CH615927A5 - Process for the preparation of novel benzocycloheptathiophene derivatives - Google Patents

Abstract

The novel benzocycloheptathiophene derivatives of the formula I and their acid addition salts are obtained from the corresponding 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-(methyl or benzyl)piperidine derivatives by reaction with a chloroformic acid ester or with cyanogen bromide and solvolytic removal of the ester or cyano group thus introduced. They are also obtained from the corresponding 4-(4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ylidene)-1-benzylpiperidin e derivatives by hydrogenolytic debenzylation. The compounds of the formula I can be used as analgesics and antihistaminics. <IMAGE>

Description

** WARNING ** Beginning of DESC field could overlap end of CLMS **.

PATENT CLAIMS 1. Process for the preparation of new benzocycloheptathiophene derivatives of the formula I,

and their acid addition salts, characterized in that compounds of the formula II,

where R1 is methyl or benzyl, with a chloroformic acid ester of the formula XII, C1COOR4 XII where R4 is lower alkyl, phenyl or benzyl, or reacts with cyanogen bromide and from the compounds of the formula XIII obtained,

in which X stands for the CN group or a COO-R4 group, in which R4 has the above meaning, the X group is split off by solvolysis and the compounds of the formula I obtained are optionally converted into their acid addition salts.

2. Process for the preparation of new benzocycloheptathiophene derivatives of the formula I,

and their acid addition salts, characterized in that compounds of the formula II,

the benzyl group is split off hydrogenolytically and the compounds of the formula I obtained are optionally converted into their acid addition salts.

3. Compounds of the formula I and their acid addition salts, prepared by the process according to patent claim 1.

4. Compounds of the formula I and their acid addition salts, prepared by the process according to claim 2.

The invention relates to processes for the preparation of new compounds of the formula I and their acid addition salts and also comprises the compounds of the formula I prepared by this process and their acid addition salts.

The Swiss patent specification 416 623 deals with the preparation of 9,10-dihydro-4- [1- (lower) alkyl-4-piperidylidene] -4H-benzo [4,5] cyclohepta [1,2-b] thiophenes. The 6- and 7-halogen analogs of the latter compounds are described in Swiss patent specification 454 898. The compounds prepared by the process according to the invention differ from the compounds of Swiss patent specification 416 623, inter alia, in a methyl radical in position 5, 6, 7 or 8 of the benzocycloheptathiophene skeleton.

According to the invention, the new compounds of the formula I and their acid addition salts are obtained by splitting off the methyl or benzyl group from compounds of the formula II in which R1 is methyl or benzyl and, if desired, converting the resulting compounds of the formula I into their acid addition salts.

The Ri group is split off from compounds of the formula II using methods known per se. For example, compounds of the formula II are reacted with a chloroformic acid ester of the formula XII, in which R4 is lower alkyl, phenyl or benzyl, or with cyanogen bromide and the compounds of the formula XIII obtained, in which X is the CN group or a COO-R4- Group in which R4 has the above meaning, the X group is cleaved solvolytically in a manner known per se.

The reaction of the compounds of the formula II with the chloroformic acid esters of the formula XII is preferably carried out in a solvent which is inert under the reaction conditions, e.g. B. an aromatic hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon such as methylene chloride, at temperatures between about 10 and 1500, preferably at an elevated temperature, e.g. B. carried out at the boiling point of the reaction mixture. The resulting urethanes of the formula XIIIa, in which R4 has the above meaning, can either be purified by methods known per se or used directly in the subsequent urethane cleavage

will. The cleavage of the -COO-R4 group from the urethanes of the formula XIIIa can be carried out in an acidic or in an alkaline medium, for example in the presence of inorganic bases, such as alkali metal hydroxides, or in the presence of strong mineral acids, e.g. B. hydrohalic acids solvolytically, e.g. B.

by means of a lower alcohol or water, optionally with the addition of an organic solvent which is inert under the reaction conditions, preferably water-miscible, at temperatures between 70 and 1800, preferably 100-130 ", for example at the boiling point of the reaction mixture.

The reaction of the compounds of the formula II with cyanogen bromide is preferably carried out in an organic solvent which is inert under the reaction conditions, for example an aromatic hydrocarbon such as benzene or toluene. The subsequent hydrolysis of the cyanamides of the formula X11Ib obtained can be carried out hydrolytically, for example by means of dilute mineral acids, and is preferably carried out at an elevated temperature.

If Rl in the compounds of the formula II is benzyl, this group is also hydrogenolytically, e.g. B. cleaved in the presence of a platinum or palladium catalyst. The hydrogenolytic debenzylation can be carried out in an organic solvent which is inert under the reaction conditions, e.g. B. in a lower alcohol such as ethanol, or in ethyl acetate, glacial acetic acid or dimethylformamide at 1-50 atm hydrogen pressure at temperatures between about 20 and 100 can be carried out.

The compounds of the formula I can be isolated from the reaction mixture and purified in a manner known per se. The free bases can be converted into their acid addition salts in the usual way and vice versa.

The compounds of the formula II can be obtained, for example, by splitting off water from compounds of the formula IIa in which Rl has the above meaning.

The elimination of water from the compounds of the formula lIa can be carried out in a manner known for analogous carbinols, e.g. B.

by the action of suitable dehydrating agents on the compounds of the formula IIa, optionally with the addition of an organic solvent which is inert under the reaction conditions, for example a lower alcohol such as ethanol or isopropanol. As dehydrating agents such. B. mineral acids or strong organic acids, e.g. B. alcoholic hydrogen chloride solutions, conc.

Hydrochloric acid / glacial acetic acid, trifluoroacetic acid, benzenesulfonic acid or acid anhydrides such as. B. acetic anhydride or acid halides such. B. thionyl chloride can be used. The elimination of water takes place preferably at temperatures between about 0 and 1000, for example at the boiling point of the reaction mixture.

The starting compounds can be obtained, for example, as follows: a) Compounds of the formula IIa can, for. B. be obtained by reacting ketones of the formula III with Grignard compounds of the formula IV, in which Rl has the above meaning and X "stands for chlorine, bromine or iodine, and hydrolyzing the complex obtained. The reaction is preferably carried out in a Grignard-type Organic solvents suitable for reactions, for example an ether such as diethyl ether or tetrahydrofuran The hydrolysis of the organometallic complex formed as an intermediate can be carried out in a manner known per se, for example with aqueous ammonium chloride solution.

b) Compounds of the formula III can be obtained, for example, by cyclizing compounds of the formula V.

The cyclization of the compounds of formula V is preferably carried out in the presence of a strongly acidic catalyst, e.g. B. a strong mineral acid such as preferably polyphosphoric acid or sulfuric acid, optionally with the addition of an organic solvent which is inert under the reaction conditions, for example a hydrocarbon such as toluene or xylene. The reaction temperature is preferably between 50 and 160 ° C. and the reaction time can be between 5 minutes and 10 hours. Instead of an acid of the formula V, for example, reactive derivatives of this acid can also be used for the cyclization. Suitable reactive derivatives are, for example, acid halides or acid anhydrides or else lower alkyl esters of the acids of the formula V. Acid halides / anhydrides can also be cyclized according to Friedel-Crafts.

c) Compounds of the formula V can be obtained, for example, by hydrolysis of compounds of the formula VI in which X1 is the CN or a COOR3 group in which R3 is lower alkyl. The hydrolysis is preferably carried out in an alkaline medium, for example with potassium or sodium hydroxide, in higher-boiling alcohols such as. B.

Diethylene glycol monoethyl ether, methyl isobutyl carbinol or n-butanol are carried out at an elevated temperature, for example at temperatures between 100 and 2000, preferably 170 to 1900 or the boiling point of the reaction mixture.

A mixture of compounds of the formula VI and compounds of the formula VIa contained therein as a by-product, in which Xl has the above meaning, can be used for the hydrolysis and the mixture of compounds of the formulas V and Va obtained therefrom in the hydrolysis can then be processed in a manner known per se Chromatography and / or fractional crystallization are separated. However, compounds of the formula V contaminated by compounds of the formula Va can also be used for the cyclization and the cyclization products of the formula III can then be isolated from the reaction mixture by chromatography.

d) Compounds of the formula VI or an isomer mixture of compounds of the formula VI and VIa can be obtained, for example, by adding compounds of the formula VII, in which X1 has the above meaning, or an isomer mixture of compounds of the formulas VII and VIIa, wherein Xl has the above meaning, catalytically hydrogenated. The catalytic hydrogenation can, for. B. in the presence of a solid catalyst, preferably a palladium catalyst, in a known manner in a solvent inert under the reaction conditions, e.g. B. in a lower alcohol or in dimethylformamide, at temperatures between preferably 30 and 100 "C at 5-100 atmospheres hydrogen pressure or by introducing hydrogen into the reaction mixture.

e) Compounds of the formula VII can be obtained, for example, by adding the dialkyl (methyl-o-X'-benzyl) phosphonates of the formula VIII, in which X 'has the above meaning, or mixtures of compounds of the formula VIII and their positionally isomeric compounds of the formula VIIIa, in which X 'has the above meaning and R2 is lower alkyl, condensed with 2-thiophenaldehyde of the formula IX. The reaction can for example take place under the reaction conditions of a Wittig reaction modified according to Horner in an organic solvent which is inert under the reaction conditions in the presence of a strongly basic condensing agent. Suitable solvents are preferably dimethylformamide, optionally diluted with lower alcohols or ethers, for example 1,2-dimethoxyethane. Alkali metal alcoholates or hydrides, for example sodium ethylate, methylate or hydride or potassium tert-butylate, are preferably suitable as basic condensing agents. The reaction temperature can be 20-150 ° C.

f) Compounds of the formula VIII or mixtures of compounds of the formula VIII and VIIIa can be obtained, for example, by brominating compounds of the formula X, in which X1 has the above meaning, and the resulting mixture of compounds of the formula XI, in which Xt has the above meaning , and XIa, where X1 has the above meaning, is reacted with trialkyl phosphite. The bromination of the compounds of the formula X can be carried out, for example, with N-bromosuccinimide in a solvent which is inert under the reaction conditions, such as, for example, carbon tetrachloride, at temperatures between about 400 and the boiling point of the reaction mixture, optionally with the addition of a catalyst such as. B.

Dibenzoyl peroxide can be carried out. The bromination can also be carried out with bromine in a solvent which is inert under the reaction conditions, for example an aromatic hydrocarbon such as benzene, at temperatures between approx.

50O and the boiling point of the reaction mixture, optionally with the addition of a catalyst such as a, a 'azoisobutyronitrile. The subsequent reaction of the bromination product with a trialkyl phosphite can be carried out at temperatures between 70 and 1400, optionally with the addition of a solvent which is inert under the reaction conditions, for example an aromatic hydrocarbon such as benzene or toluene, the reaction time being between 1 and 10 hours.

g) Compounds of the formula VII or mixtures of compounds of the formula VII and VIIa can also be effected by direct reaction of compounds of the formula X with 2-thiophenaldehyde in the presence of a basic condensing agent, for example an alkali metal alcoholate such as sodium methylate or potassium tert-butoxide . The reaction can, for example, in a solvent which is inert under the reaction conditions, such as. B. Hexamethylphosphorsäuretriamid can be carried out at temperatures between about 20 and 800, the reaction time can be between 1/2 and 8 hours.

If the preparation of the starting compounds is not described, they are known or can be prepared by processes known per se or analogously to those described here or analogously to processes known per se.

The compounds of the formula I and their physiologically acceptable acid addition salts are distinguished by interesting pharmacological properties and can therefore be used as medicaments.

In particular, the substances have more pronounced analgesic effects than can be expected for compounds of this structure type, as shown in standard tests on animals. For example, the substances inhibit in mice in doses of 0.5-20 mg / kg p.o. phenylbenzoquinone syndrome and are tested on mice in the tail-flick test in doses of 3-50 mg / kg body weight p.o. or s.c. analgesic effective.

Because of their analgesic properties, the compounds can be used for the treatment of acute or chronic pain conditions of various origins.

Daily doses of 10 to 100 mg may be suitable for treating pain, depending on the type of condition to be treated, the substance used and the form of its application.

In addition, the compounds have histaminolytic and serotonin- and acetylcholine-antagonistic properties, as shown in standard tests on animals, e.g. B. in histamine, serotonin and acetylcholine toxicity tests on guinea pigs in doses of 0.1-20 mg / kg body weight s.c. shows.

Because of their antagonistic properties towards biogenic amines, the compounds can be used as antamines, e.g. B. be used as antihistamines and for the treatment of migraines. Daily doses of 10 to 100 mg may be suitable for this, depending on the type of condition to be treated, the substance used and the application.

The compounds of the formula I and their physiologically tolerable acid addition salts can be contained as medicaments together with suitable pharmaceutical auxiliaries in solid or liquid pharmaceutical preparations suitable for enteral, preferably oral or parenteral administration, if desired with delayed release of active ingredient. Examples of such preparations for enteral administration are u. a. Powders, granules, tablets, capsules, coated tablets, syrups, drops, suppositories, etc. Examples of preparations for parenteral administration are injection solutions or injectable aqueous or oily suspensions. For oral application, for. B. tablets with 0.5, 1, 2 or 5 mg active ingredient / dose are suitable.

The pharmaceutical preparations can be produced according to processes customary in pharmaceutical technology using customary solid or liquid carriers and auxiliaries. Physiologically inert solids such as mannitol, lactose, starch, organic or inorganic calcium salts, etc. can be used as solid carriers. If it is desired to delay the release of the active ingredient, fillers such as. B. physiologically neutral polymers such as cellulose derivatives or synthetic polymers, fatty alcohols and other waxy substances are added.

For the preparation of suppositories, substances customary for this purpose can be used. Suitable liquid carriers are, for. B. water, ethanol or physiologically compatible oils. Furthermore, other pharmaceutically customary auxiliaries can be added to the preparations, for example tablet fillers such as binders, e.g. B. polyvinylpyrrolidones, tablet disintegrants, lubricants, e.g. B.

Magnesium stearate, u. a., also preservatives, buffer substances, flavor corrections, etc.

In the following example, which explains the invention in more detail but in no way restricts its scope, all temperatures are given in degrees Celsius.

example 4- (9, 10-Dihydro-7-methyl-4H-benzo [4,5] cy clohepta [1, 2-b] thiophen-4-ylidene) piperidine To a preheated to 40O solution of 5.9 g of 4- (9,10 dihydro-7-methyl-4H-benzo [4,5] cyclohepta [1, 2-b] thiophene-4ylidene) -1-methylpiperidine in 150 ml of anhydrous benzene is left within 30 minutes a solution of 8, 0 g of ethyl chloroformate in 30 ml of anhydrous benzene are added dropwise, the reaction mixture is stirred for 1 hour at the same temperature and for 3 hours at boiling temperature, it is cooled to room temperature and washed with 0.5 N hydrochloric acid and with water. The benzene solution is then dried over sodium sulfate and evaporated.

The 4- (9,10-dihydro-7-methyl4H-benzo [4,5] cyclohepta [1,2-b] thiophen-4-ylidene) -1-piperidine carboxylic acid ethyl ester remaining as residue becomes 48% pure in 10 volumes Hydrobromic acid added and heated to boiling for 30 minutes. After cooling, the reaction solution is diluted with water, with conc. Sodium hydroxide solution made alkaline and extracted with methylene chloride. The organic solution is washed with water, dried over sodium sulfate and evaporated. The title compound remaining as a residue is converted into the hydrogen fumarate. M.p .: dec. from 2100 (ethanol).

The starting material can be prepared as follows: a) To a boiling solution of 131 g of 2,4-dimethylbenzonitrile in 600 ml of anhydrous benzene, a solution of 52 ml of bromine in 300 ml of benzene and a solution of 5.0 ga, a '-Azoisobutyronitrile is added dropwise over the course of 40 minutes, the reaction mixture is stirred for 3.5 hours at boiling temperature and for 12 hours at room temperature. At 700, 183 ml of triethyl phosphite are now added dropwise over the course of 30 minutes with stirring, the temperature is slowly increased to 115-1200, the ethyl bromide formed is distilled off with benzene, and stirring is continued at this temperature for 3 hours. The reaction mixture is fractionated in a high vacuum, the mixture of (2-cyano-5-methylbenzyl) and (4-cyano-3-methylbenzyl) phosphonic acid diethyl ester passing over at 168-1720 / 0.1 Torr.

b) A solution of 15.7 g of the above isomer mixture and 65 g of 2 thiophenaldehyde is added dropwise at 35-400 to a suspension of 37 g of sodium methylate in 1000 ml of N, N-dimethylformamide, and the mixture is stirred The reaction mixture continues for 1 hour at 400, cools it down to 200 and pours it onto ice water. The organic products are extracted with ether, the extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The volatile components are removed in a high vacuum at 100-1100 and the mixture of 4-methyl-2- [2- (2-thienyl) vinyl] benzonitrile and 2-methyl 4- [2- (2-thienyl) vinyl] benzonitrile is obtained The 2-methyl isomer is separated from the mixture by crystallization from ethanol and the enriched 4-methyl-2- [2- (2-thienyl) vinyl] benzonitrile is distilled in a high vacuum. Kpo = 2102200.

c) A solution of 45 g of the above distillate in 500 ml of anhydrous ethanol is hydrogenated in the presence of 15 g of 5% palladium on charcoal at 100 ° and 25 atmospheres for 24 hours. After the filtrate has been filtered clear and the filtrate is evaporated, the hydrogenation product, the 4-methyl-2- [2- (2-thienyl) ethyl) benzonitrile contaminated with a little 2-methyl-4- [2- (2-thienyl) ethyl] benzonitrile, is processed further without purification .

d) To a solution of 74 g of potassium hydroxide in 200 ml of diethylene glycol monoethyl ether is added at 1800 within A solution of 38 g of the above product in 50 ml of diethylene glycol monoethyl ether was added dropwise for 30 minutes. The reaction mixture is stirred for a further 3 hours at the same temperature, it is cooled to 100 ", poured into 11% of water and the resulting solution is washed with ether (after cooling to room temperature). The aqueous solution is then made up with 4N sulfuric acid while cooling The extracts are washed with water, dried over magnesium sulfate and evaporated. The residue is dissolved in 1 liter of methylene chloride, filtered through silica gel and evaporated. The 4-methyl-2- [2 - (2-thienyl) ethyl] benzoic acid from ether / petroleum ether. Mp .: 75-780 (slightly contaminated with 2-methyl-4- [2- (2-thienyl) ethyl] benzoic acid).

e) A mixture of 22 g of 4-methyl-2- [2- (2-thienyl) ethyl] benzoic acid and 110 g of polyphosphoric acid is stirred at 900 for 20 minutes, cooled, poured into 300 ml of water and extracted several times with ether. The ethereal solutions are washed with water, with 5% ammonia solution and more times with water, dried over magnesium sulphate and evaporated. The residue is purified by column chromatography over 600 g of neutral aluminum oxide (activity level 11411) using methylene chloride as the eluent, and the 9,10-dihydro-7-methyl-4H benzo [4,5] cyclohepta [1,2-b ] thiophen-4-one processed further without purification.

f) 3.1 g of magnesium shavings are mixed with 10 ml of anhydrous Tetrahydrofuran is covered, etched with iodine and 1-2 drops of ethylene bromide and, after starting the reaction, a solution of 17.4 g of 4-chloro-1-methylpiperidine in 60 ml of anhydrous tetrahydrofuran is added dropwise so that the reaction always continues. After the dropwise addition, the reaction mixture is stirred for 2 hours at boiling temperature, cooled to 200 and at this temperature with a solution of 15.6 g of 9.1 0-dihydro-7-methyl-4H-benzo [4.5] cyclohepta [ 1,2-b] thiophen-4-one in 60 ml of anhydrous tetrahydrofuran was added dropwise. The reaction mixture is then stirred for 2 hours at room temperature, poured into 300 ml of 20% ammonium chloride solution and the whole thing shaken out several times with ether. The ethereal solutions are washed with water, dried over potassium carbonate and evaporated. The 9,10-dihydro-7-methyl-4- (1-methyl-4-piperidyl) -4H-benzo [4-, 5] -cyclohepta [1,2-b] thiophen-4-ol which remains as a solid residue is recrystallized from ether / petroleum ether. M.p .: 151-1540 (sint. 1470).

g) A solution of 21.5 g of 9,10-dihydro-7-methyl-4- (1-methyl-4-piperidyl) -4H-benzo [4,5] cyclohepta [1,2-b] thiophene- 4- ol in 210 ml of acetic anhydride is heated to boiling for 18 hours, evaporated under reduced pressure and the residue is poured onto 1 liter of ice water. The resulting solution is adjusted to pH 14 with sodium hydroxide solution, stirred for 30 minutes at room temperature and extracted with methylene chloride. The extracts are washed neutral with water, dried over potassium carbonate, evaporated, the residue obtained is dissolved in 500 ml of methylene chloride and filtered through 200 g of aluminum oxide of activity level II-III. After the solvent has been evaporated off, the 4- (9,10-dihydro-7-methyl-4H-benzo [4,5] -cyclo-hepta [1,2-b] thiophen-4-ylidene) -1 - methylpiperidine converted into its fumarate in methanol and recrystallized once.

M.p .: 200-2010.

Claims (4)

PATENT CLAIMS 1. Process for the preparation of new benzocycloheptathiophene derivatives of the formula I, and their acid addition salts, characterized in that compounds of the formula II, where R1 is methyl or benzyl, with a chloroformic acid ester of the formula XII, C1COOR4 XII where R4 is lower alkyl, phenyl or benzyl, or reacts with cyanogen bromide and from the compounds of the formula XIII obtained, in which X stands for the CN group or a COO-R4 group, in which R4 has the above meaning, the X group is split off by solvolysis and the compounds of the formula I obtained are optionally converted into their acid addition salts. 2. Process for the preparation of new benzocycloheptathiophene derivatives of the formula I, and their acid addition salts, characterized in that compounds of the formula II, the benzyl group is split off hydrogenolytically and the compounds of the formula I obtained are optionally converted into their acid addition salts. 3. Compounds of the formula I and their acid addition salts, prepared by the process according to patent claim 1. 4. Compounds of the formula I and their acid addition salts, prepared by the process according to claim 2. The invention relates to processes for the preparation of new compounds of the formula I and their acid addition salts and also comprises the compounds of the formula I prepared by this process and their acid addition salts. The Swiss patent specification 416 623 deals with the preparation of 9,10-dihydro-4- [1- (lower) alkyl-4-piperidylidene] -4H-benzo [4,5] cyclohepta [1,2-b] thiophenes. The 6- and 7-halogen analogs of the latter compounds are described in Swiss patent specification 454 898. The compounds prepared by the process according to the invention differ from the compounds of Swiss patent specification 416 623, inter alia, in a methyl radical in position 5, 6, 7 or 8 of the benzocycloheptathiophene skeleton. According to the invention, the new compounds of the formula I and their acid addition salts are obtained by splitting off the methyl or benzyl group from compounds of the formula II in which R1 is methyl or benzyl and, if desired, converting the resulting compounds of the formula I into their acid addition salts. The Ri group is split off from compounds of the formula II using methods known per se. For example, compounds of the formula II are reacted with a chloroformic acid ester of the formula XII, in which R4 is lower alkyl, phenyl or benzyl, or with cyanogen bromide and the compounds of the formula XIII obtained, in which X is the CN group or a COO-R4- Group in which R4 has the above meaning, the X group is cleaved solvolytically in a manner known per se. The reaction of the compounds of the formula II with the chloroformic acid esters of the formula XII is preferably carried out in a solvent which is inert under the reaction conditions, e.g. B. an aromatic hydrocarbon such as benzene or toluene, or a halogenated hydrocarbon such as methylene chloride, at temperatures between about 10 and 1500, preferably at an elevated temperature, e.g. B. carried out at the boiling point of the reaction mixture. The resulting urethanes of the formula XIIIa, in which R4 has the above meaning, can either be purified by methods known per se or used directly in the subsequent urethane cleavage ** WARNING ** End of CLMS field could overlap beginning of DESC **.