Title:
4(1-ALKYL-4-PIPERIDYLIDINE)-4H-BENZO ν,5] CYCLOHEPTA [1,2-6]
United States Patent 3682930


Abstract:
The present invention concerns novel compounds of the formula, ##SPC1## Wherein R1 is hydrogen, halogen, or alkoxy of one to four carbon atoms, R2 is alkyl of one to four carbon atoms, and --A--B-- is --CO--CH2 --CO-- or --CO--CH2 --, and pharmaceutically acceptable acid addition salts thereof. The compounds are histaminolytics. Compounds wherein --A--B-- is --CO--CH2 -- are antaminics, i.e. aside from histaminolytic properties, they possess serotonin -- antagonistic and anticholinergic properties. 20 Claims, No Drawings



Inventors:
Jean-pierre Bourquin, 4165 Magden (Magden Ag, CH)
Gustav Schwarb, Felsenweg 9. (4123 Allschwil, CH)
Erwin Waldvogel, 39 Gartenstrasse (4147 Aesch, CH)
Application Number:
05/120738
Publication Date:
08/08/1972
Filing Date:
03/03/1971
Assignee:
JEAN-PIERRE BOURQUIN
GUSTAV SCHWARB
ERWIN WALDVOGEL
Primary Class:
Other Classes:
544/129, 544/364, 549/44
International Classes:
C07D333/24; C07D333/80; (IPC1-7): C07D29/36
Field of Search:
260/293.57
View Patent Images:



Primary Examiner:
Henry, Jiles R.
Assistant Examiner:
Winters S. D.
Attorney, Agent or Firm:
Gerald, Sharkin Robert Honor Frederick Weinfeldt Richard Vila Walter Jewell D. S. H. E. F.
Claims:
1. A compound of the formula: ##SPC11## wherein R1 is hydrogen, halogen or alkoxy of one to four carbon atoms, R2 is alkyl of one to four carbon atoms, and --A--B-- is --CH2 --CO-- or --CO--CH2 --, or a pharmaceutically

2. The compound of claim 1, which is 4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H

3. The compound of claim 1, which is 4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H

4. The compound of claim 1, which is 4-(1-ethyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)

5. The compound of claim 1, which is 4-(1-ethyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)

6. The compound of claim 1, which is 4-(1-isopropyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10

7. The compound of claim 1, which is 4-(1n-butyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H

8. The compound of claim 1, which is 6-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiop

9. The compound of claim 1, which is 6-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiop

10. The compound of claim 1, which is 4-(1-isopropyl-4-piperidylidene)- 4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9(

11. The compound of claim 1, which is 4-(1-n-butyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10

12. The compound of claim 1, which is 7-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiop

13. The compound of claim 1, which is 7-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiop

14. The compound of claim 1, which is 6-bromo-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thioph

15. The compound of claim 1, which is 6-bromo-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thioph

16. The compound of claim 1, which is 7-methoxy-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thio

17. The compound of claim 1, which is 7-methoxy-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thio

18. A compound of the formula ##SPC12##

Description:
This invention relates to benzocycloheptathiophene derivatives.

In accordance with the invention, there are provided new compounds of formula I, ##SPC2## wherein R1 is hydrogen, halogen, or alkoxy of one to four carbon atoms, R2 is alkyl of one to four carbon atoms, and --A--B-- is the group --CH2 --CO-- or --CO--CH2 -- , and acid addition salts thereof.

Further, in accordance with the invention a compound of formula I is obtained by a process comprising A. hydrolyzing a compound of formula II, ##SPC3## wherein R1 and R2 are as defined above, and X is in the 9 or 10 position and is an --OR radical, Wherein R is alkyl or 1 to 4 carbon atoms, a radical of formula III, wherein R3 is hydrogen or alkyl of one to four carbon atoms, and R4 is hydrogen or alkyl of one to four carbon atoms which is unbranched on the α carbon atom, or R3 and R4, together with the nitrogen atom, form a saturated 5- or 6-membered heterocyclic ring, the heterocycle being selected from the group of heterocycles containing one or two nitrogen atoms, one nitrogen atom and a further hetero atom selected from oxygen and sulphur, and one nitrogen atom and one nitrogen atom substituted by an alkyl radical of one to four carbon atoms, Or B. alkylating a compound of formula IV, ##SPC4## wherein R1 is as defined above, To obtain a compound of formula Ia, ##SPC5## Wherein R1 and R2 are as defined above.

The resulting compound of formula I may be isolated in the form of a free base or as an acid addition salt thereof.

Particularly suitable R1 radicals are hydrogen, chlorine, bromine and methoxy.

The symbol X in formula II is suitably the tert.butoxy group, the dimethylamino, diethylamino or n-butylamino radical, and when X denotes a heterocycle, it may be, e.g., the piperidine, piperazino, morpholino, pyrrolidino or N-methyl-piperazino radical.

The term "inert solvent" as used herein signifies an organic solvent which is inert under the reaction conditions.

The production of compounds of formula I in accordance with process variant a) may, for example, be effected by heating compounds of formula II in an aqueous acid solution. The reaction temperature is not critical. A suitable reaction temperature is approximately 50° to 100° C; the reaction is preferably effected at the reflux temperature of the reaction mixture.

Suitable acids are aqueous inorganic acids, e.g. hydrochloric, sulphuric or phosphoric acid, and aqueous organic acids, e.g. formic, acetic, fumaric or oxalic acid.

The hydrolysis may also be carried out by hydrolyzing a mixture of compounds of formula II substituted in the 9 position with corresponding compounds of formula II substituted in the 10 position. Such hydrolysis results in a mixture of isomers from Ia and Ib, ##SPC6## wherein R1 and R2 are as defined above, and said isomers may be separated in conventional manner, for example by fractional crystallization of a salt, e.g. a fumarate, to give the desired isomer.

Alkylation of the compounds of formula IV in accordance with process variant b) may be effected in accordance with known methods, e.g. by treatment with alkyl halides, with esters of organic sulphonic acids, e.g. methane-, benzene- or p-toluene-sulphonic acid, or with dialkyl sulphates, in an inert solvent and in the presence of a basic condensation agent.

The compounds of formula I may be isolated from the worked up reaction mixture in conventional manner, e.g. chromatographically.

The compounds of formula II are likewise new.

Compounds of formula IIa, ##SPC7## wherein R1 and R2 are as defined above, and X' is in the 9 or 10 position and is a radical of formula III, may, for example, be obtained by reacting a compound of formula V, ##SPC8## wherein R1 and R2 are as defined above, and Y is chlorine or bromine in the 9 or 10 position, or a mixture of a compound of formula V substituted in the 9 position, with a compound of formula V substituted in the 10 position, in the presence of an acid-binding agent, e.g. an alkali metal amide or hydride or a potassium alcoholate, e.g. a potassium tert.butylate, with the corresponding amine or saturated, nitrogen-containing heterocycle.

This reaction yields a mixture of compounds of formula IIa substituted in the 9 position, with compounds of formula IIa substituted in the 10 position. A separation may be effected in accordance with known methods, but is not necessary; the worked up mixture is generally further worked up as such.

Compounds of formula IIb, ##SPC9## wherein R, R1 and R2 are as defined above, may be produced by reacting compounds of formula V with a potassium alcoholate, preferably an excess of the same, if desired in an inert organic solvent, e.g. a cyclic or open chain ether such as dioxane. The reaction is preferably effected at room temperature or at a slightly elevated temperature.

This reaction likewise yields a mixture of the compounds of formula IIb substituted in the 9 position, with the compounds of formula IIb substituted in the 10 position, which mixture is generally not separated, but further worked up after working up the reaction mixture.

The compounds of formula IV may, for example, be obtained by dealkylation of compounds of formula Ia in accordance with known methods. For example, compounds of formula Ia are treated with a cyanogen halide, preferably cyanogen bromide, or a halogen formic acid ester. In this reaction the radical R2 is first replaced by the cyano or alkoxycarbonyl group. This reaction is conveniently effected in an inert organic solvent, e.g. an open chain or cyclic ether such as diethyl ether or tetrahydrofuran, an aromatic hydrocarbon such as benzene, a chlorinated aliphatic hydrocarbon such as methylene chloride, and at a reaction temperature between room temperature and the boiling temperature of the reaction mixture. The cyano or alkoxycarbonyl group is subsequently split off in accordance with known methods, e.g. by acid hydrolysis.

The compounds of formula V, which are likewise new, may be obtained by dehydrating a compound of formula VI, ##SPC10## wherein R1, R2 and Y are as defined above.

The removal of water may, for example, be effected with a mineral acid such as hydrochloric acid in ethanol, or with a strong organic acid, acetic anhydride or an inorganic acid halide as water-removing agent. However, the reaction is preferably effected with hydrobromic acid in an inert organic solvent, e.g. a lower alcohol.

Compounds of formula VI may, for example, be produced by adding dropwise a solution of a compound of formula VII, wherein R1 and Y are as defined above, in an inert solvent e.g. an open chain or cyclic ether such as tetrahydrofuran or diethyl ether, to a magnesium organic halogen compound of formula VIII, wherein R2 is as defined above, and Hal signifies chlorine, bromine or iodine, in the same inert solvent in which it was prepared, conveniently stirring the reaction mixture for about 1 1/2 hours, preferably at room temperature, and subsequently hydrolyzing. Hydrolysis may, for example, be effected with an aqueous ammonium chloride solution in the cold.

The compounds of formula VII are likewise new and may, for example, be produced by chlorinating or brominating a compound of formula IX, wherein R1 is as defined above, to obtain the corresponding 9,10-dichloro- or 9,10-dibromo compounds, and subsequently converting the resulting compounds into compounds of formula VII under alkaline conditions, e.g. by reaction with a solution of potassium hydroxide in an inert organic solvent such as methanol, or, e.g., by heating with a commercial solution or sodium or potassium hydroxide in the presence of a lower alcohol solvent.

The above 9,10-dibromo compounds obtained from the compounds of formula IX may, for example likewise be obtained by reacting a compound of formula X, wherein R1 is as defined above, with the stoichiometric amount of N-bromosuccinimide in an inert organic solvent, e.g. a chlorinated aliphatic hydrocarbon such as carbon tetrachloride.

Insofar as the production of the starting materials is not described, the compounds are known or may be produced in accordance with known processes or in a manner analogous to the processes described herein or to known processes.

The compounds of formula I and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals. More particularly, compounds of formula Ia are useful as specific histaminolyties, as indicated by their showing significant histaminolytic properties in the histamine toxicity test in guinea pigs, without showing any significant serotonin-antagonistic or anticholinergic properties in the serotonin and acetylcholine toxicity tests in guinea pigs. Particularly pronounced histaminolytic properties are observed with compounds of formula Ia, wherein R2 is methyl, notably 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one and 6-chloro-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta-[1,2-b]thiophen-10(9H)-one.

The compounds of formula Ib, on the other hand, are useful antaminics, i.e. they are useful in antagonizing the effects of each of the biogenic amines histamine, serotonin and acetylcholine, as indicated by the above mentioned toxicity tests in guinea pigs.

For use of a compound of formula Ia as a specific histaminolytic or a compound of formula Ib as an antaminic, the dose to be administered will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, the doses are similar for compounds of formula Ia and compounds of formula Ib, and satisfactory results for each group of compounds are obtained at doses between about 0.004 mg/kg and 0.15 mg/kg animal body weight. For the larger mammals, the daily dose is from about 0.25 to about 10 milligrams of the compound, which may be administered in divided doses two to three times a day or in sustained release form. Unit dosage forms suitable for oral administration incorporate from about 0.1 to about five milligrams of the compound, in association with a pharmaceutical carrier or diluent.

The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts possess the same order of activity as the free bases and are readily prepared in conventional manner. Suitable such salt forms include mineral acid salts such as the hydrochloride, hydrobromide and sulphate, and organic acid salts such as the fumarate, maleate, tartrate, methane-, ethane- and benzene-sulphonate, citrate and malate.

The invention also provides a pharmaceutical composition comprising an active agent a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or diluent.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.

EXAMPLE 1:

4-(1-Methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one.

A mixture of 24.6 g of crude 4-(1 -methyl-4-piperidylidene)-9-piperidino- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base is dissolved in 250 cc of 2 N hydrochloric acid, and the solution is heated under reflux for one hour. The reaction mixture is subsequently made alkaline with a concentrated caustic soda solution while cooling at 20°-25°, and the precipitated base is extracted portionwise with a total of 400 cc of chloroform. The combined chloroform extracts are washed thrice with 30 cc amounts of water, are dried over sodium sulphate and concentrated. The residue is dissolved in 50 cc of chloroform and adsorbed on 1000 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first 6 liters of eluate are discarded, the following four liters are jointly concentrated. An oily material, mainly consisting of the two isomers 4-(1 -methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)- one and 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-10(9H)-one (see Example 2), is obtained as residue. The mixture is separated by dissolving 19.7 g of the residue in 200 cc of isopropanol and boiling with 7g of fumaric acid. The reaction mixture is subsequently allowed to crystallize at room temperature for approximately three hours. The crystalline product is filtered and recrystallized from a 30-fold quantity of 95 percent ethanol. Pure 4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one fumarate, having a decomposition point of 197°-199°, is obtained.

The isopropanolic filtration mother liquor is used for the isolation of 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen- 10(9H)-one (Example 2).

The base is liberated by adding 200 cc of water to 7.4 g of the fumarate and making this alkaline with 3 N caustic soda solution. The base is extracted portionwise with 150 cc of chloroform. The combined chloroform extracts are washed with 50 cc of water, dried over sodium sulphate and subsequently concentrated by evaporation, and the oily residue is crystallized by boiling with 20 cc of ethyl acetate. After recrystallizing over night at 0°-5°, the crystalline product is filtered off and dried. The pure 4-(1-methyl-4-piperidylidene)- 4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one base, having a M.P. of 148°-149°, is obtained in this manner. Microanalysis agrees with the formula C19 H19 NOS. The structure was ascertained with the infrared, nuclear magnetic resonance and mass spectrograph spectra.

The mixture of 4-(1-methyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta-[1,2-b]thiophene base, used as starting material, may, for example, be produced as follows:

A mixture of 129 g of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2- b]thiophen-4-one, 214 g of N-bromosuccinimide, 1.2 g of benzoyl peroxide and 2000 cc of absolute carbon tetrachloride is boiled under reflux while stirring for three hours. The mixture is subsequently filtered whilst hot and the filtrate is concentrated to one third of its original volume. After allowing to stand at room temperature for several hours, the crystalline product is filtered off and dried. This crude product is recrystallized from a 7-fold quantity of chloroform. Pure 9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, having a M.P. of 134°-135° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C13 H8 Br2 OS . The structure was ascertained with the nuclear magnetic resonance spectrum.

A mixture of 70 g of 9,10-dibromo-9,10-dihydro-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, 31.6 g of potassium hydroxide and 3200 cc of methanol is heated under reflux while stirring for two hours. The mixture is subsequently stirred at 0°-5° for approximately four hours, and the crystalline product is filtered off. After recrystallizing from a 100-fold quantity of methanol, pure 9,10-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, having a M.P. of 134°-135°, is obtained. Microanalysis agrees with the formula C13 H7 BrOS . In accordance with the nuclear magnetic resonance spectrum the bromine atom is in the 9 or 10 position (probably in the 10 position).

5 g of magnesium activated with iodine are covered with a layer of 15 cc of absolute tetrahydrofuran, and the mixture is heated to reflux temperature. 2 g of freshly distilled 1-methyl-4-chloropiperidine and a few drops of 1,2-dibromoethane are subsequently added, whereby the Grignard reaction commences. 22.8 g of freshly distilled 1-methyl-4-chloropiperidine, dissolved in 30 cc of absolute tetrahydrofuran, are then added dropwise, without heating, at such a rate that the mixture boils continuously. After the dropwise addition is complete, the mixture is boiled under reflux for a further two hours, whereafter the magnesium is practically completely converted. A warm solution of 30 g of 9(10)-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4- one in 160 cc of absolute tetrahydrofuran is subsequently added dropwise while cooling at 20°-25° during the course of 1 hour. After stirring at 20°-25° for 1 1/2 hour, the reaction mixture is poured on a mixture of 250 g of ice water and 35 g of ammonium chloride, and the precipitated base is extracted portionwise with a total of 600 cc of chloroform. The combined chloroform phases are washed with 50 cc of water, dried over sodium sulphate and concentrated in a vacuum. The crude 9(10)-bromo-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-4-ol base is obtained as residue and is worked up as such.

A solution of 51 g of crude 9(10)-bromo-4-(1-methyl-4-piperidyl)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol and 420 cc of a 14 percent solution of hydrobromic acid in ethanol is boiled under reflux at an oil bath temperature of 100° for 1 hour. The mixture is subsequently concentrated in a vacuum and the residue dissolved in 100 cc of water. The solution is made alkaline with a concentrated caustic soda solution, whereupon the precipitated base is extracted thrice with 100 cc of chloroform. The combined chloroform extracts are washed with 50 cc of water, dried over sodium sulphate and concentrated by evaporation in a vacuum. The residue is dissolved in 70 cc of chloroform containing 5 percent of methanol and is adsorbed on 1000 g of silica gel. Elution is effected with chloroform containing 5 percent of methanol. The first 8 liters of eluate are discarded, the following 4 liters are jointly concentrated by evaporation. An oily evaporation residue is obtained, which is dissolved by boiling in 50 cc of isopropanol and is crystallized over night at 0°-5°. After filtering off the crystalline product and drying, the pure 9(10)-bromo-4 -(1-methyl-4-piperidylidene)- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base, having a M.P. of 149°-150°, is obtained. Microanalysis agrees with the formula C19 H18 BrNS . In accordance with the nuclear magnetic resonance spectrum the bromine atom is in the 9 or 10 position (probably in the 10 position).

A mixture of 24.2 g of 9(10)-bromo-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophene, 160 cc of piperidine, 330 cc of absolute dioxane and 14.6 g of potassium tert.butylate is boiled under reflux at an oil bath temperature of 130° while stirring for 2 hours. The mixture is subsequently cooled, filtered and concentrated by evaporation in a vacuum. The residue is dissolved in 300 cc of benzene, and this solution is washed out thrice with 50 cc amounts of water. After drying the benzene solution over sodium sulphate, this is concentrated by evaporation in a vacuum. A mixture of the crude, oily 4(1-methyl-4-piperidylidene)-9-piperidino-4H-benzo[4,5]cyclohepta[1,2- b]thiophene base and the 4(1-methyl-4-piperidylidene)-10-piperidino-4H- benzo[4,5]cyclohepta-[1,2-b]thiophene base is obtained as residue and is further worked up as such.

EXAMPLE 2:

4-(1-Methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one.

The isopropanolic filtration mother liquor of Example 1 is concentrated by evaporation in a vacuum. 100 cc of water and 6 g of potash are added to the evaporation residue, and the liberated base is extracted portionwise with 200 cc of chloroform. The chloroform extracts are washed with 50 cc of water and dried over sodium sulphate. After concentrating the chloroform solution, an oily residue is obtained, which is crystallized by boiling with 20 cc of ethyl acetate. After cooling over night at 0°-50°, the product is filtered off and dried. The pure 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]-cyclohepta[1,2- b]thiophen-10(9H)-one base, having a M.P. of 152°-153°, is obtained in this manner. Microanalysis agrees with the formula C19 H19 NOS. The structure was ascertained with the infrared, nuclear magnetic resonance and mass spectrograph spectra.

The fumarate is produced by dissolving 8 g of the pure base with 3.2 g of fumaric acid in 100 cc of absolute ethanol at the boil and allowing the solution to crystallize over night at 0°-5°. After filtration and drying, the pure 4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one hydrogen fumarate, having a M.P. of 192° (decomp.), is obtained.

EXAMPLE 3:

4-(1-Ethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-9(10 H)-one.

A mixture of 43 g of crude 4-(1-ethyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-ethyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta-[1,2-b]thiophene base is dissolved in 430 cc of 3 N hydrochloric acid and the solution is kept at 90° for 30 minutes. The reaction mixture is subsequently made alkaline with a concentrated caustic soda solution while cooling at 20°-25°. The precipitated base is extracted portionwise with a total of 450 cc of chloroform. The combined chloroform extracts are washed twice with 50 cc amounts of water, and dried over sodium sulphate and concentrated. The residue is dissolved in 150 cc of chloroform containing 3 percent of methanol and is adsorbed on 1000 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first 5 liters of eluate are discarded, the following 4 liters are jointly concentrated. An oily material, mainly consisting of the two isomers 4-(1-ethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10H)-one and 4(1-ethyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]-thiophen-10(9H)-one (Example 4), is obtained as residue. The mixture is separated by dissolving 22 g of the residue in 80 cc of absolute ethanol whilst hot, and adding a hot solution of 8.3 g of fumaric acid in 140 cc of absolute ethanol. The mixture is allowed to crystallize at room temperature for 2 hours, and the crystalline product is then filtered off.

The filtration mother liquor is used for isolation of 4-(1-ethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one (Example 4).

The crystalline product is recrystallized from 750 cc of 90 percent ethanol, whereby pure 4-(1-ethyl-4-piperidylidene)-4H-benzo- [4,5]cyclohepta[1,2-b]thiophen-9(10H)-one hydrogen fumarate, having a decomposition point of 231°, is obtained. The base is liberated by suspending 7.5 g of the hydrogen fumarate in 30 cc of water and making the suspension alkaline with a 3 N caustic soda solution. The base is extracted portionwise with a total of 60 cc of chloroform. The combined chloroform extracts are washed with 25 cc of water, are dried over sodium sulphate and concentrated. The oily evaporation residue is dissolved while boiling in 12 cc of ethyl acetate, and the solution is allowed to crystallize over night at 0°-5°. The crystalline product is subsequently filtered off and dried in a vacuum. The pure 4-(1-ethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one base, having a M.P. of 128°-130°, is obtained in this manner. Microanalysis agrees with the formula C20 H21 NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 4-(1-ethyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-ethyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base, used as starting material, may be produced in a manner analogous to the process described in Example 1 for the production of the corresponding 4(1-methyl-4-piperidylidene) compounds, using 9(10)-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one as starting material, whereby 1-ethyl-4-chloropiperidine is used in place of 1-methyl-4-chloropiperidine.

The 4-(1-ethyl-4-piperidylidene)-9(10H)-bromo-4H-benzo- [4,5]cyclohepta[1,2-b]thiophene base, isolated as intermediate, has a M.P. of 130°-132°.

EXAMPLE 4:

4-(1-Ethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one.

The ethanolic filtration mother liquor of Example 3 is concentrated by evaporation in a vacuum. 80 cc of water are added to the residue, and this is made alkaline with a 3 N caustic soda solution. The precipitated base is extracted portionwise with a total of 80 cc of chloroform. The combined chloroform extracts are washed with 25 cc of water, dried over sodium sulphate and concentrated. The evaporation residue is dissolved whilst boiling in 13 cc of isopropanol and the solution is allowed to crystallize over night at 0°-5°. The crystalline product is subsequently filtered off and dried. The pure 4-(1-ethyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one base, having a M.P. of 113°-115°, is obtained in this manner. Microanalysis agrees with the formula C20 H21 NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 5:

4-(1-Methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one.

A mixture of 23.5 g of crude 9-tert.butoxy-4-(1-methyl-4-piperidylidene)- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 10-tert.butoxy-1-(1- methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base is dissolved at 50° in 235 cc of 3 N hydrochloric acid. This solution is subsequently boiled under reflux at an oil bath temperature of 130° for half an hour. The reaction mixture is subsequently cooled to room temperature and made alkaline with a concentrated caustic soda solution. The precipitated base is extracted portionwise with 300 cc of chloroform. The combined chloroform extracts are washed with 100 cc of water, dried over sodium sulphate and concentrated. The evaporation residue is dissolved in 200 cc of chloroform containing 3 percent of methanol and is adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first two liters of eluate are discarded, the following 1.5 liters are jointly concentrated. An oily material, mainly consisting of the two isomers 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one and 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-10(9H)-one (see Example 6) is obtained as residue. The mixture is separated by dissolving 15 g of the residue in 45 cc of isopropanol and adding a hot solution of 5.65 g of fumaric acid in 130 cc of isopropanol. The reaction solution is subsequently allowed to crystallize over night at 40° . The crystalline product is filtered with suction and recrystallized from a 30-fold quantity of absolute ethanol. Pure 1-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one fumarate, having a decomposition point of 197°- 199°, is thus obtained.

The isopropanolic filtration mother liquor is used for isolation of 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen- 10(9H)-one (Example 6).

The mixture of 9-tert.butoxy-4-(1-methyl-4-piperidylidene)-4H- benzo[4,s]cyclohepta[1,2-b]thiophene base and 10-tert.butoxy-4-(1-methyl- 4-piperidylidene)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophene base, used as starting material, may, for example, be produced as follows:

A mixture of 30 g of 9(10)-bromo-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base, produced as described in Example 1, 300 cc of dioxane and 18.1 g of potassium tert.butoxy is stirred at 20°-22° for 21 hours. The reaction mixture is subsequently filtered and the filtrate is concentrated in a vacuum. 300 cc of benzene are added to the residue and the solution is washed out thrice with 40 cc amounts of water. The benzene solution is subsequently dried over sodium sulphate and concentrated. A mixture of crude, oily 9-tert.butoxy-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophene base and 10-tert.butoxy-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta-[1,2-b]thiophene base is obtained as residue and is further worked up as such.

EXAMPLE 6:

4-(1-Methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one.

The isopropanolic filtration mother liquor of Example 5 is concentrated in a vacuum. 100 cc of water are added to the evaporation residue, and this is made alkaline with a concentrated caustic soda solution. The precipitated base is extracted portionwise with 90 cc of chloroform. The chloroform extracts are washed with 30 cc of water, dried over sodium sulphate and concentrated. An oily base is obtained, which is crystallized from 25 cc of isopropanol. After cooling over night the crystalline product is filtered off and dried. The crude 4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one base, having a M.P. of 152°-153°, is obtained in this manner.

EXAMPLE 7:

4-(1-Isopropyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one.

A mixture of 25 g of 4-(4-piperidylidene)-4H-benzo[4,5]-cyclohepta[1,2- b]thiophen-10(9H)-one base, 375 cc of toluene, 28.8 g of isopropyl iodide and 45 g of sodium carbonate is stirred at an oil bath temperature of 95° for 30 hours. The reaction mixture is subsequently filtered and the filtrate is concentrated in a vacuum. The evaporation residue is dissolved in 50 cc of chloroform and adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first 3 liters of eluate are discarded, the following four liters are jointly concentrated. An oily base is obtained as residue. The hydrogen fumarate is produced by dissolving 10 g of this base with 3.6 g of fumaric acid in 50 cc of absolute ethanol while boiling, filtering and allowing to crystallize over night at 0°-5°. The salt is subsequently filtered off and recrystallized from a 16-fold quantity of 95 percent ethanol. The pure 4-(1-isopropyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]-thiophen-10(9H)-one hydrogen fumarate, having a decomposition point of 225°-226°, is obtained in this manner. Microanalysis agrees with the formula C21 H23 NOS . C4 H4 O4 . The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The 4-(4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]-thiophen-10(9H)- one, required as starting material, may, for example, be obtained as follows:

A solution of 30 g of 4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one in 200 cc of toluene is added dropwise to a mixture heated to 80° of 31.6 g of chloroformic acid ethyl ester and 100 cc of toluene during the course of five minutes while stirring, whereby gaseous methyl chloride escapes. The reaction mixture is then boiled at reflux at an oil bath temperature of 140° for 4 hours, after which gas evolution is complete. The reaction mixture is subsequently concentrated in a vacuum. The solid residue is recrystallized twice from a 10-fold quantity of absolute ethanol. Pure 4-(1-ethoxycarbonyl-4-piperidylidene)-4H-benzo[4,5]- cyclohepta[1,2-b]thiophen-10(9H)-one, having a M.P. of 174°-175°, is obtained in this manner. Microanalysis agrees with the formula C21 H21 NO3 S. The structure was ascertained with the infrared and ultraviolet spectra.

A mixture of 27.4 g of 4-(1ethoxycarbonyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one, 280 cc of 50 percent sulphuric acid and 280 cc of n-butanol is heated at reflux for 16 hours. The butanol is subsequently distilled off in a vacuum. The remaining acid aqueous solution is diluted with 500 cc of water and is made alkaline with 500 cc of concentrated caustic soda solution while cooling. The precipitated base is extracted portionwise with a total of 600 cc of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulphate and concentrated in a vacuum. A solid base is obtained as residue, which is recrystallized from a 6-fold quantity of absolute ethanol. The pure 4-(4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one base, having a M.P. of 164°-166°, is obtained in this manner. Microanalysis agrees with the formula C18 H17 NOS. The structure was ascertained with the nuclear magnetic resonance spectrum.

EXAMPLE 8:

4-(1-n-Butyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one.

A mixture of 12 g of 4-(4-piperidylidene)-4H-benzo[4,5]-cyclohepta[1,2- b]thiophen-10(9H)-one base, 180 cc of toluene, 11.1 g of n-butyl bromide and 21.5 g of sodium carbonate is stirred at an oil bath temperature of 100° for 20 hours. The mixture is subsequently cooled, filtered, and the filtrate is concentrated in a vacuum. The evaporation residue is dissolved in 30 cc of chloroform and adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 1 percent of methanol. The first 4.5 liters of eluate are discarded, the following 3.2 liters are jointly concentrated. A crystalline base is obtained as residue. 8.2 of this base are dissolved in 30 cc of isopropanol while boiling and allowed to crystallize over night at 0°-5°. The pure 4-(1-n-butyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen- 10(9H)-one base, having a M.P. of 104°-105°, is obtained in this manner. Microanalysis agrees with the formula C22 H25 NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 9:

6-Chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10H)-one.

A mixture of 47 g of 6-chloro-4-(1-methyl-4-piperidylidene)-9-piperidino- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 6-chloro-4-(1-metbyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclobepta[1,2-b]thiophene base is dissolved at 50° in 470 cc of 2 N hydrochloric acid, and the solution is kept at 90° for 11/2 hours. The reaction mixture is subsequently cooled and made alkaline with a concentrated caustic soda solution. The free base is extracted portionwise with a total of 300 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. An oily base, mainly consisting of the two isomers 6-chloro-4-(1-methyl-4-piperidylidene)4H- benzo[4,5]cyclohepta[1,2-b]-thiophen-9(10H)-one and 6-chloro-4-(1-methyl- 4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one, is obtained as residue. The mixture is separated by dissolving 48 g of the oily base in 200 cc of absolute ethanol at the boil, filtering and adding a hot solution of 13.3 g of fumaric acid in 200 cc of absolute ethanol. The fumarate which crystallizes spontaneously is allowed to stand for several hours and is then filtered off at 20°. The mother liquor is used for the isolation of 6-chloro-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one in Example 10. The crude fumarate is then suspended in 200 cc of dimethyl formamide, filtered and washed out with benzene. 6-Chloro-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one fumarate is obtained in this manner and is converted into the base as follows: 9 g of the fumarate are suspended in 50 cc of water, and this is made alkaline with a 3 N caustic soda solution. The free base is extracted portionwise with chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated in a vacuum. The oily evaporation residue is dissolved in chloroform and adsorbed on 250 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first two liters of eluate are discarded, the following 0.5 liters are concentrated separately. The crystalline evaporation residue is recrystallized from a 2-fold quantity of ethyl acetate. The pure 6-chloro-4(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10H)-one base, having a M.P. of 152°-153° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C19 H18 ClNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 6-chloro-4-(1-methyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene and 6-chloro-4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta-[1,2-b]thiophene, required as starting material, was produced as follows from 6-chloro-9,10-dibromo-9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2- b]thiophen-4-one:

A mixture of 26 g of 6-chloro-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2- b]thiophen-4-one, 260 cc of absolute carbon tetrachloride, 39 g of N-bromosuccinimide and 0.5 g of dibenzoyl peroxide is heated at reflux for 41/2 hours. The suspension is subsequently cooled and allowed to crystallize over night at 0°-5°. The crystalline product is filtered off and suspended in 65 cc of absolute ethanol. The crystalline product is subsequently filtered off and washed with a large quantity of water. After drying at 60° in a vacuum, recrystallization is effected from a 20-fold quantity of chloroform/petroleum ether (1:1). Pure 6-chloro-9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-4-one, having a decomposition point of 147°- 149°, is obtained in this manner. Microanalysis agrees with the formula C13 H7 Br2 Cl0S.

A mixture of 28.5 g of 6-chloro-9,10-dibromo-9,10-dihydro-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, 320 cc of methanol and 11.8 g of potassium hydroxide is boiled at reflux for 1 hour. The reaction mixture is subsequently cooled, 320 cc of water are added, and the crystals are filtered off. The crystalline product is washed with a large quantity of water and dried in a vacuum at 60°. Recrystallization is subsequently effected from a 20-fold quantity of tetrahydrofuran. Pure 9(10)-bromo-6-chloro-4H-benzo-[4,5]cyclohepta[1,2-b]thiophen-4-one, having a M.P. of 198°-200°, is obtained in this manner. Microanalysis agrees with the formula C13 H6 BrClOS. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.

3.33 g of magnesium activated with iodine are covered with a layer of 10 cc of absolute tetrahydrofuran, and approximately 3 cc of a solution of 18.3 g of freshly distilled 4-chloro-1-methylpiperidine in 30 cc of absolute tetrahydrofuran are added. The Grignard reaction commences by the addition of a few drops of 1,2-dibromoethane. The remaining 4-chloro-1-methylpiperidine solution is then added dropwise to the magnesium at such a rate that the reaction mixture boils continuously without external heating. After the dropwise addition is complete, the mixture is boiled at reflux for 11/2 hours, whereafter the magnesium is practically completely dissolved. The reaction mixture is subsequently diluted with 40 cc of absolute tetrahydrofuran and cooled to 10°. 22.3 g of 9(10)-bromo-6-chloro-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4- one are then added portionwise at 10°-15° during the course of 1 hour while cooling. The mixture is then stirred at 10°-15° for 2 hours and is poured on a mixture of 20 g of ammonium chloride and 150 g of ice. The precipitated base is extracted portionwise with a total of 160 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The crude, oily 9(10)-bromo-6-chloro-4-(1-methyl-4-piperidyl)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol base is obtained as residue and is worked up as such.

A mixture of 31 g of crude 9(10)-bromo-6-chloro-4-(1-methyl-4-piperidyl)- 4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol base and 120 cc of 14 percent hydrobromic acid in ethanol is heated at reflux for 5 hours. The reaction mixture is subsequently concentrated in a vacuum. 100 cc of water are added to the evaporation residue, and this is made alkaline with a concentrated caustic soda solution. The precipitated base is extracted portionwise with 250 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The evaporation residue is dissolved in 50 cc of chloroform and adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first four liters of eluate are discarded, the following 3 liters are jointly concentrated. The evaporation residue is crystallized from a 10-fold quantity of ethyl acetate. The pure 9(10)-bromo-6-chloro-4- (1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base, having a M.P. of 193°-195°, is obtained in this manner. Microanalysis agrees with the formula C19 H17 BrClNS. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.

A mixture of 47.5 g of 9(10)-bromo-6-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base, 650 cc of dioxane, 325 cc of piperidine and 26.2 g of potassium tert.butylate is boiled at reflux for 2 hours. The reaction mixture is subsequently cooled, filtered and concentrated in a vacuum. The evaporation residue is dissolved in 600 cc of benzene. The solution is washed with water, dried over sodium sulphate and concentrated. A mixture of crude, oily 6-chloro-4-(1-methyl-4-piperidylidene)-9-piperidino-4H-benzo[4,5]- cyclohepta[1,2-b]thiophene base and 6-chloro-4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base is obtained as residue and is worked up as such.

EXAMPLE 10:

6-Chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-10(9H)-one.

The ethanolic fumarate mother liquor of Example 9 is concentrated in a vacuum. The evaporation residue is suspended in water, made alkaline with a 3 N caustic soda solution, and the free base is extracted several times with chloroform. The combined chloroform extracts are washed with water, dried over sodium sulphate and concentrated in a vacuum. The evaporation residue is dissolved in chloroform, adsorbed on 250 g of silica gel, and elution is effected with chloroform containing 3 percent of methanol. The first 900 cc of eluate are discarded, the following 400 cc are concentrated separately. The residue is recrystallized from a six-fold quantity of isopropanol. The pure 6-chloro-4-(1-methyl-4-piperidylidene)- 4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-10(9H)-one base, having a M.P. of 168°-169°, is obtained in this manner. Microanalysis agrees with the formula C19 H18 ClNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 11:

4-(1-Isopropyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one.

A mixture of 99 g of crude 4(1-isopropyl-4-piperidylidene)-9-piperidino- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-isopropyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base is boiled at reflux in 990 cc of 2 N hydrochloric acid for half an hour, whereby a hydrochloric crystallizes. After allowing to stand over night at 0°-5°, the hydrochloric is drawn off by suction and suspended in 500 cc of water. The suspension is made alkaline with concentrated caustic soda solution, and the free base is extracted portionwise with a total of 600 cc of chloroform. After washing with water and drying with sodium sulphate, the chloroform solution is concentrated in a vacuum. The residue is a crude, oily base, which mainly consists of the two isomers 4-(1-isopropyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one and 4-(1-isopropyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one. The two isomers are separated by dissolving 85.7 g of the crude base at the boil in 700 cc of isopropanol and adding a hot solution of 29 g of fumaric acid in 500 cc of isopropanol. The fumarate which crystallizes spontaneously is allowed to stand for several hours at room temperature, whereupon it is filtered off and washed with 200 cc of isopropanol. The mother liquor is used for the isolation of 4-(1-isopropyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]-thiophen-10(9H)-one (Example 12). The fumarate is recrystallized from an 11-fold quantity of ethanol/water 8:1. The pure 4-(1-isopropyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]-thiophen-9(10H)-one fumarate, having a M.P. of 214°-216° (decomp.), is obtained in this manner. The base is liberated by suspending 27 g of the fumarate in 100 cc of water and making this alkaline with 3 N ammonia. The free base is extracted with 200 cc of chloroform. The extract is directly adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 5 percent of methanol. The first 0.9 liters of eluate are discarded, the following 0.9 liters are concentrated separately. The oily evaporation residue is recrystallized from a 2-fold quantity of ethyl acetate/petroleum ether 1:1. The pure 4-(1-isopropyl-4-piperidylidene)-4H-benzo[4,5]- cyclohepta[1,2-b]thiophen-9(10H)-one base, having a M.P. of 117°-119° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C21 H23 NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 4-(1-isopropyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-isopropyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene base, used as starting material, is obtained in a manner analogous to that described in Example 1, except that 4-chloro-1-isopropyl-piperidine is used in place of 4-chloro-1-methyl-piperidine.

EXAMPLE 12:

4-(1-Isopropyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9)-one.

The isopropanolic mother liquor of the fumarate in Example 11 is concentrated in a vacuum. The evaporation residue is suspended in 300 cc of water and made alkaline with a concentrated caustic soda solution. The base is extracted portionwise with a total of 800 cc of chloroform. The combined extracts was washed with water, dried over sodium sulphate and concentrated in a vacuum. The evaporation residue is dissolved in chloroform and adsorbed on 1000 g of silica gel. Elution is effected with chloroform containing 5 percent of methanol. The first 2.4 liters of eluate are discarded, the following 1.5 liters are concentrated. An oily base is obtained as residue. The hydrogen fumarate is produced by dissolving 16.9 g of the base with 6.1 g of fumaric acid in 85 cc of absolute ethanol at the boil, and allowing this to crystallize over night at 0°-5°. The hydrogen fumarate is filtered off and recrystallized from a 16-fold quantity of 95 percent ethanol. The pure 4-(1-isopropyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one hydrogen fumarate, having a M.P. of 225°-226° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C21 H23 NOS.C4 H4 O4 . The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 13:

4-(1-n-Butyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 9(10H)-one.

A mixture of 47 g of crude 4-(1-n-butyl-4-piperidylidene)-9-piperidino- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-n-butyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene base is dissolved in 470 cc of 2 N hydrochloric acid at about 40°, and the solution is stirred at 90° for 30 minutes. The reaction solution is subsequently cooled to room temperature and made alkaline with concentrated caustic soda solution while cooling. The precipitated base is extracted portion-wise with a total of 600 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. A mixture of crude, oily 4-(1-n-butyl-4-piperidylidene)-4H- benzo-[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one base and 4-(1-n-butyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one base is obtained as residue. The two isomers are separated by dissolving 43 g of the crude base at the boil in 150 cc of isopropanol and adding a hot solution of 15 g of fumaric acid in 750 cc of isopropanol. After allowing to stand at room temperature for two hours, the precipitated crude fumarate is filtered off. The isopropanolic mother liquor is used for the isolation of 4-(1-n-butyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one in Example 14. The crude fumarate is is suspended in 200 cc of water and made alkaline with 3 N ammonia. The free base is extracted portionwise with a total of 200 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated in a vacuum. The evaporation residue is dissolved in chloroform and adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 2.5 percent of methanol. The first 1000 cc of eluate are discarded, the following 600 cc are concentrated separately. An oily base is obtained as residue. 8 g of this oily base are dissolved at the boil together with 3.2 g of malic acid in 60 cc of isopropanol, and the solution is allowed to crystallize over night at 0°-5°. The salt is filtered off and dried in a vacuum at 70°-80°. The pure 4-(1-n-butyl-4-piperidylidene)-4H- benzo[4,5]-cyclohepta[1,2-b]thiophen-9(10H)-one hydrogen malate, having a M.P. of 188°-190° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C22 H25 NOS.C4 H6 O5 . The structure was ascertained with the nuclear magnetic resonance spectrum.

The mixture of 4-(1-n-butyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 4-(1-n-butyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]cyclohepta-[1,2-b]thiophene base, used as starting material, may, for example, be obtained as follows:

A solution of 133 cc of thionyl chloride in 150 cc of benzene is added dropwise at the boil within 45 minutes to a mixture of 241 g of 1-n-butyl-4-piperidinol and 1200 cc of benzene. The reaction mixture is subsequently boiled at reflux for 3 hours. After cooling to room temperature, the precipitated hydrochloride is filtered off and dissolved in 370 cc of water. The solution is made alkaline with 190 cc of concentrated caustic soda solution while cooling, and the free base is extracted portionwise with a total of 700 cc of methylene chloride. The combined extracts are dried over potash and concentrated in a vacuum at 50°. The liquid residue is distilled twice in a vacuum over a Vigreux column. The pure 1-n-butyl-4-chloropiperidine base, which distils at 95°-100°/14 mm of Hg, is obtained in this manner. Microanalysis agrees with the formula C9 H18 ClN.

The process is continued in a manner analogous to that described in Example 1, except that 1-n-butyl-4-chloropiperidine is used in place of 4-chloro-1-methyl-piperidine.

EXAMPLE 14:

4-(1-n-Butyl-4-piperidylidene)-4-H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one.

The isopropanolic mother liquor of the fumarate of Example 13 is concentrated in a vacuum. The evaporation residue is suspended in 300 cc of water and made alkaline with 3 N ammonia. The free base is extracted portionwise with a total of 300 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The evaporation residue is dissolved in chloroform and adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 2 percent of methanol. The first 2.2 liters of eluate are discarded, the following 0.6 liters are concentrated separately. The evaporation residue is recrystallized twice from a three-fold quantity of isopropanol. The pure 4-(1-n-butyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen- 10(9H)-one base, having a M.P. of 104°-105°, is obtained in this manner. Microanalysis agrees with the formula C22 H25 NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 15:

7-Chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]tiophen-10(9H)-one.

A mixture of 35 g of crude, oily 7-chloro-4-(1-methyl-4-piperidylidene)- 9-piperidino-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 7-chloro-4-(1-methyl-4-piperidylidene)-10-piperdino-4H- benzo[4,5]cyclohepta[1,2- b]thiophene base is dissolved in 350 cc of 2 N hydrochloric acid at 40°, and the reaction solution is stirred at an internal temperature of 90° for half an hour. The solution is subsequently made alkaline with concentrated caustic soda solution at 20° while cooling, and the free base is extracted portionwise with a total of 400 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. An oily base mainly consisting of the two isomers 7-chloro-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one and 7-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-10(9H)-one is obtained as evaporation residue. The isomers are separated by dissolving the evaporation residue at the boil in 200 cc of absolute ethanol and slowly adding a hot solution of 9 g of oxalic acid in 200 cc of absolute ethanol while stirring. The oxalate which crystallizes spontaneously is allowed to stand for three hours at 0°-5°, whereupon it is filtered off. The oxalate mother liquor is used for the isolation of 7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10H)-one (Example 16). The crude oxalate is suspended in 150 cc of water and is made alkaline with concentrated caustic soda solution. The free base is extracted with 50 cc of chloroform. The chloroform phase is adsorbed on 500 g of silica gel. The first 1000 cc of eluate are discarded, the following 1400 cc are concentrated separately by evaporation. The crystalline residue is recrystallized twice from a 4-fold quantity of isopropanol. The pure 7-chloro-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one base, having a M.P. of 150°-151°, is obtained in this manner. Microanalysis agrees with the formula C19 H18 ClNOS. The structure was ascertained with the infrared, nuclear magnetic resonance and mass spectrograph spectra.

The mixture of 7-chloro-4-(1-methyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 7-chloro-4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene base, used as starting material, may be obtained in a manner analogous to that described in Example 1, except that 7-chloro-9,10-dihydro-4H- benzo[4,5]cyclohepta[1,2-b]-thiophen-4one is used in place of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-4-one. The 9(10)-bromo-7-chloro-4-(1-methyl-4-piperidylidene)-4H- benzol[4,5]cyclohepta[1,2-b]thiophene base, formed as intermediate during the course of the reaction, has a M.P. of 147°-149°.

EXAMPLE 16:

7-Chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10H)-one.

The ethanolic mother liquor of the oxalate of Example 15 is concentrated in a vacuum. The residue is suspended in 100 cc of water and made alkaline with concentrated caustic soda solution. The free base is extracted with 50 cc of chloroform. The organic phase is adsorbed on 250 g of silica gel. Elution is effected with chloroform containing 3 percent of methanol. The first 1400 cc of eluate are discarded, the following 600 cc are concentrated separately. The crystalline residue is recrystallized from a 5-fold quantity of ethyl acetate/petroleum ether 1:1. The pure 7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5-cyclohepta[1,2- b]thiophen-9(10H)-one base, having a M.P. of 192°-194° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C19 H18 ClNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 17:

6-Bromo-4-(1-methyl-4-pieridylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-10(9H)-one.

A mixture of 15.4 g of crude 6-bromo-4-(1-methyl-4-piperidylidene)-9- piperidino-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base and 6-bromo-4-(1-methyl-4-piperidylidene)-10-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base is dissolved in 155 cc of 2 N hydrochloric acid, and the solution is kept at 90° for half an hour. The solution is subsequently made alkaline with 3 N caustic soda solution while cooling, and the free base is extracted portion-wise with a total of 320 cc of benzene. The combined organic phases are dried over sodium sulphate and concentrated. An oily base, mainly consisting of the two isomers 6-bromo-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one and 6-bromo-4-(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one, is obtained as residue. The isomers are separated by dissolving the evaporation residue in a small quantity of chloroform and adsorbing on 500 g of silica gel. Elution is effected with chloroform containing 2 percent of methanol. The first 4 liters of eluate are discarded, the following first fraction of 0.4 liters of eluate is used for the isolation of 6-chloro-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one in Example 18. The following second fraction of 1.4 liters of eluate is concentrated. The crystalline residue is recrystallized twice from a 6-fold quantity of isopropanol. The pure 6-bromo-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one base, having a M.P. of 172°-173°, is obtained in this manner. Microanalysis agrees with the formula C19 H18 BrNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 6-bromo-4-(1-methyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 6-bromo-4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene base, used as starting material, is obtained in a manner analogous to that described in Example 1, except that 6-bromo-9,10-dihydro-4H- benzo[4,5]cyclohepta[1,2-b]-thiophen-4-one is used in place of 9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophen-4-one.

The 6,9(10)-dibromo-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b thiophene base, formed as intermediate during the course of the reaction, has a M.P. of 185°-186°.

EXAMPLE 18:

6-Bromo-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10H)-one.

The first fraction of the elution in Example 17 is concentrated and adsorbed on a 25-fold quantity of silica gel. Elution is effected with chloroform containing 2 percent of methanol. The first 300 cc of eluate are discarded, the following 80 cc are concentrated separately. The solid evaporation residue is recrystallized from a 3-fold quantity of ethyl acetate. The pure 6-bromo-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one base, having a M.P. of 143°-146° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C19 H18 BrNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 19:

7-methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-10(9H)-one.

A mixture of 10 g of crude 7-methoxy-4-(1-methyl-4-piperidylidene)-9- piperidino-4H-benzo[4,5cyclohepta[1,2-b]thiophene base and 7-methoxy-4-(1-methyl-4-piperidylidene)-10-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base is dissolved in 100 cc of 2 N hydrochloric acid, and the solution is kept at 90° for half an hour. The solution is subsequently made alkaline with a 3 N caustic soda solution while cooling, and the free base is extracted portion-wise with a total of 200 cc of benzene. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. An oily base, mainly consisting of the two isomers 7-methoxy-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one and 7-methoxy-4(1-methyl-4- piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one, is obtained as residue. The isomers are separated by dissolving the evaporation residue in a small amount of chloroform and adsorbing on 500 g of silica gel. Elution is effected with chloroform containing 2 percent of methanol. Elution is effected with chloroform containing 2 percent of methanol. A first running of 5 liters of eluate is discarded, the following first fraction of 0.5 liters of eluate is used for the isolation of 7-methoxy-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-9(10H)-one in Example 20. The following second fraction of two liters of eluate is concentrated. The crystalline residue is crystallized twice from a 10-fold quantity of isopropanol. The pure 7-methoxy-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one base, having a M.P. of 157°-158°, is obtained in this manner. Microanalysis agrees with the formula C20 H21 NO2 S. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 7-methoxy-4-(1-methyl-4-piperidylidene)-9-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]thiophene base and 7-methoxy-4-(1-methyl-4- piperidylidene)-10-piperidino-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene base, required as starting material, is produced as follows:

A solution of 27.6 g of 4-methoxy-phthalaldehydic acid, 36 g of 2-thenyl diethyl phosphonate and 55 cc of dimethyl formamide is added dropwise within approximately 10 minutes to a suspension of 18.5 g of sodium methylate in 55 cc of dimethyl formamide, whereby the internal temperature rises to 30°-35°. The reaction mixture is subsequently stirred at 20°-25° for 30 minutes, whereupon it is poured on 1700 g of ice. The aqueous solution is washed with 100 cc of benzene and the pH of the solution is subsequently adjusted to approximately 2 with 3 N hydrochloric acid. The precipitated acid is filtered off at 0°-5° and dried in a vacuum. The product is subsequently recrystallized from a 7-fold quantity of benzene. The pure 4-methoxy-2-[2-(2-thienyl)vinyl]benzoic acid, having a M.P. of 170°-172°, is obtained in this manner. Microanalysis agrees with the formula C14 H12 O3 S. The structure was ascertained with the nuclear magnetic resonance spectrum.

15.6 g of red phosphorus and 12 cc of 57 percent aqueous hydriodic acid are added to a solution heated to 70° of 13 g of 4-methoxy-2-[2-(2-thienyl)vinyl]benzoic acid and 325 cc of glacial acetic acid, and the mixture is subsequently boiled at reflux for 25 minutes. The reaction mixture is subsequently poured on a mixture of 500 g of ice and 300 cc of methylene chloride. After filtration the organic phase is separated, is first washed with 150 cc of 10 percent sodium thiosulphate and subsequently with water, is dried over sodium sulphate and concentrated. The crude 4-methoxy-2-[2-(2-thienyl)ethyl]benzoic acid is obtained as residue and is further worked up as such.

A mixture of 16.2 g of crude 4-methoxy-2-[2-(2-thienyl)-ethyl]benzoic acid, 80 cc of xylene and 67 g of polyphosphoric acid is boiled at reflux for 2 hours while stirring. The reaction mixture is subsequently poured on 300 g of ice. The organic phase is separated, the aqueous phase is extracted portionwise with a total of 300 cc of benzene. The combined organic phases are first washed with 200 cc of a saturated soda solution and then with water, are dried over sodium sulphate and concentrated. A brown, viscous liquid is obtained as residue and is distilled in a high vacuum. The product distils at 155°-170°/0.04 mm of Hg. Further purification is effected by dissolving 2.6 g of the distillate in a small quantity of chloroform and adsorbing on 250 cc of silica gel. Elution is effected with chloroform. The first 480 cc of eluate are discarded, the following 900 cc are concentrated separately. The pure, oily 9,10-dihydro-7-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-one is obtained as residue. The structure was ascertained with the mass spectrograph spectrum.

A mixture of 15 g of 9,10-dihydro-7-methoxy-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-4one, 300 cc of absolute carbon tetrachloride, 24.1 g of N-bromosuccinimide and 0.5 g of dibenzoyl peroxide is boiled at reflux for 2 hours while stirring. After allowing to stand over night at 0°-5°, the crystalline product is filtered off, is washed with 70 cc of carbon tetrachloride and suspended in 100 cc of absolute ethanol at 0°-5°. The product is subsequently filtered off and washed with approximately 500 cc of water. After drying, crude 9,10-dibromo-9,10-dihydro-7-methoxy-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-4-one is obtained and is further worked up as such.

A mixture of 16.7 g of 9,10-dibromo-9,10-dihydro-7-methoxy-4H- benzo[4,5cyclohepta[1,2-b]thiophen-4-one, 250 cc of methanol and 7 g of potassium hydroxide is heated at reflux for one hour while stirring. The crystalline product is filtered off at room temperature, is washed with 50 cc of methanol and subsequently with 500 cc of water. After drying at 70° in a vacuum, pure 9(10)-bromo-7-methoxy-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-4-one, having a M.P. of 182°-184°, is obtained. The structure was ascertained with the mass spectrograph spectrum.

Approximately 1/10 of a solution of 10.1 g of 4-chloro-1- methylpiperidine base and 40 cc of absolute tetrahydrofuran is added to a mixture of 1.83 g of magnesium and 5 cc of absolute tetrahydorfuran. A few drops of 1,2-dibromoethane are added, whereby the Grignard reaction commences. The remaining 4-chloro-1-methylpiperidine solution is then added dropwise to the magnesium at such a rate that the reaction mixture boils continuously without external heating. The mixture is subsequently boiled at reflux for a further 11/2 hours. After diluting with 300 cc of absolute tetrahydrofuran, 12.2 g of 9(10)-bromo-7-methoxy-4H- benzo[4,5]cyclohepta[1,2-b]thiophen-4-one are added at 10° within approximately 20 minutes, and the mixture is subsequently stirred at 10° for a further 11/2 hours. The reaction mixture is subsequently poured on 500 g of ice containing 50 g of ammonium chloride. The base is extracted portionwise with a total of 500 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The crude, oily 9(10)-bromo-7-methoxy-4-(4-methyl-4- piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol base is obtained as residue and is further worked up as such.

A mixture of 17.5 g of crude 9(10)-bromo-7-methoxy-4-(1-methyl-4- piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol base and 250 cc of 14.5 percent hydrochloric acid in isopropanol is boiled at reflux for two hours. The reaction mixture is subsequently concentrated in a vacuum. The residue is dissolved in 1000 cc of water, and is made alkaline with 3 N ammonia, and the free base is extracted portionwise with a total of 500 cc of chloroform. The combined extracts are washed with water, dried over sodium sulphate and concentrated. The evaporation residue is dissolved in a small quantity of chloroform and adsorbed on 500 g of silica gel. Elution is effected with chloroform containing 2 percent of methanol. The first three liters of eluate are discarded, the following 4 liters are concentrated separately. The pure, oily 9(10)-bromo-7-methoxy-4-(1-methyl- 4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene base is obtained as residue. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.

A mixture of 10 g of 9(10)-bromo-7-mpthoxy-4-(1-methyl-4-piperidylidene)- 4H-benzo[4,5]cyclohepta[1,2-b]thiophene base, 60 cc of piperidine, 120 cc of dioxane and 5.6 g of potassium tert.butylate is boiled at reflux for 4 hours. The reaction mixture is subsequently filtered and the filtrate is concentrated in a vacuum. The evaporation residue is dissolved in 150 cc of benzene. This solution is washed with water, dried over sodium sulphate and concentrated. A mixture of crude, oily 7-methoxy-4-(1-methyl- 4-piperidylidene)-9-piperidino-4H-benzo-[4,5]cyclohepta[1,2-b]thiophene base and 7-methoxy-4-(1-methyl-4-piperidylidene)-10-piperidino-4H- benzo[4,5]cyclohepta[1,2-b]-thiophene base is obtained as residue and is further worked up as such.

EXAMPLE 20:

7-Methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-9(10)-one.

The first fraction of the elution of Example 19 is concentrated and adsorbed on a 25-fold quantity of silica gel. Elution is effected with chloroform containing 2 percent of methanol. The first 400 cc of eluate are discarded, the following 100 cc are concentrated separately. The solid evaporation residue is recrystallized from a 2-fold quantity of ethyl acetate. The pure 7-methoxy-4-(1-methyl-4-piperidylidene)-4H- benzo[4,5]cyclohepta-[1,2-b]thiophen-9(10H)-one base, having a M.P. of 170°-172° (decomp.), is obtained in this manner. Microanalysis agrees with the formula C20 H21 NO2 S. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.