CS200180B2 - Process for preparing derivatives of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene - Google Patents

Description

The invention relates to a process for the preparation of novel organic tricyclic compounds. In particular, it relates to 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives and their non-toxic pharmaceutically acceptable salts, pharmaceutical preparations containing as active ingredient at least one 9-aminoalkyl-9,10-dihydro-9,10- methanoanthracene or a non-toxic pharmaceutically acceptable salt thereof, a process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-dihydro-9,10-methanoanthracene derivatives and salts thereof, and the use of 9-aminoalkyl-9,10-dihydro-9 derivatives, 10-methanoanthracene and their salts. It also relates to 9-formyl-9,10-dihydro-9,10-methanoanthracene, which is a key intermediate in the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives, and a process for its preparation.

The skeleton of 9,10-dihydro-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 has been published on the synthesis of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives or any pharmacological studies concerning

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

It has now been found that the new 9-aminoalkyl-9,102

The 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,

(I) where

A is C 1 -C 1 alkylene- or C 5 -C 6 alkenyl and each of the symbols

R1 and R2 are hydrogen, C1-C4 alkyl-, C3-C4 alkenyl-, C3-C4 alkynyl, C3-C6 cycloalkyl (C1-C3) alkyl-, phenyl (C1-C3) alkyl or (C2-C4) alkyl substituted with two or three halogen atoms on the terminal carbon atom; or

R 1 and R 2 together with the adjacent atom

Are nitrogen-containing 5- to 7-membered heterocyclic ring of the general formula wherein

Z is a direct bond, methylene, oxygen or sulfur; and m is an integer of 2 or 3.

In the above definitions of the individual symbols, the C 1 -C 1 alkylene group is a straight or branched C 1 -C 4 alkylene group (e.g., methylene, ethylene, propylene, butylene, 1-methylethylene, 1-methylpropylene, 2-methylpropylene), C 3 -C 4 alkenylene is specifically 1-propenylene-, 1-butenylene-, 2-butenylene-, 1-methyl-1-propenylene- and 2-imethyl-1-propenylene, starting with the numbering of the carbon atoms starting from the carbon atom bound to 9 , 10-dihydro-9,10-methanoathracene skeleton. C 1 -C 4 alkyl means a straight or branched alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, isobutyl). C 3 -C 4 alkenyl means a straight or branched alkynyl 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. 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. The term phenyl (C 1 -C 3) alkyl means a straight or branched alkyl group. having 1 to 3 carbon atoms (for example methyl, ethyl, propyl) which bears (C2-Cd) alkyl substituted with two or three halogen atoms on a terminal carbon atom means, for example, trifluoromethyl, trichiorethyl or trifluoropropyl. Suitable 5- to 7-membered nitrogen heterocyclic rings are, for example, pyrrolidino, piperidino, morpholino and thiomorpholino.

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-aiminoalkylmethanoanthracene derivatives") of the general Formula I are characterized by an aminoalkyl side chain at the 9-position of the 9,10-dihydro-9,10-methanoanthracene glass .

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-methanoainthracene of formula II has been synthesized

CHO (tl)

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 methylene group, optionally substituted alkyl having 1 to 3 carbon atoms, have a potentiating effect on hexacarbital anesthesia, hypothermia, ptosi, an effect on muscle relaxation as well as an antitetrabenzine effect. They are therefore useful as irritating drugs, as anti-depressant drugs, as well as potent tranquillizers,

The 9-aminoalkylmelthananthracene derivatives of formula (I) wherein A is ethylene optionally substituted with 1 to 2 carbon atoms have a potent antihistaminic, anti-collinergic and antiserotonin effect. They also have an antitetrabenazine effect. They are therefore useful antihistaminic and antiallergic drugs.

The g-aminoalkylmethanoanthracene derivatives of formula I wherein A is C 3 -C 4 alkylene or C 3 -C 4 alkenylene have a potent antitetrabenazine action. They also potentiate the effect of norepinephrine and have an antlreserpine, 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, antiseirotonin and sedative effect.

Of the compounds of formula (I) of the formula I80, preference is given to those in which R1 is C1-C2 alkyl and R2 is hydrogen or C1-C2 alkyl and A is methylene. Preferred antihistaminic or antiallergic drugs of the formula I are those wherein R 1 is C 1 -C 2 alkyl and R 2 is hydrogen or C 1 -C 2 alkyl and A is ethylene. Preferred antidepressants of compounds of formula I are those wherein A is a propylene or propenylene group. Particularly preferred are those compounds of formula I wherein each of R 1 and R 2, independently of each other, is hydrogen or C 1 -C 2 alkyl and A is propylene or propenylene. Most preferred are those wherein A is propylene, R1 is hydrogen or methyl and R2 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 500 mg / human body, preferably 25 to 500 mg / human body (about 00 kg 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), characterized in that the compound of formula (IV),

where

A is as defined above and X is a conventional leaving group such as halogen (e.g., chlorine, bromine, iodine) or sulfonyloxy (e.g., methanesulfonyloxy, p-toluenesulfonyloxy, trichloromethanesulfonyloxy) with an amine of formula V,

Rl /

Η — N \

Rz (Vj where

R 1 and R 2 are as defined above, optionally in the presence of an inert solvent such as an ether (e.g. diethyl ether, diisopropyleither, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether), an alcohol (e.g. methanol, ethanol, isopropanol), an aromatic hydrocarbon (e.g. benzene, toluene), dimethylsulfoxide , dimethylformamide or pyridine, optionally in the presence of a basic condensing agent. Examples of basic condensing agents include amines (e.g. pyridine, picoline, triethylamine, dimethylainiline), metal hydrides (e.g. sodium hydride), metal alkoxides (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide), metal carbonates (e.g. sodium carbonate, potassium carbonate) ), metal bicarbonates (e.g., sodium bicarbonate), sodium amide, etc. The reaction temperature can vary from ice cooling to the reflux temperature of the reaction mixture, both in a closed and an open 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, 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

(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 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. 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.

The rearrangement of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanhracene 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-9,1D-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 Wley 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, Reformat 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:

CHO | 0)

CHgTs

COOH (3)

where

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-β-aminoethyl-9,10-dihydro-9,10-methanoanthracene derivatives can be prepared, for example, from 9-formyl-9,10-dihydro-9,10-methanoanthracene (II) or derivatives thereof as follows:

COOH (5)

C00C, H ₅ μ *

COOH

Italy (9)

OH

OTs

CHO (9)

Italy (11)

OTs

where

Ts has the above meaning, β. 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.

7. 9,10-Dihydro-9,10-methano-9-anthrylacetic 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 diethyldlhydride, 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 methoxymethyl-triphenylphosphonium 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-α-aminobutyl-9,10-dihydro-9,10-methanoanthracene derivatives can be obtained, for example, from 9-formyl-9,10-dihydro-9,10-mothanoanthracene ( II) as follows:

where

Ts is as defined above,

12. 6- (9,10-Dihydro-9,10-methano-9-anthryl) acrylic acid prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene by Wittig reaction with 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-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-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-dlhydro-9,10-methano-9-anthryl] propionic acid is converted to β- [9,10-dihydro-9,10-methanoanthryl] propionitrile as described above.

19. N- [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-triphenylphosphate orange.

? - [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

A mixture of 9-γ-chloropropyl-9,10-dihydro-9,10-methanoanthracene (50 mg) and piperidine (0.1 mL) was heated at 100 ° C for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. There was thus obtained 9-γ-piperidinopropyl-9,10-dihydro-9,10-methanoanthracene which was converted to the hydrochloride, m.p. 280-283 ° C.

Starting 9-γ-chloropropyl-9,10-dihydro-9,10-methanoanthracene is prepared by reacting 9-γ-hydroxypropyl-9,10-dihydro-9,10-methanoanthracene with thionyl chloride in benzene.

Example 2

A mixture of 9-γ-methylaminopropyl-9,10-dlhydro-9,10-methanoanthracene (40 mg), propargyl bromide (22 mg) and sodium amide (15 mg) in dry benzene was refluxed for 6 hours. The reaction mixture was diluted with benzene, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue was purified by silica gel chromatography. 9-γ-N-methyl-N-propargylaminopropyl-9,10-dihydro-9,10-methanoanthracene is obtained, m.p. 130-131 ° 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-methanoanthracene hydrochloride, m.p. 249.5-251 ° C;

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

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

9- [1-methylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 304 DEG-305 DEG C.,

9-β-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- [5-diethylamino] -ethyl-9,10-dihydro-9,10-methanoanthracene I. Spectrum No: 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-.alpha.-N, N-dicyclopropylmethylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 137 DEG-140 DEG C .;

9- [5-allylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 242 DEG-243 DEG C.,

9-S-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-i-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 259 DEG-260 DEG C .;

9-y-methylamino-N, N-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,

9-γ-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,

9-7-isopropylaminopropyl-9,10-dibydro-9,10-methanoanthracene hydrochloride, m.p. 255-256 ° C,

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

9 - / - sec-Butylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p.

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

9- ^l- allylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 226-228 ° C,

9-t-Benzylaminopropyl-9,10-methanoanthracene hydrochloride, m.p. 197 DEG-201 DEG C .;

9-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-β-piperidinyl-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-dimethylaminobutyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 201-202.5 ° C;

9-.alpha.-dimethylamino-n-butenyl-9,10-dihydro-9,10-imethanoanthracene hydrochloride, m.p. 154.5-155 ° C;

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

9-R-methyl-N-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride, m.p. 228-230 ° C,

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

9-of-methyl-β-dimethylaminoethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 75-78 ° C;

9-α-methylaminoethyl-9,10-dihydro-9,10-methanoanthracene, I. Spectrum No: 3070,

3050, 2780, 1375, 1277, 1172, 1155,

1138, 1012, 765, 745, 665 cm ^-1 ,

9-α-aminoethyl-9,10-dihydro-9,10-methanoanthracene, m.p. 102.5-103.5 ° C, etc.

The pharmacological effect of some typical 9-aminoalkylmethanoanthracene derivatives (I) is apparent from Tables I, II and III.

Effect against maximum electroshock

ED50 (mg / kg, p.o.)

Amplifying effect on hexacarbital anesthesia

ED50 (mg / kg, p.o.)

Table I

Test animal: mouse

Blocking effect of norepinfrin

MED (mg / kg, i.p.)

Rotating rod test ED50 (mg / kg, p. O.)

9-Methylaminomethyl 1-9,10-dihydro-9,10-methanoanthracene hydrochloride

HCl

35

3.2

9-dimethylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride

35

3.6

Note:

MED - minimum effective dose,

ED50 - effective dose 50,

i. p. - Intraperitoneal administration,

- oral administration.

Table II

Test animal: guinea pig

Isolated ileum, IC 50 (g / ml)

Anti-histamine Anti-choline Anti-sotonin effect effect effect

9-methylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride

10-8

10-7

10-7

9-dimethylaminoethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride

N.

HCl

X 1010-7

X ΙΟ ^{6 CH} 3

Table III

Test animal: mouse

Anti-tetrabenazine effect of ED 50 (mg / kg, p. O.)

Body temperature drop Ptose

9-methylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride

0.84

2,0

9-dimethylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride

1,5 2,3

Claims (5)

SUBJECT A process for the preparation of 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives I (t) where A represents a C 1 -C 4 alkylene- or C 5 -C 4 alkenyl group and each of the symbols R 1 and R 2 are hydrogen, C 1 -C 6 alkyl-, C 3 -C 4 alkenyl-, C 3 -C 4 alkynyl, C 3 -C 6 cycloalkyl (C 1 -C 3) alkyl-, phenyl (C 1 -C 3) alkyl or (C 2 -C 4 alkyl substituted) two or three halogen atoms on a terminal carbon atom; or R 1 and R 2 together with the adjacent atom Are a 5- to 7-membered nitrogen-containing heterocyclic ring of the general formula 4? where Z is a direct bond, methylene, oxygen or sulfur; and m is an integer of 2 or 3. and non-toxic pharmaceutically acceptable salts thereof, characterized in that the compound of formula IV, wherein: A is as defined above and X is a leaving group, reacted with a compound of formula V, Η — N — Ri R2 (V) wherein R 1 and R 2 are as defined above, whereupon the resulting compound is optionally converted to its non-toxic pharmaceutically acceptable salt. 2. The process according to claim 1, wherein the reaction is carried out in the presence of a basic condensing agent. 3. The process according to claim 1, wherein the reaction is carried out in an inert solvent. 4. The process of item 1 for the preparation of compounds of formula I, wherein A is a group of formula --A 1 - CH 2 - wherein A 1 represents C 2 -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 6 cycloalkyl (C 1 -C 3) alkyl- or phenyl (C 1 -C 3) alkyl or R 1 and R 2 taken together with the adjacent nitrogen atom represent a 5- to 7-membered nitrogen-containing heterocyclic ring of the formula ## STR3 ## wherein: Z is a direct bond, methylene, oxygen or sulfur; and m is an integer of 2 or 3 and non-toxic pharmaceutically acceptable salts thereof, characterized in that the compound of formula IV, wherein A is as defined herein and X is as defined above. is reacted with a compound of formula V wherein R 1 and R 2 are as defined in this point, whereupon the resulting compound is optionally converted to its non-toxic pharmaceutically acceptable salt. 5. The process of item 1 for the preparation of compounds of formula I wherein A is -CH2- and each of R1 and R2 is hydrogen, C1-C4 alkyl-, C3-C4 alkenyl-, C3-C6 cycloalkyl (C1-C3) ) alkyl- or phenyl (C 1 -C 5 alkyl) or R 1 and R 2 together with the adjacent nitrogen atom represent a 5- to 7-membered nitrogen-containing heterocyclic ring of the general formula: Z is a direct bond, methylene, oxygen or sulfur; and m is an integer of 2 or 3 and non-toxic pharmaceutically acceptable salts thereof, characterized in that the compound of formula IV, wherein A is as defined herein and X is as defined above. with a compound of formula (V) wherein R 1 and R 2 are as defined in this point, whereupon the resulting compound is optionally converted to its non-toxic pharmaceutically acceptable salt.