CS200181B2 - Process for preparing derivatives od 9-aminoalkyl 9,10-dihydro-9,10-methanoanthracene - 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-dihydro-9,10-methanoanthracene has been known since 1920 and several chemical studies have been published on 9,10-dihydro-9,10-methanoanthracene derivatives, but no report on the synthesis of 9-aminoalkyl has been published anywhere -9,10-d''hydro-9,10-methanoanthracene derivatives or any pharmacological studies 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,

where

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

R 1 and R 2 are hydrogen, C 1 -C 1 alkyl-, C 5 -C 4 alkenyl-, C 3 -C 4 alkynyl, C 3 -C 6 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 definition of the individual symbols, the C 1 -C 3 alkylene group is a straight or branched alkylene group having 1 to 3 carbon atoms (for example, methylene, ethylene, propylene, 1-methylethylene). The term "C2-C3 alkenyl lens" refers specifically to 1-propenylene. The term "C 1 -C 4 alkyl" denotes a straight or branched alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, isobutyl J).

The term C3 -C4 alkenyl means a straight or branched alkenyl group having 3 or 4 carbon atoms, such as a propenyl or butenyl group. C3-C4 alkynyl means a straight or branched alkynyl group having 3 or 4 carbon atoms, such as propargyl. C 3 -C 6 cycloalkyl (C 1 -C 3) alkyl means a straight or branched (C 1 -C 3) alkyl group bearing a C 3 -C 6 cycloalkyl group, for example cyclopropylmethyl and cyclobutylmethyl. (C 1 -C 8) alkyl means 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 6 -alkyl) refers to a straight or branched (C 2 -C 4) alkyl group bearing 2 or more halogen atoms, for example trifluoroethyl, trichloroethyl or trifluoropropyl. -, piperidino-, morpholino, and triomorpholino.

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

The 9-aminoalkyl-9,10-dihydro-9,10-inethanoanthracene derivatives (hereinafter referred to as "9-aminoalkylmethanoanthracene derivatives") of the general Formula I are characterized by an ainoinoalkyl side chain at the 9-position of the 9,10-dihydro-9,10-methananthracene skeleton .

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

The 9-aminoalkylmethanoanthracene derivatives (I) are novel substances which are characterized by a wide range of valuable pharmacological effects, in particular on the central and autonomic nervous systems. In particular, the 9-aminoalkylmethanoanthracene derivatives of the formula I, in which A ‘represents a direct bond, exert a potentiating effect on hexabarbital anesthesia, hypothermia, ptosi, an effect on muscle relaxation as well as an antitetrabenazine effect. They are therefore useful as irritating drugs, as anti-depressant drugs as well as potent tranquillizers.

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

The 9-aminoalkylmethanoanthracene derivatives of the general formula I wherein A ‘represents C 2 -C 3 alkylene or C 2 -C 3 alkenylene have a potent antitetrabenazine activity. They also potentiate the action 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.

Among the compounds of formula I, preference is given to those in which R1 is C1-C3 alkyl and R2 is hydrogen or C1-C2 alkyl and A‘ is a direct bond. Preferred antihlistamine 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 alkylene or vinyl. 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 compounds wherein A 1 is ethylene, R 1 is hydrogen or methyl and R 2 is methylene.

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 1 to 500 mg / human body preferably 25 to 500 milligrams / human body (about 60 mg body weight per day as conventional pharmaceuticals). preparations.

They can be administered, for example, in the form of conventional solid pharmaceutical preparations (e.g. powders, granules, tablets, capsules) or in the form of conventional liquid pharmaceutical 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 auxiliaries (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 corresponding compound of formula III is reduced,

where

A 1, R 1 and R 2 are as defined above and the resulting compound is optionally converted to a non-toxic pharmaceutically acceptable salt.

A reducing agent, such as an alkali metal in an alcoholic solvent, a metal hydride and the like, is preferably used for the reduction. Electrolytic reductions can also be used for this purpose.

Particularly preferred is the use of a metal hydride such as lithium aluminum hydride, sodium aluminum diethyldihydride and sodium bis (2-methoxyethoxy) aluminum hydride in an inert organic solvent such as ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether) ) or mixtures thereof The reaction temperature may in this case be from the temperature corresponding to the ice-cooling bath to the reflux temperature of the reducing system.

Another example of a practically useful metal hydride reducing agent is sodium borohydride, especially when used in the presence of a salt such as aluminum chloride or with the activation of the carboxamide group of a compound of formula III with triethyloxonium fluoroborate and the like. mention diboran.

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, in turn, the free bases may be liberated from the salts in a 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, Jahn Wiley and 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. Derivation of the derivative

9,10-ethanoanthracene to 9-formyl-9,10-dihydro-9,10-methanoanhracene has not yet been disclosed and is therefore a novel process for the preparation of 9-formyl-9,10-dihydro-9,10-methanoanthracene.

The rearrangement of 9-amino-12-hydroxy-9,10-dihydro-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 of the formula 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,

where

R is hydrogen or a hydroxy 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 can be prepared from 9-formyl9,10-dihydro-9,10-methanoanthracene of formula II using conventional reactions such as oxidation, reduction, hydrolysis, carbon chain extension ( substitution, Wittig reaction, Reformat reaction, Grignard reaction) etc.

The starting materials for the synthesis of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene derivatives can be prepared, for example, by means of:

Ts is p-toluenesulfonyloxy, i.

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 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-toluenesulfonyl 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- [3-aminoethyl-9,10-dihydro-9,10-methanoanthracene derivatives can be prepared, for example, from 9-forinyl-9,10-dihydro-9,10-methanoanthracene (II) or derivatives thereof by the following: as follows:

where

Ts is as defined above.

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

7th 9,10-dihydro-9,10-methano-9-anthryloctová acid was obtained from the corresponding _e thylesteru conventional hydrolysis procedure,

8. 9- / 3'-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 is lithium aluminum hydride or sodium aluminum diethyldihydride in an inert solvent.

9. 9- (S'-tosyloxyethyl-9,10-dihydro-9,10-methanoanthracene) is obtained as described above,

10. [9,10-Dihydro-9,10-methano-9-anthryl] acetaldehyde is obtained from 9-formyl-9,10-dihydro-9,10-methanoanthracene by Wittig reaction with methoxyethoxytriphenylphosphonium chloride followed by 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 g-α-aminobutyl-10,10-dihydro-9,10-methanoanthracene derivatives can be obtained, for example, from 9-formyl-9,10-dihydro-9,10-methanoanthracene (II) as follows:

COOH

C = N 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 Wittig reaction with triethylphosphonate and hydrolysis of the ester 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 aluminum diethyldihydride in an inert solvent,

15. 9-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.? - [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. β- (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 formylmethylenetrifenylphosphorane.

Β- [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 g) in acetic acid (240 mL) was added a solution of sodium nitrite (6.7 g) in water (120 mL). ) at 2-5 ° C and the resulting mixture was stirred at the same temperature for 1 hour and then at 95-105 ° C 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 (2.8 g) was obtained, which was recrystallized to give colorless crystals (2.45 g), m.p. 99-100 ° C. After further purification by crystallization, analytically pure 9-formyl-9,10-dihydro-9,10-methanoanthracene of melting point 102.5 ° C is obtained.

Example 2

To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (50 mgj in concentrated hydrochloric acid (2 ml) and water (2 ml) was added a solution of sodium nitrite (112 mg) in water (1 ml). The 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 (35 mg) was obtained.

Example 1 a d 3

A solution of 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid (1.0 g) in benzene (10.0 mL) and thienyl chloride (4.0 mL) was refluxed for 4 hours. . Evaporation of excess thionyl chloride and benzene gave 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid chloride. The acid chloride was dissolved in dry acetone (25.0 mL) and a solution of sodium azide (0.63 gj in water (1.3 mL) was added under ice-cooling. The resulting mixture was stirred under ice-cooling for 2 hours. The benzene extract was washed with water, dried over anhydrous sodium sulfate, refluxed for 2 hours and then evaporated to dryness to give 9-isocyanato-12-acetoxy-9,10-dihydro-9,10-ethanoanthracene.

The isocyanate compound was dissolved in ethanol (12.0 mL) and 20% aqueous sodium hydroxide (12.0 mL) and the resulting solution was refluxed for 6 h. After evaporating the ethanol, the reaction mixture was diluted with water and extracted with ethyl acetate. water, dried over anhydrous sodium sulfate and evaporated to dryness to give crystalline 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (0.72 g), m.p. 181-181.5 ° C. Recrystallization from benzene gave analytically pure crystals of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene, m.p. 183.5 ° C.

Example 4

A mixture of monomethylamide / 3- (9,10-dihydro-9,10-methano-9-anthryl) propionic acid (1.0 g) and lithium aluminum hydride (0.5 g) in dioxane was stirred at 50 ° C for 2 hours. Excess lithium aluminum hydride is decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness. 9-γ-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene is obtained, which is converted to the hydrodochloride, m.p. 247-249 ° C. Recrystallization from isopropyl alcohol gave colorless crystals having a melting point of 259 DEG-260 DEG.

The starting amide is prepared as follows:

A solution of [3- (9,10-dihydro-9,10-methano-9-anthryl] -propionic acid and thionyl chloride in benzene was refluxed for 4 hours. After evaporation of the excess thionyl chloride and benzene, [3- (9,10- dihydro-9,10-methano-9-anthryl) propionic acid, which is dissolved in dry tetrahydrofuran, is added to a 30% aqueous monomethylamine solution at 0 to 5 ° C, stirred at 0 to 15 ° C, diluted The ethyl acetate layer was washed with water, dried over anhydrous sodium sulphate and evaporated to dryness to give β- (9,10-dihydro-9,10-methano-9-anthryl) propionic acid monomethylamide, m.p. 201 ° C.

The following compounds were prepared by similar procedures:

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-methoanthracene hydrochloride, m.p. 249.5-251 ° C;

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

9-sec-butylaminomethyl-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-allylammomethyl-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-N-methylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 304-305 ° C;

N, N-dimethylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 239-240.5 ° C;

9- [3-ethylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 297-299 ° C,

9- / 3-diethylaminoethyl-9,10-dihydro-9,10-methanoanthracen ID NO. 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- [3-N, N-dicyclopropylmethylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 137-140 ° C;

9β / 3-allylaminoethyl-9,10-dohydro-9,10-methanoanthracene hydrochloride, m.p. 242-243 ° C;

9-β-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-γ-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 259-260 ° C;

9-γ-methylamino-α-propenyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 244-246 ° C;

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

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

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

9-γ-iisopropylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 255-256 ° C;

9-i'-1'-Butylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 248-252 ° C;

9-y-sec-butylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 217-219 ° C;

9-N-benzyl-N-cyclopropylmethylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 207-211 ° C,

9-y-allylaminopropyl-9,10-dlhydro-9,10-methanoanthracene hydrochloride, m.p. 226-288 ° 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-methyl aminopropyl-9,10-dihydro- 9,10-methanoanthracene hydrochloride, m.p. 170-172.5 ° C;

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

9 - / - 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-α-dimethylaminobutyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 201-202.5 ° C,

Claims (7)

A process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives wherein A ‘represents a direct bond, a C 1 -C 3 alkylene- or C 2 -C 3 alkeriyl group 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 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 and non-toxic pharmaceutically acceptable salts thereof, characterized in that the compound of formula III is reduced, A 1, R 1 and R 2 are as defined above and the resulting compound of formula I is 9-'-dimethylamino-α-butenyl-9,10-dihydrin-9,10-methanoanthracene hydrochloride, m.p. 154.5-155 ° C; 9-propargylaminomethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 125-128 ° C, 9-β-methyl-N-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 228-230 ° C; 9-of-methyl-γ-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 229-232 ° C; 9- _N, N-dimethylaminoethyl 9,10-dihydro-9,10-methanoanthracene, m.p. 75-78 ° C. YNALEZU optionally converts to a non-toxic pharmaceutically acceptable salt. 2. A process according to claim 1, wherein the reduction is carried out electrolytically or using a reducing agent. 3. The process of claim 2 wherein the reducing agent is an alkali metal in an alcoholic solvent or metal hydride. 4. The process of claim 1 wherein the reduction is carried out in an inert organic solvent. 5. The process according to claim 1, wherein the reduction is carried out at a temperature from the temperature obtained by cooling with ice to the boiling point of the reaction mixture. 6. The process of item 1 for the preparation of compounds of formula I wherein A 'is C2-C3 alkylene or C2-C3 alkenylene and each of R1 and R2 is hydrogen, C1-C4-alkyl-, C3-C1 alkenyl, C 5 -C 6 cycloalkyl (C 1 -C 5 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 their non-toxic or a pharmaceutically acceptable salt thereof, wherein the compounds of formula (III) are those wherein A 1, R 1 and R 2 are as defined in this point. 7. The method 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 5 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, characterized in that the compound of formula (III) is that wherein A 1, R 1 and R 2 are as defined in this point.