Phenethylamine derivatives

by: Imai, Kazuo; Niigata, Kunihiro; Fujikura, Takashi; Hashimoto, Shinichi; Takenaka, Toichi; Honda, Kazuo;

Phenethylamine derivatives shown by the general formula ##STR1## wherein Ro represents a lower alkyl group; R.sub.1 represents a lower alkyl group or a lower alkoxy group; R.sub.2 represents hydrogen atom or a hydroxyl group; R.sub.3 and R.sub.4 each represents hydrogen atom or a lower alkyl group; R.sub.5 represents hydrogen atom or a lower alkoxy group; X represents oxygen atom or a methylene group; m is an integer of 1-3; and n is an integer of 0-2 and the acid addition salts thereof. These compounds exhibit a strong .alpha.-adrenergic blocking action and are useful as an antihypertensive agent.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel phenethylamine derivatives and the acid addition salts thereof, and more particularly to novel phenethylamine derivatives and the acid addition salts thereof exhibiting a strong .alpha.-adrenergic blocking action and useful as an antihypertensive agent.

2. Description of the Prior Art

U.K. Pat. No. 1,321,701 discloses a series of compounds represented by the following formula ##STR2## wherein R.sub.1 is RS--, RSO-- or RSO.sub.2 -- (wherein R is an alkyl of C.sub.1 -C.sub.10); R.sub.2 and R.sub.3 each is hydrogen, an alkyl of C.sub.1 -C.sub.3, an alkoxy of C.sub.1 -C.sub.4, or an alkylthio of C.sub.1 -C.sub.4 ; R.sub.4 represents hydrogen or an alkyl of C.sub.1 -C.sub.4 ; and R.sub.5 and R.sub.6 each is an alkyl of C.sub.1 -C.sub.16 which may a substituted by a phenyl group or a substituted phenyl group and states that these compounds exhibit a .beta.-adrenergic blocking action, a peripheral vasodilating effect, an antiarrhythmic effect and a hypotensitive effect.

Belgian Pat. No. 856,055 discloses a series of compounds shown by the formula ##STR3## wherein Z is OH or H; R.sub.1, R.sub.2 and R.sub.3 each is H or a lower alkyl group; n is 1-3; Ar is a phenyl group which may be substituted by 1 to 3 halogen atoms, lower alkyl groups, lower alkoxy groups or OHs; Q is lower alkyl-S(O).sub.m (m is 0, 1, or 2); and Y is H, a lower alkanoyl group, an aroyl group, a benzenesulfonyl group, or a toluenesulfonyl group and states that these compounds exhibit a .beta.-adrenergic blocking activity, a vasodilating activity, an antiarrhythmic effect and a hypotensive effect.

SUMMARY OF THE INVENTION

An object of this invention is to provide pharmacologically useful compounds which possess a hypotensive activity based on an .alpha.-adrenergic blocking action and can be used as an antihypertensive agent.

Another object of this invention is to provide a process of producing the aforesaid pharmacologically useful compounds.

According to this invention, there are provided phenethylamine derivatives shown by formula I and the acid addition salts thereof ##STR4## wherein Ro represents a lower alkyl group; R.sub.1 represents a lower alkyl group or a lower alkoxy group; R.sub.2 represents hydrogen atom or a hydroxyl group; R.sub.3 and R.sub.4 each represents hydrogen atom or a lower alkyl group; R.sub.5 represents a hydrogen atom or a lower alkoxy group; X represents oxygen atom or a methylene group; m represents an integer of 1-3; and n represents an integer of 0-2.

These compounds of this invention are useful as anti-hypertensive agents.

According to another embodiment of this invention, the compounds shown by the above-described formula I can be prepared as follows:

(1). A phenethylamine derivative shown by the general formula ##STR5## wherein R.sub.0, R.sub.1, R.sub.3, R.sub.4, R.sub.5, X, m, and n have the same significance as defined in formula I can be obtained by reacting a halohydrin shown by the formula ##STR6## wherein hal represents a halogen atom and R.sub.0, R.sub.1, R.sub.3 and n have the same significance as defined above or an epoxide shown by the formula ##STR7## wherein R.sub.0, R.sub.1, R.sub.3, and n have the same significance as defined above and an amine shown by the formula ##STR8## wherein Z represents a hydrogen atom or a benzyl group, and R.sub.4, R.sub.5, X, and m have the same significance as defined above and, when Z is a benzyl group, removing the group from the product.

(2). A phenethylamine derivative shown by the formula ##STR9## wherein R.sub.0, R.sub.1, R.sub.3, R.sub.4, R.sub.5, X, m, and n have the same significance as in formula I can be prepared by reducing an aminoketone shown by the formula ##STR10## wherein R.sub.0, R.sub.1, R.sub.3, R.sub.4, R.sub.5, X, m, and n have the same significance as defined in formula I and, when Z is a benzyl group, removing the group from the reduction product.

(3). A phenethylamine derivative shown by the formula ##STR11## wherein R.sub.0, R.sub.1, R.sub.3, R.sub.4, R.sub.5, X, m, and n have the same significance as defined in formula I can be prepared by condensing a ketone shown by the formula ##STR12## wherein R.sub.0, R.sub.1, R.sub.3 and n have the same significance as above defined and an amine shown by the formula ##STR13## wherein R.sub.4, R.sub.5, X and m have the same significance as above defined, reducing the condensation product, and, when n is 0, further treating the product with an oxidizing agent.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Now, the term "lower" used in the above-described formulae means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, for example, a lower alkyl group includes methyl group, ethyl group, propyl group, butyl group, pentyl group, isobutyl group, etc., and a lower alkoxy group includes methoxy group, ethoxy group, propoxy group, butoxy group, etc. Also, in the above-described formulae, the R.sub.5 groups which are substituents of the benzene ring may be disposed at any position (i.e., ortho, meta; and para) to the side chain. Furthermore, since compound of formula [I] of this invention can form readily the salt thereof and contains asymmetric carbon atom(s), the compounds of this invention includes the salts thereof, the racemic compounds thereof, a mixture of the racemic compounds, and each optical active substance.

The compounds of formula [I] and the acid addition salts thereof provided by the present invention exhibit .alpha.-adrenergic blocking actions. Therefore, they can be utilized for various treatments. For example, they can be used as useful agents for the treatment of hypertension, congestive heart failure, angina pectoris, lower urinary tract dysfunction, prostatic hypertrophy, pheochromocytoma and peripheral vascular disorders.

The pharmacological effects of the compounds of this invention were determined by the following experiments. The effects of the typical compounds of this invention were compared with those of 5-{1-hydroxy-2-[2-(2-methoxyphenoxy) ethylamino]ethyl}-2-methylbenzenesulfonamide (referred to as "Compound A") which is one of the typical compounds disclosed in British Patent No. 2,006,772 and phentolamine.

A. .alpha.-Adrenergic Blocking Action

The blood pressure was measured in the rats anesthetized with urethane and treated with pentolinium. The effects of the test samples (intravenous injection) to antagonize the hypertensive response to phenylephrine (10 .mu.g/Kg i.v.) were measured and the results were shown in Table I.

B. Antihypertensive Effects in Spontaneously Hypertensive Rats

Oral administration:--The systolic blood pressure was measured indirectly by the tail cuff method using a programmed electrosphygmanometer (Nacro-Bio-Systems Inc., PE-300) on spontaneously hypertensive rats having the systolic blood pressure of higher than 150 mmHg, the results being shown in Table II.

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


The clinical administration of the compounds of this invention is usually intravenous injection or orally as the free base or an acid addition salt thereof (e.g., hydrochlorides, oxalates, sulfates, maleates, acetates, fumarates, lactates, citrates, etc.,). It is proper to administer about 0.01 mg per single dose of the compound several times per day in case of intravenous administration or about 1000 mg of the compound in two or three times per day in case of oral administration. The compounds of this invention may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills solutions, etc., and in these cases, the medicaments can be prepared by conventional method using usual medical excipients.

The compounds of this invention shown by formula [I] can be produced by the following processes. y ##STR14##

Step 1: Usually the process is performed by reacting the halohydrin of formula II.sub.1 or the epoxide of formula II.sub.2 and an equimolar amount to excessive amount of the amine of formula III in a non-solvent or an organic solvent. As the organic solvent used in the reaction, there are, for example, ethanol, toluene, methyl ethyl ketone, acetonitrile, tetrahydrofuran, dimethyl formamide, etc. Also, the reaction proceeds at room temperature to under heating but for promoting the reaction, the reaction is usually performed under heating or under refluxing.

Step 2: When Z is a benzyl group in compound I.sub.1 ' shown above, the benzyl group is removed by performing an ordinary catalytic hydrogenation using for example palladium carbon as a catalyst.

The isolation and purification of the reaction product of formula I.sub.1 ' or I.sub.1 is performed by an ordinary operation such as filtration, extraction by solvent, column chromatography, recrystallization, etc. ##STR15##

Step 1: This step can be practised under the reaction conditions as in Step 1 of Process A.

Step 2: This step can be performed in an organic solvent such as methanol, ethanol, toluene, acetonitrile, tetrahydrofuran, etc., under cooling or at room temperature using a complex metal hydride such as sodium borohydride, diborane, etc., and when the reduction is performed in the presence of a ordinary hydrogenation catalyst such as palladium carbon, etc., the removal of the benzyl group can be performed simultaneously.

Step 3: The step can be performed under the same reaction conditions as in Step 2 of Process A. ##STR16##

Step 1: A compound of formula I.sub.2 is obtained by condensing the compound of formula VI and the compound of formula III in an organic solvent such as methanol, ethanol, toluene, acetonitrile, tetrahydrofuran, etc., and then reducing the condensation product in the presence of PtO.sub.2 or a Raney nickel catalyst or with NaBH.sub.4, etc.

Step 2: A sulfinyl compound of formula I.sub.3 wherein n is 1 can be obtained by treating a compound of formula I.sub.2 in an organic solvent such as methanol, ethanol, etc., using a proper oxidizing agent such as, for example, hydrogen peroxide aqueous solution (10-50%), sodium meta-periodate, etc. Also, a sulfonyl compound of formula I.sub.4 wherein n is 2 can be obtained by treating together with an oxidizing agent (hydrogen peroxide aqueous solution, etc.,) in an acid solvent such as formic acid, acetic acid, etc.

Then, the production process of this invention will be further described in the following examples. In addition, the raw materials or intermediates used in the process of this invention include novel compounds and examples of the productions of these compounds are also shown in the following reference examples.

REFERENCE EXAMPLE 1

(a). Into a suspension of 300 g of stannous chloride di-hydrate in 1100 ml of glacial acetic acid, was introduced hydrogen chloride gas with stirring until the suspension became transparent and then a solution of 50 g of 3-chlorosulfonyl-4-methylacetophenone dissolved in 100 ml of glacial acetic acid was added thereto dropwise at 25.degree.-30.degree. C. After further stirring the mixture for one hour, 2,000 ml of water was added to the reaction mixture and the product was extracted with 1,000 ml of benzene. After washing the benzene extract with water, benzene was distilled off and the residue was distilled under reduced pressure to provide 37 g of 3-mercapto-4-methylacetophenone having a boiling point of 105.degree.-115.degree. C./2 mm Hg.

(b). A mixture of 31 g of 3-mercapto-4-methylacetophenone, 31 g of anhydrous potassium carbonate, 29 g of methyl iodide, and 360 ml of acetone was stirred for 3 hours at room temperature, the reaction mixture obtained was filtered, and the filtrate was evaporated to dryness. The residue formed was dissolved in benzene and after washing the solution obtained with water, benzene was distilled off. Then, the residue was distilled under reduced pressure to provide 29 g of 4-methyl-3-methylthioacetophenone having a boiling point of 96.degree.-105.degree. C./0.7 mm Hg.

(c). In 200 ml of carbon tetrachloride was dissolved 20 g of 4-methyl-3-methylthioacetophenone and then 18 g of bromine was added dropwise to the solution with stirring at room temperature. After the reaction was over, carbon tetrachloride was distilled off and the residue obtained was recrystallized from carbon tetrachloride to provide 18 g of 4'-methyl-3'-methylthio-2-bromoacetophenone having a melting point of 85.degree.-86.degree. C.

(d). To a mixture of 18 g of 4'-methyl-3'-methylthio-2-bromoacetophenone and 300 ml of methanol was gradually added 8 g of sodium borohydrate and thereafter the mixture was stirred for one hour at 40.degree.-50.degree. C. After distilling off methanol from the reaction mixture, 200 ml of water was added to the residue and the product was extracted with 300 ml of benzene. Then, benzene was distilled off and the residue formed was purified by a silica gel column chromatography (eluant:benzene) to provide 8.5 g of oily 4-methyl-3-methylthiostyrene oxide.

Nuclear magnetic resonance spectra (CDCl.sub.3) ##STR17##

REFERENCE EXAMPLE 2

(a). To an aqueous solution of 400 g of sodium sulfite. -7H.sub.2 O dissolved in 615 ml of water was added 81 g of 3-chlorosulfonyl-4-methylacetophenone and the mixture was stirred for 30 minutes at 50.degree.-55.degree. C. After cooling, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and extracted with 1,000 ml of ethyl acetate. The ethyl acetate layer obtained was washed with 500 ml of water, and after drying by anhydrous sodium sulfate, the solvent was distilled off to provide 50 g of a colorless caramel-like powder of 5-acetyl-2-methylbenzenesulfinic acid. The product was dissolved in 500 ml of 60% ethanol and after adding thereto 8 g of sodium hydroxide and 145 g of methyl iodide, the mixture was refluxed for 15 hours. After the reaction was over, the solvent was distilled off and after adding water to the residue, the product was extracted with 1,000 ml of ethyl acetate. The ethyl acetate layer obtained was washed in succession with 300 ml of an aqueous 5% sodium thiosulfate solution, 300 ml of an aqueous 5% sodium hydroxide solution, and then 300 ml of water, and after drying with anhydrous magnesium sulfate, the solvent was distilled off to provide 44 g of methyl 5-acetyl-2-methylbenznesulfinate.

(b). In 200 ml of chloroform was dissolved 21.2 g of methyl 5-acetyl-2-methylbenzenesulfinate and then 16.8 g of bromine was added dropwise to the solution with stirring at 40.degree. C. After the reaction was over, the reaction mixture was added to 500 ml of water and the chloroform layer formed was recovered, washed with a saturated aqueous sodium hydrogen-carbonate solution, and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off and the crude crystals formed were recrystallized from ethanol to provide 26 g of methyl 5-bromoacetyl-2-methylbenzenesulfinate having a melting point of 123.degree.-125.degree. C.

REFERENCE EXAMPLE 3

(a). While ice-cooling a suspension of 84 g of stannous chloride-2H.sub.2 O in 320 ml of glacial acetic acid with stirring until a transparent solution was obtained, hydrochloric acid gas was introduced into the solution and then 14.3 g of 3-chlorosulfonyl-4-methoxyphenylacetone was added to the solution at 25.degree.-30.degree. C. After further stirring the mixture at room temperature for 30 minutes, the reaction mixture obtained was poured into 320 ml of concentrated hydrochloric acid and after diluting the mixture with 640 ml of water, the product was extracted with 400 ml of chloroform. The chloroform layer formed was washed with water and then chloroform was distilled off to provide 10 g of oily 3-mercapto-4-methoxyphenylacetone.

(b). A mixture of 10 g of 3-mercapto-4-methoxyphenylacetone, 9 g of anhydrous potassium carbonate, 42 g of methyl iodine, and 50 ml of methyl ethyl ketone was stirred under refluxing for 20 hours, and after cooling, the reaction mixture was filtered. The filtrate obtained was, then, evaporated to dryness. The residue formed was dissolved in ethyl acetate and after washing the solution obtained with water, ethyl acetate was distilled off and the crude crystals obtained were recrystallized from a mixture of n-hexane and ether to provide 9 g of 3-methylthio-4-methoxyphenylacetone having a melting point of 74.degree.-75.degree. C.

(c). By following the same procedure as in above process (b) using isopropyl iodide as an alkylating agent, oily 4-isopropylthio-3-methoxyphenylacetone was obtained. The product obtained shows the following nuclear magnetic resonance spectra.

Nuclear magnetic resonance spectra (CDCl.sub.3): ##STR18##

EXAMPLE 1 ##STR19##

A mixture of 6 g of 4-methyl-3-methylthiostyrene oxide and 7 g of 3-(4-methoxyphenyl)-1-methylpropylamine was heated to 115.degree. C. for 3 hours. After the reaction was over, the reaction mixture was dissolved in 100 ml of benzene and after washing twice each time with 200 ml of water, the benzene layer was purified by a silica gel column chromatography (eluate: a mixture of benzene, ethyl acetate, and methanol (4:3:1 by volume ratio) to provide 3.5 g of amorphous .alpha.-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methy lthiobenzenemethanol.

The product has the following physicochemical properties:

(i) Amorphous form

(ii) Elemental analysis for C.sub.21 H.sub.29 NO.sub.2 S:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3): ##STR20##

By following almost same procedure as in Example 1, the compounds shown in following Example 2 and Example 3 were obtained.

EXAMPLE 2 ##STR21##

.alpha.-{[(1-Methyl-3-phenyl)propylamino]methyl}-4-methyl-3-methylthiobenze nemethanol.

Physicochemical properties:

(i) Melting point: 48.degree.-60.degree. C.

(ii) Elemental analysis for C.sub.2 OH.sub.27 NOS:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3): ##STR22##

EXAMPLE 3 ##STR23##

.alpha.-{[2-(2-Methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methylthiobenze nemethanol hydrochloride.

Physicochemical properties:

(i) Melting point: 97.degree.-98.degree. C.

(ii) Elemental analysis for C.sub.19 H.sub.25 NO.sub.3 S+HCl:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3): ##STR24##

EXAMPLE 4 ##STR25##

In 70 ml of methanol was dissolved 2.5 g of .alpha.-{[3-(4-methoxyphenyl)-1-methylpropylamino]-methyl}-4-methyl-3-meth ylthiobenzenemethanol and then 8 ml of an aqueous 30% hydrogen peroxide solution was added dropwise to the solution under ice-cooling. After allowing the reaction mixture to stand overnight at room temperature, methanol was distilled off and after adding 50 ml of water to the residue, the product was extracted with ethyl acetate. The ethyl acetate layer formed was dried with anhydrous magnesium sulfate and after distilling off the solvent, the residue was purified by a silica gel column chromatography (eluate: a mixture of benzene, ethyl acetate, and methanol (4:3:1 by volume ratio) to provide 2.0 g of the amorphous caramel-like powder of .alpha.-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methy lsulfinylbenzenemethanol.

The product has the following physicochemical properties:

(i) Amorphous form

(ii) Elemental analysis for C.sub.21 H.sub.29 NO.sub.3 S:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3): ##STR26##

By following substantially the same procedure as in Example 4, the compound shown in the following Example 5 was obtained.

EXAMPLE 5 ##STR27##

.alpha.-{[2-(2-Methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methylsulfinylb enzenemethanol oxalate.

Physicochemical properties:

(i) Melting point: 182.degree.-184.degree. C.









(ii) Elemental analysis for C.sub.19 H.sub.25 NO.sub.4 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3) ##STR28##

EXAMPLE 6 ##STR29##

A mixture of 5.8 g of methyl 5-bromoacetyl-2-methylbenzenesulfinate, 160 ml of methyl ethyl ketone, and 10.3 g of N-benzyl-2(o-methoxyphenoxy)ethylamine was refluxed with stirring for 40 minutes. After the reaction was over, the solvent was distilled off, 150 ml of ethyl acetate was added to the residue formed, and N-benzyl-2-(2-methoxyphenoxy)ethylamine hydrobromide precipitated was removed by filtration. The solvent was distilled off from the filtrate, the residue obtained was dissolved in 125 ml of methanol, and 1.5 g of sodium borohydide was added to the solution under ice-cooling.

The mixture was stirred for 2 hours at room temperature and then methanol was distilled off. After adding 100 ml of water to the residue formed, the product was extracted with 200 ml of ethyl acetate, the ethyl acetate layer obtained was washed with water, and after drying by anhydrous magnesium sulfate, the solvent was distilled off to provide 10 g of oily .alpha.-{2-[N-benzyl-2-(2-methoxyphenoxy)ethylamino]methyl}-4-methyl-3-met hoxysulfinylbenzenemethanol. The product was dissolved in 100 ml of methanol and after adding 0.8 g of 10% palladium carbon, the product was subjected to catalytic reduction at normal temperature and normal pressure. After the reaction was over, palladium carbon was removed by filtration and the filtrate was evaporated to dryness. To the residue obtained was added a solution of 1.7 g of oxalic acid dissolved in 17 ml of methanol and the mixture was allowed to stand overnight at room temperature to provide 6 g of colorless crystals. The crystals were recrystallized from 30 ml of methanol to provide .alpha.-{[2-(2-methoxyphenoxy)ethylamino]methyl}-4-methyl-3-methoxysulfiny lbenzenemethanol oxalate.

The product has the following physicochemical properties:

Melting point: 185.degree.-188.degree. C.

Elemental analysis for C.sub.19 H.sub.25 NO.sub.5 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


Nuclear magnetic resonance spectra (d.sub.6 -DMSO): ##STR30##

EXAMPLE 7 ##STR31##

A mixture of 8.4 g of 4-methoxy-3-methylthiophenylacetone, 6.7 g of 2-methoxyphenoxyethylamine, and 150 ml of methanol was refluxed for 2 hours. The reaction mixture was cooled to a temperature below 10.degree. C. and after adding 2.5 g of sodium borohydride to the reaction mixture with stirring at temperatures below 10.degree. C., the mixture was further stirred for 3 hours at room temperature. Then, the solvent was distilled off under reduced pressure and after adding water to the residue, the product was extracted with ethyl acetate. The extract was washed with water, dried by anhydrous magnesium sulfate, and then the solvent was distilled off to provide an oily product. The product was purified by a silica gel column chromatography (eluate: chloroform) to provide 8.5 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole . The product (750 mg) was dissolved in 10 ml of methanol and after adding thereto a solution of 90 mg of anhydrous oxalic acid dissolved in 1 ml of methanol, the mixture was allowed to stand overnight at room temperature. The crystals thus formed were recovered by filtration and recrystallized from ethanol to provide 600 mg of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole oxalate having a melting point of 173.degree.-174.degree. C.

Physicochemical properties:

(i) Elemental analysis for C.sub.20 H.sub.27 NO.sub.3 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(ii) Nuclear magnetic resonance spectra (CDCl.sub.3): .delta.:1.08 (3H, d, CH.sub.3 --CH); 2.38 (3H, s, CH.sub.3 S--); 3.78 (3H, s, CH.sub.3 --O--); 3.86 (3H, s, CH.sub.3 --0--).

By following substantially the same procedure as in Example 7, the compound shown in following Example 8 was obtained.

EXAMPLE 8 ##STR32##

4-{2-[2-(2-Ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole hydrochloride.

Physicochemical properties:

(i) Melting point: 88.degree.-89.degree. C.

(ii) Elemental analysis for C.sub.21 H.sub.29 NO.sub.3 S+HCl+1/4H.sub.2 O

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3); .delta.: 2.31 (3H, s, CH.sub.3 --S); 3.84 (3H, s, CH.sub.3 --O); 4.44 (2H, t, CH.sub.2 --O).

EXAMPLE 9 ##STR33##

In 100 ml of a mixture of methanol and water (5:1) was dissolved 1.8 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole and after adding dropwise thereto 10.5 ml of an aqueous solution of 0.5M sodium metaperoiodate at 0.degree. C., the mixture was stirred overnight at 4.degree. C. The crystals formed were removed by filtration and the filtrate was concentrated under reduced pressure and the residue formed was purified by a silica gel column chromatography (eluate: a mixture of chloroform and methanol (97:3 by volume ratio) to provide 722 mg of oily 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)ani sole. The product was dissolved in 10 ml of methanol and after adding thereto a solution of 252 mg of oxalic acid di-hydrate dissolved in 6 ml of methanol, the mixture was allowed to stand overnight at room temperature. The resulting crystalline material was recovered by filtration and recrystallized from ethanol to provide 700 mg of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)ani sole oxalate having a melting point of 172.degree.-174.degree. C. The product has the following physicochemical properties:

(i) Elemental analysis for C.sub.20 H.sub.27 NO.sub.4 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(ii) Nuclear magnetic resonance spectra (d.sub.6 -DMSO): .delta.:1.12 (3H, d, CH.sub.3 --CH); 2.68 (3H, s, CH.sub.3 SO--); 3.76 (3H, s, CH.sub.3 --O--); 3.84 (3H, s, CH.sub.3 --O--).

EXAMPLE 10 ##STR34##

In 30 ml of ethanol was dissolved 1.0 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole hydrochloride and then 0.5 g of an aqueous 35% hydrogen peroxide solution was added to the solution with stirring. After stirring the mixture for 18 hours at room temperature, ethanol was distilled off under reduced pressure and the remaining sticky product was dispersed in 20 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed three times each time each with 20 ml of water and after acidifying the solution with 0.2 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. The remaining sticky material was applied to a silica gel column chromatography and eluted using a mixture of ethyl acetate and methanol (4:1 by volume ratio). The sticky product obtained was crystallized by the addition of 3 ml of isopropanol and the crystals thus formed were recovered by filtration to provide 0.4 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anis ole hydrochloride.

The product has the following physicochemical properties:

(i) Melting point: 154.degree.-160.degree. C.

(ii) Elemental analysis for C.sub.21 H.sub.29 NO.sub.4 S+HCl:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3): .delta.:2.70 (3H, s, CH.sub.3 --SO); 3.82 (3H, s, CH.sub.3 --O); 4.43 (3H, t, CH.sub.2 --O).

EXAMPLE 12 ##STR35##

In 18 ml of glacial acetic acid was dissolved 1.8 g of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole and then 1.15 g of an aqueous 30% hydrogen peroxide solution was added dropwise to the solution under ice-cooling. After heating the mixture to 60.degree. C. for one hour, 100 ml of water was added to the reaction mixture and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried with anhydrous magnesium sulfate, and then the solvent was distilled off. The residue obtained was purified by a silica gel column chromatography (eluate: a mixture of chloroform and methanol (97:3 by volume ratio) to provide 1 g of oily 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)ani sole. The product was dissolved in 10 ml of methanol and after adding thereto a solution of 230 mg of anhydrous oxalic acid dissolved in 2 ml of methanol, the mixture was allowed to stand overnight at room temperature. The crystals thus formed were recovered by filtration and recrystallized from methanol to provide 700 mg of 4-{2-[2-(2-methoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)ani sole oxalate having a melting point of 194.degree.-195.degree. C.

The product has the following physicochemical properties:

(i) Elemental analysis for C.sub.20 H.sub.27 NO.sub.5 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(ii) Nuclear magnetic resonance spectra (d.sub.6 -DMSO): .delta.:1.12 (3H, d, CH.sub.3 --CH); 3.16 (3H, s, CH.sub.3 --SO.sub.2 --); 3.72 (3H, s, CH.sub.3 --O--); 3.92 (3H, s, CH.sub.3 --O--).

By following substantially the same procedure as in Example 11, the compounds shown in the following examples were obtained.

EXAMPLE 12 ##STR36##

4-{2-[2-(2-Ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfonyl)aniso le hydrochloride.

Physicochemical properties:

(i) Melting point: 193.degree.-196.degree. C.

(ii) Elemental analysis for C.sub.21 H.sub.29 NO.sub.5 S+HCl:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (CDCl.sub.3): .delta.:3.16 (3H, s, CH.sub.3 --SO.sub.2); 3.94 (3H, s, CH.sub.3 --O); 4.44 (2H, t, CH.sub.2 --O).

EXAMPLE 13 ##STR37##

4-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(isopropylthio)aniso le oxalate.

Physicochemical properties:

(i) Melting point: 157.degree.-158.degree. C.

(ii) Elemental analysis for C.sub.22 H.sub.31 NO.sub.3 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (d.sub.6 -DMSO): ##STR38##

EXAMPLE 14 ##STR39##

4-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(isopropylsulfinyl)a nisole oxalate.

Physicochemical properties:

(i) Melting point: 146.degree.-147.degree. C.

(ii) Elemental analysis for C.sub.22 H.sub.31 NO.sub.4 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (d.sub.6 -DMSO): ##STR40##

EXAMPLE 15 ##STR41##

4-{2-[2-(2-Methoxyphenoxy)ethylamino]-2-methylethyl}-2-(isopropylsulfonyl)a nisole oxalate.

Physicochemical properties:

(i) Melting point: 200.degree.-202.degree. C.

(ii) Elemental analysis for C.sub.22 H.sub.31 NO.sub.5 S+(COOH).sub.2 :

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


(iii) Nuclear magnetic resonance spectra (d.sub.6 -DMSO): ##STR42##

The compounds of this invention can be administered orally or parenterally but intranenous injection or oral administration is preferred. The compounds of this invention are used as the free bases or the pharmacologically acceptable salts thereof and, in general, they are used as medical or pharmaceutical compositions with carriers or diluents which can be used generally for preparing medicaments.

In the case of oral administration, it is most convenient to use the medical compositions of this invention in the form of capsules or tablets but they may also be used as a sustained release preparation. Furthermore, the compositions may be used as sugarcoated preparations or syrups. The doses thereof at oral administration depend on the kind of disease, the age of the patient, etc. Generally, it is proper to administer 0.005-0.03 mg per single dose of the compound several times per day in case of intravenous administration or 200-2000 mg of the compound in two or three times per day case of oral administration.

EXAMPLE A

Medical composition--tablet for oral administration. Formulation for 1,000 tablets:

                  TABLE I
    ______________________________________
    .alpha.-blocking activity
    compounds of this
                   .alpha.-blocking activity (rat)
    invention (Ex. No.)
                   ED.sub.50 (mg/kg) i.v.
    ______________________________________
    5              0.045
    6              0.021
    8               0.0019
    12              0.00014
    known compounds:
    Compound A     0.032
    phentolamine   0.061
    ______________________________________


TABLE II ______________________________________ antihypertensive effect change in systolic blood compounds of this pressure (mm Hg) at stated invention (Ex. No.) dose (mg/kg) dose P.O. ______________________________________ 5 30 -60 6 30 -64 8 30 -48 12 30 -58 known compounds: Compound A 30 -30 phentolamine 30 -53 ______________________________________


The components shown above were granulated in an ordinary manner using starch pase as a binder and then molded into tablets each having a 9.5 mm diameter.

Liquid container

Modular station platform construction kit

Thin floss brush

Lithography process

Support for a torch

Drain-extended MOS ESD protection structure

Thread wound golf ball

Multi-channel optical transmission system

Dispenser

Ribbed clothlike nonwoven fabric

Powder dividing device for camera

Shot gun shell tracer wad

Cotton gin control

Fuel dispensing nozzle

Simultaneous telecommunication between radio stations

Front vehicle body structure

Terminal grounding unit

Gravity particle separator

Automated nut-cracking apparatus and method

Golf club stand device

Printer control system

Catalyzed fluorination of chlorocarbons

Motor vehicle wiper

Hollow fiber separatory device

Somatostatin receptors

Stacker bundler shuttle system

Photographic film and film cassette

Wheelchair motorizing apparatus

Towable "V" rake agricultural machine

Mower deck bumper

Developing unit for electro-photographic apparatus

Pharmaceutically active morpholinol

Incontinence electrode apparatus

Portable foldable splint

Flexible chain conveyor

Preparation of 2-amino-4-fluoropyrimidine derivatives

Tissue anchoring system and method

Ice body delivery apparatus

Moisture-curing polyamides

Electronic voting machine

Valve timing adjusting device

High temperature diesel deposit tester

Antimicrobial cationic peptides

Workpiece feeding-ejection mechanism

Non-aqueous electrochemical cell

Oscillator circuit

Stabilized throttle control system

Splash guard

Method of preparing ferroelectric ceramics

Sod cutter

Baby blanket

Power-generating control apparatus for vehicle

Heterocyclic-methylene-penems

Solar thermal propulsion unit

Soybean cultivar 40064423

Screw

Simultaneous production of higher chloromethanes

Golf putt training apparatus

Triarylpropyl-azabicyclooctanes

Wearable display

Electromechanical preparation of photoengraving cylinders

Device in clearing saws

Focused image tremble correcting device

Low-noise frequency synthesizer

Compact and robust spectrograph

Lime sludge press unit

Depth-resolved fluorescence instrument

Cover connecting mechanism

Intraocular lens

Compartmentalized basket truck

Security and deployment assembly

Phosphorus-containing copolyamides and fibers thereof

Insulating insert for magnetic valves

Substitute milk fat compositions

Tricyclic amides

Reversible code compander

Catalyst patterning for nanowire devices

Fluid flow reversing apparatus

Fuel system for multicylinder engines

Multipurpose exercising apparatus

Floating inlet tube

Direct conversion receiver per-selection

Polishing apparatus

Ion-channel forming peptides

Neck towel and adjustable clasp

Isothiazole and isoxazole sulphoxides

Article transferring apparatus

1-(2-Aryl-4,5-disubstituted-1,3-dioxolan-2-ylmethyl)-1H-imidazoles and 1H-1,2,4-triazoles

Optical fiber strain relief device

Thin layer ablation apparatus

Facsimile compression for transmission

Extrusion machine

Elongated flexible detonating device

Surface modifier composition

Imidazodiazepine derivative

Drum construction

Probing with backside emission microscopy

Aqueous coating composition