CA1073915A - Substituted arylalkylamines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to new substituted arylalkylamines which in general possess interesting pharmacological properties, in particular a heart frequency decreasing activity. These compounds are of the general formula I

(I) wherein R1 represents a hydrogen atom, a lower alkyl group or a phenyl group;
either R2 represents a hydrogen atom, chlorine atom or methoxy group and R3 represents a hydrogen atom or a methoxy group, or R2 or R3 together represent a methlenedioxy or ethylenedioxy group; R4 and R5, which may be the same of different, each represents a hydrogen atom or a lower alkyl group; either R6 represents a hydrogen atom or a lower alkoxy group and R7 represents a lower alkoxy group, or R6 and R7 together represent a methylene-dioxy or ethylenedioxy group; X represents a carbonyl or sulfonyl group; and n represents 2 or 3. Several processes for the preparation and inter-conversion of these compounds are described and exemplified. Examples of pharmaceutical compositions containing the new compounds are also given,

Description

'7;~l5 i~' : 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 ~ormula I, R2~<~N-(CH2)n-N-C~-CH

~- 3 wherein Rl represents a hydrogen atom, a lower alkyl group or a phenyl group; -~
' either R2 represents a hydrogen atom, chlorine atom or methoxy group and R
r' : represents a hydrogen atom or a methoxy group, or R2 ~and R3 together represent a methylenedioxy or ethylenedioxy group; R4 and R5, which may be the same or different, each represents a hydrogen atom or a lower alkyl group; either R6 represents a hydrogen atom or a lower alkoxy group and :R7 represents a lower alkoxy group, or R6 and R7 together represent a methylenedioxy or ethylene-dioxy~group; X represents a carbonyl or sulfonyl group; and n represents , ~ 2 or 3; and pharmaceutically acceptable acid addition salts thereof.
This in~ention also relates to a process for the preparation of a compound of the general formula I

R R6 ~ :~
~ N-~CR2)~-N-CI~-CH2 wherein Rl represents a hydrogen atom, a lower alkyl group or a phenyl group;
either R2 represents a hydrogen atom, chlorine atom or methoxy group and R3 represents a hydrogen atom or a methoxy group, or R2 and R3 together ~ ; -. ; represent a methylenedioxy or ethylenedioxy group; R4 and~R5, which may be - ~
:.jli,j . :
the same o~ diferent~ each represents a hydrogen atom or a lower alkyl :~
group; either R6 represents a hydrogen atom or a lower~alkoxy group and R7 ~:
:,', . :

~ ` -2~

3~

' represents a lower alkoxy group, or R6 and R7 toge~her represent a methylene- -:
dioxy or ethylenedioxy group; X represents a carbonyl or sulfonyl group; and ,n represents 2 or 3; or a pharmaceutically acceptable acid addition salt thereof, which comprises either:-'; (a) reacting a compound of formula II, : , R ~

N ( 2)n Z (II) ',.,: ~\X/ ' .

~~ R ::
.-~ 3 s'-, (wherein Rl, R2, R3, X and n are as defined above, Z represents a nucleophilic ~ leaving group) with a compound of formula III, :,, ''1 C ' 1/ ~ R6, ~III) S 5 ,,i, :-' 10 ~wherein R4, R5, R6 and R7 are as defined above);or b) reducing a compound of formula IV, :~

R4 R6 tIV) ~ ;
~ N_(CH2)n-N~CH-CH2 ~ ~ ~

,i,"~ . : ' ,,wherein R2, R3, R4~ R5, R6, R7 and n are as defined above);or ;', cl reacting a compound of formula V

~-(CH2)n-N-H ~V) .,: .
, ~wherein Rl, R2, R3, R4, X and n are as defined above) with a compound of ~. ., -. . , .` ~o~mula VI , ., .,. i .

; ~ ., .
~ 2a-:: ~ , ~ , . , . , - , -`"` 3L~1'~3~31S
. . .
. . ~` . .
. .
Z-CH-CH2 ~ 6 Rs ~ R7 ~YI) .j .
;"', (wherein R5~ R6 and R7 are as defined above and Z represents a leaving :;
:- gr~up; or (d) reacting a compound of formula VII, ~.'. : : H R
,: ~ 2~ (VlI) . ~ ~ : ¦ N-H
~/ \ X/ '. .

'r ~ ~ ~ (wherein R1J R2~ R3 and X are as defined above With a compound of formula VIII~

Z-(CH2]n~ Wj ~ 6 héreln.~ , R5~:R6, R7 and n ase as~defined 'above and Z represents~a:~
Vlng~grOUp; or 10 ~ e~ hydrolysing~a co~ound of formula IX

R2 ~ N~(CH2) -N-CH-CH2 R5 R~

herein R1J R2~ R3~ R4~ Rs~ R6~ R7 and n a~e as defined above~ to;,produce pound ~f ~ormula l~;w~erein~X TepreSentS a carbonyl group;~or . :~ : :;~ `. .
(fl cyclizing a compound of formula:XI, ~ ~

, ~

~ -2b-73~3~5 .

'' R2 11 .
. ~ CH-A (XI) i~ R CO-B
,.1 (wherein Rl, R2 and R3 are as defined above and either A represents Hal (Hal being a chlorine, bromine or idoine atom) and B represents a group of formula W, or B represents Y (Y being a leaving group) and A represents a group of formula W, the group of formula W being a group of formula: .

; ~RI-(cH2)n-N-cH-cH2 : H R5 ~ R7 tin which R~, R5, R6, R7 and n are as:dcfined above) to produce~a compound of formula I wherein X represents a carbonyl group; or (g) react m g a compound of~formula XIII, R2 ~ ~

10~ I N~tCH2)n_l~CH

~A ~ R ~ \ X ~ (XIII~ ;

t~wherein Rl,~R2, R3, X and n arc as defined above)~or an acetal dcrlvatlve :
: thercof,~with a compound of for ~ là III as;defined above in the presencc of catalytically activated hydrogen;;~or ~
h): reacting a compound of formula XIV,~ :

5-C-C * ~ (11 r 1~73915 ' (wherein R5, R6 and R7 are as defined abov~ or an acetal or ketal derivative ~; thereofJ with a compound of formula V as defined above, in the presence of ` catalytically activated hydrogen; or : (i) reacting a compound of formula I as defined above (wherein R4 represents a hydrogen atom) with an appropriate alkylating reagent; and where any of steps (a) to ~i) can be followed by the additional step of converting a base ~: of formula I into a corresponding pharmaceutically acceptable acid addition salt.
;; ~''".'"` ' ' ''.'' :: . .
" :
-, :, i ................................................................... . . .
' ~'' :''-' :.- :~
:. ~. :
.; .

'.','', ' .-..

,,.': ' .
;,~ 1 ~ '. . `

,! ~ I .;
`;1 - ~` - ~
.,,. ~ .
, '~''''; ' `
`:'.''' '' ~' `
~ 2d- ~

-- - t,V ~ L5 .', .

.~ It will be appreciated that for pharmaceutical use the acid addition salts will be physiologically compatible acid , addition salts but other acid addltion salts may, for example, rJ' be useful as interm~diates in the preparation of compounds of ~?~ 5 ~ general formula I and physiologically compatible acid addition . ~, : . .
salts thereof.
The`compounds of general formula I and the acid addition salts thereof possess interesting pharmacologlca1 propert1és and in general~exhibit heart frequency decreasing activity.
10 ~ Where Rl, R4 and/or R5 are alkyl groups, they are prefer~
ably methyl, ethyl, propyl or isopropyl groups; where R6 and/or R7 are alkoxy groups they are preferably ethoxy, ethoxy, ;~ propoxy or isopropoxy groups.
Preferred compounds according to the invention are those~
15 ~ ~ wherein~compounds~as hereinbefore defined wherein R1, R4 and R5`, which may be the;same or different, each represents a hydro-gen~atom or an alkyl group containing from l to 3 carbon~atoms;~
` either R2-and R3 each represents a methoxy group, one being in~
the 5 position and the~ other in the 6 position of the phthal~
`20~ imidine ring; or R2 and R3 together represent a methylenedioxy or ethylenedioxy group; either R6~and R7 each represents~a~
methoxy group, or R~ and R7 together represent a methylenedioxy~
or ethylenedioxy group; and X represents a carbonyl group Particularly preferred compounds according to the inven~
tioD ~are the following~

73~cj .

5,6-Dimethoxy-N-{3- [N-[2-(3,4-dimethoxyphenyl)ethyl]methyl~
' ~' amin~ propyl}phthalimidine; ~ ;
5 7 6-Dimethoxy-2-~3- ~N-[2-(3,4-dimethoxyphenyl)ethyl]methyl- ' ~. ;
amin~ propyl}-1,2-benzisothiazoline~ dioxide; ~ -.
5~ 5,6-Methylenedioxy-N-{3- ~-[2-(3,4-methylenedioxyphenyl)ethyl]-methyl~amino~ propyl}phthalimidine; : ~ :'' 5 6-Dimethoxy-N-~3- ~N-[2-(3,4-methylenedioxyphenyl)ethyl']~ .-':':~:
methylamino~propyl}phthalimidine; ~ .- ~ ;
5,6-Ethylenedioxy-N-{3-~N-[2-(3,4-methylenedioxyphenyl)ethyl]-1~ : : . :
. 10 ~ . methylamino~propyl~phthalimidine; ~ ..
and~.acid addition salts thereof. ~ .
The compounds according:~to~the present invention~may, for ; :~
s ~ ,'e e, be prep red acco ding~to~t ~foll ing p ocesses ch~
~ '; proce:sses~constitute further'features of the present inventio.n~
.: 15~ .. A..Reàcti ~of a c p d o~ ~fo la II, '' :H~ R

; (whéreLn Rl~, R2, R3, X and~n are~as hereinbefore:defined and~
; Z represents a leaving group such as, for example, a chlorine, :;'bromine or iodine~atomoran alkylsulfonyloxy or arylsulfonyloxy ~'' group) with a compound of formula III, :. ~ ~ . . , , : , 39~
..... .

. . -, H-N-CH-CH2- ~ R6 (III) ~ R5 7 s~ (wherein R4, R5, R6 and R7 are as here~inbefore defined).
The reaction is conveniently carried ~out~ in the presence of a solvent, e.g.~methanol, ether, tetrahydrofuran,methylPormamide,~
dimethylformamide, dimethylsulfoxide or benzene, and conven- ~ ~
5~ ~ iently at~temperatureg of from -50 to 250C 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 ;~
eac~ion~accél-rator;~such~ potassium~'odide~iJ;of advantage~
10 ~ B~ For the preparation of compounds of general fQrmula I wherein~
; RI represents a hydrogen at~om nd X~représénts a carbonyl~gr ~ ~edhc~OA e comp~ of formula IV,~

N (CH2)n N CH CH

2~ 3~ R4~R5,~ R6~ i7 and n are~s~he ~ inbetore 15~ The reduction is prefera~ly carried out in the presence of a solvent such as, for example~, glacial acetic acid,~water or -`
~ ~73~

` ethano~ conveniently with nascent hydrogen obtained, for examp 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 reduc~
. ~ - . .
.. . .
~ 5 ; tion will be effected at temperatures of from 0 to 2500C pre~
-, ~ ,, .
:~ -; ferably 50 to lOO~C. . :
- : .
. C~ Reaction of a compound of formula V, :

~: : R2~ H Rl R

R ~ ~ X ~ (V) , ~ - .
(wherein Rl, R2, R3, R4, X and n are as hereinbefore defined) with a compound of formula VI, - Z-CH-CH
R : ~ (VI) :~

lO~ ~ (wherein R5, R6 and R7 are as hereinbefore defined and~ ; : ; : :: Z represents~a leaving group such as, for example,~a chlorine, bromine or lodine~atom or an alkylsulfonyloxy or arylsulfonyl- ~;
oxy group).
The::reaction is conveniently carried out m the presence of a i ~:15 ::~ solvent, e~g, acetane, dimethylformamide, dimethylsulfoxide,: ~:
chlorobenzene or methylene chloride, and conveniently at ~
. :. ~ : . . - ,.
: ., ~ : ~ . : .
~ 6 -, . . . .

~-\
:

temperatures from 0 to 150C depending on the reactivity of : the group Z. The presence of an acid binding agent, e.g. an ,; . .
- ~ ~ alcoholate, alkali metal hydroxide9 alkali metal carbonatç or :, . .
:~ ~ tertiary organic base such as triethylamine or pyridine, or , ~
~5 : of a reaction accelerator such as potassium iodide is of .

~- i . advantage.

D Reaction of a compound of formula VII, : J , ;:, :

(wherein Rl, Rz, R3 and ~ are as hereinbefore defined.~ with a.
~ : compound of formula VIII, :}~ 4 ~ 6 ~ (VIII) -(CH2)n-N-CH-cH2 ~

. ;10~ (wherein R4, R5, R6,:R7 and n are as hereinbefore defined and ~ : ; -Z~represents a leaving group such as, for ~example, a chlorine, bromine or:iodine atom or:an alkylsulfonyloxy or arylsulfonyl~
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 150C . :

, . , - .

. ~ .
, , -: . . .
,. . . . .. .

~ ~t~ 9 1 S
.

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 E. For the preparation Of compounds Of general formula I~
~ wherein X represents a carbonyl group:
~ Hydrolysis Of a compound Of formula IX~
. .
,.. . .. .

(CH~)n-N-I -CD; ~ ~ (IX) 2~ R3~ 4~ R5~ R6~ R7 and n ~re~ a- hereinbefore ~lO ~ def~ined). ~ ~ ~
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 I5 ~ water. Conveniently the hydrolysis is effected at temperatures of from 50G to the boiling temperature Of the reaction mixture.
The compound of formula IX may~ be obtained by reaction Of a compound Of formula IXa, . : 8 ~ : .
-~31~S :., .':' Rl , ':` R2 CH-Hal R~ CN

twherein Rl, R2 and R3 are as defined in claim 1 and Hal represents a chlo-rine, bromine or iodine atom) with a compound of formula X, X~ H~N-(CH~)n-N-cH ~H2 ~ 6 R ~-- R

twhet~in R4, R5, R6, R7 and n~are as defincd~above, e.g. the reaction of the~compound of~formula IXa with the compound of~formula X~ls;;effected m the presence of a~ solvent, e.g. acetone, ethanol, dimethylformamide,~dimethyl~
sulfoxide or methylene;~chloride.;~ The reactlon can also~be eonvenlcntly ef~
ected in~the presence~of~an;acid-binding agent e.g.~an alcoholate,~alkali lO ~ metal~hydroxlde,~alkall~metal carbonate or tertlary~organtc~basc~such as ;~
-;t:riethylamine or pyrid m e in a similar way to~that described for process variants A~to D incluslve. The use of a~reaction accelerator such;as~
`r,~ `potassium iodide is of advantage.

i,:;" ~ ~

,:':, ~ : : : :

,.,. ~ - :

': :,, ` E- Cyclisation of a compound of formula XI, :~ , R
.: R :
~CH - A ~ .
co (XI) : ~ ~ R3 : :
.- [wherein Rl, R2 and R3 are as hereinbefore defined and either . A represents Hal (Hal being a chlorine,~bromine or iodine atom)~
~:. : J : ..
and B represents a group of formula W, or B represents Y (~
S ~- belng~a leaving group) and A represents a group of formula W,~ . .
the~group of~formula W being~a group of formula~
(CH~jn-N-CH-rH2 ~ 6 H~ R R :~

` (in which R4, R5, R6, R7~and n are as~hereinbefore defined)]
w~ereby the desired compound of formula;I-is obtained.
In the above compound of formula XI, when B represents Y then~
~ lO~ Y~may,~for example, be ~a chlorine, bromine or iodine atom or a~
r''' ~.~,i~, ''`,.. ~ mëthoxy~or phanoxy group.
lf deslred, the compound of~formula ~I may be prepared, pre~
ferably in situ, by reaction of a compound of formula XIa, : :~

. R2 ~ R~
CH~- Hal : ~ CO-Y ~ (XIa) ? . i : :
39~LS
' , .
` (wherein Rl, R2, R3, Hal and Y are as hereinbefore defined), with a compound of formula XII, H2N-(CH2)n-N-lH C 2 ~ 6 (XII) R5 7 ~ -(wherein R4, R5, R6, R7 and n are as hereinbefo/e defined).
The cyclisation and/or the reaction of the compound~of formula S ` ~ X~a with the compound of formula~XII may conveniently be ;~
effected~in the presence of a solvent, e.g. acetone, dimethyl~
,:,: , . j formamide, dimethylsulfoxide or methylene chloride, and con-~veniently at elevated temperatures, e.g. at temperatures from 50 to~lSO~C. The presence of an acid bindlng agent, e.g.~an 10 ~ 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.
G. Reaction of a compound of formula XIII, N - (CU2)n_l-CHO ~ (XI~

3 ~ ~

(wherein Rl, R2, R3, X and n are as hereinbefore defined~ or an ~ acetaI derivative thereof, with Q ~compound of formula III as hereinbefore defined, in the presence o~ catalytically ac~ivated `;

, i . . : ~ : ~
hydrogen.

.,.~ ~ : ~,.

1~73 ,; .

.
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 pre-' ' sence of a solvent such as, for example, methanol, ethanol or dio-xan and at temperatures from 0 to 100C, preferably 20 to 80C. ~ ; ~ '''.
H. Reaction of a compound of formula XIV, ., ( ~ ~ . .
.
Rs - C0 - CH2 ~ ~ ~ (XIV) ~ ~ ~

- (wherein R5, R6 and R7 are as hereinbefore defined), or an ~. ' , . . . . ...
acetal or ketal derivative thereof, with a compound of formula ~ .
V as hereinbefore defined7 in the presence of.càtalytically .''~..'~' 10~ activated hydrogen~
The reducLive i~minatioD is cAnveDiently carrled out with;~
hydrogen i~ the presence of palladium on charcoal, preferably~
" at a hydrogen pressure of about 5 atm., preferably in thè pre~
s~ence:of~a solvent such as, for example, methanol,~:~ethanol.or dio- :...
5~ xan'and~at.temperat~res from O:.to':-100C,.preferably 20 to 80C. ~':~-'':
~ii . .' ' . I. For the preparation of compounds of general fo mula~I,wherein.
R4 represents a lower alkyl group~
Alkylation with an appropriate alkyIating agent of a compound: :~
~ of formula I as hereinbefore defined~(wherein R4 represents a :~..';
'.~. 20 ~ hydrogen atom) The alkylating agent. may, for example, ::

'' :~ : ~ 12 ~

73~5 . .
; comprise an alkyl halide or dialkyl sulfate or, for the pre- ;
; paration of compounds of formula I wherein R4 represents a methyl group, a mixture of formaldehyde and formic acid.
; J~ For~the preparation of physlologicqlly compatible acid - ~5 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 exa~ple, hydrochlorlc ac~d, ~ 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 ;~
15 ~ phthalimide with zinc dust in~ glacial acetic acid and optlonal`
',''. ubsequent hydrolysis.
be zyl halide of fo la IX or XI ~is prefer~ ly o t ined~by halogenatlon of a corresponding toluene, e.g.~with N-bromo~
~ ;succinimide in carbon tetrachloride, optionally with addition id~ ;2~ of~an initiator such as~dibenzoyl; peroxide and/or with UV~ irradiatio~
As~already mentioned~above, the new compounds of general formula I and the acid addition salts thereof possess inter~
esting pharmacological properties. The compounds according to `

f~73~9iL5 ,: ' ~
.','.~ ~' ', "'', .~ 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 -- ~ 5~ - their biological properties: ~ :
., . : . . .
A = 5,:6-Dimethoxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-amino~ propyl~phthalimidine hydrochloride, B = 5,6-Dimethoxy-2-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl~
~ amino3propyl}-1,2-benzisothiazoline-1,1-dioxide ~ ~ :
.. 10.:~ : hydrochloride, ~ : .
C =~ 5,6-Methylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)~
et~y13methylamin~ propyl}phthalimidine hydrochloride, ;D~;= 5,6-Dimethoxy-N-{3- ~-[2-(3,4-methy~lenedioxyphenyl~ethyl~]-~methylamin~ propyl~phthalimidine hydrochloride and: ;:
15:~ . E =~4,5-Ethylenedioxy-N-~3- CN-[2-(3,4-methylenedioxyphenyl)~
ethyl]methylamin~ propyl}phthalimidine hydrochloride.
Activit~ on hezr requency of narcotized f inea pi s~
The~;heart;frequency of guinea~pigs under ure~thane narcosis~
was registered by an electrocardiogram.~ The substances. . ;~
20 ~ under test were administered intravenou6Ly in increasing ~:~
dosages between O.S and 20 mg/kg.
. The following table indicates the variation in heart~
frequency of the guinea pigs~

'' . ' 31 073fffg~Lff~i ".~
~ . , .
~. .
,~` _ ~ Dose ~ . ~
Substance mg/kg n Percentage decrease in heart frequency .'.. ' ' ., . 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 ~
.':` f :', . ,'~ : . '~

2. ctivity on heart frequency in the auricle of the guineapig~
Isolated spontanèously beating auricles of guinea plgS 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~/o of 2 and Sh of C02) and kept steadlly at ~30C. The contractions were registered isometrically :.. . ~ , .
. . .

. . - ~ ~ :,, .

, , ;.: , . i: :, . . ; .... . .. . . .. . . . ~ . . . ' . .. . . . . - - .
,~,, . .. , : . ,. , -, . , . . ~ . . .... ." , .. , .. , . , . .-.

., .. : . . .. . . . . . . i . .; : .. . . . . .
~i ., ., .,,,, , .. : , , , . ,, . , . ,.. , , ,. ." , , , , . , . ,., .. , . ,:, , ,;, , , . , .:, . - . . .. . . .. . . , ., . . , . . .~ . , . . . . -~.
. ~ - : . . . ~ . , ,.. . :: - ... . . .. .. .. . . . .... .. . .. .... . . .

~ ~073915 i ~ .
with a Statham-Force transducer on a Grass-polygraph. The su~-: 1 ~
stances under test were added to the organ baths, such that the ' ' .,~ 5 .
'' final concentration was 10 g/ml in each case. 5 auricles were used for each solution.
~5 The following table gives the percentage decrease in heart ~' ' 1~"' , ' ' fre~uency over an average of 5 auricles (concentration of sub- ; ' stance = 10 5 g/ml).

~ Substance Decrease of frequency in %'~ ;' .i.'-'~ ' ,, ~ - ~. ~ --- , ''~ ~ _~52 ~ ~
;~ B - 60 ~ ;~ "-, ~ D- ;, ~ 51 , ~ ~ 48 . ~ ~ . ___ ~ _ ~ ' 3'~Acute toxicit~y.
The acute toxicity oP the substances in~question~was deter~
~' 10',",~ mined in mice (obse ~ ation t- e: l4,d s)~af er or l~or~
'intravenous application. ~The~ LD50~was calculated~from the~
erGentage~ of animals which;died aftér administration~of`~
various doses within the~obser ation time (see J.,Pha macol,,~
exp.~ Therap, 96, 99 (~1949))~

Substance 50 , _ ~.... _ _ .
9 8 mg/kg i . v, A 1.570 mg/kg p.o.
B 100 mg/kg i.v.
J . i ~ ~: - -- ~ _~

.~

: 1~)739~S

:
. - According to a still further feature of the present inven-~ ... tion there are provided pharmaceutical compositions comprising '. as active ingredient at least one compound of formula I as . ~ , . .
hereinbefore defined or a physiologically com*atible 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~ta~
lets, powders, solutions,~suspensions and suppositories.
Advantageousl~ the compcsitions may be formulated~as dosage;~
15~ ;units~, each~unit being:adapted to supply a fixed~dose of ;~
active~ingredient. Suitable dosage~units for a~dult9 contain~
from:20~to-300 mg., preferably~25 to 200 mg,, of active ingredient The~;following~ùon-limiting ExamplGs serve to.illustr~te~
.~1 20 ;- the present ntion~

r ~ 17 .':1, .'~ ,, ' ` ;, , ',', ' '~,,. ' ,, .' . ' '' .` "` ` "' . '` . ' -' , ';.. " ' ' ~ ~3~
; . . .
~ .
.
"' ~ .
' N-~3- [N-[2-(3,4-dimethoxyphenyl)ethyl]methylamlno~propyl}- ~ ..
phthalimidine hydrochloride a) N-~3- [N-[2-(3,4-Dimethoxyphenyl)ethyl]~ethylamin~ propyl3- '' phthalimide_ _ ~
1'.' ~ ' 5.04 g (0.02 mol) of 1-LN-[2-(3,4-dimethoxyphenyl)ethyl]- ' ~
;, .
methylamin~-3-amino-propanè and 2.06 g (0.02 mol) of s" phthalic anhydride were dissolved in 100 ml of glacial acetic acid and the solution obtained was refluxed for 4 : : .
' 10 - - ~ hours. Subsequently the mixture was evaporated undervacuum. ~ ' ,., - . ~ . :
; ~ 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 = l/lj: 0.4 ; ' '~' ' ' b) N-{3-[N-[2-(3,4-Dimethoxyphenyl)ethyl~methylamin~ propyl}-~
phthalimidine hydrochioride _ ~ =
' ;~ 6.1 g (159 mmol~ of N- ~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]- ~
methylamin~ propyl}phthalimide, dissolved in 80 ml of ~;' glacial acetic acid, were mixed with 10 g of zinc dust and~
subsequentl~ reduced by refluxing for 3 hours. To separate q. i "~
.~.. ;: - : ' ~ . ~ .

,... .... ............ ....... . . . . .. ... ... ... .. ....... . . .. . . . . . ... . . . .... .. ..... . ...

. . . ~ . . , . - . .. . .

9~S
.'"`'. . ' . .
~ 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 '~odium carbonate solution ~' 5 ~ 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 ob- ~ ~ :~
tained by precipitation from ethereal hydrochloric acid. ~: ~ :
After digestion with ethyl acetate the hydrochloride had a~ - .
10 . ' m.p. of 146-148C. ~ :
Yield: 2.25 g'(35 % of theory) 5,6-Dimethoxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)-ethyl]methyl-~
' amin~ propyl}~hthalimldine~hydrochloride ;'. 15~ a) 5,6-Diméthoxy-N-{3- ~N-[2-(3,4-~dimethoxyphenyl)ethyl3methyl-~
amin~ propY13phthalimide~
Prép æed~analogously to Example`l:a~by~condensation of~4,5 .` di ho ~ -phthalic ~ dride 'th~ -C2-(3, 4 di~ t -~
' phenyl)ethyl]methylamino]-3-amino-propane in~glacial acetic .p.:;~ 91~g3C. .. .
.b)~5,6-Dimethoxy-N- ~ [2-(3,4-dimethoxyphen~l)ethyl]methyl~
amino~propylJphthalimidine hydrochloride ~()t7;~LS
: .
`.,` :
Prepared analogously to Example lb by reduction o~ 5,6-di-methoxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylamin~
propyl}phthalimide with zinc dust in glacial acetic acid. -,. ~ ., ~ ~ M.p.: 170-172C.

; ~ 5 Example 3 5,6-Dimethoxy-N-{3-[2-(3,4-dimethoxyphenyljethyl]amino-propyl}-phthalimidine hydrochloride .. : , ---- : ~
a) 5,6-Dimethoxy-N-{3-[2-(3,4-dimethoxyphenyl)ethyl]amino-propy-1~phthalimide 10 ~ Prepared analogously to Example la by condensation of 4,5-dimethoxy-phthalic anhydride with 1-[2-(3,4-dimethoxyphenyl)-ethyl]amino-3-amino-propane in glaciaL acetic acid.
Rf value (chloroform/methanol = 9jl): 0.25 b) 5,6-Dimethoxy-N-{3-[2-(3,4-dimethoxyphenyl)ethyl]amino~
15 ~ propyl}phthalimidine hYdrochloride ` ~ `
Prepared analogously to Example lb by reduction of 5,6-dimethoxy-N-~3-[2-(3,4-dimethoxyphenyl)ethyl]amino-propy~ -phthalimide with ZiDC dust in glacial acetic acid.
M.p.: 207-209OC.
~20~ ~ Examele 4 5,6-Dimethoxy-N-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-aminb~propy~ phthalimidine hydrochloride ~ 20-;'!;:: ~:
"'~`':i ;: . -i',~';'`' . ~ ; ' ::`
~ 3~15 , . .
5 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 chloro-form. The chloroform layer was washed with water, dried and then evaporated under vacuum. The residue was purlfied by chromatography on silica gel (chloroform/methanol = 45/1).
......
. The main fractions were evaporated and the base was precipi-tated as the hydrochloride from ethereal hydrochloric acid.
M.p.: 170 - 172C.
Example 5 5,6-Dimethoxy-N~ 3-[N-[2-(3,4-dimethoxyphenyl)ethyl]propyl-aminolpropyl}phthalimidine hydrochloride ;~ A solution of 25 g ~5.5 mmol) of 5,6-dimethoxy-N-{3-[~2-~3J4-dimethoxyphenyl)ethyl]amino-propyl}phthalimidine in 100 ml of acetone was refluxed for 6 hours after addition of 20 ml of l-bromopropane and 5 g of potassium carbonate. After coollng the solid portion was filtered off and the filtrate was evap-orated. The product was taken up in ether, the insoluble part ,.:: ~ .. , ;.
was again filtered off and, after evaporition, the hydro-chloride was precipitated from~ethereal hydrochloric acid. ~ :
M.p.: 120 - 122C ~acetone/methanol).

.; . . , : .',' . ~,.:

.'; , '.' ,'' ~ ~,'-.' ' : :
'.',~ `" :~

~ ` ' :':' . : .

. :
"'.',,: ~,; ' ~LV739~S
. .
... .
~ Example 6 .
~ ,6-Dimethoxy-N-~3-CN-[2-(3,4-dimethoxyphenyl)ethyl~methyl-., . . , _, . . . . . . . . . . . .
amin J ethy~ phthalimidine h~drochlor de ~ ..
3.81 g (lS mmol) of N-(2-bromoethyl)phthalimide were refluxed ~- 5 together with 6 g of N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-amine in 40 ml of xylene for 10 hours. The oily residue ,, i : :
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.
~` 10 ~ ~ ~ M.p.: 149-151C. ~ ;
Example 7 N-{3-CN-[2-(3,4-Dimethoxyphenyl)ethyl]methylamin~ propyl~-3-phenyl-Phthalimidine ~ `
1.75;g (5.3 mmol) of N-(3-bromopropyl)-3-phenyl-phthalimldine - 15 ~ were refluxed with 2.06 g (10.6 mmol) of N-[2-(3,4-dimethoxy-phenyl)ethyl]methylamine ln 30 ml of xylene for lO hours.
After cooling.the mixture was evaporated and the residue was ~;
purified by chromatography on silica gel ~chloroform/methanol 19~ ; The base was obtained as a highly viscous `
~20 ~ oil.
Rf value (chloroform/methanol - 19/1): 0.

y~!8 3-Phenyl-5-chloro N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-ami ¦ pro ~ ide - 22 ~

,'.. , - , ' ~ : : - -` 1~3739~S

,:
3 g (9.3 mmol) o~ N-~3-chloropropyl)-3-phenyl-5-chloro-1,2-; benzisothiazoline-l,l-dioxide were refluxed together with 3 g of N-[2-~3,4-dimethoxyphenyl)ethyl]methylamine and a spatula-full of potasslum iodide in a solution of 30 ml of dimethyl-formamide and 5 ml of triethylamine for 5 hours. Subsequently the mixture was evaporated to dryness. The residue was taken :
~ up ln chloroform and the organic layer was washed several - tlmes wlth water. After drying the mlxture was evaporated , . . . .
- and the residue was purified by chromatography on silica -~ 10 gel Cchloroform/methanol = ~0/1). The hydrochloride was ob-~ tained as an amorphous product by precipitation with ethereal - ;
,- hydrochloric acid.
Rf value (chloroform/methanol = 19/1): 0.5.
'~ C27H31ClN204S x HCl (551-54) Calculated: C 58.8 H 5.60 N 5.10 S 5.80 ~.. ~.~ .. : -ound: C 58.7 H 5.?5N 5.20 S 5.90 Example 9 ~ -5,6-Dlmethoxy-N-{3-[N-[2-(3,4-dlmethoxyphenyl)ethyl]methyl-amino]-propyl}--l~z le ~ hi~-~lr~ l,l-dloxlde hydrochloride ~-,, . : :
a) 2^Methyl-4,5-dimethoxy-benzenesulfonyl chloride 23.2 g ~0.2 mol) of chlorosulfonlc acid were slowly added dropwise to 15.2 g (0.1 mol) of 3,4-dimethoxytoluene at about -10C whilst stirring and cooling. After the addi-~- tion W2S complete, the mixture was left to warm up to room~
., ~, ~. .

" - .:
. ,~' .

::;:~;.:, .
,:,~',' ..

:. .:.1 .

',. ,:
~ - 23 -.~: ' ' : . ~ .
:,. . .
~ A, ', . .
,i! ~ ; ~ , ~ ~,,, , , ~ , ", , " ,, , , ,,, " ~

~~lS

, temperature and stirred until the hydrogen chloride evolu-. .
tion 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 ,~ 5 sodium hydrogen carbonate soIution and water and then evap-., .
orated to dryness under vacuum. A turbid oil was obtained as residue, which solidified on cooling.
... . . . i,~ - ~ ; Rf value (benzene): 0.5.
b) 2-Methyl-4 5-dimethoxy-benzenesulfonamide , 10 18 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 deslred sulfonamide W2S obtained as 5~ an~amorphous product after drying.
Rf~value (benzene/acetone = 1/1): 0.6.
c) 5.6-Dimethoxy-1,2-benzisothiazo1ine-3-one~ dioxide 16 g (0.08 mol) of 2-methyl-4,5 dimethoxy-benzenesulfonamide were~disso1ved in~S00 ml of 5% sodium hydroxide solution.
~20 ~ ~After the addition of 39.6 g (0.25 mol) of potassium per-. manganate 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.

Rf value (benzene/acetone = 3jl): 0.2-004, .:., ,, : . ~ .
:
.~. ~ , .
. .

,, , , . . ~ . , . . ~ , .
:" ' ` ': . ': ~,.!~.`, . . ..
: .~ . . : , ,, ", , .:: . : , .,. . - . " , ' . . . ..

73~3'15 d) 5~6-Dimethoxy-1~2-benzisothiazoline~ dioxide ` 7 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 ob- -tained was diluted with water and subsequently 2 N hydro-chloric acid was added thereto until the aluminium hydroxlde ` precipitate which had precipitated was redissolved. The ~ ¦
lO~ 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 ;
c ~ filteration with suction 15; ~ ej N-(3-Chloropropyl)-5,6-dimethoxy-1,2-benzisothiazoline~
dioxide~
; 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 20 ~ addition of 10 ml of 3-bromo-1-chloro propane, the solution was refluxed for 8 hours. The reaction mixture ; was then evaporated to half its volume, diluted with watsr and extracted with chloroform. After drying, the organic layer~was evaporated under vacuum and the desired product ~ -25_ ~ ~

:
. . . ~ , . : ~

:,~; : : :

1(~'739~5 ;' :.
';' was obtained as a highly viscous oil ~ Rf value (chloroform/methanol = 19/1): 0.8 'Y" f) 5,6-Dimethoxy-N-{3-CN-[2-(3,4-dimethoxyphenyl)ethyl]methyl-' amino] propyl}-1,2-benzisothiazoline-1,1-dioxide ' ~; 5' '- hydrochloride .. . _ . . _ . . . .
, - ~ .
Prepared analogously to Example 8 by reaction of N-(3-chloro-' propyl)-5,6-dimethoxy-1,2-benzisothiazoline-1,1-dioxide with ~' ~ N-[2-(3~,4-dimethoxyphenyl)ethyl]methylamine '' -- . M!p .: 196-1~8C (acetone) ; ~ ' ' ,,i. j ~ , . .
;i,10 ,xample 10 5,6-Methylenedioxy-N- {3-[N-[2-~3,4-dimethoxyphenyl)ethyl]methyl-'' am ~ o~yl~p _ alimidine ~ _ - '' a) 3.5 g (l8 mmol) of 4,5-methylenedioxy-phthalic anhydride and ~ 4-5~8 (18 mmol) of L-CN-[2-(3,4-dimethoxyphenyl)ethyl]methyl-~
'I'15~ amino]-3~amino-propane were refluxed~'in 100 ml of glacial acetic~acid for 2 hours. Subse~quently the mixture was~evap-orated under vacuum and the residue was taken up in chloro~
form. The chloroform solution was successively~washed;with ' saturated sodium hydrogen carbonate solution and water~
'"'2~ After drying over sodium sulfate, the solvent was distilled ~ ' off snd the desired substance was obtained~as an amorphous L'.,,~l ~ :, ' product.

; ~ , . .
'L'~ Yield: ,4.8 g (63 % of theory), ~ Rf value~chloroform~methanol - 9/l~: U.G

. .:: , :~
'~"~ , .: -.: : ' ,. ' , . ..
., ,, , ' -- , :: . : :: .

`; ~0~73~15 ~ , ..
b) 5,6-Methylenedioxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl3-methyls _ ~ propyl~phthalim dine hydrochloride _ : 4.8 g (11 mmol) of 5,6-methylenedioxy-N- ~-~N-[2-(3,4- -j: .
dimethoxyphenyl)ethyl]methylamin~ propyl}phthalimide, dis- :::

~;5 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 filtersd off from . .
the hot solution and .the filtrate was evaporated under vacuum.~ Th9 residue was~ dissolved in chloroform and ths --~
10 ~ 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 237-239C, was pre- ;:.
~ : cipitated by addition of ethereal hydrochloric acid.
... ~lS ~ Yield: 1.5 g (30 % of thsory).
Calculated: C 61.53 ~H 6.51 H 6.24 ~1 7.90 : Found: :~ 61.50 6.49 6.24 7.85 Example~
; 5,6-Ethylenedioxy-N-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]~
20:~ me ~ lamin~ proPy~ phthalimidine~hydrochloride .
a~. 4,5-Ethylenedioxy-N-~3-CN-[2-(3,4-dimethoxyphenyl3ethyll-met~ylamin~ pro~yl~phthalimide . ~:
Prepared analogously to Example lOa by condensation of 4,5 ?:, :`
ethylenedioxy-phthalic anhydride with l-[N-[2-(3,4-~0'73~5 dimethoxyphenyl)ethyl]methylamin~ -3-amino-propane in glacial acetic acid.
Rf value (chloroform/methanol = 9/1): 0.5 q ~ b) 5,6-Ethylenedioxy-N-{3- ~-[2-(3,4-dimethoxyphenyl)ethyl~-~; ~ 5 methylamin ~ propy~ phthalimidine hy =
Prepared analogously to Example lOb by reduction of 4,5-eth~lenedioxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]meth~
~` amin~ propyl}phthalimide with zinc dust in glacial acetic acid.
10 ~ ~` M.p.: 208-210C.
Calculated: C 62.26 H 6 75N ~ 6.05Cl 7.66 Found: 62.10 6 845.90 7 67;
xample 12 5,6-Methylenedioxy-N-~3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]-~
5~ methylamin~ propyl}phthalimidine hydrochloride ~ ~`
`a3~4,5-Methylenedioxy-N-~3-~N-[2-(3,4-methylenedioxyphenyl)~
eth~llmeth~lamin~ 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-methylènedioxy-~;~` 20~ phenyl)ethyl]methylamine were dissolved in 20 ml of~chloro~
benzene and, after addition of 2 8 g (20;mmol~ of pulverized potassium carbonate, were refluxed for a hours. Subsequently~ ;~
,.,, . ~ ~; ~ ; .
the solution~was filtered and evaporated to dryness under~ ` ;vacuum.; The residue was purified by chromatography on -28 ~

.. ,: : , . - ~ . . :

:.'.,. ` ; - :
,,., .. ~ . ; . .

1~7;~iLS

~; silica gel (chloroform/methanol = 19/1) and, after evapora-tion of the main fraction,2.1 g (51 % of theory) of the de-sired compound were obtained.
- ~ :
- Rf value (chloroform/methanol = 9/1): 0.6 b) 5,6-Methylenedioxy-N~ N-[2-t3~4-methylenedioxyphenyl) ethyl]methylsmin~ propyl~

Prepared analogously to Example lOb by reduction of 4,5- ~ ;
methylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]- ~, : ~
methylamin~ propyl}phthalimide with ZiDC dust in glacial ` --~ 10 acetic acid. ~ -.
M,p.: 206-208C.

Calculated: C 61.04 H 5.82 N 6.47 ~Cl 8.19 Found: 61.10 ~ 6.07 6.748.45 Example 13 ~ ~ -15~ 5,6~Ethylenedioxy-N-~3- CN [ 2-(3,4-methylenedioxyphenyl)ethyl~-methylamin~roPyl}phthal-imidine hydrochloride a)~4~5-Ethylenedioxy-N-{3-:cN-[2-(3~4-methylenedioxyphenyl) eth~Jmethylamin~ propvl}phthalimide ~
Prepared analogously to Example 12a by reaction of 4,5-~20~ ethylenedioxy-N-(3-chloropropyl)-phthalimide with N-[2~
(3,4-methylenedioxyphenyl)ethyl]methylamine in chloroben- ~ - -zene in the presence of potassium carbonate.
Rf value (chloroform/methanol - 9/1): 0,5.

29-~

., : ~ : , ~0~73~15, . ...... ..

'~ - b) 5,6-Ethylenedioxy-N-~3-[N-[2-(3,4-methylenedioxyphenyl)-ethyl~methylamin~ propyl~phthalimidine hydrochlor~de __ Prepared analogously to Example lOb by reduction of 4,5-` ethylenedioxy-N-~3- ~N-[2 (3,4-methylenedioxyphenyl)ethyl]-methylamin~ propyl}phthalimide with zinc dust in glacial ~`~ acetic acid.
- M.p.: 180-182C
; Calculated: C 61.81 H 6.09 N 6.27Cl 7.93 Found: 61.70 6.12 ~ 6 127.94 10 ~ Example 14 5,6-Dimethoxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]-methyrlamin~ propyl~phthalimidine hydrochloride a? 4~5-Dimethoxy-N-~3-[N-[2-(3~4-methylenedioxyphenyl)ethyl]--:. methylamin.~ pro w l}phthalimide ;; 15~ Prepared analogously to Example~12a by reaction of 4,5-ditnethoxy-N-(3-chloropropyl)-phthalimide with N-[2-(3,4-methylenedioxyphenyl)ethyl~methylamine in chlorobenzene in the p~esence of potassium carbonate.
Rf value (chloroform/methanol = 19/1): 0.7.
~ ~ b) 5,6-Dimethoxy-N-~3-CN-[2-(3,4-methylenedioxyphenyl)ethyl]-methYlamin~ propyl~p_ halimide hydrochloride Prepared analogously to Example lOb by reduction of 4,5-di-~

methoxy-N-~3- CN-~2-(3,4-methylenedioxyphenyl)ethyl]meth~
~ amin~ propyl}phthalimide with zinc dust in glacial acetic acid, - 30-, ' . : . ': :
.,: ~ . . : . :

:: : , - , . ~,: - : - ~ : . :
, : , , ~ ., , ,.,. ~ , , : ~: :

.. , . . ~

~ 3~iS
"
M.p.: 235-237C.
Calculated: C 61.53 H 6.51N 6.24 Cl 7.90 ~ Found: 61.45 6.63 6.277.92 ., , :
; Example 15 . .
5,6-Ethylenedioxy-N-{3-~N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-amin~ Propy~_1 2-benzisothiazoline-l~Ll-dioxide~hydrochloride : . .
Prepared analogously to Example 12a by reaction of N-(3-chloro- ~ -~ propyl)-5,6-ethylenedioxy-1,2-benzisothiazoline-1,1-dloxide ,,, .
with N-[2-(3,4-dimethoxyphenyl)ethyl]methylamine.
Rf value (chloroform/methanol = 9/1): 0.6.
Example 16 ~ ~ ~ 3-Methyl-5,6-dimethoxy-N-~3- ~-[2-(3,4-dimethoxyphenyl)ethyl]--~ ~ ~ r~y~ phthalimidine hydrochloride Prepared~analogously to Example 12a by reaction of 3-methyl-5,6-~
~15 ~ dimethoxy-N-(3-chloropropyl)-phthalimidine~with N-[2-(3,4-"~ ~dimeth~oxyphenyl)ethyl]methylamine in chlorobenzene in the pre-seDce of potassium car~onate.
M p.:;135-136C.
~;Calculated: C 62.68 H 7 36 N 5.85Cl 7~.40 20~Found: ~ 62.31 7.40 5.80 7.12 Example 17 ~ 5,6-Dimethoxy-N-~3-CN-[2-(3~,4-dimethoxyphenyl)-l-methyl-ethyl]-;~ methylamino~ propyl}phthalimidine hYdrochloride ,, ~. ~, ~ . - - --~~-'~3'f'3~`15 i: ~

a) 4,5-Dimethoxy-N~~3-[N-[2-(3,4-dimethoxyphenyl)-1-methyl-ethyllmethylamin~ propyl~hthalimide _ _ . - . -Prepared analogously to Example 12a by reaction of 4,5 di-.i, . . .
methoxy-N-(3-chloropropyl)-phthalimide with N-[2-(3,4-dimethoxyphenyl)-l methyl-ethyl]methylamine in chlorobenzene in~the presence of potassium carbonate.
.. , - : ~
Rf value (chloroform/methanol = 9/1): 0.9 ; ~ b) 5,6-Dimethoxy-N-~3- CN-c2-(3,4-dimethoxyphenyl)-l-methyl-eth~l]methylamin~ propyl}phthalimidir.e h~drochloride .
Prepared analogously to Example lOb by reduction of 4,5-di-methoxy-N-~3- CN-[2-(3,4-dimethoxyphenyl-l-methyl-ethyl]-~, , - , : .;~ methylamino]propyl~phthalimide with zinc dust in glacial ~ ¦
acetic~ acid.
;M.p.~ 183-185C. ~
15; ~ Calculated: C 62.68 H 7.36 N 5.85Cl 7.40 ~-Found~ 62.50 ~ 7.42~- ~ 5.92~7.30 xample 1 5,6-Methylenedioxy-N-~2-[W-[2-(3,4-dimethoxyphenyl)ethyl]-methylamin~ ethyl~phthalimidine hydrochloride ~0~ ~ ; a)-4,5-Methylenedioxy-N-~2-[N-[ (3,4-dimethoxyphenyl)ethyl]-methylamin~ ethyl3phthalimide Prepared analogously to Example lOa from 4,5-methylene~
dioxy-phthalic anhydride and 1- [N-[2-(3,4-dimethoxy-phenyl)ethyl]methylamino~ 2-amino-ethane.

32_ . ~ :
,; ~ .: , ~ -. - ~ . . ~
: -; . ,~

,,:: ~ ~ , ., : : :

~L ~)r73~ ~L 5 ,, ~ .
. . , Rf value (chloroform/methanol = g~ 0.55.

b) 5,6-Methylenedioxy N-~2-[N-[2-(3,4-dimethoxyphenyl)ethyl]-.; methylamin~ ethyl}phthalimidine hydrochloride Prepared analogously to Example lOb by reduction of 4,5-: : :
~ 5 methylenedioxy-N-~2-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-,: , ~ ~ amino~ethyl phthaIimide with zinc dust in glacial acetic . ,,.. ' , .. . .
;~ acid.

Rf value (chloroform/methanol = 9~ 0.4.
.~ -xample l9 10 ~ 5,6-Dimethoxy-N-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-~..... .. . . . .
amin~ propyl~ph-thalimidine hydrochloride 5 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~ ~ ;
15 ~ in~lOO 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~
tiops were dissolved Ln acetone and the hydrochloride was pre-20~ cipit~ated by addition of e~thereal~hydrochloric acld -; M.p~,: 170-172C.
Example 20 5,6-Dimethoxy-N-{3-[N-[2-(~3,4-dimethoxyphenyl)ethyl]methyl-amin~ pro~y~ phthalimidine hydrochloride - - 33~
!:' :~: . : :

:~0'~3~1~

i ; 0.5 g of sodium hydride were added to a solution of 3.0 g (15 mmol) of 5,~dimethoxy-phthalimidine in 100 ml ofdimethyl-formamide. The mixture obtained was subsequently heated up to 80C for 30 minutes. 8.5 g (30 mmol) of 1-CN-[2-(3,4-5 dimethoxyphenyl)ethyl]methylamino]-3-chloro-propane, dissolved , in 100 ml of dimethylformamide, were then added dropwise. The mixture thus obtained was heated up to 140C for 7 hours.
; ~ After cooling, water was added and the mixture was extracted ~ ~ ~ several times with chloroform. The organic layers were dried ~ -i, ~, . .
, 10- and then evaporated to dryness under vacuum. The crude product ~-was purified by chromatography OD silica gel. The hydro-chloride was obtained by precipitation with ethereal hydro-- chloric acid.
M.p.: 170-172C.
15 ~ ExamE~e 21 5,6-Dimethoxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl~
min~ propyl}phthal- idine hydrochloride .45 g ~5 mmol) of methyl 2-bromomethyl-4,5-dimethoxy-benzoate~
2.52 g~(10 mmol) of 1-[N-[2-(3,4-dimethoxyphenyl)ethyl~methyl-20~ ~ amin~ -3-amino-propane and 3 g of potassiuin carbonate were re-:: : ~
fluxed in 200 ml of methyl ethyl ketone for 4 hours. After cooling, the insoluble part was filtered off and the filtrate ,.,., ~ . : :
was evaporated under vacuum. The crude product was purified by ~ ~ -chromatography on silica gel (chloroform/methanol = lg/l). The 34 _ ; . ~

-". ... , .. " . ., . ~ . . , ........ .. . . . ... ~ . . . .
. . ~
. ~
. ,. ~. -:, , . ~ . .
.. . .
, . .. .
. ., ~V73~3~S

hydrochloride was obtained by precipitation with ethereal '~ hydrochloric acld M.p.: 170-172C. -Example 22 o ~ 5 ~ 5,6-Dimethoxy-N-~3-~N-[2-(3,4-dimethoxyphenyljethyl]methyl- ~; ' `~ amin~ propyl}ph~h~ ~dine~hL~5e9hloride ,::
a) l-CN-[~2-(3,4-Dimethoxyphenyl)ethyl3methylamino] -3-(1-imino-5,6-di h~y~ halimidine-2-yl)-propane 6.4 g (0.025 mol) of 2-cyano-4,5-dimethoxy-benzyl bromide '' 10 ~ and 6.3 g (0.025 mol) of 1-~N-[2-~3,4-dimethoxyphenyl)-.., '' ~ ethyl3methylamin~ -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~pro~
cessed further in reaction step b! without purification.
' ~15~' ; Rf value (chloroform/methanol = 19/1): 0.5.
b~5,6-Dimethoxy-N-{3-rN-[2-~(3,4-dimethoxyphenyl~ethyl]methyl-amin~ propyl~phthalimidine hvdrochloride ' 5 g o crude~l-CN-[2-(3,4-dimethoxyphenyl)ethyl]methyl~
'' amin~ -3-(1-imino-5,6-dimethoxy-phthalimidine-2-yl)-propane i~ -o ~ 'and ll g of potassium carbonate were refluxed for 8 hours in ~'~
a mixture of 50 ml of ethanol and 80 ml of water. The mix-ture was then evaporated under vacuum and-the crude product thus o'btained was puri~ied by~chromatograph~ on silica gel (chloroform/methanol - 19/1). The free base was obtained _ 35_ 1 ,.~. ;~; .

3~S
" ~
~ from the evaporated fractions and was precipitated as the ;
hydrochloride with ethereal hydrochloric acid.
M p : 170-172C.
.:"
; Example 23 ~ 5 5,6-Dimethoxy-N-~3-[2-(3,4-dimethoxyphenyl)ethyl]amino-propyl~-., .~,, .
~ _ .. ......
., , ~ ~- After the addition of 0.3 g of palladium/charcoal (10%) into a solution of 2.6 g (10 mmol) of 1-amino-3-(5,6-dimethoxy- ~ i phthalimidine-2-yl)-propane and 1.8 g (10 mmol) of 2-(3,4- ~ ~-.. ,., ~, ~ . -:
dimethoxyphenyl)acetaldehyde in 100 ml of ethanol, hydrogen was introduced over a period of 4 hours at a temperature of 50C
and at 5 atm.~ pressure. After;absorption of the hydrogen,~the~
; ; catalyst was filtered off and the solution thus obtained was~
evaporated under vacuum. The hydrochloride was~obtaine~d by~
15 ~ ~precipitation with ethereal hydrochloric acid.
M.p.: 207-209C.
Ex~mple 24 5,;6-Dimethoxy-N-~3-[2-(3,4-dimethoxyphenyl)ethyl~amino-propyl~
phthalimidine hydrochloride 20~ After the addition of 0.3 g of palladium/charcoal (10%) in to a solution of 3.2 g (10 mmol) of 3-(5,6-dimethoxy-phthal~imidine-2-yl)propionaldehyde-diethylacetal and 1`.8 g (10 mmol) of 2-.;: ~ ~ .(3,4-dimethoxyphenyl)ethylamine in lOO ml of ethanol, hydrogen was introduced over a period of 4 hours at a temperature of :

50C and at 5 atm pressure. After absorption of the hydrogen, the catalyst was filtered off and the solution obtained was i: .
~ evaporated under vacuum. The hydrochloride was obtained by :
precipitation with ethereal hydrochloric acid.
M.p.: 207-209C.
The following compounds were also prepared analogously to Examples l9 to 24:
N- {3-~N-[2-(3,4Dimethoxyphenyl)ethyl]methylaminoJ propyl}- ' phthalimidine hydrochloride ~10 M.p.: 146-148C.
"- :, : : .
5,6-Dimethoxy-N-{3-N-[2-(3,4-dimethoxyphenyl)ethyl]amino-propyl~phthalimidine hydrochloride M.p.: 207-2090C
5~,6-Dimethoxy-N-{3-CN-[2-(3,4-dlmethoxyphenyl)ethyl]propyl-IS~ min~ propyl}phthalimidine;hyrdochloride -M.p.: 120-122C (acetone/methanol).
5,6-Dimethoxy-N-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methyl~
amin~ thyl}phth-limidine hyrdochloride M p.:~149-151C.
~ N-r3- CN-[2-(3,4-Dimethoxyphenyl)ethyl]methylamin~ propyl~-3- ~ -phenyl-phthalimidine Rf value (ehloroform/methanol = 19/1): 0.4.

~;;, , .

"................... . : . ~ ~-,.~. .: . : . ..

.. ~i~ . . . .. .. . . . . .. .. .. ..... . .. . . .

~7~
.",,~ , .
3-Phenyl-5-chloro-N- {3-~N-[2-(3~4-dimethoxyphenyl)ethyl]-methylamin~ propyl~-1,2-benzisothiazoline-1,1-dioxide hydro-,. . .
~ chloride , ., Rf value (chloroform/methanol = 19/1): 0.5.
~ _ 5,6-Dimethoxy~N-{3- N-[2-(3,4-dimethoxyphenyl)ethyl]methyl-amin~lpropyl}-1,2-benzisothiazoline-1,1-dioxide hydrochlorlde ; M.p.: 196-198C (acetone).
,; - . .' 5,6-Methylenedioxy-N-{3-~N-[2-(3,4-dimethoxyphenyl)ethyl]-methylamin~ propyl}phthalimidine hydrochloride ~lO M~p.: 237~239C. ~ ~
." , : .
5,6-Ethylenedioxy-N-r3-[N~[2-(3,4-dimethoxyphenyl)ethyl]-methylamin~ propyl}phthalimidine hydrochloride ~ ~ ~
; M.p.: 208-210C. I
5,6-Methylenedioxy-N-~3-~N-[2-(3,4-methylenedioxyphenyl)ethyl]~
-15 methylamin~ propyI}phthalimidine hydrochloride - M~po 206-208 C .
5~,6-Ethylenedioxy-N-{3- CN-[2-(3,4-methylenedioxyphenyl)ethyl]-methylamin~ propyl}phthalimidine hydrochloride M p.~: 180-182C.
~20 ~ 5,6-Dimethoxy-N-{3- [N-[2-(3,4-methylenedioxyphenyl)ethyl]-methylamin~ propyl}phthalimidine hydrochloride ~N.p : 235-237C. ~ ~
5~6-Ethylenedioxy-N- {3-[N-C2-(3,4-dimethoxyphenyl)ethyl]-: . :.
methylamin~ propyl~-1,2-benzisothiazoline~ dioxide hydro-chloride s;` ~ - 38 ,. ,, , :

,, .: :, . . .- , ,.. , . . : . , . ., ~. ... . ~ ..
s. : . ,, .. ,, ... ,, .. , ,,... : .. ... ......

; . 1~)'7;~1S
..`, ~ Rf value ~chloroform/methanol = 9Jl): 0.6 . .
3-Methyl-5,6-dimethoxy-N-~3-CN-[2-(3,4-dimethoxyphenyl)ethyl]-methylamin~ propyl~phthalimidine hydrochloride M.p.: 135-136C.
~; 5 5,6-Dimethoxy-N~~3-CN-[2-(3,4-dimethoxyphenyl)-l-methyl-ethyl]-methylamiin~ propyl}phthalimidine hydrochloride -~ M.p.: 183-185C.
- Example 25 .. ~ . .
~ : , . . .
Tablets containing 100 mg of 5,6-dimethoxy-N-~3-CN-[2-(3,4-~10~ ~ dimethoxyphenyl~ethyl]methylamlno]propyl}phthalimidine hydro~
- chloride Composition~
Active lngredient ~lOO.O mg lactose~ 50.0 mg polyvinyl pyrrolidone ~ 5,~0 mg carboxymethylcellulose ~ 19.0 mg maignesium stsarate 1.0 mg 175.0 mg Method of~preparation ~20~ Thie active ingredient and lactose were homogeneously moisteDed~
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 tabiets in the~

usual mianner.
~ 34~

" , , : .

.ii . . , , : ., ~ .. ; . .. ., ., -. ~ .,, . -.. , . -~ 73~
.

.
: .
Example 26 ~, - Coated tablets containing 50 mg of 5,6-dimethoxy-N-~3-CN-[2-~ (3,4-dimethoxyphenyl)ethyl]methylamin~ propyl~phtha.limidine :; hydrochloride . - ----- .. ~
~ 5 1 coated tablet core: :
. ~ .
~ Active ingredient 50.0 mg ;~
: corn starch, dried 20.0 mg .
solu~le starch . 2.0 mg ;. , i:
carboxymethylcellulose 7.0 mg ;~ 10 . magnesium stearate 1.0 mg 80.0 mg~
Method of preparation: .
The mixture was processed into tablet cores as described ln Example 25. The cores were then covered with a coating con~
lS ~ sLsting of sugar and gum arablc.
Example 27 Suppositories containing 150 mg of 5,6-dimethoxy-N-~3-[N-[2- ::
(3,~4-dimethoxyphenyl)eLhyl]methyl _ino] propyl}phthalimldine~
; hydrochloride 20~ ~ ~Composition~
Active ingredienit 150.0 mg ~ :
1 ~ - ~ ~ . . . :
~ supposltory mass 1 550.0 mg . .

`,!.:, ~ . , , ,,l 1 700.0 mg ~

; ., : : ~ : - ~ -.- .
, - - -- - ~ - -: -- - - -. .

:: . : , , .... .. :. . . - . ... . :, : . : . .. ..

~) 7~9~5 .. .
Method of preparatio'n: :
. The active ingredient was homogeneously dispersed in the molten ' suppository mass and the liquid mixture thus obtaine~l was ~:
. .
poured into pre-cooled suppository moulds.
: :: 5~ .Example 28:
Suspension containing 50 mg/ml of 5,6-dimethoxy-N-~3-[N-~2- ~
: ~(3,4-dimethoxyphenyl)ethyl]methylamino]propyl}phthalimidine : :~:
oride 100 ml of suspension contain~
,.: .,: , , ,~ 10 Active ingredient 5.0 g ~ ~ :
,. ~ . . .
carboxymethylcellulose ~ ~ 0.1 g "~ methyl ~-hydroxybenzoate : : O.OS g ---propyl p-hydroxybenzoate . 0.01 g sugar ~ 10 0 ,l5 ~ Blycerine ~ ~ 5.0 g sorbit solution 70 % ~ 20.0 g flavouring ~ ~ ~ 0.3 g dis~tilled water ~ ~ ad ~ 100.0 ml Method of preparation~
Z0~ The distilied water was heated to 70C and the~ methyl and propyl ~-hydroxybenzoates, glycerine and carboxymethylcellulose were dissolved therein. The solution thus obtained was cooled ~. ~! : : .
~ : to room temperature and the active ingredient was added whilst . , ; . , . . . . : , . -- .,:' ~ . - ... : .
:.. , : ~ ............... , - . . .- . : .
~ ~A " ,, ' . . .. . .

.L173~S
; .

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 SO mg/ml of 5,6-dimethoxy-N-~3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylaminolpropyl}-phthalimidine hydrochloride

Claims (39)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of the general formula I

(I) wherein R1 represents a hydrogen atom, a lower alkyl group or a phenyl group;
either R2 represents a hydrogen atom, chlorine atom or methoxy group and R3 represents a hydrogen atom or a methoxy group, or R2 and R3 together represent a methylenedioxy or ethylenedioxy group; R4 and R5, which may be the same or different, each represents a hydrogen atom or a lower alkyl group; either R6 represents a hydrogen atom or a lower alkoxy group and R7 represents a lower alkoxy group, or R6 and R7 together represent a methylene-dioxy or ethylenedioxy group; X represents a carbonyl or sulfonyl group; and n represents 2 or 3; or a pharmaceutically acceptable acid addition salt thereof, which comprises either:-(a) reacting a compound of formula II, (II) (wherein R1, R2, R3, X and n are as defined above, Z represents a nucleophilic leaving group) with a compound of formula III, (III) (wherein R4, R5, R6 and R7 are as defined above);or (b) reducing a compound of formula IV, (IV) (wherein R2, R3, R4, R5, R6, R7 and n are as defined above; or (c) reacting a compound of formula V

(V) (wherein R1, R2, R3, R4, X and n are as defined above) with a compound of formula VI

(VI) (wherein R5, R6 and R7 are as defined above) and Z represents a leaving group; or (d) reacting a compound of formula VII, (VII) (wherein R1, R2, R3 and X are as defined above) with a compound of formula VIII, (VIII) (wherein R4, R5, R6, R7 and n are as defined above) and Z represents a leaving group; or (e) hydrolysing a compound of formula IX
(IX) (wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined above), to produce a compound of formula I wherein X represents a carbonyl group, or (f) cyclizing a compound of formula XI

(XI) (wherein R1, R2 and R3 are as defined above) and either A represents Hal (Hal being a chlorine, bromine or iodine atom) of formula W, or B represents Y (Y being a leaving group) and A represents a group of formula W, the group of formula W being a group of formula;

(in which R4, R5, R6, R7 and n are as defined above) to produce a compound of formula I wherein X represents a carbonyl group; or (g) reacting a compound of formula XIII, (XIII) (wherein R1, R2, R3, X and n are as defined above) or an acetal derivative thereof, with a compound of formula III as defined above in the presence of catalytically activated hydrogen; or (h) reacting a compound of formula XIV, (XIV) (wherein R5, R6 and R7 are as defined above), or an acetal or ketal derivative thereof, with a compound of formula V as defined above, in the presence of catalytically activated hydrogen; or (i) reacting a compound of formula I as defined above (wherein R4 represents a hydrogen atom) with an appropriate alkylating reagent; and where any of steps (a) to (i) can be followed by the additional step of converting a base of formula I into a corresponding pharmaceutically acceptable acid addition salt.

2. A compound of the general formula I, (I) wherein R1 represents a hydrogen atom, a lower alkyl group or a phenyl group;
either R2 represents a hydrogen atom, chlorine atom or methoxy group and R3 represents a hydrogen atom or a methoxy group, or R2 and R3 together represent a methylenedioxy or ethylenedioxy group; R4 and R5, which may be the same or different, each represents a hydrogen atom or a lower alkyl group; either R6 represents a hydrogen atom or a lower alkoxy group and R7 represents a lower alkoxy group, or R6 and R7 together represent a methylenedioxy or ethylene-dioxy group; X represents a carbonyl or sulfonyl group; and n represents 2 or 3; or a pharmaceutically acceptable acid addition salt thereof, whenever pre-pared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1 wherein R1, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group con-taining from 1 to 3 carbon atoms; either R2 and R3 each represents a methoxy group, one being in the 5 position and the other in the 6 position of the phthalimidine ring, or R2 and R3 together represent a methylenedioxy or ethy-lenedioxy group; either R6 and R7 each represents a methoxy group, or R6 and R7 together represent a methylenedioxy or ethylenedioxy group; and X represents a carbonyl group.

4. Compounds as claimed in claim 1 wherein R1, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group con-taining from 1 to 3 carbon atoms; either R2 and R3 each represents a methoxy group, one being in the 5 position and the other in the 6 position of the phthalimidine ring, or R2 and R3 together represent a methylenedioxy or ethylenedioxy group; either R6 and R7 each represents a methoxy group, or R6 and R7 together represent a methylenedioxy or ethylenedioxy group; and X rep-resents a carbonyl group, whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process according to claim 1 in which R1 represents a hydrogen atom, R2 and R3 are methoxy groups in the 5- and 6- positions, R4 represents a methyl group, R5 represents a hydrogen atom, R6 and R7 are methoxy groups in the 3- and 4- positions, X represents a carbonyl group and n represents three.

6. A process for the preparation of 5,6-dimethoxy-N-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl} phthalimidine and its hydrochloride which comprises either (a) reducing 5,6-dimethoxy-N-{3-[2-(3,4-dimethoxy-phenyl)ethyl]methylamino]propyl} phthalimide; or (b) methylating 5,6-dimethoxy-N-{3-[2-(3,4-dimethoxyphenyl)ethyl]aminopropyl} phthalimidine; or (c) reacting 5,6-dimethoxy-N-(3-methylaminopropyl)phthalimidine with 2-(3,4-dimethoxyphenyl)ethyl chloride; or (d) reacting 5,6-dimethoxyphthalimidine with 1-{N-[2-(3,4-dimethoxyphenyl)ethyl]methylamino} -3-chloropropane; or (e) reacting methyl 2-bromomethyl-4,5-dimethoxybenzoate with 1-{N-[2-(3,4-dimethoxyphenyl)ethyl]methylamino}-3-aminopropane; or (f) hydrolysing 1-{N-[2-(3,4-dimethoxyphenyl)ethyl]methylamino }-3-(1-imino-5,6-dimethoxy-phthalimidine-2-yl)propane; and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

7. A process according to claim 1(a) in which the reduction is effected by reaction with zinc and acetic acid.

8. A process according to claim 1(b) in which the methylation is effected by reaction with a mixture of formaldehyde and formic acid.

9. A process according to claim 1(f) in which the hydrolysis is effected by reaction with potassium carbonate.

10. 5,6-Dimethoxy-N-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylamino]
propyl} phthalimidine and its hydrochloride whenever prepared by the process of claim 6, 7 or 8 or by an obvious chemical equivalent thereof.

11. A process according to claim 1 in which R1 represents a hydrogen atom, R2 and R3 are methoxy groups in the 5- and 6-positions, R4 represents a methyl group, R5 represents a hydrogen atom, R6 and R7 are methoxy groups in the 3- and 4-positions, X represents a sulfonyl group and n represents three.

12. A process for the preparation of 5,6-dimethoxy-2-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl} -1,2-benzisothiazoline-1,1-dioxide and its hydrochloride which comprises either (a) reacting N-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisothiazoline-1,1-dioxide with N-[2-(3,4-dimethoxy-phenyl)ethyl]methylamine; or (b) reacting 3-(5,6-dimethoxyphthalimidine-2-yl) propionaldehyde-diethylacetal with (3,4-dimethoxyphenyl)ethylamine in the presence of catalytically activated hydrogen; and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

13. 5,6-Dimethoxy-2-{3-[N-[2-(3,4-dimethoxyphenyl)ethyl]methylamine]
propyl}-1,2-benzisothiazoline-1,1-dioxide and its hydrochloride whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.

14, A process according to claim 1 in which R1 represents a hydrogen atom, R2 and R3 together form a methylenedioxy group joining the 5- and 6-positions, R6 and R7 together form a methylenedioxy group joining the 3- and 4- positions, R4 represents a methyl group, R5 represents a hydrogen atom, X represents a carbonyl group and n represents three.

15. A process for the preparation of 5,6-methylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]methylamino]propyl} phthalimidine and its hydrochloride which comprises either (a) reducing 4,5-methylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]methylamino]propyl} phthalimide; or (b) reacting 3-(5,6-methylenedioxyphthalimidine-2-yl)propionaldehyde diethyl acetal with 2-(3,4-methylenedioxyphenyl)ethylamine in the presence of catalytically activated hydrogen; and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

16. A process according to claim 15(a) in which the reduction is effected by reaction with zinc and acetic acid.

17. 5,6-Methylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]
methylamino]propyl} phthalimidine and its hydrochloride whenever prepared by the process of claim 15 or 16 or by an obvious chemical equivalent thereof.

18. A process according to claim 1 in which R1 is a hydrogen atom, R2 and R3 are methoxy groups in the 5- and 6- positions, R6 and R7 together form a methylenedioxy group joining the 3- and 4- positions, R4 represents a methyl group, R5 represents a hydrogen atom, X represents a carbonyl group and n represents three.

19. A process for the preparation of 5,6-dimethoxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)-ethyl]methylamino]propyl} phthalimidine and its hydrochloride which comprises either (a) reducing 4,5-dimethoxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]methylamino]propyl} phthalimide; or (b) reacting 3-(5,6-dimethoxyphthalimidine-2-yl)propionaldehyde-diethylacetal with (3,4-methylenedioxyphenyl)ethylamine in the presence of catalytically activated hydrogen; and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

20. A process according to claim 19(a) in which the reduction is effected by reaction with zinc and acetic acid.

21. 5,6-Dimethoxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)-ethyl]
methylamino]propyl} phthalimidine and its hydrochloride whenever prepared by the process of claim 19 or 20 or by an obvious chemical equivalent thereof.

22. A process according to claim 1 in which R1 is a hydrogen atom, R2 and R3 together form an ethylenedioxy group joining the 5- and 6- positions, R4 represents a methyl group, R5 represents a hydrogen atom, R6 and R7 together form a methylenedioxy group joining the 3- and 4- positions, X
represents a carbonyl group and n represents three.

23. A process for the preparation of 5,6-ethylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)-ethyl]methylamino]propyl} phthalimidine and its hydrochloride which comprises either (a) reducing 4,5-ethylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)ethyl]methylamino]propyl} phthalimide; or (b) reacting 3-(5,6-ethylenedioxyphthalimidine-2-yl)propionaldehyde-diethyl acetal with 2-(3,4-methylenedioxyphenyl)ethylamine in the presence of catalytically activated hydrogen; and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

24. A process according to claim 23(a) in which the reduction is effected by reaction with zinc and acetic acid,

25. 5,6-Ethylenedioxy-N-{3-[N-[2-(3,4-methylenedioxyphenyl)-ethyl]
methylamino]propyl} phthalimidine and its hydrochloride whenever prepared by the process of claim 23 or 24 or by an obvious chemical equivalent thereof.

26. A process for the preparation of compounds of general formula I
as defined in claim 1 which comprises reacting a compound of formula II, (II) (wherein R1, R2, R3, X and n are as defined in claim 1 and Z represents a nucleophilic leaving group) with a compound of formula III, (III) (wherein R4, R5, R6 and R7 are as defined in claim 1).

27. A process as claimed in claim 26 wherein, in the compound of formula II, Z represents a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group.

28. A process for the preparation of compounds of general formula I
as defined in claim 1, wherein R1 represents a hydrogen atom and X represents a carbonyl group, which comprises reducing a compound of formula IV, (IV) (wherein R2, R3, R4, R5, R6, R7 and n are as defined in claim 1) whereby the desired compound of formula I is obtained.

29. A process for the preparation of compounds of general formula I
as defined in claim 1 which comprises reacting a compound of formula V, (V) (wherein R1, R2, R3, R4, X and n are as defined in claim 1) with a compound of formula VI, (VI) (wherein R5, R6 and R7 are as defined in claim 1 and Z represents a nucleophilic leaving group).

30. A process for the preparation of compounds of general formula I
as defined in claim 1 which comprises reacting a compound of formula VII, (VII) (wherein R1, R2, R3 and X are as defined in claim 1) with a compound of formula VIII, (VIII) (wherein R4, R5, R6, R7 and n are as defined in claim 1 and Z represents a leaving group).

31. 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, (IX) (wherein R1, R2, R3, R4, R5, R6, R7 and n are as defined in claim 1).

32. A process as claimed in claim 31 wherein the compound of formula IX is obtained by reaction of a compound of formula IXa, (IXa) (wherein R1, R2 and R3 are as defined in claim 1 and Hal represents a chlorine, bromine or iodine atom) with a compound of formula X, (X) (wherein R4, R5, R6, R7 and n are as defined in claim 1).

33. A process for the preparation of compounds of general formula I
as defined in claim 1, wherein X represents a carbonyl group, which comprises cyclisation of a compound of formula XI, (XI) [wherein R1, R2 and R3 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 leaving group) and A represents a group of formula W, the group of formula W being a group of formula:

(in which R4, R5, R6, R7 and n are as defined in claim 1)] whereby the desired compound of formula I is obtained.

34. A process as claimed in claim 33 wherein the compound of formula XI
is obtained by reaction of a compound of formula XIa, (XIa) (wherein R1, R2 and R3 are as defined in claim 1 and Hal and Y are as defined in claim 33) with a compound of formula XII, (XII) (wherein R4, R5, R6, R7 and n are as defined in claim 1),

35. A process for the preparation of compounds of general formula I
as defined in claim 1 which comprises reacting a compound of formula XIII, (XIII) (wherein R1, R2, R3, X and n are as defined in claim 1), or an acetal derivative thereof, with a compound of formula III as defined in claim 30, in the presence of catalytically activated hydrogen.

36. A process for the preparation of compounds of general formula I
as defined in claim 1 which comprises reacting a compound of formula XIV, (XIV) (wherein R5, R6 and R7 are as defined in claim 1), or an acetal or ketal derivative thereof, with a compound of formula V as defined in claim 29, in the presence of catalytically activated hydrogen.

37. A process for the preparation of compounds of general formula I
as defined in claim 1, wherein R4 represents a lower alkyl group, which comprises reacting a compound of formula I as defined in claim 1 (wherein R4 represents a hydrogen atom) with an appropriate alkylating reagent.

38. A process as defined in claim 1 wherein R1 represents a hydrogen atom or a phenyl group; R2 represents a hydrogen atom, a chlorine atom or a methoxy group; R3 represents a hydrogen atom or a methoxy group; R4 represents a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms; R5 represents a hydrogen atom; and R6 and R7 each represents a methoxy group, one being in the 3 position and the other in the 4 position of the phenyl ring.

39. A process as defined in claim 1 wherein R1, R4 and R5, which may be the same or different, each represents a hydrogen atom or a lower alkyl group;
either R2 and R3 each represents a methoxy group, one being in the 5 position and the other in the 6 position of the phthalimidine ring, or R2 and R3 together represent a methylenedioxy or ethylenedioxy group; and either R6 represents a hydrogen atom or a lower alkoxy group and R7 represents a lower alkoxy group, R6 and R7 not each representing a lower alkoxy group one being in the 3 position and the other in the 4 position of the phenyl ring when R1 represents a hydrogen atom, or R6 and R7 together represent a methylenedioxy or ethylenedioxy group attached in the 2 and 3 or 3 and 4 positions of the phenyl ring.