KR810001889B1 - Method for producing phenylethylamines - Google Patents

Abstract

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Description

Method for producing phenylethylamines

The present invention relates to a novel phenylethylamine of the following general formula (I) having a hypotension action and a heart rate reduction action and a method for preparing a pharmaceutically toxic acid addition salt thereof.

[Formula I]

Wherein R ₁ , R ₂ , R ₅ and R ₆ are the same or different and are hydrogen or a lower alkyl group or R ₅ may also be a benzyl group, R ₃ is a lower alkoxy group and R ₄ is a lower alkoxy group R _{3 is} methylenedioxy or ethylenedioxy group, R ₇ is hydrogen or lower alkoxy group, R ₈ is lower alkoxy group, or together with R _{7 is} methylenedioxy or ethylenedioxy group, m is 1 or 2 and n is 2 or 3.

The "lower alkyl group" used for R ₁ , R ₂ , R ₅ and R ₆ is an alkyl group having 1 to 3 carbon atoms, and the "lower alkoxy group" used for R ₃ , R ₄ R ₇ and R ₈ is carbon number. It means an alkoxy group which is 1-3. As such, R ₁ , R ₂ , R ₅ and / or R ₆ are hydrogen atoms, methyl, ethyl, propyl or isopropyl groups, R ₅ may also be benzyl groups, and R ₃ , R ₄ , R ₇ and / Or R ₈ is in particular a methoxy, ethoxy, propoxy or isopropoxy group and R ₇ is also a hydrogen atom or R ₃ is with R ₄ and / or R ₇ with R ₈ is methylenedioxy or ethylenedioxy It may be a group.

Preferred compounds according to the invention are compounds of general formula (I) having the following groups.

R ₁ , R ₂ and R ₅ are the same or different, a hydrogen atom or a methyl group, R ₃ is a methoxy group, R ₄ is a methoxy group or together with R ₃ a methylenedioxy or ethylenedioxy group and R ₆ is A hydrogen atom, R ₇ is a hydrogen atom or a methoxy group, R ₈ is a methoxy group or a methylenedioxy or ethylenedioxy group with R ₇ , m is 1 or 2 and n is 2 or 3;

The general formula (I) compound may be prepared according to the following preparation method.

The amine of the following general formula (II) is prepared by reacting with an aralkyl compound of the following general formula (III).

[Formula II] [Formula III]

In the general formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , m and n are as described above, Z is chlorine, bromine or iodine atom, alkylsulfonyloxy Or leaving groups such as aryl sulfonyloxy groups.

The reaction is optionally carried out at a temperature between 0 and 150 ° C., but preferably at the boiling point of the solvent used, depending on the reaction of the Z group in the presence of a solvent such as acetone, methylene chloride, dimethylformamide, dimethyl sulfoxide or chlorobenzene. . It is advantageous to use alcoholates, alkali hydroxides, alkali carbonates such as potassium carbonate or acid binders such as tertiary organic salts such as triethylamine or pyridine, or reaction promoters such as potassium iodide.

If a compound of formula (I) wherein R ₅ is a benzyl group is obtained according to the present method, the compound may be debenzylated or a compound of formula (I) wherein R ₅ is a hydrogen atom is obtained. It can be converted into the corresponding compound of general formula (I) by alkylation reaction.

Debenzylation is preferably carried out under catalytic hydrogenation, for example under hydrogen pressure of 1 to 7 atm between 25 and 75 ° C. using hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as ethanol or ethyl acetate. Do.

The alkylation reaction is carried out at 0 ° to 50 ° C. in a solvent such as acetone, dimethylformamide or dioxane in the presence of an inorganic or tertiary organic base with an alkylating agent such as an alkyl halide or dialkyl sulfate, such as ethyl iodide, isopropyl bromide or dimethyl sulfate. It is carried out using at temperatures between. However, the methylation can also be carried out by reacting with formaldehyde / formic acid, preferably at the boiling point of this mixture.

Moreover, the general formula (I) compound can be converted into salts with physiologically toxic inorganic or organic acids. The acid is suitable for example hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid.

Formulas (II) and (III) compounds used as starting materials can be prepared according to methods known in the literature (see Examples) or are known in the literature.

For example, the following general formula (IV) compounds are obtained by ring closure of the following general formula (IV ′) or (IV ″) compounds in the presence of an acid condensation agent such as polyphosphoric acid (see S. Karady et al., J. Org). Chem. 27, 3720 (1962).

[Formula IV]

The compound of formula (IV) thus obtained can be converted into a compound of formula (II) by alkylation reaction.

[Formula IV 'IV']

Wherein R ₁ -R ₄ and m are as described above and R ₉ is an alkoxy or alkylthio group.

As described above, the novel general formula (I) compounds and acid addition salts thereof have the selective action of reducing heart rate in addition to valuable pharmacological properties, in particular alleviated hypotension.

The following compounds were tested for their biological action.

A = 1-[-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4 -Dimethoxy-phenyl) -ethyl) -amino] -propane- hydrochloride,

B = 1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N- (2- (3,4-dimethoxy-phenyl ) -Ethyl) -amino] -propane-hydrochloride,

C = 1- [4,4-dimethyl, -6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- ( 2- (3,4-dimethoxy-phenyl) -ethyl) -amino] propane-hydrochloride,

D = 1- [4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride and

E = 1- [7,8-dimethoxy-1,2,3,4-tetrahydro-5H-2-benzazin-1-one-2-yl] -3- [N-methyl-N- ( 2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

The action of the substance in question on the heart rate is tested using two to four cats with male and female weights of 2.5 to 3.5 kg by dose. Cats are anesthetized with nembutal (30 mg / kg, intraperitoneal injection) and chloralose-urethane (chloralose 40 mg / ml + urethane 200 mg / ml). The test substance is injected into the saphenous vein or duodenum in aqueous solution. The heart rate is recorded from an electrocardiogram on a Grass-polygraph before and after administration of the compound with a Grass-tachograph.

The following table shows the results.

All doses of the substance in the test are used without side effects. For example, LD ₅₀ for Compound A in rats is 53 mg / kg intravenously (observation time: 14 days).

Therefore, general formula (I) compounds are suitable for the treatment of heart disease, especially chronic coronary insufficiency. It may also be combined with other active ingredients in common galenic compositions such as tablets, coated tablets, powders, suspensions, solutions or suppositories. Single dose is 50 to 250 mg.

The following examples illustrate the invention.

Example 1

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy -Phenyl) -ethyl) -amino] -propane-hydrochloride

6.3 g (22.6 mmol) of 1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3-aminopropane, 3,4-dimethoxy- 4.6 g of phenyl-ethyl chloride together with 5.0 g of potassium carbonate was dissolved in 100 ml of chlorobenzene and refluxed for 5 hours. After cooling the solution is filtered and the filtrate is evaporated in vacuo. The crude product is purified by chromatography on silica gel (chloroform / methanol = 19: 1). The evaporated fractions are dissolved in acetone and etheric hydrochloric acid is added to precipitate the hydrochloride.

Yield: 2.9 g (27% of theory)

Melting Point: 178 ~ 179 ℃

Example 2

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N- (2- (3,4-dimethoxy-phenyl)- Ethyl) -amino] -propane-hydrochloride

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-benzyl-N- (2- (3,4-dimethoxy To a solution of 2.17 g (4.2 mmol) of -phenyl) -ethyl) -amino] -propane was added 1 g of palladium / carbon (30%) and hydrogen was injected within 4 hours at room temperature. After absorbing hydrogen, the catalyst is filtered off and the solution is evaporated in vacuo. The residue is dissolved in acetone and precipitated with hydrochloric acid by addition of etheric hydrochloric acid.

Yield: 0.62 g (32% of theory)

Melting Point: 132 ~ 134 ℃

Example 3

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy -Phenyl) -ethyl) -amino] -propane-hydrochloride

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N- (2- (3,4-dimethoxy-phenyl)- 5.0 g (10.7 mmol) of ethyl) -amino] -propane hydrochloride are heated to 100 ° C. for 1 hour in a mixture of 1.38 g (30 mmol) of formic acid and 1.5 g (20 mmol) of formalin. After cooling, 2N sodium hydroxide solution was added to the reaction solution to make it alkaline and extracted with chloroform. The combined organic layers were washed with water, dried and evaporated in vacuo. The residue is purified by chromatography on silica gel (chloroform / methanol = 50: 1), the main fractions are evaporated and the base is precipitated in the hydrochloride state with etheric hydrochloric acid.

Yield: 2.7 g (52% of theory)

Melting Point: 178 ~ 179 ℃

The following compounds were prepared similarly according to the method of the above examples.

1- [6,7-ethylenedioxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4-dime Methoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.40 (chloroform / methanol = 19: 1)

1- [6,7-methylenedioxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-benzyl-N- (2- (3,4-dime Methoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.25 (chloroform / methanol = 19: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -2- [N-methyl-N- (2- (3,4-dimethoxy -Phenyl) -ethyl) -amino] -ethane-hydrochloride

Rf value: 0.25 (chloroform / methanol = 19: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -2- [N- (2- (3,4-dimethoxy-phenyl)- Ethyl) -amino] -ethane-hydrochloride

Rf value: 0.15 (chloroform / methanol = 19: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (4-methoxy-phenyl ) -Ethyl) -amino] -propane-hydrochloride

Rf value: 0.35 (Chloroform / Methanol = 19: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3-methoxy-phenyl ) -Ethyl) -amino] -propane-hydrochloride

Rf value: 0.30 (chloroform / methanol = 19: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4-methylenedi Oxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.40 (chloroform / methanol = 19: 1)

1- [4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.25 (chloroform / methanol = 19: 1)

1- [4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N- (2- (3,4- Dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.20 (chloroform / methanol = 19: 1)

Calculated Value: C 62.20 H 7.63 N 5.58

Found: 62.80 7.95 5.31

1- [4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -2- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -ethane-hydrochloride

Rf value: 0.40 (chloroform / methanol = 9: 1)

1- [4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -2- [N- (2- (3,4- Dimethoxy-phenyl) -ethyl) -amino] -ethane-hydrochloride

Rf value: 0.20 (chloroform / methanol = 9: 1)

1- [7,8-dimethoxy-1,2,3,4-tetrahydro-5H-2-benzazin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.20 (chloroform / methanol = 9: 1)

IR-spectrum (potassium bromide)> 1640 cm ^-1 at> CO

1- [7,8-dimethoxy-1,2,3,4-tetrahydro-5H-2-benzazin-2-one-2-yl] -3- [N- (2- (3,4 -Dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Rf value: 0.10 (chloroform / methanol = 3: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-benzyl-N- (2- (3,4-dimethoxy -Phenyl) -ethyl) -amino] -propane

Rf value: 0.8 (chloroform / methanol = 19: 1)

1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N- (2- (3,4-dimethoxy-phenyl)- Ethyl) -amino] -propane-hydrochloride

Melting Point: 132 ~ 134 ℃

1- [4,4-dimethyl-6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane-hydrochloride

Melting Point: 70 ℃ (Decomposition)

Claims (1)

A method for producing novel phenylethylamine or acid addition salts of the following general formula (I) by reacting an amine of the following general formula (II) with an aralkyl compound of the following general formula (III).

Wherein R ₁ , R ₂ , R ₅ and R ₆ are the same or different and are a hydrogen atom or a lower alkyl group or R ₅ also represents a benzyl group, R ₃ is a lower alkoxy group, R ₄ represents a lower alkoxy group or Together with R ₃ represent a methylene dioxy or ethyleneoxy group, R ₇ is a hydrogen atom or a lower alkoxy group and R ₈ is a lower alkoxy group or together with R ₇ a methylenedioxy or ethylenedioxy group and m is 1 or 2 n is 2 or 3 and z represents a leaving group such as chlorine, bromine or iodine atom, alkylsulfonyloxy or aryl sulfonyloxy group.