IL26263A - Derivatives of dibenzocycloheptenes and their preparation - Google Patents

Description

Derivntives of and their preparation ft 25028 2 This invention relates to derivatives of In the invention relates to and methods of preparing the The invention also relates to intermediates useful in the preparation of the above pounds as well as processes for the preparation of said The end compounds embraced within the scope of the present invention may be represented by the following structural formulae Z II wherein Z is one of the radicals or Z in which case an alkyl group replaces the hydrogen at the 11 R is a straight or branched chain lower preferably having up to 6 radical wherein B is halogen or lower alkyl having up to 4 carbon atoms and m is 0 or and are straight or branched chain lower preferably having up to 6 carbon is straight branched chain lower preferably having up to VI VI 6 carbon atoms or a group i which E is or and which may be the same or different may be linked together through an atom of nitrogen or gen to form a heterocyclic ring having from 5 to 6 atoms therein such as alkyl substituent of the latter preferably having up to 4 is or a group wherein is 1 or n is 0 or B is alkoxy or methylj and X and which may be the same or different are an alkylsulfonyl group having up to 4 carbon or a dialkylsulfamoyl group having up to 8 carbon end compounds encompassed scope of the present 10 cyoloheptene eloheptene The compounds represented by the structural formulae can advantageously be employed in pharmaceutical applications because they have been found to possess antidepressant As they may be administered orally in the form of sustained release pellets and the like or they may be administered orally or in the form of aqueous solutions or administered orally or level of from about one to about 300 preferably given in divided doses over day or in sustained release The compounds are preferably administered in the form of their toxic acid addition salts and these salts are within the scope of this The preparation of those compounds by structural formula wherein Z is a substituted imino radical and and are as may be accomplished by treating the corresponding compound with an appropriately substituted This process may be illustrated as The conversion of the to the corresponding no compound is preferably carried out i the presence of a suitable eolvent and at elevated preferably the reflux temperature of the Suitable solvents which may he employed are the lover of methanol is other inert organic solvents that are capable of solubilizing the hydroxylamine reagent also may be After of the the solvent is removed as by the residue dissolved and the solution rendered precipitated product that separates is readily recovered by compound of formula III used as starting material in this process by a standard Oppenauer oxidation reaction from the corresponding hydroxy compound of the formula OH which latter can be prepared by the process described in Patent cation The preparation of those compounds represented by structural formula wherein 2 is a substituted radical and X and are as is readily effected by first oxidizin the corresponding hydroxy compound obtained by the method described in Patent Specification wherein is as by a Oppenauer oxidation reaction and the treating the corresponding derivative with an appropriately substituted reagent as described in Step I process may as follows t OH 0 The preparation of those compounds of structural foxmula I wherein Z is a substituted sulfonamido radical and X and are as is accomplished by treating the corresponding derivative an appropriate sulfonyl halide or sulfonic process may be illustrated as s wherein and are previously defined and Hal represents preferably chlorine or The introduction of the sulfonyl is accomplished conventional manner employing such solven conditions as are known in the The corresponding derivatives of compounds of structural formula II readily prepared by dealkylatlng the compound as described above wherein and are both lower alkyl and preferably are the This process may be illustrated as wherein X and are as previously of the processes involves the condensation of the tertiary amino compound with a haloformate of the formula Hal where Hal is halogen and is as aryl or to the corresponding While the reaction with the haloformate can be carried out in the absence of a solvent it ie preferable to an excess of the Other suitable solvents include the aromatic hydrocarbons such as benzene and aliphatic hydrocarbons such heptane and the halogenated hydrocarbons such as chloroform end carbon The reaction may be carried out at although an elevated temperature is At conclusion of the the urethane intermediate recovered in conventional The urethane intermediate thus produced then is subjected to hydrolysis The hydrolysis of the urethane is preferably carried out under basic After completio of the the desired product is recovered in conventional such as by extraction into suitable solvent and evaporation of the The those compounds of structural formulae I and wherein is amino and Rrt X and are as defined in formulae I and II to be used as starting materials for the preparation of the corresponding sulfonamide is accomplished b reducingthe corresponding obtained in Step reduction is accomplished using metallic sodi i although othe conventional reducing agents such as the metal hydrides as well as catalytic hydrogena ion may desired product may be readily recovered by conventional The compounds of structural formula I wherein readily prepared by acylating the corresponding compound obtained by treating the compound with hydro shown in Step I with common afiylating a The preferred acylating agents are the acid anhydrides such as acetic since they can as both solvent and The yloxyimino compounds of formula II are prepared in similar manner from the corresponding derivative obtained in Step I except that the acylatio is carried out employing a of the The compounds structural formulae I II wherein 2 is the hydrazono and are as defined are prepared by reacting the ponding compound obtained in Step C with hydrazine following the procedure described by and in The preparation those compounds of structural formulae I and II wherein Z is OY and an group replaces the hydrogen at the 11 position and and Y are as is aocomplished by acylating the ponding with respect to the preparation of the compounds of structural formula the acylation is carried out in the same manner ae previously mentioned for the preparation of the compounds of structural formula employing a salt of the The preparation of the derivatives of formulae I and has been described in Patent Specification As previously indicated the invention includes within its scope the acid addition salts of the compounds represented by structural formulae I and The acid addition salts are readily prepared by reaotion of the free base with a suitable aoid in known It be appreciated by those skilled in the art that the compounds represented by structural formulae I and II wherein the atom carries two dissimilar exist as geometric geometric isomers exist as racemates and resolution into enantiomorphs is possible b conventional such as fractional crystallization of the salts with optically active When the is substituted by an or hydrazono the type of geometric isomerism possible depends on whether the is svn or to the oxygen The Invention is illustrated by way of example by the following 1 of heptene and freshly distilled oyclohexanone in 600 of dry toluene is heated boiling and 250 of toluene is Slow distillation continued while a solution of aluminum isopropoxide i 400 of dry toluene is added dropwise over a 1 hour period for an additional 30 The mixture is cooled in ice and hydrolyzed by the addition of 100 of a saturated aqueous solution of The aqueous layer is separated and extracted twice with washing with the combined organic layers are extracted with 200 of citric The citric acid extract is cooled in an rendered alkaline with sodium hydroxide and the oily base extracted into The washed and dried extract is evaporated under reduced pressure to give the product as a crystalline i a yield of An analytical sample melts at after repeated recrystallizations from Analysis for Founds Following the procedure of Example 1 and using as starting material trans b nzo c e 13 trans cyclo eptene trans trans trans t ans trans cycloheptene the following compounds are obtained cycloheptene ene 14 EXAMPLE tr g of trans in is added in portions over 30 minutes with stirring to 100 ml of ethyl The mixture is stirred and heated to 30 hours until a clear solution Solvent unde reduced pressure and the residual oil in The benzene solution is washed with citric and dried by filtration through anhydrous sodium and evaporated under reduced The trana heptene is obtained a yellow oil weighing trans o e g of trans prepared and 10 g of potassium hydroxide stirred and heated to in ml of alcohol for 16 Solvent is distilled under reduced pressure and the residue partitioned between benzene and The combined benzene extracts are washed 15 with water and extracted with citric The aqueous acid solution is rendered strongly alkaline and the oily base that separates is extracted into Evaporation of the washed and dried benzene extract leaves the crude product as a yellow oil weighing The base is converted to the hydrogen maleate by treating a solution in isopropyl alcohol with a solution of 520 of acid in isopropyl Dilution to incipient crystallization with absolute ether precipitates the hydrogen in a yield of from isopropyl ether gives Analysis for EXAMPLE 4 By replacing the trans heptene used in Example 1 with an equlmolecular amount trans prepared as in Example 3 and following substantially the same procedure as described in Example there is obtained The yield of yellow oily 16 base is quantitative The base is converted to the hydrogen maleate by dissolving it in absolute ethanol and adding a solution of a slight excess of maleic acid in absolute Dilution to incipient tion with absolute ether precipitates the hydrogen in a yield of melting point is unchanged by recrystallization from absolute Analysis for C H C the starting material used in Example 3 is replaced by trans trans trans 3 5 trans 7 the corresponding compounds bearing a group the position are may then be converted by the process of the present Example into the corresponding trans 17 trans trans trans EXAMPLE 5 g together with 500 mg of methoxyamine 825 mg of sodium acetate 5 of and 45 ml of methanol ia heated to refluxing for 19 Methanol is distilled under reduced pressure and the residue dissolved in The solutionis rendered alkaline and the oily base that separates is extracted into After washing and drying the combined benzene is evaporated under reduced pressure leaving the product as an oil weighing sample of the base from a previous experiment is converted to the hydrogen oxalate salt by treatin an ethanolic solution with one equivalent of oxalic acid dissolved in absolute Dilution with ether cipitates hydrogen oxalate as a white crystalline 18 Repeated recrystallizations from absolute ethanol give Analysis for By the same procedure as described but replacing the methoxyamine hydrochloride by propoxyamine the corresponding compounds bearing a propoxyimino group in the position is Similarly if the is replaced by any of the compounds listed in Examples 2 and the corresponding or propoxyimino oompounds are EXAMPLE 6 310 mg together with 80 mg of amine 100 mg of sodium 1 ml of and 9 ml of methanol heated to refluxing for 2 Methanol is distilled under reduced pressure and the residue dissolved in The solution is rendered alkaline and the precipitate washed with and dried The yield of is 300 mg A sample purified by repeated crystallizations from 5 ethanol melts at group are By the same method as described in Example 3 but replacing the starting compound with an compound of Example 10 the corresponding compound can be 11 A solution of 620 Example 1 in 3 of dry benzene is added dropwise to a stirred solution of of ethyl in 3 ml of dry After stirring for 1 hour at the mixture is diluted with and washed with 2 hydrochloric then with Evaporation of the benzene under reduced leaves the product as the By using as starting material any the ing cloheptene 25 for The cooled solution is diluted with water and the oily base extracted into washed benzene extract is evaporated under reduced leaving the oily base as the residue in a yield of 500 with absolute ether gives the product an oily Repeated recrystallizations from cyclohexane afford an analytical Analysis for Pounds If the compound is replaced by any of the keto compounds listed in 2 and at the end of the corresponding compounds are 14 cis A solution of cia heptene in 12 ml of acetic anhydride is heated to refluxlng for The dark yellow solution is evaporated to dryness under reduced pressure and the oily residue dissolved in 20 ml of water containing 1 ml of 6 hydrochloric After one extraction with the aqueous solution is rendered alkaline sodium hydroxide and the oily base extracted into washed benzene extract evaporated under reduced leaving the product as an oily 600 The base may be converted to the hydrogen oxalate by treating a solution in ieopropyl alcohol with a solution of oxalic acid in ieopropyl ene hydrogen oxalate obtained a white crystalline Repeated from ieopropyl alcohol and from mixtures of absolute and absolute ether give the Analysis Calc for if Magnesium 145 a crystal of and 25 of are placed in a 50 reaction fitted with a reflux condenser end inlet The apparatus is flushed with dry nitrogen and protected from atmospheric by means of a drying The reaction is initiated with a drop of methyl iodide and then methyl chloride is introduced below the surface of the stirred mixture at room Passage of the gas is continued until all of the The of the Grignard reagent then is added dropwise to a stirred solution of 900 of cyoloheptene in 25 of maintained in nitrogen atomaphere and cooled in an The mixture is stirred at room temperature for 45 mlnutea and the bulk of the tetrahydrofuran is evaporated below under reduced residue is dissolved in benzene and by the dropwise addition of 10 of The benzene layer is separated by and the gelatinous precipitate washed with several portions of After with combined benzene solutions are extracted with three 25 portions of citric The acid extract is rendered alkaline and the oily base extracted into The washed and dried benzene extract is evaporated under reduced leaving the product as an oily residue that solidifies on trituration with absolute The yield of product melting at is 700 The base may be converted to the hydrogen salt by treating an ethanolic solution with a excess of malelc acid dissolved absolute Dilution with absolute ether precipitates cycloheptene hydrogen The melting point is unchanged by further Analysis for C H By replacing the used in Example 17 with an amount of obtained as described in Example 18 following substantially the same procedure described in Example there is obtained laminopro The yield of white crystalline is An analytical sample melts at after ation a mixture of ether and petroleum ether and sublimation at and Analysis for trans trans is added in small portions with stirring to 150 of ethyl ohloroformate cooled in an The mixture is stirred in the cold for then heated to for 16 Excess ethyl formate is distilled under reduced pressure and the oily residue treated with benzene and the mixture evaporated to dryness under reduced This treatment is repeated and the residue finally is partitioned benzene The benzene layer is washed with and dried by filtration through anhydrous sodium and evaporated to dryness under reduced Crystallization of the oily residue from petroleum ether gives the in a yield of A second crop of is obtained from the mother A purified sample melts at after recrystallization a mixture of absolute ether and petroleum Analysis for EXAMPLE By replacing the trans used in Example 20 with an equimolecular amount of and following substantially the same procedure described in Example there is obtained The yield of yellow oily is A solution of prepared described in Example 21 and potassium hydroxide in 40 of alcohol is stirred and heated to refluxing in a nitrogen atmosphere for 12 The solvent is evaporated under reduced pressure and the residue partitioned between and After of the aqueous the combined benzene extracts are washed with water and then extracted with three portions of citric The citric acid extract is rendered alkaline with sodium hydroxide and the oily base extracted into The washed and dried benzene extract is evaporated to dryness under reduced leaving the crystalline base as the residue in a yield of 400 Sublimation at and mm gives an analytical Analysis for The resolution of race into optical morphs is exemplified below for the starting material used in Example trans g dissolved in 200 of boiling absolute ethanol sad treated with a solution of of tartaric acid in 150 of warm absolute The tartrate as the solution cools and several crops collected until no further precipitation ethanolic mother liquor then is evaporated to dryness under reduced pressure and the residual syrup is dissolved in 100 of The solution is rendered strongly alkaline with aqueous sodium hydroxide and the oily base extracted into Evaporation of the washed and dried benzene extract under reduced pressure leaves the crystalline base weighing Reoryatallization from benzene hexane affords of The base is dissolved in 20 of boiling absolute ethanol and treated a solution of of tartaric acid in 10 of warm absolute The tartrate separates in white Three recrystalllza lons from ethanol give a product of constant specific Analysis for C The 700 diesolved in 20 the solution made strongly basic with aqueous sodium the oily base J extracted into Evaporation of the washed and dried benzene extract under reduced pressure leaves the crystalline Eeerystalllzation from a mixture of benzene and hcxano gives 476 of to Analysis Calc for trans Racemic is dissolved in 200 of boiling absolute ethanol and treated with a solution of of tartaric acid in 150 of warm absolute After the addition of 50 of the tartrate crystallizes as the solution cools collected after several days at room The ethanolic mother liquor then is evaporated to dryness under reduced pressure and the residual eyrup is dissolved in of The solution is rendered strongly alkaline with aqueous sodium hydroxide and the oily base extracted into Evaporation of the washed and dried benzene extraot under reduced pressure crystalline base weighing The base is dissolved in 20 of boiling ethanol and with a solution of 925 of tartaric acid in 5 of warm The tartrate separates in white second crop of obtained from the mother liquor and combined with the first Three from ethanol give a product of conetant specific rotation Analysis for The 950 is dissolved 20 of the solution made strongly basic with aqueous sodium and the oily base extracted into Evaporation of the washed and dried extract under reduced pressure leaves the from a mixture of benzene and hexane 556 of to Analysis for insufficientOCRQuality

Claims (1)

1. 35 the latter preferably having up to 4 carbon atoms or a group wherein ra is 1 or n is 0 or is alkoxy or and X and which may be the same or are an alkylsulfonyl group having up to 4 carbon or a group having up to 8 carbon Compounds according to Claim 1 of the formula and salts wherein and are each lower alkyl or together with the nitrogen atom to which they attached form a or radical and X and are as defined in Claim Compounds according to Claim 1 of the formula and thereofj wherein X and are as Compound according to Claim 1 of the formula and thereo wherein and T X V are as defined in Claim 1 or Compounds according to Claim 1 of the formula 37 and salts wherein X and are as defined in Glaira according to Claim 1 of the salts wherein X and are as defined in Claim 1 or Compounds according to Claim 1 of the formula and salts wherein X and are as defined in Claim 1 or Compounds according to Claim wherein is alkyl and is the group COO where R is according to Claim 1 of the formula salts thereof5 X and are as defined in Claim lDo Compounds according to Claim 1 of the formula and salts wherein X and are as defined in Claim Compounds according to Claim 1 of the and wherein X and are as defined in 10 cycloheptene and acid addition salts corresponding to and II in Claim particularly as described and exemplified A process for the preparation of compounds according to Claim which comprises treating a of the formula with a compound of the formula wherein X and are as defined in Claim 1 or in the preeenoe of an inert A process for the preparation of compounds according to Claim which comprises treating a compound of the formula 0 with a compound of the formula wherein X and are defined in Claim in the preeenoe of an inert 20 A process for preparing a compound according to Claim which comprises acylating a compound the formula NOH wherein X and as defined in Claim 1 wit an in which Y is defined in Claim process for preparing a according to Claim which comprises an acid addition salt of a of the formula wherein and are as defined in 1 with an acylating agent in which Y is as defined in Claim A process for preparing a compound according to Claim comprises reacting a compound of the formula de of the 2 and Hal representa 42 i t 43 process preparing a compound according comprises reacting a compound of tho formula are as defined in Claim A process for preparing a compound according to Claim 10 which comprises reacting a compound of the formula wherein X and are as defined in Claim 1 with Processes for the preparation of and acid addition salts thereof of formulae I or II in Claim substantially as described 5 and acid addition salts thereof of formulae I or II in Claim when prepared by the processes according to any of Claims 29 Pharmaceutical compositions containing as an active ingredient at least one or an acid addition ealt thereof according to Dated this 2nd day of For Applicants A 7 insufficientOCRQuality