JPH0255418B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to substituted phenyl ether derivatives represented by the following general formula. In the formula, R ₁ , R ₂ , R ₃ , R ₄ , X, m and n each have the following meanings. R ₁ and R ₄ : lower alkyl group R ₂ and R ₃ : hydrogen atom or lower alkyl group It means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, and pentyl group. Moreover, -O-R ₄ may be located at any of the ortho, meta, and para positions with respect to the side chain. Furthermore, since the compound [] of the present invention forms a salt and has an asymmetric carbon atom, these salts,
It includes racemates, mixtures of racemates, and optically active forms. The compound of the present invention [] has α-adrenergic receptor blocking action and is a novel compound useful as a pressure-lowering agent. The α-adrenergic receptor blocking effect of the compound of the present invention [] was measured by the following test method, and it was found to be effective at doses of 0.001 to 0.1 mg/Kg when administered intravenously. α-Adrenergic receptor blocking effect: Blood pressure was measured in rats anesthetized with urethane and treated with pentrinum, and phenylephrine 10 μg/
The antagonistic effect of the specimen against the pressor effect of Kg (intravenous injection) was measured. The compound of the present invention [ ] is usually administered intravenously or orally as a free base or an acid addition salt thereof. For intravenous administration, administer once once.
It is appropriate to administer up to 150 mg several times a day, or in the case of oral administration, 10 to 500 mg 2 to 3 times a day. The compound [ ] of the present invention is produced by the following method. First method (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , X, m and n are the same as above). This method is a method for producing a compound [] which consists of condensing a ketone [] with an amine [] and then reducing the product []. The condensation reaction between the ketone and the amine is carried out by bringing corresponding amounts of the two into contact in an organic solvent. As the organic solvent, methanol, ethanol, toluene, acetonitrile, tetrahydrofuran, etc. are used. Further, in order to promote the reaction, the reaction is usually carried out by heating. Then, the reaction product [ ] is reduced as it is or after being isolated. Reduction can be carried out through hydrogen in the presence of a catalyst such as platinum oxide or Raney nickel, or
Alternatively, it may be carried out using a reducing agent such as sodium borohydride. The product is isolated and purified by solvent extraction, column chromatography, salt formation, and the like. Second Method Among the target compounds of the present invention, compounds where n is 1 or 2 can also be produced by the reaction of the following formula using a compound where n is 0 as a raw material. In the above oxidation reaction, a methylsulfinyl compound where n is 1 or a methylsulfonyl compound where n is 2 can be obtained by appropriately selecting oxidation conditions such as the type of oxidizing agent. Usually, when treated with an oxidizing agent such as hydrogen peroxide (10-50%) or sodium metaperiodate in an organic solvent such as methanol or ethanol, a sulfinyl compound (n = 1) is obtained, and formic acid, etc. When treated with an oxidizing agent (hydrogen peroxide, etc.) in an acidic solvent, a sulfonyl compound (n=2) is obtained. The methods for producing the compound of the present invention [] have been described above, but the main target compounds of the present invention obtained by these production methods are as follows. 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)phenetol 4-{2-[2-(2-methoxyphenoxy)ethylamino] ]-2-ethylethyl}-2-(methylthio)-anisole 4-{2-[2-(2-methoxyphenoxy)-1
-methylethylamino]-2-methylethyl}-
2-(Methylthio)-anisole 4-{2-[2-(3-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole 4-{2-[2-(2- Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)phenetol Next, the object compound of the present invention and the method for producing the same will be further explained with reference to Examples. In addition, the raw material compound 4-methyl-3-methoxyphenylacetone used in the examples was manufactured according to the following reference example. Reference example (i) 84 g of stannous chloride dihydrate and 320 ml of glacial acetic acid are suspended and stirred, and hydrogen chloride gas is introduced while cooling on ice until an almost transparent solution is obtained. 14.3 g of enylacetone was added at 25-30°C. After stirring for another 30 minutes at room temperature, add 320 ml of concentrated hydrochloric acid to 640 ml of water.
ml and extracted with 400 ml of chloroform.
After washing the chloroform layer with water, chloroform was distilled off to obtain 10 g of oily 3-mercapto-4-methoxyphenylacetone. (ii) 3-mercapto-4-methoxyphenylacetone 10g anhydrous potassium carbonate 9g, methyl iodide
A mixture containing 42 g and 50 ml of methyl ethyl ketone was stirred under reflux for 20 hours, and after cooling, the reaction compound was filtered off and the liquid was evaporated to dryness. The residue was dissolved in ethyl acetate, the resulting solution was washed with water, the ethyl acetate was distilled off, and the resulting crude crystals were recrystallized from n-hexane-ether to give 4-
9 g of methyl 3-methoxyphenylacetone was obtained. Example 1 8.4 g of 4-methoxy-3-methylthiophenyl acetone and 2-methoxyphenoxyethylamine
Mix 6.7 g and 150 ml of methanol and heat under reflux for 2 hours. Cool the reaction solution to below 10°C, add 2.5 g of sodium borohydride while stirring at below 10°C, 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. This was purified by silica gel column chromatography (eluent: chloroform), and the melting point was 65-68.
4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}- as crystals at °C.
8.5 g of 2-(methylthio)anisole was obtained. this
Dissolve 750 mg in 10 ml of methanol, add a solution of 90 mg of anhydrous oxalic acid in 1 ml of methanol, leave at room temperature overnight, collect the precipitated crystals, recrystallize with methanol, and obtain 4-{2 with a melting point of 173-174℃. -[2-
(2-methoxyphenoxy)ethylamino)]-2
-Methylethyl}-2-(methylthio)anisole oxalate (600 mg) was obtained. This product has the following physical and chemical properties. (i) Elemental analysis value (as C ₂₂ H ₂₉ NO ₇ S) C (%) H (%) N (%) Calculated value 58.52 6.41 3.10 Actual value 58.33 5.93 2.97 (ii) Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.08 (3H, d, C H ₃ -CH) 2.38 (3H, s, C H ₃ S-) 3.78 (3H, s, C H ₃ O-) 3.86 (3H, s, C H ₃ O-) The next compound was obtained in the same manner as in Example 1.

[Table] Example 3 1.8 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole in methanol water (5:1)
0.5M sodium metaperiodate solution in 100ml
10.5 ml was added dropwise at 0°C, and the mixture was stirred at 4°C overnight. The precipitated crystals were collected, the liquid was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [eluent: chloroform-methanol (volume ratio 97:3)]
to obtain oily 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole.
Obtained 722mg. Dissolve this in 10ml of methanol,
A solution of 252 mg of oxalic acid dihydrate dissolved in 6 ml of methanol was added, left overnight at room temperature, the precipitated crystals were collected and reconsolidated with ethanol, and the melting point was 172-174.
℃4-{2-[2-(2-methoxyphenoxy)
ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole oxalate 700mg
I got it. This product has the following physical and chemical properties. (i) Elemental analysis value (as C ₂₂ H ₂₉ NO ₈ S) C (%) H (%) N (%) Calculated value 56.52 6.25 3.00 Actual value 56.17 6.25 3.01 (ii) Nuclear magnetic resonance spectrum (d ₆ − DMSO) δ: 1.12 (3H, d, CH ₃ -CH) 2.68 (3H, s, CH ₃ SO-) 3.76 (3H, s, CH 3 O-) 3.84 (3H, s, CH _{3 O} -) Example 4 Add 1.0 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole hydrochloride to 30 ml of ethanol.
Dissolve 0.5 g of 35% hydrogen peroxide solution while stirring.
After stirring at room temperature for 18 hours, the ethanol was distilled off under reduced pressure, the remaining syrupy substance was dispersed in 20 ml of water, and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed three times with 20 ml of water, acidified with 0.2 ml of concentrated hydrochloric acid, and then evaporated under reduced pressure.
4-{2-[2-(2-ethoxyphenoxy) 0.4 g of ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole hydrochloride was obtained. This material has the following physical and chemical properties. (i) Melting point 154-160℃ (ii) Elemental analysis value (as C ₂₁ H ₃₀ NO ₄ SCl) C (%) H (%) N (%) Calculated value 58.93 7.06 3.27 Actual value 58.64 7.07 3.41 (iii) Nuclear magnetic resonance spectrum ( _CDCl3 ) δ: 2.70 (3H, s, CH ₃ -SO) 3.82 (3H, s, CH ₃ O-) 4.43 (3H, t, CH ₂ O-) Example 5 Dissolve 1.8 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole in 18 ml of glacial acetic acid,
1.15 g of 30% hydrogen peroxide was added dropwise under ice cooling. 60℃
After heating for 1 hour, 100 ml of water was added and extracted with ethyl acetate. After washing the ethyl acetate layer with water, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [eluent:
chloroform-methanol (volume ratio 97:3)] to give oily 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methyl sulfonyl) anisole 1
I got g. This was dissolved in 10 ml of methanol, added to a solution of 230 mg of anhydrous oxalic acid dissolved in 2 ml of methanol, left overnight at room temperature, the precipitated crystals were collected, and recrystallized with methanol. 700 mg of {2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)anisole oxalate was obtained. This product has the following physical and chemical properties. (i) Elemental analysis value (as C ₂₂ H ₂₉ NO ₉ S) C(%) H(%) N(%) Calculated value 54.65 6.04 2.90 Actual value 54.48 6.06 3.09 (ii) Nuclear magnetic resonance spectrum (d ₆ − DMSO) δ: 1.12 (3H, d, CH ₃ - CH) 3.16 (3H, s, CH ₃ - SO ₂ -) 3.16 (3H, s, H ₃ - SO ₂ -) 3.72 (3H, s, C H ₃ -O-) 3.92 (3H, s, CH 3 -O-) The following compound was obtained in the same manner as _in Example 5.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₄ are lower alkyl groups, R ₂ and R ₃ are hydrogen atoms or lower alkyl groups, X is an oxygen atom, m is an integer from 1 to 3, and n is , 0, 1 or 2 respectively).