JPH05201958A - 5-aminosulfonanilide compound - Google Patents

Abstract

(57) [Summary] [Objective] To provide a compound having an excellent anti-inflammatory action and less side effects such as digestive tract disorders. [Structure] Expression [In the formula, R ¹ represents an alkyl group, R ² represents a cycloalkyl group, R ³ represents a hydrogen atom, an alkyl group, an alkanoyl group or an alkylsulfonyl group, and R ⁴ represents a hydrogen atom, an alkyl group, a cycloalkyl group. Group, cycloalkylmethyl group, alkenyl group, phenyl group, amino group, formula-
CO-R ⁶ (wherein, R ⁶ is a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkoxy group, an alkylamino group, a phenyl group or a thienyl group.) Group or the formula -SO ₂ represented by H-R ⁷ (in the formula, R ⁷
It represents an alkyl group, a phenyl group or a cenyl group. ), Or R ³ and R ⁴ together with the adjacent nitrogen atom represent a heterocycle, R ⁵ represents a hydrogen atom or an alkanoyl group, and X represents an oxygen atom, a sulfur atom, or sulfinyl. Represents a group or a sulfonyl group. ] The compound represented by.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 5-aminosulfonanilide compound and its salt having anti-inflammatory action, antipyretic action, analgesic action and antiallergic action.

[0002]

2. Description of the Related Art As sulfone anilide compounds having an anti-inflammatory action, US Pat. No. 3,840,597,
No. 3,806,024, JP-A-61-105.
The compounds described in JP-A No. 48, JP-A No. 63-190869, and JP-A No. 2-268 are known.

[0003]

A drug having an anti-inflammatory action has a problem of gastrointestinal disorders as a clinical side effect. The present invention is more excellent in anti-inflammatory action, antipyretic action, analgesic action and antiallergic action as compared with conventional compounds,
Moreover, it is an object of the present invention to provide a highly safe new compound with few side effects such as gastrointestinal disorders.

[0004]

Means for Solving the Problems As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have shown the following 5-
The inventors have found that an aminosulfoneanilide compound can achieve the object, and completed the present invention.

The present invention has the formula

[0006]

[In the formula, R ¹ represents an alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom, and R ^1
2 represents a cycloalkyl group having 3 to 8 carbon atoms, R ³
Is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms or 1 to 5 carbon atoms
Is an alkylsulfonyl group, R ⁴ is a hydrogen atom,
Even if it is substituted with "hydroxyl group, alkoxy group having 1 to 5 carbon atoms, alkylamino group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, carboxyl group or phenyl group" Good alkyl group having 1 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, cycloalkylmethyl group having 4 to 9 carbon atoms, alkenyl group having 3 to 5 carbon atoms, phenyl group , An amino group which may be substituted with an alkyl group having 1 to 3 carbon atoms, a formula —CO—R ⁶ (in the formula, R ⁶ is a hydrogen atom, “a halogen atom, an alkoxy having 1 to 5 carbon atoms). Group or phenyl group ", which may be substituted with 1 to 1 carbon atoms.
8 alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, alkenyl groups having 2 to 5 carbon atoms, alkoxy groups having 1 to 5 carbon atoms that may be substituted with halogen atoms, carbon It represents an alkylamino group having 1 to 5 atoms, a phenyl group which may be substituted with a halogen atom, or a thienyl group. ) Or a group represented by the formula —SO ₂
—R ⁷ (in the formula, R ⁷ represents an alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom, a phenyl group which may be substituted with a halogen atom or a thienyl group). Or R ³ and R ⁴ together with the adjacent nitrogen atom represent a 5- or 6-membered heterocycle, and R ⁵ is a hydrogen atom or an alkanoyl group having 2 to 6 carbon atoms. X represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group. ] It is a compound represented by these, and its salt.

In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Moreover, an alkyl group, an alkoxy group, and an alkoxycarbonyl group mean a linear or branched one. R
¹ , the alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom is an alkyl group which may be substituted with 1 to 3 halogen atoms, for example, a methyl group, fluoromethyl Group, chloromethyl group, bromomethyl group, trifluoromethyl group, trichloromethyl group, ethyl group, n-propyl group, isopropyl group, 3-chloropropyl group, n-butyl group, t-butyl group, n-pentyl group, etc. Is. The alkenyl group having 3 to 5 carbon atoms of R ⁴ and R ⁶ is a linear or branched alkenyl group, and examples thereof include allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group. Group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-
2-propenyl group and the like. The alkoxy group having 1 to 5 carbon atoms which may be substituted with a halogen atom of R ⁶ is an alkoxy group which may be substituted with 1 to 3 halogen atoms, for example, a methoxy group, an ethoxy group. ,
2,2,2-trichloroethoxy group, 2,2,2-trifluoroethoxy group, n-propoxy group, isopropoxy group, 3-chloropropoxy group, n-butoxy group, t-
Examples thereof include butoxy group, 4-chlorobutoxy group, n-pentyloxy group and the like. The phenyl group which may be substituted with a halogen atom of R ⁶ and R ⁷ is a phenyl group which may be substituted with 1 or 2 halogen atoms, and examples thereof include a 1-chlorophenyl group and a 1-fluorophenyl group. Two
-Chlorophenyl group, 2-fluorophenyl group, 3-chlorophenyl group, 3-fluorophenyl group, 4-bromophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 2,4-dibromophenyl group, 2,4- Examples include a dichlorophenyl group and a 2,4-difluorophenyl group. The thienyl group is a 1-thienyl group or a 2-thienyl group. The 5-membered or 6-membered heterocycle includes a nitrogen atom or a nitrogen atom and an oxygen atom, and examples thereof include a 1-pyrrolidinyl group, a piperidino group and a morpholino group. The alkanoyl group having 2 to 6 carbon atoms of R ⁵ is a linear or branched alkanoyl group, for example, an acetyl group, a propionyl group, a butyryl group,
2-methylpropionyl group, 2-methylbutyryl group, 3
-Methylbutyryl group, 2,2-dimethylpropionyl group and the like. The salt of the compound of formula (I) is an alkali metal salt with sodium, potassium, etc., an alkaline earth metal salt with calcium, magnesium, etc., an ammonium salt, methylamine, ethylamine, butylamine, dimethylamine, diethylamine, triethylamine, triethylamine. It is a salt with an organic base such as butylamine, ethanolamine, pyridine, lysine, and arginine.

Preferred compounds in the present invention are R ² is a cycloalkyl group having 5 to 7 carbon atoms, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or a carbon atom which may be substituted with a hydroxyl group. An alkyl group having 1 to 8 atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 5 carbon atoms or a formula —CO—R ⁶ ′ (wherein R ⁶ ′ is a halogen atom) Represents an alkyl group having 1 to 8 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, which may be substituted with, and R ⁵ is a hydrogen atom or 2 carbon atoms. To 6 alkanoyl groups, and X is an oxygen atom.

The compound of formula (I) of the present invention can be produced, for example, by the method shown below. (1) In the formula (I), R ⁵ and R ³ are hydrogen atoms, X is an oxygen atom or a sulfur atom, R ⁴ is a hydrogen atom, “hydroxyl group, alkoxy group having 1 to 5 carbon atoms, carbon Alkylamino group having 1 to 3 atoms, 2 to carbon atoms
1 to 6 carbon atoms optionally substituted with 6 alkoxycarbonyl groups, carboxyl groups or phenyl groups
8 alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, cycloalkylmethyl groups having 4 to 9 carbon atoms,
In the case of a compound which is an alkenyl group having 3 to 5 carbon atoms, a phenyl group or an amino group which may be substituted with an alkyl group having 1 to 3 carbon atoms:

[0011]

A compound represented by the formula (wherein R ¹ and R ² have the same meanings as described above and Y represents an oxygen atom or a sulfur atom) can be obtained as a starting material [of the formula (II) The compound can be obtained from a known compound by the method described in Japanese Patent Application No. 3-126999 (or according to the method described in Japanese Patent Application No. 3-126999). ]. That is, in the compound of formula (II), the formula R ⁸ —NH ₂ (III) (in the formula, R ⁸ is a hydrogen atom, “hydroxyl group, 1 to 5 carbon atoms)
Alkoxy groups, alkylamino groups having 1 to 3 carbon atoms, alkoxycarbonyl groups having 2 to 6 carbon atoms,
An alkyl group having 1 to 8 carbon atoms which may be substituted with a carboxyl group or a phenyl group, and 3 carbon atoms
Substituted with a cycloalkyl group having 8 to 8 carbon atoms, a cycloalkylmethyl group having 4 to 9 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a phenyl group or an alkyl group having 1 to 3 carbon atoms Is an amino group. ) By reacting a compound represented by the formula

[0013]

The compound of the present invention represented by the formula (wherein R ¹ , R ² , R ⁸ and Y are as defined above) can be obtained. This reaction is preferably carried out in the presence of a base, and as the base, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate, Alkali metal hydrogencarbonates such as potassium hydrogencarbonate, alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium metal and sodium amide, or triethylamine, tributylamine, 1,5-diazabicyclo [4.3. Organic bases such as 0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, and N, N-dimethylaminopyridine can be used. The compound of formula (III) can also be used as a base. This reaction is solvent-free or water, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene, xylene,
Pyridine, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propanol,
It can be performed by arbitrarily selecting a solvent such as dichloromethane or chloroform. In addition, the compound of formula (III) and the base may be used as a solvent. In this reaction, quaternary ammonium salts such as potassium iodide, tetra-n-butylammonium chloride, benzyltriethylammonium chloride and benzyltriethylammonium bromide, crown ethers such as 18-crown-6 ether are added to effect the reaction. You can also accelerate.

(2) In the formula (I), R ⁵ is a hydrogen atom, X is an oxygen atom or a sulfur atom, and a substituent group
NR ³ R ³ and R ⁴ R ⁴ are the same or different or an alkyl group having 1 to 5 carbon atoms and, or R ³ and R ⁴ 5-membered ring together with the adjacent nitrogen atom, or In the case of a compound which is a 6-membered heterocycle, it can be obtained by reacting the compound of formula (II) as a starting material in the same manner as in the above (1).

(3) In formula (I), R ⁵ is a hydrogen atom, X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, and R ⁴ is of the formula —CO—R ⁶ (wherein R ⁶ has the same meaning as above.) Or the formula —SO ₂ —R ⁷ (in the formula,
R ⁷ has the same meaning as described above. In the case of a compound represented by the formula (4), 4-fluoro-3-nitroaniline can be obtained as a starting material. That is, 4-fluoro-3-nitroaniline is represented by the formula R ⁹ —OH (IV) [wherein R ⁹ is the formula —CO—R ⁶ (wherein R ⁶ has the same meaning as described above). Or a group of the formula --SO ₂ --R ⁷
(In the formula, R ⁷ has the same meaning as described above.). ] Or a reactive derivative thereof (for example, an acid halide, an acid anhydride, etc.)

[0017]

A compound represented by the formula (wherein R ⁹ has the same meaning as described above) can be obtained. In this reaction,
When the compound of formula (IV) is used, it is preferably carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide. When the reactive derivative of the compound of formula (IV) is used, it is preferably carried out in the presence of a base, and as the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, hydrogen carbonate is used. Inorganic bases such as potassium or triethylamine, tributylamine, 1,5-diazabicyclo [4.3.
0] -5-nonene, 1,8-diazabicyclo [5.4.
An organic base such as 0] -7-undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine, N, N-dimethylaminopyridine can be arbitrarily selected and used. This reaction is usually carried out in a solvent, and as the solvent, dichloromethane, chloroform, ethyl acetate, dioxane, tetrahydrofuran, ethyl ether, benzene,
Toluene, xylene, acetone, acetonitrile, water,
Pyridine, N, N-dimethylformamide, dimethylsulfoxide and the like can be mentioned.

Next, the compound of the formula (V) is reacted with a compound of the formula R ² -YH (VI) (wherein R ² and Y have the same meanings as described above) in the presence of a base. By the formula

[0020]

A compound represented by the formula (wherein R ² , R ⁹ and Y are as defined above) can be obtained. In this reaction, as the base, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide,
Use alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, sodium metal and sodium amide. You can This reaction is solvent-free or a solvent such as dioxane, tetrahydrofuran, ethyl ether, petroleum ether, pentane, hexane, cyclopentane, cyclohexane, benzene, toluene, xylene, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane and chloroform. Can be done in In addition, in this reaction,
The reaction can also be accelerated by adding a quaternary ammonium salt such as potassium iodide, tetra-n-butylammonium chloride, benzyltriethylammonium chloride or benzyltriethylammonium bromide, or a crown ether such as 18-crown-6 ether. ..

Then, the nitro group of the compound of formula (VII) is reduced to an amino form. The reduction may be 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, reduction using sodium sulfide-ammonium chloride. , Sodium borohydride,
Reduction using lithium aluminum hydride or the like can be mentioned. The solvent used in this reaction may be arbitrarily selected depending on the reduction method, and generally, alcohols such as methanol, ethanol, propanol, etc., water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile and the like can be used.

Subsequently, the amino compound obtained above and a sulfonic acid compound represented by the formula R ¹ -SO ₃ H (VIII) (wherein R ¹ has the same meaning as described above) or its reactive derivative ( (Eg, acid halide, acid anhydride, etc.)

[0024]

A compound represented by the formula (wherein R ¹ , R ² , R ⁹ and Y are as defined above) can be obtained. This reaction can be carried out by a usual method for sulfonylating an amino group, but when a sulfonic acid compound is used, it is preferably carried out in the presence of a condensing agent such as N, N′-dicyclohexylcarbodiimide. Also, the formula (VI
When the reactive derivative of the compound of II) is used, it is preferably carried out in the presence of a base, and as the base, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, hydrogen carbonate. Inorganic base such as potassium or triethylamine, tributylamine, 1,5-diazabicyclo [4.3.0] -5
-Nonene, 1,8-diazabicyclo [5.4.0] -7
Organic bases such as undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine and N, N-dimethylaminopyridine can be used. This reaction is usually carried out in a solvent, and as the solvent, dichloromethane, chloroform, ethyl acetate, dioxane, tetrahydrofuran,
Ethyl ether, benzene, toluene, xylene, acetone, acetonitrile, water, pyridine, N, N-dimethylformamide, dimethyl sulfoxide and the like can be used.

Finally, by nitrating the compound of formula (IX) with a nitrating agent such as nitric acid or a nitrate, the formula

[0027]

The compound of the present invention represented by the formula (wherein R ¹ , R ² , R ⁹ and Y are as defined above) can be obtained. In this reaction, sodium nitrate, potassium nitrate, iron nitrate, urea nitrate or the like can be used as the nitrate. This reaction is solvent-free or acetic acid, acetic anhydride,
It can be carried out in a solvent such as trifluoroacetic acid, sulfuric acid, dichloromethane, chloroform, benzene, dioxane or ethanol, and the solvent used is preferably selected arbitrarily according to the nitrating agent.

(4) In formula (I), R ⁵ and R ³ are hydrogen atoms, X is an oxygen atom or a sulfur atom, and R
⁴ is a hydrogen atom, "hydroxyl group, alkoxy group having 1 to 5 carbon atoms, alkylamino group having 1 to 3 carbon atoms, alkoxycarbonyl group having 2 to 6 carbon atoms, carboxyl group or phenyl group" Optionally substituted alkyl group having 1 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, cycloalkylmethyl group having 4 to 9 carbon atoms, and 3 to 5 carbon atoms A compound which is an alkenyl group, a phenyl group or an amino group which may be substituted with an alkyl group having 1 to 3 carbon atoms can also be obtained by the following method. That is, in the formula (VII), R ⁹ is a lower alkanoyl group (acetyl group, propionyl group, etc.)

[0030]

(Wherein R ² and Y have the same meanings as described above) or a salt thereof (salts are hydrochloride, hydrobromide, sulfate, nitrate, perchloric acid). Inorganic salts such as salts or organic acid salts such as formates, acetates, propionates, trifluoroacetates, methanesulfonates, paratoluenesulfonates) and the formula R ⁸ —OH (XI) (In the formula, R ⁸ has the same meaning as above.) Or a reactive derivative thereof (for example, an acid halide,
Acid anhydride and the like) by reacting in the same manner as in the above (3),

[0032]

A compound represented by the formula (wherein R ² , R ⁸ and Y are as defined above) can be obtained. Hydrolysis in this reaction is a usual hydrolysis method under acidic conditions or basic conditions, for example, under basic conditions lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, Examples thereof include a method using sodium ethoxide, potassium t-butoxide and the like, and a method using hydrochloric acid, hydrobromic acid, sulfuric acid and the like under acidic conditions. Examples of the solvent used in this reaction include water, methanol, ethanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, and the like.
It is preferable to select appropriately depending on the conditions of hydrolysis.

Subsequently, the compound of formula (XII) was added to the above (3).
The compound of the present invention can be obtained by reducing, sulfonylating, and finally nitrating the nitro group in the same manner as in.

(5) In formula (I), R ⁵ is a hydrogen atom, X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom, and R ⁴ is of the formula —CO—R ⁶ (wherein R ⁶ has the same meaning as above.) Or a compound represented by the formula —SO ₂ —R ⁷ (wherein R ⁷ has the same meaning as described above) can be obtained by the following method. You can That is, 2-fluoro-5-nitroaniline was converted to the formula (VI
II) or a reactive derivative thereof (for example, an acid halide, an acid anhydride, etc.) is reacted with a compound of formula (VI)

[0036]

A compound represented by the formula (wherein R ¹ , R ² and Y are as defined above) can be obtained. Then, the nitro group of the compound of formula (XIII) is reduced to an amino form. The compound of formula (IX) can be obtained by subsequently reacting the amino compound obtained above with the compound of formula (IV) or its reactive derivative (eg, acid halide, acid anhydride, etc.). The series of reactions up to this point can be carried out in the same manner as the above-mentioned reaction (3). Finally, the compound of formula (IX) can be converted to the compound of formula (Ib) (the compound of the present invention) according to the method of (3).

(6) In the formula (I), R ⁵ is a hydrogen atom, X is an oxygen atom or a sulfur atom, R ³ is an alkyl group having 1 to 5 carbon atoms, and R ⁴ is a carbon atom. In the case of a compound which is an alkanoyl group having 2 to 6 carbon atoms or an alkylsulfonyl group having 1 to 5 carbon atoms, in the formula (VII), R ⁹ is an alkanoyl group having 2 to 6 carbon atoms or 1 to 5 carbon atoms. Compounds having one alkylsulfonyl group, formula

[0039]

(In the formula, R ² and Y have the same meanings as described above, and R ¹⁰ represents an alkanoyl group having 2 to 6 carbon atoms or an alkylsulfonyl group having 1 to 5 carbon atoms.)
The compound represented by can be obtained as a starting material.

That is, a compound of formula (XIV) and a compound of formula R ¹¹ -Z (wherein R ¹¹ represents an alkyl group having 1 to 5 carbon atoms, Z is a chlorine atom, a bromine atom, an iodine atom, methane) A compound represented by a leaving group such as a sulfonyloxy group is represented by the formula:

[0042]

A compound represented by the formula (wherein R ² , R ¹⁰ , R ¹¹ and Y have the same meanings as described above) can be obtained. This reaction is preferably carried out in the presence of a base, and as the base, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonate such as potassium hydrogen carbonate,
Alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as metal sodium, metal potassium and sodium amide, or triethylamine, tributylamine, 1,5-diazabicyclo [4.3.0]-
5-nonene, 1,8-diazabicyclo [5.4.0]-
7-undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine, N, N-dimethylaminopyridine, butyllithium, lithium diisopropylamide,
Organic bases such as lithium dicyclohexylamide can be used. This reaction is solvent-free or water, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene,
Xylene, pyridine, N, N-dimethylformamide,
It can be performed by arbitrarily selecting a solvent such as dimethyl sulfoxide, acetonitrile, dichloromethane and chloroform. In this reaction, potassium iodide,
Quaternary ammonium salts such as tetra-n-butylammonium chloride, benzyltriethylammonium chloride and benzyltriethylammonium bromide, 18-
The reaction can also be accelerated by adding a crown ether such as crown-6 ether.

Then, the compound of formula (XV) is added to the above (3).
By reducing the nitro group of the compound of formula (VII), sulfonylating the amino group, and then reacting in the same manner as in the reaction sequence of nitration,

[0045]

The compound of the present invention represented by the formula (wherein R ¹ , R ² , R ¹⁰ , R ¹¹ and Y have the same meanings as described above) can be obtained.

(7) In the formula (I), R ⁵ is a hydrogen atom, X is an oxygen atom or a sulfur atom, R ³ and R ⁴ are the same or different and are an alkanoyl group having 2 to 6 carbon atoms, or In the case of a compound having an alkylsulfonyl group having 1 to 5 carbon atoms, the compound of the formula (XIV) can be obtained as a starting material as follows. That is, a compound represented by the formula (XIV) and a compound represented by the formula R ¹⁰ —OH (XVI) (wherein R ¹⁰ has the same meaning as described above) or a reactive derivative thereof (for example, an acid halide,
Acid anhydride, etc.)

[0048]

A compound represented by the formula (wherein R ² , R ¹⁰ and Y have the same meanings as described above) can be obtained. This reaction is preferably carried out in the presence of a base, and as the base, lithium hydroxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonate such as potassium hydrogen carbonate, alkali metal hydride such as sodium hydride and potassium hydride, inorganic base such as metal sodium, metal potassium and sodium amide or triethylamine, tributylamine, 1,5-diazabicyclo [4 .3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine, N, N-dimethylaminopyridine, butyllithium, Lithium diisopropylamide, lithium dicyclohexyl It can be used organic bases such as amides. In this reaction, no solvent or dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene, xylene,
Solvents such as pyridine, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane and chloroform can be arbitrarily selected and used.
In addition, in this reaction, potassium iodide, tetra-n
-Quaternary ammonium salts such as butylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium bromide, 18-crown-
6 The reaction can also be accelerated by adding a crown ether such as ether.

Then, the compound of the formula (XVII) is reacted in the same order as in the above reaction (3) in which the nitro group of the compound of the formula (VII) is reduced, the amino group is sulfonylated, and then nitrated. By the formula

[0051]

The compound of the present invention represented by the formula (wherein R ¹ , R ² , R ¹⁰ and Y are as defined above) can be obtained.

(8) In the formula (I), R ⁵ is a hydrogen atom, X is an oxygen atom or a sulfur atom, R ³ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms,
In the case of a compound in which R ⁴ is a hydrogen atom, in the formula (I), R ³ is a hydrogen atom or has 1 to 1 carbon atoms.
Is an alkyl group having 5 alkyl groups and R ⁴ is an alkanoyl group having 2 to 9 carbon atoms;

[0054]

(In the formula, R ¹ , R ² and Y have the same meanings as defined above, R ¹² represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and R ¹³ represents 2 to 9 carbon atoms. The compound of the present invention can be obtained by hydrolyzing the compound represented by alkanoyl group. Hydrolysis in this reaction is a usual hydrolysis method under acidic conditions or basic conditions, for example, under basic conditions lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide,
Examples thereof include a method using sodium ethoxide, potassium t-butoxide and the like, and a method using hydrochloric acid, hydrobromic acid, sulfuric acid and the like under acidic conditions. The solvent used in this reaction is water, methanol, ethanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene,
Examples thereof include xylene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like, but it is preferable to select them appropriately depending on the hydrolysis conditions.

(9) In the case where X is a sulfinyl group or a sulfonyl group in the formula (I): It can be obtained by oxidizing a compound of the formula (I) in which X is a sulfur atom. Oxidation in this reaction is a usual oxidation reaction that oxidizes sulfide to sulfoxide or sulfone, and examples thereof include hydrogen peroxide, t-butyl hydroperoxide, metachloroperbenzoic acid, peracetic acid, sodium metaperiodate, Examples thereof include a method using sodium bromate, sodium hypochlorite, periodobenzene and the like. The solvent used in this reaction is methanol, ethanol, n-propanol, isopropanol, dichloromethane, chloroform, dioxane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene. ,
Pyridine, N, N-dimethylformamide, water and the like can be mentioned, but it is preferable to select appropriately depending on the oxidation reaction.

(10) The salt of the compound of formula (I) can be obtained by treating the compound of formula (I) in which R ⁵ is hydrogen atom with a base in water or an organic solvent. Here, the base is an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, an alkali such as sodium carbonate or potassium carbonate. Carbonates, inorganic bases such as ammonia, sodium methoxide, sodium ethoxide, alcoholates such as potassium t-butoxide, methylamine, ethylamine, butylamine, dimethylamine, diethylamine,
Organic amines such as triethylamine, tributylamine, ethanolamine, pyridine, lysine and arginine can be mentioned. The organic solvent used is arbitrarily selected depending on the base, but methanol, ethanol, t-butanol, ethyl ether, tetrahydrofuran, dioxane, acetonitrile, benzene, toluene, xylene,
Examples include dichloromethane and chloroform.

[0058] (11) R ¹ -SO ₂ where R ⁵ is a compound which is a 2 to 6 alkanoyl group having a carbon atom R ⁵ is a compound of formula (I) is a hydrogen atom in (I)
A compound represented by the formula R ¹⁴ —OH (XIX) (wherein R ¹⁴ is R ⁵ other than a hydrogen atom) or a reactive derivative thereof (acid halide, acid anhydride, etc.) It can be obtained by using and alkanoylating. When the compound of formula (XIX) is used, this reaction is preferably carried out in the presence of a condensing agent such as N, N′-dicyclohexylcarbodiimide. When a reactive derivative of the compound of the formula (XIX) is used, it is preferably carried out in the presence of a base, and examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and carbonates. Alkali metal carbonates such as sodium and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, metal sodium, metal potassium and sodium amide Inorganic base or triethylamine, tributylamine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Organic compounds such as 1,8-diazabicyclo [5.4.0] -7-undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine, N, N-dimethylaminopyridine, butyllithium, lithium diisopropylamide, lithium dicyclohexylamide A base can be used. In this reaction, no solvent or dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane,
A solvent such as cyclohexane, benzene, toluene, xylene, pyridine, N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, dichloromethane or chloroform can be arbitrarily selected and used. In this reaction, potassium iodide and tetra-n-
Quaternary ammonium salts such as butylammonium chloride, benzyltriethylammonium chloride and benzyltriethylammonium bromide, 18-crown-6
The reaction can also be accelerated by adding crown ether such as ether.

The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. These include, for example, tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, injections and the like, all of which can be produced by a usual method. When used as an anti-inflammatory agent, antipyretic agent, analgesic agent, and antiallergic agent for humans, the dose is usually 5 to 1000 mg per day, although it varies depending on age, body weight, symptoms, administration route, number of administrations, and the like.

[0060]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits a strong anti-inflammatory action, antipyretic action, analgesic action, antiallergic action and the like, and has few side effects such as gastrointestinal disorders, etc. Is useful as

[0061]

EXAMPLES Next, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples. Reference Example 1 (1) Cyclohexane 164 containing 24.0 g of powdered sodium hydroxide and 5.0 g of cyclohexanol
To the ml suspension, 15.4 g of 2,5-difluoronitrobenzene was added under ice cooling, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution and extracted with cyclohexane, and the organic layer was washed with water,
The extract was washed with saturated saline in this order and dried over anhydrous magnesium sulfate. The oil obtained by distilling off the solvent was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 20: 1), and 20.5 g of yellow oily 2-cyclohexyloxy-5-fluoronitrobenzene was obtained.
Got NMR (CDCl ₃ ) δppm: 1.24 to 2.14
(10H, m), 4.35 (1H, m), 7.07 (1
H, dd, J = 4Hz, 8Hz), 7.23 (1H,
m), 7.54 (1 H, dd, J = 4 Hz, 7 Hz) (2) 2-cyclohexyloxy-5-fluoronitrobenzene 20.0 g and 5% palladium-carbon 1.0
A 167 ml ethanol solution containing g was stirred at room temperature under a hydrogen atmosphere and catalytically reduced. The palladium-carbon was filtered off, and the filtrate was concentrated to give 2-cyclohexyloxy-5-fluoroaniline (17.1 g) as a colorless oil. NMR (CDCl ₃ ) δppm: 1.14 to 2.16
(10H, m), 3.88 (1H, br), 4.11
(1H, m), 6.33 (1H, dt, J = 2Hz, 7
Hz), 6.42 (1H, dd, J = 2Hz, 8H
z), 6.70 (1 H, dd, J = 4 Hz, 7 Hz) (3) A solution of 2-cyclohexyloxy-5-fluoroaniline (16.0 g) and triethylamine (8.5 g) in dichloromethane (76.5 ml) under ice cooling, Methanesulfonyl chloride (9.6 g) was added over 30 minutes, and the mixture was further stirred for 1 hour. Water was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water, 3N hydrochloric acid, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 17.8 g of colorless prism crystals of N- (2-cyclohexyloxy-5-fluorophenyl) methanesulfonamide. m. p. 93-94 ° C. (4) Acetic acid 3 containing 9.7 g of N- (2-cyclohexyloxy-5-fluorophenyl) methanesulfonamide
To a 4 ml solution, under heating and stirring at 95 ° C, 60% nitric acid 3.7 was added.
g was added over 50 minutes and stirred for another 30 minutes. The reaction solution was returned to room temperature, water was added, the precipitate was collected by filtration, and recrystallized with ethanol to give N- (2-cyclohexyloxy-5-fluoro-4-nitrophenyl) methanesulfonamide as pale yellow needle crystals. 7.3 g was obtained. m. p. 147-148 ° C

Reference Example 2 In Reference Example 1, cyclopentanol was used in place of cyclohexanol in Reference Example 1 (1), and Reference Example 1
N- (2-cyclopentyloxy-5-fluoro-4-nitrophenyl) chloromethanesulfonamide [m] in the same manner as in Reference Example 1 except that chloromethanesulfonyl chloride was used instead of methanesulfonyl chloride in (3). ． p. 153.5-154.5 ° C. (acetone-ethanol: hereinafter, the solvent in the parentheses after the melting point indicates the recrystallization solvent used).

Example 1 N- (2-cyclohexyloxy-5-obtained in Reference Example 1
A 4.0 ml solution of methanol-tetrahydrofuran (1: 1) containing 0.54 g of fluoro-4-nitrophenyl) methanesulfonamide, 0.27 g of sodium carbonate and 0.4 ml of a 40% methylamine methanol solution was refluxed for 3 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline in this order,
It was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 0.36 g of N- (2-cyclohexyloxy-5-methylamino-4-nitrophenyl) methanesulfonamide as red-orange plate crystals. m. p. 148-149 ° C

Example 2 N- (2-cyclohexyloxy-5-obtained in Reference Example 1
A tetrahydrofuran 8.0 ml solution containing 1.3 g of fluoro-4-nitrophenyl) methanesulfonamide, 2.1 g of sodium carbonate and 20.0 ml of 70% aqueous ethylamine solution was refluxed for 96 hours. The reaction solution is returned to room temperature, acidified with 3N hydrochloric acid, extracted with ethyl acetate,
The organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 0.98 g of red-orange plate-like crystal N- (2-cyclohexyloxy-5-ethylamino-4-nitrophenyl) methanesulfonamide. m. p. 118-119 ° C

Example 3 1.0 g of N- (2-cyclohexyloxy-5-fluoro-4-nitrophenyl) methanesulfonamide obtained by the method of Reference Example 1, 0.53 g of sodium carbonate and n-
Tetrahydrofuran 1 containing 0.45 ml of butylamine
The 5.0 ml solution was refluxed for 4 hours. The reaction solution was returned to room temperature, water was added, and after ethyl acetate, the organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 0.32 g of N- [5- (n-butylamino) -2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide as reddish orange plate crystals. It was m. p. 94-96 ° C

Examples 4 to 25 Example 3 was repeated except that amines or hydrazines shown below were used instead of n-butylamine in Example 3.
The compounds shown in Table 1 were obtained in the same manner as in (1) (all ethanol was used as the recrystallization solvent). <Amines and hydrazines> n-propylamine,
n-pentylamine, n-hexylamine, n-heptylamine, isopropylamine, isobutylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cyclopropylmethylamine, allylamine, 2-hydroxyethylamine, 2-methoxyethylamine , 2-methylaminoethylamine, glycine ethyl hydrochloride, glycine, beta-alanine, benzylamine, 4-phenylbutylamine,
Hydrazine, methylhydrazine

[0067]

[Table 1]

Example 26 In Example 3, N- (2-cyclohexyloxy-
Example 3 except that N- (2-cyclopentyloxy-5-fluoro-4-nitrophenyl) chloromethanesulfonamide obtained in Reference Example 2 was used in place of 5-fluoro-4-nitrophenyl) methanesulfonamide. In the same manner as described above, N- [5- (n-butylamino) -2-
Cyclohexyloxy-4-nitrophenyl] chloromethanesulfonamide [m. p. 183-184 ° C. (ethanol)] was obtained.

Example 27 To a 4.5 ml suspension of N, N-dimethylformamide containing 0.44 g of 60% sodium hydride was added 1.0 ml of aniline at room temperature, and the mixture was stirred for 15 minutes.
1.5 g of-(2-cyclohexyloxy-5-fluoro-4-nitrophenyl) methanesulfonamide was added,
The mixture was heated and stirred at 80 ° C. for 3 hours. Return the reaction solution to room temperature, and
Normal hydrochloric acid was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to give N-
1.0 g of (2-cyclohexyloxy-4-nitro-5-phenylaminophenyl) methanesulfonamide was obtained. m. p. 192-195 ° C

Example 28 N- (2-cyclohexyloxy-5-obtained in Reference Example 1
A 5.0 ml tetrahydrofuran solution containing 0.65 g of fluoro-4-nitrophenyl) methanesulfonamide, 0.41 g of sodium carbonate and 0.32 ml of pyrrolidine was refluxed for 2 hours. The reaction solution was returned to room temperature, 3N hydrochloric acid was added, the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to give N- (2-cyclohexyloxy-4-nitro-5--5) as red-orange plate crystals.
Pyrrolidinophenyl) methanesulfonamide 0.61 g
Got m. p. 149.5-151 ° C

Examples 29, 30 N- (2-cyclohexyloxy-5-dimethylamino-4-nitro) was prepared in the same manner as in Example 28 except that dimethylamine or morpholine was used in place of pyrrolidine. Phenyl) methanesulfonamide [m. p. 109-110 ° C (ethanol)] and N
-(2-Cyclohexyloxy-5-morpholino-4-
Nitrophenyl) methanesulfonamide [m. p. 16
7.5-168.5 ° C (ethanol)] was obtained.

Example 31 (1) A solution of 160 mg of pyridine containing 50.0 g of 4-fluoro-3-nitroaniline was added to acetic anhydride 49.
0 g was added and stirred for 1.5 hours. Add water to the reaction mixture,
After extraction with ethyl acetate, the organic layer was washed with water, 3N hydrochloric acid, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethyl acetate-n-hexane to obtain 52.5 g of brown needle crystals of 4-fluoro-3-nitroacetanilide. m. p. 132-133 ° C. (2) Cyclohexanol 1 was added to 60 ml of a tetrahydrofuran solution containing 5.1 g of 60% sodium hydride at room temperature.
After adding 3.3 g and stirring for 50 minutes, 90 ml of tetrahydrofuran containing 12.0 g of the compound obtained in (1) under ice cooling.
The solution was added over 20 minutes, stirred for 1 hour, and further stirred at room temperature for 20 hours. After adding 3N hydrochloric acid to the reaction solution and extracting with ethyl acetate, the organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1) and recrystallized from ethyl acetate-n-hexane to give yellow needle crystals of 4-.
Cyclohexyloxy-3-nitroacetanilide 1
1.7 g was obtained. m. p. 95-96 ° C (3) A solution of 6.4 g of the compound obtained in (2) and 10.9 g of nickel chloride hexahydrate in 46 ml of methanol-tetrahydrofuran (1: 1) under ice-cooling, sodium borohydride 3. After gradually adding 5 g, the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was acidified with 3N hydrochloric acid, stirred for 30 minutes, and then made basic with 28% aqueous ammonia solution. After the mixed solution was extracted with ethyl acetate, the organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethyl acetate-n-hexane to obtain colorless crystals of 3-amino-4-cyclohexyloxyacetanilide (5.2 g). m. p. 103-104 ° C (4) Pyridine 21 containing 5.2 g of the compound obtained in (3)
The methanesulfonyl chloride 2.7 was added to the ml solution under ice cooling.
g was added, and the mixture was stirred for 30 minutes and further stirred for 2.5 hours. Water was added to the reaction solution, the precipitate was collected by filtration, washed with water,
The crude crystals were recrystallized from ethanol-n-hexane to obtain 5.0 g of colorless prism crystals of N- (5-acetylamino-2-cyclohexyloxyphenyl) methanesulfonamide. m. p. 157-159 ° C (5) 11 ml of acetic acid containing 3.5 g of the compound obtained in (4)
1.2 g of 60% nitric acid was added to the solution with heating and stirring at 90 ° C.
It was added over 5 minutes and stirred for another 30 minutes. The reaction solution was returned to room temperature, water was added, the precipitate was collected by filtration, and recrystallized from ethanol to give brown needle crystals of N- (5-acetylamino-2).
2.5 g of -cyclohexyloxy-4-nitrophenyl) methanesulfonamide was obtained. m. p. 140-142 ° C

Example 32 In the same manner as in Example 31, except that cyclopentanol was used in place of cyclohexanol in Example 31 (2), N- (5-acetylamino-2-
Cyclopentyloxy-4-nitrophenyl) methanesulfonamide [m. p. 178-179 ° C. (ethanol)] was obtained.

Example 33 In Example 31, except that cyclopentanol was used in place of cyclohexanol in Example 31 (2), Example 3
By repeating the same procedure as in Example 31 except that chloromethanesulfonyl chloride was used in place of methanesulfonyl chloride in 1 (4), N- (5-acetylamino-2-
Cyclopentyloxy-4-nitrophenyl) chloromethanesulfonamide [m. p. 188-189 ° C. (ethanol)] was obtained.

Example 34 In Example 31, except that n-valeryl chloride was used instead of acetic anhydride in Example 31 (1), Example 31 (2)
In the same manner as in Example 31 except that cycloheptanol was used instead of cyclohexanol, N- [2
-Cycloheptyloxy-4-nitro-5- (n-valerylamino) phenyl] methanesulfonamide [m.
p. 84-87 ° C. (ethanol)] was obtained.

Example 35 (1) 4-Cyclohexyloxy-3-nitroacetanilide 14.6 obtained by the method of Example 31 (1) or (2)
29m ethanol containing 29g and 12ml hydrochloric acid
After the solution 1 was refluxed for 2.5 hours, the reaction solution was returned to room temperature and the precipitate was collected by filtration. The precipitate was washed with ethyl acetate and air-dried for 19 hours, to give 4-cyclohexyloxy-3- pale brown crystals.
11.2 g of nitroaniline hydrochloride was obtained. m. p. 196 to 199 ° C. (2) Pyridine containing 1.0 g of the compound obtained in (1) 5.
0.50 ml of propionic anhydride was added to the 0 ml solution at room temperature, and the mixture was stirred for 10 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 3N hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1),
0.80 g of yellow oily N-propionyl-4-cyclohexyloxy-3-nitroaniline was obtained. NMR (CDCl ₃ ) δppm: 1.24 (3H, t,
J = 7Hz), 1.20 to 2.00 (10H, m),
2.40 (1H, q, J = 7Hz), 4.37 (1H,
m), 7.02 (1H, d, J = 8Hz), 7.50
(1H, brs), 7.71 (1H, dd, J = 2H
z, 8 Hz), 7.92 (1 H, d, J = 2 Hz) (3) A solution of 0.70 g of the compound obtained in (2) and 0.06 g of 5% palladium-carbon in 10 ml of ethyl acetate was added under a hydrogen atmosphere. The mixture was stirred at room temperature and catalytically reduced. After the palladium-carbon was filtered off, the filtrate was distilled off to obtain 0.60 g of colorless crystals of N-propionyl-3-amino-4-cyclohexyloxyaniline. m. p. 135-137 ° C. (4) (3) The compound obtained at (3) was treated in the same manner as the sulfonylation of Example 31 (4) and then the nitration of Example 31 (5) to give N- (2-cyclohexyloxy). −
4-nitro-5-propionylaminophenyl) methanesulfonamide [m. p. 148-149 ° C (ethanol)] was obtained.

Examples 36 to 57 In Example 35, the following acid anhydrides and acid halides were used in place of the propionic anhydride of Example 35 (2).
The compounds shown in Table 2 were obtained in the same manner as in Example 35 except that alkyl chlorocarbonate or alkyl isocyanate was used. <Acid anhydride, acid halide, alkyl chlorocarbonate and alkyl isocyanate> n-butyryl chloride, n
-Valeryl chloride, n-hexanoyl chloride, n-
Heptanoyl chloride, isobutyryl chloride, cyclopropanecarboxylic acid chloride, cyclobutanecarboxylic acid chloride, cyclohexanecarboxylic acid chloride, trifluoroacetic anhydride, 2-bromopropionyl chloride, 3
-Chlorovaleryl chloride, methoxyacetyl chloride, 5-phenylvaleryl chloride, benzoyl chloride, 4-fluorobenzoyl chloride, 2-thiophenecarboxylic acid chloride, ethyl chlorocarbonate, chlorocarbonic acid n
-Propyl, n-butyl chlorocarbonate, chlorocarbonate 2,
2,2-trichloroethyl, ethyl isocyanate, n
-Butyl isocyanate

[0078]

[Table 2]

Example 58 (1) A mixture of 4-cyclohexyloxy-3-nitroaniline hydrochloride (1.5 g) obtained in Example 35 (1), acetic anhydride (2.0 ml) and formic acid (5.0 ml) at room temperature was used.
Stir for minutes. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with water, saturated sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1), and yellow oily N-formyl-4-cyclohexyloxy-3-nitroaniline 1.5 g was obtained. Got NMR (CDCl ₃ ) δppm: 1.20 to 2.00
(10H, m), 4.42 (1H, m), 7.05 (1
H, d, J = 8 Hz), 7.69 (1H, brs),
7.76 (1H, dd, J = 2Hz, 8Hz), 7.9
8 (1H, d, J = 2Hz), 8.37 (1H, d, J
= 1 Hz) (2) The compounds obtained in (1) were used in Examples 31 (3) to (5).
N- (2-cyclohexyloxy-5-formamino-4-nitrophenyl) methanesulfonamide [m. p. 158-159 ° C (ethanol)] was obtained.

Example 59 (1) Methanesulfonyl chloride (0.51 ml) was added to an 8.0 ml solution of pyridine containing 1.5 g of 4-cyclohexyloxy-3-nitroaniline hydrochloride obtained in Example (1) at room temperature. Addition and stirring for 10 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 0.80 g of N-methylsulfonyl-4-cyclohexyloxy-3-nitroaniline. m. p. 107 to 108 ° C. (2) The compound obtained in (1) was used in Example 31 (3) to (5).
N- (2-cyclohexyloxy-5-methylsulfonylamino-4-nitrophenyl) methanesulfonamide [m. p. 173-1
74 ° C. (ethanol)] was obtained.

Examples 60 to 66 In Example 59, Table 3 shows the same as Example 59 except that the sulfonic acid derivative shown below was used in place of methanesulfonyl chloride in Example 59 (1). A compound was obtained (Ethanol was used as the recrystallization solvent). <Sulfonic acid derivative> ethanesulfonyl chloride, n-
Propanesulfonyl chloride, isopropylsulfonyl chloride, chloromethanesulfonyl chloride, benzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 2-thiophenesulfonyl chloride

[0082]

[Table 3]

Example 67 (1) 2-Fluoro-5-nitroaniline 204.0 g
165.0 g of methanesulfonyl chloride was added to 1300 ml of a pyridine solution containing pyridine under ice cooling, and the mixture was stirred at room temperature for 24 hours. 3000 ml of water was added to the reaction solution, the precipitate was collected by filtration, air-dried overnight, and recrystallized from ethanol to give 230.0 g of N- (2-fluoro-5-nitrophenyl) methanesulfonamide as colorless needle crystals. Obtained. m. p. 128-129 [deg.] C. (2) Cyclobenzene 2000 ml solution containing 60% sodium hydride 52.8 g at room temperature cyclohexanol 128.0 g, tris [2- (2-methoxyethoxy)]
8 ml of ethyl] amine was added in that order, and after stirring for 30 minutes, 100.0 g of the compound obtained in (1) was added under ice cooling, and the mixture was stirred for 19 hours. 1500 ml of 3N hydrochloric acid was added to the reaction solution,
After extraction with dichloromethane, the organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to give yellow plate crystals of N-
98.5 g of (2-cyclohexyloxy-5-nitrophenyl) methanesulfonamide was obtained. m. p. 105-106.5 ° C. (3) 98.0 g of the compound obtained in (2) and iron powder 78.
0 g was heated and stirred at 80 ° C., and a 100 ml aqueous solution containing 5.0 g of ammonium chloride was added, and the mixture was stirred for 2 hours. The reaction product was returned to room temperature, ethyl acetate and water were added, and after extraction, the organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to give N- (5-amino-2-cyclohexyloxyphenyl) methanesulfonamide 7 as colorless prism crystals.
1.7 g was obtained. m. p. 151.5-153.5 ° C. (4) Pyrrolidine 5 containing 1.5 g of the compound obtained in (3)
Under ice cooling, 1.1 g of 3-phenylpropionyl chloride was added to the ml solution, and the mixture was stirred for 15 minutes. Water was added to the reaction product, which was extracted with ethyl acetate. The organic layer is 3N hydrochloric acid, water,
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol to give N- [2-cyclohexyloxy-5-colorless prism crystals.
1.1 g of (3-phenylpropionylamino) phenyl] methanesulfonamide was obtained. m. p. 160-161 ° C (5) N- [2-cyclohexyloxy-4-nitro-5- (3-phenylpropionylamino) was obtained by nitrating the compound obtained in (4) in the same manner as in Example 31 (5). ) Phenyl] methanesulfonamide [m. p. 14
0.5-142 ° C. (Ethanol)] was obtained.

Examples 68 to 70 Same as Example 67 except that acryloyl chloride, 2-butenoyl chloride or methacryloyl chloride was used in place of 3-phenylpropionyl chloride in Example 67 (4). Then, the compounds shown in Table 4 were obtained.

[0085]

[Table 4]

Example 71 (1) Dichloromethane containing 1.1 g of 3-butenoic acid
To a 5 ml solution at room temperature was added thionyl chloride 0.9 g,
Stir for 15 minutes. The reaction solution was cooled to -78 ° C and then N- (5-amino-2) obtained by the method of Examples 67 (1) to (3).
A solution of 1.5 g of -cyclohexyloxyphenyl) methanesulfonamide and 1.1 g of pyridine in 10 ml of dichloromethane was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in this order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to give colorless crystals of N- [5
0.7 g of-(3-butenoylamino) -2-cyclohexyloxyphenyl] methanesulfonamide was obtained. m. p. 132-133.5 ° C. (2) N- [2-cyclohexyloxy-4-nitro-5- (3-butenoylamino) was obtained by nitrating the compound obtained in (1) in the same manner as in Example 31 (5). ) Phenyl] methanesulfonamide [m. p. 132.5-1
34.5 ° C. (Ethanol)] was obtained.

Examples 72 to 74 In Example 71, in place of 3-butenoic acid in Example 71 (1), 2-pentenoic acid, 3-pentenoic acid or 3-pentenoic acid was used.
The compounds shown in Table 5 were obtained in the same manner as in Example 71 except that methyl-2-butenoic acid was used.

[0088]

[Table 5]

Example 75 (1) Example 67 In a 50 ml aqueous solution containing 13.0 g of cyclopentanethiol and 5.1 g of sodium hydroxide.
10.0 g of N- (2-fluoro-5-nitrophenyl) methanesulfonamide obtained in (1) was added, and the mixture was refluxed for 2 hours. The reaction solution was returned to room temperature, 3N hydrochloric acid (30 ml) and ethanol (60 ml) were added, and the precipitate was collected by filtration and recrystallized from ethanol to give yellow crystals of N- (2-cyclopentylthio-5-nitrophenyl) methanesulfonamide 1
0.8 g was obtained. m. p. 106-107 ° C (2) The compound obtained in (1) was used in Example 31 (3)-
In Example (3), except that n-valeryl chloride was used in place of acetic anhydride in Example 31 (4) in (5).
To N- [2-cyclopentylthio-4-nitro-5- (n-valerylamino) phenyl] in the same manner as in (5).
Methanesulfonamide [m. p. 157.5-158 ° C
(Ethanol)] was obtained.

Example 76 N- [2-cyclohexylthio-4-nitro] was prepared in the same manner as in Example 75 except that cyclohexanethiol was used in place of cyclopentanethiol in Example 75 (1). -5- (n-valerylamino) phenyl] methanesulfonamide [m. p. 150-151
C. (Ethanol)] was obtained.

Example 77 (1) N, N containing 0.20 g of 60% sodium hydride
Example 5 in a 5 ml solution of dimethylformamide at room temperature
1.3 g of 4-cyclohexyloxy-3-nitroacetanilide obtained by the method of (1) or (2) was added, and after stirring for 15 minutes, 0.85 g of methyl iodide was added and further stirred for 3 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate =
It was purified by 3: 1) to obtain 1.3 g of yellow oily N-methyl-4-cyclohexyloxy-3-nitroacetanilide. NMR (CDCl ₃ ) δppm: 1.30 to 2.00
(10H, m), 1.31 (3H, s), 3.26 (3
H, s), 4.49 (1H, m), 7.11 (1H,
d, J = 8 Hz), 7.33 (1H, dd, J = 2H)
z, 8 Hz), 7.67 (1 H, d, J = 2 Hz) (2) The compounds obtained in (1) were used in Examples 31 (3) to (5).
N- [2-cyclohexyloxy-5- (N′-acetyl-N′-methylamino) -4-nitrophenyl] methanesulfonamide [m. p. 163-164 ° C (ethanol-n-hexane)] was obtained.

Example 78 (1) N, N containing 0.30 g of 60% sodium hydride
Example 59 in a 5 ml solution of dimethylformamide at room temperature
1.6 g of N-methylsulfonyl-4-cyclohexyloxy-3-nitroaniline obtained in (1) was added, and after stirring for 5 minutes, 1.3 g of ethyl iodide was added and stirred for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 3N hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 3: 1), and yellow oily N-ethyl-
N-methylsulfonyl-4-cyclohexyloxy-3
-1.4 g of nitroaniline were obtained. NMR (CDCl ₃ ) δppm: 1.18 (3H, t,
J = 7 Hz), 1.31 to 2.01 (10 H, m),
2.99 (3H, s), 3.21 (2H, q, J = 7H
z), 4.49 (1H, m), 7.11 (1H, d, J
= 8 Hz), 7.51 (1H, dd, J = 2, 8H
z), 7.78 (1 H, d, J = 2 Hz) (2) The compounds obtained in (1) were used in Examples 31 (3) to (5).
N- [2-cyclohexyloxy-5- (N′-ethyl-N′-methylsulfonylamino) -4-nitrophenyl] methanesulfonamide [m. p. 168-169 ° C (acetone-ethanol)] was obtained.

Example 79 (1) N-methylsulfonyl-obtained in Example 59 (1)
4-cyclohexyloxy-3-nitroaniline 1.6
1.1 g of acetic anhydride was added at room temperature to a solution of 8 ml of dichloromethane containing 1 g and 1.0 g of triethylamine, and the mixture was stirred for 10 minutes. Water was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with 3N hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (developing solvent; n-
It was purified with hexane: ethyl acetate = 3: 1) to obtain 1.6 g of yellow oily N-acetyl-N-methylsulfonyl-4-cyclohexyloxy-3-nitroaniline. NMR (CDCl ₃ ) δppm: 1.31 to 2.10
(10H, m), 2.23 (3H, s), 3.48 (3
H, s), 4.53 (1H, m), 7.18 (1H,
d, J = 8 Hz), 7.46 (1H, dd, J = 2H)
z, 8 Hz), 7.78 (1 H, d, J = 2 Hz) (2) The compounds obtained in (1) were used in Examples 31 (3) to (5).
N- [2-cyclohexyloxy-5- (N′-acetyl-N′-methylsulfonylamino) -4-nitrophenyl] methanesulfonamide [m. p. 143-145 ° C. (acetone-ethanol)] was obtained.

Example 80 Example 7 was repeated except that methanesulfonyl chloride was used instead of acetic anhydride in Example 79 (1).
N- {5- [N ′, N′-bis (methylsulfonyl) amino] -2-cyclohexyloxy-in the same manner as in 9.
4-nitrophenyl} methanesulfonamide [m. p.
157.5-159 ° C. (ethanol)] was obtained.

Example 81 Tetrahydrofuran-t-containing 0.50 g of N- (5-acetylamino-2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide obtained in Example 6 and 0.33 g of potassium t-butoxide. Butanol (1: 1)
1.4 g of water was added to the 5.6 ml solution, and the mixture was stirred for 2 hours.
The reaction mixture was acidified with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 3: 1), and the crude crystals were recrystallized from ethanol-n-hexane to give N- (5-amino). -2-
0.39 g of cyclohexyloxy-4-nitrophenyl) methanesulfonamide was obtained. m. p. 136-137 ° C

Example 82 N- [2-cyclopentylthio-4-obtained in Example 76
To an 8 ml solution of N, N-dimethylformamide containing 0.50 g of nitro-5- (n-valerylamino) phenyl] methanesulfonamide, 0.31 g of 70% metachloroperbenzoic acid was added under ice cooling, and the mixture was stirred for 20 minutes and then reacted. A saturated aqueous solution of sodium hydrogencarbonate was added to the solution, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography ( Developing solvent; n-hexane:
Purified with ethyl acetate = 1: 8), the crude crystals were recrystallized from ethanol to give pale yellow needle crystals of N- [2-cyclopentylsulfinyl-4-nitro-5- (n-valerylamino).
0.15 g of phenyl] methanesulfonamide was obtained. m. p. 191 to 192 ° C

Example 83 N- [2-cyclopentylthio-4-nitro-5- (n
Example 82 except that N- [2-cyclohexylthio-4-nitro-5- (n-valerylamino) phenyl] methanesulfonamide obtained in Example 75 was used in place of -valerylamino) phenyl] methanesulfonamide. In the same manner as in N- [2-cyclohexylsulfinyl-4-
Nitro-5- (n-valerylamino) phenyl] methanesulfonamide [m. p. 195.5 to 196.5 ° C
(Ethanol)] was obtained.

Example 84 N- [2-cyclopentylthio-4-obtained in Example 75
To 3 ml of N, N-dimethylformamide containing 0.30 g of nitro-5- (n-valerylamino) phenyl] methanesulfonamide was added 0.71 g of 70% metachloroperbenzoic acid at room temperature, and after stirring for 30 minutes, the reaction solution was added. Saturated aqueous sodium hydrogencarbonate solution was added, extracted with ethyl acetate,
The organic layer was washed with water and saturated brine in that order, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was recrystallized from ethanol to give N- [2-cyclopentylsulfonyl-4-nitro as a pale yellow crystal. 0.15 g of -5- (n-valerylamino) phenyl] methanesulfonamide was obtained. m. p. 268-270 ° C

Example 85 N- (2-cyclohexyloxy-5 obtained in Example 10
-Cyclopropylamino-4-nitrophenyl) methanesulfonamide containing 0.30 g of tetrahydrofuran-
To a 3.2 ml solution of methanol (1: 1) was added 0.019 g of metallic sodium at room temperature, the mixture was stirred for 10 minutes, the solvent was distilled off, and the residue was washed with ethyl ether to give red prism crystals of N- (2-cyclohexyl). 0.32 g of sodium salt 1/2 hydrate of oxy-5-cyclopropylamino-4-nitrophenyl) methanesulfonamide was obtained. m. p. 56-59 ° C

Example 86 N- (2-cyclohexyloxy-5-obtained in Example 7)
Tetrahydrofuran 2.4 containing 0.25 g of propionylamino-4-nitrophenyl) methanesulfonamide
0.014 g of sodium metal was added to the ml solution at room temperature,
After heating and stirring at 60 ° C. for 2 hours, the solvent was evaporated, the residue was washed with ethyl ether, and sodium salt of N- (2-cyclohexyloxy-5-propionamido-4-nitrophenyl) methanesulfonamide as red crystals was obtained. 0.21 g was obtained. m. p. 113-115.5 ° C

Example 87 N- [2-cyclohexyloxy-4-obtained in Example 5
0.05 g of acetic anhydride was added at room temperature to a 0.8 ml solution of pyridine containing 0.15 g of nitro-5- (n-pentylamino) phenyl] methanesulfonamide, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, the precipitate was collected by filtration, and recrystallized from ethanol to give brown prism crystals of N-acetyl-N- [2-
Cyclohexyloxy-4-nitro-5- (n-pentylamino) phenyl] methanesulfonamide 0.15 g
Got m. p. 131.5-133 ° C

Examples 88 to 98 In Example 87, N- [2-cyclohexyloxy-4-nitro-5-5 was used as the methanesulfonamide derivative.
(N-Pentylamino) phenyl] methanesulfonamide (compound obtained in Example 5), N- (5-acetylamino-2-cyclohexyloxy-4-nitrophenyl)
Methanesulfonamide (compound obtained in Example 31), N
-[5- (n-butyrylamino) -2-cyclohexyloxy-4-nitrophenyl] methanesulfonamide (compound obtained in Example 36), N- [2-cyclohexyloxy-4-nitro-5- (n- Valerylamino) phenyl] methanesulfonamide (the compound obtained in Example 37) or N- (5-amino-2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide is used as an acylating agent, and acetic anhydride or propion anhydride. acid,
The compounds shown in Table 6 were obtained in the same manner as in Example 87 except that isobutyryl chloride or n-valeryl chloride was used.

[0103]

[Table 6]

Test Example The carrageenin paw edema test was carried out by the method of Winter et al. [Pro.
c. Soc. Exp. Biol. Med. , 111
Vol. 544 (1962)]. Using Wistar rats (6 rats per group), samples suspended in a 5% aqueous solution of gum arabic [compounds a to g of the present invention and indomethacin as a control drug and N- (2-cyclohexyloxy-4-nitrophenyl) methanesulfone] Amide (compound described in JP-A-2-268)], weight 10
It was orally administered at a dose of 1 ml per 0 g. 1 hour later 1
% Carrageenin was subcutaneously administered to the left foot pad in an amount of 0.1 ml. Three hours after the administration of carrageenin, the paw volume was measured, and the edema inhibition rate was determined to examine the anti-inflammatory effect. The dose of the sample was 1 mg / kg. The results are shown in Table 7.

[0105]

[Table 7]

A; the compound prepared in Example 5; b, the compound prepared in Example 15, c; the compound prepared in Example 31, d; the compound prepared in Example 34, e; the compound prepared in Example 37, f; Compound g prepared in Example 38; Compound h prepared in Example 81; Indomethacin i; N- (2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Mariko Kashiwa 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Within Pharmaceuticals Co., Ltd.

Claims (1)

[Claims] 1. A formula [In the formula, R ¹ represents an alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom, R ² represents a cycloalkyl group having 3 to 8 carbon atoms, and R ³ represents a hydrogen atom. ,
It represents an alkyl group having 1 to 5 carbon atoms, an alkanoyl group having 2 to 6 carbon atoms or an alkylsulfonyl group having 1 to 5 carbon atoms, and R ⁴ represents a hydrogen atom, “hydroxyl group, 1 to 1 carbon atoms”. 5 alkoxy groups, alkylamino groups having 1 to 3 carbon atoms, alkoxycarbonyl groups having 2 to 6 carbon atoms, 1 to 8 carbon atoms which may be substituted with "carboxyl group or phenyl group" An alkyl group of
Cycloalkyl group having 3 to 8 carbon atoms, 4 carbon atoms
To 9 cycloalkylmethyl groups, alkenyl groups having 3 to 5 carbon atoms, phenyl groups, amino groups optionally substituted with alkyl groups having 1 to 3 carbon atoms, and formula -CO
—R ⁶ (In the formula, R ⁶ is a hydrogen atom, an “halogen atom, an alkoxy group having 1 to 5 carbon atoms or a phenyl group”, which may be substituted with an alkyl group having 1 to 8 carbon atoms, carbon; A cycloalkyl group having 3 to 8 atoms, an alkenyl group having 2 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms which may be substituted with a halogen atom, and an alkyl group having 1 to 5 carbon atoms A group represented by an alkylamino group, a phenyl group or a thienyl group which may be substituted with a halogen atom, or a formula —SO ₂ —R ⁷ (in the formula, R ⁷ may be substituted with a halogen atom) An alkyl group having 1 to 5 carbon atoms, a phenyl group which may be substituted with a halogen atom or a thienyl group), or a nitrogen atom in which R ³ and R ⁴ are adjacent to each other. Together with a 5-member ring Ku denotes a heterocyclic 6-membered ring, R ⁵ represents a hydrogen atom or a carbon atoms 2-6 alkanoyl group, X represents an oxygen atom, a sulfur atom, a sulfinyl group or a sulfonyl group. ] The compound and its salt represented by these.