CH620920A5 - Process for the preparation of sulphur-containing heterocyclic compounds - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R is a phenyl radical which is optionally substituted in a particular way or a thienyl radical and X is a sulphur atom or a sulphinyl or sulphonyl group, and the other symbols have the meaning stated in Claim 1, and acid addition salts thereof have valuable coronary-dilating properties and are accordingly particularly suitable for the treatment of angina pectoris. These compounds are prepared by appropriate substitution on the nitrogen atom of compounds of the formula <IMAGE>

Description

The present invention relates to a process for the preparation of new sulfur-containing heterocyclic compounds of the general formula

YCH ^

. (i)

wherein R is a radical of the formula or

S

(b)

I ——

are to be understood. The term "leaving group" used in the following means, within the scope of the present invention, known groups such as e.g. Halogen, preferably bromine or chlorine, arylsulfonyloxy such as tosyloxy, alkylsulfonyloxy such as mesyloxy or an epoxy group and the like.

According to the invention the compounds of formula I above and their acid addition salts are prepared by using a compound of general formula

30th

Ri, R2 and R3 are hydrogen, halogen, lower alkyl, lower alkoxy, aryl-lower alkoxy, aryloxy, phenyl, nitro,

Amino, lower alkylthio, trifluoromethyl, hydroxy, cyano, di-lower alkylamino, lower alkanoylamino, carboxyl, lower alkoxycarbonyl, lower alkylsulphonyl, hydroxymethyl, lower alkanoyloxy, aminocarbonyl, lower alkanoyl, sulfamoyl, mono- or di-lower alkyl Sulfamoyl, aminocarbonyloxy, mono- or di-lower alkylaminocarbonyloxy, lower alkylamino lower alkyl or two adjacent radicals together methylenedioxy, ethylenedioxy or butadien-l, 3-ylen-l, 4, R4 hydrogen or lower alkyl, Rs , Rö and R7 are hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or benzyloxy or two adjacent radicals together methylenedioxy or ethylenedioxy, X is a sulfur atom, SO or SO2, Y is a straight-chain or branched, optionally substituted by hydroxyl-substituted aliphatic radical with 2-8 Carbon atoms, of which 2-4 carbon atoms are in the chain and Z is a straight-chain or branched, optionally substituted by hydroxy aliphatic radical t having 1-8 carbon atoms, of which 1-4 carbon atoms are in the chain, and m are the numbers 0 or 1 and n are the numbers 2 or 3, and acid addition salts thereof.

The term “lower alkyl” in the context of the present invention means straight-chain or branched alkyl groups with 1-6 carbon atoms, such as e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert. Butyl, amyl,

Hexyl and the like. "Lower alkoxy" means lower alkyl ether groups, in which the term "lower alkyl" has the above meaning. “Halogen” comprises the 4 halogen atoms fluorine, chlorine, bromine and iodine. "Lower alkanoyl" means alkanoyl groups with up to 6 carbon atoms, e.g. Formyl, acetyl, propionyl, butyryl and the like. “Aryl” means unsubstituted or substituted phenyl, with halogen, lower alkyl, lower alkoxy, nitro and amino as substituents

/ n • _) 1

R

1

N

(II)

■ H

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

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Rr

R,

(III)

Rs-

■ (2)

m y ~ K a wherein R5-R7, Z and m have the above meaning and Rs ss represents a leaving group, and, if desired, convert a base obtained into an acid addition salt.

If desired, in a compound of the formula I obtained in which at least one of the symbols R 1, R 2, R 3, Rs, R and R 7 denotes lower alkoxy or aryl-lower alkoxy 60 or benzyloxy, this ether group (s) can be obtained by

Convert treatment with acid to hydroxy. If desired, a compound of the formula I in which at least one of the symbols R 1, R 2 and R 3 denotes hydroxyl can furthermore be converted into lower alka-65 noyloxy by esterification.

Preferred compounds falling under the above formula I can be represented, for example, by the following formula:

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4th

wherein R1-R7 and m are as defined above, R'4 is methyl or ethyl and Xi is a sulfur atom or SO2.

Further preferred compounds falling under the above formula Ia are those in which one of the radicals R 1, R 2 and R 3 is hydrogen and the other lower alkoxy, in particular methoxy, or together are butadiene-1,3-ylene-1,4 or wherein two the radicals Ri, R2 and R3 are hydrogen and the third nitro and one of the radicals Rs, Rs and R7 is hydrogen and the other two are lower alkoxy, in particular methoxy. A particularly preferred compound is the N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1,3,3-tetraoxide.

The reaction of a compound of formula II with a compound of formula III can be carried out in a manner known per se. The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, such as an ether, e.g. Dibutyl ether, dioxane, tetrahydrofuran, an alkanol, e.g. Ethanol or propanol, an aromatic hydrocarbon such as e.g. Benzene, toluene or xylene or also in acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. The reaction can be carried out at a temperature between about room temperature and the reflux temperature of the reaction mixture. It is preferable to work at the reflux temperature. If acid is split off during the reaction, this is expediently carried out in the presence of a base, e.g. one tert. Amines such as triethylamine, N-ethyl-N, N-diisopropylamine or N, N-dimethylaniline and the like. the like

The compounds of formula HI used as starting material are known. However, the compounds of the formula II are new and can be prepared, for example, by using a compound of the formula

^ (CH2) nx

X X (IV)

R ^ -C— ^ Y Cl wherein R, X, Y and n have the above meaning, with an amine of the formula

R4 NH2 (V)

where R4 has the meaning given above. Since hydrogen chloride is split off, the reaction is expediently carried out in the presence of a base or using an excess of the amine of the formula V. Furthermore, the reaction 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, tetrahydrofuran, an alkanol such as. E.g. ethanol or propanol, an aromatic hydrocarbon such as e.g. Benzene, toluene or xylene or also in acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. The reaction can be carried out at a temperature between about room temperature and the reflux temperature of the reaction mixture. Is preferably carried out at the reflux temperature. As already mentioned above, the reaction is conveniently carried out in the presence of a base, e.g. one tert. Amines such as trimethylamine, N-ethyl-N, N-is diisopropylamine or N, N-dimethylaniün u. the like

The compounds of formula V are known. The compounds of formula IV are partly. new and can be prepared, for example, by using a compound of the formula in which R, Rs and Y have the above meaning, with a compound of the formula

HS (CH2) n SH (VII)

wherein n has the meaning given above, and, if desired, converts a compound of the formula IV thus obtained, in which X represents a sulfur atom, by oxidation into a compound of the formula IV in which X represents SO or SO2.

The reaction of a compound of formula VI with a compound of formula VII can be carried out in a manner known per se. The reaction is conveniently carried out in an organic solvent which is inert under the reaction conditions, preferably in a polar solvent, such as halogenated hydrocarbons, e.g. Chloroform, methylene chloride and the like. Like. Or in ethylene glycol dimethyl ether, etc. The reaction is also conveniently carried out in the presence of a water-releasing agent such as e.g. Sulfuric acid, hydrohalic acid, phosphoric acid etc. and at a temperature between about 0 ° C and the reflux temperature of the reaction mixture, preferably at room temperature.

The conversion of a compound of formula IV thus obtained, in which X represents a sulfur atom, into a compound in which X represents SO or SO2, can be carried out in a manner known per se, e.g. by oxidation with a peracid such as e.g. Peracetic acid, perphthalic acid, m-chloroperbenzoic acid and the like. The like. For example, peracetic acid can be formed in situ from glacial acetic acid and hydrogen peroxide.

The conversion of a lower alkoxy- or aryl-lower alkoxy grappe into a hydroxyl group can be carried out in a manner known per se, for example by heating with a concentrated hydrohalic acid, in particular constant-boiling hydrobromic acid.

The esterification of an existing hydroxy group can be carried out in a manner known per se, e.g. by reaction with an appropriate halide, or with an appropriate acid halide or an acid anhydride.

The compounds of the formula I can be converted into acid addition salts, for example by treatment with an inorganic acid, such as a hydrohalic acid, for example hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid and the like, or with an organic acid such as oxalic acid, tartaric acid, citric acid,

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60

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Methanesulfonic acid and the like. Of the acid addition salts of the compounds of formula I, the pharmaceutically usable ones are preferred. If an acid addition salt of a compound of formula I is obtained in the course of the process according to the invention, such a salt can be obtained in a known manner, e.g. by treatment with alkali into the free base and, if desired, converted into another acid addition salt.

The compounds of formula I, as well as their acid addition salts, have valuable coronary dilating properties and can therefore be used, inter alia, for the treatment of angina pectoris.

The coronary dilating effect can be measured using the following method:

Bastard dogs weighing between 20 and 38 kg are used for the tests. The experimental animals are treated with approx. 30 mg / kg i.V. Anesthetize pentobarbital and maintain anesthesia with chloralose urethane. The animals are artificially ventilated with indoor air. After opening the thorax, the heart is exposed and around the ramus circumfle-

tp xus of the left coronary artery, a previously calibrated flow sample of an electromagnetic flow meter was placed to measure the amount of blood flowing through. Arterial blood pressure is measured using a catheter in the femoral artery with a pressure transducer. A calibrated stretch mark for the direct measurement of the myocardial contraction force is also sewn onto the surface of the left ventricle. The pulse wave of blood pressure triggers a tachograph to measure the heart rate. Water-soluble preparations are administered intravenously in isotonic saline, water-insoluble in propylene glycol, or administered intraduodenally as a suspension in gum arabic. The maximum effect of a substance is calculated as a percentage of the initial value after each dose and shown graphically. When measuring the coronary blood flow, particular attention is paid to the duration of action.

The results obtained are summarized in the following table, where n is the number of animals used 20.

connection

DL 50 mg / kg p.o.

CF '

Coronary Flow Enhancement (CF)

1mg IV Duration in minutes

CF%

3 mg IV Duration in minutes

N- (3,4-dimethoxyphenethyl) -

2- (3,4-dimethoxyphenyl) -N-

methyl-m-dithiane-2-propylamine

N- (3,4-dimethoxyphenethyl) -

2- (3,4-dimethoxyphenyl) -N-

methyl-m-dithian-2-propyl-

amine-1,1,3,3-tetraoxide

N- (3,4-dimethoxyphenethyl) -

2- (2-naphthyl) -N-methyl-m-

dithian-2-propylamine

N- (3,4-dimethoxyphenethyl) -

2- (m-nitrophenyl) -N-methyl-

m-dithian-2-propylamine-1,1,3,3-

tetraoxide

N- (3,4-Dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-ethyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide

250-500 + 138.6 + 8.4 10.4 ± 1.6 + 109 ± 11.8 23.4 ± 5.5 5

250-500 + 142.6 ± 23.3 20.2 ± 3.9 + 230.4 ± 20.9 54.8 ± 8.6 5

250-500 +213

500-1000 +202

500-1000 +197

25th

25th

8th

+ 194

+ 170

+ 267

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15

The process products and their pharmaceutically usable acid addition salts can be used as medicinal products in the form of pharmaceutical preparations which mix these products with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycol, petroleum jelly etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, capsules or in liquid form, e.g. are present in solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers.

The daily dose for oral administration is between about 10-200 mg; when administered intravenously between about 1-20 mg.

However, the doses given are to be understood only as examples and can be changed depending on the severity of the case to be treated and at the discretion of the treating doctor.

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example 1

0.3 g of 2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-1,3,3-tetraoxide are mixed with 0.16 g of 3,4-dimethoxy-β -phenylethyl chloride, 5 ml of N, N-diisopropyl-N-ethylamine and 1.5 ml of dimethylformamide were added and the mixture was heated at 130 ° C. for 16 hours. The solution is then distributed between water and ethyl acetate. The residue is chromatographed on silica gel and N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-l, 1, 3.3 is obtained -tetraoxid: melting point: 144 ° C (from methanol).

The 2- (3,4-dimethoxy-phenyl) -N-methyl-m-dithiane-2-propylamine-1,3,3-tetraoxide 60 used as 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 0 ° C. and 15 g of 65 methylamine are added. It is heated under pressure at 40 ° C for 18 hours. The solution is then concentrated and the crystal slurry recrystallized from a little methanol. The product mentioned above is obtained with a melting point of 164 ° C.

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Example 2

The following compounds can be prepared in a manner analogous to Example 1:

N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrobromide; Melting point 170-172 ° C (from ethanol) N- (3,4-dimethoxyphenethyl) -2- (m-methoxyphenyI) -N-'methyl-m-dithiane-2-propylamine hydrochloride:

Melting point 113-115 ° C (from acetone) N- (3,4-dimethoxyphenethyl-2- (3,4,5-trimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride:

Melting point 147-150 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -2- (p-methoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride: Melting point 160-161 ° C (from Acetone) N- (3,4-dimethoxyphenethyl) -2- (o-methoxyphenyl) -N-methyl-m-dithiane-2-propylamine hydrochloride: melting point: 151-152 ° C (from acetone) 2- (p- Chlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine hydrochloride:

Melting point 137-139 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithiane-2-propylamine hydrochloride:

Melting point 170-172 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylenedioxyphenyl) -m-dithiane-2-propylamine hydrochloride: Melting point: 139- 141 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (p-tolyl) -m-dithiane-2-propylamine hydrochloride:

Melting point 139-141 ° C (from acetone)

2- (m-chlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-

dithian-2-propylamine hydrochloride:

Melting point 108-110 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -2- (3,5-dimethoxyphenyl) -N-

methyl-m-dithian-2-propylamine oxalate (1: 1):

Melting point 155-156 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -2- (p-dimethylaminophenyl) -N-

methyl-m-dithian-2-propylamine hydrochloride:

Melting point 183-184 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-

dithian-2-propylamine hydrochloride:

Melting point 195-196 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -N-methyl -2- (2,4,5-tri-

methoxyphenyl) -m-dithian-2-propylamine hydrochloride:

Melting point 156-158 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-

m-dithian-2-propylamine hydrochloride:

Melting point 138-139 ° C (from acetone)

2- (4-biphenylyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-

dithian-2-propylamine oxalate (1: 1):

Melting point 167-169 ° C (from acetone)

N- (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithian-

2-propylamine hydrochloride:

Melting point 145-147 ° C (from acetone)

N-methyl-N-phenethyl-2-phenyl-m-dithian-2-

propylamine hydrochloride:

Melting point 136-137 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithiane-

2-ethylamine hydrochloride:

Melting point 172-174 ° C (from acetone)

N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-thienyl) -m-

dithian-2-propylamine hydrochloride:

Melting point 138-140 ° C (from acetone)

rac.-N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -

-n, ß-dimethyl-m-dithian-2-propylamine oxalate (1: 1)

Melting point 138-139 ° C (from acetone-ethyl acetate)

2- (3,4-dimethoxyphenyl) -N- [4- (3,4-dimethoxyphenyl) -

butyl] -N-methyl-m-dithiane-2-propylamine

N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-l, 1,3,3-tetraoxide hydrochloride; M.p. 167-169 ° C

N- (3,4-Dimethoxyphenethyl) -N-methyl-2- (naphthyl) -m-dithiane-2-propylamine-l, l, 3,3-tetraoxide oxalate (1: 1): melting point 190-191 ° C (from acetone-methanol) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4,5-trimethoxyphenyl) -m-dithiane-2-propylamine-1,3,3 -tetraoxid-oxalate (1: 1): melting point 146-148 ° C (from acetone-ethyl acetate) 2- (m-bromophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2- propylamine-l, l, 3,3-tetraoxide hydrochloride: melting point 158-160 ° C (from methanolic HQ and ethyl acetate)

2- (m-nitrophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride: melting point 212-214 ° C (from Acetone) N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-m-dithiane-2-propylamine-l, l, 3,3-tetraoxide hydrochloride: melting point 234-236 ° C (from methanol) N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithiane-2-propylamine-l, l, 3,3-tetraoxide hydrochloride:

Melting point 149 ° C dec. (from methanol) N- (3,4-dimetoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-ethyl-m-dithiane-2-propylamine-l, l, 3,3-tetraoxide oxalate (1: 1):

Melting point 177-179 ° C (from methanol and acetone) N- (3,4-dimethoxyphenethyl) -2- (4-isopropylphenyl) -N-methyl-m-dithiane-2-propylamine-l, l, 3,3- tetraoxide hydrochloride:

Melting point 225-227 ° C (from dioxanic HCl ethyl acetate) N- (3,4-dimethoxyphenethyl) -2- (3-trifluoromethyl-phenyl) -N-methyl-m-dithiane-2-propylamine-l, l. 3 , 3-tetraoxide oxalate: melting point: 128-130 ° C (from acetone) N, 2-bis (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine-l, l, 3, 3-tetraoxide

2- (3,4-dimethoxyphenyl) -N- [4- (3,4-dimethoxyphenyl) butyl] -m-dithiane-2-propylamine-1,1,3,3-tetraoxide N- (3,4- Dimethoxyphenethyl) -N-methyl-2- (3,4-xylyl) -m-dithiane-2-propylamine-l, l, 3,3-tetraoxide hydrochloride: melting point 176-178 ° C (from acetonitrile) 2- ( 3-butoxy-4-methoxy-phenyl) -N- (3,4-dimethoxy-phenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide:

Melting point: 84-85 ° C (from methanol isopropyl ether) N- {3- [2 / - (3,4-dimethoxyphenyl) -m-dithian-2'-yl] propyl} -N-methyl-l , 4-benzodioxan-6-ethylamine-1 1,3 ', 3' tetraoxide hydrochloride:

Melting point: 208-210 ° C (from acetonitrile) N- [4- (3,4-dimethoxyphenyl) butyl] -2- (p-isopropylphenyl) -N-methyl-m-dithiane-2-propylamine-1 , 1,3,3-tetraoxide hydrochloride:

Melting point: 148-150 ° C (from ethyl acetate-dioxamic HQ) rac.-2- (3,4-dimethoxyphenyl) -N- [3- (3,4-dimethoxyphenyl) -

1-methylpropyl] -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide:

Melting point: 115-117 ° C

N- (3,4-dimethoxyphenethyl) -2- (4-ethoxy-3-methoxyphenyl) -

N-methyl-m-dithiane-2-propylamine-

1,1,3,3-tetraoxide hydrochloride:

Melting point: 190-192 ° C (from acetonitrile)

m- / 2 '- / 3 - [(3,4-dimethoxyphenethyl) methylamino] -

propyl / -m-dithian-2-yl / -benzonitrile-

1 ', 1 3 3'-tetraoxide hydrochloride:

Melting point: 160 ° CZers.

2- (1,4-Benzodioxan-6-yl) -N- (3,4-dimethoxy-phenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride:

Melting point: 201-204 ° C

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620 920

N- (3,4-Dimethoxyphenethyl) -2- (4-methoxy-m-tolyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride:

Melting point: 146 ° C dec. (from acetone)

m- / 2 '- / 3 - / [4- (3,4-dimethoxyphenyl) butyl] methylamino / -

propyl / -m-dithian-2 / -yl / -benzonitrile-

11,3 ', 3'-tetraoxide hydrochloride:

Melting point 120-122 ° (from water)

2- (3,4-dimethoxyphenyl) -N-methyl-N- (p-methylphenethyl) -

m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride:

Melting point: 169-171 ° C (from acetone and ethyl acetate)

N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylene-

dioxyphenyl) -m-dithian-2-propylamine-

1,1,3,3-tetraoxide hydrochloride,

Mp 247-248 ° C

N- (3,4-dimethoxyphenethyl) -N-methyl-2-p-tolyl-m-dithiane-2-propylamine-l, l, 3,3-tetraoxide hydrochloride:

Melting point: 203-207 ° C. (from acetonitrile-acetone) 2- (4-benzyloxy) -3-methoxyphenyl-N- (3,4-dimethoxyphen-ethyl-N-methyl-m-dithiane-2-propylamine-1, 1,3,3-tetraoxide hydrochloride:

Melting point 220-221 ° C (from ethanol)

N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-thienyl) -m-

dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride:

Melting point 179-182 ° C (from acetone)

2- (3,4-dichlorophenyl) -N- (3,4-dimethoxyphenethyl) -

N-methyl-m-dithiane-2-propylamine-l, l, 3,3-tetraoxide-hydro-

chloride.

Melting point 175-177 ° C (from methanol) N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-ethylamine-l, l, 3,3- tetraoxide oxalate (1: 1): melting point 202-204 ° C (from acetone) 2- (3,4-dimethoxyphenyl) -N-methyl-N-veratryl-m-dithiane-2-propylamine oxalate (1st : 1), m.p. 133-136 ° C N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-butylamine oxalate (1: 1) from Mp 134-136 ° C (from acetone)

N- (3,4-Dimethoxy-phenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-pentylamine oxalate (1: 1), mp. 109-111 ° C (from Acetone)

2- (3,4-Dimethoxyphenyl) -N- [3 - (3,4-dimethoxyphenyl) propy]] - N-methyl-m-dithiane-2-propylamm oxalate (1: 1) mp 116-118 ° C (from acetone)

2- (3,4-dimethoxyphenyl) -N-methyl-N- (a-methyl-phenethyl) -m-dithiane-2-propylamine oxalate (1: 1);

Mp 131-132 ° C (from acetone-ethyl acetate) N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-l, 3-dithiolane-2-propylamine oxalate (1st : 1), mp. 150-152 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-di-thian-2-propylamine-l, l, 3.3 -tetraoxid-hydrochloride: melting point 149 ° C dec. (from methanol) N- (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride:

Melting point 246-249 ° C dec. (from methanol-methylene chloride)

N-methyl-N-phenethyl-2-phenyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride:

Melting point 165-167 ° C (from acetone) 2- (3,4-dimethoxyphenyl) -N-methyl-N-veratryl-m-di-thian-2-propylamine-l, l, 3,3-tetraoxide:

Melting point 137-139 ° C (from acetone-ethanol) N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-2-propylamine-l, l, 3,3-tetraoxide- hydrochloride: melting point 130-132 ° C (from acetone) rac.-a - [(3,4-dimethoxyphenethyl) methylamino] methyl-2- (3,4-dimethoxyphenyl) -m-dithian-2-älhanol-l , l, 3,3-tetraoxide oxalate (1: 1) crystallizes with 1 mol acetone and melts at 162-164 ° C

N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyI) -N-methyl-m-dithiane-2-propylamine-1,3-dioxide hydrochloride; Mp 148-149 ° C (mixture of diastereomers) rac.-a - [(3,4-dimethoxyphenethyl) methylamino] methyl-2- (3,4-dimethoxyphenyl) -m-dithiane-2-ethanol-hydrobromide mp. 97-99 ° C

N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-2-propylamine oxalate; M.p. 186-188 ° C a - /// - 3- [2 '- (3,4-Dimethoxyphenyl) -m-dithian-2'-yl] propyl / methylamino / methyl / veratrylalcohol-1 r, 3', 3'-tetraoxide, m.p. 132-133 ° C

N- (3,4-Dimethoxyphenethyl) -2- (3,4-dimethoxyphenyI) -N-methyl-m-dithiane-2-propylamine

N- (3,4-Dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-pentylamine-1,1,3,3-tetraoxide oxalate (1: 1) with one Melting point of 189-191 ° C (from acetone-methanol)

N- (3,4-Dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-butylamine-l, 1,3,3-tetraoxide oxalate with a melting point of 161-163 ° C (from acetone-methanol), (base 123-126 ° C from ethanol) 2- (3,4-dimethoxyphenyl) -N- [3- (3,4-dimethoxyphenyl) propyl] -N-methyl-m -dithian-2-propylamine-l, l, 3,3-tetra-oxide-hydrobromide, with a melting point of 138-140 ° C (from acetonitrile-ethyl acetate)

rac.-N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N, ß-dimethyl-m-dithiane-2-propylamine-l, 1,3,3-tetraoxide hydrochloride with one Melting point of 183-185 ° C (from acetone-ethyl acetate)

2- (3,4-Dimethoxyphenyl) -N-methyl-N- (a-methyl-phen-ethyl) -m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride with a melting point of 185 -187 ° C (from acetone-ethyl acetate).

Example 3

11.2 g of 2- [4- (benzyloxy) -3-methoxyphenyl] -N- (3,4-dimeth-oxyphenethyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3- tetraoxide (prepared according to Example 2) are heated with 100 ml of 48% hydrobromic acid on the steam bath for 2 minutes. The aqueous solution is then extracted with ether, evaporated in vacuo and azeotroped three times with ethanol-benzene. The residue is crystallized from acetone. The crystalline mass obtained in this way is recrystallized three times from methanol-acetonitrile and 4- {2 '- [3 - ((3,4-Dimethoxyphenäthyl) -methylamino} prophyl] -m-dithian-2' -yl} -2- methoxyphenol-r, l ', 3', 3'-tetraoxide hydrobromide with a melting point of 192 ° C (dec.)

C H N

Calculated: 48.23 5.83 2.25 Found: 48.12 5.93 2.07

Analogously, starting from 2- [3- (benzyloxy) -4-methoxyphenyl] -N- (3,4-dimethoxyphenethyl) -N-methyl-m-di-thian-2-propylamine-l, l, 3, 3-tetraoxide the 5- / 2 '- / 3 - [(3,4-dimethoxyphenethyl) methylamino] propyl / -m-dithian-2'-yl / -2-methoxyphenol-l', l ', 3' , 3'-tetraoxide hydrobromide are produced: melting point: 201 ° C dec. (from acetonitrile).

Example 4

2 g 5- / 2 '- / 3 - [(3,4-dimethoxyphenethyl) methylamino] propyl-m-dithian-2'-yl / -2-methoxyphenol-l', 1 ', 3', 3'-tetraoxide are dissolved in absolute pyridine and an excess of acetic anhydride is added. After 16 hours at room temperature, the solvent is evaporated and the residue to s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

620920

Chromatographed silica gel. The 5- / 2 '- / 3 - [(3,4-dimethoxy analysis:

phenethyl) methylamino] propyl / -m-dithian-2'-yl / -2-methoxy-C H N

phenylacetate-1 ', r, 3', 3'-tetraoxide was obtained as a thick oil: 55.56 6.39 2.40

Found: 55.22 6.41 2.23

B

Claims (3)

620 920 (1 II) wherein R5-R7, Z and m have the above meaning and Rs represents a leaving group, reacted and, if desired, converted-if a base obtained into an acid addition salt. 1. Process for the preparation of new sulfur-containing heterocyclic compounds of the general formula ((CH2 ^ R —- C -—Y N Kr 15 'U.N (I) NO wherein R is a radical of the formula (a) (b) Ri, R2 and R3 are hydrogen, halogen, lower alkyl, lower alkoxy, aryl-lower alkoxy, aryloxy, phenyl, nitro, Amino, lower alkycthio, trifluoromethyl, hydroxy, cyano, di-lower alkylamino, lower alkanoylamino, carboxyl, lower alkoxycarbonyl, lower alkylsulphonyl, hydroxymethyl, lower alkanoyloxy, aminocarbonyl, lower alka-30 noyl, sulfamoyl, mono- or di-lower Sulfamoyl, aminocarbonyloxy, mono- or di-lower alkylaminocarbonyloxy, lower alkylamino lower alkyl or two adjacent radicals together methylenedioxy, ethylenedioxy or butadien-l, 3-ylen-l, 4, R4 hydrogen or lower alkyl, 35 R5, Rö and R7 are hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or benzyloxy or two adjacent radicals together methylenedioxy or ethylenedioxy, X is a sulfur atom, SO or SO2, Y is a straight-chain or branched aliphatic radical which is optionally substituted by hydroxyl 2-8 carbon atoms, of which 2-4 carbon atoms are in the chain and Z is a straight-chain or branched aliphatic, optionally substituted by hydroxy is a radical with 1-8 carbon atoms, of which 1-4 carbon atoms are in the chain, and m represents the numbers 0 or 1 and n the numbers 2 or 3, and acid addition salts thereof, characterized in that a compound of general formula , (II) wherein R, R4, X, Y and n have the above meaning, with a compound of the general formula 2. The method according to claim 1, characterized in that in a compound of formula I obtained, wherein at least one of the symbols R 1, R 2, R 3, Rs, R and R 7 denotes lower alkoxy or aryl-lower alkoxy or benzyloxy, this ether group (n) converted to hydroxy by treatment with an acid. 3. The method according to claim 1, characterized in that in a compound of formula I obtained, wherein R is a radical of formula (a), wherein at least one of the symbols R 1, R 2 and R 3 is hydroxy, this by esterification in lower alkanoyloxy transferred. 4. The method according to claim 1, characterized in that a compound of formula II is used as the starting material, wherein R is a radical of the formula (a) 60 means. 5. The method according to claim 4, characterized in that a compound of formula II is used as the starting material, wherein R is a radical of formula (a) and one of the radicals R 1, R 2 and R 3 is hydrogen and the other lower alkoxy, in particular methoxy, or together represent butadien-1,3-ylene-1,4. 6. The method according to claim 1, 4 or 5, characterized in that a compound of formula III is used as the starting material, wherein one of the radicals Rs, Rö and R7 are hydrogen and the other lower alkoxy, in particular methoxy. 7. The method according to any one of claims 1 and 4-6, characterized in that one uses a starting material of formula II, wherein X represents a sulfur atom or SO2 and n is 3. 8. The method according to any one of claims 4-7, characterized in that a compound of formula II is used as the starting material, wherein Y represents the group - (CH2) 3. 9. The method according to any one of claims 1 and 4-8, characterized in that a compound of formula III is used as the starting material, wherein (Z) m represents the group - (CH2-CH2) m, wherein m is the number 0 or 1 means. 10. The method according to any one of claims 1 and 4-9, characterized in that a compound of formula II is used as the starting material, wherein R4 is the methyl or ethyl group. 11. The method according to claim 1, characterized in that a compound is used as the starting material of the formula II, in which R is 3,4-dimethoxyphenyl, X SO2, n is the number 3, Y is the trimethylene group and R4 is the methyl group, and a compound is used as the starting material of the formula III 2nd PATENT CLAIMS 3 620920 used, wherein Z is the ethylene group, m is 1, Rs is hydrogen and Re and R7 are each a methoxy group in the 3 and 4 positions.