DE2207097A1 - New amines and methods of making them - Google Patents

Description

CIBA-GEIGY AG BASEL (SWITZERLAND)

Case 4-7582 / 1 + 2

Germany

New amines and methods of making them.

The invention relates to 9- <2-A-3-R-propyl) -9,10-dihydro-9,10-ethano-anthracenes with the core of the formula

CD,.

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where R is a secondary or tertiary amino group and A is a free, etherified or acylated hydroxyl group, and methods of making them.

An N-raono-substituted is used as the secondary arr.inogroup and as a tertiary an N-disubstituted amino group. The main substituents are hydrocarbon radicals aliphatic character in question, also by heteroatoms, such as oxygen, sulfur or Nitrogen, interrupted and / or by oxo; Hydroxyl and / or amino groups can be substituted. Hydrocarbon residues of aliphatic character are radicals whose first member, connected to the nitrogen atom, is not a member of a aromatic system is. Residues of this type are, for example, aliphatic and cycloaliphatic hydrocarbon radicals and especially lower residues of this kind.

Lower aliphatic hydrocarbon radicals are radicals that have up to 7 and above all 1-4 carbon atoms contain. As lower cycloaliphatic hydrocarbon radicals residues are denoted, the 5-7 * and in particular Have 5 or 6 ring carbon atoms. The word "down" in connection with other carbonaceous groups is analogous in the following. just like for hydrocarbon residues indicated to understand. The hydrocarbon radicals can be saturated or unsaturated.

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The following are above all to be mentioned as radicals of the type mentioned: lower alkyl and alkenyl radicals, in particular radicals with not more than 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, straight and branched, branched in any place. bonded butyl, pentyl, hexyl and keptyl radicals, lower hydroxyalkyl radicals, such as 2-hydroxyethyl and 5-hydroxypropyl residues, Allyl and methallyl radicals, unsubstituted and mono-, di- or polysubstituted lower alkyl-substituted lower cycloalkyl and cycloalkenyl radicals, such as cyelopentyl, cyclohexyl, cyclopropyl, cyclopentenyl and cyclohexenyl radicals, unsubstituted and mono-, two or more lower alkyl-substituted lower cycloalkyl and alkenyl-alkyl radicals, such as cyclopentyl and cyclohexenylmethyl, ethyl and propyl radicals.

Divalent radicals are above all lower ones, optionally substituted by hydroxyl, oxo and / or amino groups Alkylene and alkenylene radicals, in particular those radicals which contain 5-7, preferably 4, 5 or 6 chain links and accordingly with the nitrogen atom of the amino groups 4-8 and preferably 5> Form 6 or 7 membered rings. Such radicals are e.g. 1,4-butylene, 1,4-pentylene, 1,4-hexylene, 1,5-pentylene like l ^ -dimethyl-l ^ -pentylene-, 5-methyl-l, 5-pentylene-, 1,5-pentenylene, 1,6-hexylene and 1,5-hexylene radicals. By Heteroatoms are interrupted residues of this type primarily

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Line 'radicals in which the heteroatom at both ends of the chain is separated by at least two carbon atoms, i.e. the Chain contains more than 4 and preferably 5 links and therefore with the nitrogen atom a more than 5-membered and preferably 6-membered ring forms. For example, be called:

Lower, ntylen- optionally substituted by hydroxy, oxo and / or amino substituiertel.Oxa-, aza and Thiaalkylenreste such as 2-aza-, oxa- 2- and 3-thia-l, 5-P ^e, such as S ^ -Dimethyl- ^ - thia-l ^ -pentylene-, 1,5-dimethyl-5-aza-l, 5-pentylene-, 3-lower alkyl-3-aza-l, 5-pentylene- like J-methyl - ^ - aza-l ^ -pentylene-, 3-hydroxy-lower alkyl-2-aza-l, 5-pentylene like ^ -hydroxyethyl - ^ - aza-l ^ -pentylene-,> -oxa-l, 6-hexylene- and 3 -Aza-l, 6-hexylene radicals, The amino group is mainly a mono- or

Di-lower alkylamino group, such as the mono- or dipropylamino, or preferably mono- or diethylamino group. But above all the dimethylamines - or especially those Monomethyl 'group, or the N-Kethyl-N-ethylamino group, a cycloalkylamino group, such as the cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexylamino group, or an optionally C-lower alkylated and / or im Ring 0-monounsaturated pyrrolidino or pi-

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peridino group or an optionally C-lower alkylated piperazino, N'-lower alkyl such as N'-methyl, or N '- (hydroxy-lower alkyl) such as N ^! - (j3-Hydroxyethyl) piperazino, thiomorpholino or morpholino group. The term "C-lower alkylated" means here, as above and below, that the radical in question on C atoms is substituted by lower alkyl radicals, such as those mentioned, and in particular by C 1-4 alkyl radicals.

An etherified hydroxy group is e.g. a phenyl-lower alkoxy, such as a benzyloxy group, an alkenyloxy, especially lower alkenyloxy, such as allyloxy or methallyloxy group or especially an alkoxy group. Alkoxy groups are mainly lower alkoxy groups, such as methoxy, ethoxy, propoxy, Isopropoxy, butoxy or pentoxy groups.

An acylated hydroxy group, i.e. acyloxy group, is primarily derived from a carboxylic acid, e.g. an aromatic carboxylic acid, such as benzoic acid, or especially an aliphatic carboxylic acid, such as an alkanoic acid, e.g. butyric, propionic or especially acetic acid.

A preferably represents a free hydroxyl group.

The one substituting the 9-position of the anthracene nucleus Propyl radical is preferably only substituted by the radicals A and R, but it can also be further substituted by lower alkyl radicals, e.g. those mentioned, especially by methyl or ethyl

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residues, be substituted. The propyl radical mentioned preferably carries no more than such a lower alkyl radical as a substituent.

In the new compounds, positions 11 and / or 12 can be substituted by lower alkyl radicals, e.g. those mentioned be, but the positions 11 and 12 are preferably unsubstituted.

The new connections are in positions 1-8

of the anthracene ring is preferably not substituted, they can but carry substituents in these positions, e.g. lower alkyl, alkoxy, alkenyloxy and / or alkyl Irrere apt o groups, lower alkylsulfonyl and / or alkanoyl groups,

but above all trifluoromethyl or halogen, such as fluorine, bromine and iodine, but very particularly chlorine, in particular as alkyl radicals Methyl, ethyl, propyl, isopropyl, butyl, i-butyl, tert. Butyl, as alkoxy or alkenyloxy groups the methoxy, ethoxy, allyloxy or methylenedioxy group, as alkyl mercapto groups the methyl or ethyl mercapto group and, as alkanoyl radicals, especially the acetyl, propionyl and butyryl radical are to be mentioned. The substitution in positions 1-8 can be multiple, but is preferably twofold or above all simple. Preferred positions for substituents are the> and especially the 2-position.

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In the ΙΟ-position, the new compounds can, for example, be an aliphatic hydrocarbon residue, such as one of the above mentioned lower alkyl or alkenyl radicals, or also a halogen atom, in particular a Chi or atom, onv / iron. The 10 position but is preferably not substituted.

In accordance with what has been said above, the invention relates, for example, to compounds of the formula

RR ¹ . R "
ο ο Α ι ο
\ \ / I
CH-C-CH-R

(R.)
At the

(la)

in which A and R have the meanings given above and A in particular is a free hydroxyl group, a lower alkoxy group or denotes a lower alkanoyloxy group, η and m each denote an integer from 0 to 4, η + m being preferred is not greater than 5, m primarily for 0 and η e.g. stands for 2, but especially for 1 or in particular 0, the radicals R. independently of one another the above as substituents of Positions 1-8 said groups and a single sub substituent R. preferably in the 3- or especially in the 2-position stands, R- is one of the above as substituents of the ΙΟ-position

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Mentioned groups or, in particular, a hydrogen atom, the symbols R, R ^ and R "represent lower alkyl radicals, for example those mentioned, such as ethyl or especially methyl groups, or primarily represent hydrogen atoms, preferably at most one of the three symbols of hydrogen is different, and Ae is a 1,2-ethylene radical which is optionally substituted in the 1- or / and 2-position by a lower alkyl radical, for example by one of the abovementioned, such as methyl, ethyl, propyl or isopropyl radicals, but is preferably unsubstituted.

The new compounds have valuable pharmacological properties, in particular a psychotropic, e.g. antidepressant, effect. In particular, they cause an inhibition the norepinephrine intake, as shown in animal experiments, for example Heart and brain of the rat with a dose of 0.5-10 mg / kg s.c, 0.2-5 mg / kg i.v. or 5-100 mg ρ.ο. shows. They also work antagonistic to reserpine, as shown, for example, in the reserpine antagonism test on mice with a dose of 100-400 mg / kg p.o. shows. The new compounds can therefore be used as psychotropic, especially as antidepressant agents Find. They can also be used as additives to animal feed as they are better for food utilization and a Cause these animals to gain weight. The new compounds can also be used as starting materials or as intermediates for production other valuable, especially pharmaceutically effective

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serve samer connections. For example, 9- (3-amino-1-propenyl) -9,10-dihydro-9,10-ethano-anthracenes be prepared by adding the radical A as AH in the new compounds, for example as water splits off.

Particularly noteworthy are compounds of the formula

■ la, where R is an amino group which is replaced by alkyl radicals, Hydroxy or aminoalkyl radicals, alkenyl, unsubstit.uierte and one, two or more lower alkyl-substituted lower ones Cycloalkyl and / or cycloalkenyl radicals, unsubstituted and mono-, di- or polysubstituted lower alkyl-substituted lower ones Cycloalkyl and / or alkenyl-alkyl radicals, monosubstituted or disubstituted, or a 1-azacycloalkyl or 1-azacycloalkenyl radical means that contains 4-8 ring members and can be substituted by hydroxyl, oxo and / or amino groups, or a 1-azaoxa, 1-aza-thia or 1-aza-azacycloalkyl radical means in which the heteroatoms are separated by at least two carbon atoms and the by hydroxy, oxo and / or amino groups can be substituted, and A represents a free hydroxy, lower alkoxy or lower alkanoyloxy group stands.

Are particularly valuable. Compounds of formula la, wherein R is a mono- or di-lower alkylamino group, a hydroxy-lower alkylamino group, an at most C-lower alkylated 1-azacycloalkyl group with 5-7 ring members or cycloalkyl

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amino group with 3-7 ring members or an optionally C-lower alkylated morpholine, thiomorpholine, N'-lower alkyl-piperazino or N '- (hydroxy-lower alkyl) -piperazino group, R. for lower alkyl, alkoxy, trifluoromethyl groups or preferably Halogen atoms, such as bromine or especially chlorine atoms and R _{10 is} a halogen atom, preferably a chlorine atom, or especially a hydrogen atom and A is a free hydroxyl group or a C ₁ j, alkoxy or C 1-4 alkanoyloxy group.

Particularly noteworthy are compounds of the formula

OH
CH ₂ -CH-CH ₂ -Am

(II),

where R. is preferably in the 2-position and a lower alkyl or alkoxy group, a trifluoromethyl group, a bromine or in particular a chlorine atom, but above all a hydrogen atom, and Am is a monosubstituted by a C "-cycloalkyl radical or mono- or disubstituted by C., - alkyl groups Amino group or an optionally

C-lower alkylated pyrrolidino, piperidino,

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Morpholino-, N'-Kethyl-piperazino-, N'-Ethyl-piperazino or Represents N '- (ß-hydroxyethyl) piperazino group.

Those compounds of the formula II in which R 1 is in the 2-position and are particularly important here Am is a mono- or di-lower alkylamino group in which the lower alkyl radicals contain 1-4 carbon atoms.

Compounds of the formula are particularly valuable

OH

I ₂ -CH-CH ₂ -Am ₂ .

(in),

where R _{p is} a methoxy group, a trifluoromethyl group, but preferably a chlorine or especially a hydrogen atom -stent - and Am _{p is} the diethylamino or monoethylamino group, but especially the dimethylamino group or especially the monomethylamino group, especially the l - (3-Dimethylamino-2-hydroxy-1-propyl) -9,10-dihydro-9,10-ethano-anthracene-methanesulfonate and especially 9- (2-hydroxy-5-methylaminopropyl) -9, 10-dihydro-9,10-ethano-anthracene of the formula

209837 / 12A 5

OH

CH ₂ -CH-CH ₂ -NH-CH

this, for example, to the heart and brain of the rat in a subcutaneous dose of 1 mg / kg, an intravenous dose of 0.5 mg / kg or a oral administration of 10 mg / kg significantly inhibited noradrenaline uptake causes, or shows a clear reserpine antagonism in the mouse with an oral dose of 200 mg / kg.

The new compounds are obtained by methods known per se.

For example, one can proceed in such a way that in a 9-X-9,10-dihydro-9,10-ethano-anthracene, in which X denotes a radical which can be converted into a 2-A-3-R-propyl group, X denotes a 2-A-5-R-propyl group converts, where R and A have the meanings given.

The radical X is, for example, reactive in the 3-position through a esterified hydroxyl group Z substituted 2-A-propyl radical. A reactive esterified hydroxyl group Z is especially one with a strong organic or inorganic acid, especially a hydrohalic acid such as

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- Lj -

Hydrochloric, hydrobromic or hydroiodic acid, or an arylsulfonic acid, such as one by lower alkyl or alkoxy radicals, e.g. those mentioned above, or by halogen atoms, such as chlorine or Bromine atoms mono-, di- or polysubstituted benzenesulfonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid, or a lower alkanesulfonic acid, e.g. Methanesulfonic acid, esterified hydroxyl group. Z can too present together with A as an epoxy bridge.

The conversion of the radical Z into the amino group R takes place, for example, by reaction with an amine of the formula HR, where R has the meaning given.

The payment is made in the usual way, preferably in the presence of a solvent and optionally in the presence of a condensing agent, e.g. a basic one Condensation agent, preferably at an elevated temperature and optionally in a closed vessel negative pressure. A basic condensing agent is, for example, a Alkali hydroxide or carbonate, e.g. sodium hydroxide or potassium carbonate, or a tertiary amine, e.g. triethylamine or Pyridine. Instead of a secondary amine, one can also release it Agent, e.g. a symmetrically disubstituted urea, used v / orden. In this case one works purposefully with heating and, if necessary, adding one

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inert diluents such as diphenyl ether or sand.

The radical X can also be, for example, a K-unsubstituted 2-A-3-aminopropyl group which is converted into an N-monosubstituted 2-A-3-aminopropyl group by exchanging a hydrogen atom. The exchange takes place in the usual Wei se, for example by reaction with a reactive ester of a corresponding alcohol. A reactive ester is above all an ester derived from a strong organic or inorganic acid, such as in particular one of the acids mentioned above, or sulfuric acid.

β- Hydroxyalkylamines can also be obtained, for example, by reaction with an optionally appropriately substituted ethylene oxide.

The radical X can also be a radical which can be converted into a 2-A-3-R-propyl group by reduction.

Such a radical is, for example, a radical corresponding to the 2-A-3-R-propyl group and having at least one optionally reactive modified oxo group .

The reduction of one or more optionally reactive modified oxo groups to corresponding compounds each having two hydrogen atoms instead of the oxo groups can be carried out in the customary manner. For example, free oxo groups with metallic reducing agents,

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such as zinc and mineral acid, e.g. hydrochloric acid, or with amalgamated zinc and hydrochloric acid, preferably concentrated hydrochloric acid, according to the method of Clemmensen, to each two water st of fat omen are reduced.

Suitable reactive oxo groups are, for example, hydrazo groups and semicarbazono groups or two geminal alkyl mercapto groups, such as two geminal methyl or ethyl mereapto groups, or also ethylene-1,2-dimercapto groups.

Hydrazono or semicarbazono groups can usually V / eise, for example with alkali metal alcoholates, such as sodium ethylate, preferably under pressure and at elevated temperature, according to the Wolff-Kishner method, or by heating one a hydrazo group-containing compound with an alkali hydroxide, like sodium or potassium hydroxide in a high boiling point Solvents such as di- or triethylene glycol can be reduced by the method of Huang-Minlon or Soffer. Here you can instead of the hydrazo compounds, the free oxo compounds

These can then be used directly, which then form hydrazones as an intermediate with hydrazine and alkali hydroxide.

The mercapto groups mentioned can be used in a customary manner, for example with Raney nickel and hydrogen peroxide Thioacetal method, or with amalgamated zinc in hydrochloric acid,

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preferably concentrated hydrochloric acid, each with two hydrogen atoms be reduced.

If oxo groups are adjacent to the nitrogen atom, a methyl group substituted by an oxo group still can be further substituted by an alkoxy, such as methoxy or ethoxy group, so X is, for example, a corresponding one 2-hydroxy-2-carbamylethyl group or a corresponding 5-acylamino-2-hydroxylpropyl group, such as, for example, a urethane grouping, or a cyclic urethane grouping in for example the X is a corresponding 3-amino-2-hydroxypropyl group in which the hydroxy and amino groups are replaced by a carbonyl group Are linked to one another to form an oxazolidinone ring, the reduction can be carried out in a conventional manner, for example with a Amide reducing agents take place, for example a simple one or complex hydride, such as a borane, e.g. diborane, or a complex light metal hydride, especially an alkali metal aluminum hydride, such as lithium or sodium aluminum hydride, or an alkoxy aluminum hydride or borohydride, e.g., sodium dibutoxy aluminum hydride or sodium trimethoxyborohydride, or an alkaline earth metal aluminum hydride such as magnesium aluminum hydride or sodium borohydride in a tertiary amine such as ryridine or triethylamine, or aluminum hydride-aluminum chloride. The reduction can also be carried out electrolytically, for example

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Cathodes with high overvoltage, such as mercury ₃ lead algae or Esikathoden take place. The catholyte used is, for example, a mixture of water, sulfuric acid and a lower alkanecarboxylic acid, such as acetic or propionic acid. The anodes can for example consist of platinum, carbon or lead, and sulfuric acid is preferably used as the anolyte.

If the oxo group is in the 2-position of the propyl radical, rr.an reduces the oxo group to a hydroxyl group.

The reduction can be carried out in the usual way, e.g. with nascent hydrogen, or with a complex one Metal hydride, for example an alkali borohydride such as lithium or sodium borohydride, in particular according to the method of Chaikin and Brown, preferably in tetrahydrofuran or ether, • e.g. Diethyl ether, or with an amalgam such as aluminum amalgam, preferably in an inert, neutral solvent such as ether, e.g. diethyl ether.

The reduction can also be done according to the method of Meerwein-Ponndorf-Verley take place. So you can, for example, the oxo compound with a lower alkanol, such as isopropanol, in Treat the presence of an appropriate alcoholate, such as aluminum iso-, propylate.

If A does not stand for a free hydroxyl group, a can be converted into a 2-A-5-R-propyl group by reduction.

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Removable radical also corresponds to one of the group mentioned Be a radical in which the nitrogen is connected to one of its substituents with a double bond and optionally carries a positive charge or wherein one of the carbon atoms bonded to the nitrogen atom is a hydroxyl group carries, like a corresponding 3-imino or 3-immonium-2-A-propyl radical, or a corresponding 3-amino or 5-ammonium-2-A-propyl radical, in which the amino group is doubly bonded to one of the amino substituents.

The conversion takes place in the usual way by reduction, e.g. of the azomethine bond. The reduction takes place in the usual way, preferably by means of a simple or complex hydride, e.g. a borane, or a light metal hydride, e.g., an alkali metal-earth metal hydride such as sodium borohydride or lithium aluminum hydride, or one Alkoxyaluminum or alkoxyborohydride, or with formic acid.

But it is also possible, with hydrogen in the presence of a catalyst, such as a platinum, palladium or nickel catalyst, or a homogeneous catalyst, e.g. a complex rhodium compound, such as a rhodium-chloro-triphenylphosphine complex, to reduce.

Another radical which can be converted into an N-monosubstituted 2-A -) - R-propyl group by reduction is e.g. also

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an N-monosubstituted 2-A-3-amino-propyl radical on the nitrogen atom additionally carries a radical Y which can be split off by reduction. The conversion is carried out by reduction, which is usual in Manner is carried out.

Y is, for example, a cc-aralkyl radical, such as a benzyl radical, or an α-aralkoxycarbonyl radical / such as a carbobenzoxy radical, which is split off, for example, by hydrogenolysis, for example by reduction with catalytically excited hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, such as a palladium or platinum catalyst can be. However, Y can also be a 2-haloalkoxy carbonyl radical, such as, for example, the 2,2,2-trichloroethoxycarbonyl radical or the 2-iodoethoxycarbonyl radical, which can be split off by reduction. Metal reduction (so-called nascent hydrogen) is particularly suitable for the reduction, such as the action of metal or metal alloys, as well as amalgams, preferably in the presence of hydrogen-releasing agents such as carboxylic acids, alcohols or water. Most of all, zinc or zinc alloys are used in acetic acid. Furthermore, chromium-II compounds, such as chromium-II chloride or chromium-II acetate, in Betracht.Y may also be a Aryisulfonylgruppe such as toluenesulfonyl, be that in a conventional manner by reduction with '"-

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nascent hydrogen, e.g. from an alkali metal, v; ie lithium or sodium, split off in liquid ammonia can be. The cleavage of an arylsulfonyl group can also with a hydride, e.g. one of the above-mentioned simple or complex hydrides, preferably lithium aluminum hydride, expediently in the presence of an inert solvent such as an ether, e.g. tetrahydrofuran.

One by reduction into a 2-hydroxy - ^ - R-propyl radical convertible radical X is also a 1,2-epoxy-3-R-propyl radical. Residues of this type can in particular by catalytically excited hydrogen, e.g. converted into 2-hydroxy-5-R-propyl radicals by hydrogen in the presence of the above-mentioned catalysts will.

A radical X which can be converted into a 2-A-3-R-propyl radical is, for example, also a 2-Ya-2-R-propyl radical, in which Ya converts one into one means free, etherified or acylated hydroxyl group convertible radical. Such 2-Ya-3-R-propyl radicals can through the conversion of Ya into A converted into 2-A-3-R-propyl radicals will.

Ya is, for example, a hydrolyzable or alcoholysable radical, such as a reactive esterified one Hydroxyl group, e.g. one of those mentioned above for Z, which can be used in the usual manner, preferably in the presence of basic or

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acidic catalysts, e.g. alkali hydroxide, such as caustic soda, or sulfuric or hydrochloric acid is hydrolyzed or alcoholized. The alcoholysis is carried out with a corresponding Alcohol, preferably with a lower alkanol such as ethanol, and carried out at an elevated temperature.

If Ya stands for a halogen atom, such as chlorine, bromine or Iodine atom, the exchange for a free hydroxyl group can also take place with moist silver oxide.

Ya can also be an unsubstituted amino group. Such a group Ya can with nitrous acid, preferably in a suitable solvent, such as, for example, water, and optionally at an elevated temperature into a hydroxyl group be convicted.

X can also stand for a 5-R-propenyl radical. A Such a residue is converted into a 2-A-J-R-propyl residue by the addition of HA, in particular water.

The addition can be carried out in the usual way, e.g. in the presence of acidic catalysts, above all Lewis acids, e.g. zinc chloride, aluminum chloride or alumina. The addition can also be carried out according to Brown, e.g. by hydroboration, i.e. reaction with a borane, e.g. diborane or a dialkylborane, expediently in an ether, e.g. Tetrahydrofuran or diethylene glycol dimethyl ether, and in the presence of an acid, e.g. boron trifluoride or aluminum chloride,

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and subsequent oxidation, preferably with hydrogen peroxide in the presence of alkali hydroxide, e.g. sodium hydroxide. The borane can also be formed in situ, e.g. from sodium borohydride and acid, for example one of the above-mentioned acids. The addition can also be carried out by oxymercuration, e.g. by reaction with mercury (II) salts, such as mercury chloride or acetate, in a suitable solvent, e.g. a tetrahydrofuran-water mixture, and subsequent reduction, e.g. with sodium • borohydride in alkaline solution.

The radical which can be converted into an N-monosubstituted 2-A - ^ - R-propyl group can also be a radical which can be converted into this radical by hydrolysis, such as an N-monosubstituted 2-A-5-aminopropyl radical which has an additional through ^{Y 1} radical which can be split off by hydrolysis carries, where the Y ¹ radical can additionally also be linked to a hydroxyl group A. The conversion takes place by hydrolytic cleavage of Y '. The radical Y 'is, for example, a silyl radical, such as trimethylsilyl radical, or above all an acyl radical, e.g. an alkanoyl radical, especially an optionally halogenated, e.g. fluorinated lower alkanoyl radical, such as the acetyl radical or trifluoroacetyl radical, a benzoyl radical, phenylalkanoyl radical, carbalkoxy radical, e.g. the tert. Butyloxycarbonyl, Carbäthoxy- or Carborr.ethoxyrest, or an aralkoxycarbonylrest, for example a

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Carbobenzoxy radical. If the radical Y ^{1 is} also linked to a hydroxy group A, then X is a (3-substituted-5-oxazolidinyl) methyl radical which can also be further substituted in the 2-position, for example by hydrocarbon radicals of aliphatic character, e.g. the above-mentioned, in particular lower alkyl radicals or phenyl-lower alkyl radicals, for example methyl, ethyl, propyl, benzyl, phenethyl or oc-methylphenethyl radicals. The radical Y ¹ can, however, also be a double bonded radical, for example an alkylidene or benzylidene group or a phosphorylidene, such as triphenylphosphorylidene group, in which case the nitrogen atom carries a positive charge.

The hydrolytic cleavage of Y ¹ takes place, for example, with hydrolyzing agents, for example in the presence of acidic agents, such as dilute mineral acids, such as sulfuric acid or hydrohalic acids, especially hydrochloric acid, or, in the case of aeyl residues, preferably in the presence of basic agents, e.g. alkali hydroxides such as sodium hydroxide.

If Y ^{1 is} a trifluoraeetyl group, the hydro-

lysis is also linked to the introduction of a further substituent and so a tertiary amine can be obtained if a more reactive one Ester of a corresponding alcohol, e.g. an ester with the acids mentioned above, such as hydrogen iodine off acid or methanesulfonic acid, together with a base,

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e.g. potassium hydroxide, is contained in the reaction mixture.

The new compounds can also be obtained by converting into a 2-A-5-R-propyl-anthracene, in which R and A are the have given meanings, a 9 * 10-Aethano-rest introduces.

The introduction of the 9,10-ethano residue takes place in the usual way Manner, this is expediently done using optionally lower alkylated ethylene according to the method of Diesl-Alder, advantageously in a suitable solvent, such as an aromatic hydrocarbon, e.g. toluene, and at elevated temperature and / or under pressure.

In the compounds obtained, substituents can be introduced or modified within the scope of the definition of the end products or split off.

For example, obtained secondary amines can be converted into tertiary amines, i.e. into obtained N-monosubstituted amines 2-A-3-aminopropyl or N * -unsubstituted piperazino groups Introduce substituents, e.g. those mentioned above. The introduction takes place in particular as above for free 2-A-3-aminopropyl groups specified.

In compounds obtained which contain free hydroxyl groups, these can be etherified. The etherification takes place in the usual way, e.g. by reaction with a reactive ester of an alkanol, preferably in the presence a strong base.

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In the compounds obtained which have etherified hydroxyl groups, these can be converted into free hydroxyl groups in the customary manner. This conversion takes place, for example, by hydrolysis , especially by means of strong acids such as hydroiodic acid or hydrobromic acid and optionally in the presence of light metal halides such as aluminum bromide or boron bromide, or with pyridine hydrochloride or aluminum chloride in pyridine.

Compounds obtained which contain a free hydroxyl group A can be acylated. The acylation takes place in the customary manner, in particular with reactive, functional derivatives of the acids in question, preferably Acid halides or anhydrides, if necessary in the presence of acid-binding agents, e.g. basic agents such as the mentioned, or optionally in the presence of acids, e.g. those mentioned above. Conversely, one can also use obtained compounds, which carry the acyloxy groups A, split off the acyl radicals. The spin-off takes place in the usual way, e.g. as given above for Y '.

In compounds obtained which contain mercapto groups, the mercapto groups can be converted into alkylsulfonyl groups oxidize. The oxidation takes place in the usual way, e.g.

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with per compounds, such as hydrogen peroxide or peracids, in particular organic peracids such as peracetic acid or a perbenzoic acid.

The invention also relates to those embodiments of the process in which one starts from a compound obtainable as an intermediate product at some stage and carries out the missing steps, or terminates the process at any stage or one of the starting materials Forms reaction conditions or optionally used in the form of a salt and / or racemate or optical antipodes. For example, one can also use a 9- (2-A-5-0xo-propyl) -9,10-dihydro-9,10-ethano-anthracene go out and treat this under reducing conditions with an amine of the formula H-R, or from an N-unsubstituted 9- (2-A-5-amino-propyl) -9,10-dihydro-9,10-ethano-anthracene go out and this under reducing conditions, e.g. in the presence of formic acid, treat with an appropriate aldehyde or ketone. The above-mentioned azomethine compounds are formed as intermediate products. A should expediently not be present as a free hydroxyl group.

The reactions mentioned are carried out in the usual V / ciso

in the presence or absence of dilution, condensation, and / or catalytic agents, at reduced, ordinary or elevated temperature, optionally in the closed Cefass carried out. .

209837/1245

. Depending on the process conditions and starting materials, the end products are obtained in free form or in the form of their acid addition salts also included in the invention. The acid addition salts of the new compounds can in a well-known manner in the free connection be transferred, e.g. with basic agents such as alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. For the production of acid addition tools, in particular those acids are used which are suitable for the formation of therapeutically useful salts. Sissn as such velvets. named for example: hydrohalic acids, sulfuric acids, Phosphoric acids, nitric acid, perchloric acid, _ali, -phatic, alicyelic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, Amber, glycol, milk, apple, viein, lemon, Ascorbic, maleic, hydroxymaleic or pyruvic acid; Phenyl acetic, benzoin, p-aminobenzoic, anthranil, ρ-hydroxybenzoic, Salicylic or p-arr.inosalicylic acid, monoboxylic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethyJlenesulphonic acid; Ilalogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; Methionine, tryptophan, lysine or arginine. . ·,. · ... ·

Serve or other salts of the new compounds, such as 209837/1245

. - 28 -

e.g. the Fikrate, can also be used to clean the obtained free easep. serve by converting the free bases into salts transferred, this separates and from the salts in turn the ■ Free bases. As a result of the close relationships between the new compounds in free form and in the form of their salts are meaningful and expedient in the preceding and following under the free connections, if necessary also to understand the corresponding salts.

Know the new connections, depending on the V / a hl the starting materials and working methods and depending on the number of asymmetric carbon atoms as optical Antipodes, racemates or as mixtures of isomers (e.g. mixtures of racemes) are present.

Obtained iGorr.crengernische (Racematgcrcische) can due to the physico-chemical differences between the components in a known manner in the two s -ereoisomers (diastereo.T.eren) pure isomers (e.g. racemates) are separated, for example by chromatography and / or fractional crystallization.

Racemates obtained can be determined by known methods decompose, for example by! ^ crystallization an optically active solvent, with the help of microorganisms, or by reacting with one with the racemischcn

209837/1245

Compound optically active acid forming salts and separation of the salts obtained in this way, e.g. on the basis of their different solubilities, into the diastereomers, followed by the release of the antipodes by the action of suitable ones Middle. Optically active acids that are particularly common are e.g. the D- and L-forms of tartaric acid, di-o-toluyltartaric acid., Malic acid, mandelic acid, carnphersulfonic acid or quinic acid. It is advantageous to isolate the more effective one both antipodes. -

Zv.'eekmässig verv; one ends for the implementation of the According to the invention, reactions are those starting materials that correspond to those mentioned at the outset, for example, or particularly emphasized Lead end materials.

If they are new, the starting materials can be obtained by methods known per se. New starting materials also form an object of the invention.

The new compounds can be used, for example, in the form of pharmaceutical preparations, which they can be used in free In the form or optionally in the form of their salts, especially the therapeutically useful salts, in admixture with a e.g. for enteral or parenteral application suitable pharrnazeuti going organic or inorganic, solid or contain liquid carrier material. For the formation of the same, such substances come into question that with the. new

209837/1245

Compounds do not react, v / ie e.g. water, gelatine, Lactose, starch, stearyl alcohol, magnesium stearate, talc,: vegetable oils, benzyl alcohol, gum ,. Propylene glycols, Petroleum jelly or other known excipients. The pharmaceutical preparations can e.g. 'as tablets, Dragees, capsules, suppositories or in liquid form as , Solutions (e.g. as an elixir or syrup), suspensions or emulsions are available ... they may be sterilized and / or contain auxiliaries, such as preservatives, stabilizers, Wetting or emulsifying agents, solubilizers or salts for increasing the osmotic pressure or buffers. she can also contain other therapeutically valuable substances. The pharmaceutical preparations are reproduced Methods won.

The new compounds can also be used in veterinary medicine, e.g. in one of the forms mentioned above or in the form of Feed or additives used in animal feed will. For example, the usual extenders and thinners or animal feed are used.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified.

209837/1245

example 1

5.9 g of 9 - [(5-methyl-5-oxa2olidinyl) -methyij-9 _i 10-dihydro-9,10-ethano-anthracene are heated to 90 for 5 hours with βθ ml of 2N hydrochloric acid. Then 5N sodium hydroxide solution is added until the reaction is alkaline and the mixture is extracted with methylene chloride. After the solvent has been separated off and evaporated, 9- (2-hydroxy-5-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene of the formula remains

OH

return. This is dissolved in 10 ml of ethanol, 1 ml of a solution of hydrogen chloride in ethanol is added and ether is added. The crystalline hydrochloride of 9_ (2-hydroxy-5-methylamino-propyl) -9 _i 10-dihydro-9,10-ethanoanthracene from P. 211-215 is obtained in this way.

The 9- [ (5-methyl-5-oxazolidinyl) -methyl] -9> 10-dihydro-9 , 10-ethano-anthracene required as starting material can be prepared in the following way:

In a solution of 46 g of 9- (chlorocarbonylmethyl) -9,10-dihydro-9i10-ethano-anthracene 10 g of 10 g palladium-carbon, which is mixed with quinoline-sulfur, are added to 200 ml of xylene.

209837/1245

- 52 -

is poisonous, and then passes hydrogen through at 120. After 7 hours, the catalyst is filtered off and evaporated in vacuo a. The residue is dissolved in methylene chloride and extracted with soda solution. After separating the organic Phase this is dried over sodium sulfate and then by adding methylene chloride to a volume of 250 ml diluted. After 1 ml of triethylamine has been added, 20 ml of hydrogen cyanide are added and the mixture is left for 12 hours Stand room temperature. It is then shaken out with water and the solvent is evaporated. The residue obtained is that crystalline 9- (2-hydroxy-2-cyano-ethyl) -9,10-dihydro-9,10-ethano-anthracene, which, after recrystallization from methylene chloride petroleum ether, has a temperature of 159-141 °.

This nitrile (18 g) is dissolved in 150 ml of tetrahydrofuran and added dropwise to 6 g of lithium aluminum hydride in 100 ml of tetrahydrofuran. After stirring at 60 for 8 hours, the mixture is cooled and 8 ml of water, 8 ml of 15% sodium hydroxide solution and 24 ml of water are successively added. The precipitate which has separated out is filtered off and the filtrate is evaporated in vacuo. What remains is the 9- (2-hydroxy-5-aminopropyl) .- 9,10-dihydro-9,10-ethano-anthracene from F.I76-177 ⁰ .

20 g of this amino alcohol are dissolved in 150 ml of formic acid warmed to 95 with 10 ml of formalin for 1 hour and then evaporated in vacuo. The residue is put through Addition of 2 N sodium hydroxide solution alkaline, extracted with methylene

209837/1245

- 53 -

Chloride and evaporates the organic phase. The 9 - [(3-methyl-5-oxazolidinyl) -methyl J-9, 10-dihydro-9,10-ethano-

anthracene from F. 106-109

209837/1245

- 54 - Example 2

A solution of 12 g of N- (p-toluenesulfonyl) -9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene 100 ml of tetrahydrofuran are slowly added dropwise to 5 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. After the reaction mixture Has boiled under reflux for 4 hours, the mixture is cooled to room temperature and carefully added) ml of water and Add 10 ml of 15 # sodium hydroxide solution. The precipitate formed is filtered and the filtrate is evaporated. The residue obtained is 9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene, which is identical to the product obtained in Example 1 and whose cyclohexylsulfaminate has the F. 143-145 °.

The toluenesulfonamide used as the starting material can be prepared as follows:

To a solution of 25 g of 9- (2-hydroxy-3-aminopropyl) -9,10-dihydro-9,10-ethano-anthracene 25 g of p-toluenesulfonyl chloride are added to 200 ml of pyridine. After 12 hours, water is added and after adding 50 ml of 5N hydrochloric acid with methylene chloride extracted. The crystalline residue remaining after drying and evaporation of the solvent is dissolved in 150 ml of dimethylformamide dissolved and mixed with a solution of diazomethane in ether. After standing at room temperature for 12 hours the solution is evaporated in vacuo. You get

20983 7/1245

as residue the crude N- (p-toluenesulfonyl) -9,10-dihydro-9,10-ethano-anthracene, which can be used for the reaction described above without further purification. "

209837/1245

- 36 - Example 3

5 g of 9- (2-p-? Osyloxy-3-din-: ethylamino-propyl) -9,10-dihydro-5, 10-ethano-anthracene v / earth with 2 g of sodium hydroxide in 50 ml of ethanol and 5 ml of water refluxed for 2 hours. Then 100 ml of water and 50 ml of 2N acetic acid are added and the mixture is extracted with ether. The aqueous Fh = 3i is separated off and made alkaline by adding 10 percent sodium hydroxide solution. After extraction with methylene chloride and evaporation of the solvent, the $ - (2- hydroxy-3-dimethylamino-propyl) -9, 10-dihydro-9 * 10-ethane anthracene of the formula remains

back as a crystalline mass, which after sublimation at 115-121 ° melts. The methanesulfonate melts at 1S5-I86.

209837/1245

-.57 -
example H

A mixture of 10 g of 9- (2-hydroxy-3-2rainoprDpyl) -9,10-dihydro-9,10-ethano-anthracene, 10 ml of a 35 percent solution of formaldehyde in water and 100 ml of formic acid is used during heated to 100 for one hour. It is then evaporated to dryness in vacuo, the residue is dissolved in 100 ml of 2N acetic acid and washed with ether. The acidic extract is mixed with 10 percent sodium hydroxide solution until it has an alkaline reaction and then shaken out with methylene chloride. After drying and evaporation of the solvent, 9 ~ (2-hydroxy-3-dimethylaminopropyl) -9,10-dihydro-9 _J 10-ethanoanthracene remains, which melts at 118-121 ° after sublimation and with the product obtained in Example 3 is identical. The methanesulfonate melts at 185-186.

209837/1245

Example 5

To a solution of 1.0 g of lithium aluminum hydride a solution of 2.1 g of 5- (9,10-dihydro-9, lO-ethano-9-anthryl-methyl] -oxazolidinone- (2) in 20 ml of tetrahydrofuran and refluxed for 4 hours. It is then cooled and then gives add 2 ml v / ater, 2 ml 15 percent sodium hydroxide solution and another 6 ml water. The deposited precipitate is filtered off the residue is evaporated, and the residue is dissolved in 2N Acetic acid. The acidic solution is washed with ether. After adding 10 percent caustic soda to the sour extract until an alkaline reaction is extracted with methylene chloride. It remains after evaporation of the solvent 9- (2-hydroxy-5-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene back, its hydrochloride at 257-259 melts and that with the product obtained in Example 1 is identical.

The oxazolidinone used as the starting material

can be made as follows:

To a solution of 2.8 g of 9- (2-hydroxy-3-aminopropyl) -9,10-dihydro-9,10-ethano-anthracene in 50 ml of benzene, 20 ml of dioxane and 5 ml of 2N sodium hydroxide solution are stirred with stirring

209837/1245

- 59 -.

20 ml of a 10 percent solution of phosgene in toluene were added dropwise at room temperature. After 5 hours, the precipitated portion is filtered off and the filtrate is evaporated. Zen residue dissolves ir.an in methylene chloride and extracted with a 3 ^percent iSn aqueous solution of methanesulfuric acid. After drying and evaporation of the solvent, the crude 5- [9,10-dihydro-9,10-ethano-9-anthryl-methyl] -oxazolidinone- (2) remains as a solid mass.

209837/1245

- 40 Example 6

18 g 9- (2,3-epoxy-propyl) -9 / 10-dihydro-9,10-

ethano-anthracene v / earth with 20 g methylamine in 150 ml etha

nol heated to 90 for 4 hours and then evaporated in vacuo. The residue is dissolved in ether and extracted with 2N acetic acid. The acidic extract is then made alkaline by adding 10 percent sodium hydroxide solution and extracted with ether. After drying and evaporation of the ether, 9- (2-hydroxy-3-methylaminopropyl) -9 »10-dihydro-9,10-ethano-anthracene remains, the hydrochloride of which melts at 237-239 ⁰ and that with the im Example 1 obtained product is identical.

The epoxy used as the starting material can be made as follows:

In a solution of Ί6 g of 9- ^ chlorocarbonylmethyl) -9,10-dihydro-9,10-ethano-anthracene in 200 ml of xylene is added 10 g of 10 percent palladium carbon, which is poisoned with quinoline-sulfur, and then leads at 120 ° hydrogen . After 7 hours, the catalyst is filtered off and evaporated in vacuo. The residue is dissolved in methylene chloride and extracted with soda solution. After the organic phase has been separated off, it is dried and evaporated. The crude 9,10-dihydro-9,10-ethano-9-anthryl-

209837/1245

acetaldehyde back.

To convert the aldehyde into the epoxy 19.6 g Trirr.ethyloxosulfoniumjodid to 2.2 g sodium hydride in 175 ml of dimethyl sulfoxide given. After the development of hydrogen has ended a solution of 21 g of the crude 9,10-dihydro-9,10-ethano-9-anthryl-acetaldehyde is added dropwise in 35 ml of dirnethyl sulfoxide and stirred for 20 minutes at room temperature and then for 30 minutes at 55-60. The reaction mixture is now poured into 300 ml v / ater and with Extracted methylene chloride. The methylene chloride solution is separated off and evaporated. The crude 9- (2,3 ~ epoxypropyl) -9 * 10-dihydro-9jlO-ethano-anthracene remains as tough oil back.

209837/1245

Example 7

To a solution of 5.6 g of 9- (2-hydroxy-3-arnincpropyl) -9 »10-dihydro-9,10-ethano-anthracene in 50 ml of Aethar.ol are added 7> 0 g of methyl iodide and heated for two Hours to 60. It is then evaporated in vacuo and the residue is dissolved in ether. The ether solution is extracted with 2N acetic acid. The acidic extract is made alkaline by adding 10 percent sodium hydroxide solution. After shaking with methylene chloride and evaporation of the solvent, an oil remains which is dissolved in 5 ml of ethanol. To this solution add rr.sr 1 * 5 6 methanesulfonic acid. Crystallization begins with the addition of ether. After repeated recrystallization from ethanol-ether, the methanesulfonate of 9- (2- hydroxy-3-dimethylamino-propyl) -9,10-dihydro-9jlO-ethanoanthracene with a melting point of 185-186 ⁰ , which is obtained with that obtained in Example 3, is obtained Product is identical.

209837/1245

Example 8

A solution of 11 g of 9- (2-hydroxy-3-dimethylaminopropyl) anthracene in 200 ml of benzene is in the autoclave with ethylene under a pressure of 70 atm for 6 hours 70 heated. It is then extracted with 200 ml of 2N hydrochloric acid. The acidic extract is made alkaline and with Shaken out methylene chloride. After evaporation of the solvent, an oil remains, which slowly crystallizes, Crystals of melting point 120-121 are obtained by sublimation. If you dissolve this in alcohol, you have an equivalent Methanesulfonic acid to, and then adds ether until crystallization to. The methanesulfonate of 9- (2-hydroxy-3-dimethylaminopropyl) -9, 10-dihydro-9,10-ethano-an- thracens the formula

OH

-CH-GH ₂ -N (CH ") CH SO H

in crystals of m.p. 185-186 °.

209837/1245

example

In an analogous manner to that described in Examples 1-8 or by another of the processes described above, the following compounds, for example, can also be prepared: ·. 9- (2-Hydroxy-3-cyclopropylamino-propyl) -9, 10-dihydro-9,10-ethano-anthracene, 9- [2-Hydroxy-5- (N ^t -ir.ethylpiperazino) -propy3J-9, 10-dihydro-9,10-ethano-anthracene, 9- [2-hydroxy -> - (ß -hydroxyäthylamino) -propylJ -9, 10-dihydro-9,10-ethano-anthracene,

9-f2-Hydroxy-5- [N'- (ß- hydroxyethyl) -piperazino] -propyl ^ 9,10-dihydro-9,10-ethano-anthracene, 2 ~ chloro-9- (2-hydroxy-5- methylamino-propyl) -9 »10-dihydro-9,10-ethano-anthracene, 2-chloro-9- (2-hydroxy-5-dimethylamino-propyl) -9 * 10-dihydro-9,10-ethano-anthracene , 2-chloro-9- (2-hydroxy-3-cycloproρ.ylamino-propy1) -9,10-dihydro-9,10-ethano-anthracene, 2-chloro-9- [2-hydroxy-5- (N '-methylpiperazino) propyl] -9 _i 30-dihydro-9,10-ethano-anthracene,

209837 / 124S

2-chloro-9- [2-hydroxy-3- (j3-hydroxyethylamino) propyl] -9, 10-di-

hydro-9 _J 10-ethano-anthracene, η

2-chloro-9-i2-hydroxy-3- [N ¹ - (ß -hydroxyäthyl) piperazino] -propylj-9,10-dihydro-9, 10-anthracene-äthano.

209837/1246

Example 10

The following connections can be established in an analogous manner:

9- (2-Hydroxy-J-isopropylamino-propyl) -9, 10-dihydro-9,10-ethano-anthracene,

2-chloro-9 - ^ - hydroxy - ^ - isopropylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene,

9- (2-methoxy-5-methylamino-propyl) -9,10-dihydro-9,10-ethanoanthracene,

2-chloro-9- (2-methoxy-5-methylamino-propyl) -9,10-dihydro-9, 10-ethano-anthracene.

209837/1245

2207087

Example 11

Tablets containing 25 ragr 9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene can be produced, for example, in the following composition: Composition

9- (2-Hydroxy-5-methylamino-propyl) -

9,10-dihydro-9,10-ethano-anthracene 25.0 mg

Milk sugar 34.0 mg

Wheat starch 30.0 mg

Colloidal silica 5 * 0 mg

Talc 5.0 mg

Magnesium stearate 1.0 mg

100.0 mg

Manufacturing

The active ingredient is mixed with the milk sugar, the colloidal silica and part of the wheat starch and the mixture is forced through a sieve. Another part of the wheat starch is pasted with 5 times the amount of water on the water bath and the powder mixture is kneaded with this paste until a weakly plastic mass is formed.

The mass is driven through a sieve, dried and the dry granulate is sieved again: The remaining wheat starch, talc and magnesium stearate are then mixed in and the mixture is pressed into tablets weighing 100 mg.

209837/1245

Claims (1)

Claims 1. Process for the preparation of new 9- (2-A-3-R-propyl) -9,10-dihydro-9,10-ethano-anthracenes with the core of the formula (D wherein R is a secondary or tertiary amino group and A is a free, etherified or acylated hydroxyl group, characterized in that in a 9-X-9 * 10-dihydro-9,10-ethano-anthracene, in which X is a 2 -A-3-R-propyl group means convertible radical, X converts into a 2-A-3-R-propyl group, where R and A have the meanings given, or into a 9- (2-A-3-R-propyl ) -anthracene, in which R and A have the meanings given, introduces a 9, 10-ethano radical and, if desired, introduces, modifies or splits off substituents in compounds obtained in the end products, and / or mixtures of isomers obtained into the pure isomers and / or separating the racemates obtained into the optical antipodes and / or converting the free compounds obtained into their salts or the salts obtained into the free compounds. 2. The method according to claim 1, characterized in that ' 209837/1245 that the radical X a in 3-position by a reactive esterified hydroxyl group Z is substituted 2-A-propyl radical. 5. The method according to claim 2, characterized in that Z is one with a hydrohalic acid, arylsulfonic acid or lower alkanesulfonic acid is an esterified hydroxyl group. 4. The method according to any one of claims 2 and 5, characterized in that it is reacted with an amine of the formula HR. 5. The method according to claim 1, characterized in that the radical X is an N-unsubstituted 2-A-3-amino-propyl group and is converted into an N-monosubstituted 2-A-3-aminopropyl group by exchanging a hydrogen atom. 6. The method according to claim 5, characterized in that one with a reactive ester of a corresponding Converts alcohol. 7. The method according to claim 1, characterized in that the radical X is a 2-A-5-R-propyl group by reduction is convertible remainder. 8. The method according to claim 7 *, characterized in that that X is a radical corresponding to the 2-A-3-R-propyl group, 209837/1245 which has at least one optionally reactive modified oxo group. 9. The method according to claim 8, characterized in that that the reduction is carried out with zinc and hydrochloric acid, with hydrazine and alkali or with Raney nickel. 10. The method according to claim J, characterized in that compounds in which an oxo group is adjacent to the nitrogen atom in the radical X, wherein a methyl group substituted by an oxo group can be further substituted by an alkoxy group, reduced with an amide reducing agent. 11. The method according to claim 10, characterized in that one reduces with a simple or complex hydride. 12. The method according to claim 8, characterized in that in compounds in which X is a 2-oxo-3-R-propyl radical means reducing the oxo group to a hydroxyl group. 13. The method according to claim 7, characterized in that that X is a radical corresponding to the 2-A-3-R-propyl group, in which the nitrogen is connected to one of its substituents with a double bond and optionally a po- 209837/1245 carries a positive charge or in which one of the carbon atoms bonded to the nitrogen atom carries a hydroxyl group. 14. The method according to claim J, characterized in that X is an N-monosubstituted 2-A-3-amino-propyl radical which additionally carries a radical Y which can be split off by reduction on the nitrogen atom. 15. The method according to claim 14, characterized in that Y is an α-aralkoxycarbonyl radical, a 2,2,2-trichloroethoxycarbonyl radical or is a 2-iodoethoxycarbonyl radical. l6. Process according to Claim Ik, characterized in that Y is an arylsulfonyl group. 17 · The method according to claim l6, characterized in that that one reduces with a simple or complex hydride or with an alkali metal in liquid ammonia. l8 '. Process according to Claim YJ, characterized in that reduction is carried out with lithium aluminum hydride. 19. The method according to claim "J _3, characterized in that X is a 1,2-epoxy-5-R-propyl radical. 209837/1245 20. The method according to claim 1, characterized in that X is a 2-Ya-3-R-propyl radical, wherein Ya one into one free, etherified or acylated hydroxyl group convertible Rest means. 21. The method according to claim 20, characterized in that dajs Ya is a hydrolyzable or alcoholysable residue or is an unsubstituted amino group. 22. The method according to claim 1, characterized in that X is a 3-R-propenyl radical which is formed by the addition of HA is converted into a 2-A-5-R-propyl radical. Process according to claim 1, characterized in that X is a convertible by hydrolysis into a 2-A-2-R-propyl group * Rest is. 24. The method according to claim 25, characterized in that X is an N-monosubstituted 2-A-3-amino-propyl radical which additionally has a radical Y ^{! Which can be split off by hydrolysis on the nitrogen atom.} wearing. 25. The method according to claim 24, characterized in that the radical Y 'additionally also with a hydroxyl group A. is linked. 209837/1245 26. The method according to claim 25, characterized in that that X represents a (3-substituted-5-oxazolidinyl) methyl radical. 27. The method according to claim 25, characterized in that Y ^{f is} an acyl radical or a double bonded radical. 28. The method according to any one of claims 23-27, characterized characterized in that hydrolyzed in the presence of acidic agents. 29. The method according to any one of claims 23, 2.h and 27, characterized in that Y ^! is a trifluoroacetyl radical and the cleavage is linked to the introduction of a further substituent. 30. .The method according to claim 1, characterized in that that the 9,10-ethano radical is introduced by reaction with optionally lower-alkylated ethylene. 31. The method according to any one of claims 1-30 * characterized in that obtained secondary amines are converted into tertiary amines. 32. The method according to any one of claims 1-30, characterized in that one obtained compounds with free 209837/1245 Hydroxy group A acylated or etherified. 33 · The method according to any one of claims 1-30, characterized in that one obtained compounds with 'acylated Hydroxy group A hydrolyzed. 34. The method according to any one of claims 1 to 33, characterized characterized in that one starts from a compound obtainable as an intermediate product at any stage of the process and carries out the missing process steps, or terminates a process at any stage, or a starting material under the reaction conditions or forms a reaction component, optionally in the form of its isomers, racemates or optical antipodes and / or in the form of their salts. 35. The method according to claim 3 ^, characterized in that that one of a 9- (2-A-3-oxo-propyl) -9,10-dihydro-9,10-ethano-anthracene goes out and this treated under reducing conditions with an amine of the formula H-R, or of an N-unsubstituted 9- (2-A-r3-amino-propyl) -9,10-dihydro-9,10-ethano-anthracene goes out and this reacts under reducing conditions with a corresponding aldehyde or ketone . 56. The method according to any one of claims 1-35 »thereby 209837/1245 characterized in that one compounds of the formula ο R ₀ A ο CH —G — OH — R (Ia) produces, wherein R is an amino group which is replaced by alkyl radicals, Hydroxy- or Aminoalkylreäse, alkenyl-, unsubstituted or mono-, di- or polysubstituted lower alkyl-substituted lower cycloalkyl and / or cycloalkenyl radicals, unsubstituted or one, two or more lower alkyl substituted lower cycloalkyl and / or alkenyl alkyl radicals, or denotes a 1-azacycloalkyl or 1-azacycloalkenyl radical, which contains 4-8 ring members and is substituted by phenyl, hydroxy, oxo and / or amino groups can be, or a 1-aza-oxa, 1-aza-thia or 1-azaazacycloalkyl radical means in which the heteroatoms are separated by at least two carbon atoms and the by Phenyl, hydroxy, oxo and / or amino groups can be substituted, η and m mean integers such that η + m is not greater than 3, the radicals R. independently of one another lower alkyl, alkoxy, alkenyloxy and / or alkyl meroapto 209837/1245 groups, lower alkylsulfonyl and / or alkanoyl groups, trifluoromethyl groups or halogen atoms, R, ~ a lower alkyl or alkenyl radical, a halogen atom or a hydrogen atom, the symbols R, R 'and R "stand for lower alkyl radicals or for hydrogen atoms, where preferably at most one of the three symbols is different from hydrogen, Ae is a 1,2-ethylene radical optionally substituted or unsubstituted in the 1- or / and 2-position by a lower alkyl radical and A is a free hydroxyl group, a lower alkoxy group or a lower alkanoyloxy group. 57. The method according to any one of claims 1-55 * thereby characterized in that one compounds of the formula OH CH ₂ -CH-CH ₂ -Am (II) produces, wherein R _{1 is} a lower alkyl or alkoxy group, a trifluoromethyl group, a bromine or chlorine atom or a water 209837/1245 means hydrogen atom and · Am one through one Cycloalkyl radical monosubstituted or by C _{1 fi} -alkyl groups mono- or disubstituted amino group or an optionally C-lower alkylated pyrrolidino, piperidino, morpholino, N'-methyl-piperazino-, N ¹ -ethyl-piperazino or N ¹ - (ß- Hydroxyethyl) piperazino group. 58. The method according to any one of claims 1-55, characterized characterized in that one compounds of the formula OH
I. CH ₂ -CH-CH ₂ -Am ₂ (III) where R _{2 is} a methoxy group, a trifluoromethyl group, a chlorine or hydrogen atom and Am _{9 is} the diethylamino or monoethylamino group, the dimethylamino group or the monomethylamino group. 39. The method according to any one of claims 1-35, characterized in that 9- (2-hydroxy-3-dimethylaminopropyl) - 209837/1245 9,10-dihydro-9,10-ethano-anthracene or 9- (2-hydroxy-3-methyl amino-propyl) -9,10-dihydro-9,10-ethano-anthracene of the formula OH CH ₂ -CH-CH ₂ -NH-CH manufactures. 40. The method according to any one of claims 1-39, characterized marked that one can make the new connections in the open Manufactures form. 41. The method according to any one of claims 1-39, characterized in that the new compounds in the form of their Manufactures salts. 42. Those produced by the method of claims 1-41 Links. · 43. 9- (2-A-3-R-propyl) -9,10-dihydro-9,10-ethano-anthracenes with the core of the formula 209837/1245 wherein R is a secondary or tertiary amino group and A is means free, etherified or acylated hydroxyl group. 44. Compounds of Formula DH R R A ι ο CH — C CH R ' ^R 10 where R is a secondary or tertiary amino group, η and m mean an integer such that η + m is not greater than 3, the radicals R are independently lower Alkyl, alkoxy, alkenyl oxy and / or alkyl rcercapto groups, lower alkylsulfonyl and / or alkanoyl groups, trifluoromethyl groups or halogen atoms, R, q a lower alkyl or alkenyl radical, a halogen atom, or means a hydrogen atom, the symbols R ^, R ^ and R ″ stand for lower alkyl radicals or for hydrogen atoms, where preferably at most one of the three symbols of hydrogen is different, Ae is one which is optionally substituted in the 1- or / and 2-position by a lower alkyl radical or unsubstituted 1,2-ethylene radical and A is a free, means etherified or acylated hydroxyl group. 209837/1245 - 6ο - 45 connections of the type described in claim 44, where R is an amino group which is replaced by alkyl radicals, hydroxy or aminoalkyl radicals, Alkenyl, unsubstituted or mono-, di- or polysubstituted lower alkyl-substituted lower ones Cycloalkyl and / or cycloalkenyl radicals, unsubstituted or mono-, di- or polysubstituted lower alkyl-substituted lower ones Cycloalkyl and / or alkenyl alkyl radicals, or a 1-azacycloalkyl or 1-Azacycloalkenylrest denotes the 4-8 ring members contains and can be substituted by phenyl, hydroxy, oxo and / or amino groups, or a 1-azaoxa, 1-azathia or 1-aza-azacycloalkyl radical in which the heteroatoms are separated by at least two carbon atoms and which can be substituted by phenyl, hydroxy, oxo and / or amino groups, and A for a free hydroxy, lower alkoxy or lower alkanoytoxy group. 46. Compounds of the type described in claim 44, wherein R is a mono- or di-lower alkylamino group, a hydroxy-lower alkylamino group, a at most C-lower alkylated 1-azacycloalkyl group with 5-7 ring members or cycloalkylamino • group with 3-7 ring members, or an optionally C-lower alkylated group Morpholino-thiomorpholino-, N-lower alkyl-piperazino- or N '- (hydroxy lower alkyl) piperazino group, R. for lower alkyl, alkoxy, alkanoyloxy, alkanoyl 209837/1245 - 6i - amino, hydroxy, trifluoromethyl groups or halogen atoms, R _{10 is} a chlorine atom or a hydrogen atom and A is a free hydroxy group or a C 1 -C alkoxy or C alkanoyloxy group. Compounds of the formula OH CH ₂ -CH-CH ₂ -Am (II) where R is a lower alkyl or alkoxy group, a trifluoromethyl group, a bromine or chlorine atom or a hydrogen atom and Am is a monosubstituted by a Cq -j-cycloalkyl radical or by C-. , Alkyl groups mono- or disubstituted amino group or an optionally C-lower alkylated pyrrolidino, piperidino, morpholino, N'-methylpiperazino, N ¹ -ethylpiperazino or N ¹ - (β-hydroxyethyl) -piperazino group. Compounds of the formula 209837/1245 OH CHpCH-CH-Am ₀ ι <- <- (III) where R _? represents a methoxy group, a trifluoromethyl group, a chlorine or a hydrogen atom and Am _p denotes the diethylamino or monoethylamino group, the dimethylamino group or the monomethylamino group. 49. 9- (2-Hydroxy-3-methylamino-propyl) -9, 10-dihydro-9,10-ethano-anthracene. 50. 9- (2-Hydroxy-3-dimethylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene, and 9- [2-hydroxy-3- (N'-methylpiperazino) propyl] -9, 10-dihydro-9,10-ethano-anthracene, and 9- | 2-hydroxy-3- [N '- (ß- hydroxyethyl) -piperazinoj-propylj -9, 10-dihydro-9,10-ethano-anthracene, and 9- (2-hydroxy-3-cyclopropylamino-propyl) -9, 10-dihydro-9,10-ethano-anthracene, and 9- [2-hydroxy-3- (ßhydroxyäthylamino) propyl] -9, 10-dihydro-9,10-ethano-anthracene, and 2-chloro-9- (2-hydroxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene, and 2-chloro-9- (2-hydroxy-3-dimethylamino-propyl) -9, 10-dihydro-9,10-ethano-anthracene, and 2-chlorine 209837/1245 9- [2-hydroxy-3- (N ¹ -methylpiperazino) propyl] -9,10-dihydro-9,10-ethano-anthracene, and Z-chloro-gj ^ -hydroxy-S- [N '- ( β-hydroxyethyl) piperazino] propyl-9, 10-dihyd.ro-9,10-ethanoanthracene, and 2-chloro-9- (2-hydroxy-3-cyclopropylamino-propyl) -9, 10-dihydro-9 , 10-ethano-anthracene, and 2-chloro-9- [2-hydroxy-3- (β-hydroxyethylamino) propyl] -9,10-dihydro-9,10-ethano-anthracene. 51. The compounds described in claims 43-48 with at least two asymmetric centers in the form their pure racemates. 52. 9- (2-Hydroxy-3-isopropylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene, and 9- (2-methoxy-3-methylamino-propyl) 9,10-dihydro-9,10-ethano-anthracene, and 2-chloro-9- (2-hydroxy-3-isopropylamino-propyl) -9, 10-dihydro-9,10-ethano-anthracene, and 2-chloro-9- (2-methoxy-3-methylamino-propyl) -9,10-dihydro-9,10-ethano-anthracene. 53. The compounds described in claims 43-51 in the form of their optical antipodes. 54. The connections described in claims 43-52 209837/1245 fertilize in the form of their optical antipodes. 55. The compounds described in any one of claims 43-51 and 53 in free form. 56. The compounds described in any one of claims 43-54 in free form. 57. The compounds described in any one of claims 43-51 and 53 in the form of their acid addition salts. 58. The compounds described in any one of claims 43-54 in the form of their acid addition salts. 59. The compounds described in any of claims 43-51 and 53 in the form of their therapeutically useful Acid addition salts. 60. The connections described in one of claims 43-54 in the form of their therapeutically useful acid addition salts. 61. The new compounds described in the examples. 209837/1245 22Ü7097 62. Pharmaceutical preparations containing compounds of the type shown in claims 43-51, 53, 55 and 59 together with a carrier material. 63. Pharmaceutical preparations containing compounds of the type shown in claims 43-56, 59 and 60 together with a carrier material. 64. Animal feed and animal feed additives containing compounds of claims 43-51, 53, 55 and 59 shown Art. 65. Containing animal feed and animal feed additives Connections of the kind shown in claims 43-56, 59 and 60. 209837/1245