US3717641A

US3717641A - Derivatives of dibenzo cycloocten-5,11-imine

Info

Publication number: US3717641A
Application number: US00041099A
Authority: US
Inventors: K Jaeggi; K Kocsis; U Renner
Original assignee: Ciba Geigy Corp
Current assignee: Novartis Corp
Priority date: 1969-05-30
Filing date: 1970-05-27
Publication date: 1973-02-20
Anticipated expiration: 1990-02-20
Also published as: NL7007464A; BR7019360D0; BE751157A; IL34622A0; DE2026486A1; ZA703657B; FR2051565A1

Abstract

Compounds of the class of 5,6,11,12-tetrahydrodibenzo(a, e)cycloocten-5,11-imine and the pharmaceutically acceptable acid addition salts thereof have anti-tussive and simultaneously musculotropic spasmolytic activities; they are the active ingredients of pharmaceutical compositions and can be used for the treatment of tussive irritation; an illustrative embodiment is 2-methoxy-5,6,11,12-tetrahydrodibenzo(a,e)cycloocten-5,11imine hydrochloride.

Description

United States Patent 1 Kocsis et al.

[54] DERIVATIVES OF DIBENZO CYCLOOCTEN-SJl-HWINE [75] Inventors: Karoly Kocsis, Basel; Ulrich Renner, Riehen; Knnt Alfred Jaeggi, Basel,

all of Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: May27, 1970 211 App]. No.: 41,099

[30] Foreign Application Priority Data May 30, 1969 Switzerland ..8228/69 [52] US. Cl. ..260/286 R, 260/283 R, 260/283 S,

260/283 CN, 260/286 Q, 260/287 R, 260/289 R, 260/649 R, 424/258 [51] Int. Cl. ..C07d 39/00 [58] Field of Search ..260/289 R, 286 R, 283 R [56] References Cited UNITED STATES PATENTS 3,518,270 6/1930 Shavel et a1. ..260/286 FOREIGN PATENTS OR APPLICATIONS 1,035,141 1/1959 Germany ..260/289 R 1 Feb. 20, 1973 OTHER PUBLICATIONS Primary ExaminerDonald G. Daus AttorneyKar1 F. Jorda and Bruce M. Collins This application filed under rule 47a.

[ 5 7 ABSTRACT Compounds of the class of 5,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-5,l l-imine and the pharmaceutically acceptable acid addition salts thereof have anti-tussive and simultaneously musculotropic spasmolytic activities; they are the active ingredients of pharmaceutical compositions and can be used for the treatment of tussive irritation; an illustrative embodiment is 2-methoxy-5 ,6,1 1,12- tetrahydrodibenzo a,e cycloocten-S ,1 1 -imine hydrochloride.

3 Claims, No Drawings compounds of the formula 1,

DERIVATIVES'OF DIBENZO CYCLOOCTEN-S ,l l-

IMINE DETAILED DESCRIPTION The present invention relates to new derivatives of dibenzo[a,e]cycloocten-5,1l-imine and their pharmaceutically acceptable acid addition salts having valuable pharmacological properties, to pharmaceutical compositions containing them and to the use thereof.

More particularly, the present invention relates to l NH k (I) wherein X and Y independently of each other are hydrogen, alkoxy containing at most four carbon atoms or together are methylenedioxy,

and the pharmaceutically acceptable acid addition salts thereof.

These compounds have been found to possess valuable pharmacological properties, especially antitussive effectiveness, which are combined with a favorable therapeutic index. They lack the analgesic properties of codeine-like anti-tussives. At the same time, the compounds of formula] have musculotropic spasmolytic effectiveness, whilst their neurotropic spasmolytic effect is very slight.

Compounds of formula I and their pharmaceutically acceptable acid addition salts are used as active ingredients in pharmaceutical compositions for oral, rectal or parenteral administration. The compounds of formula I and the pharmaceutical compositions containing them are useful for the relief and cure of tussive irritation in mammals.

In the compounds of formula I and in the starting materials, mentioned below, X and Y as lower alkoxy containing at most four carbon atoms, are for example methoxy, ethoxy, propoxy or butoxy.

Preferred compounds are the compounds of formula I wherein both X and Y are hydrogen, further wherein X is methoxy and Y is hydrogen, and X and Y together form the methylenedioxy group, as well as the hydrochlorides thereof.

Compounds of formula I and their acid addition salts are produced by allowing to act on a compound of formula II,

N ll/ Y 2 wherein The hydrogenolysis is carried out, e.g. by means of hydrogen in the presence of noble metal catalysts such as e.g. platinum, or, in particular, palladium on charcoal or on earth metal carbonates. Also platinum oxide, or alloy-skeleton catalysts such as, e.g. Raney nickel, can be used. Normal pressure and room temperature are usually sufficient, however, if necessary, especially when Raney nickel is used, pressure and/or temperature are moderately increased. Suitable solvents wherein the hydrogenolysis can be carried out are, e.g. ethanol, methanol, dimethylformamide or acetic acid. As acid addition salts, hydrochlorides can be used, which are applied either as such or are formed in situ by the addition of the corresponding amount or of a moderate excess of hydrochloric acid to the prepared solution of the base.

Starting materials of formula II are embraced by the below given formula IV and they can be analogously produced by the processes stated for those compounds.

According to a second process, compounds of formula I and their acid addition salts are produced by hydrolyzing a compound of formula III,

yll/

Ac (III) wherein Ac is the acyl group of an organic acid, and

X and Y have the meanings given under formula I, and

optionally, converting an obtained compound of formula I into an acid addition salt or, on the other hand,

liberating the base from an obtained acid addition salt.

In the starting materials of formula III, Ac is, in particular, the acyl group of cyanic acid, chloroformic acid, of

a carbonic acid or a thiocarbonic acid semi-ester, of a lower alkanecarboxylic acid or of an arenecarboxylic acid. Examples of such acyl groups are: the cyano, chlorocarbonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, tert. butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methoxythiocarbonyl, methylthio-thiocarbonyl, acetyl and benzoyl groups.

The hydrolysis of compounds of formula III is perfonned, for example, by heating such compounds for several hours in an alkanolic or aqueous-alkanolic alkali hydroxide solution, e.g. by boiling in a mixture of potassium or sodium hydroxide with ethanol or methanol and a little water. Instead of lower alkanols, it is also possible to use other solvents containing hydroxyl groups, such as ethylene glycol and its lower monoalkyl ethers. Furthermore, hydrolysis is possible, particularly of compounds of formula III, wherein Ac denotes CN, the acyl radical of the cyanic acid, by heating with wherein R is lower alkyl having at most six carbon atoms, ally] or benzyl, and

X and Y have the meanings given under formula I, by allowing to act on the stated compounds an organic acyl halide, e.g., a cyanogen halide, especially cyanogen bromide, also phosgene, a chloroformic acid alkyl ester, the chloroformic acid phenyl ester or benzyl ester, 21 chloride or bromide of a lower alkanoic acid or of benzoic acid, particularly acetyl chloride, acetyl bromide or benzoyl chloride, at room temperature or at elevated temperature, whereby the desired acylation occurs with liberation of the alkyl, allyl or benzyl halide corresponding to the group R. The reaction is performed in an inert organic solvent such as, e.g., chloroform or benzene, or optionally also in an excess of an acylhalide which is suitable as reaction medium.

The intermediates of formula IV are produced by allowing to act on a dihydroisoquinoline compound of formula V,

wherein R, X and Y have the meanings given respectively under formula IV and formula I, a concentrated mineral acid in the presence or absence of a lower alkanoic acid as reaction medium.

As mineral acid, phosphoric acid ispreferably used and, as reaction medium, formic acid or acetic acid are preferably used, at room temperature to the boiling temperature of the reaction mixture, if, in the starting material, at least X denotes a lower alkoxy group. In the case of starting materials with hydrogen atoms as X and Y, the ring closure is performed, e.g., by heating for periods ranging from several to many hours in phosphoric acid to ca. l40-l 70.

The dihydroisoquinoline compounds of formula V are obtainable, e.g., from l-benzylisoquinoline or from l-benzylisoquinolines, substituted in the benzyl group corresponding to the definition for X and Y, by quaternizing with a benzyl or allyl halide, with an alkyl halide having two to six carbon atoms or, when the l-benzyl group of the isoquinoline is substituted, also with a methyl halide, and reducing an obtained isoquinolinium halide by means of a complex hydride, e.g., of lithiurn aluminum hydride in ether, or by catalytic hydrogenation until the absorption of the equimolar amount of hydrogen is effected, e.g., at room temperature and under normal pressure in the presence of platinum oxide in methanol or in ethanol which contains an equimolar amount of sodium methoxide or sodium ethoxide. f the isoquinoline derivatives necessary for the quaternization, the l-benzylisoquinoline and the l-benzylisoquinoline and the l-veratrylisoquinoline are known. The others are produceable analogouslyto the known compounds. For example, the l-(m-methoxybenzyl)-isoquinoline is obtained by condensation of the sodium compound of the known 1- cyano-Z-benzoyl-l,Z-dihydroisoquinoline, produced, e.g., by means of sodium hydride in dimethylformamide, with m-methoxybenzylbromide to give the l-(mmethoxybenzyl)-2 benzoyl-l ,Z-dihydroisoquinaldonitrile and hydrolysis of the latter with potassium hydroxide in boiling ethanol.

According to a further process, intermediates of formula IV, wherein both X and Y are hydrogen, are produced by reacting the 5,1 l-dibromo-5,6,l 1,12- tetrahydrodibenzolaplcyclooctene of formula VI,

sin

B (VI) with a primary amine of formula VII,

R NH

wherein R has the meanings given in formula IV,

in the presence of an acid-binding agent. Used as acidbinding agent is preferably an, at least, double molar excess of amine of formula VII. This amine can, at the same time, serve as sole reaction medium, but it is also possible to add an inert organic solvent such as, e. g. benzene, toluene or ethanol. The reaction is performed preferably at temperatures between and if necessary, in a closed vessel.

The compounds of formula I are obtained as racemates. If desired, these racemates can be separated into the optically active isomers in the normal manner by salt formation with an optically active acid. By this means diastereoisomeric salts with different physical properties are obtained.

All the optically active forms of the compounds of formula I also fall within the scope of the instant invention.

For use as pharmaceuticals, the compounds of formula I may be transferred into pharmaceutically acceptable acid addition salts, i.e., salts with inorganic or organic acids, the anions of which are non-toxic and pharmaceutically acceptable if administered in therapeutic doses. It is also of advantage if such salts to be used in pharmaceutical compositions crystallize well and are not, or are only slightly hygroscopic.

For salt formation with compounds of formula I, it is possible to use, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, B-hydroxyethanesulphonic acid, acetic acid, malic acid, tartaric acid, citric acid. lactic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, .mandelic acid, embonic acid or 1,5- naphthalenedisulphonic acid.

Such salts are formed in a conventional manner. For example, the acid or a solution thereof, which is desired as the salt component, is added to a solution of a compound of formula I in an organic solvent such as, benzene, diethyl ether, methanol, ethanol or acetone, and the salt, which has precipitated immediately or after the addition of a second organic liquid such as, e.g., acetone to methanol, is separated. The liberation of the bases from their acid addition salts is likewise carried out in the usual manner by reaction with basic substances such as, e.g., sodium carbonate or sodium hydrogen carbonate.

' und Pharmakol.215, 19-24 (1952). In this test the hydrochlorides of Z-methoxy-S ,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-S,1 l-imine, of 5,6,1 1,] 2-tetrahydrodibenzo[a,e]cycloocten-5,1 1- imine and of 2,3-methylenedioxy-5,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,l l-imine are shown to be active, for example, upon intravenous administration in amounts of about 0.5 to about 3 mg/kg.

The musculotropic spasmolytic properties are demonstrated on the isolated intestine of the guinea pig.

The toxicity of the compounds of the invention is of favorable low order.

For their intended use as anti-tussives, the compounds of the invention are administered in amounts depending on the species, age, weight and the particular condition of the subject under treatment and the mode of administration. In general the daily dosages vary between about 0.1 and about 5 mg/kg for warmblooded animals. Suitable dosage units such as dragees, capsules, tablets, suppositories or ampoules, preferably contain 1-50 mg of a compound of formula I or of a pharmaceutically acceptable acid addition salt thereof.

Dosage units for oral administration preferably contain as active substance between 1 percent and 90 percent of a compound of formula I, or of a pharmaceutically acceptable acid addition salt thereof. Tablets or dragee cores are produced by combining the active substance with solid pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, and pressing the mixtures into the desired form. The latter are coated, e.g., with concentrated sugar solutions which can also contain, e.g., gum arabic, talcum and/or titanium dioxide, or with a lacquer dissolved in readily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g., to distinguish between varying dosages of active substance. 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 former preferably contain the active substance as a granulate in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilizers such as sodium metabisulphite or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby stabilizers can likewise be added.

Also suitable for the treatment of the cough are sucking tablets as well as oral preparations which are not administered in a single dosage such as cough syrups and cough drops which are prepared with the usual auxiliary agents.

Suitable dosage units for rectal administration are suppositories consisting of a combination of a compound of formula I, or of a suitable acid addition salt thereof, with a neutral fatty base. Also suitable are gelatine rectal capsules containing a combination of the active substance with polyethylene glycols.

Ampoules for parenteral, especially intramuscular and intravenous administration, preferably contain a water-soluble salt of a compound of formula I in a concentration of preferably 0.5-5 percent, optionally together with suitable stabilizing agents and butter substances in aqueous solution.

The following examples further illustrate the production of compounds of formula I and of intermediates not described hitherto. The examples should not be construed as a limitation of the scope of the present invention. The temperatures are given in degrees Centigrade.

EXAMPLE 1 a. Nitrogen gas is fed into the reaction mixture during the whole reaction period.

150.0 g of 1-cyano-2-benzoyl-l,2-dihydroisoquinoline [produced according to the specification of J .J. Padburry and I-I.G. Lindwall, J.Amer. Chem. Soc. 67, 1268 (1945)]are dissolved in 1,500 ml of distilled dimethylformamide and the solution is cooled with an ice bath to 2. To the solution are then added in portions over 2 h hrs., whilst stirring proceeds and cooling is applied by means of an ice bath, 30.0 g of sodium hydride dispersion (50 percent sodium hydride in mineral oil), whereby the temperature is maintained between 0 and 7. 122.0 g of 3-methoxybenzyl bromide [produced according to the specification of W.Q. Beard, D.N. van Eenam and Ch.R. Hauser, J.Org. Chem. 26, 2310 (1961)]are then added dropwise within 2 k hours at between 0 and 5, whilst stirring is continued, to the dark brown solution, whereby a pale precipitate is obtained. The reaction mixture is subsequently stirred for 2 hours at room temperature and the precipitate then filtered off under suction and washed with a little dimethylformamide. The filtrate is greatly concentrated in a rotary evaporator at -85 and the oil remaining dissolved in 1,500 ml. of ethanol. The solution is allowed to stand, whilst being cooled,

whereupon the 1-(3-methoxybenzyl)-2 benzoyl-1,2

dihydroisoquinaldonitrile, MP. 161 -163, crystallizes out. The yield is 135.0 g, 61.7 percent of the theoretical value.

b. 130.0 g of 1-(3-methoxybenzyl)-2-benzoyl-1,2- dihydroisoquinaldonitrile are well mixed with a solution of 108.0 g of potassium hydroxide in 325 ml of ethanol and the suspension is refluxed for one hour, whereby the starting material does not completely go into solution. To the reaction mixture are added 325 ml of water and refluxing is then continued for a further 2 hours. The ethanol is afterwards evaporated off at 50in the rotary evaporator, the mixture remaining diluted with 200 ml of water and repeatedly extracted with ether. The ether extracts are combined, washed once with water and dried over sodium sulphate. After the solvent has been evaporated off at 50 in the rotary evaporator, the 1-(3-methoxybenzyl)-isoquinoline remains behind as light-yellow oil. The yield is 83.0 g, 97.5 percent of the theoretical value.

0. 166.0 g of crude 1-(3-methoxybenzyl)-i1soquinoline are dissolved in 590 m1 of nitromethane. To the solution are added 83 ml of benzyl bromide and the reaction mixture is refluxed for 3 hours. The solution is afterwards thoroughly concentrated by evaporation at 60 in a rotary evaporator, the oil remaining dissolved in 100 ml of methanol and to the solution are added 1,300 ml of boiling acetone. The solution is allowed to stand, whilst being cooled, whereupon the 1-(3- methoxybenzyl)-2-benzylisoquinolinium bromide, M.P. 177-l78, crystallizes out; the yield is 261.0 g, 93.3 percent of the theoretical value.

d. 125.0 g of pulverized l-(3-methoxybenzy1)-2- benzylisoquinolinium bromide are introduced in portions, whilst vigorous stirring is maintained and over a period of 1.5 hours, into a suspension of 60.0 g of lithium aluminum hydride in 2,500 ml of abs. ether, whereby an exothermic reaction occurs. The reaction mixture is subsequently stirred for 18 hours at room temperature, then cooled with an ice bath to 5 and the excess lithium aluminum hydride decomposed, whilst the reaction mixture is being stirred and also cooled by means of an ice bath, by the dropwise addition of a mixture of 500 m1 of ethylacetate and 1,000 ml of benzene. To the mixture is then added a solution of 800.0 g of potassium sodium tartrate tetrahydrate (Seignettes salt) in 1,000 ml of water. The mixture is then stirred for 20 minutes at room temperature, the organic phase separated and the aqueous part extracted twice with a mixture of benzene/ether (1:1). The organic extracts are combined, washed twice with water and dried over sodium sulphate in a nitrogen atmosphere. After the solvent has been evaporated off in a rotary evaporator at 50, the oily 1-(3-methoxybenzyl)-2-benzyl-1,2- dihydroisoquinoline is obtained.

e. A mixture of 2,000 ml of anhydrous formic acid and 400 ml of 85 percent orthophosphoric acid is added all at once to 182.0 g of crude l-(3-methoxybenzyl)-2-benzyl-1,2-dihydroisoquinoline and the whole well mixed, whereby a black-violet dyed solution is immediately formed. The reaction mixture is subsequently refluxed for 24 hours. The red solution is thereupon cooled to room temperature, poured onto about 2,000 g of ice and, whilst the solution. is being cooled with an ice bath and stirred, the pl-l-value is adjusted to 910 by the addition of 2,000 ml of concentrated aqueous ammonium hydroxide solution and then of 40 percent aqueous sodium hydroxide solution. The final volume is approximately liters. The solution is then repeatedly extracted, in 5 portions, with a mixture of benzene/ether (1:1). The combined organic extracts are washed with water, dried over sodium sulphate and the solvent is evaporated off at 50 in a rotary evaporator. The oil remaining solidifies on being mixed with a little ethanol. After recrystallization from ethanol, the l3-benzyl-2-methoxy-5 ,6,1 1, l 2-tetrahydrodibenzo[ a,e ]cycloocten-5,1l-imine melts at 96-99. The yield is 140.0 g, 76.9 percent of the theoretical value.

f. A solution of 21.0 g of l3-benzyl-2-methoxy- 5 ,6,1 l,12-tetrahydrodibenzo[a,e]cycloocten-5 ,l limine in 250 ml of methanol is shaken, under normal pressure and at room temperature under hydrogen, with 2.0 g of 5 percent palladium charcoal and 27.4 ml of ethanolic hydrogen chloride solution [containing 16.4 percent (weight/volume) of hydrogen chloride in 96 percent ethanol]. The hydrogen absorption ceases after approximately 27 hours. The catalyst is then filtered off under suction, washed with 100 ml of then made alkaline with solid sodium carbonate and repeatedly extracted with benzene. The benzene extracts are combined, washed with water and dried over sodium sulphate. After the benzene has been evaporated off in a rotary evaporator at 50, the 2-methoxy- 5 ,6,1 l ,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 limine is obtained, M.P. -131.

EXAMPLE 2 a. A solution of 23.0 g of sodium in 500 ml of absolute ethanol is heated to 50 and to this solution are then added 122.0 g of S-hydroxybenzaldehyde and the whole stirred for one hour at 50. 108 ml of lbromobutane are then added dropwise and the reaction mixture is refluxed for 18 hours. The ethanol is afterwards evaporated off at 50 in a rotary evaporator, the oil remaining taken up in ether and the ether solution repeatedly washed with water. The ether phase is dried over sodium sulphate, the ether distilled off in the rotary evaporator at 50 and the oil remaining fractionated. The 3-butoxybenzaldehyde boils at 148-153 /l6 Torr. The yield is 131.0 g, 73.6 percent of the theoretical value.

b. A solution of 130.0 g of 3-butoxybenzaldehyde in 500 ml absolute ether is added dropwise, whilst vigorous stirring is maintained and within 2 k hours, to a suspension of 25.0 g of lithium aluminum hydride in 1,000 ml of absolute ether and the reaction mixture stirred for a further 1 k hours at room temperature. The excess lithium aluminum hydride is subsequently decomposed, whilst the reaction mixture is being cooled with an ice bath and vigorously stirred, by the dropwide addition of 75 ml of water and 25 ml of 2N sulphuric acid. The suspension is then stirred for 30 minutes at room temperature, the solid precipitate filtered off under suction and subsequently washed with benzene. The filtrate is dried over sodium sulphate, the solvent distilled off at 50 in the rotary evaporator and the oil remaining fractionated. The 3-butoxybenzylalcohol boils at 165-168l16 Torr. The yield is 117.0 g, 89 percent of the theoretical value.

c. A solution of 50.0 g of 3-butoxybenzyl alcohol in 300 ml of abs. ether is added dropwise, whilst stirring is maintained and cooling applied by means of an ice bath, to a solution of 50.0 g of phosphorus tribromide in 500 ml of absolute ether. The reaction mixture is subsequently stirred for 18 hours at room temperature. It is thereupon cooled with an ice bath, 150 ml of ice cold water are added and the whole is stirred for 30 minutes. The organic phase is then separated, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time, dried over sodium sulphate, the solvent distilled off in a rotary evaporator at 50 and the oil remaining fractionated. The 3-butoxybenzyl bromide boils at 159-161/l5 Torr. The yield is 59.7 g, 88.7 percent of the theoretical value.

d. Nitrogen is fed into the reaction mixture throughout the reaction period.

62.0 g of l-cyano-Z-benzoyl-l ,Z-dihydroisoquinoline [cp. Example 1 (a)] are dissolved in 600 ml of dimethylformamide and the solution is cooled with an ice bath to 2. To the solution are then added in portions over 1 /2 hours, whilst the solution is being cooled with an ice bath and stirred, 12.0 g of sodium hydride dispersion (50 percent sodium hydride in mineral oil), whereby the temperature is maintained between and 7. 59.5 g of 3-butoxybenzyl bromide are then added dropwise at between 0 and 5, within 2 )6 hours and whilst stirring is maintained, to the dark brown solution, whereby a pale precipitate is obtained. The reaction mixture is subsequently stirred at room temperature for 2 b hours, the precipitate then filtered off with suction and washed with a little dimethylformamide. The filtrate is thoroughly concentrated by evaporation at 8085 in a rotary evaporator, the oil remaining taken up in chloroform and the solution repeatedly washed with water. After the solvent has been evaporated off in a rotary evaporator at 50, the oily l- (3 -butoxybenzyl )-2 -benzoyl- 1 ,Z-dihydroisoquinaltained from 81.0 g of crude l-(3-butoxybenzyl)-2- benzoyl-l ,2-dihydroisoquinaldonitrile by boiling with a solution of 67.0 g of potassium hydroxide in 200 ml of ethanol or 200 ml of water, analogously to Example 1 (b). The yield is 50.0 g, 89.7 percent of the theoretical value.

f. 50.0 g of oily l-(3-butoxybenzyl)-isoquinoline are dissolved in 200 ml of nitromethane. To the solution are then added 23 ml of benzyl bromide and the whole is refluxed for 3 hours. The nitromethane is thereupon evaporated off at 50 in a rotary evaporator and the oil remaining mixed with 400 ml of hot acetone. The mixture is allowed to stand, whilst being cooled, whereupon the l-(3-butoxybenzyl)-2-benzylisoquinolinium bromide, M.P. l62-l64-", crystallizes out. The yield is 38.5 g, 48.4 percent of the theoretical value.

g. The oily l-(3-butoxybenzyl)-2-benzyl-1,2- dihydroisoquinoline is formed by the reduction of 42.0 g of l-(3-butoxybenzyl)-2-benzylisoquinolinium bromide with 20.0 g of lithium aluminum hydride in 800 ml of absolute ether, analogously to Example 1 (d). 'The yield is 34.0 g, 97.8 percent of the theoretical value.

h. A mixture of 400 ml of anhydrous formic acid and 80 ml of 85 percent orthophosphoric acid is added all at once to 34.0 g of crude l-(3-butoxybenzyl)-2- benzyl-1,Z-dihydroisoquinoline. The whole is well mixed and the black-violet solution refluxed for 20 hours. The reaction mixture is subsequently cooled to room temperature. Approximately 250 ml of formic acid are evaporated off in the rotary evaporator at 60. The solution which remains is then poured on to ice and, whilst the solution is being cooled with an ice'bath and stirred, the pl-l-value is adjusted to 9-10 by the addition of 150 ml of concentrated aqueous ammonium hydroxide solution and then of 40 percent aqueous sodium hydroxide solution. The solution is afterwards repeatedly extracted with a mixture of benzene/ether (1:1). The organic extracts are combined washed with water, dried over sodium sulphate and the solvent is distilled off in the rotary evaporator at 50. The oil which remains (33.0 g) is then chromatographed on 1,250 g of silica gel with a mixture of benzene/chloroform/ethanol (51510.1) as the solvent. The l3-benzyl-2-butoxy-5,6,l 1,12- tetrahydrodibenzola,e]cycloocten-S,1 l imine, obtained by evaporation of the eluate, is oily. The yield is 17.3 g, 50.9 percent of the theoretical value.

i. A solution of 1.0 g of oily 13-benzyl-2-butoxy- 5 ,6,1 1,12-tetrahydrodibenzo[a,elcycloocten-S ,1 1- imine in 40 ml of methanol is shaken with 0.20 g of 5 percent palladium charcoal and 0.85 ml of ethanolic hydrogen chloride solution [containing 16.4 percent (weight/volume) of hydrogen chloride in 96 percent ethanol] under normal pressure and at room temperature under hydrogen. The hydrogen absorption ceases after about 23 hours. The catalyst is thereupon filtered off under suction, washed with a little methanol and the filtrate concentrated by evaporation to dryness in the rotary evaporator at 50. The solid product which remains is recrystallized from a mixture of benzene/ethanol (a little)/petroleum ether. The 2-butoxy-5 ,6,l l,1Z-tetrahydrodibenzo[a,e]cycloocten- 5,11-imine hydrochloride melts at 160-164 with decomposition, The yield is 0.68 g, percent of the theoretical value.

' EXAMPLE 3 a. A mixture of 15.2 g of 5,ll-dibromo-5,6,1l,l2- tetrahydrodibenzola,e]cyclooctene [produced according to the specification of A.C. Cope and S.W. Fenton, J.Am.Chem.Soc. 73, 1668 (1951)] and 120 ml of benzylamine is heated for 18 hours to 140. The excess benzylamine is then evaporated off at in the rotary evaporator, the residue mixed with 5 percent aqueous ammonium hydroxide solution and repeatedly extracted with ether. The ether extracts are combined, washed with water, dried over sodium sulphate and the ether is distilled off. The oil which remains behind is subsequently heated for 2 hours to l4 0/0.1 Torr, then cooled to room temperature, dissolved in ether and filtered through g of aluminum oxide (Woelm, activation stage III) with ether as the solvent. After the ether has been evaporated off at 50 in the rotary evaporator, the oily l3-benzyl-5 ,6,1 1 ,12- tetrahydrodibenzo[a,e]cycloocten-S ,1 l-imine remains behind. it is dissolved in a little acetone, to the solution is added a slight excess of ethereal hydrogen chloride and the solution allowed to stand, whereby the solid hydrochloride precipitates. The 13-benzy1-5,6,1 1,12- tetrahydrodibenzo a,e cycloocten-S ,1 l-imine hydrochloride melts at 194-198 with decomposition. Yield 13.55 g, 94 percent of the theoretical value.

b. A solution of 12.0 g 'of l3-benzyl-5,6,l1,12- tetrahydrodibenzo[a,e Icycloocten-S ,1 l-imine hydrochloride in 250 ml of absolute ethanol is shaken with 3.0 gof 10 percent palladium charcoal under normal pressure and at room temperature under hydrogen. The hydrogen absorption ceases after approximately 4 hours. The catalyst is thereupon filtered off, the filtrate evaporated off at 50 in the rotary evaporator and the solid residue crystallized from a mixture of methanol and acetone. The 5,6,1 1,12- tetrahydrodibenzo a,e ]cycloocten-S l l-imine 'hydrochloride sublimes at 290295. Yield 8.0 g, 90

percent of the theoretical value. The free base is obtained by adding concentrated sodium carbonate solution to the aqueous suspension of the hydrochloride and extraction with ether. The ether extract is washed with water, dried over sodium sulphate and the solvent evaporated off at 50 in the rotary evaporator. After recrystallization from a mixture of ethanol and water, the 5,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten-5,l limine melts at 9698.

EXAMPLE 4 A suspension of 8 g 13-benzyl-2-methoxy-5,6,l1,12- tetrahydrodibenzo[a,e]cycloocten-5,1l-imine and 2.0 g Raney nickel in 100 ml absolute ethanol are stirred in a hydrogen atmosphere at 80 bar and 80. After absorption of approximately 60 percent of the calculated amount of hydrogen a further 2.0 g of Raney nickel are added and the hydrogenation is continued under the above conditions.

After about 1 1 hours the absorption of hydrogen has practically ceased. The catalyst is then removed by filtration under suction, washed with 100 ml ethanol and the filtrate evaporated to dryness in a rotary evaporator at 50.

The residual oil is dissolved in 250 ml of a mixture benzene-ether (1:1), the solution washed successively with 2 n sodium carbonate solution and water, dried over sodium sulphate and the solvent is evaporated off in a rotary evaporator at 50. Finally the oily product (6.0 g) is chromatographed on 200 g of silica gel with a mixture of benzene-ethanol (:05) as solvent. After recrystallization from methylene chloride/ether the 2- methoxy-5,6,l 1,12-tetrahydro-dibenzo[a,e]cyc1oocten-5,1l-imine melts at ll6l19. Yield 1.88 g, 31,9 percent of theoretical volue.

EXAMPLE 5 a. 30.0 g of l-cyano-Z-benzoyl-l,Z-dihydroisoquinoline [produced as in Example 1 (a)] are benzylated by successive reaction with 6.0 g of sodium hydride dispersion (50 percent sodium hydride in mineral oil) and 27.0 g of 4-(bromoethyl)-veratrole [veratryl bromide, produced according to the specification of R.D.

Haworth, W.l-l. Perkin and J. Rankin, Soc. 127, 1444 1925)]in 375 ml of dimethylformamide, analogously to example 2(d). The obtained l-veratryl-2-benzoyl- 1,2-dihydroisoquinaldonitrile is oily. The yield is 47.0 g, 99.4 percent of the theoretical value.

b. The oily l-veratrylisoquinoline is produced by the boiling of 47.0 g of crude l-veratryl-2-benzoyl-l,2- dihydroisoquinaldonitrile with a solution of 35.0 g of potassium hydroxide in 200 ml of ethanol or in 200 ml of water, analogously to Example 1( b). The yield is 20.0 g, 91.4 percent of the theoretical value.

c. The 1-veratryl-2-benzylisoquinolinium bromide,

M.P. 180-184 (after recrystallization from a mixture of chloroform and acetone) is obtained by the reaction of 35.0 g of crude l-veratrylisoquinoline with 18 ml of benzyl bromide in 120 ml of nitromethane, analogously to Example 2(f). The

yield is 12.0 g, 21.2 percent of the theoretical value.

d. The oily l-veratryl-2-benzyl-l,Z-dihydroisoquinoline is produced by the reduction of 12.0 g of 1- veratryl-Z-benzylisoquinolinium bromide with 6.0 g of lithium aluminum hydride in 250 ml of absolute ether, analogously to Example 1(d). The yield is 9.7 g, 98.4 percent of the theoretical value.

c. 10.3 g of lveratryl-2-benzyl-l,2-dihydroisoquinoline are cyclized by boiling with a mixture of 125 m1 of anhydrous formic acid and 25 ml of percent orthophosphoric acid, analogously to Example 2(h). After recrystallization from ethanol, the l3-benzyl-2,3- dimethoxy-S ,6,1 1, l 2-tetrahydro-dibenz0[ a,e] cycloocten-5,1l-imine melts at ll9l23. The yield is 2.8 g, 27.2 percent of the theoretical value.

f. A solution of 5.30 g of l3-benzyl-2,3-dimethoxy- 5 ,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 1- imine in ml of methanol is shaken with 1.0 g of 5 percent palladium charcoal and 3.60 ml of ethanolic hydrogen chloride solution [containing 14.3 percent (weight/volume) of hydrogen chloride in ethanol]ethanol] under normal pressure and at room temperature in a hydrogen atmosphere. The hydrogen absorption ceases after about 4 9% hours. The catalyst is then filtered off under suction, washed with 50 m1 of methanol and the filtrate concentrated by evaporation to dryness in the rotary evaporator at 50. The solid residue is subsequently recrystallized from methanol. The 2,3-dimethoxy-5 ,6, l l, l 2-tetrahydrodibenzo[ a,e,]cycloocten-5,l l-imine hydrochloride melts at 279282 with decomposition. (in a small sealed tube). Yield 3.0 g, 66.2 percent of theoretical value.

EXAMPLE 6 a. 80.0 g of l-cyano-2-benzoyl-l,2-dihydroisoquinoline [produced as in example 1 (a)] are benzylated by successive reaction with 16.0 g of sodium hydride dispersion (50 percent sodium hydride in mineral oil) and 70.0 g of 1 (bromomethyl)-3,4-methy1enedioxybenzene [piperonyl bromide, produced according to the specification of P. Karrer, H. l-lorlacher, F. Locher and M. Giesler, l-lelv. 6, 905 (1923)] in 850 m1 of dimethylformamide, analogously to Example 2(d). The obtained l-piperonyl-2-benzoyl-1 ,2-dihydroisoquinaldonitrile is oily. The yield is l 10 g, 90.7 percent of the theoretical value.

b. The oily l-piperonylisoquinoline is produced by the boiling of 143.0 g of crude 1-piperony1-2-benzoy1- 1,2-dihydroisoquinaldonitrile with a solution of 120.0 g of potassium hydroxide in 350 ml of ethanol or in 350 ml of water, analogously to Example 1(b). The yield is 70.0 g, 73.3 percent of the theoretical value.

c. The l-piperonyl-2-benzylisoquinolinium bromide, M.P. 209-2l4 (after recrystallization from a mixture of methanol and acetone) is obtained by the reaction of 70.0 g of crude l-piperonylisoquinolinewith 30 ml of benzyl bromide in 250 m1 of nitromethane, analogously to Example 2 (f). The yield is 50.0 g, 43.4 percent of the theoretical value.

d. The oily lpiperonyl-2-benzyl-l ,Z-dihydroisoquinoline is produced by the reduction of 20.0 g of lpiperonyl-2-benzylisoquinolinium bromide with 10.0 g of lithium aluminum hydride in 500 m1 of absolute ether, analogously to example 1(d). The yield is 16.0 g, 97.7 percent of the theoretical value.

e. 16.0 g of l-piperonyl-2-benzyll ,2- dihydroisoquinoline are cyclized by boiling with a mixture of 175 ml of anhydrous formic acid and 35 ml of 85 percent orthophosphoric acid, analogously to example 2 (h). The oily crude product l 1.0 g) is chromatographed on 500 g of silica gel with a mixture of benzene/chloroform/ethylacetate (52520.5) as solvent. After recrystallization from ethanol, the l3-benzyl-2,3- methylenedioxy-S ,6,1 l ,12-tetrahydrodibenzo[a,e ]cycloocten-5,l l-imine melts at 135l37. The yield is 6.0 g, 37.5 percent of the theoretical value.

f. A solution of 5.70 g of l3-benzyl-2,3- methylenedioxy-S ,6,1 1,12-tetrahydrodibenzo[a,e ]cycloocten-5,l l-imine in 100 ml of methanol is shaken, under normal pressure and at room temperature in a hydrogen atmosphere, with 1.0 g of 5 percent palladium charcoal and 4.1 ml of ethanolic hydrogen chloride solution [containing 14.3 percent (weight/volume) of hydrogen chloride in abs. ethanol]. The hydrogen absorption ceases after about hours. The catalyst is then filtered off under suction, washed with 100 ml of methanol and the filtrate concentrated by evaporation to dryness in the rotary evaporator at 50. The solid residue is subsequently recrystallized from a mixture of methanol and acetone. The 2,3- methylenedioxy-S ,6,1 l ,1 2-tetrahydrodibenzo[ a,e]cycloocten-5,l l-imine hydrochloride melts at 247-250 with decomposition (in a small sealed tube). The yield is 3.1 g, 64.1 percent of the theoretical value.

EXAMPLE 7 a. A solution of 4.09 g of 13-benzyl-2-methoxy- 5,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 1- imine [cp. examples 1(a) to (e)] and 1.60 g of cyanogen bromide in 15 ml of chloroform is refluxed for 6 hours. The reaction mixture is then concentrated by evaporation at 50 in the rotary evaporator and the oil which remains behind chromatographed on 450 g of silica gel with a mixture of benzene/chloroform (1:1) as solvent. The 2-methoxy-5 ,6,1 l, l 2-tetrahydrodibenzo[ a,e]cycloocten-5,l l-imine-l3-carbonitrile boils at 2l0220/0.00l Torr. Yield 2.64 g, 79.7 percent of the theoretical value.

b. A mixture of 2.0 g of 2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5,l l-imine-l 3-carbonitrile, ml of anhydrous formic acid and 4 ml of 85 percent orthophosphoric acid are refluxed for 20 hours. About 15 ml of formic acid are then distilled off at 60 in the rotary evaporator and the syrup remaining is then poured onto ice. The solution is thereupon adjusted to pH 9-l0 with concentrated aqueous ammonium hydroxide solution and repeatedly extracted with a mixture of benzene/ether (1:1). The organic extracts are combined, washed with water, dried over sodium sulphate and the solvent is evaporated off at 50 in the rotary evaporator. The oil which remains behind (1.87 g) is converted, analogously to Example 3(a), into the hydrochloride. After recrystallization from a mixture of methanol and acetone, the 2-methoxy-5,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,1 l-imine hydrochloride melts at 284290 with decomposition. Yield 0.91 g, 47.4 percent of the theoretical value.

EXAMPLE 8 a. A solution of 2.7 g of l3-benzyl-2-methoxy- 5 ,6,1 l ,12-tetrahydrodibenzo[a,e]cycloocten-S ,l limine [produced according to Example 1(a) to (e)] in 5.0 ml of chloroformic acid ethyl ester is refluxed. Since the volume of the reaction mixture decreases, 5.0 ml of chloroformic acid ethyl ester are added to the latter after 1 A hours. After a total time of 5 hours refluxing, the dark solution is allowed to stand for 18 hours at room temperature, then poured on to water and repeatedly extracted with benzene. The benzene extracts are combined, successively washed with 1N sodium carbonate solution and with water and dried over sodium sulphate. The benzene is distilled of at 50 in the rotary evaporator and the oil which remains (2.7 g) is chromatographed on 350 g of silica gel with a mixture of benzene/ethanol (1010.2) as solvent. The 2- methoxy-5,6,l 1 ,1 2-tetrahydrodibenzo[a,e] cycloocten-5,1l-imine-l3-carboxylic acid ethyl ester boils at 20l (bath temperature)/0.005 Torr. Yield 1.57 g, 61.3 percent of the theoretical value.

b. 1.07 g of 2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,1 1-imine-l3-carboxylic acid ethyl ester are well mixed with a solution of 10 g of potassium hydroxide in a mixture of 50 ml of ethanol and 2 ml of water and subsequently refluxed for 24 hours. The yellow solution is then poured on to water and repeatedly extracted with benzene. The benzene extracts are combined, washed with water and dried over sodium sulphate. After the benzene has been evaporated off in the rotary evaporator at 50, the crude 2-methoxy-5,6,l l, l 2-tetrahydrodibenzo[ a,e]cycloocten-5,1l-imine remains behind (0.92 g). It is dissolved in 5 ml of methanol, the solution made acidic with ethanolic hydrogen chloride and 10 m1 of acetone are then added to the solution. The solution is left to stand at room temperature to allow the 2- methoxy-S ,6,1 1 ,12-tetrahydrodibenzo[a,e]cycloocten- 5,1l-imine hydrochloride to cyrstallize out, M.P. 285293, with decomposition. The yield is 0.45 g, 47.3 percent of the theoretical value.

EXAMPLE 9 a. 1.0 g l3-methyl-2-methoxy-5,6,l 1,12- tetrahydrodibenzo [a,e]cycloocten-5,1l-imine is dissolved in 10 ml acetone, 6 ml of 30 percent hydrogen peroxide are added and the solution is allowed to stand in a closed flask for 48 hours at room temperature. The solution is then evaporated to dryness under a water jet vacuum at room temperature (about 24 hours) and finally the residual oil is dried at room temperature and 0.05 Torr for 8 hours. The l3-methyl-2-methoxy- 5 ,6,1 l, l 2-tetrahydro-dibenzo[a,e ]cycloocten-5 ,l limin-l3-oxide remains as a glassy mass. Yield 1.0 g, 94.3 percent of theoretical value.

b. 0.90 g of l3-methyl-2-methoxy-5,6,1 1,12- tetrahydrodibenzo[a,e ]cycloocten-5 ,l l-imin-l 3-oxide is dissolved in 15 ml of acetic anhydride and the reaction mixture boiled for 18 hours under reflux. The resulting dark brown solution is then poured into water and repeatedly extracted with benzene. The benzene extracts are combined, washed successively with 2N sodium hydroxide solution, water, 2N hydrochloride acid and water and dried over sodium sulphate. After evaporation of the solvent in a rotary evaporator at 50 the resulting oil (0.680 g) is chromatographed on 100 g of Kieselgel with a mixture of benzene-ethanol- (10:0,25) as solvent. The 13-acetyl-2-methoxy- 5,6,1 1 ,12-tetrahydrodibenzo[a,e]cyc1oocten-5,1 1- imine thus obtained exists as a foam. Yield 0,400 g, 42,6 percent of theoretical value.

c. 0.400 g of 13-acetyl-2-methoxy-5,6,11,12- tetrahydrodibenzo[a,e]-cycloocten-5,1 l-imine are well mixed with a solution of g of potassium hydroxide in a mixture of 25 ml of ethanol and 1 ml of water and then boiled for 24 hours under reflux. The yellow solution is then poured into water and repeatedly extracted with benzene. The benzene extracts are combined, washed with water and dried over sodium sulphate. After evaporation of the benzene in a rotary evaporator at 50, the crude 2-methoxy-5,6,l1,12-tetrahydrodibenzo [a,e] cycloocten-5,11-imine remains (0.31 g). This crude product is dissolved in 2.5 ml of methanol, the solution acidified with an ethanolic solution of hydrogen chloride and then mixed with 5 ml of acetone. After being left to stand at room temperature, the 2-rnethoxy-5,6,1 l ,12-tetrahydrodibenzo[ a,e]cycloocten-S,ll-imine hydrochloride crystallizes out, M.P. 285-289 (decomposition). Yield 0.17 g, 43 .4 percent of theoretical value.

EXAMPLE a. A mixture of 2.0 g 13-benzyl-2,3-methylenedioxy- 5 ,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-S ,1 imine, 30 ml of benzene and 10 ml of chloroformic acid ethyl ester is boiled for 12 hours under reflux. A further 10 ml of chloroformic acid ethyl ester are then added and the reaction mixture is again boiled under reflux for 12 hours. Finally a further 5 ml of chloroformic acid ethyl ester are added and the mixture is boiled under reflux for 6 hours. The resulting dark reaction mixture is diluted with benzene, the benzene solution washed successively with water, 2N hydrochloric acid, water, 2N sodium carbonate and water, dried over sodium sulphate and the solvent evaporated off in a rotary evaporator at 50. The residual oil solidifies on mixing with a little ether. After recrystallization from a mixture of methylene chloride-ether, the 2,3- methyIenediOxy-S ,6,1 1,12-tetrahydrodibenzol a,e]cycloocten-5,11-imine-13-carboxylic acid ethyl ester melts at 133135. Yield 1.170 g, 61.6 percent of theoretical value.

b. Analogously to Example 8(b) 1.170 g of 2.3- methylene-dioxy-S ,6,1 1 ,12-tetrahydrodibenzol a,e]cycloocten-S,1l-imine-l3-carboxylic acid ethyl ester are boiled under reflux with a solution of 10 g of potassium hydroxide in a mixture of 50 ml of ethanol and 2 ml of water for 24 hours, poured into water and repeatedly extracted with benzene. The benzene extracts are combined and washed with water. After drying over sodium sulphate the benzene is evaporated in a rotary evaporator at 50 and the crude 2,3- methylenedioxy-S ,6,1 1,12-tetrahydrodibenzo[ a,e]cycloocten-5,1l-imine (0.75 g) remains as residue. The corresponding hydrochloride melts at 247-250 with decomposition (in a sealed capillary tube). Yield 0.584 g, 56 percent of theoretical value.

EXAMPLE ll a. 2.0 g of 13-benzyl-2-methoxy-5,6,1 1,12- tetrahydrodibenzo[a,e]cycloocten-5,l l-imine are dissolved in 20 ml of benzene. The solution is mixed with 5 ml of chloroformic acid isobutyl ester and boiled for 5 hours under reflux. A further 5 ml of chloroformic.

acid isobutylester are then added to the solution and the reaction mixture is boiled for 18 hours under reflux. The resulting brown solution is diluted with benzene washed successively with 2N hydrochloric acid and water, dried over sodium sulphate and the solvent evaporated off in a rotary evaporator at 50. Finally the residual oil is purified by chromatography on 200 g of silica gel with a mixture of benzene-ether (10:05) as solvent. The 2-methoxy-5,6,1l,12'tetrahydrodibenzo[ a,e]cyc1oocten 5,1 l-imine-13-carboxylic acid isobutyl ester boils at 198-203 (bath temperature) [0.02 Torr. Yield 2.025 g, 98.3 percent of theoretical value.

b. 1.15 of the isobutyl ester prepared in (a) are hydrolyzed analgously to example 8(b) with potassium hydroxide and the 2-methoxy-5 ,6,1 1 ,12- tetrahydrodibenzo[a,e]cycloocten-5,1l-imine thus obtained is converted into its hydrochloride with an ethanolic solution of hydrogen chloride. M.P. 285-29 3 (with decomposition) Yield 0.463 g, 49.1 percent of theoretical value.

EXAMPLE 12 Separation of racemic 2-methoxy-5,6,1 1,12- tetrahydro[ a,e]cycloocten-5 ,1 l-imine:

A solution of 10.0 g of racemic 2-methoxy- 5,6,1 1,lZtetrahydrodibenzo[a,e]cycloocteri-5,1 1- imine in 50 ml of chloroform is mixed with a solution of 15 g of (-)-dibenzoyl tartaric acid monohydrate [{a 81.8 (G -0.967 percent in chloroform)] [prepared according to CL. Butler and L.H. Cretcher, J.Amer. Chem. Soc. 55, 2605 (1933) in m1 of methanol. The resulting clear solution is allowed to stand for 10 minutes at room temperature and then evaporated to dryness in a rotary evaporator at 50. After three times recrystallizing the solid residue from a mixture of methanol/ether (1:1), 4.40 g of (+)-2- methoxy-S ,6,1 1 ,1 2-tetrahydrodibenzo[ a,e Icycloocten- 5,11-imine-(--)-dibenzoyl-tartrate are obtained. M.P. 193l94.

The above salt (4.40 g) is suspended in water, the suspension is made alkaline to litmus with 2N sodium carbonate solution and repeatedly extracted with a mixture of benzene/ether (1:1). The organic extracts are combined, washed with water, dried over sodium sulphate and the solvent evaporated off in a rotary evaporator at 50. After twice recrystallizing the residual product from a little ether, the (+)-2-methoxy- 5 ,6,1 1 ,1 Z-tetrahydrodibenzo[a,e]cyc1oocten-5 ,1 1- imine obtained melts at 11l112, [a1 +1395 i 4 (c= 0.1 percent in chloroform). Yield 0.670 g, 13.4 percent of theoretical value.

0.55 g of i-)-2-methoxy-5,6,l1,l2- tetrahydrodibenzo[a,e]cycloocten-5,1l-imine are dissolved in 20 ml of chloroform., the solution is made acid to litmus by the addition dropwise of a methanolic solution of hydrogen chloride (approximately 2N allowed to stand for 10 minutes at room temperature and finally evaporated to dryness in a rotary evaporator at 50. After a single recrystallization of the residual product from a mixture of methanol/acetone (1:1,5), the (+)-2-methoxy-5,6,11,12-tetrahydrodibenzo[a,e ]cycloocten-5,1 l-imine-hydrochloride melts at 280-285, [01], 122 i 4 (c=0,l% in methanol). Yield 0.550 g, 87.5 percent of theoretical value.

The first mother liquor from the solution of the 2-methoxy-5 ,6,1 1,12-tetrahydrodibenzo[a,e]cycloocten-5,1l-imine-()-dibenzoyl-tartrate is evaporated to dryness in a rotary evaporator at 50. The residual oil is then mixed with water, the aqueous solution made alkaline to litmus with 2N sodium carbonate solution and repeatedly extracted with a mixture of benzene/ether (1:1). The organic extracts are combined, washed with water, dried over sodium sulphate and the solvent evaporated off in a rotary evaporator at 50. The residual solid product (4.80 g) is disolved in 40 ml of chloroform and then mixed with a solution of 4.50 g of (+)-camphorl O-sulphonic acid-(B)-monohydrate[[ a] =+20 1 1 (c= percent in water)] in 70 ml of methanol. The solution in then allowed to stand for 10 minutes at room temperature and finally evaporated to dryness in a rotary evaporator at 50. After three times recrystallizing the residual product from a mixture of methylene chloride/petroleum ether (1:4), 3.20 g of (-)-2-methoxy-5 ,6,l 1,12-tetrahydrodibenzo[a,e] cycloocten-S, l 1-imine-(+)-camphor-l0-sulphate, M.P. 220-224, is obtained.

The above salt (3.20 g) is suspended in water, the suspension is made alkaline to litmus with 2N sodium carbonate solution and repeatedly extracted with a mixture of benzene ether (1:1). The organic extracts are combined, washed with water, dried over sodium sulphate and the solvent evaporated in a rotary evaporator at 50. After twice recrystallizing the residual product from a mixture of methylene chloride petroleum ether (1:8), the ()-2-methoxy-5,6,l 1,12-

tetahydrodibenzo[a,ef9 cycloocten-5,l l-imine obtained melts at 102-105 [01],, l 11 i 3 (c=0.1 percent in chloroform). Yield 0,980 g, 19.6 percent of theoretical value.

0.480g ()-2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e] cycloocten-5,1l-imine are dissolved in 10 ml of methanol and the solution made acid to litmus by the addition dropwise of a methanolic solution of hydrogen chloride (approximately 2N). The solution is allowed to stand for 10 minutes at room temperature and then evaporated to dryness in a rotary evaporator at 50". After a single recrystallization of the residual product from a mixture of methanol/ether (123,5), the ()-2-methoxy-5,6,11,12- tetrahydrodibenzo[a,e]cycloocten-5,l l-imine hydrochloride thus obtained melts at 272278 [a],, 99.5 :L- 3.5 (c=0,l percent methanol Yield:0.430g, 78.3 percent of theoretical value.

The following prescriptions further illustrate the production of pharmaceutical compositions according to the invention:

EXAMPLE 13 10 g of active substance, e.g., 2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,1 l-imine hydrochloride, 30 g of lactose and 5 g of highly dispersed silicic acid are mixed together. The mixture is moistened with a solution of 5 g of gelatine and 7.5 g of glycerin in distilled water, and is then granulated through a sieve. The granulate is dried, sieved and carefully mixed with 3.5 g of potato starch, 3.5 g of talcum and 0.5 g of magnesium stearate. The mixture is pressed into 1.000 tablets each weighing 65 mg and each containing 10 mg of active substance.

EXAMPLE 14 10 g of active substance, e.g., 2-methoxy-5,6,l1,12- tetrahydrodibenzo[a,e ]cycloocten-S ,1 1 -im ine hydrochloride, 15 g of lactose and 20 g of starch are mixed together. The mixture is moistened with a solution of 5 g of gelatine and 7.5 g of glycerin in distilled water and granulated through a sieve. The granulate is dried, sieved and carefully mixed together with 3.5 g of talcum and 0.5 g of magnesium stearate. The mixture is then pressed into 1.000 dragee cores. These are subsequently coated with a concentrated syrup made from 26.66 g of crystallized saccharose, 17.5 g of talcum, 1 g of shellac, 3.75 g of gum arabic, l g of highly dispersed silicic acid and 0.090 g of dyestuff, and dried. The obtained dragees each weigh 115 mg and each contain 10 mg of active substance.

EXAMPLE 15 To produce 1.000 capsules each containing 10 mg or 25 mg of active substance, 10 g or 25 g of 2-methoxy- 5 ,6,1 l, 1 2-tetrahydrodibenzo[a,e]cycloocten-S,1 1-

'imine hydrochloride are mixed with 263 g or 248 g of EXAMPLE 16 To produce a cough syrup having an active substance content of 0.2 percent, 1.5 liters of glycerin, 42 g of phydroxybenzoic acid methyl ester, 18 g of p-hydroxybenzoic acid n-propyl ester and, with slight heating, 20 g of 2-methoxy-5,6,l1,l2-tetrahydrodibenzo[a,e]- cycloocten-5,11-imine hydrochloride are dissolved in 3 liters of distilled water. To this are added 4 liters of percent sorbitol solution, '1 .000 g of crystallized saccharose, 350 g of glucose and an aromatic, e.g., 250 g of Orange Peel Soluble Fluid of ELI LILLY & Co., Indianapolis, or 5 g of natural lemon aroma and 5 g of l-lalb und Halb essence, both of the firm HAAR- MANN & REIMER, Holzminden/Germany. The obtained solution is filtered and the filtrate is made up with distilled water to 10 liters.

EXAMPLE 17 A cough syrup containing 0.1 percent of active substance is produced as follows: 10 g of 2,3- methylenedioxy-5 ,6,1 l ,12-tetrahydrodibenzo[ a,e]cycloocten-5,ll-imine hydrochloride are dissolved, whilst heat is applied, in a mixture of 2.5 liters and 18 g of p-hydroxybenzoic acid n-propyl ester. This syrup is then carefully mixed with the active substance solution. After addition of aromatics, e.g., those mentioned under (b), and, if necessary, filtration, the obtained syrup is made up with distilled water to l liters.

EXAMPLE 18 To prepare cough drops containing 1.0 percent of active substance, 100 g of 2-methoxy-5,6,l 1,12- tctrahydrodibenzo[a,e]cycloocten-5,l l-imine hydrochloride and 3 g of saccharine sodium salt are dissolved in a mixture of 4 liters of 70 percent of ethanol (96 percent) and 1 liter of propylene glycol. A mixture is prepared separately of 3.5 liters of 70 percent sorbitol solution with l liter of water and this mixture is then added to the above active substance solution. An aromatic, e.g., 5 g of Hustenbonbon-Aroma (cough drop aroma) or 30 g of Grapefruit essence, both of the firm HAARMANN & REIMER, Holzminden/Germany, is added, the whole well mixed, filtered and madeup with distilled water to liters.

EXAMPLE 19 A suppository mixture is prepared from 2.5 g of 5,6,1 1,l2-tetrahydrodibenzo{a,e]cycloocten-S ,1 limine hydrochloride and 167.5 g of adeps solidus and from the mixture are poured 100 suppositories each containing 25 mg of active substance.

EXAMPLE 20 X and Y, independently of each other, are hydrogen or allcoxy having at most 4 carbon atoms;

and a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim I, which is 2- methoxy-S ,6,1 l ,12-tetrahydrodibenzo[a,e]cycloocten- 5,1 l-imine and the hydrochloride thereof.

3. A compound according to claim I, which is 5,6,1 1, 12-tetrahydrodibenzo[a,e]cycloocten-5,1 l-imine and the hydrochloride thereof.

Claims

1. A compound of the formula

2. A compound according to claim I, which is 2-methoxy-5,6,11, 12-tetrahydrodibenzo(a,e)cycloocten-5,11-imine and the hydrochloride thereof.