SE437520B - DIBENSOCYCLOHEPTENIMINES, PROCEDURE FOR PREPARING THESE AND PHARMACEUTICAL COMPOSITION - Google Patents

Description

The novel compounds of the present invention have the structural formula or a pharmaceutical salt thereof, wherein R represents (1) (2) (3) (4) (5) (6) (7) (1) (2) ) R represents (s) <4) (s) (6) hydrogen, lower alkyl, especially C 1-5 alkyl, preferably methyl or ethyl, in lower alkenyl, especially C 2-5 alkenyl, preferably vinyl or allyl, phenyl (or substituted phenyl lower alkyl, especially phenyl (or substituted phenyl) -C 1-3 alkyl, preferably benzyl or substituted benzyl, wherein the substituent is halogen, such as fluorine, chlorine or bromine, especially chlorine, or lower alkyl, especially C 1-3 alkyl, lower cycloalkyl, especially C 3-6 cycloalkyl, suitably cyclopropyl or cyclohexyl, lower (cycloalkyl-alkyl), especially C 3-6 cycloalkyl-C 1-3 alkyl, or di (lower alkyl) amino-lower alkyl, especially dimethylaminopropyl ; hydrogen, lower alkyl, especially C 1-5 alkyl, preferably methyl or ethyl, lower alkenyl, especially C 2-5 alkenyl, preferably vinyl or allyl,. phenyl-lower alkyl, especially phenyl-C 1-3 alkyl, preferably benzyl, lower cycloalkyl, especially C 3-6 cycloalkyl, preferably cyclopropyl or cyclohexyl, or lower (cycloalkyl-alkyl), especially C 3-6 cycloalkyl-C 1-3 alkyl, 789911 Lower alkyl, especially C 1-5 alkyl, preferably methyl or ethyl, lower alkenyl, especially C 2-5 alkenyl, preferably CH 2 R 2 denotes (1) (2), preferably vinyl or allyl, phenyl-lower alkyl, especially phenyl-C 1-5 alkyl, preferably benzyl, lower (cycloalkyl-alkyl), especially C3-6-cycloalkyl, C1-3'alkyl * (aminopropyl, or di (lower alkyl) amino-lower alkyl, especially dimethyl] -hydroxy-lower alkyl, especially hydroxy-C2-3-alkyl , preferably hydroxyethyl, and (3) (4) (5) (6) R 5 and R 4 independently of one another denote (1) (2) (3) hydrogen, halogen, such as chlorine, bromine, fluorine or iodine, lower alkoxy, especially C 1-5 -alkoxy, suitably methoxy, (4) (5) (6) (7) A suitable group of compounds is one in which R 1 represents hydrogen, trifluoromethylthio cyano, carboxy or hydroxy.

Another suitable group of compounds is one in which R 1, R 3 and R 4 represent hydrogen.

When R 3 and / or R 4 do not represent hydrogen, it is convenient for them to assume 2-, 3-, 7- or 8-position in the tricyclic ring system. Suitable definitions of -CH 2 R are lower alkyl, especially methyl or ethyl, or hydroxyethyl.

Suitable definitions of R are hydrogen, lower alkyl or benzyl.

The novel compounds of the present invention, wherein R represents hydrogen, are generally prepared by reduction of the N-hydroxy analogue. Suitable reducing agent is nascent hydrogen, which is generated by the action of a metal, preferably zinc with an acid, such as acetic acid, at 40 DEG-100 DEG C. for 1: 111 about 10 hours.

The new compounds are also prepared by cyclization of a 10-NHR-5 - (= CHR2) -10,11-dihydro-SH-dibenzo [a, ¶ cycloheptene by treatment with a strong base, such as an organometallic reactant, for example n-butyllithium in an ether solvent, such as tetrahydrofuran, 1,2-dimethoxyethane or the like at about 0 ° C to about 50 ° C for about 1 minute for 1 hour.

When -CH 2 R 2 represents hydroxy-lower alkyl, the final step in the synthesis is the reduction of the lower alkoxy-carbonyl precursor. A suitable reducing agent is lithium aluminum hydride in an ether solvent such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or the like at a temperature of about 15 ° C to about 100 ° C until the reduction is substantially complete in about 1 to about 6 hours. This process also serves to hydrogenolyze a balogen group at the brew head, which was used in the exemplified synthetic scheme.

When R is not hydrogen, the novel compounds are prepared by alkylation of compounds wherein R is hydrogen, with a suitable reagent of the formula R-halogen, wherein halogen is chlorine, bromine or iodine. The reaction is normally carried out in an inert solvent such as benzene or toluene. However, depending on its physical properties, the alkylating agent can be used in sufficient excess to act as a solvent. It is convenient that the reaction is 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 of about 50 ° C to about 100 ° C can be used for a reaction time of about 10 hours to about 5 days.

When R represents alkyl or substituted alkyl, the compounds can also be prepared by reduction of an N-acyl compound, such as alkoxycarbonyl to form methyl groups or other alkanoyl groups to form other alkyl groups. Suitable reducing system is a metal hydride, e.g. lithium aluminum hydride in an ether solvent such as ether, tetrahydrofuran or 1,2-dimethoxyethane or the like. The reduction process proceeds satisfactorily at room temperature, but temperatures of about 0 ° C to about 5 ° C are suitable with reaction times of 10-13 hours. 7809187-3 S e New compounds with substituents in the benzene rings are generally prepared by metathesis of the appropriate bromine or iodine compound. 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 1-10 hours gives the corresponding lower alkoxy compound.

The Z-, 3-, 7- or 8-hydroxy compounds are prepared from the corresponding alkoxy compounds, preferably methoxy compounds, by de-etherification. Preferably heat with pyridine hydrochloride at 200-220 ° C for 3-10 hours.

Treatment of a bromine or iodine compound with cuprous cyanide in an inert organic solvent, such as dimethylformamide, at reflux temperature for 1-10 hours gives the corresponding cyano compound.

Hydrolysis of the cyano compounds with a mineral acid, such as hydrochloric acid, at about 50-15000 and especially at reflux temperature gives the corresponding carboxy-substituted compounds. Treatment of bromine or iodine compounds with bis (trifluoromethylthio) - mercury and copper dust in an inert organic solvent, as well as dimethylformamide or quinoline, at about 100-20,000 for 1-10 hours gives trifluoromethylthioderlvate.

Thus the following compounds can be prepared: 3- (or 7) -R 3 -S-methyl-10,11-dihydro-5H-dibenzo [§, ¶ cycloheptene-, 10-imines; 3-RS-12-cyclopropylmethyl-5-methyl-10,11-dihydro-5H-dibenzo [a, ¶ cyclohepten-5,10-imines; 2-R3-1Z-dimethylaminopropyl-5-ethyl-10,11-dihydro-5H-dibenzofa, cycloheptene-5,10-imines; and 7-R3-s, 12-animal-10-11-hydro-sn-dibenzo [a, @ eyk10hepten-s, 10-imines; wherein R 3 represents 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-1-tartaric acid and the subsequent fractional crystallization and regeneration of the free base.

Starting materials and processes used to prepare the intermediates in the processes described above are described in the following examples. The present invention also relates to non-toxic, pharmaceutically acceptable salts of the novel compounds. Acid addition salts of the imine compounds are formed by mixing a solution of the imine and 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.

When the novel compounds contain a carboxylic acid group, the invention also encompasses sodium, potassium and calcium salts thereof.

The novel imines of the present invention can alleviate anxiety without causing excessive sedation or sleep at doses of about 0.01 to about 50 mg per kg of body weight, preferably about 0.05-10 mg / kg of body weight, 1-4 times per day. day. The new compounds are furthermore suitable as muscle relaxants, as anticonvulsants and for the treatment of ectrapyramidal diseases in comparable doses.

It is obvious that the exact treatment dose depends on the individual case of the animal or human being to be treated and ultimately the exact treatment dose is left to the physician's decision with reference to the guidelines given above.

The present invention also relates to pharmaceutical compositions containing the imines of the invention. These compositions are conveniently available in dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions or suppositories for oral, parenteral or rectal administration. One dosage unit contains from about 0.1 to about 500 mg of active ingredient. The invention is further illustrated by reference to the following examples.

Example 1. 5-Methyl-10,11-dihydro-5H-dibenzo [a, d} cycloheptene-5,10-imine and oxalate salt Step A: Preparation of 10- (1-piperidyl) -SH-dibenzo [a , d] cyclohepten-5-one A mixture of 71.3 g of 10-bromo-SH-dibenzo- {a, @ cyclohepten-5-one, 50 ml of piperidine, 1 liter of t-butanol and finally 33.6 g Potassium t-butoxide was stirred at reflux for 2 hours and then 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 methanol and filtered to give 59.8 g of - (1-piperidyl) -SH-dibenzo [a, d] cyclohepten-5-one with the melting point 1øs-1osëc.

Step B: Preparation of 5-hydroxy-Semethyl-10- (1-piperidyl) -5H-dibenzolia, dicycloheptene A solution of 140 ml of 1.8M methyl lithium in ether and 250 ml of ether at -10 ° C under nitrogen was treated dropwise with a solution of 59 g of - (1-piperidyl) -SH-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 carefully extracted with ether and the extract was dried (Na 2 SO 4), filtered and concentrated to dryness, the residue being used directly in the next step.

Step C: Preparation of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene The carbinol from step B was dissolved in 500 ml of 10N ethanolic hydrochloric acid and 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. On cooling, 18.5 g of solid precipitated, which after crystallization from hexane left 16.5 g of 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [a, d] cycloheptene, m.p. -86 ° C.

Step D: Preparation of 10-hydroxyimino-5-methylene-10,11-dihydro-5H-dibenzo [a, dicycloheptene A mixture of 16.5 g of the oxo compound from step C, 6.6 g of hydroxylamine hydrochloride 8.2 g of sodium acetate and 300 ml of methanol were heated under reflux for 5 hours. The solvent was evaporated and the residue was treated with 250 ml of water. The mixture was extracted with 3x150 ml of ether and the extract was dried, filtered and evaporated, yielding 16.8 g of 10-hydroxymino-5-methylene-10,11-dihydro-5H- [α, df-cycloheptene, m.p. 125 DEG-160 DEG C. was obtained. Preparation of 10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo [a, dicycloheptene A mixture of 15.3 g of oxime from step D, 500 ml of methanol, 12 g of sodium cyanoborohydride in 450 g ml of methanol was treated dropwise with a solution of 12 ml of 12N hydrochloric acid in 50 ml of methanol for 5 hours and then stirred overnight at room temperature. The residue was stirred with 200 ml of 1N aqueous hydrochloric acid, the alkali metal hydroxy was extracted with 3x175 ml of ether. The combined extracts were dried (Na 2 SO 4), filtered and evaporated. The crystalline residue was washed with methanol to give 9.6 g of 10-hydroxamino-5-methylene-10,11-dihydro-SH-dibenzo [a, Q cycloheptene, m.p. 115-147 ° C.

Step F. Preparation of 12-hydroxy-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine A solution of 8.8 g of the hydroxamino compound from step E in 200 ml of xylene was added dropwise to 80 ml of xylene under reflux. After refluxing for 1 hour, the solvent was evaporated. The residue was treated with 250 ml of water and 7 ml of concentrated hydrochloric acid, and the mixture was washed with 100 ml of ether and the washing liquid was discarded.

The aqueous phase was basified with concentrated ammonium hydroxide and extracted with 3x100 ml of ether. The extract was dried (Na 2 SO 4), 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, ¶ cycloheptene-5,10-imine, m.p. 141-144 ° C. . * Step G: Preparation of s-me: y1-10,11-dihydro-sH-dibenzo [a, d} cyclohopten-5,10-imine and oxalate salt A mixture of 1.2 g of the hydroxy-imine from step F 7 ml of acetic acid and 1.2 g of zinc dust were heated at 60-70 ° C for 3.5 hours. The mixture was filtered and the filter cake was washed with 200 ml of ether and 50 ml of water. The filtrate was basified with 5% (w / v) aqueous sodium hydroxide and extracted with ether. The extract was dried (Na 2 SO 4), filtered and evaporated to dryness to give 1.1 g of product. This material (1.1 g) was dissolved in ml of acetone and treated with 0.6 g of oxalic acid in 10 ml of acetone. After cooling overnight, 1.2 g of 5-methyl-10,11-dihydro-5H-dibenzo [a, d} cycloheptene-5,10-imine, m.p. 203-206 ° C (dec.), Were collected, which after recrystallization from methanol / acetone, the melting point was 215-217 ° C.

Example 2. S-ethyl-1b, 11-dihydro-5H-dibenzo [}, d} cycloheptene-5,10-imine '- Step A: Preparation of 5-ethylidene-10-oxo-10,11-dihydro-5H -diben- so [a, di! to a stirred slurry of ethyltriphenylphosphonium bromide (21 g, 0.057 mol) in ether (400 ml) was added dropwise butyllithium in hexane (48 ml, 1.3M). To the resulting solution was added a solution of 1- (S-keto-SH-dibenzo [}, dicyclohepten-10-yl) -4-methylpiperazine (13.5 g, 0.044 mol) in THF (100 mL). The resulting mixture was stirred and heated under reflux for 3.5 hours, cooled and poured into ice water (300 ml). The organic phase was separated and the aqueous phase was extracted with ether (Zx150 ml). The combined organic solutions were concentrated under reduced pressure. The concentrate was stirred with a mixture of 1N aqueous hydrochloric acid (300 ml) and ether (300 ml). The ether phase was separated, the aqueous phase was extracted with ether, and the combined ether solutions were dried over Na 2 SO 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 chloroform to give 1 g (98%) of 5-ethylidene-10-oxo-10,11-dihydro-5H-dibenzo [e, d] cycles lohepten with a melting point of 93-95 ° C was obtained.

If the procedure of Example 1, steps D to G, is substantially followed, but 5-methylene-10-oxo-10,11-dihydro-5H-dibenzo [}, d] cycloheptene in step D is replaced by an equimolecular amount of S-ethylidene. 10-oxo-10,11-dihydro-5H-dibenzo {a, d3cycloheptene is obtained as follows: -ethylidene-10-hydroxymino-10,11-dihydro-SH-dibenzo {a, ¶ cycloheptene, (su t, exchanged ), melting point 1zs-1s1 ° c; -ethylidene-10-hydroxamino-10,11-dihydro-5H-dibenzo [a, d] cycloheptene (se) (yield), melting point 1z1-1z4 ° c; -ethyl-12-hydroxy-10,11-dihydro-5H-dibenzo [α, ¶ cycloheptene-5,10-imine (21 h, yield), melting point 11z-116 ° c uth-ethyl-10,11-dihydro- SH-dibenzo [a, d] cycloheptene-5,10-imine (90% byte) and the hydrogen oxalate salt, m.p. 240-24100.

Using the procedure of Example 2 but replacing the ethyltriphenylphosphonium bromide in step A with an equimolecular amount of Wittig reagent of the formula (C 6 H 5) 3 P + -CH 2 R 2 (Br-), wherein CH 2 R 2 represents -CU 3, -CH 2 CH 2 CHS or - (CH 2) 3CH 3, there are obtained compounds of the formula: 7809187-3 wherein -CH 2 R 2 represents -CH 5, -CH 2 CH 2 CH 3 (mp 298-299, S ° C as HCl-1 / Z CH 3 COCH 3) and - (CH 2) 5 CH 3.

Example Gel 3. 5- (2-Hydroxyethyl) -10,11-dihydro-5H-dibenzo [d] cyclo-, 10-imine 'Step A: Preparation of 5-ethoxycarbonylmethylene-10,114-dihydro-5H-dibenzo [ag-cycloheptene] TO-one 'Triethylphosphonoacetate, 10 g (0.045 mol) was added dropwise to a slurry of 1.9 g (0.04 mol) of sodium hydride (50% in mineral oil) in 20 ml of dry toluene under nitrogen and the temperature was maintained at 30-35 ° C. The mixture was stirred for 1 hour at room temperature.

A solution of 10 g (0.0328 mol) of 1- (5 * keto-SH-dibenzo®, d] cyclohepten-10-yl) -4-methylpiperazine in 75 ml of dry toluene was added dropwise, keeping the temperature at 25 ° C. -30 ° C by cooling. The mixture was stirred at room temperature for 3 hours and kept at room temperature overnight. After decantation of the solution, the well was washed with four 25 ml portions of toluene at 6500. The combined toluene extracts were diluted with an equal volume of ether and shaken with 75 ml of 0.5N hydrochloric acid. The aqueous acid layer was separated and re-extracted with toluene ether (1: The combined organic phases were washed with water, dried over magnesium sulphate, filtered and concentrated, the oily solid was liberated from the oil by collection in a sintered glass funnel and then triturated with cyclohexane to give 4.5 g (47%). 5-Ethoxycarbonylmethylene-, 11-dihydro-5H-dibenzo [}, dicyclohepten-10-one with a melting point of 56 DEG-6 DEG-6 DEG C. DI Step B: Preparation of 5-ethoxycarbonylmethyl-1,2,2-dihydroxy-10,11- dihydro-5h-dibenzo [a, d] cyclohepten-5,10-imine The keto olefin from step A, 23.4 g (0.08 mol) together with hydroxylamine hydrochloride (6.0 g], sodium acetate trihydrate (12, 0 g) och 4.: .. ___- a ..- _- ~., _._. -..___ vší =: ï:? ”ÏšÜÜ = ÉlïâÜmïöfdes vid rumstemperätüfï” EfteT ~ + 6 ~ h ~ uppe The precipitate was collected, washed with ether and stirred with water (300 ml) for 1 hour. The solid was collected and dried, yielding 21.6 g (83%) of 5-ethoxycarbonylmethyl-10,12-dihydroxy-10,11- dihydro-5H-dibenzo, 50 D, cyclohepten-5,10-imine, m.p. 193 DEG-195 DEG C.

Step C: Preparation of 5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo [a, d} cyclohepten-5,10-imine N-hydroxy-imine from step B, 21, Q (0 .0646 mol) was suspended in glacial acetic acid (125 ml] and zinc dust (16 g] was added in portions over 157 - 1.87 - 3 11 min. When the exotherm ceased, 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 water (500 ml) and the filtered solution was basified with 15% aqueous sodium hydroxide, the precipitate was collected, washed with water and dried. whereby 15 g of 5-ethoxycarbonylmethyl-10-hydroxy-10,11-dihydro-5H-dibenzo [α, lo cycloheptene-5,10-imine with a melting point of 186-189 [deg.] C. were obtained, a filtered solution of this product in boiling acetone (350 ml) was treated with 7N ethanolic hydrochloric acid (7 ml) The precipitate of the hydrochloride salt was collected, washed with ether and dried to give 14.35 g (64%) of d melting points z47-zso ° c increase. Preparation of 10-chloro-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo, dicycloheptene-5,10-imine In the hydrochloride salt of the product from step C, 17.8 g (0.0515 mol) was slurried in thionyl chloride (250 ml) and the mixture was heated under reflux. When the following exothermic reaction ceased, the mixture was heated under reflux for 20 minutes, when the solid was completely dissolved. The thionyl chloride was evaporated under reduced pressure and the last traces were removed by repeated evaporation together with toluene. The residue was triturated with acetone to give 35 g (81%), m.p. 223 DEG-277 DEG C. (decomposition) of 10-chloro-5-ethoxycarbonylmethyl-10,11-dihydro-5H-dibenzo [a, cycloheptene-5 , 10-imine hydrochloride.

Step E: Preparation of 5- (2-hydroxyethyl) -10,11-dihydro-5H-dibenzo [α, flcycloheptene-5,10-imine Hydrochloride from Step D, 15.3 g (0.042 mol), was added in portions to a slurry of lithium aluminum hydride (5.6 g, 0.147 mol) in ether (200 ml) and tetrahydrofuran (200 ml). The mixture was stirred under reflux for 3 hours, then cooled to 0 ° C and hydrolyzed by dropwise addition of water (4 ml) and 10% aqueous sodium hydroxide (4 ml). After dilution with ether, the precipitate was collected, suspended in chloroform (250 ml) and stirred at room temperature for 1 hour. The mixture was filtered and the filtrate was combined with the previously obtained ether filtrate. The solvents were evaporated under reduced pressure and the resulting solid was recrystallized from 95% ethanol to give 8.6 g of 5- (2-hydroxyethyl) -, 11-dihydro-5H-dibenzo [a, d] cycloheptene-5 10-imine with a melting point of 181-184 ° C was obtained. Recrystallization from 70% ethanol gave a melting point of 182-184 ° C. A suspension of this product (4.4 g) in hot absolute ethanol (20 ml) was treated with 7N ethanolic hydrochloric acid (2.5 ml) and the mixture was stirred until all solids dissolved. Upon dilution with ether, the hydrochloride salt precipitated 4.8 g, mp 263-265 ° C. Recrystallization from acetonitrile gave a melting point of 262-264 ° C; In Example 4. 3- (and 7) -bromo-5-methyl-10,11-dihydro-5H-dibenzo [α, ¶-cycloheptene-5,10-imine] I Step A: Preparation of 3,10, 11-Tribromo-SH-dibenzo [a, d] cycloheptenone in A solution of bromine (53 g, 0.33 mol) in glacial acetic acid (125 ml) was added dropwise to a stirred slurry of 3-bromo-SH -dibenzo [α, fl-cyclohepten-5-one (71.25 g, 0.25 mol) in glacial acetic acid (775 ml). After the mixture was stirred at room temperature for several hours, the solid was collected, washed with glacial acetic acid and dried; yield 105.8 g (95 fa), melting point 173-17 ° C. in Step B: Preparation of 3,10-dibromo-SH-dibenzo [a, {Cycloohepten-5-one 3 The product from Step A was added to a stirred solution of sodium hydroxide (28 g, 0.7 mol) in methanol ( 2 liters). The thick mixture was stirred at reflux for 1.25 hours. After cooling, the solid was collected, washed with methanol and then with water and dried to give 81 g (90%) of a mixture of 3,10-dibromo. 5H-dibenzo a, d cyclohepten-5-one and 3,11-dibromo-5H-dibenzo-d, cyclohepten-5-one with a melting point of 146-156 ° C were obtained.

Step C: Preparation of 3-bromo-10- (4-methylpiperazinyl) -5H-dibenzo [d] cyclohepten-5-one and 3-bromo-11- (4-methylpiperazinyl) -5H-dibenzo [ α, fl cyclohepten-5-one Potassium tert-butoxide (6.8 g, 0.06 mol) was added to a stirred mixture of 3,10-dibromo-SH-dibenzo®, d] cyclohepten-5-one and 3,11-dibromo-SH-dibenzo [a, d] cyclohepten-5-one (18.2 g, 0.05 mol), 4-methylpiperazine (10 ml) and dry tert-butyl alcohol ( 200 ml) at room temperature and under nitrogen. The dark, orange mixture was heated to reflux temperature 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 ether extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated. The mixture of 3-bromo-10- (4-methylpiperazinyl) -5H-dibenz [a, dicyclohepten-S-one and 3-bromo-11- (4-methylpiperazinyl) -SH-7 809187 * '3- 13 dibenzo [a , d] cyclohepten-S-one was obtained as a red-yellow gum residue; yield 19.4 g, 100%.

Step D: Preparation of 3-bromo-5-methyls10} (α-methylpiperazinyl) -sh-dibenzo®, dicyclohepten-S-ol and 3-bromo-1- (4-methylpiperazinyl) -sh-dibenzo [a, Ü cycloheptene-5-O1. Methyl lithium, 35 ml of a 1.6 M solution in ether, was added dropwise to a stirred solution of the product from step C (18 g, 0.047 mol) in ether (200 ml) and tetrahydrofuran (60 ml). , which was cooled in an ice bath under nitrogen. Stirring was continued at room temperature for 3 hours. The mixture was cooled in ice and hydrolyzed by dropwise addition of water.

After dilution with ether and water, the layers were separated and the aqueous phase was extracted again with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The mixture of 3-bromo-5-methyl-10- (4-methylpiperazinyl) -5H-dibenzoza, dicyclohepten-5-ol and 3-bromo-5-methyl-11- (4-methylpiperazinyl) -SH- dibenzo [a, d] cyclohepten-5-ol was obtained as a dark yellow glass-like residue; yield 18 g (96%). Figure E: Preparation of 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo- [α, @-cycloheptene-10-one and 7-bromo-5-methylene-10,11-dihydro-5H- dibenzo {a, (cyclohepten-10-one A mixture of the product from step D (18 g, 0.045 mol), 95% ethanol (80 ml), 7N ethanolic hydrochloric acid (40 ml) and 6N aqueous hydrochloric acid (80 ml) was stirred at room temperature for 30 minutes and heated under reflux for 1 hour. The mixture consisted of a brown oily lower phase and an aqueous alcoholic upper phase. The latter was decanted and the alcohol was evaporated in vacuo. The remaining aqueous mixture was extracted with chloroform. The previously obtained brown oil was dissolved in chloroform and the combined chloroform phases were washed with water and dried over anhydrous magnesium sulfate. Evaporation of the filtered extract gave the crude product as a dark yellow glass-like residue. This material was chromatographed on a silica gel column and eluted with the toluene. Elution of the 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, melting point 125-158 ° C. Two recrystallizations from cyclohexane gave the melting point 158-163 ° C. Evaporation of the first cyclohexane mother liquor gave the remaining isomer of the product as a dark yellow oil. Trituration with 3 successive 10 ml portions of hexane gave a yellow solid; yield 3.3 g, melting point 75-83 ° C. Two recrystallizations from hexane gave a melting point of 84-9 ° C. The higher melting point isomer (160 DEG-140 DEG C.) has the structural formula: 7-bromo-5-methylene-10,11-dihydro-5H-dibenzo [a, cyclohepten-10-one].

The second isomer, 3-bromo-5-methylene-10,11-dihydro-5H-dibenzo [α, fl-cyclohepten-10-one (m.p. 84-9100) has the structural formula: Steps F to I: Preparation of 3- (and 7) -Bromo-5-methyl-10,11-di-hydro-5H-dibenzo [a, dicyclohepten-5,10-imine 'Using essentially the procedure described in Example 1, steps D to G but by replacing the 5-methylene-10-oxo-10,11-dihydro-5H-dibenzolagid] cycloheptene used therein with an equimolecular amount of the corresponding 3- and 7-bromo compounds, the following compounds are prepared in succession: ( Step F): 3- (and 7) -Bromo-10-hydroxymino-5-methylene-10,11-dihydro-sn-d1benzo {a, ¶ cyclohepcene, m.p. 111-17 ° C resp. 179-1 -1 ° C; (Step G): 3- (and 7) -bromo-10-hydroxamino-5-methylene-10,11-dihydro-5H-dibenzo [a, d] cycloheptene; melting points 149-15300 and 136-139 ° C, respectively; (Step H; 3- (and 7-1-bromo-1z-hydroxy-5-methyl-10,11-dihydro-5H-alibenzo [a, dicycloheptene-5,10-imine, m.p. 175-180 ° C) 187-100 ° C, respectively, and (Step II: 3- (and 7) ~ bromo-5-methyl-10,1I-dihydro-SH-dibenzo [a, fl cyclo- 73 ~ fl91 f ~ 8ï7 ~ 3-lohepten -5,10-imine hydrochloride, m.p.> 300 ° C.

In a similar manner there are prepared: 8-bromo-5-methyl-10,11-dihydro-5H-dibenzo [a, fl cyclohenten-5,10-imine; Z-bromo-5-ethyl-10,11-dihydro-5H-dibenzo [α, ¶ cyclohepten-5,10-imine and 7-bromo-5-ethyl-10,11-dihydro-SH-dibenz βxg fl cyclohepten-5 , 10-imín.

Example Gel 5. 10,11-Dihydro-5,12-dimethyl-5H-dibenzo [α, ¶ cycloheptene ', 10-imine fumaric acid salt Step A: Preparation of 10,11-dihydro-12-ethoxycarbonyl-5-methyl-5H dibenzo [a, d] cycloheptene-5,10-imine A mixture of 1.15 g of 10,11-dihydro-5-methyl-5H-dibenzo [a, d] cycloheptene-5,10-imine, 1 .0 g of anhydrous sodium carbonate, 1 ml of ethyl chloroformate and 10 ml of dry benzene were stirred under reflux temperature for 2 hours. The mixture was filtered and the filtrate was evaporated in vacuo to give 1.45 g of white, crystalline 10,11-dihydro-12-ethoxycarbonyl-S methyl-5H-dibenzo [a, dicycloheptene-5,10-imine with a melting point of 80-83 ° C was obtained.

Step B: Preparation of 10,11-dihydro-5,12-dimethyl-5H-dibenzo [α, ¶-cycloheptene-5,10-imine A solution of the urethane from step A 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 a 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 similar material and dissolved in 25 ml of ethyl acetate. A warm solution of 1.2 g of fumaric acid in 12 ml of methanol was added. The fumaric acid salt which crystallized was collected and recrystallized from methanol-ethyl acetate to give 2.1 g of 10,11-dihydro-5,12-dimethyl-5H-dibenzo [a, d] cycloheptene, 10-imine fumaric acid salt, m.p. 186-188 ° C was obtained.

Exemgel p. 1z-benzyl-110, 11-allyro-s-meryl-sn-dibenzo [am] cycloheptene-5,10-imine A mixture of 2.45 g of 10,11-dihydro-5- methyl-SH-dibenzo [a], d] cycloheptene-5,10-imine, 1.9 g of benzyl chloride, 3.2 g of anhydrous sodium carbonate and 50 ml of dry benzene were stirred at reflux temperature 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, m.p. 107 DEG-119 DEG. This was recrystallized twice from 95% ethanol to give 1.85 g of white crystalline 12-benzyl-10,11-dihydro-5-methyl-5-dibenzo [a] cyclohepten-5,10-imine, m.p. 111-114 ° C was obtained. Example 7. TZ-allyl-10,11-dihydro-5-methyl-5H-dibenzo [α] D cycloheptene-5,10-imine A mixture of 2.45 g of 10,11-dihydro-5-methyl -SH-dibenzo [a, cycloheptene-5,10-imine, 1.8 g of allyl bromide, 3.0 g of anhydrous sodium carbonate and 50 ml of dry benzene were stirred at reflux temperature for 20 hours.

The mixture was filtered and the filtrate was evaporated in vacuo to give 1.2 g of the oily free base of the product. This was dissolved in ml of acetone and added to a warm solution of 0.75 g of fumaric acid in 75 ml of acetone. The crystallized salt was collected and recrystallized from acetone to give 1.45 g of white crystalline 12-alkyl-, 1I-dihydro-5-methyl-5H-dibenzo [a, cycloheptic-5,10-imine-fumaric acid salt, m.p. 180-18Z9C was obtained.

Using the procedure of Example 7 but substituting the allyl bromide and the 10,11-dihydro-5-methyl-5H-dibenzo [α, fl-cyclo-dhepten-5,10-imine used therein for a compound of formula RI and S-RZCHZ-10,11-dihydro-SH-dibenzofa, flcycloheptene-5,10-imine, as described in Table II, prepare 5-RZCHZ-12-R-10,11-dihydro-5H-dibenzo [α, fl cycloheptene-5,10 imines, also described in Table II, according to the following reaction: - ~.-.......____...____._....,. .. al.- 7ao91a7-3 17 Table II Rz R. x -H l -c fl z '_ \ H (mp 1s2, s-1ss, s ° c) I c1 _ _ -H, -c fl z f \ -c1 H (mp 111-113 ° c, hydrogen oxamc) -cn d - c fl H (mp 16s-164 ° c) -H -CHZCHZQ H (mp 11s, s-117 ° c) -c fl zcnš -cHz- H -cnz-f \ H (mp 11z-114, s ° c) c1 H - cnz / \ n (mp 111-11s ° C, base) H -cnz-Q á-Br -cns -tcn fi swtcnzh z-Br -CHS -CZHS 7-Br _ Exemgel 8. 5, 10,12-trimethyl-10, T1-Dihydro-5H-dibenzo [a, ¶ cycloheptene-5,10-imine-hydrochloride Step A: Preparation of 10-amino-5-methylene-10,11-dihydro-5H-dibenzo [a, & Cycloheptene To a stirred slurry of zinc dust (0.9 g, 0.138 mol) in 100 ml of glacial acetic acid in an oil bath at 65 ° C was added 10-hydroxyamino-5-methylene-, 11-dihydro-5H-dibenzo [a, ¶ cycloheptene (10 g, 42 mmol). The mixture was stirred in the oil bath for 2 hours, cooled and cooled in 500 ml of water.

The mixture was basified with concentrated ammonia and then extracted with ether. The combined ether layers were washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was recrystallized from hexane to give 7.8 g, m.p. 84.5-86 ° C.

Teomg QUÃLIM 78-09187-3 18 Step B: Preparation of 10-isocyano-5-methylene-10,11-dihydro-5H-dibenzofa, ¶ cycloheptene To a solution of 10-amino-5-methylene-10,11- dihydro-5H-dibenzo- [α, ¶.cycloheptene (8.1 g, 36.6 mmol) in chloroform (180 mL) was added sodium hydroxide pellets (4.42 g, 0.11 mol) of benzyltriethylammonium chloride (0.42 g , 1.8 mmol) and water (0.5 ml). The mixture was stirred under nitrogen, until the sodium hydroxide beads were dissolved (about 4 hours), treated with anhydrous potassium carbonate, filtered and evaporated to dryness in vacuo. The resulting oil was dissolved in chloroform (180 mL), 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 again dried 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 water to give 4 g of solid, m.p. 96-98 ° C. Step C: Preparation of 10-isocyanano-O-methyl-5-methylenef10 11-dihydro-SH-dibenzo [a, fl cycloheptene. Diisopropylamine (1.1 g, 10.9 mmol) in 25 ml of dry tetrahydrofuran was stirred in a dry ice / acetone bath. This solution was treated under nitrogen with n-butyllithium / hexane (5.0 ml 2.2M solution), which was added dropwise over 10 minutes; After 5 minutes, a solution of 10-isocyanano-5-methylene-10,11-dihydro-5H-dibenzo [a, fl cycloheptene (2.4 g, 4 mmol) in 25 ml of dry tetrahydrofuran was added dropwise (over 45 minutes) to the lithium diisopropylamide solution. The resulting deep red solution was stirred in the cold for 15 minutes and then treated with methyl iodide (4.56 g, 32 mmol), which was added on a batch. The mixture was stirred for 2 hours in the cold and another 1 hour at room temperature. The solvent was removed in vacuo and the residue was chromatographed on 75 g of silica gel eluting with methylene chloride. The combined product fractions were evaporated in vacuo to give 2.2 g (86%) of solid. Recrystallization from ether gave a melting point of 146-141 ° C. Step D: Preparation of 10-methyl-10-methylamino-5-methylene-10,11-dihydro-5H-dibenzofa, flcycloheptene hydrochloride -iso-cyano-10-methyl-5-methylene-10, 11-Dihydro-5H-dibenzo®, d] cycloheptene (1.8 g, 7.3 mmol), dissolved in dry ether (100 ml) was added dropwise to a slurry of lithium tetrahydridoaluminate (0.53 g, 14 ml). mmol) in ether (40 ml), which was stirred under nitrogen. The mixture was heated under reflux for 1 hour, cooled and the excess hydride decomposed by careful dropwise addition of 1.5 ml of ice water.

The suspension was filtered and the solid was washed twice with ether. The combined ether fractions were evaporated in vacuo to 1.8 g of oil. This oil, dissolved in 10 ml of absolute ethanol, was treated with a slight excess of 8N ethanolic hydrochloric acid and cooled to give 1.7 g (81%) of powder, m.p. 238-240 ° C (dec.). Step E: Preparation of 5,10,12-trimethyl-10,11-dihydro-5H-dibenzofa, dicycloheptene-5,10-imine hydrochloride-methyl-10-methylamino-5-methylene-10,11-dihydro -SH-Dibenzo [a, d] cycloheptene (1.6 g, 6.4 mmol) was dissolved in dry tetrahydrofuran (40 mL).

To this solution, which was stirred at room temperature under nitrogen, was added n-BuLi (3.0 ml of 2.2M solution in hexane) dropwise over 5 minutes.

The mixture was stirred for 10 minutes, then treated with 3 ml of ice water.

The tetrahydrofuran was removed in vacuo and the residue was taken up in ether. The ether solution was washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The resulting oil was chromatographed on 120 g of silica gel, eluting 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 treated with a slight excess of SN ethanolic hydrochloric acid. The solvent was removed in vacuo and the residual solid was recrystallized from 20 ml of absolute ethanol to give 5,10,12-trimethyl-10,11-dihydro-5H-dibenzo [a, flcycloheptene-5,10-imine]. hydrogen chloride with a melting point of 295-296.50 ° C was obtained.

In a similar manner there are prepared: -allyl-5,12-dimethyl-; 5,10-diethyl-12-methyl-; 10-cyclopropyl-5,12-dimethyl-; and 10-cyclopropylmethyl-5,12-dimethyl-10-11-dihydro-5H-dibenzo [a, d} cycloheptene-5,10-imine. 78fl9487 f3 Hxympu] U. Qpili division Racemic 5-methyl-10,11-dihydro-SH-dibenzo [α, cycloheptene-5,10-imine (3.93 g, 0.0178 mol) and (-) di-p -toluoyl-d-tartaric acid (6.88 g, 0.0178 mol) is dissolved in 21 ml of acetone; The solution is inoculated and after several hours at room temperature the crystalline salt is collected. This product is repeatedly recrystallized from acetone to constant rotation. The salt is suspended in cold water, stirred with aqueous sodium hydroxide and the base is extracted with ether. The washed and dried ether extract is evaporated to dryness under reduced pressure leaving (-) - 5-methyl-10,11-dihydro-5H-dibenzo [a, dicyclohepten-5,10-imine as a solid residue. Melting point 71.5-73.5 ° C.

The acetone mother liquor from the first crystallization of the (-) - isomer is evaporated to dryness under reduced pressure. A suspension of the glassy residue in cold water is stirred with aqueous sodium hydroxide and the base is extracted with ether. The washed and dried ether extract is concentrated to give the optically impure (+) base as a solid residue. This product (Z, 27 g, 0.0103 mol) and (+) di-p-toluoyl-1-tartaric acid (3.9 g, 0.0103 mol) are dissolved in 20 ml of acetone.

After several hours at room temperature, the crystalline salt is collected and recrystallized repeatedly from acetone to constant rotation. The salt is converted to the base in the manner previously described, whereby (+) 5-methyl-10-11-dihydro-5H-dibenzo [a, cycloheptene-5,10] imine with a melting point of 72-74 ° C is obtained.

Example 10. Decomposition of (f) -5-methyl-10,11-dihydro-5H-dibenzo [a, dicycloheptene-5,10-imine.

Left-handed isomer: To a solution of 66.1 g (0.299 mol) of racemic 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine in 107 ml of hot acetone is added 115.4 g g (0.299 mol) of di-p-tolu-oyl-divinic acid, dissolved in 163 ml of acetone. The solution is stirred until homogeneous, left to stand for 18 hours at Z5 ° C, then cooled in a freezer at 0 ° C for 4 hours. The salt formed is removed by filtration, washed once with cold acetone, collected and dried at 50 ° C (vacuum oven), whereby 82.97 g of A were obtained in the form of a white, solid subs: ans, [a] §89 = -1zs, 9 ° (abs. Ston), melting point 141-146 ° c (foam). The filtrate of the solid A is concentrated to dryness in vacuo and the solid residue B is used in the preparation of the right-turning isomer (see below). f7aa91s7-3 21 The salt A is dissolved in 3450 ml of boiling acetone, filtered, concentrated to 1500 ml, left to stand for 18 hours at 2506, then cooled in a freezer at 0 ° C for 4 hours. The precipitate is removed by filtration, washed once with cold acetone, collected and dried at 100 ° C (vacuum oven) to give 45.5 g of C as a white solid, [α] 589 = -1s1.9 ° (abs. ston), melting point 142-144 ° (foam).

The salt C (44.8 g, 0.073 mol) is treated with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether and the mixture is stirred until the solid dissolves. The ether layer is separated, dried over MgSO 4, filtered and evaporated to dryness in vacuo to give 16.0 g of a homogeneous, colorless oil obtained by thin layer chromatography (Silica GF eluted with 1: 9 methanol / chloroform). Crystallization from 40 ml of cyclohexane gives 14.16 g of (-) - 5-methyl-10,11-dihydro-5H-dibenzo [a, d] cyclopeptene-5,10-imine as a white solid substance, [α] 589 = -16 °, s °, (c = 0.032 g / 2 ml ethanol), melting point 68.5-69, s ° c.

Right-turn isomer: The residue B from the preparation of the left-hand isomer was converted into the free base form by stirring with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether, until the solid was dissolved. The ether layer is dried over MgSO 4, filtered and the solvent is removed under reduced pressure to give 37.9 g of orange oil, which is dissolved in 61 ml of hot 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. The solution is stirred until homogeneous, left to stand for 18 hours at 25 ° C and then cooled in a freezer at 0 ° C for 4 hours. The salt formed is removed by filtration, washed once with cold acetone, collected and dried at 60 ° C. (vacuum oven), whereby 68.8 g of D are formed as a white, f & St SUbSïaHS [U] 589 = + 127.1 ° (abs. ethanol), melting point 136-144 ° c (foam).

The salt D is dissolved in 2900 ml of boiling acetone, filtered, concentrated: iii sno m1, left to stand for 18 hours at 2 ° C and then cooled in 1 freezer to 0 ° C for 4 hours. The precipitate is removed by filtration, washed once with cold acetone , is collected and dried at 60 ° C (vacuum oven) to give 36.5 g of E as a white solid, 589 = + 132.0 ° (abs. stone), melting point 142-144 ° c.

The salt E (36.5 g, 0.0601 mol) is treated with 300 ml of 10% sodium hydroxide and 300 ml of diethyl ether and the mixture is stirred until the solid dissolves. The ether is separated, dried over MgSO 4, filtered and evaporated to dryness in vacuo to give 12.6 g of a homogeneous, colorless oil after thin layer chromatography (silica GF eluted with 1: 9 methanol: chloroform].

Crystallization from 25 ml of cyclohexane gives 11.26 g of (+) - S-methyl-, 11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine as a white solid, [a] šg9 = +161.4 (C = 0.038 g / 2 ml ethanol, melting point 0s, sf0.09.0 ° C.

Example Gel 11. (+] - 5-methyl-10,11-dihydro-5H = dibenzo [a, d] cycloheptene-5-imine hydrogen maleate A solution of 10.05 g (0.0454 mol) (+) - 5 -Methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine in 25 ml of absolute ethanol is filtered into a flask and the filter is washed with absolute ethanol to a final filtrate volume of 40 ml. A solution of 5.27 g (0.0454 mol) of maleic acid in 20 ml of absolute ethanol is filtered off in the same flask.

The combined filtrates are mixed, sown, kept at room temperature for a short time and stored in the refrigerator overnight. The crystalline material is collected and dried to give (+) - methyl-10,11-dihydro-5H = dibenzo [a, d] cycloheptene-5,10 [mu] m-hydrogen maleate, m.p. 20s, s-z10 ° c; [Α] D = + 114 ° (C = 0.012s g / 2 ml of ethanol).

Example Gel 12. Preparation of Tablets Tablets containing 1.0, 2.0, 25.0, 26.0, s0.0 and 100.0, 11-dihydro-5-methyl-12-benzyl-SH-dibenzo [a cycloheptene-5,10-imine is prepared as follows: In Table of doses containing 1-25 mg of the active compound Amount - mg, 11-dihydro-5-methyl-12-benzyl-5H-di- benzofa, d} cycloheptene-5,10-imine 1.0 2,0 25,0 Microcrystalline cellulose 49,25 48.75 37.25 Modified maize starch 49,25 48.75 -37.25 Magnesium stearate _ 0.50 0, 0.50 mg of the active compound Table for doses containing 26-100 _ Amount - mg, 11-dihydro-5-methyl-12-benzyl-5H-dibenzo [a, dicyclohepten-5,10- ímin I 26.0 50.5 100.0 M1kf0kr1sta11in ee11u10sa 25.0 100.0 200.0 Modified maize starch 2.21 4.25 8.5 Magnesium stearate 0.39 0.75 1.5 7869103740 23 Total amount of active compound, lactose and part of the corn starch are mixed and granulated into a 10% corn starch paste. The resulting granulate is sieved, dried and mixed with the remainder of the corn starch and the magnesium stearate. The resulting granules are then beaten into tablets containing 1.0, 2.0, 25.0, 26.0, 50.0 and 50.0, respectively. 100.0 mg active ingredient per tablet. Other tablets are prepared using the same procedure and equivalent amounts of excipients together with equivalent amounts of any of the novel compounds of the invention.

Pšook Qtra fl išï *

Claims (10)

(ereaialæsv -3 24 Patent claim 1. Chemical compound or salts thereof incl. right- and left-handed chanantlomers and racemic mixtures, known from the structural form R | wherein R represents (1) hydrogen, (2) lower alkyl, (3) lower alkenyl, (4) phenyl-lower alkyl, (5) ) (6) (7) (8) (9) (10) 'R1 denotes (1) (2) (3) (4) (5) (6) (1) (2) (3) (4) ( s) (6) -CH 2 R 2 denotes RS (1) (2) (3) (4) (5) (6) (7) ....._..._....__..____ V, and R 4 independently represent halophenyl-lower alkyl, lower alkylphenyl-lower alkyl, lower cycloalkyl, lower (cycloalkyl-alkyl), di (lower alkyl) amino-lower alkyl or hydroxy hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl or lower cycloalkyl alkyl) § lower alkyl, lower alkenyl, phenyl-lower alkyl, lower (cycloalkyl-alkyl), di (lower alkyl) amino-lower alkyl or hydroxy-lower alkyl, and hydrogen, halogen, lower alkoxy, trifluoromethylthio, cyano, carboxy or hydroxy, in vsesrfksv-va 1 A compound according to claim 1, characterized in that R represents hydrogen. A compound according to claim 1, characterized in that R 1, R 3 and R 4 represent hydrogen, R represents hydrogen, lower alkyl or benzyl and -CH 2 R 2 represents lower alkyl or hydroxyethyl. A compound according to claim 1, which is 5-methyl-10,11-dihydro-5H-dibenzo [a, ¶ cycloheptene-5,10-imine. A compound according to claim 3, characterized in that it is 12-benzyl-5-methyl-10,11-dihydro-5H-dibenzo [a, ¶ cycloheptene-5,10-imine. Compound according to Claim 3, characterized in that it is II- (4-chlorobenzyl) -5-methyl-10,11-dihydro-5H-dibenzo [, d] cycloheptene-5, 10-imín. A process for preparing a chemical compound according to claim 1 of the formula 1 wherein R represents (1) hydrogen (2) lower alkyl (3) lower alkenyl (4) phenyl lower alkyl (4) 5) halophenyl-lower alkyl (6) lower alkylphenyl-lower alkyl, (7) lower cycloalkyl, g (8) lower (cycloalkyl-alkyl), (9) di (lower alkyl) amino-lower alkyl or 1 (10) hydroxy R represents (1) hydrogen , (2) lower alkyl, (3) lower alkenyl, (4) phenyl-lower alkyl, (5) lower cycloalkyl or (6) lower (cycloalkyl-alkyl), '(genre Qul fi irrr _' 78091874. (26 -CH 2 R 2 denotes (1) mgalkyl , (2) lower alkenyl, (3) phenyl-lower alkyl, r (4) 1αg (cycloalkyl-alkyl), (s) ai (lower alkylamine-alkylalkyls), (6) hydroxy-lower alkyl, and and R 4 independently represent (1) hydrogen, (2) halogen, (_ '(s) haloicoxy, (4) trifluoromethylthio, (5) cyano,,. (6) carboxy or,' (_ (7) hydroxy, may be of (a) reduction of a compound of the formula - R 5 - i - 2 CH 2 R to produce a compound, wherein R represents hydrogen; (b) reduction of a compound of the formula CH 2 (lower alkyl) CO 2 low alkyl for the preparation of a compound wherein R 2 represents hydroxy-lower alkyl; (C) alkylation of a compound of the formula '1r site ßCH 2 R 2 to produce a compound wherein R does not represent hydrogen; (d) treating a compound of the formula with a strong base; (e) treatment of a compound in which Rs and / or R4 represents bromine, with sodium or potassium alkoxide, with cuprocyanide or with bis (trifluoromethylthio) mercury and copper dust to form compounds, wherein Rs and / or R4 represent lower alkoxy, cyano or trifluoromethylthio; (f) hydrolysis of a compound wherein R 3 and / or R 4 represent cyano or lower alkoxy to form a compound wherein R 3 and / or R 4 represent carboxy or hydroxy. 8. Pharmaceutical composition, characterized by a pharmaceutical carrier and a compound of the structural formula CH R or a pharmaceutically acceptable salt thereof, wherein R represents (1) hydrogen, (2) lower alkyl, (3) lower alkenyl, (4) ) phenyl-lower alkyl, (5) halophenyl-lower alkyl, vw>. .w Jm »wa-arv ~ -: -n-c-.i-.vx -.-»; -. a-. u --- i - - ~ - mrfš 'Ü L' 'kl- Im- aifaißu- "utan-- u¿% mt, & ¿wa« u & ¿- ~ _ «JI t 7809187-3 (6) (7) (8) (9) (10) denotes (1) (2) (3) (4) (5) (6) -CH 2 R 2 denotes (1) (Z) (3) (4) (5) ( 6) R 1 R 3 and R 4 U) (2) (3) (4) (5) (6) (7) 9. A composition according to claim 8, characterized in that R represents hydrogen. Lower alkylphenyl-lower alkyl, lower cycloalkyl, lower (cycloalkyl-alkyl), di (lower alkyl) amino-lower alkyl or hydroxy hydrogen, lower alkyl, lower alkenyl, phenyl-lower alkyl, lower cycloalkyl or lower (cycloalkyl-alkyl); lower alkyl, lower alkenyl, phenyl-lower alkyl, lower (cycloalkyl-alkyl), di (lower alkyl) amino-lower alkyl or hydroxy-lower alkyl; and independently represent hydrogen, halogen, lower alkoxy, trifluoromethylthio, cyano, carboxy or hydroxy. 1 10. A composition according to claim 8, characterized in that 1, R 1, R 2 and R 4 represent hydrogen; R represents hydrogen, lower alkyl or benzyl; and -CH 2 R 2 represents lower alkyl or hydroxyulkyl.