CS255617B1 - 4-Aryl-3- (aminomethyl) thiacyclohexane-4-ol and the sulfoxides, sulfones and N-oxides derived therefrom - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is 4-aryl-3-(aminomethyl)thiacyclohexan-4-ols and. derived therefrom sulfoxides, sulfones and N-oxides of the general formula I, in which R denotes a hydrogen atom or methyl, R1 denotes a hydrogen atom, a halogen atom, methoxyl, hydroxyl or trifluoromethyl 2 in any of the positions 2, 3 and 4, R denotes a hydrogen atom or trifluoromethyl, m denotes one of the numbers 0, 1 or 2 and n is either 0 or 1, as well as the corresponding salts, i.e. firstly addition salts with pharmaceutically acceptable inorganic or organic acids and secondly bis-onium salts. The substances are characterized by analgesic and antitussive activity and are useful for suppressing pain sensations in various disease states. The basic method of their preparation is the reaction of the corresponding arylmagnesium bromides with 3-(dimethylaminomethyl)thiacyclohexan-4-one. In the case of methoxyphenyl derivatives, O-demethylation can be carried out using boron tribromide, and partial N- -demethylation is achieved by the action of ethyl chloroformate and alkaline hydrolysis. Sulfoxides, sulfones and N-oxides are prepared by oxidation with hydrogen peroxide in acetic acid. The most suitable salts are the hydrochlorides

Description

The invention relates to 4-aryl-3- (aminomethyl) thiacyclohexan-4-ol and the sulfoxides, sulfones and N-oxides derived therefrom,

wherein R is hydrogen or methyl, R ¹ is hydrogen, halogen, methoxy, hydroxyl or trifluoromethyl in any of positions 2, 3 and 4, R is hydrogen or trifluoromethyl, m is any of 0, 1 or 2 and either 0 or 1 as well as the corresponding salts, i.e., the editorial salts with pharmaceutically acceptable inorganic or organic acids, and the bis-onium salts derived from the addition of two alkyl halide molecules.

The compounds of the invention and their salts possess several types of practicable pharmacodynamic activity. First of all, it is an analgesic efficacy suitable for suppressing pain sensations in various disease states. Furthermore, it is antitussive, useful in practice to suppress cough attacks. Furthermore, the compounds of the present invention have mild hypotensive activity, have remarkable positive inotropic activity, in part exhibit antireserpine activity (suggesting a potential for use in the treatment of mental depression), mild spasmolytic activity (papaverine and antiacetylcholine type), and mild locally anesthetic activity.

The compounds of the invention are novel. Their closest references in the literature (Flick K., Frankus E. et al., Arzneim.-Forsch. 28, 107, 114, 122, 1978; Germany Pat. 1 199 764; US. Pat. 3,652,589) are the analogues described herein. -aryl-2- (dimethylaminomethyl) cyclohexanols which differ from the compounds of this invention by the presence of a methylene group instead of a sulfur atom. The compounds are also analgesically active, but the compounds of the present invention in some cases outperform them.

The following are pharmacological data for several typical compounds of the invention, which were obtained by pharmacological experiments on animals or on isolated organs.

The compounds were administered intravenously (i.v.), subcutaneously (s.c.), intrapeijtoneally (i.p.), and mainly orally (p.o.), as indicated at the appropriate sites.

The most active compound of the present invention is trans-4- (3-hydroxyphenyl) -4,3- (dimethylaminomethyl) thiacyclohexan-4-ol, which has been tested in the form of the hydrochloride. In a peritoneal mouse test in which pain is induced by intraperitoneal injection of a dilute acetic acid solution, the compound showed analgesic efficacy as expressed by the median effective dose ED jq = 6.2 mg / kg. For comparison, the activity of the most active substance of the cited series, ie trans-1- (3-methoxyphenyl) -2-dimethylaminomethyl) cyclohexanol hydrochloride (tramadol, ED? q = 7.6 mg / kg after D-Amour test) is reported. and Smith in mice (thermal stimulation of the mouse tail), the dose was administered subcutaneously and its activity is expressed as the mean effective dose of EDj-q = 1.6 mg / kg, for comparison tramadol activity is significantly lower, / kg In the test hot fence nky mice is expressed analgesic efficacy of oral dose which extends the nociceptive reaction latency by 25%; D ₂ = 25 mg / kg po (the efficacy of tramadol in this test is practically the same). The substance differs from tramadol in the way it affects the locomotor and total activity of mice and rats.

In the Dews Beam Test, an oral dose of 50 mg / kg significantly stimulates locomotor activity in mice; in contrast, tramadol at oral doses of up to 100 mg / kg significantly inhibits this activity. In a test that monitors the total activity of rats on a Varimex instrument, the substance at a subcutaneous dose of 5 mg / kg significantly stimulates the overall activity; higher doses act to inhibit activity; tramadol already in s.c. dose of 10 mg / kg significantly reduced the overall activity of male rats.

trans-4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol was also tested as the hydrochloride. Its acute iv toxicity in mice, LD ₅₀ - 49.5 mg / kg. Analgesic activity in the peritoneal test in mice, ED _5Q = 14.9 mg / kg for the compound showed antitussive effect in guinea pig using the method, wherein the inhalation aerosol provokes coughing citric acid, ED - 40 mg / kg (decreased frequency of cough 59%). At a concentration of 50 µg / ml, the compound exhibits a positive inotropic effect in an isolated rabbit atrium test. It also shows antireserpine effects in the mouse hypothermia test (ED = 8 mg / kg ip). At an intravenous dose of 8 mg / kg, it induces short-term and fairly profound decreases in blood pressure in normotensive rats.

4-phenyl-3- (dimethylaminomethyl) thiacyklohexan-4-ol hydrochloride: Acute toxicity in mice, LD _5Q = 37.8 mg / kg iv in the peritoneal analgesic activity test in mice

EDj-θ = 30.0 mg / kg p.o. At a concentration of 50 µg / ml it has a positive inotropic effect in said assay.

At a dose of 7 mg / kg i.v. induces decreases in blood pressure in normotensive rats.

4- (2-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride (hemihydrate): Acute toxicity in mice, LD ^ g = 29.8 mg / kg. Analgesic efficacy in the peritoneal test in mice, ^ED 5q - 18.5 mg / kg.

4- (2-chlorophenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride: Acute toxicity in mice, LD, - ₀ = 44,0 mg / kg iv Antitussive effect in guinea pig, ED = 40 mg / kg po (reduction of coughing attacks to 49%). Antireserpine effect in hypothermia test in mice,

ED = 8 mg / kg i.p .: at the same dose, an indication of antireserpine activity in the eyelid ptosis test in mice. Dose 8 mg / kg i.v. induces decreases in blood pressure in normotensive rats.

4- (3-chlorophenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride: Acute toxicity in mice, LD ^ g = 47.9 mg / kg i.v. Analgesic efficacy in peritoneal test in mice ΕΏ ^ θ = 17.0 mg / kg p.o.

4- (4-Chlorophenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride: Acute toxicity in mice, LD ^ g ~ 53.7 mg / kg i.v. Analgesic efficacy in peritoneal test in mice, ED, -q = 50 mg / kg p.o.

4- (3-Trifluoromethylphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride (hemihydrate): Acute toxicity in mice, Εϋ ^ θ = 64.7 mg / kg i.v. In the peritoneal test in mice, oral doses of 25 and 50 mg / kg cause a slight increase in the latency of the nociceptive reaction (i.e., a slight analgesic effect). Antitussive effect in guinea pigs, ED = 40 mg / kg p.o. (to 40%).

It has an antireserpine effect in both the hypothermia test in mice (ED = 4 mg / kg i.p.) and in the ptosis test in mice (ED = 8 mg / kg i.p.). At a concentration of 25 to 50 µg / ml, it exhibits a positive inotropic effect (increasing inotropy by 25%). At a dose of 8 mg / kg i.v. causes short-term decreases in blood pressure in rats.

4- (4-Trifluoromethylphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride:

Acute toxicity in mice, LD ^ g = 60.7 mg / kg i.v. At a concentration of 1% it acts locally anesthetically in guinea pigs in an infiltration anesthesia test. At concentrations of 1 to 10 µg / ml, it exhibits spasmolytic effect on isolated rat duodenum against acetylcholine and barium chloride contractions (damping contractions by 50% compared to control.) In i.p. dose of 10 mg / kg has a mild antireserpine effect in the hypothermia test in mice.

4- (3,5-bis (trifluoromethyl) phenyl-3- (dimethylaminomethyl) thiacyclohexan-4-ol hydrochloride: Acute toxicity in mice, LD ^ g = 127 mg / kg iv It shows antitussive at an oral dose of 75 mg / kg effect in guinea pigs (reduces the frequency of coughing attacks to 55% compared to control).

At a concentration of 10 µg / ml, it has a spasmolytic effect on isolated rat duodenum against barium chloride contractions (reducing contractions by 50%, papaverine type effect). At a dose of 15 mg / kg i.v. lowers blood pressure in normotensive rats in the short term.

4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyklohexan-4-ol (dimethojodid) Acute toxicity in mice, LD _5Q = 75 mg / kg IV IV doses of 15 mg / kg showed a. <· - i & - sympathomimetic effect, presoric response to adrenaline in rats prolonged 2 to 4 times.

4- (3-Methoxyphenyl) -3- (methylarainomethyl) thiacyclohexan-4-ol hydrochloride: Acute toxicity in mice, LD _S p = 58.1 mg / kg iv In the peritoneal test in rats, it induces blockage of nociceptive reactions (ie analgesic effect) at an oral dose of 30 mg / kg in 50% of the animals.

4- (3-Methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol-S-oxide hydrochloride:

Acute toxicity in mice, LD ^ q = 191 mg / kg i.v. At an oral dose of 200 mg / kg, it has an antitussive effect in guinea pigs (reducing the frequency of coughing attacks to 59%). Furthermore, it shows an antireserpine effect in mice against hypothermia, ED = 40 mg / kg i.p. At a concentration of 50 µg / ml it has a positive inotropic effect in the described assay. Finally, it suggests a sympathomimetic effect because in i.v. dose of 40 mg / kg prolongs the presoric response to adrenaline in rats 3 to 4 times.

4- (1-onethoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol-N, S, S-trioxide was tested as a water-soluble base. Acute toxicity in mice is minimal, Ι, Ό ^ θ = 1000 mg / kg i, v. It shows an antireserpine effect in mice against both ptose and hypothermia (both at an i.p. dose of 200 mg / kg). At the same dose given i.v. prolonged the duration of the presoral response to adrenaline in anesthetized rats 2 to 4 times (sympathomimetic effect).

Most of the compounds of the invention are prepared from 3- (dimethylaminomethyl) thiacyclohexan-4-one of formula II

WITH

O ch ₂ n (ch ₃ ) ₂ (II), by reaction with the corresponding aryl magnesium bromides. The starting material of formula II is new and is obtained from thiacyclohexan-4-one (Cardwell HME, J. Chem. Soc. 1949, 715, Fehnel EA and Carmack®,

J.Am.Chem.Soc. 70, 1813, 1948; Bennett G.M. Scorah L.V.D., J. Chem. 192 7 194

Adlerová E., Protiva Coll., Collect. Czech. Chem. Commun. 24, 1268 (1959)) by reaction with dimethylamine hydrochloride and paraformaldehyde in boiling water as described in Example 1. The necessary aryl magnesium bromide solutions (Grignard reagents) are prepared by reacting magnesium with the aryl bromides in ether, tetrahydrofuran, or a mixture of both. The aryl bromides used are mostly commercially available. 1-Bromo-3,5-bis (trifluoromethyl) benzene, which is thus inaccessible, can be made according to literature (Larionova Ju.A. et al., J. Prikl.

Chim. 46, 2022 (1973).

The Grignard reactions themselves are carried out in the solvents or mixtures thereof. The bases of formula I are obtained, wherein R = methyl, R denotes all said substituents except for the free hydroxyl and where m = n = 0. These bases are generally oily and represent mixtures of the predominant trans-isomers (i.e. 3-H, 4-OH (trans) and minor cis isomers, the ratio of these isomers in the mixtures is approximately 5: 1. For the isolated pure isomers, the configuration was attributed based on the iC spectra. Either the chromatography of the crude bases on silica gel or the crystallization of the hydrochlorides prepared from the crude bases as described in the Examples can be used to isolate the predominant and desired trans-isomers (these are analgesic substantially more potent than the cis-isomers).

Compounds of formula I wherein R ¹ is a hydroxyl group are prepared from the appropriate methoxy compounds by demethylation with boron tribromide in dichloromethane at room temperature as described in the example. Substances oxidized to the sulfur atom (I, m = 1 or 2), i.e. sulfoxides and sulfones, as well as substances oxidized to the nitrogen atom (N-oxides) are obtained by oxidation of the corresponding aminosulfides by oxidation with hydrogen peroxide in acetic acid. Using a small excess of hydrogen peroxide, sulfoxides (I, m - 1, n = 0) are obtained. Using a large excess of hydrogen peroxide in acetic acid and prolonged standing of the reaction mixture results in oxidation not only at the sulfur atom but also at the nitrogen atom, resulting in sulfone-N-oxides (I, m = 2, n = 1). The preparation of these compounds is also described in the Examples. Finally, the compounds of formula I wherein R = H, i.e. the monomethylaminomethyl compound, are obtained from the corresponding dimethylaminomethyl derivatives by a two-stage treatment with ethyl chloroformate and a final alkaline hydrolysis. In the first step, only the hydroxyl group is esterified and the hydrochlorides of the corresponding 4- (ethoxycarbonyloxy) compounds are formed. Further treatment of the liberated bases with ethyl chloroformate results in partial N-demethylation, yielding the corresponding carbonate-carbamates, which in the final step are subjected to alkaline hydrolysis to give the desired 3- (methylaminomethyl) compounds of formula I (R = H). This sequence of reactions is also described in the example.

The examples are only to be construed as illustrative of the synthetic possibilities of the invention, but are not intended to fully describe the possibilities for synthesizing the compounds of the invention. The substances described in the invention are novel and their identity has been assured both by analysis and by all conventional spectral methods.

Example 1

4- (3-Methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

To a mixture of 32 g of magnesium and 200 ml of ether is added 40 g of 3-bromoanisole and the reaction is started by the addition of an iodine grain. The remaining 180 g of 3-bromoanisole in 550 ml of ether is then slowly added dropwise while stirring under reflux. The addition of 100 ml of tetrahydrofuran was refluxed for 1 hour to give a solution of the Grignard reagent, i.e. 3-methoxyphenylmagnesium bromide. After cooling to 0 ° C, a solution of 102 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 300 ml of tetrahydrofuran is added dropwise with stirring, then the mixture is stirred for 1.5 h without cooling and quenched by the slow addition of a solution of 500 g. of (+) - tartaric acid in 4 L of water. After shaking, the organic phase is removed and the aqueous is washed with ether. It was then basified with sodium hydroxide solution and the liberated base was extracted with ether. The extract was washed with water, dried and evaporated. 152 g (92%) of a mixture of geometric isomers (trans: cis approximately 5: 1) are obtained. Pure trans-isomer hydrochloride can be obtained directly from this mixture by neutralization with hydrogen chloride and repeated crystallization of the crude hydrochloride.

To obtain both isomers, 12 g of said crude base is chromatographed on a 230 g silica gel column. Elution with chloroform followed by chloroform containing 1% methanol gave 10.0 g of a homogeneous oily trans-base. This was dissolved in ethanol and neutralized with a solution of hydrogen chloride in ether. Directly pure trans-isomer hydrochloride is obtained, m.p. 203-204 ° C (ethanol-ether).

Chromatography is continued by eluting with chloroform containing 3% methanol. 2.0 g of homogeneous cis-base are obtained, which crystallizes from a mixture of acetone and heptane and melts at 87-89 ° C.

Starting 3- (dimethylaminomethyl) thiacyclohexan-4-one, which has not been described in the literature, is prepared as follows:

A mixture of 159 g of thiacyclohexan-4-one (literature cited), 26 g of paraformaldehyde, 61 g of dimethylamine (hydrochloride), 80 ml of water and 3 ml of hydrochloric acid is stirred and refluxed for 10 minutes. After cooling, it is diluted with 400 ml of water and the resulting liquid is extracted with ether. Evaporation of the ethereal extract regenerates 59 g of the starting ketone. Evaporation of the aqueous solution to dryness in vacuo afforded 168 g (93% conversion) of the crude hydrochloride of the title compound, m.p. 147 DEG-149 DEG C., which is quenched with sodium hydroxide solution and the liberated base is isolated by extraction with ether. Treatment of the extract yielded 83.9 g (56%) of an oily base which was used for the Grignard reaction. Crystallization of a sample of the crude hydrochloride from an ethanol / ether mixture gave a pure substance melting at 156-158 ° C.

Example 2

4-Phenyl-3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent was prepared as in Example 1 by reacting 3.1 g of magnesium with 18 g of bromobenzene in 65 ml of ether and refluxing for 3 hours. After cooling to 5 ° C, a solution of 10.0 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one (see Example 1) in 30 ml of ether was added dropwise with stirring. Stirring is continued for 2 h at room temperature and after standing overnight is quenched with a solution of 50 g of (+) - tartaric acid in 400 ml of water. The aqueous phase was worked up as in the previous example to give 11.1 g of crude base which was chromatographed on a column of 200 g of silica gel. Elution with chloroform and then chloroform with 5% methanol gave 7.9 g of a homogeneous oily base which was dissolved in 20 ml of ethanol and neutralized with a solution of 1.15 g of hydrogen chloride in 20 ml of ether. After addition of additional ether, the hydrochloride of the title compound crystallizes, which is filtered off with suction, washed with ether and dried in vacuo, 7.3 g of m.p. Mp 240-244 ° C. Recrystallization from ethanol / ether gave pure trans.base hydrochloride, m.p. Mp 243-246 ° C.

Example 3

4- (2-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

As in the previous examples, the Grignard reagent was prepared by reacting 3.1 g of magnesium with 21.5 g of 3-bromoanisole in a mixture of 20 ml of ether and 50 ml of tetrahydrofuran. Treatment with 10.9 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran gave 15.0 g (93%) of a crude oil base. This was neutralized with hydrogen chloride in ethanol-ether to give 12.0 g of crude crystalline hydrochloride melting at 196-200 ° C. Recrystallization from ethanol / ether gave homogeneous trans-base hydrochloride, m.p. Mp 200-203 ° C. According to the analysis, it is a hemihydrate.

Example 4

4- (4-Methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent was prepared by reacting 3.1 g of magnesium with 21.5 g of 4-bromoanisole in 100 ml of ether and treated with 10.0 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of ether. Workup yielded 12.9 g of crude oily base which was chromatographed on 250 g of silica gel. Elution with chloroform gave 7.4 g of a homogeneous oily base which, by neutralization with hydrogen chloride in a mixture of ethanol and ether, gave 6.1 g of the hydrochloride, melting at 211-213.5 ° C. Recrystallization from ethanol-ether gave trans-base hydrochloride (5.2 g), m.p. 204-207 ° C.

Example 5

4- (2-chlorophenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent is prepared by reacting 3.1 g of magnesium with 22.1 g of 2-bromochlorobenzene in 70 ml of ether and treated with 10.0 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran. Workup yielded 10.4 g (63%) of a crude oily base which was chromatographed on 200 g of silica gel. Chloroform was eluted with 5.6 g of homogeneous trans-base, which provided the hydrochloride in a pure state at 256-258 ° C (ethanol-ether).

Example 6

4- (3-chlorophenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent is prepared by reacting 3.1 g of magnesium with 22.1 g of 3-bromochlorobenzene in a mixture of 20 ml of ether and 50 ml of tetrahydrofuran. It was treated with a solution of 10.0 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran and treated with the mixtures to give 12.5 g (76%) of a crude oily base. This was chromatographed on 250 g of silica gel and eluted with chloroform to give 7.1 g of homogeneous trans-base. This was converted to crystalline hydrochloride, which crystallized from ethanol and melted at 251-254 ° C in pure form.

Example 7

4- (4-chlorophenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent is prepared by reacting 3.1 g of magnesium with 22.1 g of 4-bromo-chlorobenzene in a mixture of 20 ml of ether and 50 ml of tetrahydrofuran. At 5 ° C, the solution is treated with 10.0 g

3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran and work-up gave 12.4 g (75%) of a crude oil base. This was chromatographed on a column of 250 g of silica gel and eluted with chloroform to give 7.1 g (43%) of crystalline trans-base, m.p. 98-100 ° C (acetone-heptane). It yields crystalline hydrochloride which melts in pure state at 209-211 ° C (ethanol-ether).

Example 8

4- (3-Trifluoromethylphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent is prepared by reacting 3.1 g of magnesium with 26 g of 3-bromobenzotrifluoride in 90 ml of ether. It was treated with a solution of 10 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran and treated to give 15.2 g (83%) of a crude oily base.

This was chromatographed on 270 g of silica gel and less polar trans-base (11.2 g, 61%) was obtained by eluting with chloroform. It provides the hydrochloride which crystallizes as a hemihydrate from a mixture of 95% ethanol and ether and melts at 209-211.5 ° C.

Example 9

4- (4-Trifluoromethylphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent is prepared by reacting 3.1 g of magnesium with g of 4-bromobenzotrifluoride in 90 ml of ether. It is treated with a solution of 10 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran. Workup yielded 12.8 g (70%) of a crude oily base which was chromatographed on 250 g of silica gel. Elution with chloroform gave 80.0 g (43%) of crystalline trans-base, m.p. 87-88 ° C (acetone-heptane). It gives a crystalline hydrochloride which melts at 256-259 ° C (ethanol).

Example 10

4- (3,5-bis (trifluoromethyl) phenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

The Grignard reagent is prepared by reacting 3.0 g of magnesium with 20.2 g of 1-bromo-3,5-bis (trifluoromethyl) benzene in 70 ml of ether. The reagent was treated with a solution of 8.0 g of 3- (dimethylaminomethyl) thiacyclohexan-4-one in 30 ml of tetrahydrofuran and worked up to give 9.2 g (51%) of a crude oily base which was chromatographed on a 190 g silica gel column. Elution with chloroform gave 5.9 g (33%) of a homogeneous oily trans-base which was converted to crystalline hydrochloride, m.p. Mp 239-241.5 ° C (ethanol-ether).

Example 11

4- (3-hydroxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol

A solution of 8.5 g of trans-4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol in 75 ml of dichloromethane is added dropwise to a stirred solution of 40 g of boron tribromide in 90 ml of dichloromethane at a maximum temperature of 10 ° C. The mixture was stirred at room temperature for 3 h, allowed to stand overnight, quenched by dropwise addition of 150 ml of water and then excess sodium carbonate solution. The organic phase was separated, dried and evaporated. The residue (7.2 g of crude base) was dissolved in ethanol and the solution was neutralized with a solution of 1.0 g of hydrogen chloride in 17 ml of ether. The hydrochloride formed is filtered, washed with ether and dried in vacuo, 5.2 g (57%), m.p. Mp 262-264 ° C. An analytically pure sample was obtained by recrystallization from a mixture of methanol and ether, m.p. Mp 267-270 ° C.

Example 1 and d 12;

4- (3-Methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol (dimethyliodide)

To a solution of 7.0 g of trans -4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol in a mixture of 25 ml of methanol and 30 ml of nitromethane is added 20 ml of methyl iodide and the mixture is left to stand for 6 days. . The solvents are evaporated and the solid residue is crystallized from methanol,

4.8 g (34%), m.p. 225 DEG-227 DEG C. with decomposition.

Example 13

4- (3-Methoxyphenyl) -3- (methylaminomethyl) thiacyclohexan-4-ol

To a stirred solution of 10.0 g of trans -4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol in 50 ml of benzene was added dropwise a solution of 5.8 g of ethyl chloroformate in 25 ml of benzene. The resulting solid suspension (identified as 4- (ethoxycarbonyloxy) -4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexane hydrochloride, mp 184-186 ° C (ethanol-ether) was washed several times with sodium carbonate solution and the liberated base. The extract was washed with water, dried and evaporated to give 12.5 g (theoretical amount) of crude oily 4- (ethoxycarbonyloxy) -4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexane. Dissolve in 60 ml of benzene and add dropwise with stirring a solution of 11.6 g of ethyl chloroformate in 25 ml of benzene, reflux for 3 h, wash with dilute hydrochloric acid and sodium bicarbonate solution, dry and evaporate. In almost theoretical amount (14.5 g), crude oily 4- (ethoxycarbonyloxy) -4- (3-methoxyphenyl) -3- (N-ethoxycarbonyl-N-methylaminomethyl) thiacyclohexane is obtained, which is further used in a be Dissolve in 50 ml of ethanol, add 17.0 g of potassium hydroxide in portions to the stirred solution, and reflux for 8 h. After cooling, it is strongly diluted with water and the product is extracted with ether. From the ether extract, the basic product is transferred to the aqueous phase by extraction with dilute hydrochloric acid, the separated acidic aqueous solution is basified with sodium hydroxide solution and the desired base is isolated with ether, 5.5 g (59%) of an oil. It yields crystalline hydrochloride melting at 184 ° C (ethanol-ether).

Example 14.

4- (3-Methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol-S-oxide

To a solution of 7.0 g of trans-4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol in 30 ml of acetic acid, 2.85 g of 30% hydrogen peroxide are added dropwise with stirring at 5 ° C, and Allow to stand at room temperature for 12 h. After dilution with water, the mixture is basified with aqueous ammonia and extracted with chloroform. The extract is dried and evaporated, the residue is dissolved in 20 ml of ethanol and a solution of 1.0 g of hydrogen chloride in 17 ml of ether is added with stirring. On standing, 6.6 g (80%) of the hydrochloride of the desired product crystallized, melting at 214 DEG-216 DEG C. (ethanol-ether).

Example 15

4- (3-Methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol-N, S, S-trioxide

To a solution of 7.0 g of trans -4- (3-methoxyphenyl) -3- (dimethylaminomethyl) thiacyclohexan-4-ol in 30 ml of acetic acid was added 15 ml of 30% hydrogen peroxide and the mixture was allowed to stand at room temperature for 6 days. Then some of the acetic acid was evaporated in vacuo, the residue basified with dilute aqueous ammonia and the mixture was allowed to crystallize for 12 h. The precipitated product is filtered off with suction, washed with a little water and recrystallized from a mixture of methanol and 2-propanol, 4.6 g (56%), m.p. M.p. 172-174 ° C. The infrared spectrum shows the presence of a sulfone group and polarographic reduction the presence of an N-oxide fragment.

object of the invention

Claims (1)

object of the invention 4-aryl-3- (aminomethyl) thiacyclohexan-4-ol and the sulfoxides, sulfones and N-oxides derived therefrom wherein R is hydrogen or methyl is hydrogen, halogen, methoxy, hydroxyl or trifluoromethyl . in any of positions 2, 3 and 4, R represents a hydrogen atom or trifluoromethyl, m represents any of the numbers 0, 1 or 2 and either 0 or 1 as well as the corresponding salts, i.e. addition salts with pharmaceutically acceptable inorganic or organic acids and bis-onium salts derived from the addition of two alkyl halide molecules.