CH623299A5 - Process for the preparation of novel tricyclic compounds - Google Patents

Abstract

Compounds of the formula: <IMAGE> wherein A represents alkylene or alkenylene and R1 and R2 represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl or polyhalogenoalkyl or, together with the nitrogen atom, represent a 5-membered to 7-membered heterocyclic ring are obtained by reaction of corresponding compounds having an -A-X side chain with an amine HNR1R2, or of corresponding compounds having an -A-NH-R3 side chain with a compound R5-X; X denotes a cleavable (removable) group. The compounds and their salts have a multiplicity of actions on the central nervous system; they may be used, inter alia, as anxiolytics, antidepressives and tranquillizers and in part also as antihistamines.

Description

The present invention relates to a process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methano-noanthracene derivatives and of non-toxic, pharmaceutically acceptable salts thereof, which can be processed into pharmaceutical preparations.

The 9,10-dihydro-9,10-methanoanthracene skeleton itself has been known since 1920, and various chemical studies have been carried out with 9,10-dihydro-9,10-methanoanthracene derivatives. However, no report has been published on the synthesis of 55 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives or on a pharmacological study with 9,10-di-hydro-9,10-methanoanthracene derivatives.

Furthermore, U.S. Patent No. 3,399,201 to P. Schmidt et al. Ethanoanthracene derivatives of the formula

60

65

3rd

623 299

known. These compounds are homologs of the methanoanthracene derivatives obtainable according to the invention, but the latter prove to be far superior in pharmacological terms both by a stronger antitetrabenazine activity and by a lower acute toxicity.

It has now been found that the new 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives of the following formula I and their non-toxic, pharmaceutically acceptable salts are distinguished by various pharmacological properties. These compounds correspond to the following formula in which A is an alkylene radical having 1 to 4 carbon atoms or an alkenylene radical having 3 or 4 carbon atoms and Rx and R2 are each hydrogen atoms, alkyl radicals having 1 to 4 carbon atoms, alkenyl radicals having 3 or 4 carbon atoms, alkynyl radicals having 3 or 4 carbon atoms , Cycloalkylalkyl radicals whose cycloalkyl component has 3 to 6 carbon atoms and whose alkyl component has 1 to 3 carbon atoms, aralkyl radicals whose alkyl component has 1 to 3 carbon atoms, or polyhaloalkyl radicals whose alkyl component has 2 to 4 carbon atoms, or Rj and R2, if they taken together with the neighboring nitrogen atom, form a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain a further heteroatom.

In the above meanings, the term "alkylene radical having 1 to 4 carbon atoms" means a straight-chain or branched alkylene group having 1 to 4 carbon atoms, e.g. B. methylene, ethylene, propylene, butylene, 1-methylethylene, 1-methylpropylene or 2-methylpropylene. The term "alkenylene radicals with 3 or 4 carbon atoms" include in particular 1-propenylene, 1-butenylene, 2-butenylene, 1-methyl-1-propenylene and 2-methyl-1-propenylene, the numbering starting from the carbon atom, which adheres to the 9,10-dihydro-9,10-methanoanthracene skeleton. The term “alkyl radicals with 1 to 4 carbon atoms” means straight-chain or branched alkyl radicals with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isobutyl. The term “alkenyl radicals with 3 or 4 carbon atoms” means a straight-chain or branched alkenyl group with 3 or 4 carbon atoms, such as propenyl or butenyl. The term "alkynyl with 3 or 4 carbon atoms" means a straight-chain or branched alkynyl group with 3 or 4 carbon atoms, such as propargyl. The term “cycloalkylalkyl radicals” means a straight-chain or branched alkyl group with 1 to 3 carbon atoms, which has a cycloalkyl group with 3 to 6 carbon atoms, such as cyclopropylmethyl or cyclobutylmethyl. The term "aralkyl" means a straight-chain or branched alkyl group having 1 to 3 carbon atoms, e.g. As methyl, ethyl or propyl, this alkyl group being an aryl group, e.g. B. the phenyl group. The term “polyhaloalkyl” means a branched or straight-chain alkyl group with 2 to 4 carbon atoms, which contains two or more halogen atoms,

such as trifluoroethyl, trichloroethyl or trifluoropropyl. The pyrrolidino, piperidino, morpholino and thiomorpholinores are mentioned as 5- to 7-membered, nitrogen-containing, heterocyclic rings.

The non-toxic, pharmaceutically acceptable salts of the 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives can be organic or inorganic acid addition salts thereof, such as e.g. B. hydrochlorides, hydrobromides, acetates, oxalates, citrates, tartrates, succinates, fumarates and lactates.

The 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives (hereinafter referred to as 9-aminoalkylmethanoanthracene derivatives) of the formula I are notable for the presence of an aminoalkyl side chain in the 9-position of the 9,10-dihydro- 9,10-methanoanthracene skeletons.

Although the same number of tricyclic dibenzo compounds have become known and some of them are used clinically as medicinal products, in particular as psychotropic agents, it should be noted that so far no tricyclic dibenzo compounds which have a 9,10-dihydro-9,10-me-thanoanthracene ring as a tricyclic dibenzoskeleton have been used for such purposes. The creation of 9-aminoalkylmethanoanthracene derivatives of the formula I has now been successful because the key intermediate, namely 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula, has been managed

CHO

to synthesize with success.

The 9-aminoalkyl-methanoanthracene derivatives of the formula I are new compounds and are distinguished by a wide variety of valuable pharmacological properties, in particular with regard to the central and autonomous nervous system. In particular, the 9-aminoalkylmethano-noanthracene derivatives of the formula I, in which A represents the methylene radical, which can be substituted by an alkyl radical having 1 to 3 carbon atoms, have a potentiating effect of hexobarbital anesthesia, a hypothermic and ptosis effect, as well as a muscle relaxant effect and also one Antitetrabenazine effect. These new compounds are therefore suitable as anxiolytic and antidepressant drugs and also as major tranquilizers.

The 9-aminoalkylmethanoanthracene derivatives of the formula I, in which A represents the ethylene radical, which can carry at least one alkyl radical having 1 or 2 carbon atoms as a substituent, have strong antihistamine and anti-cholinergic effects and antiserotonin effects. They also have an antitetrabenazine effect. Therefore, they are suitable as antihistamines and as antiallergics.

The 9-aminoalkylmethanoanthracene derivatives of the formula I, in which A denotes an alkylene radical having 3 or 4 carbon atoms or an alkenylene radical having 3 or 4 carbon atoms, have a strong antitetrabenazine activity. They also have a norepinephrine-potentiating effect and antire-serpin, antihistamine, antiacetylcholine and antiserotonin effects. In addition, these compounds have very low acute toxicity and acute cardiotoxicity. The new compounds are therefore suitable as antidrepressive agents and as antihistamines.

Generally speaking, the 9-aminoalkylmethanoanthracene derivatives of the formula I all have antitetrabenazine, antiacetylcholine, antihistamine and antiserotonin effects and also sedative effects. As a remedy for feelings of fear

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

623 299

4th

(Anxiolytica) those compounds of the formula I are preferred in which R] is an alkyl radical with 1 or 2 carbon atoms, R2 is the hydrogen atom or an alkyl radical with 1 or 2 carbon atoms and A is the methylene radical. Preferred antihistamines or antiallergics are those compounds of the formula I in which Rt is an alkyl radical with 1 or 2 carbon atoms, R2 is the hydrogen atom or an alkyl radical with 1 or 2 carbon atoms and A is the ethylene group. Preferred antidepressant agents are compounds of the formula I in which A denotes the propylene or propylene residue. Particular preference is given to those compounds of the formula I in which Ra and R2, which may be the same or different, are hydrogen atoms or alkyl radicals having 1 or 2 carbon atoms and A is the propylene or propenylene radical. The particularly preferred compounds are those in which A is the propylene radical, Rt is the hydrogen atom or the methyl radical and R2 is the methyl radical.

The 9-aminoalkylmethanoanthracene derivatives of the formula I and their non-toxic, pharmaceutically acceptable salts can be administered orally or parenterally in doses of normally 5 to 500 mg / body weight, preferably 25 to 500 mg / body weight (approximately 60 kg body weight) per day in the form of a conventional pharmaceutical Preparations are administered.

For example, these compounds can be in the form of conventional solid pharmaceutical preparations, such as powders, granules, tablets or capsules, or in the form of conventional liquid pharmaceutical preparations, e.g. Administer suspensions, emulsions or solutions. Such preparations can be obtained by either using a 9-aminoalkylmethanoanthracene derivative of the formula I or a non-toxic, pharmaceutically acceptable salt thereof or incorporating them in a suitable manner, such as starch, lactose or talc, in a known manner.

The 9-aminoalkylmethanoanthracene derivatives of the formula I can be obtained from 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula II, in practice by means of suitable derivatives.

According to the invention, the compounds of the formula I are prepared by adding a corresponding compound of the formula

[IV]

where A has the above meaning and X is a leaving group, e.g. B. a halogen atom, such as chlorine, bromine or iodine, or a sulfonyloxy group, such as the methanesulfonyloxy, p-toluenesulfonyloxy or trichloromethanesulfonyloxy group means with an amine of the formula

H-N

/ Ri

[vi

\

R,

where R 1 and R 2 have the meanings given above.

The reaction can be carried out in the presence or absence of an inert solvent, e.g. an ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or ethyl

lenglycoldimethyl ether, alcohols, e.g. Methanol, ethanol or isopropanol, aromatic hydrocarbons, such as. As benzene or toluene, dimethyl sulfoxide, dimethylformamide or pyridine, in the presence or in the absence of an acid-binding agent. Examples of acid-binding agents are amines, such as pyridine, picoline, diethylamine or diethylaniline, metal hydrides, such as sodium hydride, metal alkoxides, such as sodium methoxide, sodium ethoxide or potassium tert-butoxide, metal carbonates, such as sodium carbonate or potassium carbonate, metal bicarbonate, such as sodium bi- carbonate, sodium amide, etc. The reaction temperature can vary between ice cooling and the reflux temperature of the reaction mixture in a closed or an open system.

15 9-aminoalkylmethanoanthracene compounds of the formula

20th

25th

[Ic]

30 wherein A has the above meaning, R3 is the hydrogen atom, an alkyl radical having 1 to 4 carbon atoms, an alkenyl radical having 3 to 4 carbon atoms, a cycloalkylalkyl radical whose cycloalkyl component has 3 to 6 carbon atoms and its alkyl component has 1 to 3 carbon atoms, 35 an aralkyl radical whose Alkyl component having 1 to 3 carbon atoms, or a polyhaloalkyl radical whose alkyl component has 2 to 4 carbon atoms, and Rs is an alkyl radical with 1 to 4 carbon atoms, an alkenyl radical with 3 or 4 carbon atoms, a 40 alkynyl radical with 3 or 4 carbon atoms, a cycloalkylalkyl radical, whose cycloalkyl component has 3 to 6 carbon atoms and whose alkyl component has 1 to 3 carbon atoms, an aralkyl radical, whose alkyl component has 1 to 3 carbon atoms, or a polyhaloalkyl radical, 45 whose alkyl component has 2 to 4 carbon atoms, are also obtained according to the invention in that ma n is a corresponding compound of the formula

50

55

60

Cid]

65

wherein A and R3 have the above meanings, with a compound of the following formula

Rs-X (VIII)

wherein R5 and X have the meanings given above.

5

623 299

You can use the same measures that have been described in connection with the reaction of the compound of formula IV with an amine of formula V.

If a compound of the formula Id is used in which R3 represents the hydrogen atom, a 9-aminoalkylmethanoanthracene compound of the formula can be used

[Ie]

wherein A and Rs each have the above meaning obtained by reacting a compound of formula Id with not less than 2 moles of a compound of formula VIII.

The 9-aminoalkylmethanoanthracene compounds of the formula I can be separated off and purified from the reaction mixture in a known manner. The 9-aminoalkylmethanoan-thracen compounds can be converted into the corresponding salts in a manner known per se, but the salts mentioned can in turn be converted into the original free base in a manner known per se.

The key compound 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula II can be obtained from 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene of the formula

[A]

not disclosed, so it is a new process for the preparation of 9-formyl-9,10-dihydro-9,10-methanoan-thracen.

The rearrangement of 9-amino-12-hydroxy-9,10-dihydro-5 9,10-ethanoanthracene into 9-formyl-9,10-dihydro-9,10-metha-noanthracene can be carried out by treatment with nitrous acid. 9-Amino-12-hydroxy-9,10-dihydro-9, 10 O-ethanoanthracene is therefore treated with nitrous acid or a metal nitrite, e.g. Sodium nitrite, potassium ni-10 trite, in an acidic medium such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or a solution of a mixture of such acids. An inert solvent, e.g. B. water, methanol, ethanol, acetone, benzene, toluene, chloroform, 15 dichloroethane, dichloromethane, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide or dimethylformamide or a mixture thereof in this reaction system. The temperature for the treatment in this case fluctuates between ice cooling and the reflux temperature of the reaction system.

The 9-formyl-9,10-dihydro-9,10-methanoan-thracen of formula II thus obtained can be separated from the reaction mixture in a known manner and purified.

The compound [A], i.e. 9-Amino-12-hydroxy-9,10-25 dihydro-9,10-ethanoanthracene can be obtained from a compound of the following formula by rearrangement.

This rearrangement of amines and α-amino alcohol derivatives by treatment with nitrous acid is known as the Demja nov rearrangement and Tiffeneu-Demjanov rearrangement [Organic Reactions, Vol. 11, p. 157, John Wiley & Sons, Inc.] known. These rearrangement reactions have been reported for ring expansion in most of the cases reported, while only a few cases of the ring rearrangement reaction have been reported. The rearrangement of a 9,10-ethano-anthracene derivative into 9-formyl-9,10-dihydro-9,10-methanoanthracene has so far been

[B]

wherein R represents the hydrogen atom or a group protecting the hydroxyl group, such as the acetyl group, benzoyl group or tetrahydropyranyl group, by rearrangement, 40 z. B. according to the Curtius reaction or Hoffman rearrangement and hydrolysis. The rearrangement can be carried out, for example, by conventional methods according to the Curtius reaction [Organic Reactions, vol. 3, p. 337, John Wiley & Sons, Inc.], while the hydrolysis is carried out under customary hydrolysis conditions, such as those for urethane and isocyanate derivatives are known can be carried out.

The intermediates for the synthesis of the 9-amino-alkylmethanoanthracene compounds of the formula I can be obtained from 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula II using customary reaction conditions such as oxidation, reduction, hydrolysis, reaction for extension the carbon chain (substitution, Wittig reaction, Reformatsky reaction, Grignard reaction) etc.

The starting materials used for the synthesis of 9-aminomethyl-9,10-dihydro-55 9,10-methanoanthracene derivatives can be prepared, for example, as follows:

623 299

6

(1)

CHjjOH

(3)

CHO

CH-OTs A

COOH

(4)

C = N

wherein Ts represents a p-toluenesulfonyloxy group. These implementations can be reproduced as follows:

(1) 9-Formyl-9,10-dihydro-9,10-methanoanthracene is oxidized to 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid by treatment with an oxidizing agent such as e.g. B. chromium trioxide or silver oxide, in an inert solvent;

(2) 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from 9-formyl-9,10-dihydro-9,10-niethanoanthracene by treatment with a reducing agent such as e.g. Sodium borohydride or lithium aluminum hydride, in an inert solvent;

(3) 9-Tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene by treatment with p-toluene- sulfonyl chloride in the presence of a base and in an inert solvent;

(4) 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid is converted into the corresponding reaction by reaction with thionyl chloride in the presence or in the absence of an inert solvent.

35 acid chloride converted, whereupon this acid chloride is converted into 9,10-dihydro-9,10-methanoanthracene-9-carboxamide by reaction with ammonia in a manner known per se;

(5) the dehydration of 9,10-dihydro-9,10-methano-40 anthracene-9-carboxamide in 9,10-dihydro-9,10-methanoane

thracen-9-carbonitrile is carried out using phosphorus oxychloride in the presence or in the absence of an inert solvent.

The starting materials for the synthesis of 9-β-amino-45 ethyl-9,10-dihydro-9,10-methanoanthracene derivatives can, for example, from 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula II or a derivative thereof can be carried out in the following way:

(6)

COOH

OH

OTs

7

623 299

CHO

(11)

OTs

C = N

where Ts has the above meaning. These implementations therefore include the following stages:

(6) The [9,10-dihydro-9,10-methano-9-anthryl] acetic acid ethyl ester is obtained from 9,10-

Dihydro-9,10-methanoanthracen-9-carboxylic acid obtained in the usual way.

(7) [9,10-Dihydro-9,10-methano-9-anthryl] acetic acid is extracted from the corresponding ethyl ester using conventional hydro-

s received lysis measures.

(8) 9-β-hydroxyethyl-9,10-dihydro-9,10-methanoanthracene is obtained by reducing ethyl [9,10-dihydro-9,10-methano-9-anthryl] acetic acid using a reducing agent, such as B. lithium aluminum hydride or Na

10 triumaluminiumdiethyldihydrid, obtained in an inert solvent.

(9) 9- / 3-Tosyloxyethyl-9,10-dihydro-9,10-methanoanthracene is obtained in the manner described above.

(10) The [9,10-dihydro-9,10-methano-9-anthryl] acetal-15 dehyde is made from 9-formyl-9,10-dihydro-9,10-methanoanthra-

cen obtained using the Wittig method using methoxymethyltriphenylphosphonium chloride and by acidic hydrolysis.

(11) [9,10-Dihydro-9,10-methano-9-anthryl] acetonitrile 20 can be obtained from 9-tosyloxymethyl-9,10-dihydro-9,10-methanoane

thracen can be obtained by reaction with a metal cyanide in an inert solvent.

The starting materials for the synthesis of the 9-y-aminopropyl and 9-y-aminobutyl-9,10-dihydro-9,10-methanoan-25 thracen derivatives can e.g. can be obtained from 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula II in the following manner:

(12)

CHO

(13)

COOH

(19)

CHO

(14)

V

COOH

(17)

. (16)

CHO

(18)

623 299

8th

(15)

ÒTS

where Ts has the above meaning. These implementations can be reproduced as follows:

(12) The ß- [9,10-dihydro-9,10-methano-9-anthryl] acrylic acid is after the Wittig reaction from 9-formyl-9,10-dihy-dro-9,10- obtained methanoanthracene with triethylphosphonoacetate and hydrolysis of the ester function;

(13) β- [9,10-dihydro-9,10-methano-9-anthryl] propionic acid is obtained from the corresponding acrylic acid by a known hydrogenation method;

(14) 9-y-hydroxypropyl-9,10-dihydro-9,10-methanoan-thracen becomes from / 3- [9,10-dihydro-9,10-methano-9-anthryl] -propionic acid by treatment with a reducing agent, e.g. Lithium aluminum hydride or sodium aluminum ethyl dihydride, obtained in an inert solvent;

(15) 9-y-Tosyloxymethyl-9,10-dihydro-9,10-methanoan-thracen is obtained from the corresponding alcohol by the method described above;

(16) 9-y-HydroxypropyI-9,10-dihydro-9,10-methanoan-thracen is the corresponding aldehyde by treatment with an oxidizing agent, e.g. B. Cr03-pyridine complex, oxidized in an inert solvent;

(17) and (18) the / 3- [9,10-dihydro-9,10-methano-9-an-thrylj-propionic acid is dissolved in /? - [9,10-dihydro-9, 10-methanoanthryl] -propionitrile converted;

(19) ß- [9,10-Dihydro-9,10-methano-9-anthryl] acrylic acid aldehyde is made from 9-formyl-9,10-dihydro-9,10- Get me-thanoanthracene.

The compounds of the formula III can be prepared from the corresponding carboxylic acid derivatives in a manner known per se using the corresponding amine compounds. Other intermediates, e.g. B. Compounds of formula VII, can be obtained from a compound of formula IC by reaction with a compound of the following formula

R4'COY or R4'C0-0-C0-R4 '

wherein R4 'has the above meaning and Y is a halogen atom, e.g. B. represents the chlorine or bromine atom, can be obtained under customary conditions for the acylation of an amine compound.

The following examples illustrate the invention in greater detail.

Preparation of the intermediate and starting products a) A solution of 1.0 g of 12-acetoxy ~ 9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid in 10 ml of benzene and 4.0 ml of thionyl chloride is refluxed for 4 hours heated to boiling. Evaporation of the excess thionyl chloride and the benzene gives 12-acetoxy-9,10-di-

r

C = N

hydro-9,10-ethanoanthracene-9-carboxylic acid chloride. The acid 20 chloride is then dissolved in 25.0 ml of dry acetone and this solution is mixed with ice and a solution of 0.63 g of sodium azide in 1.3 ml of water while cooling. The resulting mixture is stirred under ice cooling for 2 hours. Then the reaction mixture is diluted with water and extracted with 25 benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, heated to boiling under reflux for 2 hours and evaporated to dryness to give 9-isocyanato-12-acetoxy-9,10-dihy-dro-9,10-ethanoanthracene.

30 b) To a solution of 3.0 g of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene in 240 ml of acetic acid is added a solution of 6.7 g of sodium nitrite in 120 ml of water at 2 to 5 ° C, whereupon the mixture is stirred for 1 hour at the same temperature and then for 5 hours at 35 95 to 105 ° C. The reaction mixture is then diluted with water and extracted with benzene. The benzene layer is washed with water, dried over sodium sulfate and evaporated to dryness, giving 2.8 g of crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene, 40 which are recrystallized. In this way, colorless crystals are obtained in an amount of 2.45 g from melting point 99 to 100 ° C. Further purification by recrystallization gives analytically pure 9-formyl-9,10-dihydro-9,10-methano -anthracene with a melting point of 102.5 ° C. 45 c) To a solution of 50 mg of 9-amino-12-hydroxy-9,10-dihydro-9, l 0-ethanoanthracene in 2 ml of conc. Hydrochloric acid and 2 ml of water are added to a solution of 112 mg of sodium nitrite in 1.0 ml of water at 0 ° C. The mixture thus obtained is stirred for 1 hour at 0 ° C. and then for 5 hours at room temperature. The reaction mixture is finally diluted with water and extracted with benzene. The benzene layer is then washed with water, dried over sodium sulfate and evaporated to dryness, giving 35 mg of crude crystals of 9-formyl-55 9,10-dihydro-9,10-methanoanthracene.

d) A solution of 200 mg of 9-formyl-9,10-dihydro-9,10-methanoanthracene and 60 mg of sodium borohydride in 5 ml of methanol is stirred for 30 minutes at room temperature. Then the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness, giving 9-hydroxymethyl-9,10-dihydro-9,10-methanoanthracene with a melting point of 165 to 166 ° C.

65 e) A solution of 3.5 g of 9-formyl-9,10-dihydro-9,10-me-thanoanthracene in 17 ml of acetone is added dropwise with 5.0 ml of Jones reagent at room temperature. Then the reaction mixture for 1 hour at room temperature

9

623 299

stirred, diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness, giving 9,10-dihydro-9,10-methanoanthra-cen-9-carboxylic acid with a melting point of 199.5 to 200.5 ° C.

f) A solution of 1.77 g of 9,10-dihydro-9,10-methanoan-thracen-9-carboxylic acid and thionyl chloride in benzene is heated to boiling under reflux for 4 hours and then evaporated to dryness, giving the corresponding acid chloride receives. A solution of this acid chloride in ether is added dropwise to an ethereal diazomethane solution in the presence of 1.43 g of triethylamine at 0 ° C. The mixture obtained is then stirred at 0 ° C. for 3 hours, then filtered and evaporated to dryness, giving the corresponding diazomethyl ketone compound. A mixture of this diazomethyl ketone, triethylamine and silver benzoate in 60 ml of ethanol is refluxed for 13 hours. This reaction mixture is then diluted and extracted with ethyl acetate. The ethyl acetate extract is washed with aqueous sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and evaporated to dryness, with

(9,10-Dihydro-9,10-methano-9-anthryl) -acetic acid ethyl ester of melting point 81 to 84 ° C.

g) A mixture of 125 mg (9,10-dihydro-9,10-metha-no-9-anthryl) -acetic acid ethyl ester and 80 mg lithium aluminum hydride in 6 ml ether is stirred for 1 hour at room temperature. The excess lithium aluminum hydride is added by adding water. Then the reaction mixture is diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness, whereby crystals of 9-β-hydroxyethyl-9,10-dihydro-

9,10-methanoanthracene with a melting point of 99 to 100.5 ° C.

h) A solution of 72 mg of 9- / 3-hydroxyethyl-9,10-dihydro-9,10-methanoanthracene and 100 mg of p-toluenesulfonylchloride in 1 ml of pyridine is stirred overnight. The mixture thus obtained is then diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed with water, with 2N hydrochloric acid and again with water, dried over anhydrous sodium sulfate and evaporated to dryness, giving crude crystals of 9-β-tosyloxyethyl-9,10-dihydro-9,10-methanoanthracene which are recrystallized from ethanol. In this way, pure crystals with a melting point of 135.5 to 138 ° C. are obtained.

i) A solution of 30 mg of 9,10-dihydro-9,10-methanoan-thracen-9-carboxamide and 0.15 ml of thionyl chloride in 1 ml of toluene is heated to boiling under reflux for 18 hours. Evaporation of the toluene and the excess thionyl chloride gives 9,10-dihydro-9,10-methano-anthracene-9-carbonitrile with a melting point of 120 to 123 ° C.

j) A mixture of 188 g of 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene and 40 mg of potassium cyanate in 2 ml of dimethylformamide is heated to 150 ° C. for 7 hours. The reaction mixture is then diluted with water and extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give crude crystals of (9,10-dihydro-9,10-methano-9-anthryl) acetonitrile. This material is recrystallized from isopropanol, giving pure crystals with a melting point of 130 to 131 ° C.

k) A mixture of 250 mg / 3- (9,10-dihydro-9,10-methano-no-9-anthryl) propionitrile and 100 mg lithium aluminum hydride in 12 ml dioxane is stirred at 60 ° C. for 5 hours. The excess lithium aluminum hydride is then added by adding water. The reaction mixture is then diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness, giving 9 -; '- aminopropyl-9,10-dihydro-9,10-methanoanthracene, which is dissolved in the hydrochloride with a melting point of 275 ° C ( with decomposition).

1) 2.65 g of triethylphosphonoacetate in benzene is treated with a 50 "/ own sodium hydride dispersion in 0.66 g of mineral oil and then at room temperature in a nitrogen atmosphere with a solution of 2.0 g of 9-formyl-9,10-dihydro-9 , 10-methanoanthracene in 20.0 ml of benzene. The reaction mixture is then stirred for 5 hours at room temperature and then for 1 hour at 70 ° C., diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, over anhydrous Dried sodium sulfate and evaporated to dryness to give ethyl / 3- (9,10-dihydro-9,10-methano-9-anthryl) acrylic acid A solution of this ethyl ester in 53 ml of methanol and 12 ml of a 10% aqueous solution Sodium hydroxide solution is heated to boiling under reflux for 4 hours, then the reaction mixture is diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate, the ethyl acetate extract is washed with water, over dried anhydrous sodium sulfate and evaporated to dryness to give / 3- (9,10-dihydro-9,10-me-thano-9-anthryl) acrylic acid. Melting point 219.5 to 222 ° C.

m) A mixture of 612 mg / 3- (9,10-dihydro-9,10-me-thano-9-anthryl) acrylic acid and 120 mg of 5% palladium-on-carbon in ethanol is added in a hydrogen atmosphere for 2 hours Room temperature stirred. The catalyst is removed by filtration and the solution is evaporated to dryness to give / î- (9,10-dihydro-9,10-me-thano-9-anthryl) propionic acid, melting point 185 to 189 ° C.

n) A mixture of 110 mg of 9-formyl-9,10-dihydro-9,10-methanoanthracene and 186 mg /? - carboxyethyltriphenyl-phosphonium chloride in 2 ml of dimethyl sulfoxide and 2 ml of tetrahydrofuran is mixed with a 65.4% sodium hydride dispersion in 37 mg mineral oil at 0 ° C in a nitrogen atmosphere. The reaction mixture is stirred at 0 ° C. for 6 hours, then diluted with water, acidified with hydrochloric acid and then extracted with benzene. The benzene extract is shaken with aqueous 2N sodium hydroxide solution. The basic layer is acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness, with y- (9,10-dihydro-9,10-methano-9-anthryl) - / 3-butenoic acid having a melting point of 166 to 167 ° C receives.

The following connections can be made in a similar manner:

9-aminomethyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp> 300 ° C, 9-methylaminomethyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 281.5 to 283 ° C, 9-dimethylaminomethyl-9.10-dihydro-9.10-methanoanthracene hydrochloride, mp. 257 to 259 ° C, 9-ethylaminomethyl-9.10-dihydro- 9,10-methanoanthracene

hydrochloride, mp. 283 to 284 ° C, 9-ethylmethylaminomethyl-9,10-dihydro-9,10-methanoantra-cene hydrochloride, mp. 249.5 to 251 ° C, 9-isopropylaminomethyl-9,10-dihydro- 9,10-methanoanthra-cen, mp. 103 to 103.5 ° C,

9-sec-butylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, mp. 234 to 235.5 ° C, 9-isobutylaminomethyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 227 to 229 ° C,

s io

15

20th

25th

30th

35

40

45

50

55

60

65

623 299

10th

9-cyclopropylmethylaminomethyl-9,10-dihydro-9,10-metha-noanthracene hydrochloride, mp. 240.5 to 243.5 ° C, 9-allylaminomethyl-9,10-dihydro-9,10-methanoanthracene -

hydrochloride, mp. 208 to 209 ° C, 9-benzylaminomethyl-9,10-dihydro-9,10-methanoanthracene,

Mp 94 to 97 ° C, 9-piperidinomethyl-9,10-dihydro-9,10-methanoanthracene,

Mp 114-115 ° C, 9-morpholinomethyl-9,10-dihydro-9,10-methanoanthracene,

M.p. 160 to 163 ° C, 9 - /? - aminoethyl-9,10-dihydro-9,10-methanoanthracene,

Mp 158 to 160 ° C, 9- / 3-methylaminoethyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 304 to 305 ° C, 9- / j-dimethylaminoethyl-9,10-dihydro-9,10-methanoanthra-cene hydrochloride, mp. 239 to 240,5 ° C, 9 - /? - ethylaminoethyl 9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 297 to 299 ° C, 9-β-diethylaminoethyl-9,10-dihydro-9,10-methanoanthracene, IR spectra: 3065, 1468, 1445, 1380, 1280, 1205, 1155. 1010, 765, 745 cm-1, 9- / S-sec-butylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, mp. 267 to 268 ° C, 9 - /? - N, N-dicyclopropylmethylaminoethyl- 9,10-dihydro

9,10-methanoanthracene hydrochloride, mp. 137 bis

140 ° C hydrochloride, mp. 242 to 243 ° C,

9-ß-allylaminoethyl-9,10-dihydro-9,10-methanoanthracene -

hydrochloride, mp. 242 to 243 ° C, 9 - /? - benzylaminoethyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 233 to 235 ° C, 9-ß-morpholinoethyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 263 to 264 ° C, 9-y-aminopropyl-9,10-dihydro-9,10-methanoanthracene -

hydrochloride, mp. 275 ° C, 9-y-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, mp. 259 to 260 ° C,

9 - / - methylamino-g-propenyl-9,10-dihydro-9,10-methanoan-thracen hydrochloride, mp. 244 to 246 ° C, 9 -; '- dimethylaminopropyl-9,10-dihydro-9,10 -methanoanthra-cen-hydrochloride, mp. 247 to 247.5 ° C, 9-y-ethylaminopropyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 184 to 186 ° C, 9-y-N-ethyl-N-methylaminopropyl-9,10-dihydro-9,10-

methanoanthracene oxalate, mp. 168 to 169 ° C, 9-y-isopropylaminopropyl-9,10-dihydro-9,10-methanoanthra-

cen-hydrochloride, mp. 255 to 256 ° C, 9-y-isobutylaminopropyl-9,10-dihydro-9,10-methanoanthra-

cen-hydrochloride, mp. 248 to 252 ° C, 9-y-sec-butylaminopropyl-9,10-dihydro-9,10-methanoan ~ thracen hydrochloride, mp. 217 to 219 ° C, 9 -} '- N-benzyl-N-cyclopropylmethylaminopropyl-9,10-dihydro-9,1O-methanoanthracene hydrochloride,

M.p. 207-211 ° C, 9 -} '- allylaminopropyl-9,10-dihydro-9,10-methanoanthracene

hydrochloride, mp. 226 to 228 ° C, 9 -} '- benzylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, mp. Ì97 to 201 ° C, 9-yN-methy] -N- propargylaminopropyl-9,10-dihydro-9,10-

methanoanthracene, mp. 130 to 131 ° C, 9-v-N- (2,2,2-trifluoroethyl) -N-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride,

M.p. 170 to 172.5 ° C, 9 -; '- piperidinopropyl-9,10-dihydro-9,10-methanoane-thracen-

hydrochloride, mp. 280 to 283 ° C, 9-y-pyrrolidinopropyl-9,10-dihydro-9,10-methanoane thracen-

hydrochloride, mp. 244 to 248 ° C, 9-y-morpholinopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, mp. 174 to 177 ° C,

9-ó-dimethylaminobutyl-9,10-dihydro-9,10-methanoanthra-

cen hydrochloride, mp. 201 to 202.5 ° C,

9-ô -dimethylamino-a -butenyl-9,10-dihydro-9,10-

methanoanthracene hydrochloride, mp. 154.5 to 155 ° C, s etc.

The following compounds can be obtained in a similar manner:

9-propargylaminomethyl-9,10-dihydro-9,10-methano-anthracene, mp. 125 to 128 ° C, io 9-ß-methyl-y-methylaminopropyl-9,10-dihydro-9,10-

methanoanthracene hydrochloride, mp. 228 to 230 ° C, 9 - «- methyl-y-methylaminopropyl-9,10-dihydro-9,10-

methanoanthracene hydrochloride, mp. 229 to 232 ° C, 9 -a-methyl - /? - dimethylaminoethyl-9,10-dihydro-9,10-15 methanoanthracene, mp. 75 to 78 ° C, 9-a-methylaminoethyl- 9,10-dihydro-9,10-methano-

anthracene, IR spectrum: 3070, 3050, 2780, 1375, 1277, 1172, 1155, 1138, 1012, 765, 745, 665 cm "1, 9-a-aminoethyl-9,10-dihydro-9,10-methanoanthracene , 20 mp 102.5 to 103.5 ° C etc.

o) A solution of /? - (9,10-dihydro-9,10-methano-9-an-thryl) propionic acid and thionyl chloride in benzene is heated to boiling under reflux for 4 hours. Evaporation of the excess thionyl chloride and the benzene gives / 3- (9,10-dihydro-9,10-methano-9-an-thryl) propionic acid chloride, which is dissolved in dry tetrahydrofuran. This solution is added to a 30% aqueous monomethylamine solution at 0 to 5 ° C. Then the reaction mixture is stirred at 0 to 15 ° C, diluted with water 30 and extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness, using ß- (9,10-dihydro-9,10-methano-9-anthryl) propionic acid re-monomethylamide with a melting point of 200 to 201 ° C. 35 p) A mixture of 1.0 g /? - (9,10-dihydro-9,10-methano-no-9-anthryl) propionic acid monomethylamide and 0.5 g of lithium aluminum hydride is at 2 ° C for 2 hours touched. The excess lithium aluminum hydride is decomposed by adding water. Then the reaction-40 mixture is diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-y-methylaminopropyl-9,10-dihydro-9,10-methanoan-thracen, which is converted into the hydrochloride of melting point 247 to 249 ° C transferred. Recrystallization from 45 isopropyl alcohol gives colorless crystals with a melting point of 259 to 260 ° C.

q) A solution of 235 mg of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene and 217 mg of acetic anhydride in 5.0 ml of ethanol is heated to boiling under reflux 50 for 3 hours. The reaction mixture is then diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, then with aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and evaporated to dryness, with 9-acetylamino-methyl-9,10-dihydro-9,10-methanoanthracene Melting point 184 to 185.5 ° C obtained.

r) A mixture of 70 mg of 9-y-acetylaminopropyl-9.10-60 dihydro-9.10-methanoanthracene and 35 mg of lithium aluminum hydride in 2 ml of dioxane is stirred at 40 to 50 ° C. for 9 hours. The excess lithium aluminum hydride is decomposed by adding water. Then the reaction mixture is diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-y-ethylaminopropyl-9,10-dihydro-9,10-methanoanthracene, which is converted into the chlorohydrate from melting point 182 to 186 ° C transferred.

11

623 299

s) Methoxymethyltriphenylphosphonium chloride (2 mmol) is treated with sodium hydride (2 mmol) in 6 ml of dimethyl sulfoxide, after which 9-formyl-9,10-dihydro-9,10-methanoanthracene is added at room temperature. The mixture obtained is stirred at room temperature for 1 hour and then at 50 ° C. for 3 hours, then diluted with water and extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give an oily compound. This oil is treated with 5 ml of 2N hydrochloric acid in 15 ml of dioxane for 2 hours at 50 ° C. The usual workup and purification by silica gel chromatography gives (9,10-dihydro-9,10-methano-9-an-thryl) acetaldehyde. IR spectra: 2740, 1715, 1440, 1375, 1165, 1135, 1065, 935, 760, 715, 660 cm-1.

t) A solution of 220 mg of 9-formyl-9,10-dihydro-9,10-methanoanthracene and 1 mmol of formylmethylene triphenylphosphorane in 6 ml of benzene is heated to boiling under reflux for 16 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue is purified by silica gel chromatography, giving crystals of β- (9,1O-dihydro-9,10-methano-9-anthryl) -acrylic acid aldehyde with a melting point of 135 to 138 ° C.

u) A solution of 150 mg of β- (9,10-dihydro-9,10-methano-no-9-anthryl) propionic acid aldehyde and 100 mg of sec-butylamine in methanol is stirred for 30 minutes at -5 ° C stirred to 0 ° C. This solution is then mixed with 50 mg of sodium borohydride and the mixture obtained is stirred at about 0 ° C. for 2 hours. The reaction mixture is then diluted with water and extracted with benzene. The benzene extract is shaken with hydrochloric acid. The acidic layer is made alkaline by adding aqueous ammonia and then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-y-sec-butylaminopropyl-9,10-dihydro-9,10-methano-anthracene, which is obtained in the chlorohydrate, melting point 216 to 219 ° C transferred.

example 1

A mixture of 50 mg of 9-j'-chloropropyl-9,10-dihydro-9,10-methanoanthracene and 0.1 ml of piperidine is heated at 100 ° C. for 3 hours. Then the reaction mixture is diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-y-piperidinopropyl-9,10-dihydro-9,10-methanoanthracene, which is dissolved in the chlorohydrate of melting point 280 transferred to 283 ° C.

The 9-y-chloropropyl-9,10-dihydro-9,10-methanoanthracene used as the starting material is obtained by reacting 9-y-hydroxypropyl-9,10-dihydro-9,10-methanoanthracene with thionyl chloride in benzene.

Example 2

A mixture of 40 mg of 9-y-methylaminopropyl-9,10-di-hydro-9,10-methanoanthracene, 22 mg of propargyl bromide and 15 mg of sodium amide in dry benzene is heated to boiling under reflux for 6 hours. The reaction mixture is then diluted with benzene, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue is purified by silica gel chromatography to give 9-y-N-methyl-N-propargylaminopropyl-9,10-dihydro-9,10-methanoanthracene, melting point 130 to 131 ° C.

Example 3

A solution of 200 mg of 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene in 5 ml of a 30% strength methylamine solution in ethanol is heated to 140 ° C. in a sealed tube for 14 hours. The solution is concentrated in vacuo, diluted with water and extracted with ethyl ether. The ethyl ether extract is extracted with 20% hydrochloric acid, the acidic layer is made basic with ammonia water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. This gives 9-methylaminomethyl-9,10-dihydro-9,10-methanoanthracene, which is converted into its hydrochloride from melting point 281 to 283 ° C.

15

20th

25th

30th

35

s

Claims (6)

623 299 2nd PATENT CLAIMS 1. Process for the preparation of new compounds of the formula (I) wherein A is an alkylene radical with 1 to 4 carbon atoms or an alkenylene radical with 3 or 4 carbon atoms and Ra and R2 are each hydrogen atoms, alkyl radicals with 1 to 4 carbon atoms, alkenyl radicals with 3 or 4 carbon atoms, alkynyl radicals with 3 or 4 carbon atoms, cycloalkylalkyl radicals, their Cycloalkyl component 3 to 6 carbon atoms and their alkyl component have 1 to 3 carbon atoms, aralkyl radicals whose alkyl component has 1 to 3 carbon atoms, or polyhaloalkyl radicals whose alkyl component has 2 to 4 carbon atoms, or if Rt and R2 are taken together with the adjacent nitrogen atom , can form a 5- to 7-membered nitrogen-containing heterocyclic ring which may have an additional heteroatom, and non-toxic, pharmaceutically acceptable salts thereof, characterized in that a compound of the formula (IV) wherein A has the above meaning and X represents a cleavable group, with a compound of the formula H-N-Rx (V) R2 where R 1 and R 2 have the meanings given above. 2. The method according to claim 1, characterized in that one carries out the reaction in the presence of an acid-binding agent. 3. The method according to claim 1 or 2, characterized in that one carries out the reaction in an inert solvent. 4. Process for the preparation of compounds of the formula (Ic) wherein A has the meaning given in claim 1, R3 is the hydrogen atom, an alkyl radical having 1 to 4 carbon atoms, an alkenyl radical having 3 or 4 carbon atoms, an alkynyl radical having 3 or 4 carbon atoms, a cycloalkyl-5 alkyl radical, the cycloalkyl component having 3 to 6 carbon atoms and whose alkyl component has 1 to 3 carbon atoms, an aralkyl radical whose alkyl component has 1 to 3 carbon atoms, or a polyhaloalkyl radical with 2 to 4 carbon atoms and R5 an alkyl radical with 1 10 to 4 carbon atoms, an alkenyl radical with 3 or 4 carbon atoms, an alkynyl radical with 3 to 4 carbon atoms, a cycloalkylalkyl radical whose cycloalkyl component has 3 to 6 carbon atoms and its alkyl component has 1 to 3 carbon atoms, an aralkyl radical whose 15 alkyl component has 1 to 3 carbon atoms, or a polyhaloalkyl radical with 2 to 4 carbon atoms, and non-toxic, pharmaceuticalpermissible salts thereof, characterized in that a compound of the formula (Id) 25th HN-R- 30 wherein A and R3 have the above meanings, with a compound of the formula Rs-X (VIII) 35 where Rs has the meaning given above and X represents a leaving group. 5. The method according to claim 4, characterized in that one carries out the reaction in the presence of an acid-binding agent. 6. The method according to claim 4 or 5, characterized in that one carries out the reaction in an inert solvent. 40 45