T is the amount of IL-1β or IL-6 produced at each concentration of the test compound, and C is the amount of control IL-1β or IL-6 produced].

[Results] Table 5 shows the test results.

[0108]

[Table 5]

Test Example 2 Inhibitory Effect on IL-5 Production [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 RPMI-1640 medium (Gibco) supplemented with mM and 0.05 mM β-mercaptoethanol to adjust the cell number to 2 × 10 ⁵ cells / ml.

The antigen-presenting cells were obtained from C3 / Hen mice (8
Spleen cells (week-old, female) were suspended in RPMI-1640 medium (Gibco), incubated with 30 μg / ml of mitomycin C at 37 ° C. for 30 minutes, and washed three times with the above medium to reduce the number of cells to 1 × 10 ^6. It was adjusted to cells / ml.

[0111] After the sample is dissolved in ethanol,
It was prepared by diluting with the above medium solution so that the final concentration of ethanol was 0.03%.

Prepared D10. 100 μl each of cell suspensions of G4.1 cells and antigen-presenting cells, 400 μg / ml of ConA (Sigma) and 10 μl of each of the above-mentioned medium solutions of test compounds (compounds of the present invention) in V-bottom 96-well plates (Nippon Intermed Co., Ltd.) 5% CO ₂
The cells were cultured in an incubator at 37 ° C. for 48 hours. After culturing, IL-5 (pg / ml) was analyzed by ELISA in the cell supernatant.
The measurement was performed using an A 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).

[Production suppression rate (%) = (1−T / C) × 1
00: 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].

[Results] Table 6 shows the test results.

[0115]

[Table 6]

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 31/195 ABF A61K 31/195 ABF 31/38 ADF 31/38 ADF C07C 317/48 7419-4H C07C 317/48 323/37 7419-4H 323/37 323/63 7419-4H 323/63 C07D 213/70 C07D 213/70 333/34 333/34

Claims (1)

[Claims] (1) Formula (1) (Wherein, R ¹ is a tetrahydronaphthyl group, a phenyl group,
Or "carbon atoms 1-5 alkyl group, a halogen atom or a phenyl group" indicates one or two at a substituted phenyl group, R ² is a pyridyl group, a thienyl group, a naphthyl group, or "halogen atom, Amino group, 1 carbon atom
5 alkoxy group, a carboxy group or a phenyl group substituted with -C 2-6 carboxyalkyl group ", X is -S -, - SO- or -SO ₂ - in the group represented by is there. 4-aryloxy- represented by
5-arylthionitroaniline compounds or salts thereof.