IE42962B1 - Phthalimidine and benzisothiazoline derivatives - Google Patents

Abstract

Novel substituted arylalkylamines of the accompanying formula I, in which the symbols R1 to R7, X and n have the meaning given in Patent Claim 1, are prepared by reacting a compound of the accompanying formula II, in which Z denotes a removable radical, with an appropriately substituted phenylethylamine. The compounds of the formula I and their acid addition salts are distinguished by useful pharmacological properties. In addition to a mild hypotensive action, they particularly have a selective heart rate-lowering action.

Description

This invention relates to novel aralkylamines, to processes for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general formula I, R^ represents a hydrogen atom, a lower C-j_4 group or a phenyl group; either represents a hydrogen atom, chlorine atom or methoxy group and R^ represents a hydrogen atom or a methoxy group, or and ^3 together represent a methylenedioxy or ethylenedioxy group; R^ and R^,. which may be the same or different, each represents a hydrogen atom or a Cp4 alkyl group; either Rg represents a hydrogen atom or a Cy_4 alkoxy group and R? represents a C^_4 alkoxy group, or Rg and R? together represent a methylenedioxy or ethylenedioxy group; X represents.a carbonyl or sulfonyl group; and n represents 2 or 3; and acid addition salts thereof.

It will be appreciated that for pharmaceutical use the acid addition salts will be physiologically compatible acid addition salts but other acid addition salts may, for example, be useful as intermediates in the preparation of compounds of ,1 general formula I and physiologically compatible acid addition salts thereof.

The compounds of general formula I and the acid addition salts thereof possess interesting pharmacological properties and in general exhibit heart frequency decreasing activity.

Where R^, R^ and/or Rg are alkyl groups, they are preferably methyl, ethyl, propyl or isopropyl groups; where R^ and/or R^ are alkoxy groups they are preferably methoxy, ethoxy, propoxy or Isopropoxy groups.

Preferred compounds according to the invention are those wherein Rp and Rg, which may be the same or different, each represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; R2 and Rg each represents a methoxy group, one being in the 5 position and the other in the 6 position of the phthalimidine ring; or R^ and R^ together represent a methylenedioxy or ethylenedioxy group; either Ηθ and R? each represents a methoxy group, or and R? together represent a methylenedioxy or ethylenedioxy group; and X represents a carbonyl group.

Particularly preferred compounds according to the invention are the following: _ 59S3 amino .6- Dimethoxy-N- 03- [n- [2- (3 ,4-dimethoxyphenyl)ethyl ]methylamim; .6- Dimethoxy-2-03- 0Ϊ- [2-(3,4-dimethoxyphenyl)ethyl3methylaminojpr0pylj-l,2-ben2isothia2ole -1,1 -dioxide; .6- Mebhyldnedioxy-N-(3- 01- [2- (3,4-methyIenedioxyphenyl )ethyl ]- ,6-Dimethoxy-N- 03= 01- [2-(3,4-methylenedioxyphenyl)ethyl]- and acid addition salts thereof.

The compounds according to the present invention may, for example, be prepared according to the following processes which processes constitute further features of the present invention* A. Reaction of a compound of formula II, R, H R.

(II) R. wherein R^, R£, R^, X and n are as hereinbefore defined and ? represents a nucleophilic leaving group such as, for example, a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group) with a compound of formula III, 43962 ι H-N-CH-CH, (III) (wherein R^, Rg, and R? are as hereinbefore defined).

The reaction is conveniently carried out in the presence of a solvent, e.g. methanol, ether, tetrahydro furan, methylformamide, dimethylformamide, dimethylsulfoxide or benzene, and conveniently at temperatures of from -50 to 250 °C depending on the reactivity of the group Z. The presence of an acid binding agent, e.g. an alcoholate, alkali metal hydroxide or tertiary organic base such as triethylamine or pyridine, or of a reaction accelerator such as potassium iodide is of advantage.

B. For the preparation of compounds of general formula I wherein Rj represents a hydrogen atom and X represents a carbonyl group: Reduction of a compound of formula IV, R„ Λ N-(CH2)n-N“CH-CH2 R-, (IV) (wherein R , R_, R R , R R_ and n are as hereinbefore z o 4 b 6 / defined).

The reduction is preferably carried out in the presence of a solvent such as, for example, glacial acetic acid, water or ethanol, conveniently with nascent hydrogen obtained, for exampί le, from a mixture of zinc and glacial acetic acid, tin and hydrochloric acid or tin(II) chloride and hydrochloric acid or with catalytically activated hydrogen. In general the-reduce tion will be effected at temperatures of from 0 to 250°C preferably 50 to 100°C.

C. Reaction of a compound of formula V, (wherein R^, R^, Rg, R^, X and n are as hereinbefore defined) with a compound of formula VI, (wherein Rg, R^ and-R? are as hereinbefore defined and Z represents -a nucleophilic leaving group such as, for example, a chlorine bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group).

The reaction is conveniently carried out in the presence of a solvent, e.g. acetone, dimethylformamide, dimethylsulfoxide, chlorobenzene or methylene chloride, and conveniently at 43962 temperatures from 0 to 150°C depending on the reactivity of the group Z. The presence of an acid binding agent, e.g, an alcoholate, alkali metal hydroxide, alkali metal carbonate or tertiary organic base such as triethylamine or pyridine, or of a reaction accelerator such as potassium iodide is of advantage.

D. Reaction of a compound of formula VII, (VII) (wherein R^, R2, R^ and X are as hereinbefore defined) with a compound of formula VIII, Z-(CH„) -N-CH-CH. z η ι z (VIII) (wherein R^, R^, Rg, R? and n areas hereinbefore defined and Z represents a nucleophilic leaving group such as, for example, a chlorine bromine or iodine atom or an alkylsulfonyloxy or arylsulfonylliT oxy group).

The reaction is conveniently carried out in the presence of a solvent, e.g. acetone, dimethylformamide, dimethylsulfoxide or methanol, and conveniently at temperatures from 0 to 150°C depending on the reactivity of the group Z. The presence of an acid binding agent, e.g, an alcoholate, alkali metal hydroxide, alkali metal amide or tertiary organic base such as triethylamine or pyridine, or of a reaction accelerator such as potassium iodide is of advantage.

I i E. For the preparation of compounds of general formula I, wherein X represents a carbonyl group: Hydrolysis of a compound of formula IX, (wherein R^, R2, Rg, R^, Rg, Rg, R? and n are as hereinbefore defined).

The hydrolysis is conveniently carried out in the presence of a base such as, for example, potassium carbonate or in the presence of an acid such as, for example, hydrochloric acid, preferably in a mixture of ethanol and water or dioxan and water. Conveniently the hydrolysis is effected at temperatures of from 50 °C to the boiling temperature of the reaction mixture. Hie compound of formula IX may be obtained by reaction of a compound of formula IXa, (wherein Rp Rg and Rg represents a chlorine, Hal (IXa) are as hereinbefore defined and Hal bromine or iodine atom) with a compound of (wherein R,. R-. R,, R-, and n are as hereinbefore defined). 6’ 7 Preferably the compound of formula X thus obtained will be further hydrolysed without isolation.

The reaction of the compound of formula IXa with the compound of formula X is conveniently carried out in the presence of a solvent, e.g. acetone, ethanol, dimethylformamide, dimethyl10 sulfoxide or methylene chloride, and conveniently at temperatures of from 50°C to the boiling point of the reaction mixture, e.g. at a temperature of from 50 to 150°C. The presence of an acid binding agent, e.g. an alcoholate, alkali metal hydroxide, alkali metal carbonate or tertiary organic ,5' base such as triethylatnine or pyridine, or of a reaction accelerator such as potassium iodide is of advantage.

F. For the preparation of compounds of general formula I, wherein X represents a carbonyl group: Cyclisation of a compound of formula XIt (XI) [wherein R^, R2 and Rg are as hereinbefore defined and either A represents Hal (Hal being a chlorine, bromine or iodine atom) and B represents a group Of formula W, or B represents Y (Y being a nucleophilic leaving group) and A represents a group of formula W, the group of formula W being a group of formula: -n-icap,· K N-CH-CtL R (in which R^, R^, R&, R_, and n are as hereinbefore defined)] whereby,thexdesired compound of formula I is obtained.

In the above compound of formula XI, when B represents Y then Y may, for example, .be a chlorine, bromine or iodine atom or a methoxy or phenoxy· group.

If desired, the compound of formula ΧΪ. may be prepared, pre:.· •'t ferahly in situ, by reaction of a compound of formula - 10 42962 (wherein Rp R2> Rg, Hal and Y are as hereinbefore defined), with a compound of formula X as hereinbefore defined. The cyclisation and/or the reaction of the compound of formula XII with the compound of formula X may conveniently be effected in the presence of a solvent, e.g. acetone, dimethylformamide, dimethylsulfoxide or methylene . chloride, and conveniently at temperatures of from 50°C to the boiling point of the reaction mixture, e.g. at temperatures from 50 to 150°C. The presence of an acid binding agent, ! e.g. an alcoholate, alkali metal hydroxide, alkali metal carbon10 ate or tertiary organic base such as triethylamine or pyridine, or of a reaction accelerator such as potassium iodide is of advantage. ,, G. Reaction of a compound of formula XIII, (wherein Rp Rg, Rg, X and n are as hereinbefore defined) or an acetal derivative thereof, with a compound of formula III as hereinbefore defined, in the presence of catalytically activated hydrogen. .1 The reductive aminition is conveniently carried out with hydrogen in the presence of palladium on charcoal, preferably at a hydrogen pressure of about 5 atm., preferably in the presence of a solvent such as, for example, methanol, ethanol or dio xan and at temperatures from 0 to 100°C, preferably 20 to 80ΰ0.

H. Reaction of a compound of formula XIV, (wherein Rg, βθ and R? are as hereinbefore defined), or an acetal or ketal derivative thereof, with a compound of formula V as hereinbefore defined, in the presence of catalytically activated hydrogen.

The reductive amination is conveniently carried out with hydrogen in the presence of palladium on charcoal, preferably at a hydrogen pressure of about 5 atm., preferably in the presence of a solvent such as, for example, methanol, ethanol or dioxan and at temperatures from 0 to 100°C, preferably 20 to 80°C.

I. For the preparation of compounds of general formula I,wherein R^ represents a alkyl group: Alkylation with an appropriate alkylating agent of a compound of formula I as hereinbefore defined (wherein R^ represents a hydrogen atom). The alkylating agent may, for example, - 12 42962 comprise an alkyl halide or dialkyl sulfate or, for the pre-, paration of compounds of formula I wherein represents a methyl group, a mixture of formaldehyde and formic acid.

J. For the preparation of physiologically compatible acid addition salts of compounds of general formula I: Reaction of a compound of formula I as hereinbefore defined with an appropriate acid.

Suitable acids include, for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid and maleic acid.

The compounds of general formulae II to XIV, used as starting materials, may be prepared according to known processes. Thus, for example a phthalimidine of formula V or a lH-phthalimidine of formula VII may be obtained by reduction of a corresponding phthalimide with zinc dust in glacial acetic acid and optional subsequent hydrolysis.

A benzyl halide of formula IX or XI is preferably obtained by halogenation of a corresponding toluene, e.g. with N-bromosuccinimide in carbon tetrachloride, optionally with addition of an initiator such as dibenzoyl peroxide and/or with UV irradiation.

As already mentioned above, the new compounds of general formula I and the acid addition salts thereof possess interesting pharmacological properties. The compounds according to - 13 9S2 the invention which we have tested have exhibited not only a weak hypotensive activity but also, in particular, a selective heart frequency decreasing activity.

For example the following compounds were tested with regard to their biological properties: A = 5,6-Dimethoxy=N-'{3-[N-[2-(3,4-dimethoxyphenyl)ethylimethyi amino] propyl} phthalimidine hydrochloride, B = 5,6-Dimethoxy-2-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl 'amino]propyl] -1,2-benzisothiazoline-l,1-dioxide hydrochloride, C = 5,6“Methylenedioxy-N-£3-|N-[2-(3,4-methylenedioxyphenyl)ethyljmethylaminoj propyl]phthalimidine hydrochloride, D = 5,6-Dimethoxy-N-|3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]- 1. Activity on heart frequency of narcotized guinea pigs: The heart frequency of guinea pigs under urethane narcosis was registered by an electrocardiogram. The substances under test were administered intravenously in increasing dosages between 0.5 and 20 mg/kg.

The following table indicates the variation in heart frequency of the guinea pigs: - 14 429Gg Substance Dose mg/kg i .v. n Percentage decrease in heart frequency 0.5 3 -23.5 1.0 3 -36.1 l 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. Activity on heart frequency in the auricle of the guinea pig: Isolated spontaneously beating auricles of guinea pigs of both male and female sex, having a body weight of between 300 and 400 g, were investigated in an organ bath filled with tyrode solution. The nutritive solution was infused with carbogen (95% of 02 and 5% of C02) and kept steadily at 30°C. The contractions were registered isometrically with a Statham-Force transducer on a Grass-polygraph. The substances under test were added to the organ baths, such that the final concentration was 10 g/ml in each case. 5 auricles were used for each solution.

The following table gives the percentage decrease in heart frequency over an average of 5 auricles (concentration of substance = 10 5 g/ml).

Substance ' ...................................... —.............. Decrease of frequency in % A - 52 B - 60 D - 51 E - 48 3. Acute toxicity; The acute toxicity of the substances in question was determined in mice (observation time; 14 days) after oral or intravenous application. The LD-θ was calculated from the percentage of animals which died after administration of various doses within the observation time (see J. Pharmacol, exp. Therap. 96, 99 (1949)): SubstanceLD50 A 98 mg/kg i.v. A ' 1,570 mg/kg p.o. B 100 mg/kg i.v. 4β*9ΰ2 According to a still further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I as hereinbefore defined or a physiologically compatible acid addition salt thereof, in association with a pharmaceutical carrier or excipient. ' For pharmaceutical administration the compounds of general formula I may be incorporated into conventional pharmaceutical preparations, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal, or parenteral administration. Preferred forms include tablets, coated tablets, powders, solutions, suspensions and suppositories. Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults conLain from 20 to 300 mg., preferably 25 to 200 mg., of active ingredient.

The following non-limiting Examples serve to illustrate the present invention: - 17 S20S2 Example 1 N-(3-[N-[2-(3,4-0 ime thoxypheny1)e thyl]me thylaminojpropyl}phthalimidine hydrochloride__ a) N-03- 0i- [2-(3,4-Dimethoxyphenyl)ethyl]methylaminoj propyl}phthalimide_. _. .04 g (0.02 mol) of 1-0i-[2-(3,4-dimethoxyphenyl)ethyl 3methylamiiloJ-3-amino-propane and 2.06 g (0.02 mol) of phthalic anhydride were dissolved in 100 ml of glacial acetic acid and. the solution obtained was refluxed for 4 hours. Subsequently the mixture was evaporated under vacuum. The residue was taken up in chloroform and the chloroform solution thus formed was successively washed with saturated sodium hydrogen carbonate solution and water. After drying over sodium sulfate, the solvent was distilled off and the product was obtained in an amorphous state.

Yield; 6.1 g (79.8 % of theory), Rf value (benzene/acetone = 1/1): 0.4 b) N-£3-0N-[2-(3,4-Dimethoxyphenyl)ethyl]methylamino| propyljphthalimidine hydrochloride - ~__ 6.1 g (159 mmol) of N-'0-0r“[2-(3,4-dimethoxyphenyl)ethyl]methylaminojpropyl} phthalimide, dissolved in 80 ml of glacial acetic acid, were mixed with 10 g of zinc dust and subsequently reduced by refluxing for 3 hours. To separate - 1843962 off the zinc dust, the hot solution was filtered and the filtrate was then evaporated under vacuum. Subsequently the residue was dissolved in chloroform and the chloroform layer was extracted with saturated sodium carbonate solution and water, dried over sodium sulfate and then evaporated.

The crude product was purified by chromatography on silica gel (chloroform/methanol = 19/1). The hydrochloride was obtained by precipitation from ethereal hydrochloric acid. After digestion with ethyl acetate the hydrochloride had a m.p. of 146-148°C.

Yield: 2.25 g (35 % of theory).

Example 2 ,6-Dimethoxy-N-£3-[n-[2-(3,4-dimethoxyphenyl)ethylJmethylaminojpropyljphthalimldine hydrochloride a) 5,6-Dimethoxy-N-£3-Jn-[2-(3,4-dimethoxypheny1)ethy1]methy1amin<3 propyl}phthalimide Prepared analogously to Example la by condensation of 4,5- : dimethoxy-phthalic anhydride with 1- (N-[2-(3,4-dimethoxyphenyl)ethyl]methylamin<£J-3-amino-propane in glacial acetic acid.

M.p.: 91-93°C. b) 5,6-Dimethoxy-N-t3-{n-[2-(3,4-dimethoxyphenyl)ethyljmethylamlnojpropylj'phthalimidine hydrochloride -19 ^39δ2 Prepared analogously to Example lb by reduction of 5,6-dimethoxy-N- £3-£n-[2-(3,4-dimethoxyphenyl)ethyl]methylaminojpropyl] phthalimide with zinc dust in glacial acetic acid, M.p.: 170-172°C.

Example 3 ,6-Dimethoxy-N- £3- [2-( 3,4-dimethoxyphenyl)ethyl]amino-propyl] phthalimidine hydrochloride, .1 a) 5,6-Dimethoxy-N-£3-[2-(3,4-dimethoxyphenyl)ethyl]aminopropylj phthal imide Prepared analogously to Example la by condensation of 4,5dimethoxy-phthalic anhydride with l-[2-(3,4-dimethoxyphenyl) ethyl]amino-3»amino-propane in glacial acetic acid.

Rf value (chloroform/methanol = 9/1): 0.25 b) 5,6-Dimethoxy-N-£3-[2-(3,4-dimethoxyphenyl)ethyl]aminopropyllphthalimidine hydrochloride Prepared analogously to Example lb by reduction of 5,6dimethoxy-N-£3-[2-(3,4-dimethoxyphenyl)ethyl]amino-propy phthalimide with zinc dust in glacial acetic acid, M.p.: 207-209°C. mmol Example 4 ', 6-Dimethoxy-N-{3-pN- [2- (3,4-dimethoxyphenyl) ethyl jmethyl'lojjpyopyl}phthalimidine hydrochloride_ g (12.1 mol) of the compound obtained according to Example 3 were heated up to 100C in a mixture of 1.38 g (30 mmol) of formic acid and 1.5 g (20 mmol) of formaline for 1 hour. After cooling the reaction mixture was made alkaline by addition of 2 N sodium hydroxide solution and then extracted with chloroform. The chloroform layer was washed with water, dried and then evaporated under vacuum. The residue was purified by chromatography on silica gel (chloroform/methanol = 45/1). The main fractions were evaporated and the base was precipitated as the hydrochloride from ethereal hydrochloric acid. ’ · 1 M.p.i 17O-172C.

Example 5 ,6-Dimethoxy-N-f3-[n-[2-(3,4-dimethoxyphenyl)ethyljprop'ylaminal propyl}phthalimidine hydrochloride A solution of 25 g (5.5 mmol) of 5,6-dimethoxy-N-f3- [2-(3,4aimethoxyphenyl)ethyljamino-propy^ phthalimidine in 100 ml of acetone was refluxed for 6 hours after addition of 20 ml of 1-bromopropane and 5 g of potassium carbonate. After cooling the solid portion was filtered off and the filtrate was evaporated. The product was taken up in ether, the insoluble part was again filtered off and, after evaporation, the hydrochloride was precipitated from ethereal hydrochloric acid.

M.p.: 120-122°C (a^etone/methanol), 215,6-Dimethoxy-N- {3-[ν-[2-(3,4-dimethoxyphenyl)ethyl]methylaminolethy]J phthalimidine hydrochloride 3.81 g (15 mmol) of N-(2-bromoethyl)phthalimide were refluxed together with 6 g of N-[2-(3,4-dimethoxyphenyl)ethylJmethylamine in 40 ml of xylene for 10 hours. The oily residue obtained after evaporation under vacuum was converted into the desired compound analogously to Example lb by reduction with zinc dust in glacial acetic acid without further purification. M.p.: 149-151 °C.

Example 7 N- {3- 0N-[2-(3,4-Dimethoxyphenyl)ethyljmethylaminoj propyl}-3aheny 1 - phthal imid ine L.75 g (5.3 mmol) of N-(3-bromopropyl)-3-phenyl-phthalimidine fere refluxed with 2.06 g (10.6 mmol) of N-[2-(3,4-dimethoxy3henyl)ethyl]methylamine in 30 ml of xylene for 10 hours, kfter cooling the mixture was evaporated and the residue was mrified by chromatography on silica gel (chloroform/methanol = 19/1). The base was obtained as a highly viscous >il.

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

Example 8 l-Phenyl-5-chloro-N- £3-£n- [2- (3,4-dimethoxyphenyl)ethyl jmethyl· mino] propyl·}-1.2-benzisothiazoline-l,]-dioxide hydrochloride - 22 429G2 g (9,3 mmol) of N-(3-chloropropyl)-3-phenyl-5-chloro-l,2J benzisothiazoline-l,l-dioxide were refluxed together with 3 g of N-[2-(3,4-dimethoxyphenyl)ethyl]methylamine and a spatulafull of potassium iodide in a solution of 30 ml of dimethyl5 formamide and 5 ml of triethylamine for 5 hours. Subsequently the mixture was evaporated to dryness. The residue was taken up in chloroform and the organic layer was washed several times with water. After drying the mixture was evaporated and the residue was purified by chromatography on silica gel (chloro10 form/methanol = 40/1). The hydrochloride was obtained as an amorphous product by precipitation with ethereal hydrochloric acid.

Rf value (chloroform/methanol = 19/1): 0.5. 15 Co-Ho,ClNo0 .S x HC1 (551.54) 27 31 2 4 Calculated: C 58.S H 5.60 N 5.10 S 5.80 Found: C 58.7 5.75 N 5.20 S 5.90 Example 9 ,6-Dimethoxy-N- T- Γ» -[2-(3,4-d imethoxyphenyl)e thyl]me thyiaminj -propyl) -l,2-benzisothiazoline-l,l-dioxide hyrdochlori.de a) 2-Methyl-4,5-dimethoxy-benzenesulfonyl chloride 23.2 g (0.2 mol) of chlorosulfonic acid were slowly added dropwise to 15.2 g (0.1 mol) of 3,4-dimethoxytoluene at about -10°C whilst stirring and cooling. After the addition was complete, the mixture was left to warm up to room - 23 52 temperature and stirred until the hydrogen.chloride evolution had ceased. The reaction mixture was poured on ice and the sulfonyl chloride thus precipitated was extracted with ether. The organic layer was successively washed with sodium hydrogen carbonate solution and water and then evaporated to dryness under vacuum. A turbid oil was obtained as residue, which solidified on cooling.

Rg value (benzene): 0.5. b) 2-Methy1-4.5-dimethoxy-benzenasulfonamide g (0.07 mol) of the compound obtained according to Example 9a were suspended in 200 ml of concentrated ammonium. hydroxide and stirred at room temperature for 4 hours. The mixture was filtered with suction and the residue was washed again with water. The desired sulfonamide was obtained as an amorphous product after drying.

Rg value (benzene/acetone = l/l): 0.6. c) 5,6-Dimethoxy-l,2-benzisothiazoline-3-one-1,1-dioxide g (0.08 mol) of 2-methyl-4,5-dimethoxy-benzenesulfonamide were dissolved in 500 ml of 5% sodium hydroxide solution. After the addition of 39.6 g (0,25 mol) of potassium permanganate the solution obtained was boiled for 2 hours . On cooling the mixture was filtered with suction on celite. The desired product was precipitated by addition of concentrated hydrochloric acid.

Rg value (benzeue/acecone = 3/1): 0.2-0.4. - 2442963 d) 5,6-Dimethoxy-l.2-benzisothiazoline-l,l-dioxi.de g (288 mmol) of the compound obtained according to Example 9c were ,refluxed with 3.3 g (865 mmol) of lithium aluminium hydride in 400 ml of tetrahydrofuran for 2 hours.

After cooling, the excess lithium aluminium hydride was decomposed by addition of ethyl acetate. The mixture obtained was diluted with water and subsequently 2 N hydrochloric acid was added thereto until the aluminium hydroxide precipitate which had precipitated was redissolved. The reaction solution was then extracted with ethyl acetate and the organic layer was washed with water and dried. The mixture was evaporated under vacuum. The residue was digested in ether and the desired compound was isolated by filtration with suction. e) N-(3-Chloropropyl)-5,6-dimethoxy-l,2-benzisothiazoline-l,1dioxide 2.4 g (10.5 mmol) of the compound obtained according to , -Example 9d were dissolved in a mixture of 15 ml of 2.5% sodium hydroxide solution and 30 ml of ethanol. After addition of 10 ml of 3-bromo-l-chloro propane, the solution was refluxed for 8 hours. The reaction mixture was then evaporated to half its volume, diluted with water and extracted with chloroform. After drying, the organic layer was evaporated under vacuum and the desired product - 25 2 was obtained as a highly viscous oil.

Rf value (chloroform/methanol = 19/1): 0.8. f) 5,6-Dimethoxy-N-{3-^-[2-(3,4-dimethoxyphenyl) ethyljmethylaminoj propyl}-1,2-benzisothiazoline-l,1-dioxide hydrochloride Prepared analogously to Example 8 by reaction ofN-(3-chloropropyl)-5,6-dimethoxy-l,2-benzisothiazoline-l,1-dioxide with N- [ 2- ( 3,4-dimethoxyphenyl)ethyljmethylamine.

M.p.: 196-198,°C (acetone).

Example 10 ,6-Methylenedioxy-N- {3- Ql- [2-(3,4-dimethoxyphenyl)ethyl jmethylpropylj phthalimidine hyrdochloride a) 3.5 g (18 mmol) of 4,5-methylenedioxy-phthalic anhydride and 4.5 g (18 mmol) of l-|1sr-[2-(3,4-dimethoxyphenyl)ethyi]methylaminoj-3-amino-propane were refluxed in 100 ml Of glacial acetic acid for 2 hours. Subsequently the mixture was evaporated under vacuum and the residue was taken up in chloroform. The chloroform solution was successively washed with saturated sodium hydrogen carbonate solution and water.

After drying over sodium sulfate, the solvent was distilled off and the desired substance was obtained as an amorphous product.

Yield: 4.8 g (63 % of theory), Rf value (chloroform/methanol = 9/1): 0.6, - 2642962 -. jr~b) 5,6-Methylenedioxy-N-|3-[_N- [2-(3,4-dimethoxyphenyl)ethyl ]methylamingj propyl} phthalimidine hydrochloride_ 4.8 g (11 mmol) of 5,6-methylenedioxy-N--{3-0}-[2-(3,4dimethoxyphenyl)ethyl]methylamino]propyl]phthalimide, dis5 solved in 40 ml of glacial acetic acid, were mixed with 5 g of zinc dust and the solution obtained was refluxed for 2 hours. The zinc dust was subsequently filtered off from the hot solution and the filtrate was evaporated under vacuum. The residue was dissolved in chloroform and the chloroform layer was extracted with saturated sodium carbonate solution and water, dried over sodium sulfate and then evaporated. The residue was dissolved in chloroform and the hydrochloride, having a m.p. of 237-239°C, was precipitated by addition of ethereal hydrochloric acid.

Yield: 1.5 g (30 % of theory).

Calculated: C 61.53 H 6.51 H 6.24 Cl 7.90 Found: 61.50 6.49 6.24 7.85 Example 11 ,6-Ethylenedioxy-N-£3-Qs(- [2- ( 3,4-dimethoxyphenyl) ethyl ]20 me thy lamino] propy]} phthalimidine hydrochloride_ a) 4,5-Ethylenedioxy-N-£3-[n-[2-(3,4-dimethoxyphenyl)ethyl]methylamingl propyl]phthalimide Prepared analogously to Example 10a by condensation of 4,5ethylenedioxy-phthalic anhydride with 1-£n-[2-(3,4-272 dimethoxyphenyl)ethyl]methylamino|-3-amino-propane in glacial acetic acid.

Rf value (chloroform/methanol = 9/1): 0.5. b) 5,6-Ethylenedioxy-N- 03-Jn-[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyj}phthalimidine hydrochloride Prepared analogously to Example 10b by reduction of 4,5ethylenedioxy-N- 03-[n-[2-(3,4-dimethoxyphenyl)ethyljmathylaminoj propyljphthalimide with 2inc dust in glacial acetic acid.

M.p.: 208-210°C.

Calculated: C 62.26 H 6.75 N 6.05 Cl 7.66 Found: 62.10 6.84 5.90 7.67 Example 12 >,6-Methylenedioxy-N-{3- 01-[2-(3,4-methylenedioxyphenyl)ethyl]ethylaminpj propyl}phthalimidine hydrochloride .) 4,5-Methylenedioxy-N- 03- j~N- [2-(3,4-methylenedioxyphenyl) ethyl Imethylamincd propyl}· phthalimide 2.7 g (10 mmol) of 4,5-methylenedioxy-N-(3-chloropropyl)phthalimide and 1.8 g (10 mmol) of N-[2-(3,4-methylenedioxyphenyl)ethyl]methylamine were dissolved in 20 ml of chlorobenzene and, after addition of 2.8 g (20 mmol) of pulverized potassium carbonate, were refluxed for 8 hours. Subsequently the solution was filtered and evaporated to dryness under vacuum. The residue was purified by chromatography on -28 429G2 silica gel (chloroform/methanol = 19/1) and, 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 5 b) 5,6-Methylenedioxy-N--{3-[N-[2-(3,4-methylenedioxyphenyl)ethylImethylamino]propyl} phthalimidine hydrochloride Prepared analogously to Example 10b by reduction of 4,5methylenedioxy-N-{3-[n-[2-(3,4-methylenedioxyphenyi) ethyl]methylamino]propyl} phthalimide with zinc dust in glacial acetic acid.

M.p.: 206-208°C.

Calculated: C 61.04 H 5.82 N 6,47 Cl 8.19 Found: 61.10 6.07 6.74 8.45 Example 13 ,6-Ethylenedioxy-N- {3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]me thyl ami'nq] propyl} phthalimidine hydrochloride a) 4,5-Ethylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl· ]methylamina? propyl} phthal imide Prepared analogously to Example 12a by reaction of 4,520 ethylenedioxy-N-(3-chloropropyl)-phthalimide with N-[2(3,4-methylenedioxyphenyl)ethyl]methylamine in chlorobenzene in the presence of potassium carbonate.

Rf value (chloroform/methanol = 9/1): 0.5. - 29 Θ2 b) 5,6-Ethylenedioxy-N-£3-£n»[2-(3,4-methylenedioxyphenyi)ethyljmethylaminftj propyl; phthalimidine hydrochloride Prepared analogously to Example 10b by reduction of 4,5ethylenedioxy-N- {3-(n-[2-(3,4-methylenedioxyphenyl)ethyl]methylaminojpropyl] phthalimide with zinc dust in glacial acetic acid.’ M.p.; 180-182°C.

Calculated: C 61.81 H 6.09 N 6.27 Cl 7.93 Found: ;! 61.70 6.12 6.12 7.94 ,6-Dimethoxy-N--jp-Jn-[2-(3,4-methylenedioxyphenyl)ethyl]methylaminp]propyl}phthalimidine hydrochloride __ a) 4,5-Dimethoxy-N-{3-0F-[2-(3,4-methylenedioxyphenyl)ethyl]methylaminaJ propyl} phthal imide___ Prepared analogously to Example 12a by reaction of 4,5dimethoxy-N-(3-chloropropyl)-phthalimide with N-[2-(3,4methylenedioxyphenyl) ethyl jmethylamine in chlorobenzene in the presence of potassium carbonate.

Rf value (chloroform/methanol = 19/l): 0.7. b) 5,6-Dimethoxy-N- £3-£n-[2-(3,4-methylenedioxyphenyl)ethyl]methylaminbjpropyl} phthalimide hydrochloride _ Prepared analogously to Example 10b by reduction of 4,5-dimethoxy-N- £3-[n-[2-(3,4-methylenedioxyphenyl)ethyljmethylaminojpropyl] phthalimide with zinc dust in glacial acetic acid. -3042992 M.p.: 235-237°C.

Calculated: C 61.53 H 6.51 N 6.24 C.1 7.90 Found: 61,45 6.63 6.27 7.92 Example 15 ,6-Ethylenedioxy-N- £5-04-[2-(3,4-dimethoxyphenyl)ethyljmethylamino]propyl}-!,2-benzisothlazollne-l,1-dioxide hydrochloride ισ Prepared analogously to Example 12a by reaction of N-(3-chloropropyl)- 5,6-ethylenedioxy-l,2-benzisothiazoline-l,1-dioxide with N-[2-(3,4-dimethoxyphenyl)ethyljmethylamine.

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

Example 16 3-Methyl-5,6-dimethoxy-N-{3-04-[2-(3,4-dimethoxyphenyl)ethyl]methylamingjpropyl}phthallmidine hydrochloride Prepared analogously to Example 12a by reaction of 3-methyl-5,6dimethoxy-N-(3-chloropropyl)-phthalimidine with N-[2-(3,4dimethoxyphenyl)ethyljmethylamine in chlorobenzene in the presence of potassium carbonate.

M.p.: 135-136°C.

Calculated: C 62.68 H 7.36 N 5.85 Cl 7.40 Found: 62.31 7.40 5.80 7.12 Example 17 ,6-Dimethoxy-N- 03-04-[2-(3,4-dimethoxyphenyl)-1-methyl-ethylj methylamina)propylj’phthalimidine hydrochloride - 31 962 a) 4,5-Dimethoxy-N- {3- [n- [2-( 3,4-dimethoxyphenyl)-l-methylethyl jmethylaminoj propyl}phthalimide Prepared analogously to Example 12a by reaction of 4,5-dimethoxy-N-(3-chloropropyl)-phthalimide with N-[2-(3,4dimethoxyphenyl)-l-methyl-ethyl]methylamine in chlorobenzene in the presence of potassium carbonate.

R. value (chloroform/methanol = 9/1): 0.9. b) 5,6-Dimethoxy-N-£3-[n~[2-(3,4-dimethoxyphenyl)-1-methylethyljmethylaminojpropyl·}phthalimidine hydrochloride Prepared analogously to Example 10b by reduction of 4,5-dimethoxy-N-£3-[n-[2-(3,4-dimethoxyphenyl-l-methyl-ethyl]methylamino}propylj phthalimide with zinc dust in glacial acetic acid.

M.p.: 183-185°C.

Calculated: C 62.68 H 7.36 N 5.85 Cl 7.40 Found: 62.50 7.42 5.92 7.30 Sxample 18 ,6-Methylenedioxy-N- ^2- Qi-[2-(3,4-dimethoxyphenyl)ethyl]nethylaminpl ethyl}phthalimidine hydrochloride a) 4,5-Methylenedioxy-N-£2-pl- [2-(3,4-dimethoxyphenyl)ethyl] methylamino] ethyl} phthal imide_ Prepared analogously to Example 10a from 4,5-methylenedioxy-phthalic anhydride and 1-[n-[2-(3,4-dimethoxyphenyl) ethyljmethylaminoj2-amino-ethane. - 32429 Rf value (chloroform/methanol = 9:1): 0.55. b) 5,6-Methylenedioxy-N-{2-[n-[2-(3,4-dimethoxyphenyl)ethyljmethylaminql ethyl}phthalimidine hydrochloride Prepared analogously to Example 10b by reduction of 4,55 methylenedioxy-N-{2-(n-[2-(3,4-dimethoxyphenyl)ethyljmethyl aminojethyl} phthalimide with zinc dust in glacial acetic acid.

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

Example 19 ,6-Dimethoxy-N-(3-[n-[2-(3,4-dimethoxyphenyl)ethylJmethylaminaj propyl}phthalimidine hydrochloride .3 g (0.02 mol) of 5,6-dimethoxy-N-(3-methylamino-propyl)phthalimidine, 4.0 g (0.02 mol) of 2-(3,4-dimethoxyphenyl)ethyl 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 filtrate was evaporated under vacuum. The crude product was purified by chromatography on' silica gel (chloroform/methanol = 19/1). The evaporated frac tions were dissolved in acetone and the hydrochloride was pre cipitated by addition of ethereal hydrochloric acid.

M.p.: 170-172°C.

Example 20 ,6-Dimethoxy-N-£3- JSl-[2-(3,4-dimethoxyphenyl)ethyljmethylaminqjpropyl} phthalimidine hydrochloritle -33}02 0.5 g of sodium hydride were added to a solution of 3.0 g (15 mmol) of 5,6-dimethoxy-phthal imidine in 100 ml of dimethylformamide. The mixture obtained was subsequently heated up to 80°C for 30 minutes. 8.5 g (30 mmol) of 1-[n-[2-(3,4] dimethoxyphenyl)ethyl]methylamino]-3-chloro-propane, dissolved in 100 ml of dimethylformamide, were then added dropwise. The mixture thus obtained was heated up to 140°C for 7 hours.

After cooling, water was added and the mixture was extracted several times with chloroform. The organic layers were dried and then evaporated to dryness under vacuum. The crude product was purified by chromatography on silica gel. The hydrochloride was obtained by precipitation with ethereal hydrochloric acid.

M.p.: 170-172°G.

Example 21 ,6-Dimethoxy-N- {3-[n-[2-(3,4-dimethoxyphenyl)ethylJmethylamino) propyl) phthalimidine hydrochloride 1.45 g (5 mmol) of methyl 2-bromomethyl-4,5-dimethoxy-benzoate, 2.52 g (10 mmol) of l-[N-[2-(3,4-dimethoxyphenyl)eEhylJmethylaminoj-3-amino-propane and 3 g of potassium carbonate were refluxed in 200 ml of methyl ethyl ketone for 4 hours. After cooling, the insoluble part was filtered off and the filtrate jas evaporated under vacuum. The crude product was purified by ihromatography on silica gel (chloroform/methanol = 19/1). The -34 4 2.9 G 2 . .1. · ^ . hydrochloride was obtained by'precipitation with ethereal hydrochloric acid, M.p.: 170-172°C.

Example 22 ,6-Dimethoxy-N-£3-[N-[2-(3,4-dimethoxyphenyl)ethyljmethylamino]propyl}phthalimidine hydrochloride_ a) 1-0N-[2-(3,4-Dimethoxypheny1)ethylJmethylamino]-3-(1-imino5,6-dimethoxy-phthalimid ine- 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 l-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylaminoj-3-amino propane were refluxed in 80 ml of ethanol for 6 hours. After cooling, the solvent was removed under vacuum and the crude product thereby obtained was processed further in reaction step b) without purification.

Rf value (chloroform/methanol = 19/1): 0.5, b) 5,6-Dimethoxy-N- 03-[n-[2-(3,4-dimethoxyphenyl)ethyljmethylaminolpropyl} phthalimidine hydrochloride g of crude l-0N-[2-(3,4-dimethoxyphenyl)ethyl]methylaminoj-3-(1-imino-5,6-dimethoxy-phthalimidine-2-yl)-propane and 11 g of potassium carbonate were refluxed for 8 hours in a mixture of 50 ml of ethanol and 80 ml of water. The mixture was then evaporated under vacuum and the crude product thus obtained was purified by chromatography on silica gel (chloroform/methanol - 19/1). The free base was obtained _ 35from the evaporated fractions and was precipitated as the hydrochloride with ethereal hydrochloric acid.

M.p.: 170-172°C.

Example 23 i,6-Dimethoxy-N- £3-[2-(3,4-dimethoxyphenyl)ethyl]amino-propyl]'hthalimidine hydrochloride. ~ iter the addition of 0.3 g of palladium/charcoal (10%) into a olution of 2.6 g (10 mmol) of 1-amino-3-(5,6-dimethoxyhthalimidine-2-yl)-propane and 1.8 g (10 mmol) of 2-(3,4imethoxyphenyl)acetaldehyde in 100 ml of ethanol, hydrogen was introduced over a period of 4 hours at a temperature of 50 °C nd at 5 atm. pressure. After absorption of the hydrogen, the atalyst was filtered off and the solution thus obtained was vaporated under vacuum. The hydrochloride was obtained by recipitation with ethereal hydrochloric acid. ,p.: 207-209°C. xample 24 , 6-Dimethoxy-N- {3-[2-(3,4-dimethoxyphenyl)ethyl]amino-propyl]· hthalimidine hydrochloride. fter the addition of 0.3 g of palladium/charcoal (10%) into a slution of 3.2 g (10 mmol) of 3-(5,6-dimethoxy-phthalimidine-yl)propionaldehyde-diechylacetal and 1.8 g (10 mmol) of 23,4-dimethoxyphenyl)ethylamine in 100 ml of ethanol, hydrogen is introduced over a pe-iod of 4 hours at a temperature of - 3642962 50°C and at 5 atm. pressure. After absorption of the hydrogen, the catalyst was filtered off and the solution obtained was evaporated under vacuum. The hydrochloride was obtained by precipitation with ethereal hydrochloric acid.

M.p.: 207-209°C.

The following compounds were also prepared analogously to Examples 19 to 24: N- [3-04-[2-(3,4-Dimethoxyphenyl )ethyljmethylaminojpropyl}phthalimidine hydrochloride M.p.: 146-148 °C. ,6-Dimethoxy-N-{3-N-[2-(3,4-dimethoxyphenyl)ethyljaminopropy lj phthalimid ine hydrochloride M.p.: 207-209 °C .6- Dimethoxy-N-£3-04- [2-( 3,4-dimethoxyphenyl)ethyljpropylaniinoj propyljphthal imid ine hyrdochloride M.p.: 120-122°C (acetone/methanol). .6- Dimethoxy-N-{3-04-[2-(3,4-dimethoxyphenyl)ethyl]methylaminojethyljphthalimidine hyrdochloride M.p.: 149-151°C.

N- }3-0!-[2-(3,4-Dimethoxyphenyl)ethyl Jmethylaminoj propyl}-3phenyl-phthalimidine Rf value (chloroform/methanol = 19/1): 0.4. - 37 9C2 3-Phenyl-5-chloro-N-0S-[n-[2-(3,4-dimethoxyphenyl) ethyl]methylaminoj propyl} -1,2-benzisothiazoline-l,1-dioxide hydrochloride Rg value (chloroform/methanol = 19/1): 0.5. .6- Dimethoxy-N-{3-[n-[2-(3,4-dimethoxyphenyl)ethyl]methylaminojpropyl}-1,2-benzisothiazoline-l,1-dioxide hydrochloride M.p.: 196-198°C (acetone). .6- Methylenedioxy-N- (3,4-dimethoxyphenyl )ethyl ]methylaminoj propyljphthalimidine hydrochloride M.p.: 237-239°C. .6- Ethylenedioxy-N- 0-05- [2- (3,4-όΰηεϋΜχγρίιεηγ1)ει;Τιγϊ ]methylaminoj propyl} phthalimidine hydrochloride M.p.: 208-210°C. .6- Methylenedioxy-N- 0-0T-[2-(3,4-methylenedioxyphenyl)ethyl] methylaminoj propyljphthalimidine hydrochloride M.p.: 2Q6-208°C. .6- Ethylenedioxy-N-{3-^N-[2-(3,4-methylenedioxyphenyl)ethyl]methylaminoj propyl}phthalimidine hydrochloride M.p.: 180-182C. .6- Dimethoxy-N- {3- jjl-[2-(3,4-methylenedioxyphenyl)ethyl]methylaminoj propyl}phthalimidine hydrochloride M.p.: 235-237°G. .6- Ethylenedioxy-N-^3-0N- [2-(3,4-dimethoxyphenyl)ethyl]methylaminojpropyl}-l,2-benzisothiazoline-l,1-dioxide hydrochloride 38'4 2963 Rf value (chloroform/methanol = 9/1): 0.6. 3-Methyl-5,6-dimethoxy-N-(3-Qj-[2-(3,4-dimethoxyphenyl)ethyl]methylamino] propyljphthalimidine hydrochloride M.p.: 135-136°C. , ,6-Dimethoxy-N- £3-[n~[2-(3,4-dimethoxyphenyl)-1-methyl-ethyl ]methylamino]propyl}phthalimidine hydrochloride M.p,: 183-185°C.

Example 25 Tablets containing 100 mg of 5,6-dimethoxy-N-{3-Qj-[2-(3,410 dimethoxyphenyl)ethylJmethylaminojpropyl}phthalimidine hydrochloride Composition: Active Ingredient 100.0 mg lactose 50.0 mg polyvinyl pyrrolidone 5.0 mg carboxymethylcellulose 19.0 mg magnesium stearate 1.0 mg 175.0 mg Method of preparation: The active ingredient and lactose were homogeneously moistened with the aqueous PVP solution and the homogenate obtained was granulated. After drying, the granulate was mixed with the remaining auxiliary products and pressed into tablets in the usual manner. _ 39_ Example 26 Coated tablets containing 50 mg of 5,6-dimethoxy-N-{3-(N-[2 (3,4-dimethoxyphenyl) ethyl jmethyl aminoj propyl} phthal imidine hydrochloride _* 1 coated tablet core: 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 was processed into tablet cores as described in Example 25. The cores were then covered with a coating con· sisting of sugar and gum arabic.

Example 27 Suppositories containing 150 mg of 5s6-dimethoxy-N-£i-[N-[2· (3,4-dimethoxyphenyl)ethyl]methylaminojpropyl}phthalimidine hydrochloride Composition: Active ingredient' 150.0 mg suppository mass 1 550.0 mg 700.0 mg Method of preparation: The active ingredient was homogeneously dispersed in the molten suppository mass and the liquid mixture thus obtained was poured into pre-cooled suppository moulds.

Example 28 Suspension containing 50 mg/ml of 5,6~dimethoxy-N-{3-[N-[2(3,4-dimethoxyphenyl)ethyljmethylaminoj propyl} phthalimidine hydrochloride 100 ml of suspension contain: Active ingredient 5.0 g carboxyrnethylcellulose 0.1 g methyl £-hydroxybenzoate 0.05 g propyl £-hydroxybenzoate 0,01 g sugar 10.0 g glycerine 5.0 g sorbit solution 70 % 20.0 g flavouring 0.3 g distilled water ad 100.0 ml Method of preparation: The distilled water was heated to 70°C and the methyl and propyl £-hydroxybenzoates, glycerine and carboxyrnethylcellulose were dissolved therein. The solution thus obtained was cooled co room temperature and the active ingredient was added whilst stirring. The solution was then made homogeneous. After addition of the sugar, sorbit solution and flavouring, the suspension was de-aerated by evacuation whilst stirring.

The suspension contains 50 mg/ml of 5,6-dimethoxy-N-£3-[N [2-(3,4- dimethoxyphenyl) ethyl ]me thylaminoj propyl]· phthalimidine hydrochloride

Claims (1)

1. CLAIMS wherein R^ represents a hydrogen atom, a alkyl group or a phenyl group; either R represents a hydrogen atom, chlorine atom 2. Or methoxy group and Rg represents a hydrogen atom or a methoxy group, or Rg and Rg together represent a methylenedioxy or 10 ethylenedioxy group; R^ and R^, which may be the same or different, each represents a hydrogen atom or a C^ alkyl group; either R^ represents a hydrogen atom or a alkoxy group and R? represents a alkoxy group, or Αθ 1s and R? together represent a methylenedioxy or ethylenedioxy group; X represents a carbonyl or sulfonyl group; and n represents 2 or 3; and acid addition salts thereof. 20 2. Compounds as claimed in claim 1 wherein Rp R^ and R^, which may be the same or different, each represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; - 43 52 Ether and R^ each represents a methoxy group, one being i the 5 position and the other in the 6 position of the ithalimidine ripg, or R£ and together represent a sthylenedioxy or ethylenedioxy group; either Κθ and R? ich represents a methoxy group, or Κθ and R? together represent methylenedioxy or ethylenedioxy group; and X represents carbonyl group. . 5,6-Dimethoxy-N-(3-0J-[2-(3,4-dimethoxyphenyl)ethyl]lethylaminojpropyl^phthalimidine and acid addition salts hereof. 5,6-Dimethoxy-2-{ 3-[n- [ 2- ( 3,4-dimethoxyphenyl)ethyl]- -1,2-benzisothiazoline-l,1-dioxide and acid addition salts thereof. phthalimidine and acid addition salts hereof. alts thereof. Compounds as claimed in claim 1 wherein the salts e physiologically compatible acid addition salts. 9. Compounds of general formula I as defined in claim 1 wherein R^ represents a hydrogen atom or a phenyl group; Rg represents a hydrogen atom, a chlorine atom or a methoxy group; Rg represents a hydrogen atom or a methoxy 6 group; R^ represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; Rg represents a hydrogen atom; and Κθ and R? each represents a methoxy group, one being in the 3 position and the other in the 4 position of the phenyl ring; and the physiologically .compatible acid 10 addition salts thereof. 10. Compounds of general formula I as defined in claim 1 wherein R^, R^ and Rg, which may be the same or different, each represents a hydrogen atom or a alkyl group; either R 2 and Rg each represents a methoxy group, one being 15 in the 5 position and the other in the 6 position of the phthalimidine ring, or R 2 and Rg together represent a methylenedioxy or ethylenedioxy group; and either R^ represents a hydrogen atom or a alkoxy group and R? represents a C-|_ 4 alkoxy group, Rg and R? not each representing a 20 alkoxy group one being in the 3 position and the other in the 4 position of the phenyl ring when represents a hydrogen atom, or Rg and R? together represent a methylenedioxy or ethylenedioxy group attached in the 2 and 3 or 3 and 4 positions of the phenyl ring; and the physiologically - 45 2 compatible acid addition salts thereof. 11. Compounds of general formula I as defined in claim 1 other than those compounds claimed in any of claims 3 to 7 as herein specifically disclosed in any of Examples 1 to 24. 12. Compounds of general formula I as defined in claim 1 other than those compounds claimed in any of claims 3 to 7 as herein specifically disclosed in any of Examples 19 to 22. 13. Compounds of general formula I as defined in claim 9 other than the compounds claimed in claim 3 or claim 4 as herein specifically disclosed in any of Examples 1 to 9. 14. Compounds of general formula I as defined in claim 10 other than the compounds claimed in any of claims 5 to 7 as herein specifically disclosed in aiiy of Examples 12 to 17. 15. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula II, (wherein Rp Rg, Rg, X and n are as defined in claim 1 and Z represents a' nucleophilic leaving group) with a con, P° und of f °™ la ΙΠ ’ R, ¢4 H-N-CH-CH O t + R, R, (III) 4296 (wherein R^, R^, R^ and R? are as defined in claim 1), 16. A process as claimed in claim 15 wherein, in the compound of formula II, Z represents a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group . 17. A process as claimed in claim 15 or claim 16 wherein, the reaction is effected in the presence of a solvent. 18. A process as claimed in claim 17 wherein the solvent comprises methanol, ether, tetrahydrofuran, methylformamide, dimethylformamide, dimethylsulfoxide or benzene. 10 19. A process as claimed in any of claims 15 to 18 wherein the reaction is effected at temperatures of from -50 to 250°C. 20. A process as claimed in any of claims 15 to 19 wherein the reaction is effected in the presence of an acid 1 5 binding agent. 21. A process as claimed in claim 20 wherein the acid binding agent comprises an alcoholate, alkali metal hydroxide or tertiary organic base. 22. A process as claimed in claim 21 wherein the acid 20 binding agent comprises triethylamine or pyridine. 23. A process as claimed in any of claims 15 to 19 wherein the reaction is effected in the presence of potassium iodide A process for the preparation of compounds of general 16 2 24. formula I as defined in claim 1, wherein represents a hydro gen atom and X represents a carbonyl group, which comprises reducing a compound of formula IV, wherein R2, Rg, R^, Rg, Rg, R? and n are as defined in claim ) whereby the desired compound of formula 1 is obtained. 25. A process as claimed in claim 24 wherein the reduction s effected with nascent hydrogen. A process as claimed in claim 2,5 wherein the nascent ydrogen is produced from a mixture of zinc and glacial acetic cid, tin and hydrochloric acid or tin(ll) chloride and ydrochloric acid. 7. . A process as claimed in claim 24 wherein the reduction s effected with catalytically activated hydrogen. A process as claimed in any of claims 24 to 27 lerein the reduction is effected at temperatures of from to 250°C. . A process as claimed in claim 28 wherein the reduction 3. Effected at temperatures of from 50 to 100°C. g fJ A process as claimed in any of claims '24 to 29 wherein the reduction is effected in the presence of a solvent. 31 - A process as claimed in claim 30 wherein the solvent comprises glacial acetic acid, water or ethanol. 4. 5 32. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises (wherein Rp Rg, Rg, R^, X and n are as defined in claim 1) with a compound of formula VI, (wherein Rg, R^/and R? are as defined in claim 1 and Z represents a nucleophilic leaving group). 33. A process as claimeu..in claim. 32 wherein, in the 15 compound of formula VI, Z represents a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group. 34. A process as claimed in claim 32 or claim 33 wherein the reaction is effected in the presence of a solvent. 35. A process as claimed in claim 34 wherein the solvent 20 comprises acetone, dimethylformamide, dimethylsulfoxide, - 49 G2 chlorobenzene or methylene chloride. 36. A process as claimed in any of claims 32 to 35 wherein the reaction is effected at temperatures of from 0 to 150°C. 37. A process as claimed in any of claims ..32 to 36 wherein the reaction is effected .in the presence of an acid binding agent. 33, A process as claimed in claim 37 wherein the acid binding agent comprises an alcoholate, alkali metal hydroxide, alkali metal carbonate or tertiary organic base. jg, A process ,as claimed in claim 38 wherein the acid binding agent comprises triethylamine or pyridine. tO. A process as claimed in any of claims .32 to 36 wherein :he reaction is effected in the presence of potassium iodide. . H, A process for the preparation of compounds of general formula I as defined in cLaim 1 which comprises reacting a compound of formula VII, (wherein Rp R 2> R^ and X are as defined in claim 1) with a compound of formula VIII, •R. R. (VIII) (wherein R^, Rg, Χθ, R? and n are as defined in claim 1 and Z represents a nucleophilic leaving group). 5 -42. A process as claimed in claim 41 wherein, in the compound of formula VIII, Z represents a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group. 43. A process as claimed in claim 41 or claim 42 wherein 10 the reaction is effected in the presence of a solvent. -44. A process as claimed in claim 43 wherein the solvent comprises acetone, dimethylformamide, dimethylsulfoxide or methanol. 45. A process as claimed in any of claims 41 to 44 wherein 15 the reaction is effected at temperatures of from 0 to 150°G, 46. A process as claimed in any of claims 41 to 45 wherein the reaction is effected in the presence of an acid binding agent. 47· A process as claimed in claim 46 wherein the acid binding agent comprises an alcoholate, alkali metal hydroxide, alkali metal amide or tertiary organic base. g A process as claimed in claim 47 wherein the acid >inding agent comprises triethylamine or pyridine. 9. A process as claimed in any of claims 41 to 45 wherein ;he reaction is effected in the presence of potassium iodide. 0. A process for the preparation of compounds of general formula I as defined in claim 1, wherein X represents a carbonyl group, which comprises hydrolysing a compound of formula IX, (wherein R^, R^, Rg, R^, Rg, Rg, R? and n are as defined in .laim l). I - A process as claimed in claim 50 wherein the hydrolysis .s carried out in the presence of a base or an acid. A process as claimed in claim 51 wherein the reaction ,s effected in the presence of potassium carbonate or hydrochloric icid. j. A process as claimed in any of claims 50 to 5Z wherein he hydrolysis is effected in a mixture of ethanol and water or dioxan and water. 54. A process as claimed in any of claims 50 to 53 wherein the hydrolysis is effected at temperatures of from 50°C to the boiling temperature of the reaction mixture. 55. A process as claimed in any of claims 50 to 54 wherein the compound of formula IX is obtained by reaction of a (wherein R^, Rj and R^ are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) with a compound of formula X, R, »4 H„N-(CH_) -N-CH-CH r 2 ' 2 n , 2 (IXa) (wherein R^, R^, Rg, R? and n are as defined in claim 1). 56. A process as claimed in claim 55 wherein the reaction 1 5 of the compound of formula IXa with the compound of formula X is effected in the presence of a solvent. 57. A process as claimed in claim 56 wherein the solvent comprises acetone, ethanol, dimethylformamide, dimethylsulfoxide or methylene chloride. 20 58. A process as claimed in any of claims 55 to 57 wherein the reaction of the compound of formula IXa with the compound of formula X is effected at temperatures of from 50°C to the boiling point of the 53 eaction mixture. 9, A process as claimed in claim 58 wherein the reaction f the compound of formula IXa with the compound of formula is effected at temperatures of from 50 to 150°C. 0. A process as claimed in any of claims 55 to 59 herein the reaction of the compound of formula IXa with he compound of formula X is effected in the presence of an cid binding agent. , '1 · A process as claimed in claim 60 wherein the acid inding agent comprises an alcoholate, alkali metal hydroxide, Ikali metal carbonate or tertiary .organic base. 12-. A process as claimed in claim 61 wherein the acid inding agent comprises triethyiamine or pyridine. 3. A process as claimed in any of claims .55 to 59 herein the reaction of the compound of formula IXa with the ompound of formula X is effected in the presence of itassium iodide. ’* A process as claimed in any of claims 55 to 63 wherein he compound of formula IX is prepared in situ. j A process for the preparation of compounds of general - 54 42962 formula I as defined in claim 1, wherein X represents a carbonyl group, which comprises cyclisation of a compound of formula XI, (XI) 5 [wherein R^, 1^ and Rg are as defined in claim 1 and either A represents Hal (Hal being a chlorine, bromine or iodine atom) and B represents a group of formula W, or B represents Y (Y being a nucleophilic group) and A represents a group of formula W, the group of formula W being a group of formula: '6 R. R, (in which R^, Rg, Rg, R? and n are as defined in claim 1)] whereby the desired compound of formula I is obtained. 5. 6θ· A process as claimed in claim 65 therein, in the compound of formula XI, A represents a group of formula W and B represents a chlorine, bromine or iodine atom or a methoxy or phenoxy group. 67 A process as claimed in claim 65 or claim 66 wherein the compound of formula XI is obtained by reaction of a compound of formula XII. CO-Y /herein Rp Rg and R 3 are as defined in claim 1 and al and Y are as defined in claim 65) with a compound of ormula X, as defined in claim 1. 3. A process as claimed in claiPi 67 wherein the compound £ formula XI is formed in situ. ). A process as claimed in any of claims 55 to 68 herein the cyclisation reaction and/or the reaction of ne compound of formula XII with the compound of formula X> 3 effected in the presence of· a solvent. A process as claimed in claim 69 wherein the solvent omprises acetone, dimethylformamide, dimethylsulfoxide or sthylene chloride. I A process as claimed in any of claims 64 to 69 wherein le cyclisation reaction and/or the reaction of the compound E formula XII with the compound of formula X is effected : temperatures of from 50°C to the boiling point of the 429G2 reaction mixture. 72. A process as claimed in claim 71 wherein the cyclisation reaction and/or the reaction of the compound of formula ΧΙΓ with the compound of formula X, is effected at temperatures of from 50 to 150°C, 5 73. A process as claimed in any of claims 65 to 72 wherein the cyclisation reaction and/or the reaction of the compound of formula XII tfith the compound of formula X, is effected in the presence of an acid binding agent. 74. A process as claimed in claim 73 wherein the acid 10 binding agent comprises an alcoholate, alkali metal hydroxide, alkali metal carbonate or tertiary organic base. A process as claimed in claim 74 wherein the acid binding agent comprises triethylamine or pyridine. 76. A process as claimed in any of claims 65 to /2 15 wherein the cyclisation reaction and/or the reaction of the compound of formula XII with the compound of formula X, is effected in the presence of potassium iodide. 20 77 . a process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula XIII, - 57 (XIII) wherein Rp Rp Rg, X and n are as defined in claim l), n acetal derivative thereof, with a compound of formula .s defined In claim 15, in the presence of catalytically etivated hydrogen. '8. A process for the preparation of compounds of ;eneral formula I as defined in claim 1 which comprises eacting a compound of formula XIV, R 6 R 5 -CO-CH 2 or III (XIV) wherein Rg, R^ and R? are as defined in claim 1), or an .cetal or ketal derivative thereof, with a compound of ormula V as defined in claim 32, in the presence of •atalytically activated hydrogen. 6. 9. A process as claimed in claim 77 or claim 78 wherein he reaction is effected in the presence of hydrogen and •alladium on charcoal. 0. A process as claimed in claim 79 wherein the pressure if hydrogen is about 5 atmospheres. £2962 31. A process as claimed in any of claims 77 to 80 wherein the reaction,is effected in the presence of a solvent. 82. A process as claimed in claim 81 wherein the solvent comprises methanol, ethanol or dioxan. 5 83. A process as claimed in any of claims 77 to 82 wherein the reaction is effected at temperatures of from 0 to 100°C. 34. A process as claimed in claim 83 wherein the reaction is effected at temperatures of from 20 to 80°C. 1θ 35. A process for the preparation of compounds of general formula I as defined in claim 1, wherein R^ represents a alkyl group, which comprises reacting a compound of formula I as defined in claim 1 (wherein represents a hydrogen atom) with an appropriate alkylating reagent. 15 8Θ. A process as claimed in claim 35 w/herein the alkylation is effected using an appropriate alkyl halide or dialkyl sulfate. 87. A process as claimed in claim 85, for the preparation of compounds of general formula I as defined in claim 1 in 20 which R^ represents a methyl group, wherein the alkylation is effected using a mixture of formaldehyde and formic acid. 88. a process for the preparation of physiologically compatible acid addition salts of compounds of general formula I as defined in claim 1 which comprises reacting a compound of formula I as defined in claim 1 with an appropriate acid. 89. A process as claimed in claim §8 wherein the acid comprises hydrochloric, phosphoric, hydrobromic, sulfuric, lactic, tartaric or maleic acid. 90. A process as claimed in any of claims 15 to 31 and 85 to 89 foii the preparation of compounds as defined in claim 9. 91. A process as claimed in any of claims 15 to 31 and 85 to 89 for the preparation of compounds as defined in claim 7. 10. 92. A process for the preparation of compounds as defined in claim 1 substantially as herein described. 93. A process for the preparation of compounds as defined in claim 1 substantially as herein described in any one 3f Examples 1 to · 24. '· 94. Compounds as defined in claim 1 whenever prepared ay a process as claimed in any of claims 15 to 89, 92 and 93. 95. A process for the preparation of compounds of general Eormula I as defined in claim 1 and physiologically compatible acid addition salts thereof substantially as herein described Ln any one of Examples 19 to 22. 36. Compounds of general formula I as defined in claim 1 md physiologically compatible acid addition salts thereof - 60 429G2 whenever prepared 'by a process as claimed in any -of claims 32 to 76, 35 to 89 'and 95. 97 _ A process for the preparation of compounds as defined in claim 9 substantially as herein described in any 5 one of Examples i to 9. 33. Compounds as defined in claim 9 whenever prepared by a process as claimed in any of claims 15 to 31 , 85 to 90 and 97. 99. A process for the preparation of compounds as defined 10 in claim 10 substantially as herein described in any one of Examples 10 to 18« 100. Compounds as defined in claim 10 whenever prepared by a process as claimed in any of claims 15 to 31, 85 tc 89, 91 and 99. 8. 15 101. Pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula I as defined in claim 1, or a physiologically compatible acid addition salt thereof, in association with a pharmaceutical carrier or excipient. 9. 20 102. Compositions as claimed in claim 101 in a form suitable for oral, rectal or parenteral administration. 103. Compositions as claimed in claim 101 or claim 102 in the form of tablets, coated tablets, suppositories, powders or solutions. 3S2 104. Compositions as claimed in any of claims 101 to 1.03 in the form of dosage units. 105. Compositions as claimed in claim 1 04 wherein each dosage unit contains from 20 to 300 mg of active ingredient. 106. Compositions as claimed in claim 105’ wherein each dosage unit contains from 25 to 200 mg of active ingredient. 107. Compositions as claimed in any of claims . 101 to 106 wherein the said active ingredient comprises a compound of formula I as defined in any one of claims 3 to 7 or a physiologically compatible acid addition salt thereof. 108. Compositions as claimed in any of claims 101 to 106 wherein the said active ingredient comprises a compound of formula I as defined in claim 9 or a physiologically compatible acid addition salt thereof. 109. Compositions as claimed in any of claims 101 to 106 therein the said active ingredient comprises a compound if formula! as defined in claim 10 or a physiologically compatible acid addition salt thereof. 110; Pharmaceutical compositions as claimed in claim 101 substantially as herein described. 1Π . Pharmaceutical compositions substantially as herein lescribed in any of Examples 25 to 28.