FI67216C - REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC MEASURE 1, -DITIOLANYL (2) - OCH 1,3-DITIANYL (2) -FOERENINGAR - Google Patents

Description

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48Tä W UTLA6GNINGSSKIIIFT 0/216 C ^ Patents granted 11 C2 1935 ^ ^ (51) K * Jiu /te.ct3 C 07 D 339/08, 339/06 FINLAND — FINLAND <ii) ρΚμμμ ^ -ρκ «μμ ^ 3527 / 74 (22) «* - *» * «- Ai-ekÄf ^ e 05.12, // * '' (23) AfotpUvi — GNdgtotadag 05.12.7 /.

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Patent * and register sharkIHvs ...... Ί _ -UD- / b PMant> och regfatwstyrahw ^ /WMaT^do£31.10.84 (32) (33) (31) * η * · «* τ« MO * - -B «t» rd prtorttac 21.12.73 Svei tsi-Schweiz (CH) 18030/73 (71) F. Hoffmann-La Roche ε Co. Aktiengesel1schaft, Grenzacherstrasse 124-184, Basel, Switzerland-Switzerland (CH) (72) Hen '·! Ramuz, Birsfelden, Switzerland-Schweiz (CH) (74) Oy Kolster Ab (54) Method for the preparation of therapeutically useful 1,3 "dithiolanyl (2) and 1,3-dithianyl (2) compounds - Förfarande för framstälIning av therapeutiskt användbara This invention relates to a process for the preparation of therapeutically useful 1,3-dithiolanyl (2) and 1,3-dithianyl (2) compounds having the general formula is XX R. / R5 \ / l4 / = \ * -CYN—, Z, m- ^ Λ- »6 1 6721 6 where R represents a group R '\ R2-4 / - fi f—]

«3 ^ - ^ AA

<a) (b) wherein and R 2 represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or benzyloxy, or one of the groups and is phenyl, nitro, trifluoromethyl or di-lower alkylamino, the other being hydrogen, or is cyano and R 2 is hydrogen, or and R 2 together form a methylenedioxy, ethylenedioxy or butadiene-1,3-diene-1,4-chain, R 1 is hydrogen or lower alkoxy, R 1 is hydrogen or lower alkyl, R 1 and each is hydrogen or lower alkyl, or together form an ethylenedioxy chain, or R 1 is hydrogen and R 1 is halogen or lower alkyl, X is a sulfur atom, SO or SO 2, Y is a straight or branched alkylene chain optionally containing a hydroxy substituent having 2 to 5 carbon atoms, and Z is a straight or branched, optionally hydroxy-substituted alkylene chain having 1 to 4 carbon atoms, and m corresponds to 0 or 1 and n to 2 or 3, and to prepare these acid addition salts.

DE-A-1 154 810 and 2 000 435 disclose structurally similar compounds which also have coronary dilating properties as calcium antagonists as calcium antagonists. However, these compounds have a potent and long-lasting antihypertensive effect and a negative effect on muscle contraction # thus detrimental side effects. In contrast, the compounds prepared according to the invention do not have these negative properties at all, but even have pulse-regulating properties # while having a good tolerability.

The process according to the invention is characterized in that 3 6721 6 a) a compound of the general formula

f <AVJ

X x \ /

R- C- “H

wherein R, X and n are as defined above, are reacted with a compound of the general formula

f- __ / = C

R8-ϊ-N- (Z) B- <Λ) - R6 111 wherein - Rg, Z and m are as defined above and Rg is a leaving group, or b) a compound of the general formula / R5

0 R *, -S

Il I4 / =%

R-C-Y —— N- (Z) - ΛΧ — r6 IV

wherein R, R 1 - R 9, Y, Z and m are as defined above, are reacted with a compound of the general formula HS- (CHO) -SH v Z n wherein n has the above meaning, or 4 67216 c) a compound having the general formula

X X VI

R - ^ - Y-Rg wherein R, Rg, X, Y and n are as defined above are reacted with a compound of general formula R / _ / R5 1 / \ HN- Z m - <\ b— \ VI1 wherein R 1 - R 8, Z and m are as defined above, or d) a compound of the general formula f, cVn \ X x '»4

\ / I

R-C-Y-N-H

wherein R, R 2, X, Y and n are as defined above, is reacted with a compound of general formula / R 5

E8 (z, m \ _ ^ - "6 XI

wherein Rg - Rg, Z and m are as defined above, or 5 67216 e) in compounds of the general formulas' / (CH2 »^ XXR —- \ / t4 Γ \„ RC-Y1 - N-Z1-Λ> - Rg XI1 / <CH2> n \ R, X x} I / 5 \ / | "° / = \

R-C-Y- N- Z1-Λ Λ-Rg XIII

wherein R, R 4 to R 9, X, Y, Z, m and n are as defined above, and Y 1 and Z 2 are groups corresponding to Y or Z, wherein at least one of Y 1 and Z 2 contains a carbonyl group, reducing the carbonyl group, followed, if desired, by oxidizing a compound of formula 1 in which X represents a sulfur atom to a compound of formula I and in which X represents SO or SO 2 or, if desired, N-alkylating a compound of formula I in which R represents hydrogen, if desired the lower alkoxy group or the benzyloxy group is converted into a hydroxy group, if desired the etherification or esterification of the hydroxy group or, if desired, the base obtained is converted into an acid addition salt.

Preferred compounds of formula I above may be represented, for example, by the following formula (CH -) x R, ° x, \ / Xi i V - \ _ j> - ^ - <C «2'3 - '* -« CVCH2'm- \ _ / “R6 R3 h

Ia 6 67216 wherein Rq to R8 are as defined above, R'4 is methyl or ethyl, and is a sulfur atom or SC4.

Other preferred compounds of formula Ia above are those in which one of Rq to R1 represents hydrogen and the others lower alkoxy, in particular methoxy, or R1 and together represent butadiene-1,3-dienene-1,4, or wherein two of Rq - R1 represent hydrogen and the third nitro and one of Rg and Rg represents hydrogen and the other two lower alkoxy, especially methoxy. A particularly preferred compound is N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide.

The reaction of a compound of formula II with a compound of formula III can be carried out in a known manner. Most conveniently, the reaction takes place under reaction conditions in inert organic solvents and at a temperature between about -80 ° C and the boiling point of the reaction mixture, preferably about 0 ° C to about 50 ° C, and especially at about room temperature.

As the solvent, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, aromatic hydrocarbons such as benzene, toluene, xylene, etc., or also dimethylformamide, dimethyl sulfoxide and the like can be mentioned. The reaction takes place in the presence of a strong base such as, for example, butyllithium, a Grignard compound, sodium or sodium hydride, in which case, if X is a sulfur atom, it is expedient to use a particularly strong base such as butyllithium or Grignard compound.

The starting compounds of the above formulas II and III are partly known and partly new. The novel compounds are also included within the scope of the invention. They can be prepared in a known manner.

Compounds of formula II in which X is a sulfur atom may be obtained, for example, by administering an aldehyde of formula

R-C

wherein R is as defined above, react with ethane or propane dithiol. The reaction is preferably carried out in an inert organic solvent, e.g. chloroform, at a temperature below room temperature.

7,67216

Compounds of formula II in which X is SO or SO 2 »can be obtained by oxidation of the corresponding compounds in which X is a sulfur atom. The oxidation can preferably take place in a suitable solvent with a peracid such as peracetic acid, phthalic acid, m-chloroperbenzoic acid and the like. Peracetic acid can be formed, for example, in a reaction mixture of glacial acetic acid and hydrogen peroxide.

The reaction of a compound of formula IV with a compound of formula V can be carried out in a known manner. Most preferably, the reaction takes place under reaction conditions in inert organic solvents, mainly polar solvents such as halogenated hydrocarbons, e.g. at a temperature between about 0 ° C and the boiling point of the reaction mixture, mainly at about 0-25 ° C.

The compounds of formula V used as starting materials are known or can be prepared in a known manner.

The compounds of formula IV used as starting materials are novel and are within the scope of this invention. Compounds of formula IV may be prepared, for example, by administering a compound of formula

O

R-C-Y-Cl XIVa wherein R and Y are as defined above, react with a compound of formula R «= 14 / = <VI1 wherein R1 - R8, Z and m are as defined above.

The reaction is preferably carried out in the presence of an acid scavenger, for example a tertiary amine such as N-ethyl-N, N-diopropylamine, which simultaneously acts as a solvent. Reaction 8 67216 also preferably takes place at a higher than normal temperature, mainly up to about 130 ° C, depending on the boiling point of the solvent.

The above-mentioned compounds of formula XIVa are partly known and partly new compounds. They can be prepared in a known manner. The compounds of formula VII are known compounds.

The reaction of a compound of formula VI with a compound of formula VII can be carried out in a known manner, preferably under reaction conditions in inert organic solvents such as ethers, e.g. dibutyl ether, dioxane, or tetrahydrofuran, an alkanol such as e.g. ethanol or propanol, an aromatic hydrocarbon. , such as, for example, benzene, toluene or xylene or also acetonitrile, dimethylformamide, dimethyl sulfoxide and the like. The reaction can be carried out at a temperature between room temperature and the boiling point of the reaction mixture, mainly at boiling temperature. If the reaction is cleaved by an acid, it is most preferably carried out in the presence of a base, e.g. a tertiary amine such as triethylamine, N-ethyl-N, N-diisopropylamine or N, N-dimethylaniline and the like base.

The compounds of formula VII used as starting materials are known compounds. However, the compounds of formula VI are novel and are within the scope of this invention. Compounds of formula VI may be prepared, for example, by administering a compound of formula

O

r-c-y-r8 XIV

wherein R, Rg and Y are as defined above, react with a compound of formula

HS- (CH 2) -SH V

2. n wherein n is as defined above and, if desired, the compound of formula VI thus obtained, in which X is a sulfur atom, is converted by oxidation to a compound of formula VI in which X is SO or SO 2 - 6721 6

The reaction of a compound of formula XIV with a compound of formula V may be carried out in a known manner, preferably under reaction conditions in inert organic solvents, mainly polar solvents such as halogenated hydrocarbons, e.g. chloroform, methylene chloride and the like. such as in the presence of sulfuric acid, hydrohalic acid, phosphoric acid, etc. and at a temperature between about 0 ° C and the boiling point of the reaction mixture, mainly at room temperature.

The conversion of a compound of formula VI thus obtained, in which X is a sulfur atom, to a compound in which X is SO or SO 2 can be carried out in a known manner, e.g. by oxidation with peracid, such as peracetic acid, phthalic acid or m-chloroperbenzoic acid. Peracetic acid can be formed, for example, in situ from glacial acetic acid and hydrogen peroxide.

The reaction of a compound of formula VIII with a compound of formula IX may be carried out in a known manner, preferably under reaction conditions in inert organic solvents such as ethers, e.g. tetrahydrofuran, dioxane, diethylene glycol diethyl ether and the like, or acetonitrile, etc. in dimethylformamide, dimethylformamide. between room temperature and the boiling point of the reaction mixture, mainly at boiling temperature. The reaction takes place in the presence of a strong base such as, for example, butyllithium, Grignard compound, sodium or sodium hydride and the like, and when X is a sulfur atom, it is convenient to use a particularly strong base such as butyllithium or Grignard compound.

The compounds of formula VIII used as starting materials are known compounds. However, the compounds of formula IX are novel and are within the scope of this invention. Compounds of formula IX may be prepared, for example, by administering a compound of formula ΛΗ2'λ

X X

\ /

H-C -H XV

10 6721 6 wherein X and n are as defined above, react with a compound of formula III. This reaction can be carried out in a known manner, preferably under reaction conditions in an inert organic solvent and at a temperature between about -80 ° C and the boiling point of the reaction mixture, mainly at about 0 to 50 ° C and especially at about room temperature. As the solvent, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, or also dimethylformamide, dimethyl sulfoxide can be mentioned. and the like. The reaction takes place in the presence of a strong base such as butyllithium, Grignard compound, sodium or sodium hydride or the like, in which case, if X is a sulfur atom, it is expedient to use a particularly strong base such as butyllithium or Grignard compound.

The compounds of formula XV are known compounds. The compounds of formula III are partly new and partly known.

The novel compounds of the formula III can be prepared in a known manner.

The reaction of a compound of formula X with a compound of formula XI may be carried out in a known manner, preferably under reaction conditions in inert organic solvents such as ethers, e.g. dibutyl ether, dioxane or tetrahydrofuran, an alkanol such as ethanol or propanol, an aromatic hydrocarbon such as benzene, toluene, toluene , or also in acetonitrile, dimethyl sulfoxide and the like solvent. The reaction temperature is approximately between room temperature and the boiling point of the reaction mixture, mainly the boiling point. If the reaction cleaves an acid, it is conveniently carried out in the presence of a base, e.g. a tertiary amine such as triethylamine, N-ethyl-N, N-diisopropylamine or tai, Ν-dimethylaniline and the like.

The compounds of formula XI used as starting materials are known compounds. The compounds of formula X are novel compounds and are included within the scope of this invention. Compounds of formula X may be prepared, for example, by administering a compound of formula 6721 6

X X

r- ^ c —-- Y-Cl Via wherein R, X, Y and n are as defined above, react with an amine of formula

R -NH XVI

4 2 where R 1 is as defined above.

Since hydrogen chloride is then cleaved, the reaction is most preferably carried out in the presence of a base or using an excess of an amine of formula XVI. Further, the reaction may be carried out in the same manner if it is desired to react a compound of formula VI with a compound of formula VII.

The compounds of formula XVI are known compounds. Compounds of formula Via, which are in part novel compounds, can be prepared in the same manner as compounds of formula VI.

The reduction of the carbonyl group or group A of the compound of formula XII or XIII can be carried out in a known manner.

Thus an amide of formula XII or XIII, i. a compound in which the carbonyl group is directly attached to a nitrogen atom can be reduced by treatment with metal hydrides such as lithium aluminum hydride, diisobutylaluminum hydride or diborane or the like. This is preferably carried out under reaction conditions in an inert organic solvent such as ether, e.g. diethyl ether, tetrahydrofuran, etc., or diglyme and at a temperature between about 0 ° C and the boiling point of the reaction mixture, mainly at about room temperature.

Also other carbonyl groups, i.e. reduction of groups not directly attached to the nitrogen atom can be performed in a known manner. The reduction can be carried out in particular to form a hydroxymethylene group which can then be further reduced to a methylene group; reduction directly to the methylene group is also possible.

6721 6 12

The reduction to the hydroxymethylene group can be carried out by treatment with a metal hydride complex such as an alkali metal aluminum hydride or an alkali metal borohydride.

The reduction with alkali metal aluminum hydride or alkali metal borohydride can be preferably carried out at room temperature or above or below and in an inert organic solvent. When carrying out the reduction with an alkali metal aluminum hydride, suitable solvents include e.g. anhydrous ethers such as diethyl ether and tetrahydrofuran, and when reduced with alkali metal borohydride, these include alkanols having 1 to 4 carbon atoms such as methanol, ethanol or dioxane and the like solvents. The alkali metal aluminum hydride used is mainly lithium aluminum hydride and the alkali metal borohydride is mainly sodium borohydride.

Further reduction of the hydroxymethylene group to the methylene group can be carried out in a known manner, in particular by conversion to the corresponding sulfonic acid esters or halides and reduction of these with metal hydride complexes. These reductions can be carried out in the same manner as described above for the reduction of carbonyl groups.

The reduction of the carbonyl group directly to the methylene group can take place in a known manner by means of the Wolff-Kischner reaction, i. by reacting the ketone with hydrazine to the corresponding hydrazone and decomposing the hydrazone under basic conditions.

The compounds of formulas XII and XIII used as starting materials are novel compounds and are included within the scope of this invention.

Amides of formula XII can be prepared, for example, by administering an acid of formula fiCa 2 ^ XX _

R --- C - Y-C ^ XVII

"" OH

wherein R, Y, X and n are as defined above, react with an amine of formula 6721 6 13 R „Rc I _ / = <_

H — N— (Z) - <v \ —R. VII

m \ _y- e where R 1 - R 8, Z and m have the same meaning as above. The reaction may preferably take place in the presence of a tertiary amine such as triethylamine and a halocarboxylic acid ester such as chloroformic acid butyl ester (mixed anhydride method) in an inert organic solvent, e.g. tetrahydrofuran and at a temperature of about 0 ° to about 30 ° C.

Compounds of formula XVII may be prepared by the same method as described above for the preparation of compounds of formula VI, starting from compounds of formula

R-C-Y-C ^ XVIII

OH

The compounds of formula XVIII are known compounds.

Ketones of formula XII can be prepared in a known manner, e.g. by oxidation of the corresponding alcohols. The oxidation can take place, for example, by using a chromium trioxide / pyridine complex in pyridine at a temperature of about -20 ° C to + 25 ° C, mainly about 0 ° C.

The amides of the formula XIII can be prepared in a known manner, e.g. by acylation of a compound of the formula I in which R 1 represents hydrogen. The acylation can take place, for example, with a halide of a low molecular weight carboxylic acid in a tertiary amine such as pyridine at a temperature of about 0 ° to about 30 ° C, mainly at about room temperature.

14 6721 6

Conversion of a compound of formula I wherein X is a sulfur atom to a compound wherein X is SO or may be accomplished by oxidation in a suitable solvent with peracids such as peracetic acid, phthalic acid or m-chloroperbenzoic acid or the like. For example, peracetic acid can be formed in situ from glacial acetic acid and hydrogen peroxide.

The compounds of the formula I obtained in which hydrogen represents can be alkylated in a known manner, e.g. with the aid of lower alkyl halides. In this case, it is expedient to react the compound in question immediately with the alkyl halide at low temperature.

The conversion of an alkoxy or arylalkoxy group to a hydroxy group can be carried out in a known manner, for example by heating with concentrated hydrohalic acids, in particular hydrobromic acid boiling at constant temperature.

The reduction of the nitro group to the amino group can take place in a known manner chemically or catalytically, e.g. using a zinc / hydrochloric acid system or with hydrogen in the presence of a noble metal catalyst. The hydrogenation is carried out mainly in alkanol, in particular ethanol in the presence of palladium on carbon or platinum oxide at normal pressure and at room temperature.

The saponification of the cyano group can be carried out in a known manner with the aid of an acid or a base.

The esterification or amidation of the carboxyl group can be carried out in a known manner, for example by treatment with the corresponding alcohol or the corresponding amine.

The amino group in the compound can be alkylated in the above-mentioned manner or also acylated in a known manner by treatment with an acid halide or anhydride.

The etherification of the hydroxy group in the compound as well as the esterification can take place in a known manner, e.g. by reacting the compound with the corresponding halide, or with the corresponding acid halide or acid anhydride.

The reduction of the carboxyl group can be carried out in a known manner, e.g. with diborane or lithium aluminum hydride in an inert organic solvent.

The oxidation of the alkylthio group can take place in a known manner, e.g. with hydrogen peroxide.

is 6721 6

The compounds of formula I may be converted into acid addition salts, for example, by treatment with an inorganic acid such as hydrohalic acid, for example hydrochloric or hydrobromic acid, sulfuric acid, phosphoric acid or the like, or an organic acid such as oxalic acid, tartaric acid, citric acid, citric acid, methane. Preferred acid addition salts of the compounds of formula I are the pharmacologically acceptable salts. If an acid addition salt of a compound of formula I is obtained in carrying out the process according to the invention, the salt obtained can be converted into the free base by base treatment in a known manner and, if desired, this can be converted into another acid addition salt.

Compounds of formula I having an asymmetric carbon atom may exist in racemic or optically active form and the invention relates to both racemic and optically active forms. If desired, the racemate can be resolved into optical antipodes in a known manner; for example by fractional crystallization of the corresponding salts of an optically active acid.

The compounds of formula I, as well as their acid addition salts, have valuable coronary vasodilatory properties and thus may have utility in, inter alia, the treatment of angina pectoris.

The coronary dilating effect was determined by the following method:

Mixed breed dogs weighing between 20 and 38 kg were used in the experiments. Experimental animals were anesthetized using approximately 30 mgAg i.v. Pentobarbital and anesthesia were maintained on Chloralose-Urethan. The animals were given artificial respiration using room air. After opening the thorax, the heart was exposed and a pre-calibrated electromagnetic flowmeter flow probe was placed around the curved arm of the left coronary artery to measure the amount of blood flowing through. Arterial blood pressure was measured from the femoral artery via a catheter using a pressure transducer. In addition, a calibrated stretch tape was sewn to the surface of the left heart chamber to directly measure the contractile force of the myocardium. A pulse wave of blood pressure triggered a tachograph to measure heart rate. Aqueous soluble preparations were applied to isotonic saline, water-insoluble propylene glycol dissolved by intravenous injection, or administered as an acacia suspension in the duodenum. The maximum effect of the substance was calculated after each dose as a percentage of the initial value and plotted. In connection with the measurement of the amount of blood that passed through the coronary artery, special attention was paid to the duration of action.

The following table summarizes the results obtained, where n is the number of animals used.

17

Compound n Maximum coronary- Dose of arterial flow- i.v.

its growth% 6721 6

Table N- (3,4-dimethoxyphenethyl) -2- (m-methoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrochloride 2,133 l N- (3,4-dimethoxyphenethyl) -2- (3, 4,5-Trimethoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrochloride 2,140 l N- (3,4-dimethoxyphenethyl) -2- (p-methoxyphenyl) -N-methyl-m-dithian -2-propylamine hydrochloride 2,223 l N- (3,4-dimethoxyphenethyl) -2- (o-methoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrochloride 2,172 l 2- (p-chlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine hydrochloride 2,172 1 N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithian-2 -propylamine hydrochloride 2,241 3 N- (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride 2,132 1 N - (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine hydrochloride 2,210 3 N-methyl-N-phenethyl-2-phenyl-m-dithian-2-propylamine hydrochloride 2,155 3 N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylene-di oxyphenyl) -m-dithian-2-propylamine hydrochloride 2,145 l N- (3,4-dimethoxyphenethyl) -N-methyl-2- (p-tolyl) -rn-dithian-2-propylamine hydrochloride 2 130 1 18 6721 6

Compound n Maximum coronary- Dose of arterial flow- i.v.

its growth% N- (3,4-dimethoxyphenethyl) -2- (3,5-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine D-tartrate 2,145 l N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-dithian-2-propylamine hydrochloride 2,213 l N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-m-dithian -2-propylamine hydrochloride 2,153 l 2- (m-bromophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetra - oxide hydrochloride 2,185 0.3 N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylenedioxyphenyl) -m-dithian-2-propylamine-1,1,3,3 Tetraoxide hydrochloride 2,130 3 N- (3,4-dimethoxyphenethyl) -N-methyl-2- (p-tolyl) -m-dithian-2-propylamine-1,1,3,3-tetraoxide hydro - chloride 2,290 3 2- (m-nitrophenyl) -N- (3,4-dimethoxyphenethyl) -N- 'methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride 2,202 1 N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithian-2-ethylamine hydrochloride 2,182 3 N- (3,4-dimethoxyphenethyl) -2- [p- (dimethylamino) -phenyl / -N-methyl-m-dithiane-2-propylamine hydrochloride 2,130 3

Compound n Maximum coronary- Dose of arterial flow- i.v.

its growth% 19 6721 6 ras. np (N- (3,4-dimethoxy-phenethyl) -methylamino) -methyl] -2- (3,4-dimethoxy-phenyl) -m-dithiane-2-ethanol D-tartrate 2,140 3 N- (3, 4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-pentylamine D-tartrate 2,208 3 N- (3,4-dimethoxyphenethyl) -2- (3, 4-Dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrochloride 5,138 1 N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian -2-propylamine-1,1,3,3-tetraoxide hydrochloride 5,230 3 N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-ethyl-m-dithiane -2-propylamine-1,1,3,3-tetraoxide hydrochloride 2,267 3

Reference compounds 5 - [(3,4-dimethoxyphenethyl) -methylamino] -2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride (Verapamil) 5,128 0.3 Λ-isopropyl 1 i - << -, E (N-methyl-1N-homoveratryl) -Y-aminopropyl] -3,4-ethylenedioxyphenylacetonitrile 2,108 0.3 6721 6 20

The compounds prepared by the process according to the invention proved to be considerably superior to, for example, a very similar compound known from DE 1 154 810, verapamil (see table above), and an ethylenedioxy compound known from DE 2 000 435 (see table above). It should be noted that in the absence of a straightforward effect-dose relationship, the maximum achievable effect of the compounds is the most important and the dose required for it is secondary.

The daily oral dose is about 10 to 200 mg; when administered by intravenous injection, it is about 1 to 20 mg.

Preparation of starting material of formula II A. 74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1,250 ml of chloroform, 50 ml of 1,3-propanedithiol are added and the mixture is cooled to 0 [deg.] C. with stirring. To this is added 20 ml of boron trifluoride etherate and the reaction mixture is allowed to refrigerate for 18 hours. It is then washed successively with 500 ml of 7% potassium hydroxide solution and 500 ml of 10% sodium chloride solution 3 times. The organic extracts are combined, dried over magnesium sulphate and evaporated to dryness. The residue is crystallized twice from ether. 102.6 g of 2- (3,4-dimethoxyphenyl-m-dithian, m.p. 99-101 ° C) are obtained.

In a similar manner, the following dithians can be prepared: 2- (o-methoxyphenyl) -m-dithian; mp. 126-127 ° C (from CH 2 Cl 2 / isopropyl ether) 2-phenyl-m-dithian; mp. 72-73 ° C (from Cl 2 Cl 2 /isopropyl ether) 2- (p-chlorophenyl) -m-dithian; mp. 87-88 ° C (Cl 2 Cl 2 /isopropyl ether) 2- (m-methoxyphenyl) -m-dithian; mp. 62-63 ° C (from isopropyl ether) 2- (3,4,5-trimethoxyphenyl) -m-dithian; mp. 88-89 ° C (CHOCl 2 / isopropyl ether) 2- (m-chlorophenyl) -m-dithian; mp. 63-64 ° C (from cyclohexane)

2- (3,5-dimethoxyphenyl) -m-dithiane; mp. 90-91 ° C

p- (m-dithian-2-yl) -Ν, Ν-dimethylaniline; mp. 118-119 ° C (from cyclohexane) 2- (m-nitrophenyl) -m-dithian; mp. 117-118 ° C (from CH 2 Cl 2 / methanol) 21 6721 6 2- (3,4-methylenedioxyphenyl) -m-dithiane; mp. 86-87 ° C (from cyclohexane) 2-p-tolyl-m-dithian; mp. 89-90 ° C (from ether / hexane) 2- (m-bromophenyl) -m-dithiane; mp. 78-79 ° C (from cyclohexane) 2- (2-naphthyl) -m-dithiane; mp. 110-111 ° C (from cyclohexane) 2- (2,4,5-trimethoxyphenyl) -m-dithian; mp. 156-157 ° C (from CH 2 Cl 2 / methanol) 2- (ρ-fluorophenyl) -m-dithian; mp. 105-106 ° C (from cyclohexane) 2- (4-biphenylyl) -m-dithian; mp. 148-151 ° C (from tetrahydrofuran / cyclohexane) 2- (OL, OL, CL-trifluoro-p-tolyl) -m-dithian; mp. 103-104 ° C (from cyclohexane) 2- (1-naphthyl) -m-dithian; mp. 147-148 ° C (from cyclohexane) 2- (3-benzyloxy-4-methoxyphenyl) -n-dithian; mp. 168-170 ° C (from cyclohexane) 2- (4-benzyloxy-3-methoxyphenyl) -m-dithian; mp. 118-119 ° C (from cyclohexane) 2- (2-thienyl) -m-dithian; mp. 74-75 ° C (from cyclohexane) 2- (OL, OL, OL-trifluoro-m-tolyl) -m-dithian; mp. 69-71 ° C (from heptane) 2- (p-isopropylphenyl) -m-dithian; mp. 58-59 ° C (from hexane) 2- (3,4-xylyl) -m-dithian; mp. 74-75 ° C (from petroleum ether) 2- (3-butoxy-4-methoxyphenyl) -m-dithiane; mp. 72-73 ° C (from cyclohexane) 2- (4-ethoxy-3-methoxyphenyl) -m-dithian; mp. 88-90 ° C (from a mixture of methylene chloride and isopropyl ether) m- (m-Dithian-2-yl) -benzonitrile; mp. 84-86 ° C (from isopropyl ether) 6-m-Dithian-2-yl-1,4-benzodioxane; mp. 140-142 ° C (from a mixture of methylene chloride and isopropyl ether) 2- (4-methoxy-m-tolyl) -m-dithian; mp. 75-77 ° C (from cyclohexane).

B. Dissolve 60 g of 2- (3,4-dimethoxydiphenyl) -m-dithiane (prepared according to A) in 470 ml of glacial acetic acid and add 235 ml of 30% H 2 O 2 at room temperature, raising the temperature of the solution to about 40 ml. ° C. The solution is allowed to stand overnight at room temperature. It is then heated for 2 hours at 100 ° C. After cooling to room temperature, the crystalline precipitate is filtered off with suction, washed with a small amount of glacial acetic acid, dried overnight under vacuum at 60 [deg.] C. and then recrystallized from acetonitrile. 57.1 g of 2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide are obtained, m.p. is 243-245 ° C.

The following dithian tetraoxides can be prepared as described above: 2- (m-bromophenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 230-231 ° C (from acetonitrile) 2- (p-fluorophenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 283-284 ° C (from acetonitrile) 2- (m-nitrophenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 256-257 ° C (from acetonitrile) 2- (3,4,5-trimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. > 310 ° C (from acetonitrile) 2- (2-naphthyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 277-278 ° C (from a mixture of acetone and acetonitrile) 2-p-tolyl-m-dithiane-1,1,3,3-tetraoxide; mp. 284-285 ° C (from acetonitrile) 2- (4-benzyloxy-3-methoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 220-223 ° C (from acetone / acetonitrile) 2- (3,4-diraethoxyphenyl) -1,3-dithiolane-1,1,3,3-tetraoxide; mp. 194-196 ° C (acetone / acetonitrile) 2- (3,4-methylenedioxyphenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. > 300 ° C (from acetone / acetonitrile) 2- (2'-thienyl) -m-dithian-1,1,3,3-tetraoxide; mp. > 300 ° C (from acetone / acetonitrile) 2- (3,4-dichlorophenyl) -m-dithiane-1,1,3,3-tetraoxide, m.p. 254-255 ° C (from glacial acetic acid / water) 2- (O, O-trifluoro-m-tolyl) -m-dithian-1,1,3,3-tetraoxide; mp.

239-242 ° C (from glacial acetic acid / water) 2- (p-isopropylphenyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 204-205 ° C (from acetonitrile / ethanol) 2- (3,4-xylyl) -m-dithiane-1,1,3,3-tetraoxide; mp. 268-269 ° C (from acetonitrile / methanol) 2- (3-butoxy-4-methoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide; mp.

225-227 ° C (from glacial acetic acid / water) 2- (4-ethoxy-3-methoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide; mp.

242-244 ° C (from acetone / acetonitrile) 23 6 7 2 1 6 m- (m-Dithian-2'-yl) -benzonitrile-1 ', 1', 3 ', 3'-tetraoxide; mp.

259-260 ° C (from glacial acetic acid / water) 6-m-dithian-2'-yl-1,4-benzodioxane-11,1 ', 3 *, 3'-tetraoxide, m.p. 232 ° C with decomposition (from glacial acetic acid / water) 2- (4-methoxy-m-tolyl-m-dithian-1 ', 133'-tetraoxide, mp 225-227 ° C (from glacial acetic acid / water)

Example 1 19.2 g of 2- (3,4-dimethoxyphenyl) -m-dithian (see preparation of starting material, point A) and 200 ml of tetrahydrofuran are cooled in a sulphidation cooking flask under argon to -60 ° C and 33 ml of butyllithium are slowly added dissolved in hexane. The mixture is then stirred for 2 hours at -20 ° C. A solution of 18 g of N- (3-chloropropyl) -3,4-dimethoxy-N-methylphenethylamine in 200 ml of tetrahydrofuran is added dropwise over 15 minutes at -70 ° C. The mixture is then allowed to stand for 18 hours at -20 ° C in a deep freezer and for 3 hours at room temperature. The reaction solution is then poured into water and extracted 3 times with ether. The ether extracts are extracted 3 times with 250 ml of 1N hydrochloric acid. The pH of the acidic extracts is adjusted to 12 with 3N sodium hydroxide and the oil which separates is extracted with ether. The organic extracts are dried over magnesium sulfate and evaporated to dryness. The oil thus obtained (30 g) is dissolved in ethyl acetate and an ethereal solution of HBr is added. The separated precipitate is recrystallized from ethanol. N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrobromide is obtained, m.p. is 170-172 ° C.

Analysis for C 29 H 21 N 2 O 2 S 2 HBr Calculated: C 54.54 H 6.69 N 2.45 Br 13.95

Found: C 54.54 H 6.74 N 2.31 Br 14.05 The starting N- (3-chloropropyl) -3,4-dimethoxy-N-methylphenethylamine can be prepared as follows: 292.5 g of N-methylhomoveratrylamine are dissolved in 1000 to 1 ml of dimethylformamide and 415 g of anhydrous potassium carbonate are added to the solution. The mixture is stirred at 5 [deg.] C., 237 g of 1,3-bromochloropropane dissolved in 500 ml of dimethylformamide are added, the mixture is stirred for a further 4 hours at room temperature and then poured into 6 liters of water. The oil which separates is extracted 3 times with 2 liters of ether.

24 6 7 2 1 6

The organic extracts are dried over magnesium sulfate and evaporated to dryness in vacuo. The residual oil is distilled using a mercury diffusion pump under a 0.005 torr vacuum at 69-70 ° C. 206.7 g of N- (3-chloropropyl) -3,4-dimethoxy-N-methylphenethylamine are obtained; boiling point 69-70 ° C under a vacuum of 0.005 torr.

In the same manner as described above, the following compounds can be prepared: N- (3,4-dimethoxyphenethyl) -2- (m-methoxyphenyl) -N-methyl-m-dithiamin-2-propylamine hydrochloride; mp. 113-115 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -2- (3,4,5-trimethoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrochloride; mp. 147-150 ° C (from acetone) N- (3,4-dimethoxyphenyl) -2- (p-methoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrochloride; mp. 160-161 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -2- (o-methoxyphenyl) -N-methyl-m-dithianane-2-propylamine hydrochloride; mp. 151-152 ° C (from acetone) 2- (p-chlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine hydrochloride; mp. 137-139 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-rhodithian-2-propylamine hydrochloride; mp. 170-172 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylenedioxyphenyl) -m-dithian-2-propylamine hydrochloride; mp. 139-141 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (p-tolyl) -m-dithiane-2-propylamine hydrochloride; mp. 139-141 ° C (from acetone) 2- (m-chlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine hydrochloride; mp. 108-110 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -2- (3,5-dimethoxyphenyl) -N-methyl-m-dithiane-2-propylamine oxalate (1: 1); mp. 155-156 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -2- (p-dimethylaminophenyl) -N-methyl-m-dithian-2-propylamine hydrochloride; mp. 183-184 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-dithian-2-propylamine hydrochloride; mp. 195-196 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2,4,5-trimethoxyphenyl) -m-dithian-2-propylamine hydrochloride; mp. 156-158 ° C (from acetone) 6721 6 N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-m-dithian-2-propylamine hydrochloride; mp. 138-139 ° C (from acetone) 2- (4-biphenylyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine oxalate (1: 1); mp. 167-169 ° C (from acetone) N- (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine hydrochloride, m.p. 145-147 ° C (from acetone), starting from 2-phenyl-m-dithian and N- (3-chloropropyl) -4-chloro-N-methylphenethylamine.

N-methyl-N-phenethyl-2-phenyl-m-dithiane-2-propylamine-hydro-chloride; mp. 136-137 ° C (from acetone), starting from 2-phenyl-m-dithian and N- (3-chloropropyl) -N-methyl-phenethylamine (boiling point 78-80 ° C / 0.001 torr).

N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithiane-2-ethyl-amine hydrochloride; mp. 172-174 ° C (from acetone), starting from 2-phenyl-m-dithian and N- (2-chloroethyl) -3,4-dimethoxy-N-methyl-phenethylamine.

N- (3,4-diraetoksifenetyyli) -N-methyl-2- (2-thienyl) -m-dithiane-2-propylamine hydrochloride; mp. 138-140 ° C (from acetone) ras.-N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -β, β-dimethyl-m-dithian-2-propylamine oxalate ( 1: 1); mp. 138-139 ° C (from acetone / ethyl acetate) using 2- (3,4-dimethoxyphenyl) -m-dithian and N- (3-chloro-2-methylpropyl) -3,4-dimethoxy-N-methylphenethylamine as starting materials .

Example 2 35.2 g of 2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide (see preparation of starting material, point B) are suspended in 180 ml of anhydrous dioxane and 2 .53 g of sodium. The mixture is boiled under argon for 20 hours, at which point the sodium is completely dissolved. 27.2 g of N- (3-chloropropyl) -3,4-dimethoxy-N-methylphenethylamine (prepared according to Example 1) are then added at room temperature, the cloudy solution is stirred for 1 hour at room temperature and refluxed for 3 hours. The mixture is poured into ice-water and extracted 3 times with ethyl acetate. The vinegar ester extracts are combined and extracted 3 times with 1N hydrochloride. The acidic extracts are basified and extracted 3 times with chloroform. The chloroform extracts are combined, washed with water, dried over magnesium sulphate and evaporated to dryness. The crystalline residue is recrystallized from methanol to give crystals of m.p. is 143-145 ° C.

To prepare the hydrochloride, the base is dissolved in acetone and 20 ml of hydrogen chloride in dioxane are added in an ice bath. The crystalline salt is filtered off with suction and recrystallized from acetonitrile-acetone (1: 3). The N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride thus obtained is dried overnight under high vacuum at 120 ° C. 38.9 g of material are obtained, m.p. is 167-169 ° C.

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

In the same manner as described above, the following compounds can be prepared: N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-dithian-2-propylamine-1,1,3,3-tetraoxide oxalate (1: 1); mp. 190-191 ° C (from acetone / methanol) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4,5-trimethoxyphenyl) -m-dithian-2-propylamine-1,1, 3,3-tetraoxide oxalate (1: 1); mp. 146-148 ° C (from acetone / ethyl acetate) 2- (m-bromophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3- tetroxide hydrochloride; mp. 158-160 ° C (from methanolic HCl and ethyl acetate) 2- (m-nitrophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3 -tetraoksidi hydrochloride; mp. 212-214 ° C (from acetone) N- (3,4-dimethoxyphenethyl) -2- (p-fluorophenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 234-236 ° C (from methanol) N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 149 ° C (decomposes) (from methanol) N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-ethyl-m-dithian-2-propylamine-1,1,3,3 -tetraoxide oxalate (1 :); mp.

177-179 ° C (from methanol and acetone) 27 6721 6 / Starting materials 2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide and N- (3-chloropropyl) -3 , 4-dimethoxy-N-ethyl-phenethylarino-N- (3,4-dimethoxyphenethyl) -2- (4-isopropylphenyl) -N-methyl-radithia-2-propylamine-1,1,3,3- tetroxide hydrochloride; mp. 225-227 ° C (from a mixture of HCl in dioxane and ethyl acetate) N- (3,4-dimethoxyphenethyl) -2- (3-trifluoromethyl-phenyl) -N-methyl-m-dithian-2-propylamine-1,1, 3,3-tetraoxide oxalate; mp. 128-130 ° C (from acetone) N, 2-bis- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 140-150 ° C (from ether) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-xylyl) -m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 176 DEG-178 DEG C. (from acetonitrile) 2- (3-butoxy-4-methoxyphenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1,3 3-tetrao.ksidi; mp. 84-85 ° C (from a mixture of methanol and isopropyl ether) N- [3- [2 '- (3,4-dimethoxyphenyl) -m-dithian-2'-yl] -propyl] -N-methyl-1,4-benzodioxane- 6-ethyl-1 ', 1', 3 ', 3'-tetraoxide-hydro-chloride; mp. 208-210 ° C (from acetonitrile) N- [4- (3,4-dimethoxyphenyl) -butyl] -2- (p-isopropylphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3 tetraoxide hydrochloride, m.p. 148-150 ° C (from a mixture of ethyl acetate and HCl in dioxane)

ras.-2- (3,4-dimethoxyphenyl) -N- [3- (3,4-dimethoxyphenyl) -1-methylpropyl] -N-methyl-m-dithian-2-propylamine-1,1, 3,3-tetraoxide; mp. 115-117 ° C

N- (3,4-dimethoxyphenethyl) -2- (4-ethoxy-3-methoxy-phenyl) -N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetroxide hydrochloride; mp.

190-192 ° C (from acetonitrile) m - [(2- [3- (3,4-dimethoxyphenethyl) -methylamino] -propyl] -m-dimethyl-2'-yl-7-benzonitrile-1 ', 1 ', 3', 3'-tetroxide hydrochloride; mp. 160 ° C (decomposes) 28 6 7 2 1 6 2- (1,4-benzodioxan-6-yl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1, 1,3,3-tetroxide hydrochloride; mp.

201-204 ° C

N- (3,4-dimethoxyphenethyl) -2- (4-methoxy-m-tolyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 146 ° C (decomposes) (from acetone) m-N, N '- (3,4-dimethoxyphenethyl) -butyl] -methylamino-propyl-N-dithian-2'-yl-4-benzonitrile -11 , 11 ', 3', 3'-tetraoxide hydrochloride; mp. 120-122 ° C (from water) 2- (3,4-dimethoxyphenyl) -N-methyl-N- (p-methylphenethyl) -m-dithianine-2-propylamine-1,1,3,3-tetraoxide- hydrochloride; mp. 169-171 ° C (from a mixture of acetone and ethyl acetate).

Example 3

A mixture of 6.08 g of 2- (3,4-methylenedioxyphenyl) -m-dithiane-1,1,3,3-tetraoxide and 25 ml of anhydrous dimethylformamide is stirred under argon and 0.8 g of 55- % sodium hydride suspension. The mixture is allowed to react for half an hour at room temperature and for one hour at 40 ° C. After cooling to room temperature, 4.8 g of N- (3-chloropropyl) -3,4-dimethoxy-N-methylphenethylamine (prepared according to Example 1) are added and the mixture is heated at 100 ° C for 16 hours. The cooled mixture is then poured onto ice and extracted 3 times with ethyl ether. The organic extracts are washed with water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residual oil is dissolved in acetone and 5 ml of 6N hydrogen chloride in dioxane are added to the solution. The separated precipitate is recrystallized from acetone. 7.5 g of N- (3,4-dimethoxyphenethyl) -N-methyl-2- (3,4-methylenedioxyphenyl) -m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride are obtained. - a slide with a melting point of 247 to 248 C.

Analysis: Calculated: C 52.12 H 5.95 N 2.43 Found: C 51.91 H 5.86 N 2.23

In the same manner as described above, the following compounds can be prepared: N- (3,4-dimethoxyphenethyl) -N-methyl-2-p-tolyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 203-2.07 ° C (from a mixture of acetonitrile and acetone) 29 6 7 2 1 6 2- (4- (benzyloxy) -3-methoxyphenyl-N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian- 2-propylamine-1,1,3,3-tetraoxide hydrochloride, mp 220-221 ° C (from ethanol) N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2'-thienyl) -m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride, mp 179-182 ° C (from acetone) 2- (3,4-dichlorophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride, mp 175-177 ° C (from methanol) N- (3,4-dimethoxyphenethyl) -2- ( 3,4-dimethoxyphenethyl) -N-methyl-m-dithiane-2-ethylamine-1,1,3,3-tetraoxide oxalate (1: 1);

202-204 ° C (from acetone).

Example 4 10 g of 3 ', 4'-dimethoxy-4- (methylveratrylamino) -butyrophenone hydrochloride are dissolved in 50 ml of chloroform and 3.25 g of 1,3-propanedithiol are added to the solution. Hydrogen chloride is introduced into the mixture at room temperature. The mixture is allowed to stand for 24 hours, after which it is poured into water, basified with 3N sodium hydroxide solution and extracted with ether. After drying and evaporation of the solvent, the oily residue is dissolved in acetone and an equivalent amount of anhydrous oxalic acid is added. The crystalline precipitate is recrystallized from acetone. 2- (3,4-Dimethoxy-phenyl) -N-methyl-N-veratryl-m-dithian-2-propylamine oxalate (1: 1) is obtained, m.p. is 133-136 ° C.

Analysis:

Calculated: C 57.12 H 6.57 N 2.47

Found: C 56.88 H 6.64 N 2.46 The starting 3 ', 41-dimethoxy-4- (methylveratrylamino) -butyrophenone can be prepared as follows:

Place 500 g of knee phosphoric acid and 69 g of veratrol in a one-liter round-bottomed flask. To this is added 61 g of 4-chlorobutyric acid, whereby the temperature rises continuously to 55 ° C. After one hour, the whole mixture is poured onto ice. It is then extracted with a mixture of ether and methylene chloride (3: 1). The organic extracts are washed with water, then with saturated sodium bicarbonate solution and finally once more with water, dried over magnesium sulphate and evaporated to dryness in vacuo. The remaining crystalline mass is recrystallized from ether. 62.9 g of 3,4-dimethoxy-'Y' -chlorobutyrophenone are obtained, m.p. is 91-92 ° C.

To 30 g of 3,4-dimethoxy-N-chlorobutyrophenone are added 40 ml of N-ethyl-N, N-diisopropylamine and 9 g of N-methylhomoveratrylamine and the mixture is stirred for 6 hours at 120 ° C. . After evaporation of the solvent in vacuo, the viscous mass is treated with ether and sodium hydroxide solution. The organic extracts are washed with water and extracted with 1N hydrochloric acid. The acidic extracts are then basified and extracted with ether. The ether extracts are combined, dried over sodium sulfate and evaporated to dryness. The 3 ', 4'-dimethoxy-4- (methylveratrylamino) -butyrophenone thus obtained, which has been found to be almost pure by plate chromatography, can be used without further purification.

In the same manner as described above, the following compounds can be prepared: N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-butylamine oxalate (1: 1), by sp. crystallized from acetone is 134-136 ° C; using 1,3-propanediithiol and 5- (13,4-dimethoxyphenethyl) -methylamino] -3,3,4'-dimethoxyvalerophenone (m.p. 165-166 ° C of the hydrochloride) as starting materials; obtained from 3,4-dimethoxy-6-chlorovalerophenone and N-methyl-homoveratrylamine.

N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl rhodithiane-2-pentylamine oxalate (1: 1), m.p. is 109-111 ° C crystallized from acetone; using 1,3-propanedithiol and 6- (13,4-dimethoxyphenethyl) -methylamino-7- (31,4'-dimethoxy-hexanophenone (m.p. 128-129 ° C) as starting materials); obtained from 6-chloro-3 ', 4'-dimethoxyhexanophenone and N-methylhomoveratrylamine.

2- (3,4-dimethoxyphenethyl) -N- [5- (3,4-dimethoxyphenyl) propyl] -N-methyl-m-dithiane-2-propylaramine oxalate (1: 1), m.p. is 116-118 ° C crystallized from acetone; using 1,3-propanedithiol and 3,4,4'-dimethoxy-4- (3,4-dimethoxyphenyl) -propyl] -methylamino-4-butyrophenone as starting material from 3,4-dimethoxy-γ-chlorobutyrophenone and 3- ( 3,4-dimethoxyphenyl) -metyylipropyy-amines.

2- (3,4-dimethoxyphenyl) -N-methyl-N- (Cf-methylphenethyl) -m-dithian-2-propylamine oxalate (1: 1); mp. 131-132 ° C (crystallized from a mixture of acetone and ethyl acetate); using as starting materials 31- (6721 6 1,3-propanedithiol and 4- (1,3,4-dimethoxy-α-methylphenethyl) -methylamino) -31,41-dimethoxybutyrophenone obtained from 3,4-dimethoxy-? chlorobutyrophenone and N, Cfc-dimethyl- / 6-phenylethylamine (boiling point 130-140 ° C / 20 Torr).

N- (3/4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-1,3-dithiolane-2-propylamine oxalate (1: 1), m.p. is 150-152 ° C crystallized from acetone; using 4- (3,4-dimethoxyphenethyl) -methylamino-β-3 ', 4'-dimethoxybutyrophenone and 1,2-ethanedithiol as starting materials.

Example 5 To 10.4 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide is added 5.11 g of N-methylhomoveratrylamine, 30 ml of N-ethyl-N, N-diisopropylamine and 70 ml of dimethylformamide, the solution is heated at 120 ° C for 6 hours. After evaporation to dryness, the residue is further treated as in Example 3. N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride is obtained by sp. is 167-169 ° C.

In the same manner as described above, the following compounds can be prepared: N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride ; mp. 149 ° C (decomposes), methanol list crystallized N- (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride ; mp. 246-249 ° C (decomposes) crystallized from a mixture of methanol and methylene chloride N-methyl-N-phenethyl-2-phenyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 165-167 ° C crystallized from acetone 2- (3,4-dimethoxyphenyl) -N-methyl-N-veratryl-m-dithian-2-propylamine-1,1,3,3-tetraoxide; mp. 137-139 ° C crystallized from a mixture of acetone and ethanol N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-2-propylamine-1,1,3,3-tetraoxide hydrochloride; mp. 130-132 ° C crystallized from acetone.

The 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide used as a starting material in the process described above can be prepared as follows: 32 6 7 2 1 6 10.9 g of 3,4-dimethoxy-β-chlorobutyrophenone (prepared according to Example 4) are dissolved in 120 ml of chloroform and 5 ml of 1,3-propanedithiol and 1 ml of boron trifluoride etherate are added to the solution at room temperature. the chloroform solution is washed 3 times with water, 3 times with 1N sodium hydroxide solution and a further 3 times with water, the organic phases are dried over magnesium sulphate and evaporated to dryness in vacuo, the oily residue is immediately dissolved in 500 ml of chloroform and added at 45.7%. solid m-chloroperbenzoic acid so that the reaction temperature does not rise above 5 [deg.] C. The mixture is then left in the refrigerator for 64 hours, the organic phase is washed 3 times with 1N sodium hydroxide solution and 3 times with water, dried over magnesium sulphate and allowed to dry in vacuo. The residue is recrystallized from methylene chloride / isopropyl ether. 2- (3-Chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide is obtained, m.p. is 183-184 ° C.

The 2- (3-chloropropyl) -2-phenyl-m-dithiane-1,1,3,3-tetraoxide used as a starting material in the process described above can be prepared as follows: 19.63 g of 2-phenyl-m-dithiane are dissolved in 300 ml. tetra-hydrofuran. At -70 ° C, 43.5 ml of a solution of butyllithium in hexane are slowly added dropwise under argon. The mixture is stirred for a total of 1 1/2 hours at -20 ° C. The resulting red solution is added at -70 ° C to a solution of 15.74 g of 1,3-bromochloropropane in 250 ml of anhydrous tetrahydrofuran. The solution thus obtained is allowed to stand for one hour at -20 ° C and for one hour at room temperature. The solvent is evaporated off in vacuo and the oily residue is dissolved in ether. The ether phase is washed with 1N sodium hydroxide solution and water, dried over magnesium sulphate and evaporated to dryness in vacuo. The 2- (3-chloropropyl) -2-phenyl-m-dithian peroxide thus obtained is oxidized as described above in chloroform with m-chloroperbenzoic acid at 0-5 ° C. After recrystallization from ethyl acetate, 2- (3-chloropropyl) -2-phenyl-m-dithianane-1,1,3,3-tetraoxide is obtained, m.p. is 182 ° C.

Example 6

A mixture of 3.76 g of 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithiane-1,1,3,3-tetraoxide, 50 ml of ethanol, 30 ml of chloroform and 1.95 g of N-methylhomoveratrylamine, boil for 33 6721 6 18 hours under argon. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform-ethanol (98: 2). The resulting oil is dissolved in acetone and an equivalent amount of anhydrous oxalic acid is added to the solution. The precipitate is filtered off and recrystallized from methanol-acetone. Sent ras. - C 1- [(3,4-dimethoxyphenethyl) -methylamino] -methyl-2- (3,4-dimethoxyphenyl) -m-dithiane-2-ethanol 1,1,3,3-tetraoxide oxalate (1 : 1) crystallizes with 1 mole of acetone and melts at 162-164 ° C.

Analysis:

Calculated: C 51.73 H 6.30 N 1.95

Found: C 51.68 H 6.53 N 2.00 The starting 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithiane-1,1,3,3-tetraoxide can be is prepared as follows: 9.6 g of 2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide are dissolved in 35 ml of dimethylformamide and 1.2 g are added at room temperature under stirring under argon. sodium hydride. The suspension is stirred for a further 1/2 hour at 40 ° C, then cooled and 2.8 g of epichlorohydrin are added. The mixture is then heated at 100 ° C for 16 hours. After cooling to room temperature, the suspension is poured into water and the oily substance is extracted with chloroform. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform-acetone (98: 2). The resulting 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithiane-1,1,3,3-tetraoxide is recrystallized from a mixture of methylene chloride and ethanol and m.p. is 175-176 ° C.

Example 7

A mixture of 3.65 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,3-dioxide, 7.8 g of N-methylhomoveratrylamine and 20 ml of dimethyl sulfoxide, heated under argon for 1 to 6 hours at 50 ° C. The solution is then poured into 200 ml of water and made strongly basic. Excess N-methylhomoveratrylamine is extracted with ether. The basic solution is then extracted with methylene chloride. The methylene chloride extracts are dried over magnesium sulfate. After evaporation of the solvent, the residual solvent 34 6721 6 is taken up in acetone and a solution of hydrogen chloride in dioxane is added (until the pH is = 2). The crystalline residue is recrystallized from a mixture of acetone and acetonitrile to give N- (3,4-dimethoxyphenethyl) -2- (3,4-deraethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,3-dioxide. hydrochloride; mp. 148-149 ° C (mixture of diastereomers).

The starting 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,3-dioxide can be prepared as follows: 76.9 g of 2- (3,4-dimethoxyphenyl) - The m-dithian is dissolved in 900 ml of anhydrous tetrahydrofuran, the solution is cooled to -70 ° C and 128 ml of butyllithium solution are added so that the temperature does not rise above -60 ° C. The mixture is then kept at -20 ° C for 2 hours, whereupon a precipitate forms. It is then re-cooled to -70 [deg.] C. and a solution of 47.3 g of 1,3-bromochloropropane in 750 ml of anhydrous tetrahydrofuran is added. The mixture is then kept for one hour at -20 ° C and for one hour at room temperature. The tetrahydrofuran is then evaporated off, the residue is dissolved in ether and extracted. After evaporation of the solvent, 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane is obtained.

55.25 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian are dissolved in 500 ml of glacial acetic acid. With stirring at 5 ° C, a solution of 34 g of 30% hydrogen peroxide in 300 ml of glacial acetic acid is added dropwise over 2 hours. The mixture is then allowed to stand for 60 hours at room temperature, after which it is evaporated to dryness in vacuo at 40 ° C. The oil obtained is chromatographed using 1.5 kg of silica gel and a chloroform-ethanol mixture, the ratios of the latter solvents being first 92: 8 and then 95: 5. Recrystallization from acetonitrile gives 2- (3-chloropropyl) -2- (3,4-diraethoxyphenyl) -m-dithiane-1,3-dioxide; mp. 163-164 ° C (mixture of diastereomers).

Example 8 Using 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithiane and N-methylhomoveratrylamine as starting materials in the same manner as in Example 6, ras.-C 1 -Z- (3,4- dimethoxyphen-ethyl) -methylcunino-N-methyl-2- (3,4-dimethoxyphenyl) -m-dithian-2-ethanol. The corresponding hydrobromide crystallizes from acetonitrile-ethyl acetate and melts at 97-99 ° C.

35 6721 6 The starting 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithiane can be prepared in an exemplary manner using 2- (3,4-dimethoxyphenyl) -m-dithian as the starting material and 1 , Epichlorohydrin instead of 3-bromochloropropane.

Example 9

A mixture of 3.4 g of lithium aluminum hydride in 60 ml of tetrahydrofuran is heated to reflux. A solution of 14.7 g of N- (3,4-dimethylphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithian-2-propionamide in 80 ml of tetrahydrofuran is then added dropwise. The resulting suspension is heated at reflux for a further 3 hours, then cooled to 0 [deg.] C. and 50 ml of saturated sodium sulphate solution are carefully added. The whole mixture is filtered off with suction, the solution is diluted with water and extracted with ether. The ether extracts are washed with 1N sodium hydroxide solution, then with water, dried over magnesium sulphate and evaporated to dryness, the oily residue is chromatographed on silica gel and chloroform-ethanol (95: 5). The base obtained is dissolved in acetone and an equivalent amount of anhydrous oxalic acid is added. The resulting precipitate is recrystallized from methanol-acetone. The N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithian-2-propylamine oxalate (1: 1) thus obtained melts at 186-188 ° C.

Analysis:

Calculated: C 57.12 H 6.57 N 2.67

Found: C 56.97 H 6.73 N 2.39 N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithian-2-propionamide can be prepared as a starting material as follows:

To a mixture of 50 g of 3-veratroylpropionic acid in 400 ml of chloroform and 22.7 g of 1,3-propanedithiol is added hydrogen chloride with stirring until the mixture is saturated. After 3 hours at room temperature, the solution is concentrated to 50 ml and diluted with ether. The corresponding solution is extracted 3 times with 5% sodium carbonate. The basic phases are combined and acidified with concentrated hydrochloric acid. The precipitated product is extracted with ether-methylene chloride (1: 3). The organic extracts are dried and evaporated to dryness. The residue is recrystallized from ethanol to give 2- (3,4-dimethoxyphenyl) -m-dithian-2-propionic acid, m.p. is 134-135 ° C.

36 6721 6

A mixture of 13.2 g of 2- (3,4-dimethoxyphenyl) -m-dithian-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran is cooled to 0 [deg.] C. and a solution is added dropwise over 10 minutes. is 5.44 g of chloroformic acid isobutyl ester in 80 ml of tetrahydrofuran. The mixture is then kept at room temperature for 3 hours and then a solution of 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran is added at 0 ° C. The suspension is kept for 48 hours at 3 [deg.] C., then it is evaporated to dryness, water is added and the mixture is extracted with ether-methylene chloride (3: 1). The ether extracts are washed with water, sodium bicarbonate, 1N tartaric acid and water. The organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is crystallized from methylene chloride / ether at 0 ° C. N- (3,4-dimethyloxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithian-2-propionamide is obtained, m.p. is 135-136 ° C.

In the same manner as above, N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine hydrobromide can be prepared; mp. crystallized from ethanol at 170-172 ° C.

Example 10 0.5 g of 2- [3- [2 "- (3,4-dimethoxyphenyl) -m-Dithian-2" -yl-7-propyl] -4-methylamino-3 ', 4'-dimethoxyacetophenone-1 ", The 1 ", 3", 3 "tetraoxide is dissolved in 15 ml of ethanol and 30 ml of tetrahydrofuran, and 50 mg of sodium borohydride is added to the solution. After stirring for 16 hours, 15 ml of 1N hydrochloride and then 12 ml of 1N sodium hydroxide are added to the mixture. The tetrahydrofuran is evaporated off and the residue is extracted with methylene chloride. The organic extracts are washed with water, dried over magnesium sulphate and evaporated to dryness in vacuo. The obtained crystals are recrystallized from methanol to give 0.3 g of C 1-4 -N- [3- (3- (4-dimethoxyphenyl) -m-dithian-2'-yl) -propyl] -methylamino-methyl N-veratryl alcohol-1 ', 1', 3 ', 3'-tetraoxide, mp 132-133 ° C.

The starting material used was 2 - [(3- [2 "- (3,4-dimethoxyphenyl) -m-dithian-2" -yl] -propyl-4-methylamino] -31,4'-dimethoxyacetophenone-1 ", 1", 3 ", 3" tetraoxide can be obtained by reacting 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithiane-1,1,3,3-tetraoxide with 61-methylamino-3,4 with dimethoxyacetophenone, mp 140 ° C (decomposes) (crystallized from acetone).

37 6721 6

Example 11 10 g of N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-pentylamine (prepared according to Example 4) are dissolved in 50 ml of glacial acetic acid and the solution is treated at room temperature with 20 ml of 30% hydrogen peroxide. After 3 hours, the mixture is heated for 3 hours at 35 ° C and then for 18 hours at 40 ° C. The solution is then poured into water, basified with sodium hydroxide and extracted with methylene chloride. After removal of the solvent, the residue is chromatographed on silica gel with ammonia-saturated chloroform-methanol (97: 3). The product obtained is dissolved in acetone and an equivalent amount of oxalic acid is added to the solution. The resulting precipitate is recrystallized from a mixture of acetone and methanol. N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithiane-2-pentylamine-1,1,3,3-tetraoxydioxalate (1: 1) is obtained. ), sp. is 189-191 ° C.

Analysis:

Calculated: C 53.48 H 6.43 N 2.08

Found: C 53.37 H 6.50 N 1.87

The following compounds can be prepared as described above: N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-butylamine-1,1,3,3-tetraoxide- oxalate, m.p. 161-163 ° C (crystallized from acetone / methanol), (base 123-126 ° C from ethanol); using N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-butylamine (prepared according to Example 4) as starting material.

2- (3,4-Dimethoxyphenyl) -N- [(3,4-dimethoxyphenyl) -propyl] -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrobromide having mp. is 138-140 ° C crystallized from a mixture of acetonitrile and ethyl acetate; using 2- (3,4-dimethoxyphenyl) -N- [3- (3,4-dimethoxyphenyl) -propyl] -N-methyl-m-dithian-2-propylamine (prepared according to Example 4) as starting material.

ras.-N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N, β-dimethyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride -di, m.p. 183-185 ° C (crystallized from acetone / ethyl acetate); using ras.-N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N, β-dimethyl-m-dithian-2-propylamine (prepared according to Example 1) as starting material.

6721 6 38 2- (3,4-dimethoxyphenyl) -N-methyl-N- (Ot-methylphenethyl) -m-dithian-2-propylamine-1,1,3,3-tetraoxide hydrochloride, having mp. 185-187 ° C (crystallized from acetone / ethyl acetate); using 2- (3,4-dimethoxyphenyl) -N-methyl-N- (CW-methylphenethyl) -m-dithian-2-propylamine (prepared according to Example 4) as starting material.

Example 12

A mixture of 11.2 g of 2- [4- (benzyloxy) -3-methoxyphenyl] -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1, 1,3,3-Tetraxide (prepared according to Example 3) and 100 ml of 48% hydrobromic acid are heated for 2 minutes in a water bath. The aqueous solution is then extracted with ether, evaporated to dryness in vacuo and distilled 3 times with an azeotropic ethanol / benzene mixture. The residue is crystallized from acetone. The crystalline mass thus obtained is recrystallized 3 times from methanol / acetonitrile to give 4- [2 1- [3- (3,4-dimethoxyphenethyl) methylamino] -propyl] -N-dithian-2'-yl / -2-methoxyphenol. -11.1 ', 3', 3'-tetraoxide hydrobromide, m.p. is 192 ° C (decomposes).

Analysis for C25H35NO8S2 * HBr;

Calculated: C 48.23 H 5.83 N 2.25

Found: C 48.12 H 5.93 N 2.07

In a similar manner, starting from 2- [3- (benzyloxy) -4-methoxyphenyl] -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3 -tetraoxide can be prepared from 5- (2 '- (3- (73,4-dimethoxyphenethyl) -methylamino) -propyl-4-m-dithian-2'-yl) -2-methoxyphenol-1', 1 ', 3', 3'-tetraoxide hydrobromide; mp. 201 ° C (decomposes) (crystallized from acetonitrile).

Example 13 To 0.3 g of 2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide is added 0.16 g of 3,4-dimethoxy- N-phenylethyl chloride, 5 ml of N, N-diisopropyl-N-ethylamine and 1.5 ml of dimethylformamide and heated at 130 ° C for 15 hours.

The solution is then shaken with a mixture of water and ethyl acetate. The residue is chromatographed on silica gel to give N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1,3,3-tetraoxide; mp. 144 ° C (crystallized from methanol).

39 6721 6 The starting 2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,3,3,3-tetraoxide can be prepared as follows: 3.95 g of 2- (3-chloropropyl ) -2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide is dissolved in 50 ml of dimethylformamide. The solution is cooled to 0 ° C and 15 g of methylamine are added. The mixture is heated at 40 ° C under pressure for 18 hours. The solution is then concentrated and the crystalline mass is recrystallized from a small amount of methanol. The above-mentioned product is obtained, m.p. is 164 ° C.

Example 14 1 g of N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -m-dithian-2-propylamine (prepared according to Example 9) is dissolved in 20 ml of anhydrous pyridine and 200 ml of acetic acid are added. an acid anhydride. After 18 hours, the solvent is evaporated off and the residue is shaken with ether and sodium carbonate (5%). After evaporation of the solvent, an oil (1.2 g) is obtained, which is dissolved in 20 ml of anhydrous tetrahydrofuran. This solution is slowly added dropwise to a suspension of 0.4 g of lithium aluminum hydride and 20 ml of anhydrous tetrahydrofuran. Aqueous concentrated sodium sulfate is slowly added to the mixture and filtered. After evaporation of the solvent, the residue is shaken with ether and water and the organic extracts are further treated, the oily residue is treated with oxalic acid in acetone / ethyl acetate to give a crystallization from N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl). ) -N-ethyl-m-dithian-2-propylamine 1,1,3,3-cetraoxide oxalate; mp. 126-127 ° C.

Example 15 1 g of homoveratrumic acid is dissolved in 15 ml of anhydrous tetrahydrofuran and 0.15 g of triethylamine is added to the solution. At 0-5 ° C, 0.72 g of chloroformic acid isobutyl ester is slowly added dropwise and the mixture is stirred for 1 hour at 5-10 ° C. To this mixture is added dropwise a solution of 1.63 g of 2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine (prepared as in Example 14 in 2- (rp-chloropropyl) -2- ( 3,4-dimethoxyphenyl) -m-dithiane and methylamine) in 5 ml of tetrahydrofuran. The mixture is allowed to stand overnight at room temperature.

40 6721 6

After evaporation of the solvent, the residue is shaken with a mixture of 1N hydrochloric acid and ether. The organic extracts are washed with 5% sodium carbonate solution and water. After drying over magnesium sulphate, the solvent is evaporated off. the oily residue (1.5 g) is dissolved in 15 ml of tetrahydrofuran and added dropwise to a boiling suspension protected under argon with 0.15 g of lithium aluminum hydride. The mixture is boiled for 2 hours and then slowly concentrated aqueous sodium sulphate solution is added, followed by 10 ml of methylene chloride. The mixture is filtered and the solution is evaporated to dryness. The residue is chromatographed on silica gel to give N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine as a thick oil. The resulting oil is dissolved in ethyl acetate and hydrogen bromide (dissolved in ether) is added. The precipitate formed is recrystallized from ethanol to give the pure hydrobromide salt; mp. 170-172 ° C.

Λ

Claims (10)

41 6721 6 A process for the preparation of therapeutically useful 1,3-dithiolanyl (2) and 1,3-dithianyl (2) compounds having the general formula / CH2'nN \ / t4 __ / = <5 RCYN— (Z) „ -Λ Λ-Κ6 I wherein R represents a group R '\ "UL R3 (a) (b) wherein and R2 represent hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy or benzyloxy, or one of Rn and R? is phenyl, nitro, trifluoromethyl or di-lower alkylamino the other being hydrogen, or R 1 is cyano and R 2 is hydrogen, or R 1a 3 R 2 together form methylenedioxy, ethylenedioxy or butadiene-1,3-generalene-1 , The 4-chain, is hydrogen or lower alkoxy, R 1 is hydrogen or lower alkyl, R 1. and R 1 each represent hydrogen or lower alkyl, or together form an ethylene-dioxy chain, or R 1 - is hydrogen and R 1 - is halogen or lower alkyl, X is a sulfur atom, SO or SO 2, Y is straight or branched, optionally containing a hydroxy substituent an alkylene chain having 2 to 5 carbon atoms, and Z is a straight or branched alkylene chain optionally containing a hydroxy substituent having 1 to 4 carbon atoms, and m corresponds to 0 or 1 and n corresponds to 2 or 3, 42 6721 6 and their acid addition salts characterized in that a) a compound of the general formula / (CH2> A <x J \ / R- CH in which R, X and n have the same meaning as above is reacted with a compound of the general formula r4 _S R5 R8- Y - "- (Z) m - R 6 111 wherein R 1 - R 2, Y f Z and m are as defined above and R 8 is a leaving group, or b) a compound of general formula 0 R. 7_ / R5 11 1 / \ RCYN- <Z) --Λ Λ-R IV "6 wherein R, R 1 - R 9, Y, Z and m are as defined above, are reacted with a compound of general formula HS- (CH-) -SH V 2. n wherein n has the meaning given above, or 43 6721 6 c) a compound of the general formula XX VI R - ^ C-Y-Rg wherein R, Rg, X , Y and n are as defined above, are reacted with a compound of the general formula Rc f- / = C HN- (Z) - (v λ-R, VII m \ _ # 6 where R 1 - R 9, Z and m or d) a compound of the general formula / ', CH2> n'S X χ) »4 \ /' R-CYNH wherein R, R1, X, Y and n are as defined above, is reacted with a compound of the general formula r8 (Z) m - Re XI where R5 “Rg, Z and m have the same meaning as above, or 44 6721 6 e) in compounds of the general formulas \ / i4 r = K5 RC-Ϊ, -N-ΖΛ -Λ— »6 *« / <CH) \ R i I4 \ /? ~ ° / = \ RCY- N- Z .- (..) - R, XIII \ L · - / where R, R. - Rc , X, Y, Z, m and n have the same meaning as above, and and Z 1 represents groups corresponding to Y or Z, at least one of Y 1 and containing a carbonyl group, reducing the carbonyl group, followed, if desired, by oxidizing a compound of formula 1 in which X represents a sulfur atom to a compound of formula I and in which X represents SO or SO 2 or, if desired, N-alkylating a compound of formula I in which R 1 represents hydrogen, optionally converting a lower alkoxy group or a bentoyloxy group to a hydroxy group, optionally etherifying or esterifying a hydroxy group or, if desired, converting the base obtained to an acid addition salt. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -2- (p-methoxyphenyl) -N-methyl-m-dithian-2-propylamine or hap-addition salt thereof. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine or an acid addition salt thereof is prepared. 45 6721 6 Process according to Claim 1, characterized in that N- (p-chlorophenethyl) -N-methyl-2-phenyl-m-dithian-2-propylamine or an acid addition salt thereof is prepared. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -N-methyl-2- (2-naphthyl) -m-dithian-2-propylamine or an acid addition salt thereof is prepared. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -N-methyl-2- (p-tolyl) -m-dithian-2-propylamine-1,1,3, 3-tetraoxide or an acid addition salt thereof. Process according to Claim 1, characterized in that 2- (m-nitrophenyl) -N- (3,4-dimethoxyphenethyl) -N-methyl-m-dithian-2-propylamine-1,1 , 3,3-tetraoxydia or an acid addition salt thereof. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-pentylamine or an acid addition salt thereof is prepared. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-ethyl-m-dithian-2-propylamine-1, 1,3,3-tetraoxide or an acid addition salt thereof. Process according to Claim 1, characterized in that N- (3,4-dimethoxyphenethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,1 , 3,3-tetraoxide or an acid addition salt thereof. 46 6721 6