JPH06100525A - Oxamide-containing sulfonanilide compound - Google Patents

Abstract

PURPOSE:To obtain an oxamide-containing sulfonanilide compound useful as an anti-inflammatory agent, antipyretic, analgesic, antiallergic having low side effects such as digestive tract disorder and high stability to stand long-term administration. CONSTITUTION:A compound of formula I (R<1> is 1-3C alkyl; R<2> is phenyl or 5-7C cycloalkyl; R<3> is H or 1-4C alkyl; R<4> is 1-8C alkyl, 3-8C cycloalkyl, 4-6C cycloalkylmethyl, 3-5C alkenyl, 2-4C hydroxyalkyl, benzyl or R<3> and R<4> are bonded to form heterocyclic ring of 5-to 9-membered ring) such as N-[4- nitro-5-(n-pentylaminooxalylamino)-2phenoxyphenyl]methanesulfonamide. The compound is obtained by reacting 2-fluoro-5-nitroaniline with a sulfonic acid to give a compound of formula II, reacting this compound with phenol or a cycloalkyl alcohol to give a compound of formula III, reducing the nitro group of the compound, reacting the resulting substance with a compound of the formula Cl-COCO2-R<5>, nitrating the prepared compound of formula IV and reacting the resultant substance with an amine of formula V.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sulfoneanilide compound having an oxamide having anti-inflammatory action, antipyretic action, analgesic action and antiallergic action.

Various compounds are known as sulfone anilide compounds, and as the sulfone anilide compound having an amino group at the 5-position, compounds described in US Pat. No. 3,856,859 are known. However, the sulfonanilide compound having an oxamide of the present invention is not known.

However, the above-mentioned sulfonanilide compound having an amino group at the 5-position is not sufficiently effective.

The purpose of the present invention is to have anti-inflammatory action, antipyretic action,
It is to provide an excellent compound having an analgesic action and an antiallergic action.

As a result of intensive studies aimed at solving the above-mentioned problems, the present inventors have found that the sulfonanilide compound having an oxamide shown below can achieve the purpose, and completed the present invention. did.

That is, the present invention uses the formula

[0004]

(In the formula, R ¹ is an alkyl group having 1 to 3 carbon atoms, and R ² is a phenyl group or 5 to 5 carbon atoms.
7 cycloalkyl groups, R ³ is a hydrogen atom or an alkyl group having 1 to ⁴ carbon atoms, R ⁴ is an alkyl group having 1 to 8 carbon atoms, 3 to 8 carbon atoms A cycloalkyl group, a cycloalkylmethyl group having 4 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a hydroxyalkyl group having 2 to 4 carbon atoms or a benzyl group, or R ³ and R ⁴ together represents a 5- to 9-membered heterocycle. ) Is a sulfone anilide compound having an oxamide.

In the present invention, R1 has 1 to 3 carbon atoms.
The alkyl group is a methyl group, an ethyl group, or an n-propyl group. The cycloalkyl group having 5 to 7 carbon atoms of R ² is a cyclopentyl group, a cyclohexyl group or a cycloheptyl group. The alkyl group having 1 to 4 carbon atoms of R ³ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group or a t-butyl group. The alkyl group having 1 to 8 carbon atoms of R ⁴ is a linear or branched alkyl group, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Isobutyl group, t-butyl group, n-
Pentyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 3-methylpentyl group, 4-methylpentyl group, 2-ethylbutyl group, n-heptyl group,
An n-octyl group and the like. The cycloalkyl group having 3 to 8 carbon atoms for R ⁴ is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group. The cycloalkylmethyl group having 4 to 6 carbon atoms represented by R ⁴ is a cyclopropylmethyl group, a cyclobutylmethyl group or a cyclopentylmethyl group. The alkenyl group having 3 to 5 carbon atoms of R ⁴ is a linear or branched alkenyl group, for example, an allyl group, 2-butenyl group, 3-methyl-2.
A butenyl group and the like. The hydroxyalkyl group having 2 to ⁴ carbon atoms for R ⁴ is, for example, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group or the like. The 5- to 9-membered heterocycle formed by R ³ and R ⁴ together includes, for example, a pyrrolidino group, a piperidino group, a hexamethyleneimino group, a heptamethyleneimino group, an octamethyleneimino group, a morpholino group and a thiomorpholino group. Group, piperazino group, 4-methylpiperazino group, and 4-diphenylmethylpiperazino group. With salts, alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with calcium, magnesium, etc., ammonium salts and methylamine, ethylamine, butylamine, dimethylamine, diethylamine, triethylamine, tributylamine, ethanolamine, pyridine, It is a salt with organic bases such as 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-nitroa
Nirin, the formula  R¹-SO₃H (II) (wherein R¹Is as defined above. ) Represented by
Fonic acid or its reactive derivatives (eg acid halogenated
Substance, acid anhydride, etc.)

Expression

A compound represented by can be obtained.

When the sulfonic acid represented by the formula (II) is used in this reaction, it is preferably carried out in the presence of a condensing agent such as N, N'-dicyclohexylcarbodiimide. Further, when using a reactive derivative, it is preferably carried out in the presence of a base, as the base lithium hydroxide,
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate 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, 4-methylmorpholine, 1-methylpiperidine, pyridine, N, N-dimethylaminopyridine and the like can be mentioned.

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 (III) with phenol or a cycloalkyl alcohol having 5 to 7 carbon atoms in the presence of a base,

[0014]

A compound represented by the formula (wherein R ¹ and R ² are as defined above) 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, 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) The nitro group of the compound of formula (IV) is then reduced to give a compound of formula

[0020]

A compound represented by the formula (wherein R ¹ and R ² have the same meanings as described above) 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, etc. 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 the formula (V) and the formula Cl-COCO ₂ -R ⁵ (VI) (wherein R ⁵ is a linear or molecular chain having 1 to 10 carbon atoms).
5 alkyl groups. ) By reacting a compound represented by the formula

[0025]

A compound represented by the formula (wherein R ¹ , R ² and R ⁵ have the same meanings as described 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) Then, by nitrating the compound of formula (VII) with a nitrating agent such as nitric acid or a nitrate, the compound of formula

[0030]

A compound represented by the formula (wherein R ¹ , R ² and R ⁵ are as defined above) can be obtained.

As the nitrate in the nitration reaction, sodium nitrate, potassium nitrate, iron nitrate, urea nitrate and the like can be used, and the solvent to be used is preferably selected arbitrarily 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) and the formula

[0034]

The compound of formula (I) of the present invention can be obtained by reacting with an amine represented by the formula (wherein R ³ and R ⁴ are as defined above).

This reaction is carried out without solvent or in a solvent under the temperature conditions of room temperature to the boiling point of amines in the case of no solvent, and the boiling point of solvent in the case of using a solvent. It can be reacted with amines represented by IX).

As the solvent used in this reaction, water, methanol, ethanol, propanol, t-butanol,
Diethyl ether, tetrahydrofuran, dioxane,
Acetone, acetonitrile, benzene, toluene, xylene, chlorobenzene, N, N-dimethylformamide, dimethyl sulfoxide and the like can be mentioned.

The compounds of the present invention can be administered orally or parenterally in conventional dosage forms. These include, for example, tablets, 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.

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.

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. 128-129 ° 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 to 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 a solution of 65 g of dichloromethane containing 10.4 g of N- (5-amino-2-phenoxyphenyl) methanesulfonamide and 3.3 g of pyridine was added 5.6 g of ethyloxalyl chloride under ice cooling,
Stir for 1.5 minutes. Water was added to the reaction solution and the mixture was extracted with dichloromethane. 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 recrystallized from ethanol to give colorless crystals of N-
11.9 g of (5-ethyloxalylamino-2-phenoxyphenyl) methanesulfonamide was obtained.

M. p. 140.5-142.5 ° C

(5) N- (5-ethyloxalylamino-2-phenoxyphenyl) methanesulfonamide 1
To 31 ml of acetic acid solution containing 1.8 g, 3.5 g of 60% nitric acid was added with heating and stirring at 110 ° C., and the mixture was stirred for 30 minutes.
The reaction solution was returned to room temperature, water was added, the precipitate was filtered, and then recrystallized from ethanol-n-hexane to obtain yellow needle crystals of N-.
8.6 g of (5-ethyloxalylamino-4-nitro-2-phenoxyphenyl) methanesulfonamide was obtained.

M. p. 194.5-195.5 ° C

(6) 3.5 ml of tetrahydrofuran containing 1.5 g of N- (5-ethyloxalylamino-4-nitro-2-phenoxyphenyl) methanesulfonamide
0.93 g of n-pentylamine was added to the solution at room temperature, and 1
It was stirred for a while. The reaction mixture was neutralized with 3N hydrochloric acid, and the precipitate was collected by filtration and recrystallized from tetrahydrofuran-ethanol to give yellow needle crystals of N- [4-nitro-5- (n-pentylaminooxalylamino). 1.1 g of 2-phenoxyphenyl] methanesulfonamide was obtained.

M. p. 205-206 ° C

Examples 2 to 25 Example 1 Using N- (5-ethyloxalylamino-4-nitro-2-phenoxyphenyl) methanesulfonamide obtained by the method of (1) to (5) as a raw material, Example 1 (6)
By the same procedure as in Example 1 (6) except that the following amines were used in place of the n-pentylamine used in 1.
The compounds of the present invention shown in Tables 1-1 and 2 were obtained. However,
As the recrystallization solvent for each compound, the solvents shown in Tables 1 and 2 were used.

[Amines] n-propylamine, n-butylamine, n-hexylamine, n-heptylamine, isopropylamine, isobutylamine, t-butylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, cyclo Octylamine, cyclopropylmethylamine, allylamine, 2-hydroxyethylamine, 2,3-dihydroxypropylamine, benzylamine, diethylamine, pyrrolidine, piperidine, hexamethyleneimine, heptamethyleneimine, morpholine, 1-diphenylmethylpiperazine.

[0052]

[Table 1]

Note) THF: tetrahydrofuran, n-H
exane; n-hexane, EtOH: ethanol, A
cetone: acetone

[0054]

[Table 2]

Note) THF: tetrahydrofuran, n-H
exane; n-hexane, EtOH: ethanol, A
Cetone: Acetone Examples 26 to 30 (1) To a 2500 ml solution of chlorobenzene containing 72.0 g of 60% sodium hydride, 174.0 g of cyclohexanol and tris [2- (2-methoxyethoxy)] at room temperature.
Ethyl] amine (10.0 ml) was added in that order, and the mixture was stirred for 30 minutes and then cooled with ice to obtain N- (2-fluoro-5-nitrophenyl) methanesulfonamide 136.
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 give pale yellow needle crystals of N- (2-cyclohexyloxy-5-nitrophenyl) methanesulfonamide 13
1.0 g was obtained.

M. p. 105-106.5 ° C

(2) N- (2-cyclohexyloxy-
5-nitrophenyl) methanesulfonamide was used in Example 1.
By reducing in the same manner as in the method (3), N- (5-
Amino-2-cyclohexyloxyphenyl) methanesulfonamide was obtained.

M. p. 151.5-153.5 ° C

(3) To 200 ml of dichloromethane containing 8.0 g of oxalyl chloride, 3.8 g of n-propanol and then 5.0 g of pyridine were added under ice cooling, and the mixture was stirred for 15 minutes. The reaction solution was cooled at −78 ° C., 100 ml of a dichloromethane solution containing 15.0 g of N- (5-amino-2-cyclohexyloxyphenyl) methanesulfonamide and 5.0 g of pyridine was added, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution and the mixture was extracted with dichloromethane. 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 recrystallized from ethanol to obtain 14.1 g of colorless crystals of N- [2-cyclohexyloxy-5- (n-propyloxalylamino) phenyl] methanesulfonamide.

M. p. 152-153 ° C

(4) N- [2-cyclohexyloxy-
By nitrating 5- (n-propyloxalylamino) phenyl] methanesulfonamide in the same manner as in Example 1 (5), N- [2-cyclohexyloxy-
4-Nitro-5- (n-propyloxalylamino) phenyl] methanesulfonamide was obtained.

M. p. 176-177 ° C

(5) N- [2-cyclohexyloxy-
4-nitro-5- (n-propyloxalylamino) phenyl] methanesulfonamide and the following amines were used and treated in the same manner as in Example 1 (6) to give the compounds of the present invention shown in Table 2. It was However, as the recrystallization solvent for each compound, the solvents shown in Table 2 were used.

[Amines] n-pentylamine, n-hexylamine, allylamine, piperidine, hexamethyleneimine

[0065]

[Table 3]

Note) THF: tetrahydrofuran, n-H
exane; n-hexane, EtOH: ethanol, A
cetone: acetone

Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/18 ABE 9283-4C ABF 9283-4C (72) Inventor Mariko Kashiwa 3-24 Takada, Toshima-ku, Tokyo No. 1 within Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Within Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A formula (In the formula, R ¹ is an alkyl group having 1 to 3 carbon atoms, R ² is a phenyl group or a cycloalkyl group having 5 to 7 carbon atoms, and R ³ is a hydrogen atom or 1 carbon atom. To 4 alkyl groups, R ⁴ has 1 to 8 carbon atoms
Alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, cycloalkylmethyl groups having 4 to 6 carbon atoms, alkenyl groups having 3 to 5 carbon atoms, hydroxy having 2 to 4 carbon atoms Alkyl group or benzyl group, R
³ and R ⁴ together represent a 5- to 9-membered heterocycle. ) A sulfonanilide compound having an oxamide represented by: