CS219003B1 - 6-/4-piperidyl/-6h-dibenz/b,e/-1,4-oxythiepins,the salts thereof and method of preparation - Google Patents

Description

The present invention relates to novel 6- (4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepenes of general formula (I).

in which

R @ ¹ denotes hydrogen, methyl, hydroxyalkyl of 2 to 5 carbon atoms or acyloxyalkyl of a total of at most 15 carbon atoms,

R ² is hydrogen or methyl,

R ³ is hydrogen, chloro, methoxy, trifluoromethyl, or trifluoromethylthio,

R ⁴ is a hydrogen atom or a fluorine atom, furthermore their S-oxides, N-oxides and salts with pharmaceutically acceptable inorganic or organic acids, and finally also processes for their preparation.

The compounds of the invention exhibit therapeutically useful neuroleptic and tranquilizing activity at acceptable to moderate toxicity. Some are neuroleptics with a high degree of centrally depressing, cataleptic and antiapomorphine activity. For compounds of formula I wherein R ⁴ is a fluorine atom, the neuroleptic effect is escalated and shows signs of prolongation when administered orally. For compounds of formula I in which R ³ -R ⁴ -H retains mild to marked central buffering activity and the corresponding substances may be referred to as tranquilizers.

For the esters of the neuroleptically active amino alcohols according to the invention, in particular the esters with higher fatty acids, an intramuscular injection application of solutions of these substances in vegetable oils is possible. These are depot neuroleptics and the treatment effect of a single dose of 10-25 mg of the substance lasts for one to several weeks. As can be seen, the pharmacological activity suggests the utility of the compounds of the invention in the therapy of schizophrenic psychosis and in the treatment of neurotic conditions.

As yet the pharmacological effects of the compounds according to the invention, the properties of a number of typical substances are specifically described. Unless otherwise indicated, all agents were administered orally and the doses indicated are calculated on a base basis. In particular, the following pharmacological methods were used in the evaluation, which have been described in the literature:

Acute toxicity was determined in mice, female, in groups of 10. Death was monitored within 7 days after oral administration. Results are reported as mean lethal doses of LD 50 in mg / kg.

The incoordination effect as a criterion of central suppressive action was observed in mice in a rotating rod test (J. Metzova et al., Arzneim.-Forsch. 13, 10139, 1963). Mean ataxia-inducing active substances (ED 50) at the time of optimal effect of the test substances were determined.

The inhibitory effect on mouse mobility - also as a criterion of centrally depressant action - was observed in the observational test of Ther (L. Ther, Deut. Apoth. - Ztg. 93, 292, 1953). The doses (D50) producing an effect corresponding to 50% of the average control value of motility,

Hypothermal activity in mice is also typical of centrally depressants and neuroleptics (J. Metyšová and J. Metyš, Int. J. Neuropharmacol. 4, 111, 1965).

The cataleptic effect was studied in rats, females, by the method of Boissier and Simon (Therapy 18, 1257, 1963). Mean effective doses of ED 50 that induce catalepsy in half of the animals in the experiment are reported.

The antiapomorphine effect - as another indicator of neuroleptic activity - has been studied in rats, males, in a test by Janssen et al. (Arzneim-Forsch. 10, 1003, 1960; 17,841,1967). D 50 doses that inhibit apomorphine-induced "chewing" (oral stereotyping) and "agitation" to 50% of the control apomorphine group are reported.

In depressant neuroleptics, the antiapomorphine effect was evaluated in dogs using Jansenna and Niemegeers (Arzneim.-Forsch. 9, 7165, 1959) methodology, and weekly intervals were evaluated for blocking of vomiting induced by subcutaneous administration of apomorphine hydrochloride.

Some other reported effects (e.g., adrenolytic, spasmolytic, antihistamine, locally anesthetic, antiamphetamine) were determined using generally known methods.

In order to allow comparison, the results obtained in the most important tests with several standards are listed first:

Acute toxicity, LD 50 values in mg / kg: chlorpromazine, 198; chlorothepine, 78.

Incoordination effect (ataxia), ED 50 values in mg / kg: chlorpromazine, 8.2; chlorothepine, 2.2.

Inhibition of mobility by Ther, ED 50 values in mg / kg: chlorpromazine, 4.8.

Hypothermal effect, threshold dose in mg / kg that lowers body temperature: chlorpromazine, 5.0.

Cataleptic effect, ED50 doses in mg / kg:

chlorpromazine, 16.0; chlorothepine, 4.3.

Antiapomorphine effect in rats, doses

D 50 in mg / kg (a) for chewing and (b) for agitation: chlorpromazine, (a) 69, (b) 38; chlorothepine, (a) 10.8.

Note _: For neuroleptics listed as standards (chlorpromazine, chlorothepine), it should be noted that their effects do not show prolongation over time, ie they virtually fade within 24 hours in all tests performed.

Now the pharmacological data for the individual substances according to the invention:

6- (1-Methyl-4-piperidyl) -6H-diben (b, e) -1,4-oxathiepine (tested as hydrogen maleate, substance 14018): Toxicity, LD 50 between 200 (non-toxic dose) and 500 mg / kg (100 percent death of mice). Incoordination effect, ED 50 = 4.2 mg / kg. Mobility Inhibition (Ther), D 50 = 3.5 µg / kg. Hypothermal effect, 5 mg / kg dose decreases the temperature by 2.31 (the same dose of chlorpromazine and perfenazine, respectively, decreases by 1.92 and 2.86, respectively); dose 10 milligrams / kg reduced by 3.75 (same dose of chlorpromazine and perfenazine, respectively, decreased by 3.86 and 3.85 ° C, respectively). Catalepsia, ED 50 between 50 (catalepsy in 15% of animals) and 100 mg / kg ( catalepsy in 60% of the animals), the effect is strongly overlapped by deep central depression, at 50 mg / kg the substance potentiates the cataleptic action of perfenazine and should be evaluated as a very effective tranquillizer with minimal cataleptic component of action.

8-Chloro-6- (1-methyl-4-piperidyl) -OH-dibenzyl] -1,4-oxathiepine (tested as hydrogen maleate, 14107): Toxicity, LD 50 = 108 mg / kg. Incoordination effect, ED 50 = 2.0 mg / kg. Cataleptic effect, ED 50 = 4.2 milligrams / kg. The substance is a neuroleptic substantially more potent than chlorpromazine; intensity and effects are very similar to chlorothepine.

8-Chloro-6-methyl-6- (1-methyl-4-piperidyl) -6H-dibenz (h, e) -1,4-oxathiepine (tested as hydrogen oxalate, compound 14085): Incoordination effect, ED 50 = 75 mg / kg. Catalepsy, a dose of 100 mg / kg induces catalepsy in 20% of animals. The substance is a mild tranquilizer almost devoid of cataleptic action.

8-Methoxy-6- (1-methyl-4-plperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (tested as hydrogen maleate, 14087): Toxicity, LD 50 = 98 mg / kg. Incoordination effect, ED 50 = 0.92 mg / kg. Cataleptic effect, ED 50 = 3.8 mg / kg. The substance is a highly potent neuroleptic with an effect intensity higher than that of chlorpromazine or chlorothepine.

8-Trifluoromethyl-6- (1-methyl-4-plperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (tested as hydrogen oxalate, 14088): Toxicity, LD 50 = 115 mg / kg. Incoordination effect, ED 50 = 2.6 mg / kg. Cataleptic effect, ED 50 = 1.8 mg / kg. The substance is a highly potent neuroleptic that outperforms both chlorpromazine and chlorothepine.

2-Fluoro-8-chloro-8- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (tested as hydrogen maleate, substance 14135): Toxicity, LD50 = 1884 mg / kg. The incoordinating effect is delayed and strongly protracted; at 2 hours after administration, the ED 50 is 0.9 mg / kg, at 3 hours the ED 50 max is 0.3 mg / kg. At 14 hours the ED50 is still 1.4 mg / kg, at 48 hours 3.2 mg / kg, at 72 hours 5.0 mg / kg. Even after 96 hours, 20% of the mice showed ataxia. Cataleptic effect, ED50 = 1.7 mg / kg. Antiapomorphine effect in rats, D50 = 1.14 mg / kg (chew loss) and 1.66 mg / kg (agitation depression). The substance is an extremely potent neuroleptic that outperforms chlorpromazine by almost two orders of magnitude in the antiapomorphine test; the depressant effects show a high degree of prolongation.

2-Fluoro-8-methoxy-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (tested as hydrogen maleate, 14105): Toxicity, LD 50 = ^! 164 mg / kg. For iv administration, LD 50 = 60 mg / kg. The incoordinating effect is delayed and greatly delayed; at 2 hours of administration, the ED50 is 0.77 mg / / kg, the optimum effect is at 4 hours - - ED50 = '0', 45 mg / kg, at 24 hours ED50 = 2.3 milligrams / kg, at 48 hours 3, 6 mg / kg. Cataleptic effect, ED50 = 3.0 mg / kg. Antiapomorphine effect in rats, D 50 = 2.9 mg / kg (chew depression), 3.5 mg / kg (agitation depression). The substance has an anaigetic effect in the Haffner test at doses of 1-5 mg / kg iv, at a concentration of 0.1-0.5% it has a local anesthetic effect in the corneal anesthesia test, it is highly effective α-adrenolytic (dose 0.01 mg / kg iv decreases adrenaline presoric response in rats by 501%), at 0.1 (Ug / ml suppresses acetylcholine contractions of isolated rat duodenum by 50%, similarly at 1 - 10 µg / ml suppresses barium chloride contractions. mg / kg reduces the rectally measured rat body temperature by 1 ° C (hypothermal effect) At doses of 0.1 - 1.0 mg / kg sc, 50% of guinea pigs protect against lethal histamine (antibistamine effect) at doses of 6.1 —1.0 mg / kg iv prolongs the duration of thiopental sleep in mice by 100% over the control thiopental group, with a pronounced antiamphetamine effect, doses of 0.01-0.1 mg / kg protect 10% of the mice from the lethal effect of a standard amphetamine dose. is a highly effective sun uroleptic with a higher intensity of action than chlorpromazine or chlorothepin are particularly knocked out by antlapomorphine activity and strong prolongation of the suppressive effect.

2-Fluoro-8- (trifluoromethylthio) -6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxaphthiepine (tested as hydrogen maleate, substance 14716): Toxicity, LD50 = 33 8 mg / kg. As in previous cases, the incoordinating effect is delayed and is strongly p-rolonged; after 2 hours of administration ED50 is 3.0 mg / kg, optimum effect occurs at 5 hours after administration - ED50 = 1.8 mg / kg, after 24 hours ED50 = '6, G milligrams / kg, dose 48 hours 10 mg / kg induces incoordination in 310% of the mice, in 72 hours in 10% of the mice.

Antiapomorphine effect in rats, D50 = 1.6 mg / kg (both chewing and agitation); the effect subsides within 24 hours after administration. Like previous agents, it is a highly potent neuroleptic with strongly protracted cushioning effects.

8-Methoxy-6- [1- (2-hydroxyethyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-O'Xathiepine (tested as hydrogen fumarate, substance 14106): Incoordination effect, ED50 = = 2.8 mg / kg, at 24 hours 10 mg / kg. Cataleptic effect, ED 50 = 8.0 mg / kg. The substance is a neuroleptic more effective than chlorpromazine.

8-Methoxy-6- [1- (4-hydroxypentyl) -4-piperidyl] -6H-dibenz [b, e] -1,4-oxathiepine (tested as hydrogen fumarate, substance 1410'δ): Incoordination effect, ED50 = 10 mg / kg (at 2 hours post-administration), at 24 hours 19.5 milligrams / kg. Cataleptic effect, ED 50 = 5.6 mg / kg. Antiapomorphine effect in rats, D50 = 3.1 mg / kg (for chew control) and

2.5 mg / kg (for inhibiting agitation). The substance is a potent neuroleptic with a relatively low depressant component of action.

2-Fluoro-8-chloro-6- [1- (2-decanoyloxyethyl) -4-piperidyl] -6H-dibenz; (b, e) -1,4-oxathiepine (tested as base 14717, on the one hand as hydrogen maleate - substance 14719): Toxicity, LD50 = 425 mg / kg (orally in the form of hydrogen maleate). Antiapomorphine effect in rats at i.m. administration of a base solution in miglyol, a single dose of 25 mg / kg produces an anti-apomorphine effect of 3 days, a dose of 50 mg / kg has an effect of 8 days. In the antiapomorphine test in dogs, the dose blocks 5 mg / kg i.m. apomorphine emesis 2 weeks after application, in the third week the effect subsides. The substance has the properties of a depot neuroleptic such as flufenazinedecanoate.

As already mentioned, the present invention also includes salts of the compounds of formula I with pharmaceutically acceptable inorganic or organic acids. Particularly useful are the hydrochlorides and the acid salts with dicarboxylic aliphatic acids (oxalic, maleic, fumaric), which are slightly soluble in science and suitable for the preparation of dosage forms for oral use. They are also preferable to free bases for pharmacological testing. The free bases in the case of highly lipophilic esters are suitable for intramuscular administration in the form of oily solutions.

The present invention further provides processes for the preparation of the compounds of formula I and their salts and / or oxidation products (S-oxides and N-oxides), respectively. In the synthesis of the compounds according to the invention, the following methods are applied:

(a) A very important part of the invention compounds of formula I wherein R ¹ is methyl and R ² to R ⁴ is the same as mentioned in the first paragraph is obtained by intramolecular substitution reaction of fluorinated aminoalcohols of the formula II,

(ii) in which:

R ² to R ⁴ have the same meaning as indicated for formula I. This intramolecular substitution reaction is carried out with sodium hydride in a suitable inert · solvent, preferably dimethylformamide, at temperatures 50-1'0íO ^q C, preferably at 70 ° C, in an inert - - preferably nitrogen atmosphere.

The starting amino alcohols of formula II are prepared by reacting carbonyl compounds of formula III,

F COR

R '(fll) where

R ² to R ⁴ is again the same as in formula I, with 1-methyl-4-piperidylmagnesium halides, preferably 1-methyl-4-piperidylmagnesium chloride. These Grigard reactions are preferably carried out in absolute boiling tetrahydrofuran. The starting carbonyl compounds of formula III are mostly novel and the methods for their preparation are described in the examples; if known, reference is made to the relevant literature.

(bj Compounds of formula I in which R ¹ = H can be prepared from the corresponding compounds of formula I in which R ^{1 =} CH 3, accessible by the process of (aj), by a two-step process which remains in the first phase under ethyl chloroformate in boiling benzene; resulting in carbamates of formula IV,

in which

R ² to R ⁴ have the same meaning as in formula I, and in a second phase in the alkaline hydrolysis of compounds of formula IV. The carbamates of formula IV need not be isolated in pure form, but only as crude neutral products of the first phase of the reaction sequence. For alkaline hydrolysis, preferably potassium hydroxide in a very concentrated solution in ethanol is used; the hydrolysis is carried out at the boiling point of this solution.

(c) Compounds of formula I in which R ¹ is hydroxyalkyl are prepared, for example, by alkylation of the corresponding secondary amines of formula I in which R ¹ = H, haloalkanols, for example 2-bromoethanol. The reaction is preferably carried out in boiling acetone in the presence of alkaline hydrogen halide binding agents, preferably anhydrous potassium carbonate.

(d) Compounds of formula I in which R @ ¹ is hydroxyalkyl may also be prepared by alkylation of the corresponding secondary amines of formula I in which R @ ¹ = H with the appropriate haloaldehydes or haloketones and subsequent reduction of the carbonyl intermediates obtained. Conditions for alkylation may be similar to those described in Method (c) and the reduction may be carried out by any of the general methods for preparing alcohols from aldehydes or ketones, preferably sodium borohydride.

e) For the preparation of compounds of formula I wherein R ¹ is acyloxyalkyl, it is appropriate to acylate the compounds of (c) and (d), i.e. compounds of formula I wherein R ¹ is hydroxyalkyl, with the appropriate fatty acids or reactive derivatives thereof ( halides, anhydrides, ester esterification). Particularly preferred is acylation with the free acids under "azeotropic" esterification conditions, consisting in the distillation of a mixture of the starting aminoalkanol, fatty acid and xylene, wherein the distilling xylene removes the water formed by the reaction in the form of an azeotropic mixture.

(f) The S-oxides of the compounds of formula I are prepared by oxidizing the compounds of formula I with a slight excess of hydrogen peroxide in acetic acid or in an aqueous solution of methanesulfonic acid at room temperature. It is also possible to use other oxidizing agents customary to this reaction (m-chloroperbenzoic acid, pure acid).

(g) N-oxides derived from compounds of Formula I, which are also an object of this invention, are prepared by oxidizing solutions of bases of Formula I in ethanol with a slight excess of hydrogen peroxide at room temperature.

The process for the preparation of the salts of the invention also consists in neutralizing the bases of the formula I with the appropriate inorganic or organic acids in suitable solutions, in particular ethanol or in a mixture of ethanol and ether. The salts obtained are crystalline and are also suitable for characterizing the bases of formula I. The identity of all critical substances described in the invention, i.e. end products and novel intermediates (IV), was assured by analyzes and by all commonly used spectral methods (UF, IC, iH). -NMR and MS spectra).

Further details of the implementation of the invention will be apparent from the following examples, which, however, are merely illustrative of the possibilities of the invention and are not intended to fully describe these possibilities.

Examples

He did

6- (1-Methyl-4-piperidyl) -6H-dlbenz (b, e) -1,4-oxathiepine

To a stirred suspension of 25 g of sodium hydride in 103 ml of dimethylformamide, a solution of 13.25 g of (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) benzyl alcohol in 80 ml of dimethylformamide was added dropwise over 9 hours under nitrogen. 70 ° C and the mixture was heated at the same temperature for an additional 5 hours. It is then decanted by pouring into 2.1 l of water. extract with ether, dry with potassium carbonate and evaporate. The residue (12.1 g) is chromatographed on a column of 500 g of neutral alumina (activity II). Elution with benzene and a mixture of benzene and chloroform elutes a total of 7.3 * 3 g of the desired base, which crystallizes from a mixture of cyclohexanes and petroleum ether and melts in a pure state at 77-79 ° C. Neutralization with maleic acid yielded crystalline hydrogen maleate, which in the pure state melts at 152-1-53 ^q C (acetone-ether).

The starting α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) benzyl alcohol is a novel substance and is prepared as follows:

To a solution of 43.8 g of ^2-fluořth: oíenolu (I. Red and spores., Collect. Czech. Commun. 44, 213 ^, 1979) in 85 ml of hexamethylphosphoramide under nitrogen is added first a solution of 13.8 g of sodium hydroxide 20 ml of water followed by 450 g of 2-chlorobenzaldehyde and the mixture was heated at 10 ° C for 3.5 h. It is then poured into 500 ml of water and the product is extracted with benzene. The extract was dried (MgSO4) and evaporated. The residue crystallizes after mixing with 120 ml of petroleum ether. 57.1 g (77%) of 2- (2-fluorophenylthio) benzaldehyde are obtained, which crystallizes from benzene and melts in the pure state at 50-57 ° C.

By reacting 1 40 g of magnesium with 8.0 g of 1-methyl-4-chloropiperidine (SM McElvain and K. Rorig, J. Amer. Chem. Soc. 70, 1826, 1948) in 25 ml of tetrahydrofuran, a solution of the Grignard reagent is prepared. A solution of 9.3 g of 2- (2-fluorophenyltro) benzaldehyde in 15 ml of tetrahydrofuran was added dropwise over 30 minutes and the mixture was refluxed for 3 hours. After standing overnight, it was quenched by addition of 50 ml of 20% ammonium chloride solution and the product was extracted with ether. The extract was dried over potassium carbonate and evaporated. The residue - 13.25 g (ΙΟΟΨο) - - is a crude oily α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) benzyl alcohol which crystallizes from cyclohexanes and melts in the pure state on white. 114 ° C.

Example 2

8-Chloro-6- (1-methyl-4-piperidyl) -6H- ^; (dibenz (b, e) -1,4-oxathiepine

To a suspension of 5.7 g of sodium hydride in 180 ml of dimethylformamide, a solution of 26.8 g of α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthlo) -5-chlorobenzyl alcohol is slowly added under stirring under nitrogen. in 135 ml of dimethylformamide, stirred for 14 hours at 70 ° C, then quenched by pouring into water and extracted with ether. The extract was washed with water, dried over potassium carbonate and evaporated. The residue (20 g of oil) is chromatographed on a 1 kg neutral alumina column (activity II), eluting with bonzen to first remove at least the polar product and then eluting with 6.57 g of homogeneous desired base to give 3.52 g of a mixture of this base. The mixture was rechromatographed on a column of 2.20 g of sillcagel, eluting with chloroform to give an additional 2.18 grams of pellet, increasing the yield to 8.75 g. crystalline hydrogen maleate, mp 188.5-190 ° C (acetone-ethanol-ether).

The starting α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-chlorobenzylalcohol is new and is obtained as follows:

To a solution of 10.8 g of 2-fluorothiophenol (cited) in 20 ml of hexamethylphosphoric triamide is added a solution of 3.4 g of sodium hydroxide in 6 ml of water and then 14 g of 2-5-dichlorobenzaldehyde (H. Erdmann, Justus Liebigs Ann. Chem. 272, 155, 1893) and the mixture heated for 5.5 ^hr: ny at 10O ° C. After cooling, it is diluted with 150 ml of water and extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. Crude 2- (2-fluorophenylthio) -5-chlorobenzaldehyde is obtained, which is recrystallized from 20 ml of ethanol; 16.0 g, mp 85,5-83 ^O C. Further crystallization gives analytically pure product with mp 87-83 ° C.

By reacting 2.7 g of magnesium with 13.7 g of 1-methyl-4-chloropiperidine (cited) in 80 ml of tetrahydrofuran, a solution of Grignard reagent is prepared, to which a solution of 20 g of 2- (2-fluoro- (phenylthio) -5-chlorobenzaldehyde in 40 mL of tetrahydrofuran. The mixture was refluxed for 45 hours, quenched by addition overnight. 20% ammonium chloride solution and extracted with benzene. The extract was washed with water, dried over potassium carbonate and evaporated. 27.4 g (100%) of crude α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-chlorobenzyl alcohol are obtained, a sample of which can be characterized by conversion to crystalline 2, m.p. 4,0-trinitrobenzoate, mp 100-101.5 degrees Celsius with decomposition (ethanol ether).

219 0 0 3

Example 3

8-Chloro-8-methyl-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine

To a stirred suspension of 4.5 g of sodium hydride in 150 ml of dimethylformamide was added dropwise a solution of 20 g of crude 1- [2- (2-fluorophenylthio) -5-chlorophenyl] -1- (1-methyl-4-piperidyl) dropwise over 6 hours. ethanol in 120 ml of dimethylformamide at 70 ° C under a nitrogen atmosphere. After stirring for 8 hours at the same temperature, the reaction mixture is quenched by pouring into water and the product is extracted with benzene. The extract was dried with potassium carbonate and evaporated. The residue (20 g) is chromatographed on a column of 500 g of neutral alumina (activity II). Elution with benzene firstly removed 2.25 g of less polar fractions and then eluted with 4.45 g of crude product, which was rechromatographed on silica gel (90 g) to give a homogeneous product. Neutralization with oxalic acid affords crystalline hydrogen oxalate, mp 167-169 ^and C (acetone-ether).

The starting material 1- [2- (2-fluorophenylthio) -5-chlorophenyl] -1- (1-methyl-4-piperidyl) ethanol is new and is prepared as follows:

Reaction of 2.92 g of magnesium with 16.03 g of 1-methyl-4-chloropiperidine (cited) in 50 ml of tetrahydrofuran (initiation by iodine bead) gives a Grignard reagent solution in the usual manner. To this was added a solution of 22.5 g of 2- (2- (fluorophenylthio) -5-chloroacetophenone (I. Red et al., Collect. Czech. Chem. Commun. 44, 21130, 1979) in 40 ml of tetrahydrofuran and a mixture of After standing overnight, the reaction was quenched by the addition of 100 ml of 20% ammonium chloride solution and extracted with ether, dried over potassium carbonate and evaporated to give 24.8 g (82%) of crude oily 1- / 1- (2-chloro-2-ol) solution. 2- (2-fluorophenylthio) -5-chlorophenyl] -1- (1-methyl-4-piperidyl) ethanol, which was used for further work without further purification.

Example 1 a d 4

8-Methoxy-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine

To a suspension of 5.4 g of sodium hydride in 170 ml of dimethylformamide, a solution of 23.7 g of a- _; (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-methoxybenzyl alcohol in 120 ml dimethylformamide and stirred at this temperature for an additional 11 hours. It is then decomposed by pouring into water and extracted with ether. The extract was dried over potassium carbonate and evaporated. The residue is worked up by combining crystallization from a mixture of cyclohexane and petroleum ether and chromatography of the residue of the mother liquors on a column of 500 g of neutral alumina (activity II); the desired compound is eluted with a mixture of benzene and chloroform.

A total of 17.1 g of the desired base is obtained, which crystallizes from a mixture of cyclohexane and petroleum ether and melts in the pure state at 103-105 ° C. Neutralization with maleic acid affords crystalline hydrogen maleate, m.p. 182.5-183.5 ° C (acetone-ethanol).

The starting α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-methoxybenzyl alcohol is a novel substance which can be prepared by the following procedure:

A mixture of 27.1 g of 2-bromo-5-methoxybenzaldehyde (T. Kametani et al., Chem. Pharm. Bull. 23, 26134, 1975), 17.0 g of 2-fluorothiophenol (cited), 19.3 g of anhydrous potassium carbonate, 100 ml of dimethylformamide and 3 g of copper are heated under stirring for 8 hours in a bath of 150. After partial cooling, the mixture is diluted with water and benzene, come together. Wash with water, dry over magnesium sulphate and evaporate. The oil obtained is chromatographed on a column of 500 g of neutral alumina (activity II). Benzene is eluted (18.9 g, 57%) homogeneous 2- (2-fluorophenylthio) -5-methoxybenzaldehyde, boiling at 153 ^Q · C / 40 Pa · crystallizing from a mixture of cyclohexane and petroleum ether, m.p. 58-59 ^Q C

By reacting 2.5 g of magnesium with 13.35 g of 1-methyl-4-chloropiperidine (cited) in 80 ml of tetrahydrofuran, a Grignard reagent solution is prepared in a conventional manner. An amount of 18.2 g of 2- (2-fluorophenylthio) -5-methoxybenzaldehyde in 40 ml of tetrahydrofuran was added dropwise with stirring over 15 minutes, and the mixture was refluxed for 4 hours. After cooling, it is quenched with 20% ammonium chloride solution and extracted with benzene. The extract was dried over potassium carbonate and evaporated. Gets. with 23.7 g (100% of crude oily? - (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-methoxybenzyl alcohol which is used in the next operation without purification. .

Example 5

8-Trifluoromethyl-O- (1-methyl-4-piperidyl) -OH-dibenz (b, e) -1,4-oxathiepine

To a suspension of 4.5 g of sodium hydride in 140 ml of dimethylformamide is added dropwise a solution of 23.2 g of crude α - (1,1-methyl-4-piperidyl) -2- (2- Fluorophenylthio) -5-trifluoromethylbenzyl alcohol in 100 ml of dimethylformamide, stirred for 16 hours at this temperature, decomposed by pouring into water and extracted with a mixture of benzene and ether, washed with water, dried over potassium carbonate and evaporated. on a 500 g neutral alumina column (activity IIj. Eluting with benzene removes less polar fractions and then elutes with a mixture of benzene and chloroform to elute

1.48 g of homogeneous desired substance. Neutralization with acid, hydrogenated packaging provides crystalline oxalate melting at 215.5 to 216.5 C with decomposition ^Q (acetone-ethanol).

The starting α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-trifluoromethylbenzyl alcohol is a new substance obtained by the following procedure:

To a solution of 260 ml of hydrochloric acid in 230 ml of water is slowly added 212.2 g of 3-amino-4-chlorobenzotrifluoride (AE Porai-Kosice et al., Z. Prikl. Chim. 28, 969, 1965; Chem. Abstr.). 50, 4880 (1956), the resulting hydrochloride suspension is cooled, 450 g of ice are added and diazotized at 0-5 ° C by dropwise addition of a solution of 80 g of sodium nitrite in 110 ml of water. The mixture was stirred at this temperature for 1 hour and a cold solution of 100 g of sodium acetate trihydrate in 150 ml of water was added. The precipitated insoluble material was separated (70.8 g of the starting 3-amino-4-chlorobenzotrifluoride was recovered by distillation) and the diazonium salt solution was added to the formaldoxime solution at 10-20 ° C with stirring (prepared by boiling for 57 minutes with 57.5 g of paraformaldehyde). 131.5 g of hydroxylamine hydrochloride in 850 ml of water with the addition of 255 g of sodium acetate trihydrate) and a solution

32.5 g of copper sulphate pentahydrate, 5 g of sodium sulfite and 800 g of sodium acetate trihydrate in 300 ml of water are added with 300 ml of toluene.

The mixture was stirred for 2 hours, 1100 ml of hydrochloric acid was added and refluxed for 2 hours. It is then distilled with steam and the distillate is extracted with benzene. The extract was washed with 5% sodium hydrogen carbonate solution and evaporated. The residue is dissolved in 200 ml of ether and the solution is stirred for 2 hours with 450 ml of 40% sodium sulfite solution. After standing overnight, the precipitated adduct is filtered off with suction, washed with ether, suspended in water, added 200 ml of hydrochloric acid and boiled for 2 hours. under reflux.

After cooling, it is extracted with benzene, the extract is dried over magnesium sulphate, evaporated and the residue is worked up by distillation. 49.1 g (31% by conversion) of 2-chloro-5-trifluoromethylbenzaldehyde, m.p. 93 DEG -96 DEG C./20 mbar, are obtained.

To a solution of 12.2 g of 2-fluorothiophenol (lit. quoted) in 25 ml of hexamethylphosphoric triamide was added a solution of 4.0 g of sodium hydroxide in 7 ml of water, followed by 16.8 g of 2-chloro-5-trifluoromethylbenzaldehyde. at 100 ° C, poured into water, and the product extracted with benzene to give 25.5 g (97%) of crude 2- (2-fluorophenylthio) -5-trifluoromethylbenzaldehyde melting at 130-132 ° C. A mixture of benzene and petroleum ether gives an analytically pure substance, melting at the same temperature.

By reaction of 12.0 g of 1-methyl-4-chloropiperidine with 2.3 g of magnesium in 70 ml of tetrahydrofuran, a Grignard reagent solution is prepared to which a solution is added dropwise over 10 minutes.

17.4 g of 2- (2-fluorophenylthio) -5-trifluoromethylbenzaldehyde in 40 ml of tetrahydrofuran. The mixture was refluxed for 4 hours, quenched with 20% ammonium chloride solution and extracted with benzene. The extract was dried over potassium carbonate and evaporated. 23.2 g (100%) of crude oily α- (1-methyl-4-piperidyl) -2- (2-fluorophenylthio) -5-trifluoromethylbenzyl alcohol are obtained, which is used as is in the final reaction.

Example 6

2-Fluoro-8-chloro-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e -1,4-oxathiepine)

To a suspension of 3.9 g of sodium hydride in 140 ml of dimethylformamide was added a solution of 21.2 g of crude α- (1-methyl-4-piperidyl) -2- (2,5-difluorophore) under stirring under nitrogen at 70 ° C. enylthio} -5-chlorohenzyl alcohol in 100 ml of dimethylformamide and stirred under the conditions for 14 hours, then quenched by pouring into water and extracted with ether, washed with water, dried over potassium carbonate and evaporated. g of neutral alumina (activity II).

By eluting with benzene, 2.13 g of less polar fraction were first eluted and then eluted

7.1 g of the desired base, which crystallizes from cyclohexane and melts in a pure state at 127-129 degrees Celsius. Neutralization with maleic acid affords hydrogen maleate, which crystallizes from a mixture of acetone and ether or ethanol and melts at 190-192 ° C in the pure state.

The starting α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthia) -5-chlorobenzyl alcohol is a novel substance and is prepared as follows:

A solution of 13.1 g of 2,5-difluorothiophenol (I. Red et al., Collect. Czech. Commun. 45, 2688, 1988) in 20 ml of hexamethylphosphoric triamide is added a solution of 3.6 g of sodium hydroxide in 6 ml of water and 13.65 g of 2,5-dichlorobenzaldehyde (cited), and the mixture was heated to 100 ° C with stirring for 5.5 hours. It is then diluted with 150 ml of water and extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. The residue was crystallized from a mixture of benzene and petroleum ether; 16.4 g (74%) of 2- (2,5-difluorophenylthio) -5-chlorobenzaldehyde are obtained, which melts at 88-90 ° C in pure form.

By reaction of 11.35 g of 4-chloro-1-methylpiperidine with 2.3 g of magnesium in 70 ml of tetrahydrofuran, a Grignard reagent solution is prepared, to which a solution is added dropwise over 10 minutes.

16.1 g of 2- (2,5-difluorophenylthio) -5-chlorobenzaldehyde in 40 ml of tetrahydrofuran. The mixture was refluxed for 4 hours, quenched with 20% ammonium chloride solution and extracted with benzene.

ltí

1S

The extract was washed with water, dried over potassium carbonate and evaporated. 21.7 g (100%) of crude oily α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5-chlorobenzyl alcohol are obtained, which is used as it is in the last step.

Example 7

2-Fluoro-8-methoxy-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) 1,4-oxathiepine

To a suspension of 2.5 g of sodium hydride in 80 ml of dimethylformamide, a solution of 12.5 g of α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5-methoxybenzyl alcohol in 60 ml of dimethylformamide is added in one portion. stirring under nitrogen atmosphere. The mixture was stirred at 70 ° C for 11 hours, then poured into water and extracted with ether. The extract was washed with water, dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 500 g of neutral alumina (activity II). Elution with benzene removes the less polar portions and then elutes with a mixture of benzene and chloroform 7.17 g of the desired base which is oily and neutralizes with maleic acid to provide 8.0 g of hydrogen maleate. This crystallizes from a mixture of acetone and ether and melts in the pure state at 180-181.5 ° C.

The starting α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5-methoxybenzyl alcohol is new and is prepared as follows:

A mixture of 19.7 g of 2-bromo-5-methoxybenzaldehyde (cited), 14.1 g of 2,5-difluorothiophenol (cited), 14.0 g of potassium carbonate, 75 ml of dimethylformamide and 2.1 g of copper catalyst ^The reaction mixture was diluted with 150 ml of water and extracted with benzene. The extract was washed with water, dried (MgSO4) and evaporated. The residue is worked up by distillation. 13.3 g (52%) of 2- (2,5-difluorophenylthio) -5-methoxybenzaldehyde are obtained, boiling at 163-165 DEG C./40 mbar.

The product crystallizes from cyclohexane and melts in the pure state at 67-68 ° C.

By reacting 6.7 g of 4-chloro-1-methylpiperidine with 1.25 g of magnesium in 40 ml of tetrahydrofuran, a solution of Grignard reagent is prepared, to which a solution of 9.35 g of 2- (2,5-difluorophenylthio) is added dropwise over 10 minutes. 5-Methoxybenzaldehyde in 20 mL tetrahydrofuran. The mixture was refluxed for 3 hours, quenched with 20% ammonium chloride solution and extracted with benzene. The extract was washed with water, dried over potassium carbonate and evaporated. It is obtained

12.6 g (100%) of crude oily α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5-methoxybenzyl alcohol, which is used as such in the next reaction. For characterization, crystalline hydrogen oxalate crystallizes from acetone and melts at 160-163 ° C in pure state by neutralizing the sample with oxalic acid.

Example 8

2-Fluoro-8- (trifluoromethylthio) -6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine

To a suspension of 4.3 g of sodium hydride in 150 ml of dimethylformamide was added a solution of 26.9 g of crude α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5-trifluoromethylthiobenzylalcohol in 10 ml of dimethylformamide. stirring and under a nitrogen atmosphere. The mixture was stirred at 70 ° C for 15 hours, then quenched by pouring into water and extracted with ether. The extract was washed with water, dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 1 kg of neutral alumina (activity II). After eluting the less polar portions with benzene, 5.3 g of the desired base are eluted with chloroform, which crystallizes from petroleum ether and melts at 77-81 ° C. Neutralization with maleic acid affords hydrogen maleate, which crystallizes from a mixture of acetone and ether and melts in the pure state at 151-153 ° C.

The starting α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5- (trifluoromethylthio) benzyl alcohol is a novel substance which is prepared by the following procedure:

To a mixture of 106.3 g of 4- (trifluoromethylthio) chlorobenzene (LM Jegupolsky and MS Marenec, Z. Obc. Chim. 29, 278, 1959) and 20 g of paraformaldehyde, 61 g of chlorosulfonic acid are added dropwise with stirring at -5 ° C. The mixture is stirred for 3 hours at max. 0 ° C, then for 12 hours at + 5 ° C and decomposed by pouring onto ice. The product was isolated by extraction with a mixture of benzene and chloroform, dried over magnesium sulfate, evaporated and the residue distilled.

58 g of unchanged starting material is recovered as the lowest fraction having a melting point of about 70 DEG C./6 mbar. 26.8 g of a fraction boiling at 115-140 ° C / 2 kPa, which is a mixture of monochloromethyl derivatives, are then collected. According to gas chromatography and 1 H-NMR spectrum, it contained 80% of the desired 2-chloromethyl-4- (trifluoromethylthio) chlorobenzene and the remainder of the undesired isomer. The redistilled sample has a m.p. of 118-120 ° C / 1.6 kPa. The substance is in the raw state suitable for further processing.

A mixture of 55.7 g of crude 2-chloromethyl-4- (trifluoromethylthio) chlorobenzene, 2 (3 g of potassium acetate, 150 ml of dimethylsulfoxide and 10 g of triethylbenzylammonium chloride is stirred for 5 hours at 60 DEG C. It is decanted by pouring into water, shaking with benzene and benzene. The oily residue is dissolved in 200 ml of ethanol, 100 ml of water and 20 ml of hydrochloric acid are added and the mixture is refluxed for 7 hours, then ethanol is distilled off, the residue is mixed with water and extracted with benzene. The oil obtained in the extract was distilled in vacuo to give 40.2 g of crude 2219003

-chloro-5- (trifluoromethylthio) benzyl alcohol boiling at 140-150 ° C / 2 kPa. According to 1 H-NMR spectrum, the product contains approximately 80% of the title compound and the remainder is the positional isomer. In this state, the substance is suitable for further processing.

To a solution of 39.9 g of crude 2-chloro-5- (trifluoromethylthio) benzyl alcohol in 400 ml of dichloromethane is added 3.6 g of triethylbenzylammonium chloride and a solution of 20.6 g of potassium dichromate in 270 ml is added dropwise with stirring at 15-20 ° C. of water containing 135 ml of sulfuric acid, stirred for 4 hours at room temperature, allowed to stand overnight, the aqueous layer was separated, the organic phase was washed with water and 5% sodium hydroxide solution, dried over magnesium sulphate and evaporated. 34.1 g of crude 2-chloro-5- (trifluoromethylthio) benzaldehyde boiling at 120-130 ° C / 2 kPa are obtained, according to 1 H-NMR spectrum, the product contains approximately 80% of the title compound and the remainder is the positional isomer. the condition is suitable for further processing.

To a solution of 27.6 g of crude 2-chloro-5- (trifluoromethylthio) benzaldehyde in 30 ml of hexamethylphosphoric triamide was added 13.4 g of 2,5-difluorothiophenol (cited) and a solution of 4.0 g of sodium hydroxide in 7 ml of water. After the spontaneous reaction has settled, the mixture is stirred

5.5 hours at 100 DEG C., decomposed by pouring into water, the precipitated crystalline substance is suctioned off after several hours, dried in vacuo and recrystallized from cyclohexane. 24.0 g of crude 2- (2,5-difluorophenylthio) -5- (trifluoromethylthio) benzaldehyde melting at 92-102 ° C are obtained. The pure material is obtained by further crystallization from cyclohexane, m.p.

104.5 ° C.

By reaction of 12.0 g of 4-chloro-1-methylpiperidine with 2.4 g of magnesium in 70 ml of tetrahydrofuran, a Grignard reagent solution is prepared, to which a solution is added dropwise over 10 minutes.

21.2 g of 2- (2,5-difluorophenylthio) -5- (trifluoromethylthio) benzaldehyde in 40 ml of tetrahydrofuran. The mixture is refluxed for 5 hours, quenched with 2% ammonium chloride solution after cooling and extracted with benzene. The extract was washed with water, dried over potassium carbonate and evaporated. 26.9 g of crude oily α- (1-methyl-4-piperidyl) -2- (2,5-difluorophenylthio) -5- (trifluoromethylthiobenzyl alcohol) are obtained, which is used as it is in the next reaction.

Example 9

8-Methoxy-6- (4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine

To a solution of 13.1 g of 8-methoxy-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (Example 4) in 50 ml of benzene was added dropwise with stirring over 1 hour. A solution of 6.5 g of ethyl chloroformate in 30 ml of benzene was added for 5 hours and the mixture was refluxed for 1.5 hours. After cooling, it is washed with water, 10% sulfuric acid, 5% sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated. The residue (carbamate) is dissolved in 17 ml of ethanol, 15 g of potassium hydroxide are added and the mixture is refluxed in a 140 ° C bath for 2 hours. It is then diluted with water and extracted with benzene. From the benzene solution, the base is extracted into excess 10% hydrochloric acid, the acidic extract is basified with aqueous ammonia and the liberated base is extracted with benzene. The extract was dried over potassium carbonate and evaporated. It is obtained

11.1 g (88%) of an oily base which, by neutralization with oxalic acid in acetone, gives a hemioxalate (i.e., neutral oxalate) crystallizing as a hemihydrate, mp 234-235.5 degrees Celsius (95% ethanol).

Example 10

2-Fluoro-8-chloro-6- (4-piperidyl) -6H-dibenzyl, e) 1,4-oxathiepine

To a boiling solution of 11.0 g of 2-fluoro-8-chloro-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (Example 6) in 50 ml of benzene was added. a solution of 5.7 ml of ethyl chloroformate in 30 ml of benzene is added dropwise over 30 minutes and the mixture is refluxed for 1.5 hours. After cooling, a small amount of the hydrochloride (monohydrate) of the starting material is filtered off with suction, the filtrate is washed with water, 10% sulfuric acid, 5% sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue (carbamate) is dissolved in 15 ml of ethanol, 13 g of potassium hydroxide are added and the mixture is refluxed for 2 hours (bath 125 ° C). After cooling, it is diluted with water and extracted with benzene. From the benzene solution, the base is extracted into excess 10% hydrochloric acid, the precipitated hydrochloride is filtered off with suction, suspended in the acidic aqueous layer of the filtrate and the suspension is basified with aqueous ammonia. The free base is extracted with benzene, the extract is dried over potassium carbonate and evaporated. 9.0 g of a crystalline base are obtained, which crystallizes from cyclohexane and melts in the pure state at 120-122 ° C. Neutralization with hydrogen chloride gives the hydrochloride, which crystallizes from aqueous ethanol and melts in the pure state at 313-317 ° C with decomposition.

Example 11

8-Methoxy-6- [1- (2-hydroxyethyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine

A mixture of 0.05 g of methoxy-6- (4-piperidyl) -6H-dibenzophb, e) -1,4-oxathiepine (Example 10), 5.8 g of 2-bromoethanol, 5.0 g of potassium carbonate and 100 ml of acetone is refluxed for 8 hours. After cooling, insoluble matter was filtered off and the filtrate was evaporated.

r. The residue is chromatographed on a column of 400 g of neutral alumina (activity II). Elution with a mixture of benzene and chloroform removes the less polar portions and then elutes with chloroform 2.16 g of a homogeneous oily base which, by neutralization with fumaric acid in ether, provides the hydrogen fumarate melting at 101-104 ° C.

Example 12

2-Fluoro-8-chloro-6- [1- (2-hydroxyethyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine

A mixture of 7.0 g of 2-fluoro-8-chloro-6- (4-piperidyl) -6-dibenz (b, e) -1,4-oxathiepine (Example 10), 3.75 g of 2-bromoethanol, 5 1.0 g of potassium carbonate and 100 ml of acetone were stirred and refluxed for 6 hours. After cooling, the solid was filtered off and washed with acetone and the filtrate was evaporated. The residue was dissolved in ether, a small amount of insoluble material was filtered off, and the filtrate was neutralized with 2.0 g of oxalic acid in acetone. 5.55 g of hydrogen oxalate crystallized, which was purified by crystallization from acetone, m.p. 141-143 ° C.

Example 13

8-Methoxy-6- [1- (4-hydroxypentyl ') - 4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine

To a solution of 5.90 g of 8-methoxy-6- [1- (4-oxopentyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine in 100 mL of ethanol was added 1.0 g sodium borohydride in 5 ml of water and 1 drop of 20% sodium hydroxide solution, and the mixture was refluxed for 3 hours with stirring. It is then diluted with 10 ml of acetone, stirred for 30 minutes, evaporated under reduced pressure and the residue is partitioned between dilute sodium hydroxide solution and benzene. The benzene solution was evaporated and neutralized with 2.0 g of maleic acid in a mixture of acetone and ether. The resulting oily maleate was isolated by decantation and washed with ether, then quenched with aqueous ammonia and extracted with ether to yield 5.6 g of an oily base. Neutralization with ethereal fumaric acid gives a crystalline hydrogen fumarate melting at 95-99 [deg.] C.

The starting 8-methoxy-6- [1- (4-oxopentyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine used is a novel substance obtained by the following procedure:

To a solution of 5.65 g of 8-methoxy-6- (4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (Example 9) and 3.9 g of 5-bromopentan-2-one ( A. Lipp, Ber. Deut. Chem. Ges. 22, 1196, 1889) in 100 ml of acetone, 5.0 g of potassium carbonate are added and the mixture is refluxed for 7 hours with stirring. After cooling, it is filtered and the filtrate is evaporated. The residue was dissolved in acetone, neutralized with maleic acid, and oily maleate was added by addition of ether. Isolate by decantation and wash with ether. Decomposition with dilute sodium hydroxide releases the base again and is isolated by extraction with ether. Treatment of the extract yielded 7.0 g of an oily base of 8-methoxy-6- [1- (4-oxopentyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine which was neutralized with oxalic acid in a mixture of acetone and ether provides crystalline hydrogen oxalate which melts at 87-89 degrees Celsius (acetone-ethanol) in pure form.

They did

2-Fluoro-8-chloro-6- [1- (2-decanoyloxyethyl) -4-piperidyl] -6H-dibenz (b, e) -1,4-oxathiepine

From a mixture of 4.35 g of 2-fluoro-8-chloro-6- [1- (2-hydroxyethyl) -4-piperidyl] -6H-dihenz (b, e) -1,4-oxathiepine (Example 12) 6.0 g of decanoic acid and 50 ml of xylene are slowly distilled off by moist xylene, which is replaced by anhydrous xylene. 350 ml of wet xylene are distilled off over 6 hours and the same amount of anhydrous xylene is added dropwise to the mixture. The residue was diluted with benzene, washed with 5% sodium hydroxide solution and water, dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 150 g of neutral alumina (activity II). Elution with benzene first removes a small amount of less polar contaminant and then 3.35 g of homogeneous ester base is eluted with the same solvent. That samples can be prepared for characterization by neutralizing maleic acid in acetone-ether, hydrogen maleate crystallized, which in the pure state melted at 135-136,5 ^three C (acetone-ether).

Example 15

8-Chloro-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine-11-oxide

2.18 g of 8-chloro-6- (1-methyl-4-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (Example 2) are dissolved in a solution of 0.80 g of methanesulfonic acid in 20 ml of water. 36 ml of a 30% hydrogen peroxide solution are added and the mixture is left to stand at room temperature for 36 hours. It was then basified with aqueous ammonia and extracted with benzene. The extract was dried over potassium carbonate and evaporated. Neutralization of the crude base obtained (2.23 g) with oxalic acid in a mixture of acetone and ether yielded

2.6 g of hemioxalate (neutral oxalate), which crystallizes from a mixture of aqueous ethanol and ether as a solvate with an ethanol molecule, 1.1. 150-154 ° C (residue 160 ° C).

Example 16

8-Chloro-6- (1-methyl-4-plperidyl) -6H-dibenzyl, e) -1,4-oxathiepine N-oxide

To a solution of 2.24 g of 8-chloro-6- (1-methyl-4219003 at room temperature) After standing for an additional 12 hours at 0 ° C, the precipitated product is filtered off with suction: 1.50 g, mp 126-129 ° C (residue) 140 degrees Celsius] (ethanol).

-piperidyl) -6H-dibenz (b, e) -1,4-oxathiepine (Example 2) in 15 ml of ethanol is added 1.5 ml of 28% hydrogen peroxide, the mixture is stirred for 4 hours at 0 ° C and then left 3 days at

Claims (3)

SUBJECT 6- (4-Piperidyl) -6H-dibenz (b, e) -1,4-oxathiepines of the general formula I, (IJ in which R ¹ denotes hydrogen, methyl, hydroxyalkyl of 2 to 5 carbon atoms or, acyloxyalkyl a total of up to 15 carbon atoms, R ² is hydrogen or methyl, R ³ is hydrogen, chloro, methoxy, trifluoromethyl, or trifluoromethylthio, R ⁴ is hydrogen or fluorine, as well as their S-oxide, N-oxides and salts with pharmaceutically acceptable inorganic or organic acids. 2. A process for preparing compounds of formula I according to claim 1, wherein R ¹ is limited to methyl, and R ² to R ⁴ denotes in its entirety, what was the noted for compounds of the formula I, characterized in that the fluorinated aminoalcohols of formula (II), (f / ynAlez -methylderiváty formula I where R ¹ = methyl, obtained according to point 2 is subjected to the action of ethyl chloroformate in refluxing benzene and the obtained crude carbamates of general formula III wherein R ² to R ⁴ have the same meaning as in formula I, is subjected to alkaline hydrolysis. 4. A process for the preparation of compounds of formula I according to item 1, wherein R ¹ is limited to hydroxyalkyl, while R ² to R ⁴ denote in full what has been said for compounds of formula I, characterized in that the secondary amines of formula I, wherein R ¹ = H obtained according to item 3, alkylates haloalkanols in the presence of alkaline agents, preferably potassium carbonate, in boiling acetone. 5. A process for the preparation of compounds of formula I according to item 1, wherein R ¹ is limited to hydroxyalkyl, while R ² to R ⁴ denote in full what has been said for compounds of formula I, characterized in that the secondary amines formula I where R ¹ = H, obtained according to point 3, the halo or alkylated with an appropriate halo ketone carbonyl and the resulting intermediate is reduced, preferably sodium sodnoboritým. 6. A process for the preparation of compounds of formula I according to item 1, wherein R ¹ is limited to acyloxyalkyl, while R ² to R ⁴ denote in full what has been said for compounds of formula I, characterized in that amino alcohols of formula I Where R @ ¹ = hydroxyalkyl obtained in 4 and 5, acylated with the appropriate fatty acids or reactive derivatives thereof, i.e., halides, anhydrides or esters, preferably free acids in boiling xylene under conditions of " azeotropic esterification ". 7. A process for the preparation of the S-oxides of the compounds of formula (I) according to claim 1, wherein the compounds of formula (I) are selectively oxidized with hydrogen peroxide in an acid medium. A process for the preparation of N-oxides of compounds of formula I wherein R ¹ is limited to methyl and hydroxyalkyl, wherein R ² to R ⁴ denote the same as given for formula I, cyclize by an intramolecular substitution reaction sodium hydride in dimethylformamide at temperatures of 50-100 ° C in an inert atmosphere. 3. A process for preparing compounds of formula I according to claim 1, wherein R ¹ is limited to hydrogen, while R ² and R ⁴ denotes fully what was described for compounds of formula I wherein the N219003 formula They are neutralized with pharmaceutically acceptable inorganic or organic acids in suitable solvents, preferably ethanol, acetone or mixtures thereof with an ether. The solutions of the bases of formula I in ethanol are oxidized with a slight excess of hydrogen peroxide at room temperature. 9. A process for the preparation of salts of the compounds of the formula I according to claim 1, characterized in that the base is used Severography, n. P., Plant 7 Most Price 2,40 Kčs