JPH06206859A - N-acyl-5-aminosulfonanilide compound - Google Patents

Abstract

PURPOSE:To provide a new compound reduced in side effects such as digestive tract disorders, etc., capable of being administered for long periods, excellent in safety, and useful as an antiinflammatory agent, antipyretic agent, analgesic agent, or antiallergic agent. CONSTITUTION:A compound of formula I (R<1> is 1-3C alkyl; R<2> is H, 1-4C alkyl; R<3> is 5-7C cycloalkyl, phenyl, halophenyl), e.g. N-acetyl-N-(5-amino-4-nitro-2- phenoxyphenyl)methanesulfonamide. The compound of formula I is obtained by subjecting 2-fluoro-5-nitroaniline of formula II to sulfonylation, etherification, reduction, amidation, nitration and hydrolysis reactions, and subsequently reacting the reaction product with a carboxylic acid of formula: R<2>-COOH or its reactive derivative. When the carboxylic acid is used, the reaction is preferably performed in the presence of a condensing agent, and when the reactive derivative is used, the reaction is preferably carried out in the presence of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an N-acyl-5-aminosulfonanilide compound having anti-inflammatory action, antipyretic action, analgesic action and antiallergic action.

[0002]

Various kinds of sulfone anilide compounds are known. As the sulfoneanilide compound having an amino group at the 5-position, the compounds described in US Pat. No. 3,856,859 are known, but the N-acyl-5 of the present invention is known.
-Aminosulfonanilide compounds are not known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a highly safe and excellent compound having anti-inflammatory action, antipyretic action, analgesic action and antiallergic action.

[0004]

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

That is, the present invention has the formula (I)

(In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms, and R ² is a hydrogen atom or 1 to 4 carbon atoms.
Indicates the number of alkyl groups, R ³ represents a cycloalkyl group, a phenyl group or a halophenyl group 5-7 carbon atoms. ) Is an N-acyl-5-aminosulfoneanilide compound.

In the present invention, R ¹ has 1 to 3 carbon atoms.
The individual alkyl group is a linear alkyl group, and examples thereof include a methyl group, an ethyl group, and an n-propyl group. The alkyl group having 1 to 4 carbon atoms of R ² is a linear or molecular chain alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
Isobutyl group and the like. The cycloalkyl group having 5 to 7 carbon atoms for R ³ is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group. The halophenyl group of R ³ is the same or different and is a phenyl group in which one or two fluorine atoms, chlorine atoms, bromine atoms or iodine atoms are substituted, and examples thereof include a 2-chlorophenyl group and 3-
Chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 4-iodophenyl group, 2,4-dichlorophenyl group, 2,4-difluoro group Examples thereof include a phenyl group and a 2-chloro-4-fluorophenyl group.

The compound of formula (I) of the present invention is, for example, 2
It can be obtained using -fluoro-5-nitroaniline as a starting material and the following production method.

(Reaction formula)

(In the reaction formula, R ¹ , R ² and R ³ are as defined above, and R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 2 to 6 carbon atoms. It is a carbonyl group.)

(A) That is, first, 2-fluoro-5
-By sulfonylating the amino group of nitroaniline with a sulfonic acid represented by formula (II) or a reactive derivative thereof (for example, an acid halide, an acid anhydride, etc.), a compound of formula (III) is obtained. Obtainable.

When the sulfonic acid represented by the formula (II) is used in this reaction, N, N'-dicyclohexylcarbodiimide, 1,1'-carbodiimidazole,
It is preferably carried out in the presence of a condensing agent such as methanesulfonyl chloride or ethyl chloroformate. Further, when using the reactive derivative, 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,
Inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate or triethylamine, tri-n-butylamine,
1,5-diazabicyclo [4.3.0] -5-nonene,
Examples of the organic base include 1,8-diazabicyclo [5.4.0] -7-undecene, 4-methylmorpholine, 1-methylpiperidine, pyridine, and N, N-dimethylaminopyridine.

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.

(B) Next, the compound of formula (V) can be obtained by subjecting the compound of formula (III) and the compound of formula (IV) to an etherification reaction in the presence of a base. it can.

Examples of the base in this reaction include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate. Alkali metal hydrides such as metal hydrogen carbonate, sodium hydride and potassium hydride, inorganic bases such as metal sodium and sodium amide, or triethylamine, tri-n-butylamine, 1,5-diazabicyclo [4.3.0]- Examples thereof include organic bases such as 5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene, pyridine, and N, N-dimethylaminopyridine.

The reaction is solvent-free or dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-
Hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, dichloromethane,
It can be performed by arbitrarily selecting a solvent such as chloroform or water.

In this reaction, potassium iodide, tris [2- (2-methoxyethoxy) ethyl] amine, tetra-n-butylammonium chloride, tetra-n-
The reaction can also be accelerated by adding a quaternary ammonium salt such as butylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, tricaptylmethylammonium chloride, or a crown ether such as 18-crown-6 ether.

(C) Then, the nitro group of the compound of formula (V) is reduced to obtain the compound of formula (VI).

The reduction may be carried out by a conventional reduction method in which a nitro group is reduced 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-ammonium chloride. And reduction using sodium borohydride, lithium aluminum hydride and the like.

The solvent used in this reaction may be arbitrarily selected according to the reduction method, and generally, alcohols such as methanol, ethanol and n-propanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran and acetonitrile are used. Can be mentioned.

(D) Next, the amino group of the compound of formula (VI) is amidated with a carboxylic acid of formula (VII) or a reactive derivative thereof to give a compound of formula (VII).
A compound represented by I) can be obtained.

The amidation in this reaction is a usual method for amidating an amino group, and when the compound of the formula (VII) is used, for example, a method using sulfuric acid or the like and a condensing agent (eg N, N ') are used. -Dicyclohexylcarbodiimide, triphenylphosphine, tetrachlorosilane, etc.) and the like. When the reactive derivative of the compound of the formula (VII) is used, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
Examples thereof include a method using an inorganic base such as sodium hydrogen carbonate, an organic base such as pyridine and triethylamine, and the like.

(E) Next, the compound of formula (VIII) can be obtained by nitrating the compound of formula (VIII) with a nitrating agent such as nitric acid or a nitrate.

As the nitrate in the nitration reaction, sodium nitrate, potassium nitrate, iron nitrate, urea nitrate or the like can be used, and the solvent to be used is preferably selected according to the nitrating agent, and acetic acid or acetic anhydride is used. ,
Examples include trifluoroacetic acid, sulfuric acid, dichloromethane, chloroform, benzene, dioxane, ethanol and the like.

(F) Then, the compound of formula (IX) can be hydrolyzed to obtain the compound of formula (X).

Hydrolysis in this reaction is a usual amide hydrolysis method under basic or acidic conditions. For example, basic conditions include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. , Sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.,
Examples of the acidic condition include a method using hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

The solvent used in this reaction includes water, methanol, ethanol, propanol, t-butanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid and the like. Although it can be mentioned, it is preferable to select appropriately depending on the hydrolysis conditions.

(G) Finally, the compound of formula (X) and the compound of formula (X
The compound of the present invention [compound of formula (I)] can be obtained by reacting a carboxylic acid represented by I) or a reactive derivative thereof (eg, acid halide, acid anhydride, etc.).

When the carboxylic acid represented by the formula (X) is used in this reaction, N, N'-dicyclohexylcarbodiimide, 1,1'-carbodiimidazole, methanesulfonyl chloride, ethyl chloroformate and the like are used. It is preferably carried out in the presence of a condensing agent. When the reactive derivative 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, sodium carbonate and potassium carbonate. Of alkali metal carbonates,
Alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium metal and sodium amide, or triethylamine, tri-n-butylamine, 1,5 -Diazabicyclo [4.
3.0] -5-nonene, 1,8-diazabicyclo [5.
4.0] -7-undecene, pyridine, organic bases such as N, N-dimethylaminopyridine, and the like.

The reaction is solvent-free or dioxane, tetrahydrofuran, ethyl ether, petroleum ether, n-
Solvents such as hexane, cyclohexane, benzene, toluene, xylene, chlorobenzene, pyridine, ethyl acetate, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, dichloromethane, chloroform and water can be arbitrarily selected and used.

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 manufactured 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, weight, symptoms, administration route, number of administrations and the like.

[0032]

INDUSTRIAL APPLICABILITY The compound of the present invention exhibits anti-inflammatory action, antipyretic action, analgesic action, antiallergic action and the like, and since it has few side effects such as digestive tract disorders, it is used as an antiinflammatory drug, antipyretic drug, analgesic and antiallergic agent. It is useful.

[0033]

EXAMPLES Next, the present invention will be described in more detail with reference to examples.

Example 1 N-Acetyl-N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide (1) To a 334 ml solution of pyridine containing 52.1 g of 2-fluoro-5-nitroaniline, 42.1 g of methanesulfonyl chloride was added under ice cooling, and the mixture was stirred at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was filtered, and the crude crystals were recrystallized from ethanol to give pale yellow needle crystals of N- (2-fluoro-5-nitrophenyl) methanesulfonamide 56.9.
g was obtained.

M. p. 162.5-163.5 ° C

(2) To a 250 ml aqueous solution containing 73.5 g of phenol and 31.2 g of sodium hydroxide, N-
(2-Fluoro-5-nitrophenyl) methanesulfonamide (50.0 g) was added and the mixture was refluxed for 5 hours. The reaction mixture was ice-cooled, 36% hydrochloric acid (50 ml) and ethanol (200 m) were stirred.
1 were added in order. The precipitate was filtered, washed with ethanol and water in this order, and air-dried to give yellow prism crystals of N- (5-nitro-2-phenoxyphenyl) methanesulfonamide 5
2.2 g was obtained.

M. p. 112-113.5 ° C

(3) A 51 ml aqueous solution containing 2.7 g of ammonium chloride was added to 52.1 g of N- (5-nitro-2-phenoxyphenyl) methanesulfonamide, and the mixture was heated at 80 ° C.
With heating and stirring, 42.5 g of iron powder was added to the above and stirred for 2 hours. The reaction mixture was cooled to 50 ° C, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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 obtain 29.6 g of N- (5-amino-2-phenoxyphenyl) methanesulfonamide.

M. p. 111.5-113.5 ° C

(4) To 180 ml of dichloromethane containing 13.7 g of oxalyl chloride, 9.5 g of n-pentatanol and 8.5 g of pyridine were added under ice cooling, and the mixture was stirred for 5 minutes. The reaction solution was cooled to -78 ° C under N- (5-amino-2-phenoxyphenyl) methanesulfonamide 2
A 70 ml solution of dichloromethane containing 0.0 g and 8.5 g of pyridine was added, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution and extracted with dichloromethane.
The mixture was washed with normal hydrochloric acid and saturated brine in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol to obtain 17.2 g of colorless crystals of N- [5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide.

M. p. 164-165 ° C

(5) A 25% solution of tetrahydrofuran containing 2.5 g of N- [4-nitro-5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide was added at room temperature to a 10% aqueous sodium hydroxide solution 2
5 ml was added and stirred for 10 minutes. The reaction mixture was neutralized with 3N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water.
The extract was washed successively with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from acetone-n-hexane to obtain 1.6 g of orange needle crystals of N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide.

M. p. 175-176 ° C

(7) N- (5-amino-4-nitro-2
-Phenoxyphenyl) methanesulfonamide 0.7 g
Acetic anhydride 0.38 at room temperature in a 10 ml pyridine solution containing
g was added and stirred for 4 hours. Water was added to the reaction solution, the precipitate was filtered, and the crude crystals were recrystallized from ethanol to give yellow crystals of N-acetyl-N- (5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide 0 0.25 g was obtained.

M. p. 211.5-212.5 ° C

Examples 2 to 4 By following the same procedure as in Example 1 except that propionic anhydride, n-butyryl chloride and isobutyryl chloride were used instead of acetic anhydride in Example 1 (7), The following compounds of the invention were obtained.

N- (5-amino-4-nitro-2-phenoxyphenyl) -N-propionylmethanesulfonamide m.p. p. 207-208 ° C

N- (5-amino-4-nitro-2-phenoxyphenyl) -N- (n-butyryl) methanesulfonamide m. p. 188-189 ° C

N- (5-amino-4-nitro-2-phenoxyphenyl) -N-isobutyrylmethanesulfonamide m.p. p. 205-206 ° C

Examples 5 and 6 2-fluorophenol and 2,4-difluorophenol were used in place of phenol in Example 1 (2), and propionic anhydride was used in place of acetic anhydride in Example 1 (7). Otherwise in the same manner as in Example 1, the following compound of the present invention was obtained.

N- [5-amino-2- (2-fluorophenoxy) -4-nitrophenyl] -N-propionylmethanesulfonamide m.p. p. 213 ~ 214 ℃

N- [5-amino-2- (2,4-difluorophenoxy) -4-nitrophenyl] -N-propionylmethanesulfonamide m.p. p. 182-183.5 ° C

Example 7 N-Acetyl-N- (5-amino-2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (1) Cyclobenzene was dissolved in 2500 ml of chlorobenzene containing 60% sodium hydride (72.0 g) at room temperature. Hexanol 174.0 g, tris [2- (2-methoxyethoxy)
Ethyl] amine (10.0 ml) was added in that order, and the mixture was stirred for 30 minutes, and then N- (2-fluoro-5-nitrophenyl) methanesulfonamide 1 obtained by the method of Example 1 (1) under ice cooling.
36.0 g was added, and the mixture was stirred at room temperature for 16 hours. 1500 ml of 3N hydrochloric acid was added to the reaction solution, the mixture was extracted 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 obtain 131.0 g of N- (2-cyclohexyloxy-5-nitrophenyl) methanesulfonamide as pale yellow needle crystals.

M. p. 105-106.5 ° C

(2) N- (2-cyclohexyloxy-
5-nitrophenyl) methanesulfonamide was used in Example 1.
By performing the same as (3) to (7), N-acetyl-N- (5-amino-2-cyclohexyloxy-4-).
Nitrophenyl) methanesulfonamide was obtained.

M. p. 193-194 ° C

Example 8 N- (5-amino-2-cyclohexyloxy-4-nitrophenyl) -N-propionylmethanesulfonamide N- (2-cyclohexyloxy-5-nitro obtained in Example 7 (1) N- (5-) was obtained in the same manner as in Examples 1 (3) to (7) except that phenyl) methanesulfonamide was replaced with propionic anhydride in place of the acetic anhydride used in Example 1 (7). Amino-2-cyclohexyloxy-4-nitrophenyl) -N-propionylmethanesulfonamide was obtained.

M. p. 226 ~ 227 ℃

Test Example 1 Carrageenin paw edema test 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), 1 ml of a sample [the present compounds a to e and a control drug (indomethacin)] suspended in a 5% aqueous solution of gum arabic was added per 100 g of body weight.
Orally. One hour later, 0.1% of carrageenin was subcutaneously administered to the foot pad of the left limb. Carrageenin administration 3
After a lapse of time, the paw volume was measured, and the edema inhibition rate was determined to examine the anti-inflammatory effect. The dose of the sample is 1 mg / kg.
And

The results are shown in Table 1.

[0061]

[Table 1]

A; Compound of Example 1 b; Compound of Example 2 c; Compound of Example 3 d; Compound of Example 5 e; Compound of Example 6

 ─────────────────────────────────────────────────── ─── 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 Inside Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A formula (In the formula, R ¹ represents an alkyl group having 1 to 3 carbon atoms, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ³ has 5 to 7 carbon atoms. N-acyl-5-aminosulfonanilide compound represented by a cycloalkyl group, a phenyl group or a halophenyl group.