JPH04283555A - 4-substituted sulfonaniliode compound - Google Patents

Abstract

PURPOSE:To obtain a new 4-substituted sulfonanilide compound having anti- inflammatory, antipyretic, analgesic and antiallergic actions and its pharmaceutically permissible salt. CONSTITUTION:A 4-substituted sulfonanilide compound expressed by formula I (Ra is alkyl; Rb is cycloalkyl; Rc is alkyl, halogen, OH, alkoxy, phenoxy, formyloxy, alkanoyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, phenylthio, phenylsulfinyl, phenylsulfonuyl, alkoxycarbonylmethylthio, etc.) and its pharmaceutically permissible salt, e.g. N-(2-cyclohexyloxy-5-methyl-4-nitrophenyl) methanesulfonamide. A compound in which Rc is alkyl in the compound expressed by formula I is obtained by reacting a compound expressed by formula II with a compound expressed by the formula Rb-OH in the presence of a base.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to 4-substituted sulfonanilide compounds and pharmaceutically acceptable salts thereof. More specifically, the present invention relates to novel 4-substituted sulfonanilide compounds and pharmaceutically acceptable salts thereof having anti-inflammatory, antipyretic, analgesic and anti-allergic effects.

0002

[Prior Art] Sulfonanilide compounds having anti-inflammatory effects are described in U.S. Pat. No. 3,840,597, U.S. Pat.
Compounds described in JP-A No. 0548, JP-A-63-190869, and JP-A-2-268 [for example, N-
(4-nitro-2-phenoxyphenyl)methanesulfonamide, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide, etc.], but nothing has been disclosed regarding 4-substituted sulfonanilide compounds. Not yet.

0003

SUMMARY OF THE INVENTION An object of the present invention is to provide a highly safe drug that can withstand long-term administration.

0004

[Means for Solving the Problems] As a result of intensive studies aimed at the above-mentioned purpose, the present inventors have found that the present inventors have developed an anti-inflammatory agent, an antipyretic agent, an analgesic agent, and an antiallergic agent, which have anti-inflammatory, antipyretic, analgesic, and antiallergic effects. We have discovered a highly safe compound that is useful as a gastrointestinal tract and has fewer side effects such as gastrointestinal disorders.
The invention has been completed.

[0005] The present invention is based on the formula

[In formula 2, Ra is a lower alkyl group, Rb is a cycloalkyl group, and Rc is a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, a formyloxy group, a lower alkanoyloxy group. group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, phenylthio group, phenylsulfinyl group, phenylsulfonyl group, lower alkoxycarbonylmethylthio group, lower alkoxycarbonylmethylsulfinyl group, lower alkoxycarbonylmethylsulfonyl group or formula -CH2Rd (In the formula, Rd is a hydroxyl group, a lower alkoxy group, a phenoxy group, a lower alkanoyloxy group,
It is a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkoxycarbonylmethyl group, a carboxymethyl group, or an amino group substituted with one or two lower alkyl groups. ). ] These are 4-substituted sulfonanilide compounds and pharmaceutically acceptable salts thereof.

In the present invention, the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The lower alkyl group is a linear or branched alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, 3-pentyl, and the like. Cycloalkyl group has 3 or more carbon atoms
Eight cycloalkyl groups, such as cyclopropyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc. The lower alkoxy group is a linear or branched alkoxy group having 1 to 5 carbon atoms, such as a methoxy group, an ethoxy group, a propyloxy group, a butyloxy group, a 3-pentyloxy group, and the like. The lower alkanoyloxy group is a linear or branched alkanoyloxy group having 2 to 6 carbon atoms, such as an acetoxy group, a propionyloxy group, an isopropionyloxy group, a butyryloxy group, and the like. A lower alkylthio group is a linear or branched alkylthio group having 1 to 5 carbon atoms, such as methylthio group, ethylthio group, propylthio group, butylthio group,
-pentylthio group, etc. A lower alkylsulfinyl group is a linear or branched alkylsulfinyl group having 1 to 5 carbon atoms, such as methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, 3-pentylsulfinyl group. etc. A lower alkylsulfonyl group is a linear or branched alkylsulfonyl group having 1 to 5 carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, 3-pentylsulfonyl group. etc. A lower alkoxycarbonylmethylthio group is a linear or branched alkoxycarbonylmethylthio group having 3 to 7 carbon atoms, such as methoxycarbonylmethylthio group, ethoxycarbonylmethylthio group, propyloxycarbonylmethylthio group, butyloxy Carbonylmethylthio group, etc. A lower alkoxycarbonylmethylsulfinyl group is a linear or branched alkoxycarbonylmethylsulfinyl group having 3 to 7 carbon atoms, such as methoxycarbonylmethylsulfinyl group, ethoxycarbonylmethylsulfinyl group, propyloxycarbonylmethyl group. These include sulfinyl group, butyloxycarbonylmethylsulfinyl group, etc. A lower alkoxycarbonylmethylsulfonyl group is a linear or branched alkoxycarbonylmethylsulfonyl group having 3 to 7 carbon atoms, such as methoxycarbonylmethylsulfonyl group, ethoxycarbonylmethylsulfonyl group, propyloxycarbonylmethyl group. Sulfonyl group, butyloxycarbonylmethylsulfonyl group, etc. A lower alkoxycarbonylmethyl group is a linear or branched alkoxycarbonyl group having 3 to 7 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, an isopropyloxycarbonyl group, Butyloxycarbonyl group, etc.

The compound of formula 2 of the present invention can be produced from known compounds by the method shown below. (1) The compound of formula 2 in which Rc is a lower alkyl group has the formula

[Chemical formula 3]

A compound represented by the formula (in formula 3, Re is a lower alkyl group) can be obtained as a starting material. That is, in the presence of a base, the compound of formula Rb-OH
(In the formula, Rb has the same meaning as above.) By reacting the compound represented by the formula

[C4]

A compound represented by the formula (in formula 4, Rb and Re have the same meanings as above) can be obtained.

Bases used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal hydrides such as sodium hydride and potassium hydride, and alkali metal carbonates such as sodium carbonate and potassium carbonate. , alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, metal sodium, and sodium amide. This reaction can be carried out without solvent or with dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene,
The reaction can be carried out in a solvent such as , xylene, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, or chloroform. Further, in this reaction, the reaction can be accelerated by adding potassium iodide, a quaternary ammonium salt such as benzyltriethylammonium chloride, a crown ether such as 18-crown-6 ether, and the like. Then chemical formula 4
The compound is converted into an amino form. The reduction may be carried out by a conventional reduction method in which a nitro group is reduced to an amino group, such as catalytic reduction using palladium-carbon, Raney-nickel, or platinum as a catalyst, reduction using iron or tin, or reduction using sodium sulfide-ammonium chloride. reduction using sodium borohydride, lithium aluminum hydride, etc. The solvent used in this reaction may be arbitrarily selected depending on the reduction method, but generally includes alcohols such as methanol, ethanol, and propanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran, and acetonitrile.

[0011] Subsequently, the amino compound obtained above was given the formula RaSO
A sulfonic acid compound represented by 3H (wherein Ra has the same meaning as above) or a reactive derivative thereof (for example,
These include acid halides and acid anhydrides. ) by reacting with the formula

[C5]

A compound represented by the formula (in formula 5, Ra, Rb and Re have the same meanings as above) can be obtained.

In this reaction, when a sulfonic acid compound is used, it is preferably carried out in the presence of a condensing agent such as N,N-dicyclohexylcarbodiimide. When using a reactive derivative, it is preferable to carry out the reaction in the presence of a base. The bases used here are inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, 1-methylmorpholine, 1-methylpiperidine, pyridine, N,N - An organic base such as dimethylaminopyridine. Additionally, this reaction is usually performed in a solvent such as dichloromethane, chloroform, ethyl acetate, dioxane, tetrahydrofuran, ethyl ether, benzene, toluene, xylene, acetone, acetonitrile, water, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, etc. be exposed.

Next, by nitrating the compound of formula 5 using nitric acid or a nitrate, the compound of formula

[C6] (In Chemical Formula 6, Ra, Rb and Re have the same meanings as above. ) can be obtained.

The nitrates used in this reaction include sodium nitrate, potassium nitrate, iron nitrate, and urea nitrate. The reaction is carried out without a solvent or using acetic acid, acetic anhydride, trifluoroacetic acid, sulfuric acid, dichloromethane, chloroform, benzene, dioxane, methanol, ethanol, propanol, etc. as a solvent.

(2) The compound of formula 2 in which Rc is a fluorine atom can be prepared by using 2,5-difluoronitrobenzene as a starting material in the same manner as in (1) above.

[C7]

The compound of the present invention represented by the formula (in formula 7, Ra and Pb have the same meanings as above) can be obtained.

(3) Rc is Rf (Rf is a chlorine atom,
A bromine atom, an iodine atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, a lower alkanoyloxy group, a lower alkylthio group, a phenylthio group or a lower alkoxycarbonylmethylthio group. ) The compound represented by formula 2 can be obtained using the compound represented by formula 7 obtained in (2) above as a starting material. That is, the compound of formula 7 is expressed as formula Rf
-H (wherein, Rf has the same meaning as above), the formula

[Chemical formula 8]

The compound of the present invention represented by the formula (in formula 8, Ra, Rb and Rf have the same meanings as above) can be obtained.

This reaction is preferably carried out in the presence of a base, and the base used here is an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. Alkali metal hydrides, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium metal, sodium metal, potassium metal, sodium amide , or organic bases such as triethylamine, 1-methylmorpholine, 1-methylpiperidine, pyridine, N,N-dimethylaminopyridine. This reaction can be carried out without a solvent or in a solvent such as water, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene, xylene, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane, chloroform, etc. It can be done with Further, in this reaction, the reaction can be accelerated by adding potassium iodide, a quaternary ammonium salt such as benzyltriethylammonium chloride, a crown ether such as 18-crown-6 ether, or the like.

(4) Rc is of the formula -CH2Rg (in the formula, Rg
is a hydroxyl group, a lower alkoxy group, a phenoxy group, a lower alkanoyloxy group, a lower alkylthio group, a phenylthio group, or an amino group substituted with one or two lower alkyl groups. ) The compound of chemical formula 2 is a group represented by
A synthetic intermediate of the compound of formula 6 in which Re in (1) above is a methyl group can be obtained as a starting material. That is,
The formula obtained by halogenating the compound of formula 4 in which Re is a methyl group

[Chemical formula 9]

(In formula 9, Rb has the same meaning as above, and R
h is a halogen atom. ) and the formula Rg
By reacting a compound represented by -H (wherein Rg has the same meaning as above) or a salt thereof, a compound represented by the formula

[Chemical formula 10]

A compound represented by the formula (in formula 10, Rb and Rg have the same meanings as above) can be obtained.

The halogenation in this reaction is a conventional halogenation reaction at the benzyl position using a halogenating agent such as N-bromosuccinimide. In addition, the reaction between the compound of Chemical Formula 9 and the compound represented by the formula Rg-H (wherein Rg has the same meaning as above) is preferably carried out in the presence of a base, and the base used here is: Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal carbonates such as lithium carbonate, sodium carbonate, and potassium carbonate; and hydrogen carbonate. Alkali metal bicarbonates such as lithium, sodium bicarbonate, potassium bicarbonate, inorganic bases such as lithium metal, sodium metal, potassium metal, sodium amide, or triethylamine, 1-methylmorpholine, 1-methylpiperidine, pyridine, N,N - An organic base such as dimethylaminopyridine. This reaction can be carried out without solvent or with water, dioxane, tetrahydrofuran, ethyl ether, petroleum ether, hexane, cyclohexane, benzene, toluene, xylene, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile,
This can be carried out in a solvent such as dichloromethane or chloroform. Further, in this reaction, the reaction can be accelerated by adding potassium iodide, a quaternary ammonium salt such as benzyltriethylammonium chloride, a crown ether such as 18-crown-6 ether, and the like.

Next, the compound of formula 10 was reduced, sulfonamidated, and nitrated in order by the method (1) above to obtain the compound of formula

[Chemical formula 11]

The compound of the present invention represented by the formula (in formula 11, Ra, Rb and Rg have the same meanings as above) can be obtained.

(5) Rc is the formula -CH2CH2CO2Ri
(In the formula, Ri is a lower alkyl group.) The compound represented by Chemical Formula 2 can be obtained using the compound represented by Chemical Formula 10 in (4) above as a starting material. That is, by reacting the compound of formula 10 with a compound of the formula CH2(CO2Ri)2 (wherein Ri has the same meaning as above), the compound of the formula

[Chemical formula 12]

A compound represented by the formula (in formula 12, Rb and Ri have the same meanings as above) can be obtained.

Next, after dealkoxycarbonylating the compound of formula 12, reduction, sulfonamidation, and nitration are sequentially performed by the method (1) above to obtain the compound of formula

[Chemical formula 13]

The compound of the present invention represented by the formula (in formula 13, Ra, Rb and Ri have the same meanings as above) can be obtained.

This dealkoxycarbonylation reaction uses an aprotic polar solvent such as dimethyl sulfoxide or N,N-dimethylformamide and water, and generally uses an inorganic salt such as sodium chloride, lithium chloride, magnesium chloride. , sodium bromide, lithium bromide, magnesium bromide, etc. are added and reacted.

(6) The compound of formula 2 in which Rc is the formula -CH2CH2CO2H can be obtained by hydrolyzing the compound of formula 13 above.

Hydrolysis in this reaction refers to a conventional hydrolysis method under acidic conditions or basic conditions, for example, a method using a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. as basic conditions. This method uses an acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid as the acidic condition. The solvent used here is arbitrarily selected, but generally includes water, methanol, ethanol, tetrahydrofuran, dioxane, benzene, toluene, formic acid, acetic acid, and the like.

(7) In the compound of formula 2, in which Rc is a group represented by the formula -(CH2)mOH (wherein m is an integer of 0 or 1), Rf obtained in the above (3) is A compound with a lower alkanoyloxy group, or R obtained in (4)
It can be obtained by hydrolyzing a compound in which g is a lower alkanoyloxy group by the method (6) above.

(8) Rc has the formula -(CH2)mS(O)n
Rj (where m has the same meaning as above, and n is 1 or 2
Rj is an integer of , and Rj is a lower alkyl group, a lower alkoxycarbonylmethyl group, or a phenyl group. ) is a group represented by formula 2, which is obtained by the above (3) or (4).

[Chemical formula 14]

A compound represented by the formula (in formula 14, Ra, Rb, Rj and m have the same meanings as above) can be obtained as a starting material. That is, the usual oxidation method of converting the sulfide into a sulfoxide or sulfone in the compound of Chemical Formula 14 (for example, a method using hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, potassium permanganate, sodium periodate, etc.) It can be obtained by oxidizing with

(9) A pharmaceutically acceptable salt of the compound of formula 2 can be obtained by treating the compound of formula 2 with a base in water or an organic solvent. Here, the base is
These include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alcoholates such as sodium methoxide, sodium ethoxide, and potassium t-butoxy; and organic amines such as triethylamine and ethanolamine.

[0038]

[Effects of the Invention] The compounds of the present invention exhibit anti-inflammatory, antipyretic, analgesic, and antiallergic effects, and have few side effects such as gastrointestinal disorders, so they are useful as antiinflammatory agents, antipyretics, analgesics, and antiallergic agents. .

For this purpose, the compounds can be administered orally or parenterally in the customary dosage forms. These include, for example, tablets, powders, granules, powders, capsules, liquids, emulsions, suspensions, injections, etc., and any of them can be manufactured using conventional formulation techniques. When used as an anti-inflammatory agent, antipyretic, or analgesic for humans, the dosage varies depending on age, body weight, symptoms, route of administration, frequency of administration, etc., but is usually 20 to 1000 mg per day.

[0040]

[Example] Next, the method for producing the compound of the present invention will be explained in detail with reference to Examples. Example 1 (1) 375 cyclohexane containing 32.2 g of powdered sodium hydroxide and 24.2 g of cyclohexanol
25.0 g of 4-fluoro-3-nitrotoluene was added to the ml suspension under ice cooling, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction solution, extracted with cyclohexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized from n-hexane to obtain 28.3 g of 4-cyclohexyloxy-3-nitrotoluene. m. p. 61-62℃

(2) 5.0 g of 4-cyclohexyloxy-3-nitrotoluene and 0.2 g of 5% palladium-carbon
A 22 ml ethanol solution containing 5 g was stirred at room temperature under a hydrogen atmosphere for catalytic reduction. After removing the palladium-carbon by filtration, the filtrate was distilled off to obtain 4.2 g of 2-cyclohexyloxy-5-methylaniline in the form of colorless needles. m. p. 30-31℃

(3) Into 20 ml of pyridine solution containing 4.0 g of 2-cyclohexyloxy-5-methylaniline,
Under ice cooling, 2.7 g of methanesulfonyl chloride was added over 3 minutes, and the mixture was further stirred at room temperature for 16 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was mixed with water, 3N hydrochloric acid,
After washing with water and saturated saline in that order, it was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol-n-hexane to give colorless crystals of N-(2-cyclohexyloxy-5-methylphenyl)methanesulfonamide 4.
．． 8g was obtained. m. p. 116-118℃

(4) N-(2-cyclohexyloxy-
To 3.5 ml of acetic acid solution containing 1.0 g of 5-methylphenyl)methanesulfonamide was heated at 80°C with stirring for 60 min.
% nitric acid was added and further stirred for 20 minutes. The reaction solution was returned to room temperature, neutralized by adding a saturated aqueous sodium bicarbonate solution, and 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-n-hexane to give yellow crystals of N-(2-cyclohexyloxy- 5-Methyl-4-nitrophenyl)methanesulfonamide 0.
77g was obtained. m. p. 119-121℃

Example 2 Using 2,5-difluoro-nitrobenzene, Example 1
The following compound was obtained in the same manner as above. N-(2-cyclohexyloxy-5-fluoro-4-
nitrophenyl) methanesulfonamide m. p. 147
~148°C (Recrystallized from ethanol; hereinafter, the solvent name in parentheses next to the melting point value indicates that it was recrystallized from that solvent.)

Example 3 N-(2-cyclohexyloxy-5-
To a 1.2 ml solution of tetrahydrofuran containing 0.75 g of fluoro-4-nitrophenyl)methanesulfonamide, 3.0 ml of a 20% aqueous sodium hydroxide solution was added at room temperature, and the mixture was refluxed for 2 hours. The reaction solution was returned to room temperature, water was added, and the aqueous layer was washed with dichloromethane, made acidic by adding 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 recrystallized from ethanol-n-hexane to obtain 0.64 g of N-(2-cyclohexyloxy-5-hydroxy-4-nitrophenyl)methanesulfonamide in the form of pale yellow needles. m. p. 133-134℃

Example 4 N-(2-cyclohexyloxy-5-
0.74 g of sodium methoxide was added to 4.5 ml of tetrahydrofuran solution containing 0.75 g of fluoro-4-nitrophenyl)methanesulfonamide, and the mixture was refluxed for 1.5 hours. The reaction solution was returned to room temperature, acidified with 3N hydrochloric acid, extracted with ethyl acetate, and 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 recrystallized from ethanol-n-hexane to give N-(2-cyclohexyloxy-5-methoxy-4-nitrophenyl)methanesulfonamide in the form of pale yellow needles.
．． 70g was obtained. m. p. 121.5-123°C The following compound was obtained in the same manner as in Example 4. N-[2-cyclohexyloxy-5-(t-butoxy)-4-nitrophenyl]methanesulfonamide m. p
．． 112-113°C (ethanol-n-hexane)

Example 5 N-(2-cyclohexyloxy-5-
Add 1.5 ml of a 15% aqueous sodium methyl mercaptan solution to 5.0 ml of tetrahydrofuran solution containing 0.53 g of fluoro-4-nitrophenyl)methanesulfonamide.
was added and refluxed for 3 hours. The reaction solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine in that order.
It was dried with anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethanol-ethyl acetate to give pale yellow needle-like crystals of N-(2-cyclohexyloxy-5-methylthio-4
-nitrophenyl)methanesulfonamide 0.40 g was obtained. m. p. 178-179℃

Example 6 N-(2-cyclohexyloxy-5-
A 3.0 ml solution of tetrahydrofuran containing 0.58 g of fluoro-4-nitrophenyl)methanesulfonamide, 0.19 g of thiophenol, and 0.37 g of sodium carbonate was refluxed for 3 hours. The reaction solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol to obtain 0.53 g of N-(2-cyclohexyloxy-4-nitro-5-phenylthiophenyl)methanesulfonamide in the form of pale yellow needles. m. p. 182-183℃

The following compound was obtained in the same manner as in Example 6. N-(2-cyclohexyloxy-5-ethoxycarbonylmethylthio-4-nitrophenyl)methanesulfonamide m. p. 130-131℃ (ethanol)

[0050]
Example 7 (1) 106 ml of carbon tetrachloride containing 25.0 g of 4-cyclohexyloxy-3-nitrotoluene obtained by the method of Example 1 (2), 28.4 g of N-bromosuccinimide, and 0.5 g of benzoyl peroxide. After refluxing the solution for 16.5 hours,
The reaction solution was returned to room temperature, and the precipitate was filtered off. The filtrate was washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine in this order, and then 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=40:1) to obtain 22.6 g of 4-cyclohexyloxy-3-nitrobenzyl bromide as a yellow oil. 1H-NMR (CDCl3) δ (ppm); 1.20~
2.15 (10H, m) 4.46 (3H, m) 7.05 (1H, d, J = 7Hz) 7.51 (1H, dd, J = 2,7Hz) 7.83 (1
H, d, J=2Hz)

(2) A 6.6 ml methanol solution containing 2.1 g of 4-cyclohexyloxy-3-nitrobenzyl bromide and 0.72 g of sodium methoxide was refluxed for 1 hour, then returned to room temperature and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and then 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 =
10:1) to obtain 1.6 g of 2-cyclohexyloxy-5-methoxymethylnitrobenzene as a yellow oil. 1H-NMR (CDCl3) δ (ppm); 1.27~
2.04 (10H, m) 3.39 (3H, s) 4.40 (2H, s) 4.44 (1H, m) 7.07 (1H, d, J=7Hz) 7.45 (1H, dd, J=2,7Hz)7.76(1
H, d, J=2Hz)

(3) 2-Cyclohexyloxy-5-methoxymethylnitrobenzene in Example 1 (2) to (4)
In the same manner as above, N-(2-cyclohexyloxy-5-methoxymethyl-4-nitrophenyl)methanesulfonamide was obtained. m. p. 109.5-110.5°C (ethanol-n-
hexane)

Example 8 (1) 8 ml of tetrahydrofuran suspension containing 0.32 g of 60% sodium hydride was added with 8 ml of tetrahydrofuran solution containing 0.75 g of phenol, and after stirring at room temperature for 10 minutes, Example 7 (1) A 7 ml solution of tetrahydrofuran containing 2.1 g of 4-cyclohexyloxy-3-nitrobenzyl bromide obtained by the above method was added, and the mixture was refluxed for 2.5 hours. The reaction solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (developing solvent: n-8 xane: dichloromethane: ethyl acetate = 10:5:1) to obtain 2-cyclohexyloxy-5-phenoxymethylnitrobenzene 2 as a yellow oil. .2g was obtained. 1H-NMR (CDCl3) δ (ppm); 1.19~
2.09 (10H, m) 4.45 (1H, m) 5.00 (2H, s) 6.90-7.04 (3H, m) 7.08 (1H, d, J=7Hz) 7. 30 (2H, m) 7.55 (1H, dd, J = 1,7Hz) 7.87 (1
H, d, J=1Hz)

(2) 2-Cyclohexyloxy-5-phenoxymethylnitrobenzene in Example 1 (2) to (4)
) in the same manner as N-(2-cyclohexyloxy-4-
Nitro-5-phenoxymethylphenyl)methanesulfonamide was obtained. m. p. 140-142°C (ethanol-n-hexane)

Example 9 (1) Using 4-cyclohexyloxy-3-nitrobenzyl bromide obtained by the method of Example 7 (1), 2-cyclohexyloxy-5-methylthiomethyl was prepared in the same manner as in Example 5. Nitrobenzene was obtained. 1H-NMR (CDCl3) δ (ppm); 1.30~
2.10 (10H, m) 2.01 (3H, s) 3.64 (2H, s) 4.42 (1H, m) 7.03 (1H, d, J=8Hz) 7.44 (1H, dd, J=2,8Hz)7.81(1
H, d, J=2Hz)

(2) 2-Cyclohexyloxy-5-methylthiomethylnitrobenzene in Example 1 (2) to (4)
) in the same manner as N-(2-cyclohexyloxy-5-
Methylthiomethyl-4-nitrophenyl)methanesulfonamide was obtained. m. p. 102-103℃ (ethanol)

[0057]
Example 10 (1) 4-cyclohexyloxy-3-nitrobenzyl bromide obtained by the method of Example 7 (1) 3.09, 50%
1.8 ml of dimethylamine aqueous solution and potassium carbonate2.
3.5 ml of tetrahydrofuran suspension containing 8 g
Refluxed for an hour. The reaction solution was returned to room temperature, extracted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine, 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 = 1:2) to obtain 2.1 g of 2-cyclohexyloxy-5-dimethylaminomethylnitrobenzene as a yellow oil. Ta. 1H-NMR (CDCl3) δ (ppm); 1.30~
2.00 (10H, m) 2.27 (6H, s) 3.41 (2H, s) 4.41 (1H, m) 7.03 (1H, d, J=8Hz) 7.47 (1H, dd, J=2,8Hz)7.71(1
H, d, J=2Hz)

(2) 2-Cyclohexyloxy-5-dimethylaminomethylnitrobenzene from Example 1 (2) to
Similarly to (4), N-(2-cyclohexyloxy-
5-dimethylaminomethyl-4-nitrophenyl)methanesulfonamide was obtained. m. p. 109-110℃ (ethanol)

[0059]
Example 11 (1) A 4.0 ml solution of acetic acid containing 5.1 g of 4-cyclohexyloxy-3-nitrobenzyl bromide obtained by the method of Example 7 (1) and 1.6 g of sodium acetate was refluxed for 1 hour, and then the solvent was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. After washing the organic layer in the order of water and saturated brine, the residue was subjected to silica gel column chromatography (developing solvent: n-hexane: ethyl acetate =
5:1) and recrystallized from dichloromethane-n-hexane to obtain 4.6 g of 5-acetoxymethyl-2-cyclohexyloxynitrobenzene as yellow crystals. m. p. 54.5-55.5℃

(2) 5-acetoxymethyl-2-cyclohexyloxynitrobenzene in Example 1 (2) to (4)
) to obtain N-(5-acetoxymethyl-2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide. m. p. 120-122°C (ethanol-n-hexane)

Example 12 (1) 9.0 g of 4-cyclohexyloxy-3-nitrobenzyl bromide obtained by the method of Example 7 (1), 4.6 g of diethyl malonate, 6.1 g of sodium carbonate, tetra-n After stirring a mixture of 0.18 g of -butylammonium bromide at 110°C for 6 hours, the reaction mixture was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 3N hydrochloric acid, water, and saturated brine, 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 = 20:1) to obtain 3-(4-cyclohexyloxy-3-nitrophenyl)-2 as a pale yellow oil. 4.5 g of ethyl -ethoxycarbonylpropionate was obtained. 1H-NMR (CDCl3) δ (ppm); 1.23~
2.00 (10H, m) 1.23 (6H, t, J = 6Hz) 3.17 (2H, d, J = 6Hz) 3.60 (1H, t, J = 6Hz) 4.18 (4H, q, J=6Hz) 4.40 (1H, m) 6.99 (1H, d, J=7Hz) 7.34 (1H, dd, J=2,7Hz) 7.65 (1
H, d, J=2Hz)

(2) 3-(4-cyclohexyloxy-
After stirring 11.4 ml of dimethyl sulfoxide solution containing 4.5 g of ethyl 3-nitrophenyl)-2-ethoxycarbonylpropionate, 0.67 g of sodium chloride, and 0.41 g of water at 170 to 180°C for 3 hours, the reaction solution was cooled to room temperature. and extracted with ethyl acetate. The organic layer was washed with saturated brine and then 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 = 10:1),
2.9 g of ethyl 3-(4-cyclohexyloxy-3-nitrophenyl)propionate was obtained as a yellow oil. 1H-NMR (CDCl3) δ (ppm); 1.17~
2.00 (10H, m) 1.23 (3H, t, J=7Hz) 2.61 (2H, m) 2.93 (2H, m) 4.13 (2H, q, J=7Hz) 4. 39 (1H, m) 7.00 (1H, d, J = 8Hz) 7.32 (1H, dd, J = 2,8Hz) 7.62 (1
H, d, J=2Hz)

(3) 3-(4-cyclohexyloxy-
Ethyl 3-nitrophenyl)propionate was prepared from Example 1 (
N-[2-cyclohexyloxy-5-(2-ethoxycarbonylethyl)-4-nitrophenyl]methanesulfonamide was obtained in the same manner as in 2) to (4). 1H-NMR (CDCl3) δ (ppm); 1.25 (
3H, t, 7Hz) 1.30-2.12 (10H, m) 2.70 (3H, t, J=7Hz) 3.10 (2H, s) 3.22 (2H, t, J=7Hz) 4.14 (4H, q, J=7Hz) 4.88 (1H, m) 7.13 (1H, br) 7.53 (1H, s) 7.58 (1H, s)

Example 13 A solution of 4 ml of ethanol containing 0.84 g of N-[2-cyclohexyloxy-5-(2-ethoxycarbonylethyl)-4-nitrophenyl]methanesulfonamide obtained by the method of Example 12 was added to a solution of 4 ml of ethanol at room temperature. 20% sodium hydroxide in 2
．． 0ml aqueous solution was added and stirred for 1 hour. The reaction solution was made acidic by adding 3N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was recrystallized from ethanol-n-hexane to give yellow needle-like crystals of N-[5-(2-carboxyethyl)-2-cyclohexyloxy-4-nitrophenyl]methanesulfonamide. 58g was obtained. m. p. 168.5-170℃

N-(5-acetoxymethyl-2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide obtained by the method of Example 11 was hydrolyzed by the method of Example 13 to obtain N-(2-cyclohexyloxy). -5-hydroxymethyl-4-nitrophenyl)methanesulfonamide was obtained. m. p. 115.5-116.5℃ (ethanol)

0
Example 14 A solution of 3.0 ml of N,N-dimethylformamide containing 0.80 g of N-(2-cyclohexyloxy-5-methylthio-4-nitrophenyl)methanesulfonamide obtained by the method of Example 5 was poured with ice. Under cooling, m-chloroperbenzoic acid 0.
46 g was added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it basic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was recrystallized from ethanol-dichloromethane to obtain 0.51 g of N-(2-cyclohexyloxy-5-methylsulfinyl-4-nitrophenyl)methanesulfonamide as pale yellow crystals. m. p. 192-193℃

Example 15 A solution of 0.64 g of N-(2-cyclohexyloxy-5-methylthio-4-nitrophenyl)methanesulfonamide obtained by the method of Example 5 in 3.0 ml of N,N-dimethylformamide was added. At room temperature, m-chloroperbenzoic acid 0.
92 g was added and stirred for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it basic, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then 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-dichloromethane to give pale yellow crystals of N-(2 0.13 g of -cyclohexyloxy-5-methylsulfonyl-4-nitrophenyl)methanesulfonamide was obtained. m. p. 173.5-174℃

In the same manner as in Example 15, N-(2-cyclohexyloxy-5-methylthiomethyl-4-nitrophenyl)methanesulfonamide obtained by the method of Example 9 was oxidized to give N-(2-cyclohexyl Oxy-5-methylsulfonylmethyl-4-nitrophenyl)methanesulfonamide was obtained. m. p. 154-155℃ (ethanol)

[0069]
Example 16 1.7 methanol in which 0.02 g of metallic sodium was dissolved
ml solution was added with 0.3 g of N-(2-cyclohexyloxy-5-methoxy-4-nitrophenyl)methanesulfonamide obtained by the method of Example 4, and after stirring for 10 minutes, the solvent was distilled off. The residue was washed with diethyl ether to obtain 0.3 g of sodium N-(2-cyclohexyloxy-5-methoxy-4-nitrophenyl)methanesulfonamide 1/2 hydrate as yellow crystals. m. p. 245℃ (decomposition)

Claims (1)

[Claims] [Claim 1] [Formula 1] [In formula 1, Ra is a lower alkyl group, Rb is a cycloalkyl group, and Rc is a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, a formyloxy group. group, lower alkanoyloxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, phenylthio group, phenylsulfinyl group, phenylsulfonyl group, lower alkoxycarbonylmethylthio group, lower alkoxycarbonylmethylsulfinyl group, lower alkoxycarbonylmethylsulfonyl group group or formula -CH2Rd (wherein Rd is a hydroxyl group, a lower alkoxy group, a phenoxy group, a lower alkanoyloxy group,
It is a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a lower alkoxycarbonylmethyl group, a carboxymethyl group, or an amino group substituted with one or two lower alkyl groups. ). ] A 4-substituted sulfonanilide compound and a pharmaceutically acceptable salt thereof.