DE2449102A1 - Tetrahydro-5,10-methane-(5H)-bicyclononene-12-amines - Google Patents

Abstract

Title cpds. of formula (I) (where R is H, lower alkyl, or phenyl-lower alkyl, R' is CH3, C2H5 or lower alkenyl, and R2 and R3 are each H, lower alkyl, lower alkenyl, lower alkynyl or phenyl-lower alkyl) may be reduced by catalytic hydrogenation to cpds. of formula (III) which are analgesics

Description

Benzobicycloalkenamines and Related Compounds and Processes for Their Preparation This invention relates to benzobicycloalkenamines useful as analgesic agents and as intermediates in the preparation of other analgesic agents; benzobicycloalkanamines and processes for their preparation. In particular. The invention relates to 6,9,10,11-tetrahydro-5,10-methane-5H-benzocyclononen-12-amines, processes for their preparation and their use in alternative processes for the preparation of 6,7,8,9,10, 11-hexahydro-5,10-methane-5H-benzocyclonone 12-amines. The invention thus creates new chemical compounds of the formula I. wherein R is hydrogen, lower alkyl, or phen (lower) alkyl; R1 represents methyl, ethyl or lower alkenyl and wherein R2 and. R3 are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl and phen (lower) alkyl and their acid addition salts, preferably the pharmaceutically active acid addition salts. The new compounds of the formula I in the form of the acid salts are crystalline solids which are essentially insoluble in ether and soluble in polar solvents containing hydroxyl groups, such as methanol and ethanol. The investigation of the compounds prepared according to the method described below provides, after infrared and kerrimagnetic resonance spectrographic analyzes, spectral data which support the molecular structures listed.

The compounds of the formula I and their acid addition salts can be used as intermediates in the synthesis of Benzobicycloalkanaminen, in which it are analgesic agents, and continue to effect primary and secondary Amine forms of the compounds of formula 1 and their pharmaceutically active acid addition salts analgesic effects in laboratory animals.

The invention also provides a process for the preparation of a compound of the formula I or an acid addition salt thereof, which is characterized in that the group = NY of a compound of the formula II where R and Ri have the above meanings and where Y is hydrogen, hydroxy, lower alkoxy, phen (lower) alkoxy, lower alkyl or phen (lower) alkyl, selectively reduced, a primary or secondary amine being formed, where R3 stands for hydrogen and in which R2 has the meanings hydrogen, lower alkyl or phen (lower) alkyl and - if desired - carries out one or more of the following stages, namely (a) etherification of a compound in which R stands for H, where a compound forms, in which R stands for lower alkyl or phen (lower) alkyl, (b) converting a primary amine into a secondary or tertiary amine according to formula I or converting a secondary amine obtained into a tertiary amine according to formula I, (c) columns the ether group of a compound in which R is lower alkyl or phen (lower) alkyl, forming a phenolic compound, (d) separating a mixture of optical isomers into a diastereomer es pair or into a single enantiomer, and (e) converting a compound of the formula I into an acid addition salt thereof or converting an acid addition salt form of the compound according to formula I into the free amine.

The starting materials of the formula II are new compounds and can can be produced by a method described below. The selective one Reduction can be done with an alkali metal, for example sodium in an alkanol, for example, ethanol or isopropanol, can be carried out.

When a compound of formula I is obtained by selective reduction it can be one or more of the standard methods of forming other compounds the formula I are subjected. For example, a phenolic compound, in which R stands for hydrogen, are etherified, whereby a compound is formed, wherein R is lower alkyl or phen (lower) alkyl. Etherification can be carried out in a manner known per se, for example, a methyl or Ethyl ethers can be prepared by treating the phenolic compound with dimethyl sulfate or diethyl sulfate in an alkaline, aqueous medium.

However, it is generally preferred to carry out this stage by choosing one suitable ether, as starting material of the formula II for selective reduction, which has the desired alkyl or phen (lower) alkyl group, to avoid.

If there is a primary amine of the formula I, wherein R2 and R3 are hydrogen stand, or have formed an acid addition salt thereof, it can be converted into a secondary or tertiary amine using standard methods. To this Methods include reductive alkylation under conditions which are chosen so that the non-aromatic double bond of the primary amine is not reduced.

An example of reductive alkylation of the primary amine is Formation of the dimethyl-tert-amino derivative by means of formaldehyde and formic acid. Alternatively the primary amine can be converted into a secondary amine, where R2 is hydrogen and in which R3 has the meanings lower alkyl, lower alkenyl or lower Alkynyl or phen- (lower) alkyl possesses by interacting with a halogen compound of the general formula Hal-R3 wherein Hal is a halogen, such as chlorine or bromine or Iodine and wherein R3 is lower alkyl, lower alkenyl, lower alkynyl or Phen (lower) alkyl means, preferably reacted in the presence of an organic base. In the same way, a secondary amine, in which R2 is hydrogen and in which R3 lower alkyl, lower alkenyl, lower alkynyl or phen (lower) alky represents, are converted into a tertiary amine, wherein R and R are each independently are selected from one another from lower alkyl, lower alkenyl, lower Alkynyl or phen (lower) alkyl, by reaction with a suitable lower alkyl halide, lower alkenyl halide, lower alkynyl halide, or phen (lower) alkyl halide be convicted.

If desired, a compound of the formula I or an acid addition salt can be used of which R is a lower alkyl or phen (lower) alkyl group, one Cleavage of the ether bond is subjected to a phenolic compound forms, wherein R is hydrogen. For examples of splitting agents for splitting of ethers include Lewis acids, for example aluminum chloride or Boron tribromide and hydrohalic acids such as hydrobromic acid.

The compounds of formula I have the property of optical Isomerism and mixtures of the optical isomers can be separated into individual isomers will. Thus, the compounds of the formula II can be obtained as racemic mixtures and their reduction gives the amines of the formula as diastereomers. The separation the diastereomeric pairs and their separation into enantiomers can, if desired be done by well-known procedures.

The new compounds of the formula I can be isolated as such or in the form of acid addition salts. The acid addition salt forms can be made by adding an acid to the compound of formula I. As an acid, from from which the salt can be derived can hydrochloric acid, maleic acid, Citric acid, acetic acid, benzoic acid or other pharmaceutically acceptable Acids are used. The addition of the acid is preferably carried out by the acid is added in alcoholic solution. Acid addition salts can be added to the Amine can be converted as such in the usual way by adding a base.

The invention also provides a process for the preparation of a 6,7,8,9,10,11-hexahydro-5,10-methane-5H-benzocyclononen-12-amine or a pharmaceutically acceptable acid addition salt thereof by adding a corresponding 6,9 , 10,11-tetrahydro-5,1 0-methane-5H-benzocyclononen-12-amine or an acid addition salt. Thus the invention provides a process for the preparation of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein R is hydrogen, lower alkyl or phen (lower) alkyl, R1 is lower alkyl, R2 is hydrogen, lower alkyl or phen (lower) alkyl and R3 is hydrogen, lower alkyl, lower Alkenyl, lower alkynyl and phen (lower) alkyl, which is characterized in that the non-aromatic, unsaturated bond or bonds of a compound of the formula I, as explained and defined above, or an acid addition salt thereof, are reduced and, if desired, one or carries out more of the following steps: (a) etherification of a compound in which R is hydrogen, a compound being formed in which R is lower alkyl or phen (lower) alkyl, (b) conversion of a primary amine into a secondary amine or a tertiary amine or converting a secondary amine into a tertiary amine, (c) cleaving the ether group of a compound in which R is low is alkyl or phen (lower) alkyl; whereby a phenolic compound is formed, (d) separation of a mixture of optical isomers into a diastereomeric pair or into a single enantiomer, and (e) converting a compound of the formula III into a pharmaceutically acceptable acid addition salt or converting an acid addition salt form of the compound according to formula III into the free amine.

The products of the formula III and their pharmaceutically acceptable ones Acid addition salts are useful as analgesic agents. Such connections are in our Belgian patent specification No. 776 173, published June 2nd 1972, described.

When a compound of formula III was obtained by the reduction, it can use one or more standard methods of forming other compounds of the Formula III are subjected. For example, a phenolic compound, where R is hydrogen, are etherified to form a compound, wherein R is lower alkyl or phen (lower) alkyl. Etherification can be carried out in a manner known per se, for example, a methyl or Ethyl ethers can be prepared by treating the phenolic compound with dimethyl sulfate or diethyl sulfate in an alkaline aqueous medium. However, in general it is preferred, this stage by choosing a suitable ether as the starting material Formula 1 for the reduction of the desired alkyl or phen (lower) alkyl group owns to avoid.

If there is a primary amine of the formula III, wherein R2 and R3 are hydrogen stand, or have formed an acid addition salt thereof, it can be converted into a secondary or tertiary amine using standard methods.

Reductive alkylation is one of these methods. An example a reductive alkylation of the primary amine is the formation of the dimethyl-tert-amino derivative with formaldehyde and formic acid. Alternatively, the primary amine can be converted into a secondary Amine are converted, where R2 is hydrogen and R3 is lower alkyl, lower Alkenyl or lower alkynyl or phen (lower) alkyl represents by man a halogen compound of the general formula Hal-R³ @ wherein Hal represents a halogen atom, such as chlorine or bromine or iodine and R3 is lower alkyl, lower alkenyl, lower Is alkynyl or phen (lower) alkyl, preferably in the presence of an organic one Base implements. In the same way, a secondary amine, where R2 is hydrogen and R3 is lower alkyl, lower alkenyl, lower alkynyl or phen (lower) alkyl means, are converted into a tertiary amine, in which R² is lower alkyl or 3 is phen (lower) alkyl and R3 is lower alkyl, lower alkenyl, lower Means alkynyl or phen (lower) alkyl, by reaction with an appropriate lower one Alkyl halide or phen (lower) alkyl halide. In the same way, a tertiary Amine where R³ is lower alkenyl or lower 2 alkynyl and where R2 lower alkyl or phen (lower) alkyl means from a primary amine in which R2 and R are hydrogen by reaction with a lower alkyl halide or phen (lower) alkyl halide with formation of a secondary amine and subsequent Reaction made with a lower alkenyl halide or lower alkynyl halide will. Alternatively, the secondary amine can be reacted with a haloformate ester and then reduced to obtain the tertiary amine, in which R stands for methyl. The Haloformiatester can in the same way with the primary amine in which both R2 and hydrogen are reacted, where there is an N-methyl sec. -Amin forms. Other tertiary amines can be made by aoylating the secondary amine to give a compound where R2 is acyl and then reducing the acylated amine.

If desired, a compound of the formula III or an acid addition salt can be used where R is a lower alkyl group, cleavage of the ether bond below, where a phenolic compound is formed, where R is hydrogen stands. Examples of splitting agents for splitting ethers include Lewis acids, for example aluminum chloride or boron tribromide and hydrogen halide acids, for example hydrobromic acid.

The compounds of formula III have the property of optical Isomerism and mixtures of the optical isomers can be converted into an optically active one Form can be separated. Alternatively, optically active forms of the compound of the formula III or their acid addition salts are prepared by one optically active form of the compound according to formula I reduced.

The compounds of the formula III can be used as such or in the form of a Acid addition salt can be isolated. The acid addition salt forms can be made by adding an acid to the compound of formula III. As an acid, from from which the salt can be derived can hydrochloric acid, maleic acid, Citric acid, acetic acid, benzoic acid or other pharmaceutically acceptable acids be used. The addition of the acid is preferably carried out by adding the acid carried out in alcoholic solution. Acid addition salts can be used in the amine as such can be converted in the usual way by adding a strong base. One Compound of formula III or a pharmaceutically acceptable salt thereof be prepared from a toxic acid addition salt of the compound of formula I, provided that the toxic component is removed during manufacture will.

In the above-mentioned method of making the compounds of formula III is the reduction of the compound of formula 1 or its acid addition salt preferably by catalytic hydrogenation, for example using a Raney nickel catalyst carried out. It is evident that during the reduction of the olefinic double bond shown in formula I, any non-aromatic Double bond in groups R1, R2 and R3 and any triple bond in the groups R2 and R3 is reduced to a single bond. So if an end product of the formula III is desired, in which R3 is lower alkenyl or lower alkynyl, it is necessary to introduce the group R³ after the reduction.

The compounds of the formula III and their pharmaceutically acceptable ones Acid addition salts can also be obtained by direct reduction of the compounds of the formula II can be prepared without isolating the compounds of the formula I. Thus creates the invention also provides a process for the preparation of a compound of the formula III, as explained and defined above, or a pharmaceutically acceptable acid addition salt of which, which is characterized in that a compound of the formula II, such as described and defined above, reduced and, if desired, one or more stages, listed under (a) to (e) on page 7. The reduction of Compound according to formula II is preferably by catalytic hydrogenation, for example using Raney nickel as a catalyst. It is obvious, that in the reduction product the group R3 denotes hydrogen and R2 denotes hydrogen in the case in which starting materials are used in which Y is hydrogen, Represents hydroxy, lower alkoxy or phen (lower) alkoxy, or in the others Cases with Y, i.e. lower alkyl or phen (lower) alkyl is. Where R1 represents a lower alkenyl group in formula II, the corresponding one is obtained lower alkyl group in the reduction product.

Any subsequent stages, such as ether splitting and the like, can be carried out as described on pages 7 to 11 of this text.

The compounds of formula II where R is hydrogen, lower alkyl or phen (lower) alkyl, R1 is methyl, ethyl or lower alkenyl and where Y is hydrogen, hydroxy, lower alkoxy, phen (lower) alkoxy, lower alkyl or phen (lower) alkyl , are new compounds created by the present invention. The invention also provides a process for the preparation of a new compound of the formula II, which is characterized in that a compound of the formula IV in which R and R1 have the meanings given in connection with formula II, treated with a compound of the formula H2NY in which Y has the above meanings.

The new compounds according to the invention include those of the formula IV where R is hydrogen, lower alkyl or phen (lower) alkyl and where R1 is methyl, ethyl or lower alkenyl. The new compounds of formula IV are generally high-boiling liquids or crystalline solids which are essentially insoluble in water and soluble in benzene, lower alkanols such as methanol, ketonic solvents such as acetone and methyl ethyl ketone and the like. The investigation of the compounds, which are prepared according to the methods described below, yields spectral data in infrared and nuclear magnetic resonance spectrographic analysis which support the molecular structures given here for the tricyclic ketones.

The invention also provides a process for the preparation of the tricyclic ketone of formula IV, which thereby. indicates that a compound of the formula V where R is lower alkyl or phen (lower) alkyl, R1 is methyl, ethyl or lower alkenyl and where X is chlorine or bromine, with a strong base, preferably an alkali metal alcoholate, hydride or amide, with a tricyclic ketone Formula IV is formed in which R stands for lower alkyl or phen (lower) alkyl and, if a ketone in which R stands for hydrogen is desired, the ether bond is cleaved, the phenolic compound being formed. The strong base used for the reaction with the compound of the formula V is suitably used in an excess amount in a suitable solvent. The strong base can be, for example, potassium t-butoxide in t-butanol or sodium hydride or sodium amide in dimethylformamide. Where an ether bond is to be cleaved, the cleavage can be carried out in a manner known per se using, for example, a Lewis acid.

The compounds of formula V are new products created by the invention. The invention also provides a process for the preparation of a compound of the formula V, which is characterized in that a compound of the formula VI wherein R is lower alkyl or phen (lower) alkyl and R1 is methyl, ethyl or lower alkenyl, with a cis compound of the formula where X is chlorine or bromine, in the presence of a strong base, preferably an alkali metal alcoholate hydride or amide. The strong base is preferably used in an excessive amount in a suitable solvent. The product (V) obtained can be used directly to form the tricyclic ketone (IV) without isolating the adduct (V).

The starting materials for producing the adduct (V) are known Products or can be obtained by known methods. In particular are cis-1,4-dichloro-2-butene and cis-1,4-dibromo-2-butene known compounds. The connections of the formula VI, namely 1-alkyl, - or 1-alkenyltetralones, can according to below methods described are produced.

It is obvious that by combining the above described Process the new compounds of the formula I and also the compounds of the formula III can synthesize. For example, the following syntheses can be performed according to Invention are mentioned.

The first synthesis creates a compound of the formula wherein R is lower alkyl or phen (lower) alkyl and R 'is methyl, ethyl or lower alkenyl, prepared by a process which is characterized by a) treating a ketone of the formula wherein R and R1 have the meanings mentioned above in connection with formula VI, with cis-l 4-dichloro- or 1,4-dibromo-2-butene in the presence of excess alkali metal alcoholate, hydride or amide, an adduct compound of the formula forms in which R and R1 have the meanings given above in connection with formula VI and in which X is chlorine or bromine; b) Treating the adduct with a further excess of an alkali metal alcoholate, hydride or amide, a tricyclic ketone of the formula arises, in which R and R1 have the meanings given above in connection with formula VI; c) Treating the tricyclic ketone with a compound of the formula H2NY 'in which y1 is hydrogen, hydroxy, lower alkoxy or phen (lower) alkoxy, an imino compound of the formula is formed in which R und'R1 have the meanings given above in connection with formula VI and in which Y has the meanings given above; and d) selectively reducing the imino group of the imino compound.

A second synthesis according to the invention is a process for the preparation of compounds of the formula wherein R¹ is methyl, ethyl or lower alkenyl, which is characterized in that a) a ketone of the formula wherein R and R¹ have the meanings given above in connection with formula VI, treated with cis-1,4-dichloro- or cis-1,4-dibromo-2-butene in the presence of excess alkali metal alcoholate, hydride or amide, wherein an adduct compound of the formula forms in which R and R1 have the meanings given above in connection with formula VI and in which X is chlorine or bromine; b) the adduct compound is treated with a further excess of alkali metal alcoholate, hydride or amide, a tricyclic ketone of the formula arises, in which R and R1 have the meanings given above in connection with formula VI; c) the tricyclic ketone with a compound of the formula H2NY in which Y1 stands for hydrogen, hydroxy, lower alkoxy or phen (lower) alkoxy, treated with an imino compound of the formula arises in which R and R1 have the meanings given above in connection with formula VI, and in which yl has the meanings given above; d) the imino group of the imino compound is selectively reduced, a compound of the formula arises, in which R and R1 have the meanings given above in connection with formula VI; and e) splits the ether function. A third synthesis according to the invention is a process for the preparation of compounds of the formula in which R is lower alkyl or phen (lower) alkyl and in which R1 is methyl or ethyl, which is characterized in that a) a ketone of the formula wherein R and R have the meanings given above in connection with formula XII, with cis-1,4-dichloro- or 1,4-dibromo-2-butene in the presence of excess alkali metal alcoholate, hydride or amide, wherein an adduct compound of the formula forms in which R and R1 have the meanings given above in connection with formula XII and in which X is chlorine or bromine; b) the adduct compound is treated with a further excess, alkali metal alcoholate, hydride or amide, a tricyclic ketone of the formula arises, in which R and R have the meanings given above in connection with formula XII; c) treating the tricyclic ketone with a compound of the formula in which yl is hydrogen, hydroxy, lower alkoxy or phen (lower) alkory, an imino compound of the formula forms in which R and R1 have the meanings given above in connection with formula XII and in which y1 has the above meanings; and d) selectively reducing the imino group, a compound of the formula forms in which R and R1 have the meanings given above in connection with formula XII; and e) reducing the non-aromatic double bond.

The invention also provides a process for the preparation of a chemical compound of the formula in which R is lower alkyl or phen (lower) alkyl and in which R1 is methyl or ethyl, which is characterized in that a) a ketone of the formula wherein R and Rl have the meanings given above in connection with formula VIII, treated with cis-1,4-dichloro- or 1,4-dibromo-2-butene in the presence of excess alkali metal alcoholate, hydride or amide, whereby an adduct compound of the formula forms in which R and R1 have the meanings given above in connection with formula XIII and in which X is chlorine or bromine; b) the adduct compound is treated with a further excess of alkali metal alcoholate, hydride or amide, a tricyclic ketone of the formula arises in which R and R1 have the meanings given above in connection with formula XIII; c) treating the tricyclic ketone with a compound of the formula H2NY¹, wherein Y¹ represents hydrogen, hydroxy, lower alkoxy or phen (lower) alkoxy, with an imino compound of the formula arises in which R and R1 have the meanings given above in connection with formula XIII and in which y1 has the above meanings; and d) reducing the imino and non-aromatic double bond.

A fifth synthesis according to the invention relates to a process for the preparation of chemical compounds of the formula wherein R1 is methyl or ethyl, which is characterized in that a) a ketone of the formula where R1 is methyl or ethyl and where R is lower alkyl or phen (lower) alkyl, with cis-1, 4-dichloro- or -1, 4-dibromo-2-butene in the presence of excess alkali metal alcoholate, hydride or - amide treated, whereby an adduct compound of the formula forms where R1 is methyl or ethyl and where R is lower alkyl or phen (lower) alkyl and X is chlorine or bromine; b) the adduct compound is treated with a further excess of alkali metal alcoholate, hydride or amide, resulting in a tricyclic ketone of the formula forms where R is lower alkyl or phen (lower) alkyl and where R1 is methyl or ethyl; c) the tricyclic ketone treated with a compound of the formula H2NY1, in which Y1 is hydrogen, hydroxy, lower alkoxy or phen (lower) alkoxy, an imino compound of the formula formed in which R is lower alkyl or phen (lower) alkyl, R1 is methyl or ethyl and in which has the above meanings; d) selectively reducing the imino group; e) the ether bond splits, forming a compound of the formula forms where R1 is methyl or ethyl; and f) reducing the non-aromatic double bond.

When describing the process of making a specific Embodiment of the invention reference is made to the accompanying drawing, where the connections for identification are schematically assigned Roman numerals are and wherein the synthesis of specific embodiments of formula I, viz 12-Amino-5-ethyl-6,9,10,11-tetrahydro-5,1 0-methane [5H] -benzocyclononen-3-ol (X) and 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benæocyclononen-12-amine (IX) and a specific embodiment of the formula IV, namely 5-ethyl-6,7,10,11-tetrahydro-3-methoxy-5,10-methan [5H] -benzocyclononen-12-one (III) are explained.

The drawing also explains the use of the invention Process aspect for the production of specific 6,7,8,9,10,11-hexahydro-5,10-methane [5H] -benzocyclononen-12-amines, namely 5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,1 0-methane [5H] -benzocyclononen-12-amine (VIII) and 12-amino-5-ethyl-6,7,8, 9,10,1 1-hexahydro-5, 10-methane [5H] -benzocyclononen-3- ol (XI).

1-ethyl-7-methoxy-2-tetralone (III) and an excess of cis-1,4-dichloro-2-butene (IV) are conveniently at room temperature in an inert atmosphere with a slight excess of one equivalent of a strong base, conveniently potassium t-butoxide for about 12 to about 24 hours, conveniently about 18 hours to manufacture of compound V. Isolation of the connection V is not required and treating the reaction mixture containing them with a further excess the strong base, followed by a heating time, conveniently 6 hours The reflux temperature of the solvent used is in turn of an additional Reaction time followed, which is conveniently at room temperature for about 16 further hours runs. The exact times and reaction temperatures are self-evident not critical. The strong base to be used and the appropriate solvent are in the same way not particularly critical and many suitable Combinations such as potassium t-butoxide in t-butanol and sodium hydride or sodium amide in dimethylformamide are available to those skilled in the art of organic chemistry Disposal; if the strong base used is potassium t-butylate, t-butanol is a particularly suitable solvent. The connection established in this way VI is then isolated using standard procedures. The oxime VII is then by treating compound VI with hydroxylamine in an inert solvent, favorably methanol, initially at an elevated temperature, favorably the The reflux temperature of the solvent used, for a short time, is favorable 6 hours, followed by a longer time, preferably 18 hours, at room temperature, manufactured. The compound VII is obtained by standard methods. link VII can, if desired, be reduced directly to compound VIII; catalytic Hydrogenation is a particularly convenient means for this transformation.

Cleavage of the compound VIII to produce the compound IX can if desired in the usual way by treatment with hydrohalic acids, such as hydrogen bromide or hydrogen iodide can be achieved in hot, aqueous solution. Alternatively, if desired, the oximino function of compound VII can be used selectively can be reduced, the Bouveault Blanc method being particularly convenient to-die Establish compound IX. If desired, the compound IX can be reduced, to produce compound VIII. Catalytic hydrogenation is particular convenient to perform this reduction. The compound IX can, if desired conveniently with a Lewis acid such as boron tribromide to produce compound X be split.

If desired, compound X can be reduced to the compound XI to manufacture. A catalytic hydrogenation is required to carry out this reduction cheap. The isolation of compounds VIII, IX, X and XI can if desired by standard methods.

While the inventive method with reference to the drawing, which explains its application to 1-ethyl-7-methoxy-2-tetralone, was described, it is obvious to a person skilled in the art that the procedure applies in the same way other tetralons can be used, which in the 1- and 7-positions the different, carry substituents falling within the scope of the invention.

The production of the variously substituted secondary and tertiary Amines that fall within the scope of the present invention are similar obvious and standard methods for this purpose are well known to those skilled in the art. For example, dimethyl tert. -amino derivatives by means of a Leukart-QIallach reaction using formic acid and formaldehyde.

For the person skilled in the art, it is equally obvious that the Ether linkage of compound VI can be cleaved in a manner that the corresponds to the cleavage of the ether linkage of compound IX. The one made in this way phenolic compound is of course compound VI in terms of further conversions completely equivalent. It is evident that the other tricyclic ketones are the Formula IV which fall within the scope of the present invention and which have an ether grouping in the 3-position in the same way in the corresponding phenolic Compound can be split, the non-phenolic with regard to further reactions Connections are completely equivalent.

The starting materials for carrying out the invention, namely the 1-alkyl or 1-alkenyl-2-tetralone can be selected from the easily accessible 2-tetralones after a well-known alkylation reaction, as is typical in Stork and Schulenberg, "Journal of the American Chemical Society", 84, 284 (1962) will. The tetralons are made with pyrrolidine in an inert solvent such as Benzene, and then treated with an appropriate lower alkyl or lower Alkenyl halide in an inert solvent such as benzene or dioxane at elevated levels Temperatures, advantageously the reflux temperature of the solvent used, treated. You can also choose from a suitable, commercially available 1-tetralone as described by Howell and Taylor in "Journal of the Chemical Society "1958, 1249, with an Orignard reagent prepared from a suitable lower alkyl or lower alkenyl halide and the 1-substituted dihydronaphthalene obtained can with peracid be oxidized.

Many of the tetralones are commercially available and syntheses for these, where this is not the case are readily available in the literature. For example is the synthesis of a-tetralone in "Organic Synthesis", Collective Volume IV, p 898 * described; the synthesis of ß-tetralone is in the same work on page 903 and a general synthesis of β-tetralons is described by Nagata et al. in the netherlands U.S. Patent 67 09534 (Jan. 10, 1968).

It is obvious to those skilled in the art that the ketones of the formula IV are prepared as racemic mixtures, and that the reduction of their oximes provides the amines of the formula I as diastereomers. The separation of the diastereomers Couples and their separation into enantiomers can if desired be carried out according to well-known procedures. The diastereomers, enantiomers and Mixtures thereof all fall within the scope of the present invention. The analgesic Activity of the compounds of the formula I and their pharmaceutically suitable acid addition salts can be determined by taking a modification of that of D'Amour and Smith-in Journal of Pharmacology, 72, 74 (1941), an approved test for analgesic Means, the procedure described follows. In this test, the compound is administered orally, administered intraperitoneally and intramuscularly to rats and used for response one caused by a high intensity beam of light shining on the tail Pain stimulus required time is measured. The compounds of formula I. and their pharmaceutically acceptable acid addition salts show analgesic activity in rats at doses greater than 1.56 mg / kg intraperitoneally and particularly at Doses from 6.25 to 25.0 mg / kg.

6,7,8,9,10,11-hexahydro-5,10-methane-5H-benzocyclononen-12-amines, the the useful products of a number of the alternative methods of the invention represent, also cause analgesic activity in warm-blooded animals and are in the Belgian patent 776 173 (June 2, 1972).

When the compounds of formula I and their pharmaceutically active Addition salts are used as analgesic agents, they can be used in warm-blooded Animals such as mice, rats, rabbits, monkeys, etc. alone or in conjunction administered with pharmaceutically acceptable carriers.

The dose of the compounds of the invention used upon administration varies with the form of administration and the selected connection. It continues to vary with the individual being treated. in the generally, treatment is initiated with small doses, which are essentially are less than the optimal dose of the compound.

The dose is then increased in small increments until those below the Optimal effect is achieved under certain circumstances. In general it is most desirable when the compounds according to the invention are administered at a concentration level which generally gives effective results without any deleterious or adverse side effects occur.

In the present invention, the term "means lower alkyl a saturated hydrocarbon radical, including straight and branched ones Radicals having 1 to 6 carbon atoms; in this regard, for explanation, but without restricting the generality of the above statements methyl, Called propyl and i-butyl. The term "lower alkenyl" means an unsaturated one Hydrocarbon radicals, including straight-chain and branched-chain radicals, of the 3 to Has 5 carbon atoms; in this regard are for explanation, but without the To restrict the generality of the above statements, allyl, 2-butenyl, 3-methyl-2-butenyl and called 2-pentenyl. The term "phen (lower) alkyl" means a lower one Alkyl radical, as previously defined, which is in the terminal position by a phenyl radical or a phenyl radical substituted by lower alkyl or lower alkoxy radicals is substituted; in this regard are for explanation, but without the generality to limit the above, benzyl, phenethyl, o-, m-, p-anisyl, Veratryl and called o-, m- or p-xylyl.

The following examples explain the invention in more detail.

Example 1 1 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methane-r5H] -benzocyclononen-12-one A solution of 40 g (0.21 mol) of 1-methyl-7-methoxy-2-tetralone is added under a nitrogen atmosphere in 100 ml of t-butanol dropwise to a freshly prepared solution of potassium t-butoxide (9.8 g, 0.25 mol of potassium in 400 ml of t-butanol). The mixture is at room temperature Stirred 1 hour after the addition and then under nitrogen in a Added dropping funnel and added dropwise to a solution of 53 g (0.42 mol) of cis-1,4-dichloro-2-butene added in t-butanol with stirring under nitrogen. After adding 1 g of potassium iodide the mixture is stirred for a further 18 hours at room temperature. An additional amount of fresh potassium t-butylate solution (15 g, 0.38 mol of potassium in 400 ml of t-butanol) is then added dropwise and the mixture is refluxed for a further 6 hours after the addition has ended.

After the reflux, the mixture is stirred for about 16 hours. at room temperature. Then the reaction mixture in water (approximated 4 Ltr.) And the organic phase is extracted into benzene. The benzene solution is washed twice with water, dried over magnesium sulfate and the solvent is distilled off in vacuo to give 57 g of a crude oil. distillation of the crude oil provides 36 g of a product with a boiling point of 155-165 ° C (0.5 mm), the is crystallized from hot heptane, and has a melting point of 79-810C.

Example 2 6,9,10,11-Tetrahydro-3-methoxy-5-methyl-5,10-methane-E5H] -benzocyclononen-12-one, Oxime A clear solution of 23 g of sodium acetate in 15 ml of methanol is clear with a Solution of 19.5 g of hydroxylamine hydrochloride mixed in 200 ml of methanol and the obtained Sodium chloride precipitate is separated off by filtration. To this mixture a solution of 13.5 g of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5-10-methan [5H] -benzocyclononen-12-one is added in 50 ml of methanol. After the addition is complete, the reaction mixture is allowed to stand for about 4 hours. held under reflux and then allowed to stir for about an additional 16 hours. The solvents are then distilled off in vacuo and the residue is in Slurried water, whereby a solid is formed, which is separated off by filtration is, treated thoroughly with water and dried, giving 14.2 g of a Product with melting point 122-1250C is obtained. Recrystallization from isopropanol provides 11.7 g of the title compound with melting point 124-1260C.

Example 3 6,7,8,9,10,1 1-hexahydro-3-methoxy-5a-methyl-5,10-methane [5-Hibenzocyclononen-12ß-amine 5 g of the oxime of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,1 0-methan- [5H] -benzocyclononen-12-one, 150 ml ethanol, 30 ml concentrated ammonium hydroxide and two teaspoons (2 tsps.) of Raney nickel are applied at 2.81 kg / cm2 (40 psi) pressure Shaken with hydrogen for 5 hours at room temperature.

The catalyst is separated off by filtration and the solvents are removed in vacuo. The oil left behind becomes between ether and water distributed. Separation of the ether layer, drying over magnesium sulfate and removal of the ether in vacuo gives 4.5 g of a crude product.

Treating an ethereal solution of the crude product with water free hydrogen chloride gives 3.5 g of a precipitate with a melting point of 265-272 ° C. Recrystallization from hot water gives 1.6 g of the title compound in the form of the hydrochloride salt Melting point 301-303 ° C.

For example 4 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methan [5H] -benzocyclononen-12-one Following a procedure similar to that of Example 1 for the preparation of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methane [5H] -benzocyclononen-12-one The procedure is analogous, is obtained from 20.4 g of 1-ethyl-7-methoxy-2-tetralone and 25 g of cis-1,4-dichloro-2-butene, 17.8 g of the title compound with a boiling point of 150-185 ° C (0.4 mm).

Example 5 5-Ethyl-6,9,10,1 1 -tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclonones-1 2-one, oxime Following a procedure similar to that of Example 2 for Preparation of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methane [5H] -benzocyclononen-12-one oxime applied working method is analogous, is obtained from 16.0 g of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methan [5H] -benzocyclononen-12-one and a clarified mixture of 25.5 g N, atrium acetate and 22 g hydroxylamine hydrochloride 10.3 g of the title compound with a melting point of 150-153 ° C. in 200 ml of methanol.

Example 6 5α-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine Following a procedure similar to that of Example 3 for the preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methane [5H] -benzocyclononen-12-amine is analogous to the procedure used is obtained from 3.0 g of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,1 0-methane [5H] benzocyclononen-12-one oxime, 1.4 g of the hydrochloride salt of the title compound with melting point 247-250 ° C.

For example 7 6,9,10,11-tetrahydro-3-methoxy-5α-methyl-5,10-methane [5H] -benzocyclononen-12β-amine One gives over a period of approximately 90 min.

Add 4.4 g of clean sodium pellets to a stirred, rick-flow Solution of 2.5 g of 6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10-methane [5H] -benzocyclononen-12-one oxime in 2.5 ml of dry ethanol while keeping under nitrogen. After completion the addition is stirred and refluxed for approximately 1 hour. The reaction is cooled to 20 ° C and diluted with 25 ml of dry ethanol. One still stirs like that long until no sodium particles are more visible. The solution is cooled again to 200C and an ice-water mixture (approx. 200 ml) becomes admitted. The ethanol is removed by concentration in vacuo and the remaining aqueous solution is mixed with ether. The ether fraction is made with saline washed, dried over sodium sulfate, and concentrated in vacuo to an oil. This oil is taken up in ether and with excess dry hydrogen chloride treated, with 2.07 g of product with melting point 287-2890C (decomposition). Recrystallize this product from methanol / water with concentrated hydrochloric acid is acidic, gives 1.56 g of the hydrochloride salt of the title compound having a melting point 300-302 ° C.

Analysis C1 6H22C1N0: C H N Cl calc .: 68.68 7.93 5.01 12.67% found: 68.81 8.23 5.21 12.38% RIR analysis: signal at # 5.55, 5.1 (triplets, total 2 protons) ppm.

For example 8 5α-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine Following a procedure similar to that of Example 7 for the preparation of 6,9,10,11-tetrahydro-3-methoxy-5α-methyl-5,10-methane [5H] -benzocyclonones-1 2ß-amine is analogous to the procedure used, is obtained from 3.8 g of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12-one oxime 1.76 g of the title product with melting point 77-78 ° C. and 0.6 g of a second fraction with melting point 74-760C.

Analysis C17H230N: C H N calc .: 79.33 9.01 5.44% found: 79.36 9.35 5.38 % NMR Analysis: Signals at # 5.2 (broad, multiplet) ppm Mass Spectral Analysis: Calculated m / e 257.0 Found m / e 257.0 The second fraction of the material of the free Base, along with sufficient material from the first fraction, so that in total approximately 0.7 g is present, is dissolved in. Ether and with excess dry Treated hydrogen chloride gas, whereby 0.98 g of the hydrochloride salt of the title compound with melting point 285-286 ° C can be obtained.

Analysis C17H24ClON: C H N Cl calc .: 69.49 8.23 4.77 12.07% found: 69.14 8.66 4.78 12.32,% Example 9 12β-Amino-5α-ethyl-6,9,10,11-tetrahydro-5,10-methan [5H] -benzocyclononen-3-ol A solution of 3.0 g of 5-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12-amine in 100 ml of dry methylene chloride is cooled to -200C and while it is under While maintaining nitrogen, a solution of 6.7 g of boron tribromide in dry methylene chloride becomes added over 30 min while maintaining the temperature at approximately -200C and while stirring. After the addition has ended, the reaction is allowed to come to room temperature heat and stir under nitrogen for about 16 hours 150 ml of cold water are added to the cooling of the reaction mixture to 0 ° C. and the mixture is stirred about 1 hour more. The layers formed on standing are separated and the water layer is made basic with concentrated ammonium hydroxide. Filtration is used to separate a product that has separated out Has; Weight 2.1 g; Melting point 178-186 ° C. Recrystallization from methanol gives 0.7 g of the title compound with melting point 216-2180C.

For example 10 N, N, 5α-trimethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [SHJ-benzocyclononen-12R-amine 5 g of 6,9,10,11-tetrahydro-3-methoxy-5α-methyl-5,10-methane [5H] -benzocyclononen-12β-amine are dissolved in 5.2 g of 90% formic acid. 4.5 ml of 40 point aqueous formaldehyde are added and the stirred solution is slowly warmed. Once the temperature of the solution is 40 ° C reached, a violent development of CQ2 begins. When the reaction temperature begins to fall, the external heating resumes and the reaction is kept at 900C for 8 hours. After cooling, the reaction mixture is in vacuo concentrated. The residue is dissolved in water, and excess dilute sodium hydroxide solution is added to and treat the mixture with ether.

The ether part is washed with saline solution and dried over sodium sulfate and concentrated in vacuo to 4.8 g of an oil.

This oil is dissolved in ethanol and treated with excess hydrogen chloride gas treated. On standing, 3.5 g of the hydrochloride salt of the title compound separate in the form of crystals with a melting point of 228-2300C.

Analysis C18H26ClNO: C H X Cl calc .: 70.22 8.51 4.55 11.52% found: 70.31 8.68 11.311 1l., 84% 3 e i 5 p i e 11 N, N-Dimethyl-6,9,10,11-tetrahydro-3-methoxy-5α-ethyl-5,10-methane-C5H] -benzocyclononen-12D-amine Following a procedure similar to that of Example 10 for the preparation of N, N, 5α-trimethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine is analogous to the procedure used, is obtained from 6,9,10,11-tetrahydro-3-methoxy-5α-ethyl-5,10-methane [5H] -benzocyclononen-12ß-amine the title compound which, according to standard methods, is converted into its hydrogen chloride salt with a melting point 236-2370C is transferred.

Analysis C1 9H28N0Cl: C H N Cl calc .: 70.89 8.77 4.35 11.02 g found: 70.90 8.97 4.31 10.70% 3 ei 5 pie 1 12 5α-ethyl-6,9,10,11-tetrahydro-3-methoxy-N-methyl-5,10-methane [5H] -benzocyclonones-1 2β-amine A solution of 6.5 g (0.25 moles) of 5α-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclonone-12β-amine and 4.0 g of methyl iodide in 200 ml of acetone is refluxed for 12 hours. Man cools the solution to room temperature and removes the hydroiodide salt of the title compound, which separates out as a white precipitate, by filtration. 5.3 g are obtained with melting point 251-254 ° C.

Distribute the hydroiodide salt between ether and dilute sodium hydroxide solution, followed by drying the ethereal solution over MgSO4 and treating with excess Hydrogen chloride gives the hydrochloride salt of the title compound in the form of a white Precipitate, which is removed by filtration and recrystallized from ethanol. 2.6 g with a melting point of 279-281 ° C. are obtained.

Analysis C18H26ClNO.¼ H2O: C H N calc .: 69.21 8.39 4.48 Z found: 69.53 8.64 4.42% 3 e i 5 p i e 1 13 Resolution of 5α-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclonone-12β-amine A. A solution is added to a solution of 50 g of d-tartaric acid in 1.5 liters of methanol of 76.5 g of 5α-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12βamine in methanol. The solution obtained is diluted to 3.0 liters and left to stand overnight. Filtering gives 56 g of salt with melting point 1 99-2020C (decomposition).

Three recrystallizations of this salt from methanol give 28.4 g Salt with melting point 209-211 ° C. (decomposition) [α] D25 -47.6 °.

D The salt is diluted into the free base by partitioning between Sodium hydroxide and ether transferred. The ether phase is concentrated after drying, 17 g of base are obtained which crystallize on standing.

Melting point 50-530C, [α] D25 -85.4 °.

A portion of 4 g of base is converted into its hydrochloride salt in ether. Recrystallization of the salt from ether / ethanol gives 4.0 g of product with a melting point 272-275 ° C, [α] D25 -69.6 °.

Analysis C17H24NOCl: C H N calc .: 69.49 8.23 4.77% found: 69.33 8.51 4.63% B. The mother liquors from the recrystallization of the d-tartrate salt of part A, above, are united and concentrated. the residue is transferred to the free one Base by partitioning between ether and dilute sodium hydroxide. The ether phase is dried and concentrated to give 50 g of crude base. This base solves are dissolved in methanol and added to a solution of 33 g of (1) -tartaric acid in methanol. The solution obtained is diluted to 2.8 liters and left to stand overnight. Filter gives 55 g of the salt with a melting point of 200-205 ° C. Two recrystallizations of this Resulting salt from methanol. 31.4 g salt with melting point 210-211 ° C (decomposition) and [α] D25 + 47.7 °.

The salt becomes the base in the same way as the (-) - rotain above mers / transferred to give 19 g of product which crystallizes on standing. Melting point 48-51 ° C, [a325 +84.30.

A sample of 4 g is converted into the hydrogen chloride salt, the when recrystallized from ethanol / ether a melting point of 260-265 ° C, [α] D25 +69.30, autograph.

Analysis C17H24NOCl: C H N calc .: 69.49 8.23 4.77% found: 69.60 8.59 4.69% B e i 5 p i e 1 14 (+) - 12 [beta] -amino-5α-ethyl-6,9,10,11-tetrahydro-5,10-methan [5H] -benzocyclononen-3-ol Following a procedure similar to that of Example 9 for the preparation of 1 2β-Amino-5a-ethyl-6,9,10,1 1-tetrahydro-5,1 0-methane [5H] -benzocyclone-3-01 is analogous, is obtained from 15 g of (+) - 5a-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12ß-amine 11.4 g solid base with melting point 167-172 ° C. This turns into their hydrogen chloride salt converted into methanol / ether. Recrystallization of the salt from ethanol / ether results 12.0 g (+) - salt with melting point 261-263 ° C; [α] D25 + 83.0 °.

Analysis C16H22NOCl: C H N calc .: 68.68 7.93 5.01% found: 68.53 8.25 4.89% Example of 15 (-) - 12 [beta] -amino-5α-ethyl-6,9,10,11-tetrahydro-5,10-methan [5H] -benzocyclononen-3-ol Following a procedure similar to that of Example 9 for the preparation of 12ß-Amino-5a-ethyl-6,9,10,11-tetrahydro-5,10-methan [5H] -benzocyclononen-3-ol were used The procedure is analogous to obtain from 13 g of (-) - 5α-ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine 9.0 g solid base. This is converted into its hydrogen chloride salt in methanol / ether. Recrystallization of the salt from ethanol / ether gives 7.5 g of (-) - salt with a melting point 260-262 ° C; [α] D25 -82.8 ° Analysis C16H22NOCl: C H N calc .: 68.68 7.93 5.06 O / o Found: 68.80 8.23 4.91% Be-Example 1 16 12β-amino-5α-methyl-6,9,10,11-tetrahydro-5 , 10-methane [5H] benzocyclononen-3-ol Following a procedure that der. according to Example 9 for the preparation of 12β-Amino-5α-ethyl-6,9,10,11-tetrahydro-5,10: methane-55H] -benzocyclononen-3-ol The procedure described is analogous, is obtained from 2.0 g of 6,9,10,11-tetrahydro-3-, methoxy-5a-methyl-5, 10-methane [5H] -benzocyclononen-12β-amine 0.25 g of the hydrochloride addition salt of the title compound in the form of an ethanol solvate with a melting point of 1800C (decomposition).

Claims (1)

PATENT CLAIMS 1. Compound of the formula wherein R is hydrogen, lower alkyl or phen (lower) alkyl, R1 is methyl, ethyl or lower alkenyl and R and R3 are independently selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl and phen (lower) alkyl and their pharmaceutically active acid addition salts, 2. A compound according to claim 1, wherein R2 and R3 are hydrogen. 3. A compound according to claim 1, wherein R is methyl or ethyl and R2 and R3 are independently selected from hydrogen, lower Alkyl or phen (lower) alkyl. 4. 12-Amino-6,9,10,11-tetrahydro-3-methoxy-5-methyl-5,10 methane [5H] -benzocyclonones. 5. 12-Amino-6,9,10,11-tetrahydro-3-methoxy-5-ethyl-5,10 methane [5H] -benzocyclonones. 6. 12-Amino-6,9,10,1 1-tetrahydro-5-ethyl-5,10-methane [5H] benzocyclononen-3-ol. 7. 12-Amino-6,9,10,11-tetrahydro-5-methyl-5,10-me'tha, n- [5H] benzocyclononen-3-ol 8. Process for the preparation of a compound of the formula wherein R is lower alkyl or phen (lower) alkyl and R¹ is methyl, ethyl or lower alkenyl, characterized in that a) a ketone of the formula wherein R and R 'have the above meanings, treated with cis-1,4-dichloro- or -1,4-dibromo-2-butene in the presence of excess alkali metal alcoholate, hydride or amide, an adduct compound of the formula: in which R and R1 have the above meanings and X is chlorine or bromine; b) the adduct compound is treated with a further excess of alkali metal alcoholate, hydride or amide, a tricyclic ketone of the formula: forms, wherein R and R1 have the above meanings; c) the tricyclic ketone is treated with a compound of the formula H2NY in which Y is hydrogen, hydroxy, lower alkoxy or phen (lower) alkoxy, an imino compound of the formula: forms, wherein.R, R1 and'Y have the above meanings; and d) selectively reducing the imino group of the imino compound. 9. The method according to claim 8, characterized in that one Reduction of the Bouveault-Blanc type used to selectively reduce the imino group. 10. Process for the preparation of a compound of the formula wherein R1 is methyl, ethyl or lower alkenyl, characterized in that a) according to the process according to claim 8, a compound of the formula where R is lower alkyl or phen (lower) alkyl and R has the above meanings; and b) splits the ether function. 11. The method according to claim 10, characterized in that as Lewis acid used for cleavage reagent. 12. The method according to claim 11, characterized in that as Lewis acid boron tribromide is used. 13. Process for the preparation of compounds of the formula: wherein R is lower alkyl or phen (lower) alkyl and R1 is methyl or ethyl, characterized in that, according to the method of claim 8, a compound of the formula: produces, wherein R and R1 have the above meanings and reduces the non-aromatic double bond. 14. The method according to claim 13, characterized in that the Reduction of the non-aromatic double bond is carried out by catalytic hydrogenation. 15. Process for the preparation of compounds of the formula: wherein R is lower alkyl or phen (lower) alkyl and R1 is methyl or ethyl, characterized in that an imino compound of the formula: where R and R1 have the meanings given above and Y is hydrogen, lower alkoxy or phen (lower) alkoxy and reduces the imino and nonaromatic double bond. 16. The method according to claim 14, characterized in that the Reduction of the imino and non-aromatic double bond through catalytic hydrogenation performs. 17. Process for the preparation of compounds of the formula: in which R1 is methyl or ethyl, characterized in that, according to a process according to claim 10, a compound of the formula produces, wherein R1 has the above meanings and reduces the non-aromatic double bond. 18. The method according to claim 16, characterized in that the Reduction of the non-aromatic double bond is carried out by catalytic hydrogenation. 19. Compound of the formula: where R is hydrogen, lower alkyl or phen- (lower) alkyl and R1 is methyl, ethyl or lower alkenyl. 20. N, N, 5a-trimethyl-6,9,1 0,11 tetrahydro-3-methoxy-5,1 0-methane [5H] -benzocyclononen-12β-amine. 21,5a-ethyl-6s9w10,11-tetrahydro-3-methoxy-N-methyl-5S10-methane [5H] -benzocyclononen-1 2ß-amine. 22. (+) - 5α-Ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine. 23. (-) - 5α-Ethyl-6,9,10,11-tetrahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine. 24. (+) - 12β-Amino-5α-ethyl-6,9,10,11-tetrahydro-5,10-methan [5H3-benzocyclononen-3-ol. 25. (-) - 12β-Amino-5α-ethyl-6,9,10,11-tetrahydro-5,10-methan [5H] -benzocyclononen-3-ol. 26. Process for the preparation of a compound of formula 1 or an acid addition salt thereof, characterized in that the group = NY of a compound de.r formula II wherein R and R1 have the above meanings and Y is hydrogen, hydroxy, lower alkoxy, phen (lower) alkoxy, lower alkyl or phen (lower) alkyl, selectively reduced, forming a primary or secondary amine, wherein R³ is Is hydrogen and R² is hydrogen, lower alkyl or phen (lower) alkyl and, if desired, one or more of the following stages: a) etherification of a compound in which R is H to form a compound in which R is lower alkyl or phen ( lower) -alkyl, b) converting a primary amine into a secondary or tertiary amine according to formula I or converting a secondary amine obtained into a tertiary amine according to formula, c) splitting the ether group of a compound in which R is lower alkyl or phen ( lower) alkyl, forming a phenolic compound, d) separating a mixture of optical isomers into a diastereomeric pair or into a single enantiomer, and e) converting ei ner compound of formula 1 into an acid addition salt thereof or converting an acid addition salt form of a compound according to formula I into the free amine. '27. Products of the method according to claim 8. 28. Products of the method according to claim 10. 29. Products of the method according to claim 26. 30. 6,9,10,11-tetrahydro-5,10-methane [5H] -benzobicyclononen-12-amines. 31. Process for the preparation of a compound of the formula or a pharmaceutically acceptable acid addition salt thereof, wherein R is hydrogen, lower alkyl or phen (lower) alkyl, R1 is lower alkyl, R2 is hydrogen, lower alkyl or phen (lower) alkyl and R3 is hydrogen, lower alkyl, lower alkenyl, Lower alkynyl and phen (lower) alkyl, characterized in that the non-aromatic, unsaturated bond or bonds of a compound of the formula I or an acid addition salt thereof are reduced, and if desired one or more of the following stages a) etherification of a compound, where R is hydrogen, a compound is formed in which R is lower alkyl or phen (lower) alkyl, b) converting a primary amine into a secondary amine or a tertiary amine or converting a secondary amine into a tertiary amine, c) Cleavage of the ether group of a compound in which R stands for lower alkyl or phen (lower) alkyl, where a phenolic compound forms, d) separating a mixture of optical isomers into a diastereomeric pair or into a single enantiomer and e) converting a compound of formula III into a pharmaceutically acceptable acid addition salt or converting an acid addition salt form of a compound according to formula III into the free amine . 32. 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methane [5H] -benzocyclonone-1,2-amine. 33. 12-Amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methane [5H] -benzocyclononen-3-ol. 34. 5-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12-amine. 35. 12-Amino-6,7,8,9,10,11-hexahydro-5-ethyl-5,10-methane [5H] -benzocyclononen-3-ol. 36. (-) - 5α-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine. 37. (+) - 5α-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methane [5H] -benzocyclononen-12β-amine. 38. (-) -12β-Amino-Sa-ethyl-6, 7,8,9, 10,11-hexahydro-5, 10-methan [5H] -benzocyclononen-3-ol. 39. (+) - 12β-Amino-5α-ethyl-6,7,8,9,10,11-hexahydro-5,10-methan [5H] -benzocyclononen-3-ol. 40. 5α-Ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-N-methyl-5,10-methane [5H] -benzocyclononen-12β-amine. 41. 12β-Amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methane [5H] -benzocyclononen-3-ol. 42. 12α-Amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methane [5H] -benzocyclononen-3-ol. 43. Products of the method according to claims 13 or 31. 44. 6,7,8,9,10,11-hexahydro-5,10-methane [5H] -benzocyclononen-12-amines. 45. The method according to claims 26 or 31, wherein first a ketone of the formula IV is formed, in which R is hydrogen, lower alkyl or phen (lower) alkyl and R1 is methyl, ethyl or lower alkenyl, characterized in that a compound of the formula V where R is lower alkyl or phen (lower) alkyl, R1 is methyl, ethyl or lower alkenyl and X is chlorine or bromine, treated with a strong base, preferably an alkali metal alcoholate, hydride or amide, a tricyclic ketone of the formula IV 'is formed, in which R is lower alkyl or phen (lower) alkyl and, if a ketone is desired in which R is hydrogen, the ether bond is cleaved, the phenolic compound being formed. 46. The method according to claim 45, wherein first a compound of formula V is formed, in which R is lower alkyl or phen (lower) alkyl, R1 is methyl, ethyl or lower alkenyl and X is chlorine or bromine, characterized in that a compound of the formula VI wherein R is lower alkyl or phen (lower) alkyl and R1 is methyl, ethyl or lower alkenyl, with a cis compound of the formula wherein X is chlorine or bromine, treated in the presence of a strong base, preferably an alkali metal alcoholate, hydride or amide.