JPH059168A - Methanesulfonamide compound - Google Patents

Abstract

(57) [Summary] [Purpose] To provide an anti-inflammatory agent, an antipyretic agent and an analgesic agent which have higher efficacy and can withstand long-term administration with high safety. [Structure] N- [2- (3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide and a pharmaceutically acceptable salt thereof.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a methanesulfonamide compound, and more particularly to a novel methanesulfonamide compound having an anti-inflammatory effect and a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication No. 2-268 discloses N- [2
-(2-Hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide and N- [2-
(4-Hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide] is disclosed.

[0003]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a highly safe drug which is more potent and can withstand long-term administration.

[0004]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted by the present inventors for the above-mentioned purpose, methane which is included in the structural formula in the specification of JP-A-2-268 but has no specific description The present invention was completed by finding that the sulfoneanilide compound has an extremely strong anti-inflammatory effect.

That is, the present invention is N- [2- (3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide and pharmaceutically acceptable salts thereof.

The compounds of the present invention include stereoisomers (cis and trans isomers) derived from the 3-hydroxycyclohexyloxy group and their respective optical isomers (d and l isomers).
Body), but the present invention includes any of them.

The pharmaceutically acceptable salts include inorganic salts such as lithium salts, sodium salts, potassium salts and calcium salts, and salts with organic amines such as triethylamine and ethanolamine.

The compound of the present invention can be produced, for example, from a known compound by the method shown below.

(1) 2-halonitrobenzene and 1,3-
Cyclohexanediol is reacted in the presence of a base to give 3-
(2-Nitrophenoxy) cyclohexanol is obtained.
2-halonitrobenzene in this reaction means 2-fluoronitrobenzene, 2-chloronitrobenzene, 2-
Bromonitrobenzene and the like, and the base is an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, an alkali metal hydride such as sodium hydride and potassium hydride, and an alkali metal carbonate such as sodium carbonate and potassium carbonate. Alkali metal alkoxides such as sodium ethoxide and potassium butyrate
Triethylamine, 1,8-diazabicyclo [5,4,
0] Undecen, etc. This reaction is solvent-free or water,
It can be carried out in a solvent such as dioxane, tetrahydrofuran, ethyl ether, hexane, toluene, xylene, pyridine, N, N-dimethylformamide. In addition, this reaction is carried out using potassium iodide, benzyltriethylammonium chloride, tetrabutylammonium bromide, 18-crown-6 (1,4,7,10,13,1).
The reaction can also be accelerated by adding 6-hexaoxacyclooctadecane), copper powder, or the like.

Then, 3- (2-nitrophenoxy) cyclohexanol is reduced to an amino compound or a salt thereof. The reduction may be a usual reduction method for reducing a nitro group to an amino group, and for example, catalytic reduction using palladium-carbon, Raney-nickel or platinum, reduction using iron or tin, sodium sulfide-ammonium chloride is used. Reduction, reduction using sodium borohydride, reduction method using lithium aluminum hydride and the like. The solvent used for this reduction may be arbitrarily selected depending on the reduction method, but is generally alcohols such as methanol, ethanol and propanol, water, acetic acid, ethyl acetate, dioxane, tetrahydrofuran, acetonitrile and the like.

Subsequently, the amino compound obtained above is reacted with methanesulfonyl chloride to give N- [2-
(3-Hydroxycyclohexyloxy) phenyl] methanesulfonamide is obtained. The reaction is preferably carried out in the presence of a base, and the base used here is an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide or triethylamine, morpholine, piperidine, pyridine, etc. Is an organic base. In addition, this reaction is usually dichloromethane, chloroform, dioxane, tetrahydrofuran,
It is carried out in a solvent such as ethyl ether, toluene, acetone, acetonitrile, ethyl acetate, water, pyridine, N, N-dimethylformamide.

Then, the compound of the present invention can be obtained by reacting N- [2- (3-hydroxycyclohexyloxy) phenyl] methanesulfonamide with nitric acid or a nitrate in an organic solvent. The nitrate in this reaction is sodium nitrate, potassium nitrate, iron nitrate and the like, and the organic solvent is acetic acid, acetic anhydride, trifluoroacetic acid, sulfuric acid, dichloromethane, chloroform, benzene, dioxane and the like.

(2) The cis form of the compound of the present invention is cis-
It can be obtained by reacting 1,3-cyclohexanediol in the same manner as in the above (1).

(3) The trans form of the compound of the present invention can be obtained by reacting trans-1,3-cyclohexanediol in the same manner as in the above (1).

(4) The cis and trans forms of the compound of the present invention can also be obtained by the following method. That is, 3- (2-nitrophenoxy) cyclohexanol obtained in (1) above is benzoylated to give 3- (2-nitrophenoxy) cyclohexylbenzoate, and the cis- and trans-isomers are separated by silica gel column chromatography or the like. To do.

Then, each is hydrolyzed and subsequently reacted in the same manner as in the above (1) to obtain the cis isomer and trans isomer of the compound of the present invention.

(5) Optical isomer (-)-N- [2
-(Cis-3-hydroxycyclohexyloxy) -4
-Nitrophenyl] methanesulfonamide and (+)
-N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide is obtained from the cis-racemic compound obtained by the above methods (1), (2) and (4). You can That is, (±) -N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl] which is a cis-racemate.
Methanesulfonamide in the presence of lipase in an organic solvent,
By reacting with acetic ester, (+)-N- [2
-(Cis-3-acetoxycyclohexyloxy) -4
-Nitrophenyl] methanesulfonamide and the present invention (-)-N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide can be obtained.

In the present reaction, lipase means lipase P
(Manufactured by Amano Pharmaceutical Co., Ltd.), lipase MY (manufactured by Meito Seika Co., Ltd.) and the like are lipolytic enzymes used as catalysts for esterification or hydrolysis. Acetates are vinyl acetate, 1-propenyl acetate, 2-propenyl acetate, 1-cyclohexenyl acetate, etc., and organic solvents are n-hexane, cyclohexane, n.
Solvents such as heptane, benzene, toluene, xylene can be used. Further, this reaction is preferably carried out at 0 to 40 ° C. Further, fatty acids such as oleic acid, palmitic acid, stearic acid, and lauric acid can be used instead of the acetic acid ester.

On the other hand, by hydrolyzing (+)-N- [2- (cis-3-acetoxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide, (+)-N- [which is the compound of the present invention. 2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl]
Mekunsulfonamide can be obtained. This reaction is
Conventional methods of hydrolyzing the esters may be used, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
Examples thereof include a method using a base such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and a method using an acid such as hydrochloric acid, sulfuric acid and perchloric acid.

(6) The pharmaceutically acceptable salt of the compound of the present invention can be obtained by treating the compound of the present invention obtained above with a base in water or an organic solvent. The base used in this reaction includes alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, sodium ethoxide, alkali metal alkoxides such as potassium tert-butoxide, organic amines such as triethylamine and ethanolamine, and metals. Examples include sodium.

[0021]

INDUSTRIAL APPLICABILITY Since the compound of the present invention exhibits an extremely strong anti-inflammatory effect, it is useful as an anti-inflammatory agent, antipyretic agent and analgesic agent.

For this purpose, the compounds can be administered orally or parenterally in conventional dosage forms. These are, for example, tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions, injections and the like, all of which can be manufactured by a usual formulation technique. When used as an anti-inflammatory agent, antipyretic agent, and analgesic agent for humans, the dose is usually 10 to 1000 mg per day, although it varies depending on age, body weight, symptoms, administration route, administration frequency and the like.

Test examples will be given below. Test Example 1 [Edema Suppression Test Using Carrageenin] The method of Winter et al. Using Carrageenin [Journa
l of Pharmacology and Exp
clinical Therapeutics, No. 1
41, 369 (1963)].

To Wistar male rats (6 rats per group),
A solution of the compound of the present invention made into a sodium salt with an aqueous sodium hydroxide solution is intravenously administered at a dose volume of 0.25 ml per 100 g of body weight 0.5 hour before the administration of carrageenin, and the edema inhibitory rate is calculated to obtain an anti-inflammatory effect. Examined. The results are shown in Table 1.

[0025]

[Table 1]

(Note) a: N- [2- (3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide b: N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl ] Methanesulfonamide

[0027]

EXAMPLES Next, the production method of the compound of the present invention will be explained in detail with reference to examples.

Example 1 (1) N, N-dimethylformamide 10 containing 25.0 g of 1,3-cyclohexanediol (cis, trans mixture) and 14.1 g of o-fluoronitrobenzene 10
To the 0 ml solution, 16.8 g of potassium hydroxide powder was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was poured into ice water and extracted with dichloromethane, and the dichloromethane layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The yellow oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent; dichloromethane to dichloromethane: ethyl acetate = 5: 1) to obtain 13.2 g of 3- (2-nitrophenoxy) cyclohexanol. Obtained.

¹ H-NMR (CDCl ₃ ) δ (pp
m); 1.40 to 2.26 (8H, m), 2.38 (1
H, s), 3.78 to 3.96 (0.8H, m), 4.
06-4.23 (0.2H, m), 4.53-4.70
(0.8H, m), 4.80 to 4.92 (0.2H,
m), 6.90-7.20 (2H, m), 7.42-
7.64 (1H, m), 7.75 to 7.95 (1H,
m)

(2) To 50 ml of pyridine containing 11.9 g of 3- (2-nitrophenoxy) cyclohexanol, 7.7 g of benzoyl chloride was added dropwise over 15 minutes under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was acidified with diluted hydrochloric acid and extracted with dichloromethane. The dichloromethane layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The yellow oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent; n-hexane: dichloromethane = 10: 1 to 1: 1) to give cis-3- (2-nitrophenoxy) cyclohexyl. 8.8 g of benzoate and 1.1 g of trans-3- (2-nitrophenoxy) cyclohexylbenzoate were obtained.

¹ H-NMR (CDCl ₃ ) δ (pp
m); cis form; 1.20 to 2.30 (7H, m), 2.50
2.68 (1H, m), 4.35 to 4.55 (1H,
m), 4.95-5.14 (1H, m), 6.95-
7.20 (2H, m), 7.35 to 7.65 (4H,
m), 7.77 (1H, dd, J = 8, 2Hz), 7.
96-8.10 (2H, m)

Trans form: 1.35 to 2.30 (8H,
m), 4.75-4.95 (1H, m), 5.40-
5.55 (1H, m), 6.90 to 7.20 (2H,
m), 7.35 to 7.70 (4H, m), 7.81 (1
H, dd, J = 8, 2 Hz), 7.98-8.13 (2
H, m)

(3) 3.5 g of sodium hydroxide powder was added to 100 ml of ethanol solution containing 8.8 g of cis-3- (2-nitrophenoxy) cyclohexylbenzoate.
A 35 ml water solution containing water was added, and the mixture was stirred at room temperature for 1.5 hours. 100 ml of water was added to the reaction solution, which was concentrated and then extracted with dichloromethane. The dichloromethane layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 6.1 g of a yellow oily substance, cis-3- (2-nitrophenoxy) cyclohexanol.

¹ H-NMR (CDCl ₃ ) δ (pp
m); 1.33 to 2.23 (8H, m), 2.35 (1
H, bs), 3.82 to 3.93 (1H, m), 4.5
7 to 4.68 (1H, m), 6.98 to 7.13 (2
H, m), 7.47 to 7.57 (1H, m), 7.88
(1H, dd, J = 8, 2Hz)

(4) A 50 ml ethanol solution containing 5.9 g of cis-3- (2-nitrophenoxy) cyclohexanol and 0.4 g of 5% palladium-carbon was stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for catalytic reduction. .. Palladium-carbon was removed by filtration, and the crude liquid obtained by distilling off the filtrate was recrystallized from ethanol-n-hexane to give colorless cis-3- (2-aminophenoxy). 4.5 g of cyclohexanol was obtained. m. p. 99-101 ° C

(5) 50 m of pyridine containing 2.7 g of cis-3- (2-aminophenoxy) cyclohexanol
2.0 g of methanesulfonyl chloride was added to the 1-solution while stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, acidified with diluted hydrochloric acid, and extracted with ethyl acetate.
The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The crude crystals obtained by distilling off the solvent were recrystallized from ethanol-n-hexane to give (±) -N- [2- (cis-3-hydroxycyclohexyloxy) phenyl] methanesulfonamide (3.1 g).
Got m. p. 117-119 ° C

(6) N- [2- (cis-3-hydroxycyclohexyloxy) phenyl] To a solution of 30 g of acetic acid containing 2.0 g of methanesulfonamide was added 1.1 g of 60% nitric acid while heating at 85 to 90 ° C.
The mixture was added dropwise over 5 minutes and stirred for another 30 minutes. The reaction solution was poured into ice water and neutralized with a 5% sodium carbonate aqueous solution,
It was extracted with dichloromethane. The dichloromethane layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The yellow oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography (developing solvent; dichloromethane to
After purification by applying dichloromethane: ethyl acetate = 4: 1), the crystals were recrystallized from ethanol-n-hexane to give N- [2-
(Cis-3-hydroxycyclohexyloxy) -4-
1.8 g of nitrophenyl] methanesulfonamide was obtained. m. p. 134 ~ 135 ℃

Example 2 The 3- (2-nitrophenoxy) cyclohexanol obtained in Example 1 (1) was reacted in the same manner as in Examples 1 (4) to (6) to produce N- [2- (3- Hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide was obtained. m. p. 119-120 ° C (recrystallized from ethanol-n-hexane)

Example 3 The trans-3- (2-nitrophenoxy) cyclohexylbenzoate obtained in Example 1 (2) was used in Example 1 (3).
~ N- [2- (trans-3
-Hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide was obtained. m. p. 151-153 ° C (recrystallized from ethanol-n-hexane)

Example 4 (±) -N- [2- (cis-3-) obtained in Example 1 (6)
Hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide 2.2 g of toluene 240 m
15 g of lipase P was suspended in the 1 solution, 3 ml of 2-propenyl acetate was added at room temperature, and the mixture was stirred for 12 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to remove the residue, which was then subjected to silica gel column chromatography (developing solvent; ethyl acetate: n-hexane = 1: 3 to ethyl acetate). From the ethyl acetate-n-hexane stream (+)
1.0 g of -N- [2- (cis-3-acetoxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide was obtained. Further, the product obtained from the ethyl acetate flow fraction was recrystallized from ethanol to give pale yellow needle crystals of (-)-N-.
[2- (cis-3-hydroxycyclohexyloxy)
-4-Nitrophenyl] methanesulfonamide 1.0 g
Got

M. p. 144-145 ° C. [α] _D- 18.72 (c = 0.908, chloroform)

1 g of the above (+)-N- [2- (cis-3-acetoxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide was dissolved in 4 ml of methanol, 1.1 g of potassium carbonate was added, and the mixture was allowed to stand at room temperature. Stir for 4 hours. After the reaction, water and ethyl acetate were added, the ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
After distilling off the solvent, the obtained residue was recrystallized from ethanol to give pale yellow needle crystals of (+)-N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl].
0.78 g of methanesulfonamide was obtained.

M. p. 146.5-147.5 ° C. [α] _D +18.76 (c = 0.81, chloroform)

According to the X-ray structural analysis, the above compound was found to have a pure optical purity, and the absolute configuration of the (-) form was (1R, 3
S) and (+) body were determined to be (1S, 3R). This was determined using an R-value method that refined the two enantiomers and compared the resulting R-values (reliability factors). Absolute configuration of (+) body R = 3.33% R = 3.55%

Example 5 0.10 g of N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide obtained in Example 1 was added to a solution prepared by dissolving 7 mg of metallic sodium in 1 ml of methanol. In addition, the mixture was stirred at room temperature for 5 minutes. The solvent was distilled off and the resulting residue was washed with ether to give 0.10 g of N- [2- (cis-3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide sodium salt as yellow-orange crystals. Obtained. m. p. 140-143 ° C

Front page continuation (72) Yutaka Ouchi 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Within the corporation

Claims (1)

Claims: 1. N- [2- (3-hydroxycyclohexyloxy) -4-nitrophenyl] methanesulfonamide and pharmaceutically acceptable salts thereof.