JPS6139305B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention has the general formula: and its pharmaceutically acceptable acid addition salts with inorganic or organic acids. In the above formula, R ₁ represents a hydrogen atom, a methyl group or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, R ₃ represents a hydrogen atom or a methoxy group,
Alternatively, together with R ₂ it represents methylenedioxy or ethylenedioxy value, R ₄ and R ₅ may be the same or different, and may be a hydrogen atom or
represents an alkyl group having 3 carbon atoms,
R ₆ represents a methoxy group, R ₇ represents a methoxy group or together with R ₆ represents a methylenedioxy group, X represents a carbonyl group, and n represents the number 2 or 3. represent. Regarding the alkyl radicals mentioned in the definition of the radicals R ₄ and R ₅ , the meaning of the methyl, ethyl, propyl or isopropyl radicals can be considered in particular. The compounds of the above general formula and their acid addition salts exhibit useful pharmacological properties, particularly heartbeat-reducing activity.
frequency decreasing activity). The novel compounds of the above general formula can be prepared according to the following method: a general formula, (wherein R ₁ , R ₂ , R ₃ and ) with the general formula, (wherein R ₄ , R ₅ , R ₆ and R ₇ are as defined above) with phenylethylamine. This reaction can be carried out for example with methanol, ether,
It is optionally carried out in the presence of a solvent such as tetrahydrofuran, methylformamide, dimethylformamide, dimethylsulfoxide or benzene, suitably at a temperature of -50 to 250 DEG C., depending on the reactivity of the group Z. the presence of acid binders such as alcoholates, alkali hydroxides or tertiary organic salts such as triethylamine or pyridine;
Alternatively, the presence of a reaction accelerator such as potassium iodide may be advantageous. b To produce a compound of the formula in which R ₁ represents a hydrogen atom; (d) general formula, (wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and n are as defined above) the compound is reduced. This reduction is carried out in the presence of a solvent such as glacial acetic acid, water or ethanol, suitably using a generator of hydrogen, such as zinc-glacial acetic acid, tin-hydrochloric acid or tin(-)-
Preference is given to using chloride-hydrochloric acid or using catalytically activated hydrogen at temperatures of 0 to 250°C, preferably 50 to 100°C. c general formula, (wherein R ₁ , R ₂ , R ₃ , R ₄ , X and n are as defined above), a phthalimidine of the general formula, Aralkyl compounds of the formula (wherein R ₅ , R ₆ and R ₇ are as defined above and Z represents a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group) react with. This reaction is carried out in the presence of a solvent such as acetone, dimethylformamide, dimethylsulfoxide, chlorobenzene or methylene chloride, suitably between 0 and 150, depending on the reactivity of the group Z.
Optionally performed at a temperature of °C. The presence of acid binders, such as alcoholates, alkali hydroxides, alkali carbonates or tertiary organic bases, such as triethylamine or pyridine, or the presence of reaction promoters, such as potassium iodide, is advantageous. d general formula, (wherein R ₁ , R ₂ , R ₃ and X are as defined above), 1H-phthalimidine of the general formula, (wherein R ₄ , R ₅ , R ₆ , R ₇ and n are as defined above, Z represents a leaving group such as chlorine, bromine or iodine atom, alkylsulfonyloxy or arylsulfonyloxy group) )
of alkylamines. This reaction is carried out, for example, in the presence of acetone, dimethylformamide, dimethylsulfoxide or methanol, suitably depending on the reactivity of the group Z.
Optionally, the temperature is between 150°C and 150°C. The presence of acid binders such as alcoholates, alkali hydroxides, alkali amides or tertiary organic bases such as triethylamine or pyridine, or the presence of reaction promoters such as potassium iodide is advantageous. e general formula, (In the formula, R ₁ to R ₃ are as defined above, and Hal represents a chlorine, bromine or iodine atom)
The benzyl halide has the general formula, (wherein R ₄ to R ₇ are as defined above), and then the obtained 1-imino-phthalimidine is hydrolyzed. This reaction can be performed, for example, using acetone, ethanol,
This is optionally carried out in the presence of a solvent such as dimethylformamide, dimethylsulfoxide or methylene chloride, suitably at elevated temperatures, for example from 50 to 150°C. Acid binders such as alcoholates, alkali hydroxides, alkali carbonates or tertiary agents such as triethylamine or pyridine.
The presence of a class organic base or a reaction accelerator such as potassium iodide is advantageous. This subsequent hydrolysis is carried out 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 at temperatures between 50°C and the boiling temperature of the solvent used. It is appropriate to carry out the test at a temperature of . f general formula XI, (In the formula, R ₁ to R ₃ are as defined above, Hal represents a chlorine, bromine or iodine atom,
Y represents a leaving group such as a chlorine, bromine or iodine atom, or a methoxy or phenoxy group). (wherein R ₄ to R ₇ are as defined above). This reaction is optionally carried out in the presence of a solvent such as acetone, dimethylformamide, dimethyl oxide or methylene chloride, suitably at an elevated temperature, for example from 50 to 150°C. The presence of acid binders, such as alcoholates, alkali hydroxides, alkali carbonates or tertiary organic bases, such as triethylamine or pyridine, or the presence of reaction promoters, such as potassium iodide, is advantageous. For this purpose, the general formula formed on the fly
XII, [In the formula, R ₁ to R ₃ are as defined above, one of the groups A or B has the meaning described above for Hal or Y, and the other one of the groups A or B has the formula, (wherein R ₄ to R ₇ and n are as defined above)] benzamide -
The derivative can be isolated if desired and then further reacted. g general formula, (wherein R ₁ , R ₂ , R ₃ , X and n are as defined above) or its acetal is represented by the general formula, (wherein R ₄ to R ₇ are as defined above) in the presence of catalytically activated hydrogen. This reductive amination uses hydrogen in the presence of a hydrogenation catalyst. For example, in the presence of palladium/charcoal under a hydrogen pressure of 5 atmospheres, in the presence of a solvent such as methanol, ethanol or dioxane.
Temperature between 100°C and 20°C, preferably between 20°C and 80°C
Perform at a temperature of h general formula, (R ₅ to R ₇ are as defined above)
The carbonyl compound or its acetal or its ketal has the general formula: (R ₁ to R ₄ , X and n are as defined above) in the presence of catalytically activated hydrogen. This reductive amination uses hydrogen in the presence of a hydrogenation catalyst, e.g. hydrogen in the presence of palladium on charcoal under a hydrogen pressure of 5 atmospheres, and in the presence of a solvent such as methanol, ethanol or dioxane. Temperature of 100℃, preferably
It is carried out at a temperature of 20 to 80°C. If a compound of the formula in which R ₄ represents a hydrogen atom is obtained according to processes a) to h), this compound is alkylated, for example by reaction with the corresponding alkyl halide or dialkyl sulfate. or can be methylated by reaction with formaldehyde/formic acid. The compounds of the formula obtained can be converted into their pharmaceutically acceptable salts with inorganic or organic acids. Suitable acids have proven to be, for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or malic acid. Compounds of general formulas used as raw materials can be produced according to known methods. Thus, for example, phthalimidine of general formula V or 1H-phthalimidine of general formula is obtained by reducing the corresponding phthalimide in glacial acetic acid with zinc dust and then optionally hydrolyzing. Benzyl halides of formula It is preferably obtained by halogenation under or under UV-irradiation. As already mentioned above, the new compounds of the general formula and their acid addition salts have useful pharmacological properties, in particular a strong heart rate reducing activity with a weak blood pressure lowering activity. As an example, the following compounds were tested for their biological properties: A=5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-
Methyl-amino]-propyl)-phthalimidine-hydrochloride, B=5,6-dimethoxy-2-(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-methylenedioxy)-phenylethyl-methyl-amino]-propyl)
-Phthalimidine-hydrochloride, D=5,6-dimethoxy-2N-(3-[2-
(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride, E=5,6-ethyledioxy-2N-(3-[2
-(3,4-methylenedioxy)-phenylethyl-methylamino)-propyl)-phthalimidine-hydrochloride. 1 Activity against heartbeat of anesthetized guinea pigs The heartbeat of guinea pigs under urethane anesthesia was recorded on an electrocardiogram, and the test substance was administered intravenously at increasing doses from 0.5 to 20 mg/Kg. The following table shows the fluctuations in heart motion:

【table】

[Table] 2. Activity against cardiac oscillations in the auricles of Guiana pigs: Isolated spontaneously swinging auricles of male and female Guiana pigs weighing 300 to 400 g were filled with tyrode solution. Researched in an argan bath. The nutrient solution was leached with carbogen (95% O ₂ and 5% CO ₂ ) and kept uniformly at 30°C. This concentrated liquid was then collected using a glass polygraph (Grass).
Equally recorded using a Statham-Force-transducer (polygraph). The test substance was added to this organ bath, with a final concentration of 10 ⁻⁵ g/ml in each case. Five auricles were used for each solution. The following table shows the % reduction in heart motion averaged over the 5 auricles (concentration of test substance = 10 ^-5 g/ml).

[Table] 3 Acute toxicity: The acute toxicity of the test substance was measured in mice after oral or intravenous administration (observation period: 14 days). The LD ₅₀ was calculated from the percentage of animals that died within the observation period at different drug doses [J. Huamacol. Exp. Serape. (J.Pharmacol.exp.
Therap.), 96 , 99 (1949)]:

[Table] For pharmaceutical use, compounds of the formula as well as their pharmaceutically acceptable acid addition salts may be combined optionally with other active ingredients, in tablets, coated tablets,
They can be incorporated into conventional pharmaceutical compositions such as powders, suppositories, solutions or suspensions. The primary dosage is
The amount is between 20 and 300 mg, preferably between 25 and 200 mg. The following examples are intended to illustrate the invention: Example 1 2N-(3-[2-(3,4-dimethoxy)-
phenylethyl-methylamino]-propyl)
-Phthalimidine-hydrochloride a 2N-(3-[2-(3,4-dimethoxy)
-Phenylethyl-methylamino]-propyl]-phthalimide 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methyl-amino]-amino-propane 5.04 g (0.02 mol) and phthalic anhydride
Dissolve 2.06g (0.02mol) in 100ml of glacial acetic acid,
Reflux for an hour. The mixture is then evaporated under reduced pressure, the residue is taken up in chloroform and the chloroform solution is washed successively with saturated sodium bicarbonate solution and water. After drying over sodium sulfate, the solvent is evaporated to give the title material as an amorphous product. Yield: 6.1g (79.8% of theory), Rf value (benzene/acetone = 1/1): 0.4 b 2N-(3-[2-(3,4-dimethoxy))
-Phenylethyl-methylamino]propyl)
-Phthalimidine-hydrochloride 2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]propyl)-phthalimide 6.1g
(159 mmol) was mixed with 10 g of zinc powder and refluxed for 3 hours for reduction. The zinc dust was separated, the hot solution was filtered and the liquid was evaporated under reduced pressure. The residue was then dissolved in chloroform and the chloroform phase was extracted with saturated sodium carbonate solution and water, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (chloroform/methanol = 19/
1). The hydrochloride salt was obtained by precipitation from ethanolic hydrochloric acid. After soaking in ethyl acetate, this hydrochloride salt had a melting point of 146-148°C. Yield: 2.25g (35% of theory). Example 2 5,6-dimethoxy-2N-(3-[2-
(3,4dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride a 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimide 4,5-dimethoxy-phthalic anhydride 1-
The title compound was prepared analogously to Example 1a by condensation with [2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-amino-propane in glacial acetic acid. Melting point: 91-93
℃. b Similar to Example 1b, 5,6-dimethoxy-2N-
(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimide is reduced with zinc dust in glacial acetic acid,
The title compound was prepared. Melting point: 170-172℃. Example 3 5,6-dimethoxy-2N-(3-[2-
[3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine-hydrochloride a 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimide Similarly to Example 1a, 1-[2-(3,4-dimethoxy-
The title compound was prepared by condensation with phenyl)-ethylamino]-3-amino-propane in glacial acetic acid. Rf-value (chlororum/methanol=9/
1):0.25 b 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine-hydrochloride Similarly to Example 1b, 5,6-dimethoxy-2N-
The title compound was purified by reducing (3-[2-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid. Melting point: 207~209
℃. Example 4 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-
Hydrochloride 5 g (12.1 mol) of the compound obtained according to Example 3 were heated to 100° C. for 1 hour in a mixture of 1.38 g (30 mmol) formic acid and 1.5 g (20 mmol) formalin. After cooling, the reaction solution was made alkaline by the addition of 2N sodium hydroxide solution, extracted with chloroform, the chloroform phase was washed with water, dried and
It was then evaporated under reduced pressure. The residue was purified by chromatography on silica gel (chloroform/methanol = 45/1), the main fraction was evaporated and the base was precipitated as the hydrochloride salt from ethanolic hydrochloric acid.
Melting point: 170-172℃. Example 5 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-n
-propylamino]-propyl)-phthalimidine-hydrochloride 5,6-dimethoxy-2N-(3-[2-
After adding 20 ml of 1-bromopropane and 5 g of potassium carbonate to a solution of 25 g (5.5 mmol) of (3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine in 100 ml of acetone,
It was refluxed for 6 hours. After cooling, remove the solid material,
The liquid was evaporated. Take up the product in ether,
After removing the insoluble portion again and evaporating, the title hydrochloride was precipitated from the ethanolic hydrochloride. Melting point: 120-122°C (acetone/methanol). Example 6 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl)-
Methylamino〕-ethyl)-phthalimidine-
Hydrochloride 3.81 g (15 mmol) of 5,6-dimethoxy-N-(2-bromoethyl)-phthalimide were refluxed with 3,4-dimethoxyphenylethyl-N-methylamine in 40 ml of xylene for 10 hours.
The oily residue obtained after evaporation under reduced pressure was converted to the desired compound analogously to Example 1b by reduction with zinc dust in glacial acetic acid without further purification. Melting point: 149-151℃. Example 7 2N-(3-[2-(3,4-dimethoxy)-
phenylethyl-methylamino]-propyl)
-3-phenyl-phthalimidine N-(3-bromopropyl)-3-phenyl-
1.75 g (5.3 mmol) of phthalimidine in xylene
3,4-dimethoxyphenyl-ethyl- in 30ml
The mixture was refluxed for 10 hours with 2.06 g (10.6 mmol) of N-methylamine. After cooling, the mixture was evaporated and purified by chromatography on silica gel (chloroform/methyl alcohol = 19/
1). The title base was obtained as a highly viscous oil. Rf-value (chloroform/methanol=19/
1): 0.4. Example 8 (Reference example) 3-phenyl-5-chloro-2N-(3-[2
-(3,4-dimethoxy)-phenylethyl-
Methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide-hydrochloride N-(3-chloropropyl)-3-phenyl-
5-chloro-1,2-benzisothiazoline-
3g (9.3 mmol) of 1,1-dioxide in 3,4
The mixture was refluxed for 5 hours in a solution of 30 ml of dimethylformamide and 5 ml of triethylamine with 3 g of -dimethoxy-phenylethyl-N-methylamine and a spatula amount of potassium iodide. The mixture was then evaporated to dryness, the residue was taken up in chloroform and the organic phase was washed several times with water. After drying, the mixture was evaporated and the residue was purified by chromatography on silica gel (chloroform/methanol = 40/1). Precipitation with ethanolic hydrochloric acid gave the title hydrochloride salt as an amorphous product. Rf-value (chloroform/methanol=19/
1): 0.5. C ₂₇ H ₃₁ ClH ₂ O ₄ S×HCl (551.54) Calculated value: C58.8 H5.60 N5.10 S5.80 Actual value: C58.7 H5.75 N5.20 S5.90 Example 9 (Reference example) 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide-hydrochloride a 2-methyl-4,5-dimethoxy-benzenesulfochloride 3,4- 23.2 g (0.2 mol) of chlorosulfonic acid was gradually added dropwise to 15.2 g (0.1 mol) of dimethoxy-toluene with stirring and cooling at about -10°C. The mixture was then allowed to warm to room temperature and stirred until the evolution of hydrogen chloride had ceased.
The reaction mixture was poured onto ice and the precipitated title sulfochloride was extracted with ether. The organic phase was washed successively with sodium bicarbonate solution and water and evaporated to dryness under reduced pressure. A cloudy oil was obtained as a residue. This solidified after cooling. Rf-value (benzene): 0.5. b 2-Methyl-4,5-dimethoxy-benzenesulfonamide 18 g (0.07 mol) of the compound obtained according to Example 9a
was suspended in 200 ml of concentrated ammonia and stirred at room temperature for 4 hours.
Stir for hours. The mixture was filtered off with suction and washed again with water, giving after drying the desired sulfonamide as an amorphous product. Rf-value (benzene/acetone = 1/1):
0.6. c 5,6-dimethoxy-1,2-benzisothiazolin-3-one-1,1-dioxide 16 g (0.08 mol) of 2-methyl-4,5-dimethoxy-benzenesulfonamide in 500 ml of 5% sodium hydroxide solution After adding 39.6 g (0.25 mol) of potassium permanganate,
Heat to room temperature for 2 hours. After cooling, the mixture was filtered with suction over Celite and the desired product was precipitated by addition of concentrated hydrochloric acid. Rf-value (benzene/acetone = 3/1): 0.2
~0.4. d 5,6-Dimethoxy-1,2-benzisothiazoline-1,1-dioxide 7 g (288 mmol) of the compound obtained according to Example 9c are refluxed for 2 hours with 3.3 g (865 mmol) of lithium aluminum hydride in 400 ml of tetrahydrofuran. I let it happen. After cooling, excess lithium aluminum hydride was destroyed by addition of ethyl acetate, then the mixture was diluted with water and 2N hydrochloric acid was added until the aluminum hydroxide precipitate was dissolved. The reaction solution was extracted with ethyl acetate, and the organic phase was washed with water and dried. The mixture was evaporated under reduced pressure, the residue was taken into ether and the title compound was sucked off. e N-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisothiazoline-1,
1-Dioxide 2.4 g (10.5 mmol) of the compound obtained according to Example 9b were dissolved in a mixture of 15 ml of a 2.5% solution of sodium oxide and 30 ml of ethanol.
After addition of 10 ml of 1-chloropropane, the mixture was refluxed for 8 hours. The reaction mixture was evaporated to half its volume, diluted with water and extracted with chloroform.
After drying the organic phase, the mixture was evaporated under reduced pressure to obtain the desired product as a highly viscous oil. Rf-value (chloroform/methanol=19/
1): 0.8. f 5,6-dimethoxy-2N-(3-[2-
3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-oxide-hydrochloride Same as Example 8, N-(3-chloropropyl)
The title compound was prepared by reacting -5,6-dimethoxy-1,2-benzisothiarine-1,1-dioxide with 3,4-dimethoxyphenylethyl-N-methylamine. Melting point: 196-198℃ (acetone). Example 10 5,6-methylenedioxy-2N-(3-[2
-(3,4-dimethoxy)-phenylethyl-
Methylamino]-propyl)-phthalimidine-hydrochloride a 4,5-methylenedioxy-phthalic anhydride
3.5 g (18 mmol) and 1-[2-(3,4
-Dimethoxy-phenyl)-ethylmethylamino]-3-aminopropane 4.5g (18 mmol)
was refluxed in 100 ml of glacial acetic acid. The mixture was then evaporated under reduced pressure, the residue was taken up in chloroform and the chloroform solution was washed successively with saturated sodium bicarbonate solution and water. After drying over sodium sulfate, the solvent was distilled off,
The desired material was obtained as an amorphous product. yield:
4.8g (63% of theory), Rf value (chloroform/methanol) 9/
1): 0.6. b 5,6-methylenedioxy-2N-(3-
[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride 5,6-methylenedioxy-2N-(3-[2-(3, 4.8 g (11 mmol) of 4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimide was mixed with 5 g of zinc dust and refluxed for 2 hours. The zinc dust was then removed from the hot solution and the liquid was evaporated under reduced pressure. The residue was then dissolved in chloroform and the chloroform phase was extracted with saturated sodium carbonate solution and water, dried over sodium sulfate and then evaporated. The residue was dissolved in chloroform and added with ethereal hydrochloric acid.
The title acid salt was precipitated with a melting point of 237-239°C. Yield: 1.5g (30% of theory). Calculated value: C61.53 H6.51 N6.24 Cl7.90 Actual value: C61.50 H6.49 N6.24 Cl7.85 Example 11 5,6-ethylenedioxy-2N-(3-[2
-(3,4-dimethoxy)-phenylethyl-
Methylamino〕-propyl)-fluimidine-
Hydrochloride a 4,5-ethylenedioxy-2N-(3-
[2-(3,4-dimethoxy)-phnylethyl-methylamino]-propyl)-phthalimide 4,5-ethylenedioxy-phthalic anhydride and 1-[2-(3,4-dimethoxy) -Phenyl)-ethyl-methylamino]-
The title compound was prepared by condensation with 3-aminopropane in glacial acetic acid. Rf-value (chloroform/methanol=9/
1): 0.5. b 5,6-ethylenedioxy-2N-(3-
[2-(3,4-dimethoxy)phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride 4,5-ethylenedioxy-2N-(3-[α-(3,4- dimethoxy)
The title compound was prepared by reducing -phenylethyl-methylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid. Melting point: 208-210℃ Calculated value: C62.26 H6.75 N6.05 Cl7.66 Actual value: C62.10 H6.84 N5.90 Cl7.67 Example 12 5,6-Methylenedioxy-2N-(3 ―[2
-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride a 4,5-methylenedioxy-2N-(3-
[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide 2.7 g (10 mmol) of 4,5-methylenedioxy-N-(3-chloropropyl)-phthalimide and 3, 4-Methylenedioxy-phenylethyl-N-methylamine 1.8g (10 mmol)
was dissolved in 20 ml of chlorobenzene and refluxed for 8 hours after addition of 2.8 g (20 mmol) of powdered potassium carbonate. The solution was then filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (chloroform/methanol = 19/1) and then after evaporation of the main fraction:
2.1 g (51% of theory) of the desired compound were obtained. Rf
-value (chloroform/methanol = 9/1):
0.6. b 5,6-methylenedioxy-2N-(3-
[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride 4,5-methylenedioxy-2N-(3-[2-(3 ,4-Methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide was reduced with zinc dust in glacial acetic acid to produce the title compound. Melting point: 206-208℃. Calculated value: C61.04 H5.82 N6.47 Cl8.19 Actual value: C61.10 H6.07 N6.74 Cl8.45 Example 13 5,6-ethylenedioxy-2N-(3-[2
-(3.4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride. a 4,5-ethylenedioxy-2N-(3-
[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phtaimide 4,5-ethylenedioxy-
N-(3-chloropropyl)-phthalimide and 3,4-methylenedioxy-phenylethyl-
The title compound was prepared by reacting N-methylamine in chlorobenzene in the presence of potassium carbonate. Rf-value (chloroform/methanol=9/
1): 0.5. b 5,6-ethylenedioxy-2N-(3-
[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride 4,5-ethylenedioxy-2N-(3-[α-(3 ,4-Methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide was reduced with zinc dust in glacial acetic acid to produce the title compound. Melting point: 180-182℃. Calculated value: C61.81 H6.09 N6.27 Cl7.93 Actual value: C61.70 H6.12 N6.12 Cl7.94 Example 14 5,6-dimethoxy-2N-(3-[2-
(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride a 4,5-dimethoxy-2N-(3-[2-
(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide 4,5-dimethoxy-N-
(3-chloropropyl)-phthalimide and 3,
4-Methylenedioxy-phenylethyl-N-
The title compound was prepared by reaction with methylamine in chlorobenzene in the presence of potassium carbonate. Rf-value (chloroform/methanol=19/
1): 0.7. b 5,6-dimethoxy-2N-(3-[2-
(3,4-methylenedioxy)phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride 4,5-dimethoxy-2N-
(3-[2-(3,4-methylenedioxy)-
phenylethyl-methylamino]-propyl)
-The title compound was prepared by reducing phthalimide with zinc dust in glacial acetic acid. Melting point: 235-237℃ Calculated value: C61.53 H6.51 N6.24 Cl7.90 Actual value: C61.45 H6.63 N6.27 Cl7.92 Example 15 (Reference example) 5,6-ethylenedioxy 2-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide-hydrochloride As in Example 12a, N-(3-chloropropyl)
The title compound was prepared by reacting -5,6-ethylenedioxy-1,2-benzisothiazoline-1,1-dioxide and 3,4-dimethoxy-phlethyl-N-methylamine. Rf-value (chloroform/methanol=9/
1): 0.6. Example 16 3-methyl-5,6-dimethoxy-2N-(3
-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride 3-methyl-5,6-dimethoxy-N-(3-chloropropyl)- Phthalimidine to 3,4-dimethoxy-phenylethyl-N
The title compound was prepared by reacting -methylamino with chlorobenzene in the presence of potassium carbonate. Melting point: 135-136℃. Calculated value: C62.68 H7.36 N5.85 Cl7.40 Actual value: C62.31 H7.40 N5.80 Cl7.12 Example 17 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidine-hydrochloride a 4,5-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl-phthalimide 4,5-dimethoxy-N-
(3-chloropropyl)-phthalimide 3,
4-dimethoxyphenyl-isopropyl-N-
The title compound was prepared by reacting methylamine in chlorobenzene in the presence of potassium carbonate. Rf-value (chloroform/methanol=9/
1): 0.9. b 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidine-hydrochloride 4,5-dimethoxy-2N-
(3-[2-(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)
-The title compound was prepared from phthalimide in glacial acetic acid with zinc dust. Melting point: 183-185℃. Calculated value: C62.68 H7.36 N5.85 Cl7.40 Actual value: C62.50 H7.42 N5.92 Cl7.30 Example 18 5,6-Methylenedioxy-2N-(2-[2
-(3,4-dimethoxy)-phenylethyl-
Methylamino〕-ethyl)-phthalimidine-
Hydrochloride a 4,5-methylenedioxy-2N-(3-
[2-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimide 4,5-methylenedioxy-phthalic anhydride and 1-[2-(3,4-dimethoxy) The title compound was prepared from -phenyl)-ethyl-methylamino]-2-amino-ethane. Rf-value (chloroform/methanol = 9:
1): 0.55. b 5,6-methylenedioxy-2N-(2-
[2-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidine-hydrochloride 4,5-methylenedioxy-2N-(2-[2-(3,4 -dimethoxy)
-phenylethyl-methylamino]-ethyl)
-The title compound was prepared by reducing phthalimide with zinc dust in glacial acetic acid. Rf-value (chloroform/methanol = 9:
1): 0.4. Example 19 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine-hydrochloride 5,6-dimethoxy-N-(2-N methylamino)-propyl-phthalimidine 5.3 g (0.02 mol), 3,4- 4.0 g (0.02 mol) of dimethoxy-phenylethyl chloride and 4.2 g of potassium carbonate were refluxed in 100 ml of chlorobenzene for 5 hours. After cooling, the solution was filtered and the liquid was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (chloroform/methanol = 19/
1). The evaporated fraction was dissolved in acetone and the title hydrochloride salt was precipitated by addition of ethereal hydrochloric acid. Melting point: 170-172℃ Example 20 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine-hydrochloride 5,6-dimethoxy-phthalimidine 3.0g (15
Add 0.5 g of sodium hydride to a solution of 100 ml of dimethylformamide (mmol) and the mixture then
Heated to 80°C for 30 minutes. Next, 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino] dissolved in 100 ml of dimethylformamide.
8.5 g (30 mmol) of -3-chloropropane was added dropwise to the mixture and the mixture was heated to 140° C. for 7 hours. After cooling, water was added and the mixture was extracted several times with chloroform. The organic phase was dried and evaporated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel. Precipitation with ethereal hydrochloric acid gave the title hydrochloride salt. Melting point: 170-172℃. Example 21 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine-hydrochloride Methyl 2-bromomethyl-4,5-dimethoxybenzoate 1.45 g (5 mmol), 1-[2-(3,
2.52 g (10 mmol) of 4-dimethoxy-phenyl)-ethyl-methylamino]-3-aminopropane and 3 g of potassium carbonate were refluxed in 200 ml of methyl-ethyl ketone for 4 hours. After cooling, the insoluble portion was removed and the liquid was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (chloroform/methanol = 19/1). Precipitation with ethereal hydrochloric acid gave the title hydrochloride salt. Melting point: 170-172℃. Example 22 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine-hydrochloride a 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-(1-imino-5 ,6-dimethoxy-phthalimidine-
2-yl)-propane 6.4 g (0.025 mol) of 2-cyano-4.5-dimethoxy-benzyl bromide and 1-[2-
(3,4-dimethoxy-phenyl)-ethyl-
Methylamino]-3-aminopropane 6.3g
(0.025 mol) was refluxed in 80 ml of ethanol for 6 hours. After cooling, the solvent was removed under reduced pressure and the crude product obtained was further processed in reaction step b without purification. Rf-value (chloroform/methanol=19/
1): 0.5. b 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine-hydrochloride 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-(1-imino-5, 6-dimethoxy-phthalimidine-
2-yl)-propane 5g and potassium carbonate
11 g was refluxed for 8 hours in a mixture of 50 ml ethanol and 80 ml water. The mixture was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel (chloroform/methanol = 19/
1). The title free base was obtained from the evaporation fraction. This was precipitated as the hydrochloride salt from ethereal hydrochloric acid. Melting point: 170-172℃. Example 23 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine-hydrochloride 1-amino-3-[N-(5,6-dimethoxy-phthalimidine)]-propane 2.6 g (10 mmol) and 2 A solution of 1.8 g (10 mmol) of -(3,4-dimethoxy-phenyl)-acetaldehyde in 100 ml of ethanol was added with palladium on charcoal (10
After addition of 0.3 g (%), hydrogen was introduced at a temperature of 50° C. and a pressure of 5 atm over a period of 4 hours. After hydrogen uptake, the catalyst was removed and the solution was evaporated under reduced pressure. Precipitation with ethereal hydrochloric acid gave the title hydrochloride salt. Melting point: 207-209℃. Example 24 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine-hydrochloride 3-[N-(5,6-dimethoxy-phthalimidine]-propionaldehyde-diethyl acetal 3.2 g (10 mmol) and 3, 4-dimethoxy-phenyl-ethylamine 1.8 g (10 mmol)
After adding 0.3 g of palladium/charcoal (10%) to a solution of 100 ml of ethanol at a temperature of 50 °C and 5
Hydrogen was introduced at a pressure of atmospheric pressure over a period of 4 hours. After uptake of hydrogen, the catalyst was removed and the solution was evaporated under reduced pressure. Precipitation with ethereal hydrochloric acid gave the title hydrochloride salt. Melting point: 207-209℃. According to Examples 19 to 24, the following compounds were also prepared: 2N-(3-[2-(3,4-dimethoxy)-
Phenylethyl-methylamino]propyl)-phthalimidine-hydrochloride Melting point: 146-148°C. 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine-hydrochloride Melting point: 207-209°C. 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-n-
Propylamino]-propyl)-phthalimidine-hydrochloride Melting point: 120-122°C (acetone/methanol). 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidine-hydrochloride Melting point: 149-151°C. 2N-(3-[2-(3,4-dimethoxy)-
phenylethyl-methylamino]-propyl)-
3-phenyl-phthalimidine Rf-value (chloroform/methanol = 19/
1): 0.4. 5,6-methylenedioxy-2N-(3-[2
-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 237-239℃ 5,6-diethylenedioxy-2N-(3-
[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 208-210°C. 5,6-methylenedioxy-2N-(3-[2
-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 206-208°C. 5,6-ethylenedioxy-2N-(3-[2
-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 180-182°C. 5,6-dimethoxy-2N-[3-[2-
(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 235-237°C. 3-methyl-5,6-dimethoxy-2N-(3
-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 135-136°C. 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidine-hydrochloride Melting point: 183-185°C. Example A 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-
Tablet composition containing 100 mg of hydrochloride: Active ingredient 100.0 mg Lactose 50.0 mg Polyvinylpyrrolidone 5.0 mg Carboxymethylcellose 19.0 mg Magnesium stearate 1.0 mg 175.0 mg Preparation method: Wet the active ingredient and lactose homogeneously with an aqueous PVP solution. and made into granules. After drying, the granules were mixed with the remaining auxiliary ingredients and compressed into tablets in a conventional manner. Example B 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-
Coated tablet containing 50 mg of hydrochloride 1 coated tablet core: Active ingredient 50.0 mg Dried corn starch 20.0 mg Soluble starch 2.0 mg Carboxylmethyl cellulose 7.0 mg Magnesium stearate 1.0 mg 80.0 mg Preparation method: Prepare the mixture as described in Example A. Processed to produce coated tablet cores. This was then covered with a dressing consisting of sugar and gum arabic. Example C 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-
Suppository containing 150 mg of hydrochloride Composition: Active ingredient 150.0 mg Suppository base material 1550.0 mg 1700.0 mg Preparation method: The active ingredient was homogeneously dispersed in the molten suppository base material, and the liquid mixture was pre-cooled. It was poured into suppository molds. Example D 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-
100 ml of a suspension containing 250 mg of hydrochloride per 5 ml contains the following components:

【table】

[Table] Method for adjusting the amount: Distilled water was heated to 70°C and methyl and ethyl esters of p-hydroxybenzoic acid, glycerin and carboxymethylcellulose were dissolved therein. The solution was allowed to cool to room temperature and the active ingredient was added with stirring. The solution was then homogenized. After adding the sugar, sorbitol solution and flavoring, the suspension was degassed with stirring. 5ml of this suspension is 5,6-dimethoxy-2N
Contains -(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine-hydrochloride.

Claims (1)

[Claims] 1 General formula, (In the formula, R ₁ represents a hydrogen atom, a methyl group or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom or a methoxy group, or together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and
R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₆ represents a methoxy group, and R ₇ represents a methoxy group or ₆ represents a methylenedioxy group, X represents a carbonyl group, and n represents a number of 2 or 3) and their pharmaceutical preparation with inorganic or organic acids. Acid addition salts that are acceptable as 2 R ₁ , R ₄ and R ₅ may be the same or different and represent a hydrogen atom or a methyl group, and R ₂ is 5
-represents a methoxy group present in position, and R ₃ is 6-
represents a methylenedioxy or ethylenedioxy group together with a methoxy group or R ₂ present in the position,
R ₆ represents a methoxy group, R ₇ represents a methoxy group or
Novel substituted _arylalkyl and inorganic or a pharmaceutically acceptable acid addition salt thereof to an organic acid. 3 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine and the novel substituted arylalkylamine as claimed in claim 1 which is an acid addition salt thereof, and its medicament using an inorganic or organic acid. Acid addition salts that are acceptable as 4 5,6-methylenedioxy-2N-(3-
[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine and its acid addition salt, the novel substituted arylalkylamine according to claim 1, and inorganic or its pharmaceutically acceptable acid addition salts with organic acids. 5 5,6-dimethoxy-2N-(3-[2-
(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine and the novel substituted arylalkylamine according to claim 1, which is an acid addition salt thereof, and an inorganic or organic acid. A pharmaceutically acceptable acid addition salt thereof. 6 5,6-ethylenedioxy-2N-(3-
[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine and its acid addition salt, the novel substituted arylalkylamine according to claim 1, and inorganic or its pharmaceutically acceptable acid addition salts with organic acids. 7 5,6-dimethoxy-2N-(3-[2-
(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine or its acid addition salt, optionally together with one or more inert pharmaceutical carriers or auxiliaries. Pharmaceutical composition. 8 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom or a methoxy group, or together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different, and represent a hydrogen atom or 1 to 3
represents an alkyl group having R ₆ carbon atoms;
represents a methoxy group, R ₇ is a methoxy group or R ₆
together with a methylenedioxy group, A method for producing an acid addition salt having the general formula, (In the formula, R ₁ , R ₂ , R ₃ , X and n are as defined above, and Z represents a leaving group such as chlorine, bromine or iodine atom, alkylsulfonyloxy or arylsulnyloxy group) The compound represented by the general formula, (wherein R ₄ , R ₅ , R ₆ and R ₇ are as defined above), and if desired, the resulting compound of the general formula is treated with an inorganic or organic acid as a pharmaceutical. A process comprising converting the compound into an acid addition salt which is acceptable as a compound. 9. The method according to claim 8, wherein the reaction is carried out in the presence of a solvent at a temperature of -50 to 250°C. 10. The method according to claim 8, wherein the reaction is carried out in the presence of an acid binder and/or a reaction promoter. 11 General formula (In the formula, R ₁ represents a hydrogen atom, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom or a methoxy group, or together with R ₂ , a methylenedioxy or ethylenedioxy group) represents R ₄ and
R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₆ represents a methoxy group, and R ₇ represents a methoxy group or together with R ₆ represents a methylenedioxy group,
X represents a carbonyl group, and n is 2 or 3
A process for producing a novel substituted arylalkylamine represented by the formula (representing the number of (wherein R ₂ to _{R 7} and n are as defined above) is reduced, and if desired,
A process comprising converting the compound of the general formula obtained into a pharmaceutically acceptable oxidized salt with an inorganic or organic acid. 12. The method according to claim 11, wherein the reduction is carried out in the presence of a solvent at a temperature of 0 to 250°C. 13 Claim 11 in which the reduction is carried out with nascent hydrogen or with catalytically activated hydrogen
The method described in section. 14 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group, or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom, a methoxy group, or
together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; , R ₆ represents a methoxy group, R ₇ represents a methoxy group or a methylenedioxy group together with R ₆ , X represents a carbonyl group, and n represents a number of 2 or 3) A process for the preparation of novel substituted arylalkylamines and their pharmaceutically acceptable acid addition salts with inorganic or organic acids, comprising the general formula: (wherein R ₁ to _{R 4} , X and n are as defined above) is represented by the general formula, (wherein R ₂ , R ₆ and R ₇ are as defined above and Z represents a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group) A process consisting of reacting the compound with the general formula obtained and optionally converting the obtained compound of the general formula with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt. 15. The method according to claim 14, wherein the reaction is carried out in the presence of a solvent at a temperature of 0 to 150°C. 16. The method according to claim 14, wherein the reaction is carried out in the presence of an acid binder and/or a reaction promoter. 17 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, R ₃ represents a hydrogen atom or a methoxy group, or R ₂
together with represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R ₆ represents a methoxy group, R ₇ represents a methoxy group or a methylenedioxy group together with R ₆ , X represents a carbonyl group, and n represents a number of 2 or 3). A process for producing substituted arylalkylamines and their pharmaceutically acceptable acid addition salts with inorganic or organic acids, comprising the general formula: (wherein R ₁ , R ₂ , R ₃ and X are as defined above), (wherein R ₄ , R ₅ , R ₆ , R ₇ and n are as defined above, Z represents a leaving group such as chlorine, bromine or iodine atom, alkylsulfonyloxy or arylsulfonyloxy group) ) and optionally converting the resulting compound of the general formula with an inorganic or organic acid into a pharmaceutically acceptable acid addition salt. 18. The method of claim 17, wherein the reaction is carried out in the presence of a solvent at a temperature of 0 to 150°C. 19. The method according to claim 17, wherein the reaction is carried out in the presence of an acid binder and/or a reaction promoter. 20 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group, or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom, a methoxy group, or
together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; , R ₆ represents a methoxy group, R ₇ represents a methoxy group or a methylenedioxy group together with R ₆ , X represents a carbonyl group, and n represents a number of 2 or 3) A process for the preparation of novel substituted arylalkylamines and their pharmaceutically acceptable acid addition salts with inorganic or organic acids, comprising the general formula: (In the formula, R ₁ to _{R 3} are as defined above, and Hal
represents a chlorine, bromine or iodine atom), the benzyl halide is represented by the general formula: (wherein R ₄ to R ₇ and n are as defined above), and then the obtained 1-imino-phthalimidine is hydrolyzed, and if desired, the obtained general formula A process comprising converting a compound into a pharmaceutically acceptable acid addition salt with an inorganic or organic acid. 21. The method according to claim 20, wherein the reaction is carried out in the presence of a solvent at a temperature of 50 to 150°C. 22. The method according to claim 20, wherein the reaction is carried out in the presence of an acid binder and/or a reaction promoter. 23. The process according to claim 20, wherein the subsequent hydrolysis is carried out in the presence of a base at a temperature from 50°C to the boiling temperature of the solvent used. 24 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group, or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom, a methoxy group, or
together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; , R ₆ represents a methoxy group, R ₇ represents a methoxy group or a methylenedioxy group together with R ₆ , X represents a carbonyl group, and n represents a number of 2 or 3) A novel process for preparing substituted arylalkyl amines and their pharmaceutically acceptable acid addition salts with inorganic or organic acids, comprising one-step formula XI: (In the formula, R ₁ to _{R 3} are as defined above, and Hal
represents a chlorine, bromine or iodine atom, Y is chlorine,
A benzyl halide represented by a bromine or iodine atom or a leaving group such as a methoxy or phenoxy group is represented by (wherein R ₄ to R ₇ and n are as defined above), and if desired, the resulting compound of the general formula is subjected to a pharmaceutically acceptable acid addition with an inorganic or organic acid. A method consisting of converting it into salt. 25. The method according to claim 24, wherein the reaction is carried out in the presence of a solvent at a temperature of 50 to 150°C. 26. The method according to claim 24, wherein the reaction is carried out in the presence of an acid binder and/or a reaction promoter. 27 General formula XII, [In the formula, R ₁ to _{R 3} are as defined above, one of the groups A or B has the meaning described above for Hal or Y, and the other one of the groups A or B has the formula 25. A method according to claim 24, for isolating the in situ formed benzamide derivative of the formula: wherein _R4 to _R7 and n are as defined above. 28 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group, or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom, a methoxy group, or
together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; , R ₆ represents a methoxy group, R ₇ represents a methoxy group or a methylenedioxy group together with R ₆ , X represents a carbonyl group, and n represents a number of 2 or 3) A novel method for producing substituted arylalkylamines and their pharmaceutically acceptable acid addition salts with inorganic or organic acids, comprising: (wherein R ₁ , R ₂ , R ₃ , X and n are as defined above) or its acetal is represented by the general formula, (wherein R ₄ to _{R 7} are as defined above) in the presence of catalytically activated hydrogen, and if desired, the resulting compound of the general formula can be inorganic or organic. A process comprising converting with an acid into a pharmaceutically acceptable acid addition salt. 29 Reductive amination in the presence of a solvent from 0 to
29. The method according to claim 28, carried out at a temperature of 100°C. 30. A process according to claim 28, wherein the reaction is carried out with hydrogen in the presence of palladium/charcoal. 31 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group, or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom, a methoxy group, or
together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ and R ₅ may be the same or different and represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; , R ₆ represents a methoxy group, R ₇ represents a methoxy group or a methylene dioxy group together with R ₆ , X represents a carbonyl group, and n represents a number of 2 or 3) A process for the preparation of novel substituted arylalkylamines and their pharmaceutically acceptable acid addition salts with inorganic or organic acids, comprising the general formula: A carbonyl compound represented by (wherein R ₅ to _{R 7} are as defined above) or its acetal or its ketal is represented by the general formula, (wherein R ₁ to R ₄ , X and n are as defined above) in the presence of catalytically activated hydrogen, and if desired, the resulting compound of the general formula A process consisting of conversion into a pharmaceutically acceptable acid addition salt with an inorganic or organic acid. 32 Reductive amination in the presence of a solvent from 0 to
32. The method according to claim 31, carried out at a temperature of 100<0>C. 33. A process according to claim 31, wherein the reaction is carried out with hydrogen in the presence of palladium/charcoal. 34 General formula (In the formula, R ₁ represents a hydrogen atom, a methyl group, or a phenyl group, R ₂ represents a hydrogen atom or a methoxy group, and R ₃ represents a hydrogen atom, a methoxy group, or
together with R ₂ represents a methylenedioxy or ethylenedioxy group, R ₄ represents an alkyl group having 1 to 3 carbon atoms, and R ₅ represents a hydrogen atom or 1
represents an alkyl group having ~3 carbon atoms,
R ₆ represents a methoxy group, R ₇ represents a methoxy group or
(together with R ₆ represents a methylenedioxy group, X represents a carbonyl group, and n represents a number of 2 or 3) and its pharmaceutical use with inorganic or organic acids A process for producing an acceptable acid addition salt, comprising alkylating a compound corresponding to the general formula as defined above except that R ₄ represents a hydrogen atom, and optionally converting the resulting compound of the general formula into an inorganic or is converted into a pharmaceutically acceptable acid addition salt with an organic acid.