CA1057295A - Heterocyclic compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Compounds of the formula I
wherein R represents a group of the formula or

Description

~~ -7Z~S

The present invention relates to novel sulphur-containing compounds of the general formula , -~ (CH~ ~ R5 --- R \ C _Y - N-- (Z) _ _ 7 : -: wherein R represents a group of the formula ~:
Rl .~ : -,. ~ ~ or ~1 (a) (b) ~
.¦ in which Rl, R2 and R3 each represent a hydrogen or fluorine, chlorine, ~ ~-, bromine or iodine atom or a lower alkyl, lower alkoxy, aryl-(lower alkoxy~9 ~ ~
:~ p~enyl, nitro, trifluoromethyl, hydroxy, Cy~lo, di(lower alkyl~amino, lower ; :: .
alkanoyloxy or two adjacent Rl, R2 and R3 symbols together represent a methyl~
; 10 enedioxy~ ethylenedioxy or butadien-1,3-ylene-1,4 group, R4 represents a ;~
hydrogen atom or a lower alkyl group, R5, R6 and R7 each represent a hydrogen ~ or ~luorine~ chlorine, bromine or iodine atom or a lower alkyl or lower alkoxy g~oup or two adjacent R5, R6 and R7 symbols together represent an ethylene- ;~
;-1 dioxy group, X represents a sulphur atom~ SO or SO2, Y represents a straight-chain or branched-chain, optionally hydroxy-substi~uted, aliphatic group , containing 2-8 carbon atoms, of which 2-4 carbon atoms are present in the ~'i chain, and Z represents a straight-chain cr branched-chain, optionally hydroxy~
substituted, aliphatic group containing 1-8 carbon atoms, of which 1-4 carbon .:: .
atoms are present in the chain, m stands for zero or 1 and n stands for 2 or . . , -~. .
3, but excluding M-~3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-;~ m-dithiane-2-propylamine-1,1,3,3-tetraoxide and its acid addition salts, to phaxmaceutically acceptable acid addition salts thereof, as well as to a process for their manufacture.
.
As used in this description and in the accompanying claims, the '"` ;~ ~ ,''~
,1 - 1 -. . ,-, , , .. .. .. ... . . . . . . . . .

,f "_.~
~7~

term "lower alkyl" means strai~ht-chain or branched~chain alkyl groups con-~ tainin~ 1-6 carbon atoms (c.g. methyl, ethyl, n~propyl, isopropyl, n-butyl, -~ isobutyl~ tert.butyl, amyl, hexyl and the like). The term "lower alkoxy"
means lower alkyl ether groups in which the "lower alkyl" moiety has the aforementioned significance. The term "lower alkanoyl" means alkanoyl groups ~ ~-containing up to 6 carbon aton~s (e.g. formyl, ac0tyl, propionyl, butyryl and the like). The ter~ "aryl" means unsubstituted or substituted phenyl, the substituent(s~ being selected from halogen, lower alkyl, lower alkoxy, nitro and amino. The term "leaving atom or group" used hereinafter means known atoms and groups such as, for example, halogen, preferably bromine or chlorine, ; arylsulphonyloxy such as tosyloxy, alkylsulphonyloxy such as mesyloxy or an ' ! epoxy group and the like.
Preferred compounds of formula I are, for example, those of the following general formula ~-

2 ~ 1\ / ~1 IR~ r ~ 6 Ia - C (CH2)3 N (CH2 CH2) ~, R3 \~~~~/ R
,', .: :
wherein Rl-R7 and m have the significance given earlier, R4 represents a methyl or ethyl group and Xl represents a sulphur atom or S02.
Preerred compounds falling within formula la are those in which one of the symbols Rl,~ R2 and R3 represents a hydrogen atom and the other symbols each represent a lower alkoxy group, especially methoxy, or together represent a butadien-1,3-ylene-1,4 group and those in which two of the symbols Rl, R2 and R3 each repTesent a hydrogen atom and the third symbol represents a nitro group and one of the symbols R59 R6 and R7 represents a hydrogen atom and the other two symbols each represent a lower alkoxy group, especially methoxy.

According to the process prsvided by ~he present invention, the -~

.: , . . .

~L~57~95i sulphur-containing derivatives aforesaid (i.e~ the compounds of formula I and their pharmaceutically acceptable acid addition salts) are manufactured by : :
a) reacting a compound o the general formula : .

~ ~CH2 ) i~
X X II
R - C - H

wherein R, X and n have the significance given earlier, with a compound of the general formula 14 ~ R6 ~ ~;
:. R~ y N - ~Z) ~ III

.;1 7 i t.~herein R4-R7, Y, Z and m have the significance given earlier and R8 represents. a leaving atom or group, or b) reacting a compound of the general formula :, 5~ , .
: 14 ~ 5 , ~ ~:
R - C y _ N (Z)m ~ R6 IV

20.
t~herèin R, R4-R7, Y, Z and m have the significance given earlier, with a compound of t~e general formula ;

HS - (CH2)n - SH V .

wherein n has the significance given earlier, or c) reacting a compound of the general formula (CH2)~
X ~ X VI
R - C - Y - R~ . .
wherein R, R8, X, Y and n have the significance given earlier~ with a compound i of the general formula _ 3 -.~ .

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

:
~s7~as , H - N - ~Z) ~ Vll 7 :
~herein R4-R7, Z and m have the significance given earlier, or -d) reacting a compound of the genaral formula ~;
: ~.
; ~(CH2) ; X ~ X 14 X
R - --C - Y - N - H

~herein R, R4, X, Y and n have the signi:Eicance given earlier, with a compound .
of the general formula R

R8 - (Z)m - ~ XI ,~

~4erein R5-~8, Z and m have the significance given earlier, or .~ e) reducing the carbonyl group or the group denoted by A in a compound of the general formula ~CH2) ~ IR4 ~ 6 2Q R \ C - Yl N Zl ~ R

~' or ~CH2) ~ ¦5 R - C - Y - A - ~Z) ~ ~ XIII

wherein R, R4-R7, X, Y, Z, m and n have the significance given earlier, Yl ; and Zl represent respectively a group corresponding to Y or Z containing a - carbonyl group and A represents the group ~-R4 - fo ~ ~:
N

,., ~. ::
~. Ir~

: , : .:
, ......... . " , .

~C957Z9~ ;

in which R4 represents a hydrogen atom or an alkyl group with 1-5 carbon atoms;
and for preparing a compound of formula I in which X represents S0 or S2J
oxidising a compound of formula I in which X represents a sulphur atom to a compound of formula I in which X represents S0 or S02; for preparing a com-pound of formula I in which R4 represents a lower alkyl group, N-(lower alkylating) a compound of formula I in which R~ represents a hydrogen atom, ~ ~i for preparing a compound of formula I in which at least one of Rl, R2 and R3 represents a hydroxy group, converting a corresponding lower alkoxy group or `~
aryl-(lower alkoxy) group substituted compound of formula I into a hydroxy group substituted compound for preparing a compound of formula I in which at least one of Rl, R2 and R3 represents a lower alkoxy, aryl-(lower alkoxy) or ; lower alkanoyloxy group, etherifying or esterifying a corresponding hydroxy group substituted compound of formula I; and for preparing a pharmaceutically ; -acceptable acid addition salt of a compound of formula I converting a base obtained into a pharmaceuticall~ acceptable acid addition salt.
i, The reaction of a compound of formula II with a compound of formula ; III according to embodiment a) of the proces~ can be carried out in a manner kno~n per-se. The reaction is expediently carried out in an organic solvent which i5 inert under the reaction conditions and at a temperature between I
.
about -80~ and the reflux temperature of the reaction mixture, preferably between about 0C and about 50C and especially at about room temperature.
As solvents, there may be mentioned ethers (e.g. diethyl ether, tetrahydro-furan, dioxane or the like), aromatic hydrocarbons ~e.g. benzene, toluene, xylene etc), dimethylformamide, dimethyl sulphoxide or the like. The reaction is carried out in the presence of a strong base such as butyl lithium, a ~
Grignard compound, sodium or sodium hydride. An especially strong base such ;
as butyl lithium or a Grignard compound is expediently used when X represents ;
a sulphur atom.
The starting materials of formulae II and III are partly known and 3U partly~novel. Those which are novel also form part of the present invention.
', :

: :.

,'' '' ' .

~315729~ :

The novel compounds can be prepared in a manner known per se, namely in a manner analogous ~o the preparation of the known compounds.
Those compounds of formula II in which X represents a sulphur a~om can be prepared, for example~ by reacting an aldehyde of ~he general formula ~ ~.

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

' ~

,, . ,; t J
~t,'Y~ rJ,~k; ' :' : ................. . .

~572~5 \

, wherein R has the significance given earlier, with ethanedithiol or propanedithiol. The reaction is con~eniently carried out in an inert organic solvent (e.g.
chloro~orm) and at a temperature below room temperature.

- ~ho~e compounds of ~ormula II in which X represents S0 or S02 can be prepared by oæidising a corresponding compound 'f of formula II in which X represents a sulphur atom. The ;
` 10 oxidation can be conveniently carried out in a suitable ~olvent using a peracid such as peracetic acid9 perphthalic acid, ~` m~chloroperbenzoic acid or the likeO Peracetic acid can9 for example, be formed in sltu from glacial acetic acid and hydroge~
peroxide.

~he reaction of a compound of formula IV with a compound of ~ormula V according to embodiment b) of the process can be carried out in a manner known per se. ~he reaction is 1~ expedientlg carried out in an organic solvent which is inert S under the reaction conditions9 preferably in a polar solvent 20 such as a halogenated hydrocarbon (e.g. chloroform, methylene chIoride or the like) or ethyleneglycol dimethyl ether etc.
` ~he reaction is also expediently carried out in the presence of a water-cleaving agent (e.g. sulphuric acid, a hydrohalic acid, phosphoric acid etc) and at a temperature between about ~i 25 0C and the reflux temperature of the reaction mixture, preferably at room temperature.
:

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

~1357~

The starting material~ Or formula V are known and can be prepared in a known ma~ner.

The starting materials of formula IV are novel and also ~ form part of the present invention.
:' The starting materials of formula IV can be preparedg for example, by reacting a compound of the general formula ,' O
11 ~
`~ R - C - Y - Cl XIVa ~:
wherein R and Y have the signifieance I given earlier, with a compound o~ the general ~ormula Rl~ ~ R~

wherein R4-R7, Z and m have the significance given earlier.

:;
~he reaotion is expediently carried out in the pre~e~ce of an acid~binding agent such as a tertiary amine (e.g. N-~,j -ethyl-N,N-diisopropylamine) which simultaneously serves as j the solvent. ~he reaction is also expediently carried out at an elevated temperature, preferably at a temperature up to i about 130C, depending on the boiling point of the solvent.

~he compounds of formula XIVa are partly known and partly novel. The novel compounds can be prepared in a manner kno~

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

r.~'~' '\

z~

per se, namely in a manner analogous to the p~eparation of the known compounds. ~he compounds of formul~ VII are known.

~ he reaction of a compound of formula VI with a compound of formula VII in accordance with embodiment c) of the process can be carried out in a manner known per se. The reaction is expediently carried out in an organic solvent which is inert under the reaction conditions, such as an ether ~e.g. dibutyl ether, dioxane or tetrahydrofuran),an alkanol (e.g. ethanol or ; propanol), an aromatic hydrocarbon (e.g. benzene7 toluene or xylene), acetonitrile9 dimethylformamide, dimethyl sulphoxide or the like. ~he reaction can be carried out at a temperature between about room temperature and the reflux temperature of the reaction mixtureO ~he reaclion is preferably carried out at the reflux temperature. ~he reaction is expediently carried out in the presence of a base (e.g. a tertiary amine such as trimethylamine, N-ethyl-N~N-diisopropylamine, N,~--dimethylaniline or the lik~) in the case where acid is cleaved ~-~ during the reaction~
,.
~he starting materials of ~ormula VII are known. The , starting materials of formula VI, however, are novel and also form part of the pre~ent invention. ~he starting materials of formula VI can be prepared, for example, by reacting a compound of the general formula ; 8 :

', , wherein R, R~ and Y have the si~nificance given earlier, ~ ` 9 ., ~ . . . .. . .

~ ~57291!5 ..

with a compound of the general form~la HS - ICH~n - SH V

, wherein n has the significance given earlier, i~d, if de~ired, converting a thus obtained compound of formula VI in which X represent~ a sulphur atom i~to a compound of formula VI in which X represents S0 or S02 by oxidation.

~ he reaction of a compound of formula XIV with a compound of formula V can be carried out in a manner known per se. ~he ~;
reactio~ is expedientl~ carried ou~ in an organic solvent which i~ inert under the reaction conditions, preferably in a polar ~;
solvent such as a halogenated hydrocarbon (e.g. chloroform methylene chloride or the like) or ethyleneglycol dimeth~
ether etc. ~he reaction iR also expedie~tly carried out in the presence of a water-cleaving agent ~e.g~ sulphuric acid~
a hydrohalio acid, pho~phoric acid etc~ and at a temperature ~ ~ between about 0C and the reflux temperature of the reaction ; mixture, preferably at room temperature~

he conversion of a thus obtained compound of formula VI
in which X represent~ a sulphur atom i~to a compound of formul~
i VI in which~X representæ S0 or S02 can be carried out in a ~1 manner k~own per se; for exam~le, by oxidation with a peracid ~uch as, for example9 per~cetic acid, perphthalic acid, m~
-chloroperbenzoic acid and the like. Peracetic acid can, for example, be formed in situ from glacial acetic acid and ,~, ~ hydrogen peroxide.
,,,, ~,", '' ~ O

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

57~ld95i '.

~he reaction of a compound of formula VIII with a compound of ~ormula IX i~ accordance with embodime~t d) of the process can be carried out i~ a manner known per se. rhe reaction i9 expedientl~ carried out in an organic solvent which is inert under the reaction conditions, such as an ether (e.g.
tetrahydrofura~, dioxane~ diethyleneglycol diethyl ether or the like), acetonitrile, dimethylformamide etc. ~he reaction is carried out at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferabl~
at the re~lux temperature~ ~he reaction is carried out in the ~ presence of a strong base such as butyl lithium, a Grignard ~;
-' compound, ~odium, sodium hydride and the like. An especially strong base such as butyl lithium or a Grignard compou~d is expedientl~ used when X represents a sulphur atom.

. i The starting materials of formula VIII are kno~n. The starting materials of formula IX~ howe~er, are novel and also form part of the present invention~ rhe startin~ materials of formNla IX can be prepa~ed, for example, b~ reacting a ~ oompound of the general formula ''s ~ ~ .
jfCH~
~ ) ~
, ' X~ ~ )(V ' ~, H - e - H
~- , wherein X and n have the significance given earlier, with a compound of formula III hereinbe~ore. This reaction , can be Garried out i~ a manner known per seO The reaction is ~! 25 expediently carried out in an or~anic sol~ent which is inert ~ under the reaction conditions a~d at a temperature between '~ ' l / ' ' l ! .

~57 ,~

about -80C and the reflux temperature of -the re~ction mixture~
preferably between about 0C and about 50C and especially at about room temperat~re. As solvents, there may be mentioned ethers (e ~. dieth~l ether, tetrahydrofuran, dioxane or the like), aromatic hydrocarbons (e.g. benzene, toluene, xylene etc), dimethylformamide, dimethyl sulphoxide or the like.
~he reaction is carried out in the presence of a strong base such as butyl lithium~ a Grignard compound, sodium, sodium hydride or the likeO An especially strong base such a~ butyl lithium or a Grignard compound is expediently used when represents a sulphur atom.
, . :

~ he compounds of formula XV are known. ~he compounds of formula III are partly novel and partly known. ~he novel compounds of formula III can be prepared in a manner known per se, namely in a manner analogous to the preparation of the known com~ounds.

~ e rbaction of a co~pound of formula X with a compound of formula XI in~aocordance with embodiment e) of the process can be carried out in a manner known per se. The reaction is 20 ~ expediently carried out in an organic solvent which is inert : "
under the reaction conditions, such as an ether (e.g. dibutyl ether, dioxane or tetrah~drofuran)~ an alkanol (e.gO ethanol or propanol), an aromatic hydrocarbon (e.g. benzene, toluene or ~rylene), acetonitrile, dimethylformamide, dimethyl sulphoxide ~ -or the like. ~he reaction can be carried out at a temperaturebetween about room temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature.
The reaction is expedientl~ carried out in the presence of a ,",~
~,,, ~ J ~

... . . . .
. . . . . .

~ ;i;7~5 base (e g. a tertiary amine such as triethylamine~ N-ethyl-N,N--diisopropylamine, N~N-dimethylaniline or the like) in the case where acid is cleaved durin~ the reaction.

The starting materials of formula XI are known. The starting materials of formula X, however, are novel and also form part of the present invention. The starting material~s of formula X can be prepared, for example, by reacting a compound of the general for~ula f ~ .:
R - C - y _ Cl VIa ~

, wherein R, X, Y and n h~ve the significance ~
: .
given earlier, ~, .
with an amine of the general for~lula `;
R ~,_ NH~ X V I

:

wherei~ R~ has the significance given earlier.
Since, in carrying out this reaction, hydro~en chloride is cleaved off, the reactio~ is~expedie~tly carried out in the presence of a base or using an excess o~ the amine of formula XVI. Furthermore, the reaction can be c~rried out in a ~
manner analogous to that described earlier in cannection with ~ `
the reaction of a compound of formula VI with a compound of `
formula VII.
~, The compounds of formula XVI are known. ~he compounds of formula VIa, which are partly novel, can be prepared in a ~
,: `
. ~ /3 ~~ :

... , .;. , ; , . , ~1~57~

mc~nner analogous to the preparation of the compounds of formula VI.

The reduction of ~ carbonyl group or a grou~ A in a compound of formula XII or XIII in accordance with embodiment f) of the process can be carried out in a manner kno~m per se.

Thus, an amide of ~ormula XII or XIII (i.e. a compound ; in which the carbonyl group is bonded directly to the nitrogen ; atom) can be reduced by treatment with a metal hydride (e.g.
lithium aluminium hydride or diisobutyl aluminium hydride) or with diborane or the like. ~his reduction is expediently carried out in an organic solvent which is inert under the reduct;ion conditions (e~g. an et~ler such as diethyl ether, tetrahydrofuran etc or diglyme) and at a temperature between about O~C and the reflux temperat;ure of the reduction mixture, ` 15 preferably at about room tem~erat;ure.

~ .
~ he reduc~io~ of other carbonyl groups (i.e. those which are not bonded direct;ly to the nitrogen atom) ca~ also be carried out in a manner known per se. In particular, the reduotion can be carried out in such a manner that it either leads to a hydrox~methylene group, which can then be further reduced to a methylene group, or lead~ direotly to a methylene group.
., ~ he reduction to a hydroxyme-thylene group can be carried out by treatment with a complex metal hydride such as an alkali metal alumlnium hydride or an alkali metal borohydride.

""~, ' ' /

., :, . , ,, . ,; , ; , Z~

~ he reduction using an alkali metal aluminium hydride or an alkali metal borohydride can be e~pediently caxried out at room temperature or at a temperature below or above room temperature and in an inert organic solvent. Suitable solvents which can be used in the case of reduction usin~ an alkali metal aluminium hydride include, inter alia, anhydrous ethers such as diethyl ether and tetrahydrofuran. Suitable solvents ~-which can be used in the case of reduction using an alkali metal borohydride include alkanols containing 1-4 carbon atoms (e.g, methanol or ethanol)~ dioxane or the like, ~ithium aluminium hydride is preferably used as the alkali metal aluminium hydride and sodium borohydride is preferably used as ~-the alkali metal borohydride~ ;~

~he further reduction of a hydroxymethylene group to a methylene group can be carried out in a manner known per se, ., .
especially by con~ersion into a corresponding sulphonic acid ester or into a halide and reduction thereof with a complex metal hydride. ~hese reduc-tions can be carried out in a -.~ ;.. :
manner analogous to the reduction of carbonyl groups described hereinbefore.
,1. ' ':

~he direct reduction of a carbonyl group to a methylene group can ~e carried out by means of a Wolff-Kishner reaction in a manner known per se, namely by reaction of the ketone with hydrRzine to give the corresponding hydrazone and decomposition of the hydraæone under basic condi-tions. ~;

The starting materials of formulae XII and XIII are novel and also form part of the present invention.
:' . ;

~ .

3l~S7~

Amides of form~la XII can be prepared, for example, by reacting an acid of the general formula ~C~
X~" ~X 01~
R - C - Y - C~ XVII
OH
` ~ wherein R, Y, X and n have the si~ni~icanGe given earlier, with an amine of the general formula H N IZ)m~ Vll wherein R4-R7, ~ and m hav~ the si~nificance given earlier.
The reaction can be expediently carried out Ln the preæence of a tertiary amine (e.g. triethylamine) and a halocarboxylic aaid ester ~e.g. chloroformic acid isobutyl ester) (mixed anhydride ~ ~
method3 in an inert organic solvent (e.g. tetrahydrofuran~ and ~-at a temperature of from about 0C to about 30C, ., .
~he acids of formula XVII can be prepared in a manner analogous to that described hereinbefore for the preparation of compounds of formula VI starting from compounds of the general formula Q
R - C - Y - C ~ X V II I
OH
wherein R has the significance given earlier.

~;",,,,,"

, . .

The compounds of formula XVIII are known.
'.

~he ketones of formula XII can be prepared in a manner `~ known per se; for ex~mple, by oxidising a correspondinK
alcohol. ~he oxidation can be carried out, for example, using chromium trioxide/pyridine in pyridine at a temperature of from a~out -20C to about room temperature 7 preferably at about 0C.

~he amides of formiula XIII can be prepared in a manner ,~
~nown per se; for example, by acy~ating a compound of formiula I i~ which R4 repre~ents a h~drogen atom. ~he acylation can be carried out, ~or exaEple, usi~g a halide of a lower carboxylic acid in a tertiary amine (e.g~ pyrlaine) at a temperature of from about 0C to about 30UC, prefer~bly at about room temperatuxe.
~: .

The conversion of a compound of formula I in which X
represe~ts a sulphur atom lnto a compound of formula I in which ;;~
represents S0 or S02 can be carxied out by oxidation, in a ~ --.
~uitable solvent, with a peracid such as peracetic acid, ~ pe~phthalic acld, m-chloroperben~oic acid or the like.
Peracetic acid can, for example, be formied in~ situ from glacial ~ -l ac0tic acid and h~drogen peroxide.
,' ¦ Compou~ds of formula I in which R4 represents a hydrogen atom ca~ be N-(lower alkylated) in a manner known per se; for ~;~
example, u~ing a lower alkyl halide. In this procedure, the particular compound of formula I is expediently reacted directly with the alkyl halide at a low temperature.

:: : ' :: . . ' . ' ' : .

The conversion of a lower alkoxy group or .~n aryl-(lo~er ; alkoxy) group into a hydroxy group can be carried out in a manner known per se; for example, by heating with a concentrated hydrohalic acid, especially constant boiling hydrobromic acid.

The reduction of ~ nitro group to an amino group can be carried out chemically or catalytically in a manner known per se; for example, using tin~hydrochloric acid or hydrogen in the presence of a noble metal catalyst. ~he hydrogenation is preferably carried out in an alkanol, especially ethanol, in the pre~ence of palladium/carbon or platinum oxide under normal pressure at room temperatureJ
~ , ~he saponification of a cyano group can be carried out using an acid or a base in a manner k~own per se. ~`, .: , ` ` ' The esterification or amidation of a carboxyl group can be carried out in a manner kno-~n per se; for example, by treatment with an appropriate alcohol or an appropriate amine.

An amino group present can be alkylated as described hereinbefore or can be acylated by treatment with an acid halide or acid anhydride in a manner known per se.

The etherification or esterification of a hydroxy group present can be carried out in a manner known per se; for :
example, by reaction with an appropriate halide or with an appropriate acid halide or acid anhydride.
.' The reduction of a carboxyl group can be carried out in a manner known per se; for exa~ple using diborane or lithium ' ' , ' "''''' " ' ' ,' ' , ;~

S7~:9S
aluminium hydride in an inert or~anic solvent.

The oxidation o~ an alk~lthio group can be carried out in a manner kno~m per se; for example, using hydrogen peroxide.

The compounds of formula I can be converted into acid -~ -addition salts, for example by treatment with an inorganic acid such as a hydrohalic acid (e.g. hydrochloric acid or hydrobromic acid) ~ sul~huric acid9 phosphoriG acid or the like or with an organic acid such as oxalic acid, tartaric acid, cit~ic acid, methanesulphonic acid or the like. Of the acid addition salts of compounds of formula I, the pharmaceutically aoceptable acid addition salts are preferred. If, in the course of the process of t~is invention, an acid addition salt of a compound Q~ formula I is obtained, then such a salt can be ~: .
conv~rted into the free base in a kno~m manner (e.g. by ; 15 treatment with alka1i~ and the free base can, if desired, be conYerted into anoth~r acid addition salt.
-~

Those compounds of formula I which contain an asymmetric carbon atom can be present in a racemic or optically active form and it will be understood that this inYention includes not only the racemio but also the optically active ~orms. A
racemate can, if desired, be resolved into the optical antipodes in a manner known per se; for example, by fractional crystallisation of the corresponding salts with an optically active acid.
~.
The compounds of formula I and their acid addition salts possess valuable coronary-dilating properties and can '~3 Iq ;, . . . .
, , . . .. . ,, . :.

~q~57,,~

accordingly be used, inter alia, for the treatment of angina pectoris.

The coronary-dilating activity can be measured by the following method:
~, i 5 Mongrels weighing between 20 and 38 kg are used for the tests. The test animal~ are anaesthetised with ca 30 mg/kg i~v. pentobarbital and the anaesthesia is maintained with chloralose-urethane. The animals are artificially respired with atmospheric air. After opening the thorax, the heart is exposed and a previously calibrated flow-probe of an electro-magnetic flowmeter for measuring the blood flow-ra-te is placed around the ramus circumflexNs of the left coronary artery.
The arterial blood pre~sure is meas~red with a pressure ;~
transducer ~ia a catheter in the arteria femoralis. Further, a calibrated extensible measurin~ strip for the direct measurement of the myocardial contraction force is sutured on to the surface of the lef-t ventricle. The pulse wave of the blood pressure triggers a tachograph for measuring the heart frequency. Water-soluble compounds are administered intra~enously dissolved i~ an isotonic sodium chloride solution7 , ~ .
water i~soluble compounds are administered dissolved in propylene glycol or the compounds are administered intra-duodenally as a suspension in B arabic. ~he maximum activity of a compound is calculated according to each dosa~e in per cent of the starting value and represented graphically. In the measurement of the coronary blood-flow, the duration of activity is also carefully observed.

~ æo : ~ , , .................. . .. I , . ~ - . .
~, , .. ~

~s~9~

~he results obtained are compiled in the :Eollowin~ ~able, n deIlotlng the number o~ animals u~ed.

:, . :~
.~

,'~: ";'' ,:~ ': , ' '~:

~05~2~5 . ~ ..
~ IJ~ N ~J ~tJ
_, ~
r~ ~ Ll~ co ~
.~.~ +~ O ~
_~ ; E~ ~ ~
h ~r~ o ~ ~ ~ ~

~ ~ ~ ~ D ~ ~ ~
h I~ ~ r~ .1 r1 + N
O _ . ~ ~ u~ tD ~ , . ' .
~ r~ r~ tO
~ ~ ~ ~ ~U ~
r ~.
O P E~ E r-l ~U
~:) ~r; _ _ _ _ _ 1 : ~0 ~ . ~: ' , ~ ~ ~ r-l ~ ~1 ~ r~ O ~ ~ . .
¢t QO ~ ~ ~J r~
E ~ ~ r-l r+
,', _ _, _ ~ . , . -. ' :

F~ O O ~
~: 2 bD ~ r-l 1 :~ :

~; ~: ~ , . ~ ~ ' ' . .
! I ~ z~
~ 0 ~ ; r~ O
~ ~ !~ 3~ ~ 3 ~ ~ r~ h ~ ~
O r~ h ~, V ~ ~ a) o ~ rlN~
; ~ $ ~ I r ~ ~1 .~ ;~ r~r-l ;~ I r-l rl ^ ~ .~ :
~_~4 ~ 4 N~
I ~ Tl -:
. _ z N ~ ~ ~
~ O~a ~57~:9~

The compounds of formula I and their pharmaceutically acceptable acid addition salte m~y be used as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material.
~his carrier material may be an organic or inorganic, inert carrier material suit~ble for enteral or parenteral administration such as, for example, water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable ~
oils, polyalkyleneglycols, petroleum jelly etc. ~he ~ ;
pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragaes or capsules) or in a liquid form (e.g. as solutions, suspen~io~s or emulsions). The pharmaceutical preparations may be sterilised and/or may l .
contain adjuvants such as preservatives, stabilisers, wetting agents, emulsifiers, salts for varying the osmotic pressure or buffers~

` ~ ~ The daily dose in the case of oral administration lies between about 10 m~ and 200 mg. ~he daily dose in the case ~ -of intravenous administration lies between about 1 mg and 1 20 mg.

~ he aforementioned dosages are1 however, only given by way of example and can be modified accordlng to the severity of the case to be treated and the directions of the attending ;~
physician.
', ,. ~

:
, . .

~3 ",.. , , - . . . .
.
.. ~, . . . . . .... . . .
: ~ , . . . .

~5~2~

The following Ex~mples illus~rate the proce~s provided by the present invention: ~-, ~ , ~ .
':.' 74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in ::
1250 ml of chloroform~ treated with 50 ml of l,~-propanedithiol ; -;and cooled at 0C with stirring. 20 ml of boron trifluoride ~
etherate are added and the mixture is left to stand in a ~-refrigerator for 18 hours. The mixture i5 then washed three ~:
times successively with 500 ml of a 75S~.potassium hydroxide solution and 500 ml of a l~/o sodium chloride solution~ The organic extracts are combined, dried over magnesium sulphate '~
and evaporated~ ~he residue is recrystallised twice from :-.-.
ether. There are obtained 102.6 g of 2-(3,4-dimethoxyphenyl)-m-dithiane of melting point 99-101C. - :~

~he following dithianes can be manufactured in an analogous~manner;~
2-(o-Methoxyphenyl)~m-dithl~ne of melting point 126-127G
(from methylene chloride/isopropyl ether);
2-phenyl-m-dithi~ne~of melti~g poi~t 72-73C (from ~ -methylene chloride/isopropyl ether);
, : 2-(p-chlorophenyl)-m~dithiane of melting poi~t 87-88C
(from methylene chloride/lsopropyl ether~
, ~ 2-(m-methoxyphenyl)-m-dithi.ane of melting point 62-63C .
(from iiopropyl ether); -~ 25 : 2-(~,4,5-trimethoxyphenyl)-m-dithi~lne of melting point s 88-89C (from methylene chloride/isopropyl ether);
.J
:', 2-(m-chlorophenyl)-m-dithiane of melting point 63-64C
(from cyclohexane);
~ ~4 ,., . .. . , . . . ~. . . .

~LOS~

2-(3,5-dimethoxyphenyl)-m-dithi.~ne of ~eltir~ point 90-91C ~from cyclohexane);
: p-(m-dithian-2-yl)-N,N-dimethylaniline of meltin~ }ioirt ~:
118-119C (from cyclohexane);
~ 5 2-(m-nitrophenyl)-m-dithiane of meltin~ poin~ 117-118C
:. (from methylene chloride/methanol); :~
2-(3,4-methylenedioxyphenyl)-m-dithlane of melting point 86-87C (from cyclohexane);
,j 2-p-tolyl-m-dithiane of melting point 89~-90C (from .~ : 10 ether/hexane);
2-(m-bromophenyl)-m-dithiane of melting point 78-79C
(from cyclohexan:e);
2-(2-naphthyl)-m-dithiane of melt`ing point 110-111C
., , (from cyclohexane);:
: 15 ~ 2-(2,4,5-trimethoxyphenyl)-m-dith1ane of meltin6 ~oint 156-157C ~from methylene chloride/methanol);
: 2-(p-~luorophenyl)-m-dithiane of melting point 105-106C
:.'1 `: .
~-; :(from cyclohexane);
2-~(4-biphenylyl)-m-d~thiane of melting point 148-151C .
20 ~ ~(from t~etrahydrofuran~cyclohexanej;
2-(,a~,a-trlfluoro-p-tolyl)-m dithiane of melting point 103-104C (from~oyclohexane);
2~ naphthyl)-m-dithi~ane of melting po1nt 147~-148C~
(from cyclohexane);
~r 25 2~(3-benzyloxy~4-methoxyphenyl~-m-dithiane of melting ;`it point 168~-170C (~rom cyclohexane);
1 1 :
i~ 2-(4-benzyloxy-3-methoxyphenyl)-m-dithiane of meltin~
-~ point 118-119C (from cyclohexane);
, 2-(2-thienyl)-m-dithiane of melting point 74-75C (from : :
, ~

~. 30 cyclohex~ne);
.''~ , ' ~ ~?S `

, , . , , ~ ,, . ~ .

Z:~S

2-(a,~ trifluoro-m-tolyl)-m-dlthiane of melting poi~t 69-71C (from hepta~e);
2-~p~isopropylphenyl)-m-dithi~ne of melting point 58-59C
(from hexan~);
2-(3,4-xylyl)-m-dithiane of melti~g point 74-75~C (from petroleum ether);
. :
: 2-(3-butoxy 4-methox~phenyl)-m-dithians; ~
2-(4-etho~y-3-methoxyphenyl)-m_dithiane of meltin~ point ~ :
88-90C (from methylene chloride/i~opropyl ether); ~- :
i: 10 m-(m-dithian-2-yl)-benzonitrile of melting point 84-86C
; ~ (from isopropyl ether); ;- .
: 6-(m-dithian-2-yl)-1~4-benzodioxan of melting point 140-142C (from methylene chloride/isopropy~ ether);
2-(4~methoxy-m-~olyl)-m-dithiane of melting point 75-77C
(from cyclohexane). ~ ~ .

:1 :! :
6t) g of 2-(3,4-dimethoxyphenyl)-m-dithia~e (prepared as : described in Excmple 1~ are d1ssol~ed in 470 ml o~ glacial acetic acid and treated at room temperature with 235 ml of .

3~/o hydrogen peroxide, the tempexature of the 801ution rising : to ca 40C. The ~olution is left to stand overDiKht at room ~, . .
temperature. ~he solution is then heated for 2 hours at 100Cr s After cooling to room temperature, the crystalline precipitate is filtere~ of~ under a vacuum, washed with some glacial aceti~
. 25 acid, dried in vacuo at 60C overnight and then recrystallised from acetonitrile. '~here are obtained 57.1 g of 2-~3~4 ;~
-dimethoxyphenyl)-m-dithiane~ 3,3-tetraoxide of melting ~;
poi~t 243~-245C.
. .

,.i.s ~
,.
: : ,, , . . ~ : .

~he following dithi~ne tetraoxides can be manufactured i~ an analogou~ manner:
- 2-(m~bromophenyl)-m-dithi~ne-1~1,394-tetraoxide of melting point 230~231C (from acieto~itrile~;
2-(p-~luorophen~13-m-dithiane l,l,3,3-tetraoxide of melting point 283-~84~C (from ~cetonitrile);
., . ~
. 2-~m-nitrophenyl)-m-dithiane-1,1,3,3-tetraoxide of .
.~ melting point 256-257C ~from acetonitrile);
-` 2-(3,4,5~trimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide . .
:~ 10 of melting point ~310G (~rom acetonitrile);
2-(2-naphthyl~-m-dithiane 1~ ,3-tetraoxide of melting point 277-278C ~from acetone/acetonitrile);
i . 2-p-tolyl-m dithiane-1,1,393-tetraoxide of melting point 284~285C (from a¢eto~itrile);
~: 15 2~ benzyloxy-3~methoxyphenyl)-m dithiane-1,1,3,3- :
. .-.
: -tetraoxide of melting poi~t 220-223C (~rom a~etone/
~; acetonitrile); ' ~-- ~ 2-(~t4-dimethoxyphe~yl)-1~3-dithiolane~ 3-tetraoxlde ~ :
o~ melting point 194-196~C (from acetone/acetonitrile), ~ ~.
20 ~ 2 (3,~-methylenedioxyphenyl)-m-dithiane-1,1,3,3-tetra~
il ~ oxide:of melting point ~300~a (from acetone~acetonitrile);
2-(2'-th1enyl)-m-dithi~ne-1~173,3-tetraoxide of melting point 300C (from acetone/acetonu.trile3;
: 2-(3,4-dichlorophenyl)-m-dithiane-1,1,3,3-te~raoxide of melti.nK poin~ 254-255C (from glaoial acetic acid/water); ~ :~
2-(~,a~a-trifluoro m tolyl)-m-dithiane-1,1,3,3-tetra-oxide of m~lti~g point 239-242C (from glacial acetic acid/
.. ~
'"t water);
~ 2-(p-isopropylphenyl)-m-dithiane 1,1,3,3-tetraoxide of ,t ~0 meltin~ point 204-205C (from acstonitrile/ethanol);
'~.-~, ~ c~7 .. - - ~~

.. . .
-.

S

2-(3,4-xylyl)_m_dithiane 1,1,3,3-tetraoxide of melting : poi~t 268-269C (~rom ~catonitrile~me~hanol);
2-~3~buto~y-4-~etho~yphenyl~-m-dithi~n~1,1,3,3~tetr~-oxide of melt~ng point 2~5-227C (~rom glacial acetic acid/
5 water);
. 2-(4 ethoxy~3-methoxyph~n~ m-dithiane~ 3,3-tetra-`. oxide of melt~ng poi~t 242~244~C (from acetone/acetonitrile~;
m-~m-dithia~-2'-yl) ben~onitrile-1',1',3',3'-tetraoxide o~ melti~g po~nt 259-260C (~rom glacial acetic acid~water);
lO6~(m-dithian-2l-yl3-194-benzod~^oxan~ 3',~' tetra-o~ide o~ meltl~g poi~t 232C ~decompo~itio~ (fr~m glaci~l ~-I acetic acid/water);
~, 2-(4-methoxy-m-tolyl)-m-dithiane-1',1'~3',3'-tetraoxide ~- ,of melti~g point 225~227C (~ro~ glRcial acetic acid/water~.
,. . ..
~ ~
. . , . :
.

`. 19~2 g o~ 2-(3,4-dim~thox~phenyl)-m-dithia~e (prepared ~: a~ de~oribed in Example 13 and 200 ml Or tetrahydrofura~ are:
~: : cooled to -60C i~ a sulphonation fla~k while ~a~si~g with ~,:
argon a~d ~lowl~ treated with 33 ml of butyl lithium in hexane.
The mi~ture i8 ~hen stirred at -20C for 2 hour~. A solutio~
~ . .
of 18 g o~ ~-(3 chloropropyl)-3,4-dimethoxy-N-meth~l-phe~eth~
:~ ami~e in 200 ml of tetrahydrofuran is added dropwise thereto at -70C wi~hi~ 15 minutes. The mixture is then left to stan~ ::
, for 18 hour~ at -20QC in a deep-freezer and ~or 3 hours at room ! 25 tempsrature. ~he ~olution is then poured on to water a~d : .
; extracted three tim~s with ether. The ethereal extracts are - extractod three time7s with 250 ml of 1-N h~drochloric acid.
~he acidic oxtracts ~re treated with 3 N sodium hydroxide up ~' . . -- ~ ~ .

7 .
.~
.. . . . .
.... .. . . . . .

~ 3~ g~i to pH ~12 an~ the separated oil is ~xtracted with ether. ~he orga~ic extract~ are dried over mMgnesium sulphate and evaporated.
The thus obtained oil ~0 g) i8 dissolved in ethyl acetate and treated with ethereal hydrogen bromider The precipitate which separates i~ recr~stallised from ethanol. 'rhere is obtained N-(~,4-dimethoxyphenethyl)-2-(3~4-dimethoxyphenyl3~N-methyl-m--~- -dithiane-2-propylamine h,ydrobromide of melting point 170-172C.
AnalysiS for C26H37N4S2-HB
Calculated: C 54.54 H 6.69 N 2.45 Br 13.95 Fo~d: C 54.54 H 6.74 N 2031 Br 14.05 ' q!he N-(3-chloropropyl)-3,4 dimethoxy-N-meth~l-phenethyl-amine used as the starting material can be prepared as follows~
.. ~ : ,, 292.5 g of N-methyl-homoveratrylamine are dissolved in ~i 1000 ml of dimethylforma~ide and treated with 415 g of anhydrous potassium carbo~ate. q~he mixture is stirred at 5C, treated with 237 g of 1,3-bromochloropropane in 500 ml of dimethyl-formamide, stirred for a f~rther 4 hours at room temperature and then poured into 6 litres OI water. The separated oil is extracted three times with 2 litres of ether each time, The ;~ 20 organic extracts are dried with magnesium sulphate and e~Tapo~ated `, in vacuo. The residual oil is distilled at between 69C and 70C with a mercury diffusion pump at 0.005 Torr. ~here are obtained 206.7 g of N-(3-chloropropyl)-3,4 dimethoxy-N methyl--phenethylamine of boiiing poi~t 69-70C/0.005 IrorrO

~he following compounds can be manufactured i~ ~n analogous manner to that described in this Example:

~.,~ I ' .
~,? 9 ~

:

~57,~5 N-(3,4-dimethoxyphenethyl)-2-(m-methoxyphenyl)-N-methyl-m-dithian~-2-propylamine hydrochloride sf meltin~ point 113-115C ~from acetone);
N-(3,4-dimethoxyphenethyl)-2-(3,4,5-trimethox~phenyl)--N-methyl-m-dithiane-2-propylamine hydrochloride of mel~ing point 147-1509C (from acetone);
N-(3,4-dimethoxyphenethyl)-2-(p-methoxyphenyl)-N-methyl--m-dithiane-2-propylamine hyd.rochloride of melting point 160-161C (from acetone);
~j 10 N-(3,4-dimethoxyphenethyl)-2-(o-methoxyphenyl)-N-methyl-.1 -m-dithiane-2-propylamine hydrochloride of melting point :~
151-152a (~rom acetone);
2-(p-chlorophenyl)-N-(3,4-dimethoxyphenethyl)-N-methyl-~ 1 -m-dithiane-2-prop~lamine hydroc~iloride of melting point 1~7-139~C (from acetone);
-(3,4 dimethoxgphenethyl~-~-methyl-2-phen~l-m-dithiane--2-propylamine hydrochloride of melting point 170-172C (from aceton~
N-(~,4-dimethoxyphene~hyl)--N-methyl-2-~,4-methylene- ~;
2~ dioxyphenyl)-m-dithiane-2-prop~lamine hydrochloride of melting point 139U-141C (from acetone); ~ -~
N-(3,4-dimethoxyphenethyl)-N~methyl-2-(p-tolyI)-m--dithiane-2-propylamine hydrochloride of melting point 139-141C (from acetone); ~ ;
2-(m-chlorophenyl)-~-(3,4-dimethoxyphenethyl)-N-methyl- ;
-m~dithiane-Z-propylamine hydrochloride of melting point 108-110C (from acetone);
. N-(3,4-dLmethoxyphenethyl)-2 (3,5-dimethoxyphenyl)-N--methyl-m-dithiane-2-propylamine oxalate (1:1) o~ melting point 155~-156C (from acetone);
' . ` .

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

j7;~

~ N-(3,4-dimethoxgphenethyl)-2-(p-di~ethylaminophenyl)-N-! -methyl-m-dithiane-2-propylamine hydrochloride of melting point .. `. 183-184C (~rom acetone);
. N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m--dithi~ne-2-propylamine hydrochloride of melting point 195-196C (from acetone);
N-(3l4-dimethoxyphenethyl)-N-methyl-2-(2,475-trimethoxy-phenyl3-m-dithic~ne-2-propylamine hydrochloride of melting point 156-158C ~from acetone);
-`~ 10 N-(3,4-dimethoxyphene~hyl~-2-(p-fluorophenyl)-N-methyl-.` -m-dithiane-2-propylamine hydrochloride of melting point 138-139C (from acetone); ~ :
: 2-(4 biphenylyl)-N-(3,4-dimethoxyphenethyl)-N-methyl-m--dithia~e-2 propylamine oxalate (1:1) of melting point ~ 15 167-169C (from acetone);
.I N-(p-chlorophenethyl)-N-methyl-2-phenyl-m-dithiane-2- ~;
:1 -propylamine hydrochloride of melting point 145-147C (from : `
: ~ acetone), ~tarting from 2-phenyl-m-dithiane and N-(3-chloro- :

~ : propyl)-4-chloro-N-methyl-phenethylamine;
~ .
~ :~ 20 : N-methyl-N-phenethyl-2-phenyl-m-dithiane-2-propylamine .:
: ~ hydrochloride of melting point 136-137C (from acetone), starting ~rom 2-phenyl-m-dithiane and N-(3-chloropropyl)-N--methyl-phenethylamine (boiling point 78-80C/0.001 Torr);

N-(3,4-dimethoxyphenethyl)-N-methyl 2-phenyl-m-dithiane--. .
-2-ethylamine:hydrochlori~e of melting point 172-174C (from acetone~, starting from 2-phenyl-m-dithiane and N-(2-chloro- `~

ethyl)-3,4~dimethoxy-N-methyl-phenethylamine;

N-(3~4-dimethoxyphenethyl)-N-methyl-2 (2-thienyl)-m~ .

-dithiane-2-propylamine hydrochloride of melting point 138-140~C (from acetone);

_ ,~ _ 5~ 5 rac~N-(3,4-dimethoxyphenethyl)~2~(3,4-dimethoxyphenyl)-N,B-dimethyl-m-dithiane~2-propylamine oxalate (1:1) of melting point 138-139UC (from acetone/ethyl acetate)~ startin~ from 2-(3,4-dimethoxyphenyl)-m dithiane and N-(3-chloro-2-methyl-propyl)-3,4-dimethoxy-N-methyl-phenethyla~ine;
2-(3,4-dimethoxyphenyl)-N-~ 4-(3,4-dimethoxyphenyl)-butyl ~ ~N-methyl-m-dithiane-2-propylamine.
: -.' ~

`~ 35.2 g of 2-(3,~-dimethoxyphenyl)-m-dithiane-1,1,3,3-~:, -tetraoxide (prepared as described in ~xample 2) are suspended m 180 ml of absolute dioxane and treated with 2.53 g of sodium.
~he mixture is boiled under argon for 20 hours, the sodium passing completely into solution. 27.2 g of N-(3-chloro-~ propyl)-3,4-dimethoxy-N-methyl phenethylamine (prepared as J 15 described in Example 3) are then added at room temperature, - the cloudy solution is stirred at room temperature for 1 hour and boiled at reflux for 3~houræ. The mixture is poured on to ico~water and extracted three times with ethyl acetate.
The ethyl aoetate extracts are combined and extracted three times with l-N hydrochloric acid~ The acidic extracts are made alkaline and extracted three times with chloroform. ~he chloroform extracts are combined, washed with water, dried -~
over magnesium sulphate and evaporated. ~he crystalline residue is rec~ystallised from methanol and there are obtained crystals of melting point 143~145C.
.,` :
For the preparation of the hydrochloride, the base is dissolved in acetone and treated in an ice-bath with 20 ml o'~

St7Z~

hydro~en chloride in dioxane. 'l'he crystalline ~alt is filtered off under a vacuum and recrystallised from aceto-nitrile/acetone (1:3). The thus-obtained N-(3,4 dimethoxy-phenethyl)-2-(3,4 dimethoxyphenyl)-N-methyl-m-dithiane-2-~propylamine-1,1,3,3-tetraoxide hydrochloride is dried over- -night in a high vacuum at 120C. ~here are obtained 38.9 g of a ~ubstance of melting point 167-169C.
~nalysis:
. . i .
~ Calculated: C 52.74 H 6.47 N 2.36 Cl 5.99 S 10~83 :. .
10Found: C 52.58 H 6.58 N 2.16 Cl 6.19 S 10.53 The following compounds can be manufactured in an an~logous 1 manner to that described in thl~ Example:
- N_(394-dimethoxyphenethyl)_~-methyl-2-(2-naphthyl)-m--dithiane-2-propylamine-1,1,3,3-tetraoxide oxalate (lol) of meltin~ point 190-191C (from acetone/methanol);
N (3,4-dimethoxyphenethyl)-N-methyl-2-(3,4,5-trimethoxy-phenyl)-m-dithiane-2-propylamine~ 313-tetraoxide oxalate (1;1) of mel~ing point 146-148C (from acetone/ethyl acetate~;
2-(m-bromophenyl)-N-(3,4-dimethoxyphenethyl)-N-methyl--m-dithian~-2-propylamine-1,1,3,3-tetraoxide hydrochloride of melting point 158-160C (from methanolic hydrogen chloride/
ethyl acetate);
2-(m-nitrophenyl)-~-(3~4-dimethoxyphenethyl)-N-methyl--m-dithiane-2-propylamine-1,1,3,3 tetraoxide hydrochloride of melting point 212-214C (from acetone);
N-(3,4-dimethoxyphenethyl)-2-(p-fluorophenyl)-N-methyl--m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloriae of melting point 234-236C ~from methanol);

~r ~3 _ ~ _ ~57~2~5 N-(3,4-dimetho~yphe~ethyl~-N methyl-2-phenyl-m-dithi~ne-: -2-propylamine-1,1,3,3-tetraoxide hydrochloride of meltin~
: point 149~C (decomposition) (from methanol);
`~ N-(3,4-dimethoxyphenethyl)-2-(3~4-dimethoxyphenyl)-N--ethyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide oxalate o~ melting point 177~179C (from methanol/acetone) - [from 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide and N-(3 chloropropyl)-3,4-dimethoxy-N-ethyl-phenethylamine~; - -~:~ N-(3,4-dimethoxyphenethyl)-2-(4-isopropylphenyl)-N- :;
-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride ~: of melting point 225-227C (from hydrogen chloride in dioxane/
ethyl acetate);
N-(3,4-dimethoxgphenethyl)-2-(3-trifluoromethylphenyl)-l -N-methyl-m-dithiane-2-propylami:ne-1,1,3,3-tetrao2ide oxalate :~ 15 of melting point 128-130C (from acetonè); ~ -: N,2-bis(3,4-dimetho2ypheny~ N-methyl-m-dithiane-2 -prop~lamine-1,1,3,3-tetraoxide;
.~: 2-(3,~-dimethoxyphqnyl)-N-r 4-(3,~-dimethoxyphenyl)--butyl ~-m-dithiane-2-propylamine-1,1,3,3-tetraoxide;
N-(3,4-dlmethoxyphenethyl3-N-methyl-2-(3,4-xylyl)-m- -~ -dithia~e~2-propylamine-1,1,3,~-tetraoxide hydrochloride of melting point 176-1789C (from acetonitrile); :
~ .
2-(3-butoxy-4-methox~phenyl)-N-(3,4-dimethoxyphenethyl)--N-methyl-m-dithiane-2~propylamine-1,1,3,3-tetraoxide of melting point 84-85C (from methanol/isopropyl ether);
1 ' N- ~ 3-[2'-(3,4-dimethoxyphenyl)-m-dithian-2'-yl~-propyl 3 --N-methyl-1,4-benzodioxan-6-ethylamine-1',1',3',3'-tetraoxide :
~ hydrochloride o`f melting point 208-210C (from acetonitrile); :
"~ N-L4-(3,4-dimethox~phenyl)~butyl~-2-(p-isopropylphenyl)-~ 30 N-methyl-m-dithia~e-2-propylamine-1,1,3,3-tetraoxide hydro-,L~",~1 . , . ., ~ , . ~

~5~'Z~5 . :
chloride of meltin~ point 148-150C (from ethyl acetate/
hydrogen chloride in dioxane);
rac-2-(3,4-dimethoxyphenyl)-M~[3-(3,4-dimethoxyphenyl)--l-methylpropyl]-N-methyl-m-dithi~ne-2-propylamine-1,1,3,3--tetraoxide of melting point 115-117C;
N-(3,4~dimethoxyphenethyl)-2-(4-e-thox~-3-methoxyphenyl)--N-methy~-m-dithiane-2~propylamine-1,1,3,3-tetraoxide hydro-~: chloride o~ melting point l9oQ-192C (from acetonitrile);
m-~2'- r 3-~(3~4-dimethoxyphenethyl)-methylamino]-propyl_7--m-dithian~-2'-yl~-benzonitrile-1',1',3',3'-tetraoxid0 hydro-chloride of melting point 160C (decomposition);
1 2~ 4-benzodioxan-6~yl)-N-(3~4-dimethoxyphenethyl)-N-.
-methyl-m-dithiane-2-propylamin~-1,1,3,3-tetr~oxlde hydro-~ chloride of mSslting point 201 204C;
.~; 15 ~-(3,4-dimethox~phenethyl)-2-(4-methoxy-m-tolyl)-N-methyl--m-dithiane-2-propylamine 1,1,3,3-tetraoxide hydrochloride of melting point 146C (decomposition) (from acetone);
m-{2'~ 3-~4-(3,4-dimethoxyphenyl)-butyl3-methylamino- ~.
; propyl~ -m~dithi~n-2'-yl}-~enzonitrile-1',1'73'13'-tetraoxide :~
.
hydrochloride of melting point 120-122C (from water);
2-(3,4-dimethoxyphenyl)-N~methyl N-(p-methylphenethyl)--m-dithiane 2-propylamine-1~1,3,3-tetraoxide hydrochloride of : : melting poi~t 169-171C (from acetone/ethyl acetate).
: -~
:
''1 ~
:-6.08 g of 2-(3,4-methylenedioxyphenyl)-m-dithiane-1,1, 3,3-tetraoxide (prepared as described in Example 2) are stirred under argon with 25 ml of absolute dimethylform~mide and treated with 0.8 g of a 5~/o sodium hydride suspension. S~he mixture is "' ''~7' ~S

,.~ ~ . : , . . .
"s, , .

?e~7~:9Si left to react for 0~5 hour at room temperature elld for 1 hour at 40C. After cooling to room temperature, 4.3 ~ oî ~T-(3--chloropropyl)-3,4-diIQethoxy~N-methyl-phenethylamine (prepared as described in Example 3) are added and the mixture is heated at 100C for 16 hours. The cooled mixture i~ then poured on to ice and extracted three times with ethyl acetate. The organic extracts are washed with water, dried over magnesium ;~ sulphate aIld evaporated in vacuo. The residual oil is dissolved in acetolle and treated with 5 ml of a 6-N hydro~;en chloride solution in dioxane. The precipitate, which is filtered off under a vacuum, i5 recrystallised from ~cetone.
;~ There are obtained 7.5 g of N-3,4-dimethoxyphenethyl)~ -methyl-; -2-(3t4_methylenediox~phenyl)-m~dithiane-2-propylamine-1,1,3,3--tetraoxide hydrochloride of melting point 247-248C.
Analysi~:
` ~ Calculated: C 52.12 H 5~95 N 2.43 Found: C 51.91 H 5~86 N 2.23 `, ,~
~he following compourlds can be manufactured in a manner analogous to that described irl this Example N-(3,4-dimethox;s1phenethyl)-N-methyl-2-p-tolyl-m-dithiane--2-propylami~e-1,1,3,3-tetraoxide hydrochloride of melting `, point 203V-207C (from acetonitrile/acetone); ~;
2- ~4-benzyloxy)-3-methoxyphenyl-N-(3,4-dimethoxyphen-ethyl)-N methyl-m dithiane-2-propyla~nine-1,1,3,3-tetraoxide h;ydrochloride of melting point 220"-221C, (from ethanol);
N-(3,4-dimethoxyphenethyl)-N-methyl-2 (2'-thienyl)-m-- -dithiane-2-propylamine~ 3~3-tetr~oxide hydrochloride OI
. ~
melting point 179-182C (from acetone);

, :, . :

~. 3~_ :, . . . . - , .,: .~ , ,, , . . . , .......... : , . . . . . .

~5729~

2-(3,4-dichlorophenyl)-N-(3,4-dimethoxyphenethyl)-N--methyl-m-dithiane-2-propylamine-l,l,3,3-tetraoxide hydro-chloride of melting point 175-177C (from methanol);
N-(3,4-dimethoxyphenethyl)-2~ dimethox~phenyl)-N--methyl-m-dithiane-2-ethylamine-l,l,3,3-tetraoxide oxalate (l:l) of melting point 202-204C (from acetone)0 , .
' - :.~' 10 g of 3',4'~dimethoxy 4-(methylveratrylamino)butyro~
phenone hydrochloride are dissol`ved in 50 ml of chloroform and treated with 3.25 g of 1~3-propanedithiol. Hydrogen chloride is conducted into the mixture at room temperature. After standing for 24 hours, the mixture is poured on to water, made -basic with 3-N sodium hydroxide and extracted with ether.
After dryi~g and evaporation of the solvent, the oily residue ` ~ 15 is dissolved in acetone and treated with an equivale~t amount of anhydrous oxalic acid. The crystalline precipitate is -~ recrystallised from acetone. There is obtained 2-~3,4--dimethoxyphenyl)~N-methyl-N-veratryl-m-dithlane-2-propylamine ;~ oxalate (l:l) of melting pOiIlt 133-136C.
, AnaIysis:
Calculated: C 57.12 H 6 57 N 2.47 ~ou~d: C 56.88 H 6.64 N 20~6 ', .. j ,,.
~he 3',4'-dimethoxy-4-(methylveratrylamino)butyrophenone used as the starting material can be prepared as follows:
., 500 g of polyphosphoric acid and 69 g oL ~eratrol are added to a l litre round~bottomed flask. ~o this are added ,~ ..
?7 . --~
, . . ~ ,,, , . .
.. . . .

~L~,572 .~
61 g of 4-chlorobutyric acid in one portion, the temperature rising steadily to 55C. After 1 hour, the entire mixture is poured on to ice. The mlxture is -then extr~cted with a mixture of ether/methylene chloride (3~ he organic extracts are extracted with water, then with a saturated sodium bicarbonate solution and finall~ again with water, dried over magnesium sulphate and evaporated in vacuo. The residual c~ystal mass is recrystallised from ether. There are obtained 62.9 g o~ 3,4-dimethoxy-Y-chlorobutyrophenone of melting point 91-92C.
, 12 g of 3,4-dimethoxy-~-chlorobutyrophenone are treated . - .
with 40 ml of N-ethyl~ diisopropylamine and 9 g of N-methyl--homoveratrylamine and stirred at 120a for 6 hours. After evaporation of the solvent in vacuo, the viscous mass is ., treated with ether and sodium hydroxide. ~he organic extracts are washed with water and extracted with l-N hydrochloric acid.
~he acidic extracts are then made alkaline and extracted with ether. The ether extracts are combined, dried over sodium ulphate and evaporated. ~he thus-obtained 3',4'-dimethoxy~

-4-(methyl~eratrylamino)~butyrophe~one, which is pure according to thin-layer chrom~tography, can be used wi-thout further .
purification.
, ............ .
' :
~he following compounds can be manufactured in a manner - analogous to that described in this Example:
N-(3,4-dimethoxyphenethyl)-2-(~,4-dimethoxgphenyl)-N--methyl-m-dithiane-2-butylamine oxalate (1:1) of melting point 1~4-136C (from acetone) starting from .i . . ;~ '. ".
, ~ _ , . .

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

~5~7Z~S

1,3-propa~edithiol ~nd 5-C(3,4-dimethoxyphenethyl)-~methylamino]-3',4'-dimethoxy~alerophenone (melting point of the h~drochloride 165-166C), obtained from

5 3,4-dimethoxy-~-chlorovalerophenone and N-methyl homo-~erat.rylamine.

N-(3,4-Dimethoxgphenethyl)-2-(3,4 dimethoxyphenyl)-N-~ -methyl-m-dithiane 2-pentylamine oxalate (1:1) of melting .
: point 109--111C (fro~ acetone3;
starting :Erom 1,3~propanedithiol and 6-~(3,4-dimethoxyphe~ethyl)--methylamino]-3',4'-dimethoxyhexanophenone (melting point ; of the hydrochloride 128-129C), ., : obtained ~rom

6-chloro~3',4'-dimethoxyhexanophenone and N-methyl-homo- :
. veratrylamine.

!:
2-(3,4-Dimethoxyphenyl)-N-[3-(3,4-dimethoxyphenyl)-: . -propyl~-N-methyl-m-dithiane;2-propylamine oxalate (1 .. : of:melting point 116-118C (from acetone);
`~ 20 s~arting from ~`~
1,3-propanedithiol and 3',4'-dimethoxy-4-~(3,4--dlmethoxyphenyl)-propylJ_methylamino~ -butyrophenone, obtained f~om : .~
.( : ' .. ~ 3,4-dimethoxy-r~chlorobutyrophenone and 3-(3,4-dimethoxy- ~`
phenyl)-N-methylpropylamine~

2-(3 9 4-Dimethoxyphenyl)-N methyl-N-(a-methylphenethyl)--m-dithiane-2-propylamine oxalate (1.:1) o~ melting point 131-132C (from acetone/ethyl acetate);

.,. ~ _ -~ . , . . .: -57~ 9 starting from 1,3-propanedithiol and 4-[(3,4-aimetho~y-a-methylphen-ethyl)-methylamino]-3',4'-dimethoxybutyrophenone, ~ obtained from .~ 5 3,4-dimethoxy-Y-chlorobutyrophenone .~nd N,~-dimethyl-~--phenylethylamine (boiling point 130-140C/20 mm Hg).

N-(3 t 4-Dimethoxyphenethyl)-2-(3,4-dimethox~phenyl)-~--methyl-1~3-dithiolane~2-propylamine oxalate (1:1) of ?
: melting point 150-152C (from acetone);
~ 10 starting ~rom .~ 4-~(3,4-dimethox~phenethyl~-methylamino]-3',4'-dimethoxy-~ but~rophe~o~e and 1,2~ethanedithiol.

, ~ .;.

10.4 g of 2~(3-chloropropy.1)-2-(3,4-dimetho~yphenyl)-m~
. ; ~
: 15 -dithiane-1~1~3~3-tetraoxide are treated with 5.11 ~ of N-methyl-homoveratrylamine,-30 ml of ~-eth~l-N,N-diisopropyl-: ~ amine and 70 ml of dimethylformamide. ~he sQlution is heated ~ at 120C ~or 6 hour~. After evaporation, the residue is .~.
'3~ ~ wo~ked-up i~n a manner analo~ous to that de~cribed in ~xample 5.
.. ; 20 There is obtained N-t3,4-dimethoxypheneth~1)-2-(3,4-dimethoxy- ~; :
1~ phenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3~tetraoxide .~
;1~ hydrochloride of meltlng point 167-169C. .~ -.

~he ~ollowing compounds can be manufactured in a manner .
~:: analogous to the foregoing:
N-(3,4~dimethoxyphenethyl)-N methyl-2-phenyl-m-dithiane~
-2-propylamine 1,1,3,3-te~r~oxide hydrochloride o~ meltin~ .
point 149C (decomposition) (from methanol); `~
~' , i ' !
.~ ~
.' ~ . _,~- , ' 7Z~D5 N-(p~chlorophenethyl)-l~T-methyl-2-phenyl-m-dithisne-2--propylamine-1,1,3~3-tetraoxide hydrochloride of meltin~ point 246~-249C (decomposition) (from methanol/~ethylene chloride);
N-methyl~-phenethyl-2~phenyl-m dithiane-2-prop~lamine--1,1,3 7 3-tetraoxide hydrochloride of meltin~ point 165-167C
(from acetone);
2-(3,4-dimethoxyphenyl)-N-methyl-N-veratryl-m-dithiane--2-prop~lamine-1,1,3,3-tetraoxide of melting point 137-139C
(from acetone/ethanol);
N-(3,4-dimethoxyphenethyl)-2-(3,4-dime-thoxyphenyl)-m--dithiane-2-propylamine-1~1,3,3-tetraoxide hydrochloride of melting point 130-132C (from acetone).

The 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl~ m--dithiane-1,1,3,3-tetraoxide used as a starting material in : 15 this Example can be prepared as follows:

.~ 10.9 g of 3,4-dimethoxy-r-chlorobutyrophenone (prepared ~: as described in Example 6) are dissolved in 120 ml of chloro-fo~m and treated with 5 ml of 1,3-propanedithiol and 1 ml of boron ~rifluoride etherate at room temperature. After 1 hour ., ~
at room temperature, ~he chloroform solution is washed three - times with water, three times with l-N sodium hydroxide and again three times with water. ~he or~anic phases are dried over magnesium ~ulphate and evaporated in vacuo. The oily j residue is immediately disQolved in 500 ml of chloroform at o-sa and treated with 45.7 g of solid m-chloroperbenzoic acid in such a manner that the temperature does not exceed 5C. The mixture is subsequently left in a refrigerator for 64 hoursO
~he organic phase is washed three times with l-~J sodium ' . ~, S~/

: : . ~ ,, ~5'~5 hydroxide and three times wlth water, dried over ma~nssium sulphate and evaporated in vacuo~ ~he residue is recrystallised from methylene chloride/isopropyl ether. There is obtained 2-(3-chloropropyl)-2-(3~4-dimet}loxyphenyl)-m dithiane~l,l,3,3--tetraoxide of melting point 183-184C.
.
.~:
~he 2-(3-chloropropyl)-2-phenyl-m-dithiane-1,1,3,3-tetra-oxide also used as a starting material in this Example can be , prepared as follows: ~
:
'.
19.63 g of 2-phenyl-m~dithiane are dissol~ed in 300 ml ~; :
of tetrahydrofuran. 43.5 ml of a solution of butyl lithium in hexane are slowly added dropwise at -70C while gassing with ` argon. The mixturè is stirred for a total of 1.5 hours at .
- -20C. The red ~olution obtained is added to a solution of 15.74 g of 1,3-bromochloropropanle in 250 ml of absolute tetra~
hydrofuran at -70C. The thus-obt~ined solution is left to stand for 1 hour at -20C a~d for 1 hour at roo~ temperature.
~ ~he solvent is evaporated in vacuo and the oily residue taken `~ up in ether~ The ethereal phase is washed with l-N sodium hydroxide and with water, dried over ma~nesium sulphate and evaporated in vacuo. The thus-obtained 2-(3-chloropropyl)-2 -phenyl-m-dithiane is peroxidised at o-soa with m-chloro-perbenzoic acid in chloroform as described in the previous .
paragraph. ~fter recrystallisation from ethyl acetate, there is obtained 2-(3-chloropropyl~-2-phenyl-m-dithiane-1,1~,3--tetraoxide of melting point 182C.
'' ~

i" ~ ~, ', :
3076 g of 2 (3,4-dimethoxyphenyl)-2-(2,3-~ epoxypropyl )-, . . . .. ..
~ ~ ~ . . r ': '. , ~ " ''' ' ` ~ ' ` : ' ' . . `:~ . , ", ~ :

-m-dithiane-1,1,3,3-tetraoxide are heated at reflux for 18 hours under argo~ with 50 ml of ethanol, 30 ml of chloroform and 1.95 g Or N-methyl-homovetratrylamine. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform/eth~nol (98:2). The oil obtained is dissolved in acetone and treated with ~n e~uivalent amount of anhydrous oxalic acid. The precipitate is filtered off and recrystallised from methanol/acetone. ~he racemic a-[(3,4-dimethoxyphen~
ethyl)-methylamino]-methyl-2-(3,4-dimethoxyphenyl)-m-dithiane--2-ethanol-1,1,3,3-tetraoxide oxalate (1:1) obtained crystallises with 1 mol of acetone and melts at 162~-164C. ~-~: Analysis: :~
~ aalculated: a 51.73 H 6.30 N 1.95 ~
" --`` ~ound: C 51.68 EI 6.53 N 2.00 :
,., , ~

~he 2-(3,4-dimethoxyphenyl.)-2-(2,3-epoxypropyl)-m--dithiane 1,1,393=tetraoxide used as the starting material can be prepared as follows: .

. .
: 9.6 g of 2-(3 t 4~dimethoxyphenyl)-m-dithi~ne-1,1,3,3--tetraoxide (prepared as described in Example 2) are dissolved in 35 ml of dimeth~lformamide and~ with stirring under argon, :1 , treated with 1.2 g of sodium h~dride at room temperature. ~he suspension lS stirred at 40C for a ~urther 0.5 hour, then .~ cooled and treated with 2~8 g of epichlorohydrin~ ~he mixture is then heated at lOO~C for 16 hours. After coolin~ to room temperature7 the suspension i5 poured on to water .-md the oily material extracted with chloroform. After eva.poration Or the solvent, the residue is chromatogr-lphed on silica gel with .. ; ,, .
chloroform/ethanol (98:2). ~he 2-(37~-dimethoxyphenyl)-2~
.'' ; ''.

~' _ ~3 ....... . . . . .. . .

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

`~

~57~
:
-(2,3-epoxypropyl)-m-dithiane-l,1,3,3-tetraoxide obtained is ;~ recrystallised from methylene chloride~ethanol and has a meltin~ point of 175~176C.

3.65 g of 2-(3~chloropropyl)-2-(~,4-dimethoxyphenyl) m--dithiane-1,3-dioxide, 7.8 g of N-me~hyl~homoveratrylamine and 20 ml of dimethyl sulphoxide are heated at 50C under argon for '~
16 hours. The solution i5 then poured into 200 ml of water .~ .
` and made stron~ly alkaline. ~he exce~s N-methyl-homoveratryl-amine is extracted with ether. The alkaline solution is then extracted with methylene chloride. ~he methylene chloride -~ .
extracts are dried over magnesium sulphate. After evaporation of the solvent, the residue is taken up in acetone and treated with hydrogen chloride in dioxa~e (up to pH 2). ~he crystalline residue i~ recrystallised from acetone/acetonitrile and there is obtained N-(374-dimethoxyphenethyl)-2-(3,4- ~
-dimethoxyphe~yl)-N-methyl-m-dithiane-2-propylamine-173-dioxide hydrochloride of melting point 148~-149C (diastereomeric mixture~

The 2-(3-chloropropyl)-2-(~,4-dimethoxyphenyl)-m-dithiane-1,3-dioxide used as the starting material can be prepared as follow~:
.;' :" .
. .1 . , .76~9 g of 2-(3,L~imethoxyphenyl)-m-dithiane (prepared i as described in Example 1) are dissolved in 900 ml of absolute tetrahydrofuran, the solution is cooled to -70C ~nd treated with 128 ml of a butyl lithium solution in such a manner that . - .,~,.,~,............. .

........ .

~.6~7~
.

the temparature does not exce~d -60C. ~he mi~ture i~ then held for ~ hour~ at -20C, ~ precipit~te rO~ming. The mixture is again cooled to -70C ~nd ~7~3 ~ Or 1,3-bromochloro~rop~ne in 750 ml of absolute tetrahydro~ur~n are a~ded. The mixture i9 then held for 1 hour at -20~C r~nd for 1 hour ~t room temperature. The tetrahydrofuran is then evaporated, the re3idue taken up in ether flnd extracted. ~.fter evaporation of the solvent, there is obtained 2-(3-chloropropyl)-2 (3,4--dimethoxyphenyl)-m-dithiane.
.
'~ 10 55.25 g of 2-(3-chloropropyl)-2-(3,4 dim~thoxyphenyl)-m--dithiane ~re dissolved in 500 ml of glacial acetic acid.
While stirring at 5C~ a solution of ~4 g of 30% hydro~en peroxide in 300 ml of ~lacial acetic acid is ~dded thereto within 2 hours. ~he mlxture i'3 then le~t to stand for ~0 ~ .
~' 15 hours at room temperature and t~len concentrated in vacuo t 40C.
The oil obt~ined is chromatographed on 1.5 kg of silica gel ~-~` with chloroform/ethanol, initially 98:2 and then 95:5. After recry~alli~ation from acotonitrile, t~ere is obtained 2-(3--chloropropyl)-2 ~3,4-dimethoxgphenyl)-m-dithiane-1,3-dioxide of mslting point 163-164C (diastereomeric mixture).

~: ' .. ~e~
:., ' .,' ~' ; In Q manner analogous to that described in ~xample 8, but ~
` starting ~rom 2-~3,4-dimethoxyphen~ 2-(2,3-epoxypropyl~-m- '--~ ~dithiane and'N-methyl-homoveratrylamine, there can be '''' manu~actured racemic a~ 7 4-dimethoxyphenethyl)-methylamino~-- -methyl 2-(3,4~dimethoxyphenyl)-m-dithiane-2-e-thanol. ~he hydrobromide of thl~ compound crystallises ~rom acetonitrile/
ethyl acetate and melt~ at 97-99C.

s i~

'' , , I :':'' " :', ~57~2~5 The 2-(3, 4-dimethoxyphenyl)-2 r (2,~-epoxypropyl) m-dithiane ~ u~ed as the starting material can be prepared in a ma~ner ; analogous to that de3cri~ed i~ Example 9 star~in~ from 2-(~,4--dimathoxyphenyl~-m-dithiane (prepared as described in ~xample ; 5 1) usin~ epichlorohydri~ instead of 1,3-bromochloropropane.
:

. ~ ~, 3.4 g of lithium aluminium hydride in 60 ml of tetrahydro-~uran are heated to reflux. 14.7 g of N-(3,4-dimethylphen-; ethyl)~2 (3,4-dimsthoxyphenyl)-m-dithiane-2-propionamide in :;
80 ml of tetrahydrofuran are then added dropwise. The suspension obtai~ed is heated at re~lux for a ~urther 3 hours, , then cooled to 0C and carefull;y treated with 50 ml of a -~ saturated ~odium sulphate solution. The mixture is the~
filtered off under a vacuum, thls ~olutio~ diluted with water ~ -and extracted with ether. ~he ethereal extracts are washed ~;
with 1 ~ ~odium hydroxide, then~with water, dried over magnesium ;;~-sulphate and evaporat~d. ~he oily re~idue i~ chromatographed , ~ on silica gel using chloroform/ethanol (95:5). The base ., o~tained is dissolved in aeeto~e and treated with an equivale~ ~
,.,. ~ .
amou~t o$ anh~drou~ oxalic acid. ~he reisulting precipitate i8 reoryit~11ised from methanol/acetone. ~he thus-obtained .. : .
I N-(3,~-dimethoxgpheneth~ 2-(3,4-dimethox~phenyl)-m-dithiane- ~
. . ..
-2-propylamine oxalate (1:1) melts at 186-188C.
is: .
Calculated: C 57~12 H 6.57 ~ 2.67 Found: C 56.97 H 6.73 N 2.39 . ~

,,, ' ( .. . .

... . . ~

S7~
.., ~
~he N-t3,4 dimethoxyphene-thyl~-2-(39~-dimethoxyphenyl)--m-dithiane-2-propionamide used as the startin~ material can be prepar0d as follows:

50 g of 3-veratroylpropionic acid in 400 ml of chloroform and 22.7 g of 1,3~pxopanedithiol are treated with hydrogen chloride up to saturation while stirrin~. ~fter 3 hours at room temperature, the solution is ev~porated to 50 ml and diluted with ether. The resulting ~olution is extracted three times with ~/o ~odium carbonateO ~he basic phases are combined and made acidic with concentrated hydrochloric acid.
~he precipitated product is extracted with ether/me~hylene chlorid~ tl:3). ~he organic extracts are dried and s~aporated.
he residue is recrystallis~d from ethanol, there being obtained 2-(3,4-dimethoxyphenyl) m-dithiane-2~propionic acid of melting point 134-1~5Co ~, . ~ .
13 2 g o~ 2-(3,4-dimetho~phenyl)-m dithia~e-2 propionic acid, 4 g of triethyl~mine and :L80 ml of tetrahydrofuran are cooled to 0C and treated dropwise withi~ 10 minutes with ~ g of chloroformic acid isobutyl ester in 80 ml of tetrahydro~uran ~ 20 The mixture is then held at room temperature for 3 hsurs and -'~ treated ~t O~C with 7.25 ~ of homoveratrylamine in 40 ml of -~
tetrahydro~uran. ~he ~usperl~ion is left to stand at 3C for 48 hours, then evaporated, treated with water and extracted with eth~r/methylene chloride (3~ he ethereal extracts are washed with water, sodium bicarbonate solution~ l-N tartaric acid and water. The org~nic phase is dried over magnesium sulphate and evaporated. The residue is crystallised from methylene chloride/ether at 0C. ~here is obtained N-(3~4-:~ .
,:, - ~

. ;,....................... . .. ~ -72~S
-dimethox;yphenethyl)-2-(3,~-dimethoxgphenyl)-m-dithiarle-2--propionamide of melting point 135-136C.

N-(3,4-Dimethoxypheneth~ 2-(3,L~-dimethoxyphenyl)-;~T--methyl-m-dithi~e-2-propylamine hydrobromide can be manufactured in a manner analogous to that described in the foregoing; melting point 170-172UC (from ethanol~

Example 12 0.5 g of 2-~r3-[2"-(3,4-dimethoxyphenyl)-m-dithian-2"--yl]-propyl~-methylamino)-3'~4'-dimethoxyacetophenone~
~l',3"-tetraoxide i~ dis~olved in 15 ml of ethanol and 30 mI of tetrahydroflur~ and treated with 50 m~; of sodium borohydride.
After stirring for 16 hours, the mixture is treated with 15 ml ; of 1-~ hydrochloric acid and then with 12 ml of l-N sodium hydroxide solutio~. ~he tetrahydrofuran is removed by evaporation and the residue extra~ted with methylene chloride.
Thc orga~c extracts are washed with water; dried over magnesium sulphate and evaporated in a vacuum. ~he crystals obtained are recr~stallised from methanol and there is obtained 0.3 g of a-/{~3-[21~(3,4 dimethox~phenyl)-m-dithian-2' yl]~
-propyï_~-methylam~no3-methyl/-veratrylalcohol-1',1',3',3'~
-tetraoxide of melt1ng point 132-133C. i ~he 2 {~3-[2"-(3,4-dimethoxyphenyl)-m-dithian-2"-yl]--propyl~-methylam~no}-3',4'-dimethoxyacetophenone-1",1",.",3"- ~ ~
-tetraoxide used as khe st~rting material can be prepared by ~;
reacting 2-(3-chloropropyl)--2-(3,4-dimethoxyphenyl)-m-dithiane- ~ ;
-1,1,3,3-tetraoxide with ~-methylamixlo-3,4-dimethoxyaceto-phenone; melting point 140C (decomposition) (from acetone).

_ ~ _ , . .
: ' ~ '. , ".
,: , .
, . . . .

~ \

~)57~5 &~ :

10 g of 1~ (394-dimethoxyphenethyl)~2-(3~4-dimetho~y-phenyl)-N methyl-m-dithiane-2-pentylamine (prepared as described -~
in Example 6) are dis~olved in 50 ml of glacial acetic acid and treated at room temperature with 20 ml of 30% hydrogen peroxide.
After 3 hours, the rnixture is heated at 35C for 3 hours and then at 40C for 18 hours. The solution is then poured on to water, made basic with sodium hydroxide and extractsd with methylene chlorideO After removal of the solvent7 the residue is chromatographed on silica gel using a mixture of chloroform, methanol and saturated ammonia (97:7). The product obtained is di3sol~ad in acetone and treated with an equivalent amount ` of oxalic acid. The re~ulting precipitate is recrystallised ~ ~
~rom acetone/methanol. There i~3 obtained~N-(374-dimethoxy- ~ ;
phenethyl)-2 (3,~dimethoxgphenyl)-N-methyl-m-dithiane-2~
-pe~t~lamin~ l,1,393-tetraoxida oxAlate (1:1) of melting point : l~9~-l9Ioa.
nalysis;
Calculated: C 53.4B H 6.43 N 2.08 20Found: C 53.~7 H 6.50 ~ 1.87 ~-~he ~ollowing compounds can be manufactured in a manner -analogous to that desoribed in the foregolng:
N-(~,4-I)imethoxyphenethyl)-2-(3?4-dimethoxyphenyl)-N--meth~l-m-dithiane-2-butylamlne-1,1,3,3-tetraoxide oxalate of melting point 161-163C (~rom acetoneJ
methanol), (ba~e: 123-126C $rom ethanol), start m g ~rom ,r~"",, s~'9 ~57Z~5 N-(3,4-dimethoxyphenethyl)-2-(214-dimethoxyphsnyl)-N~- --methyl-m-dithi~ne-2-but~lRmine (prepared as described in Example 6)~

2-(3,4-Dimethoxyphenyl)-N~3-(3,4-dimethoxyphenyl)- :
-propyl]-N-methyl m-dithiane-2-propyli~mine-1,1,3,3 -tetraoxide hydrobromide o~ melti~g point 138-140C ~
: (~rom acetonitrile/ethyl acetate), ~ ~ -~tarting ~rom ~ `
2~t3,4-dimethoxyphenyl)-~-L3-(3,4-dimethoxyp~en~
propyl~-N-methyl-m;dithic~ne-2-propylamine (prepared a~
described in Example 6)~

~; ~: Racemic N-(3,4-Dimethoxyphenethyl)-2 ~3,4-dimethoxyphenyl)-N,~-dimethyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide~
hydrochloride of melting point 183-185C (~rom acetone/: .: ;-, ~
15:~ ethyl acetate), : ;~
star~ing from , racemic;~-(3,4-dime~hoxgphenethyl)-2-(3,4-dimethoxy-phe~ N,~-dimeth~l-m-dithia~e 2-propyl~mi~e (prepared ~ -as~desoribed i~ Example~3). :~

~ 2-(~,4-Dimethox~phenyl~-N-methyl-N-~-methylpheneth~
:~ -m-dithiane-2-propylami~e-1,1,3,3-~tetraoxide hydrochlorid~of melting~polnt 185-187C (from acetone/ethyl acet~ate), ; starting from ~: ~ 2-(~,4-dimethoxyphe~yl)-N-meth~l-N-(a-methylphen~t~yl)-25 ~ -m-dithiane-2~prop~1amine (prepared as described in ~ ;
Exi~mple 6). ~ :

5~
" _ ,,~ _ .. ..

, , .. ., , , , ., ~ . ; , .

~572~ ~

.

11~2 ~ of 2-(4-benzyloxy-3-methoxyphenyl?-N-(3,4~
-dimethoxyphenethyl)-N-methyl-m~dithiane-2-propylamine-1,1,3,3--tetraoxide (prepared as described in Example 5) are heated with 100 ml of ~ hydrobromic acid for 2 minutes on ~ steam bath. ~he aquebus solution is then extracted with ether, evaporated in vacuo and azeotropically distilled three times with ethanol/benzene. ~he residue is crystallised from acetone~ The thus-obtained crystalline mass is recrystalliQed three times from metha~ol/acetonitrile and there is obtained 4~2'~ 3-~(3 9 4-din~thoxyphenethyl)-methylamino]-propyl~ -m--dithian 2'-yl~-2-methoxyphenoI-1',1'~3',3'-tetraoxide hydro- -bromide of meltiag point 192C (decomposition)0 ; ~ -~ .
; ~nalysis for C2sH35N8~2-HBr Calculated: a 48.23 H 5.83 N 2~25 ~ound: C 48.12 H 5.~3 N 2.07 In a~ analogou~ manner starting from 2-(3-benz~loxy-3--methoxyphe~yI)-~(3,4-aimethoxyphenethyl)-N-methyl-m-dithiane--2-propylamine-1~1,3,3-tetraoxide there can be obtained 5-{Z'--~ 3-[(3,4-dimethoxyphenethyl)-methylamino]-propyl ~-m-dithian~
`
-2'-yl)-2-methoxyphenol-1',1',3',3'-tetraoxide hydrobromide of melting point 201C (deco~position) (from acetonitrile). `~

2 g of 5-{2'~ 3~ 4~dimethoxyphenethyl)-methylamino-prop~ m-dithian 2' yl}-2-methoxyphenol-1',1',3',3'-tetra-oxide are dissolved in absolute pyridine and treated ~ith an ::

.

: \

~ ~7~9 ~ .
excess of acetic anhydride. After leavin~ for 16 hours at room temperature, the solvent is removed by evaporation and the residue chromatographed on silica gel. ~he 5-~2'-r 3--(3,4-dimethoxyphenethyl)-methylaminopropyl~ m-dithian-2~
-yl}-2-methoxyphenyl acetate 1',1'93',~'-tetraoxide is obtained as a thick oil.
Analysis:
Calculated: C 55.67 H 6.39 ~ 2.40 ~ou~d: C 55.~2 H 6.41 N 2.23 . .
~e~

0.3 g of 2-(3,4-dimethosyphen~ N~méthyl-m~dithiane-2--propylamine-1,1,3,3-tetraoxide are treated with 0.16 g of 3,4-dimethoxy~-phenethyl chloride, 5 ml of ~,N-diisoprop~
-N-ethylamine and 105 ml of dimethylformamide a~d the mixture ~: 15 i~ heated at l30C ~or 16 hour~. ~he solution is the~
.~ partitioned between wa~er and ethyl acetate. ~he residue i~
: chromatographed on silica Kel and there i9 obtained N-(3,4-dimetho ~ e~e~hyl~-2-(3,4-dimethoxyphenyl)-N-methyl-m~
-dithiane-2-prop~lamine-1,1,3,3-te~raoxide of melting point 20 ~ 144a (from~me~hanol). ~ ~;

~ he 2-( 3 ,4-di methoxgphen~ N-methyl~m-dithiane-2-propyl-amine-1,1,3,3~tetraoxide used as the starti~g material can be prepared as fol~ow8:
' 3.95 g of 2-(3-chloropropyl~-2-(3,4-dimethoxyphenyl)-m-.
-dithiane~ 353-tetraoxide are dissolved in 50 ml of dimethyl~
formamide. ~he ~olution i~ cooled to 0C and treated with .. . .

' , ' ~ ', -~357~5 15 g of methylamina. ~he mixture is heated at 40C under pressure for 18 hour~. ~he solution is then concentrated and the cry~talline residue recrystallised ~rom a small amount of methanol. ~here is thus obtained the desired starting material of melting point 164~C.

~Z :.

1 g of N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-; -m-dithiane-2-propylamine i~ dissolved in 20 ml of absolute pyridine and treated with 200 ml of acetic anhydride. After 18 hours, the mixture is concentrated and the residue partitioned betwee~ ether and sodium carbonate (5%). After evaporation of the solvent, there are obtained 1~2 g of an oil which is dissolved in 20 ml o~ absolute tetrahydrofuran.
This solution is slowly added dropwise to a suspension o~ 0.4 6 of lithium aluminium hydride and 20 ml of absolute tetrahydro-furan. ~he mixture i8 ~lowly treated with a concentrated : :
- aqueous ~odium sulphat0 ~o1ukion and then ~iltered under suct1on.
After evaporation of the ~ol~ent~ ths residue is partitioned between ether and water and the organic extracts are worked-up.
The oily re~ldue i8 treated with oxalic acid in acetone/ethyl acetate, there crystallising out N-(3,4-dimetho~yphensth~
-2-(3,4-dime$hoxyphenyl)-~ ethyl-m dithiane-2-propylamlne~
-~T~ d-'r~e -r- h-oxalate of melting point 12~-127C. `~
:,:, 1 g of homoveratric acid is dis~olved in 15 ml of absolute tetrahydrofuran and treated with 0.15 g of triethylamine.

' ~3 .

~ 7~5 0.72 g of chloroformic acid isobutyl e~ter are then slowly added dropwise at 0-5C and the mixture is stirred for 1 hour at 5-10C. There i~ then added dropwise a solution of 1.63 of 2-(314-dimethoxyphenyl~-N-~ethyl m-dithiane-2-propylamine ~prepared in a manner analogous to that described in Example 15 from 2-(Y-chl,oropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane and methylamine] in 5 ml of tetrahydrofuran. ~he resulting mixture is left to stand at room temperature overnight.
After evaporation of the solvent~ the residue is p~rtitioned between l-M hydrochloric acid and ether. The o~ganic extracts are washed with ~h sodium carbonate solution and water. After drying over mag~esium sulphate, the solvent is removed by -evaporation. ~h~ oily re~idue (1.5 ~3 is dissol~ed in 15 ml of tetrahydro~uran and added dropwise to a suspension of ~; ~ 15 0.15 ~ of lithium ~ ;nium hydride under re~lux and under ~ ;~
, argon. ~he mixture is boiled for 2 hours and then treated ~ ~ -slowly with a concentrated sodium sulphate solution in water and then with 10 ml o~ methylene chloride. ~he mixture i filtered under ~u~tion and~then conc0ntrated. ~he residue is chromato6raphed on ~ilica gel and there is obtai~ed N-(3,4 -dimethox~phenethyl~2-(3,4-dlmethoxyphenyl)-N-methyl-m~
-dithiane-2-prop~lamine in the form of a thick oil, ~-.

Capsules containing the following ingredlents are prepared in the u3ual manner:
. ' ' ~.

.,~,.,~ "

/

N-(3,LL-dimethoxyphenethyl)-2-(3,4--dimethoxyphenyl)-N-methyl m-dithiane 2-propylami~e 25 mg Mannitol 115 mg Maize starch 40 mg . .:
Talc 18 mg Magnesium stearate 2 mg 200 mg Exam~le 20 ~ablets containing the following ingredients are prepared :
in the usual manner:
N-(3,4-dimethoxyphenethyl)-2-(3,4--dimethoxyphenyl)-N-methyl-:m--dithia~e-2 propylamine-1,1,3,3- : <
-tetraoxide 25 mg ,~
~actose 90 mg l:
Maize starch 75 m ~ Magnesium stearate 1 mg ~ :
: ~alc 9 ~g 200 mg ' ',.", '.: .:,; , ,'~: ~,`

~ ~- 5S~ ~
~ , _~ _ , ~ , . , - - .
.. . . .. . . . . . . .

Claims (25)

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

1. Process for the manufacture of a compound of the general formula I

, wherein R represents a group of the formula (a) (b) in which R1, R2 and R3 each represent a hydrogen or fluorine, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy, aryl-(lower alkoxy), phenyl, nitro, trifluoromethyl, hydroxy, cyano, di(lower alkyl)amino, lower alkanoyloxy, or two adjacent R1, R2 and R3 symbols together represent a methylenedioxy, ethylenedioxy or butadien-1,3-ylene-1,4 group, R4 represents a hydrogen atom or a lower alkyl group, R5, R6 and R7 each represent a hydrogen or fluorine, chlorine, bromine or iodine atom or a lower alkyl or lower alkoxy group or two adjacent R5, R6 and R7 symbols together represent an ethylenedioxy group, X represents a sulphur atom, SO or SO2, Y represents a straight-chain or branched-chain, optionally hydroxy-substituted aliphatic group containing 2-8 carbon atoms, of which 2-4 carbon atoms are present in the chain, and Z represents a straight-chain or branched-chain, optionally hydroxy-substituted, aliphatic group containing 1-8 carbon atoms, of which 1-4 carbon atoms are present in the chain, m stands for zero or 1 and n stands for 2 or 3, or a pharmaceutically acceptable acid addition salt thereof, but excluding the compound N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide and its acid addition salts comprising a) reacting a compound of the general formula II

, wherein R, X and n have the significance given above, with a compound of the general formula III

, wherein R4-R7, Y, Z and m have the above meanings and R8 represents a leaving atom or group, or b) reacting a compound of the general formula IV
, wherein R, R4-R7, Y, Z and m have the above meanings, with a compound of the general formula V

, wherein n has the above meanings, or c) reacting a compound of the general formula VI
, wherein R, X, Y, R8 and n have the above meanings, with a compound of the general formula VII

, wherein R4-R7, Z and m have the above meanings, or d) reacting a compound of the general formula X

, wherein R, R4, X, Y and n have the above meanings, with a compound of the general formula XI

, wherein R5, R6, R7, R8, Z and m have the above meanings, or e) reducing the carbonyl group or the group denoted by A in a compound of the general formula XII

or XIII

, wherein R, R4-R7, X, Y, Z, m and n have the above meanings, Y1 and Z1 represent respectively a group corresponding to Y or Z containing a carbonyl group and A represents the group in which R? represents a hydrogen atom or an alkyl group with 1-5 carbon atoms; and for preparing a compound of formula I in which X represents SO or SO2, oxidising a compound of formula I in which X represents a sulphur atom to a compound of formula I in which X represents SO or SO2; for preparing a compound of formula I in which R4 represents a lower alkyl group, N-(lower alkylating) a compound of formula I in which R4 represents a hydrogen atom; for preparing a compound of formula I in which at least one of R1, R2 and R3 represent a hydroxy group, converting a corresponding lower alkoxy group or aryl-(lower alkoxy) group substituted compound of formula I

into a hydroxy group substituted compound for preparing a compound of formula I in which at least one of R1, R2 and R3 represents a lower alkoxy, aryl-(lower alkoxy) or lower alkanoyloxy group, etherifying or esterifying a corresponding hydroxy group substituted compound of formula I; and for preparing a pharmaceutically acceptable acid addition salt of a compound of formula I converting a base obtained into a pharmaceutically acceptable acid addition salt.

2. A process according to claim 1, wherein there is used as the starting material a compound of formula II, IV, VI, X, XII or XIII in which R represents a group of the formula (a) in which R1, R2 and R3 have the significance given in claim 1.

3. A process according to claim 2, wherein in the group of formula (a) one of the symbols R1, R2 and R3 represents a hydrogen atom and each of the other two symbols represents a lower alkoxy group, or together represent a butadien-1,3-ylene-1,4 group.

4. A process according to claim 1, wherein there is used a starting material of formula III, IV, VII, XI, XII or XIII in which one of the symbols R5, R6 and R7 represents a hydrogen atom and each of the other symbols represents a lower alkoxy group.

5. A process according to claim 1, wherein there is used a starting material of formula II, VI, X, XII or XIII in which X represents a sulphur atom or SO2 and n stands for 3.

6. A process according to claim 1, wherein there is used a starting material of formula III, IV, VI, X or XIII in which Y represents the group -(CH2)3- or a compound of formula XII in which Y1 represents a carbonyl group-containing moiety convertible into the group -(CH2)3-.

7. A process according to claim 1, wherein there is used a starting material of formula III, IV, VII, XI or XIII in which (Z)m represents the group -(CH2-CH2)m wherein m stands for zero or 1 or a compound of formula XII in which Z1 represents a carbonyl group-containing moiety convertible into the group -(CH2-CH2)m.

8. A process according to claim 1, wherein there is used a starting material of formula III, IV, VII, X or XII in which R4 represents a methyl or ethyl group or a compound of formula XIII in which A represents a formyl or acetylamino group.

9. A process according to claim 1 wherein there are used starting materials of formulae II to VII and X to XIII in which R represents a 3,4-dimethoxyphenyl group, X represents SO2, n stands for 3, Y represents a trimethylene group, Y1 represents a trimethylene group or a carbonyl-substituted group which can be converted into a trimethylene group, Z1 represents an ethylene group or a carbonyl-substituted group which can be converted into an ethylene group, R? represents a hydrogen atom, R4 represents a methyl group, Z represents an ethylene group, m stands for 1, R5 represents a hydrogen atom and R6 and R7 each represent a methoxy group in the 3- and 4-positions.

10. A compound of the general formula I

wherein R represents a group of the formula (a) (b) in which R1, R2 and R3 each represent a hydrogen or fluorine, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy, aryl-(lower alkoxy), phenyl, nitxo, trifluoromethyl, hydroxy, cyano, di(lower alkyl)amino, lower alkanoyloxy, or two adjacent R1, R2 and R3 symbols together represent a methylenedioxy, ethylenedioxy or butadien-1,3-ylene-1,4 group, R4 represents a hydrogen atom or a lower alkyl group, R5, R6 and R7 each represent a hydrogen or fluorine, chlorine, bromine or iodine atom or a lower alkyl, or lower alkoxy group or two adjacent R5, R6 and R7 symbols together represent an ethylenedioxy group, X represents a sulphur atom, SO or SO2, Y represents a straight-chain or branched-chain, optionally hydroxy-substituted, aliphatic group containing 2-8 carbon atoms, of which 2-4 carbon atoms are present in the chain, and Z represents a straight-chain or branched-chain, optionally hydroxy-substituted, aliphatic group containing 1-8 carbon atoms, of which 1-4 carbon atoms are present in the chain, m stands for zero or 1 and n stands for 2 or 3, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 1, or by an obvious chemical equivalent thereof.

11. A compound according to claim 10, wherein R represents a group of the formula (a) wherein R1, R2 and R3 have the significance given in claim 11, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 2, or by an obvious chemical equivalent thereof.

12. A compound according to claim 10, wherein one of the symbols R1, R2 and R3 represents a hydrogen atom and the other symbols each represent a lower alkoxy group, or together represents a butadien-1,3-ylene-1,4 group, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 3, or by an obvious chemical equivalent thereof.

13. A compound according to claim 10, wherein one of the symbols R5, R6 and R7 represents a hydrogen atom and the other symbols each represent a lower alkoxy group, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 4, or by an cbvious chemical equivalent thereof.

14. A compound according to claim 10, wherein X represents a sulphur atom or SO2 and n stands for 3, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 5, or by an obvious chemical equivalent thereof.

15. A compound according to claim 10, wherein Y represents the group -(CH2)3-, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 6, or by an obvious chemical equivalent thereof.

16. A compound according to claim 10, wherein (Z)m represents the group -(CH2-CH2)m in which m stands for zero or 1, or a pharmaceutically aoceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 7, or by an obvious chemical equivalent thereof.

17. A compound according to claim 10, wherein R4 represents a methyl or ethyl group, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 8 or by an obvious chemical equivalent thereof.

18. A process according to claim 1 in which X is a sulphur atom or SO2, n stands for 3, Y represents a trimethylene greup, Y1 represents a trimethylene group or a carbonyl-substituted group which can be converted into a tri-metllylene group, R4 represents a methyl or ethyl group, R4 represents a hydrogen atom or a methyl group, Z represents an ethylene group, Z1 represents an ethylene group or a carbonyl-substituted group which can be converted into an ethylene group and R1, R2, R3, R5, R6, R7 and m are as defined in claim 1.

19. A compound of the general formula Ia wherein R1, R2 and R3 each represent a hydrogen or fluorine, chlorine, bromine or iodine atom or a lower alkyl, lower alkoxy, aryl-(lower alkoxy), phenyl, nitro, trifluoromethyl, hydroxy, cyano, di(lower alkyl)amino, lower alkanoyloxy, or two adjacent R1, R2 and R3 symbols together represent a methylenedioxy, ethylenedioxy or butadien-1,3-ylene-1,4 group, R4 represents a methyl or ethyl group, R5, R6 and R7 each represent a hydrogen or fluorine, chlorine, bromine or iodine atom or a lower alkyl or lower alkoxy group or two adjacent R5, R6 and R7 symbols together represent an ethylenedioxy group, X1 represents a sulphur atom or SO2, n stands for 3 and m stands for zero or 1, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process as claimed in claim 18, or by an obvious chemical equivalent thereof.

20. A process according to claim 19 wherein one of the symbols R1, R2 and R3 represents a hydrogen atom and each of the other symbols represents a lower alkoxy group or they together represent a butadien-1,3-ylene-1,4-group, and the other symbols are as defined in claim 18.

21. A compound according to claim 19, wherein one of the symbols R1, R2 and R3 represents a hydrogen atom and each of the other symbols represents a lower alkoxy group, or they together represent a butadien-1,3-ylene-1,4 group and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process as claimed in claim 20, or by an obvious chemical equivalent thereof.

22. A process according to claim 20 wherein one of the symbols R5, R6 and R7 represents a hydrogen atom and each of the other symbols represents a lower alkoxy group, and the remaining symbols are as defined in claim 20.

23. A compound according to claim 19 wherein one of R1, R2 and R3 represents a hydrogen atom and each of the other two symbols represents a lower alkoxy group or they together represent a butadien-1,3-ylene-1,4 group, one of R5, R6 and R7 represents a hydrogen atom and each of the other two symbols represents a lower alkoxy group and X1, n, R? and m are as defined in claim 19, whenever prepared by the process as claimed in claim 22 or by an obvious chemical equivalent thereof.

24. A process according to claim 2 in which in the group of formula (a) one of the symbols R1, R2 and R3 represents a hydrogen atom and each of the other two symbols represents a methoxy group, or they together represent a butadien-1,3-ylene-1,4 group.

25. A process according to claim 1, wherein there is used a starting material of formula III, IV, VII, XI, XII or XIII in which one of the symbols R5, R6 and R7 represents a hydrogen atom and each of the other two symbols represents a methoxy group.