IL27991A - Dibenzocycloheptenyl amines and their preparation - Google Patents

Description

Dibenzoeyclohepteayl amines and their preparation 543 2 The invention concerns new tricyclic processes for the production pharmaceutical tions which contain the new compounds and the use The new tricyclic amines according to the invention have the general formula wherein R is hydr or a second bond between the cyclic atom and the first atom of the side The invention also includes addition salts with inorganic or organic one group of compounds of this invention are those of the formula where R has the same meaning as used for oral or rectal and the aqueous solutions of their salts for parenteral all this in the treatment of mental particularly of and for the treatment of If they can also be combined with other Another group compounds according to the invention has the formula has the same meaning as in formula The compounds of formula II are intermediates in the productio of compounds of formula The also consists in a process for the production of compounds of formula wherein a pound of formula is subjected to dehydration if the product is converted into an acid addition For the acid desired as salt or a solution is added to a solution of the compound of formula I an organic Preferably organic solvents in the salt formed is difficultly soluble are chosen for this so that the salt precipitates and can be recovered by Such solvents ether or The following for may be used for the salt ethane phenyl mandelic and The dehydration is preferably performed with ethanolic hydrochloric acid or with concentrated phosphoric conventional dehydrating substances may sulphuric acetyl thionyl phosphorus acetic acid chloride or potassium hydrogen The reaction may be performed at 20 An excess of the dehydrating substance may serve as a solvent or or another solvent may be a low alkanol such as methanol or glacial acetic a halogenated hydrocarbon such as or the The compounds of formula can be for of the which in its turn can be for as The known substance 1 is subjected to a reaction with methyl magnesium iodide to form this latter is dehydrated to form and this dehydration product is then with hydrogen with a catalyst to form which is oxidized in the with selenium The substance of formula VI can be converted into a compound of formula II for reaction with a compound of the ormula wherein Y is preferably chlorine or and R has the same meaning as and hydrolysis of the reaction compound thus in a saturated ammonium chloride Or compounds of the formula II can be prepared by reaction of a compound of formula the presence of sodium amide in liquid with a compound of formula wherein R has the same meaning as hydrolysis of the metal compound thereby formed with and hydrogenation of the triple bond in the side with hydrogen with the aid of a suitable catalyst such as Raney A compound of formula 1 can be by another process according to the by reacting a reactive ester of a compound of the formula preferably in the presence of an acid binding with an amine of the formula IV wherein has the same meaning as As reactive esters of compounds of formula particularly or sulphonic acid esters such as a methane or sulphonic acid be reaction of these esters with amines of formula IV is preferably performed in a solvent a hydrocarbon such as benzene or or an such as acetone or ethyl An excese of amine may serve as acid binder if even as the sole reaction The bromides or iodides of compounds of formula III are for as of formula VI reacted with a eyclopropyl magnesium preferably the in ah ura the addition product thus formed is hydrolysed this compound is converted with hydrogen bromide in glacial acetic acid into and such bromo compound is optionally converted into the iodide by reaction with potassium The sulphonic acid ester or sulphonic acid ester of the compound of formula III are for by rearranging with perchloric acid in to form the corresponding and this compound is reacted with methane sulphonic acid or sulphonic acid A compound of formula I can be prepared by a third process according to the by hydrolyeing or l a compound of the formula wherein an organic a carboxylic acid radical or a radical of a monofunctional the cyano radical f derivative of carbonic acid or of thiocarbonio Aa acyl radical of a carboxylic may for a low or the benzoyl radicalj radical of a monofunctional derivative of carbonic or thiocarbonio it may for the 1 a low alkoxycarbonyl the phenoxycarbonyl or phenylthiocarbonyl These radicals can be split off by acid or alkaline Acid hydrolysis is preferably performed by treatment with an inorganic acid sueh as chloric acid or sulphuric Alkaline is performed with an alkali metal hydroxide such as potassium preferably at an elevated temperature and preferably in a solvent a low alkanol or ethylene lene glycol or dlethylene glycol monoethyl The starting materials of formula 7 can for from reactive esters of of These esters are reacted with an alkali metal particularly a sodium or potassium of an amine of the formula H A second possibility of producing starting substances of the formula is the reaction of a compound of the formula wherein a low or with cyanogen bromide a carboxylic acid halide or particularly acetyl bromide or benzoyl a carbonic or thiocarbonlc acid ester particularly ethyl chloroformate or ethyl chlorothioformate or with Examples of starting substances of formula are ethyl methyl ethyl thiocarbamate and carbamlc acid As mentioned the new bases of formula I or their salts can be administered rectally and The daily dosages of the free bases or of pharmaceutically acceptable salts thereof vary between and 800 mg for adult Suitable dosage units such as dragees coated suppositories or preferably contain 5 50 mg of an active substance according to the invention or of a pharmaceutically acceptable salt Also ponding amounts of forms not made up into single dooages such ointments or powders can be Dosage units for oral administration preferably tain between 1 of a compound of general formula I or of are produced by combining the active substance pulverulent carriers such as starches such as potato maize starc or also laminaria powder or citrus pulp cellulose derivatives or optionally with the addition of lubricants such as magnesium or calcium stearate or ethylene glycols of suitable molecular to form tablets or The latter are with concentrated sugar solutions which can also gum talcum titanium or with a lacquer dissolved in easily volatile organic solvents or mixtures of can be to these to distinguish between different dosages of active Examples of dosage units for rectal administration are suppositories which consist of a combination of an active stance or a suitable salt thereof with a neutral fatty or also gelatine rectal capsules which contain a combination of the active substance or a suitable salt thereof with ethylene glycols of suitable molecular Ampoules for particularly preferably contain a water soluble salt of an active substance in a concentration in aqueous optionally together with suitable stabilising agents and buffer The following prescriptions further illustrate the production of tablets and 250 g of hydrochloride are mixed with g of lactose and g of potato the mixture is moistened with an alcoholic solution of 10 g of stearic acid 200 g of g of magnesium and 5 g of colloidal silicon dioxide are mixed in and the mixture is pressed into tablets each weighing 100 mg and containing 25 rag of active If the tablets can be grooved for facilitating their breaking up into smaller A granulate is prepared from 250 g of g of lactose and the alcoholic solution of 10 g of stearic After the granulate is mixed with g of colloidal silicon 165 g of 20 g of potato starch and g of magnesium stearate and the mixture is pressed into are then ooated with a concentrated syrup made from g of crystallised 6 g of g of gum g of dyestuff and g of titanium dioxide and obtained each weigh rag and contain 25 mg of active The invention is illustrated by the following Examples to which it is not The temperatures are stated in degrees Example 1 of crude are dissolved in ml of anhydrous ethanol and 70 ml of no ic hydrochloric acid are The reaction mixture is left to stand for 24 hours at room temperature and then excess chloric acid and ethanol are evaporated under The oily residue is taken up in the aqueous solution is made alkaline with concentrated ammonia and the crude base is ted with The ethereal extract is washed with The oily residue is under high vacuum at the distillate is dissolved in ether and oxalate is precipitated by the addition of ethereal oxalic The oxalate is recrystallised from acid ethyl it melts at The starting the crude enzo is produced according to b f A solution is from g of 2 g of methyl iodide and 300 ml of anhydrous A solution of g of Leonard et 5078 5083 is added dropwise within hours to the stirred Grignard the reactio temperature being kept at to While stirring is continued the temperature is raised to within 2 hours within a further to and finally to This temperature of is maintained for 20 the reaction mixture is cooled to and poured with stirring into a solution of 300 g of ammonium chloride in 500 ml of ice After stratification the organic phase is separated and the aqueous phase is extracted with The combined organic extracts are washed with dried over potassium carbonate and evaporated to Recrystallisation of the residue from cyclohexane yields 1 A solution of g of this latter compound in 300 ml of 2K hydrochloric acid is refluxed for 2 then cooled to and extracted with petroleum The extract is washed with dried over potassium carbonate and evaporated to 5 g of this latter compound are dissolved i 1 litres of ethanol and hydrogenated with hydrogen under normal pressure at 50 with the aid of a Ho more hydrogen is taken up after 35 The catalyst is filtered with ethanol and the solvent is evaporated in The being 1 A solution of 42 g of this in 300 ml of admixed with 34 g of selenium is vigorously refluxed for The reaction mixture is then cooled to precipitated selenium is filtered off and washed with and the filtrate is concentrated in The residue of this concentrating operation is dissolved in the ether solution is washed with sodium carbonate solution and dried over sodium sulphate and concentrated in The oil which remains is distilled under high The thus obtained boils g 1 of magnesium cauterised with iodine and a few drops of methyl iodide are added to 30 ml of anhydrous A solution of g of distilled chloride in 20 ml of anhydrous hydrofuran is then added dropwise within 20 minutes at On completion of the the suspension is refluxed for 1 hour until the magnesium has The reaction mixture is then cooled to and a solution of g of in 50 ml of anhydrous tetrahydrofuran is added dropwise within 10 The solution is refluxed for 50 ml of into a mixture of 50 ml of saturated chloride 200 ml of aqueous sodium chloride solution and 100 g of suspension obtained is made alkaline with 20 ml of concentrated ammonia and extracted with The ethereal extract is washed with water and extracted three times with 100 ml of molar citric acid each The acid aqueous extract is made alkaline with concentrated ammonia and the crude base which precipitates is extracted with combined ethereal extracts are washed with over magnesium sulphate and the solvent is removed in The crude imeth is dissolved in acetone and the dissolved free base is converted into the hydrochloride with ethanolic hydrochloric After recrystalliaation from o anhydrous the hydrochloride melts at Example 2 of are dissolved in 50 ml of cial acetic At 100 ml of a solution of hydrogen bromide in glacial acetic acid are added dropwise to the On completion of the the reaction mixture is stirred for 1 hour at and then poured into 500 ml of ice The aqueous phase is saturated with sodium chloride and extracted with The ethereal extract is then washed with saturated aqueous solution and with sodium hydrogen carbonate solution until the reaction is dried over magnesium sulphate and The oil which crude dissolved in 50 ml of anhydrous of is The reaction mixture is heated for hours at 80 in a scaled tube and then poured into 200 ml of To the aqueous benzene 10 ml of concentrated ammonia are added and the is extracted with ethereal extract is washed with then extracted three times with 100 ml of molar citric acid solution each and the acid aqueous extract is made alkalin with concentrated The precipitated crude base is taken up in the ethereal extract is washed with dried over magnesium sulphate and the solvent is evaporated in The viscous oil which remains is dissolved in and the oxalate is precipitated from the ether solution with oxalic Recrystallisat on from yields The starting is prepared as g of magnesium are added to 50 ml of drous tetrahydrofuran at g of cyclopropyl bromide dissolved in 10 ml of tetrahydrofuran are slowly added The reaction mixture is en luxed for 1 hour until the magnesium has almost completely The mixture is then co ied to a solution of g of in 10 ml of anhydrous tetrahydrofuran is added dropwise within 1 minutes and the mixture is for 2 then cooled to and poured into a mixture of ml of saturated ammonium chloride 200 ml of concentrated aqueous sodium chloride solution and g of The crude product thus is extracted with the ethereal extract is washed with concentrated aqueous sodium chloride and dried over magnesium After evaporation of the the residue is crystallised from petroleum The obtained melts at Example g of are dissolve in 50 ml of at the solution is added dropwise to a solution of g of cyanogen in m of anhydrous benzene within The reaction mixture is then refluxed for 1 cooled to 100 ml of ether are added and it is extracted with 100 ml of aqueous citric organic phase is washed with dried over magnesium sulphate and the solvent is evaporated in The crude cyanamide is taken up in a slight amount of ether and is added at dropwise and with thorough to 1 0 ml of hydrochloric The ether is the reaction mixture is refluxed for 16 made alkaline with concentrated ammonia and extracted with The ether extract is extracted three times with 100 ml of molar citric the acid aqueous extract is made alkaline with concentrated ammonia and the crude which precipitates is dissolved in ethereal solution is washed with dried over magnesium sulphate and the solvent is evaporated in The oily residue obtained is distilled under high vacuum at and the oxalate is produced from the pure distilled recrystallised from the purified 1 cycloheptene oxalate melts at insufficientOCRQuality

Claims (1)

1. wherein R is hydrogen or a methyl group and is a group or a second bond between the cyclic atom and the first atom of the side and their addition salts with inorganic or organic amines according to Claim having the general ormula wherein 1 has the same meaning as in Claim and their addition salts with inorganic or organic tricyclic amines according to Claim having the formula 18 where has the same meaning as in Claim h and its addition salts with inorganic or organic and its addition salts with inorganic or organic A process for the production of new tricyclic amines of the in Claim wherein a corresponding compound of formula II in Claim 3 is subjected to dehydration and the base thus obtainedis optionally converted into an addition salt with an inorganic or organic A process for the preparation of compounds of formula I in Claim wherein a reactive ester of a compound of formula II in Claim 3 is preferably in the presence of an acid binding with an amine of the general formula R where R has the same meaning as in Claim 1 and the base of formula I thus obtained is optionally converted into an addition salt with inorganic or organic A process for the preparation of compounds of formula I in Claim wherein a compound of the general formula wherein is an radical o an organic 19 a acid radical or a radical of a monofunctional derivative of carbonic acid or of or the cyano radical carbonic acid is subjected to hydrolysis or thermolysis and the base of formula I thus obtained is optionally converted into an addition salt with an inorganic or organic Compounds of the general formula A in Claim substantially as herein described with reference to the Processes for the preparation of compounds of formula I in Claim substantially as herein described with reference to the compositions containing as active ingredient at least one compound of formula A in Claim 1 or an addition salt thereof with a pharmaceutically acceptable inorganic or organic For the Applicants insufficientOCRQuality