CH624403A5 - Process for the preparation of piperidylidene derivatives - Google Patents

Description

The invention relates to a process for the preparation of piperidylidene derivatives which are suitable as active ingredients which produce an antipsychotic effect without extrapyramidal symptoms. Extrapyramidal symptoms (EPS) are among the most undesirable and common side effects of antipsychotic or neuroleptic drugs. The compounds produced according to the invention have a neuropharmacological profile which indicates a strong antipsychotic effect, but essentially does not tend to EPS.

The compounds have the general formulas Ia, Ib and II, which are defined in claim 1.

Non-toxic, pharmacologically acceptable salts of the aforementioned compounds of general formulas I or II with acids are also suitable as active ingredients. These salts can easily be prepared by conventional methods. The base is reacted with either the calculated amount of an organic or inorganic acid in a water-miscible solvent, such as acetone or ethanol, after which the salt is concentrated or cooled or by adding an excess of acid in a water-immiscible solvent, such as Diethyl ether or chloroform, is precipitated. Salts with organic acids are derived, for example, from the following acids: maleic, fumaric, benzoic, ascorbic, pamoa, amber, bismethylene salicyl, methane sulfone, ethane disulfone, vinegar, propion, wine, salicyl , Lemon, glucon, mich, apple, almond, cinnamon, citracon, asparagine, stearin, palmitin, itacon, glycol, p-aminobenzoe, glutamine, benzenesulfone or theophyllines acetic acid, as well as 8-halogen theophyllins, such as 8-bromo-theophyl-lin. Salts with inorganic acids are derived, for example, from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, cyclohexylsulfamic acid, phosphoric acid and nitric acid. These salts can of course also be produced by the classic process of double decomposition of suitable salts.

The compounds of the general formulas Ia, Ib and II are prepared as defined in the characterizing part of claim 1. In general, a suitably substituted xanthone, thioxanthone or dibenzoxepinone is used for 30 minutes to 4 hours in an inert organic solvent, e.g. an ether, such as diethyl ether, dioxane or tetrahydrofuran, at temperatures from room temperature to the reflux temperature of the solvent with an N-methylpiperidyl magnesium halide. The tricyclocarbinol intermediate is dehydrated to the olefin by acid or heat treatment.

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624 403

To prepare the N-unsubstituted compounds of the general formula Ia and Ib, the N-methylpiperidylidene derivative is treated with cyanogen bromide. The N-cyanamide obtained is reacted with an acid to give the N-unsubstituted derivative, which can be N-alkylated by one of the following methods:

a) Direct alkylation with an alkyl bromide;

b) acylation with an acyl chloride to the corresponding amide with subsequent reduction with lithium aluminum hydride; or c) reaction with ethylene oxide.

U.S. Patents 3,275,640 and 3,055,903 describe piperidylidene thioxanthenes. Piperidylidene-dibenzoxepin is known from the South African patent specification 67/04371. Furthermore, US Pat. No. 3,470,188 describes piperidylidene xanthenes and thioxanthenes. However, none of the cited documents indicate that the compounds of the general formula I have an antipsychotic effect without EPS. BE-PS 808 347 describes dinuclear substituted thioxanthenes with a heterocyclically substituted propyl or propylidene side chain, which act as neuroleptics with reduced extrapyramidal symptoms.

There is evidence that antipsychotic drugs cause EPS by interacting with neurotransmission in a nigrostriatal, dopaminergic way. They are believed to block the dopamine receptors in the neostriatum. Therefore, the ability of a drug to block the striatal dopamine receptors is a measure of their EPS tendency.

To determine the extent to which drugs block the striatal dopamine receptors, a test procedure was developed by Unger-stedt; see. Ungerstedt and Arbuthnott, Brain Res. Vol. 24 (1970), p. 485; Ungerstedt, Actaphysiol. scand., Suppl. Vol. 367 (1971) p. 49. Rats are used in which unilateral pathological changes in the substantia nigra are caused by injection of 6-hydroxydopamine. This treatment causes a degeneration of the nigrostriatal, dopaminergic pathway, combined with a marked decrease in the dopamine content of the neostriate on the side of the pathological change. Animals with this pathological change develop postural and motor asymmetries, which are changed by drugs that influence dopaminergic activity. Amphetamine, which releases dopamine and norepinephrine from catecholaminergic neurons, causes these rats to turn in a direction toward the pathological change. Since a much larger amount of dopamine is released by amphetamine from the intact nigrostratal neurons on the unchanged side than is the case on the pathologically changed side, the rotation or gyro behavior is obviously due to the predominance of the activation of striatal dopamine receptors the intact side. The ability of a drug to counteract this gyro behavior is therefore a measure of its ability to block the striatal dopamine receptors, and thus an indication of its ability to produce EPS.

In order to predict the potential ability of a drug to cause EPS, the R / A ratio is calculated by a method for determining antipsychotic activity in rats. The R / A ratio is the ratio of EDso (ip) for the antagonism of the rotational movement induced by amphetamine to the EDso (ip) for blocking the acquisition of the prevention of shock. The ED 50 values of some clinically recognized antipsychotics in the avoidance and rotation test and the R / A ratios are given in Table I. Chlorpromazine has an R / A ratio of 1.3. Antipsychotics with a significantly higher propensity to cause EPS than chlorpromazine, e.g. Trifluoperazine, haloperidol and pimozide have ratios of 0.3 to 0.5. The two antipsychotics that are known to cause EPS to a lesser extent than chlorpromazine, i.e. Thioridazine and clozapine have ratios of 2.7 and 3.8, respectively. A high R / A ratio therefore allows the prediction that a drug has a low tendency to cause EPS.

Table I

Drug

A

R

R / A

Antagonism of the

Antagonism of the

Acquisition of amphetamine

Avoidance induced

reaction in rats

Rotary motion

EDso mg / kg (ip)

in rats

ED50 mg / kg (ip)

Chlorpromazine

1.5

2.0

1.3

Trifluorperazine

0.26

0.12

0.46

Haloperidol

0.16

0.05

0.31

Pimozide

0.24

0.08

0.30

Thioridazine

5.1

13.7

2.7

Clozapine

6.6

25.4

3.8

Special piperidylidene derivatives of the general formulas Ia, Ib and II as well as subsequent reaction products with a large R / A ratio, which should be free of EPS tendencies, are listed below.

I.4- (2-chloro-9-xanthenylidene) -l-methylpiperidine

2. l-Methyl-4- (2-methylthio-9-xanthenylidene) piperidine

3. 4- (2-fluoro-9-xanthenylidene) -l-methylpiperidine

4. 4- (2-bromo-9-xanthenylidene) -l-methylpiperidine 5.4- (2-cyano-9-xanthenylidene) -1-methylpiperidine

6. 4- (6-Oilor-2-fluorine-9-xanthenylidene) -l-methylpiperidine

7. 4- (2-chloro-9-xanthenylidene) piperidine

8.4- (2-chloro-9-xanthenylidene) -l-ethylpiperidine

9. 4- (2-chloro-9-xanthenylidene) -l- (β-hydroxyethyl) piperidine

10. 4- (2-chloro-9-xanthenylidene) -l-n-propylpiperidine

II.4- (2-chloro-9-xanthenylidene) -l-cyclobutylmethylpiperidine

12. 4- (2-bromo-9-xanthenylidene) piperidine

13. 4- (2-bromo-9-xanthenylidene) -l- (β-hydroxyethyl) piperidine

14. 4- (9-chloro-l (6H) -dibenz- [b, e] -oxepinylidene) -1-methylpiperidine

15.4- (2-cyano-9-thioxanthenylidene) -l-methylpiperidine 16. 4- (2-chloro-9-xanthenylidene) -l- (3-hydroxypropyl) piperidine

17.4- (2-trifluoromethyl-9-xanthenylidene) -l-n-butylipiperidine 18. 4- (2-bromo-9-xanthenylidene) -l-n-butylpiperidine

The ED 50 values of these compounds for the avoidance and rotational movement studies and their R / A ratios are listed in Table II.

Tables

Connection A R R / A

Antagonism of Acquisition Antagonism of the Avoidance Reaction Induced by Amphetamine in Rats

EDso mg / kg (ip) movement in rats

ED50 mg / kg (ip)

1

0.23

2.8

12.2

2nd

0.6

1.8

3.0

3rd

0.71

5.6

7.9

4th

0.3

1.6

5.3

5

0.09

0.29

3.2

6

0.15

1.12

7.5

7

1.7

8.1

4.8

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0.5

1.8

3.6

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Table II (continued)

connection

A

R

R / A

Antagonism of the acquisition

Antagonism of the

the avoidance reaction by amphetamine

in rats induced rotation

ED5 (1 mg / kg (ip)

movement in rats

EDso mg / kg (ip)

9

0.2

1.3

6.5

10th

0.6

2.4

4.0

11

0.5

1.6

3.2

12th

0.6

4.0

6.7

13

0.6

2.1

3.5

14

1.6

> 24

> 15

15

0.16

0.67

4.0

16

0.2

0.78

3.9

17th

0.1

1

10th

18th

0.6

3.0

5.0

The pharmaceutical preparations preferably contain an amount of active ingredient of about 1 to 300 mg, in particular about 5 to 200 mg, per dose unit.

Both solid and liquid carriers can be used. Examples of solid carriers are lactose, magnesium stearate, kaolin, sucrose, talc, stearic acid, gelatin, agar, pectin and gum arabic. The preparations can be tableted or processed into powders. They can be placed in hard gelatin capsules or made into pastilles. The amount of solid support is not critical, preferably about 25 mg to 1 g is used. Examples of liquid carriers are syrup, peanut oil, olive oil, sesame oil and water. Liquid preparations can be in the form of soft gelatin capsules, syrups, emulsions or liquid suspensions. In the same way, the carriers or diluents can comprise a material which disintegrates over time, such as glyceryl monostearate or glyceryl distearate, optionally together with a wax.

Preparations which can be administered parenterally, for example for intramuscular administration, are obtained by dissolving a water-soluble salt of the drug in water or a salt solution in a concentration such that about 2 to 50 mg of active ingredient are contained in 1 ml of solution. This solution can then be filled into single vials or multiple dose vials.

The compounds of the formulas Ia, Ib or II as well as their derivatives and non-toxic salts with acids are used internally, preferably together with a pharmacologically acceptable carrier, in a non-toxic amount which is sufficient for the need for an antipsychotic influence, in a non-toxic amount which is sufficient to achieve the desired antipsychotic effect without causing extrapyramidal symptoms. The active compounds are administered orally or intramuscularly, preferably in one dose unit each, in an active, non-toxic amount of about 1 to 300 mg, based on the compounds of the general formulas I or II. Consistent doses are advantageously given until the desired effect is achieved, for example two or three times a day. The daily active ingredient doses are about 2 to 900 mg, preferably about 10 to 600 mg. If one proceeds in the manner described above, there is an antipsychotic effect with low EPS.

The examples illustrate the invention.

example 1

4.3 g (0.175 gram atom) of magnesium shavings, which just with slightly refluxing, anhydrous tetrahydrofu-

are covered, 1 ml of a tetrahydrofuran solution of base obtained from 29.8 g (0.175 mol) of 4-chloro-N-methylpiperidine hydrochloride (base in about 50 ml of tetrahydrofuran) are added under nitrogen. The base has previously been released by treatment with diethyl ether, potassium hydroxide cookies and 1 ml of water, by extraction with diethyl ether and evaporation under reduced pressure of the anhydrous diethyl ether solution. A small amount of methyl magnesium bromide in diethyl ether is added. As soon as the reaction begins, the remaining base is diluted with about 150 ml of tetrahydrofuran with stirring. This solution is added dropwise over the course of 90 minutes, with slight heating. The resulting mixture is refluxed for one hour and stirred. While refluxing gently, 27.0 g (0.117 mol) of 2-chloro-xanthone are added in portions with stirring. The reaction mixture is then stirred for one hour and boiled under reflux. The reaction mixture is then poured into a mixture of ice, water and ammonium chloride, as a result of which an oil which later solidifies precipitates. By recrystallization from ethyl acetate, 2-chloro-9- (l-methyl-4-piperidyl) -xanthen-9-ol of mp 206 to 208 ° C. is obtained.

A mixture of 12.5 g (0.038 mol) of the xanthene-9-ol, 14.0 g (0.76 mol) of o-sulfobenzoic anhydride and 380 ml of propionic acid is heated under reflux for three hours. The reaction mixture is then heated to 100 ° C. under reduced pressure. The syrup obtained is dissolved in water, made strongly alkaline with 40% sodium hydroxide solution and extracted with diethyl ether. The dried extract is evaporated. The free base obtained is dissolved in ethyl acetate and 4.4 g of maleic acid are added. 4- (2-Chloro-9-xanthenylidene) -l-methylpiperidine maleate of mp 206 ° to 207 ° C. is obtained.

Example 2

According to Example 1, a Grignard reagent consisting of 2.4 g (0.1 gram atom) of magnesium and 13.3 g (0.1 mol) of 4-chloro-N-methylpiperidine with 12.1 g (0.05 mol) is 2 -Thiomethylxanthon to 9- (l-methyl-4-piperidyl) -2-thiomethylxanthen-9-ol of mp 169 ° C.

The xanthene-9-ol (10.8 g, 0.032 mol) prepared in this way is dehydrated by refluxing with 11.6 g (0.064 mol) of sulfobenzoic anhydride and 258 ml of propionic acid. After working up the reaction mixture, extraction with methylene chloride and addition of diethyl ester, unreacted xanthene-9-ol precipitates, which is filtered off. The filtrate is concentrated to an oil. This oil is converted in diethyl ether into the maleate of l-methyl-4- (2-methylthio-9-xanthenylidene) piperidine, melting at 172 to 180 ° C.

Example 3

A Grig-nard reagent made from 0.53 g (0.0216 gram atom) of magnesium and 2.9 g (0.0216 mol) of 4-CMor-N-methylpiperidine is mixed with 2.3 g (0.0108 mol) of 2 -Fluorxanthone implemented according to Example 3. The reaction mixture is heated for four hours and then decomposed with a saturated ammonium chloride solution. 2-Fluoro-9- (l-methyl-4-piperidyl) xanthene-9-ol of mp 193 to 200 ° C. is obtained.

A mixture of 0.58 g (0.002 mol) of the xanthene-9-ol obtained above, 0.34 g (0.004 mol) of sulfobenzoic anhydride and 20 ml of propionic acid is heated under reflux for about 15 minutes and then cooled without heating with stirring. The reaction mixture is then evaporated under reduced pressure. The residue is taken up in methylene chloride. The product is converted with maleic acid into the maleate of 4- (2-fluoro-9-xanthenylidene) -l-methylpiperidine, melting point 189 to 193 ° C.

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Example 4

A stirred suspension of 2.43 g (0.1 gram atom) of magnesium shavings in 5 ml of tetrahydrofuran is mixed with a few drops of ethyl bromide under nitrogen. After the start of the reaction, 13.4 g (0.1 mol) of 4-chloro-l-methylpiperidine in 50 ml of tetrahydrofuran were added at a rate sufficient to maintain the reflux. The mixture is stirred and heated under reflux for one hour, then cooled to 0 ° C. and 20.6 g (0.075 mol) of 2-bromoxanthone are added in portions. The mixture is stirred for four hours and heated under reflux and then poured into a solution of 26.5 g (0.5 mol) of ammonium chloride in 500 ml of ice water. The crystalline alcohol, 2-bromo-9- (l-methyl-4-piperidyl) -xanthene-9-ol, from mp 201 to 202 ° C. is filtered off.

The alcohol obtained above (20.0 g, 0.053 mol) is dissolved in 200 ml propionic acid and 20.0 g (0.011 mol) sulfobenzoic anhydride. The solution is heated under reflux for one hour and concentrated under reduced pressure. The residue is then diluted with water. The mixture is made alkaline with 2.5 N sodium hydroxide solution and extracted with diethyl ether. The ether extracts are dried and concentrated. This gives 4- (2-bromo-9-xanthenylidene) -l-methylpiperidine, the maleate of which has a melting point of 206 ° C. (decomposition).

Example 5

A stirred solution of 7.0 g (0.065 mol) of cyanogen bromide in 150 ml of benzene is at 50 to 55 ° C with 19.5 g (0.055 mol) of 4- (2-bromo-9-xanthenylidene) -l-methylpiperidine in 150 ml of benzene transferred. The solution is heated for two and a half hours and then evaporated under reduced pressure. The residue is dissolved in methylene chloride and the solution obtained is washed with in hydrochloric acid, water and saturated, aqueous sodium chloride solution. The organic solution is concentrated to a semi-crystalline residue which is heated under reflux for sixteen hours with a solution of 225 ml of acetic acid and 25 ml of 12N hydrochloric acid in 125 ml of water. The solution is then concentrated and the residue is dissolved in water. The solution obtained is then made alkaline with sodium hydroxide and the mixture extracted with ethyl acetate. The extracts are concentrated. A solution of the crystalline residue in acetonitrile is treated with methanesulfonic acid in acetonitrile / diethyl ether. 4- (2-Bromo-9-xanthenylidene) piperidine methanesulfonate of mp 257.5 to 258.5 ° C. is obtained in the form of colorless crystals.

Example 6

Phenol (1.0 mol) in about 200 ml of dimethylformamide is added dropwise to 1.0 mol of sodium hydride which is suspended in about 300 ml of dimethylformamide, the reaction temperature being kept at about 25 ° C. The mixture is stirred until the evolution of hydrogen has ended. 6-Chlorophthalide (1.0 mol) in about 250 ml of dimethylformamide is then slowly added. The mixture obtained is heated under reflux for two hours and then left to stand at room temperature overnight. The reaction mixture is then diluted with ice / water and extracted several times with diethyl ether. The aqueous phase is acidified with dilute hydrochloric acid and extracted with diethyl ether. The extract is dried and concentrated to a rubber-like solid. This solid is recrystallized from the smallest possible volume of alcohol. 2-Phenoxymethyl-5-chlorobenzoic acid of mp 149 ° to 155 ° C. is obtained.

A mixture of 1.0 mole of the benzoic acid obtained above, 570 g of Supercel and about 2200 ml of xylene is stirred. About 300 ml of the xylene are then distilled off. After cooling, 570 g of phosphorus pentoxide is added along with a sufficient amount of anhydrous xylene to facilitate stirring. This mixture is stirred for 17 hours and refluxed, then cooled and filtered. The filter cake is washed thoroughly with xylene and then with diethyl ether. The filtrates are combined and concentrated to an oil which crystallizes after treatment with hexane. 9-Chloro-ll-keto-6, ll-dihydrodibenzo [b, e] -oxepine of melting point 82 to 83 ° C. is obtained.

A Grignard reagent in tetrahydrofuran obtained from 0.70 mol of 4-chloro-N-methylpiperidine and 0.54 gram atom of magnesium is mixed with 0.38 mol of the oxepinone obtained above in 750 ml of tetrahydrofuran at such a rate that the mixture is moderately reduced to Reflux boils. The mixture is then heated under reflux for about 90 minutes and stirred overnight at room temperature. The reaction mixture is poured onto ice, treated with ammonium chloride and extracted several times with diethyl ether. The combined ether fractions are dried and evaporated. This gives 9-chloro-ll- (l-methyl-4-piperidyl) -6, ll-dihydrodibenzo- [b, e] -oxepin-ll-ol; F. Hydrochloride 150 to 160 ° C.

0.5 mol of the oxepinol obtained above is stirred with 1.15 mol of o-sulfobenzoic anhydride and 3400 ml of propionic acid. The mixture is heated on a steam bath for one hour, made alkaline and extracted with methylene chloride. The organic extract is dried and concentrated under reduced pressure to an oil which is chromatographed on silica gel eluting with chloroform. The combined oil crystallizes when treated with petroleum ether. 4- (9-Chloro-ll (6H) -dibenz- [b, e] -oxepinylidene) -l-methylpiperidine of melting point 145 to 146 ° C. is obtained; Hydrochloride F. 289 ° C (decomposition).

Example 7

A solution of 14.1 g (0.133 mol) of cyanogen bromide in 200 ml of benzene is at 35 ° C for 15 minutes with a solution of 31.2 g (0.10 mol) of 4- (2-chloro-9-xanthenylidene) -l - treated methylipiperidine in 250 ml of benzene. The solution is then heated to 55 ° C for four hours. The solvent is then evaporated off and the residue is recrystallized from ethanol. 4- (2-Chloro-9-xanthenylidene) -l-cyanopiperidine of melting point 148 to 150 ° C. is obtained. A solution of this compound (27.2 g, 0.084 mol) in 450 ml of glacial acetic acid, 250 ml of water and concentrated hydrochloric acid is heated under reflux for 18 hours. The major part of the solvent is then evaporated. The residue is made alkaline and extracted with ethyl acetate. The extracts are washed with water and the solvent is evaporated off. The residue is treated with ethanol and filtered off.

The filtrate is evaporated. 4- (2-Chloro-9-xanthenylidene) piperidine is obtained as the residue. The free base is dissolved in acetonitrile and treated with 1 equivalent of methanesulfonic acid. 4- (2-Chloro-9-xanthenylidene) piperidine methanesulfonate of melting point 256 to 260 ° C. is obtained.

Example 8

10.7 g (0.038 mol) of 2-iodo-4-chlorobenzoic acid, 4.3 g (0.038 mol) of 4-fluorophenol, 5.25 g (0.038 mol) of calcium carbonate and 1.14 g of copper (I) Chloride in 180 ml of pyridine heated under reflux overnight. After appropriate work-up, 4-chloro-2- (4-fluorophenoxy) benzoic acid of mp 154 to 173 ° C is obtained. Heating the acid for one hour (5.0 g, 0.019 mol) with 75 g of sulfuric acid gives the corresponding 2-fluoro-6-chloro-9-xanthone, mp 210 ° C.

By reacting the xanthone (4.9 g, 0.0197 mol) with

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6

a Grignard reagent obtained from 5.3 g (0.039 mol) of 4-CMor-N-methylpiperidine and 0.95 g (0.039 mol) of magnesium in tetrahydrofuran gives 6-chloro-2-fluoro-9- (l -methyl-4-piperidyl) -xanthene-9-ol of mp 107 to 127 ° C.

The xanthene-9-ol (1.7 g, 0.0049 mol) is dehydrated by heating with 1.8 g (0.0098 mol) of o-sulfobenzoic acid anhydride in 35 ml of propionic acid for one hour. The product is isolated as hydrochloride. 4- (6-Chloro-2-fluoro-9-xanthenylidene) -l-methylpiperidine hydrochloride of mp 235 ° C. is obtained.

Example 9

A solution of 18.6 g (0.176 mol) of cyanogen bromide in 200 ml of anhydrous benzene is gradually mixed with a solution of 57.9 g (0.168 mol) of 1-methyl-4- (2-trifluoromethyl-) at 50 ° C within four hours. 9-xanthenylidene) -piperidine added. The reaction mixture is heated and stirred for one and a half hours. Excess water is then added. The benzene solution is extracted with excess dilute acetic acid. The acetic acid extract is washed with water and the benzene solution is evaporated. The 1-cyano intermediate is obtained. This product (20 g, 0.0561 mol) is heated under reflux for 18 hours with a solution of 420 ml of acetic acid, 280 ml of water and 42 ml of concentrated hydrochloric acid. The reaction mixture is concentrated under reduced pressure to a volume of approximately 125 ml, diluted with 400 ml of water and extracted with diethyl ether. The aqueous phase is made alkaline with excess sodium hydroxide solution. The mixture obtained is extracted with diethyl ether. Nadulem evaporation of the ether extract gives 4- (2-trifluoromethyl-9-xanthenylidene) -piperidine.

is Example 10

A solution of 4- (2-chloro-9-xanthenylidene) -l-methylpi-peridine in acetonitrile is converted with 1 equivalent of methanesulfonic acid into the corresponding methanesulfonate, melting point 225 to 228 ° C.

B

Claims (6)

624403 2. The method according to claim 1, characterized in that one carries out the reaction with an N-methylpiperidylmagnesium halide for 30 minutes to four hours in an inert organic solvent at temperatures from room temperature to the reflux temperature of the solvent. 2nd PATENT CLAIMS 1. Process for making compounds of the formulas 0 ! CH3 (Ia) £ h3 he*) (H) where in the formula la X is a 2-chloro, 2-fluorine or 2-bromo atom, the 2-methylthio or 2-cyano group and Z is a hydrogen atom, or X is a 2-fluorine atom and Z is a 6-chlorine atom , and their salts with acids, characterized in that an appropriately substituted 9-xanthone, 9-thioxanthone or dibenzoxepin-ll-one is reacted with an N-methyl-piperidylmagnesium halide and the carbinol formed as an intermediate is dehydrated and the base obtained is optionally in a Converts salt. 3. The method according to claim 1, characterized in that the carbinol obtained as an intermediate is dehydrated with an acid or by heating. 4. The method according to claim 1, characterized in that 2-chloro-9-xanthone is reacted with N-methylpiperidylmagnesium chloride and the 2-chloro-9- (methyl-4-piperidyl) xanthene-9-ol obtained as an intermediate dehydrated by heating with o-sulfobenzoic anhydride and propionic acid. 5. The method according to claim 4, characterized in that the product is converted into the corresponding methanesulfonate with methanesulfonic acid. 6. A process for the preparation of the N-unsubstituted derivative of the formulas Ia, Ib and II, characterized in that the compounds of the formulas Ia, Ib and II are prepared by the process of claim 1 and these are reacted with cyanogen bromide and the N-cyanamide obtained reacted with an acid to form the N-unsubstituted derivative.