US3682930A - 4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9 - Google Patents

4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9 Download PDF

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US3682930A
US3682930A US3682930DA US3682930A US 3682930 A US3682930 A US 3682930A US 3682930D A US3682930D A US 3682930DA US 3682930 A US3682930 A US 3682930A
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benzo
piperidylidene
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Jean-Pierre Bourquin
Gustav Schwarb
Erwin Waldvogel
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Gustav Schwarb
Erwin Waldvogel
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    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic 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 sulfur
    • C07D333/06Heterocyclic 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 sulfur with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/78Heterocyclic 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
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    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The present invention concerns novel compounds of the formula,

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.

Description

United States Patent Bourquin et al.

l S 41 l-ALKYL-4-PIPERIDYLIDINE)-4H- BENZO v] CYCLOHEPTA [1,2-6]

[72] inventors: Jean-Pierre Bourquin, 4165 Magden, Magden Ag; Gustav Schwarb, 9 Felsenweg, 4123 Allschwil; Erwin Waldvogel, 39 Gartenstrasse, 4147 Aesch, all of Switzerland 22 Filed: March3, 1971 211 Appl.No.: 120,738

[30] Foreign Application Priority Data March 11, 1970 Switzerland ..3598/70 July 31, 1970 Switzerland.............11593/70 [52] US. Cl. ..260/293.57, 424/267, 260/268 TR, 260/247.1, 260/330.5

3,491,103 1/1970 .lucker et a1. ..260/293.57

Primary Examiner-Henry R. Jiles Assistant Examiner-S. D. Winters Attorney-Gerald D. Sharkin, Robert S. Honor, Frederick H. Weinfeldt, Richard E. Vila and Walter F.

Jewell [151 3,682,930 1 Aug. 8, 1972 [57] ABSTRACT The present invention concerns novel compounds of the formula,

A-B S wherein R is hydrogen, halogen, or alkoxy of one to four carbon atoms,

R, is alkyl of one to four carbon atoms, and

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.

20 Claims, No Drawings 4( l -ALKYL-4-PlPERlDYLlDlNE)-4H-BENZO v] CYCLOHEPTA [1,2-6]

This invention relates to benzocycloheptathiophene derivatives. In accordance with the invention, there are provided new compounds of formula I,

A-B S 9 10 10 i l R: I

wherein R, is hydrogen, halogen, or alkoxy of one to four carbon atoms,

R, is alltyl of one to four carbon atoms, and

-AB is the group CH C0 or -COCl-l 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 ll,

wherein 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,

HIR] it. ill

wherein R is hydrogen or alkyl of one to four carbon atoms, and

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,

b. alkylating a compound offormula IV,

o I s l l N l n W wherein R, is as defined above, to obtain a compound of formula la,

N l R1 Ia wherein R and R. 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 R 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 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,

wherein R and R 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.

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 lla,

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,

may, for example, be obtained by reacting a compound of formula V,

wherein 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.

Compounds of formula llb,

S R. f

wherein R, R, and R 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 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. For example, compounds of formula la are treated with a cyanogen halide, preferably cyanogen bromide, or a halogen formic acid ester. In this reaction 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.

The compounds of formula V, which are likewise new, may be obtained by dehydrating a compound of formula VI,

wherein 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. However, the reaction is preferably effected with hydrobromic acid in an inert organic solvent, e.g. a lower alcohol.

Compounds of formula V] may, for example, be

produced by adding dropwise a solution of a compound of formula Vll,

wherein 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,

wherein 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,

VII

VIII

wherein 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. 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 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. Particularly pronounced histaminolytic properties are observed with compounds of formula la, wherein R is methyl, notably 4-( l-methyl-4-piperidylidene)-4H-benzo[ 4,5 lcycloheptal l,2-b]thiophenl 0( 9H )-one and 6-chloro- 4-( l-methyl-4-piperidylidene )-4H-benzo[ The compounds of formula lb, 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 la as a specific histaminolytic or a compound of formula lb 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 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. 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-, ethaneand benzene-sulphonate, citrate and malate.

The invention also provides 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.

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

EXAMPLE l:

4-( l-Methyl-4-piperidylidene)-4H-benzo[ 4,5 lcycloheptad'l l ,2-b]thiophen-9( lOH )-one.

A mixture of 24.6 g of crude 4-( l methyl-4-piperidylidene )-9-piperidino-4l-l-benzo[4,5 ]cyclohepta[ 1,2- b]thiophene base and 4-( l-methyl-4-piperidylidene)- l-piperidino-4H-benzo{4,5 ]cyclohepta[ l ,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 -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 [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 crystalline product is filtered and recrystallized from a 30-fold quantity of 95 percent ethanol. Pure 4-(l-methyl-4- piperidylidene )-4H-benzo[4,5]cyclohepta[ 1,2 b]thiophen-9(l0H)-one fumarate, having a decomposition point of l97-l99, is obtained.

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 pure 4-( l-methyl-4-piperidylidene)-4H- benzo[4,5 ]cyclohepta[ l ,2-b]thiophen-9( 10H )-one base, having a M.P. of l48-l49, is obtained in this manner. Microanalysis agrees with the formula C H NOS. The structure was ascertained with the infrared, nuclear magnetic resonance and mass spectrograph spectra.

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 mixture of 129 g of 9,l0-dihydro-4H-benzo[4,5]- cyclohepta[ l ,2b]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 ofits 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,l0-dibromo-9,l0-dihydr0-4H- benzo[4,5][ l,2b]thiophen-4-one, having a MP. of l34l35 (decomp.), is obtained in this manner. Microanalysis agrees with the formula C HHBrOS. The structure was ascertained with the nuclear magnetic resonance spectrum.

A mixture of g of 9,lO-dibromo-9, l 0-dihydro4l-lbenzo[4,5 l,2b]thiophen-4-one, 3 l .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-$ for approximately four hours, and the crystalline product is filtered off. After recrystallizing from a l00-fold quantity of methanol, pure 9,l0-bromo-4H-benzo[4,5]cyclohepta[1,2-b] thiophen-4-one, having a MP. of l34-l35, is obtained. Microanalysis agrees with the formula C l-bBr 08 In accordance with the nuclear magnetic resonance spectrum the bromine atom is in the 9 or ID position (probably in the IQ 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 l-methyl-4-chloropiperidine and a few drops of l,2-dibromoethane are subsequently added, whereby the Grignard reaction commences. 22.8 g of freshly distilled l-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( l0)-bromo-4H-benzo[4,5]cyclohepta[1,2- blthiophen-4-one in I60 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 l a 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( l0)-bromo-4-( l-methyl-4- piperidyl )-4H-benzo[ 4,5]cycloheptal l,2b]thiophen- 4-ol base is obtained as residue and is worked up as such.

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. After filtering off the crystalline product and drying, the pure 9( l0)-bromo-4 -(l-methyl-4-piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l,2-b]thiophene base, having a M.P. of l49-l50, is obtained. Microanalysis agrees with the formula C l-l BrNS In accordance with the nuclear magnetic resonance spectrum the bromine atom is in the 9 or position (probably in the 10 position).

A mixture of 24.2 g of 9(l0)-bromo-4-( l-methyl-4- piperidylidene)-4H-benz0[4,5 ]cycloheptal l ,2- blthiophene, 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]cycloheptal,2b]thiophene base and the 4(1- methyl-4-piperidylidene l 0-piperidino-4H-benzo[ 4,5]cyclohepta-ll,2-b]thiophene base is obtained as residue and is further worked up as such.

EXAMPLE 2:

4-( l-Methyl-4-piperidylidene)-4H-benzo[ 4,5 ]cycloheptad'l l ,2-blthiophenl O(9H)-one.

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 pure 4-( l-methyl-4-piperidylidene)-4H- benzo{4,5 ]-cyclohepta[ l,2b]thiophen-l0(9H )-one base, having a M.P. of l52-l53, is obtained in this manner. Microanalysis agrees with the formula C H 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 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.

thiophene base and 4-(l-ethyl-4-piperidylidene)-l0- piperidino-4H-benzo[4,5 ]cyclohepta-I l,2b]t

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 first 5 liters of eluate are discarded, the following 4 liters are jointly concentrated. An oily material, mainly consisting of the two isomers 4-( l-ethyl-4-piperidylidene)-4H- benzo[4,5 ]cyclohepta[ l,2-b]thiophen-9( 10H )-one and 4( l -ethyl-4-piperidylidene )-4H-benzo[4,5 ]cyclohepta[ l ,2-b1-thiophen-l0(9H)-one (Example 4), is obtained as residue. 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 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-( l-ethyl-4-piperidylidene)-4H- benzo[4,5 ]cyclohepta[ l ,2b]thiophen-9( 10H )'one base, having a MP. of l28l30, is obtained in this manner. Microanalysis agrees with the formula C H NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

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.

EXAMPLE 4;

4-( l-Ethyl-4-piperidylidene )-4H-benzo[ 4,5 lcycloheptad? l ,2b1thiopheni (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 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 pure 4-( l-ethyl-4- piperidylidene)-4H-benzo[ 4,5 ]cyclohepta[ l ,2 b]thiophen-lO(9H)-one base, having a MP. of ll3-l 15, is obtained in this manner. Microanalysis agrees with the formula C H NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 5:

4-( l -Methyl-4-piperidylidene )-4H-benzo[ 4,5 ]cycloheptad7 l ,2b]thiophen-9( 10H)-one.

A mixture of 23.5 g of crude 9-tert.butoxy-4-(lmethyl-4-piperidylidene)-4H-benzo[ 4,5 ]cyclohepta[ l ,2-b] l0-tert.butoxyl l-methyl- 4-piperidylidene )-4l-I-benzo[4,5 ]cyclohepta[ l ,2b] 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-( 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. 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 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).

atotal The mixture of 9-tert.butoxy-4-( l-methyl-4- piperidylidene)-4H-benzo[4,s]cyclohepta[ l,2-b] thiophene base and l0-tert.butoxy-4-( l-methyl-4- piperidylidene )-4H-benzo[4,5 )cyclohepta-l l ,2- blthiophene base, used as starting material, may, for example, be produced as follows:

A mixture of 30 g of 9(l0)-bromo-4-( l-methyl-4- piperidylidene)-4H-benzo{4,5 ]cyclohepta[ l ,2- blthiophene base, produced as described in Example I, 300 cc of dioxane and l8.l 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-(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.

EXAMPLE 6:

4-( l-Methyll-piperidylidene )-4H-benzo[ 4,5 lcycloheptad7l ,2-b]thiopheni 0( 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 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 crude 4-( l-methyl-4-piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l,2b]thiophenl 0(9H)-one base, having a MP. of l52l 53, is obtained in this manner.

EXAMPLE 7:

4-( l -lsopropyl-4-piperidylidene )-4H-benzo[ 4,5 lcycloheptad7 l ,2-blthiophenl 0( 9H )-one.

A mixture of 25 g of 4-(4-piperidylidene)-4H- benzo[4,5 l,2b}thiophen-l0( 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 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 05. The salt is subsequently filtered off and recrystallized from a 16-fold quantity of 95 percent ethanol. The pure 4-( l -isopropyl-4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ 1 ,2b]-thiophen-l0( 9H)-one hydrogen fumarate, having a decomposition point of 225226, is obtained in this manner. Microanalysis agrees with the formula C H NOS C H,,O 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-l(9H)-one, required as starting material, may, for example, be obtained as follows:

A solution of 30 g of 4-( l-methyl-4-piperidylidene)- 4Hbenzo[4,5 ]cyclohepta[ l,2-b]thiophen- I 0(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 I00 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 -fold quantity of absolute ethanol. Pure 4-( l-ethoxycarbonyl-4-piperidylidene )-4H-benzo[4,5 ]-cyclohepta[ l,2b]thiophenl 0 (9H)-one, having a M.P. of l74l75, is obtained in this manner. Microanalysis agrees with the formula C IHMNO S. The structure was ascertained with the infrared and ultraviolet spectra.

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. 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-l0(9H)-one base, having a M.P. of l64l66, is obtained in this manner. Microanalysis agrees with the formula C H NOS. The structure was ascertained with the nuclear magnetic resonance spectrum.

EXAMPLE 8:

4-( ln-Butyl-4-piperidylidene)-4H-benzo[ 4,5 ]cycloheptad7 l ,2-b ]thiophenl 0( 9H )-one.

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 pure 4-( l-n-butyl-4-piperidylidene)-4H benzo[4,5 ]cyclohepta-l l,2b]thiophen-l0(9H)-one base, having a M.P. of l04-l05, is obtained in this manner.

Microanalysis agrees with the formula C,,H,,NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE 9:

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

A mixture of 47 g of 6-chloro-4-(l-methyl-4- piperidylidene )-9-piperidino-4H-benzo[ 4,5 ]cyclohepta[l,2-b]thiophene base and 6-chloro-4-( l-metbyl-4- piperidylidene)- l 0-piperidino-4H-benzo[4,5] cyclobeptal l,2b]thiophene base is dissolved at 50 in 470 cc of 2 N hydrochloric acid, and the solution is kept at for l e 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-(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. 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(l-methyl-4-piperidylidene)-4H- benzo[4,5 ]cyclohepta[ l,2-b]thiophen-9( 10H )-one base, having a M.P. of l52-l53 (decomp.), is obtained in this manner. Microanalysis agrees with the formula C H ClNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 6-chloro-4-( l-methyl-4-piperidylidene)-9-piperidino-4H-benzo[4,5]cyclohepta[ 1,2- blthiophene and 6-chloro-4-(l-methyl-4-piperidylidene l 0-piperidino-4H-benzo[4,5 ]cyclohepta-[ 1,2- blthiophene, required as starting material, was produced as follows from 6-chloro-9, l 0-dibromo-9, l 0- dihydro-4H-benzo[4,5 ]-cyclohepta[ l,2-b]thiophen-4- one:

A mixture of 26 g of 6-chloro-9,l0-dihydro-4H- benzo-[4,5]cyclohepta[ l ,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 4% 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 l: l Pure 6-chloro-9,10- dibromo-9, l 0-dihydro-4H-benzo[4,5 ]cyclohepta[ 1,2 blthiophen-4-one, having a decomposition point of l47-l49, is obtained in this manner. Microanalysis agrees with the formula C H Br,Cl0S.

A mixture of 28.5 g of 6-chloro-9,l0-dibromo-9,l0- dihydro-4H-benzo[4,5 ]cyclohepta[ l,2-blthiophen-4- one, 320 cc of methanol and ll.8 g of potassium hydroxide is boiled at reflux for l 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 efiected from a 20fold quantity of tetrahydrofuran. Pure 9(l0)-bromo-6-chloro-4H- benzo-[4,5 ]cyclohepta[ l,2-b]thiophen-4-one, having a MP. of l98-200, is obtained in this manner. Microanalysis agrees with the formula C H BrcloS. The structure was ascertained with the nuclear mag netic resonance and mass spectrograph spectra.

3.33 g of magnesium activated with iodine are covered with a layer of IO cc of absolute tetrahydrofuran, and approximately 3 cc of a solution of l8.3 g of freshly distilled 4-chloro l -methylpiperidine in 30 cc of absolute tetrahydrofuran are added. The Grignard reaction commences by the addition of a few drops of l,2-dibromoethane. The remaining 4-chloro-l-methylpiperidine solution is then added dropwise to the magnesium at such a rate that the reaction mixture boils continuously without external heating. After the drop wise addition is complete, the mixture is boiled at reflux for 1% hours, whereafter the magnesium is practically completely dissolved. The 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 crude, oily 9( 10)- bromo-6-chloro4-( l-methyl-4-piperidyl)-4H- benzol4,5}cyclohepta[l,2-b1thiophen-4-ol base is ob tained as residue and is worked up as such.

A mixture of 3l g of crude 9( l0)-bromo-6-chloro-4- l-methyl-4-piperidyl)-4H-benzo[4,5 ]cyclohepta[ l,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. I00 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( l0)-bromo-6-chloro- 4-( l-methyl-4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l,2-b] thiophene base, having a MP. of l93-l95, is obtained in this manner. Microanalysis agrees with the formula C fl BrClNs. The structure was ascertained with the nuclear magnetic resonance and mass spectrograph spectra.

A mixture of 47.5 g of 9( l0)-bromo-6-chloro-4-( lmethyl-4-piperidylidene)-4H-benzo[4,5 ]cyclohepta[ 1,2-b1thiophene 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-( l-methyl-4-piperidylidene)-9- piperidino-4H-benzo[4,5 l-cyclohe'ptal 1,2- blthiophene base and 6-chloro-4-( l-methyl-4- piperidylidene l0-piperidino-4l-l-benzol 4,5] cycloheptal l,2b]thiophene base is obtained as residue and is worked up as such.

EXAMPLE l0:

6-Chloro-4-( l-methyl-4-piperidylidene )-4H-benzo [4,5lcycloheptal l,2-blthiophenl 0(9H )-one.

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. The pure 6- chloro-4-( l-methyl-4-piperidylidene)-4H-benzo[4,5 cycloheptal l ,2b]thiophenl 0(9H)-one base, having a MP. of l68l69, is obtained in this manner. Microanalysis agrees with the formula C H ClNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE I l:

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 pure 4-( l-isopropyl- 4-piperidylidene )-4H-benzo[4,5 ]cyclohepta[ l,2b]- thiophen-9( l0H) one fumarate, having a MP. of 2 l4-2l6 (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 l:l. The pure 4-( l-isopropyl-4 -piperidylidene )-4 H-benzo[4,5 ]-cyclohepta[ l,2- b]thiophen-9( l0H)-one base, having a MP. of l l7-l l9 (decomp.), is obtained in this manner. Microanalysis agrees with the formula C H NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 4-( l-isopropyl-4-piperidylidene)-9- piperidino-4H-benzol 4,5 ]cyclohepta[ l,2-b1thiophene base and 4-( l-isopropyl-4-piperidylidene l0- piperidino-4H-benzo[4,5 ]-cyclohepta[ l,2b] thiophene base, used as starting material, is obtained in a manner analogous to that described in Example I, except that 4-chloro-l-isopropyl-piperidine is used in place of 4chlorol -methyl-piperidine.

EXAMPLE l2:

4-(1-lsopropyl-4-piperidylidene)-4H-benzo[ 4,5 ]cycloheptad7 l ,2b]thiophen-l0(9)-one.

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. The pure 4-( l-isopropyl-4-piperidylidene )-4H-benzo[ 4,5]cycloheptal,2b]thiophenl0(9H)-one hydrogen fumarate, having a MP. of 225226 (decomp. is obtained in this manner. Microanalysis agrees with the formula C, H NOS.C,H O,. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE l3:

4-( l-n-Butyl-4-piperidylidene )-4H-benzo[ 4,5 lcycloheptad? l ,2-b ]thiophen-9( IOH )-one.

A mixture of 47 g of crude 4-( l-n-butyl-4-piperidy lidene )-9-piperidino4H-benzo[4,5 ]cyclohepta[ l ,2-b] thiophene base and 4-( l-n-butyl-4-piperidylidene)-l0- piperidino-4H-benzo[4,5 ]-cyclohepta[ l ,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-( l-n-butyl-4- piperidylidene)-4H-benzo-[4,5 ]cyclohepta[ 1,2 -b]thiophen-9( l0H)-one base and 4-( l-n-butyl-4- piperidylidene)-4H-benzo[4,5 ]cyclohepta[ 1,2 -b]thiophen-l0(9H)-one base is obtained as residue. 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. The salt is filtered off and dried in a vacuum at 7080. The pure 4-( l-n-butyl-4- piperidylidene) 4H-benzo[4,5 ]-cyclohepta[ 1,2 -b]thiophen-9( l0H)-one hydrogen malate, having a MP. of l88-l90 (decomp.), is obtained in this manner. Microanalysis agrees with the formula C, H ,,NOS.C,H,O,. 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[ l ,2-b]thiophene base and 4-( l-n-butyl-4-piperidylidene)- l-piperidino 4Hbenzo[4,5 ]cyclohepta-[ l,2-b]thiophene base, used as starting material, may, for example, be ob tained as follows:

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. 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 l-n-butyl-4- chloropiperidine base, which distils at 95l00/ l4 mm of Hg, is obtained in this manner. Microanalysis agrees with the formula C,H, ClN.

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

EXAMPLE l4:

4-( l-n-Butyl-4-piperidylidene)-4-H-benzo[ 4,5 lcycloheptad? l ,2-blthiophenl0( 9H )-one.

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. The pure 4-( l-n-butyl-4-piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l,2-b]thiophen-l0(9H)'one base, having a M.P. of l04-l05, is obtained in this manner. Microanalysis agrees with the formula C H NOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

EXAMPLE l:

7-Chloro-4-( 1-methyl-4-piperidylidene)-4H-benzo [4.5 ]cyclohepta[ l,2-b]tiophenl0(9H)-one.

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 combined extracts are washed with water, dried over sodium sulphate and concentrated. An oily base mainly consisting of the two isomers 7-chloro-4-( l-methyl-4-piperidyiidene)-4H- benzo[4,5 ]cyclohepta[ l,2-b]thiophen-9( lOH )-one and 7-chloro-4-( l-methyl-4-piperidylidene )-4H- benzo[4,5 ]cyclohepta-[ l ,2-b]thiophenl0( 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 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 mixture of 7-chloro-4-( l-methyl-4-piperidylidene )-9-piperidino-4H-benzo[4,5 ]cyclohepta[ l ,2- blthiophene base and 7-chloro-4-( l-methyl-4- piperidylidene l 0-piperidino-4Hbenzo[4,$ cyclohepta[l,2-blthiophene base, used as starting material, may be obtained in a manner analogous to that described in Example I, except that 7-chloro-9, l0- dihydro-4H-ben2o{4,5 ]cyclohepta[ l,2-bl-thiophen 4one is used in place of 9,l0-dihydro-4H-benzo[4,5]- cyclohepta[ l,2-blthiophen-4-one. The 9( 10)-bromo-7 -chloro-4-( l-methyl-4-piperidylidene)-4H-benzol[4,5 ]cyclohepta[l,2-b]thiophene base, formed as intermediate during the course of the reaction, has a M.P. of l47l49.

EXAMPLE l6:

7-Chloro-4-( l-methyl-4-piperidylidene)-4H-benzo [4,5 ]cyclohepta[ l,2-blthiophen-9( lOH )-one.

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.

EXAMPLE l7:

6-Bromo-4-( l-methyl-4-pien'dylidene )-4H-benzo [4,51cycloheptal l,2-b]thiophen- I (9H )-one.

A mixture of 15.4 g of crude 6-bromo-4-( l-methyl-4- piperidylidene )-9-piperidino-4H-benzo[4,5 ]cyclohepta{ l,2-blthiophene base and 6-bromo-4-(l-methyl4- piperidylidene l0-piperidino-4H-benzo[4,5] cyclohepta[ l,2blthiophene 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- l methyl-4-piperidylidene )-4Hbenzo[4,5]cycl0hepta l,2-b]thiophen-9( H )-one and 6-bromo-4-( lmethyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[ l,2-b1thiophen-l0(9H)-one, is obtained as residue. The isomers are separated by dissolving the evapora tion 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-( 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. The pure 6-bromo-4-( l-methyl-4- piperidylidene)-4H-benzo[4,5 ]cyclohepta[ l,2- b]thiophen-l0(9H)-one base, having a MP. of l72-l73, is obtained in this manner. Microanalysis agrees with the formula C l'l BrNOS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 6-bromo-4-(l-methyl-4-piperidylidene)-9-piperidino-4H-benzo[4,5 ]cyclohepta[ l,2- b]thiophene base and 6-bromo-4-(l-methyl-4- piperidylidene)- 10-piperidino-4H-benzo[4,5]- cyclohepta[ l,2-blthiophene base, used as starting material, is obtained in a manner analogous to that described in Example I, except that 6-bromo-9,l0- dihydro-4H-benzo[4,5 ]cyclohepta[ l ,2-bl-thiophen-4- one is used in place of 9,lO-dihydro-4H-benzo[4,5]- cyclohepta[ l,2-blthiophen-4-one.

The 6,9( l0)-dibromo-4-( l-methyl-4-piperidylidene)-4H-benzo[ 4,5 ]cyclohepta[ l ,2-b thiophene base, formed as intermediate during the course of the reaction, has a M.P. of l85-l 86.

EXAMPLE l8:

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

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.

EXAMPLE I):

7-methoxy-4-( l-methyl-4-piperidylidene )-4H-benzo [4,5 ]cyclohepta[ l ,2-blthiophenl 0(9H)-one.

A mixture of IO g of crude 7-methoxy-4-( l-methyl- 4-piperidylidene)-9-piperidino-4Hbenzo[4,5cycloh eptal l,2b]thiophene base and 7-methoxy-4-( 1- methyl-4-piperidylidene l 0-piperidino-4H- benzo[4,5][ l,2-blthiophene base is dissolved in I00 cc of 2 N hydrochloric acid, and the solution is kept at 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-( l-methyl- 4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l ,2-b] thiophen-9(l0H)-one and 7-methoxy-4(l-methyl-4- piperidylidene)-4H-benzo[4,5 ]cyclohepta{ l ,Z-b] thiophen-l0(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-( 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. The pure 7-methoxy-4-( lmethyl-4-piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l,2b]l0(9H)-one base, having a MP. of l57l58, is obtained in this manner. Microanalysis agrees with the formula C H NO S. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

The mixture of 7-methoxy-4-(l-methyl-4-piperidylidene)-9-piperidino-4H-benzo[ 4,5 ]cyclohepta[ l ,2- b]thiophene base and 7-methoxy-4-( l-methyl-4- piperidy|idene)- l 0-piperidino-4H-benzo[ 4,5 cyclohepta[ l,2-blthiophene base, required as starting material, is produced as follows:

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. 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 MP. of [70-172, is obtained in this manner. Microanalysis agrees with the formula C I-1 ,0 -,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-I2-(2-thienyl)viny1] 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 percent sodium thiosulphate and subsequently with water, is dried over sodium sulphate and concentrated. The crude 4-methoxy-2-[2- (Z-thienyUethyllbenzoic 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-l70/0.04 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, l 0-dihydro-7-methoxy-4 H-benzo[4,5 ]cyclohepta[ l ,2-blthiophen-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 l,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 05, the crystalline product is filtered off, is washed with 70 cc of carbon tetrachloride and suspended in 100 cc of absolute ethanol at 05. The product is subsequently filtered oh and washed with approximately 500 cc of water. After drying, crude 9, l 0-dibromo-9, l O-dihydro-7-methoxy-4H-benzol 4,5 ]cyclohepta[l,2b]thiophen-4-one is obtained and is further worked up as such.

A mixture of 16.7 g of 9, l0-dibromo-9,l0-dihydro-7- methoxy-4H-benzo[4,5cycloheptal l ,Z-b lthiophen-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 in a vacuum, pure 9( l0)-bromo-7-methoxy-4H-benzo[ 4,5 ]cyclohepta[1,2-b1thiophen-4-one, having a M.P. of 182-184, is obtained. The structure was ascertained with the mass spectrograph spectrum.

Approximately l/lO of a solution of 10.1 g of 4- chloro-l-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-l-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 1% 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-b1thiophen-4-one are added at 10 within approximately 20 minutes, and the mixture is subsequently stirred at 10 for a further 11,1 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( l0)-bromo-7methoxy-4-( 4-methyl-4 -piperidyl)-4H-benzo[4,5 lcycloheptal l,2-b]thiophen- 4-01 base is obtained as residue and is further worked up as such.

A mixture of 17.5 g of crude 9( l0)-bromo-7- methoxy-4-( 1-methyl-4-piperidyl )-4H-benzo[4,5 lcycloheptal1,2-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( 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.

A mixture of 10 g of 9( l0)-bromo-7-mpthoxy-4-( 1- methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[ 1,2-blthiophene base, 60 cc of piperidine, 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 cc of benzene. This solution is washed with water, dried over sodium sulphate and concentrated. A mixture of crude, oily 7-methoxy-4-( l-methyl-4-piperidylidene)-9- piperidino-4H-benzo-[ 4 ,5 ]cyclohepta[ l ,2- blthiophene base and 7-methoxy-4-(l-methyl-4- piperidylidene l -piperidino4H-benzo[ 4,5] cycloheptall,2b]-thiophene base is obtained as residue and is further worked up as such.

EXAMPLE 7-Methoxy-4-( l-methyl-4-piperidylidene)-4H-benzo V [4.5 ]cyclohepta[ l ,2-b]thiophen-9( l0)-one.

C H NOBZS. The structure was ascertained with the infrared and nuclear magnetic resonance spectra.

What is claimed is: l. A compound of the formula:

wherein R, is hydrogen, halogen or alkoxy of one to four carbon atoms,

R, is alkyl of one to four carbon atoms, and

pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim I, which is 4-( l-methyl-4- piperidylidene )-4H-benzo[ 4,5 ]cyclohepta[ l,2 -blthiophen-9( 10H )-one.

3. 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.

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

6. The compound of claim l, which is 4-( l-isopropyl- 4-piperidylidene)-4H-benzo[4,5 lcycloheptal l ,2 -b]thiophenlO(9H)-one.

7. The compound of claim 1, which is 4-( ln-butyl-4- piperidylidene )-4H-benzo[ 4,5 lcycloheptal l,2 b]thiophen-l0(9H)-one.

8. The compound of claim 1, which is 6-chloro 4-( lmethyl-4-piperidylidene )-4H-benzo[4,5 ]cyclohepta[ l, 9 l0l-l com p 3?id of claim I, which is 6-chloro-4-( lmethyl-4-piperidylidene )-4l-l-benzo[ 4,5 ]cyclohepta[ l,2-b] 10(9H )-one.

10. The compound of claim 1, which is 4-( lisopropyl-4-piperidylidene)-4H-benzo[4,5]cycloheptal l,2-b]thiophen-9( 20H )-one.

11. The compound of claim 1, which is 4-( l-n-butyl- 4-piperidylidene)-4H-benzo[ 4,5 lcycloheptal l ,2 -b]thiophen-9( l0l-I)-one.

12. The compound of claim 1, which is 7-chloro-4- (1-methyl'4-piperidylidene)-4H-benzo[4,5]cyclohepta [l ,2-b] l0(9H)-one.

13. The compound of claim 1, which is 7-chloro-4- (l-methyl-4-piperidylidenel-4H-benzo[4,5 lcyclohapta 14. The compound of claim 1, which is 6-bromo-4- (l-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohapta .2-b] l 0(9H)-one.

15. The compound of claim 1, which is 6-bromo-4- (l-methyl-4piperidylidene)-4H-benzo[4,5 lcyclohepta l,2-b]9(lOH)-one.

16. The compound of claim 1, which is 7-methoxy-4- l-methyl-4-piperidylidene )-4H-benzo[4,5 lcyclohepta I l ,2-blthiophen-lD(9H)-one.

17. The compound of claim 1, which is 7-methoxy-4- l-methyl-4-piperidylidene)-4H-benzo[4,5lcyclohepta l ,2-b]thiophen9( 10H )-one.

l8. A compound of the formula wherein R and R are as defined in claim 1.

19. A compound of claim 18 in which R is methyl. 20. A compound of the formula:

wherein R and R are as defined in claim I.

i i i

Claims (19)

  1. 2. The compound of claim 1, which is 4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-9(10H) -one.
  2. 3. The compound of claim 1, which is 4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9H) -one.
  3. 4. The compound of claim 1, which is 4-(1-ethyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-9(10H) -one.
  4. 5. The compound of claim 1, which is 4-(1-ethyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9H) -one.
  5. 6. The compound of claim 1, which is 4-(1-isopropyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen -10(9H)-one.
  6. 7. The compound of claim 1, which is 4-(1n-butyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9H) -one.
  7. 8. The compound of claim 1, which is 6-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2 -b)thiophen-9(10H)-one.
  8. 9. The compound of claim 1, which is 6-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2 -b)thiophen-10(9H)-one.
  9. 10. The compound of claim 1, which is 4-(1-isopropyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen -9(20H)-one.
  10. 11. The compound of claim 1, which is 4-(1-n-butyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-9(10H)-one.
  11. 12. The compound of claim 1, which is 7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2 -b)thiophen-10(9H)-one.
  12. 13. The compound of claim 1, which is 7-chloro-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2 -b)thiophen-9(10H)-one.
  13. 14. The compound of claim 1, which is 6-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9H)-one.
  14. 15. The compound of claim 1, which is 6-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-9(10H)-one.
  15. 16. The compound of claim 1, which is 7-methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2 -b)thiophen-10(9H)-one.
  16. 17. The compound of claim 1, which is 7-methoxy-4-(1-methyl-4-piperidylidene)-4H-benzo(4,5)cyclohepta(1,2 -b)thiophen-9(10H)-one.
  17. 18. A compound of the formula
  18. 19. A compound of claim 18 in which R2 is methyl.
  19. 20. A compound of the formula:
US3682930A 1970-03-11 1971-03-03 4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9 Expired - Lifetime US3682930A (en)

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US3770728A Expired - Lifetime US3770728A (en) 1970-03-11 1971-09-07 Substituted 4h-benzo(4,5)cyclohepta(1,2-b)thiophen-10(9h)-ones
US3749786A Expired - Lifetime US3749786A (en) 1970-03-11 1972-08-07 Organic compounds in treating allergic conditions
US3853915A Expired - Lifetime US3853915A (en) 1970-03-11 1972-08-08 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones

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US3749786A Expired - Lifetime US3749786A (en) 1970-03-11 1972-08-07 Organic compounds in treating allergic conditions
US3853915A Expired - Lifetime US3853915A (en) 1970-03-11 1972-08-08 9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862156A (en) * 1972-01-24 1975-01-21 Sandoz Ag 4h-benzo{8 4,5{9 cyclohepta{8 1,2-6{9 thiophenes
US4032640A (en) * 1975-06-16 1977-06-28 Sandoz Ltd. 4H-Benzo[4,5]cyclohepta[1,2-b]thiophenes
US4072756A (en) * 1973-05-17 1978-02-07 Sandoz Ltd. Tricyclo piperidino ketones and soporific compositions thereof
US4073915A (en) * 1975-05-20 1978-02-14 Sandoz Ltd. Treating asthma
US4128549A (en) * 1976-02-27 1978-12-05 Sandoz Ltd. Precursors of 4-(1-alkyl-4-piperidylidene-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-10(9H)-ones
US4223035A (en) * 1973-10-08 1980-09-16 Sandoz Ltd. Treating prostate hypertrophy with 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidines
US4615881A (en) * 1980-11-29 1986-10-07 Sandoz Ltd. Pharmaceutical compositions
GB2191696A (en) * 1986-06-21 1987-12-23 Sandoz Ltd Ketotifen compositions
US5089496A (en) * 1986-10-31 1992-02-18 Schering Corporation Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies
US5393753A (en) * 1990-10-10 1995-02-28 Schering Corporation Substituted imidazobenzazepines
US5438062A (en) * 1986-10-31 1995-08-01 Schering Corporation Benzo(5,6)cycloheptapyridines, compositions and methods of use
US5891460A (en) * 1995-06-07 1999-04-06 University Of Southern California University Park Campus Method for reducing or preventing post-surgical adhesion formation using ketotifen and analogs thereof
WO2001039774A1 (en) * 1999-12-01 2001-06-07 Klein Pharmaceuticals Topical administration of ketotifen
EP1218007A1 (en) * 1999-09-13 2002-07-03 Bridge Pharma, Inc. Optically active isomers of ketotifen and therapeutically active metabolites thereof
US20030212078A1 (en) * 2001-05-17 2003-11-13 Klein Gerald L. Topical administration of pharmacological compositions for non-systemic treatment of pruritus
US20070077295A1 (en) * 2005-06-13 2007-04-05 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US20070099902A1 (en) * 2005-06-13 2007-05-03 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form
US20090036408A1 (en) * 2003-01-14 2009-02-05 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US20100166804A1 (en) * 2007-05-23 2010-07-01 Dennis Penn Methods
US8377967B2 (en) 2008-01-30 2013-02-19 Nippon Zoki Pharmaceutical Co., Ltd. Piperidine derivative
US8557846B1 (en) 2012-10-23 2013-10-15 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in dogs
WO2014066212A1 (en) 2012-10-23 2014-05-01 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in companion animals with norketotifen
WO2015020878A1 (en) 2013-08-06 2015-02-12 Bridge Pharma, Inc. Methods of treating pruritic conditions mediated through histamine h-4 receptors
US9345697B2 (en) 2013-08-06 2016-05-24 Bridge Pharma, Inc. Methods of treatment of non-histaminic pruritus
US9439895B2 (en) 2013-08-06 2016-09-13 Bridge Pharma, Inc. Methods of treating pruritic conditions mediated through non-histaminergic mechanisms in diabetic patients
WO2016200578A1 (en) 2015-06-11 2016-12-15 Bridge Pharma, Inc. Methods of treatment of non-histaminic pruritus in mammals
US9649303B2 (en) 2008-05-23 2017-05-16 Mastcell Pharmaceuticals, Inc. Methods and treatment for allergies and inflammation associated with gastrointestinal diseases
US9808419B2 (en) 2012-10-30 2017-11-07 Bridge Pharma, Inc Medicinal treatment of dermal infectious disorders with norketotifen

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682930A (en) * 1970-03-11 1972-08-08 Jean Pierre Bourquin 4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9
US3960894A (en) * 1972-01-24 1976-06-01 Sandoz Ltd. 9-Bromo-or chloro-9,10-dihydro-10-dihydro-10-alkoxy-4H-benzo[4,5]cyclo-hepta[1,2-b]thiophen-4-ones
CA1041100A (en) * 1973-10-04 1978-10-24 Herbert G. Johnson Pyridine-diyldioxamic acid and derivatives
US4282233B1 (en) * 1980-06-19 2000-09-05 Schering Corp Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines
GB8926392D0 (en) * 1989-11-22 1990-01-10 Scras Selenophen derivatives
CA2038417A1 (en) * 1990-04-11 1991-10-12 Yasuo Ito Piperidine compounds, method for preparation thereof, and a pharmaceutical composition comprising the same
US6207684B1 (en) 1997-06-09 2001-03-27 Bridge Pharma, Inc. Compounds with combined antihistaminic and mast cell stabilizing activities, intended for ophthalmic use
US6221897B1 (en) * 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
CA2732282C (en) * 2008-08-01 2016-03-29 Nippon Zoki Pharmaceutical Co., Ltd. Aminopropylidene derivative
US8536342B2 (en) * 2009-07-28 2013-09-17 Nippon Zoki Pharmaceutical Co., Ltd. Process for producing thiabenzoazulene-propionic acid derivative

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272826A (en) * 1962-08-31 1966-09-13 Sandoz Ltd Substituted 4[piperidylidene(4')]-9, 10-dihydro-4h-benzo [4, 5] cyclohepta [1, 2-b] thiophene and the 4 piperidyl 4 ol compounds
US3491103A (en) * 1963-12-19 1970-01-20 Sandoz Ag Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1437412A (en) * 1963-12-19 1966-05-06 Sandoz Sa New cyclohepta-benzo-thiophene and their preparation
NL162371C (en) * 1968-03-20 1980-05-16 Hoffmann La Roche A process for the preparation of 5h-dibenzoÿa, dÿcyclo- heptenes with a 5- (3-dimethylaminopropyl) - or 5- (3-dimethylaminopropylidene) -n-oxide group having anti-depressant activity, process for the preparation of pharmaceutical compositions and the shaped compositions.
US3574199A (en) * 1968-06-28 1971-04-06 Searle & Co 6-(aminoalkyl- and aminoalkylidene)-1,1a,6,10b -tetrahydro-dibenzo(a,e)cyclopropa(c)cycloheptenes
US3682930A (en) * 1970-03-11 1972-08-08 Jean Pierre Bourquin 4(1-alkyl-4-piperidylidine)-4h-benzo {84,5{9 {0 cyclohepta {8 1,2{14 6{9
US3709947A (en) * 1971-07-26 1973-01-09 Searle & Co 6-chloropropylidene-1,1a,6,10b-tetrahydrobenzo(a,e)cyclopropa(c)cycloheptenes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272826A (en) * 1962-08-31 1966-09-13 Sandoz Ltd Substituted 4[piperidylidene(4')]-9, 10-dihydro-4h-benzo [4, 5] cyclohepta [1, 2-b] thiophene and the 4 piperidyl 4 ol compounds
US3491103A (en) * 1963-12-19 1970-01-20 Sandoz Ag Certain 4h-benzo(4,5)cyclohepta-(1,2-b) thiophenes

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862156A (en) * 1972-01-24 1975-01-21 Sandoz Ag 4h-benzo{8 4,5{9 cyclohepta{8 1,2-6{9 thiophenes
US4072756A (en) * 1973-05-17 1978-02-07 Sandoz Ltd. Tricyclo piperidino ketones and soporific compositions thereof
US4223035A (en) * 1973-10-08 1980-09-16 Sandoz Ltd. Treating prostate hypertrophy with 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-methylpiperidines
US4073915A (en) * 1975-05-20 1978-02-14 Sandoz Ltd. Treating asthma
US4032640A (en) * 1975-06-16 1977-06-28 Sandoz Ltd. 4H-Benzo[4,5]cyclohepta[1,2-b]thiophenes
US4128549A (en) * 1976-02-27 1978-12-05 Sandoz Ltd. Precursors of 4-(1-alkyl-4-piperidylidene-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-10(9H)-ones
US4615881A (en) * 1980-11-29 1986-10-07 Sandoz Ltd. Pharmaceutical compositions
GB2191696B (en) * 1986-06-21 1991-01-16 Sandoz Ltd Pharmaceutical compositions
GB2191696A (en) * 1986-06-21 1987-12-23 Sandoz Ltd Ketotifen compositions
US5089496A (en) * 1986-10-31 1992-02-18 Schering Corporation Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies
US5438062A (en) * 1986-10-31 1995-08-01 Schering Corporation Benzo(5,6)cycloheptapyridines, compositions and methods of use
US5151423A (en) * 1989-05-01 1992-09-29 Schering Corporation Heterocyclic n-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, compositions and methods of use
US5393753A (en) * 1990-10-10 1995-02-28 Schering Corporation Substituted imidazobenzazepines
US5891460A (en) * 1995-06-07 1999-04-06 University Of Southern California University Park Campus Method for reducing or preventing post-surgical adhesion formation using ketotifen and analogs thereof
US20080287498A1 (en) * 1999-09-13 2008-11-20 Aberg A K Gunnar Optically active isomers of ketotifen and therapeutically active metabolites thereof
EP1218007A1 (en) * 1999-09-13 2002-07-03 Bridge Pharma, Inc. Optically active isomers of ketotifen and therapeutically active metabolites thereof
EP1218007A4 (en) * 1999-09-13 2003-04-09 Bridge Pharma Inc Optically active isomers of ketotifen and therapeutically active metabolites thereof
US7557128B2 (en) 1999-09-13 2009-07-07 Bridge Pharma, Inc. Optically active isomers of ketotifen and therapeutically active metabolites thereof
US20090149502A1 (en) * 1999-09-13 2009-06-11 Aberg A K Gunnar Optically active isomers of ketotifen and therapeutically active metabolites thereof
US7872025B2 (en) 1999-09-13 2011-01-18 Bridge Pharma, Inc. Optically active isomers of ketotifen and therapeutically active metabolites thereof
US7226934B1 (en) 1999-09-13 2007-06-05 Bridge Pharma, Inc. Optically active isomers of ketotifen and therapeutically active metabolites thereof
WO2001039774A1 (en) * 1999-12-01 2001-06-07 Klein Pharmaceuticals Topical administration of ketotifen
US20030212078A1 (en) * 2001-05-17 2003-11-13 Klein Gerald L. Topical administration of pharmacological compositions for non-systemic treatment of pruritus
US20090036408A1 (en) * 2003-01-14 2009-02-05 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US20090143314A1 (en) * 2003-01-14 2009-06-04 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9744181B2 (en) 2003-01-14 2017-08-29 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9457036B2 (en) 2003-01-14 2016-10-04 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8716264B2 (en) 2003-01-14 2014-05-06 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8592397B2 (en) 2003-01-14 2013-11-26 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8871271B2 (en) 2005-06-13 2014-10-28 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US20070077295A1 (en) * 2005-06-13 2007-04-05 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US8598185B2 (en) 2005-06-13 2013-12-03 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US9545414B2 (en) 2005-06-13 2017-01-17 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form
US20070099902A1 (en) * 2005-06-13 2007-05-03 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form
US9018192B2 (en) 2005-06-13 2015-04-28 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US20100166804A1 (en) * 2007-05-23 2010-07-01 Dennis Penn Methods
US8377967B2 (en) 2008-01-30 2013-02-19 Nippon Zoki Pharmaceutical Co., Ltd. Piperidine derivative
US9649303B2 (en) 2008-05-23 2017-05-16 Mastcell Pharmaceuticals, Inc. Methods and treatment for allergies and inflammation associated with gastrointestinal diseases
WO2014066212A1 (en) 2012-10-23 2014-05-01 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in companion animals with norketotifen
US8557846B1 (en) 2012-10-23 2013-10-15 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in dogs
US8778971B2 (en) 2012-10-23 2014-07-15 Bridge Pharma, Inc. Medicinal treatment of dermal diseases in companion animals
US9808419B2 (en) 2012-10-30 2017-11-07 Bridge Pharma, Inc Medicinal treatment of dermal infectious disorders with norketotifen
US9345697B2 (en) 2013-08-06 2016-05-24 Bridge Pharma, Inc. Methods of treatment of non-histaminic pruritus
US9333199B2 (en) 2013-08-06 2016-05-10 Bridge Pharma, Inc. Methods of treatment of histamine H-4 receptor-related pruritus associated with nerve disorders
WO2015020878A1 (en) 2013-08-06 2015-02-12 Bridge Pharma, Inc. Methods of treating pruritic conditions mediated through histamine h-4 receptors
US9439895B2 (en) 2013-08-06 2016-09-13 Bridge Pharma, Inc. Methods of treating pruritic conditions mediated through non-histaminergic mechanisms in diabetic patients
US9138431B2 (en) 2013-08-06 2015-09-22 Bridge Pharma, Inc. Methods of treatment of histamine H-4 receptor-related pruritus
WO2016200578A1 (en) 2015-06-11 2016-12-15 Bridge Pharma, Inc. Methods of treatment of non-histaminic pruritus in mammals

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GB1355537A (en) 1974-06-05 application
DE2144490A1 (en) 1972-03-30 application
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CA960673A (en) 1975-01-07 grant
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LU62757A1 (en) 1971-10-13 application
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US3770728A (en) 1973-11-06 grant
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US3749786A (en) 1973-07-31 grant
DE2111071A1 (en) 1971-09-23 application
GB1355538A (en) 1974-06-05 application
BE764019A1 (en) grant
NL7111808A (en) 1972-03-28 application
US3853915A (en) 1974-12-10 grant
FR2107917A1 (en) 1972-05-12 application
GB1360219A (en) 1974-07-17 application
DE2111071B2 (en) 1978-11-09 application
DE2111071C3 (en) 1979-07-12 grant
CA947767A (en) 1974-05-21 grant

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