NO115027B

NO115027B -

Info

Publication number: NO115027B
Application number: NO16493865A
Authority: NO
Inventors: E Jucker; A Stoll; E Rissi; A Ebnoether; J Bastian
Original assignee: Sandoz Ag
Priority date: 1964-08-11
Filing date: 1965-08-09
Publication date: 1968-07-08
Also published as: SE326453B; NO115026B; BE668053A; SE326197B; NO115025B; SE326454B; NL6510328A; CH473823A; FR4866M; DE1250449B; GB1112601A

Description

Fremgangsmåte for fremstilling av nye, terapeutisk aktive 9,10-dihydro-4H-benzo-[4,5] cyklohepta [1,2-b] tiofen-derivater. Process for the preparation of new, therapeutically active 9,10-dihydro-4H-benzo-[4,5] cyclohepta [1,2-b] thiophene derivatives.

Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av nye, terapeutisk The present invention relates to a method for the production of new therapeutic agents

aktive 9,10-dihydro-4H-benzo[4,5]cyklohepta active 9,10-dihydro-4H-benzo[4,5]cyclohepta

[1,2-b] tiofen-derivater med den alminnelige [1,2-b] thiophene derivatives with the usual

formel Iformula I

og deres syreaddisjonssalter, hvori R3 betyr en and their acid addition salts, wherein R3 is a

lavere alkylgruppe. lower alkyl group.

I henhold til oppfinnelsene fremstilles de nye forbindelser med den alminnelige formel I og deres syreaddisjonssalter ved at en forbindelse med den alminnelige formel II According to the inventions, the new compounds of the general formula I and their acid addition salts are prepared by a compound of the general formula II

hvori R3har den ovennevnte betydning, omsettes med en klormaursyreester med den alminnelige formel III hvori R4betyr en lavere alkyl- eller aralkyl-gruppe, hvoretter den dannede forbindelse med den alminnelige formel IV in which R3 has the above-mentioned meaning, is reacted with a chloroformic acid ester of the general formula III in which R4 means a lower alkyl or aralkyl group, after which the formed compound of the general formula IV

hvori R3og R4 har den ovenfor angitte betydning, underkastes hydrolyse, og de erholdte forbindelser med den alminnelige formel I over-føres eventuelt i sine syreaddisjonssalter. in which R 3 and R 4 have the meaning indicated above, are subjected to hydrolysis, and the obtained compounds of the general formula I are optionally transferred into their acid addition salts.

Fremgangsmåten utføres f. eks. ved at opp-løsningen av en klormaursyreester, f. eks. klor-maursyreetylester eller klormaursyrebenzylester, i et indifferent, organisk, vannfritt oppløs-ningsmiddel, fortrinnsvis benzen, toluen, kar-bontetraklorid eller tetrahydrofuran, tilsettes den i det samme oppløsningsmiddel oppløste forbindelse med formel II ved romtemperatur. For fullstendig omsetning oppvarmes blandingen ennå i 1—3 timer til koking under tilbakeløp og reaksjonsblandihgen får henstå i flere timer ved romtemperatur. Den som mellomprodukt erholdte forbindelse med formel IV isoleres og renses etter kjente metoder. The procedure is carried out e.g. in that the solution of a chloroformate ester, e.g. chloroformic acid ethyl ester or chloroformic acid benzyl ester, in an indifferent, organic, anhydrous solvent, preferably benzene, toluene, carbon tetrachloride or tetrahydrofuran, is added to the compound of formula II dissolved in the same solvent at room temperature. For complete reaction, the mixture is further heated for 1-3 hours to boiling under reflux and the reaction mixture is allowed to stand for several hours at room temperature. The compound of formula IV obtained as an intermediate is isolated and purified according to known methods.

I det neste trinn erstattes alkoksykarbonyl-eller aralkoksykarbonylgruppen hydrolytisk med et hydrogenatom. Det gås herunder f. eks. frem på den måte at forbindelsen oppvarmes i flere timer med et alkalihydroksyd, f. eks. kalium-hydroksyd, med en lavere alkanol, fortrinnsvis n-butanol. In the next step, the alkyloxycarbonyl or aralkylcarbonyl group is hydrolytically replaced with a hydrogen atom. This is explained below, e.g. carried out in such a way that the compound is heated for several hours with an alkali hydroxide, e.g. potassium hydroxide, with a lower alkanol, preferably n-butanol.

Avspaltingen av alkoksykarbonyl- eller aral-koksykarbonylresten lykkes også i surt medium, f. eks. ved oppvarming med sterke uorganiske syrer f. eks. med 48 pst. hydrogenbromid. The cleavage of the alkoxycarbonyl or aral-oxycarbonyl residue is also successful in an acidic medium, e.g. by heating with strong inorganic acids, e.g. with 48 percent hydrogen bromide.

Den erholdte forbindelse isoleres på kjent måte fra reaksjonsblandingen og renses ved kry-stallisering eller ved overføring i et egnet salt. Slike salter er f. eks. hydrokloridene, hydrobro-midene, fosfatene, sulfatene, acetatene, malona-tene, fumaratene, malemåtene, tartratene, ma-latene, heksahydrobenzoatene, benzensulfonat-ene eller p-toluensulfonatene. The compound obtained is isolated in a known manner from the reaction mixture and purified by crystallization or by transfer into a suitable salt. Such salts are e.g. the hydrochlorides, hydrobromides, phosphates, sulfates, acetates, malonates, fumarates, malates, tartrates, malates, hexahydrobenzoates, benzenesulfonates or p-toluenesulfonates.

Fra Angew. Chem. 75, s. 524—538 (1963) er det kjent en forbindelse som bare avviker fra de foreliggende forbindelser ved strukturen i si-dekjeden. Den nevnte forbindelse har imidlertid en helt annen virkning enn de foreliggende, idet det dreier seg om en forbindelse med histamin-hemmende egenskaper for behandling av mi-grene og allergiske lidelser. I motsetning hertil er de foreliggende forbindelser, som mer utførlig omhandlet i det følgende, spesifikke antidepressiva for behandling av nevrotiske og psykotiske forstyrrelser. From Angew. Chem. 75, pp. 524-538 (1963), a compound is known which differs from the present compounds only by the structure of the side chain. The aforementioned compound, however, has a completely different effect to the present ones, as it is a compound with histamine-inhibiting properties for the treatment of migraines and allergic disorders. In contrast, the present compounds, as discussed in more detail below, are specific antidepressants for the treatment of neurotic and psychotic disorders.

De nye forbindelser med formel I har således verdifulle farmakodynamiske egenskaper, som ikke kunne forutsies på grunnlag av deres konstitusjon. Således utmerker de seg ved sterke, for antidepressiva typiske virkninger, som ved dyreforsøk blant annet ytrer seg ved en hem-ming av de ved reserpin eller tetrabenazin frem-kalte vegetative og motoriske symptomer. Forbindelsene potensierer noradrenalinvirkningen og besitter overveiende sentralt rettede antiko-linergiske effekter. De sedative/nevroleptiske egenskaper er ved substansene bare måtelig utviklet. Den antidepressive virkning er altså forsåvidt spesifikk, da de dempende egenskaper ved forbindelsene trer tidligere tilbake. Toksisi-teten av de ved fremgangsmåten fremstillbare produkter er forholdsvis liten. The new compounds of formula I thus have valuable pharmacodynamic properties, which could not be predicted on the basis of their constitution. Thus, they are distinguished by strong effects typical of antidepressants, which in animal experiments manifests itself, among other things, in an inhibition of the vegetative and motor symptoms induced by reserpine or tetrabenazine. The compounds potentiate the norepinephrine effect and have mainly centrally directed anticholinergic effects. The sedative/neuroleptic properties of the substances are only moderately developed. The antidepressant effect is therefore certainly specific, as the dampening properties of the compounds recede earlier. The toxicity of the products that can be produced by the method is relatively small.

De nye forbindelsene kan derfor med fordel anvendes for behandling av nevrotiske og psykotiske forstyrrelser, fremfor alt innenfor det depressive typeområde, likeledes kan de anvendes for terapi ved psykosomatiske forstyrrelser. De administreres fortrinnsvis i form av deres fysiologisk tålbare, vannoppløselige salter. The new compounds can therefore be used with advantage for the treatment of neurotic and psychotic disorders, above all within the depressive type area, and they can also be used for therapy in psychosomatic disorders. They are preferably administered in the form of their physiologically tolerable, water-soluble salts.

De som utgangssubstanser anvendte forbindelser med den alminnelige formel II er nye og kan f. eks. fremstilles ved at oppløsningen av en forbindelse med formel V. The compounds with the general formula II used as starting substances are new and can e.g. is produced by the solution of a compound of formula V.

hvori Rs har den i det foregående angitte betydning, som f. eks. 4-(3-dimetylamino-propyli-den)-9,10-dihydro-4H-benzo[4,5]cyklohepta [l,2-b]tiofen oppvarmes ved 120°C i iseddik i fra 10 min. til 2 timer med rødt fosfor og jodhydrogensyre. Etter filtrering av reaksjonsblandingen og inndamping av filtratet utrystes resten i nærvær av alkalier, f. eks. 20 pst. natronlut, med et organisk oppløsningsmiddel, fortrinnsvis metylenklorid. Fra den organiske fase fjernes jod ved hjelp av natriumtiosulfat, og det ønskede .sluttprodukt isoleres på kjent måte og renses fortrinnsvis ved overføring i et egnet salt. in which Rs has the previously stated meaning, such as e.g. 4-(3-Dimethylamino-propylidene)-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene is heated at 120°C in glacial acetic acid for from 10 min. for 2 hours with red phosphorus and hydroiodic acid. After filtering the reaction mixture and evaporating the filtrate, the residue is shaken out in the presence of alkalis, e.g. 20 percent caustic soda, with an organic solvent, preferably methylene chloride. Iodine is removed from the organic phase using sodium thiosulphate, and the desired end product is isolated in a known manner and preferably purified by transfer into a suitable salt.

I de etterfølgende eksempler som illustrerer utførelsen av fremgangsmåten er alle tempera-turangivelser i °C og er ikke korrigert. In the following examples which illustrate the execution of the method, all temperature indications are in °C and are not corrected.

Eksempel 1: 4- ( 3- metylamino- propyl) - 9, 10-dihy dr o- 4H- benzo[4,5] cyklohepta{ l, 2- b'] tiofen. Example 1: 4-(3-methylaminopropyl)-9,10-dihydro-4H-benzo[4,5]cyclohepta{1,2-b']thiophene.

a) 4- (3-metyl-3-etoksykarbonylamino-propyl) 9,10-dihydro-4H-benzo[4,5]cyklohepta[l,2-b] a) 4-(3-methyl-3-ethoxycarbonylamino-propyl) 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]

tiofen.thiophene.

Til en oppløsning av 21,0 g klormaursyre-etylester i 70 ccm abs. benzen tildryppes i løpet av 30 min. ved romtemperatur en oppløsning av 18 g 4-(3-dimetylamino-propyl)-9,10-dihydro-4H-benzo[4,5]-cyklohepta[l,2-b] tiofen i 70 ccm abs. benzen. Deretter oppvarmes reaksjonsblandingen under omrøring ennå i'5 timer til koking, den vaskes etter avkjøling tre ganger med 2-n. saltsyre, deretter ennå to ganger med vann og oppløsningen tørres over magnesiumsulfat. Etter inndamping av oppløsningsmidlet fås det rene 4- (3-metyl-3-etoksykarbonylaminopropyl)-9,10-dihydro-4H-benzo[4,5]cyklohepta [1,2-b] tiofen. To a solution of 21.0 g of chloroformic acid ethyl ester in 70 ccm abs. benzene is added dropwise over the course of 30 min. at room temperature a solution of 18 g of 4-(3-dimethylamino-propyl)-9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b] thiophene in 70 ccm abs. benzene. The reaction mixture is then heated with stirring for a further 5 hours until boiling, and after cooling it is washed three times with 2-n. hydrochloric acid, then two more times with water and the solution is dried over magnesium sulphate. After evaporation of the solvent, pure 4-(3-methyl-3-ethoxycarbonylaminopropyl)-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene is obtained.

nD25 = 1.5745. b) 4-(3-metylaminopropyl)-9,10-dihydro-4H-benzo[4,5]-cyklohepta[l,2-b] tiofen. nD25 = 1.5745. b) 4-(3-methylaminopropyl)-9,10-dihydro-4H-benzo[4,5]-cyclohepta[1,2-b]thiophene.

Oppløsningen av 16,5 g 4-(3-metyl-3-etoksy-karbonylamino-propyl)-9,10-dihydro-4H-benzo [4,5]-cyklohepta[l,2-b]tiofen, 13,5 g kalium-hydroksyd og 140 ccm n-butanol oppvarmes under omrøring i 4 timer i nitrogenatmosfære til koking. Deretter avdampes oppløsningsmidlet, resten løses ved 80°C i en blanding av 140 ccm vann og 180 ccm 2-n. svovelsyre og oppløsningen av-kjøles. Oppløsningen utrystes nå to ganger med heksan, den organiske ekstrakt ekstraheres ennå to ganger med 2-n. svovelsyre, de vandige ekstrakter innstilles alkalisk under avkjøling med natronlut og ekstraheres tre ganger med metylenklorid. Etter tørring av de forente metylenkloridekstrakter over magnesiumsulfat avdampes oppløsningsmidlet under redusert trykk. Oppløsningen av resten i 20 ccm etanol tilsettes deretter den beregnede mengde etanolisk saltsyre. Etter noen tid utkrystalliserer hydrokloridet. Det omkrystalliseres fra etanol. Smeltepunkt 210,5—212°C. The solution of 16.5 g of 4-(3-methyl-3-ethoxy-carbonylamino-propyl)-9,10-dihydro-4H-benzo [4,5]-cyclohepta[1,2-b]thiophene, 13.5 g of potassium hydroxide and 140 ccm of n-butanol are heated with stirring for 4 hours in a nitrogen atmosphere to boiling. The solvent is then evaporated, the residue is dissolved at 80°C in a mixture of 140 ccm of water and 180 ccm of 2-n. sulfuric acid and the solution is cooled. The solution is now shaken twice with hexane, the organic extract is extracted twice more with 2-n. sulfuric acid, the aqueous extracts are made alkaline under cooling with caustic soda and extracted three times with methylene chloride. After drying the combined methylene chloride extracts over magnesium sulfate, the solvent is evaporated under reduced pressure. The solution of the residue in 20 ccm of ethanol is then added to the calculated amount of ethanolic hydrochloric acid. After some time, the hydrochloride crystallizes out. It is recrystallized from ethanol. Melting point 210.5—212°C.

Det som utgangsmaterial anvendte 4-(3-dimetylamino-propyl)-9,10-dihydro-4H-benzo [4,5]cyklohepta[l,2-b] tiofen fremstilles på føl-gende måte: Oppløsningen av 12,4 g 4-(3-dimetylamino-propyliden)-9,10-dihydro-4H-benzo[4,5]cyklohepta[l,2-b]-ti'ofen-hydroklorid i 240 ccm iseddik tilsettes 12,0 g rødt fosfor og 64 ccm 56 pst. jodhydrogensyre, og blandingen oppvarmes ved 120°C i 15 min. under omrøring. Deretter filtreres reaksjonsblandingen og filtratet ihndampes under redusert trykk. Den oljeaktige rest løses i 20 pst. natronlut og i metylenklorid, den organiske fase fraskilles og den vandige del ekstraheres ennå to ganger med metylenklorid. De forente metylenkloridekstrakter vaskes to ganger med 5 pst. natriumtiosulfat-oppløsning, deretter to ganger med vann, tørres over kalium-karbonat og inndampes under redusert trykk. Oppløsningen av resten i 35 ccm aceton tilsettes nå deretter den beregnede mengde hydrogen-klorid i aceton og oppløsningen får langsomt avkjøles til romtemperatur. Det utfelte hydro-klorid frafiltreres og krystalliseres fra aceton. Smeltepunkt 158.5—160°C. The 4-(3-dimethylamino-propyl)-9,10-dihydro-4H-benzo [4,5]cyclohepta[1,2-b] thiophene used as starting material is prepared in the following way: The solution of 12.4 g 4-(3-Dimethylamino-propylidene)-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]-thiophene hydrochloride in 240 ccm of glacial acetic acid is added 12.0 g of red phosphorus and 64 ccm of 56% hydroiodic acid, and the mixture is heated at 120°C for 15 min. while stirring. The reaction mixture is then filtered and the filtrate is evaporated under reduced pressure. The oily residue is dissolved in 20% caustic soda and in methylene chloride, the organic phase is separated and the aqueous part is extracted twice more with methylene chloride. The combined methylene chloride extracts are washed twice with 5% sodium thiosulphate solution, then twice with water, dried over potassium carbonate and evaporated under reduced pressure. The solution of the residue in 35 ccm of acetone is now added to the calculated amount of hydrogen chloride in acetone and the solution slowly becomes cool to room temperature. The precipitated hydrochloride is filtered off and crystallized from acetone. Melting point 158.5—160°C.

Eksempel 2: 4-( 3- metylamino- propyl)- 9, 10-dihydro- 4H- benzo[ 4, 5~\ cykloheptail, 2- b'] tiofen. Example 2: 4-(3-methylamino-propyl)-9,10-dihydro-4H-benzo[4,5~\cycloheptyl, 2-b'] thiophene.

Avspaltingen av etoksykarbonylgruppen fra den i henhold til eksempel la) fremstilte forbindelse kan også utføres med hydrogenbromid. The removal of the ethoxycarbonyl group from the compound prepared according to example la) can also be carried out with hydrogen bromide.

Oppløsningen av 2 g 4-(3-metyl-3-etoksy-karbonylaminopr opyl) - 9,10- dihydr o-4H-benzo [4,5]cyklohepta[l,2-b]tiofen i 25 ccm 48 pst. bromhydrogensyre oppvarmes i nitrogenatmosfære i' 30 min. til koking. Deretter uthelles i 250 ccm isvann, den erholdte oppløsning innstilles alkalisk med natronlut og oppløsningen rystes tre ganger med metylenklorid. De organiske ekstrakter vaskes med vann, tørres over natriumsulfat og oppløsningsmidlet inndampes. Oppløsningen av resten i etanol tilsettes deretter den beregnede mengde etanolisk saltsyre. Etter noen tid utkrystalliserer hydrokloridet. Smeltepunkt 210,5—212°C fra etanol. The solution of 2 g of 4-(3-methyl-3-ethoxy-carbonylaminopropyl)-9,10-dihydro-4H-benzo [4,5]cyclohepta[1,2-b]thiophene in 25 ccm of 48% hydrobromic acid heated in a nitrogen atmosphere for 30 min. for cooking. It is then poured into 250 cc of ice water, the resulting solution is made alkaline with caustic soda and the solution is shaken three times with methylene chloride. The organic extracts are washed with water, dried over sodium sulphate and the solvent is evaporated. The solution of the residue in ethanol is then added to the calculated amount of ethanolic hydrochloric acid. After some time, the hydrochloride crystallizes out. Melting point 210.5—212°C from ethanol.

Claims

Process for the preparation of new, therapeutically active 9,10-dihydro-4H-benzo[4,5] cyclohepta[1,2-b]-thiophene derivatives of the general formula I

and their acid addition salts, wherein R 3 means a lower alkyl group, characterized by that a compound of the general formula II

in which R 3 has the above-mentioned meaning, is reacted with a chloroformate ester of the general formula III

wherein R 4 means a lower alkyl or aralkyl group, after which the formed compound of the general formula IV

in which R 3 and R 4 have the meaning indicated above, are subjected to hydrolysis, and the obtained compounds of the general formula I are optionally transferred into their acid addition salts.