JPS6213344B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a phenylethanolamine derivative represented by the following general formula and a method for producing the same. X, R ₁ , R ₂ , n, Y and
R ₃ has the following meanings. X: Lower alkoxy group or hydroxyl group R ₁ : Hydrogen atom or lower alkyl group R ₂ : Lower alkyl group n: 2 or 3 Y: Methylene group or oxygen atom R ₃ : Phenyl optionally substituted with a hydroxyl group or lower alkoxy group Group Here, the term "lower" refers to a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, for example, lower alkyl groups include methyl, ethyl, propyl, butyl, pentyl, isobutyl, etc., and lower alkoxy groups include methoxy, ethoxy, propoxy, butoxy, etc. be. Furthermore, since the compound [ ] of the present invention forms a salt and has two asymmetric carbon atoms, the compound of the present invention includes these salts and separated isomers,
It includes all mixtures of isomers. The compound [ ] provided by the present invention has both α-adrenergic blocking action and β-adrenergic blocking action. Therefore, the compound of the present invention can be used as a blood pressure lowering agent with few side effects and as a treatment agent for peripheral disorders such as Raynaud's disease. Furthermore, it is effective as a treatment for angina pectoris. These pharmacological effects of the compounds of the present invention were measured by the following test method, and α-
For receptor blocking effect, intravenous injection is 0.2 to 8.7 mg/
Kg, β-receptor blocking effect is 0.02~ for intravenous injection.
1 mg/Kg, and the antihypertensive effect in hypertensive animals is effective at doses of 0.3 to 10 mg/Kg intravenously and 3 to 100 mg/Kg orally. α receptor blocking effect: Blood pressure was measured in rats anesthetized with urethane and treated with pentolinium, and phenylephrine 10μ
The antagonistic effect of the specimen against the pressor effect of g/Kg (intravenous injection) was measured. β receptor blocking effect: Measuring method by Tachikawa and Take et al. (Pharmaceutical Journal 93)
(12) 1573-1580 (1973)). Reserpine was administered intraperitoneally, and 18 to 24 hours later, the rats were anesthetized with pentobarbital and the cervical vagus nerve was excised, and the heart rate was measured. The antagonistic effect of the specimen on the number-increasing effect was determined. Antihypertensive effect on hypertensive animals: Intravenous administration - Spontaneously hypertensive rats with a systolic blood pressure of 150 mmHg or higher were used under the method of Mizokami et al. Blood pressure and heart rate were measured manually.For oral administration - Using spontaneously hypertensive rats with a systolic blood pressure of 150 mmHg or higher, blood pressure was measured by the tailcuff method using a non-invasive blood pressure measuring device. Clinical administration of the compounds of the present invention, either as the free base or as an acid addition salt thereof, is usually carried out intravenously or orally.
150mg several times a day, or 50mg once orally
It is appropriate to administer ~500mg in three divided doses a day. The compound [ ] of the present invention is produced by the following method. (In the formula, Hal means a halogen atom, X, R ₁ ,
R ₂ , n, Y and R ₃ have the meanings given above. ) This method is a method for producing the target compound [ ] by aminating a halohydrin of the formula [ ₁ ] or an epoxide of the formula [ ₂ ] with an amine of the formula [ ₁ ]. These reactions can be carried out under substantially the same conditions. This is usually carried out by reacting halohydrin [ ₁ ] or epoxide [ ₂ ] with equimolar to excess amount of amine [ ₁ ] in an organic solvent. Examples of organic solvents include ethanol,
Toluene, methyl ethyl ketone, acetonitrile, tetrahydrofuran, etc. are used. Also,
The reaction proceeds at room temperature or under elevated temperature, but is usually carried out under heating and reflux to accelerate the reaction. To isolate and purify the reaction product, extraction with a solvent, separation by column chromatography, crystallization, etc. can be used as appropriate. (In the formula, Z means a hydrogen atom or a benzyl group, and X, R ₁ , R ₂ , n, Y and R ₃ are the same as before.) This method reduces the aminoketone of the formula [ ₃ ] to obtain the target compound. [ ] is manufactured. That is, (i) the carbonyl group (-CO- group) of the side chain of the aminoketone of formula [ ₃ ] is reduced to a -CHOH group with a suitable reducing agent, for example, a complex metal hydride such as sodium borohydride or diborane. Then, the target compound of formula [] is obtained. The reduction is carried out in an organic solvent at a temperature ranging from cooling to room temperature. When Z is a benzyl group, the benzyl group is not affected when reduced using the above reducing agent, so to convert the benzyl group to a hydrogen atom, catalytic hydrogenolysis is carried out using palladium carbon as a catalyst after reduction by a conventional method. . (ii) Alternatively, if the aminoketone of the formula [ ₃ ] is reduced by catalytic hydrogenation in the presence of a commonly used hydrogenation catalyst such as palladium on carbon, even if Z is a benzyl group, the ketone group in the side chain is reduced. The reduction and debenzylation reactions can be carried out simultaneously. Examples will be described below to further explain the manufacturing method of the present invention. In addition, among the symbols indicating the physical and chemical properties of the products in the examples, mp is the melting point, Anal is the elemental analysis value,
NMR respectively means nuclear magnetic resonance spectrum. Example 1 (1) 12.1 g (0.05 mol) N-benzyl-2-(2-methoxyphenoxy)ethylamine, 50 ml methyl ethyl ketone and 7.4 g (0.023 mol) 5-(2-bromopropionyl)-2-methoxybenzenesulfonamide Mix and heat under reflux for 4 hours while stirring. After cooling, methyl ethyl ketone was distilled off under reduced pressure, the residue was dissolved in benzene, ether was added to remove the precipitated amine hydrobromide, and the solvent was distilled off under reduced pressure to obtain crude 5-{2-[N- Benzyl-2-(2-methoxyphenyl)ethylamino]propionyl}-
2-Methoxybenzenesulfonamide is obtained. (2) Dissolve this in 50 ml of ethanol, add an excess amount of sodium boron hydride, stir at room temperature for 2 hours, and then evaporate the ethanol under reduced pressure. The residue was dissolved in ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain about 9 g of a pale yellow viscous oil. This was subjected to silica gel column chromatography,
Benzene, then benzene-ethyl acetate (volume ratio)
10:1) When eluted with a mixed solvent, 5-{1-
Hydroxy-2-[N-benzyl-2-(2-methoxyphenoxy)ethylamino]ethyl}-
2-Methoxybenzenesulfonamide was obtained. (3) Add 3.0g of the compound obtained above to 50ml of methanol.
1 g of 10% palladium on carbon was added and catalytic reduction was carried out at room temperature and pressure. After absorbing the theoretical amount of hydrogen,
The catalyst was separated and the liquid was distilled off under reduced pressure to obtain a colorless viscous oil. When this is treated with ethanol-hydrochloric acid, 2.34 g of a colorless amorphous solid (hydrochloride) is obtained. This was recrystallized from isopropyl alcohol to give 5-{1-hydroxy-2-[2-(2-
Methoxyphenoxy)ethylamino]propyl}-2-methoxybenzenesulfonamide is obtained. This material has the following physical and chemical properties. (i) mp 151-153℃ (ii) Anal. (as C ₁₉ H ₂₆ N ₂ O ₆ S) C (%) H (%) N (%) Calculated value 55.60 6.38 6.82 Actual value 55.25 6.38 6.66 (iii) NMR (d ₆ -DMSO) δ: 0.79 (3H, d, CHC H ₃ ) 3.76 or 3.90 (3H + 3H, s, [Formula] or [Formula]) 4.30 (1H, d, C H OH) Above Example 1 In the same manner as above, the following compounds of Examples 2 and 3 were produced. 【table】

Claims (1)

[Claims] 1. General formula [Wherein, X is a lower alkoxy group or a hydroxyl group, R ₁ is a hydrogen atom or a lower alkyl group, R ₂
represents a lower alkyl group, n represents 2 or 3, Y represents a methylene group or an oxygen atom, and R ₃ represents a phenyl group optionally substituted with a hydroxyl group or a lower alkoxy group. ] A phenylethanolamine derivative represented by.