DK148323B - ANALOGY PROCEDURE FOR PREPARING 1,3-DITHIOLANYL (2) - OR 1,3-DITHIANYL (2) COMPOUNDS - Google Patents

Description

148323

The present invention relates to an analogous process for the preparation of novel 1,3-dithiolanyl (2) or 1,3-dithianyl (2) compounds of the general formula I

x \ ^ x 14 Ye r6 r -> c - yN - (Z) m 1 R7 where R represents a group of the general formula a or b 2 R 1 or ab 12 3 where R, R and R each represent hydrogen, halogen, lower alkyl, lower alkoxy, benzyloxy, phenyl, nitro, trifluoromethyl, hydroxy, cyano, di-lower alkylamino or lower alkanoyloxy or two adjacent groups together represent methylenedioxy, ethylenedioxy 4 or butadiene-1,3-ylene-1,4, R represents hydrogen or lower alkyl, R 6, R and R each represent hydrogen, halogen, lower alkyl or lower alkoxy or two adjacent groups together represent ethylenedioxy, X represents sulfur, SO or SO 2 / Y represents a straight chain or branched, optionally hydroxy-substituted aliphatic hydrocarbon chain of 2-5 carbon atoms, Z represents a straight or branched, optionally hydroxy-substituted aliphatic hydrocarbon chain of 1-4 carbon atoms, m represents 0 or 1, and n represents 2 or 3, or acid addition salts thereof.

The term "lower alkyl" here denotes a straight or branched alkyl group having 1-6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, textbutyl, amyl or hexyl. "Lower alkoxy" means a lower alkyl ether group, the term "lower alkyl" having the meaning given above. "Halogen" includes the four halogen atoms fluorine, chlorine, bromine and iodine. "Lower alkanoyl" means a lower alkanoyl group having a maximum of 6 carbon atoms such as formyl, acetyl, propionyl or butyryl. The term "leaving group" as used herein denotes known groups such as halogen, preferably bromine or chlorine, arylsulfonyloxy such as tosyloxy, alkylsulfonyloxy such as mesyloxy or epoxy.

The process of the present invention for the preparation of compounds of the above general formula I or salts thereof is characterized in that:

(a) a compound of general formula II

/ (CIi2> n \

X X

R - C - Η II

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

4 is R5 where R4 - R7, Y, Z and m each have the meaning given above, and

ISLAND

R represents a leaving group, or

(b) a compound of general formula IV

OR4 c I! ! / = VR5 h-c-y-n - (z) m-iv R7

wherein R, R4 - R7, Y, Z and m each have the meaning given above are reacted with a compound of the general formula V

HS - (CH2) n - SH V

where n has the meaning given above, or

(c) a compound of general formula VI

/ (CH2> iN

X X

\ X 8

R - C - Y - R VI

148323 4

Q

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

r4 6 H - »- VI1 R7 4 7 wherein R - R, Z and m each have the meaning given above, or

d) a compound of general formula X

^ m2K 'R4 n x f

R-C ^ Y-N-H X

wherein R, R4, X, Y and n are each as defined above are reacted with a compound of general formula XI

R5

r8 - <Z> m R XI

R7 wherein R 1 - R 2, Z and m each have the meaning given above, or

e) in a compound of general formula XII or XIII

148323 5 / <CH2> S \ R4 f R X> C <Y1 - 1 - S1 ^ '' R7 R'4 r5 x \ / f ° / hr r6

R - C - Y - H - (Z) m XIII

wherein R, R4 - R7, X, Y, Z, m and n each have the meaning given above, Y 1 and Ί? each represent Y and Z respectively or a corresponding oxo-substituted group, at least one of the groups and in 4 Z however, a carbonyl group contains and R 'represents hydrogen or a C 1-4 alkyl group, the carbonyl group is reduced, whereupon a compound of general formula I produced, wherein X represents a sulfur atom, if desired, is oxidized to a compound of general formula I, wherein X represents SO or SO2, a compound of formula 4 of general formula I wherein R represents hydrogen, if desired, N-lower is alkylated to a compound of general formula I wherein 4 R represents C1-6 alkyl, a lower alkoxy or benzyloxy group 1 2 3 for R, R or R if desired is converted to a hydroxy group, a 12 3 hydroxy group for R, R or R if desired is O-lower alkylated or esterified with a lower alkane carboxylic acid and a recovered base if desired is converted to an acid addition salt.

Examples of preferred compounds of general formula I may be mentioned compounds of general formula Ia (CH2) n, R5 R v = k </ '* / 4v * 6 β_β-C - (CH2) 3- S - (CH 2 -CH 2) m "R 3 R 7 17 4 wherein R - R and m each have the meaning given above, R" represents methyl or ethyl, and X 3 represents sulfur or SC 2. As examples of further preferred compounds with the general advantages 1 2

between compounds 1a may be indicated in which one of the symbols R, R

and R represents hydrogen and the others represent lower alkoxy, especially methoxy, or together represent butadiene-1,3-ylene-1,4, or two of the symbols R, R 2 and R represent hydrogen, and the third represents 5 6 7 nitro, and one of the symbols R * R and R represents hydrogen and the other two represent lower alkoxy, especially methoxy. A particularly preferred compound is N- (3,4-dimethoxyphenylethyl) -2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-propylamine-1,3,3,3-tetraoxide.

The reaction of a compound of general formula II with a compound of general formula III is carried out in a manner known per se. The reaction is conveniently carried out in an organic solvent inert under the reaction conditions at a temperature between ca. -80 ° C and the reflux temperature of the reaction mixture, preferably between ca. 0 and approx. 50 ° C, especially around room temperature. Examples of solvents include ethers such as diethyl ether, tetrahydrofuran or dioxane, aromatic hydrocarbons such as benzene, toluene or xylene, dimethylformamide or dimethylsulfoxide. The reaction may be carried out in the presence of a strong base such as butyllithium, a Grignard compound, sodium or sodium hydride, suitably, where X represents sulfur, a particularly strong base such as butyllithium or a Grignard compound is used.

The compounds used as starting compounds of the above general formulas II and III are partly known and partly new. The novel compounds can be prepared in a manner known per se, the compounds being prepared analogously to the preparation of the known compounds.

148323 7

The compounds of the general formula II wherein X represents sulfur may e.g. is prepared by reacting an aldehyde of the general formula \ h wherein R is as defined above with ethane or propane thiol. The reaction is conveniently carried out in an inert organic solvent, e.g. chloroform, below room temperature.

The compounds of general formula II wherein X represents SO or SO2 can be prepared by oxidation of the corresponding compounds where X represents sulfur. The oxidation may conveniently be carried out in a suitable solvent using peracids such as peracetic acid, perphthalic acid or m-chloroperbenzoic acid. Peracetic acid may e.g. is formed in situ from glacial acetic acid and hydrogen peroxide.

The reaction of a compound of general formula IV with a compound of general formula V is carried out in a manner known per se. The reaction is conveniently carried out in an inert organic solvent under the reaction conditions, preferably in a polar solvent such as halogenated hydrocarbons, e.g. chloroform or methylene chloride or in ethylene glycol dimethyl ether. The reaction is also conveniently carried out in the presence of a water-scavenging agent such as sulfuric acid, hydrogen halide acids, or phosphoric acid at a temperature between 0 ° C and the reflux temperature of the reaction mixture, preferably at room temperature.

The starting compounds of general formula V are known and can be prepared in known manner.

The compounds of the general formula IV used as starting compounds are novel.

Compounds of general formula IV may, for example, is prepared by a compound of general formula XIVa 8 148323

ISLAND

R - C - Y - Cl XIVa

wherein R and Y each have the meaning given above are reacted with a compound of general formula VII

4 r5 H - "- (Z) m VI1 R7 4 7 where R - R, Z and nt each have the meaning given above.

The reaction is conveniently carried out in the presence of an acid-binding agent such as a tertiary amine, e.g. N-ethyl-N, N-diisopropylamine, which may simultaneously constitute the solvent. The reaction is also conveniently carried out at elevated temperature, preferably at a temperature up to approx. 130 ° C, depending on the solvent boiling temperature.

The above-used compounds of the general formula XIVa are partly known and partly new. The compounds may be prepared in a manner known per se, e.g. analogous to the preparation of the known compounds. Compounds of general formula VII are known.

The reaction of a compound of general formula VI with a compound of general formula VII is carried out in a manner known per se. The reaction is conveniently carried out in an organic solvent inert under the reaction conditions such as an ether, e.g. dibutyl ether, dioxane or tetrahydrofuran, an alkanol such as ethanol or propanol, an aromatic hydrocarbon such as benzene, toluene or xylene or in acetonitrile, dimethylformamide or dimethylsulfoxide. The reaction can be carried out at a temperature between approx. room temperature and the reflux temperature of the reaction mixture. The reaction is preferably carried out at the reflux temperature. If acid is cleaved off by reaction, it is conveniently carried out in the presence of a base, e.g. a tertiary amine such as trimethylamine, N-ethyl-N, N-diisopropylamine or N, N-dimethylaniline.

The compounds of general formula VII used as starting compounds are known. Compounds of general formula VI are novel. Compounds of general formula VI may e.g. is prepared by a compound of general formula XIV

0

Il 8

R - C - Y - R ° XIV

Q

wherein R, R and Y each have the meaning given above are reacted with a compound of general formula V

HS "(CH2} n" SfI V

where n has the meaning given above and a won compound of the general formula VI, where X represents sulfur, if desired by oxidation is converted to a compound of the general formula VI where X represents SO or SO2.

The reaction of a compound of general formula XIV with a compound of general formula V can be carried out in a manner known per se. The reaction is conveniently carried out in an inert organic solvent under the reaction conditions, preferably in a polar solvent such as halogenated hydrocarbons, e.g. chloroform or methylene chloride, or in ethylene glycol dimethyl ether.

The reaction is also conveniently carried out in the presence of a water-scavenging agent such as sulfuric acid, hydrogen halide or phosphoric acid at a temperature between 0 ° C and the reflux temperature of the reaction mixture, preferably at room temperature.

The conversion of a won compound of the general formula VI, where X represents sulfur, to a compound where X represents SO or SO2 can be carried out in a manner known per se, e.g. by oxidation with a peracid, e.g. peracetic acid, perphthalic acid or m-chloroperbenzoic acid. Peracetic acid may e.g. is formed in situ from glacial acetic acid and hydrogen peroxide.

ίο 148323

The reaction of a compound of general formula X with a compound of general formula XI is carried out in a manner known per se. The reaction is conveniently carried out in an organic solvent inert under the reaction conditions such as an ether, e.g. dibutyl ether, dioxane or tetrahydrofuran, an alkanol, e.g. ethanol or propanol, an aromatic hydrocarbon, e.g. benzene, toluene or xylene, or in acetonitrile, dimethylformamide or dimethylsulfoxide. The reaction can be carried out at a temperature between approx. room temperature and the reflux temperature of the reaction mixture. The reaction is preferably carried out at the reflux temperature. If acid is cleaved off by reaction, 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 N, N-dimethylaniline.

The compounds used as starting compounds of the general formula XI are known. Compounds of general formula X are novel. Compounds of the general formula X is produced by a compound of the general formula Via

X X

R Y - Cl Via

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

R4 - NH2 XVI

4 where R has the meaning given above. Since hydrogen chloride is thereby decomposed, the reaction is conveniently carried out in the presence of a base or using an excess of the amine of the general formula XVI. Furthermore, the reaction can be carried out analogously to the reaction of a compound of the general formula VI with a compound of the general formula VII.

148323 11

Compounds of general formula XVI are known. Compounds of general formula Via, which are, to some extent, novel, can be prepared analogously to the preparation of compounds of general formula VI.

The reduction of a carbonyl group in a compound of general formula XII or XIII is carried out in a manner known per se.

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

The reduction of other carbonyl groups, viz. those not directly bonded to the nitrogen atom are also carried out in a manner known per se. In particular, the reduction can be carried out so that either the corresponding hydroxymethylene group is formed, which is then reduced further to the methylene group or the methylene group is formed directly.

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

The reduction using an alkali metal aluminum hydride or an alkali metal borohydride may conveniently be carried out at room temperature or at or above room temperature in an inert organic solvent. Examples of suitable solvents for the reduction with an alkali metal aluminum hydride may be given anhydrous ethers such as diethyl ether or tetrahydrofuran, and the reduction with an alkali metal borohydride may be used alkanols of 1-4 carbon atoms such as methanol or ethanol or dioxane. Preferably, lithium aluminum hydride is used as alkali metal aluminum hydride and sodium borohydride is used as alkali metal borohydride.

148323 12

The further reduction of a hydroxymethylene group to a methylene group is carried out in a manner known per se, especially by conversion to the corresponding sulfonic acid ester or to the halide and reduction thereof or complex metal hydrides. The reduction can be carried out by analogy with the reduction of carbonyl groups described above.

The direct reduction of a carbonyl group to a methylene group can be carried out in a manner known per se using a Wolff-Kisnner reduction, ie. by reacting the ketone with hydrazine to prepare the corresponding hydrazone and decomposing the hydrazone under basic conditions.

The compounds used as starting compounds of general formulas XII and XIII are novel compounds.

For example, amides of general formula XII may be used. is produced by the fact that one

acid of general formula XVII

7 <α, 2> '\

R - c - Y - cr XVII

\

OH

wherein R, Y, X and n are each as defined above are reacted with an amine of the general formula VII

R4 R5 h "(i) -" is 4 7 where R - R, Z and m each have the meaning given above. The reaction may conveniently be carried out in the presence of a tertiary amine such as triethylamine and a halogenated carboxylic acid ester such as chloroformic acid isobutyl ester (mixed anhydride method) in an inert organic solvent, e.g. tetrahydrofuran, at a temperature between ca.

0 and approx. 30 ° C.

148323 13

Compounds of general formula XVII can be prepared analogously to the preparation of compounds of general formula VI described above from compounds of general formula XVIII

0

Il

R - C - Y - C

\

OH

wherein R and Y each have the meaning given above. Compounds of general formula XVIII belong to a known compound class.

Ketones of general formula XII can be prepared in a manner known per se, e.g. by oxidation of the corresponding alcohols. The oxidation may e.g. is carried out with complex chromium trioxide / pyridine in pyridine at a temperature between ca. -20 ° C and approx. room temperature, preferably at approx. 0 ° C.

The preparation of amides of general formula XIII can be carried out in a manner known per se, e.g. by acylating a compound of general formula I wherein R 4 represents hydrogen. The acylation may e.g. is carried out with a halide of a lower carboxylic acid in a tertiary amine, e.g. pyridine, at a temperature between ca. 0 and approx.

30 ° C, preferably about room temperature.

The conversion of a compound of general formula I wherein X represents sulfur to a compound where x represents SO or SO2 can be accomplished by oxidation in a suitable solvent using peracids such as peracetic acid, perphthalic acid or m-chloroperbenzoic acid. Peracetic acid may e.g. are prepared in situ from glacial acetic acid and hydrogen peroxide.

4

Resulting compounds of general formula I wherein R represents hydrogen may be alkylated in a manner known per se, e.g. using lower alkyl halides. Consequently, the compounds concerned are reacted immediately with the alkyl halide at lower temperature.

The conversion of a lower alkoxy or benzyloxy group to a hydroxy group is carried out in a manner known per se, e.g. heating with a concentrated hydrogen halide acid, especially constant boiling bromine

The etherification or esterification of a hydroxy group present is carried out in a manner known per se, e.g. by reacting a corresponding halide, e.g. with a corresponding acid halide or acid anhydride.

Compounds of general formula I can be converted to acid addition salts, e.g. by treatment with an inorganic acid such as a hydrogen halide acid, e.g. hydrochloric or hydrobromic, sulfuric or phosphoric or with an organic acid such as oxalic, tartaric, citric or methanesulfonic. Among the acid addition salts of compounds of general formula I, pharmaceutically useful compounds are preferred. If, by the process of the present invention, an acid addition salt is obtained from a compound of the general formula I, such a salt may be known per se, e.g. upon treatment with alkali, it is converted to the free base and, if desired, can be converted to another acid addition salt.

The compounds of the general formula I which contain an asymmetric carbon atom can be in racemic or optically active form, and the present invention relates to a process for preparing both the racemic and optically active forms. A racemate can be known in a manner known per se, e.g. by fractional crystallization of the corresponding salts with an optically active acid, if desired, split into the optical antipodes.

Compounds of general formula I and their acid addition salts have valuable coronary dilating properties. used to treat angina pectoris.

The eoronardilating effect can be determined using the following method:

For the study, bastard dogs weighing 20 - 38 kg are used. The test animals are anesthetized by approx. 30 mg / kg pentcbarbital intravenously and the anesthetic is maintained with chloralose-urethane. The animals receive artificial respiration with the air of the room. After opening the thorax, the heart is opened and around the left coronary artery's Ramus circumflexus a pre-adjusted "Flow" sensor is placed from an electromagnetic "Flowmeter" to determine the flow of blood. Water-soluble preparations are applied intravenously dissolved in an isotonic saline solution, and water-insoluble preparations are applied intravenously in propylene glycol. The maximum effect of a preparation is calculated after each dosing as a percentage of the initial value and graphed. In determining coronary hemorrhage, the duration of action is particularly taken into account.

Connections with a similar structure are known from the German disclosures 1,154,810 and 2,000,435. However, the compounds of the process according to the invention differ substantially from the known compounds, in particular by containing the group

X X

\ / - c - wherein n and X have the above meaning, instead of the group

C = N

- C - H1 'where R - * - 1 is a hydrocarbon group. From the present writings, inter alia, mentioned is the compound best known by the name of Verapamil, namely 5 - [(3,4-dimethoxyphenethyl) methylamino] -2- (3,4-dimethoxyphenyl) -2-isopropylvaleronitrile hydrochloride, as well as the corresponding ethylenedioxy derivative α-isopropyl -a - [(N-methyl-N-homoveratryl) -γ-aminopropyl] -3,4-ethylenedioxyphenylacetonitrile, which also, as calcium antagonists, has coronardilating properties. However, the compounds produced by the method of the invention cause a higher maximal coronary hemorrhage increase than the known compounds, which are also loaded with a strong and long-acting hypotensive and negative-inotropic effect, that is, with adverse effects which may be negative. In contrast, the compounds prepared by the process of the invention do not have these negative properties but, on the contrary, exhibit good antiarrhythmic properties at good tolerability.

The following table lists the efficacy maxima for a number of compounds prepared by the process of the invention as well as for the known compound Verapamil.

Table

Compound Maximum Coronary Transmission Dose, mg bleeding increase,% intravenous N- (3,4-Dimethoxyphenethyl) - N-methyl-3 [2- (m-methoxy-phenyl) -m-dithian-2-yl] - propylamine hydrochloride 133 '1 N- (3,4-dimethoxyphenethyl) -N-methyl-3 [2β (3,4,5-trimethoxyphenyl) -m-dithian-2-yl] propylamine hydrochloride 140 (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (p-methoxy-phenyl) -m-dithian-2-yl] -propylamine hydrochloride 223 L N- (3,4-dimethoxyphenethyl) - -N-methyl-3 [2- (o-methoxy-phenyl) -m-dithian-2-yl] -propylamine hydrochloride 172 L N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (p-chlorophenyl) -m-dithian-2-yl] propylamine hydrochloride 172 1 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2-phenyl-m-diethian-2 yl] propylamine hydrochloride 17

Table continued N- (p-chlorophenethyl) -N-methyl-3 [2-phenyl-m-dithian-2-yl] -propylamine-1,1,3,3-tetraoxide hydrochloride 132 1 N- (p -chlorophenethyl) -N-methyl - 3 [2-phenyl-m-dithian-2-yl] -propylamine hydrochloride 210 3 N-methyl-N-phenethyl-3 [2-phe-ny1-m-dithian-2 -Y1] propylamine hydrochloride 155 3 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (3,4-methylene-dioxyphenyl) -m-dithian-2-yl] propylamine hydrochloride 145 1 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (p-tolyl) -methithian-2-yl] propylamine hydrochloride 130 1 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (3,5-dimethoxy-phenyl) -m-dithian-2-yl] -propylamine-D-tartrate 145 L N- (3,4-dimethoxyphenethyl) -N-methyl -3 [2- (2-naphthyl) - m -dithian-2-yl] propylamine hydrochloride 213 1 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (p-fluorophenyl) Nyl) -m-dithian-2-yl] propylamine hydrochloride 153 1 N- (3,4-dimethoxyphenethyl) -N-methyl-3 [2- (m-bromophenyl) -m-dithian-2-yl ] propylamine-1,3,3-tetraoxide hydrochloride 185 0.3 N- (3,4-dimethoxyphenethyl) -N-methyl-3 [2- (3,4-methylenedio] xyphenyl) -m-dithian-2-yl] propylamine-1,1,3,3- tetraoxide hydrochloride 130 3 N- (3,4-dimethoxyphenethyl) -N-methyl-3 [2- (p tolyl) -m-dithian-2-yl] propylamine - 1,1,3,3-tetraoxide hydrochloride 290 3

Table continued N- (3,4-Dimethoxyphenethyl) -N-methyl-3 [2- (m-nitrophenyl) -m-dithian-2-yl] propylamine-1,3,3-tetraoxide- hydrochloride 202 1 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2-phenyl-m-di-thian-2-yl] ethylamine hydrochloride 182 3 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- [p- (dimethylamino) phenyl] -m-dithian-2-yl] propylamine hydrochloride 130. rac.-a - / [(3,4-dimethoxyphenethyl) -methylaminolmethyl-2- (3,4-dimethoxyphenyl) - m -dithian-2-ethanol-D-tartrate 140 3 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2 - (3,4-dimethoxyphenyl) -m-dithian-2-yl] - pentylamine-D-tartrate 208 3 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (3,4-dimethoxyphenyl) ) -m-dithian-2-yl] propylamine hydrochloride 138 1 N- (3,4-dimethoxyphenethyl) - N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl ] -propylamine-1,1,3,3-tetraoxide hydrochloride 230 3 N- (3,4-dimethoxyphenethyl) -N-ethyl-3 [2- (3,4-dimethoxyphenyl) m -dithian 2-yl] -propylamine-1,1,3,3-tetra-oxide hydrochloride 267 3 - [(3,4-dimethoxyphenethyl) methylamino] -2- (3,4- dimethoxyphenyl) -2-isopropylvalonitrile hydrochloride (Verapamil) 128 0.3

The compounds of the invention and pharmaceutically useful acid addition salts thereof can be used as pharmaceuticals in the form of pharmaceutical compositions containing these compounds in admixture with a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral application, such as water, gelatin, gum arabic , lactose, starch, magnesium tearate, talc, vegetable oils, polyalkylene glycols or vaseline. The pharmaceutical compositions may be in solid form, e.g. in the form of tablets, dragees or capsules, or in liquid form, e.g. in solutions, suspensions or emulsions. The compositions are optionally sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers.

The daily dose of oral administration is between approx. 10 and 200 mg and by intravenous administration between ca. 1 and 20 mg.

However, the dosages indicated should only be construed as examples and may change depending on the severity of the case to be treated and on the basis of the treating physician's judgment.

The process of the invention is illustrated in more detail by the following examples, while the following preparations illustrate the preparation of starting materials.

Preparation 1.

74.7 g of 3,4-dimethoxybenzaldehyde are dissolved in 1250 ml of chloroform, 50 ml of 1,3-propanedithiol is added and cooled with stirring at 0 ° C. 20 ml of boron trifluoride etherate are added and the reaction mixture is allowed to stand for 18 hours in a refrigerator. The mixture is then washed three times successively with 500 ml of a 7% potassium hydroxide solution and 500 ml of a 10% sodium chloride solution. The organic extracts are combined, dried with magnesium sulfate and evaporated. The residue is recrystallized twice by ether. 102.6 g of 2- (3,4-di-methoxyphenyl) -m-dithian are obtained, mp 99-101 ° C.

148323 20

The following dithians can be prepared in an analogous manner: 2- (o-methoxyphenyl) -m-dithian, m.p. 126 - 127 ° C (of CH 2 Cl 2 / isopropyl ether), 2-phenyl-m-dithian, m.p. 72 - 73 ° C (of CH2 Cl2 / isopropyl ether), 2- (p-chlorophenyl) -m-dithian, m.p. 87-88 ° C (of GH2C12 / isopropyl ether), 2- (m-methoxyphenyl) -m-dithian, mp 62-63 ° C (of isopropyl ether), 2- (3,4,5-trimethoxyphenyl) -m-dithian, m.p. 88 - 89 ° C (of CH 2 Cl 2 / isopropyl ether), 2- (m-chlorophenyl) -m-dithian, m.p. 63 - 64 ° C (of cyclohexane), 2- (3,5-dimethoxyphenyl) -m-dithian, m.p. 90-191 ° C (of cyclohexane), p- (m-dithian-2-yl) -Ν, Ν-dimethylaniline with mp 118 - 119 ° C (of cyclohexane), 2- (m-nitrophenyl) -m-dithian with mp 117-118 ° C (of CH 2 Cl 2 / methanol), 2- (3,4-methylenedioxyphenyl) -m-dithian with m.p. 86 - 87 ° C (of cyclohexane), 2-p-tolyl-m-dithian, m.p. 89-90 ° C (of ether / hexane), 2- (m-bromophenyl) -m-dithian, m.p. 78 - 79 ° C (of cyclohexane), 2- ( 2-naphthyl) -m-dithian, m.p. 110-111 ° C (of cyclohexane), 2- (2,4,5-trimethoxyphenyl) -m-dithian, mp 156-157 ° C (of Cl 2 Cl 2 / methanol), 2- (p-fluorophenyl) -m-dithian with melting point 105 - 106 ° C (of cyclohexane), 2- (4-biphenylyl) -m-dithian of melting point 148 - 151 ° C (of tetrahydrofuran / cyclohexane), 2- (α, α, α-trifluoro-p-tolyl) -m-dithian with melting point 103 - 104 ° C (of cyclohexane), 2- (1-naphthyl) -m-dithian of melting point 147 - 148 ° C (of cyclohexane) ), 2- (3-benzyloxy-4-methoxyphenyl) -m-dithian, m.p. 168-170 ° C (of cyclohexane), 2- (4-benzyloxy-3-methoxyphenyl) -m-dithian, m.p. 118-199 ° C (of cyclohexane), 2- (2-thienyl) -m-dithian, m.p. 74 - 75 ° C (of cyclohexane), 2- (α, α, α-trifluoro-m-tolyl) -m-dithian, m.p. 69-71 ° C (of heptane), 2- (p-isopropylphenyl) -m-dithian with m.p. 58-59 ° C (of hexane), 2- (3,4-xylyl) -m-dithian of boiling point 74 - 75 ° C (of petroleum ether), 2- (3-butoxy-4-erothoxyphenyl) -midienyl, m.p. 72-73 ° C (of cyclohexane), 2- (4-ethoxy-3-methoxyphenyl) -m-dithian with boiling point 88 - 90 ° C (of methylene chloride and isopropyl ether), m- (m-dithian-2-yl) -benzonitrile with bp 84 - 86 ° C (of isopropyl ether), 6-m-dithian-2-yl -1,4-benzodioxane with boiling point 140 - 142 ° C (of methylene chloride and isopropyl ether) and 2- (4-methoxy-m-tolyl) ) -m-dithian with boiling point 75 - 77 ° C (of cyclohexane).

Preparation 2.

60 g of 2- (3,4-dimethoxyphenyl) -m-dithian (prepared according to Preparation 1) are dissolved in 470 ml of glacial acetic acid and at room temperature 235 ml of 30% hydrogen peroxide are added, raising the temperature of the solution to approx. 40 ° C. The solution is left to stand overnight at room temperature. The mixture is then heated for 2 hours at 100 ° C. After cooling to room temperature, the crystalline precipitate which is washed with glacial acetic acid is filtered off, dried overnight in vacuo at 60 ° C and then recrystallized from acetonitrile. 57.1 g of 2- (3,4-dimethoxyphenyl) m -dithian 1,1,3,3-tetraoxide, mp 243 - 245 ° C.

The following dithiolano and dithianotetra oxides may be prepared by analogy to the procedure described above: 2- (m-bromophenyl) -m-dithian-1,1,3,4-tetraoxide, mp 230-231 ° C (of acetonitrile), 2- (p-fluorophenyl) -m-dithian-1,1,3,3-tetraoxide, mp 283 -284 ° C (of acetonitrile), 2- (m-nitrophenyl) -m-dithian-1,1,3,3 -tetra oxide, m.p. 256 -257 ° C (of acetonitrile), 2- (3,4,5-trimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide, mp> 310 ° C (of acetonitrile) ), 2- (2-naphthyl) -m-dithian-1,1,3,3-tetraoxide, m.p. 277 -278 ° C (of acetone / acetonitrile), 2-p-tolyl-m-dithian-1.1 , 3,3-tetraoxide, m.p. 284 - 285 ° C (of acetonitrile), 2- (4-benzyloxy-3-methoxyphenyl) -m-dithian-1,1,3,3-tetraoxide, mp 220 - 223 ° C (of acetone / acetonitrile), 2- (3,4-dimethoxyphenyl) -1,3-dithiolane-1,3,3-tetraoxide, m.p. 194 - 196 ° C (of acetone / acetonitrile), 2- (3 4-methylenedioxyphenyl) -m-dithian-1,1,3,3-tetraoxide, m.p. 300, eC (of acetone / acetonitrile) , 2- (2 * -thienyl) -m-dithian-1,1,3,3-tetraoxide, m.p.> 300 ° C (of acetone / acetonitrile), 2- (3,4-dichlorophenyl) -m-dithian 1,1,3,3-tetraoxide, m.p. 254 - 255 ° C (of glacial acetic acid / water), 2- (a, a, α-trifluoro-m-tolyl) -m-dithian-1,1,3,3-tetraoxide m.p. 239 - 242 ° C (of glacial acetic acid / water), 2- (p-isopropylphenyl) -m-dithian-1,1,3,3-tetraoxide, mp 204-205 ° C (of acetonitrile / ethanol), 2- (3,4-xylyl) -m-dithian-1,1,3,3-tetraoxide, mp 268 -269 ° C (of acetonitrile and methanol), 2- (3-butoxy-4-methoxyphenyl) -m -dithian-1,1,3,3-tetraoxide, mp 225 - 227 ° C (of glacial acetic acid / water), 2- (4-ethoxy-3-methoxyphenyl) -m-dithian-1,1,3,3- tetraoxide, m.p. 242 - 244 ° C (of acetone / acetonitrile), m- (m-dithian-2'-yl) -benzonitrile-1 ^ 1 ^ 3 ^ 31 -tetra oxide, mp 259-260 ° C (of glacial acetic acid) / water), 6-m-dithian-2, -yl-1,4-benzodioxane-1 ', 1', 3 ', 3'-tetraoxide, mp 232 ° C decomp. (of glacial acetic acid / water) and 2- ( 4-Methoxy-m-tolyl) -m-dithian-11,1 ', 31,3'-tetraoxide with melt sections 225 - 221 ° Q, (of glacial acetic acid / water).

Example 1.

In a sulphonation flask, with argon, 19.2 g of 2- (3,4-dimethoxyphenyl) -m-dithian (prepared according to Preparation 1) and 200 ml of tetrahydrofuran are cooled to -60 ° C and 33 ml of butyl lithium in hexane are slowly added. . Then the mixture is stirred for 2 hours at -20 ° C.

Within 15 minutes, a solution of 18 g of N- (3-chloropropyl) -N-methyl-3,4-dimethoxy-phenylethylamine in 200 ml of tetrahydrofuran is added dropwise at -70 ° C. The mixture is then allowed to stand for 18 hours at -20 ° C in a freezer and for 3 hours at room temperature. The reaction solution is then poured onto water and extracted three times with ether.

The ethereal extracts are then extracted three times with 250 ml of 1N hydrochloric acid. To the acidic extracts is added 3N sodium hydroxide solution to a pH above 12 and the separated oil is extracted with ether. The organic extracts are dried over magnesium sulfate and evaporated. The resulting oil (30 g) is dissolved in ethyl acetate and ethereal HBr is added. The precipitated precipitate is recrystallized from ethanol. N- (3,4-dimethoxyphenylethyl) -1H-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine hydrobromide is obtained, mp 170 DEG-172 DEG.

Analysis:

Calculated for C₂2H37NNO4S₂-HBr: 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) -N-methyl-3,4-dimethoxy-phenylethylamine used as the starting compound can be prepared as follows: Dissolve 292.5 g of N-methylhomoveratrylamine in 1000 ml of dimethylformamide and add 415 g of anhydrous potassium carbonate. The mixture is stirred at 5 ° C, 237 g of 1,3-bromochloropropane is added in 500 ml of dimethylformamide and the mixture is stirred for 4 hours at room temperature and then poured into 6 liters of water. The separated oil is extracted three times with 2 liters of ether each time. The organic extracts are dried over magnesium sulfate and evaporated in vacuo. The resulting oil is distilled at a temperature between 69 and 70 ° C at 0.005 mm Hg using a mercury diffusion pump. 206.7 g of N- (3-chloropropyl) -N-methyl-3,4-dimethoxy-phenylethylamine are obtained at boiling point 69-70 ° C / 0.005 mm Hg.

The following compounds can be prepared analogously to the procedure described above: N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (m-methoxyphenyl) - m -dithian-2-yl] propylamine hydrochloride, m.p. 113 - 115 ° C (of acetone).

N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,4,5-trimethoxyphenyl) - m -dithian-2-yl] propylamine hydrochloride, m.p. 147-150 ° C ( of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (p-methoxyphenyl) -m-diethian-2-yl] propylamine hydrochloride, m.p. 160 - 161 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (o-methoxyphenyl) -m-diethian-2-yl] propylamine hydrochloride, m.p. 151 - 152 ° C (of acetone ), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (p-chlorophenyl) -m-di-. thian-2-yl] propylamine hydrochloride, m.p. 137 - 139 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2-phenyl-m-dithian-2-yl] - propylamine hydrochloride, m.p. 170 DEG-172 DEG C. (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,4-methylenedioxyphenyl) - m -dithian-2-yl] propylamine hydrochloride, mp 139-141 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (p-tolyl) -m-dithian-2-yl] propylamine hydrochloride with m.p. 139-141 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-m-3 [2- (m-chlorophenyl) -m-dithian-2-yl] propylamine hydrochloride with mp 108 - 110 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,5-dimethoxyphenyl) - m -dithian-2-yl] propylamine oxalate ( 1: 1), mp 155 - 156 "C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (p-dimethylaminophenyl) - m -dithian-2-yl] propylamine hydrochloride, m.p. 183 - 184 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (2,4,5-trimethoxyphenyl) - md ithian-2-yl] propylamine hydrochloride, mp 156 - 158 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (p-fluorophenyl) -m-diethian-2 -yl] propylamine hydrochloride, m.p. 138-139 ° C (of acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (4-biphenylyl) -m-diethian-2-yl] propylamine oxalate (1: 1), m.p. 167 - 169 ° C (of acetone), N- (p-chlorophenylethyl) -N-methyl-3 [2-phenyl-m-dithian-2-yl] -propylamine hydrochloride, m.p. 145 - 147 "C (of acetone), from 2-phenyl-m-dithian and N- (3-chloropropyl) -N-methyl-4-chloro-phenylethylamine, N-methyl-N-phenylethyl 3 [2-phenyl-m-dithian-2-yl] propylamine hydrochloride, m.p. 136-137 ° C (of acetone) from 2-phenyl-m-dithian ~ and N- (3-chlorophenyl) -N- methylphenylethylamine (b.p. 78 - 80eC / 0.001 mm Hg), N- (3,4-dimethoxyphenylethyl) -N-methyl-2 [2-phenyl-m-dithian-2-yl] ethylamine hydrochloride, m.p. 172 - 174 " C (of acetone) from 2-phenyl-m-dithian and N- (2-chloroethyl) -3,4-dimethoxy-N - methylphenyl thylamine, N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (2-thienyl) -m-dithian-2-yl] propylamine hydrochloride, mp 138-140 ° C (of acetone), rac.N- (3,4-dimethoxyphenylethyl) -N, 5-dimethyl-3 [2- (3,4-dimethoxy-phenyl) -m-dithian-2-yl] propylamine oxalate (1: 1), m.p. 138 - 139 ° C (of acetone / ethyl acetate), from 2- (3,4-dimethoxy-phenyl) -m-dithian and N- (3-chloro-2-methylpropyl) -N-methyl-3,4- dimethoxy-phenylethylamine and N- [4- (3,4-dimethoxyphenyl) butyl] -N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine.

Analysis:

Calculated: C 64.70 H 7.95 N 2.69 Pound: C 64.42 H 8.11 N 2.58

Example 2.

35.2 g of 2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraOXide (prepared according to Preparation 2) are suspended in 180 ml of absolute dioxane and 2.53 g of sodium is added. The mixture is boiled for 20 hours under argon, thereby completely dissolving the sodium. Then 27.2 g of N- (3-chloropropyl) -N-methyl-3,4-dimethoxy-phenylethylamine (prepared according to Example 1) is added at room temperature and the turbid solution is stirred for 1 hour at room temperature and boiled for 3 hours. reflux. The mixture is poured onto ice-water and extracted three times with ethyl acetate. The ethyl acetate extracts are combined and extracted three times with 1 N hydrochloric acid. The acidic extracts are made alkaline and extracted three times with chloroform. The chloroform extracts are combined, washed with water, dried with magnesium sulfate and evaporated. The crystalline residue is recrystallized from methanol to give crystals of mp 143-145 ° C.

To prepare the hydrochloride, the base is dissolved in acetone and in an ice bath 20 ml of dioxanic hydrogen chloride is added. The crystalline salt is filtered off and recrystallized from acetonitrile-acetone (1: 3).

The resulting N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride is dried overnight in high vacuum at 120 ° C. 38.9 g of a product of melting point 167 - 169 ° C is obtained.

.. 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.

The following compounds can be prepared analogously to the procedure described above: N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (2-naphthyl) -m-dithian-2-yl] propylamine-1, 1,3,3-tetraoxide oxalate (1: 1) mp 190 - 191 ° C (of acetone / methanol), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,4,5) -trimethoxyphenyl) -m-dithian-2-yl] propylamine-1,1,3,3-tetraoxide oxalate (1: 1), m.p. 146-148 ° C (of acetone / ethyl acetate), N- (3.4 dimethoxyphenylethyl) -N-methyl-3 [2- (m-bromophenyl) -m-dithian-2-yl] -propylamine-1,1,3,3-tetraoxide hydrochloride, mp 158-160 ° C (of methanolic HCl and ethyl acetate), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (m-nitrophenyl) -m-dithian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, mp 212 -214 ° C (of acetone), N- (3,4-dimethoxyphenyl) - N-methyl-3 [2- (p-fluorophenyl) -m-dithian-2-propylamine-1, 1,3,3-tetraoxide hydrochloride, mp 234 - 236 ° C (of methanol), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2-phenyl-m-dithian-2-y l] propylamine-1,3,3-tetraoxide hydrochloride, mp 149 DEG C. (decomposition) (of methanol), N- (3,4-dimethoxyphenylethyl) - N-ethyl-3 [2- (3.4 -dimethoxyphenyl) -m-di-thian-2-yl] propylamine-1,3,3-tetraoxide oxalate (1: 1), m.p. 177 - 179 ° C (of methanol and acetone), from 2- (3 4-Dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide and N- (3-chloropropyl) - N-ethyl-3,4-dimethoxy-phenylethylamine, N- (3,4-dimethoxyphenylethyl) ) -N-methyl-3 [2- (4-isopropylphenyl) -m-diethian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, mp 225-2227 ° C (of dioxanic HCl (ethyl acetate), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3-trifluoromethylphenyl) - m -dithian-2-yl] propylamine-1,1,3,3-tetraoxide oxalate, m.p. 128-130 ° C (of acetone), N- (3,4-dimethoxyphenyl) -N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-di-thian-2-yl] propylamine-1, 1,3,3-tetraoxide, m.p. 140-150 ° C (of ether), N- [4- (3,4-dimethoxyphenyl) butyl] -3 [2- (3,4-dimethoxyphenyl) -m-di , thian-2-yl] propylamine-1,1,3,3-tetrao dioxide,

Analysis:

Calculated: C 57.61 H 7.08 N 2.40 Found: C 57.78 H 7.10 N 2.39 N- (3,4-Dimethoxyphenylethyl) -N-methyl-3 [2- (3.4 -xylyl) -m-dithian-2-yl] -propylamine-1,1,3,3-tetraoxide hydrochloride, m.p. 176 -178 ° C (of acetonitrile), N- (3,4-dimethoxyphenylethyl) -N- methyl 3 [2- (3-butoxy-4-methoxyphenyl) - m -dithian-2-yl] propylamine-1,1,3,3-tetraoxide, mp 84-85 ° C (of methanol / isopropyl ether).

N- (3- [21- (3,4-dimethoxyphenyl) -m-dithian-2'-yl] propyl) -N-methyl-1,4-benzodioxane-6-ethylamine-11.3 -tetraoxide hydrochloride, m.p. 208 - 210 ° C (of acetonitrile), N- [4- (3,4-dimethoxyphenyl) butyl] -N-methyl-3 [2- (p-isopropylphenyl) -m-dithian-2- yl] propylamine-1,1,3,3-tetraoxide hydrochloride, mp 148-150 ° C (of ethyl acetate / dloxanic HCl), rac.-N- [3- (3,4-dimethoxyphenyl) -1-methylpropyl] -N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine-1,1,3,3-tetraoxide, m.p. 115 - 117 ° C, N- (3.4 dimethoxyphenylethyl) -N-methyl-3 [2- (4-ethoxy-3-methoxyphenyl) - m -dithian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, m.p. 190 - 192 ° C (of acetonitrile), m - [2 '- (3- (3,4-dimethoxyphenylethyl) methylamino] propyl) -m-dithian -, - 2, -yl] benzonitrile-1', 1 ', 3', 3'-tetraoxide hydrochloride, m.p. 160 ° C (decomposition), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (1,4-benzodioxan-6-yl) - m -dithian 2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, m.p. 204 ° C, N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (4-methoxy-m-tolyl) -N - methyl-m-dithian-2-yl] propylamine-1.1 , 3,3-tetraoxide hydrochloride, m.p. 146 DEG C. (decomposition) (of acetone), m- (2 '- [3 - ([4- (3,4-dimethoxyphenyl) butyl] methylamino) propyl] -m- di-thian-2 * -yl) benzonitrile-1 ', 1', 3 ', 3'-tetraoxide hydrochloride, mp 120 - 122 ° C (water) and N-methyl-N- (p-methylphenylethyl) - 3 [2- (3,4-Dimethoxyphenyl) -m-di-thian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, mp 169-171 ° C (of acetone and ethyl acetate).

Example 3

6.08 g of 2- (3,4-methylenedioxyphenyl) -m-dithian-1,1,3,3-tetraoxide (prepared according to Preparation 2) are stirred under argon with 25 ml of absolute dimethylformamide and 0.8 g of and 55% sodium hydride suspension. The mixture is allowed to react for 0.5 hour at room temperature and for 1 hour at 40 ° C. After cooling to room temperature, 4.8 g of N- (3-chloropropyl) -N-methyl-3,4-dimethoxy-phenylethyl-amine (prepared according to Example 1) is added and the mixture is heated at 100 ° C for 16 hours. The cooled mixture is then poured onto ice and extracted three times with ethyl acetate. The organic extracts are washed with water, dried with magnesium sulfate and evaporated in vacuo. The resulting oil is dissolved in acetone and 5 ml of a 6N dioxanic hydrogen chloride solution is added. The filtered precipitate is recrystallized from acetone. 7.5 g of N- (3,4-dimethoxyphenyl-ethyl) -N-methyl-3 [2- (3,4-methylenedioxyphenyl) -m-dithian-2-yl] propylamine - 1.13 3-tetraoxide hydrochloride, mp 247 - 248 ° C.

Analysis:

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

29 148323

The following compounds may be prepared by analogy to the procedure described above: N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2-p-tolyl-m-dithian-2-yl] propylamine-1,1,3 , 3-tetraoxide hydrochloride, mp 203-207 ° C (of acetonitrile / acetone), N- (3,4-dimethoxyphenylethyl) -N-methyl ~ 3 [2- (4- (benzyloxy) -3-methoxyphenyl) - m-dithian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, m.p. 220-221 ° C (of ethanol), N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2 - (21-Thienyl) -m-dithian-2-yl ·] - propylamine -1,1,3,3-tetraoxide hydrochloride, m.p. 179 -182 ° C (of acetone), N- (3.4 dimethoxyphenylethyl) -N-methyl-3 [2- (3,4-dichlorophenyl) -m-di-thian-2-yl] propylamine-1,3,3-tetraoxide hydrochloride, m.p. 175 DEG-177 DEG C. (of methanol ) and N- (3/4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,4-dimethoxyphenyl) -midithian-2-yl] ethylamine-1,1,3,3-tetraoxide oxalate (1 : 1), mp 202 - 204 ° C (of 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 is added. Hydrochloride is added to the mixture at room temperature.

After standing for 24 hours, the mixture is poured onto water, basified with a 3N sodium hydroxide solution and extracted with ether. After drying and evaporating the solvent, the oily residue is dissolved in acetone and the equivalent amount of anhydrous oxalic acid is added. The crystalline precipitate is recrystallized from acetone. N-methyl-N-veratryl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine oxalate (1: 1) is obtained, mp 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 3 ', 4'-dimethoxy-4- (methylveratrylamino) butyrophenone used as the starting material can be prepared as follows: 500 g of polyphosphoric acid and 69 g of veratrol are placed in a 1 liter round bottom flask. 61 g of 4-chlorobutyric acid is added in one portion, raising the temperature to 55 ° C. After stirring for 1 hour, the whole mixture is poured onto ice. Then, the mixture is extracted with a mixture of ether and methylene chloride (3: 1). The organic extracts are washed with water and then with a saturated sodium bicarbonate solution, then extracted with water, dried with magnesium sulfate and evaporated in vacuo.

The resulting crystal porridge is recrystallized from ether. 62.9 g of 3,4-dimethoxy-γ-chlorobutyrophenone are obtained, mp 91-92 ° C.

To 12 g of 3,4-dimethoxy-Y-chlorobutyrophenone are added 40 ml of N-ethyl-N, N-diisopropylamine and 9 g of N-methylhomoveratrylamine and stirred at 120 ° C for 6 hours. 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 made alkaline and extracted with ether. The ether extracts are combined, dried with sodium sulfate and evaporated. The resulting 3 ', 4'-dimethoxy-4- (methylveratrylamino) butyro-phenone, which, by thin layer chromatography, is almost pure, can be used without further purification.

The following compounds can be prepared analogously to the procedure described above: N- (3,4-dimethoxyphenylethyl) - N-methyl-3 [2- (3,4-dimethoxyphenyl) m -dithian-2-yl] butylamine oxalate (1 : 1) with melting point 134 - 136 "C (of acetone), from 1,3-propanedithiol and 5 - [(3,4-dimethoxyphenylethyl) methylamino] -3 ', 4'-dimethoxyvalerophenone (the hydrochloride has melting point 165 - 166 ° C) obtained from 3,4-dimethoxy- <5 -chlorovalerophenone and N-methylhomoveratrylamine, N- (3,4-dime thoxyphenylethyl) -N-methyl-3 [2- (3,4-dimethylamino) dimethoxyphenyl) -m-di-thian-2-yl] pentylamine oxalate (1: 1), m.p. 109-111 ° C (of acetone) from 1,3-propanedithiol and 6 - [(3,4-dimethoxyphenylethyl) -me -thylamino] -3 ', 4'-dimethoxyhexanophenone (m.p. 128 - 129eC) obtained from 6-chloro-3', 4'-dimethoxyhexanophenone and N-methylhomoveratrylamine, N- [3- (3,4-dimethoxyphenyl ) propyl] -N-methyl-3 [2- (3,4-dimethoxyphenyl) - m -dithian-2-yl] propylamine oxalate (1: 1) m.p. 116-118 ° C (of acetone) from 1,3-P ropanedithiol and 3 ', 4'-dimethoxy-4- (T3,4-di-methoxyphenyl) propyl] methylamino) butyrophenone obtained from 3,4-dimethoxy-γ-chlorobutyrophenone and 3- (3,4-dimethoxyphenyl) -N - methylpropylamine, N-methyl-N- (α-methylphenylethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine oxalate (1: 1), m.p. - 132 ° C (of acetone / ethyl acetate), from 1,3-propanedithiol and 4 - [(3,4-dimethoxy-α-methyl-phenylethyl) methylamino] -3 ', 4'-dimethoxybutyrophenone, obtained from 3,4-dimethoxy-γ-chlorobutyrophenone and N, α-dimethyl-p-phenylethylamine (boiling point = 130-140 ° / 20 mm Hg), and N- (3,4-dimethoxyphenyl ethyl) -N-methyl1-3 [2- (3,4-dimethoxyphenyl) -1,3-dithiolan-2-yl] propylamine oxalate (1: 1) m.p. 150 DEG-152 DEG C. (of acetone), starting from 4 - [(3,4-dimethoxyphenylethyl) methylamino] - 3 '-' - dime thoxybuty rophenone and 1,2-ethanedithiol.

Example 5

To 10.4 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide are 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, the residue is treated in an analogous manner as described in Example 3. N- (3,4-dimethoxy-phenylethyl) -N-methyl-3- [2- (3.4 -dimethoxyphenyl) -m-dithian-2-yl] propylamine-1,1,3,3-tetraoxide hydrochloride, mp 167-169 ° C.

The following compounds can be prepared analogously to the procedure described above: N- (3,4-dimethoxyphenylethyl) -N-methyl-3- [2-phenyl-m-dithian-2-yl] propylamine-1,1,3, 3-tetraoxide hydrochloride, m.p. 149 ° C (dec., Of methanol), N- (p-chlorophenylethyl) -N-methyl-3 [2-phenyl-m-dithian-2-yl] propylamine - 1.1, 3,3-tetraoxide hydrochloride, mp 246 - 249 ° C (decomposition, of methanol / methylene chloride), N-methyl-N-phenylethyl-3 [2-phenyl-m-dithian-2-yl] propylamine-1.1 , 3,3-tetraoxide hydrochloride, mp 165 - 167 ° C (of acetone), N-methyl-N-veratryl-3 (2- (3,4-dimethoxyphenyl) -m-dithian-2-yl) ] propylamine -1,1,3,3-tetraoxide, mp 137-139 ° C (of acetone / ethanol) and N- (3,4-dimethoxyphenylethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] - propylamine-1,1,3,3-tetraoxide hydrochloride, mp 130-132 ° C (of acetone).

The 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide used as the starting compound can be prepared as follows: 10.9 q 3.4 -Dimethoxy-Y-chlorobutyrophenone (prepared according to Example 4) is dissolved in 120 ml of chloroform and at room temperature 5 ml of 1,3-propanedithiol and 1 ml of boron trifluoride etherate are added. After stirring at room temperature for 1 hour, the chloroform solution is washed three times with water, three times with 1N sodium hydroxide solution and three times with water. The organic phases are dried over magnesium sulfate and evaporated in vacuo. The oily residue is immediately dissolved at 0 - 5 ° C in 500 ml of chloroform, and 45.7 g of solid m-chloroperbenzoic acid are added in such a way that the reaction temperature does not rise above 5 ° C. The mixture is then left in the refrigerator for 64 hours. The organic phase is washed three times with 1N sodium hydroxide solution and three times with water, dried over magnesium sulfate and evaporated in vacuo. The residue is recrystallized from methylene chloride / isopropyl ether. There is obtained 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetra-oxide, mp 183 - 184 ° C.

The 2- (3-chloropropyl) -2-phenyl-m-dithian-1,1,3,3-tetraoxide used as the starting material can be prepared as follows: 19.63 g of 2-phenyl-m-dithian are dissolved in 300 ml of tetrahydrofuran. At a temperature of -70 ° C, 43.5 ml of a solution of butyllithium in hexane is slowly added dropwise with argon. The mixture is stirred at -20 ° C for a total of 1.5 hours. The resulting red solution is added at -70 ° C to a solution of 15.74 g of 1,3-bromochloropropane in 250 ml of absolute tetrahydrofuran. The resulting solution is allowed to stand for 1 hour at -20 ° C and for 1 hour at room temperature. The solvent is evaporated in vacuo and the oily residue is taken up in ether. The etheric phase is washed with 1N sodium hydroxide solution and with water, dried over magnesium sulfate and evaporated in vacuo. The resulting 2- (3-chloropropyl) -2-phenyl-m-dithian is peroxidized at 0 - 5 ° C with m-chloroperbenzoic acid in chloroform in an analogous manner as described in the previous section. After recrystallization of ethyl acetate 2- (3-chloropropyl) -2-phenyl-m-dithian-1,1,3,3-tetraoxide is obtained, mp 182 ° C.

148323 33

Example 6

3.76 g of 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithian-1,1,3,3-tetraoxide is heated under reflux under argon for 18 hours with 50 ml of ethanol , 30 ml of chloroform and 1.95 g of N-methylhomoveratrylamine. 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. The precipitate is filtered off and recrystallized from methanol / acetone. The resultant rac-α - [(3,4-dimethoxyphenylethyl) methylamino] -2- [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] 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 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithian-1,1,3,3-tetraoxide used as starting material can be prepared as follows: 9.6 g of 2- ( Dissolve 3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide (prepared according to Preparation 2) in 35 ml of dimethylformamide and, with stirring under argon, add 1.2 g of sodium hydride at room temperature. The suspension is stirred for an additional 0.5 hour at 40 ° C and then cooled, adding 2.8 g of epichlorohydrin. The mixture is then heated for 16 hours at 100 ° C. After cooling to room temperature, the suspension is poured onto water and the oily product is extracted with chloroform. After evaporation of the solvent, the residue is chromatographed on silica gel with chloroform / ethanol (98: 2). The resulting 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithian-1,1,3 3-Tetraoxide is recrystallized from methylene chloride / ethanol and has a melting point of 175 - 176 ° C.

Example 7

3.65 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,3-dioxide, 7.8 g of N-methylhomoveratrylamine and 20 ml of dimethylsulfoxide are stored under reduced pressure. argon for 16 hours at 50 ° C. Then pour the solution into 200 ml of water and make it highly alkaline. Excess N-methylhomoveratrylamine is extracted with ether. The alkaline solution is then extracted with methylene chloride. The methylene chloride extracts are then dried over magnesium sulfate. After evaporation of the solvent, the residue is taken up in acetone and dioxanic hydrochloride is added until a pH of approx. 2. The crystalline residue is recrystallized from acetone / acetonitrile to give N- (3,4-dimethoxy-phenylethyl) -N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propyl -amine-1,3-dioxide hydrochloride, mp 148-149 ° C (diastereomer mixture).

The starting compound used for 2- (3-chloropropyl) -2- (3,4-dimethoxy-xyphenyl) -m-dithian-1,3-dioxide can be prepared as follows: 76.9 g of 2- (3.4- dimethoxyphenyl) -m-dithian (prepared according to Preparation 1) is dissolved in 900 ml of absolute tetrahydrofuran, the solution is cooled to -70 ° C and 128 ml of a butyl lithium solution is added in such a way that the temperature does not rise above -60 ° C. The mixture is then kept for 2 hours at -20 ° C to form a precipitate.

The mixture is then cooled to -70 ° C and 47.3 g of 1,3-bromochloropropane are added in 750 ml of absolute tetrahydrofuran. The mixture is then kept for 1 hour at -20 ° C and for 1 hour at room temperature. Then the tetrahydrofuran is evaporated and The residue is taken up in ether and extracted After evaporation of the solvent, 2- (3-chloropropyl) - 2- (3,4-dimethoxyphenyl) -m-dithian is obtained.

Dissolve 55.25 g of 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian in 500 ml glacial acetic acid. With stirring, a solution of 34 g of 30% hydrogen peroxide in 300 ml of glacial acetic acid is added dropwise at 5 ° C over 2 hours. The mixture is then allowed to stand for 60 hours at room temperature and then evaporated in vacuo at 40 ° C. The resulting oil is chromatographed on 1.5 kg of silica gel with chloroform / ethanol (first 98: 2, then 95: 5). There is obtained after recrystallization of acetonitrile 2- (3-chloropropyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,3-dioxide, mp 163 -164 ° C (diastereomer mixture).

Example 8.

In an analogous manner as described in Example 6, from 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithian and N-methylhomoveratrylamine rac. [(3,4-dimethoxyphenylethyl) methylamino] -methyl-2 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] ethanol. The corresponding hydrobromide is crystallized by acetonitrile / ethyl acetate and melts at 97 - 99 ° C.

The 2- (3,4-dimethoxyphenyl) -2- (2,3-epoxypropyl) -m-dithian used as starting material can be prepared from 2- (3,4-dimethoxyphenyl) by analogy as described in Example 7. m-dithian (prepared according to Preparation 1) using epichlorohydrin instead of 1,3-bromochloropropane.

Example 9

3.4 g of lithium aluminum hydride is heated to reflux in 60 ml of tetrahydrofuran. Then 14.7 g of N- (3,4-dimethyl-phenylethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propionamide is added dropwise in 80 ml of tetrahydrofuran. The resulting suspension is heated at reflux for 3 hours and then cooled to 0 ° C and gently added 50 ml of a saturated sodium sulfate solution. The mixture is filtered and the solution is diluted with water and extracted with ether.

The ethereal extracts are washed with 1N sodium hydroxide solution and then with water, dried over magnesium sulfate and evaporated. The oily residue is chromatographed on silica gel with chloroform / ethanol (95: 5). The resulting base is dissolved in acetone and the equivalent amount of anhydrous oxalic acid is added. The resulting precipitate is recrystallized from methanol / acetone. The resulting N- (3,4-dimethoxyphenylethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine oxalate (1: 1) 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.

The N- (3,4-dimethoxyphenylethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propionamide used as the starting material can be prepared as follows:

To 50 g of 3-veratroylpropionic acid in 400 ml of chloroform and 22.7 g of 1,3-propanedithiol are added with stirring hydrogen chloride until saturation. After 3 hours at room temperature, the solution is evaporated to 50 ml and diluted with ether. The solution is extracted three 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. The residue is recrystallized from ethanol to give 2- (3,4-dimethoxy-phenyl) -m-dithian-2-propionic acid, mp 134-135 ° C.

13.2 g of 2- (3,4-dimethoxyphenyl) -m-dithian-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran are cooled to 0 ° C and 5.44 g are added dropwise over 10 minutes. chloromyric acid oreobutyl ester in 80 ml of tetrahydrofuran. Then, the mixture is kept at room temperature for 3 hours and then 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran is added at 0 ° C. The suspension is allowed to stand for 48 hours at 3 ° C and then evaporated and water is added and extracted with ether / methylene chloride (3: 1). The ethereal extracts are washed with water, sodium hydrogen carbonate, 1N tartaric acid and water. The organic phase is dried over magnesium sulfate and evaporated. The residue is crystallized at 0 ° C by methylene chloride / ether. N- (3,4-dimethyloxyphenyl-ethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propionamide is obtained, mp 135-136 ° C.

By analogy as described above, N- (3,4-dimethoxyphenyl-ethyl) -3 [2- (3,4-dimethoxyphenyl) -N-methyl-m-dithian-2-yl] propylamine hydrobromide can be prepared . Melting point 170 - 172 ° C (of ethanol).

Example 10.

0.5 g of 2 - ['(3- [2 "- (3,4-dimethoxyphenyl) -midithian-2" -yl] -propyl) -methylamino] -31,4'-dimethoxyacetophenone-1 ", Dissolve 1 ", 3", 3 "tetraoxide in 15 ml of ethanol and 30 ml of tetrahydrofuran and add 50 mg of sodium borohydride. After 16 hours of stirring, 15 ml of 1N hydrochloric acid and then 12 ml 1N sodium hydroxide are added to the mixture. The tetrahydrofuran is evaporated and the residue is extracted with methylene chloride.

The organic extracts are washed with water, dried with magnesium sulfate and evaporated in vacuo. The resulting crystals are recrystallized from methanol to give 0.3 g of α - ([(3- [2 '- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propyl) methylamino] methyl) veratryl alcohol -l ', 1 ^ 3 ^ 3 ^ -tetra oxide. Melting point 132 - 133 ° C.

The starting material used was 2 - [(3- [2 "- (3,4-dimethoxyphenyl) - m -dithian-2" -yl] propyl) methylamino] -3 ', 4'-dimethoxyacetophenone - 1 " , 1 ", 3", 3 "tetraoxide can be prepared by reacting 2- (3-chloro-propyl) -2- (3,4-dimethoxyphenyl) -m-dithian-1,1,3,3-tetraoxide and o) methylamino-3,4-dimethoxyacetophenone. Melting point 140 ° C (decomposition, of acetone).

Example 11.

10 g of N- (3,4-dimethoxyphenylethyl) -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 treated at room temperature with 20 ml of 30% hydrogen peroxide. After 3 hours, the mixture is heated to 35 ° C for 3 hours and then to 40 ° C for 18 hours. 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 a mixture of chloroform / methanol / saturated ammonia (97: 3). The resulting product is dissolved in acetone and the equivalent amount of oxalic acid is added. The resulting precipitate is recrystallized from acetone / methanol. N- (3,4-dimethoxyphenylethyl) -N-methyl-5 [2- (3,4-dimethoxyphenyl) -N-methyl-m-di-thian-2-yl] pentylamine-1,1,3 3-tetraoxide oxalate (1: 1), m.p. 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 analogously to the procedure described above: N- (3,4-dimethoxyphenylethyl) -N-methyl-4- [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] butylamine -1,1,3,3-tetraoxide oxalate, m.p. 161 - 163 ° C (of acetone / methanol), (base: 123 - 126 ° C (of ethanol)) from N- (3,4-dimethoxyphenylethyl) -N -methyl 1- [2- (3,4-dimethoxyphenyl) -N - methyl-m-dithian-2-yl] butylamine (prepared according to Example 4), N- [3- (3,4-dimethoxyphenyl) propyl] -N-methyl-3- [2- (3,4-dimethoxyphenyl) - m -dithian-2-yl] propylamine-1,1,3,3-tetraoxide hydrobromide, m.p. 138-140 ° C (of acetonitrile / ethyl acetate). from N- [3- (3,4-dimethoxyphenyl) propyl] -N-methyl-3- [2- (3,4-dimethoxyphenyl-m-dithian-2-yl] propylamine (prepared according to Example 4), rac.-N- (3,4-dimethoxyphenylethyl) -N, 8-dimethyl-3 [2- (3,4-dimethoxyphenyl-m-dithian-2-yl] propylamine-1,1,3,3- tetraoxide hydrochloride, mp 183 - 185 ° C (of acetone / ethyl acetate), from rac-N - (3,4-dimethoxyphenylethyl) -N, 8-dimethyl-3 [2- (3,4-dimethoxyphenyl) - m -dithian-2-yl] propylamine (prepared according to Example 1j) and N-methyl-N- (α-methylphenylethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl ] propylamine-1,1,3,3-tetraoxide hydrochloride, mp 185 -187 ° C (of acetone / ethyl acetate), from N-methyl-N- (α-methyl-phenyl-ethyl) -3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine (prepared according to Example 4).

Example 12.

11.2 g of 2- [4- (benzyloxy) -3-methoxyphenyl] -N- (3,4-dimethoxyphenylethyl) - N-methyl-m-dithian-2-propylamine-1,3,3-tetraoxide (prepared according to Example 3) is heated for 2 minutes on a steam bath with 100 ml of 48% hydrochloric acid. The aqueous solution is then extracted with ether, evaporated in vacuo and distilled azeotropically three times with ethanol / benzene. The residue is crystallized by acetone. The resulting crystalline mass is recrystallized three times by methanol / acetonitrile to give 4- [2 '- (3 - [(3,4-dimethoxyphenylethyl) methylamino] propyl) - m -dithian 1 ', 3', 3'-tetraoxide hydrobromide, mp 192 ° C (dec.).

Analysis:

Calcd for C25H35NO8S2HHbr: C, 48.23;

Analogously obtained from N- (2,4-dimethoxyphenylethyl) -N-methyl-3 [2- [3- (benzyloxy) -4-methoxyphenyl] -m-dithian-2-yl] pro] ylamine -1,1,3,3-tetra-oxide 5- [2 '- (3 - [(3,4-dimethoxyphenylethyl) methylamino] propyl)' -m-dithian-2'-yl] -2-methoxyphenol -1,1 ', 31,3'-tetraoxide hydrobromide, mp 201 ° C (decomposition, of acetonitrile).

Example 13

2 g of 5- [2 '- (3 - [(3,4-dimethoxyphenylethyl) methylamino] propyl) -m-di-thian-2'-yl] -2-methoxyphenol-1', ,31,3 ', 3' -tetra oxide is 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 is chromatographed on silica gel. 5- [2 '- (3 - [(3,4-dimethoxyphenylethyl) methylamino] propyl) -m-dithian-2'-yl] -2-methoxyphenyl acetate-1', 1 ', 3', 3'- tetraoxide in the form of a thick oil.

Analysis:

Calculated: C 55.56 H 6.39 N 2.40 Found: C 55.22 H 6.41 N 2.23.

Example 14.

To 0.3 g of N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine - 1,1,3,3-tetraoxide is added 0.16 g of dimethoxy-β-phenylethyl chloride, 5 ml of N, N-diisopropyl-N-ethylamine and 1.5 ml of dimethylformamide and heated for 16 hours at 130 ° C. The solution is then partitioned between water and ethyl acetate. The residue is chromatographed on silica gel to give N- (3,4-dimethoxyphenylethyl) -N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine-1,3 3-tetraoxide, m.p. 144 ° C (of methanol).

The N-methyl-3 [2- (3,4-dimethoxyphenyl) - m -dithian-2-yl] propylamine-1,1,3,3-tetraoxide used as the starting material can be prepared as follows: 3.95 g 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. Heat for 18 hours at 40 ° C under pressure. The solution is then evaporated and the crystal crop is recrystallized from a small amount of methanol. The above product is obtained, m.p. 164βC.

Example 15

1 g of H- (3,4-dimethoxyphenylethyl) -312- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine (prepared according to Example 9) is dissolved in 20 ml of absolute pyridine and 200 ml is added. acetic anhydride. After 18 hours, the solvent was evaporated and the residue partitioned between ether and sodium carbonate (5%). After evaporation of the solvent, an oil (1.2 g) is dissolved in 20 ml of absolute tetrahydrofuran. This solution is slowly dripped to a suspension of 0.4 g of lithium aluminum hydride and 20 ml of absolute tetrahydrofuran. To the mixture is slowly added a concentrated aqueous sodium sulfate solution and the mixture is filtered. After evaporation of the solvent, the residue is partitioned between ether and water and the organic extracts are worked up. The oily residue is treated in acetone / ethyl acetate with oxalic acid to give N- (3,4-dimethoxyphenylethyl) -N-ethyl-3- [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine-1, 1,3,3-tetraoxide oxalate, mp 126 - 127 ° C crystallizes.

Example 16.

Dissolve 1 g of homoveratrum acid in 15 ml of absolute tetrahydrofuran and add 0.15 g of triethylamine. At a temperature of 0-5 ° C, 0.72 g of chloromyric acid isobutyl ester is slowly added dropwise and the mixture is stirred for 1 hour at 5-10 ° C. Then a solution of 1.63 g of N-methyl-3 [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine (prepared from 2- (γ-chloropropyl) -2- (3)) is added dropwise. 4-Dimethoxyphenyl) -m-dithian and methylamine in analogous manner as described in Example 14) in 5 ml of tetrahydrofuran. The mixture is allowed to stand overnight at room temperature. After evaporation of the solvent, the residue is partitioned between 1N hydrochloric acid and ether. The organic extracts are washed with 5% sodium carbonate solution and water. After drying with magnesium sulfate, the solvent is evaporated. The oily residue (1.5 g) is dissolved in 15 ml of tetrahydrocarbon.

Claims (5)

1A 8 3 2 3 hydrofuran and drip under reflux under argon to a suspension of 0.15 g of lithium aluminum hydride. The mixture is boiled for 2 hours and then a concentrated sodium sulfate solution is added slowly in water and then 10 ml of methylene chloride. The mixture is filtered and the solution is evaporated. The residue is chromatographed on silica gel to give N- (3,4-dimethoxyphenylethyl) -N-methyl-3- [2- (3,4-dimethoxyphenyl) -m-dithian-2-yl] propylamine in the form of a thick oil ( cf. example 1). An analogous process for the preparation of 1,3-dithiolanyl (2) or 1,3-dithianyl (2) compounds of general formula I / - <CH2> n \ in R5 R - I - wherein R represents a group of the general formula a or b R 1 R 3 4 or Qb ab 12 3 wherein R, R and R each represent hydrogen, halogen, lower alkyl, lower alkoxy, benzyloxy, phenyl, nitro, trifluoromethyl, hydroxy, cyano, di-lower alkylamino lower alkanoyloxy, or two adjacent groups together represent methylenedioxy, ethylene-4-dioxy or butadiene-1,3-ylene-1,4, R represents hydrogen or lower alkyl, R, R and R each represent hydrogen, halogen, lower alkyl or lower alkoxy, or two adjacent groups together represent ethylenedioxy, X represents sulfur, SO or SO 2 aliphatic hydrocarbon chain having 1-4 carbon atoms, m represents 0 or 1 and n represents 2 or 3 wherein the "lower" groups contain 1-6 carbon atoms, or acid addition salts thereof, characterized in that a) a compound of the general formula II / (CH 2> n XXRC Η II wherein R, X and n each have the meaning given above are reacted with a compound of general formula III R5 4 r r8 - Y - "- (Z)" VSi where R4 - R7, Y, Z and m are each has the meaning given above, O and R represent a leaving group, or b) a compound of the general formula IV S f = V H = "-c -1 -" (z) "R 7 4 7 where R, R - R, Y, Z and m each have the meaning given above, are reacted with a compound of the general formula V HS - (CH₂) - SH V λ n where n has the meaning given above, or c) a compound of the general formula VI 148323 / (CH2) f 2'N 'XXR - CY - R8 VI Q wherein R, R, X, Y and n each have the meaning given above are reacted with a compound of the general formula VII' - '- <* > »R 4 7 where R - R, Z and m each have the meaning given above, or d) a compound of the general formula X / 2 \ R 4 R - C - YNH X 4 wherein R, R, X, Y and n each have the meaning given above. , is reacted with a compound of general formula XI 5 8 wherein R - R, Z and m are each as defined above, or e) in a compound of general formula XII or XIII 4CH, '(ch2) \ r'4 / 2 n \ j R5 xxc = o I. β R - C - Y - N - (Z) m ^ XIII R7 4 7 148323 where R, R - R in X; Y; Z, m and n each have the meaning given above, Y 1 and Z 1 each represent Y and Z respectively or a corresponding oxo-substituted group, however, at least one of the groups Y 1 and Z contains one carbonyl group and R 1 represents a hydrogen atom or a C1-5 alkyl group, the carbonyl group is reduced, whereupon a compound of general formula I wherein X represents a sulfur atom is optionally oxidized to a compound of general formula I where X represents SO or SO-, a prepared 4 z compound having the general formula X, wherein R represents hydrogen, if desired, N-lower is alkylated to a compound of general formula 4 1. wherein R represents C1-6 alkyl, a lower alkoxy or benzyloxy group for R, R or R if desired is converted to a hydroxy group, 12 is a hydroxy group for R, R or R if desired is O-lower alkylated or esterified with a lower alkane carboxylic acid, and a recovered base if desired is converted to an acid addition salt, wherein they are designated as "lower" group are containing 1-6 carbon atoms. Process according to claim 1, characterized in that N- (3,4-dimethoxy-phenylethyl) -N-methyl-3 [2- (p-methoxyphenyl) -m-dithian-2-yl] propylamine or an acid addition salt thereof. Process according to claim 1, characterized in that N- (3,4-dimethoxy-phenylethyl) -N-methyl-3 [2-phenyl-m-dithian-2-yl] propylamine or an acid addition salt thereof is prepared. Process according to claim 1, characterized in that N- (p-chlorophenyl-ethyl) -N-methyl-3 [2-phenyl-m-dithian-2-yl] propylamine or an acid addition salt thereof is prepared. Process according to claim 1, characterized in that N- (3,4-dimethoxy-phenylethyl) -N-methyl-3 [2- (2-naphthyl) -m-dithian-2-yl] propylamine or a acid addition salt thereof.