NO167309B

NO167309B - HOLE POLYESTER FIBER FOR USE AS FIBER FILL, PROCEDURE, AND SPIN CRAFT FOR MANUFACTURE OF POLYESTER FIBER AND USE OF IT AS FIBER FILL.

Info

Publication number: NO167309B
Application number: NO885050A
Authority: NO
Inventors: Clarke Rust Broaddus
Original assignee: Du Pont
Priority date: 1987-11-13
Filing date: 1988-11-11
Publication date: 1991-07-15
Also published as: NO885050L; DK630588D0; JPH01148809A; AU607278B2; HK78893A; NO885050D0; CN1033657C; DE3879110T2; AU2502788A; DE3879110D1; KR890008363A; NZ226935A; CA1314368C; KR910008667B1; PT88997A; IE883384L; FI885221A0; IN171801B; CN1042742A; DK630588A

Abstract

New polyester fiberfill of round cross-section, but containing multiple peripheral voids around an axial void, and preferably seven such voids in a hexagonal packing arrangement, and processes for preparation and use, and articles filled with such new fiberfill.

Description

Fremgangsmåte ved fremstilling av terapeutisk aktive 3-(substituert amino)-1,2,3,4-tetrahydrocarbazoler. Process for the preparation of therapeutically active 3-(substituted amino)-1,2,3,4-tetrahydrocarbazoles.

Foreliggende oppfinnelse angår fremstilling av carbazol-derivater og spesielt en rekke 3-(substituert amino)-1,2,3,4-tetra-hydrocarbazoler med farmakologiske egenskaper. The present invention relates to the production of carbazole derivatives and in particular a number of 3-(substituted amino)-1,2,3,4-tetrahydrocarbazoles with pharmacological properties.

Forbindelsene som fremstilles ifdlge oppfinnelsen har den generelle formel: The compounds produced according to the invention have the general formula:

hvor R er lavere alkyl, R1 er hydrogen eller lavere alkyl, R2 er hydrogen eller lavere alkyl, og R3 er hydrogen, hydroxyl eller lavere alkoxy. where R is lower alkyl, R 1 is hydrogen or lower alkyl, R 2 is hydrogen or lower alkyl, and R 3 is hydrogen, hydroxyl or lower alkoxy.

Disse forbindelser fremstilles bekvemt ved hjelp av Fischer-indolsyntesen under anvendelse av det passende fenylhydrazin og keton til å danne fenylhydrazonforloperen som ved ringslut-ning i nærvær av syre eller ved termiske midler forer til det dnske-de carbazolderivat. Reaksjonen som tar del i syntesen av forbindelsene som fremstilles ifolge oppfinnelsen kan illustreres ved folgen-de reaksjonsrekke: These compounds are conveniently prepared by the Fischer indole synthesis using the appropriate phenylhydrazine and ketone to form the phenylhydrazone precursor which by ring closure in the presence of acid or by thermal means leads to the Danish carbazole derivative. The reaction that takes part in the synthesis of the compounds produced according to the invention can be illustrated by the following reaction sequence:

hvor R, R1? R2 og Rg er som ovenfor angitt. where R, R1? R2 and Rg are as indicated above.

Det sure ringslutningsmiddel kan være et hvilket som helst av de vanlige uorganiske hydrohalogenider, som HC1, HBr eller HJ, eller en hvilken som helst av de vanlige mineralsyrer, som svovelsyre eller fosforsyre, en organisk syre, som eddiksyre, eller en Lewis-syre, som BF^ eller ZnClg. The acidic ring-closing agent may be any of the usual inorganic hydrohalides, such as HC1, HBr or HJ, or any of the usual mineral acids, such as sulfuric or phosphoric acid, an organic acid, such as acetic acid, or a Lewis acid, such as BF^ or ZnClg.

De dannede 3-(substituert amino)-1,2,3,4-tetrahydrocarb-azoler kan overfores til et farmakologisk«godtagbart salt som hydrokloridet, hydrobromidet, maleatet eller oxalatet og lignende. Andre salter som er av en giftig natur kan anvendes, for å skille den onskede forbindelse fra blandinger i hvilke den er tilstede. The 3-(substituted amino)-1,2,3,4-tetrahydrocarbazoles formed can be converted to a pharmacologically acceptable salt such as the hydrochloride, hydrobromide, maleate or oxalate and the like. Other salts which are of a toxic nature may be used to separate the desired compound from mixtures in which it is present.

I form av farmakologisk godtagbare syreaddisjonssalter er forbindelsene,fremstillet ifolge oppfinnelsen, nyttige som analgetiske midler. In the form of pharmacologically acceptable acid addition salts, the compounds produced according to the invention are useful as analgesic agents.

Den analgetiske effekt blev undersokt i det alt vesentlir ge i henhold til fremgangsmåten beskrevet av Biahchi, C. og Franceschini, J. i "Experimental Observations On Haffner<*>s Method For Testing Analgesic Drugs", Brit. J. Pharmacol., i, 280 (1954). For forbindelsene blev ED5Q funnet å ligge mellom 15 og 35 mg/kg vetl intraperitonal administrering. ;Ved en sammenligning av den analgetiske effekt for den kjente analgetiske forbindelse Darvon (a-d-4-dimethylamino-3-methyl-l,2-difenyl-2-butanolpropionat) og en forbindelse i henhold til foreliggende oppfinnelse, nemlig 3-methylamino-l,2,3,4-tetrahydrocarbazol som begge blev administrert oralt til en gruppe mus. ble den analgetiske effektivitet bestemt som tidligere beskrevet. En ED^-verdi på ca. 16,2 - 26 mg/kg blev funnet for 3-methylamino-l,2,3,4-tetrahydrocarbazol, og en ED^q på ca. 44 mg/kg blev funnet for Darvon. ;Oppfinnelsen vil så bli belyst ved fdlgende eksempler: ;Eksempel 1 ;3- methylamino- l, 2, 3, 4- tetrahydrocarbazol ;A. 4- methylaminocyclohexanol. En 230 g prove av p-methylamino-fenolsulfat blev opplost i 800 ml vandig methanol (1:3). Hydrogenering blev utfort ved 100°C og 105 kg/cm under anvendelse av 1,0 g rutheniumdioxyd som katalysator. Hydrogeneringen var fullstendig i lopet av ca. 2 timer. Katalysatoren blev fjernet ved filtrering og det meste av opplosningsmidlet blev avdestillert i vakuum. 200 ml 20 %- lg natriumhydroxydopplos-ning blev tilsatt til den gjenværende sirup, og den dannede opplosning blev underkastet kontinuerlig ekstraksjon med kloroform i én dag. Ekstraktet blev torret og konsentrert, og residuet destillert i vakuum, hvilket ga 123 g produkt, kokepunkt 105 - HO°C (5 mm). Materialet blev helt i vannfri ether for å danne hvite krystaller (108 g) med smeltepunkt 78 - 79°d I et annet forsSk var smelte-punktet 88 - 89°C. Denne forandring i smeltepunkt kan ékyldes vari-erende mengder av cis- og trans-i9omerene. ;Analyse beregnet for C^-j^NO: N IO,85 ;Funnet: N IO,59. ;B. 4- methylaminocyclohexanon■ Til en blanding av 12,9 g ;(0,10 mol) 4-methylaminocyclohexanol og 33 g kalium-t-butoxyd i 300 ml torr benzen blev tilsatt en opplosning av 90 g benzofenon i 2O0 nil benzen. Blandingen blev omrort ved romtemperatur under nitrogenatmosfære i 3 dager. 200 ml vann blev så tilsatt, og blandingen blev omrort kraftig i flere minutter. Benzenskiktet blev ekstrahert med 4 x lOO ml<1>s porsjoner 10 %-ig saltsyre. De forenede vandige opplosninger blev så moteks-trahert med ether. Efter konsentrering i vakuum av den vandige opplosning til ca. halvt volum blev fast kaliumcarbonat tilsatt for å frigjore den frie base. Oppløsningen blev så kontinuerlig ekstrahert med kloroform i 1 dag. Torring og konsentrering av ekstraktet ved atmosfæretrykk fulgt av vakuumdestillasjon ga 5,09 g farvelos væske med kokepunkt 105 - 110°C (15 mm);- v ^ks 1715 cm" ;C. 3- methylamino- 1, 2, 3, 4- tetrahydrocarbazol. En opplosning av ;15,4 g (O,121 ' mol) 4-methylaminocyclohexanon og 13,5 g (0,125 mol) fenylhydrazin i 200 ml benzen inneholdende 0,1 g p-toluensulfonsyre blev oppvarmet under tilbakelbp i 2 timer, idet det frigjorte vann blev oppsamlet i et Dean-Starke-apparat. Efter konsentrasjon av benzenopplos-ningen blev fenylhydrazonsirupen (24,7 g) opplost i 300 ml eddiksyre og opplosnin gan blev oppvarmet ved 90 - 95°C i 3 timer. Eddik-syren blev avdestillert i vakuum og residuet omrort med fortynnet natriumhydroxydopplbsning. Eks tråksjon med kloroform, torring og inndampning i vakuum fra 20,1 g av et fettaktig fast stoff med smeltepunkt 125 - 129°C. For analyse blev en prove omkrystallisert fra benzen-ether (trekullbéhandling) og hadde da smeltepunkt 134-135°C; ;V maks 3480 (indol-N-H)> 3410 (w-> CH3NH-), spisser ved 1630 og 1600 cm"1; A Me?H 226 mu. (£. 18.500) og 280 mu- (£ 5460). ;ro 3 les Analyse beregnet for C13H16<N>2<:> C 78,00; H 8,05: N 14,00 ;Funnet: C 77,48; H 8,18; N 13,96 ;D. 3- methylamino- l, 2, 3, 4- tetrahydrocarbazol- maleat. En 11,3 g ;prove av 3-methylamino-1,2,3,4-tetrahydrocarbazol (sm.p. 125 - 129°C) blev opplost i aceton. Opplosningen blev behandlet med trekull, og det kla-rede filtrat behandlet med 1 molekvivalent maleinsyre i en minimal mengde aceton. Ca. et halvt volum av ether blev tilsatt, og efter ;noen få minutter fant krystallisering sted. Produktet blev oppsam- ;let, vasket0med aceton-ether, pulverisert og torret over natten i en Abderhalden-pistol ved 60°C, hvilket ga 13,1 g materiale med smeltepunkt 159 - 160°C; ;X 224 mn (É 25 600) og 279 mu. ( £ 6040). ;Analyse beregnet for C13<H>16<N>2<:> (<C>HC02H)2: ;N(basisk) 4,43; N(totalt) 8,86 ;Funnet: N(basisk) 4,33; N(totalt) 8,79 ;Eksempel 2 ;3- methylamino- l, 2, 3, 4- tetrahydrocarbazol ;A. 4- acetamidocyclohexanol. 390 g (2,62 mol) acetyl-p-aminofenol blev redusert i en 2 liters autoklav ved 100°C, 105 kg/cm ? under anvendelse av methanol som opplosningsmiddel og 2 g rutheniumdioxyd som katalysator. Reduk- ;sjonen var fullstendig i lopet av 8 timer. Katalysatorene blev fjernet ved filtrering, og filtratet konsentrert under vakuum. Residuet blev omrort med 1 liter kold aceton, og der blev erholdt 348 g (86 % utbytte) av et hvitaktig fast stoff; sm.p. 135 - 137°C. ;Analyse: beregnet for C8H15N02: C 61,12; H 9,62; N 8,91 ;funnet: C 61,32; H 9,75; N 8,90 ;B. 4- acetamidocyclohexanon. Til en kold omrort opplosning av ;685 g natriumdikroraat i 225 g konsentrert svovelsyre og 1,5 1 vann blev tilsatt en opplosning av 180 g (1,15 mol) 4-acetaraidocyclohexanol i 300 ml vann.- Opplesnin- ;gen blev ho\dt under 10°C under en tilsetningsperiode på 1 time. Opplosningen-blev omrort og avkjolet i ytterligere 2 timer. Reaksjonsblandingen blev derefter ekstrahert med kloroform i 2 dager i en kontinuerlig væskeekstraktor. Den organiske fase blev tdrket over MgS04, og derefter konsentrert under vakuum, og der blev er- ;holdt 119 g av forbindelsen (69 %); sm.p. 136 - 137°C. Ved en annen fremstilling hadde en analytisk prove et sm.p. på 125 - 128°C. In-frardde spektra for de to provef var identiske, og der var ingen nedsetning av smeltepunkt for en blanding av de to prover. ;Analyse: beregnet for C8H13N02: C 61,91; H 8,44; N 9,04 ;funnet: C 61,51; H 8,56; N 8,79 ;C. 3- acetamido- l, 2, 3, 4- tetrahydrocarbazol. En opplosning av ;51,O g (p,33 mol) 4-acetamidocyclohexanon og 36,0 g (0,33 mol) fenylhydrazin i 650 ;ml eddiksyre blev omrort og oppvarmet til 80 - 90°C i 5 timer. Ed-diksyren blev derefter fradestillert under vakuum, og residuet omrort med vann, oppsamlet og torket. Omkrystallisering fra en blanding av aceton og "Skelly B" ga 78,0 g (64 % utbytte) av forbindelsen med sm.p. 180 - 181°C. ;Analyse: beregnet for <c>i4<H>i6<N>2°<:> N 12,27 ;funnet: N 12,34 ;D. 3- amino- 1, 2, 3, 4- tetrahydrocarbazol. En opplosning av ;48,O g (0,21 mol) 3-acetamido-1,2,3,4-tetrahydrocarbazol i 500 ml ethanol og 500 ml 50 %-ig vandig KOH opplosning blev "tomrbrt og oppvarmet under tilbakelop i 3 dager. E^hanolen blev derefter avdestillert under vakuum, og det brune faststoff som blev dannet under destillasjonen blev ;oppsamlet og vasket med vann. Utbytte 36 g (92 %) ; sm.p. 176-184°C. Det urene produkt blev renset ved omdannelse til cyclohexansulfamin-syresalt i aceton, sm.p. 194 196°C (utbytte 67 g, 95 %). Den frie base blev regenerert ved hjelp av NH40H opplosning; utbytte 32 g (94 %); sm.p. 188 - 189°C. ;E. 3- formylamino- 1, 2, 3, 4- tetrahydrocarbazol. En opplosning av ;30,O g (0,161 mol) 3-amino-l,2,3,4-tetrahydrocarbazol i 200 ml formamid blev oppvarmet på dampbad 4 timer. Ved avkjbling utkrystalliserte forbindelsen; utbytte 24,5 g (66 %), sm.p. 154 - 155°C. ;Analyse: beregnet for C13H14<N>2<0:> N 13>07;funnet: N 12,92 ;F. 3- methylamino- l, 2, 3, 4- tetrahydrocarbazolmaleat. En opplosning ;av 24,5 g (0,115 mol) 3-formylamino-1,2,3,4-tetrahydrocarbazol i 500 ml tetrahydrofuran blev tilsatt til en omrort suspensjon av 22 g LiAlH4 i 700 ml tetrahydrofuran. Reaksjonsblandingen blev omrort under tilbakeldp over natten. Overskudd av hydridet blev dekompo-nert ved langsom tilsetning av en blanding av tetrahydrofuran og vann (9:1), efterfulgt av en tilsetning av fortynnet natriumhydrox-ydopplosning (25 ml). De inorganiske salter blev frafiltrert, og filtratet konsentrert under vakuum. Residuet blev opplost i 2-pro- ;panol, opplosningen blev klargjort og behandlet med 15 g maleinsyre i 2-propanol. Ved avkjbling krystalliserte forbindelsen ut; utbytte 27,5 g (77 %); sm.p. 167 - 168°C. ;Analyse: beregnet for c17H2oN2°4: ;N(basisk) 4,43; nbytral ekvivalent 158 funnet: N(basisk) 4,37; nbytral ekvivalent 156 ;(se eksempel 1). ;Eksempel 3 ;3- ethylamino- 1., 2, 3, 4- tet r ahydr ocarbazol ;A. 3- ethylamino- l, 2, 3, 4- tetrahydrocarbazol. En opplosning av ;6,29 g (0,027 mol) ;3-acetamido-l,2,3,4-tetrahydrocarbazol i 50 ml tetrahydrofuran blev tilsatt en omrort suspensjon av LiAlH4 (5,12 g, 0,135 mol) i lOO ml tetrahydrofuran. Blandingen blev omrort under tilbakelbp 24 timer; overskudd av LiAlH^ blev bdelagt på vanlig måte, og inorganiske salter blev frafiltrert, og filtratet konsentrert under vakuum. Residuet blev opplost i 1500 ml torr ether, behandlet med "Nuchar", filtrert og konsentrert ved innkokning til en fjerdedel av det opp-rinnelige volum. Ved avkjbling blev erholdt 2 g av den rene frie base som smeltet ved 125 - 126°C. ;Analyse: beregnet for <C>14<H>18<N>2<:> C 78,46; H 8,47; N 13,09 ;funnet: C 77,50; H 8,57; N 12,96 ;rur -i i ;I.R.D j^£s cm 3470 ( m in<3ol), intet amid C = 0 ;absorpsjon ved 1670 cm-1. ;B. 3- ethylamino- l, 2, 3, 4- tetrahydrocarbazolmaleat. Maleinsyresal-tet blev fremstillet i aceton og bunnfeldt med ether. Efter gjentatte omkrystalliseringer fra en blanding av aceton og ether blev erholdt 2,8 g av saltet; sm.p. 179 - 180°C. ;Analyse: beregnet for C18H22<N>2°4: N(basisk) 4,25; N(totalt) 8,49 ;funnet: N(basisk) 4,36; N(totalt) 8,45 ;o ;Eksempel 4 ;3- dimethylamino- 1, 2, 3, 4- tetrahydrocarbazol ;A. 4-( N- formyl- N- methyl) aminocyclohexanol. Forbindelsen blev ;fremstillet fra 120 g (0,93 mol) 4-methylaminocyclohexanol og 5O0 ml formamid. Blandingen blev oppvarmet til 90°C i tre timer. Overskudd av formamid blev fjernet under redusert trykk (vannpumpe) på dampbad. Residuet blev destillert under vakuum og ga 127,^1 g (86,7 %) av N-formyl-derivatet. ;Analyse: beregnet for CgH^NO^ C 61,12; H 9,62; N 8,90 ;funnet: C 61,07; H 10,02; N 8,80 ;T _ , CHC1_ 3300-3550 cm"1 , -1 ;I.R. V , 3 OH (bundet); 3620 cm ;maks .. \ / » ;OH (fri); 1660 cm amid (C = 0). ;B. 4-( N- formyl- N- methyl) aminocyclohexanon. Til en kold omrort ;opplosning (10°C) Na2Cr20? • 2H20 (375,5 g, 1,3 mol) og H2S04 (123,4 g, 1,3 mol) i 630 ml vann blev tilsatt dråpevis til en vandig opplosning av 4-(N-formyl-N-methyl)aminocyclohexanol (98,9 g, 0,65 mol) i' lbpet av 1 time. Opplosningen blev ekstrahert med CHCl^ inntil ekstraktet blev farveldst. CHC1„ ekstraktet blev tdrket, filtrert og konsentrert under vakuum. Residuet blev destillert under redusert trykk og ga 52,6 g, kp. 128 - 134°C/0,2 mm. Der blev ytterligere erholdt 13,1 g, kp. 128 - 134°C/0,2 mm ved å underkaste den vandige fase en kontinuerlig ekstraksjon med ethylacetat i 18 timer. Totalutbytte 65,7 g (65 %). ;I.R. V 1675 cm-1 amid (C =0); 1725 cm"1 keton ;— maks v ' ;(C=0). ;C. 3-( N- formyl- N- methyl) amino- 1, 2, 3, 4- tetrahydrocarbazol. ;En opplosning bestående av 4-(N-formyl-N-methyl)aminocyclohexanon (23,6 g, 0,15 mol) fenylhydrazin (18,4 g, 0,17 mol) og 200 ml iseddik blev oppvarmet til lO0<o>C i 3 timer. Opplbsningsmid-let blev fjernet under vakuum. Residuet blev opplost i en minimal mengde CHCl^ og helt på en "Florisil" kolonne. Tetrahydrocarbazolet blev erholdt ved eluering med ether som de fdrste 1500 ml opplds- ;o ningsmiddel. Utbytte 31,5 g. ;CHC1 — 1 -1;I . R . T) maks3 3475 cm N-H (fri); 3300 cm N-H (bundet); ;1600 cm<-1> amid (C = O) . ;D. 3- dimethylamino- l, 2, 3, 4- tetrahydrocarbazolhydroklorid. ;En opplosning av forbindelsen som beskrevet ovenfor ;(13,5 g, 0,06 mol) i 50 ml tetrahydrofuran blev tilsatt dråpevis til en omrort suspensjon av LiAlH^ (11,2 g, 0,3 mol) i 100 ml tetrahydrofuran. Blandingen blev omrort under tilbakelop i 18 timer. LiAlH^ blev odelagt på vanliq måte. De inorganiske salter blev frafiltpert, og filtratet konsentrert under vakuum. Aminet blev separert fra residuet ved opplosning i aceton og behandling med overskudd av cyclohexansulfaminsyre. Det erholdte salt blev oppsamlet ved filtrering, opplost i kokende vann og oppiosningen gjort alkalisk med K^CO^- Den frie base som krystalliserte ut ved hen-stand over natten i et kjoleskap blev oppsamlet og omdannet til hydrokloridet ved tilsetning av en blanding av saltsyre og isopropylalkohol. Ved avkjoling faldt hydrokloridet ut, og efter omkrystallisering fra isopropylalkohol blev 2,8 g av forbindelsen erholdt; sm.p. 259 - 259,5°C. ;Analyse: beregnet for C..H C1N : N(basisk) 5,58; N(totalt) ;(Kjeldahl) 11,16 ;funnet: N(basisk) 5,70; N(totalt 10,91. ;Eksempel 5 ;3- methylamino- 9- methyj- l, 2, 3, 4- tetrahydrocarbazol ;A. 4- formamidofenol. En opplosning av p-aminofenol (IO,9 g, 0,1 mol) i 25 ml 97 %-ig maursyre blev kokt under tilbakelop i 1 time. Maursyren blev fjernet under vakuum, og 100 ml vann tilsatt. Ved avkjoling faldt forbindelsen ut som et hvitt pulver. Utbytte 10,7 g, sm.p. 138 - 139°C. ;B. 4- formamidocyclohexanol. 210 g 4-formamidofenol blev hydrogenert i en autoklav under anvendelse av methanol som oppldsningsmiddel og RuO„ som katalysator (105 kg/ cm 2 , 150°C). Hydrogeneringen krevet 2 ' dager for opptak av 3 molekvivalent. Katalysatoren blev fjernet ved filtrering,, og methanol-en avdestillert under vakuum. Destillasjon av den gjenværende olje gjennom en kort Vigreaux kolonne ga 137 g av forbindelsen, k.p. 170-175°C/1,0 mm. ;C. 4- formamidocyclohexanon. Til en kold omrort opplosning av ;Na2Cr2Oy • 2H20 (238,4 g, 0,8 mol) og H2S04 (78,4 g, 0,8 mol) i 200 ml vann blev tilsatt dråpevis en vandig opplosning av 4-formamidocyclohexanol (57,2 g, 0,4 mol). Opplosningen blev omrort koldt i 1,5 timer og derefter ekstrahert kontinuerlig med CHC13 i 2 dager. CHCl^ ekstraktet blev torket over K2C03, filtrert og konsentrert under vakuum. Residuet blev destillert under redusert trykk og ga 24,9 g av forbindelsen, k.p. 145 - 170°C/0,2 mm. ;I.R. 1/ mak, s3 cm <-1> 3445 amid NH; 3325 amid NH; 1720 ;C = 0 (keton); 1670 C = 0 (amid). ;( ;D. 3- formamido- 9- methyl- l, 2, 3, 4- tetrahydrocarbazol. En blanding av 4-formamidocyclohexanon (10,7 g, 0,07 mol), 1-methyl-l-fenylhydrazin (9,3 g, 0,076 mol), p-toluensulfonsyre (katalytisk mengde) og 200 ml torr benzen blev oppvarmet under tilbakelop i 10 timer. Det dannede vann blev oppsamlet i en Dean-Starke felle. Opplosningen blev fjernet under vakuum og ga 17 g av en mdrk viskos olje. I. R. V ^ks3 cm 1685 c = 0 (amid); fullstendig fjernelse av C = 0 (keton) ved 1710; 1600 og 1500 (sterkt aromatisk absorpsjon); 3445 NH (amid); 3310 (N-H). ;En IO g's prove av hydrazonet blev oppvarmet 5 timer i eddiksyre. Opplosningsmidlet blev fjernet under vakuum, og residuet opplost i CHC13, vasket med Na2O03 opplosning, torket over MgS04 og konsentrert under vakuum. Residuet blev opplost i benzen og helt på en Florisil kolonne, og tetrahydrocarbazolet blev eluert med ethylacetat; utbytte 9,4 g. Forbindelsen blev omkrystallisert fra en blanding av aceton og pentan; sm.p. 219 - 220aC. ;Analyse: beregnet for C14<H>15<N>2<0:> N 12>32 ;funnet: N 12,40 ;E. 3- methylamino- 9- methyl- l, 2, 3, 4- tetrahydrocarbazolmaleat. ;En opplosning av 3-formamido-9-methyl-l,2,3,4-tetrahydrocarbazol (9,4 g, 0,041 mol) i tetrahydrofuran blev tilsatt til en omrort suspensjon av LiAlH^ (7,96 g, 0,21 mol) i 100 ml tetrahydrofuran. Blandingen blev omrort under tilbakelop over natten. Overskudd av hydridet blev odelagt på vanlig måte, og de inorganiske salter filtrert fra, og filtratet konsentrert under vakuum. Maleatet blev fremstillet i en acetonopplosning og feldt ut ved tilsetning av torr ether. Det erholdte salt blev omkrystallisert fra en blanding av aceton og ether og ga 2,2 g av forbindelsen; sm.p. 193 - 194°C. ;Analyse: beregnet for C^HnoN^ • <C>.<H>.<O>.<:> C 65,39; H 6,71; N 8,48 ;J 3 14 18 2 444 ' 7 77 ;funnet: C 65,36; H 6,86; N 8,44. ;Eksempel 6 ;3-( 2- propyl) amino- 1, 2, 3, 4- tetrahydrocarbazol ;A. 3-( 2- propyl) amino- 1, 2, 3, 4- tetrahydrocarbazol. En 10 g's prove ;av 3-amino-1,2,3,4-tetrahydrocarbazol blev kokt under tilbakelop i 300 ml aceton i 24 timer. Opplosningsmidlet blev fjernet under vakuum. Det infrarode absorpsjonsspektrum viste en absorpsjon ved 1675 cm (C = N). Residuet blev opplost i ethanol og hydrogenert i en Parr ryster (3,5 kg/cm ) under anvendelse av platina som katalysator. Den teoretiske mengde hydrogen blev absorbert i lopet av 3 timer. ;Et infrarddt absorpsjonsspektrum av residuet efter inndampning av ethanoloppldsningen viste fullstendig fjernelse av absorpsjonsbåndet ved 1675 cm"^. Den frie base stdrknet ved omrdring med ether. ;B. 3- ( 2- propyl) amino- 1, 2, 3, 4- tetrahydrocarbazolrnaleat. ;Den frie base blev opplost i aceton og behandlet med et lite overskudd av maleinsyre. Tilsetning av ethylacetat og ether forårsaket bunnfelling av saltet som blev omkrystallisert fra en blanding av isopropylalkohol, ethylacetat og ether og ga 5,6 g av forbindelsen; sm.p. 188 - 189°C. ;Analyse: beregnet for C19H24N2°4: N (Dasisk) 4>07; N (totalt) 8,14 ;funnet: N (basisk) 4,05; N (totalt) 8,29. ;Eksempel 7 ;3- methylamino- 6- methoxy- l, 2, 3, 4- tetrahydrocarbazol ;A. 3- amino- 6- methoxy- l, 2, 3, 4- tetrahydrocarbazol. En opplosning av ;p-methoxyfenyl-hydrazin (19,9 g, 0,14 mol) og 4-acetamidocyclohexanon (22,4 g, 0,14 mol) i 400 ml torr benzen blev oppvarmet under tilbakelop mens frigjort vann blev oppsamlet i en Dean-Starke felle. Benzenen blev avdestillert under vakuum, og residuet opplost i iseddik. Opplosningen blev oppvarmet til 90°C i 3 timer. Iseddiken blev avdestil- ;lert under vakuum, og det gjenværende opplost i 200 ml methanol og 500 ml 50 % KOH opplosning. Blandingen blev omrort under tilbakelop i 5 dager. Opplosningen blev surgjort med konsentrert HC1 og rystet med CHCl^. Vannfasen blev behandlet med et overskudd av K2C03 og derefter ekstrahert med CHC13. Torking og konsentrering ;av ekstraktet under vakuum ga 26 g av et fast stoff fra hvilket en liten analytisk prove blev fremstillet ved omkrystallisering fra benzen; sm.p. 131 - 131,5°C. ;Analyse: beregnet for C13H16<N>2°<:> N (Dasisk) 6,47; N (totalt) 12,95 ;funnet: N (basisk) 6,51; N (totalt) 12,77. ;B. 3- formamido- 6- methoxy- l, 2, 3, 4- tetrahydrocarbazol. ;i ;3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazol (16 g) blev blandet med 100 ml formamid og kokt under tilbakelop 3 timer. Den morke opplosning blev helt på knust is og det organiske materiale ekstrahert med CHC13. Ekstraktet blev torket over MgSO^, filtrert og konsentrert under vakuum. Residuet som var et morkt "glass" ;blev opplost i CHC13, og vasket med en vandig opplosning av oxalsy-re, Na^COg opplosning og vann. CHC13 ekstraktet blev torket, omrort med trekull IO minutter og filtrert. Oppldsningsmidlet blev ;CHC1 — 1 ;fjernet under vakuum; utbytte 1<4> g V cm 3450 (NH) ; ;1675 (C = O) amid. ;C. 3- methylamino- 6- methoxy- l, 2, 3, 4- tetrahydrocarbazolhemisuccinat ;Til en omrort suspensjon av LiAlH^ (11,4 g, 0,3 mol) i tort tetrahydrofuran (200 ml) blev tilsatt dråpevis en opplosning av 3-formamido-6-methoxy-l,2,3,4-tetrahydrocarbazol (14 g, 0,057 mol) i tort tetrahydrofuran (50 ml). Blandingen blev kokt under tilbakelop og omroring 3 dager. Overskudd av LiAlH^ blev odelagt med fortynnet THF (10 %), NaOH (20 %) og H20. De inorganiske salter blev oppsamlet ved filtrering og vasket gjentatte ganger med kokende tetrahydrofuran. Filtratet blev konsentrert til torrhet under vakuum, og residuet utgjorde 12 g. ;"<i*> ^aks3 viste fullstendig fjernelse av absorpsjonsbåndet ved The analgesic effect was examined substantially according to the method described by Biahchi, C. and Franceschini, J. in "Experimental Observations On Haffner<*>'s Method For Testing Analgesic Drugs", Brit. J. Pharmacol., i, 280 (1954). For the compounds, the ED5Q was found to be between 15 and 35 mg/kg of body weight after intraperitoneal administration. ;In a comparison of the analgesic effect of the known analgesic compound Darvon (α-d-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanolpropionate) and a compound according to the present invention, namely 3-methylamino-1 ,2,3,4-tetrahydrocarbazole, both of which were administered orally to a group of mice. the analgesic efficacy was determined as previously described. An ED^ value of approx. 16.2 - 26 mg/kg was found for 3-methylamino-1,2,3,4-tetrahydrocarbazole, and an ED^q of approx. 44 mg/kg was found for Darvon. ;The invention will then be illustrated by the following examples: ;Example 1 ;3-methylamino-1,2,3,4-tetrahydrocarbazole;A. 4- methylaminocyclohexanol. A 230 g sample of p-methylamino-phenol sulfate was dissolved in 800 ml of aqueous methanol (1:3). Hydrogenation was carried out at 100°C and 105 kg/cm using 1.0 g of ruthenium dioxide as catalyst. The hydrogenation was complete in the course of approx. 2 hours. The catalyst was removed by filtration and most of the solvent was distilled off in vacuo. 200 ml of 20% lg sodium hydroxide solution was added to the remaining syrup, and the resulting solution was subjected to continuous extraction with chloroform for one day. The extract was dried and concentrated, and the residue distilled in vacuo, yielding 123 g of product, bp 105 - HO°C (5 mm). The material was poured into anhydrous ether to form white crystals (108 g) with a melting point of 78-79°C. In another study, the melting point was 88-89°C. This change in melting point can be attributed to varying amounts of the cis and trans isomers. ;Analysis calculated for C^-j^NO: N IO.85 ;Found: N IO.59. B. 4-methylaminocyclohexanone To a mixture of 12.9 g (0.10 mol) 4-methylaminocyclohexanol and 33 g of potassium t-butoxide in 300 ml of dry benzene was added a solution of 90 g of benzophenone in 200 nil benzene. The mixture was stirred at room temperature under a nitrogen atmosphere for 3 days. 200 ml of water was then added and the mixture was stirred vigorously for several minutes. The benzene layer was extracted with 4 x 100 ml<1>s portions of 10% hydrochloric acid. The combined aqueous solutions were then counter-extracted with ether. After concentration in vacuum of the aqueous solution to approx. half volume of solid potassium carbonate was added to liberate the free base. The solution was then continuously extracted with chloroform for 1 day. Drying and concentration of the extract at atmospheric pressure followed by vacuum distillation gave 5.09 g of a colorless liquid with a boiling point of 105 - 110°C (15 mm); - tetrahydrocarbazole A solution of 15.4 g (0.121 mol) 4-methylaminocyclohexanone and 13.5 g (0.125 mol) phenylhydrazine in 200 ml benzene containing 0.1 g p-toluenesulfonic acid was heated under reflux for 2 hours , the liberated water being collected in a Dean-Starke apparatus. After concentration of the benzene solution, the phenylhydrazone syrup (24.7 g) was dissolved in 300 ml of acetic acid and the solution was again heated at 90 - 95°C for 3 hours. Vinegar -acid was distilled off in vacuo and the residue stirred with dilute sodium hydroxide solution. Extraction with chloroform, drying and evaporation in vacuo from 20.1 g of a fatty solid with melting point 125 - 129°C. For analysis, a sample was recrystallized from benzene- ether (charcoal treatment) and then had a melting point of 134-135°C; ;V max 3480 (indole-N -H)> 3410 (w-> CH3NH-), peaks at 1630 and 1600 cm"1; A Me? H 226 m. (£. 18,500) and 280 mu- (£ 5,460). ;ro 3 read Analysis calculated for C13H16<N>2<:> C 78.00; H 8.05: N 14.00 ;Found: C 77.48; H 8.18; N 13.96;D. 3-methylamino-1,2,3,4-tetrahydrocarbazole maleate. An 11.3 g sample of 3-methylamino-1,2,3,4-tetrahydrocarbazole (m.p. 125 - 129°C) was dissolved in acetone. The solution was treated with charcoal, and the clarified filtrate treated with 1 molar equivalent of maleic acid in a minimal amount of acetone. About. half a volume of ether was added, and after a few minutes crystallization took place. The product was collected, washed with acetone-ether, pulverized and dried overnight in an Abderhalden gun at 60°C, yielding 13.1 g of material mp 159-160°C; ;X 224 mn (É 25,600) and 279 mu. (£6040). ;Analysis calculated for C13<H>16<N>2<:> (<C>HC02H)2: ;N(basic) 4.43; N(total) 8.86 ;Found: N(basic) 4.33; N(total) 8.79 ; Example 2 ; 3-methylamino-1, 2, 3, 4- tetrahydrocarbazole ; A. 4-acetamidocyclohexanol. 390 g (2.62 mol) of acetyl-p-aminophenol was reduced in a 2 liter autoclave at 100°C, 105 kg/cm ? using methanol as solvent and 2 g of ruthenium dioxide as catalyst. The reduction was complete within 8 hours. The catalysts were removed by filtration, and the filtrate concentrated under vacuum. The residue was stirred with 1 liter of cold acetone, and 348 g (86% yield) of a whitish solid was obtained; sm.p. 135 - 137°C. ;Analysis: calculated for C8H15N02: C 61.12; H 9.62; N 8.91; found: C 61.32; H 9.75; N 8.90; B. 4-acetamidocyclohexanone. A solution of 180 g (1.15 mol) 4-acetaraidocyclohexanol in 300 ml water was added to a cold stirred solution of 685 g sodium dicroate in 225 g concentrated sulfuric acid and 1.5 1 water. dt below 10°C during an addition period of 1 hour. The solution was stirred and cooled for a further 2 hours. The reaction mixture was then extracted with chloroform for 2 days in a continuous liquid extractor. The organic phase was dried over MgSO 4 , and then concentrated under vacuum, and 119 g of the compound were obtained (69%); sm.p. 136 - 137°C. In another preparation, an analytical sample had a m.p. at 125 - 128°C. Infrared spectra for the two samples were identical, and there was no melting point depression for a mixture of the two samples. ;Analysis: calculated for C8H13N02: C 61.91; H 8.44; N 9.04; found: C 61.51; H 8.56; N 8.79; C. 3-acetamido-1,2,3,4-tetrahydrocarbazole. A solution of ;51.0 g (p.33 mol) of 4-acetamidocyclohexanone and 36.0 g (0.33 mol) of phenylhydrazine in 650 ;ml of acetic acid was stirred and heated to 80-90°C for 5 hours. The acetic acid was then distilled off under vacuum, and the residue stirred with water, collected and dried. Recrystallization from a mixture of acetone and "Skelly B" gave 78.0 g (64% yield) of the compound, m.p. 180 - 181°C. ;Analysis: calculated for <c>i4<H>i6<N>2°<:> N 12.27 ;found: N 12.34 ;D. 3-amino-1,2,3,4-tetrahydrocarbazole. A solution of ;48.0 g (0.21 mol) of 3-acetamido-1,2,3,4-tetrahydrocarbazole in 500 ml of ethanol and 500 ml of 50% aqueous KOH solution was evaporated and heated under reflux for 3 days. The ethanol was then distilled off under vacuum, and the brown solid formed during the distillation was collected and washed with water. Yield 36 g (92%); mp 176-184°C. The crude product was purified by conversion to cyclohexanesulfame acid salt in acetone, mp 194-196°C (yield 67 g, 95%). The free base was regenerated by NH 4 OH solution, yield 32 g (94%), mp 188 - 189° C. ;E. 3-formylamino-1,2,3,4-tetrahydrocarbazole A solution of ;30.0 g (0.161 mol) of 3-amino-1,2,3,4-tetrahydrocarbazole in 200 ml of formamide was heated on a steam bath for 4 hours. Upon cooling, the compound crystallized; yield 24.5 g (66%), m.p. 154 - 155°C. ;Analysis: calculated for C13H14<N>2<0:> N 13 >07; found: N 12.92 ; F. 3- methylamino- 1, 2, 3, 4- tetrahydrocarbazole maleate. A solution ; of 24.5 g (0.115 mol) of 3-formylamino-1,2,3,4-tetrahydrocarbazole in 500 ml of tetrahydrofuran was added to a stirred suspension of 22 g of LiAlH 4 in 700 ml of tetrahydrofuran. The reaction mixture was stirred under reflux overnight. Excess hydride was decomposed by slow addition of a mixture of tetrahydrofuran and water (9:1), followed by addition of dilute sodium hydroxide solution (25 mL). The inorganic salts were filtered off, and the filtrate concentrated under vacuum. The residue was dissolved in 2-propanol, the solution was prepared and treated with 15 g of maleic acid in 2-propanol. When decoupled, the compound crystallized out; yield 27.5 g (77%); sm.p. 167 - 168°C. ;Analysis: calculated for c17H2oN2°4: ;N(basic) 4.43; nbytral equivalent 158 found: N(basic) 4.37; nbytral equivalent 156 ;(see example 1). ; Example 3 ; 3- ethylamino- 1., 2, 3, 4-tet r ahydr ocarbazole ; A. 3-ethylamino-1,2,3,4-tetrahydrocarbazole. A solution of ;6.29 g (0.027 mol) ;3-acetamido-1,2,3,4-tetrahydrocarbazole in 50 ml of tetrahydrofuran was added to a stirred suspension of LiAlH 4 (5.12 g, 0.135 mol) in 100 ml of tetrahydrofuran . The mixture was stirred under reflux for 24 hours; excess LiAlH^ was removed in the usual manner, and inorganic salts were filtered off, and the filtrate concentrated under vacuum. The residue was dissolved in 1500 ml of dry ether, treated with "Nuchar", filtered and concentrated by boiling to a quarter of the original volume. On cooling, 2 g of the pure free base was obtained which melted at 125 - 126°C. ;Analysis: calculated for <C>14<H>18<N>2<:> C 78.46; H 8.47; N 13.09; found: C 77.50; H 8.57; N 12.96 ;rur -i i ;I.R.D j^£s cm 3470 ( m in<3ol), no amide C = 0 ;absorption at 1670 cm-1. B. 3-ethylamino-1,2,3,4-tetrahydrocarbazole maleate. The maleic acid salt was prepared in acetone and precipitated with ether. After repeated recrystallizations from a mixture of acetone and ether, 2.8 g of the salt were obtained; sm.p. 179 - 180°C. ;Analysis: calculated for C18H22<N>2°4: N(basic) 4.25; N(total) 8.49 ;found: N(basic) 4.36; N(total) 8.45 ;o ;Example 4 ;3-dimethylamino-1,2,3,4-tetrahydrocarbazole ;A. 4-(N-formyl-N-methyl)aminocyclohexanol. The compound was prepared from 120 g (0.93 mol) of 4-methylaminocyclohexanol and 500 ml of formamide. The mixture was heated to 90°C for three hours. Excess formamide was removed under reduced pressure (water pump) on a steam bath. The residue was distilled under vacuum to give 127.7 g (86.7%) of the N-formyl derivative. ;Analysis: calculated for CgH^NO^ C 61.12; H 9.62; N 8.90; found: C 61.07; H 10.02; N 8.80 ;T _ , CHC1_ 3300-3550 cm"1 , -1 ;I.R. V , 3 OH (bound); 3620 cm ;max .. \ / » ;OH (free); 1660 cm amide (C = 0 ).;B. 4-(N-formyl-N-methyl) aminocyclohexanone. To a cold stirred solution (10°C) Na2Cr20?2H20 (375.5 g, 1.3 mol) and H2SO4 (123.4 g , 1.3 mol) in 630 mL of water was added dropwise to an aqueous solution of 4-(N-formyl-N-methyl)aminocyclohexanol (98.9 g, 0.65 mol) over 1 hour. The solution was extracted with CHCl^ until the extract became pale. The CHCl„ extract was dried, filtered and concentrated under vacuum. The residue was distilled under reduced pressure to give 52.6 g, bp 128-134°C/0.2 mm. There was further obtained 13.1 g, mp 128 - 134°C/0.2 mm by subjecting the aqueous phase to a continuous extraction with ethyl acetate for 18 hours.Total yield 65.7 g (65%). ;IR V 1675 cm-1 amide (C =0); 1725 cm"1 ketone ;— max v ' ;(C=0). C. 3-(N-formyl-N-methyl)amino-1,2,3,4-tetrahydrocarbazole. ;A solution consisting of 4-(N-formyl-N-methyl)aminocyclohexanone (23.6 g, 0.15 mol) phenylhydrazine (18.4 g, 0.17 mol) and 200 ml of glacial acetic acid was heated to lO0<o >C for 3 hours. The solvent was removed under vacuum. The residue was dissolved in a minimal amount of CHCl^ and poured onto a "Florisil" column. The tetrahydrocarbazole was obtained by elution with ether which contained 1500 ml of solvent. Yield 31.5 g. ;CHC1 — 1 -1;I . R . T) max3 3475 cm N-H (free); 3300 cm N-H (bound); ;1600 cm<-1> amide (C = O) . D. 3-dimethylamino-1,2,3,4-tetrahydrocarbazole hydrochloride. A solution of the compound as described above (13.5 g, 0.06 mol) in 50 ml of tetrahydrofuran was added dropwise to a stirred suspension of LiAlH 2 (11.2 g, 0.3 mol) in 100 ml of tetrahydrofuran. The mixture was stirred under reflux for 18 hours. LiAlH^ was decomposed in the usual way. The inorganic salts were filtered off, and the filtrate concentrated under vacuum. The amine was separated from the residue by dissolution in acetone and treatment with an excess of cyclohexanesulfamic acid. The resulting salt was collected by filtration, dissolved in boiling water and the solution made alkaline with K^CO^- The free base which crystallized on standing overnight in a refrigerator was collected and converted to the hydrochloride by adding a mixture of hydrochloric acid and isopropyl alcohol. On cooling, the hydrochloride precipitated, and after recrystallization from isopropyl alcohol, 2.8 g of the compound were obtained; sm.p. 259 - 259.5°C. ;Analysis: calculated for C..H C1N : N(basic) 5.58; N(total) ;(Kjeldahl) 11.16 ;found: N(basic) 5.70; N (total 10.91. ; Example 5 ; 3- methylamino- 9- methylj- l, 2, 3, 4- tetrahydrocarbazole ; A. 4- formamidophenol. A solution of p-aminophenol (10.9 g, 0.1 mol) in 25 ml of 97% formic acid was refluxed for 1 hour. The formic acid was removed under vacuum, and 100 ml of water was added. On cooling, the compound precipitated as a white powder. Yield 10.7 g, m.p. 138 - 139°C. ;B. 4-formamidocyclohexanol. 210 g of 4-formamidophenol was hydrogenated in an autoclave using methanol as solvent and RuO„ as catalyst (105 kg/cm 2 , 150°C). The hydrogenation required 2 ' days for uptake of 3 mole equivalents. The catalyst was removed by filtration, and the methanol distilled off under vacuum. Distillation of the remaining oil through a short Vigreaux column gave 137 g of the compound, b.p. 170-175°C/1.0 mm. ;C. 4-formamidocyclohexanone To a cold stirred solution of ;Na2Cr2Oy 2H20 (238.4 g, 0.8 mol) and H2SO4 (78.4 g, 0.8 mol) in 200 ml of water was added dropwise an aqueous solution sition of 4-formamidocyclohexanol (57.2 g, 0.4 mol). The solution was stirred cold for 1.5 hours and then extracted continuously with CHCl 3 for 2 days. The CHCl 3 extract was dried over K 2 CO 3 , filtered and concentrated under vacuum. The residue was distilled under reduced pressure to give 24.9 g of the compound, b.p. 145 - 170°C/0.2 mm. I.R. 1/ mak, s3 cm <-1> 3445 amide NH; 3325 amide NH; 1720 ;C = 0 (ketone); 1670 C = 0 (amide). ;( ;D. 3- formamido- 9- methyl- 1, 2, 3, 4- tetrahydrocarbazole. A mixture of 4-formamidocyclohexanone (10.7 g, 0.07 mol), 1-methyl-l-phenylhydrazine (9 .3 g, 0.076 mol), p-toluenesulfonic acid (catalytic amount) and 200 mL of dry benzene were heated under reflux for 10 h. The water formed was collected in a Dean-Starke trap. The solution was removed under vacuum to give 17 g of one mdrk of viscous oil. I. R. V ^ks3 cm 1685 c = 0 (amide); complete removal of C = 0 (ketone) at 1710; 1600 and 1500 (strong aromatic absorption); 3445 NH (amide); 3310 (N-H). ;A 10 g sample of the hydrazone was heated for 5 hours in acetic acid. The solvent was removed under vacuum, and the residue dissolved in CHCl3, washed with Na2O03 solution, dried over MgSO4 and concentrated under vacuum. The residue was dissolved in benzene and poured onto a Florisil column , and the tetrahydrocarbazole was eluted with ethyl acetate; yield 9.4 g. The compound was recrystallized from a mixture of acetone and pentane; mp 219 - 220aC. ;A analysis: calculated for C14<H>15<N>2<0:> N 12>32 ;found: N 12.40 ;E. 3- methylamino- 9- methyl- 1, 2, 3, 4- tetrahydrocarbazole maleate. A solution of 3-formamido-9-methyl-1,2,3,4-tetrahydrocarbazole (9.4 g, 0.041 mol) in tetrahydrofuran was added to a stirred suspension of LiAlH^ (7.96 g, 0.21 mol) in 100 ml of tetrahydrofuran. The mixture was stirred under reflux overnight. Excess of the hydride was decomposed in the usual way, and the inorganic salts filtered off, and the filtrate concentrated under vacuum. The maleate was prepared in an acetone solution and precipitated by the addition of dry ether. The salt obtained was recrystallized from a mixture of acetone and ether to give 2.2 g of the compound; sm.p. 193 - 194°C. ;Analysis: calculated for C^HnoN^ <C>. <H>. <O>. <:> C 65.39; H 6.71; N 8.48 ;J 3 14 18 2 444 ' 7 77 ;found: C 65.36; H 6.86; N 8.44. ;Example 6 ;3-(2-propyl)amino-1,2,3,4-tetrahydrocarbazole ;A. 3-(2-propyl)amino-1,2,3,4-tetrahydrocarbazole. A 10 g sample of 3-amino-1,2,3,4-tetrahydrocarbazole was refluxed in 300 ml of acetone for 24 hours. The solvent was removed under vacuum. The infrared absorption spectrum showed an absorption at 1675 cm (C = N). The residue was dissolved in ethanol and hydrogenated in a Parr shaker (3.5 kg/cm 2 ) using platinum as catalyst. The theoretical amount of hydrogen was absorbed in the course of 3 hours. ;An infrared absorption spectrum of the residue after evaporation of the ethanol solution showed complete removal of the absorption band at 1675 cm"^. The free base was dried by stirring with ether. ;B. 3- ( 2- propyl) amino- 1, 2, 3, 4- tetrahydrocarbazole rnaleate. ;The free base was dissolved in acetone and treated with a small excess of maleic acid. Addition of ethyl acetate and ether caused precipitation of the salt which was recrystallized from a mixture of isopropyl alcohol, ethyl acetate and ether to give 5.6 g of the compound; sm .p. 188 - 189°C. ;Analysis: calculated for C19H24N2°4: N (Dasic) 4>07; N (total) 8.14 ;found: N (basic) 4.05; N (total) 8, 29. ;Example 7 ;3- methylamino- 6- methoxy- 1, 2, 3, 4- tetrahydrocarbazole ; A. 3- amino- 6- methoxy- 1, 2, 3, 4- tetrahydrocarbazole. A solution of ; p- methoxyphenylhydrazine (19.9 g, 0.14 mol) and 4-acetamidocyclohexanone (22.4 g, 0.14 mol) in 400 mL of dry benzene were heated under reflux while liberated water was collected in a Dean-Stark a trap. The benzene was distilled off under vacuum, and the residue dissolved in glacial acetic acid. The solution was heated to 90°C for 3 hours. The glacial acetic acid was distilled off under vacuum, and the remainder dissolved in 200 ml methanol and 500 ml 50% KOH solution. The mixture was stirred under reflux for 5 days. The solution was acidified with concentrated HCl and shaken with CHCl 2 . The aqueous phase was treated with an excess of K 2 CO 3 and then extracted with CHCl 3 . Drying and concentration of the extract under vacuum gave 26 g of a solid from which a small analytical sample was prepared by recrystallization from benzene; sm.p. 131 - 131.5°C. ;Analysis: calculated for C13H16<N>2°<:> N (Dasic) 6.47; N (total) 12.95 ; found: N (basic) 6.51; N (total) 12.77. B. 3-formamido-6-methoxy-1,2,3,4-tetrahydrocarbazole. 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole (16 g) was mixed with 100 ml of formamide and refluxed for 3 hours. The dark solution was poured onto crushed ice and the organic material extracted with CHCl 3 . The extract was dried over MgSO 4 , filtered and concentrated under vacuum. The residue, which was a dark "glass", was dissolved in CHCl3, and washed with an aqueous solution of oxalic acid, Na^COg solution and water. The CHC13 extract was dried, stirred with charcoal for 10 minutes and filtered. The solvent was ;CHC1 — 1 ;removed under vacuum; yield 1<4> g V cm 3450 (NH) ; ;1675 (C = O) amide. C. 3- methylamino- 6- methoxy- 1, 2, 3, 4- tetrahydrocarbazole hemisuccinate; To a stirred suspension of LiAlH^ (11.4 g, 0.3 mol) in dry tetrahydrofuran (200 ml) was added dropwise a solution of 3 -formamido-6-methoxy-1,2,3,4-tetrahydrocarbazole (14 g, 0.057 mol) in dry tetrahydrofuran (50 mL). The mixture was boiled under reflux and stirring for 3 days. Excess LiAlH 2 was decomposed with dilute THF (10%), NaOH (20%) and H 2 O. The inorganic salts were collected by filtration and washed repeatedly with boiling tetrahydrofuran. The filtrate was concentrated to dryness under vacuum, and the residue was 12 g. ;"<i*> ^aks3 showed complete removal of the absorption band at

1675 cm<-1> (amid). Det urene amin blev omdannet til hemisuccinatet i ethanol og blev bunnfeldt ved tilsetning av ethylacetat. Efter gjentatte omkrystalliseringer fra vann blev 0,7 g av det rene salt erholdt; sm.p. 231 - 232°C. 1675 cm<-1> (amide). The impure amine was converted to the hemisuccinate in ethanol and was precipitated by the addition of ethyl acetate. After repeated recrystallizations from water, 0.7 g of the pure salt was obtained; sm.p. 231 - 232°C.

Analyse: beregnet for C-^H^N^O - 1/2 (CH2COpH)2: N(basisk) 4,84 Analysis: calculated for C-^H^N^O - 1/2 (CH2COpH)2: N(basic) 4.84

funnet N(basisk) 4,79 found N(basic) 4.79

Claims

Process for the preparation of therapeutically active <3->(substituted amino)-1,2,3,4-tetrahydrocarbazoles of the formula

where R is lower alkyl R 1 is hydrogen or lower alkyl, R 2 is hydrogen or lower alkyl, and R 2 is hydrogen, hydroxyl or lower alkoxy, or an acid ad- sion salt thereof, characterized in that a compound of the formula: where R2 and R_ are as indicated above, react with a compound of the formula: where R and R^ are as above, to form a substituted phenylhydrazone of the formula: where R, R^, R2 and R3 are as indicated above, and that the obtained substituted phenylhydrazone is ring-closed to form the desired tetrahydr<p>carbazole derivative, which is optionally converted to an acid addition salt thereof in and of itself known way.