KR800001287B1 - Process for the production of substituted arylalkylamines - Google Patents

Abstract

Title compds. (I; R1 = H, lower alky1, Ph; R2 = H, Cl, MeO; R3 H, MeO or forming MeO2 bonded together R2; R4, R5 = H, lower alky1; R6 = H, lower alky1; R7 = lower alkoxy or forming MeO2 or EtO2 bonded together R6; X = carbony1, sulfony1; n = 2,3), useful as heart rate decreasing agent were prepd. by reaction of II and III. Thus, 3-[N-(5,6-dimethoxy)-phthalimidine -propionaldehyde-diethylacetal and 3,4-dimethoxy-pheny1-methylamine in EtOHwere reduced with H2, using Pd/C(10%), and treated with HCl to give 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylamino -propy1)-phtalimidine-HCl.

Description

Process for preparing substituted arylalkyl amines

The present invention relates to a process for preparing substituted aryl alkylamines of the following formula (I) and their pharmaceutically harmless acid addition salts, which are effective as heart rate reducing agents.

In the above structural formula

R ₁ is hydrogen, lower alkyl, or a phenyl group,

R ₂ is hydrogen, chlorine or a methoxy group,

R ₃ represents methylenedioxy or ethylene dioxy group together with hydrogen, methoxy or R ₂ ,

R ₄ and R ₅ are the same or different and represent hydrogen or a lower alkyl group,

R ₆ represents hydrogen or a lower alkoxy group,

R ₇ together with lower alkoxy, or R ₆ represents a methylenedioxy or ethylene dioxy group,

X is a carbonyl or sulfonyl group,

n is 2 or 3.

Lower alkyl in R ₄ and R ₅ in particular refers to methyl, ethyl, propyl or isopropyl groups, and in R ₆ and R ₇ an alkoxy group refers in particular to methoxy, ethoxy, propoxy or isopropoxy groups.

Structural formula (I) compounds and acid addition salts thereof have useful pharmacological properties, particularly those that lower heart rate.

The phthalimidine-aldehydes or their acetals of the following formula (II) of the compounds of formula (I) of the present invention are prepared by reacting with amines of the following formula (III) in the presence of catalytically activated hydrogen.

In the above structural formula,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and n are as described above.

The reductive amination is carried out using hydrogen in the presence of a hydrogenation catalyst, for example from 0 ° to 100 in a solvent such as methanol, ethanol or dioxane at a hydrogen pressure of 5 atm in the presence of a catalyst such as palladium / carbon. The reaction is carried out at a temperature of preferably 20 to 80 ° C.

When a compound of formula (I) is obtained wherein R ₄ is hydrogen, the compound is methylated by reaction with the corresponding alkyl halide or dialkyl sulfate or by reaction with formaldehyde / formic acid.

The obtained compound of formula (I) can be converted into a pharmaceutically toxic salt using an inorganic or organic acid. Suitable acids are hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid.

The compounds of the formulas (II) and (III) to be used as starting materials can be prepared by known methods.

As described above, the compound of formula (I) and acid addition salts thereof have useful pharmacological properties such as the effect of reducing the heart rate, in addition to the weak blood pressure lowering effect.

The biological properties were tested with the following compounds.

A = 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methyl-amino] -propyl) -phthalimidine-hydrochloride

B = 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methyl-amino] -propyl) -1,2-benzisothiazoline-1,1- Dioxide-hydrochloride

C = 5,6-dimethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethyl-methylamino] -propyl) -phthalimidine-hydrochloride

D = 5,6-Dimethoxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethylmethylamino] -propyl) -phthalimidine-hydrochloride

E = 5,6-Ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethyl methylamino] -propyl) -phthalimidine-hydrochloride

1. Effect on heart rate in anesthetized malmot

Record the urine anesthetized molar and heart rate in an electronic cardiogram, and then administer the test substance in increasing doses between 0.5 and 20 mg / kg intravenously.

The following table shows the changes in heart rate.

2. Effect on heart rate measured in the malmot atrial

The pulsating atrium of male and female male malmots, weighing 300-400 g, is extracted and placed in an organ bath filled with tyrode solution.

The nutrient solution is infiltrated with carbogen (95% oxygen and 5% carbon dioxide) and kept at 30 ° C continuously. Shrinkage is recorded in the Grass-polygraph in the same size by Statham-Force-transducer. Add the test substance to the long-term bath and adjust the final concentration to 10 ^-5 g / ml in each case. Use five atria for each solution.

The following table shows the percent reduction in average heart rate in five atria. (Substance concentration = 10 ^-5 g / ml)

3. Acute Toxicity

Acute toxicity in mice is determined following oral or intravenous administration. (Observation time: 14 days).

LD ₅₀ is calculated from the percentage of animals that died at different doses within the observation period.

(See J. Pharmacol. Exp. Therap 96,99 (1949)).

When the compound of formula (I) of the present invention and its pharmaceutically toxic acid addition salts are used as drugs, they may be made into conventional pharmaceutical preparations such as tablets, coated tablets, powders, suspensions, solutions or suppositories, and optionally with other active substances. It can be used in combination. One dose is 20 to 300 mg, preferably 25 to 200 mg.

The present invention is illustrated by the following examples.

Example 1

5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-amino] -propyl) -phthalimidine-hydrochloride

3.2 g (10 mmol) of 3- [N- (5,6-dimethoxy) -phthalimidine] -propionaldehyde-diethylacetal and 1.8 g (10 mmol) of 3,4-dimethoxy-phenyl-methylamine 0.3 g of palladium / carbon (10%) was added to a solution dissolved in 100 ml of ethanol, and hydrogen was introduced at a temperature of 50 ° C. and hydrogen at 5 atm for 4 hours. After the uptake of hydrogen, the catalyst is filtered off and the solution is evaporated in vacuo. Treatment with etheric hydrochloric acid gives hydrochloride. Melting Point 207-209 ° C

Example 2

5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methylamino] -propyl) -phthalimidine-hydrochloride

1.38 g of formic acid, 5 g (12.1 mmol) of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylamino) -propyl) -phthalimide at a melting point of 207 to 209 ° C (30 mmol) and formalin 1.5 g (20 mmol) were heated to 100 ° C. for 1 hour. After cooling, the reaction solution was made alkaline by adding 2N-sodium hydroxide solution, extracted with chloroform, the chloroform layer was washed with water, dehydrated and evaporated in vacuo. The residue is purified by silica gel chromatography (chloroform / methanol = 45/1). The main fractions are evaporated and the base is treated with etheric hydrochloric acid to precipitate hydrochloride. Melting Point 170-172 ° C.-Dimethoxy

Example 3

5,6-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-n-propylimino] -propyl) -phthalimidine-hydrochloride

1- to a solution in which 2.5 g (5.5 mmol) of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylamino] -propyl) phthalimine was dissolved in 100 ml of acetone. 20 ml of bromopropane and 5 g of potassium carbonate were added and refluxed for 6 hours. After cooling the solid material is filtered off and the filtrate is evaporated. The product is treated with ether and the refractory is filtered again and then evaporated and treated with ether hydrochloric acid to precipitate with hydrochloride. Melting point 120-122 ° C. (acetone / methanol).

The following compounds are also prepared by the methods of Examples 1 to 3.

Claims (1)

The phthalimidine-aldehyde or acetal thereof of formula (II) is then reacted with an amine of formula (III) in the presence of catalytically activated hydrogen and a compound of formula (I) wherein R ₄ is hydrogen is produced. Alkylation if necessary to produce compounds of formula (I) and their pharmaceutically toxic acid addition salts.

In the above structure, R ₁ is hydrogen, lower alkyl or phenyl group, R ₂ is hydrogen chlorine or methoxy group, R ₃ is hydrogen or methoxy group or together with R ₂ represents methylenedioxy group, R ₄ and R ₅ are Are the same or different and are hydrogen or lower alkyl group, R ₆ is hydrogen or lower alkoxy group, R ₇ is lower alkoxy or together with R _{6 is} methylene dioxy or ethylene dioxy group and X is carbonyl or sulfonyl group, n Is 2 or 3.