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

Derivatives of dibenzo cycloocten-5,11-imine Download PDF

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US3717641A
US3717641A US00041099A US3717641DA US3717641A US 3717641 A US3717641 A US 3717641A US 00041099 A US00041099 A US 00041099A US 3717641D A US3717641D A US 3717641DA US 3717641 A US3717641 A US 3717641A
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percent
cycloocten
acid
imine
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K Jaeggi
K Kocsis
U Renner
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/10—Quaternary compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • noble metal catalysts such as e.g. platinum, or, in particular, palladium on charcoal or on earth metal carbonates.
  • 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.
  • 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.
  • Ac is, in particular, the acyl group of cyanic acid, chloroformic acid, of
  • acyl groups are: the cyano, chlorocarbonyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, tert. butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, methoxythiocarbonyl, methylthio-thiocarbonyl, acetyl and benzoyl groups.
  • 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.
  • alkanols it is also possible to use other solvents containing hydroxyl groups, such as ethylene glycol and its lower monoalkyl ethers.
  • 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.
  • 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.
  • phosphoric acid is preferably 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • Such salts are formed in a conventional manner.
  • 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.
  • a second organic liquid such as, e.g., acetone to methanol
  • 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.
  • 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.
  • 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
  • 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.
  • the active substance is preferably dissolved or suspended in suitable liquids such as liquid polyethylene glycols, whereby stabilizers can likewise be added.
  • sucking tablets as well as oral preparations which are not administered in a single dosage
  • oral preparations which are not administered in a single dosage
  • 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.
  • EXAMPLE 1 a Nitrogen gas is fed into the reaction mixture during the whole reaction period.
  • the 1-(3-methoxybenzyl)-isoquinoline remains behind as light-yellow oil.
  • the yield is 83.0 g, 97.5 percent of the theoretical value.
  • 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.
  • 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.
  • 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.
  • 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.
  • Nitrogen is fed into the reaction mixture throughout the reaction period.
  • 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.
  • 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.
  • 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 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.
  • 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 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 8(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.
  • 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.
  • 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.
  • 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 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-
  • 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.
  • active substance e.g., 2-methoxy-5,6,l 1,12- tetrahydrodibenzo[a,e]cycloocten-5 ,1 l-imine hydroch
  • 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.
  • active substance e.g., 2-methoxy-5,6,l1,12- tetrahydrodibenzo[a,e ]cycloocten-S ,1 1 -im ine hydrochloride
  • 15 g of lactose 15 g of lactose
  • 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.
  • 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.
  • 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;
  • 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.
  • 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.

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Cited By (10)

* Cited by examiner, † Cited by third party
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US3892756A (en) * 1972-02-04 1975-07-01 Roussel Uclaf Novel dibenzocycloheptenes
US4232158A (en) * 1979-06-04 1980-11-04 Merck & Co., Inc. 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines
US4329465A (en) * 1977-09-19 1982-05-11 Merck & Co., Inc. Dibenzo[a,d]cycloocten-6,12-imines
US4414154A (en) * 1977-09-19 1983-11-08 Merck & Co. Inc. Dibenzo[a,d]cycloocten-5,12-imines
US4477668A (en) * 1982-04-07 1984-10-16 Merck & Co., Inc. Process for 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine
US5011834A (en) * 1989-04-14 1991-04-30 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon PCP receptor ligands and the use thereof
US5196415A (en) * 1989-05-09 1993-03-23 The United States Of America As Represented By The Department Of Health And Human Services 5-aminocarbonyl-5H-dibenzo[a.d]cyclohepten-5,10-imines for treatment of epilepsy and cocaine addiction
US5688789A (en) * 1989-04-14 1997-11-18 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon PCP receptor ligands and the use thereof
US20080027090A1 (en) * 2006-07-27 2008-01-31 Wyeth Tetracyclic indoles as potassium channel modulators
US20080027049A1 (en) * 2006-07-27 2008-01-31 Wyeth Benzofurans as potassium ion channel modulators

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GB8727989D0 (en) * 1987-11-30 1988-01-06 Merck Sharp & Dohme Therapeutic agents
KR200210795Y1 (ko) * 1998-03-20 2001-02-01 윤종용 영구자석 매립형 모터

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US3518270A (en) * 1967-04-27 1970-06-30 Warner Lambert Pharmaceutical 6,7,12,13 - tetrahydro - 6,12 - imino - 5h - benzo(5,6)cyclooct(1,2 - b)indole derivatives and process for their production

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3892756A (en) * 1972-02-04 1975-07-01 Roussel Uclaf Novel dibenzocycloheptenes
US4009273A (en) * 1972-02-04 1977-02-22 Roussel-Uclaf Substituted 10,11-dihydro-5,10-imino-[5H] dibenzo (a,d)-cycloheptene
US4329465A (en) * 1977-09-19 1982-05-11 Merck & Co., Inc. Dibenzo[a,d]cycloocten-6,12-imines
US4414154A (en) * 1977-09-19 1983-11-08 Merck & Co. Inc. Dibenzo[a,d]cycloocten-5,12-imines
US4232158A (en) * 1979-06-04 1980-11-04 Merck & Co., Inc. 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines
US4477668A (en) * 1982-04-07 1984-10-16 Merck & Co., Inc. Process for 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine
US5011834A (en) * 1989-04-14 1991-04-30 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon PCP receptor ligands and the use thereof
US5688789A (en) * 1989-04-14 1997-11-18 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon PCP receptor ligands and the use thereof
US6017910A (en) * 1989-04-14 2000-01-25 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon PCP receptor ligands and the use thereof
US5196415A (en) * 1989-05-09 1993-03-23 The United States Of America As Represented By The Department Of Health And Human Services 5-aminocarbonyl-5H-dibenzo[a.d]cyclohepten-5,10-imines for treatment of epilepsy and cocaine addiction
US20080027090A1 (en) * 2006-07-27 2008-01-31 Wyeth Tetracyclic indoles as potassium channel modulators
US20080027049A1 (en) * 2006-07-27 2008-01-31 Wyeth Benzofurans as potassium ion channel modulators
US7601856B2 (en) 2006-07-27 2009-10-13 Wyeth Benzofurans as potassium ion channel modulators
US7662831B2 (en) 2006-07-27 2010-02-16 Wyeth Llc Tetracyclic indoles as potassium channel modulators

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