FI61694B - FRAMEWORK FOR FRAMSTERING OF SUBSTITUTES WITH A BLOOD TRYCKET WITH A SHORT-BASED SAFETY NETWORK - Google Patents

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«R · W (11) UTLÄGGNINCSSKMfT 616 94 qgjgviR C Patent rnyonetty 10 09 1932 (45) Patent meddelat V v '(51) Kv.ik? /Int.ci.3 C O? D 209/46, 275/06 ENGLISH - EN N LAN D (21) PMunttlhukumu * - teMCUMaknlng 760k65 (22) HakamlipUvl - An * eknlnpd »g 2U.02.T6 (23) Initial procedure Got slipped - Bllvit offantllg 07.09.76

Ptenents and registries (44) NlhttvUulpVK> n,. KUuL | uik.i «.n date. _ 31.05.82

Patent · och registratyrelsen Antökan utlagd och utl.tkrifwn pubHcarmd (32) (33) (31) Requested «tuolkuui - Buslrd priority 06.03 .'7 5 23.I2.75, 23.12.75 Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2509797.6 , p 2558273.u, p 255827U.5 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, Biberach an der Riss, Federal Republic of Germany Tyskland (DE) (72) Wolfgang Eberlein, Biberach, Eberhard Kutter, Biberach, Joachim Hach , Warthausen, Volkhard Austel, Biberach, Rudolf Kadatz, Biberach, Willi Diederen, Biberach, Jiirgen Dämmgen, Warthausen, Federal Republic of Germany (DE), Walter Kobinger, Vienna, Christian Lillie, Vienna, Austria-Austria (ATU) (7U ) Leitzinger Oy (5U) Method for the preparation of substituted arylalkylamines having a hypotensive and heart rate lowering effect - Förfarande för framställning av substituerade arylalkylaminer med blodtrycket och hjärt-slagfrekvensen sänkande verkan

The present invention relates to a process for the preparation of substituted arylalkylamines having an antihypertensive and heart rate lowering effect and of formula I wherein R 1 is a hydrogen atom, a lower alkyl group or a phenyl group, 1 * 2 is a hydrogen atom, a chlorine atom or a methoxy group, or R 3 is a hydrogen group or together with the group R2, a methylenedioxy or ethylenedioxy group, R4 and R5, which may be identical or different, denote hydrogen atoms or lower alkyl groups,

Rg is a hydrogen atom or a lower alkoxy group, R7 is a lower alkoxy group or together with the group Rg a methylenedioxy or ethylenedioxy group, X is a carbonyl or sulfonyl group and 261694 n is an integer of 2 or 3, and their physiologically acceptable acid addition salts with inorganic or organic acids. with.

The groups R., R4 and R1. Suitable alkyl groups for the purposes of the definitions are, in particular, methyl, ethyl, propyl or isopropyl groups, and in the context of the definition of the groups R 1 and R 2, the alkoxy groups mentioned are, in particular, methoxy, ethoxy, propoxy or isopropoxy.

The compounds of the general formula I and their acid addition salts have valuable pharmacological properties, in particular a heart rate-lowering effect.

The novel compounds of the general formula I above can be prepared by the following methods: a) The compound of the general formula II "H .Rt 2χγ * \ 1 N- (CH2) nZ (II) R3 as above, and Z is a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group, is reacted with a phenylethylamine of the general formula III R, 1 f-k 6 HN-CH-CH ' , R 1, R 8 and R 7 have the same meaning as above.

The reaction is optionally carried out in a solvent, for example methanol, ether, tetrahydrofuran, methylformamide, dimethylformamide, dimethylsulfoxide or benzene, and suitably 61694 depending on the reactivity of the group Z at temperatures between -50 and 250 ° C. Preferably, an acid scavenger such as an alcoholate, an alkali hydroxide or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide is present.

b) For the preparation of compounds of general formula I in which R 1 is a hydrogen atom and X is a carbonyl group:

A compound of general formula IV -O * R30 is reduced in which R_, R_, R., Rr, R-, R_ and n have the same meaning as above.

2. j 4 o 6 /

The reduction is best carried out in a solvent such as glacial acetic acid, water or ethanol with suitably evolving hydrogen, for example zinc glacial acetic acid, stannous hydrochloric acid or stannous chloride hydrochloric acid, or catalytically activated hydrogen at temperatures between 0 and 250 ° C, but preferably between 50 and 50 ° C. and 100 ° C.

c) Phthalimidine H R of general formula V.

VA,, f

1] N- (CH2) n-N-H

R 3 in which R 1, R 2, R 1 and R 2 # X and n have the same meaning as above, is reacted with an aralkyl compound of the general formula VI (R

Rc, R1 and R have the same meaning as above, and Z is a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group.

The reaction is optionally carried out in a solvent, for example acetone, dimethylformamide, dimethyl sulfoxide, chlorobenzene or methylene chloride, suitably depending on the reactivity of the group Z at temperatures between 0 and 150 ° C. Preferably, an acid scavenger such as an alcoholate, an alkali metal hydroxide, an alkali metal carbonate or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide is present.

d) 1H-phthalimidine of general formula VII

TOILET

Cl 1 / R 3 wherein R 1, R 2, R 2 and X are as defined above is reacted with an alkylamine of general formula VIII. > (VIII) '5 2Λ ^ Α 5 7 wherein R4' R5 'R6' R7 3a n have the same meaning as above, and 61694 Z is a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group.

The reaction is optionally carried out in a solvent, for example acetone, dimethylformamide, dimethyl sulphoxide or methanol, and suitably, depending on the reactivity of the group Z, at temperatures between 0 and 150 ° C. Preferably, an acid scavenger such as an alcoholate, an alkali metal hydroxide, an alkali amide or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide is present.

e) For the preparation of compounds of general formula I in which X represents a carbonyl group:

The benzyl halide R1 * 2 1 ζΧ R3 cn of the general formula IX in which R1 to R3 have the same meaning as above, and

Hai is a chlorine, bromine or iodine atom, is reacted with an amine of general formula X R4

1 J ~ kH

H2N- (CH2) n-N-CH-CH2 -ί> (X) R5 "R7 wherein - R1 and n represent a sauna as above, and then the resulting 1-imino-phthalimidine is hydrolyzed.

61694

The reaction is optionally carried out in a solvent, for example acetone, ethanol, dimethylformamide, dimethyl sulphoxide or methylene chloride, and suitably at an elevated temperature, for example at a temperature between 50 and 150 ° C. An acid scavenger, for example an alcoholate, an alkali metal hydroxide, an alkali metal carbonate or a tertiary organic base such as diethylamine or pyridine, or a reaction accelerator such as potassium iodide is preferably present.

The hydrolysis in the next step is conveniently carried out in the presence of a base such as potassium carbonate or an acid such as hydrochloric acid in an aqueous medium such as ethanol / water or dioxane / water at a temperature between 50 ° C and the boiling point of the solvent used.

f) For the preparation of compounds of general formula I in which X represents a carbonyl group:

Benzyl halide of general formula XI

R I

CH - Hai (XI)

R3 'CO-Y

where

R1 to R3 have the same meaning as above,

Hai is a chlorine, bromine or iodine atom, and Y is a leaving group such as a chlorine, bromine, iodine atom, methoxy or phenoxy group is reacted with an amine of general formula X

R, R

1 f ~ X

H2N- (CH2) n-N-CH-CH2- <i (X) * 5 R7 where 'R) and n have the same meaning as above.

61694

The reaction is optionally carried out in a solvent, for example acetone, dimethylformamide, dimethyl sulphoxide or methylene chloride, and at a suitably elevated temperature, for example at a temperature between 50 and 150 ° C. Preferably, an acid scavenger such as an alcoholate, an alkali metal hydroxide, an alkali metal carbonate and a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide is present.

In this case, the benzamide amide derivative R1 of the general formula XII can be formed in situ

R2 I

> sCsyCH "A (xii)

/ ^^> C0B

R 3 wherein - R 2 is as defined above, one of A and B is as defined above for Hal or Y, and the other of A or B is as defined for f 4 -N- (CH 2 -N-CH-CH- - (>

i 2n i 2 \ -> E

wherein R 1 -R 2? and n have the same meaning as above, if desired, and then further reacted.

g) Phthalimidine aldehyde of general formula XIII 8 61 694 r2 HwRi

XV'N

IN - (CH 2) n 1 -CHO (XIII) R 3 wherein R 1, R 2, R 2, X and n are as defined above, or its acetal is reacted with an amine of general formula III> 4 tT ** hn-ch- ch2 - ^ ^ (I11) R7 R5 wherein R1 - R4 are as defined above, in the presence of catalytically activated hydrogen.

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

h) A carbonyl compound of the general formula XIV J ~ k * 6 R5 - CO - CH2-V. (XIV) R 7 where R 1 - R 2? mean the same as above, or its acetal or ketal is reacted with a phthalimidine of general formula V in the presence of catalytically activated hydrogen 61694

r VRl 2χ ^ \ I

f λ J * ~ (CH2) n-N-H (V) where R 1 - R 2, X and n have the same meaning as above.

The reductive amination is performed with hydrogen in the presence of a hydrogenation catalyst, for example hydrogen in the presence of palladium / carbon at 5 atm, in a solvent such as methanol, ethanol or dioxane, and at temperatures between 0 and 100 ° C, but preferably at 20-80 ° C.

If one of the processes a to h gives a compound of general formula I in which a hydrogen atom is present, this can be alkylated, for example by reaction with the corresponding alkyl halide or dialkyl sulphate, or methylated by reaction with formaldehyde / formic acid.

The compounds of the general formula I obtained can be converted into their physiologically acceptable salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid and maleic acid.

The compounds of the general formula II to XIV used as starting materials can be prepared by methods known per se. Thus, for example, a phthalimidine of the general formula V or a 1H-phthalimidine of the general formula VII is obtained by reduction of the corresponding phthalimide with zinc powder in glacial acetic acid and, if appropriate, subsequent alkylation.

The benzyl halide of general formula IX or XI is best obtained by halogenating the corresponding toluene, for example with N-bromosuccinimide in carbon tetrachloride, optionally with the addition of a radical-generating agent such as dibenzoyl peroxide and / or by UV irradiation.

As already mentioned above, the new compounds of the general formula I and their acid addition properties have valuable pharmacological properties, in addition to a mild antihypertensive effect and a selective heart rate-lowering effect.

For example, the biological properties of the following compounds were studied: A = 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methylamino] propyl) phthalimidine hydrochloride, B = 5.6- Dimethoxy-2- (3- [2- (3,4-dimethoxy) -phenylethyl-methylamino] -propyl) -1,2-benzisothiazoline-1,1-dioxide-hydrochloride, C = 5,6-methylenedioxy -2N- (3- / 2- (3,4-methylenedioxy) -phenylethylmethylamino-7-propyl) -phthalimidine hydrochloride, D = 5,6-dimethoxy-2N- (3- / 2- (3,4-methylenedioxy) ) -phenylethylmethylamino (7-propyl) phthalimidine hydrochloride, and E = 5,6-ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride .

1. Effect on heart rate of narcotic guinea pigs:

The heart rate of guinea pigs under urethane anesthesia was recorded on an electrocardiogram. Test substances were administered in increasing doses ranging from 0.5 to 20 mg / kg i.v.

The following table shows the changes in heart rate: 616 9 4

Compound Dose n Decrease in heart rate in mg / kg as a percentage i. V.

0.5 3 -23.5 1.0 3 -36.1 2.0 3 -47.2 A 5.0 3 -51.6 10.0 3 -59.1 20.0 3 -67.2 0.5 5 - 9.8 1.0 5 -20.0 2.0 5 -27.4 B 5.0 5 -37.6 10.0 5 -46.9 20.0 5 -53.9 2. Effect on guinea pig heart rate

Isolated spontaneously striking atria of guinea pigs of either sex weighing 300 to 400 g were examined in an organ bath in tyrodi solution. The nutrient solution was treated with carbogen (95% O + + 5% (X 2)) and maintained at a constant temperature of 30. Contractions were recorded isometrically with strain gauge strips on a Grass polygraph. Test substances were added to the organ baths to a final dilution of 10 5 g / ml.

The following table shows the percentage decrease in heart rate as the mean of the atrium at a compound concentration of 10 μg / ml.

61 694 12

Compound Decrease in heart rate,% A - 52 C - 60 D - 51 E - 48 3. Acute toxicity:

The acute toxicity of test compounds was determined in mice (observation period: 14 days) after oral or intravenous administration. The LD50 value was calculated from the percentage of animals that died at pre-doses within the observation period (see

J. Pharmacol, exp. Therap. 9_6, 99 (1949)):

Compound LDr ^ 50 A 98 mg / kg i.v.

A 1570 mg / kg p.o.

B 100 mg / kg i.v.

For pharmaceutical use, the compounds of the general formula I and their physiologically acceptable acid addition salts, optionally in combination with other active ingredients, can be processed into customary galenic preparations, such as tablets, granules, powders, suspensions, solutions or suppositories. The single dose is then 20 to 300 mg, preferably 25 to 200 mg.

The following examples further illustrate the invention: 616 94

Example 1 2N- (3- [1- (3,4-Dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride) 2N- (3- [2- (3,4-dimethoxy) -phenylethyl) methylamino / propyl) phthalimide 5.04 g (0.02 moles) of 1- [2- (3,4-dimethoxyphenyl) ethylmethylamino] -3-aminopropane and 2.06 g (0, 02 moles) of phthalic anhydride is dissolved in 100 ml of glacial acetic acid and heated at reflux for 4 hours. It is then evaporated in vacuo, the residue is taken up in chloroform and the chloroform solution is washed successively with saturated sodium hydrogen carbonate solution and water. After drying over sodium sulfate, the solvent is distilled off to give the desired compound as an amorphous product.

Yield: 6.1 g (79.8% of theory),

Rf value (benzene / acetone = 1/1): 0.4.

b.) 2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride to 6.1 g (159 mmol) of 2N- (3- [2- (3,4- dimethoxy) -phenylethylmethylamino / propyl-7-phthalimide dissolved in 80 ml of glacial acetic acid, 10 g of zinc powder are added and the mixture is reduced by refluxing for 3 hours. saturated sodium carbonate solution and water, dried over sodium sulfate and evaporated, The crude product is purified by chromatography on silica gel (chloroform / methanol = 19/1).

Yield: 2.25 g (35% of theory).

Example 2 14 61 6 9 4 5.6-Dimethoxy-2N- (3- [2 - (, 3-dimethoxy) -phenylethylmethylamino] 2N- (3- [2- (3,4-Dimethoxy) -phenylethyl-methylamino] -propyl) -phthalimide__

Prepared according to Example 1a by condensing 4,5-dimethoxy-phthalic anhydride with 1- [2- (3,4-dimethoxy-phenyl) -ethylmethyl-amino] -3-aminopropane in glacial acetic acid.

Melting point: 91-93 ° C.

b.) Prepared according to Example Ib by reduction of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methylamino] -propyl) -phthalimide with zinc powder in glacial acetic acid.

Melting point: 170-172 ° C.

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-7-propyl) -phthalimide_______________________________________

Prepared according to Example 1a by condensing 4,5-dimethoxy-phthalic anhydride with 1- [2- (3,4-dimethoxy-phenyl) -ethylamino] -3-aminopropane in glacial acetic acid.

Rf value (chloroform / methanol = 9/1): 0.25.

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

Prepared according to Example Ib by reduction of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylamino] propyl) phthalimide with zinc powder in glacial acetic acid.

Melting point: 207-209 ° C.

1 ».h \

Example 4 5,61694 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride 5 g (12.1 moles) of the compound obtained in Example 3 and a mixture thereof, containing 1.38 g (30 mmol) of formic acid and 1.5 g (20 mmol) of formalin are heated at 100 ° C for 1 hour. After cooling, the reaction mixture is made alkaline by adding 2N sodium hydroxide, extracted with chloroform and the chloroform phase is washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel (chloroform / methanol = 45/1), the main fraction is evaporated and the base is precipitated as the hydrochloride with ethereal hydrochloric acid.

Melting point: 170-172 ° C.

Example 5 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-N-propylamino] -7-propyl) -phthalimidine hydrochloride

To a solution of 25 g (5.5 mmol) of 5,6-dimethoxy-2N- (3 / 2- (3,4-dimethoxy) -phenylethylamino] propyl) -phthalimidine in 100 ml of acetone is added 20 ml of 1-bromopropane and 5 g of potassium carbonate, followed by heating at reflux for 6 hours. After cooling, the solids are filtered off and the filtrate is evaporated. Take up in ether, separate the insolubles by filtration and, after evaporation, precipitate the hydrochloride with ethereal hydrochloric acid.

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 N- (2-bromoethyl) ) phthalimide and 6 g of 3,4-dimethoxyphenylethyl-N-methylamine are heated at reflux in 40 ml of xylene for 10 hours. After evaporation in vacuo! ' The oily residue obtained is converted without purification into the desired compound 61 694 16 by reduction with zinc powder in glacial acetic acid according to Example Ib. Melting point: 149-151 ° C.

Example 7 2N- (3- / 2- (3,4-Dimethoxy) -phenylethylmethylamino] propyl) -3-phenyl-phthalimidine__ 1.75 g (5.3 mmol) of N- (3-bromopropyl) -3-phenyl -phthalimidine and 2.06 g (10.6 mmol) of 3,4-dimethoxyphenylethyl-N-methylamine are heated at reflux in 30 ml of xylene for 10 hours. After cooling, evaporate and chromatograph on silica gel (chloroform / methyl alcohol = 19/1). The base is obtained as a viscous oil.

Rf value (chloroform / methanol = 19/1): 0.4.

Example 8 3-Phenyl-5-chloro-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -1,2-benzisothiazoline-1,1-dioxide hydrochloride 1 2 3 g (9.3 mmol) of N- (3-chloropropyl) -3-phenyl-5-chloro-1,2-benzisothiazoline-1,1-dioxide, 3 g of 3,4-dimethoxyphenylethyl-N-methylamine and a spatula tip potassium iodide is heated at reflux for 3 hours in a solution of 30 ml of dimethylformamide and 5 ml of triethylamine. After evaporation to dryness, the residue is taken up in chloroform and the organic phase is washed several times with water. After drying, it is evaporated and the residue is chromatographed on silica gel (chloroform / methanol = 40/1). Precipitation with ethereal hydrochloric acid gives the hydrochloride as an amorphous product.

Rf value (chloroform / methanol = 19/1): 0.5.

C27H31ClN2O4S x HCl <551/54

Calc .: C 58.8 H 5.60 N 5.10 S 5.80

Found: C 58.7 H 5.75 N 5.20 S 5.90 616 94

Example 9 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -1,2-benzisothiazoline-1,1-dioxide hydrochloride (a) 2-methyl -4,5-Dimethoxy-benzenesulfochloride 23.2 g (0.2 mol) of 3,4-dimethoxy-toluene are slowly added dropwise to 15.2 g (0.1 mol) of stirring and cooling at about -10 ° C. chlorosulfonic acid. After the addition, allow to warm to room temperature and stir until the evolution of hydrogen chloride has ceased.

The reaction mixture is added to ice and the separated sulfochloride is extracted with ether. The organic phase is washed successively with sodium bicarbonate solution and water and evaporated to dryness in vacuo. The residue is a solid oil which solidifies on cooling.

Rf value (benzene): 0.5.

b) 2-Methyl-4,5-dimethoxy-benzenesulfonamide 18 g (0.07 mol) of the compound obtained in Example 9a are suspended in 200 ml of concentrated ammonia and stirred for 4 hours at room temperature. Separate by suction, wash once more with water to give the desired sulfonamide as an amorphous product after drying. Rf value (benzene / acetone = 1/1): 0.6.

o) 5,6-dimethoxy-1,2-benzisothiazolin-3-one 1,1-dioxide 16 g (0.08 mol) of 2-methyl-4,5-dimethoxybenzenesulphonamide are dissolved in 500% sodium hydroxide, 39.6 g (0.25 mol) of potassium permanganate are added and the mixture is heated at reflux for 2 hours. After cooling, it is filtered through celite and the desired product is precipitated by adding 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 and 3.3 g (865 mmol) of lithium aluminum hydride are heated at reflux in 400 ml of tetrahydrofuran for 2 hours. After cooling, the excess lithium aluminum hydride is evaporated off by adding 18,61694 ethyl acetate, diluted with water and then 2N hydrochloric acid is added until the aluminum hydroxide precipitate dissolves. The reaction solution is extracted with ethyl acetate, and the organic phase is washed with water and dried. Evaporate in vacuo, triturate the residue with ether and remove the compound by suction.

e) N- (3-chloropropyl) -5,6-dimethoxy-1,2-benzisothiazoline-1,1-dioxide 2.4 g (10.5 mmol) of the compound obtained in Example 9d are dissolved in a mixture of 14 ml of 2.5- sodium hydroxide and 30 ml of ethanol, 10 ml of 3-bromo-1-chloropropane are added and the mixture is refluxed for 8 hours. The reaction mixture is evaporated to half volume, diluted with water and extracted with chloroform. After drying the organic phase, it is evaporated in vacuo to give the desired product as a viscous oil.

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

f) 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] propyl) -1,2-benzisothiazoline-1,1-dioxide-hydrochloride

Prepared according to Example 8 by reacting N- (3-chloropropyl) -5,5-dimethoxy-1,2-benzisothiazoline-1,1-dioxide with 3,4-dimethoxyphenylethyl-N-methylamine.

Melting point: 196-198 ° C (acetone).

Example 10 5,6-Methylenedioxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride a) 4,5-methylenedioxy-2N- (3- / 2- (3,4-Dimethoxy) -phenylethyl-methylamino-7-propyl) -phthalimide_ 3.5 g (18 mmol) of 4,5-methylenedioxy-phthalic anhydride and 4.5 g (18 mmol) of 1- [3- (3,4- dimethoxy-phenyl) -ethylmethyl-amino-3-aminopropane is heated at reflux for 2 hours in 100 ml of glacial acetic acid. It is then evaporated in vacuo, the residue is taken up in chloroform and the chloroform solution is washed successively with saturated sodium hydrogen carbonate solution and water. After drying over sodium sulfate, the solvent is distilled off to give the desired compound 61,694,19 as an amorphous product.

Yield: 4.8 g (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_

To a solution of 4.8 g (11 mmol) of 5,6-methylenedioxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimide in 40 ml of glacial acetic acid is added 5 g of zinc powder. and refluxed for 2 hours. After the reaction, the zinc powder is separated from the hot solution by filtration and the filtrate is evaporated in vacuo. The residue is then dissolved in chloroform and the chloroform phase is shaken with saturated sodium carbonate solution and water, dried over sodium sulfate and evaporated. The residue is dissolved in chloroform and the hydrochloride is precipitated by adding ethereal hydrochloric acid. The melting point of the hydrochloride is 237-239 ° C.

Yield: 1.5 g (30% of theory)

Calc .: C 61.53 H 6.51 N 6.24 Cl 7.90

Found: C 61.50 6.49 6.24 7.85

Example 11 5,6-Ethylenedioxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride__ a) 4,5-Ethylenedioxy-2N- (3- / S- (3,4-dimethoxy) -phenylethyl-methyl-amino7-propyl) -ftalimidi_

Prepared according to Example 10a by condensing 4,5-ethylenedioxy-phthalic anhydride with 1- [N- (3,4-dimethoxy-phenyl) -ethylmethylamino] -3-aminopropane in glacial acetic acid.

Rf value (chloroform / methanol = 9/1): 0.5.

616 9 4 20 b) 5,6-Ethylenedioxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride__

Prepared according to Example 10b by reduction of 4,5-ethylenedioxy-2N- (3- / 2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) phthalimide with zinc powder in glacial acetic acid.

Melting point: 208-210 ° C

Calc .: C 62.26 H 6.75 N 6.05 Cl 7.66

Found: 62.10 6.84 5.90 7.67.

Example 12 5,6-Methylenedioxy-2N- (3- / 5- (3,4-methylenedioxy) -phenylethyl-methylamino-7-propyl) -phthalimidine hydrochloride) 4,5-Methylenedioxy-2N- (3- / 2- (3,4-Methylenedioxy) -phenylethyl-methylamino-7-pgopyl) -phthalimide 2.7 g (10 mmol) of 4,5-methylenedioxy-N- (3-chloropropyl) phthalimide and 1.8 g (10 mmol) ) 3,4-Methylenedioxyphenylethyl-N-methylamine is dissolved in 20% chlorobenzene, 2.8 g (20 mmol) of powdered potassium carbonate are added and the mixture is refluxed for 8 hours. The solution is then filtered and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (chloroform / methanol = 19/1) to give, after evaporation of the main fraction, 2.1 g (51% of theory). Rf value (chloroform / methanol = 9/1): 0.6.

b) 5,6-Methylenedioxy-2N- (3- / 2- (3,4-methylenedioxy) -phenylethyl-methylamino-7-propyl) -phthalimidine hydrochloride

Prepared according to Example 10b by reduction of 4,5-methylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) phthalimide with zinc powder in glacial acetic acid.

Melting point: 206-208 ° C.

Calc .: C 61.04 H 5.82 N 6.47 Cl 8.19

Found: 61.10 6.07 6.74 8.45 6ο 616 94

Example 13 21 5,6-Ethylenedioxy-2N- (3- / 2- (3,4-methylenedioxy) -phenylethylmethylamino-7-propyl) -phthalimidine hydrochloride) 4,5-Ethylenedioxy-2N- (3- / 2- ( 3,4-Methylenedioxy) -phenylethylmethylamino-7-propyl) -phthalimide_

Prepared according to Example 12a by reacting 4,5-ethylenedioxy-N- (3-chloropropyl) phthalimide with 3,4-methylenedioxyphenylethyl-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) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride

Prepared according to Example 10b by reduction of 4,5-ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) phthalimide with zinc powder in glacial acetic acid.

Melting point: 180-182 ° C.

Calc .: C 61.81 H 6.09 N 6.27 Cl 7.93

Found: 61.70 6.12 6.12 7.94

Example 14 5,6-Dimethoxy-2N- (3- [2-O-4-methylenedioxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride a) 4,5-Dimethoxy-2N- (3- [2- 3,4-Methylenedioxy) phenylethyl-methylamino-7-propyl) phthalimide

Prepared according to Example 12a by reacting 4,5-dimethoxy-N- (3-chloropropyl) phthalimide with 3,4-methylenedioxyphenylethyl-N-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) phenylethylmethylamino] -propyl) phthalimidine- hydrokloridi_______

Prepared according to Example 10b by reduction of 4,5-dimethoxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethyl-methylamino] -propyl) -phthalimide with zinc powder in glacial acetic acid.

Melting point: 235-237 ° C.

Calc .: C 61.53 H 6.51 N 6.24 Cl 7.90

Found: 61.45 6.63 6.27 7.92

Example 15 5.6-Ethylenedioxy-2- (3- {2- (3,4-dimethoxy) -phenylethyl-methylamino] -propyl) -1,2-benzisothiazoline-1,1-dioxide-hydrochloride

Prepared according to Example 12a by reacting N- (3-chloropropyl) -5,5-ethylenedioxy-1,2-benzisothiazoline-1,1-dioxide with 3,4-dimethoxyphenylethyl-N-methylamine.

Rf value (chloroform / methanol = 9/1): 0.6.

Example 16 3-Methyl-5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride

Prepared according to Example 12a by reacting 3-methyl-5,6-dimethoxy-N- (3-chloropropyl) phthalimidine with 3,4-dimethoxyphenylethyl-N-methylamine in chlorobenzene in the presence of potassium carbonate.

Melting point: 135-136 ° C

Calc .: C 62.68 H 7.36 N 5.85 Cl 7.40

Found: 62.31 7.40 5.80 7.12

Example 17 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenyl-isopropyl-methylamino / propyl) -phthalimidine hydrochloride) 4,5-Dimethoxy-2N- (3- [2- (3,4-Dimethoxy) -phenyl-isopropyl-methyl-amino-7-propyl) -phthalimide ____

Ct .. · '' 61694

Prepared according to Example 12a by reacting 4,5-dimethoxy-N- (3-chloropropyl) phthalimide with 3,4-dimethoxy-phenyl-isopropyl-N-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) -phenyl-isopropyl-methyl-amino] -propyl} -N-propyl}

Prepared according to Example 10b by reduction of 4,5-dimethoxy-2N-3- [2- (3,4-dimethoxy) -phenylisopropylmethylamino] -propyl) -phthalimide with zinc powder in glacial acetic acid.

Melting point: 183-185 ° C

Calc .: C 62.68 H 7.36 N 5.85 Cl 7.40

Found 62.50 7.42 5.92 7.30

Example 18 5,6-Methylenedioxy-2N- (2- [2- (3,4-dimethoxy) -phenylethylmethylamino] -ethyl) -phthalimidine hydrochloride) 4,5-Methylenedioxy-2N- (3- [2- (3,4-Dimethoxy) -phenylethyl-methylamino] -ethyl) -phthalimide__

Prepared according to Example 10a from 4,5-methylenedioxy-phthalic anhydride and 1- [2- (3,4-dimethoxy-phenyl) -ethylmethylamino] -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

Prepared according to Example 10b by reduction of 4,5-methylenedioxy-2N- (2- [2- (3,4-dimethoxy) -phenylethyl-methylamino] -ethyl) -phthalimide with zinc powder in glacial acetic acid.

Rf value (chloroform / methanol = 9: 1): 0.4.

Example 19 24 61 694 5.6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl-phthalimidine hydrochloride 5.3 g (0.02 mol) 5,6-dimethoxy -N- (2-N-methylamino) -propyl-phthalimidine, 4.0 g (0.02 mol) of 3,4-dimethoxy-phenylethyl chloride and 4.2 g of potassium carbonate are heated at reflux for 5 hours in 100 ml of chlorobenzene. 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 the hydrochloride is precipitated by adding ethereal hydrochloric acid.

Melting point: 170-172 ° C.

Example 20 5.6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methylamino] -7-propyl-phthalimidine hydrochloride

To a solution of 3.0 g (15 mmol) of 5,6-dimethoxy-phthalimidine in 100 ml of dimethylformamide is added 0.5 g of sodium hydride and then heated at 80 ° C for 30 minutes. 8.5 g (30 mmol) of 1- [2- (3,4-dimethoxy-phenyl) -ethylmethylamino] -3-chloropropane dissolved in 100 g of dimethylformamide are then added dropwise and the mixture is heated at 140 [deg.] C. for 7 hours. After cooling, add water and shake several times with chloroform. The organic phases are dried and evaporated to dryness in vacuo. The crude product is purified by column chromatography on silica gel. The hydrochloride is obtained by mixing with ethereal hydrochloric acid.

Melting point: 170-172 ° C.

Example 21 5.6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride__ 1.45 g (5 mmol) of 2-bromomethyl-4,5- dimethoxybenzoic acid methyl ester, 2.52 g (10 mmol) of 1- [2- (3,4-dimethoxyphenyl) - ** 25 61 694 ethyl methylamino] -3-axninopropane and 3 g of potassium carbonate are heated at reflux for 4 hours at 200 ml of methyl ethyl ketones. After cooling, the insolubles are filtered off and the filtrate is evaporated in vacuo. The crude product is purified by chromatography on silica gel (chloroform / methanol = 19/1). The hydrochloride is obtained by precipitation with ethereal hydrochloric acid. Melting point: 170-172 ° C.

Example 22 5,6-Dimethoxy-2N- (3- [5- (3,4-dimethoxy) -phenylethyl-methylamino] -propyl) -phthalimidine hydrochloride) 1- [2- (3,4-dimethoxy-phenyl)] -ethylmethylamino-3- (1-imino-5,6-dimethoxy-phthalimidin-2-yl) -propane-6.4 g (0.025 mol) of 2-cyano-4,5-dimethoxy-benzyl bromide and 6.3 g (0.025 mol) of 1- [5- (3,4-dimethoxy-phenyl) -ethylmethylamino] -3-aminopropane is heated at reflux for 6 hours in 80 ml of ethanol. After cooling, the solvent is removed in vacuo and the crude product is used without purification in reaction step b).

Rf value: (chloroform / methanol = 19/1): 0.5.

b) 5,6-Dimethoxy-2N-3- [5- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride 5 g 1- [2- (3,4-dimethoxy-phenyl) Ethyl methylamino-3- (1-imino-5,6-dimethoxy-phthalimidin-2-yl) -propane and 11 g of potassium carbonate are heated at reflux for 8 hours in a mixture of 50 ml of ethanol and 80 ml of water. Evaporate in vacuo and purify the crude product by chromatography on silica gel (chloroform / methanol = 19/1). The evaporated fractions give the free base, which is precipitated from acetone as the hydrochloride with ethereal hydrochloric acid.

Melting point: 170-172 ° C.

,

Example 23 26 6 1 6 9 4 5.6-Dimethoxy-2N- (3- / 5- (3,4-dimethoxy) -phenylethylamine-7-propyl) -phthalimidine hydrochloride

To a solution of 2.6 g (10 mmol) of 1-amino-3- [N- (5,6-dimethoxy-phthalimidine) .7-propane and 1.8 g (10 mmol) of 2- (3,4- dimethoxyphenyl) acetaldehyde, 0.3 g of palladium / carbon (10%) are added and hydrogen is introduced over 4 hours at a pressure of 5 atm and a temperature of 50 ° C. After uptake of hydrogen, the catalyst is filtered off and the solution is evaporated in vacuo. The hydrochloride is obtained by precipitation with ethereal hydrochloric acid.

Melting point: 207-209 ° C.

Example 24 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylamino] -propyl) -phthalimidine hydrochloride

To a solution of 3.2 g (10 mmol) of 3- [N- (5,6-dimethoxy-phthalimidine) -7-propionaldehyde diethyl acetal and 1.8 g (10 mmol) of 3,4-dimethoxy-phenylethylamine in 100 ml: 0.3 g of palladium / carbon (10%) are added and hydrogen is introduced over a period of 4 hours at a pressure of 5 atm and a temperature of 50 [deg.] C. After cessation of water consumption, the catalyst is filtered off and the solution is evaporated in vacuo to give the hydrochloride. - 209 ° C.

The following compounds were further prepared according to Examples 19-24: 2N- (3- / 2- (3,4-dimethoxy) -phenylethyl-methylamino-propyl) -phthalimidine hydrochloride Melting point: 146-148 ° C.

5.6-Dimethoxy-2N- (3- [5- (3,4-dimethoxy) -phenylethylamino] -propyl) -phthalimidine hydrochloride

Melting point: 207-209 ° C.

27 61 694 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, 7-ethyl) phthalimidine hydrochloride

Melting point: 149-151 ° C.

2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -3-phenylphthalimidine Rf value (chloroform / methanol = 19/1): 0.4.

3-Phenyl-5-chloro-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -1,2-benzisothiazoline-1,1-dioxide hydrochloride (chloroform / methanol = 19/1): 0.5.

5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -1,2-benzisothiazoline-1,1-dioxide hydrochloride Melting point: 196-198 ° C ( acetone).

5.6-Methylenedioxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methyl-amino] -7-propyl) -phthalimidine hydrochloride

Melting point: 237-239 ° C.

<5,6-Ethylenedioxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methyl-amino] -7-propyl) -phthalimidine hydrochloride

Melting point: 208-210 ° C.

5.6-Methylenedioxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethylmethylamino] -propyl) -phthalimidine hydrochloride Melting point: 206-208 ° C.

5.6-Ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethyl-methyl-amino] -7-propyl) -phthalimidine hydrochloride

Melting point: 180-182 ° C.

5.6-Dimethoxy-2N- (3- [2- (3,4-methylenedioxy) -phenylethyl-methylamino] -propyl) -phenidine dihydrochloride

Melting point: 235-237 ° C.

'7'. ' 28 61694 5.6-Ethylenedioxy-2- (3- [2- (3,4-dimethoxy) -phenylethylmethylamino] -propyl) -1,1-benzisothiazoline-1,1-dioxide hydrochloride Rf value ( chloroform) methanol = 9/1): 0.6.

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- [5-) 3,4-dimethoxy) -phenyl-isopropyl-methyl-amino-7-propyl) -phthalimidine hydrochloride

Melting point: 183-185 ° C.

Example A

Tablets containing 100 mg of 5,6-dimethoxy-2N- (3- / 2- (3,4-dimethoxy) -phenylethylmethylamino / propyl) -phthalimidine hydrochloride

With darkness:

Active ingredient 100.0 mg

Milk sugar 50.0 mg

Polyvinylpyrrolidone 50.0 mg

Carboxymethylcellulose 19.0 mg

Magnesium stearate 1.0 mg 175.0 mg

Manufacturing methods:

The active ingredient and milk sugar are uniformly moistened with an aqueous solution of polyvinylpyrrolidone and granulated. After drying, the granulate is mixed with other substances and the mixture is compressed into tablets in the usual way.

Example B

Drug granules containing 50 mg of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride, 1 core of the drug granule contains: '' k.

") 61 694 29

Active ingredient 50.0 mg

Corn starch, dried 20.0 mg

Soluble starch 2.0 mg

Carboxymethylcellulose 7.0 mg

Magnesium stearate 1.0 mg 80.0 mg

Method of preparation:

The mixture is made according to Example A into cores of drug granules, which are then granulated with sugar and acacia.

Example C

Suppositories containing 150 mg of 5,6-dimethoxy-2N- (3- / 2- (3,4-dimethoxy) -phenylethylmethylamino / propyl) “phthalimidine hydro-

Composition:

Active ingredient 150.0 mg Medicinal suppository mass 1550.0 mg 1700.0 mg

Method of preparation:

The active ingredient is mixed and suspended evenly in the molten medicated swab mass and the liquid mixture is poured into cooled medicated swab molds.

Example D

Suspension containing 250 mg of 5,6-dimethoxy-2N- (3 - ['2- (3,4-dimethoxy) -phenylethylmethylamino] propyl) -phthalimidine hydrochloride pro 5 ml 100 ml of suspension contains: 30 61 6 9 4

Active ingredient 5.0 g

Carboxymethylcellulose 0.1 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g

Sugar 10.0 g

Glycerin 5.0 g

Sorbitol solution 70% 20.0 g

Aromas 0.3 g

Distilled water ad 100.0 ml

Method of preparation: p-Hydroxybenzoic acid methyl ester and propyl ester and glycerin and carboxymethylcellulose are dissolved in distilled water heated to 70 ° with stirring. The solution is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After the addition and dissolution of the sugar, sorbitol solution and flavor, the suspension is evacuated with stirring to remove air. 1 ml of suspension contains 250 mg of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) -phenylethyl-methylamino] -propyl) -phthalimidine hydrochloride.

Claims (2)

A process for the preparation of substituted arylalkylamines having a hypotensive and heart rate lowering effect and having the formula I is (pb 1 -N-nrOC R 3 R 7 wherein R 1 is a hydrogen atom, a lower alkyl group or a phenyl group, I 2 is a hydrogen atom, a chlorine atom or a methoxy group, R 3 is a hydrogen atom or a methoxy group or together with the group R 2 a methylenedioxy or ethylenedioxy group, R 4 and R 5, which may be the same or different, denote hydrogen atoms or lower alkyl groups, R 8 is a hydrogen atom or a lower alkoxy group, R 7 is a lower alkoxy group or together with the group Rg a methylenedioxy or ethylenedioxy group, X is a carbonyl or sulfonyl group and n is a number 2 or 3, and their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a.) a compound of the general formula II 61 694 32 H 2 N- (CH 2) -Z (II) R 3 wherein R 1, R 2, R 1, X and n are as defined above and Z is a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group, reacting with phenylethylamine of general formula III Ry1-Ry- 'J ~ X hn-ch-ch9- \ 7 dii) I \ = XR R57 wherein Ry, R_, R1 and R_ have the same meaning as above, or b.) to prepare compounds of general formula I in which R 1 is a hydrogen atom and X is a carbonyl group, reducing a compound of general formula IV 0 (CH 2) 6 (IV) 10 wherein R 2 'R 3' R 4 'R 5' R 6 'R 7 n have the same meaning as above, or c. ) a phthalimidine of general formula V 33 61 694 ysX '* OT N- (CH2) nNH (V) R3 in which R1, Ry Rj, X and the same as above are reacted with an aralkyl compound of general formula VI // V R6 z-ch -ch 2 - / Q (VI) R 5 R 7 wherein R 1, R 8 and R 2 are as defined above, and Z is a leaving group such as a chlorine, bromine or iodine tower, an alkylsulfonyloxy or arylsulfonyloxy group, or d.) according to general formula VII 1H-phthalimidine H Rx (vii> UA / R3 wherein R1 # R2 'R3 X are as defined above is reacted with an alkylamine of general formula VIII.> 34616 9 4 r4 1 f / 5c 6 (viii) Z- (CHO) -N-CH-CH- - / v) I \ J (, R5 wherein R1, R4, R8, R., and n are as defined above, and Z is a leaving group such as chlorine, bromine - or an iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group, or e.) for the preparation of compounds of the general formula I in which X is a carbonyl group, a benzyl of the general formula IX ihalo-genid R1 * 2 ^ 1 - Hai | (IX) R CN R 3 wherein R 1, R 2 and R 2 are as defined above, and Hal is a chlorine, bromine or iodine atom, is reacted with an amine of general formula X R 1 - H 2 N - (CH 2) n N -CH-CH 2 (X) R 5 R 7 wherein R 4 'R 5' R 6 / * 9 3a n have the same meaning as above, and the resulting 1-imino-phthalimidine is hydrolysed, or f.) For the preparation of compounds of general formula I in which X represents a carbonyl group, of general formula XI benzyl halide · '· * ·, 35 61 694 Ri Ro I D'CH · Hal v co-y R3 wherein R1 ·' R3 execute the same. as above, Hal is a chlorine, bromine or iodine tower, and Y is a leaving group such as a chlorine, bromine, iodine atom, methoxy or phenoxy group, is reacted with an amine of general formula X r4___R6 H2N- (CH2) nN- CH-CH 2 - (x) R 5 R 7 wherein R 4, R 1, R 8 and R 2 are as defined above, or g) phthalimidine aldehyde HR of the general formula XIII, N - (CH) 4 -CHO (XIII ) R 1, R 2, R 2, X and n are as defined above, or its acetal is reacted in the presence of catalytically activated hydrogen with an amine of general formula III f 4 H - N - CH - CH 2 - <( iii) R 5, R 5, R 8 and R 7 are as defined above, or h) a carbonyl compound of the general formula XIV * 6 R 5 - CO - CH 2 - (XIV) R 7 wherein R 5, R 8 and R 7 have the same meaning as above, or its acetal or ketal is reacted with a phthalimidine of the general formula V in the presence of catalytically activated hydrogen H R 1 R V V R 4 I XN “<CH 2> nNH (V) R3 wherein R1, R2, ^ 3 »R4F X and n have the same meaning as above, and if desired, if methods ah give a compound of general formula I in which R4 represents a hydrogen atom, these are alkylated and / or obtained The compound according to claim 1 is converted with an inorganic or organic acid into a physiologically acceptable acid addition salt. 37 6169 4 For the preparation of a substituent on an arylalkylamine up to a mixture with a high frequency and a high frequency, the first of which is represented by the formula I R3 5 7 for which R1 is an unsubstituted group, an alkyl group or a phenyl group R3 is a substituent or a methoxy group or a substituent of the group R2 and a methylenedioxy or ethylenedioxy group, R4 and R5, which may be a residue or an alkyl atom, an alkyl atom or a alkyl group, Rg a hydrogen atom or an alcohol group, R7 is an alkoxy group tillsammans med Gruppen Rg en methylyldioxi- ellet ethylenedioxygupp, X avser en carbonarbon- eller sulfonylgroup och n avser talet 2 eller 4 velt deras physiologiskt warmpliga syra-additionsalter med oograniska eller organiska syror, kanne-t ecknat därav, pict a) för formula li 38 61 6 9 4 II (II) * 3 for R 1, R 2, R 2, X and the same as in the case of Z and a group having a chlorine, bromine or iodine atom, an alkyl, a sulphonyloxy or an aryl-ulfonyloxy group, a ring or a reactant with a phenylamine having the formula III f4 // \ U Ii-U-CH-CH2-V ^ 7 (III) ^ 5 Rj is R4, R, R ^ oc and Ry are further selected from the group consisting of or b.) For the preparation of a compound having all of the formulas I, which is an optional atom and X is a carbonyl group, reducing the form of the lower form IV 0 f4 / TV'6 |] <CH2) nM-ClI-CH2- <> (IV) 0 is R2, R1, R4, R1, R8, Ry and a third of the same, or c. ) and the phthalitride is all of the form V 39 61 694 H: <2> V <| K- (CII2) n-ii-n (V) R3 is R3, F2, R3, R3, X and N are selected from the group consisting of radicals having an aralkyl derivative of formula VI // V R8 -ch-ch2 — C} (VI) 4 ^ - = - ^ r7 for Rj-, Ιίβ och and R7 are selected from the group consisting of, and Z is selected from the group consisting of chloro, bror.i-. -11 or an atom, an alkylsulfonyloxy or an arylsulfonyloxy group, or d.) And 1H-phthalimidine with the formula VII HR R2, VvX or R1, R2, R3 and X are decimated, the ring is reacted with an alkylamine with the formula VIII f Z- (CII9) -N-CH-CH0 - {f N) 1 2λ = Α (V1II) R5 7 40 61 694 for R4, R5, Rg, R7 and other decamma of tidigare, och 7, avser en avlägsnande grupp, säsom en chlor-, bromo- eller iodatom, en alkylsulfonyloxi- eller arylsulfonyloxygroup, eller e. benzyl halides with all the compounds of formula IX R2 "are" R3 for R1, R2 and R3 with the decomposition of chlorine, bromine or iodine, with the aid of the reactants with the amine of the formula X H2N- <cH2 ) n- ^ H-CH2-VQ ^ (X) R5 \ ^ R7 to R4, R5, R8, R7 and the same as the first, and preferably 1-iminophthalimized hydrolysers, or f.) for The reaction of a compound of the formula I, with X being a carbonyl group, with benzyl halides of the formula XI R2 \ ^ ifv'3 - Hal I (XI) R3 of R1, R2 and R3 of a third of the formula, is preferred chlorine, bromine or iodine and 61 694 41 Y is a chlorine group, a chlorine, bromine, iodine, methoxy or phenoxy group, a ring having a reactor with an amine having the formula X H2N- (CH2, n - ', V'CH2 - ^^ 6 W are R4, R5, Rg, Rη and n are selected from the group consisting of g. ) and phthalimidine aldehydes with all the compounds of formula XIII HR (XIII) / - λ3 are R, f R2, R3, X and are further reacted with acetal rings to react in the nerve with catalytic activation of the amine under formula III HVcH2 ~ f ^ 6 (III) 5 R4, R4, R5, R8 and R7 are selected from the group consisting of, or h.) And carbonylated with all of the compounds of formula XIV of catalytic activates, including phthalimides of all formulas V