CH637954A5 - 5-SUBSTITUTED 10,11-DIHYDRO-5H-DIBENZO (A, D) -CYCLOHEPTEN-5,10-IMINE. - Google Patents

Description

The invention relates to new 5-substituted 10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imines, derivatives, optical isomers and pharmaceutically acceptable salts thereof, which are useful as agents against anxiety, depression, and minimal brain dysfunction or mixed anxiety / depression states, can be used as muscle relaxants and in the treatment of extrapyramidal disorders such as Parkinson's disease. It is known that structurally related compounds have qualitatively similar properties. For example, US Pat. No. 3,892,756 describes 10.1 l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine and derivatives which are unsubstituted on the 5-bridgehead atom and BE-PS 829 075 describes 9,10-dihydro-anthracen-9,10-imines and derivatives thereof.

The invention provides new compounds, 5-substituted 10, ll-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imines, which are surprisingly more active than the unsubstituted analogs; and the provision of new processes for their synthesis; and pharmaceutical compositions containing them as an active ingredient.

The compounds according to the invention have the following structural formula

4th

R

or set a, preferably pharmaceutically usable,

Salt thereof, in which R has the meaning of

(1) hydrogen,

(2) lower alkyl, in particular Ci-s-alkyl, preferably methyl or ethyl,

(3) low alkenyl, especially C2-5 alkenyl, preferably vinyl or allyl,

(4) phenyl (or substituted phenyl) lower alkyl, especially phenyl (or substituted phenyl) -Ci-3-alkyl, preferably benzyl or substituted benzyl, wherein the substituent is halogen, such as fluorine, chlorine or bromine, especially chlorine , or lower alkyl, especially Ci-3-alkyl.

(5) low-cycloalkyl, in particular C3-6-cycloalkyl, preferably cyclopropyl or cyclohexyl,

(6) lower (cycloalkyl-alkyl), in particular C3-6-cyclo-alkyl-Ci-3-alkyl,

(7) di (lower alkyl) amino lower alkyl, especially dimethylaminopropyl or

(8) hydroxy;

R1 has the meaning of

(1) hydrogen,

(2) lower alkyl, in particular Ci-s-alkyl, preferably methyl or ethyl,

(3) low alkenyl, especially C2-5 alkenyl, preferably vinyl or allyl,

(4) phenyl-lower alkyl, especially phenyl-C3-6-alkyl-,

3rd

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

637954

4th

preferably benzyl,

(5) low-cycloalkyl, especially C3-6-cycloalkyl, preferably cyclopropyl or cyclohexyl, or

(6) lower (cycloalkyl-alkyl), especially C3-6-cyclo-alkyl-Ci-3-alkyl;

R2 has the meaning of

(1) lower alkyl, in particular Ci-5-alkyl, preferably methyl or ethyl,

(2) low alkenyl, in particular C2-5 alkenyl, preferably vinyl or allyl,

(3) phenyl-lower alkyl, especially phenyl-Ci-3-alkyl, preferably benzyl,

(4) lower (cycloalkyl-alkyl), in particular C3-6-cyclo-alkyl-Ci-3-alkyl,

(5) di (lower alkyl) amino lower alkyl, especially dimethylaminopropyl,

(6) Hydroxy-lower alkyl, especially hydroxy-C2-3-alkyl, preferably hydroxyethyl or

(7) hydrogen and

R3 and R4 independently of one another have the meaning of

(1) hydrogen,

(2) halogen such as chlorine, bromine, fluorine or iodine,

(3) lower alkoxy, especially Ci-s-alkoxy, preferably methoxy,

(4) trifluoromethylthio,

(5) Cyano

(6) carboxy or

(7) hydroxy.

A preferred group of compounds is the group where R1 is hydrogen.

In a further preferred group of compounds, R1, R3 and R4 are hydrogen.

In another preferred compound, R is hydroxy and R1, R2, R3 and R4 are hydrogen.

s If R3 and / or R4 are different from hydrogen, they preferably occupy the 2-, 3-, 7- or 8-positions of the tricyclic ring system.

Preferred definitions for R2 are lower alkyl, especially methyl or ethyl, or hydroxyethyl. 10 Preferred definitions for R are hydrogen, lower alkyl or benzyl.

The new compounds according to the invention, in which R is hydrogen, are prepared by reducing the N-hydroxy analog. The preferred reducing agent 15 is nascent hydrogen generated by the action of a metal, preferably zinc, on an acid such as acetic acid at 40 to 100 ° C for about 1 to 10 hours.

The new compounds can also be prepared by ring closure of a 10-NHR-5 - (= CHR2) -10, l 1-20 dihydro-5H-dibenzo [a, d] cycloheptene by treatment with a strong base, such as an organometallic reagent, for example n-butyllithium, in an ethereal solvent such as tetrahydrofuran, 1,2-dimethoxyethane or the like, at about 0 ° C to about 30 ° C for about 5 minutes to about 1 hour.

If R2 is hydroxy-lower alkyl, the final stage of its synthesis usually consists in the reduction of the lower alkoxy-carbonyl precursor. The preferred reducing agent is lithium aluminum hydride in an ethereal solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or the like, at a temperature from about 15 ° C to about 100 ° C until the reduction is substantially complete. in about 1 to about 6 hours. The method is also used for the hydrogenolysis of a bridgehead halogen group, 3S, which is used in the following example for a synthetic scheme.

R

CH2C02 alkyl

V /

CH2CH2OH

If R is different from hydrogen, the new compounds can be prepared by alkylating the compounds where R is hydrogen with the appropriate reagent of the formula R-halogen where halogen is chlorine, bromine or iodine. The reaction is usually carried out in an inert solvent such as benzene or toluene. However, depending on its physical properties, the alkylating agent can be used in an excess amount sufficient to act as a solvent. The reaction is preferably carried out in the presence of an acid acceptor, such as an inorganic carbonate, such as sodium carbonate, an organic base, such as pyridine, or a basic resin. Temperatures from about 50 ° C to about 100 ° C can be used during reaction times from about 10 hours to about 5 days.

If R is alkyl or substituted alkyl, the compounds can also be prepared by reducing an N-acyl compound, such as alkoxycarbonyl, to form methyl, or by reducing other alkanoyl groups to form other alkyl groups. The preferred reduction system is a metal hydride such as lithium aluminum hydride, an ethereal solvent such as ether, tetrahydrofruan or 1,2-dimethoxyethane or the like. The reaction proceeds satisfactorily at room temperature, but temperatures from about 0 ° C. to about 50 ° C. are suitable with reaction times of 10 to 13 hours.

New compounds with substituents on the benzene or benzene-like rings are generally prepared by exchange reaction of the corresponding bromine or iodine compound. For example, treatment with a sodium lower alkoxide in the presence of copper dust in an inert organic solvent such as dimethylformamide at 50-150 ° C for 1 to 10 hours leads to the corresponding lower alkoxy compound. so The 2-, 3-, 7- or 8-hydroxy compounds are normally prepared from the corresponding alkoxy, preferably methoxy, compounds by ether cleavage. The preferred method is to warm to 200-220 ° C with pyridine hydrochloride for 3 to 10 hours.

Treatment of a bromine or iodine compound with copper (I) cyanide in an inert organic solvent such as dimethylformamide at the reflux temperature

5

637954

during 1 to 10 hours leads to the corresponding cyano compound.

Hydrolysis of the above cyano compounds with a mineral acid such as hydrochloric acid at about 50 to 150 ° C, and especially at the reflux temperature, leads to the corresponding carboxy-substituted compounds.

Treatment of the bromine or iodine compounds with bis (trifluoromethylthio) mercury and copper dust in an inert organic solvent, such as dimethylformamide or quinoline, for 1 to 10 hours at about 100-200 ° C. leads to trifluoromethylthio derivatives.

For example, the following connections are made:

3- (or 7) -R3-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine;

3-R3-12-cyclopropylmethyl-5-methyl-10,11-dihydro-5H-

dibenzo [a, d] cyclohepten-5,10-imines;

2-RM2-dimethylaminopropyl-5-ethyl-10.1 l-dihydro-5 H-

dibenzo [a, d] cyclohepten-5,10-imines; and

7-R3-5,12-diethyl-10,11-dihydro-5H-dibenzo [a, d] cyclo-

hepten-5,10-imine wherein

R3 denotes lower alkoxy, hydroxy, cyano, carboxy or trifluoromethylthio.

The new compounds can be broken down into their optical isomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-) - di-p-toluoyl-d-tartaric acid and / or (+) - di- p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base.

The starting materials and the processes for producing the intermediates used in the processes described above are described in more detail in the examples.

The invention also includes the, preferably non-toxic, pharmaceutically acceptable salts of the new compounds. Acid addition salts of the imine compounds are normally prepared by mixing a solution of the imine with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, phosphoric acid or the like. If the new compound contains a carboxylic acid group, the invention also includes the sodium, potassium and calcium salts thereof.

In the treatment method according to the invention, the new imines according to the invention are suitable for relieving anxiety states without excessive sedation or sleep at a dose level of approximately 0.01 to approximately 50 mg / kg body weight, preferably approximately 0.05 to 10 mg / kg body weight an administration sequence of 1 to 4 times a day. In addition, the new compounds according to the invention are suitable as agents for depression and minimal brain dysfunction or mixed anxiety / depression states, as muscle relaxants, anticonvulsants and for the treatment of extrapyramidal disorders if they are administered in comparable dosages. It is understood that the exact treatment will depend on the animal or human patient's medical history and that the final analysis or level of treatment will be left to the therapist within the guidelines above.

The invention also encompasses compositions which contain the imines according to the invention. Preferably, these compositions are in unit dosage forms, such as

Tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions or suppositories for oral, parenteral or rectal administration. One dose unit contains 0.1 to about 500 mg of active ingredient.

The following examples serve to explain the products, processes, treatment methods or compositional features according to the invention without representing any restriction.

10th

example 1

5-methyl-10,11-dihydro-5 H-dibenzo [a, d] cyclohepten-5,10-imine and the oxalate salt

15 level A:

Preparation of 10- (l-piperidyl) -5H-dibenzo [a, d] cyclo-hepten-5-one

A mixture of 71.3 g of 10-bromo-5H-dibenzo [a, d] cyclo-hepten-5-one, 50 ml of piperidine, 11 tert-butanol and 2o finally 33.6 g of potassium tert-butoxide 2 hours under reflux and then stirred overnight at room temperature. The mixture was filtered and concentrated to dryness. The residue was slurried with water and decanted. The residue was slurried with Me-25 ethanol and filtered to give 59.8 g of 10- (l-piperidyl) -5H-dibenzo [a, d] cyclohepten-5-one, mp 103-105 ° C.

Level B:

30 Preparation of 5-hydroxy-5-methyl-10- (1-piperidyl) -5H-dibenzo [a, d] cycloheptene

A solution of 140 ml of 1.8 m methyl lithium in ether and 250 ml of ether was added dropwise at 5-10 ° C under nitrogen with a solution of 59 g of 10- (1-piperidyl) -5H-35 dibenzo [a, d ] cyclohepten-5-one in 250 ml of tetrahydrofuran. After a total of 2 hours, the mixture was poured onto ice and left to stand until the ice melted. The mixture was extracted well with ether and the extract was dried over NazSCU, filtered and evaporated to dryness; the residue was used directly for the next stage.

Level C:

Preparation of 5-methylene-10-oxo-10,11-dihydro-5H-45 dibenzo [a, d] cycloheptene

The carbinol of stage B was dissolved in 500 ml of 10% ethanolic hydrogen chloride and 30 ml of concentrated hydrochloric acid and heated under reflux overnight. The solvent was evaporated and the residue was extracted with 500 ml of benzene. The extract was dried and concentrated to dryness. The residue was extracted with 300 ml of boiling hexane. When cooling, 18.5 g of solid separated out of the extract, which after recrystallization from hexane 16.5 g of 5-methylene-10-oxo-55 10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene Mp 84-86 ° C.

Level D:

60 Preparation of 10-hydroximino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene

A mixture of 16.5 g of the stage C oxo compound, 6.6 g of hydroxylamine hydrochloride, 8.2 g of sodium acetate and 300 ml of methanol was heated under reflux for 5 hours.

65 The solvent was evaporated and the residue was treated with 250 ml of water. The mixture was extracted with 3 x 150 ml ether and the extract was dried, filtered and evaporated to give 16.8 g

637954

6

10-hydroximino-5-methylene-l 0.11-dihydro-5H-dibenzo [a, d] cyclohepten, mp 156-160 ° C.

Level E:

Preparation of 10-hydroxamino-5-methylene-10, 1 1-dihydro-5H-dibenzo [a, d] cycloheptene

A mixture of 15.3 g of the stage D oxime, 500 ml of methanol, 12 g of sodium cyanoborohydride in 450 ml of methanol was added dropwise with a solution of 12 ml of 12N hydrogen chloride in 50 ml of methanol over 5 hours and overnight at room temperature touched. The solvent was evaporated, the residue was stirred with 200 ml of aqueous hydrochloric acid, made alkaline with concentrated ammonium hydroxide and extracted with 3 × 175 ml of ether. The combined extracts were dried over Na2SC> 4, filtered and evaporated. The crystalline residue was washed with methanol to give 9.6 g of 10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene, mp 145-147 ° C.

Level F:

Preparation of 12-hydroxy-5-methyl-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

A solution of 8.8 g of the hydroxamino compound of stage E in 200 ml of xylene was added dropwise to 80 ml of refluxed xylene. After refluxing for 1 hour, the solvent was evaporated. 250 ml of water and 7 ml of concentrated hydrochloric acid were added to the residue, and the mixture was washed with 100 ml of ether and the washing solution was discarded. The aqueous phase was made basic with concentrated ammonium hydroxide and extracted with 3 × 100 ml of ether. The extract was dried over NaaSCh, filtered and evaporated. The residue was recrystallized from cyclohexane to give 8.5 g of 12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine, mp 141-144 ° C .

Step G. Preparation of 5-methyl-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine and the oxalate salt

A mixture of 1.2 g of stage F hydroxyimine, 7 ml of acetic acid and 1.2 g of zinc dust was heated at 60-70 ° C for 3.5 hours. The mixture was filtered and the filter cake was washed with 200 ml ether and 50 ml water. The filtrate was basified with 5% (w / v) aqueous sodium hydroxide and extracted with ether. The extract was dried over Na2SC> 4, filtered and evaporated to dryness to give 1.1g of a product. This material (1.1 g) was dissolved in 20 ml acetone and treated with 0.6 g oxalic acid in 10 ml acetone. After cooling overnight, 1.2 g of 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5, 10-imine of mp 203-206 ° C. (dec.) Were obtained. which, after recrystallization from methanol / acetone, had an mp of 215-217 ° C. (dec.).

Example 2

5-ethyl-10, ll-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

Level A:

Preparation of 5-ethylidene-10-oxo-10, l l-dihydro-5H-dibertzo [a, d] cycloheptene

To a stirred slurry of 21 g (0.057 mol) of ethyl triphenylphosphonium bromide in 400 ml of ether, 48 ml (1.3 m) of butyllithium in hexane was added dropwise. A solution of 13.5 g (0.044 mol) of 1- (5-keto-5H-dibenzo [a, d] cyclohepten-10-yl) -4- was added to the resulting solution.

methylpiperazine added in 100 ml THF. The resulting mixture was stirred and heated under reflux for 3.5 hours, cooled and poured into 300 ml of ice water. The organic phase was separated and the aqueous phase 5 extracted with 2 x 150 ml ether. The combined organic solutions were concentrated under reduced pressure. The concentrate was stirred with a mixture of 300 ml of aqueous hydrochloric acid and 300 ml of ether. The ethereal phase was separated, the aqueous phase was extracted with ether, and the combined ethereal solutions were dried over Na2SC> 4, filtered, and the filtrate was concentrated to 100 ml. Triphenylphosphine oxide was removed by filtration and the filtrate was chromatographed on silica gel, eluting with chloro-is form to give 10.1 g (98%) of 5-ethyl-iden-10-oxo-10, l 1 - dihydro-5H-dibenzo [a, d] cyclohepten, mp. 93-95 ° C.

If the procedure was essentially as described in Example 1, stages D to G, the 5-methylene-10-oxo-20 replaced 10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene of stage D by one Equimolar amount of 5-ethylidene-l 0-oxo-10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene, the following was obtained in sequence:

25 5-ethylidene-10-hydroximino-10, l l-dihydro-5H-

dibenzo [a, d] cyclohepten (86% yield), mp. I28-13l ° C;

5-ethylidene-10-hydroxamino-10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene (89% yield), mp. 121-124 ° C;

30th

5-ethyl-12-hydroxy-10, ll-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine (21% yield), mp 112-116 ° C; and

5-ethyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-35 imine (90% yield) and hydrogen oxalate salt, mp. 240-241 ° C.

The procedure was essentially as described in Example 2, but the ethyl triphenylphosphonium bromide used in stage A 40 was replaced by an equimolar amount of a Wittig reagent of the formula (CsH5) 3P + -CH2R2 (Br), in which -CH2R2 has the meaning of - CH3, -CH2CH2CH3 or - (CH2) 3CH3, the compounds of the formula were obtained

45

50

where -CH2R2 has the meaning of -CH3, -CH2CH2CH3 (mp. 298-299.5 ° C as HCl - '/ î CH3COCH3) and - (CHi ^ Cm.

Example 3

5- (2-Hydroxyethyl) -10, ll-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine

55

60 level A:

Preparation of 5-ethoxycarbonylmethylene-10, l 1-dihy dro-5H-dibenzo [a, d] cyclohepten-10-one

10 g (0.045 mol) of triethylphosphonoacetate was added dropwise to a slurry of 1.9 g (0.04 mol) of 65 sodium hydride (50% in mineral oil) in 20 ml of dry toluene under nitrogen, the temperature being cooled at 30-35 ° C was held. The mixture was stirred at room temperature for 1 hour. A solution of 10 g

7

637 954

(0.0328 mol) l- (5-Keto-5H-dibenzo [a, d] cyclohepten-10-yl) -4-methylpiperazine in 75 ml of dry toluene was added dropwise, the temperature being reduced by cooling at 25-30 ° C was held. The mixture was stirred at room temperature for 3 hours and kept at room temperature overnight. After decanting the solution, the precipitate was washed with 4x25 ml portions of toluene at 65 ° C. The combined toluene extracts were diluted with an equal volume of ether and shaken with 75 ml of 0.5N hydrochloric acid. The aqueous layer • was decanted off and extracted again with toluene ether (1: 1). The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting oily solid was freed from the bulk of the oil by collecting on a sintered glass funnel and then triturated with cyclohexane to give 4.5 g (47%) of 5-ethoxycarbonylmethylene-10.1 l-dihydro-5H- dibenzo [a, d] cyclohepten-10-one, mp 56-62 ° C.

Level B:

Preparation of 5-ethoxycarbonylmethyl-10,12-dihydroxy-10,11-dihydro-5 H -dibenzo [a, d] cyclohepten-5,10-imine

23.4 g (0.08 mol) of the keto-olefin from stage A were stirred together with 6.0 g of hydroxylamine hydrochloride, 12.0 g of sodium acetate trihydrate and 300 ml of moist ether at room temperature. After 16 hours, the precipitate was collected, washed with ether and stirred with 300 ml of water for 1 hour. The solid was collected and dried to give 21.6 g (83%) of 5-ethoxycarbonylmethyl-10,12-dihydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine mp 193-195 ° C (dec.).

Level C:

Preparation of 5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

21 g (0.0646 mol) of the N-hydroxyimine of stage B was suspended in 125 ml of glacial acetic acid, and 16 g of zinc dust was added in portions over 15 minutes. After the exothermic reaction was stopped, the mixture was stirred and heated in an oil bath at 65 ° C. for 3 hours. The cooled mixture was filtered and the filtrate was evaporated under reduced pressure. The remaining syrup was dissolved in 500 ml of water and the filtered solution was made basic with 15% aqueous sodium hydroxide. The precipitate was recovered, washed with water and dried to give 15 g of 5-ethoxycarbo-nylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine, mp . 186-189 ° C (dec.). A filtered solution of this product in 350 ml of boiling acetone was treated with 7 ml of 7N ethanolic hydrogen chloride. The precipitation of the hydrochloride salt was obtained, washed with ether and dried with a yield of 14.35 g (64%), mp. 247-250 ° C. (dec.).

Level D:

Preparation of 10-chloro-5-ethoxycarbonylmethyl, -10, 1 1-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

17.8 g (0.0515 mol) of the hydrochloride salt of the Step C product was slurried in 250 ml of thionyl chloride and the mixture was heated to reflux. After the exothermic reaction that occurred ceased, the mixture was heated under reflux for 20 minutes when the solid had completely dissolved. The thionyl chloride was evaporated under reduced pressure and last traces were removed by repeated co-evaporation with toluene. The residue was triturated with acetone and dried to give 15.35 g (81%) of 10-chloro-5-ethoxycarbonyl-

methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrochloride, mp 223-227 ° C (dec.).

5

Level E:

Preparation of 5- (2-hydroxyethyl) -10, l l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

15.3 g (0.042 mol) of the hydrochloride of stage D was added in portions to a slurry of 5.6 g (0.147 mol) of lithium aluminum hydride in 200 ml of ether and 200 ml of tetra-hydrofuran. The mixture was stirred under reflux for 3 hours, then cooled to 0 ° C. and hydrolyzed by the dropwise addition of 4 ml of water and 4 ml of 15 10% aqueous sodium hydroxide. After dilution with ether, the precipitate was collected, suspended in 250 ml of chloroform and stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was combined with the ethereal filtrate obtained previously. Solvents 2 "were evaporated under reduced pressure and the solid obtained was recrystallized from 95% ethanol to give 8.6 g of 5- (2-hydroxyethyl) -10.1 l-dihydro-5H-dibenzo [a, d] cyclohepten-5, l 0-imine, mp 181-184 ° C. Recrystallization from 70% ethanol gave a 25 mp of 182-184 ° C.

A suspension of 4.4 g of this product in 20 ml of warm absolute ethanol was treated with 2.5 ml of 7N ethanolic hydrogen chloride and the mixture was stirred until the collected solid was dissolved. By diluting with ether, 4.8 g of the hydrochloride salt of mp. 263-265 ° C. precipitated. Recrystallization from acetonitrile gave an mp of 262-264 ° C (dec.).

Example 4

35 3- (and 7) -bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

Level A:

Preparation of 3,10,1 l-tribromo-5H-dibenzo [a, d] cyclo-4o hepten-5-one

A solution of 53 g (0.33 mol) of bromine in 125 ml of glacial acetic acid was added dropwise to a stirred slurry of 71.25 g (0.25 mol) of 3-bromo-5H-dibenzo [a, d] cyclohepten-5-one added in 775 ml of glacial acetic acid. After stirring the mixture 45 at room temperature for several hours, the solid was collected, washed with glacial acetic acid and dried; Yield 105.8 g (95%), mp 173-175 ° C.

Level B:

thus preparation of 3,10-dibromo-5H-dibenzo [a, d] cyclo-hepten-5-one and 3.1 l-dibromo-5H-dibenzo [a, d] cyclohepten-5-one

The product of Step A was added to a stirred solution of 28 g (0.7 mol) of sodium hydroxide in 21% methanol. The thick mixture was stirred under reflux for 1 hour. After cooling, the solid was collected, washed with methanol and then with water and dried to give 81 g (90%) of the mixture of 3,10-dibromo-5H-dibenzo [a, d] cyclohepten-5-one and 3 , 11-60 dibromo-5H-dibenzo [a, d] cyclohepten-5-one, mp 146-156 ° C.

Level C:

Preparation of 3-bromo-10- (4-methylpiperazinyl) -5H-65 dibenzo [a, d] cyclohepten-5-one and 3-bromo-11- (4-methylpiperazinyl) -5H-dibenzo [a, d] cyclohepten-5-one

6.8 g (0.06 mol) of potassium tert-butoxide were added to a stirred slurry of 18.2 g (0.05 mol) of 3.10-

637954

Dibromo-5H-dibenzo [a, d] cyclohepten-5-one and 3,11-dibromo-5H-dibenzo [a, d] cyclohepten-5-one, 10 ml of 4-methyl-piperazine and 200 ml of dry tert.- Butyl alcohol added at room temperature and under nitrogen. The dark orange mixture was heated under reflux for 2 hours and then stirred at room temperature overnight. The mixture was poured into about 800 ml of ice and water and extracted with ether. The ethereal extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. A mixture of 3-bromo-10- (4-methylpiperazin-yl) -5H-dibenzo [a, d] cyclohepten-5-one and 3-bromo-l l- (4-methylpiperazinyl) -5H- dibenzo [a, d] cyclohepten-5-one in the form of a remaining reddish-yellow gummy mass; Yield 19.4 g, 100%.

Level D:

Preparation of 3-bromo-5-methyl-10- (4-methylpiperazin-yl) -5H-dibenzo [a, d] cyclohepten-5-ol and 3-bromo-5-methyl-11 - (4-methylpiperazinyl) - 5H-dibenzo [a, d] cyclohepten-5-ol

35 ml of a 1.6 m solution of methyl lithium in ether were added dropwise to a stirred solution of the product of step C (18 g, 0.047 mol) in 200 ml ether and 60 ml tetra-hydrofuran, cooled in an ice bath and under nitrogen . The mixture was stirred at room temperature for a further 3 hours. The mixture was cooled in ice and hydrolyzed by adding water dropwise. After dilution with ether and water, the layers were separated and the aqueous phase was extracted again with ether. The combined ethereal extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. A mixture of 3-bromo-5-methyl-10- (4-methylpiperazinyl) -5 H-dibenzo [a, d] cyclohepten-5-ol and 3-bromo-5-methyl-l l- (4- methylpiperazinyl) -5H-dibenzo [a, d] cyclohepten-5-ol as a dark yellow glassy mass remaining; Yield 18 g (96%).

Level E:

Preparation of 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one and 7-bromo-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-10-one

A mixture of 18 g (0.045 mol) of the product of Step D, 80 ml of 95% ethanol, 40 ml of 7N ethanolic hydrogen chloride and 80 ml of 6N aqueous hydrochloric acid was stirred for 30 minutes at room temperature and for 1 hour at the reflux temperature. The mixture consisted of a brown oily lower phase and an aqueous-alcoholic upper phase. The latter was decanted and the alcohol stripped in vacuo. The remaining aqueous mixture was extracted with chloroform. The brown oil obtained above was dissolved in chloroform and the combined chloroform phases were washed with water and dried over anhydrous magnesium sulfate. Evaporation of the filtered extract left a crude product as a dark yellow glassy mass. This material was chromatographed on a silica gel column eluting with toluene. Evaporation of the appropriately combined fractions left a partially purified product as an oily solid (8.5 g). Trituration with cyclohexane gave one of the isomers of the product as a white solid; Yield 2.6 g, mp 125-158 ° C. Two recrystallizations from cyclohexane gave an mp of 158-163 ° C. Evaporation of the first cyclohexane mother liquor left the remaining isomer of the product as a dark yellow oil. Trituration with three successive portions of 10 ml of hexane gave a yellow solid; Yield 3.3 g, mp 75-83 ° C. Two recrystallizations from hexane gave an mp of 84-89 ° C.

The higher melting isomer (mp. 160-164 ° C) has the following structural formula:

'Br

CH

and is referred to as 7-bromo-5-methylene-10, l 1-dihydro-5 H-dibenzo [a, d] cyclohepten-10-one.

The other isomer, 3-bromo-5-methylene-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten-10-one (mp. 84-91 ° C) has the following structural formula:

Level F to I:

Preparation of 3- (and 7) -bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine

Using essentially the procedure described in Example 1, steps D to G, but replacing the 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene used there by an equimolecular amount of the corresponding 3- and 7-bromine compounds are obtained in succession:

(Level F):

3- (and 7) -bromo-10-hydroximino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cyclohepten, mp. 171-175 ° C or

179-181 ° C;

(Level G):

3- (and 7) -bromo-10-hydroxamino-5-methylene-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten, mp. 149-153 ° C or

136-139 ° C;

(Level H):

3- (and7) -bromo-12-hydroxy-5-methyl-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten-5, l 0-imine, mp. 175-180 ° C or 187-189 ° C; and (level I):

3- (and 7) -bromo-5-methyl-10, l l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrochloride, m.p. > 300 ° C.

The following are prepared in the same way: 8-bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine;

2-bromo-5-ethyl-10, ll-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine; and

7-bromo-5-ethyl-10, ll-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine.

Example 5

10,11 -dihydro-5,12-dimethyl-5H-dibenzo [a, d] cyclo-hepten-5,10-imine fumaric acid salt

Level A:

Preparation of 10,11-dihydro-12-ethoxycarbonyl-5-methyl-5H-dibenzo [a, d] cyclohepten-5,10-imine

A mixture of 1.15 g 10.1 l-dihydro-5-methyl-5H-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

637 954

dibenzo [a, d] cyclohepten-5, 10-imine, 1.0 g of anhydrous sodium carbonate, 1 ml of ethyl chloroformate and 10 ml of dry benzene were heated under reflux for 2 hours. The mixture was filtered and the filtrate was evaporated in vacuo to give 1.45 g of white crystalline 10.1 l-dihydro-12-ethoxycarbonyl-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10- imin mp 80-83 ° C.

Level B:

Preparation of 10,11-dihydro-5,12-dimethyl-5H-dibenzo [a, d] cyclohepten-5,10-imine

A solution of the stage A urethane in 15 ml of absolute ether was added dropwise to a slurry of 190 mg of lithium aluminum hydride in 15 ml of absolute ether with stirring and under nitrogen. After 24 hours at room temperature, the mixture was cooled in an ice bath and hydrolyzed by dropwise addition of the minimal volume of water containing a few drops of 5% (w / v) aqueous sodium hydroxide. After dilution with ether, the mixture was filtered. The filtrate was evaporated in vacuo to give 1.1 g of the free base of the product as a colorless oil. This was combined with 0.9 g of the same material and dissolved in 25 ml of ethyl acetate. A warm solution of 1.2 g fumaric acid in 12 ml methanol was added. The fumaric acid salt which crystallized out was collected and recrystallized from methanol-ethyl acetate to give 2.1 g of 10, 11-dihydro-5,12-dimethyl-5H-dibenzo [a, d] cyclohepten-5,10-imine-fumaric acid -resalz of mp. 186-188 ° C.

Example 6

12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo [a, d] cyclo-hepten-5,10-imine

A mixture of 2.45 g of 10.1 l-dihydro-5-methyl-5H-dibenzo [a, d] cyclohepten-5, l 0-imine, 1.9 g of benzyl chloride, 3.2 g of anhydrous sodium carbonate and 50 ml dry benzene was stirred under reflux for 4 days. The mixture was filtered and the filtrate evaporated in vacuo to give 3.1 g of the product as an oily solid, mp.

107-111 ° C. This was recrystallized twice from 95% ethanol to give 1.85 g of white crystalline 12-benzyl-10,11-dihydro-5-methyl-5H-dibenzo [a, d] cyclo-hepten-5,10-imine from Mp 111-114 ° C.

Example 7

12-Allyl-10,11-dihydro-5-methyl-5 H-dibenzo [a, d] cycIo-hepten-5,10-imine

A mixture of 2.45 g of 10.1 l-dihydro-5-methyl-5H-dibenzo [a, d] cyclohepten-5,10-imine, 1.8 g of allyl bromide, 3.0 g of anhydrous sodium carbonate and 50 ml of dry Benzene was stirred under reflux temperature for 20 hours. The mixture was filtered and the filtrate evaporated in vacuo to give 1.2 g of the oily free base of the product. This was dissolved in 5 ml of acetone and added to a warm solution of 75 g of fumaric acid in 75 ml of acetone. The salt that crystallized was recovered and recrystallized from acetone to give 1.45 g of white crystalline 12-allyl-10.1 l-dihydro-5-methyl-5H-dibenzo [a, d] cyclo-hepten-5, 10-imine fumaric acid salt, mp 180-182 ° C.

Using the same procedure as in Example 7, but replacing the allyl bromide and the 10,11-dihydro-5-methyl-5H-dibenzo [a, d] cyclohepten-5,10-imine used there with one Compound of the formula RI and 5-R2CH2-10, 11-dihydro-5H-dibenzo [a, d] -cyclohepten-5,10-imine, described in Table II, gives the 5-R2CH2-12-R- 10, 1 l-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imines, which are also described in Table II, according to the following reaction:

Table II

R2

-H

-CH.

15

H

(Mp 132.5-135.5 ° C)

H -CH2- (3-Cl H (mp 111-113 ° C,

-CH "CH"

Hydrogen oxalate) (mp. 115.5-117 ° C) (mp. 163-164 ° C) (mp. 132.5-135.5 ° C) (mp. 112-114.5 ° C)

(Mp 111-113 ° C, base)

35

H

-CHs

-cm

-cm

<

3-br

- (Cm) 3N (Cm) 3 2-Br -C2H5 7-Br

40.

Example 8

5,10,12-trimethyl-10,11-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine hydrochloride

45

Level A:

Preparation of 10-amino-5-methylene-10, l l-dihydro-5H-dibenzo [a, d] cycloheptene

To a stirred slurry of 0.9 g (0.138 mol) of 50 zinc dust in 100 ml of glacial acetic acid, stirred on an oil bath at 65 ° C., 10 g (42 mmol) of 10-hydroxamino-5-methylene-10,11-dihydro-5 H were added -dibenzo [a, d] cycloheptene added. The mixture was stirred in the oil bath for 2 hours, cooled and quenched in 500 ml of water. The mixture was made basic with concentrated ammonia and then extracted with ether. The combined ethereal layers were washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from hexane; Yield 7.8 g, mp. 84.5-86.5 ° C.

Level B:

Preparation of 10-isocyano-5-methylene-10, l 1-dihydro-5 H-dibenzo [a, d] cyclohepten 65 To a solution of 8.1 g (36.6 mmol) of 10-amino-5-me- Ethylene-10,11-dihydro-5 H-dibenzo [a, d] cycloheptene in 180 ml of chloroform were 4.42 g (0.11 mol) of sodium hydroxide pellets, 0.42 g (1.8 mmol) of benzyltriethylammonium chloride and

637 954

10th

0.5 ml of water added. The mixture was stirred under nitrogen until the sodium hydroxide pellets were dissolved (about 4 hours), treated with anhydrous potassium carbonate, filtered and evaporated to dryness in vacuo. The resulting oil was dissolved in 180 ml of chloroform, treated with an additional 1.5 g (37.5 mmol) of sodium hydroxide and 0.2 g (0.86 mmol) of benzyltriethylammonium chloride and stirred overnight under nitrogen. The mixture was dried again over potassium carbonate, filtered and evaporated to dryness in vacuo. The resulting oil was chromatographed on 120 g of silica gel and eluted with methylene chloride. The combined product fractions were evaporated to dryness in vacuo and the resulting solid was recrystallized from ether to give 4 g of a solid, mp 96-98 ° C.

Level C:

Preparation of 10-isocyano-10-methyl-5-methylene-10, 1 1-dihydro-5H-dibenzo [a, d] cycloheptene

1.1 g (10.9 mmol) of diisopropylamine were stirred in 25 ml of dry tetrahydrofuran in a dry ice-acetone bath. Under a nitrogen blanket, 5.0 ml of a 2.2 m solution of n-butyllithium / hexane was added dropwise to this solution over 10 minutes. After 5 minutes, a solution of 2.4 g (10.4 mmol) of 10-isocyano-5-methylene-10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene in 25 ml of dry tetrahydrofuran was added over 45 minutes dropped the lithium diisopropylamide solution. The resulting deep red solution was stirred in the cold for 15 minutes and then treated with 4.56 g (32 mmol) of methyl iodide, which was added all at once. The mixture was stirred in the cold for 2 hours and at room temperature for a further hour. The solvent was removed in vacuo and the residue was chromatographed on 75 g of silica gel and eluted with methylene chloride. The combined product fractions were evaporated in vacuo to give 2.2 g (85%) of a solid. By recrystallization from ether, an mp of 146-147.5 ° C was obtained.

Level D:

Preparation of 10-methyl-10-methylamine-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene hydrochloride chloride

1.8 g (7.3 mmol) of 10-isocyano-10-methyl-5-methylene-10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene, dissolved in 100 ml of dry ether, were added dropwise to one Slurry of 0.53 g (14 mmol) of lithium tetrahydridoaluminate in 40 ml of ether, stirred under nitrogen, added. The mixture was heated under reflux for 1 hour, cooled, and the excess hydride was decomposed by carefully adding 1.5 ml of ice water dropwise. The suspension was filtered and the solids were washed twice with ether. The combined ethereal fractions were evaporated in vacuo to 1.8 g of an oil. This oil, dissolved in 10 ml of absolute ethanol, was treated with a slight excess of 8N ethanolic HCl and cooled to give 1.7 g (81%) of a powder of mp 238-240 ° C (dec.).

Level E:

Preparation of 5,10,12-trimethyl-10, l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrochloride

1.6 g (6.4 mmol) of 10-methyl-10-methylamino-5-methylene-10,11-dihydro-5 H-dibenzo [a, d] cyclöheptten were dissolved in 40 ml of dry tetrahydrofuran. To this solution, which was stirred at room temperature under nitrogen, 3.0 ml of a 2.2 m solution of n-BuLi in hexane were added dropwise over a period of 5 minutes. The mixture was stirred for 10 minutes and then treated with 3 ml of ice water. The tetrahydrofuran was removed in vacuo and the residue. was taken up in ether. The ethereal solution was washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The resulting oil was chromatographed on 120 g silica gel, eluted with methylene chloride and 1%, 1.5%, 2%, 3% and 5% methanol in methylene chloride.

The combined product fractions were evaporated to dryness in vacuo, dissolved in 50 ml of absolute ethanol, and a slight excess of 8N ethanolic HCl was added to 10. The solvent was removed in vacuo and the remaining solid was recrystallized from 20 ml of absolute ethanol to give 5,10,12-tri-methyl-10,11-dihydro-5 H-dibenzo [a, d] cyclohepten-5, 10-15 imine hydrochloride, mp 295-296.5 ° C.

In the same way were made:

10-allyl-5,12-dimethyl-; 5,10-diethyl-12-methyl-; 10-Cyclo-20 propyl-5,12-dimethyl; and 10-cyclopropylmethyl-5,12-dimethyl-10.1 l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine.

25th

Example 9

Optical separation

3.93 g (0.0178 mol) of racemic 5-methyl-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten-5, l 0-imine and 6.88 g (0.0178 mol) ( -) - Di-p-toluoyl-d-tartaric acid were dissolved in 21 ml acetone. The solution was inoculated and after standing for several hours at room temperature, the crystalline salt was obtained. This product was repeatedly recrystallized from acetone to a constant rotation value. The salt was suspended in cold water, stirred with aqueous sodium hydroxide and the base extracted in ether. The washed and dried ethereal extract was evaporated to dryness under reduced pressure, leaving (-) - 5-methyl-10, ll-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine as a solid residue; Mp 71.5-73.5 ° C.

The acetone mother liquor of the original crystallization of the (-) isomer was evaporated to dryness under reduced pressure. A suspension of the remaining glassy product in cold water was stirred with aqueous sodium hydroxide and the base extracted in ether. The washed and dried ether extract was concentrated to form the optically impure (+) base as a residual solid. This product (2.27 g, 0.0103 mol) and 3.9 (0.0103 mol) (+) - di-p-toluoyI-l-tartaric acid were dissolved in 20 ml acetone. After standing for several hours at room temperature, the crystalline salt was obtained and repeatedly recrystallized from acetone to a constant rotation value. The salt was converted back to the base in the manner described above to give (+) - 5-methyl-10,1-l-dihydro-5H-dibenzo [a, d] cyclo-hepten-5,10-imine, mp 72-74 ° C.

55

Example 10

Separation of (±) - (5-methyl-10,11-dihydro-5 H-dibenzó [a, d] cyclohepten-5,10-imine)

Left-handed isomer. 155.4 g were added to a solution of 66.1 g (0.299 60 mol) of racemic 5-methyl-10.1 l-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine in 107 ml of warm acetone (0.299 mol) di-p-toluoyl-d-tartaric acid dissolved in 163 ml of Aceto ri. The solution was stirred until it was homogeneous, left to stand at 25 ° C. for 18 hours and then cooled to 0 ° C. in the refrigerator for 4 hours. The salt that formed was separated by filtration, washed once with cold acetone, collected, dried at 50 ° C. (vacuum oven) and it was so

50

11

637 954

82.97 g of A as a white solid, [a] ° 89 = -125.9 ° (absolute EtOH), mp. 141-146 ° C (foam) obtained. The filtrate of solid A was evaporated to dryness under vacuum and solid residue B was used to prepare the right-handed isomer (see below).

Salt A was dissolved in 3450 ml of boiling acetone, filtered, concentrated to 1500 ml, left to stand at 25 ° C. for 18 hours and then cooled to 0 ° C. in the refrigerator for 4 hours. The precipitate was separated off by filtration, washed once with cold acetone, collected, dried at 60 ° C. (vacuum oven) and 45.5 g of C. as a white solid, [a] ° 89 = -131.9 ° ( abs. EtOH), mp 142-144 ° C (foam). The separated salt C (44.8 g, 0.0737 mol) was treated with 300 ml of 10% sodium hydroxide solution and 300 ml of diethyl ether and the mixture was stirred until the solid had dissolved. The ether phase was separated off, dried over MgSO4, filtered, evaporated to dryness in vacuo in order to obtain 16.0 g of a colorless oil which was uniform by TLC (silica gel, 1: 9 methanol: chloroform). Crystallization from 40 ml cyclohexane gives 14.16 g of (-) - 5-methyl-10.1 l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine as a white solid [a] ss9 = -160.8 °, (C = 0.032 g / 2 ml ethanol, mp. 68.5-69.5 ° C.

Right-turning isomer. Residue B from the preparation of the left-handed isomer was converted into the free base by stirring with 300 ml of 10% sodium hydroxide solution and 300 ml of diethyl ether until the solid was dissolved. The ether phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure to give 37.9 g of an orange oil which was dissolved in 61 ml of warm acetone and treated with a solution of 69.3 g (0.171 mol) of Di p-toluoyl-1-tartaric acid monohydrate in 98 ml of acetone was added. The solution was stirred until it was homogeneous, left to stand at 25 ° C. for 18 hours and then cooled to 0 ° C. in the refrigerator for 4 hours. The salt which formed was separated off by filtration, washed once with cold acetone, collected, dried at 60 ° C. (vacuum oven) and 68.8 g of D were thus obtained as a white solid, [a] 589 = + 127.1 ° (abs. EtOH), mp 136-144 ° C (foam). Salt D was dissolved in 2900 ml of boiling acetone, filtered, concentrated to 900 ml, left to stand at 25 ° C. for 18 hours and then cooled to 0 ° C. in a refrigerator for 4 hours. The precipitate was separated off by filtration, washed once with cold acetone, collected, dried at 60 ° C. (vacuum oven) and 36.5 g of E as a white solid, [a] 5S9 = −132.0 ° (abs EtOH), mp 142-144 ° C (foam).

The separated salt E (36.5 g, 0.0601 mol) was treated with 300 ml of 10% sodium hydroxide solution and 300 ml of diethyl ether and the mixture was stirred until the solid had dissolved. The ether phase was separated, dried over MgSÛ4, filtered, concentrated to dryness in vacuo, around 12.6 g one by TLC. uniform (silica gel, 1: 9 methanohloroform) colorless oil. Crystallization from 25 ml of cyclohexane gives 11.26 g of (+) - 5-methyl-10.11-dihydro-5H- [a] ^, = + 161.4 °, (C = 0.038 g / 2 ml of ethanol) , Mp 68.5-69.0 ° C.

The filter was washed with absolute ethanol so that the final filtrate volume was 40 ml. A solution of 5.27 g (0.0454 mol) of maleic acid in 20 ml of absolute ethanol is filtered in the same flask. The combined filtrates were mixed, inoculated, kept at room temperature for a short time and then left in the refrigerator overnight. The crystalline material was collected and dried and it became (+) - 5-methyl-10,1-l-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate, m.p. 10,208,5-210 ° C; [a] 2D ° + 114 °, (C = 0.0128 g / 2 ml ethanol) obtained.

Example 12 Preparation of tablets

Tablets containing 1,0,2,0,25,0,26,0, 50.0 and 100.0 mg of 10.11-15 dihydro-5-methyl-12-benzyl-5H-dibenzo [a, d ] containing cyclohepten-5,10-imine were prepared as exemplified below.

Tablet for doses of 1 to 25 mg of the active compound

Amount - mg

10.1 l-Dihydro-5-methyl-12-25 benzyl-5H-dibenzo [a, d] cyclo-hepten-5,10-imine modified microcrystalline cellulose

Food maize starch 30 magnesium stearate

Tablet for doses of 26 to 100 mg of active compound

1.0

2.0

25.0

49.25

48.75

37.25

49.25

48.75

37.25

0.50

0.50

0.50

Amount - mg

10,11 -Dihydro-5-methyl-12-40 benzyl-5H-dibenzo [a, d] cyclo-hepten-5,10-imine modified microcrystalline cellulose

Food corn starch 45 magnesium stearate

26.0

50.0

100.0

25.0

100.0

200.0

2.21

4.25

8.5

0.39

0.75

1.5

Example 11

(+) - 5-Methyl-l 0.11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate

A solution of 10.05 g (0.0454 mol) of (+) - 5-methyl-10, l 1-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine in 25 ml of absolute ethanol was added filtered a flask and the

The entire active compound, the lactose and a portion of the corn starch were mixed and granulated into a 10% corn starch paste. The resulting granules were sieved, dried and mixed with the rest of the corn starch and the magnesium stearate. The resulting granules were then pressed into tablets which contained 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg of active ingredient per tablet. Other tablets were made using the same procedures and equivalent amounts of excipients along with equivalent amounts of any of the novel compounds of the invention.

In summary, the invention relates to 5-substituted-10, ll-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imines, derivatives and pharmaceutically acceptable salts thereof, which are useful as anti-anxiety, depression and anti-depressants minimal brain dysfunction or mixed anxiety / depression states that can be used as muscle relaxants and in the treatment of extrapyramidal disorders such as Parkinson's disease.

B

Claims (14)

637954 PATENT CLAIMS 1. Compound of the structural formula or a salt thereof, in which R has the meaning of (1) hydrogen, (2) lower alkyl, (3) low alkenyl, (4) phenyl lower alkyl, (5) halophenyl lower alkyl, (6) lower alkylphenyl lower alkyl, (7) low-cycloalkyl, (8) low (cycloalkyl-alkyl), (9) di (lower alkyl) amino lower alkyl or (10) hydroxy; R1 has the meaning of (1) hydrogen, (2) lower alkyl, (3) low alkenyl, (4) phenyl lower alkyl, (5) low-cycloalkyl or (6) lower (cycloalkyl alkyl); R2 has the meaning of (1) lower alkyl, (2) low alkenyl, (3) phenyl lower alkyl, (4) low (cycloalkyl-alkyl), (5) di (lower alkyl) amino lower alkyl, (6) hydroxy lower alkyl or (7) hydrogen; and R3 and R4 independently of one another have the meaning of (1) hydrogen, (2) halogen, (3) low alkoxy, (4) trifluoromethylthio, (5) cyano, (6) carboxy or (7) hydroxy. 2. A compound according to claim 1, wherein R1 is hydrogen. 3. A compound according to claim 1, wherein R1, R3 and R4 are hydrogen, R is hydrogen, lower alkyl or benzyl, and R2 is lower alkyl or hydroxyethyl. 4. A compound according to claim 1, wherein R1, R2, R3 and R4 are hydrogen and R is hydroxy. 5. 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine according to claim 3, an optical isomer or a pharmaceutically acceptable salt thereof. 6. (+) - 5-methyl-10,1-l-dihydro »5H-dibenzo [a, d] cyclo-hepten-5,10-imine according to claim 3, or an optical isomer or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1, characterized in that it is present as an optical isomer. 8. A process for producing a compound of the structural formula wherein R has the meaning of hydrogen, R1 has the meaning of (1) hydrogen, (2) lower alkyl, (3) low alkenyl, (4) phenyl lower alkyl, (5) low-cycloalkyl or (6) lower (cycloalkyl alkyl); R2 has the meaning of (1) lower alkyl, (2) low alkenyl, (3) phenyl lower alkyl, (4) low (cycloalkyl-alkyl), (5) Di (lower alkyl) amino lower alkyl (6) hydroxy lower alkyl or (7) hydrogen; and R3 and R4 independently of one another have the meaning of (1) hydrogen, (2) halogen (3) low alkoxy, (4) trifluoromethylthio, (5) cyano, (6) carboxy or (7) hydroxy; and salts thereof, characterized in that a compound of the formula is reduced and any compounds obtained are converted into the salts. 9. The method according to claim 8, characterized in that the implementation is followed by an optical resolution. 10. Pharmaceutical composition containing a pharmaceutical carrier and a compound of the structure 2nd s 10th 15 20th 25th 30th 35 40 45 50 55 60 65 formula 4 years or a salt thereof, in which R has the meaning of (1) hydrogen, (2) lower alkyl, (3) low alkenyl, (4) phenyl lower alkyl, (5) halophenyl lower alkyl, (6) lower alkylphenyl lower alkyl, (7) low cycloalkyl, (8) low (cycloalkyl-alkyl), (9) di (lower alkyl) amino lower alkyl or (10) hydroxy; R1 has the meaning of (1) hydrogen, (2) lower alkyl, (3) low alkenyl, (4) phenyl lower alkyl, (5) low-cycloalkyl or (6) lower (cycloalkyl alkyl); R2 has the meaning of (1) lower alkyl, (2) low alkenyl, (3) phenyl lower alkyl, (4) low (cycloalkyl-alkyl), (5) di (lower alkyl) amino lower alkyl, (6) hydroxy lower alkyl or (7) hydrogen; and R3 and R4 independently of one another have the meaning of (1) hydrogen, (2) halogen, (3) low alkoxy, (4) trifluoromethylthio, (5) cyano, (6) carboxy or (7) hydroxy. 11. The composition of claim 10, wherein R1 is hydrogen. 12. The composition of claim 10, wherein R1, R3 and R4 are hydrogen, R is hydrogen, lower alkyl or benzyl, and R2 is lower alkyl or hydroxyethyl. 13. The composition according to claim 10, characterized in that the compound (X) -5-methyl-10, l 1-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine or a pharmaceutically acceptable salt thereof . 14. The composition according to claim 10, characterized 637 954 characterized in that the compound is present as an optical isomer.