IE44084B1 - Tetrahydropyridine and piperidine derivatives and processes for the preparation thereof - Google Patents

Abstract

The novel 4-(7-bromo-5-methoxy-2-benzofuranyl)piperidine of the formula is prepared by solvolysis of derivatives thereof which contain on the nitrogen atom an appropriate group which can be replaced by hydrogen. The compound of the formula I can be converted into its acid addition salts. These new substances have pharmacological properties characteristic of antidepressants; the selective, reversible inhibition of the A form of monoamine oxidase should be particularly emphasised.

Description

The present invention relates to new tetrahydropyridine and piperidine derivatives having valuable pharmacological properties, to processes for the production of these compounds, as well as to therapeutic preparations containing them The tetrahydropyridine and piperidine derivatives according to the invention correspond to the general formula I wherein H - R„ (I) represents hydrogen or methyl, and X and Y each represent hydrogen, or, if is methyl, together can represent an additional bond.

The invention likewise relates to addition salts, especially to pharmaceutically acceptable addition salts of the compounds of the general formula I with inorganic and organic acids, •15 as well as to the production of these addition salts.

The compounds of the general formula I, 4-(7-bromo-5methoxy-2-benzofuranyl)-l-methyl-l,2,3,6-tetrahydropyridine, 4-(7-bromo-5-methoxy-2-benzofuranyl)-1-methylpiperidine and 4-(7-bromo-5-methoxy-2-benzofuranyl)-piperidine, and their addition salts with inorganic and organic acids possess valuable pharmacological properties. As is shown by the results of the isotopic determination of the enzyme activity, they inhibit - 2 44084 in the rat and in other species of experimental animals mono-amine oxidase, in particular selectively and reversibly the A-form thereof, after oral or subcutaneous administration of doses down to 1.0 mg/kg in the case of the first- and second-mentioned compounds, whilst the last-mentioned compound is effective even in doses down to 0.1 mg/kg. At the same time, the compounds of the general formula I exhibit in the rat, in comparison with the very strong MAO-A inhibition, also a less pronounced inhibition of the absorption, of noradrenaline into the heart after oral or subcutaneous administration of doses of 10 to 100 mg/kg, and inhibit also the absorption of serotonin into the midbrain synaptosomes of rats. Furthermore, they' antagonise, in the case of intraperitoneal administration of doses of 2 to 40 mg/kg, the hypothermal action of reserpine IS in the rat. Together with a favourable therapputic index, the above-mentioned properties characterise the compounds of the general formula I and their pharmaceutically acceptable salts with inorganic and organic acids as antidepressants which, for example, can be administered orally or parenterally for the treatment of mental depression.

The tetrahydropyridine and piperidine derivatives of the general formula I and their acid addition salts are produced according to the invention by a process in which, in a manner known per S£, a) a compound of the general formula II wherein Ζ θ represents a monovalent anion or the normal equivalent 5 of a polyvalent anion, is partially reduced to the corresponding compound of the general formula I wherein R^ represents methyl, and X and Y together represent an additional bond; or b) a compound of the general formula III - R-, (III) wherein Rjb represents methyl or benzyl, in the benzene ring of which at most three hydrogen atoms can be replaced with substituents selected from halogen up to atomic number 35, lower alkyl groups and lower alkoxy groups, methylenedioxy groups and trifluoromethyl groups, is catalytically hydrogenated to a compound of the general formula I wherein represents methyl or hydrogen, and X and Y each represent hydrogen; or - 4 20 c) in a compound oi the general formula IV Br wherein Ac represents a radical which can be split of! Liu* radical Ac is split oil; or d) a compound of the general formula V Br (V) wherein X and Y have the meaning given under the formula I, is reacted with a reactive ester of methanol, or with formaldehyde under reducing conditions; or c) in a compound of the general formula VI. wherein J<2 represents hydrogen or lower alkoxy, and - 5 440 8 4 X and Y have the meaning given under the formula I, the formyl or alkoxycarbonyl group is reduced; and optionally, a compound of the general formula I obtained by any one of the processes defined under a) to e) is converted into an addition salt with an inorganic or organic acid.

Throughout this specification, the term lower is used to denote that a radical or compound has up to 4 carbon atoms.

The partial reduction of a compound of the general formula II according to a) is preferably performed with the aid of sodium or potassium borohydride in an. organic-aqueous medium by a process wherein, for example, there is slowly added to the solution of the starting material of the general formula II in an organic solvent miscible with water, e.g. in a lower alkanol such as methanol or ethanol or in a mixture thereof with water, an aqueous solution of sodium borohydride, and the reaction mixture is subsequently allowed to further react for some time, whereby a reaction temperature of between about 5 and 60°C, preferably between room temperature and 35°C, is maintained. The production of the starting materials of the general formula II is described later in the text.

The catalytic hydrogenation of a compound of the general - 6 440S4 formula 111 according to h) can be performed with the use of a customary hydrogenation catalyst, for example noble metal catalyst such as palladium on charcoal or platinum oxide, rhodium catalyst such as rhodium on charcoal or on aluminium oxide, or an alloy-skeleton catalyst suoh as Raney nickel, in an inert organic solvent such as methanol, ethanol or dioxane, and optionally with the addition of hydrobromic acid, at room temperature and normal pressure, or at a moderately elevated temperature up to about 100°C and at an elevated pressure up to 100 bars. If Kj in the starting material is methyl, the hydrogenation is terminated after absorp!ion of the equimolar amount of hydrogen; and if R^1’ is a benzyl group optionally substituted as defined, which is to be replaced with hydrogen, .i.e. is to be hydrogenolytieally split off, it is terminated after absorption of the double-molar amount of hydrogen.

The starting material of the gene.ral formula III having a methyl group as R^ is embraced by the general formula 1. and can br? produced for example by process a) . Tlie further compounds of the general formula I can be produced, e.g., analogously to process a) with the use of corresponding starting materials which contain on the quaternary nitrogen atom, instead of the methyl group, a benzyl group optionally substituted as defined. - 7 44084 In the starting materials of the general formula IV, tho radical Ac which can he split off is, in particular, an acyl radical. It is split of, for example, by hydrolysis, solvolysis, hydrogenolysis or reduction. In the starting materials of the general formula IV, Ac can be for example any desired organic acyl group, e.g. a lower alkanoyl group such as an acetyl group, an arenecarhonyl group such as the benzoyl group, an alkanesulphonyl group or arenesulphonyl group, such as the methanesulphonyl group or a p-to]ucnesulphonyl group. However, acyl groups are preferred which ensure the easy ohtainment of the compounds of the general formula IV which contain them and/or which are relatively easily split off. Accordingly, therefore, suitable acyl groups Ac on the one hand are, in particular, acyl groups of semi-esters of carbonic acid and thiocarbonic acid, especially groups that can be split off by hydrolysis, e.g. lower alkoxycarbonyl groups, such as the methoxycarbonyl, ethoxycarbonyl and tert.butoxycarbonyl groups, also phenoxycarbonyl and benzyloxycarbonyl groups, as well as methoxythiocarbonyl and methylthio-thiocarbonyl groups; and on the other hand acyl groups of further derivatives of carbonic acid, such as a chlorocarbonyl group and, in particular, a cyano group. - 8 4 4 0 8 4 The hydro Lysi s of compounds of the general formula IV according to process c) can be performed in an alkaline or acid medium. It is performed, for example, by prolonged heating with an aik3l.i hydroxide, especially with sodium or potassium hydroxide, in a hydroxy compound in the presence of a little water at a temperature of between about 80 and 200'C. A suitable reaction medium is, for example, ethylene glycol or a lower' monoalkyl ether thereof and, with performance of the hydrolysis in a closed vessel, Lo also a lower alkanol such as methanol, ethanol or butanol. Furthermore, in particular the compound of the general formula IV wherein Ac represents a cyano group, i.e. the acyl radical of cyanic acid, or a chlorocarbonyl group, can be hydrolysed also by being heated with a mineral acid iii an organic-aqueous or aqueous medium, e.g. by several hours' boiling in a mixture of 85% phosphoric acid and formic acid, or by several hours' heating in 48% hydrobromic acid or in a mixture of hydrobromic acid and acetic acid at 60 - 100°C, preferably 60 - 70°C, or by boiling in dilute hydrochloric acid, e.g. in 0.5N hydrochloric acid.

A radical that can be split off by solvolysis is, for example, the tert.butoxycarbonyl radical, which can be 440S4 split off under anhydrous conditions by treatment with a suitable acid, such as trifluoroacetic acid.

Acyl radicals Ac that can be split off by reduction are, for example, α-aralkoxycarbonyl radicals, such as benzyloxycarbonyl radicals, which can be split off in the usual manner by hydrogenolysis, particularly by catalytically activated hydrogen, such as by hydrogen in the presence of a hydrogenation catalyst, for example platinum, palladium or Raney nickel. Further radicals that can be split off by re.duction are, for example, 2-haloalkoxycarbonyl radicals, such as the 2,2,2-trichloroethoxycarbonyl radical or the 2-iodoethoxy- or 2,2,2-tribromoethoxycarbonyl radical, which can be split off in the usual manner, especially by metallic reduction (so-called nascent hydrogen). Nascent hydrogen can be obtained by the action of metal, or metal alloys such as amalgams, on hydrogen-releasing agents, such as carboxylic acids, alcohols or water, whereby, in particular, zinc or zinc alloys together with acetic acid are suitable.

The reduction of 2-halogen-alkoxycarbonyl radicals can also be performed by means of chromium(II)-compounds, such as chromium(II)-chloride or chromium(II)-acetate.

A radical Ac that can be split off by reduction can also be a sulphonyl group, such as a lower alkanesulphonyl group 44084or aryl sulphonyl group, such as methonesulphonyl or g-toluenesulphonyl, which can be split off in the usual ir.annii- by reduction with nascent hydrogen, e.g. by an alkali metal such as lithium or sodium, in liquid ammonia, or can be split, off electrolytieally.

The production of thf1 s t a r ting rn a t e:: i a 1 ε of th ·, -1 formula TV is do:.'..: ribed later in the text. Suitab J. e reac t:ive est? rs of methanol for the - with compounds, of the general formula V according to the process d) are, for example; hydrohalic acid esters, especially bromide or iodide, also lower alkanesulphonic acid esters and arenesulphonie acid esters, such as methanesulphonic acid esters, or benzenesulphonic acid esters and p-toluenesulphonic acid esters, as well as esters of other strong acids, e.g. the sulphuric acid ester, i.e. dimethylsulphate. The reactions with compounds of tha general formula V are preferably performed in the presence of an acidbinding agent in an organic solvent inert under the reaction conditions. Preferred acid-binding agents are tertiary organic bases, such as triethylamine, pyridine, sym. collidine and, in particular, ethyldiisopropylamine, or inorganic, basic substances such as sodium carbonate or potassium carbonate; and suitable solvents are, e.g., lower alkanols such as methanol, ethanol, isopropanol or hutanol, ethereal compounds such as dioxane, tetrahydrofuran or 2-methoxyethanol, lower aliphatic ketones such as methyl ethyl ketone, and N-substituted acid amides such as dimethylformamide or Μ,Ν,Ν1 ,N* ,Ν'',Ν''-hexamethylphosphoric acid trismicle. The reaction temperature is between 0° and 200vG, preferably between room temperature and 120°C.

Reactions of compounds of the general formula V with formaldehyde can be performed, for example, in formic acid at a temperature of between, about 70 and 100°C,· optionally also by the action of hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum oxide or palladium charcoal, at normal or moderately elevated pressures and temperatures, in a suitable organic solvent such as ethanol or dioxane. Of the compounds of the general formula V, that with hydrogen atoms as X and Y is embraced by the general formula 1, and can be produced, for example, according to process b) or c). Analogously to process c) can also bo produced the compound of the general formula V having an additional bond as X and Y from corresponding starting materials which, for their part, are obtainable fully analogously to those of the general formula IV.

The reduction of the formyl or lower alkoxycarbonyl group of compounds of the general formula VI according to e) to the methyl group is performed, for· example, by means of Jithiiun aluminium hydride or diborane in an ethereal solvent., such as diethyl ether, tetrahydrofuran, dibutyl ether or diethylene glycol, diethyl ether, or in. mixtures thereof, at a temperature of between about 20 and J.OO°C, or et the boiling temperature of the employed reaction medium, whore this temperature is below 100°C. Ths diborane can be either prepared separately and introduced, or formed in s1tu from sodium borohydride and boron trifluoride ethorate. Tlie production of the starting materials of the general formula VI. is described late.· in the text.

The starting materials for the above-mentioned processes which arc not already embraced by the general formula 1 and which, have not already received particular mention c; he produced, in one oi* more stages, from 4-(7-bromo5-mi'I.ho::y-2~ben:’ofuranyl·)-pyridine. This compound can in its turn be produced, for example, by reacting 3-bromo5-ins·thoxycalieylaldchyde with a 4- (haiogenomethyl)-pyridine, particularly 4-(chioromethyl)- or 4-(bvoiuomethyl)-pyridine, in tho presence of an acid-binding agent such as potassium carbonate, as well as, optionally, sodium iodide or potassium iodide, with heating in an organic solvent such as dimethyl13 £ormamide, whereby in addition to the ether formation to the intermediate 2-[(4-pyridyl)-methoxy]-3-bromo-5methoxybenzaldehyde there also occurs, with the elimination of water, the formation of the benzofuran ring.

From 4-(7-bromo-5-raethoxy-2-benzofuranyl)-pyridine is obtained, in a manner known per se. by quaternisation with a reactive ester of methanol, e.g. one of those mentioned in connection with process d) , a compound of the general formula II. Quaternisation can be performed in the usual manner in an inert organic solvent, e.g. in methanol, ethyl methyl ketone, ethyl acetate, tetrahydrofuran or dioxane, at room temperature or at moderately elevated temperatures up to 100°C.

By cm.·'tern I nation of 4- (7-bmiiO“5-meth.oxy-2-benzofuranyl) pyridine with a reactive ester of a benzyl alcohol, or of a benzyl alcohol substituted according to the definition for given under formula III, there is obtained in an analogous manner a quaternary pyridinium compound which contains, instead of the methyl group, an optionally substituted benzyl group and which, as already mentioned, can be reduced analogously to process a) to a starting material of the general formula III for the process b).

Starting materials of the general formula IV in which - 14 44084 Ac is the acyl radical of a carbonic acid serai-ester or thiocarbonic acid serai-ester, or a cyano radical or a chlorocarbonyl radical, c.an be produced, for example, from 4-(7-broKio-5-methoxy-2-bonzofuranyl)-1-methyl-piperidine embraced by the general formala. I, or from an analogous compound containing, instead of the methyl group, another group readily split off, such, as the allyl or bensyl group, by reaction with chloro formic acid ester or a chloroformic acid t’lio-cster, particularly with chloroformic acid ethyl ester, chloroformic acid tert.butyl ester, chloroformic acid benzyl ester or chloroformic acid phenyl ester, or with cllorothiofoviaic acid-S-methyl ester, or with cyanogen bromide or phosgene, in an inert orgaaic solvent at elevated temperature, e.g. in toluene or benzene at rhe boiling temperature thereof. Instead of using one of the aforementioned carbonic aci.d derivatives, if is also possible to use, e.g., a carboxylic acid halide such as acetyl bromide or benzoyl chloride, but the corresponding reaction for splitting off the methyl group or another group which can be split, off usually requires more energetic conditions and is less complete than, e.g., with the use of chloroformic acid ethyl ester and, in particular, cyanogen bromide.

Starting materials of the general formula VI with 44064 hydrogen as X and Y are obtained, for example, in a manner known per se from 4-(7-bromo~5-methoxy-2-benzofuranyl)piperidine by reaction with formic acid/acetic acid anhydride at room temperature or at moderately elevated temperatures up to 100°C, preferably at 50°C, or by heating vzith a formic acid lower alkyl ester, especially with formic acid methyl ester, or reaction vzith a ch'Loroformic acid lower alkyl ester, particularly chloroformic acid methyl ester or chloroformic acid ethyl, ester, in the presence of an acid-binding agent such as potassium carbonate, in an inert organic solvent such as dioxane, or in pyridine or mixtures thereof with an inert organic solvent, at moderately' elevated temperatures.

.Si arti'n:; materials of the general formula VI with hydrogen a:, X and Y, and lower alkoxy, especially ethoxy oj: methoxy, as R,;, can be obtained, e.g., from corresponding compounds having a radical, which is readily split off, in the Imposition, such as 1-allyl- or l-benzyl-4-(7-bromo-5-methoxy2-benzofuranyl)-piperidine, by reaction with chloroformic acid lower alkyl esters in the manner given for the production of compounds of the general formula IV. In an analogous manner it is possible to produce from the l-benzyl-4(7-bromo-5-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine embraced by the general formula III, or from the corresponding 1-allyl or 1-methyl compound, compounds of the general formula VI having an additional bond as X and Y, and lower alkoxy as R?· Depending on the conditions of the process and on the starting materials, the starting materials are obtained in. the free form, or in the form, likewise included in the Invention, of their acid addition salts. The acid addition salts of the new compounds of tha general formula I can be converted in a known manner into the free bases, a.g. with basic agents such as alkalies or ion exchangers.

On the other hand, the compounds of the general formula X obtained by tho process according to the invention can, optionally, be converted in the usual manner into their eddition salts with inorganic or organic acids. For example, the acid desired as salt component is added to a solution of a compound of the general formula I in an organic solvent. Sol vents preferably used for the reaction are those in which the occurring salt is difficultly soluble, so that the salt can ho separated by filtration. Such solvents are, for example, ethyl acetate, methanol, ether, acetone, ethyl methyl ketone, acetone/ether, acetone/ethanol, methanol/ether or ethanol/etlier.

Ihe invention also provides a pharmaceutical preparation for the treatment of mental depression, which preparation comprises a compound of the general formula I, or a pharmaceutically acceptable acid addition salt thereof, in admixture or conjugation with a pharmaceutically suitable carrier. It is possible to use as pharmaceutically active substances, instead of free bases, pharmaceutically acceptable acid addition salts, i.e. salts with acids of which the anions are not toxic in the dosage amounts concerned. Moreover, it is of advantage if the salts to be used as pharmaceutically active substances readily crystallise and are not, or are only slightly, hygroscopic. For salt formation with compounds of the general formula I, it is possible to use, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, 2-hydroxycthanesulphouic acid, acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

The active substances of the invention are administered orally, reactally or putenterally. The dosage amounts depend on the mode of administration, on the species, on the age and on the individual condition. The daily doses of a free base or of a pharmaceutically acceptable acid addition salt of a free base vary between 0.01 mg/kg and 1.0 mg/kg for warm-blooded animals. Suitable dosage units, such as dragees, tablets, suppositories or ampoules, preferably contain 0.5 - 10 mg of an active substance according to the invention.

Dosage units for oral administration contain as active substance preferably between 0.5 and 10% of a compound of the general formula I, or of a pharmaceutically acceptable salt thereof. The said dosage units are produced by combination of the active substance with, e.g., a solid pulverulent carrier, such as lactose, saccharose, sorbitol or mannitol; a starch such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; a cellulose derivative or gelatine, optionally with the addition of a lubricant, such as magnesium or calcium stearate or polyethylene glycols, to form tablets or dragee cores. The dragee cores are coated, for example, with a concentrated sugar solution which can also contain, e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in a readily volatile organic solvent or solvent mixture. A dyestuff can be added to these coatings, e.g.,for identification of the various dosage amounts.

Further suitable oral dosage units are hard gelatine capsules, as well as soft closed capsules made from gelatine and a softener such as glycerin. The hard gelatine capsules contain the active substance preferably as a granulate, e.g.,in admixture with a filler(s) such as maize starch, and/or a lubricant such as talcum or magnesium stearate, ahd optionally· a stabiliser such as sodium metabisulphite (Na^S^O^) or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in a suitable liquid, such as in a polyethylene glycol, whereby likewise a stabiliser may be added.

Suitable dosage units for rectal administration are, e.g., suppositories consisting of a combination of an active substance with a suppository foundation substance. Suppository foundation substances which can ba used are, e.g., natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Also suitable are gelatine rectal capsules consisting of a combination of the active substance with a foundation substance. Suitable foundation substances are, e.g., liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Ampoules for parenteral administration, especially intramuscular administration, preferably contain a watersoluble salt of an active substance in a concentration preferably of 0.1 - 2%, optionally together with a suitable stabiliser and buffer substance, in aqueous solution.

The following examples further illustrate the production of tablets, dragees, capsules, suppositories and ampoules: - 20 44084 a) 25.0 g of 4-(7-bromo-5-methoxy-2~benzofuranyl)-piperidinehydrochloride is mixed with 300.80 g of lactose and 269.70 g of potato starch; the mixture is moistened with an alcoholic solution of 1.0 g of stearic acid, and then granulated through a sieve. After drying of the granulate, 160 g of potato starch, 200 g of talcum, 2.50 g of magnesium stearate and 32 g of colloidal silicon dioxide are mixed in, and tha mixture is subsequently pressed out to form 10,000 tablets each weighing 100 mg and each containing 2.5 mg of active substance; if required, the tablets can be provided with grooves to obtain a more precise adjustment of the dosage amount. b) A granulate is prepared from 50.0 g of 4-(7-btcmo-5· methoxy--2-benzofuranyl)-4-methyl-pi peridine-hydrochloride, 175.90 g of lactose and the alcoholic solution of 10 g of stearic acid; after drying, the granulate is mixed with 56.60 g of colloidal silicon dioxide, 165 g of talcum, 20 g of potato starch and 2.50 g of magnesium stearate, and the mixture is subsequently pressed out to form 10,000 dragee cores. These are afterwards coated with a concentrated syrup prepared from 502.28 g of cryst. saccharose, 6 g of shellac, 10 g of gum arabic, 0.22 g of dyestuff and 1.5 g of titanium dioxide, and finally dried. The dragees obtained each weigh 100 mg and each contain 5 mg of active substance. c) To produce 1000 capsules each containing 1.0 mg of active substance, 1.0 g of 4-(7-bromo-5-methoxy-2-benzofuranyl)-piperidine-hydrochloride is mixed with 2.57 g of lactose; tha mixture is uniformly moistened with an aqueous solution of 2 g of gelatine, and then granulated through a suitable sieve (e.g. of 1.2 mm mesh size). The granulate is mixed with 10.0 g of dried maize starch and 15.0 g of talcum, and the mixture is evenly filled into 1000 hard gelatine capsules, size 1. d) A suppository mixture is prepared frcm 1.0 g of 4-(7bromo-5-methoxy-2-benzofuranyl)-1-methyl-1,2,3,6-tetrahydropyridine-hydrochloride and 169.0 g of adeps solidus, and the mixture in used to pour 100 suppositories each containing '1.0 mg of active substance, c) Λ solution of 2.0 g of 4-(7-bromo-5-methoxy-2-benzofuranyl)piperidine-hydrochloride in one litre of water is filled into 1000 ampoules, and then sterilised. An ampoule contains a 0.2% solution of 2.0 mg of active substance.

The following Examples further illustrate the production of the new compounds of the general formula I and of intermediates not hitherto described; these Examples however are in no way intended to limit the scope of the invention. Temperatures are expressed in degrees Centigrade.

Example 1 A solution of 10.7 g of sodium borohydride in 60 ml of water is added dropwise, with stirring and external cooling, to a solution of 31.2 g (0.07 mole) of 4-(7-bromo5-mcthoxy~2-benzofurany])-l-methyl-pyridi.nium-iodide in 200 ml of methanol, the addition being made in such a manner that the reaction temperature does not exceed 35°.

The solution is subsequently stirred for 20 hours at room temperature. The methanol is thereupon evaporated off in vac-uo; the aqueous phase remaining is extracted twice with 500 ml of chloroform each time; the chloroform solution is dried over sodium sulphate, filtered and concentrated by evaporation. The residue is crystallised from methanol/ water to obtain 4-(7-bromo-5-methoxy-2-benzofuranyl)-lmothyl-l,2,3,6-tetrahydropyridine, m.p. Τ3··Π°. The hydrochloride, prepared therefrom with a solution of hydrogen chloride: in ether/tetrahydrofuran melts at 247-2501 after recrystallisation from ethanol.

The starting material can be produced in the following manner: a) 75.5 g (0.327 mole) of 3-bromo-5-methoxysalicylaldehyde, 53.6 g (0.327 mole) of 4-(chloromethyl)-pyridine-hydrochloride, 194 g of potassium carbonate and 15 g of potassium iodide - 24 in 320 ml of dimethylformamide are heated under nitrogen at 150° for 20 hours. The reaction mixture is thereupon cooled to about 50° and at this temperature filtered with suction. The filter residue is heated with 200 ml of dimethylformamide to 100° and filtered off with suction; and the new filter residue is subsequently washed with dimethylformamide. The combined filtrates are concentrated in vacuo, and the residue is subsequently freed from volatile constituents by heating for 2 hours at 80° in a high vacuum. The; residue is dissolved in a small amount of methylene chloride, and chromatographed on 800 g of aluminium oxide (activity II, neutral). The first fraction, eluted with 2 litres; of chloroform, is 4-(7-bromo-5-meth.oxy2-henz.ofuranyl)-pyridine, which melts at 149-152° after recrystallisation from ethyl acetate. b) 23.4 g (0.767 mole) of 4-(7-brcmo-5-methoxy-2-ben;;ofuranyl)-pyridine is dissolved in 470 ml of ethyl methyl ketone, and stirred with 11.5 ml of methyl iodide for 15 hours at about 50°. The solution is thereupon cooled to -6“ and the precipitated salt is filtered off with suction.

The filter residue is subsequently washed with ether/ petroleum ether. The resulting 4-(7-bromo-5-methoxy-2benzofuranyl)-1-methyl-pyridinium-iodide melts at 260-265° and can. be directly further processed. - 25 44084 Example 2 .1 g (0.078 mole) of 4-(7-bromo-5-methoxy-2-benzo~ furanyl)-l-methyl.-l,2,3,6-tetrahydropyridine is dissolved in 970 ml of methanol, and the solution is hydrogenated in the presence of 1.2 g of platinum dioxide catalyst and 13.1 g of 48% aqueous hydrobromic acid at a temperature of between 20 and 25° under normal pressure until about 100% of the theoretically requited amount of hydrogen has been absorbed. Hydrogenation is terminated, the catalyst is filtered off and the filtrate is concentrated in vacuo.. The residue is distributed between ethyl acetate and aqueous 2N ammonia solution; the ethyl acetate phase is separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation.

The residue is distilled in high vacuum (molecular distillation). The fraction passing over at 180-200° and 0.1 torr is 4-(7-bromo-5-methoxy-2-benzofuranyl)-1-methyl-piperidine.

The hydrochloride prepared from a solution of the base with a solution of hydrogen chloride in ethyl methyl ketone melts at 231-234°. - 26 44084 Example 3 13.0 g (0.04 mole) of 4-(7-bromo-5-methoxy“2“benzofuranyl)- Γ-methy1-piper idino is dissolved in 2^0 ml of toluene. 20.7 g of chloroformic. acid ethyl ester is slcwly added dropwise, and under a strong flew of nitrogen to effect a more rapid removal of the liberated methyl chloride, 'i'he solution is thereupon stirred for 20 hours at 60''; it is then cooled, filtered with, suction, and the filter residue is subsequently v?ashed with 240 ml of toluene. The combined filtrates are successively washed with 250 ml of water, 250 ml of a 10% solution of methanesulphonic acidin water. 250 ral of water, 250 ml of 2N sodium hydroxide solution and 500 ml of water; they are then dried over sodium sulphate, filtered and concentrated by evaporation. The 4-(7-bromo-5~methoxy-2-benzofurnnyl)-Γpiporidinecarboxylic acid ethyl ester remaining is an oil which is pure according to thin-layer chromatography and can be further processed without additional purification. 7.6 g (about. 0.02 mole) of 4-(7“bromo-5-methoxy-2“banzofuranyl)-l-piperidinecarboxylic acid ethyl ester is dissolved in 80 ml of ethylene glycol. After the addition of 19.4 g of 86% potassium hydroxide, the formed cloudy solution is heated, with vigorous stirring, at 160° for 18 hours. The 440 8 4 reaction solution is afterwards cooled to 100°, diluted with 80 ml of toluene and then cooled to 20°. The organic phases are extracted firstly twice with one litre of water each time and then four times with 200 ml of a 10% solution of methanesulphonic acid in water each time. The pH value of the methanesulphonic acid solution is adjusted to 12 by the addition of a 307, sodium hydroxide solution, and the solution is extracted with one litre of chloroform. The chloroform solution is dried with sodium sulphate, filtered and concentrated by evaporation to yield 4-(7-bromo-5methoxy-2-benzofuranyl)~piperidine, which solidifies on cooling. The hydrochloride is prepared from the base with hydrogen chloride in methanol., and is recrystailised from methanol/ ether, whereupon it melts at 242-243°.

Example 4 66.8 g (0.20 mole) of 4-(7-bromo-5-methoxy-2-benzo~ furanyl)-1-piperidinecarbonitrile is refluxed in 400 ml of 0.5N hydrochloric acid for 5 hours. The clear reaction solution is rendered alkaline with cone, aqueous ammonia solution, and extracted with ether. The combined ether extracts are washed with water, dried over sodium sulphate and concentrated in a water-jet vacuum. There is Obtained 4-(5--methoxy-7-bromobenaofurany1-2)-piperidine as oil, which - 28 4 4 0 8 4 crystallises cn standing, rn.p. 66-68°. The 4-(5-methoxy7-bromo-2-benzofuranyl)-piperidine-hydrochloride produced from the above base with methanolic hydrochloric acid is crystallised from methanol/ether, m.p. 242-243°.

The starting material can be produced as follows: a) Λ solution of 31.6 g (0.299 mole) of cyanogen bromide in 500 ml of benzene is added dropwise, within 15 minutes at room temperature, to a solution of 88.0 g (0.272 mole) of 4- (7-bromo-5“inethoxy2-benzofurariyl)-l-methylpiperidine io in 1000 ml of benzene. The reaction mixture is subsequently refluxed for one hour. Tha reaction mixture is well washed, with water and then extracted ice-cold with 2N hydrochloric aeid. The combined benzene extracts are dried over sodium sulphate- and completely concentrated in a water-jet vacuum, Tut. resulting 4-(7-bromo-5-methoxy-2benzofuranyl)-lpipeid dinecn.ebon.Ltri.le crystallises on standing. It is recrystallised from ether/petroleum ether to obtain the pure substance, m.p. 94-96°. 44064 Example 5 A solution of 0.8 g (0.00165 mole·) of 4-(7-bromo-5methoxy-2-benzofuranyl)-l-piperidinecarboxylic acid2,2,2-tri chloroethyl ester in a mixture of 7.2 ml of acetic acid and 0.8 ml of water is cooled to 5°, and to this solution is added portionwise, with stirring, 0.64 g of zinc powder. After two hours, the reaction mixture is filtered and the filtrate is concentrated by evaporation. 'flic residue is distributed between ?.N sodium hydroxide solution and methylene chloride. The organic, phase is separated, washed with saturated sodium sulphate solution, dried over sodium sulphate and concentrated by evaporation.

As residue is obtained 4- (7-bromo-5-iiiethoxy-2-benzofuranyl)piperidine in the form of yellow oil. This is dissolved in ethyl acetate, and ethereal hydrochloric acid is added until the mixture produces an acid reaction. It is then cooled, the. formed crystals are filtered off with suction and washed with ether. The resulting 4-(7-broroo-5-nietboxy2-benznl’urau.yl)-pi peridine-hydrochlori.de malts at 229-230°.

The starting material is produced as follows; a) 1.0 g (0.0031 mole) of 4-(7-bromo-5~methoxy-2-benzofuranyl)1-methyl-piperidine is dissolved in 15 ml of toluene, and 1.97 g of chloroformic acid-2,2,2-tric.l;loroetbyl ester is slowly added. The mixture is than stirred for 21 hours at 70° under nitrogen and afterwards cooled. Toluene and water are added, the mixture is acidified with cone. hydrochloric acid, and the organic phase is separated.

This is washi d with water and cone, aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The oily residue is·. 4-(7-bromo5-metboxy-2-bi'Czofitrany 1) ~1--pipc-rid.Litecaj boxylic acidio 2,2,2-trichloroethyl ester, which can be further processed without additional purification.

Claims (15)

1. CLAIMS:1. A process for the production of a tetrahydropyridine or piperidine derivative of the general formula I wherein R. represents hydrogen or methyl, and X and Y each represent hydrogen, or, if R^ is methyl, together can. represent an additional bond, or an addition salt thereof with an inorganic or organic acid, in which process u) a compound of the general formula 11 Br wherein Ζ θ represents a monovalent anion or the normal equivalent of a polyvalent anion, is partially reduced to the corresponding compound of the general formula I wherein Rj represents methyl, Y together - represent an additional bond; or b) a compound of the general formula III and X and Br (in) 5 wherein K^‘ represents methyl or benayl, in the benzene ring of which at most three hydrogen atoms can be replaced with substituents selected from halogen up to atomic number 35, lower alkyl groups io and lower alkoxy groups, the methylenedioxy group and the trifluoromethyl group, is catalytically hydrogenated to a compound of the general formula I wherein represents methyl or hydrogen, and X and Y each represent hydrogen; or 15 c) in a compound of the general formula IV ch 3 o. Br Ac (IV) 33 440 8 4 wherein Ac represents a radical which can he split off, the radical Ac is split off; or d) a compound of the general formula V ch 3 o--d? N - Ii (V) wherein X. and Y have the meaning given under formula I, is reacted with a reactive ester of methanol, or with iennaJdvhyde under reducing conditions; or c) in a compound of the general formula VI. wherein represents hydrogen or lower alkoxy, and X and Y have the meaning given under the formula I, the formyl or alkoxycarbonyl group is reduced; 15 and, optionally, a compound of the general formula I obtained by any one of the processes defined under a) to e) 34 is converted into an addition salt with an inorganic or organic acid.

2. A process according to Claim 1, wherein 4- (7-brcmo5-methoxy-2-benzofuranyl)-l-methyl-l,2,3,6-tetrahydro5 pyridine or an acid addition salt thereof is produced by one of the processes a), d) or e).

3. A proem's·; according to Claim 1, wherein 4- (7-bromt5·metboxy-2-benzofuraayl)-1-methyl-piperidine or an acid addition salt thereof is produced by one of the processes 10 i>) , d) oj' e) .

4. A procefs according to Claim 1, wherein 4-(7-bromo5-met.ho::y-2-benzofuranyl)-piperidine or an acid addition salt thereof is produced by one of the processes b) or c).

5. A compound of the general foj-jnula .( given in Claim 1, 15 ' wherein Kp X and Y have the meaning defined therein, and acid addition salts thereof.

6. 4- (7-r>romo-5-methoxy-2-bonzofuranyl) -l-methyl-l, 2,3, (:letrahydro-pyridine and its acid addition salts.

7. 4- (7-Bronn)“5-inethoxy--2-benzof , .irany 1) -1 -nx-cbyl- piperidine 20 and its acid addition salts. - 35

8. 4-(7-Bromo-5-methoxy-2-benxofuranyl)-piperidine and its acid addition salts.

9. · A pharmaceutical preparation for the treatment of mental depression, which preparation comprises a compound of the 5 general formula I given in Claim 1, wherein R^, X and Y have the meaning defined therein, or a pharmaceutically acceptable acid addition salt of a compound of the general formula I, in admixture or conjunction with a pharmaceutically suitable carrier.

10. λ pharmaceutical preparation according to Claim 9 which can10 prises 4-(7-bromo-5-methoxy-2-benzofuranyl)-1-inethyl1,2,3,6-tetrahydro-pyridine or a pharmaceutically acceptable acid addition salt thereof.

11. A pharmaceutical preparation according to Claim 9 which comprises 4-(7-bromo-5-methoxy-2-bcnzofuranyl)-1-methyl15 piperidine or a pharmaceutically acceptable acid addition salt thereof.

12. A pharmaceutical preparation according to Claim 9 which comprises 4-(7-bromo-5-methoxy-2-benzofuranyl)-piperidine or a pharmaceutically acceptable acid addition salt thereof. - 36 44084

13. A process for the manufacture of a compound of the general formula I as claimed in claim 1, substantially as described in any one of Examples 1 to 5 herein.

14. A compound of the general formula I as defined in 5 claim 1, whenever prepared by a process as claimed in any one of claims 1 Lo 4.

15. A pharmaceutical preparation as claimed in claim 9, substantially as described in any one of Examples a to e herein.