CS200182B2 - Process for preparing 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracenes - Google Patents

Description

The invention relates to a process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives and non-toxic pharmaceutically acceptable salts thereof.

The skeleton of 9,10-dlhydro-9,10-methanoanthracene has been known since 1920 and several chemical studies have been published concerning 9,10-dihydro-9,10-methanoanthracene derivatives, but no report on the synthesis of 9-aminoalkyl has been published anywhere -9,10-dihydro-9,10-methanoanthracene derivatives or any pharmacological study concerning

9,10-dihydro-9,10-methanoanthracene derivatives.

It has now been found that the novel 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives and their non-toxic pharmaceutically acceptable salts are characterized by having different pharmacological properties. These compounds have the general formula I,

x ^R ' ^R z where

A ‘represents a direct bond, C 1 -C 8 alkylene or C 2 -C 3 alkenylene and each of the symbols

R 1 and R 2 are hydrogen, C 1 -C 4 alkyl-, C 3 -C 4 alkenyl-, C 3 -C 4 alkynyl, C 3 -C 4 cycloalkyl (C 1 -C 3) alkyl-, ar (C 1 -C 3) alkyl- or polyhalogen (C 2 -C 4) alkyl); or

R 1 and R 2 taken together with the adjacent nitrogen atom represent a 5- to 7-membered nitrogen-containing heterocyclic ring optionally containing an additional heteroatom.

In the above definitions of the individual symbols, the C 1 -C 8 alkylene group is a straight or branched C 1 -C 3 alkylene group (for example, methylene, ethylene, propylene, 1-methylethylene). The term "C 2 -C 3 alkenylene" specifically refers to 1-propenylene. the term "C 1 -C 4 alkyl" means a straight or branched (C 1 -C 4) alkyl group (for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, isobutyl). C 3 -C 4 alkenyl means a straight or branched alkenyl group having 3 or 4 carbon atoms, such as propenyl or butenyl, C 3 -C 4 alkynyl means a straight or branched alkynyl group having 3 or 4 carbon atoms, such as propargyl. —Cs cycloalkyl (C1-C3) -alkyl means a straight or branched alkyl group containing from 1 to 3 carbon atoms; C 3 -C 6 -cycloalkyl, for example cyclopropylmethyl and cyclobutylmethyl. The term ar (C 1 -C 6 alkyl) denotes a straight or branched (C 1 -C 3) alkyl group (for example methyl, ethyl, propyl) which bears an aryl group, for example a phenyl group. The term polyhalogen (C 2 -C 4) alkyl group means a straight or a branched alkyl group having 2 to 4 carbon atoms which carries 2 or more halogen atoms, for example trifluoroethyl, trichloroethyl or trifluoropropyl.

Suitable non-toxic pharmaceutically acceptable salts of the 9-aminoalkyl-9,10-methanoanthracene derivatives of the general formula I are addition salts with organic and inorganic acids, for example hydrochlorides, hydrobromides, acetates, oxalates, citrates, tartrates, succinates, fumarates and lactates,

The 9-aminoalkyl-9,10-dihydro-9,10-niethanoanthracene derivatives (hereinafter referred to as "9-aminoalkylmethanoanthracacene derivatives") of formula I are characterized by an aminoalkyl side chain at the 9-position of 9,10-dihydro-9,10 -methanoanthracene skeleton.

Although a large number of dibenzotricyclic compounds have been known and some are used as clinical drugs, particularly as psychotropic agents, no dlbenzotricyclic compounds containing a 9,10-dihydro-9,10-methanoanthacene ring, such as a dibenzotricyclic skeleton, have been used for this purpose. The 9-aminoalkylmethanoanthracene derivatives (I) have now become accessible when the key intermediate 9-formyl-9,10-dihydro-9,10-methanoanthracene II has been synthesized.

CHO (in

9-Aminoalkylmethanoanthracene derivatives (IJ) are novel substances which are characterized by a broad spectrum of valuable pharmacological effects, in particular on the central and autonomic nervous system. , ptosi, an effect on muscle relaxation as well as an antitetrabenazine effect, and are therefore useful as an irritating drug, as an anti-depression drug, and also as a powerful means of soothing.

The 9-aminoalkylmethanoanthracene derivatives of the general formula I, in which A‘ represents a methylene group, optionally substituted with 1 to 2 carbon atoms, have a strong antihistaminic, anticolinergic and antiserotonin effect. They also have an antitetrabenine effect. They are therefore useful antihistametic and antiallergic drugs.

The O-aminoalkylmethanoantliracene derivatives of formula I wherein A is C 2 -C 3 alkyl- or C 2 -C 3 alkenyl have potent antitetrabenazine activity. They also potentiate the effect of norepinephrine and have an antireserpine, antihistaminic, anticolinergic and antiserotonin effect. Their acute toxicity and acute cardiotoxicity are low. They are therefore useful antidepressant and antihistaminic drugs.

All 9-aminoalkylmethanoanthracene derivatives of the general formula I have a certain degree of antitetrabenazine, anticolinergic, antihistaminic, antiserotonin and sedative effect.

As the quencher, the compounds of the formula I are preferably those in which R1 is C1-C2 alkyl and R2 is hydrogen or C1-C2 alkyl and A‘ is a direct bond. Preferred antihistaminic or antiallergic drugs of the formula I are those in which R 1 is C 1 -C 2 alkyl, R 2 is hydrogen or C 1 -C 2 alkyl and A 1 is methylene. Preferred antidepressants of the compounds of formula (I) are those wherein A A is ethylene or vinylene. Particularly preferred are those compounds of formula I wherein R 1 and R 2 are each independently hydrogen or C 1 -C 2 alkyl and A 1 is ethylene or vinylene. Most preferred are those wherein A 1 is ethylene, R 1 is hydrogen or methyl and R 2 is methyl.

The 9-aminoalkylmethanoanthracene derivatives of the formula I and their non-toxic pharmaceutically acceptable salts can be administered orally or parenterally, usually at a dose of 5 to 509 mg / human body, preferably 25 to 500 mg / human body (about 60 kg body weight per day). pharmaceutical preparations.

They can be administered, for example, in the form of conventional solid pharmaceutical preparations (for example, powders, granules, tablets, capsules) or in the form of conventional liquid pharmaceuticals. preparations (e.g., suspensions, emulsions, solutions). These preparations are obtained by conventional processing of either the 9-aminoalkylmethanoanthracene derivatives (I) or non-toxic pharmaceutically acceptable salts thereof alone or in combination with suitable adjuvants (e.g. starch, lactose, talc).

The 9-aminoalkylmethanoanthracene derivatives of the formula I can be prepared from the 9-formyl-9,10-dihydro-9,10-methanoanthracene of the formula II conveniently via their suitable derivatives.

The present invention provides a process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives of formula (I) and non-toxic pharmaceutically acceptable salts thereof, characterized in that the compound of formula (VI),

where

A ‘is as defined above, together with an amine of formula V

Η — N — Rt

Rz (V) where

R 1 and R 2 have the same meaning as described above simultaneously by condensation and reduction, whereupon the resulting compound of formula I is optionally converted to its non-toxic pharmaceutically acceptable salt.

Simultaneous condensation and reduction can be carried out by known methods. For example, a conventional Leuckart-Wallachic formic acid reaction (Organic Reactions, vol. 5, p. 301, John Wiley & Sons, Inc.J) can be used. In this procedure, a compound of formula VI is added to the aminoformormamine of formula V The reaction may also be carried out in the presence of an inert solvent such as benzene, toluene, nitrobenzene, tetrahydrofuran or dioxane.

The simultaneous condensation and reduction can also be carried out by hydrogenating a mixture of a compound of formula VI and an amine of formula V in the presence of Raney nickel, platinum oxide or palladium, optionally in the presence of an inert solvent. The hydrogenation pressure can vary from atmospheric pressure to higher pressure. A condensing agent such as sodium acetate may be used in the reaction.

Simultaneous condensation and reduction can also be carried out using the sodium-alcohol, zinc-acid or zinc-alkali hydroxide system. Optionally, the reaction can be carried out in an inert solvent such as an alcohol (e.g. methanol, ethanol, isopropanol), liquid ammonia, acetic acid or ethers (e.g. diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran).

The condensation and reduction can also be carried out by reducing in a conventional manner a Schiff base or an enamine prepared from a compound of formula VI and an amine of formula V. The reduction can be carried out catalytically as described above or using reducing agents such as sodium borohydride. diborane, lithium aluminum hydride, sodium aluminum diethyldihydride, sodium borohydride or sodium bis (2-methoxyethoxy) aluminum hydride in an inert solvent such as methanol, ethanol, isopropanol, n-butanol, t-butanol, benzene, toluene, diethyl ether, dioxane or diisopropyl ether. in this case, vary from -10 ° C to the reflux temperature of the reduction system.

The 9-aminoalkylmethanoanthracene compounds of the formula I thus prepared according to the invention can be separated from the reaction mixture and purified in a conventional manner.

The 9-aminoalkylmethanoanthracene compounds of formula (I) may be converted into their salts by conventional means, or the free bases may be liberated with the salt in conventional manner.

The key intermediate, 9-formyl-9,10-dihydro-9,10-methanoanthracene of formula II, can be prepared from 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene of formula A

rearrangement.

The rearrangement of amine derivatives and .alpha.-aminoalcohols by nitrous acid is known as the Demjan rearrangement and the Tiffeneu-Demjan rearrangement [Organic Reactions, Vol. 11, p. 157, John Wiley Sons, Inc.]. Rearrangements of this type have been used in most published cases in ring expansion reactions, and only a few cases where this rearrangement has been applied to ring shrinkage have been reported. The rearrangement of the 9,10-ethanoanthracene derivative to 9-formyl-9,10-dihydro-9,10-methanoanthracene has not been published and is therefore a novel method for preparing 9-formyl-9,10-dihydro-9,10-methanoanthracene.

Rearrangement of 9-amino-12-hydroxy-9,10-dihydro200182

-9,10-ethanoanthracene to 9-formyl-9,10-dihydro-9,10-methanoanthracene can be carried out by treatment with nitrous acid. 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene is treated with nitrous acid or a metal nitrite such as sodium nitrite or potassium nitrite in an acidic medium such as acetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or a mixed solution thereof. The reaction may optionally be carried out in an inert solvent such as water, methanol, ethanol, acetone, benzene, toluene, chloroform, dichloroethane, dichloromethane, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, dimethylsulfoxide or dimethylformamide or mixtures thereof. The reaction temperature in this case may vary from the temperature given by the ice-cooling bath to the reflux temperature of the reaction system.

The 9-formyl-9,10-dihydro-9,10-methanoanthracene II thus obtained can be isolated from the reaction mixture in a conventional manner and purified.

Compound A (i.e. 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene) can be prepared from a compound of formula B,

C = N where

Ts represents nu, ie.

p-toluenesulfonyloxy-

where

R is hydrogen or a hydroxyl protecting group such as acetyl, benzoyl or tetrahydropyranyl by a rearrangement such as Curtius reaction or Hoffman rearrangement and hydrolysis. The rearrangement can be carried out, for example, by the general procedure of the Curtius reaction (Organic Reactions, vol. 3, p. 337, John Wiley and Sons, Inc) and the hydrolysis can be carried out under conventional hydrolysis conditions of urethane or isocyanate derivatives.

Intermediates for the synthesis of 9-aminoalkylmethanoanthracene compounds of formula (I) may be prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene of formula (II) using conventional reactions such as oxidation, reduction, hydrolysis, carbon expansion reactions. chains (substitution, Wittig reaction, Reformats reaction, Grignard reaction) etc.

Starting materials for the synthesis of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene derivatives can be prepared, for example, 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 chromium oxide 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-methanoanthracene by treatment with a reducing agent such as sodium hydride 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-toluenesulfenyl chloride in the presence of a base in an inert solvent.

4. The 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid is converted to the corresponding acid chloride by reaction with thionyl chloride, optionally in the presence of an inert solvent, and the acid chloride is converted to 9,10-dihydro-9,10-methanoanthracene -9-carboxamide by conventional reaction with ammonia,

5. The dehydration of 9,10-dihydro-9,10-methanoanthracene-9-carboxamide to 9,10-dihydro-9,10-methanoanthracene-9-carbonitrile is carried out using phosphorus oxychloride, optionally in the presence of an inert solvent.

Starting materials for the synthesis of 9 -? - aminoethyl-9,10-dihydro-9,10-methanoanthracene derivatives can be prepared, for example, from 9-formyl-9,10-dihydro-9,10-methanoanthracene (II) or its derivatives as follows. :

where

Ts is as defined above.

6. 9,10-Dihydro-9,10-dlethano-9-anthrylacetic acid ethyl ester is obtained from 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid by conventional Arndt-Eistert synthesis,

7. 9,10-Dihydro-9,10-methano-9-anthrvlacetic acid is obtained from the corresponding ethyl ester by a conventional hydrolysis procedure,

8. 9-β-hydroxyethyl-9,10-dihydro-9,10-methanoanthracene is obtained by reduction of [9,10-dihydro-9,10-methano-9-anthryl] acetic acid ethyl ester with a reducing agent such as lithium aluminum hydride or sodium aluminum trimethyldihydride in an inert solvent,

9. 9-R-tosyloxyethyl-9,10-dihydro-9,10-methanoanthracene is obtained as described above,

10. [9,10-dlhydro-9,10-methano-9-anthryl] acetaldehyde is obtained from 9-formyl-9,10-dihydro-9,10-methanoanthracene by Wtlg reaction with methoxymethyltriphenylphosphonium chloride and subsequent acid hydrolysis,

11. [9,10-Dihydro-9,10-methano-9-anthryl] acetonitrile can be obtained from 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene by reaction with metal cyanide in an inert solvent.

Starting materials for the synthesis of 9-γ-aminopropyl- and 9- (5-aminobutyl-9,10-dihydro-9,10-methanoanthracene derivatives) can be obtained, for example, from 9-formyl-9,10-dihydro-9,10-methanoanthracene (II) as follows:

where

Ts is as defined above, i.

12. β- [9,10-Dihydro-9,10-methano-9-anthryl] acrylic acid prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene by Wtlg reaction with triethylphosphone acetate and ester hydrolysis function,

13. β- [9,10-Dihydro-9,10-methano-9-anthryl] propionic acid is prepared from the corresponding acrylic acid by conventional hydrogenation,

14. 9-γ-Hydroxypropyl-9,10-dihydro-9,10-methanoanthracene is prepared from β- [9,10-dihydro-9,10-methano-9-anthryl] propionic acid by treatment with a reducing agent such as lithium aluminum hydride or sodium 2U0182 aluminum diethyldihydride in an inert solvent,

15. 9-γ-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from the corresponding alcohol as described above,

16. 9-p-Hydroxypropyl-9,10-dihydro-9,10-methanoanthracene is oxidized to the corresponding aldehyde by treatment with an oxidizing agent as a complex of chromium trioxide with pyridine in an inert solvent,

17. and 18. 5- [9,10-dihydro-9,10-methano-9-anthryl] propionic acid is converted to β- [9,10-dihydro-9,10-methanoanthryl] propionitrile as described above,

19. [9,10-Dihydro-9,10-methano-9-anthryl] acrylic acid aldehyde prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene by Wittig reaction with formylmethylene-triphenylphosphoric orange.

? - [9,10-Dihydro-9,10-methano-9-anthrylbutyric acid derivatives can be prepared in the same manner as described above.

The compound of formula (III) may be prepared from the corresponding carboxylic acid derivative by a conventional procedure using the corresponding amine.

The following examples are for illustrative purposes only, but do not limit the scope of the invention in any way.

Example 1

To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (3.0 gj in acetic acid (240 mL)) was added a solution of sodium nitrite (6.7 gj in water (130 mL) at The reaction mixture was diluted with water and extracted with benzene, and the benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness. Crude 9-formyl-9,10-dihydro-9,10-methanoanthracene (2.8 g) was obtained, which was recrystallized to give colorless crystals (2.45 g), m.p. 99-100 ° C. further purification by crystallization gave analytically pure 9-formyl-9,10-dihydro-9,10-methanoanthracene, m.p. 102.5 ° C.

Example 2

To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (50 mg) in concentrated hydrochloric acid (2 mL) and water (2 mL) was added a solution of sodium nitrite (112 mg) in water. (1.0 mL) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour and then at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness. Crude 9-formyl-9,10-dihydro-9,10-methanoanthracene (35 mg) was obtained.

Example 3

To a mixture of morpholine (870 mg) and formic acid (460 mg) heated to 60 ° C was added 3- (9,10-dihydro-9,10-methano-9-anthryl) -proplonaldehyde (50 mg) and the resulting mixture was stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-morpholinopropyl-9, m.p. 10-dihydro-9,10-methanoanthracene, which is converted to the hydrochloride with a melting point of 173-176.5 degrees Celsius.

Starting β- (9,10-dihydro-9,10-methano-9-anthryl) propionaldehyde (m.p. 135-140 ° C) was prepared from 9-γ-hydroxypropyl-9,10-dihydro-9,10-methanoanthracene by treatment with of chromium trioxide-pyridine complex in dichloromethane for 5 minutes at room temperature.

Example 4

A solution of β- (9,10-dihydro-9,10-methano-9-antbryl) propionaldehyde (150 mg) and sec-butylamine (100 mg) in methanol was stirred at -5 and 0 ° C for 30 minutes. Sodium borohydride (50 mg) was added to the solution, and the resulting mixture was stirred at 0 ° C for 2 hours, diluted with water, extracted with benzene, shaken with hydrochloric acid, basified with aqueous ammonia, and extracted with ethyl acetate. It was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-sec-butylaminopropyl-9,10-dihydro-9,10-methanoanthracene, which was converted to the hydrochloride, m.p. 216-219 ° C.

The following compounds were prepared by similar methods:

9-aminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. > 300 ° C;

9-methylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 281.5-283 ° C;

9-dimethylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 257-259 ° C;

9-ethylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 283-284 ° C;

9-ethylmethylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 249.5-251 ° C;

9-isopropylaminomethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 103-103.5 ° C;

9-sec-butylanomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 234-235.5 ° C,

9-isobutylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 227-229 ° C;

9-cyclopropylmethylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 240.5-243.5 ° C,

9-allylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 208 DEG-209 DEG C .;

9-benzylaminomethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 94-97 ° C;

9-piperidinomethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 114-115 ° C;

9-morpholinomethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 160-163 ° C;

9-, 3-aminoethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 158-160 ° C;

9- [3-methylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 304 DEG-305 DEG C., g-4-dimethylaminoethyl g. ,

9n (3-ethylaminoethyl-9,10-dihydro-9,10-methynoanthracene hydrochloride, m.p. 297-299 ° C),

9- [3-diethylaminoethyl-9,10-dihydro-9,10-methanoanthracene, I. Spectrum: 3065, 1468, 1445, 1380, 1280, 1205, 1155, 1010, 765, 745 cm < -1 >

9- (3-sec-butylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 267-268 ° C),

9-d-N, N-dicyclopropylmethylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 137-140 ° C;

9- <3-allylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 242-243 ° C;

9-N-benzylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 233-235 ° C;

9-) S-morpholinoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 263-264 ° C;

9-y-aminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 275 ° C;

9-.gamma.-methylaminopropyl-9,10-dihydro-9,10-methyliananthracene hydrochloride, m.p. 259 DEG-260 DEG C .;

9-t-Methylamino-α-propenyl-9,10-dlhydro-9,10-methanoanthracene hydrochloride, m.p. 244-246 ° C;

9 - [- dimethylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 247-247.5 ° C,

9-t-ethylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 184-186 ° C;

9 - [- N-ethyl-N-methylaminopropyl-9,10-dihydro-9,10-methanoanthracenoxalate, m.p. 168-169 ° C,

9-t-isopropylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 255-256 ° C,

9-t-isobutylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 248-252 ° C,

217 DEG-219 DEG C. 9-.beta.-butylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 207-211 ° C,

9-y-allylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 226-228 ° C;

9-γ-benzylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 197-201 ° C;

9-γ-N-methyl-N-propargylaminopropyl-9,10-dihydro-9,10-methanoanthracene, m.p. 130-131 ° C;

9-y-N- (2,2,2-trifluoroethyl) -N-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 170-172.5 ° C,

9 - piperidinopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 280-283 ° C;

9-γ-pyrrolidinopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 244-248 ° C;

174 DEG-177 DEG C. 9-.gamma.-morpholinopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride,

9- <5-dimethylaminobutyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 201-202.5 ° C,

9- [S-dimethylamino-α-butenyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 154.5-155 ° C;

9-propargylaminomethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 125-128 ° C,

9- [3-methyl-γ-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 228-230 ° C;

9-N-methyl-γ-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 229-232 ° C;

9-.alpha.-methyl-1,3-dimethylaminoethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 75-78 ° C.

Claims (9)

A process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives of the general formula I, wherein: A ‘represents a direct bond, C 1 -C 3 alkylene- or C 2 -C 3 alkenylene and each of the symbols R 1 and R 2 are hydrogen, C 1 -C 4 alkyl-, C 3 -C 4 alkenyl-, C 3 -C 4 alkynyl, C 3 -C 6 cycloalkyl (C 1 -C 5 alkyl-, ar (C 1 -C 3) alkyl- or polyhalogen (C 2 -C 4) alkyl groups or R 1 and R 2 taken together with the adjacent nitrogen atom represent a 5- to 7-membered nitrogen-containing heterocyclic ring optionally containing an additional heteroatom and non-toxic pharmaceutically acceptable salts thereof, characterized in that the compound of formula VI, wherein A ‘is as defined above, together with an amine of formula V Η — N — Ri R2 (Vj where R 1 and R 2 have the same meaning as described above simultaneously by condensation and reduction, whereupon the resulting compound of formula I is optionally converted to its non-toxic pharmaceutically acceptable salt. 2. The process of claim 1 wherein the simultaneous condensation and reduction is carried out by heating the mixture of the starting tricyclic compound with the amine formate or the mixture of the starting tricyclic compound with the amine and formic acid to a temperature of from room temperature to 250 ° C. 3. Process according to claim 2, characterized in that the simultaneous condensation and the reduction are carried out optionally in the presence of a solvent. 4. The process of claim 1 wherein the condensation and reduction is carried out by reacting a mixture of the starting tricyclic compound and the amine with hydrogen in the presence of a catalyst, optionally in the presence of an inert solvent, at atmospheric or higher pressure, optionally using a condensing agent. 5. The process of claim 1 wherein the simultaneous condensation and reduction is carried out by reacting a mixture of the starting tricyclic compound and the amine with sodium in alcohol or zinc in acid or alkaline hydroxide. 6. The process of claim 1 wherein the simultaneous condensation and reduction is carried out by reducing a Schiff base or an enamine prepared from a starting tricyclic compound and an amine. 7. A process according to claim 1, wherein the reduction is carried out using a reducing agent in an inert solvent at a temperature of from -10 DEG C. to the boiling point of the reaction system. 8. The process of item 1 for preparing compounds of formula I wherein A 'is C2-C3 alkyl len- or C2-C3 alkenylene and each of R1 and R2 is hydrogen, C1-C4 alkyl-, C3-C4 alkenyl- , C 3 -C 6 cycloalkyl (C 1 -C 3) alkyl- or ar (C 1 -C 3) alkyl or R 1 and R 2 together with the nitrogen atom to which they are attached represent a 5- to 7-membered nitrogen-containing heterocyclic ring optionally containing an additional oxygen heteroatom and non-toxic pharmaceutically acceptable salts thereof, wherein A 1, R 1 and R 2 are as defined in this paragraph. 9. The process of item 1 for preparing compounds of formula I wherein A 'is a direct bond and each of R 1 and R 2 is hydrogen, C 1 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 6 cycloalkyl (C 1 -C 3) ) an alkyl or ar (C 1 -C 3) alkyl group or R 1 and R 2 'together with the nitrogen atom to which they are attached form a 5- to 7-membered nitrogen-containing heterocyclic ring optionally containing an additional oxygen heteroatom and non-toxic pharmaceutically acceptable salts thereof; The method of claim 1, wherein A 1, R 1 and R 2 are as defined in this point.