CS200184B2 - Method of preparing 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives - 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-dihydro-9,10-methanoanthracene derivatives and no pharmacological study of 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 are represented by formula (I) wherein

A * is a direct bond, C 1 -C 3 alkylene or C 2 -C 3 alkenylene.

In the above definition of the individual symbols, the C 1 -C 3 alkenyl 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 alkenylene" is especially 1-propenylene.

Suitable non-toxic pharmaceutically acceptable salts of the 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives of the formula I are the 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-methanoanthracene derivatives (hereinafter referred to as "9-aminoalkylmethanoanthracene derivatives") of formula I are characterized by the aminoalkyl side chain at the 9-position of the 9,10-dihydro-9,10-methanoanthracene skeleton .

Although a large number of dibenzotricyclic compounds have been known and some are used as clinical drugs, in particular as

(AND)

203184 psychotropic agents, no dibenzotricyclic compounds containing a 9,10-dlhydro-9,10-methanoanthracene ring, such as a dibenzotricyclic skeleton, were 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.

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 general formula I, in which A ‘represents a direct bond, show 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 * is a methylene group, optionally substituted with 1 to 2 carbon atoms, have a potent antihistaminic, anticolinergic and antiserotonin effect. They also have an antltetrabenazine effect. They are therefore useful antihistaminic and antiallergic drugs.

The 9-aminoalkylmethanoanthracene derivatives of the general formula I in which A ‘represents a C 1 -C 3 alkylene- or a C 1 -C 3 alkenylene group have a potent antltetrabenazine 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.

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 500 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 (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, which comprises reducing a compound of formula (X),

where

A ‘is as defined above and

R 7 represents a nitrile group (- C = N) or an aldehyde oxime group (- C = NOH), whereupon the resulting compound of formula I is optionally converted to its non-toxic pharmaceutically acceptable salt.

A reducing agent, such as an alkali metal in an alcoholic solvent, metal hydrides and the like, is preferably used for the reduction. Also electrolytic reductions can be used for this purpose.

Particularly preferred is the use of metal hydrides 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, dlisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether) , cyclohexane), aromatic hydrocarbons (e.g. benzene, toluene) 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 reduction system.

Another example of a practicable metal hydride as a reducing agent is sodium borohydride, and diborane.

The reduction can also be carried out by per se known hydrogenation on a catalyst such as Reney nickel, platinum (IV) oxide or palladium (IV) oxide, optionally in the presence of an inert solvent. The hydrogenation pressure may vary from atmospheric pressure to elevated pressure.

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 α-aminoalcohols by nitrous acid is known as the Demyan rearrangement and the Tiffeneu-Demyan rearrangement (Organic Reactions, vol. 11, p. 157, John Wiley and Sons, Inc.j. ring expansion reactions, and only a few cases where this rearrangement has been applied to ring shrinkage have been reported.

9,10-ethanoanthracene to 9-formyl-9,10-dihydro-9,10-1-methanoanthracene 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 dimethylformaimide 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-dlhydro-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 may 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 may 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:

where

Ts is p-toluenesulfonyloxy.

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-methananthracene is prepared from 9-formyl9,10-dihydro-9,10-methanoanthracene by treatment with a reducing agent such as sodium borohydride or lithium aluminum hydride in an inert solvent,

3. 9-Toxyloxymethyl-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.

4th 9,10-dihydro-9,10-methanoanthracen-9-carboxylic acid was converted to the corresponding acid chloride by reaction with thionyl chloride optionally in an inert solvent and the acid chloride is converted to ^9,10-J-9,10 idlhydro methanoanthracen- 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-β-aminoethyl-9,10-dlhydro-9,10-methanoanthracene derivatives can be prepared, for example, from 9-formyl-9,10-dihydro-9,10-methanoanthracene (II) or its derivatives as follows. :

CHO

CHO

OTs

CzN kde

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 a conventional Arndt-Eistert synthesis procedure,

7. 9,10-Dihydro-9,10-methano-9-anthrylacetic acid is obtained from the corresponding ethyl ester by a 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 lithium aluminum hydride or sodium aluminum diethyldihydride in an inert solvent,

9. 9- (3-Toxyloxyethyl-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 methoxymethyltriphenylphosphonium 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 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.

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 and triethylphosphonoacetate and hydrolysis of the ester function,

13. 3- (9,10-dihydro-9,10-methano-9-anthryl) propionic acid prepared from the corresponding acrylic acid by conventional hydrogenation,

14. 9-p-Hydroxypropyl-9,10-dihydro-9,10-methanoanthracene prepared from [3- [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-γ-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene is prepared from the corresponding alcohol as described above,

16. 9-γ-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-anthrylpropionic acid) is converted to? - (9,10-dihydro-9,10-methanoanthryl) propionitrile as described above,

19. 1- (9,10-Dihydro-9,10-methano-9-anthryl) acrylic acid aldehyde is prepared from:

9-formyl-9,10-dihydro-9,10-methanoanthracene by Wittig reaction with formylmethylene-triphenylphosphorane.

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

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). The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated. Crude crystals are obtained

3-formyl-9,10-dihydro-9,10-methanoanthracene (2.8 g), which were 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 mg) in concentrated hydrochloric acid (2 mL) and water (2 mL) was added a solution of sodium nitrite (112 mgj in water ( 1.0 mL] at 0 [deg.] C. The resulting mixture was stirred at 0 [deg.] C. for 1 hour and then at room temperature for 5 hours, diluted with water, and extracted with benzene, washed with water, dried over sodium sulfate and evaporated to dryness. The crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (35 mg) were obtained.

Example 3

A solution of 12-acetoxy-9,10-dihydro-9,10-ethanoanthracene-9-carboxylic acid (1.0 g) in benzene (10.0 mL) and thionyl 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, which was dissolved in dry acetone (25.0 mL) and added to ice with ice cooling. A solution of sodium azide (0.63 g) in water (1.3 ml) was added, the mixture was stirred under ice-cooling for 2 hours, diluted with water, extracted with benzene, washed with water, dried over anhydrous sodium sulfate, boiled 2. The reaction mixture was concentrated to dryness to give 9-isocyanato-12-acetoxy-9,10-dlhydro-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 hours. After evaporation of the ethanol, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallized 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 / 3- (9,10-dihydro-9,10-methano-9-anthryl) propionitrile (250 mg) and lithium aluminum hydride (100 mg) in dioxane (12 mL) was stirred at 60 ° C for 5 hours. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-γ-aminopropyl-9,10-dihydro-9,10-methanoanthracene which was converted to the hydrochloride, m.p. 275 ° C. (decomposition).

The following compounds were prepared in a similar manner:

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

9- [3-Aminoethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 158-160 ° C.

Claims (3)

SUBJECT 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, a C 1 -C 3 alkylene- or a C 2 -C 3 alkenylene group and non-toxic pharmaceutically acceptable salts thereof, characterized in that a compound of formula X, ynAlezu is reduced wherein: A ‘is as defined above and R 7 represents a nitrile group (CC = N) or an aldehyde oxime group (CHCH = NOH), and the resulting compound of formula I is optionally converted to its non-toxic pharmaceutically acceptable salt. 2. A process according to item 1 for the preparation of compounds of formula I, wherein A * is C2-C3 alkylene or C2-C3 alkenylene, characterized in that the compound of formula X is reduced, wherein A ‘is as defined in this point. 3. A process according to item 1 for the preparation of compounds of formula I wherein A ‘is a direct bond, characterized in that a compound of formula X wherein A A is as defined in this point is reduced.