CA1072966A

CA1072966A - Heterocyclic compounds

Info

Publication number: CA1072966A
Application number: CA324,132A
Authority: CA
Inventors: Henri Ramuz
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1973-12-21
Filing date: 1979-03-26
Publication date: 1980-03-04
Also published as: LU71530A1; NL7416507A; ATA38978A; DE2460593A1; IL52843A0; CH620921A5; AU511714B2; NL158496B; ES433172A1; NO744615L; FI352774A; ES451134A1; CH611614A5; DE2463173C2; GB1489088A; AT344693B; FR2255064B1; AT349013B; FI67216C; SE434746B

Abstract

ABSTRACT OF THE DISCLOSURE

The compound of the formula

Description

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me present invention relates to the novel sulphur-containing compound of the formula ,CE~`

3 ~ ~ 02S ~ ~S2 1 3 ~ OCH3 3 C - (CH2)3 N (CH2)2 ~ OCH3 (Ia) and to pharmaceutically acceptable acid addition salts thereof, as well as to a process for their manufacture.
The term "leaving atom or group" used hereinafter means known atoms and groups such as, for exa~lple, halogen, preferably bromine or chlorine, arylsulphonyloxy such as tosyloxy, alkylsulphonyloxy such as mesyloxy or an epoxy group and the like.
According to the process provided by the present invention, the compound of formula Ia and its pharmaceutically acceptable acld addition salts are manufactured by a process which comprises either:

(a) reacting the compound of the formula:

CH 0 ~CH2 ~
3 \ CH2 T2 (IIa) ~ ~ S02~ ,SO2 CH 0 ~ ) CH

or a metal salt thereof, with a compound of the gener~1 formula:

R8 - OE32CH2CH2 - N - CH2CH2~J'3a33 (IIIa) ., ~ .

I

~herein R8 represents a leaving atom or group; or (b) reacting a compound of the general formula:
~ CH2 ~
OCH3: ~ Cl2 CIH2 \ SO? ,S2 3 ~ C . (CH2)3-R8 (Vla) wherein R8 represents a leaving atom or group, with a compound of the formula:

1 3 ~ OCH3 (VIIa) H - N - CH2CH2 ~ OCH3 ; or (c) reacting a compound of the formula:
CH2~
CH30 C ~ ClH2 ~ ~ ~ 2 ICH3 (Xa) 3 ~ ~ C (CH2)3 - N - H
with a compound of the formula:

~a CH2 CH2 ~ H3 OCH3 (XIa) wherein R8 represents a leavlng atom or group; or (d) reducing the carbonyl group in a compound of the formula " ~H2 ~
CH30 ~ ~ ~ 2 Yl N 1 ~ 0CH (XIIa)

- 2 -~.
~.~

. ` ~, `
.

Z~t~6 .~here at least one of Yl and Zl is a group containing a carbonyl group and Y
is -(CH2)3 - or a corresponding group containing a carbonyl group and Zl is -CH2-CH2- or a corresponding group containing a carbonyl group, or reducing a compound of the formula:

CH30 ~ ~ 52 H-OO ~ ~ ~

(XIIIa) (e) oxidising a compound of the formula:
~ CH2~
CH30 CIH2 CIH2 3 ~ OCH3

3 ~ C -(CH2)3 - N - C~12CH2 ~ 3 (Ib) which X represents -S- or -SO-; or (f) N-m.ethylating a compound of the formula:

CH30 / CH~ OCH3 ~ S~2 ~S2 3 ~ ~C (C1~2)3 - N - C~I2 C~I2 ~ OCH3 ; or (Ic) (g) methylating a corresponding compound in which one or more of the methoxy groups in for~la Ia is replaced by hydroxy, and where any one of steps (a) to (g) can be followed by converting the base of formula Ia obtained into a corresponding phaxmaceutically acceptable acid addition salt.

,A~
~ ,...

- ~ :

I

The reaction of the compound of formula IIa with the compound of formula IIIa according to embodiment (a) 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 and at a temperature between about -80C and the reflux temperature of the reaction mixture, pre-ferably between about 0C and about ~0C and especially at about room temper-ature. As solvents there may be mentioned ethers (e.g. diethyl ether, tetrahydrofuran; 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.
The reaction of the compound of formula VIa with the compound of formula VIIa in accordance with embodiment (b) 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. benzene, toluene or xylene), acetonitrile, dimethylformamide, dimethyl sulphoxide or the like. The reaction can be carried out at a temperature between about room temperature and the reflux temperature of the reaction mixture. The reaction is preferably carried out at the reflux tem~erature. The 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,N-dimethylaniline or the like) in the case where acid is cleaved during the reaction.
The reaction of the compound of formula Xa with the compound of formula XIa in accordance with embodim.ent (c) of the process can be carried out in a manner known per se. The reaction is expediently carried out in an

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organic solvent which is inert under the reaction conditions, such as an ether (e.g. dibutyl ether, dioxane or tetrahydrofuran), an aIkanol (e.g.
ethanol or propanol), an aromatic hydrocarbon (e.g. benzene, toluene or xylene), acetonitrile, dimethylformamide, dimethyl sulphoxide or the like. me reaction can be carried out at a temperature between about room temperature and the reflux temperature of the reaction mixture, preferably at the reflux temperature. me reaction is expediently carried out in the presence of a 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 during the reaction.
me reduction of the carbonyl group in the compound of formula XIIa or XIIIa in accordance with embodiment (d) of the process can be carried out in a manner known per se.
Thus, an amide of formula XIIa or XIIIa (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. This reduction is expediently carried out in an organic solvent which is inert under the reduction conditions (e.g. an ether such as diethyl ether, tetrahydrofuran etc or diglyme) and at a temperature between about pC and the reflux temperature of the reduction mixture, preferably at about room temperature.
The reduction of other carbonyl groups (i.e. those which are not bonded directly to the nitrogen atom) can also be carried out in a manner known per se. In particular, the reduction can be carried out in such a manner that it either leads to a hydroxymethylene group, which is then further reduced to a methylene group, or leads directly to a methylene group.
me reduction to a hydroxymethylene group can be carried out by

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.
.

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~reatment with a complex metal hydride such as an alkali metal aluminium hydride or an alkali metal borohydride.
The reduction using an aIkali metal aluminium hydride or an alkali metal borohydride can be expendiently carried out at room temperature or at a temperature below or above room temperature and in an inert organic ~olvent.
Suitable sclvents which can be used in the case of reduction using an alkali metal aluminium hydride include, inter alia, anhydrous ethers such as diethyl ether and tetrahydrofuran. Suitable sQlvents which can be used in the case of reduction using an alkali metal borohydride include a~kanols containing l-LI carbon atoms (e.g. methanol or ethanol), dioxane or the like. Lithium aluminium hydride is preferably used as the alkali metal aluminium hydride and sodium borohydride is preferably used as the alkali metal borohydride.
The further reduction of a hydroxymethylene group to a methylene group can be carried out in a manner known per se, especially by conversion into a corresponding sulphonic acid ester or into a halide and reduction there-of with a complex metal hydride. These reductions can be carried out in a manner analogous to the reduction of carbonyl groups described hereinbefore.
The direct reduction of a carbonyl group to a methylene group can be carried out by means of a Wolff-Kishner reaction in a manner known per se, namely by reaction of the ketone with hydrazine to give the corresponding hydrazone and decomposition of the hydrazone under basic conditians.
The conversion of the corrlpound of formula Ib into the cGmpound of formula Ia can be carried out by oxidation, in a suitable solvent, with a peracid such as peracetic acid, perphthalic acid, m-chloroperbenzoic acid or the like. Peracetic acid can, for example, be formed in situ from glacial acetic acid and hydrogen peroxide.
; m e compound of formula Ic can be N-methylated in a m~nner kno~n

- 6 -~,~

. :
. ' ,: ' , ' ~ :

z~
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~er se; for example, using a methyl halide. In this procedure, the particular compound of formula Ic is expediently reacted directly with the methyl halide at a low temperature.
Ihe etherification of a hydroxy group in accordance with embodiment (g) of the process 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 corr,pound of formula Ia 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), sulphuric acid, phosphoric acid or the like or with an organic acid such as oxalic acid, tartaric acid, citric acid, methanesulphonic acid or the like. Of the acid addition salts of the compound of formula Ia, the pharmaceutically acceptable acid addition salts are preferred. If, in the course of the process of this invention, an acid addition salt of the corr,pound of formula Ia is obtained, then such a salt can be converted into the free base in a known manner (e.g. by treatment with alkali) and the free base can, if desired, be converted into another acid addition salt.
The various starting materials are partly known and partly novel.
In the following exarr,ples the preparation of various of these starting materials ls described in detail. The remaining starting rnaterials can be prepared in a rnanner analogous to the preparation of the compound of formula Ia according to process ernbodiments (a) and (c) using appropriate pre-starting rnaterials.
The compound of formula Ia and its acid addition salts possess valuable ~ coronary-dilating properties and can accordingly be used, inter alia, for the treatrnent of angina pectoris.
The coronary-dilating activity can be measured by the following '~ ~
,., ~ ~
, .
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: :
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.. . .
- . -. . . .
: . : .- . .. .. .

2't1~iti I

method:
Mongrels weighing between 2a and 38 kg are used for the tests. The test animals are anaesthetised with ca 30 mg~kg i.v. pentobarbital and the anaesthesia is maintained with chloralose-urethane. The animals are artifically respired with atmospheric air. After opening the thorax, the heart is exposed and a previously calibrated flow-probe or an electro-magnetic flowmeter for measuring the blood flow-rate is placed around the ra~ls circumflexus of the left coronary artery. The arterial blood pressure is measured with a pressure transducer via a catheter in the arteria f~moralis.
Further, a calibrated extensible measuring strip for the direct measurement of the myocardial contraction force is sutured on to the surface of the left ventricle. The pulse wave of the blood pressure triggers a tachograph for measuring the heart frequency. The water-soluble compound is administered intravenously dissolved in an isotonic sodium chloride solution. The maximum activlty of the compound is calculated according to each dosage in per cent of the starting value and represented graphically. ~n the measurement of the coronary blood-flow, the duration of activity is also carefully observed.
The results obtained are compiled in the following Table, n denoting the number of animals used.

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~ 9 ~6 The cornpound of formula Ia and its pharmaceutically acceptable acid addition salts may be used as medicament in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material. This carrier material may be an organic or inorganic, inert carrier material suitable for enteral or parenteral administration such as, for example, water, gelatine, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkyleneglycols, petroleum jelly etc. The pharmaceutical preparations can be made up in a solid form (e.g. as tablets, dragées or capsules) or in a liquid form (e.g. as solutions, suspensions or emulsions). The pharmaceutical preparations may be sterilised and/or may contain adjuvants such as preservatives, stabilisers, wetting agents, emulsi-fiers, salts for varying the osmotic pressure or buffers.
The daily dose in the case of oral administration lies between about 10 mg and 200 mg. The daily dose in the case of intravenous administration lies between about 1 mg and 20 mg.
The aforementioned dosages are, however, only given by way of example and can be modified according to the severity of the case to betAeated and the directions of the attending physician.
me following examples illustrate the process provided by the present invention:

35.2 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide are suspended in 180 ml of absolute dioxane and treated with 2.53 g of sodium.
me mixture is boiled under argon from 2Q hours, the sodium passing completely into solution. 27.2 g of N-(3-chloropropyl)-3,4-dimethoxy-N-methyl-phenethyl-amine are then added at room temperature, the cloudy solution is stirred at room temperature for 1 hour and boiled at reflux for 3 hours. m e mixture . -', ' ' ', .
: , , . . , , ; . - ,. . :, - . ' . :, : . . :- , , .. . . .
-~ 6 is poured on to ice/water and extracted three times with ethyl acetate. The ethyl acetate ex~racts are combined and extracted three times with l-N hydro-chloric acid. Ihe acidic extracts are made aIkaline and extracted three times with chloroform. The chlorofrom extracts are combined, washed with water, dried over magnesium sulphate and evaporated. The crystalline residue is recrystallised 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 of hydrogen chloride in dioxane.
The crystalline salt is filtered off under a vacuum and recrystallised from acetonitrile/acetone (1:3). The thus-obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride is dried overnight in a high vacuum at 120C. There are obtained 38.9 g of a substance of melting point 167 - 169C.
Analysis:
Calculated: C 52.74 H 6.47 N 2.36 Cl 5.99 S 10.83 Found: C 52.58 H 6.58 N 2.16 Cl 6.19 S 10.53 (a) The 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide used as the starting material can be prepared as follows:
74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of chloroform, treated with 50 ml of 1,3-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. me mixture is then washed three times successively with 500 ml of a 7% potassium hydroxide solution and 500 ml of a 10% sodium chloride solution. me organic extracts are combined, dried over magnesium sulphate and evaporated. me residue is recrystallised twice from ether. There are obtained 102.6 g of 2-(3,4-dimethoxyphenyl)-m~

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~ 9 6 dithiane of melting point 99 - 101C.
60 g of 2-(3,4-dimethoxyphenyl)-m}dithiane are dissolved in 470 ml of glacial acetic acid and treated at room tem~erature with 235 ml of 30%
hydrogen peroxide, the temperature of the solution rising to ca 40C. me solution is left to stan~ overnight at room temperature. The solution is then heated for 2 hours at 100C. After cooling to room temperature, the crystal-line precipitate is filtered off under a vacuum, washed with some glacial acetic acid, dried in vacuo at 60C overnight and then recrystallised from : acetonitrile. mere are obtained 57.1 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide of melting point 243 - 245C.

(b) me N-(3-chloropropyl)-3,4-dimethoxy-N-methyl-phenethyl-amine also used as the starting material can be prepared as follows:

292.5 g of N-methyl-homoveratrylamine are dissolved in 1000 ml of dimethylformamide and treated with 415 g of anhydrous potasslum carbonate.
The mixture is stirred at 5C, treated with 237 g of 1,3-bromochlor~propane in 500 ml of dimethylfornE~)ide, stirred for a further 4 hours at room temperature and then poured into 6 litres of water. The separated oil is ex-tracted three times with 2 litres of ether each time. The organic extracts are dried with magnesium sulphate and evaporated in vacuo. The residual oil is distilled at between 69C and 70C with a mercury diffusion pump at 0.005 Torr. m ere are obtained 206.7 g of N-(3-chloropropyl)-3,4-dimethoxy-N-methyl-phenethylamine of boiling point 69 - 70C/0.005 Torr.

10.4 g of 2-(3-chlorophenyl)-2-(3,4,-dimethoxyphenyl)-m-dithiane -1,1,3,3-tetraoxide are treated with 5.11 g of N-methyl-homoveratryl~mine, 30ml of N-ethyl-N,N-diisopropylamine and 70 ml of dimethylformamide. The ,. .~}-., , ' :, :

7 ~ ~ 6~

~olution is heated at 120C for 6 hours. After evaporation, the residue is dissolved in acetone and treated with a 6-N-hydrogen chloride solution in dioxane. The precipitate, which is filtered off under a vacuum is recrystal-lised from acetone. There is obtained ~(3,4-dimethoxyphenethyl)-2-(3,4-di-methoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydro-chloride of melting point 167 - 169C.

(a) The 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-1,1, 3,3-tetraoxide used as a starting material in this example can be prepared as follows:
500 g of polyphosphoric acid and 69 g of veratrol are added to a 1 litre round-bottomed flask. To this are added 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 mixture is then extracted with a mixture of ether/methylene chloride (3:1). The organic extracts are extracted wlth water, then with a saturated sodium bicarbonate solution and finally again with water, dried over magnesium sulphate and evaporated in vacuo. The residual crystal mass is recrystallised from ether. There are obtained 62.9 g of 3,4-dimethoxy-~-chlorobutyrophenone of melting point 91 - 92C.
10.9 g of 3,4-dimethoxy-~-chlorobutyrophenone are dissolved in 120 ml of chloroform and treated with 5 ml of 1,3-propanedithiol and 1 ml of boron trifluoride etherate at room temperature. After 1 hour at room temperature, the chlorofrom solution is washed three times with water, three times with 1-N sodium hydroxide and again three times with water. The organic phases are dried over magnesium sulphate and evaporated in vacuo. The oily residue is immediately dissolved in 500 ml of chloroform at 0 - 5C and treated with ", .
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~5.7 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 hours. The organic phase is washed three times with l-N sQdium hydroxide and three times with water, dried over magnesium sulphate and evaporated in vacuo. The residue is recrystallised from methylene chloride/isopropyl ether.
There is obtained 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-1,1, 3,3-tetraoxide of melting point 183 - 184C.

0.3 g of 2-(3,4-dimethoxyphenyl)-N-methyl-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,N-diisopropyl-N-ethylamine and 1.5 ml of dimethylformamide and the mixture is heated at 130C for 16 hours. m e solution is then partitioned between water and ethyl acetate. The residue is chromatographed on silica gel and there is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl-N-methyl-m-dithiane-2-propylamine-1,1,3,3,-tetraoxlde of melting point 144C (from methanol).
(a) The 2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide used as the starting material can be prepared as follows:
3.95 g of 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-1, 1,3,3-tetraoxide are dissolved in 50 ml of dimethylformamide. The solution is cooled to 0C and treated with 15 g of methylamine. The mixture is heated at 40C under pressure for 18 hours. The solution is then concentrat-ed and the crystalline residue recrystallised from a small amount of methanol.
There is thus obtained the desired starting material of melting point 164C.
F~AMPLE 4 Capsules containing the following ingredients are prepared in the ..~

a..................................... :

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

~sual manner:
N-(3,4-dimethoxyphenethyl)-2-(3,4--dimethoxyphenyl)-N-methyl-m--dithiane-2-propylamine 25 mg Mannitol 115 n~
Maize starch 40 mg Talc 18 mg Magnesium stearate 2 mg 200 mg Tablets containing the following ingredients are prepared in the usual m~lner:
N-(3,4-dimethoxyphenethyl)-2-(3,4--dimethoxyphenyl)-N-methy-m-.
-dithiane-2-propylamine-1,1,3,3--tetraoxide 25 mg Lactose 90 mg Maize starch 75 mg Magneslum stearate 1 mg Talc 9 mg 200 mg L ~

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Claims

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 formula:

Ia or a pharmaceutically acceptable acid addition salt thereof, which comprises either:-(a) reacting the compound of the formula:

IIa or a metal salt thereof, with a compound of the general formula:

IIIa wherein R8 represents a leaving atom or group ; or (b) reacting a compound of the general formula:

VIa wherein R8 represents a leaving atom or group, with a compound of the formula:

VIIa (c) reacting a compound of the formula:

Xa with a compound of the formula:

XIa wherein R8 represents a leaving atom or group;
(d) reducing the carbonyl group in a compound of the formula where at least one of Y1 and Z1 is a group containing a carbonyl group and Y1 is -(CH2)3- or a corresponding group containing a carbonyl group and Z1 is -CH2-CH2- or a corresponding group containing a carbonyl group, or reducing a compound of the formula:

; or (e) oxidising a compound of the formula:

;

in which X represents -S- or -SO- ; or (f)N-methylating a compound of the formula:

; or (g) methylating a corresponding compound in which one or more of the methoxy groups in formula Ia is replaced by hydroxy, and where any one of steps (a) to (g) can be followed by converting the base of formula Ia obtained into a corresponding pharmaceutically acceptable acid addition salt.

2. A compound of the formula Ia given in claim 1 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process in which N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetra oxide (Formula Ia) and its hydrochloride are prepared by reacting 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetra oxide with N-(3-chloropropyl)-3,4-dimethoxy-N-methylphenethylamine and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

4. N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetra oxide of Formula Ia given in claim 1 and its hydrochloride whenever prepared by the process of claim 3 or by an obvious chemical equivalent thereof.

5. A process in which N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetra oxide (Formula Ia) and its hydrochloride are prepared by reacting 2-(3-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetra oxide with N-methylhomoveratrylamine and when the hydrochloride is required reacting the base so obtained with hydrogen chloride.

6. A process in which N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetra oxide is prepared by reacting 2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetra oxide with 3,4-dimethoxy-.beta.-phenethyl chloride.

7. A process according to claim 6 in which the reaction is effected in the presence of a base.

8. N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetra oxide of formula Ia given in claim 1 whenever prepared by the process of claim 6 or 7 or by an obvious chemical equivalent thereof.