IE49741B1 - New dextrorotatory basic derivative of 9,10-ethanoanthracene,process for the manufacture thereof,pharmaceutical compositions containing this compound and their use - Google Patents

Abstract

For all designated states : BE, CH, DE, FR, GB, IT, LU, NL, SE 1. S-(+)-alpha-[methylamino)methyl]-9-10-ethano anthracene-9(10H)-ethanol of the formula I see diagramm : EP0014434,P11,F1 or an acid addition salt thereof. For the contracting state : AT 1. A process for the production of S-(+)-alpha-([methylamino)methyl]-9-10-ethano anthracene-9(10H)-ethanol of the formula I ad indicated in claim 1, or of an acid addition salt thereof, which process comprises a) resolving the racemic alpha-[(methylamino)-methyl]-9-10-ethanoanthracene- 9(10H)-ethanol and isolating S-(+)-alpha-[(methylamino)-methyl]-9-10-ethano anthracene-9(10H)-ethanol, if desired in the form of an acid addition salt, or b) reacting a compound of the formula II see diagramm : EP0014434,P12,F1 with a compound of the formula III X2 -CH3 wherein one of X1 and X2 is the amino group and the other is a reactive esterified hydroxyl group, and Y1 is a free hydroxyl group, and X1 together with Y1 can also be an epoxy group, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, or c) in a compound of the formula IV see diagramm : EP0014434,P12,F2 in which at least one of Z1 and Z2 is a removable radical and the other may be hydrogen, or Z1 and Z2 together are a divalent removable radical, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, removing Z1 and/or Z2 , d) reducing a compound which differs from the compound of the formula I only in that, in said compound, a carbon atom adjacent to the nitrogen atom is attached to this latter through a double bond or is substituted by a hydroxyl group or an oxo radical, optionally together with lower alkoxy, or e) adding ethylene to S-alpha-[(methylamino)-methyl]-9(10H)-anthracene, or hydrolyzing the intermediate obtained, and, if desired, converting the resultant S-(+)-alpha-[(methylamino)methyl]-9,10-ethanoanthracen- e-9(10H)-ethanol into an acid addition salt and/or liberating the base from a resultant acid addition salt.

Description

The present invention relates to a novel dextrorotatory basic derivative of 9,10-ethanoanthracene and the acid addition salts thereof, processes for the manufacture of these compounds, pharmaceutical compositions containing them and their use.

The compound of Che invention is s-(+)-tx-[(methylamino) meehyl]-9,10-ethanoanthracene-9(10H)-ethanol of the formula and is the (+)-antipode of the racemic a-[methylamino)methyl]-9,10ethanoanthracene-9(10H)-ethanol described in US patent specification 4 017 542 and corresponding patent specifications of other countries having the Swiss priority of 23.2.1971. Acid addition salts of the compound of Che formula 1 are in particular pharmaceutically acceptable salts, such as the hydrobromide, phosphate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, acetate, lactate, malonate, succinate, fumarate, maleate, malate, tartrate, citrate, benzoate, salicylate, phenylacetate, mandelate or embonate, and especially the hydrochloride, as well as in general readily crystallising salts with optically active acids, besides those 9 7 41 already mentioned,e.g. also the (1:1) salt with bis-0,0'-(p-toluoyl)D-tartaric acid. Because of the close relationship between the free base and its acid addition salts, reference to the base and to its acid addition salts will be understood by analogy as applying also to the acid addition salts and the free base respectively.

S—(+)-a—[ (Methylamino)methyl]-9,10-ethanoanthracene-9(l0H)ethanol and its acid addition salts possess valuable pharmacological properties. In particular, they are very highly active in tests which are characteristic of antidepressants. A distinct antagonism of hypothermia induced in male mice by 2 mg/kg sc. of reserpine (Askew, Life Sci. 10, 725 (1963), and Benz and Waser, Doctoral Thesis 1971, Pharmacol. Inst, of the University of Zurich] can be observed even in doses from 0.3 mg/kg of the hydrochloride of the compound of the formula I, and is more pronounced than the action of multiple doses of the corresponding racemate. The ptosis induced in male rats by 2 mg/kg sc. of reserpine [Rubin et al., J. Pharmacol. Exp.

Therap. 120, 125 (1957)] is clearly reduced by 0.1 mg/kg p.o. of the hydrochloride of the compound of the formula I and relieved by 0.3 mg/kg p.o., whereas the corresponding racemate, which is likewise essentially highly potent, only relieves the ptosis completely when administered in a substantially higher dosage.

The neurobiochemical action of the hydrochloride of the compound of the formula I is observed in a pronounced inhibition of the uptake of noradrenaline in the heart of rats according to the method of L. Maitre, M. Staehelin and H. Bein, Biochem. Pharmacol. 20, 2169 (1971), with an Εϋ^θ oi about 0.3 mg/kg p.o., whereas the Εϋ^θ of the corresponding racemate is in the region of about 1.5 mg/kg p.o., and also in a pronounced inhibition of the noradrenaline depletion caused by H 77/77 (3-hydroxy-4,a-dimethylphenethylamine) in the brain of rats as an indirect indication of the inhibition of the uptake of noradrenaline [A. Carlsson, H. Corrodi, K. Fuxe and Γ. 9 7 4 1 Hoefkelt, Europ. J. Pharmacol. 5, 367 (1969)] with an Εϋ^θ of about 2 mg/kg p.o. compared with an ΕΠ^θ of about 10 mg/kg p.o. of the corresponding racemate. The endogenic concentrations of noradrenaline and of dopamine in the brain of rats, measured in accordance with the method of P. Waldmeier, de Herdt and L. Maitre [Chir. Chem. 20, 81, (1974)] are influenced neither by the hydrochloride of the compound of the formula I in doses up to 100 mg/kg and up to 30 mg/kg p.o. respectively, nor by the corresponding racemate in doses up to 10 mg/kg and up to 100 mg/kg respectively.

The findings relating to the uptake of noradrenaline suggest that the pronounced antagonism of the compound of the formula I and of its acid addition salts to reserpine is based on a corresponding influence on Che transportation and metabolism of noradrenaline. At any rate, the far more than twofold increase in potency in these tests cannot be explained by the fact that only the (+)-antipode present in the known racemate is active, and this increase must therefore be considered surprising.

In a series of further assays, the compound of the formula I, tested in the form of the hydrochloride, is about as potent to at most twice as potent as the corresponding racemate. Equal doses of both compounds have about the same effect, e.g. in the antagonism of histamine toxicity in guinea pigs, in the test of the exploratory activity of mice (A. Delini-Stula and R. Meier, Neuropharmacology, , 383-388 (1976)], and in the aggression induced in mice by foot shock (Tedeschi et al., J. Pharmacol. Exptl. Therap. 125, 28 - 34 (1959)], whereas in the antagonism of catalepsy induced in rats by tetrabenazine after oral administration, and in the potentiation of anesthesia induced in mice by G 29 505 [2-(4-allyl-2-methoxyphenoxy)-N,N-diethylacetamide] after intraperitoneal administration [W. Theobald and R. Domenjoz, Arzneimittelforsch. 9,285-286 1959)], the hydrochloride of the compound of the formula I is as potent as the corresponding racemate in about half the dosage.

The compound of the formula I and the corresponding racemate have about the same acute toxicity when administered orally and intravenously. In concentrations about half as high, the compound of the formula I had the same negative inotropic action as the racemate on the isolated left atrium of guinea pigs which had received premedication with reserpine, whereas the negative chronotropic action of the compound of the formula I on the isolated right atrium was weaker than that of the racemate. The comparison of the action of 1 mg/ml of each of the two compounds on isolated atria of guinea pigs which have not received premedication with reserpine and of those which have, indicates an approximately identical cardiostimulating action.

It follows from the above and further assays that the significant increase in the reserpine antagonism, and in the inhibition of the noradrenaline uptake, as well as the approximately jg twofold tetrabenazine antagonism effected by the compound of the formula I and its acid addition salts as pharmacological properties especially characteristic of antidepressants, in comparison to the racemate and its acid addition salts is in no way accompanied by a similar increase in toxicity and/or side-effects. S-(+)-e-((Methyl20 amino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol of the formula I and its pharmaceutically acceptable salts can he employed as antidepressants, especially for the treatment of emotional depressions.

S-( +)-a-[(Methylamino)methy1]-9,10-ethanoanthracene-9(10H)ethanol of the formula I and its acid addition salts are obtained according to the invention by a) resolving the racemic a-[methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol and isolating S-(+)-«-((methylamino)methyl]-9,10ethanoanthracene-9(10H)-ethanol, if desired in the form of an acid addition salt, or b) reacting a compound of the formula II 9 7 4 1 CH,— C—CH,-X.

I 2 1 2 1 A H (ΣΙ) , with a compound of the formula III X2 - ch3 (III) wherein one of X^ and X, is the amino group and the other is a reactive esterified hydroxyl group, and Y^ is a free hydroxyl group, and X together with Y^ can also be an epoxy group, and A is the 9,10-ethanoanthracen-9(l0H)-yl radical, or c) in a compound of the formula IV r i -c—CH i H (XV) in which at least one of Z^ and is a removable radical and the other may be hydrogen, or and Z^ together are a divalent removable radical, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, removing Z^ andZor Z2> or d) reducing a compound which differs from the compound of the formula I only in that, in said compound, a carbon atom adjacent to the nitrogen atom is attached to this latter through a double bond or is substituted by a hydroxyl group or an oxo radical, optionally together with lower alkoxy, or e) the addition of ethylene to S-o-[(methylamino)methyl]-9(10H) anthracene, or f) reacting a compound of the general formula V ι Η Τ -CH2-N-CH3 (V) in which R^ is an unsubstituted or substituted hydrocarbon radical or an unsubstituted or substituted heterocyclic radical, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, with a strong oxygen-con5 taining inorganic or organic acid or with a halide thereof, and hydrolysing the intermediate obtained, and, if desired, converting the resultant s*(+)-a-[(methylamino)methylJ-9,10-ethanoanthracene-9(10H)ethanol into an acid addition salt andZor liberating the base from a resultant acid addition salt.

The resolution and isolation in accordance with process a) is accomplished iii .a manner known per se. For example, it is possible to convert the racemate with salt-forming optically active acids, such as organic carboxylic or sulfonic acids, e.g. the (D)- and (Informs of tartaric acid, bis-0,0'-(p-toluoyl)-tartaric acid, malic ^5 acid, mandelic acid, camphorsulfonic acid, quinic acid, lactic acid, glutamic acid or asparaginic acid, into acid addition salts. The mixtures obtained of the corresponding salts can be resolved into the diastereoisomeric salts on the basis of physicochemical differences, e.g. the solubility or crystallisability, and, if desired, the optically active (+)-base liberated from the salt.

The (+)-base can also be separated from the racemate by fractional crystallisation from a suitable solvent, if appropriate also from an optically active solvent, or by chromatography, especially thin-layer chromatography, on an optically active carrier.

A reactive esterified hydroxyl group in a compound of the formula II or III is especially a hydroxyl group which is esterified 9 7 41 with a strong organic or inorganic acid, in particular with a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid, or with an arylsulfonic acid, such as a benzenesulfonic acid which is mono-, di- or polysubstituted by lower alkyl or alkoxy radicals, e.g. those mentioned above, or by halogen atoms, such as chlorine or bromine atoms, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid, or with a lower alkanesulfonic acid, e.g. methanesulfonic acid, or, especially as X^, also a hydroxyl group esterified by sulfuric or methylsulfuric acid. together with Y^ can also form an epoxy bridge.

The reaction according to process b) is carried out in conventional manner, preferably in the presence of a solvent and, if desired, in the presence of a condensation agent, e.g. a basic condensation agent, preferably at elevated temperature and optionally in a closed vessel under pressure. A basic condensation agent is e.g. an alkali hydroxide or carbonate, e.g. sodium hydroxide or potassium carbonate, or a tertiary amine, e.g. triethylamine or pyridine.

In the starting materials of the general formula IV for process c), removable radicals and Z^, as also divalent removable radicals formed by Z^ and Z^ together, are radicals which can be removed e.g. by solvolysis, especially hydrolysis, or by reduction, e.g. hydrogenolysis.

Suitable radicals Z^ and Z^ which are removable by solvolysis, especially hydrolysis, are e.g. acyl radicals, such as alkanoyl radicals, especially unsubstituted or halogenated, e.g. fluorinated, lower alkanoyl radicals, such as the acetyl radical or the trifluoroacetyl radical, and also e.g. aroyl and aryl-lower alkanoyl radicals, such as the benzoyl or phenylacetyl radical, or acyl radicals of carbonic acid hemiesters, a.g. lower alkoxycarbonyl radicals, such as the methoxycarbonyl, ethoxycarbonyl or tert-butoxy49741 carbonyl radical, or aralkoxycarbonyl radicals, such as the benzyloxycarbonyl radical, as well as e.g. silyl radicals, such as the trimethylsilyl radical, A divalent radical formed by Z^ and Z^ is e.g. a geminal divalent hydrocarbon radical, especially a lower alkylidene radical, such as the methylene, ethylidene or 1-methylethylidene radical (isopropylidene radical), or an aralkylidene radical, such as the benzylidene radical, and e.g. a phosphorylidene group, especially a lower alkoxyphosphorylidene group, such as the methoxy- or ethoxyphosphorylidene group.

The removal of and/or Z^ by hydrolysis is carried out with hydrolysing agents, e.g. in the present of acids, e.g. dilute mineral acids, such as sulfuric acid or hydrohalic acids, especially hydrochloric acid, or if and Z^ are acyl radicals, preferably in the presence of bases, e.g. alkali metal hydroxides, such as sodium hydroxide, in suitable organic or organic-aqueous solvents, at low temperature, e.g, at room tmeperature, or preferably with heating. The removal of a divalent radical formed by Z^ and Z^ by hydrolysis can be effected in analogous manner.

Radicals Z^ and Z^ which are removable by reduction are e.g. 1-aryl-lower alkyl radicals, such as the benzyl radical, or 1-ary1lower alkoxycarbonyl radical, such as the benzyloxycarbonyl radical, which can be removed e.g. by hydrogenolysis, for example by reduction with catalytically activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, e.g. a palladium or platinum catalyst. Aralkylidene radicals, such as the benzylidene radical, formed by Z^ and Zj together can likewise be removed by hydrogenolysis. However, Z^ or Z^ can also be a 2-haloalkoxycarbonyl radical, e.g. the 2,2,2-trichloroethoxycarbonyl radical or the 2-iodoethoxycarbonyl radical, which can be removed by reduction. A suitable 9 7 4 1 nethod of reduction is metallic reduction (nascent hydrogen), e.g. the action of metal or metal alloys and also amalgams, preferably in the presence of hydrogen donors, such as carboxylic acids, alcohols or water. In particular, zinc or zinc alloys in acetic acid are used. Further suitable reducing agents are chromium(II) compounds, such as chromium(II) chloride or chromium(II) acetate. can also be an arylsulfonyl group, such as the toluenesulfonyl group, which can be removed in conventional manner by reduction with nascent hydrogen, e.g. by an alkali metal, such as lithium or sodium, in liquid ammonia. The removal of an arylsulfonyl group can also be accomplished with a hydride, e.g. one of the simple or complex hydrides mentioned above in connection with process c), preferably lithium aluminium hydride, advantageously in the presence of an inert solvent, such as an ethereal organic solvent, e.g. tetrahydrofurane.

Starting materials for process d) containing a double bond between the nitrogen atom and an adjacent carbon atom are S-ct-[ (methyleneamino)-methyl]-9,10-ethanoanthracene-9(10H)-ethanol and S-o-[(methylimino)-methyl]-9,10-ethanoanthracene-9(10H)-ethanol. The compounds which are substituted in the adjacent position to the 2q nitrogen atom by hydroxyl are s-"_[(hydroxymethylamino)methyl-9,10ethanoanthracene-9(10H)-ethanol and S-l-(methylamino)-9,10-ethanoanthracene-9(10H)-propane-l,2-diol. The reduction of the above mentioned four compounds can be carried out in conventional manner, preferably with a simple or complex hydride, e.g. a borane, or with a di-light metal hydride, e.g. an alkaline earth metal hydride, such as sodium borohydride or lithium aluminium hydride, or with an alkoxyaluminium hydride or alkoxyborohydride, e.g. one of those referred to hereinafter.

It is also possible, however, to perform the reduction as a hydrogenation with hydrogen in the presence of a catalyst, such as a platinum, palladium or nickel catalyst, or of a homogeneous catalyst, 40741 e.g. ι ciunplt· i rhodium compound, such .is ι rhodium chloror r ipiu-uv Iphosphine complex.

If a carbon atom adjacent to the nitrogen atom is substituted by an oxo radical, the corresponding starting compounds are, on the one hand, S-S-methyl-9,10-ethanoanthracene-9(10H)lactamide and, on the other, N-[3-(9,10-ethanoanthracen-9(10H)-yl)2(S)-hydroxypropyl]-formamide, as well as lower alkyl esters of carbamic acid which are substituted at the nitrogen atom by the same radical, such as the methyl and ethyl ester. Their reduction can be carried out by the conventional methods of amide reduction, for example with a simple or complex hydride, such as a borane, e.g. diborane, or with a complex di-light metal hydride, especially an alkali metal aluminium hydride, such as lithium or sodium aluminium hydride, in an ethereal solvent, such as diethyl ether or tetrahydrofurane, or with an alkali metal alkoxyaluminium hydride or alkali metal alkoxyborohydride, e.g. sodium dibutoxy aluminium hydride or sodium trimethoxy borohydride, or with an alkaline earth metal aluminium hydride, such as magnesium aluminium hydride, or with sodium borohydride in a tertiary amine, such as pyridine or triethylamine, or with aluminium hydride-aluminium chloride.

The introduction of the 9,10-ethano radical in accordance with process e) can be effected in conventional manner, e.g. by reaction of the anthracene derivative with ethylene by the Diels-Alder method, advantageously in a suitable solvent, such as an aromatic hydrocarbon, e.g. benzene or toluene, and at elevated temperature, e.g. in the range from 50° to 25O°C, and/or und.er pressure, e.g. at 2 to 150 atmos.

In the starting materials of the general formula V for process f), an unsubstituted or substituted hydrocarbon radical R^ is e.g. lower alkyl, such as ethyl, propyl, isopropyl, butyl or tert4 9 7 4 1 butyl, and especially methyl, as well as e.g. phenyl-lower alkyl, such as henayl or 2-phenvleChy1, or phenyl, whilst in these or other radicals R^ substituents can be e.g. halogen up to atomic number 35, lower alkyl, e.g. methyl, lower alkoxy, e.g. methoxy, or aryloxy, e.g. phenoxy. As a heterocyclic radical, is e.g. furyl, such as 2-furyl, thienyl, such as 2-thienyl, or pyridinyl, such as 3- or 4-pyridinyl.

The corresponding starting materials of the formula V can be obtained by conventional acylation methods from the free R-(+)-a10 [(methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol obtained as by-product in the separation of racemic a-[(methylamino)methyl]-9,10ethanoanthracene-9(10H)-ethanol, in particular using carboxylic acid halides or lower alkyl esters, or, especially for obtaining the compound in which is methyl and which is a particularly suitable starting material, using anhydrides, such as acetic anhydride.

Suitable oxygen-containing inorganic or organic acids in process f) are in particular concentrated sulfuric acid or phosphoric acid, and also e.g. strong organic sulfonic acids, such as aliphatic sulfonic acids, e.g. methanesulfonic acid, or aromatic sulfonic acids, such as an unsubstituted or substituted phenyIsulfonic acid, e.g. 4-methyl-, 4-bromo-, 4-nitro- or 2,4-dinitrophenylsulfonic acid, or naphthalenesulfonic acids, e.g. 1-naphthalenesulfonic acid. Suitable halides of these acids are especially the chlorides or bromides, in particular thionyl chloride, and also e.g. thionyl bromide, sulfuryl chloride, chlorosulfonic acid, phosphorus trichloride, phosphorus pentachloride, phosphoroxy chloride or methanesulfonyl chloride. It is also possible to employ mixed ester halides corresponding to the above halides of polyvalent acids, such as a lower alkoxysulfonyl halide, e.g. methoxy- or ethoxysulfonyl chloride, or lower alkyl ester halides of phosphoric acid, e.g. dimethoxyphosphoryl chloride.

The reactions with strong acids, especially concentrated sulfuric acid or phosphoric acid, are carried out in the presence or absence of solvents or diluents, e.g. acetic anhydride, in the temperature range from about -50° to +200°C, and the reactions with acid halides, e.g. thionyl chloride, are carried out also in the presence or absence of solvents or diluents, e.g. hydrocarbons or especially chlorinated hydrocarbons, such as methylene chloride, in the temperature range from about -10° to +70° C, preferably from about +10° to +50°C. Xt may be assumed that the reaction products of these reactions are 2-1^-5-(9,10-ethanoanthracen-9 (10H)-yl)-4,5-dihydro-3methyl-oxazolium salts, the anion of which corresponds to the acid employed in the reaction or, if the reactions are carried out with acid halides^ is the corresponding halogen ion.

The hydrolysis of the intermediates is carried out in acid or basic medium. Suitable acids are e.g. aqueous acids, such as aqueous mineral acids, e.g. aqueous hydrochloric acid, sulfuric acid or phosphoric acid. The acid hydrolysis is carried out in a temperature range from 0° to 120°C, advantageously from 10° to 50°C. Examples of suitable bases are aqueous lyes, such as those of alkali metals or alkaline earth metals, such as sodium hydroxide or potassium hydroxide, or the hydroxides of calcium or magnesium, and the cited reagents are advantageously employed at elevated temperature, e.g. in the range from 50° to 150°C.

The hydrolysis can be carried out stepwise by hydrolysing an intermediate, optionally via the corresponding free base as intermediate stage, in aqueous medium,to produce the corresponding N-acyl compound of the general formula V having inverse steric configuration to that of the respective starting material of the formula V, and subsequently hydrolysing this compound to a compound of the formula I. 9 7 41 The process according to f) can also advantageously be carried out by reacting a starting material of the general formula V obtained directly beforehand without isolating it in the pure form, in the same batch with a suitable acid or halide thereof, and hydrolysing the intermediate thereby obtained, likewise without further purification.

The optically active starting materials required for processes b) to e) can be obtained either by resolution of known racemic, especially basic, starting materials in a manner known per se, or in a manner analogous to that employed for obtaining the racemic starting materials required for the preparation of the kncwn racemate using optically active instead of racemic precursors.

Acid addition salts, especially pharmaceutically acceptable acid addition salts, of the compound of the formula I, e.g. those referred to above, can be obtained in conventional manner. For example, a solution of the base in an organic solvent, e.g. methylene chloride, ethyl acetate, ethanol or isopropanol, is reacted with the acid desired as salt component, or with a solution thereof in the same or another organic solvent, such as ethyl acetate or di20 ethyl ether, and, if desired after cooling or concentrating or after addition of a solvent having poorer solubility for salts, e.g. diethyl ether, collecting the precipitated salt by filtration.

The present invention also relates to the compound of the formula I and the pharmaceutically acceptable acid addition salts thereof for use as medicaments, especially as antidepressants, e.g. for treating the disorders mentioned above, and also to their use for the production of pharmaceutical, in particular antidepressant compositions. • 49741 The dosage of the compound of the formula X and its pharmaceutically acceptable acid addition salts for warm-blooded animals depends on the species, body weight and age, and on the individual condition and the mode of application. The daily doses are between about 0.05 and 3.0 gm/kg, preferably between about 0.08 and 1.5 mg/kg of body weight. On average, a daily dose of about 10 to about 150 mg, preferably about 30 to about 75 mg, will be administered to a warmblooded animal having a body weight of about 7o kg.

The present invention also relates to pharmaceutical compositions which contain the compound of the formula I or pharmaceutically acceptable acid addition salts thereof. The pharmaceutical compositions of the invention are in particular those for enteral, such as oral or rectal as well as parenteral, administration, which contain the pharmacologically active ingredient alone or preferably together with at least one pharmaceutically acceptable carrier. Such compositions contain the active ingredient, i.e. the compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, in an amount and concentration suitable for the administration of the above daily doses in one or more, preferably three, single doses.

Pharmaceutical compositions of the invention in dosage unit formulations, such as sugar-coated tablets, tablets, capsules, suppositories or ampoules, contain, as active ingredient in each dosage unit, preferably 2.5 to 50 mg, especially 5 to 25 mg, of the compound of the formula I or preferably of a pharmaceutically acceptable acid addition salt of this base, together with at least one pharmaceutical carrier.

Dosage unit formulations for peroral administration contain, as active ingredient, preferably between 1 Z and 50 Z of the compound of the formula I or of a pharmaceutically acceptable acid addition 497 41 salt thereof. They are prepared by combining the active ingredient i·..·. with ..olid pulvi-riib’nt r.irrii’rs, such ns lactose, saccharose, sorbitol, mannitol; starches, such as potato starch, maize starch or amylopectin, and also laminaria or powdered citrus pulp; cellulose derivatives or gelatin, optionally with the addition of glidants, such as magnesium or calcium stearate or polyethylene glycols, to produce tablets or cores for sugar-coated tablets.

The tablet cores are coated e.g. with concentrated sugar solutions which additionally contain e.g gum arabic, talc andZor titaniumdioxide, or with a lacquer which is dissolved in mobile organic solvents or solvent mixtures. Colourants can be added to these coatings, e.g. to identify different doses of active ingredient.

Further suitable dosage unit formulations for oral administration are dry-filled capsules made of gelatin and also soft j_5 sealed capsules made from gelatin and a plasticiser, such as glycerol. The dry-filled capsules can contain the active ingredient in Che form of granules, for example in admixture with fillers such as maize starch, binders andZor lubricants, such as talc or magnesium stearate, and optionally stabilisers, such as sodium metabisulfite (Na2S2O3) or ascorbic acid. In soft capsules, the active ingredients are preferably dissolved or suspended in suitable liquids,' for example in liquid polyethylene glycols, to which stabilisers can also be added.

Suitable dosage formulations for rectal administration are e.g. suppositories, which consist of a combination of an active ingredient with a suppository base. Examples of suitable suppository bases are natural ot synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alcohols. Gelatin rectal capsules, which consist of a combination of the active ingredient with a base material, can also be employed. Suitable base materials are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Anpoules for p.ir<-ntwr il, especially intr.imiiscul.ir, administration preferably contain a water-soluble pharmaceutically acceptable salt of the compound of the formula I in a preferred concentration of 0.5 to 5 Z, optionally together with suitable stabilisers and buffer substances, in aqueous solution.

The following Examples illustrate the production of the compound of the formula I and also of a number of typical dosage unit formulations, but are not to be construed as implying any restriction of che scope of the invention.

Example 1; 184.8 g (0.63 mole) of racemic a-[(methylamino)methyl]9,10-ethanoanthracene-9(10H)-ethanol and 127.5 g (0.315 mole) of (-)-bis-0,0'-(p-toluoyl)-L-tartaric acid are dissolved in 2500 ml of methanol at a temperature up to 40° C and the solution is then allowed to stand at room temperature for 24 hours. The precipitated crystals of R-(-)-a-[(methylamino)methyl]-9,10-ethano-anthracene-9(10H) ethanol (-)-bis-0,0'-(p.toluoyl)-L-tartrate-{h 1) are filtered with suction and washed with two 50 ml portions of ice cold methanol.

The filtrate is evaporated in a water-jet vacuum. The residue is dissolved in 500 ml of methylene chloride and this solution is extracted with three 100 ml portions of ZN sodium hydroxide solution and then with two 100 ml portions of water. The methylene chloride is evaporated off, affording 132.5 g of base which is partially enriched with S-(+)-a-[(methylamino)methyl]-9.10ethanoanthracene-9(10H)-ethanol»This base (0.452 mole) and 91.4 g (0.226 mole) of (+)-bis-0,0’-(p-toluoyl)-D-tartaric acid are dissolved in 1800 ml of methanol at 40°C and the solution is allowed to stand for 24 hours at room temperature. The precipitated crystals are filtered with suction and dissolved in methanol. This solution is concentrated to about a third of its volume and allowed to stand 3q for 24 hours at room temperature. The precipitated crystals are filtered with suction and washed with a small amount of methanol, 4974 1 affording S-(+)-«-[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)ethanol (+)-bis-0,0'-(p-toluoyl)-D-tartrate (1:1), which melts at 178°C with decomposition; ["1^° =+63° (c=0.774 in methanol).

In order to obtain the free base, 4.9 g (0.01 mole) of the above salt is dissolved in 50 ml of methylene chloride. This solution is extracted with three 15 ml portions of IN sodium hydroxide solution and then with two 15 ml portions of water, and thereafter evaporated at about 14 mbar. The residual, crystallised S-(+)-a-[(methylamino) methyl]-9,10-ethanoanthracene-9(10H)-ethanol melt at 1O6-1O7°C, [a]Q = +9.5 (c = 1,06 in methanol.If desired, it can be recrystallised from ether.

The hydrochloride is obtained by dissolving 88,4 g (0.18 mole) S-(+)-a-[(methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-ethanol (+)-bis-0,0’-(p-toluoyl)-D-tartrate-(l:l) in 300 ml of methylene chloride and, with stirring, adding at room temperature an ethereal solution of hydrogen chloride until the supernatant vapours permanently colour Congo paper blue. The hydrochloride of S-(+)-a-[(methylamino) methyl]-9,10-ethanoanthracene-9(10H)-ethanol crystallises out in the process. After addition of 450 ml of ether, the crystals are filtered with suction and then recrystallised once from ethanol/methanol.

The hydrochloride thus obtained melts at 231° to 232°C; [α]^θ = +9° (c = 2.1 in methanol).

Example 2: a) 1.9 ml of acetic anhydride are added dropwise at ° - 10° C to a solution of 2.93 g (0.010 mole) of R-(-)-a[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol in 8 ml of dimethyl formamide. The solution is stirred for 4 hours at room temperature, then poured into 60 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. The residual crude R-(-)-a-((N-methylacetamido) methyl]-9,10-ethanoanthracene-9(10H)-ethanol can be further processed direct. 9 7 41 b) The crude product of a) (2.5 g) is dissolved in 6 ml of methylene chloride. With stirring, a sob-cion of 0.77 ml of chionyl chloride in 4 ral of methylene chloride is added at 5° - 10° C in the course of 15 minutes. The reaction solution is stirred for 2 hours at 20°C and then for 1 hour at 35°C, and subsequently evaporated to dryness at about 14 mbar (water jet vacuum). c) The residue of b) is dissolved in 10 ml of ethanol, then 2.5 ml of water and 1.6 g of sodium hydroxide are added and the mixture is refluxed for 3 hours. The reaction mixture is then concentrated at about 14 mbar and, after addition of 50 ml of ice-water, extracted with 100 ml of ethyl acetate. The ethyl acetate solution is washed neutral with water, dried over sodium sulfate, and concentrated at about 14 mbar, affording as residue the crude base with inverted configuration. The residue is dissolved in 10 ml of methylene chloride and the hydrochloride of S-(-)-a-[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol is precipitated by addition of ethereal hydrogen chloride solution. The crystals are filtered with suction and recrystallised from isopropanol,Melting point 229°-231°C; [α]^θ " +9° (c 2,1 in methanol).

The starting material for a) is obtained as follows: g of the R-(-)-a-[(methylamino)methyl]-9,10-ethanoanthracene-9(lOH)-ethanol (-)-bis-0,0'-(p-toluoyl)-L-tartrate-(l:1) [cp. . . 20 Example 1, melting point 180°C with decomposition, [a]^ = -64°C (c = 1.135 in methanol)] are dissolved in 500 ml of methylene chloride and extracting this solution with three 100 ml portions of 2N sodium hydroxide solution and then with two 100 ml portions of water. The methylene chloride is evaporated off and the residual R-(-)-a-[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol (m.p. 1O7-1O8°C) can be used direct for the acetylation according to a).

Example 3: 2.93 g (0.010 mole) of R-(-)-a-[ (methylaminn)mprhy1 ]-91 inethanoanthracene-9(10H)-ethanol are dissolved in portions in 14 ml of acetic anhydride. To this solution is added, with stirring, a solution of 1.75 g of 96 Z sulfuric acid in 6 ml of acetic anhydride and the mixture is then refluxed for 3 hours. The resultant solution is concentrated at about 14 mbar and the reaction product resulting from N-acetylation and cyclisation is taken up in 30 ml of IN sulfuric acid and the solution is refluxed for 2 hours. After addition of 50 g of ice the mixture is adjusted with aqueous ai»™'a solution to pH 9 and extracted with two 50 ml portions of ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to dryness. The residual crude base is dissolved in 10 ml of methylene chloride and the hydrochloride ofs-(+)-a[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol is precipitated by addition of ethereal· hydrogen chloride solution. The precipitated crystals are filtered with suction and recrystallised from isopropanol. Melting point: 228° - 230°C.

Example 4: 3.9 g of the crude 5-(S)-[(9,10-ethanoanthracen-9(10H)yl)methyl]-3-methyl-oxazolidine and 60 ml of 2N hydrochloric acid are heated for 3 hours to 90°C. Then 5N sodium hydroxide is added until the reaction is alkaline. The reaction mixture is extracted with methylene chloride and the organic phase is concentrated. The residual crude S-e-(+)~[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)ethanol is dissolved in 10 ml of ethanol and 1 ml of a 10 2 ethanolic hydrogen chloride solution is added. The hydrochloride of the above base is crystallised by addition of ether. The crystallised hydrochloride is filtered with suction and, if desired, further purified as in Example 1 or 2.

The starting material can be obtained as follows: a) 20.0 g of S-a-(aminomethyl)-9,10-ethanoanthracene-9(10H)ethanol (obtainable e.g. in analogy to Example 1 above from the 4-9741 corresponding racemic compound with a melting point of 176°-177°C described in VS patent specification 4 017 542, Example 1) are heated in a mixture of 10 ml of 351 aqueous formaldehyde solution and 150 ml of formic acid for 1 hour to 95°C. The reaction mixture is concentrated in vacuo and the residue is made alkaline by addition of 2N sodium hydroxide and extracted with methylene chloride. The organic phase is concentrated, affording as residue 5(S)-[(9,1Oethanoanthracen-9(10H)-yl)methyl]-3-methy1-oxazolidine.

Example 5: To a suspension of 0.7 g of lithium aluminium hydride in 20 ml of tetrahydrofurane is added a solution of 1.5 g of N-[3-(9jO-ethanoanthracen-9(10H)-yl)-2(S)-hydroxypropyl]-formamide in 20 ml of tetrahydrofurane, and the mixture is refluxed for 4 hours. The reaction mixture is cooled, then 1.4 ml of water are added, followed by the subsequent addition of 1.4 ml of 15 Z sodium hydroxide and a further 5 ml of water. The precipitate is collected by filtration and the filtrate is concentrated and the residue dissolved in 2N acetic acid. The acid solution is washed with ether and then 10 Z sodium hydroxide is added until the reaction is alkaline. The solution is extracted with methylene chloride, then the solvent is evaporated off and the residual crude S-(+)-a[(methylamino)methyl]-9,10-ethanoanthracene-9(10H)-ethanol is converted into the hydrochloride with a melting point of 231’-232°C as described in Example 1 or 2.

The substituted formamide employed as starting material can be obtained as follows: a) (S)~a-(Aminomethyl)-9,10-ethanoanthracene-9(10H)-ethanol (cf.

Example 4a) are refluxed for 2 hours in 75 ml of ethyl formate. The cooled solution is evaporated to dryness at about 14 mbar. The residue is dissolved in 75 ml of methylene chloride and this solution is washed with 40 ml of IN hydrochloric acid, dried over sodium sulfate, and again evaporated to dryness at about 14 mbar. The residual N-[3-(9,10-ethanoanthracen-9(10H)-y1)-2(S)-hydroxypropyl]-formamide can be used direct for the reduction.

Example 6: In an autoclave, a solution of 10 g of s-a-[(methylamino) methyl]-anthracene-9(10H)-ethanol in 200 ml of benzene is heated under a pressure of 70 atmos. for 6 hours to 70°C. The solution is then extracted with 200 ml of 2N hydrochloric acid. The acid extract is made alkaline and extracted with methylene chloride. The organic phase is concentrated and the residual crude S-a-(+)-[(methylamino) methyl]-9,10-ethanoanthracene-9(10H)-ethanol is converted into its hydrochloride as described in Example 1.

Example 7: a) 100 g of the hydrochloride of S-(+)-a-[(methylamino) methyl]-9,10-ethanoanthracene-9(10)-ethanol are mixed with 202 g of lactose and 195 g of potato starch. The nixture is moistened with an alcoholic solution of 10 g of stearic acid and granulated through a sieve. After it has been dried, the granulate is mixed with 200 g of potato starch, 250 g of talc, 3.0 g of magnesium stearate and 40 g of colloidal silica, and the mixture is compressed to 10,000 tablets each weighing 100 mg and containing 10 mg of active ingredient. The tablets can be provided with a breaking notch for a finer adjustment of the dose. b) A granulate is prepared from 50 g of the hydrochloride of S-(+)-a—[(methylamino)methy1]-9,10-ethanoanthracene-9-(10H)ethanol, 228.40 g of lactose and an alcoholic solution of 7.5 g of stearic acid. After it has been dried, this granulate is mixed with 56.60 g of colloidal silica, 200 g of talc, 20 g of potato starch and 2.50 g of magnesium stearate, and the mixture is compressed to 10,000 sugar-coated tablet cores. These cores are then coated with a concentrated syrup consisting of 417.3 g of crystalline saccharose, 6 g of shellac, 10 g of gum arabic, 0.2 g of colourant and 1.5 g of titanium dioxide, and dried. Each coated tablet weighs 120 mg and contains 5 mg of active ingredient. 9 7 41 c) 1000 capsules each containing 10 mg of active ingredient are prepared as follows: 10 g of hydrochloride of S-(+)-<*-[(methylamino) methyl]-9,10-ethanoanthracene-9(lOH)-ethanol are mixed with 263 g of lactose and the mixture is moistened uniformly with an aqueous solution of 2 g of gelatin and granulated through a suitable sieve (e.g. sieve III in Ph. Helv. V). The resultant granulate is mixed with 10 g of dried maize starch and 15 g of talc, and the mixture is packed uniformly into 1000 size 1 hard gelatin capsules. d) 100 suppositories each containing 20 mg of active ingredient are prepared from a suppository base material consisting of 2.0 g of hydrochloride of S-(+)-u-[(methylamino)methyl]~9,10-ethanoanthracene9(10H)-ethanol and 168.0 g of adeps solidus. e) 1000 ampoules are filled with a solution of the hydrochloride of S"(+)-"-[(raethylamino)methyl]-9,10-ethanoanthracene-9(10H)ethanol in 1 litre of water and sterilised. One ampoule contains a 2.5 Z solution of 25 mg of active ingredient.

Claims (5)

1. · S- (+) -α-/7 Methy lamino) irethy 1/-9 ,lO-ethanoairthracene-9 (1QH) ethanol of the formula X

2. The pharmaceutically acceptable acid addition salts of the compound of the formula I in claim 1.

3. The hydrochloride of the compound of the fornula I in claim 1. 4. 9 7 41 9. A pharmaceutical composition according to any of claims 5-8 for use as an antidepressant. 10. A process according to claim 4, substantially as herein described. 4 2 OH (V) 4974 1 ir. which is an unsubstituted or substituted hydrocarbon radical cr an unsubstituted or substituted heterocyclic radical, and A is the 9,lO-ethanoanthracen-9(LCH)-yl radical, with a strong oxygentontaining inorganic or organic acid or with a halide thereof, and hydrolysing the intermediate obtained, and, if desired, converting the resultant s-(+)-o-Zitfethyltimino)inethy 17-9,10-ethanoanthracene9(10H)-ethanol into an acid addition salt and/or liberating the base from a resultant acid addition salt. 5. A pharmaceutical conposition containing a compound of the formula I in claim 1, or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutical carrier. 6. A pharmaceutical composition according to claim 5 in dosage unit form, which contains, per dosage unit, from 2.5 to 50 mg of the compound of the formula I in claim 1, or of a pharmaceutically acceptable acid addition salt thereof. 7. A pharmaceutical composition according to claim 5 in dosage unit form,, which contains, per dosage unit, from 5 to 25 mg of the compound of the formula I in claim 1, or of a pharmaceutically acceptable acid addition salt thereof. 8. A pharmaceutical composition according to any one of claims 5, 6 or 7, which contains the hydrochloride of the compound of the formula I in claim 1. ?7

4. A process for the production of s-(+)“~/(tfethylamino)methyl79,10-ethanoanthracene-9(10H)-ethanol of the formula I indicated in claim 1, and of the acid addition salts thereof, which process comprises a) resolving the racemic e-/(jfethylamino)methyl7-9,10-ethanoanthra cene-9(10H)-ethanol and isolating S-(+)-a-/(Msthylamino)rnethyl7-9,10ethanoanthracene-9(10H)-ethanol, if desired in the form of an acid addition salt, or b) . reacting a conpound of the formula II (II) with a compound of the formula III χ - CHj (III) wherein one of X^ and Xj is the amino group and the other is a reactive esterified hydroxyl group, and Y^ is a free hydroxyl group, 5 and X^ together with Y^ can also be an epoxy group, and A is the 9,l0-echanoanchracen-9(10H)-yl radical, or c) in a compound of the formula IV in which at least one of and is a removable radical and the 10 other may be hydrogen, or Z^ and Z^ together are a divalent removable radical, and A is the 9,10-ethanoanthracen-9(10H)-yl radical, removing Z^ and/or Z 2> d) reducing a compound which differs from the compound of the formula I only in that, in said compound, a carbon atom adjacent to 15 the nitrogen atom is attached to this latter through a double bond or is substituted by a hydroxyl group or an oxo radical, optionally together with lower alkoxy, or e) the addition of ethylene to S-a-/(Methylamino) methyl7~9 (10H)anthracene, or 20 f) reacting a compound of the general formula V CH,ι 2 A H CO-R ▼ I •C---CH.-N-CH.

5. 11. A compound according to claim 1, whenever prepared by a process claimed in a preceding claim.