JPH0212948B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to benzenesulfonamide derivatives that have an α-adrenergic receptor blocking effect and are useful as antihypertensive agents, therapeutic agents for congestive heart palsy, and the like.
For more information, see the general formula (In the formula, R ₁ is an amino group, a mono- or di-lower alkylamino group, or an aralkylamino group,
R ₂ is a hydrogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, R ₃ is a hydrogen atom, phenylthio group, phenylsulfinyl group, lower alkyl group or lower alkoxy group, R ₄ , R ₅ , R ₆ ,
R ₇ , R ₈ and R ₉ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₁₀ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower alkenyloxy group, and Y represents an oxygen atom or a methylene group. . However, when R ₁ is an amino group or a mono-lower alkylamino group and R ₃ is a hydrogen atom, R ₄ and R ₅ are both lower alkyl groups, or R ₆ is a lower alkyl group, or R ₇ and R ₈ are Both are lower alkyl groups, R ₇ is a lower alkyl group, or R ₁₀ is a lower alkenyloxy group. ) or a pharmacologically acceptable salt thereof. In the above general formula [], the word "lower" means a straight or branched carbon chain having up to 5 carbon atoms. Therefore, examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, pentyl group, etc., and examples of lower alkoxy groups include methoxy group, ethoxy group, propoxy group, isopropyl group, etc. Examples of the lower alkenyloxy group include a propoxy group and a butoxy group, and examples of the lower alkenyloxy group include a vinyloxy group, an allyloxy group, a butenyloxy group, an isobutenyloxy group, and a pentenyloxy group. Examples of the aralkylamino group include a benzylamino group, a phenethyl amino group, and a phenylpropylamino group. In the present invention, the compound [] is a pharmacologically acceptable salt, such as an inorganic acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid, or an organic acid such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, or lactic acid. Since it forms an acid addition salt and can further have 1 to 4 asymmetric carbon atoms, a racemate, a mixture of racemates, and each optically active form may exist, but all of these are included in the present invention. It is something that will be done. Since the compound of the present invention [] has a strong α-adrenergic receptor blocking effect, it can reduce hypertension,
It is a useful compound as a therapeutic agent for congestive cardioplegia, angina pectoris, lower ureteral dysfunction, prostatic hypertrophy, chromophilic cell tumor, peripheral vascular disorder, etc. The experimental method and results for this α-adrenergic receptor blocking effect are described below. Experimental example α-adrenergic receptor blocking effect: Blood pressure was measured in rats anesthetized with urethane and treated with pentolinium.
The antagonistic effect of the specimen against the pressor effect of g/Kg (intravenous injection) was measured. Table 1 α-Adrenergic receptor blocking effect Sample α-Adrenergic receptor blocking ED ₅₀
(mg/Kg) iv Compound Example 1 of the present invention 0.00035 〃 2 0.00026 Known compound Compound A* 0.034 Phentolamine 0.061 * Compound A: 5-{1-hydroxy-2-
[2-(2-Methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide (JP-A-54-95544) For clinical administration, the compound of the present invention [] is administered as a free base, or The acid addition salt is prepared into tablets, capsules, pills, injections, etc. using commonly used pharmaceutical carriers, and is usually administered intravenously or orally. For intravenous injection, 10ng to 10 per dose
mg several times a day, orally 1 to 100 mg per dose
It is appropriate to administer 2 to 3 times at a time. Next, a typical manufacturing method for manufacturing the compound of the present invention [] will be shown. Method 1 A compound in which R ₃ is a hydrogen atom or a lower alkyl group in the general formula (In the formula, X represents a halogen atom, R ₃ ' represents a hydrogen atom or a lower alkyl group, R ₁ , R ₂ , R ₄ ,
R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and Y have the same meanings as above. ) It can be produced by reducing the compound shown below. This reduction can be carried out by catalytic reduction using palladium on carbon, platinum oxide, etc. in an organic solvent such as methanol, ethanol, toluene, acetonitrile, tetrahydrofuran, etc. in a hydrogen stream at room temperature and normal pressure. Second method A compound in which R ₃ is a phenylthio group or a lower alkoxy group and R ₆ is a hydrogen atom, in the general formula [], R′ ₃ and
A compound in which R ₆ is a hydrogen atom is treated with an alkaline substance to form the general formula (In the formula, R ₁ , R ₂ , R ₄ , R ₅ , R ₇ , R ₈ , R ₉ , R ₁₀
and Y have the same meaning as above. ) It can be produced by obtaining a compound represented by the following and then reacting it with a lower alcohol or thiophenol. In this method, the compound [] is treated with an alkaline substance in an organic solvent such as ethyl acetate, ethanol, dioxane, benzene, etc. at room temperature to 50°C.
This can be carried out using an alkaline substance such as sodium carbonate, metal alcoholate, sodium hydroxide, or potassium hydroxide. The reaction between the compound [] thus obtained and a lower alcohol can be carried out at room temperature in the presence of a BF ₃ catalyst in an organic solvent such as chloroform, ethyl acetate, dioxane, or benzene, and the reaction between the compound [] and a thiophenol can be carried out in the presence of a BF3 catalyst in an organic solvent such as chloroform, ethyl acetate, dioxane, or benzene. The reaction can be carried out in an organic solvent such as methanol, chloroform, ethyl acetate, dioxane, benzene, etc. at room temperature. Third method A compound in which R ₄ and R ₆ are hydrogen atoms in the general formula (In the formula, R ₁ , R ₂ , R ₃ and R ₅ have the same meanings as above.) Compounds represented by the formula (In the formula, R ₇ , R ₈ , R ₉ , R ₁₀ and Y have the same meanings as above.) It can be produced by reacting a compound represented by the following and then reducing it. In this method, compound [] and compound [] are reacted in an organic solvent such as methanol, ethanol, toluene, acetonitrile, or tetrahydrofuran, and then catalytic reduction is performed in the presence of a catalyst such as PtO ₂ or Raney Nickel, or NaBH ₄ ,
This can be done by reduction with LiAlH ₄ or the like. Fourth method A compound in which R ₃ is a phenylsulfinyl group in the general formula [] can be obtained by the second method.
Compounds in which R ₃ is a phenylthio group can be prepared by oxidizing with H ₂ O ₂ at 50-60° C. in an acetic acid solvent. Fifth method A compound in which R ₃ is a phenylthio group or a lower alkoxy group in the general formula [] is a compound in which R' ₃ is a hydrogen atom in the general formula [] and a lower alcohol in the presence of thiophenol or BF ₃ . It can be produced by reaction. Isolation and purification of the compounds of the present invention [] produced in the above-mentioned methods 1 to 5 can be carried out by filtration, extraction with a solvent, separation by column chromatography, recrystallization, etc. In addition, in the compound [] used in the first method, a compound in which R' ₃ is a lower alkyl group is a new compound, but this compound [] in which R' ₃ is an oxo group ( Japanese Unexamined Patent Publication 1973-
95544) as a Grignard reagent [(lower alkyl)
-MgX]. Next, the present invention will be explained in more detail with reference to Examples. Reference example 1 (a) Add 50 g of 4-methoxyphenylacetone dropwise to 250 g of chlorosulfonic acid at 0 to 5°C. After stirring at room temperature for 4 hours, the reaction solution was poured into 2500 ml of ice water and extracted three times with 500 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained crude crystals were recrystallized from a benzene-ether mixed solvent to obtain 3
32 g of -chlorosulfonyl-4-methoxyphenyl ayatone was obtained. Melting point: 80-81°C (b) Dissolve 2.6g of the above product in 26ml of tetrahydrofuran, and add 1.2g of 40% methylamine dropwise at below 10°C. After stirring for 1 hour at room temperature, the solvent was distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The obtained crude crystals were recrystallized from a mixed solvent of isopropanol and ether to obtain 1.8 g of 4-methoxy-3-N-methylsulfamylphenylacetone. Melting point 100
~101℃ Reference example 2 By the same operation as in (b) of Reference Example 1, 2.6 g of 3-chlorosulfonyl-4-methoxyphenylacetone was obtained.
was reacted with 0.6 g of dimethylamine to obtain 2.5 g of oily 4-methoxy-3-N,N-dimethylsulfamylphenylacetone. Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.18 (3H, s, -COC H ₃ ) 2.82 (6H, s, -N( CH ₃ ) ₂ ) 3.69 (2H, s

[Formula]) 3.90 (3H, s, C H ₃ O-) Example 1 1.5 g of 4-methoxy-3-N,N-dimethylsulfamylphenylacetone, 1 g of 2-methoxyphenoxyethylamine and 30 ml of methanol are mixed and refluxed for 1 hour. After cooling, add 60 mg of platinum oxide catalyst and reduce at room temperature and pressure. After the theoretical amount of hydrogen has been absorbed, the catalyst is removed by filtration. After adding 5% hydrochloric acid alcohol to the filtrate to make it acidic, the solvent was distilled off under reduced pressure to obtain 1.6 g of crude crystals. This was recrystallized from ethanol to give 2-methoxy-5-{2-[2-
(2-methoxyphenoxy)ethylamino]-2
1.3 g of colorless crystals of N,N-dimethylbenzenesulfonamide hydrochloride (methylethyl)-N,N-dimethylbenzenesulfonamide hydrochloride were obtained. This material has the following physical and chemical properties. Melting point 185-187℃ Elemental analysis value (as C ₂₁ H ₃₀ N ₂ O ₅ S・HCl) C (%) H (%) N (%) Calculated value 54.95 6.81 6.10 Actual value 54.73 6.88 5.85 Nuclear magnetic resonance spectrum (d ₆ -DMSO) δ: 1.16 [3H, d, >CHC H ₃ ] 2.71 [6H _{, S, -N (CH 3} ) ₂ ] 3.76 and 3.87 [3H + 3H, s, -OC H ₃ ] Example 2 Mix 3.65 g of 4-methoxy-3-sulfamylphenylacetone, 2.9 g of 2-allyloxyphenoxyethylamine, and 130 ml of methanol, and heat under reflux for 2 hours. Cool the reaction solution to below 10℃, and add 0.9g of sodium borohydride to 10℃ while stirring.
Add the mixture below and stir for an additional 3 hours at room temperature. Next, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain an oil.
When this was dissolved in 20 mg of ethanol and acidified with hydrochloric acid and ethanol, crystals were precipitated. When the crystals are taken, washed with ethanol, and dried, 5-{2-
4.7 g of [2-(2-allyloxyphenoxy)ethylamino]-2-methylethyl}-2-methoxybenzenesulfonamide hydrochloride was obtained. This material has the following physical and chemical properties. Melting point 238-240℃ Elemental analysis value (as C ₂₁ H ₂₈ N ₂ O ₅ S・HCl) C (%) H (%) N (%) Calculated value 55.19 6.40 6.13 Actual value 55.04 6.42 6.00 Nuclear magnetic resonance spectrum (d ₆ ―DMSO) δ: 1.14 (3H, d, > CH― CH ₃ ) 3.85 (3H, S,

[Formula] 5.93 (1H, m, -CH ₂ -C H =CH ₂ ) Compounds of Examples 3 to 5 were obtained in the same manner as in Example 2.

【table】

[Table] Example 5 (a) Suspend 4.35 g of 5-{1-chloro-2-[2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide hydrochloride in 50 ml of ethyl acetate, and add 10% sodium carbonate while stirring. 50 ml of water was added, and the mixture was stirred vigorously for one day and then separated. The ethyl acetate layer was passed through a silica gel column (50 ml of silica gel) to remove inorganic substances, and then evaporated to dryness to obtain a colorless resinous 5-
3.2 g (88%) of {1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide was obtained. This material has the following physical and chemical properties. Amorphous form Elemental analysis value (as C ₁₈ H ₂₂ N ₂ O ₄ S) C (%) H (%) N (%) Calculated value 59.65 6.12 7.73 Actual value 59.37 6.12 7.61 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.74 and 1.95 (1H+1H, d

【formula】) 2.43 (1H, q,

【formula】) 2.55(3H,s,

[Formula]) 4.10 (2H, t, -C H ₂ O -) (b) Dissolve 2.5 g of the above product in 50 ml of methanol,
After adding 1 g of thiophenol, stir overnight at room temperature. Methanol was distilled off, subjected to silica gel column chromatography, and chloroform-
Elution with methanol (volume ratio 9:1) mixed solvent yields a viscous oil, 5-{2-[2-(2-
2.4 g of methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide was obtained. This material has the following physical and chemical properties. Amorphous form Elemental analysis value (as C ₂₄ H ₂₈ N ₂ O ₄ S ₂ ) C (%) H (%) N (%) Calculated value 60.99 5.97 5.93 Actual value 60.72 6.11 5.71 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.58(3H,s,

[Formula]) 3.74 (3H, s, -OC H ₃ ) 3.98 (2H, t, -C H ₂ O-) 4.38 (1H, t, >C H -S-) Example 6 5-{1 obtained by the same operation as Example 5-(a)
-[2-(2-methoxyphenoxy)ethyl]aziridine-2-methylbenzenesulfonamide
Dissolve 2.5 g in 50 ml of methanol and add 2 ml of boron trifluoride ether complex at room temperature.
Stir at night. Methanol was distilled off under reduced pressure, and the residue was subjected to silica glu column chromatography and eluted with a mixed solvent of chloroform-methanol (volume ratio 9:1) to obtain 1.5 g of a colorless viscous oil. Add 5 ml of methanol and a few drops of ammonia to this, crystallize, separate, wash with water, and dry to obtain 5-{1-methoxy-2-[2-(2-methoxyphenoxy)].
1.2 g of ethylamino]ethyl}-2-methylbenzenesulfonamide was obtained. This material has the following physical and chemical properties. Melting point 150-152℃ Elemental analysis value (as C ₁₉ H ₂₆ N ₂ O ₅ S) C (%) H (%) N (%) Calculated value 57.85 6.64 7.10 Actual value 57.58 6.79 7.24 Nuclear magnetic resonance spectrum (CD ₃ OD) δ: 2.65 (3H, s

[Formula]) 2.98 (2H, t, -C H ₂ N<) 3.80 (3H, s,

[Formula] 3.26 (3H, s, > CH-OC H ₃ ) 4.10 (2H, t, -C H ₂ O-) 4.40 (1H, q, > C H -O-) Example 7 5-{2-[2-(2-methoxyphenoxy)
ethylamino]-1-phenylthioethyl}-2
- 2g of methylbenzenesulfonamide in 20ml of acetic acid
Add _0.5ml of 30% _H2O2 and incubate at 50-60℃.
Heat for an hour. Add 100ml of water and 200ml of ethyl acetate
After washing the ethyl acetate layer with 1% sodium carbonate water, ethyl acetate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography,
Elution was carried out with a mixed solvent of chloroform and methanol (volume ratio 9:1), and the obtained colorless viscous oil was crystallized with ethyl acetate to obtain 5-{2-[2-(2
1.3 g of methoxyphenoxy)ethylamino]-1-phenylsulfinylethyl}-2-methylbenzenesulfonamide was obtained. This substance has the following physical and chemical properties Melting point 139-141℃ Elemental analysis value (as C ₂₄ H ₂₈ N ₂ O ₅ S ₂ ) C (%) H (%) N (%) Calculated value 59.00 5.78 5.73 Actual value 58.91 5.74 5.72 Example 8 5-{1-chloro-2-[2-methoxyphenoxy)ethylamino]-2,2-dimethylethyl}-2-methylbenzenesulfonamide hydrochloride
Dissolve 1.0 g in 150 ml of methanol, add 0.5 g of 10% palladium on carbon, dechlorinate in a hydrogen stream at room temperature and normal pressure, separate the palladium on carbon, concentrate the liquid under reduced pressure, and obtain 5-{2- [2-(2-methoxyphenoxy)ethylamino]-2,2-dimethylethyl}-2-methylbenzenesulfonamide hydrochloride is obtained. Recrystallize this from methanol to obtain 0.5 g of colorless crystals. This material has the following physical and chemical properties. Melting point 199-202℃ Elemental analysis value (as C ₂₀ H ₂₈ N ₂ O ₄ S・HCl・CH ₃ OH) C (%) H (%) N (%) Calculated value 54.71 7.21 6.08 Actual value 54.50 7.17 6.14 Nuclear magnetism Resonance spectrum (d ₆ -DMSO) δ: 1.24 (6H, s,

【formula】) 2.56(3H,s,

【formula】) 3.74(3H,s,

[Formula]) 4.30 (2H, t, -C H ₂ O-) Compounds of Examples 9 to 12 were obtained in the same manner as in Example 8.

【table】

【table】

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is an amino group, a mono- or di-lower alkylamino group, or an aralkylamino group,
R ₂ is a hydrogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, R ₃ is a hydrogen atom, phenylthio group, phenylsulfinyl group, lower alkyl group or lower alkoxy group, R ₄ , R ₅ , R ₆ ,
R ₇ , R ₈ and R ₉ are the same or different and represent a hydrogen atom or a lower alkyl group, R ₁₀ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower alkenyloxy group, and Y represents an oxygen atom or a methylene group. . However, when R ₁ is an amino group or a mono-lower alkylamino group, and R ₃ is a hydrogen atom,
Either R ₄ and R ₅ are both lower alkyl groups, R ₆ is lower alkyl, R ₇ and R ₈ are both lower alkyl groups, R ₉ is lower alkyl group, or R ₁₀ is lower alkenyloxy group. It is. ) A benzenesulfonamide derivative or a pharmacologically acceptable salt thereof.