KR800001284B1 - Process for the production of substituted arylalkylamines - Google Patents

Abstract

Title compds. (I; R1 = H, lower alky1, pheny1; R2 = H, C1 or methoxy; R3 = H, methoxy; R4 and R5 are same or not H or lower alky1; R6 H, lower alkoxy; R7 = lower alkoxy; X = carbony1 or sulfony1; n = 2-3), useful as heart rate decreasing agent, were prepd. by reaction of 1-H-phthalimidine(II) and alkylamine(III; Z = C1, Br, iodo, alkylsulfonyloxy, arylsulfonyloxy). Thus, 3.0 g 5,6-dimethoxy-phthalimidine were treated with NaH and 8.5 g 1-[2-(3,4-dimethoxypheny1)-ethy1-methylamino -3-chloropropane to give I.

Description

Process for preparing substituted arylalkylamines

The present invention relates to a process for preparing substituted arylalkylamines of the following formula (I) and their pharmaceutically toxic 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 1H-phthalimimidine of the following formula (II) of the compound of formula (I) of the present invention is prepared by reacting with an alkylamine of formula (III).

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 and Z is chlorine, bromine or an iodine atom or an alkylsulfonyloxy or arylsulfonyl oxy group Leaving group.

The reaction is carried out at temperatures between 0 ° and 150 ° C., depending on the reactivity of atomic group Z, optionally in the presence of a solvent such as acetone, dimethylformromamide, dimethylsulfoxide or methanol. It is advantageous to react in the presence of an acid binder such as an alcoholate, an alkali hydroxide, an alkaliamide, or a tertiary organic base such as triethylamine or pyridine or a reaction accelerator such as potassium iodide.

When a compound of formula (I) is obtained in which R ₄ is hydrogen, the compound is alkylated by reaction with the corresponding alkyl halide or dialkylsulfate or methylated 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. For example, 1H-phthalimine of formula (II) is prepared by reducing the corresponding phthalimide to zinc powder in glacial acetic acid and optionally hydrolyzing it.

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-Methylenedioxy-2N- (3- [2- (3,4-methyllindioxy) -phenylethyl-methyl amino] -propyl) -phthalimidine-hydrochloride

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

E = 5.6-Ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethylmethyl amino] -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 with the same size as 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 other active substances It can be used in combination with. 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-methylamino] -propyl) -phthalimidine hydrochloride

To a solution of 3.0 g (15 mmol) of 5,6-dimethoxy-phthalimimidine in 100 ml of dimethylformamide, 0.5 g of sodium hydride was added and the mixture was heated to 80 ° C. for 30 minutes. A solution of 8.5 g (30 mmol) of 1- [2- (3,4-dimethoxyphenyl) -ethyl-methylamino] -3-chloropropane dissolved in 100 ml of dimethylformromamide was added dropwise to this mixture, followed by 140 ° C. Heat up to 7 hours. After cooling, water is added and washed several times with chloroform. The organic layer is dehydrated and evaporated in vacuo. The crude product is purified by silica gel chromatography. The hydrochloride is obtained by adding etheric hydrochloric acid to precipitate. Melting Point 170 ~ 172 ℃

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 alkalized with 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 ℃

Example 3

5,6-Dimethoxy-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 insolubles are again filtered off and then evaporated and treated with ether hydrochloric acid to precipitate with hydrochloride.

Melting point 120-122 ° C. (acetone / methanol).

The following compounds were also prepared by the method of Example 1-3.

Claims (1)

1-H phthalimidine of the following formula (II) is reacted with an alkylamine of the following formula (III), and when a compound of formula (I) is produced in which R ₄ is hydrogen, alkylation is necessary to produce a compound of formula (I) And methods for preparing their pharmaceutically harmless acid addition salts.

In the above formula, 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 or ethylenedioxy group, R ₄ And R ₅ 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} methylenedioxy or ethylenedioxy group and X is carbonyl or sulfo And is n or 2. Z represents a leaving group such as chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy group.