Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
  • C07D333/80—Seven-membered rings

Definitions

• R is alkyl of one to four carbon atoms
• AB is -COC1-l CO or COCH,, and pharmaceutically acceptable acid addition salts thereof.
• the compounds are histaminolytics.
• Compounds wherein -AB is COCH are antaminics, i.e. aside from histaminolytic properties, they possess serotonin antagonistic and anticholinergic properties.
• This invention relates to benzocycloheptathiophene derivatives.
• new compounds of formula I there are provided new compounds of formula I,
• R is hydrogen, halogen, or alkoxy of one to four carbon atoms
• R is alltyl of one to four carbon atoms
• -AB is the group CH C0 or -COCl-l and acid addition salts thereof.
• a compound of formula I is obtained by a process comprising a. hydrolyzing a compound of formula ll,
• R and R are as defined above, and X is in the 9 or l0 position and is an --OR radical, wherein R is alkyl or 1 to 4 carbon atoms, a radical of formula III,
• R is hydrogen or alkyl of one to four carbon atoms
• R is hydrogen or alkyl of one to four carbon atoms which is unbranched on the a carbon atom,or
• R and R 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 5 nitrogen atom substituted by an alkyl radical of one to four carbon atoms,
• the resulting compound of formula I may be isolated in the form of a free base or as an acid addition salt thereof.
• R radicals are hydrogen, chlorine, bromine and methoxy.
• 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.
• inert solvent 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 ll in an aqueous acid solution.
• the reaction temperature is not critical.
• a suitable reaction temperature is approximately 50 to l00 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 ll substituted in the 9 position with corresponding compounds of formula ll substituted in the IQ position. Such hydrolysis results in a mixture of isomers from In and lb,
• isomers may be separated in conventional manner, for example by fractional crystallization of a salt, e.g. a fumarate, to give the desired isomer.
• a salt e.g. a fumarate
• the compounds of formula I may be isolated from the worked up reaction mixture in conventional manner, e.g. chromatographically.
• RI: / Hm wherein R and R are as defined above, and X is in the 9 or l position and is a radical of formula ll I,
• R and R are as defined above, and
• This reaction yields a mixture of compounds of formula lla substituted in the 9 position, with compounds of formula Ila substituted in the l0 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.
• reaction 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.
• 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 lib substituted in the 9 position, with the compounds of formula llb 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 la in accordance with known methods.
• compounds of formula la are treated with a cyanogen halide, preferably cyanogen bromide, or a halogen formic acid ester.
• the radical R is first replaced by the cyano or alkoxycarbonyl group.
• This reaction is conveniently effected in an inert organic solvent, eg 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.
• R, R, 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.
• a mineral acid such as hydrochloric acid in ethanol
• a strong organic acid such as acetic anhydride or an inorganic acid halide
• the reaction is preferably effected with hydrobromic acid in an inert organic solvent, e.g. a lower alcohol.
• R, and Y are as defined above, in an inert solvent eg an open chain or cyclic ether such as tetrahydrofuran or diethyl ether, to a magnesium organic halogen compound of formula Vlll,
• R 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 I & 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 Vll are likewise new and may, for example, be produced by chlorinating or brominating a compound of formula lX,
• R 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.
• an inert organic solvent e.g. a chlorinated aliphatic hydrocarbon such as carbon tetrachloride.
• the compounds of formula l and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals. More particularly, compounds of formula la 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.
• 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 la and compounds of formula lb, 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.
• 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-, ethaneand benzene-sulphonate, citrate and malate.
• the invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising an active agent a compound of formula l or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or diluent.
• 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 [000 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 -niethyl-4-piperidylidene)-4H-benzo[ 4,5]cycloheptal ,2-b]thiophen-9( IOHl-one and 4-( lmethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[ l,2-b)thiophen-l0(9l-l)-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 isopropanolic filtration mother liquor is used for the isolation of 4-( l-methyl-4-piperidylidene)-4H- benzo[4,5 ]-cyclohepta[ l ,2-blthiophenl 0(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 mixture of 4-( l-methyl-4-piperidylidene)-9- piperidino-4H-benzo[4,5 ]cyclohepta[ l ,2-b1thiophene base and 4-( l-methyl-4-piperidylidene l0'piperidino- 4H-benzo[4,5 ]cyclohepta-[ l ,2b]thiophene base, used as starting material, may, for example, be produced as follows:
• a solution of 51 g of crude 9( l0)-bromo-4-( lmethyl-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 l00 for 1 hour.
• the mixture is subsequently concentrated in a vacuum and the residue dissolved in cc of water.
• the solution is made alkaline with a concentrated caustic soda solution, whereupon the precipitated base is extracted thrice with [00 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 ad sorbed on I000 g of silica gel. Elution is effected with chloroform containing 5 percent of methanol.
• the first 8 lite rs 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 -5.
• the isopropanolic filtration mother liquor of Example l 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 portionwisc 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 cc of ethyl acetate. After cooling over night at 0-50", the product is filtered oil and dried.
• the fumarate is produced by dissolving 8 g of the pure base with 3.2 g of fumaric acid in I00 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- benzol 4,5 ]cyclohepta[ l,2b]thiophenl 0(9H )-one hydrogen fumarate, having a MP. of l92 (decomp), is obtained.
• hiophene 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 chlorofonn 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 mixture is separated by dissolving 22 g of the residue in cc of absolute ethanol whilst hot, and adding a hot solution of 8.3 g of fumaric acid in I40 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 l-ethyl-4-piperidylidene )-4H-ben zo[4,5 ]cyclohepta[ l,2-b]thiophen-l0(9H)-one (Example 4).
• the crystalline product is recrystallized from 750 cc of percent ethanol, whereby pure 4-( l-ethyl-4- piperidylidene)-4H-benzo-[4,5]cyclohepta[1,2 -b]thiophen-9( l0l-l)-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 mixture of 4-( l-ethyl-4-piperidylidene)-9- piperidino-4H-benzo[4,5 ]cyclohepta[ 1,2b]thiophene base and 4-( l-ethyl-4-piperidylidene)- l O-piperidino- 4H-benzo[4,5 ]cyclohepta[ l,2-b]thiophene base, used as starting material, may be produced in a manner analogous to the process described in Example l for the production of the corresponding 4( l-methyl-4- piperidylidene) compounds, using 9( l0)-bromo-4H- benzo ⁇ 4,5 l,2-b]thiophene-4-one as starting material, whereby l-ethyl-4-chloropiperidine is used in place of l-methyl-4-chloropiperidine.
• the 4( l-ethyl-4-piperidylidene)-9( 10H )-bromo-4 H-benzo-[4,5 ]cyclohepta[ l ,2-b]thiophene base, isolated as intermediate, has a MP. of l30-l 32.
• 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 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 05. The crystalline product is sub sequently filtered off and dried.
• 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-( l-methyl-4-piperidylidene )-4l-[-benzo ⁇ 4,5 ]cyclohepta[ l ,2b]thi0phen- 9( 10H )-one and 4-( l-methyl-4-piperidylidene)-4H- benzo[4,5 ]cyclohepta[ l,2-b ⁇ thiophenl 0(9H)-one (see Example 6) is obtained as residue.
• the mixture is separated by dissolving g of the residue in 45 cc of isopropanol and adding a hot solution of 5.65 g of fu maric acid in I30 cc of isopropanol.
• 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 l-(1-methyl-4-piperidylidene)-4 H- benzo[4,5 l,2-b]thiophen-9( lOH)-one fumarate, having a decomposition point of l97-l99, is thus obtained.
• the isopropanolic filtration mother liquor is used for isolation of 4-( l-methyl-4-piperidylidene )-4H- benzo[4,5]cyclohepta-[ l ,2blthiophenl 0( 9H)-one (Example 6).
• a mixture of crude, oily 9-tert.butoxy-4-(lmethyl-4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l ,2b] l0-tert.butoxy-4-( l-methyl- 4-piperidylidene)-4H-benzo[4,5 ]cyclohepta-[ l ,2-b] thiophene base is obtained as residue and is further worked up as such.
• 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 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 ofi and dried.
• the 4-( 4-piperidylidene)-4H-benzo[ 4,5 )cyclohepta[ 1 ,2-b]-thiophen-l(9H)-one, required as starting material, may, for example, be obtained as follows:
• a mixture of 27.4 g of4-(l-ethoxycarbonyl-4- piperidylidene)-4H-benzo[4,5 ]cyclohepta[ 1,2 -b]thiophen-l0(9H)-one, 280 cc of 50 percent sulphuric acid and 280 cc of n-butanol is heated at reflux for l6 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.
• a mixture of 12 g of 4-(4-piperidylidene)-4H- benzo[4,5 l,2-b]thiophenl0(9H )-one base, 180 cc of toluene, 1 LI g of n-butyl bromide and 21.5 g of sodium carbonate is stirred at an oil bath temperature of 100 for 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 l 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 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-(lmethyl-4-piperidylidene)4H-benzo[4,5]cyclohepta[ l,2-b]9( l0H)-one and 6-chloro-4-( lmethyl-4-piperidylidene )-4H-benzo[4,5 ]cyclohepta[ l,2b]l0(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-( l-methyl- 4-piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l .2-b] thiophen-l0(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-( I-methyl-4-piperidylidene )-4H-benzo[ 4,5 ]cycloheptal ,2-b]thiophen-9( lOH )-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.
• reaction mixture is subsequently diluted with 40 cc of absolute tetrahydrofuran and cooled to 22.3 g of 9(l0)- bromo-6-chloro-4H-benzo[4,5 ]cyclohepta[ 1,2 b]thiophen-4-one are then added portionwise at l0l5 during the course of 1 hour while cooling.
• the mixture is then stirred at l0l5 for 2 hours and is poured on a mixture of g of ammonium chloride and ISO 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 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.
• Microanalysis agrees with the formula C fl BrClNs. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.
• the ethanolic furnarate 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 ex tracts 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.
• a mixture of 99 g of crude 4( l-isopropyl-4-piperidylidene)-9-piperidino-4H-benzo[4,5 ]cyclohepta[ l ,2-b] thiophene base and 4-(i-isopropyl-4-piperidylidene)- l0-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 -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-( isopropyl-4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l,2b]thiophen-9(10H)-one and 4-( l-isopropyl-4- piperidylidene )-4H-benzo[4,5]cyclohepta[ l,2 -b]thiophen-l0(9l-l)-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-( l-isopropyl-4-piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l ,2b]-thiophenl0( 9H )-one (Example l2).
• the fumarate is recrystallized from an ll-fold quantity of ethanol/water 8: l.
• 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.
• the isopropanolic mother liquor of the fumarate in Example 1 l 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 chlorofon'n.
• 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 l.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 cc of absolute ethanol at the boil, and allowing this to crystallize over night at 05.
• the hydrogen fumarate is filtered off and recrystallized from a 16-fold quantity of percent ethanol.
• Microanalysis agrees with the formula C, H NOS.C,H O,.
• the structure was ascertained with the infrared and nuclear magnetic resonance spectra.
• 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.
• the two isomers are separated by dissolving 43 g of the crude base at the boil in 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 fiitered off.
• the isopropanolic mother liquor is used for the isolation of 4-( I-n-butyl-4-piperidylidene) 4H- benzo[4,5 ]cyclohepta[ l,2b1thiophenl0(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 i000 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.
• a solution of I33 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 l-n-butyl-4-piperidinol and 1200 cc of benzene.
• the reaction mixture is subsequently boiled at reflux for 3 hours.
• 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 isopropanolic mother liquor of the fumarate of Example I3 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 ofeluate are discarded, the following 0.6 liters are concentrated separately.
• the evaporation residue is recrystallized twice from a three-fold quantity of isopropanol.
• a mixture of 35 g of crude, oily 7-chloro-4-(lmethyl-4-piperidylidene)-9-piperidino-4H-benzo[4,5] cycloheptall,2b]thiophene base and 7-chloro-4-(lmethyl-4-piperidylidene)-l0-piperdino-4H-benzo[4,5] cycloheptal l ,2b]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 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 chlorofonn.
• 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 5, whereupon it is filtered off.
• the oxalate mother liquor is used for the isolation of 7-chloro-4-( l-methyl- 4-piperidylidene )-4H-benzo ⁇ 4,5 ]cyclohepta[ l,2-b] thiophen-9(l0H)-one (Example 16).
• the crude oxalate is suspended in ISO 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 I000 cc of eluate are discarded, the following I400 cc are concentrated separately by evaporation.
• the crystalline residue is recrystallized twice from a 4- fold quantity of isopropanol.
• the pure 7-chloro-4-( l methyl-4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l,2-b]l0(9H)-one base, having a M.P. of l50-l5l, is obtained in this manner.
• Microanalysis agrees with the fonnula C H ClNOS.
• the structure was ascertained with the infrared, nuclear magnetic resonance and mass spectrograph spectra
• the ethanolic mother liquor of the oxalate of Exam ple l5 is concentrated in a vacuum.
• the residue is suspended in I00 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 lzl.
• the pure 7-chloro-4-( l- The structure was ascertained with the infrared and nuclear magnetic resonance spectra.
• 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-( Lmethyl-4-piperidylidene )-4H-benzo[ 4,5]cycloheptal,2-b]thiophen-9( l0H)-one in Example IS.
• the following second fraction of L4 liters of eluate is concentrated.
• the crystalline residue is recrystallized twice from a 6-fold quantity of isopropanol.
• Example I 7 The first fraction of the elution in Example I 7 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 cc are concentrated separately. The solid evaporation residue is recrystallized from a 3-fold quantity of ethyl acetate. The pure 6-bromo-4-( l-methyl-4-piperidylidene )-4H-benzo[ 4,5]cycloheptal ,2-b]thiophen-9( l0l-l)-one base, having a MP. of l43-l46 (decomp), is obtained in this manner. Microanalysis agrees with the formula C H BrNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.
• 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-( l-methyl- 4-piperidylidene )-4l-lbenzo[4,5]cyclohepta[ l ,2-b] thiophen-9( IOH )-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.
• Microanalysis agrees with the formula C H NO S. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.
• a solution of 27.6 g of 4-methoxy-phthalaldehydic acid, 36 g of Z-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 011' at 5 and dried in a vacuum.
• 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-l70/0.04 mm of Hg.
• 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( l0)-bromo-7-methoxy-4-( l-methyl-4-piperidylidene)-4H-benzo ⁇ 4,5 ]cyclohepta[ l,2-b]thiophene base is obtained as residue. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.
• R is hydrogen, halogen or alkoxy of one to four carbon atoms
• R is alkyl of one to four carbon atoms
• the compound of claim 1 which is 4-( l-methyl-4- piperidylidene)-4H-benzo[ 4,5 lcycloheptal l,2 -b]thiophen-l0(9H)-one 4.
• the compound of claim I which is 4-( l-ethyl-4- piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l,2 -b]thiophen-9( lOH )-one.
• the compound of claim 1 which is 7-chloro-4- (l-methyl-4-piperidylidenel-4H-benzo[4,5 lcyclohapta 14.

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• Heterocyclic Compounds Containing Sulfur Atoms (AREA)
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