NO143153B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC ACTIVE 9,10-DIHYDRO-9,10-METANOANTRACENDER DERIVATIVES - Google Patents

Description

The present invention relates to an analog method

for the production of new therapeutically active '9,10-dihydro-9,10-methanoanthracene derivatives with formula:

wherein A is C 1 -C 4 alkylene or C 3 -C 4 alkenylene and R, and R 2

each is hydrogen, C^-C^ alkyl, C3-C4 alkenyl, C3~C4 alkynyl,

C3~C6 cYcloalkyl (C1-C3)alkyl, phenyl (C^-C^) alkyl or tri-

fluorine (C2~C4)alkyl or together with the adjacent nitrogen-

atom forms a 5- to 7-membered nitrogen-containing heterocyclic ring which may contain a further hetero-atom, and the distinctive feature of the analog method according to the invention is that either

a) a compound of formula:

wherein A' is a direct bond, C 1 -C 1 -alkylene or C 2 -C 3

the alkenyl and R. and R 2 have the above meaning, are reduced,

or

b) a compound of formula

wherein A has the above meaning and X is a substitutable group is reacted with a compound of formula:

in which R. and R^ nar ^a above meaning in the presence or

absence of a basic binding agent, optionally in the presence of an inert solvent, or

c) a compound of formula:

in which A' has the above meaning, and an amine of formula:

in which R 1 and R 2 have the above-mentioned meaning, is subjected to a condensation-reduction, or

d) a compound of formula:

wherein A has the above meaning, R 3 is hydrogen,

C^-C^ alkyl, <C>3~<C>4 alkenyl, c3~c6 cycloalkyl (C^-C-j) alkyl, phenyl (C^-C-j) alkyl or trifluoro (C2-C4)alkyl and R4 is hydrogen . R 2 is C 1 -C 4 alkyl, C 3 -C 4 alkenyl, benzyl or C 1 -C 4 cycloalkylmethyl, or

e) a provision with formula:

wherein A and R^ ^ are the above meaning, are reacted with

the connection with formula

where R[. is C^-C4 alkyl, C^-C^ alkenyl, C^-C4 alkynyl, C^-C6 cycloalkyl (C^-C-j) alkyl, phenyl (Cj-C-j) alkyl or trifluoro (C2-C4)alkyl and X is halogen or a substitutable group for the preparation of a compound of formula I in which A has the above meaning and R^ and R2 have the same meanings as R^ and R^ respectively, or

f) a compound of formula:

wherein A, R 1 and R 4 have the above meaning, is hydrolysed to produce a compound of formula I, wherein A has the above meaning, R 2 has the same meanings as R 2 and R 2 is hydrogen, or

g) a compound of formula:

wherein A and R^ have the above meaning, and an aldehyde

with formula:

R 6 -CHO

wherein R6 is hydrogen, C1-C3 alkyl, C2-C3 alkenyl, phenyl or C3-C8 cycloalkyl, is subjected to a condensation-reduction to prepare a compound of formula I wherein A has the above meaning, R^ has the same meanings as R3, and R2 is C1-C4 alkyl, C3*C4 alkenyl, benzyl or C3-C8 cycloalkylmethyl, or

h) a compound of formula:

wherein A' is as defined above, is reduced to produce a compound of formula I, wherein A is as defined above and R, and R are each hydrogen.

The new compounds are useful as anti-anxiety agents, anti-depressants, and can be used as a powerful sedative, anti-histamine or anti-allergy agent.

The new compounds can advantageously be prepared from a new starting material, namely 9-formyl-9,10-dihydro-9,10-methano-anthracene using different methods.

The 9,10-dihydro-9,10-methanoanthracene skeleton has been known since 1920 and some chemical studies have been carried out concerning the 9,10-dihydro-9,10-methanoanthracene derivatives, but no reports have been published either on the synthesis of the 9,aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives or any pharmacological investigation concerning the 9,10-dihydro-9,10-methanoanthracene derivatives.

In the above designations, "C1-C4 alkylene" is a straight or branched alkylene group with 1 to 4 carbon atoms such as e.g. methylene, ethylene, propylene, butylene, 1-methylethylene, 1-methyl-propylene, 2-methylprooylene. The term "C^-C^ alkenylene" includes in particular 1-propenylene, 1-butenylene, 2-butenylene, 1-methyl-1-propenylene and 2-methyl-1-propenylene, in which the numerical designations begin from the carbon atom which is linked to the 9,10-dihydro-9,10-methanoanthracene skeleton. The term "C₁-C₁ alkyl" means a straight or branched alkyl group with 1 to 4 carbon atoms such as e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, isobutyl. The term "C-^-C^ alkenyl" means a straight or branched alkenyl group with 3 or 4 carbon atoms such as e.g. propenyl or butenyl. The term "C₁-C₁ alkynyl" means a straight or branched alkynyl group with 3 or 4 carbon atoms such as e.g. propar-gyl. The term "C^-C^ cycloalkyl (C1~C3)alkyl" means a straight or branched alkyl group with 1 to 3 carbon atoms and which carries a cycloalkyl group consisting of 3 to 6 carbon atoms, such as e.g. cyclopropylmethyl and cyclobutylmethyl. The term "phenyl(C^-C^)alkyl" means a straight or branched alkyl group with 1 to 3 carbon atoms such as e.g. methyl, ethyl propyl and bearing a phenyl group. The term "trifluoro(C2-C4)alkyl" means a straight or branched alkyl group with 2 to 4 carbon atoms and which carries 3 fluorine atoms, e.g. trifluoroethyl or freefluoropropyl. As examples of 5- to 7-membered nitrogen-containing heterocyclic rings, pyrrolidino, piperidino, morpholino and thiomorpholino were mentioned.

The non-toxic pharmaceutically acceptable salts of the 9-aminoalkyl-9,10-dihydro-9,10-methanoanthracene derivatives of formula (I) may include organic and inorganic acid addition salts thereof, e.g. the hydrochloride, hydrobromide, acetate, oxalate, citrate, tartrate, succinate, fumarate and lactate.

The 9-aminoalkyl-9,10-dlhydro-9,10-methanoanthracene derivatives (hereinafter referred to as "9-aminoalkylmethanoanthracene derivatives") of formula (I) are characterized by their aminoalkyl chain which is attached in the 9-position to 9 ,10-dihydro-9,10-metanc~ the anthracene skeleton.

Although a lot of dibenzotricyclic compounds are known and some of them are now used clinically as drugs, especially as psychotropic substances, not any dibenzotricyclic compounds with a 9»10-dihydro-9,1°-methanoan'tracene ring like the dibenzotricyclic skeletons have been used for this purpose. The possibility of producing the 9-aminoalkyl-raethano-anthracene derivatives with formula (I) is provided by synthesizing a key starting material, namely 9-formyl-9,10-dihydro-9,10-methanoanthracene with formula

The 9-aminoalkyl-methanoanthracene derivatives of formula (I) are new and characteristically exhibit a wide range of valuable pharmacological effects, particularly on the central nervous system and the autonomic nervous system. More particularly, the 9-aminoalkyl methanoanthracene derivatives of formula (I) wherein A is methylene which may be substituted with alkyl of 1 to 3 carbon atoms show potentiating action on hexabarbital anesthetic, hypothermic, ptosis and muscle relaxant activity and also anti-tetra-

benazine activity. They are thus useful as anti-anxiety agents, anti-depressants and also as strong sedatives.

The aminoalkyl methanoanthracene derivatives of formula (I) wherein A is ethylene; which may be substituted with alkyl with 1 or 2 carbon atoms shows powerful anti-histamine, anti-cholinergic and anti-serotonin effects. They also show anti-tetrabenazine activity. They are thus useful as anti-histamines and anti-allergy agents.

The 9-aminoalkyl-methanoanthracene derivatives of formula (I) in which A stands for C^-C^ alkylene or C^-C^ alkenylene show strong anti-tetrabenazine action. They also show norepinephrine-potentiating action, and anti-reserpine, anti-histamine, anti-cholinergic and anti-serotonin action. Furthermore, their acute toxicity and acute cardiotoxicity are found to be small. They are thus useful as anti-depressants and anti-histamines.

In any case, the 9-aminoalkyl-methanoanthracene derivatives of formula (I) all have anti-tetrabenazine activity. anti-cholinergic effect, anti-histamine effect, anti-serotonin effect and sedative effect to some extent.

As anti-anxiety agents, the compounds of formula (I) are preferred in which R 1 is -C 2 alkyl, R 2 is hydrogen or C-j-C 8 alkyl and A is methylene. As an anti-histamine or anti-allergic agent, the compounds of formula (I) are preferred in which R1 is ^-C^ a-Lkylj R2 is hydrogen or ^^-^ 2 alkyl °6 A is ethylene. As an anti-depressant, the compounds of formula CE) in which A is propylene or propenylene are preferred. Particular preference is given to the compounds of formula (I) in which R 1 and R 2 independently of each other are hydrogen or C 1 -C 2 alkyl and A is propylene or propenylene. The most preferred are those compounds in which A is propylene, R 1 is hydrogen or methyl, and R 2 is methyl.

The 9-aminoalkyl-methanoanthracene derivatives of formula (I) and their non-toxic pharmaceutically acceptable salts can be administered orally or parenterally in a dosage of generally 5 - 500 mg/person,

preferably 25 - 500 mg/person (corresponding daily dose for a person with a body weight of 60 kg) in the form of a common pharmaceutical preparation.

They can e.g. administered in the form of conventional solid pharmaceutical preparations such as powders, granules, tablets or capsules or in the form of conventional liquid pharmaceutical preparations such as suspensions, emulsions or solutions. These preparations can be prepared by mixing the 9-aminoalkyl-methanoanthracene derivatives of formula (I) or their non-toxic pharmaceutically acceptable salts either alone in combination with suitable additives such as e.g. starch, lactose or talc in the conventional way.

The 9-aminoalkyl-methanoanthracene derivatives of formula (I) can be prepared from 9-formyl-9,10-dihydro-9,10-methanoanthracene of formula (II), practically from its suitable derivatives. Some typical examples of the method according to the invention are shown in the following: Method (a);

The 9-aminoalkyl-methanoanthracene compound of formula

where R1 and R? each has the above meaning and A<1> is a direct bond, the C-j-C^ alkylene or the C^-C-^ alkenyl may be prepared from the corresponding compound

where A<1>, R.| and R 2 each has the above meaning, by reduction of the latter.

For the reduction, the preferred reducing agent is an alkali metal in an alcoholic solvent, a metal hydride or the like. An electrolytic reduction can also be used for this purpose.

It is particularly preferred to use a metal hydride such as e.g. lithium aluminum hydride, sodium aluminum diethyl dihydride and sodium bis(2-methoxyethoxy) aluminum hydride in an inert organic solvent such as e.g. ether Cf.eg diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether), aliphatic hydrocarbons (eg heptane, hexane, cyclohexane), aromatic hydrocarbons (eg benzene, toluene) or mixtures thereof. The temperature for the treatment in this case can be varied from ice cooling to the return temperature for the reduction system.

Sodium borohydride is another example of a practically usable metal hydride as a reducing agent, especially used in the presence of a salt such as aluminum chloride or by activating the carboxamide group in the compound of formula (III) with triethyloxonium fluoroborate or the like. Dlborane is a further example of metal hydrides which are effective as reducing agents.

Method ( b) ;

The 9-aminoalkyl-methanoanthracene compound of formula (I) can also be prepared by reacting the corresponding compound of formula

wherein A has the above meaning and X is a conventional reactive group such as e.g. halogen (e.g. chlorine, bromine, iodo) or sulfonyloxy (e.g. methanesulfonyloxy, p-toluenesulfonyloxy, trichloromethanesulfonyloxy) with an amine of formula

wherein R 1 and R 2 each have the above meaning, in the presence or absence of an inert solvent such as e.g. ether (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether), alcohols (e.g. methanol, ethanol, isopropanol), aromatic hydrocarbons (e.g. benzene, toluene), dimethylsulfoxide, dimethylformamide or pyridine in presence or absence of a basic agent. Examples of basic agents are amines (e.g. pyridine, picoline, triethylamine, dimethylaniline), 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 bicarbonyls (i.g. sodium bicarbonate), sodium amide, etc. The reaction temperature can vary from ice cooling to the reflux temperature of the reaction system in a closed or an open system.

Method (c):

The 9-aminoalkyl-methanoanthracene compound of formula (Ia) can be prepared by condensation-reduction of the corresponding compound of formula

wherein A<1> has the above meaning, with the amine of formula

(V).

The condensation reduction can be carried out using known methods, e.g. the usual procedure of the Leuckart-Wallach reaction using formic acid (Organic Reactions, vol. 5, page 301, John Wiley & Sons, Inc.). This means that the compound of formula (VI) is added to an amine formate of the amine of formula (V) or a mixture of the amine of formula (V) and formic acid, and the reaction is carried out at a temperature from room temperature to 250°C. The reaction can also be carried out in the presence of an inert solvent such as e.g. benzene, toluene, nitrobenzene, tetrahydrofuran or dioxane.

The condensation reduction can also be carried out by hydrogenation of a mixture of the compound of formula (VI) and the amine of formula (V) over a catalyst such as e.g. Raney nickel, platinum oxide or palladium in the presence or absence of an inert solvent. The pressure during the hydrogenation can vary from atmospheric pressure to elevated pressure. Condensing agent in the form of sodium acetate can be used for this treatment.

Furthermore, the condensation reduction can be carried out by using sodium alcohol or the acid or basic zinc method. An inert solvent such as alcohols (e.g. methanol, ethanol, isopropanol), liquid ammonia, acetic acid or ether

(e.g. diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran)

can be used.

Furthermore, the condensation reduction can be carried out by reduction of the Schiff base or the enamine prepared from the compound of formula (VI) and the amine of formula (V) by a conventional method. The reduction can be carried out by catalytic hydrogenation as described above, or by using a reducing agent such as e.g. sodium borohydride, diborane, lithium aluminum hydride, sodium aluminum diethyl dihydride, sodium borocyanohydride or sodium bis(2-methoxyethoxy)aluminum hydride in an inert solvent such as e.g. methanol, ethanol, isopropanol, n-butanol, t-butanol, benzene, toluene, diethyl ether, isopropyl ether, dioxane or tetrahydrofuran. The temperature in this case can vary from -10°C to the return temperature for the reduction system.

Method (d):

The 9-aminoalkyl-methanoanthracene compound of formula

wherein A has the above meaning, IU is hydrogen, -C^ alkyl, C^-C^ alkenyl, C^-C^ cycloalkyl(C, -C^)alkyl, speciesC^-C^) alkyl or polyhalo<C> ^<-C>^)alkyl and R^ is hydrogen, C^-C^ alkyl, C^-C^ alkenyl, aryl or C-^-C^ cycloalkyl can be prepared from the corresponding compound of formula:

wherein A and R^ each have the above meaning and R^' is hydrogen, C-j-C^ alkyl, C2-C3 a^ enyl, aryl, C-^-C^ cycloalkyl, C| -C 4 alkoxy by reduction. The reduction can be carried out by the same method as mentioned above with regard to the reduction of the compound of formula (III).

Method ( e) ;

The 9-aminoalkyl-methanoanthracene compound of formula

wherein A and R^ have the above meaning and R^ is C-j-C^ alkyl,

C^-C^ alkenyl, C^-C^ alkynyl, C^-C^ cycloalkyl(C^-C^)alkyl, ar(C^-C^)alkyl or polyhalo(C2-Cl+)alkyl can be prepared by react the corresponding compound with formula

wherein A and R^ have the above meaning, with a compound of formula R?-X (VIII) wherein R^ and X have the above meaning, by means of the same procedure as mentioned above with regard to the reaction of the compound of formula ( IV) with the amine of formula (V). When the compound of formula (Id) in which R^ is hydrogen is used, the 9-aminoalkyl-methanoanthracene compound of formula in which A and R^ have the above meaning can be obtained by reacting the compound of formula (Id) with not less than 2 mol of the compound of formula (VIII) by the same procedure. Method ( f) ; The 9-aminoalkyl-raethanoanthracene compound of formula (Id) can be prepared from the corresponding compound of formula (VII) by hydrolysis. The hydrolysis can be carried out under conventional conditions under which amide and urethane derivatives are hydrolysed, e.g. by treatment with an alkali (eg potassium hydroxide, sodium hydroxide) or a mineral acid (eg hydrochloric acid, hydrobromic acid, sulfuric acid) in an inert solvent such as water, alcohols (e.g. methanol, ethanol, isopropanol, t-butanol, n-butanol, ethylene glycol), ether (e.g. diethyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether) or aromatic hydrocarbons (e.g. .benzene, toluene). The temperature for the treatment can vary from ice cooling to the reflux temperature of the reaction system. Method ( g) ; The 9-aminoalkyl-methanoanthracene compound of formula (Ib) kah is prepared by reacting the corresponding compound of formula (Id) with an aldehyde of formula

wherein RL has the above meaning in reductive amination. The reductive amination can be carried out by means of the method mentioned above with regard to the condensation-reduction of the compound of formula (VØ with the amine of formula

(V).

When the compound of formula (Id) in which R^ is hydrogen is used, the 9-aminoalkyl-methanoanthracene compound of formula (If) of formula in which A and R^ have the above meaning can be obtained by reacting the compound of formula (Id) with not less than 2 moles of the compound of formula (IX) by the same method.

Method ( h) t

The 9-aminoalkyl-methanoanthracene compound of formula

in which A' has the above-mentioned meaning, can be prepared from the corresponding compound of formula in which A' has the above-mentioned meaning and R,^ is a nitrile group (-C=N) or a carbaldehyde oxime group C-CH=NOH) by reduction. The reduction can be carried out by the method mentioned above with regard to the reduction of the compound of formula (III), or by catalytic hydrogenation as mentioned in method (c). The 9-aminoalkyl-methanoanthracene compound of (I) thus prepared can be separated from the reaction mixture and purified by conventional methods. The 9-aminoalkyl-methanoanthracene compound of formula (I) can be converted into its salts by conventional methods, and conversion from the salts to the original free base can also be carried out in conventional ways. The Nokkel output product, i.e. The 9-formyl-9,10-dihydro-9,10-methanoanthracene compound of formula (II) can be prepared from the 9-amino-12-hydroxy-9,10-dihydro-9,10-ethaneanthracene of formula

by means of relocation.

Rearrangement of amines and α-amino alcohol derivatives upon treatment with nitric acid is known as Demjanov rearrangement and Tiffeneu-Demjanov rearrangement (Organic Reactions, vol. 11, page 157, John Wiley & Sons, Inc.). These rearrangement reactions have been used for ring-enlarging reactions in most of the reported examples, and only a few examples of the use of the rearrangement reaction for ring-contracting reactions have been reported. Practically, rearrangement of 9,10-ethaneanthracene derivatives to 9-formyl-9,10-dihydro-9,10-methanoanthracene has not been reported and this is a new method for the preparation of 9-formyl-9,1O-dihydro-9 ,1O-methanoanthracene.

The rearrangement of 9-amino-12-hydroxy-9,1O-dihydro-9,1O-ethane-anthracene to 9-formyl-9,1O-dihydro-9,1O-methanoanthracene can be carried out by treatment with nitric acid. I.e. that 9-amino-12-hydroxy-9,1O-dihydro-9,10-ethaneanthracene is treated with nitric acid or 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 phosphoric acid or a mixture of these acids. An inert solvent such as e.g. water, methanol, ethanol, acetone, benzene, toluene, chloroform, dichloroethane, dichloromethane, diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, dimethylsulfoxide or dimethylformamide or mixtures thereof can be used in the reaction system. The temperature for the treatment in this case can be varied from ice cooling to the return temperature for the reduction system.

The 9-formyl-9,1O-dihydro-9,1O-methanoanthracene of formula (II) produced in this way can be separated from the reaction mixture and purified by conventional methods.

The compound (A) (i.e. 9-amino-12-hydroxy-9,1O-dihydro-9,10-ethaneanthracene) can be prepared from a compound of formula

in which R is hydrogen or a hydroxyl protecting group - such as e.g. acetyl, benzoyl or tetrahydropyranyl by rearrangement such as e.g. The Curtius reaction or Hoffman rearrangement and hydro-

bright. The relocation can e.g. is carried out by the general procedure for the Curtius reaction (Organic Reactions, volume 3, page 337» John Wiley & Sons, Inc.), and the hydrolysis can be carried out under the usual hydrolysis conditions for urethane or isocyanate derivatives.

The starting products for the synthesis of the 9-aminoalkyl-mctanoanthracene compounds of formula (I) can be prepared from 9-formyl-9,10-dihydro-9,1O-methanoanthracene of formula (II) using conventional reactions such as e.g. oxidation, reduction, •hydrolysis, carbon chain-lengthening reaction (substitution, Wittig reaction, Reformatsky reaction, Grignard reaction), etc.

The starting materials for the synthesis of 9-amino-methyl-9,10-dihydro-9,10-methanoanthracene derivatives can e.g. produced in the following way:

where Ts stands for a p-toluenesulfonylloc::y group, namely:

(1) 9-formyl-9,1O-dihydro-9,1O-methanoanthracene is oxidized to 9,1O-dihydro-9,10-methanoanthracene-9>carboxylic acid by treatment with an oxidizing agent such as e.g. chromium trioxide or sblv oxide in an inert solvent.. (2) 9-hydroxymethyl-9,1 O-dihydro-9,1 O-methanoanthracene is prepared from 9-formyl-9,1O-dihydro-9,1O-methanoanthracene by treatment with a reducing agent such as sodium borohydride or lithium aluminum hydride in an inert solvent. (3) 9-Tosyloxymethyl-9,1O-dihydro-9,1O-methanoanthracene is prepared from 9-hydroxymethyl-9,1O-dihydro-9,1O-methanoanthracene by treatment with p-toluenesulfonyl chloride in the presence of a base in an inert solvent .

(k) 9,1O-dihydro-9,10-methanoanthracene-9-carboxylic acid is converted to the corresponding acid chloride by reaction with thionyl chloride in the presence or absence of an inert solvent, and the acid chloride is converted to 9,1O-dihydro-9,1O- methanoanthracene-9-carboxamide by reaction with ammonia by a conventional method.

(5) Dehydration of 9,1O-dihydro-9,10-methanoanthracene-9-carboxamide to 9,1O-dihydro-9,1O-methanoanthracene-9-carbonitr11 is carried out by using phosphorus oxychloride in the presence or absence of an inert solvent. -

The starting materials for the synthesis of 9-P-aminoethyl-9,10-dihydro-9,10-methanoanthracene derivatives can e.g. is prepared from 9-formyl-9,1O-dihydro-9,1O-methanoanthracene of formula (II) or its derivatives in the following manner:

in which Ts eir as stated above, namely:

(6) (9-1O-dihydro-9,10-methano-9-anthryl)acetic acid ethyl ester is obtained from 9,1O-dihydro-9,10-methanoanthracene-9-carboxylic acid by the usual procedure for an Arndt-Eistert -synthesis. (7) (9,1O-dihydro-9,10-methano-9-anthryl)acetic acid is prepared from the corresponding ethyl ester by the usual method of hydrolysis. (8) 9-B-hydroxyethyl-9,1O-dihydro-9,1O-methanoanthracene is obtained by reduction of (9,1O-dihydro-9,10-methano-9-anthryl)acetic acid ethyl ester using a reducing agent which e.g. lithium aluminum hydride or sodium aluminum diethyl dihydride in an inert solvent. (9) 9-P-tosyloxyethyl-9,1O-dihydro-9,10-matanoanthracene is obtained in the same manner as described above. (10) (9,10-dihydro-9,10-methano-9-anthryl)acetaldehyde is obtained from 9-formyl-9,10-dihydro-9,1O-methanoanthracene by applying the procedure for a Wittig reaction with methoxymethyl- triphenylphosphonium chloride and acid hydrolysis. (11) (9,10-dihydro-9,10-methano-9-anthryl)acetonitrile can be obtained from 9-tosyloxymethyl-9,1O-dihydro-9,1O-methanoanthracene by reaction with metal cyanide in an inert solvent.

The starting materials for the synthesis of 9-y-aminopropyl and 9-8-aminobutyl-9,1O-dihydro-9,1O-methanoanthracene derivatives can e.g. is prepared from 9-formyl-9,1O-dihydro-9,1O-methanoanthracene with formula (II) in the following way:

wherein Ts has the above meaning, namely: (12) (3-(9,1O-dihydro-9,10-raethano-9-anthryl)acrylic acid is prepared from 9-formyl-9,10-dihydro-9,10- methanoanthracene by the Wittig reaction with triethylphosphonoacetate and hydrolysis of the ester function.(13) P-(9»10-dihydro-9,10-methano-9-anthryl)-propionic acid is prepared from the corresponding acrylic acid by a conventional hydrogenation method. (1^) 9-T-Hydroxypropyl-9,1O-dihydro-9,1O-methanoanthracene is prepared from 6-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid by treatment with a reducing agent such as lithium aluminum hydride or sodium aluminum diethyl dihydride in an inert solvent 05) 9-f-tosyloxymethyl-9,10-dihydro-9,1 O-methanoanthracene is prepared from the corresponding alcohol by the method described above. (16) 9- Y -hydroxypropyl-9,1O-dihydro-9,1O-methanoanthracene is oxidized to the corresponding aldehyde by treatment with an oxidizing agent such as e.g. CrO^-pyridine complex in an inert solvent. (17) & (18) (3-(9,1 O-dihydro-9,10-methano-9-anthryl)propionic acid is converted to (3-(9,1 O-dihydro-9,10-methanoanthryl)propionitrile

by the method described above.

(19) B-(9,1O-dihydro-9,10-methano-9-anthryl)-acrylaldehyde is prepared from 9-formyl-9,1O-dihydro-9,1O-methanoanthracene by means of the Wittig reaction method with formyImethylene- triphenylphosphorane.

The derivatives of γ - (9,1O-dihydro-9,10-metaho-9-anthryl)butyric acid can be prepared by the same method as described above.

The compound of formula (III) can be prepared from the corresponding carboxylic acid derivative by means of a conventional method with the corresponding amine compound. Another starting material, i.e. the compound of formula (VII), can be prepared from the compound of formula (Ic) by reaction with the compound of formula:

in which R^ has the above-mentioned meaning and Y is a halogen such as e.g. chlorine or bromine relieve the usual conditions for acylation of an amine compound.

The fbTgendc examples illustrate the invention.

Example 1

To a solution of 9-amino-12-hydroxy-9,1O-dihydro-9,1O-ethano-anthracene (3.0 g) in acetic acid (2h0 ml) is added a solution of sodium nitrite (6.7 g) in water (120 ml) at 2 - 5°C, and the resulting mixture is stirred at the same temperature for 1 hour and at 95 - 105°C for 5 hours. The reaction mixture is diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness to give crude crystals of 9-formyl-9,1O-dihydro-9,1O-methanoanthracene (2.8 g) which were recrystallized to give colorless crystals ( 2.W5 g). Melting point 99 - 100°C. Purification by recrystallization further gave analytically pure 9-formyl-9,1O-dihydro-9,1O-methanoanthracene, melting point 102.5°C.

Example 2

A solution of sodium nitrite (112 mg) is added to a solution of 9-amino-12-hydroxy-9,1O-dihydro-9,10-ethane-anthracene (50 mg) in concentrated hydrochloric acid (2 ml) and water (2 ml) in water (1.0 ml) at 0°C. The resulting mixture is stirred at 0°C for 1 hour and at room temperature for 5 hours. The reaction mixture is diluted with water and extracted with benzene. The benzene layer is washed with water, dried over sodium sulfate and evaporated to dryness to give crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (35 mg).

Example 3

A solution of 12-acetoxy-9,1O-dihydro-9,10-ethaneanthracene-9-carboxylic acid (1.0 g) in benzene (10.0 mL) and thionyl chloride

(1+.0 ml) was refluxed for k hours. Evaporation of excess thionyl chloride and benzene gave 12-acetoxy-9,10-dihydro-9,10-ethaneanthracene~9-carboxylic acid chloride. The acid chloride was dissolved in dry acetone (25.0 ml) and a solution of sodium azide (0.63 g) in water (1.3 ml) was added thereto under ice-cooling. The resulting mixture was stirred under ice-cooling for 2 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate, refluxed for 2 hours and evaporated to dryness to give 9-isocyanato-12-acetoxy-9,10-dihydro-9,10-ethaneanthracene.

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 evaporating 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 to give 9-amino-12-hydroxy-9,10-dihydro-9,10-ethaneanthracene as crystals (0.72 g). Melting point 181 - 181.5°C Recrystallization from benzene gave analytically pure crystals of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethaneanthracene. Melting point 183.5°C.

Example h

A mixture of 8-(9,10-dihydro-9,10-methano-9-anthryl)propionic acid monomethylamide (1.0 g) and lithium aluminum hydride (0.5 g)

in dioxane was stirred at 50°C for 2 hours. Excess lithium aluminum hydride was decomposed by the addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9- " Y -methyl-aminopropyl-9,10-dihydro-9,16-methanoanthracene which was converted to its hydrochloride. M.p. 2h7 - 2^- 9° G. Recrystallization from isopropyl alcohol gave colorless crystals, mp 259 - 260°C.

The starting amide was prepared in the following way

A solution of 6-(9,1O-dihydro-9,10-methano-9-anthryl)propionic acid and thionyl chloride in benzene was refluxed for h hours. Evaporation of excess thionyl chloride and benzene gave B-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid chloride which was dissolved in dry tetrahydrofuran. The solution was added to a 30% aqueous monomethylamine solution at 0 - 5°C. The reaction mixture was stirred at 0-15°C, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give b-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid monomethylamide. Melting point 200 - 201°C.

Example 5

A mixture of 9-γ-chloropropyl-9,1O-dihydro-9,1O-methanoanthracene (50 mg) and piperidine (0.1 ml) was heated at 100°C for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-y-piperidinopropyl-9,10-dihydro-9,10-methanoanthracene which was converted to its hydrochloride.

Melting point 280 - 283°C

The starting compound 9-T-chloropropyl-9,1O-dihydro-9,1O-methanoanthracene was prepared by reacting 9-T-hydroxypropyl-9,10-dihydro-9,1O-methanoanthracene with thionyl chloride in benzene.

Example 6

To a mixture of morpholine (870 mg) and formic acid (*+60 mg) heated at 60°C was added B-(9,10-dihydro-9,10-methano-9-anthryDpropionaldehyde (50 mg). The resulting mixture was stirred at 60°C for 30 minutes and at 80°C for 1.5 hours.The reaction mixture was diluted with water and extracted with ethyl acetate.The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9- Y -morpholino-propyl-9,1O-dihydro-9,1O-methanoanthracene which was converted to

the hydrochloride. Melting point 173 - 176.5°C.

The starting compound B-(9,10-dihydro-9,10-methano-9-anthryl)-propionaldehyde (m.p. 135 - Jl]+ 0°C) was prepared from 9-y-hydroxypropyl-9,10-dihydro-9, 1O-methanoanthracene by treatment with chromium trioxide-pyridine complex in dichloromethane for 5 minutes at room temperature.

Example 7

A solution of B-(9,10-dihydro-9,10-methano-9-anthryl)propionaldehyde (150 mg) and sec-butylamine (100 mg) in methanol was stirred at -5 - 0°C for 30 minutes. To the solution was added sodium borohydride (50 mg) and the resulting mixture was stirred for 2 hours at about 0°C. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was shaken with hydrochloric acid. The acid layer was basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-T-sec-butylaminopropyl-9,10-dihydro-9,1O-methanoanthracene which was converted to its hydrochloride. Melting point 216 - 219°C.

Example 8

A mixture of 9-Y-acetylaminopropyl-9,10-dihydro-9,1O-methanoanthracene (70 mg) and lithium aluminum hydride (35 mg) in dioxane

(2 ml) was stirred at h0 - 50 C for 9 hours. Excess lithium aluminum hydride was decomposed by the addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-Y-ethylamino-propyl-9,1O-dihydro-9,1O-methanoanthracene which was converted to its hydrochloride. Melting point 182 - 186°C.

Example 9

A mixture of 9-γ-methylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene (h0 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 to give 9-γ-methylpropargylaminopropyl-9,10-dihydro-9,10-methanoanthracene. Melting point 130 - 131°C.

Example: 10

A mixture of 9-γ-acetylallylaminopropyl-9,1O-dihydro-9,10-methanoanthracene (100 mg) in ethanol and 25% aqueous sodium hydroxide was refluxed for 10 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium acetate and evaporated to dryness to give 9-Y-allylaminopropyl-9,10-dihydro-9,10-methanoanthracene which was converted to its hydrochloride. Melting point 227 - 228°C.

Example 11 •■

A mixture of 9-Y-aminopropyl-9,10-dihydro-9,1O-methanoanthracene (12J mg), 90% formic acid (300 mg) and 37% aqueous formaldehyde solution (0.25 ml) was heated at 90 - 100°C for 8 hours. tfN hydrochloric acid was added to the cooled reaction mixture and the reaction mixture was evaporated to dryness. The residue was diluted with water, basified with aqueous ammonia and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-Y-dimethylaminopropyl-9,10-dihydro-9,1O-methanoanthracene which was converted to its hydrochloride (mp 2hp - 21+7° C). Recrystallization from isopropyl alcohol gave colorless crystals. Melting point 2h7 - 2^-7.5°C.

Example 12

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. Excess lithium aluminum hydride was cleaved by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to give 9-Y-aminopropyl-9,1O-dihydro-9»1O-methanoanthracene which was converted to its hydrochloride Melting point 275°C (decomposition).

Example 13

To a solution of 9-formyl-9,1O-dihydro-9,1O-raethanoanthracene (3>5 g) in acetone (17 ml) was added dropwise Jones' reagent (5.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, 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 to give 9,10-dihydro-9,10-methanoanthracene-9-carboxylic acid. Melting point 199.5 - 200.5°G.

Example 1*+

A solution of 9-formyl-9,10-dihydro-9,10-methanoan^rocene" (200 mg) and sodium borohydride (60 mg) in methanol (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was diluted

with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-hydroxymethyl-9,1O-dihydro-9,10-methanoanthracene. Melting point 165 - 166°C.

Example 15

A solution of 9,1O-dihydro-9,10-methanoanthracene-9-carboxamide (30 mg) and thionyl chloride (0.15 mL) in toluene (1 mL) was refluxed for 18 hours. Evaporation of toluene and excess thionyl chloride gave 9510-dihydro-9,10-methanoanthracene-9-carbonitrile. Melting point 120 - 123°C.

Example 16

A solution of 9-aminomethyl-9,10-dihydro-9,10-methanoanthracene (235 mg) and acetic anhydride (217 mg) in ethanol (5.0 mL) was refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with water, aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-acetylaminomethyl-9,10-dihydro-9,10-methanoanthracene.

Melting point ^ 8k - 185.5°C

Example 17

A solution of 9,1O-dihydro-9,1O-methanoanthracene-9-carboxylic acid (1 >77 g) and thionyl chloride in benzene was refluxed in

h hours and evaporated to dryness to give the corresponding acid chloride. A solution of the acid chloride in ether was added dropwise to an ethereal diazomethane solution in the presence of triethylamine (1,*+3s) at 0°C. The resulting mixture was stirred at 0°C for 3 hours, filtered and evaporated to dryness to give the corresponding diazomethyl ketone compound. A mixture of the diazomethyl ketone, triethylamine and solvobenzoate in ethanol (60 ml) was refluxed for 13 hours. The reaction mixture was diluted and extracted with ethyl acetate. The ethyl acetate extract was washed with aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and evaporated to dryness to give (9,10-dihydro-9,10-methano-9-anthryl)acetic acid ethyl ester. Melting point 81 - 8h°C.

Example 18

A mixture of (9,10-dihydro-9,10-methano-9-anthryl)acetic acid ethyl ester (125 mg) and lithium aluminum hydride (80 mg) in ether (6 mL) was stirred at room temperature for 1 hour. Excess lithium aluminum hydride was decomposed by the addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give crystals of 9-S-hydroxyethyl-9,1O-dihydro-9,1O-methanoanthracene. Melting point 99 - 100.5°C.

Example 19

A solution of 9~|3-hydroxyethyl-9,1 O-dihydro-9,10-methanoanthracene (72 mg) and p-toluenesulfonyl chloride (100 mg) in pyridine (1 ml)

was stirred overnight. The resulting mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate and evaporated to dryness to give crude crystals of 9-β-tosyloxyethyl-9,10-dihydro-9,10-methanoanthracene which were recrystallized from ethanol to to give pure crystals. Melting point 135.5 - 138°C

Example 20

Methoxymethyl-triphenylphosphonium chloride (2 mmol) was treated

with sodium hydride (2 mmol) in dimethylsulfoxide (6 ml) and 9-formyl-9,1O-dihydro-9,1O-methanoanthracene was added thereto at room temperature. The resulting mixture was stirred at room temperature for 1 hour and at 50°C for 3 hours, diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give an oily compound. The oil was treated with 2N hydrochloric acid (5 ml) in dioxane (0 5 ml) at 50°C for 2 hours. Usual work-up and purification by silica gel chromatography gave (9,10-dihydro-9,10-methano-9-anthryl)acetaldehyde. I.R. spectrum: 27^0, 1715, 1M*0, 1375, 1165, 1135, 1065, 935, 760, 715,

660 cm"<1>.

Example 21

A solution of (3-fø,10-dihydro-9,10-methano-9-anthryl)propionic acid (0.7 g) and thionyl chloride in benzene was refluxed in

2 hours and evaporated to dryness to give the corresponding acid chloride which was dissolved in acetone (3.7 ml). A solution of sodium azide (0.52 g) in water was added to the acetone solution under ice-cooling. The resulting mixture was stirred at 0°C for 2 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 to give the corresponding acid azide. A solution of the acid azide in ethanol (7.5 mL) was refluxed for 10 h and evaporated to dryness to give 9- S-ethoxycarbonylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene. Melting point 122 - 123°C.

Example 22

A mixture of 9-tosyloxymethyl-9,1O-dihydro-9,10-methanoanthracene (188 mg) and potassium cyanate (k0 mg) in dimethylformamide (2 ml) was heated at 150°C for 7 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give crude crystals of (9,10-dihydro-9,10-methano-9-anthryl)acetonitrile which were recrystallized from isopropanol to give pure crystals . Melting point 130 - 131°C.

Example 23

Triethylphosphonoacetate (2.65 g) in benzene was treated with 50% sodium hydride dispersion in mineral oil (0.66 g) and a solution of 9-formyl-9,1O-dihydro-9,1O-methanoanthracene (2.0 g ) in benzene (20.0 mL) was added thereto at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 5 hours and at 70°C for 1 hour, 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 to give (3-(9,10-dihydro-9,10-methano-9-anthryl)acrylic acid ethyl ester. A solution of the ethyl ester in methanol (53 mL ) and 10% aqueous sodium hydroxide (12 mL) were refluxed for h hours. The reaction mixture was diluted with water, acidified with hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give G-(9,10-dihydro-9,10-methano-9-anthryl)acrylic acid Melting point 219.5 - 222°C.

Example 2h

A mixture of 8-(9,1O-dihydro-9,1O-methano-9-anthryl)acrylic acid (612 mg) and % palladium charcoal (120 mg) in ethanol was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration and the solution was evaporated to dryness to give p-(9,10-dihydro-9,10-methano-9-anthryl)-propionic acid. Melting point 185 - 189°C.

Example 25

A solution of 9-formyl-9,1O-dihydro-9,1O-methanoanthracene (220 mg) and formylmethylenetriphenylphosphorane (1 mmol) in benzene (6 mL) was refluxed for 16 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The oily residue was purified by silica gel chromatography to give crystals of p-(9,1O-dihydro-9,10-methano-9-anthryl)acrylaldehyde. Melting point 135 - 138°C.

Example 26

To a mixture of 9-formyl-9,1O-dihydro-9,1O-methanoanthracene (110 mg) and P-carboxyethyltriphenylphosphonium chloride (186 mg) in dimethylsulfoxide (2 ml) and tetrahydrofuran (2 ml) was added 65.1+% sodium hydride dispersion in mineral oil (37 mg) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 6 hours, diluted with water, acidified with hydrochloric acid and extracted with benzene. The benzene extract was shaken with 2N aqueous sodium hydroxide. The basic layer was acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give T-(9j10-dihydro-9,10-methano-9-anthryl)-p-butenoic acid.

Melting point 166 - 167°C

The following compound was prepared by a similar method: 9-aminomethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point ^> 300°C.

9-Methylaminomethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 281.5 - 283°C.

9-Dimethylaminomethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 257 - 259°C.

9-Ethylaminomethyl-9?10-dihydro-9,10-methanoanthracene hydrochloride. Melting point 283 - 28k°C.

9-Ethylmethylaminomethyl-9?10-dihydro-9,10-methanoanthracene hydrochloride. Melting point 2<1>+9.5 - 251 °C.

9-isopropylaminomethyl-9,1O-dihydro-9,1O-methanoanthracene. Melting point 103 - 103.5°C

9-sec.-butylaminomethyl-9,510-dihydro-9,10-methanoanthracene hydrochloride. Melting point 23<»>f - 235.5°C.

9-isobutylaminomethyl-9,10-dihydro-9,10-methanoanthracene hydrochloride. Melting point 227 - 229°C.

9-Cyclopropylmethylaminomethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 2<>>+0.5 - 2^3.5°C.

9-allylaminomethyl-9>10-dihydro-9,10-methanoanthracene hydrochloride. Melting point 208 - 209°C

9-Benzylaminomethyl-9}10-dihydro-9,10-methaneanthracene. Melting point 9h - 97°C

9-piperidinomethyl-9,10-dihydro-9,10-methanoanthracene. Melting point 11<1>+ _ 115°C.

in

9-morpholinomethyl-9,1O-dihydro-9,1O-methanoanthracene. Melting point 160-163°C.

9-8-aminoethyl-9,1O-dihydro-9,1O-methanoanthracene. Melting point 158 - 160°C.

9-B-methylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 30^ - 305°C.

9-B-dimethylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 239 - 2»+0,<5>°C

9-8-Ethylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 297 - 299°C.

9-8-diethylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene. I.R. spectrum: 3065, 1V68, l¥+5, 1380, 1280, 1205, 1155, 1010, 765, 7*+5 cm"1.

9-8-sec,-Butylaminoethyl-9,1O-dihydro-9,10-methanoanthracene hydrochloride. Melting point 267 - 268°C.

9-8-Dicyclopropylmethylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 137 - 1<I>+0°C.

9-8-allylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 2^+2 - 2h3°C

9-8-Benzylaminoethyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 233- 235°C.

9-P-morph olinoethyl-9,1O-dihydro-9,10-;;ethanoanthracene hydrochloride. Melting point 263 - 26k°C.

9-γ-aminopropyl-9,10-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 275°C.

9-γ-Methylaminopropyl-9,10-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 259 - 260°C.

9- Y ~methylaminopropenyl-9,1O-dihydro-9,10-methanoanthracene hydrochloride. Melting point 2kh - 2i+6°C.

9-Y-dimethylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 2h7 - 2k7.5°C.

9-Y-ethylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 181+ - 186°C.

9-Y-ethylmethylaminopropyl-9,1O-dihydro-9,10-methanoanthracene oxalate..Melting point 168 - 169°C.

9- Y -isopropylaminopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride. Melting point 255 - 256°C.

9- y -isobutylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 2l+8 - 252°C.

9- Y -sec.-butylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 217 - 219°C.

9- Y -benzylcyclopropylmethylaminopropyl-9,1O-dihydro-9,10-methanoanthracene hydrochloride. Melting point 207 - 211°C.

9-γ-allylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 226 - 228°C.

9-γ-Benzylaminopropyl-,9,1O-dihydro-9,10-methanoanthracene hydrochloride. Melting point 197 - 201°C.

9- Y -methylpropargylaminopropyl-9,10-dihydro-9,1O-methanoanthracene. Melting point 130 - 131°C.

9- y -(2,2,2-trifluoroethyl)methylamihopropyl-9,10-dihydro-9,10-methanoanthracene hydrochloride. Melting point 170 - 172.5°C.

9-y-piperidinopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 280 - 283°C.

9- T pyrrolidinopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 2¥+ - 2^8°C.

9-Y-morpholinopropyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 17<*>+ - 177°C

9- f -Dimethylaminobutyl-9,1O-dihydro-9,1O-methanoanthracene hydrochloride. Melting point 201 - 202.5°C.

9- 6 -dimethylamino-oc-butenyl-9,10-dihydro-9,1 O-methanoanthracene hydrochloride. Melting point 15^.5 - 155°C.

The following compound can be prepared by a similar method: 9-propargylaminomethyl-9,1O-dihydro-9,1O-methanoanthracene.

9-(2,2,2-trifluoroethyl)aminomethyl-9,1O-dihydro-9,10-methanoanthracene.

9-B-propargylaminoethyl-9,10<->dihydro-9,10-methanoanthracene.

9-S-piperazinoethyl-9,1O-dihydro-9,1O-methanoanthracene.

9-B-methyl-Y-methylaminopropyl-9,1O-dihydro-9,1O-methanoanthracene.

9-a-methyl-B-dimethylaminoethyl-9,10-dlhydro-9,10-methanoanthracene.

Claims (1)

Analog production method for the production of new therapeutically active 9,10-dihydro-9,10-methanoanthracene derivatives with formula: wherein A is C 1 -C 4 alkylene or C 3 -C 4 alkenylene and R 1 and R 2 are each hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 alkynyl, C3~C6 cycloalkyl (C^-C-j) alkyl, phenyl (C^-C^)alkyl or trifluoro (C2~C4)alkyl or together with the adjacent nitrogen atom form cn 5 to 7-membered nitrogen-containing heterocyclic ring which may contain a further hetero atom, characterized in that either a) cn compound with formula: in which A' is a direct bond, C^-C^-alkylene or C2~C3 alkenyl and and R2 has the above meaning, is reduced, or b) a compound of formula wherein A has the above meaning and X is a substitutable group is reacted with a compound of formula: wherein and R_ has the above meaning in the presence or absence of a basic binding agent, optionally in the presence of an inert solvent, or c) a compound of formula: in which A' has the above meaning, and an amine of formula: wherein and R£ have the above meaning, is subjected to a condensation-reduction, or d) a compound of formula: wherein A has the above meaning, R^ is hydrogen, C1~C4 alkyl, C3~C4 alkenyl, C^-C^ cycloalkyl (C^-Cj) alkyl, phenyl (C^-C^)alkyl or trifluoro (C2~C4)alkyl and R4 is hydrogen, C1~C3 alkyl, <C>2~<C>3 alkenyl, phenyl, C3-C8 cycloalkyl or C^~C4 alkoxy is reduced to produce a compound of formula I wherein A has the above meaning, R^ has the same meanings as R3, and R2 is C1-C4 alkyl, C3-C4 alkenyl, benzyl or C1-C4 cycloalkylmethyl, or e) a connection with formula: in which A and R_^ when <jen the above meaning, are reacted with a compound with formula wherein R 5 is C 1 -C 4 alkyl, C 3 -C 4 alkenyl, C 3 -C 4 alkynyl, C 3 -C 6 cycloalkyl (C 1 -C 1 )alkyl, phenyl (C 1 -C 1 )alkyl or trifluoro (C 2 -C 4 )alkyl and X is halogen or a substitutable group for the preparation of a compound of formula I in which A has the above meaning and R^ and R2 have the same meanings as R3 and R^ respectively, or f) a compound of formula: in which A, R.j and R.sup.j have the above-mentioned meaning, is hydrolysed to produce a compound of formula I, in which A has the above-mentioned meaning, R.sup. has the same meanings as R-j and R.sup.2 is hydrogen, or g) a compound of formula: in which A and R^ have the above meaning, and an aldehyde of formula: R6-CHO wherein Rg is hydrogen, C1-C3 alkyl, C1-C3 alkenyl, phenyl or C-j-C8 cycloalkyl, is subjected to a condensation-reduction to prepare a compound of formula I wherein A has the above meaning, R^ has the same meanings as R^, and R2 is C^-C^j alkyl, C3-C4 alkenyl, benzyl or C-j-Cg cycloalkylmethyl, or h) a compound of formula: wherein A' is as defined above, is reduced to produce a compound of formula I, wherein A is as defined above and R 1 and R 2 are each hydrogen.