JPH0656759A - 5-amino-2-phenoxysulfonanilide compound - Google Patents

Abstract

PURPOSE:To provide the new compound useful as an anti-inflammatory agent, antipyretic, analgesic or anti-rheumatic agent. CONSTITUTION:This compound, N-(5-amino-4-nitro-2-phenoxyphenyl) methanesulfonamide of formula I. The compound can be obtained by the following process: 2-fluoro-5-nitroaniline is made to react with methanesulfonic acid (or a reactive derivative therefrom) to form a compound of formula II, which is then made to react with phenol in the presence of a base to produce a compound of formula III. The nitro group of this compound is then reduced and the resulting compound is made to react with a compound of formula Cl-CO-R (R is 1-5C alkyl, 1-5C alkoxy or a 2-6C alkoxycarbonyl) followed by nitration with a nitrating agent into a compound of formula IV, which is then hydrolyzed.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a 5-amino-2-phenoxysulfonanilide compound having anti-inflammatory action, antipyretic action, analgesic action and anti-rheumatic action.

[0002]

Various compounds are known as 2-phenoxysulfonanilide compounds. Among them, the compound having a structure similar to that of the compound of the present invention is disclosed in JP-A-57-140712.
The publication is known.

[0003]

However, some of the compounds described in the above specification have not been sufficiently effective.

The objects of the present invention are anti-inflammatory action, antipyretic action,
It is intended to provide an excellent drug having an analgesic action and an antirheumatic action.

[0005]

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-
It was found that the amino-2-phenoxysulfoneanilide compound has a very useful anti-inflammatory action, and the present invention has been completed.

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

[0007]

A 5-amino-2-phenoxysulfoneanilide compound represented by and a pharmaceutically acceptable salt thereof.

In the present invention, the salt is an alkali metal salt such as sodium and potassium, an alkaline earth metal salt such as calcium and magnesium, an ammonium salt and a salt with an organic base such as ethanolamine, lysine and arginine. .

The compound of formula (I) of the present invention can be obtained, for example, by the production steps (a) to (f) shown below.

(A) First, 2-fluoro-5-nitroaniline is reacted with methanesulfonic acid or a reactive derivative thereof (for example, an acid halide, an acid anhydride, etc.) to give a compound of formula (II).

[0012]

A compound represented by can be obtained.

When methanesulfonic acid is used in this reaction, it is preferably carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide. When using a 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, by reacting the compound of formula (II) with phenol in the presence of a base, the compound of formula (II)
I)

[0017]

A compound represented by can be obtained.

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.

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

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

(C) Then, the nitro group of the compound of formula (III) is reduced to give a compound of formula (IV)

[0023]

The compound represented by can be obtained.

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, acetonitrile and the like are used. Can be mentioned.

(D) Next, the compound of formula (IV) and the formula (V) Cl-CO-R (V) (wherein, R is an alkyl group having 1 to 5 carbon atoms, and 1 to 5 carbon atoms). Represents an alkoxy group or an alkoxycarbonyl group having 2 to 6 carbon atoms) or a formula (VI) (R-CO) ₂ O (VI) (In the formula, R is an alkyl having 1 to 5 carbon atoms. Group, an alkoxy group having 1 to 5 carbon atoms or an alkoxycarbonyl group having 2 to 6 carbon atoms) is reacted to give a compound of the formula (VII)

[0028]

A compound represented by the formula (wherein R has the same meaning as defined above) can be obtained.

This reaction is preferably carried out in the presence of a base,
Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and hydrogen. 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]-
Organic bases such as 7-undecene, pyridine, N, N-dimethylaminopyridine and the like can be mentioned.

This 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.

(E) The compound of formula (VII) is then nitrated with a nitrating agent such as nitric acid or a nitrate to give a compound of formula (VIII)

[0033]

A compound represented by the formula (wherein R has the same meaning as defined above) can be obtained.

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) Finally, the compound of formula (VIII) of the present invention can be obtained by hydrolyzing the compound of formula (VIII).

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.

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 anti-rheumatic agent for humans, the dose is usually 5 to 600 mg per day, although it varies depending on age, body weight, symptoms, administration route, administration frequency and the like.

The compound which is the active ingredient of the present invention exhibits strong anti-inflammatory action, antipyretic action, analgesic action and anti-rheumatic action, and has few side effects such as digestive tract disorders. It is useful as an antipyretic, analgesic and antirheumatic agent.

Test Example 1 [Carrageenin paw edema inhibition test] The carrageenin paw edema inhibition test was carried out by the method of Winter et al. [Pr.
oc. Soc. Exp. Biol. Med. 111th
Vol. 544 (1962)].

Using Wistar rats (6 rats per group),
Samples [inventive compound (a) and control compound (b)] suspended in a 5% aqueous solution of gum arabic were added at 1 per 100 g of body weight.
It was orally administered at a dose of ml. One hour later, 0.1% of carrageenin was subcutaneously administered to the foot pad of the left limb. Three hours after the administration of carrageenin, the paw volume was measured, and the edema inhibition rate (%) was determined to investigate the anti-inflammatory effect.

The dose of the sample was 0.3 mg / kg.

Test Example 2 [Adjuvant Arthritis (Treatment) Test] The adjuvant arthritis (treatment) test is carried out by the method of Winter et al. [Arthritis Rheum. , Volume 12, Fourth
72 (1969)].

Adjuvant arthritis was induced by subcutaneously injecting 0.7% Mycobacterium tuberculosis suspended in liquid paraffin into the foot pads of Lewis rats (7 rats per group). 15-18 days after administration of adjuvant,
Using well-developed arthritic rats, samples [present compound (a) and control compound (b)] suspended in a 5% aqueous solution of gum arabic were orally administered once a day for 4 days at a dose of 1 ml per 100 g of body weight. .

On the day after the final administration, the paw volume was measured, and the swelling suppression rate (%) was determined to examine the therapeutic effect. The administration dose of the sample was 0.2 mg / kg.

Test Example 3 [Adjuvant Arthritis (Pain) Test] Adjuvant arthritis (pain) test is performed by the method of Kuzuno et al. [Ch
em. Pharm. Bull. , Vol. 23, No. 6, p. 1184 (1975)].

Adjuvant arthritis was induced by subcutaneously injecting 0.7% Mycobacterium tuberculosis suspended in liquid paraffin into the footpads of the left limbs of Lewis rats (1 group: 10). 15-18 days after administration of adjuvant,
Using arthritis rats showing a squealing response to flexion-extension stimulating pain of the right hind ankle, samples [present compound (a) and control compound (b)] suspended in a 5% aqueous solution of gum arabic per 100 g of body weight It was orally administered at a dose of 1 ml. The presence or absence of a squeaking reaction was measured with time up to 5 hours after the administration, and the inhibition rate (%) was determined to examine the analgesic effect. The administration dose of the sample was 1.0 mg / kg.

The results of Test Examples 1 to 3 are summarized in Table 1 above.
It was shown to.

[0049]

[Table 1]

Compound (a) of the present invention; Compound of Example 1 Control compound (b); N- (4-nitro-2-phenoxyphenyl) methanesulfonamide

Test Example 4 [IL-1 Production Inhibition Test] Heparinized normal human peripheral blood was layered on Lymphoprep (Daiichi Pharmaceutical Co., Ltd.) under sterile conditions to remove red blood cells, and then the cells were fetal bovine serum 10% and penicillin. RPMI-1640 supplemented with 100 U / ml, streptomycin 100 U / ml, Hepes buffer 10 mM and L-glutamine 2 mM
Suspend in a medium (Gibco) to obtain a cell count of 2 × 10 ⁶ ce
lls / ml.

500 μl of the prepared cell suspension, ConA
(Sigma) 2.0 μg and the above medium solution 250 of the sample [the present compound (a) and the control compound (b)]
μl was added to a microplate (flat bottom, 24 holes, manufactured by Iwaki Glass Co., Ltd.) and cultured in a 5% CO ₂ incubator for 48 hours. The medium solution of the sample was prepared by dissolving the sample in ethanol and then diluting it with the above medium solution so that the final concentration of ethanol was 0.05%. After culturing, measure the amount of IL-1β (pg / ml) in the cell supernatant by ELISA.
It was measured with a kit (Amersham), the IL-1β production inhibition rate (%) was determined, and the IC ₅₀ value was calculated.

The concentrations of the samples are 0, 3, 10 and 30.
μg / ml.

As a result, the compound of the present invention (a), IL-1
The IC ₅₀ value of the production inhibitory action was calculated to be 13.3 μg / ml, but the control compound (b) did not show an inhibitory action of 50% or more at the above concentration, and the IC ₅₀ value was not obtained.

EXAMPLES Next, the present invention will be described in more detail with reference to examples. Example 1 (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 water and ethanol in this order, and dried in air to obtain 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 product was cooled to 50 ° C., ethyl acetate and water were added, the insoluble material was filtered, 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 a dichloromethane solution containing 13.7 g of oxalyl chloride, 9.5 g of n-pentanol 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 the solvent was distilled off, 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) To 60 ml of acetic acid solution containing 17.1 g of N- [5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide, 2.7 g of 60% nitric acid was added with stirring at 90 ° C. under heating. Was added and stirred for 10 minutes. The reaction solution was returned to room temperature, water was added, the precipitate was collected by filtration, and recrystallized from ethanol to give yellow needle crystals of N- [4-nitro-5- (n-pentyl) oxalylamino-2-phenoxyphenyl. ] 11.5 g of methanesulfonamide was obtained. m. p. 123.5-125.5 ° C

(6) A 25% solution of N- [4-nitro-5- (n-pentyl) oxalylamino-2-phenoxyphenyl] methanesulfonamide in 25 ml of tetrahydrofuran at room temperature containing 10% aqueous sodium hydroxide 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 distilling off the solvent, the residue was recrystallized with ethanol,
Orange Prism N- (5-amino-4-nitro-2-)
1.6 g of phenoxyphenyl) methanesulfonamide was obtained. m. p. 175-176 ° C

Example 2 The procedure of Example 1 was repeated except that the residue was recrystallized from ethanol-n-hexane instead of ethanol. (5-Amino-4-nitro-2-phenoxyphenyl) methanesulfonamide was obtained.

M. p. 164-165 ° C

Front page continued (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 Pharmaceutical Co., Ltd. In the company

Claims (1)

[Claims] 1. A formula And a salt thereof.