KR810001891B1 - Process for preparing pheylethylamines - Google Patents

Abstract

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Description

Method for producing phenyl ethyl amines

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.

In the above formula, R ₁ , R ₂ , R ₅ and R ₆ are the same or different, hydrogen or lower alkyl group or R ₅ may also be benzyl group, R ₃ is lower alkoxy group, R ₄ is lower alkoxy group M is a methylenedioxy or ethylenedioxy group with R ₃ , R ₇ is hydrogen or a lower alkoxy group, R ₈ is a lower alkoxy group or is a methylenedioxy or ethylenedioxy group with R _7, and 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 It means an alkoxy group having 1 to 3 carbon atoms. As such, R ₁ , R ₂ , R ₅ and / or R ₆ are hydrogen atoms, methyl, ethyl, propyl or isopropyl groups and R ₅ may also be benzyl groups, R ₃ , R ₄ , R ₇ and / or R ₈ is in particular a methoxy, ethoxy, propoxy or isopropoxy group, 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 and are 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, 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 together with R ₇ , m is 1 or 2, n is 2 Or three.

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

The aralkyl compound of the following general formula (II) is prepared by reacting with an amine of the following general formula (III) and hydrolyzing the detoxified 1-amino-compound.

In the above 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, alkylsulfonyl Leaving groups such as oxy or arylsulfonyloxy groups.

The reaction is optionally carried out at a moderately elevated temperature, for example between 50 ° and 150 ° C., in the presence of a solvent such as acetoneethanol, dimethyl formamide, dimethyl sulfoxide or methylene chloride. It is advantageous to use acid binders such as alcoholates, alkali hydroxides, alkali carbonates or tertiary organic bases such as triethylamine or pyridine, or reaction promoters such as potassium iodide.

Continuous hydrolysis is suitably carried out at temperatures of 50 ° C. to the boiling point of the solvent used in the presence of a base such as potassium carbonate or in the presence of an acid such as hydrochloric acid in an aqueous medium such as ethanol / water or dioxane / water.

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.

Debenzylation is preferably carried out under a hydrogen pressure of 1 to 7 atmospheres at a temperature between 25 and 75 ° C. using catalytic hydrogenation, for example 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 ° 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 methyl iodide, ethyl iodide, isopropyl bromide or dimethyl sulfate. It is carried out using at a temperature between about 50 ℃. However, the methylation reaction can also be carried out by reacting with formaldehyde / formic acid, preferably at the boiling point of this mixture.

Moreover, the general formula (I) compounds 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.

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

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 male and female weighing 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 the electrocardiogram on the Grass-polygraph before and after administration of the compound with the Grass-tachograph.

The following table shows the results.

TABLE 1

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.

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

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

6.7 g (25 mmol) 2-cyano-4,5-dimethoxy-phenylethyl-bromide and 1- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethylamino]- 6.3 g (25 mmol) of 3-amino-propane are refluxed in 80 ml of ethanol for 6 hours After cooling the solvent is removed in vacuo and used in the next step 1b without further purification of the crude product.

Rf value (chloroform / methanol = 19: 1): 0.6

b) 1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl] -3- [N-methyl-N- (2- (3,4- Dimethoxy-phenyl) -ethyl) -amino] -1- [6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-amino-2-yl] -3- [N-methyl- 5.2 g (10.8 mmol) of N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane and 10 g of potassium carbonate were refluxed for 8 hours in a mixture of 50 ml of ethanol and 80 ml of water.

The mixture is evaporated in vacuo and the residue is purified by chromatography on silica gel (chloroform / methanol = 50: 1 to 30: 1), the main fraction is evaporated and etheric hydrochloric acid is added to precipitate the hydrochloride.

Yield: 1.07 g (9% 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) in 50 ml of methanol 1 g of palladium / carbon (30%) was added to a solution of 2.17 g (4.2 mmol) of -dimethoxy-phenyl) -ethyl) -amino] -propane 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-methyl-N- (2- (3,4-dimethoxy 5.0 g (10.7 mmol) of -phenyl) -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 fraction is evaporated, and the base is precipitated by hydrochloric acid 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-methylenedioxy-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-methyl-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- (2,4- 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- (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): 1640cm ^-1 at> CO

1- [7,8-dimethoxy-1,2,3,4-tetrahydro-5H-2-benzazin-1-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 new phenylethylamine or acid addition salts of the following general formula (I) by reacting an aralkyl compound of the following general formula (II) with an amine 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 and R ₅ also represents a benzyl group, R ₃ is a lower alkoxy group and R ₄ is a lower alkoxy group M or a methylenedioxy or ethylenedioxy group together with R ₃ , 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, m Is 1 or 2 and n is 2 or 3, and Z represents a leaving group such as chlorine, bromine or iodine atom, alkylsulfonyloxy or arylsulfonyloxy group.