NO158742B

NO158742B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BETA CARBON LINER DERIVATIVES.

Info

Publication number: NO158742B
Application number: NO814260A
Authority: NO
Inventors: Claus Thyco Braestrup; Joergen Anders Christensen; Mogens Engelstoft
Original assignee: Schering Ag
Priority date: 1981-02-27
Filing date: 1981-12-14
Publication date: 1988-07-18
Also published as: FI73427B; ES8308876A1; ES516976A0; SE447573B; SE8107494L; NO814260L; FI814044L; FI73427C; NO158742C

Description

Oppfinnelsen vedrører en analogifremgangsmåte til The invention relates to an analogous method to

å fremstille terapeutisk aktive 6-karbolinderivater med den generelle formel I to prepare therapeutically active 6-carboline derivatives of the general formula I

hvori in which

Y betegner 0, NOR"'', hvori R^" betegner hydrogen, laverealkyl, Y denotes 0, NOR"'', in which R^" denotes hydrogen, lower alkyl,

fenyl, CHCOOR 3 , hvori R 3 betegner hydrogen eller laverealkyl; phenyl, CHCOOR 3 , wherein R 3 denotes hydrogen or lower alkyl;

4 5 4 5

hvori R og R hver betyr hydrogen, wherein R and R are each hydrogen,

laverealkyl, fenyl, eller hvori R og R sammen med det naboplasserte nitrogenatom danner en del av en 5- eller 6-leddet heterocyklisk ring, bestående av triazolyl, piperidinyl, morfolinyl, N-metylpiperazinyl eller pyrrolidinyl, lower alkyl, phenyl, or in which R and R together with the neighboring nitrogen atom form part of a 5- or 6-membered heterocyclic ring, consisting of triazolyl, piperidinyl, morpholinyl, N-methylpiperazinyl or pyrrolidinyl,

Z betyr hydrogen, en laverealkylgruppe, en gruppe med formel Z means hydrogen, a lower alkyl group, a group of formula

og hvori Y og Z sammen med det naboplasserte C- and wherein Y and Z together with the neighboring C-

atom kan utgjøre en del av en 5- eller 6-leddet heterocyklisk ring, bestående av pyrazolonyl, triazolyl, tetrazolyl, isoksazolyl, fenyltiazolyl, oksazolyl, oksadiazinyl eller oksadia- atom may form part of a 5- or 6-membered heterocyclic ring, consisting of pyrazolonyl, triazolyl, tetrazolyl, isoxazolyl, phenylthiazolyl, oxazolyl, oxadiazinyl or oxadia-

zolyl, som eventuelt er substituert med en laverealkylgruppe, zolyl, which is optionally substituted with a lower alkyl group,

en cykloalkyl eller fenylgruppe, allyl eller laverealkoksy- a cycloalkyl or phenyl group, allyl or lower alkoxy-

alkyl, alkyl,

R betegner hydrogen, et halogenatom, N0„, CN, SCH,, lavere- R denotes hydrogen, a halogen atom, N0„, CN, SCH,, lower-

16 1V 16 17 16 1V 16 17

alkoksyalkyl, NR R , hvori R og R hver betyr hydrogen alkoxyalkyl, NR R , wherein R and R each represent hydrogen

16 17 16 17

eller laverealkyl, allyl, propargyl eller hvori R og R or lower alkyl, allyl, propargyl or wherein R and R

.sammen kan danne en piperidinring, hvilken ring eventuelt er substituert med en laverealkylgruppe med opptil 3 karbon- .together can form a piperidine ring, which ring is optionally substituted with a lower alkyl group with up to 3 carbon

at ome r , that ome r ,

29 29 29 29

en OR , idet R betyr laverealkyl eller benzyl, an OR , where R means lower alkyl or benzyl,

23 24 23 24 23 24 23 24

SO,NR R , hvori R og R hver betyr laverealkyl, SO,NR R , wherein R and R are each lower alkyl,

en gruppe a group

hvori R"^ og R"^ hver betyr lavere- wherein R"^ and R"^ each mean lower-

alkyl, med opptil 3 karbonatomer, eller CsC-O-tetrahydropyra-nyl, idet hvert molekyl kan inneholde to eller flere iden-: alkyl, with up to 3 carbon atoms, or CsC-O-tetrahydropyranyl, each molecule may contain two or more iden-:

frFr

tiske eler ulike R -grupper, og tical or different R -groups, and

R C betyr hydrogen, en laverealkylgruppe, eller laverealkoksyalkyl. R C means hydrogen, a lower alkyl group, or lower alkoxy alkyl.

Fra canadisk patent nr. 786351 er det kjent B-karbolin-3-kar-boksylsyreamidderivater som er substituerende i 1-stilling med en alkylgruppe som ikke inneholder mer enn 5 karbonatomer, en trifluormetyl-, fenyl- eller benzylgruppe såvel som to forbindelser som ikke har noen substituent i 1-stilling, nemlig B-karbonlin-3-karbohydrazid og B-karbolin-3-karboksylsyreamid. From Canadian patent no. 786351, B-carboline-3-carboxylic acid amide derivatives are known which are substituted in the 1-position with an alkyl group containing no more than 5 carbon atoms, a trifluoromethyl, phenyl or benzyl group as well as two compounds which do not has some substituent in the 1-position, namely B-carboline-3-carbohydrazide and B-carboline-3-carboxylic acid amide.

Dansk patent nr. 98436 vedrører en fremgangsmåte til fremstilling av metyl-B-karbolin-3-karboksylat. Danish patent no. 98436 relates to a method for the production of methyl-B-carboline-3-carboxylate.

Fra dansk patentsøknad nr. 3703/80 er det kjent B-karbolin-3-karboksylsyrederivater i form av estere, amider og amidiner, samt tioanaloger herav. From Danish patent application no. 3703/80, B-carboline-3-carboxylic acid derivatives are known in the form of esters, amides and amidines, as well as thio analogues thereof.

Forbindelsene med formel I fremstilles ved analo-gifremgangsmåter som erkarakterisert vedat The compounds of formula I are prepared by analogous methods which are characterized by

a) en forbindelse med formel II a) a compound of formula II

A C A C

hvori R og R har den ovenfor angitte betydning, oksyderes, eller at en forbindelse med formel III in which R and R have the meaning stated above, is oxidized, or that a compound of formula III

34 35 36 hvori R betyr OH eller laverealkoksy eller NR R , hvori R<5>og r hver betyr laverealkyl eller aryl, og hvori RA og R Char den ovenfor angitte beytdning, reduseres til å danne det tilsvarende aldehyd med formel IV hvori R A og R C har den ovenfor angite betydning, og at den således dannede forbindelse omsettes med 1) en forbindelse med formel H2N0r\hvori R^" har den ovenfor angitte betydning for å danne en forbindelse med formel 34 35 36 in which R means OH or lower alkoxy or NR R , in which R<5> and r each means lower alkyl or aryl, and in which RA and R Char the above-mentioned meaning, is reduced to form the corresponding aldehyde of formula IV in which R A and R C has the meaning stated above, and that the compound thus formed is reacted with 1) a compound of formula H2N0r\in which R^" has the meaning stated above to form a compound of formula

1 AC 1 AC

I, hvori Y betyr NOR , Z betyr hydrogen og R og R har den tidligere angitte betydning, I, in which Y means NOR , Z means hydrogen and R and R have the previously indicated meaning,

2) en forbindelse med formel 2) a compound with formula

4 5 hvori R og R 4 5 in which R and R

har den tidligere angitte betydning, has the previously stated meaning,

under dannelse av en forbindelse med formel I, hvori Y betyr to form a compound of formula I, wherein Y means

A C A C

Z betyr hydrogen og R og R har den tidligere Z means hydrogen and R and R has it earlier

angitte betydning, eller stated meaning, or

3) malonsyre eller en malonsyreester for å danne en forbindelse med formel I, hvori Y betyr CHCOOR 3 , hvori R 3 har den tidligere angitte betydning, Z betyr hydrogen og R A ogR<C>har den tidligere angitte betydning, eller 3) malonic acid or a malonic acid ester to form a compound of formula I, wherein Y is CHCOOR 3 , wherein R 3 is as previously stated, Z is hydrogen and R A and R<C> are as previously stated, or

34 34

b) en forbindelse med formel III, hvori R betyr en lavere alkoksygruppe eller NR^<R>^,hvori R^ og R"^ har tidligere b) a compound of formula III, in which R means a lower alkoxy group or NR^<R>^, in which R^ and R"^ have previously

angitte betydning, omsettes med en forbindelse med formel Z Mg Hal, hvori Z har den tidligere angitte betydning og Hal betyr et halogenatom for oppnåelse av en forbindelse med formel I, indicated meaning, is reacted with a compound of formula Z Mg Hal, in which Z has the previously indicated meaning and Hal means a halogen atom to obtain a compound of formula I,

A C A C

hvori Y betegner 0, og R og R har tidligere angitte betydning, og at den således fremstilte forbindelse eventuelt omsettes med H9N0R"'", hvori R^" har den tidligere angitte in which Y denotes 0, and R and R have the previously indicated meaning, and that the compound thus prepared is optionally reacted with H9N0R"'", in which R^" has the previously indicated

betydning, eller med en forbindelse med formel meaning, or with a compound of formula

hvori R og R har den tidligere angitte betydning under dannelse av en forbindelse med formel I, hvori Y betyr NOR"*" wherein R and R have the previously indicated meaning while forming a compound of formula I, wherein Y means NOR"*"

4 A C 4A C

eller R , hvori R og R har den tidligere angitte or R , wherein R and R have the previously indicated

NN NN

R<5>R<5>

betydning, eller meaning, or

c) en forbindelse med formel V c) a compound of formula V

A C A C

hvori R og R har den tidligere angitte betydning, omsettes med en forbindelse som har formel R 3 7 C(0R 3 8)-N(CH,)9, hvori in which R and R have the previously indicated meaning, is reacted with a compound having the formula R 3 7 C(OR 3 8)-N(CH,)9, in which

3 7 3 8 3 7 3 8

R betyr hydrogen eller laverealkyl, og R betegner laverealkyl, under dannelse av en forbindelse med formel I, hvori Y betyr 0 og Z betyr N=CR 37N(CH3)2 og at den således frem-' ; stilte forbindelse eventuelt omsettes med guanidin, en for-i R means hydrogen or lower alkyl, and R means lower alkyl, forming a compound of formula I, in which Y means 0 and Z means N=CR 37N(CH3)2 and that it thus produces stilted compound is optionally reacted with guanidine, a for-i

39 39 39 39

bindelse med formel H2N0R , hvori R betyr hydrogen eller laverealkyl, eller med en forbindelse med formel H9NNHR<40>, bond with the formula H2N0R, where R means hydrogen or lower alkyl, or with a compound of the formula H9NNHR<40>,

40 40

hvori R betyr hydrogen eller laverealkyl, for å danne en forbindelse med formel I, hvori Y og Z sammen med det wherein R is hydrogen or lower alkyl, to form a compound of formula I, wherein Y and Z together with it

naboplasserte C-atom utgjør en del av en 5-leddet hetero-A C neighboring C atoms form part of a 5-membered hetero-AC

cyklisk ring, og R og R har den tidligere angitte betydning eller cyclic ring, and R and R have the previously indicated meaning or

d) at et g-karbonlin-3-karbonitril med formel VIII d) that a g-carbonyl-3-carbonitrile of formula VIII

hvori R A og R C har den ovenfor angitte betydning, omsettes in which R A and R C have the meaning stated above, are traded

med NH^for å danne en forbindelse med formel I, hvori Y og Z sammen med det naboplasserte C-atom utgjør en del av en tetrazolring, eller with NH^ to form a compound of formula I, in which Y and Z together with the neighboring C atom form part of a tetrazole ring, or

e)3-karbolin-3-karboksylsyrederivat med formel VI e) 3-carboline-3-carboxylic acid derivative of formula VI

A C A C

hvroi R og R har ovennevnte betydning, omsettes med et amidoksym, tidligere fremstilt fra hydrosylamin og karboni-tril, ved dannelse av en forbindelse med formel I, hvori Y og Z betyr et oksadiazol-5-yl-ringsystem, eller where R and R have the above meaning, is reacted with an amidoxime, previously prepared from hydrosylamine and carbonitrile, by forming a compound of formula I, in which Y and Z represent an oxadiazol-5-yl ring system, or

f) et S-karbolin-3-karbonitril med formel VIII f) an S-carboline-3-carbonitrile of formula VIII

A C A C

hvori R og R har ovennevnte betydning, omsettes med hydroksylamin med dannelse av et 6-karbolin-3-karboksylsyre amidoksyd som deretter behandles med det reaktive syreanhydrid med dannelse av en forbindelse med formel I, hvori Y og Z betyr et oksadiazol-3-ringsystem, in which R and R have the above meaning, is reacted with hydroxylamine to form a 6-carboline-3-carboxylic acid amide oxide which is then treated with the reactive acid anhydride to form a compound of formula I, in which Y and Z represent an oxadiazole-3 ring system ,

idet det i A-ringen kan innføres en nitrogruppe og hydro-genering av denne til en aminogruppe eller innføring av en dialkoksyfosforylgruppe. in that a nitro group can be introduced into the A ring and hydrogenation of this to an amino group or the introduction of a dialkoxyphosphoryl group.

En foretrukket metode til fremstilling av utgangs-materialene består i at et substituert eller usubstituert tryptofan eller tryptofanester kondenseres med formaldehyd ved hevet temperatur til frembringelse av tetrahydro-3-karbolin-3-karboksylsyreester. Reaksjonen mellom en tryptofanester og formaldehyd utføres fortrinnsvis i et ikke-vandig medium, f.eks. toluen. Det dannede vann fjernes ved fordampning. Tetra-hydro-|3-karbolin-3-karboksylsyreesteren aromatiseres ved koking med svovel i xylen. En annen metode er å omsette formyl-tryptofanesteren med fosforoksyklorid eller polyfosforsyre til frembringelse av en 3,4-dihydro-fJ-karbolin-3-karboksylsyre-ester som imidlertid disproporsjoneres til den tilsvarende tetrahydroforbindelse og den fullt aromatiserte forbindelse. A preferred method for producing the starting materials consists in a substituted or unsubstituted tryptophan or tryptophan ester being condensed with formaldehyde at an elevated temperature to produce tetrahydro-3-carboline-3-carboxylic acid ester. The reaction between a tryptophan ester and formaldehyde is preferably carried out in a non-aqueous medium, e.g. toluene. The water formed is removed by evaporation. The tetra-hydro-|3-carboline-3-carboxylic acid ester is aromatized by boiling with sulfur in xylene. Another method is to react the formyl-tryptophan ester with phosphorus oxychloride or polyphosphoric acid to produce a 3,4-dihydro-fJ-carboline-3-carboxylic acid ester which, however, is disproportionated to the corresponding tetrahydro compound and the fully aromatized compound.

3-karbolin-3-karboksylsyreesteren kan hydrolyseres for frembringelse av den tilsvarende syre, som kan omsettes med et amin til frembringelse av det tilsvarende amid, som kan omdannes til det tilsvarende nitril ved hjelp av velkjente metoder. The 3-carboline-3-carboxylic acid ester can be hydrolyzed to produce the corresponding acid, which can be reacted with an amine to produce the corresponding amide, which can be converted to the corresponding nitrile by well-known methods.

Utskiftningen av substituentene i A-ringen kan som nevnte foretas ved hjelp av i og for seg kjente metoder. F.eks. The replacement of the substituents in the A ring can, as mentioned, be carried out using methods known per se. E.g.

rr

kan en forbindelse I, hvor Z, Y og R har den ovenfor angitte betydning og R A betegner halogen omsettes med et dialkylfosfit med formel a compound I, where Z, Y and R have the above meaning and R A denotes halogen can be reacted with a dialkyl phosphite of the formula

18 19 hvor R og R har den ovenfor nevnte betydning for dannelse av en forbindelse med formel I, hvor Z, Y og R har den ovenfor angitte betydning og R fr betegner 18 19 where R and R have the above-mentioned meaning for the formation of a compound of formula I, where Z, Y and R have the above-mentioned meaning and R fr denotes

eller den kan omsettes med en forbindelse med formel or it can be reacted with a compound of formula

27 — 27 27 — 27

R -C=C-H, hvor R har den ovenfor angitte betydning for dannelse av en i A-ringen alkynylsubstituert forbindelse med formel I, hvor Z, Y og R har den ovenfor angitte betydning. R -C=C-H, where R has the above-mentioned meaning for the formation of an alkynyl-substituted compound of formula I in the A ring, where Z, Y and R have the above-mentioned meaning.

For utskiftning av en aminogruppe i A-ringen kan For replacement of an amino group in the A ring can

en forbindelse med formel I, hvor Z, Y og R Char den ovenfor hanagloigtetne ibd emteyd dnifnorg meog l R (R 1b7 e)tR e1g6nHealr , NHhv_o, r omHsael teter s kmloerd , et broam lkeyll-ler jod, og hvor R 16 og R 17 har den ovenfor angitte betydning for frembringelse av en forbindelse med formel I, hvor Z, Y og R<C>har den ovenfor angitte betydning og RA betyrNR<16>R17. a compound of formula I, where Z, Y and R Char the above hanagloigtetne ibd emteyd dnifnorg meog l R (R 1b7 e)tR e1g6nHealr , NHhv_o, r omHsael teter s kmloerd , a broam lkeyll-ler iodine, and where R 16 and R 17 has the above-mentioned meaning for producing a compound of formula I, where Z, Y and R<C> have the above-mentioned meaning and RA means NR<16>R 17 .

Det er kjent (Squires, R.F. og Bræstrup, C, It is known (Squires, R.F. and Bræstrup, C,

Nature (London) 266 (1977), 734) at spesifikke steder i sentralnervesystemet hos hvirveldyr har en spesifikk stor affinitet for binding av 1,4- og 1,5-benzodiazepiner. Disse steder kalles benzodiazepinreseptorer. Nature (London) 266 (1977), 734) that specific sites in the central nervous system of vertebrates have a specific high affinity for binding 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.

De farmakologiske egenskaper av forbindelsene ifølge oppfinnelsen er blitt undersøkt ved å bestemme deres evne til å fortrenge radioaktivt merket flunitrazepam fra slike benzodiazepinreseptorer. The pharmacological properties of the compounds of the invention have been investigated by determining their ability to displace radiolabeled flunitrazepam from such benzodiazepine receptors.

Fortrengningsaktiviteten av forbindelsene ifølge oppfinnelsen er blitt bestemt ved å bestemme IC,. Q-verdien og ED,.0-verdien. The displacement activity of the compounds according to the invention has been determined by determining the IC,. The Q value and the ED,.0 value.

IC,-Q-verdien representerer den konsentrasjon hvorved det skjer en fortrengning av 5 0% av den spesifikke binding av ^H-flunitrazepam (1,0 nM, 0°C) i prøver omfattende et samlet volum på 0,55 ml av en suspensjon av hjernemembran, f.eks. fra rotter. The IC,-Q value represents the concentration at which there is a displacement of 50% of the specific binding of ^H-flunitrazepam (1.0 nM, 0°C) in samples comprising a total volume of 0.55 ml of a suspension of brain membrane, e.g. from rats.

Fortrengningsprøven utføres på følgende måte: The displacement test is carried out in the following way:

0,50 ml av en suspensjon av ubehandlet rottefor-hjerne i 25 mM KI^PO^, pH= 7,1 (5-10 mg vev/prøve)" inkuberes i 40-60 minutter ved 0°C sammen med ^H-diazepam (spesifikk aktivitet 14,4 Ci/mmol, 1,9 nM) eller<3>H-flunitrazepam (spesifikk aktivitet 87 Ci/mmol, 1,0 nM). Etter inkubering filtre-res suspensjonen gjennom "Whatman GF/C" glassfiberfiltre, filterresten vaskes to ganger med kold bufferoppløsning, og radioaktiviteten måles ved scintillasjonstelling. 0.50 ml of a suspension of untreated rat forebrain in 25 mM KI^PO^, pH= 7.1 (5-10 mg tissue/sample)" is incubated for 40-60 minutes at 0°C together with ^H- diazepam (specific activity 14.4 Ci/mmol, 1.9 nM) or <3>H-flunitrazepam (specific activity 87 Ci/mmol, 1.0 nM). After incubation, the suspension is filtered through "Whatman GF/C" glass fiber filters, the filter residue is washed twice with cold buffer solution, and the radioactivity is measured by scintillation counting.

Forsøket gjentas idet det forut for tilsetningen The experiment is repeated as it precedes the addition

av det radioaktivt merkede benzodiazepin tilsettes en bestemt mengde eller overskudd av den forbindelse, hvis fortrengnings-evne ønskes bestemt. På basis av de oppnådde måleresultater kan IC(-Q-verdien beregnes. of the radioactively labeled benzodiazepine, a specific amount or excess of the compound is added, the displacement capacity of which is to be determined. On the basis of the obtained measurement results, the IC(-Q value can be calculated.

ED,.Q-verdien representerer den dose (mg/kg) av et prøvestoff, hvorved den spesifikke binding av flunitrazepam til benzodiazepinreseptorer i en levende hjerne reduseres til 50% av kontrollverdien. Et slikt in vivo forsøk utføres på følgende måte: Grupper av mus injiseres med prøvestoffer ved forskjellige doser og vanligvis subcutant. 15 minutter senere gis<3>H-flunitrazepam intravenøst til musene og etter ytterligere 2 0 minutter drepes musene og deres forhjernemem-braner fjernes, og radioaktiviteten i forhjernemembranene måles ved scintillas jonstelling. ED,. Q-verdien bestemmes ut fra dosis-responskurver. The ED,.Q value represents the dose (mg/kg) of a test substance at which the specific binding of flunitrazepam to benzodiazepine receptors in a living brain is reduced to 50% of the control value. Such an in vivo experiment is carried out in the following way: Groups of mice are injected with test substances at different doses and usually subcutaneously. 15 minutes later<3>H-flunitrazepam is given intravenously to the mice and after another 20 minutes the mice are killed and their forebrain membranes are removed and the radioactivity in the forebrain membranes is measured by scintillation ion counting. OATH,. The Q-value is determined from dose-response curves.

De oppnådde resultater vil fremgå av følgende tabell I. The results obtained will appear in the following table I.

Forbindelsene ifølge oppfinnelsen har antiaggres-siv effekt på mus. Hemmingen av aggresjonen er blitt bestemt på hanmus (NMR fra Møllegaard, Danmark), som har en vekt på 20-22 g. Musene isoleres i 3 uker i plastbur, og når to mus deretter bringes i samme bur, vil de spontant og nesten øye-blikkelig begynne å sloss. Denne aggresjon hemmes effektivt av en rekke psykoaktive legemidler inklusiv benzodiazepiner (Valcelli, Mod. Probl. Pharmacopsych., 1979, 14, 143-156). Forbindelsene ifølge oppfinnelsen hemmet totalt aggresjonen i en prøve som er beskrevet av Buus Lassen, Europ.J.Pharmacol., 1978, 47, 45-49. Forbindelsene ifølge oppfinnelsen ble inn-gitt subcutant og oralt, og den antiaggressive effekt ble bestemt etter en halv time. Basert på de oppnådde resultater er EDgg-verdien blitt beregnet. The compounds according to the invention have an anti-aggressive effect on mice. The inhibition of aggression has been determined on male mice (NMR from Møllegaard, Denmark), which have a weight of 20-22 g. The mice are isolated for 3 weeks in plastic cages, and when two mice are then brought into the same cage, they will spontaneously and almost -immediately start fighting. This aggression is effectively inhibited by a number of psychoactive drugs including benzodiazepines (Valcelli, Mod. Probl. Pharmacopsych., 1979, 14, 143-156). The compounds according to the invention completely inhibited the aggression in a test described by Buus Lassen, Europ.J.Pharmacol., 1978, 47, 45-49. The compounds according to the invention were administered subcutaneously and orally, and the antiaggressive effect was determined after half an hour. Based on the results obtained, the EDgg value has been calculated.

Forsøksresultater som er oppnådd ved å undersøke noen av forbindelsene ifølge oppfinnelsen og noen kjente beroligende midler, vil fremgå av følgende tabell I. Experimental results which have been obtained by examining some of the compounds according to the invention and some known tranquilizers, will appear in the following table I.

Motvirkningen av pentazol-indusert krampe ble også undersøkt. De oppnådde resultater vil fremgå av tabell II. The anticonvulsant effect of pentazole-induced convulsion was also investigated. The results obtained will appear in table II.

> >

) )

5 5

Oppfinnelsen skal beskrives nærmere under hen-visning til eksemplene som viser spesifikke utførelsesformer for oppfinnelsen. The invention shall be described in more detail with reference to the examples which show specific embodiments of the invention.

Eksempel 1 Example 1

[ 3- karbolin- 3- karboksaldehyd [ 3- carboline- 3- carboxaldehyde

En blanding av 3,3 g 3-hydroksymetyl-(3-karbolin, A mixture of 3.3 g of 3-hydroxymethyl-(3-carboline,

300 ml vannfritt pyridin og 9,9 g blytetraacetat ble oppvarmet i 4 timer i et oljebad, som hadde en temperatur på 300 ml of anhydrous pyridine and 9.9 g of lead tetraacetate were heated for 4 hours in an oil bath, which had a temperature of

ca. 80°C. Etter avkjøling og inndampning tilsattes 150 ml vann. Det krystallinske produkt ble frafUtrert og vasket med vann, 5% vandig kaliumkarbonatoppløsning og dernest med vann igjen. Det lufttørkede produkt, 3,5 g, ble kokt i 0,7 1 2-propanol med aktivt kull og filtrert varmt. Inndampning ga 2,7 g 3-karbolin-3-karboksaldehyd, smp.^270°C under spaltn. about. 80°C. After cooling and evaporation, 150 ml of water was added. The crystalline product was filtered off and washed with water, 5% aqueous potassium carbonate solution and then with water again. The air-dried product, 3.5 g, was boiled in 0.7 L 2-propanol with activated charcoal and filtered hot. Evaporation gave 2.7 g of 3-carboline-3-carboxaldehyde, m.p.^270°C under cleavage.

TLC (CHClo-CH,CN-CH-0H-EtoN): R„ = 0,90 . R_ . TLC (CHCl 2 -CH,CN-CH-OH-EtoN): R 1 = 0.90. R_ .

J Jj.ir r,y J Jj.ir r,y

Y = 3-karbetoksy-3-karbolin. Y = 3-carbethoxy-3-carboline.

På lignende måte ble det fremstilt 6-dimetylsulfa-moyl-3-karbolin-3-karboksaldehyd, smp. 172-4°C og 192-5°C spaltning fra 6-dimetyl-sulfamoyl-3-hydroksymetyl-|3-karbolin og 4-etyl-3-karbolin-3-karboksaldehyd, smp. 199-205°C, Rp=0,86 . R„ 1 r Y fra 4-etyl-3-hydroksymetyl-&-karbolin. In a similar manner, 6-dimethylsulfamoyl-3-carboline-3-carboxaldehyde was prepared, m.p. 172-4°C and 192-5°C cleavage from 6-dimethyl-sulfamoyl-3-hydroxymethyl-|3-carboline and 4-ethyl-3-carboline-3-carboxaldehyde, m.p. 199-205°C, Rp=0.86. R„ 1 r Y from 4-ethyl-3-hydroxymethyl-&-carboline.

Ek sempe1 2 Oak Sempe1 2

g- karbolin- 3- karboksaldehydoksim g- carboline- 3- carboxaldehyde oxime

Til en blanding av 150 ml dimetylformamid, 6,9 g (3-karbolin- 3-karboksaldehyd og 3,1 g hydroksylaminhydroklorid ble det satt en oppløsning av 3,1 g kaliumhydroksyd i 40 ml metanol. Blandingen ble hensatt til neste dag ved værelsetemperatur. Etter inndampning ble det tilsatt 50 ml vann. A solution of 3.1 g of potassium hydroxide in 40 ml of methanol was added to a mixture of 150 ml of dimethylformamide, 6.9 g of (3-carboline-3-carboxaldehyde and 3.1 g of hydroxylamine hydrochloride). The mixture was set aside until the next day at room temperature After evaporation, 50 ml of water was added.

Det faste produkt ble frafUtrert. 6,9 g av det lufttørkede produkt ble oppvarmet på et dampbad med 35 ml 2-propanol. The solid product was filtered. 6.9 g of the air-dried product was heated on a steam bath with 35 ml of 2-propanol.

Etter avkjøling ble produktet f raf Utrert. After cooling, the product f raf Utrert.

Utbyttet var 5,0 g |3-karbolin-3-karboksaldehydoksim, smp. 229-31°C. The yield was 5.0 g |3-carboline-3-carboxaldehyde oxime, m.p. 229-31°C.

På tilsvarende måte ble det fremstilt: 3-karbolin-3-karboksaldehydoksim-benzyleter, smp. 157-159°C, RF= 1,11 . Rp , 3-karbolin-3-karboksaldehydoksimmetyleter, smp. 215-217^C, Rp= 0,94 . Rp p-karbolin-3-karboksaldehydsemikarba-zon, smp. 252-255°C. The following was prepared in a similar manner: 3-carboline-3-carboxaldehyde oxime benzyl ether, m.p. 157-159°C, RH=1.11. Rp , 3-carboline-3-carboxaldehyde oxime methyl ether, m.p. 215-217°C, Rp=0.94. Rp p-carboline-3-carboxaldehyde semicarbazone, m.p. 252-255°C.

E ksempel 3 Example 3

3- acetyl- p- karbolin 3- acetyl-p-carboline

En Grignardoppløsning fremstilles av 8 g magnesium i 100 ml eter og 47 g metyljodid i 100 ml eter. En oppløs-ning av 5,0 g 3-karbolin-3-dimetylkarboksamid i 4 00 ml tetrahydrofuran ble tilsatt Grignardoppløsningen. Blandingen ble omrørt i én time ved værelsetemperatur og tilbakeløpskokt deretter i 2 timer på et dampbad. 10 ml vann i 20 ml tetrahydrofuran ble tilsatt og blandingen inndampet under nedsatt trykk. 48 0 ml 2N saltsyre ble tilsatt etterfulgt av 100 ml konsentrert ammoniumhydroksyd. Ekstrahering med 300 + 100 ml kloroform ga 4,3 g råprodukt. Omkrystallisering fra 20 ml 2-propanol ga 2,6 g 3-acetyl-p-karbolin med smp. 240-244°C. A Grignard solution is prepared from 8 g of magnesium in 100 ml of ether and 47 g of methyl iodide in 100 ml of ether. A solution of 5.0 g of 3-carboline-3-dimethylcarboxamide in 400 ml of tetrahydrofuran was added to the Grignard solution. The mixture was stirred for one hour at room temperature and then refluxed for 2 hours on a steam bath. 10 ml of water in 20 ml of tetrahydrofuran were added and the mixture evaporated under reduced pressure. 480 ml of 2N hydrochloric acid was added followed by 100 ml of concentrated ammonium hydroxide. Extraction with 300 + 100 ml of chloroform gave 4.3 g of crude product. Recrystallization from 20 ml of 2-propanol gave 2.6 g of 3-acetyl-p-carboline with m.p. 240-244°C.

TLC : Rp = 1,10 . RFfY. TLC: Rp = 1.10. RFfY.

På lignende måte fremstilles: 3-pentanoyl-fJ-karbolin, smp. 174-175°C, Rp = 1,38 . Rp , og 3-benzoyl-|3-karbolin, smp. 226-227°C, Rp = 1,24 . Rp . In a similar manner is prepared: 3-pentanoyl-fJ-carboline, m.p. 174-175°C, Rp = 1.38. Rp , and 3-benzoyl-|3-carboline, m.p. 226-227°C, Rp = 1.24. Rs.

Eksempel 4 Example 4

3- acetyl-( 3- karbolinoksim 3- acetyl-( 3- carbolinoxime

En oppløsning av 1,0 g kaliumhydroksyd i 25 ml metanol ble tilsatt en blanding av 0,85 g 3-acetyl-p-karbolin, 75 ml metanol og 1,0 g hydroksylaminhydroklorid. Blandingen ble hensatt i 4 timer ved værelsetemperatur. Etter inndampning ble det tilsatt vann og deretter iseddik til pH 7. Det faste produkt ble frafiltrert og vasket med vann og eter. A solution of 1.0 g of potassium hydroxide in 25 ml of methanol was added to a mixture of 0.85 g of 3-acetyl-p-carboline, 75 ml of methanol and 1.0 g of hydroxylamine hydrochloride. The mixture was left for 4 hours at room temperature. After evaporation, water and then glacial acetic acid were added to pH 7. The solid product was filtered off and washed with water and ether.

Utbytte: 0,6 g 3-acetyl-3-karbolinoksim, Yield: 0.6 g of 3-acetyl-3-carboline oxime,

smp. 'Vi 250°C, under spaltning. m.p. 'We 250°C, during cleavage.

På lignende måte ble det fremstilt: 3-pentanoyl-3-karbolinoksim, smp. 95-120°C. In a similar manner was prepared: 3-pentanoyl-3-carboline oxime, m.p. 95-120°C.

Eksempel 5 Example 5

ft- karbolin- 3- karboksaldehyddimetylhydrazon ft- carboline- 3- carboxaldehyde dimethylhydrazone

En blanding av 1,0 g |3-karbolin-3-karboksaldehyd, 10 ml dimetylformamid og 3 ml N,N-dimetylhydrazin ble anbragt i en glassautoklav. Luften ble erstattet med nitrogen. A mixture of 1.0 g of 3-carboline-3-carboxaldehyde, 10 ml of dimethylformamide and 3 ml of N,N-dimethylhydrazine was placed in a glass autoclave. The air was replaced with nitrogen.

Etter omrøring i 3 timer ble blandingen hensatt ved værelsetemperatur til neste dag. Etter tilsetning av 25 ml vann, ble blandingen ekstrahert med 100 + 50 ml kloroform. After stirring for 3 hours, the mixture was left at room temperature until the next day. After addition of 25 ml of water, the mixture was extracted with 100 + 50 ml of chloroform.

Kloroformfasen ble tørket med magnesiumsulfat, filtrert og kloroformen avdampet. 10 ml eter ble tilsatt og det faste produkt frafiltrert. The chloroform phase was dried with magnesium sulfate, filtered and the chloroform evaporated. 10 ml of ether was added and the solid product was filtered off.

Utbyttet var 0,9 g 3~karbolin-3-karboksaldehyddimetylhydrazon, smp. 203-206°C. The yield was 0.9 g of 3~carboline-3-carboxaldehyde dimethylhydrazone, m.p. 203-206°C.

TLC: R„ = 0,59 . R_ . TLC: R 1 = 0.59. R_ .

F F, y F F, y

På lignende måte ble det fremstilt: In a similar way, it was produced:

p-karbolin-3-karboksaldehydmetylhydrazon, p-carboline-3-carboxaldehyde methylhydrazone,

smp. 162-166°C, m.p. 162-166°C,

Ø-karbolin-3-karboksaldehydfenylhydrazon, Ø-carboline-3-carboxaldehyde phenylhydrazone,

smp. 242-246°C,RF=0,50 . m.p. 242-246°C, RF=0.50.

F,Y F. Y

p-karbolin-3-karboksaldehyddietylhydrazon, p-carboline-3-carboxaldehyde diethylhydrazone,

smp. 133-140°C, Rp= 0,85 . Rp , 3-acetyl-p-karbolindimetylhydrazon, m.p. 133-140°C, Rp= 0.85. Rp , 3-acetyl-p-carbolindimethylhydrazone,

smp. 70-72°C, 3- [ (4- (1,2,4-triazolyl) iminometylen] -(3-karbolin, m.p. 70-72°C, 3-[ (4-(1,2,4-triazolyl)iminomethylene]-(3-carboline,

smp. %260°C spaltn.,-R ^0,22 m.p. %260°C split,-R ^0.22

3-[(N-piperidinyl)iminometylen]-p-karbolin, 3-[(N-piperidinyl)iminomethylene]-p-carboline,

smp. 247-249°C, Rp^0,42 m.p. 247-249°C, Rp^0.42

3-[(N-morfolinyl)iminometylen]-3-karbolin, 3-[(N-morpholinyl)iminomethylene]-3-carboline,

smp. 233-235°C, R^,^0,38 m.p. 233-235°C, R^,^0.38

3-[(4-(l-metylpiperazinyl)iminometylen]-3-karbolin, 3-[(4-(1-methylpiperazinyl)iminomethylene]-3-carboline,

smp. 212-214°C, Rp%0,18 m.p. 212-214°C, Rp%0.18

3- ](N-pyrrolidinyl)iminometylen]-3-karbolin, 3- ](N-pyrrolidinyl)iminomethylene]-3-carboline,

smp. 217-223°C, Rp^0,28. m.p. 217-223°C, Rp^0.28.

På lignende måte, men ut fra 1,0 g 6-dimetylsulfa-moyl-3_karbolin-3-karboksaldehyd, ble det fremstilt: 6-dimetylsulfamoyl-3-karbolin-3-karboksaldehyddimetylhydrazon, smp. 242-249°C, Rp ^ 0,30, In a similar manner, but from 1.0 g of 6-dimethylsulfamoyl-3-carboline-3-carboxaldehyde, the following was prepared: 6-dimethylsulfamoyl-3-carboline-3-carboxaldehyde dimethylhydrazone, m.p. 242-249°C, Rp ^ 0.30,

) 6-dimetylsulfamoyl-3-[(N-pyrrolidinyl)iminometylen] -3-karbolin, smp. 215-226°C, Rp^0,31. 4- etyl-3_karbolin-3-karboksaldehyd-dimetylhydrazon, smp. 162-166°C, Rp = 0,28, fremstilles på samme måte ut fra 4-etyl-3~karbolin-3-karboksaldehyd. ) 6-dimethylsulfamoyl-3-[(N-pyrrolidinyl)iminomethylene]-3-carboline, m.p. 215-226°C, Rp^0.31. 4- ethyl-3_carboline-3-carboxaldehyde-dimethylhydrazone, m.p. 162-166°C, Rp = 0.28, is prepared in the same way from 4-ethyl-3-carboline-3-carboxaldehyde.

Eksempel 6 Example 6

3-( 3- 3- karbolinyl)- acrylsyre 3-( 3- 3- carbolinyl)-acrylic acid

En blanding av 2,0 g 3-karbolin-3-karboksaldehyd, A mixture of 2.0 g of 3-carboline-3-carboxaldehyde,

2,0 g malonsyre, 4 0 ml vannfritt pyridin og 10 yl piperidin ble oppvarmet i 4 timer på et dampbad. Oppløsningsmidlet ble fjernet ved nedsatt trykk og etter tilsetning av 20 ml 2-propanol f raf Utrertes et fast produkt. . Utbyttet var 2,3 g 3-(3-3-karbolinyl)-acrylsyre, smp. 240-260°C under spaltning. TLC: R_ r = 0,00. 2.0 g of malonic acid, 40 ml of anhydrous pyridine and 10 µl of piperidine were heated for 4 hours on a steam bath. The solvent was removed under reduced pressure and after the addition of 20 ml of 2-propanol from raf, a solid product was obtained. . The yield was 2.3 g of 3-(3-3-carbolinyl)-acrylic acid, m.p. 240-260°C during decomposition. TLC: R_ r = 0.00.

D D

Eksempel 7 Example 7

Etyl- 3-( 3- 3- karbolinyl)- acrylat Ethyl-3-(3-3-carbolinyl)-acrylate

En blanding av 2,3 g 3-(3-3-karbolinyl)-acrylsyre, 70 ml 99% etanol og 10 ml konsentrert svovelsyre ble tilbake-løpkokt i 5 timer. Etter avkjøling ble blandingen helt i en blanding av 100 g knust is og 40 ml konsentrert ammoniumhydroksyd. Det faste produkt ble frafiltrert for dannelse av 2,2 g etyl-3-(3-3-karbolinyl)-acrylat, smp. 132-134°C. A mixture of 2.3 g of 3-(3-3-carbolinyl)-acrylic acid, 70 ml of 99% ethanol and 10 ml of concentrated sulfuric acid was refluxed for 5 hours. After cooling, the mixture was poured into a mixture of 100 g of crushed ice and 40 ml of concentrated ammonium hydroxide. The solid product was filtered off to give 2.2 g of ethyl 3-(3-3-carbolinyl)acrylate, m.p. 132-134°C.

2,2 g etyle-3-(3-3-karbolinyl)-acrylat ble oppvarmet med 5 ml etylacetat. Etter avkjøling ble det faste produkt frafiltrert for dannelse av 1,6 g etyl-3-(3-3-karboli-nyl ) -acrylat , smp. 142-144°C. TLC viste en blanding av cis-og transester. 2.2 g of ethyl 3-(3-3-carbolinyl)-acrylate was heated with 5 ml of ethyl acetate. After cooling, the solid product was filtered off to form 1.6 g of ethyl 3-(3-3-carbolinyl)-acrylate, m.p. 142-144°C. TLC showed a mixture of cis and trans esters.

Eksempel 8 Example 8

3-( 3-( l- metyl- pyrazolon- 5)- yl)- 3- karbolin 3-( 3-( 1- methyl- pyrazolon-5)- yl)- 3- carboline

En blanding av 1,4 g 3-karbetoksyacetyl-3-karbolin, 30 ml dimetylformamid og 4 ml metylhydrazin ble oppvarmet til 80°C i 6 timer i en glassautoklav. Blandingen ble deretter inndampet og etter tilsetning av 10 ml metanol f raf Utrertes det faste produkt og ble vasket med 10 ml metanol. A mixture of 1.4 g of 3-carbethoxyacetyl-3-carboline, 30 ml of dimethylformamide and 4 ml of methylhydrazine was heated to 80°C for 6 hours in a glass autoclave. The mixture was then evaporated and after addition of 10 ml of methanol from raf, the solid product was precipitated and washed with 10 ml of methanol.

Utbyttet var 1,0 g 3-(3-(l-metyl-pyrazolon-5)-yl)-3-karbolin, smp. 267-270°C under spaltning. The yield was 1.0 g of 3-(3-(1-methyl-pyrazolon-5)-yl)-3-carboline, m.p. 267-270°C during decomposition.

På lignende måte ble det fremstilt 3-(3-pyrazolon-5-yl)-3-karbolin med smp. >300°C under spaltning, TLC: R F^ O; 3-(3-isoksazolon-5-yl)-3-karbolin, smp. >350°C under spaltning, TLC: R„ 0. In a similar manner, 3-(3-pyrazolon-5-yl)-3-carboline was prepared with m.p. >300°C during cleavage, TLC: R F^O; 3-(3-isoxazolon-5-yl)-3-carboline, m.p. >350°C during decomposition, TLC: R„ 0.

F F

Eksempel 9 Example 9

3-( 3-( 1, 2, 4- trlazol) yl)- 3- karbolin 3-( 3-( 1, 2, 4- trilazol) yl)- 3- carboline

En blanding av 1,0 g N-[(dimetylamino)metylen]-0-karbolin-3-karboksamid, 10 ml iseddik og 270 yl 80% hydrazin-hydrat ble oppvarmet i 2 timer i et oljebad, Tbad<\ > 90°C. Etter inndampning ble det tilsatt 10 ml eter. Krystallene ble samlet på et filter og vasket med eter. A mixture of 1.0 g of N-[(dimethylamino)methylene]-0-carboline-3-carboxamide, 10 ml of glacial acetic acid and 270 µl of 80% hydrazine hydrate was heated for 2 hours in an oil bath, Tbath<\ > 90° C. After evaporation, 10 ml of ether was added. The crystals were collected on a filter and washed with ether.

Utbyttet var 0,9 g 3-(3-(1,2,4-triazol)yl~3-karbolin, smp. 285-290°C, TLC: Rp = 0. The yield was 0.9 g of 3-(3-(1,2,4-triazol)yl~3-carboline, mp 285-290°C, TLC: Rp = 0.

På lignende måte ble det fremstilt 3-(3-(1-metyl-1,2,4-triazol)-yl)-3-karbolin, smp. 277-278°C, TLC: Rp= 0,85 . In a similar manner, 3-(3-(1-methyl-1,2,4-triazol)-yl)-3-carboline was prepared, m.p. 277-278°C, TLC: Rp=0.85.

På På lignende måte ble det fra N-[(dimetylamino)-etyliden]-3-karbolin-3-karboksamid fremstilt: 3-(3-(2,5-dimetyl-l,2,4-triazol)-yl)-3-karbolin, smp. 192-198°C, TLC: Rp= 0,32 og In a similar manner, from N-[(dimethylamino)-ethylidene]-3-carboline-3-carboxamide was prepared: 3-(3-(2,5-dimethyl-1,2,4-triazol)-yl)- 3-carboline, m.p. 192-198°C, TLC: Rp= 0.32 and

3-(3-(5-metyl-l,2,4-triazolhyl)-3-karbolin, 3-(3-(5-methyl-1,2,4-triazolyl)-3-carboline,

smp. 151-155°C. m.p. 151-155°C.

Eksempel 10 Example 10

3-( 5-( 3- metyl- 1, 2, 4- oksadiazol)- yl)- 3- karbolin 3-( 5-( 3- methyl- 1, 2, 4- oxadiazol)- yl)- 3- carboline

Eh blanding av 1,3 ml vann, 1,3 ml 4M natrium-hydroksyd, 7 ml iseddik, 5 ml dioksan, 0,35 g hydroksylamin-hydroklorid og 1,0 g N-[(dimetylamino)etyliden]-3-karbolin-3-karboksamid ble oppvarmet i 2 timer ved 90°C (ytre temperatur). Etter avkjøling og tilsetning av 20 ml vann ble det faste produkt samlet på et glassfilter og vasket med 4 0 ml vann.. Eh mixture of 1.3 ml water, 1.3 ml 4M sodium hydroxide, 7 ml glacial acetic acid, 5 ml dioxane, 0.35 g hydroxylamine hydrochloride and 1.0 g N-[(dimethylamino)ethylidene]-3-carboline -3-carboxamide was heated for 2 hours at 90°C (external temperature). After cooling and adding 20 ml of water, the solid product was collected on a glass filter and washed with 40 ml of water.

Utbyttet var 0,8 g, smp. 314-316°C, TLC: Rp^0,47. The yield was 0.8 g, m.p. 314-316°C, TLC: Rp^0.47.

Eksempel 11 Example 11

3-( 5- tetrazolyl)- 3- karbolin 3-(5-tetrazolyl)-3-carboline

En oppløsning av 500 mg 3-karbolin-3-karbonitril A solution of 500 mg of 3-carboline-3-carbonitrile

1 10 ml dimetylformamid ble blandet med 185 mg natriumazid og 370 mg anilinhydroklorid i en glassautoklav. Blandingen ble oppvarmet i et oljebad ved 125°C (ytre temperatur) i 15 timer under omrøring. Ytterligere 185 mg azid ble tilsatt ved værelsetemperatur og blandingen omrørt ved 155°C i ytterligere 19 timer. Oppløsningsmidlet ble fjernet under redusert trykk. Produktet ble utrørt med 25 ml vann, filtrert etter at pH-verdien var blitt innstilt til 2 med 4N saltsyre og vasket 2 ganger med 10 ml vann. 3-(5-tetrazolyl)-[3-karbolin (452 mg) smeltet ved en temperatur over 300°C. 1 10 ml of dimethylformamide was mixed with 185 mg of sodium azide and 370 mg of aniline hydrochloride in a glass autoclave. The mixture was heated in an oil bath at 125°C (external temperature) for 15 hours with stirring. A further 185 mg of azide was added at room temperature and the mixture stirred at 155°C for a further 19 hours. The solvent was removed under reduced pressure. The product was stirred with 25 ml of water, filtered after the pH value had been adjusted to 2 with 4N hydrochloric acid and washed 2 times with 10 ml of water. 3-(5-Tetrazolyl)-[3-carboline (452 mg) melted at a temperature above 300°C.

Eksempel 12 Example 12

6- brom- 3- ( 5- ( 3- metyl- l, 2, 4- oksadiazol) - yl) -[ 3- karbolin 6- bromo- 3-( 5-( 3- methyl- 1, 2, 4- oxadiazol) - yl) -[ 3- carboline

2 ml brom i 20 ml kloroform ble tilsatt dråpevis en blanding av 1,0 g 3-(5-(3-métyl-l,2,4-oksadiazol)-yl)-B-karbolin, 50 ml kloroform og 3,5 ml pyridin under omrøring ved 0-5°C. Etter omrøring i 2 timer ved 0-5°C og tilsetning av 50 ml kloroform ble oppløsningen vasket med natriumthiosulfat-oppløsning og deretter med vann. Etter tørking over magnesiumsulfat og filtrering ble oppløsningen inndampet til tørrhet for å danne 1,0 g råprodukt. Omkrystallisering fra pyridin ga 0,6 g 6-brom-3-(5-(3-metyl-l,2,4-oksadiazol)-yl)-3-karbolin. Smp. 290-295°C. TLC: R_ = 1,05 . R_ . 2 ml of bromine in 20 ml of chloroform was added dropwise to a mixture of 1.0 g of 3-(5-(3-methyl-1,2,4-oxadiazol)-yl)-B-carboline, 50 ml of chloroform and 3.5 ml of pyridine with stirring at 0-5°C. After stirring for 2 hours at 0-5°C and adding 50 ml of chloroform, the solution was washed with sodium thiosulphate solution and then with water. After drying over magnesium sulfate and filtering, the solution was evaporated to dryness to give 1.0 g of crude product. Recrystallization from pyridine gave 0.6 g of 6-bromo-3-(5-(3-methyl-1,2,4-oxadiazol)-yl)-3-carboline. Temp. 290-295°C. TLC: R_ = 1.05. R_ .

f F ' F, y f F ' F, y

Eksempel 13 Example 13

3-( 5-( 3- metyl- l, 2, 4- oksadiazol)- yl)- 6- nitro- 3- karbolin 3-( 5-( 3- methyl- 1, 2, 4- oxadiazol)- yl)- 6- nitro- 3- carboline

1,0 g 3-(5-(3-metyl-l,2,4-oksadiazol)-yl)-3-karbolin ble satt til 20 ml konsentrert salpetersyre (65%) . Blandingen ble omrørt ved værelsetemperatur i 2 timer. Etter tilsetning av 100 g isvann ble det faste produkt samlet på et glassfilter, vasket med vann og lufttørket. Omkrystallisering 1.0 g of 3-(5-(3-methyl-1,2,4-oxadiazol)-yl)-3-carboline was added to 20 ml of concentrated nitric acid (65%). The mixture was stirred at room temperature for 2 hours. After adding 100 g of ice water, the solid product was collected on a glass filter, washed with water and air dried. Recrystallization

fra pyridin ga 0,6 g 3-(5-(3-metyl-l,2,4-oksadiazol)-yl)-6-hitro-B-karbolin, smp. 330°C under spaltning. TLC : R„ = 1,0 .R„ from pyridine gave 0.6 g of 3-(5-(3-methyl-1,2,4-oxadiazol)-yl)-6-hydro-B-carboline, m.p. 330°C during decomposition. TLC : R„ = 1.0 .R„

F = 1,0 . F, y F = 1.0. F, y

Eksempel 14 Example 14

6- amino- 3-( 5-( 3- metyl- l, 2, 4- oksadiazol)- yl)- g- karbolin 6- amino- 3-( 5-( 3- methyl- 1, 2, 4- oxadiazol)- yl)- g- carboline

En blanding av 0,2 g 3-(5-(3-metyl-l,2,4-oksadiazol) -yl)6-nitro-3-karbolin, 100 ml 99% etanol og 0,2 g 5% palladium på kull ble hydrogenert ved atmosfærisk trykk og værelsetemperatur. Blandingen ble deretter filtrert og oppløsningsmidlet ble fjernet ved fordampning for dannelse av 0,15 g 6-amino-3-(5-(3-metyl-l,2,4-oksadiazol)-yl)-B-karbolin, smp. 310-320°C under spaltning. TLC: Rp= 0,61 . Rp . A mixture of 0.2 g of 3-(5-(3-methyl-1,2,4-oxadiazol)-yl)6-nitro-3-carboline, 100 ml of 99% ethanol and 0.2 g of 5% palladium on coal was hydrogenated at atmospheric pressure and room temperature. The mixture was then filtered and the solvent removed by evaporation to give 0.15 g of 6-amino-3-(5-(3-methyl-1,2,4-oxadiazol)-yl)-B-carboline, m.p. 310-320°C during decomposition. TLC: Rp=0.61. Rs.

Eksempel 15 Example 15

A. B- karbolin- 3- karboksylsyreimidazolid A. B- carboline- 3- carboxylic acid imidazolide

1,8 ml thionylklorid oppløst i 25 ml tørr tetrahydrofuran (THF) ble tildryppet 6,8 g imidazol oppløst i 75 ml tørr THF. Etter én times omrøring ble blandingen filtrert og filtratet ble dryppet til 2,6 5 g tørr B-karbolin-3-karboksylsyre i 100 ml tørr dimetylformamid (DMF). Blandingen ble hensatt ved 20°C til neste dag. 1.8 ml of thionyl chloride dissolved in 25 ml of dry tetrahydrofuran (THF) was added dropwise to 6.8 g of imidazole dissolved in 75 ml of dry THF. After stirring for one hour, the mixture was filtered and the filtrate was added dropwise to 2.65 g of dry B-carboline-3-carboxylic acid in 100 ml of dry dimethylformamide (DMF). The mixture was kept at 20°C until the next day.

Propionamidoksim Propionamidoxime

2,3 g natrium oppløst i 40 ml metanol ble satt til 6,9 g hydroksylamin.hydroklorid oppløst i 100 ml metanol. Etter én times henstand ble blandingen filtrert og til filtratet ble det satt 6,0 g propionitril. Denne blanding ble hensatt i 2 døgn ved værelsetemperatur. 2.3 g of sodium dissolved in 40 ml of methanol was added to 6.9 g of hydroxylamine hydrochloride dissolved in 100 ml of methanol. After standing for one hour, the mixture was filtered and 6.0 g of propionitrile was added to the filtrate. This mixture was left for 2 days at room temperature.

3-( 5'-( 3'- etyl- l', 2', 41- oksadiazol)- yl)- B- karbolin Oppløsningen av propionamidoksim.i metanol ble inndampet i vakuum med toluen. Til den inndampede propionamidoksim ble det satt oppløsningen av Ø-karbolin-3-karboksylsyreimidazolid i THF-DMF. Neste dag ble blandingen inndampet i vakuum og tilsatt 200 ml toluen. Denne blanding ble tilbake-løpskokt under magnetomrøring i 3 timer, hvorpå den varme blanding ble filtrert og filtratet ble inndampet. ' Tilsetning av 20 ml H20 ga 1,5 g krystallinsk stoff. Omkrystallisering av 15 ml n-butanol ga 1,1 g 3-(5'-(3'-etyl-1<1>,2',4'-oksadiazol)-yl)-3-karbolin, smp. 257-260°C. 3-(5'-(3'-ethyl-1',2',41-oxadiazol)-yl)-B-carboline The solution of propionamidoxime in methanol was evaporated in vacuo with toluene. To the evaporated propionamidoxime was added the solution of Ø-carboline-3-carboxylic acid imidazolide in THF-DMF. The next day, the mixture was evaporated in vacuo and 200 ml of toluene was added. This mixture was refluxed under magnetic stirring for 3 hours, after which the hot mixture was filtered and the filtrate was evaporated. Addition of 20 ml of H 2 O gave 1.5 g of crystalline material. Recrystallization from 15 ml of n-butanol gave 1.1 g of 3-(5'-(3'-ethyl-1<1>,2',4'-oxadiazol)-yl)-3-carboline, m.p. 257-260°C.

TLC: Rp^0,50 CHCl^ :CH^CN :CH.jOH :Et^N = 18:4:2:1. TLC: Rp^0.50 CHCl^ :CH^CN :CH.jOH :Et^N = 18:4:2:1.

Etter samme metode, men ved kombinasjon av forskjellige karboksylsyreimidazolider med forskjellige amid-oksimer ble det fremstilt følgende stoffer: Following the same method, but by combining different carboxylic acid imidazolides with different amide oximes, the following substances were produced:

6-brom-3-(5'-(3<1->metyl-1',2',4'-oksadiazol)-yl)-Ø-karbolin, 6-bromo-3-(5'-(3<1->methyl-1',2',4'-oxadiazol)-yl)-O-carboline,

smp. 353-358°C (spaltning), m.p. 353-358°C (decomposition),

3- (5'-(31-etyl-11,21,4'-oksadiazol)-yl)-B-karbolin, 3-(5'-(31-ethyl-11,21,4'-oxadiazol)-yl)-B-carboline,

smp. 245-251°C, m.p. 245-251°C,

4- etyl-3-(5'-(3'-metyl-11,2',4'-oksadiazol)-yl)-B-karbolin, 4- ethyl-3-(5'-(3'-methyl-11,2',4'-oxadiazol)-yl)-B-carboline,

smp. 266-268°C, m.p. 266-268°C,

3-(5,-(3'-propyl-l',2',4'-oksadiazol)-yl)-B-karbolin, 3-(5,-(3'-propyl-1',2',4'-oxadiazol)-yl)-B-carboline,

smp. 187-208°C, m.p. 187-208°C,

3-(5'-(3'-butyl-1',2<1>,4'-oksadiazol)-yl)-B-karbolin, 3-(5'-(3'-butyl-1',2<1>,4'-oxadiazol)-yl)-B-carboline,

smp. 208-211°C, m.p. 208-211°C,

3-(5'-(3<1->etyl-1',2',4<1->oksadiazol)-yl)-6-piperidino-B-karbolin,smp. 152-170°C, 3-(5'-(3<1->ethyl-1',2',4<1->oxadiazol)-yl)-6-piperidino-B-carboline, m.p. 152-170°C,

3-(5'-(3<1->isopropyl-1<1>,2',4<1->oksadiazol)-yl)-Ø-karbolin, 3-(5'-(3<1->isopropyl-1<1>,2',4<1->oxadiazol)-yl)-O-carboline,

smp. 220-225°C, m.p. 220-225°C,

6-diallylamino-3-(51 -(3'-metyl-1',2',4'-oksadiazol)-yl)-0-karbolin (spaltning) 6-diallylamino-3-(51-(3'-methyl-1',2',4'-oxadiazol)-yl)-0-carboline (cleavage)

6-dipropargylamino-3-(5'-(3'-etyl-1 ',2',41-oksadiazol)-yl)-Ø-karbolin, smp. 217-220°C, 6-dipropargylamino-3-(5'-(3'-ethyl-1',2',41-oxadiazol)-yl)-O-carboline, m.p. 217-220°C,

6-diallylamino-3-(51 -(3'-etyl-1',2',4'-oksadiazol)-yl)-0-karbolin, smp. 181-186°C, 6-diallylamino-3-(51-(3'-ethyl-1',2',4'-oxadiazol)-yl)-O-carboline, m.p. 181-186°C,

3- (5'-(3'-allyl-1',2',4'-oksadiazol-)yl)-B-karbolin, 3-(5'-(3'-allyl-1',2',4'-oxadiazol-)yl)-B-carboline,

smp. 194-205°C, m.p. 194-205°C,

4- etyl-3-(5'-etyl-1',2',4'-oksadiazol)-yl)-B-karbolin, 4- ethyl-3-(5'-ethyl-1',2',4'-oxadiazol)-yl)-B-carboline,

smp. 235-240°C, m.p. 235-240°C,

3-(5'-(3<1->metoksymetyl-1',21,4'-oksadiazol)-yl)-Ø-karbolin, smp. 220-229°C, 3-(5'-(3<1->methoxymethyl-1',21,4'-oxadiazol)-yl)-O-carboline, m.p. 220-229°C,

6-diallylamino-3-(5'-(3'-etyl-l' ,2' ,4 '-oksadiazol)-yl)-4-metyl-Ø-karbolin, smp. 154-160°C, 6-diallylamino-3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-4-methyl-O-carboline, m.p. 154-160°C,

3-(5'-(3<1->cyklopropyl-1',2',4'-oksadiazol)-yl)-Ø-karbolin, smp. 241-243°C, 3-(5'-(3<1->cyclopropyl-1',2',4'-oxadiazol)-yl)-O-carboline, m.p. 241-243°C,

3-(5'-(3'-allyl-1',2',4'-oksadiazol)-yl)-6-diallylamino-Ø-karbolin, smp. 168-193°C, 3-(5'-(3'-allyl-1',2',4'-oxadiazol)-yl)-6-diallylamino-Ø-carboline, m.p. 168-193°C,

3-(5'-(3'-fenyl-1',2',4'-oksadiazol)-yl)-Ø-karbolin, 3-(5'-(3'-phenyl-1',2',4'-oxadiazol)-yl)-O-carboline,

smp. 275-278°C, spaltning, m.p. 275-278°C, cleavage,

6-dimetylsulfamoyl-3-(5'-(3'-etyl-1',2',4'-oksadiazol)-yl)-Ø-karbolin, smp. 266-270°C, 6-dimethylsulfamoyl-3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-O-carboline, m.p. 266-270°C,

3-(5'-(3<1->cyklopropyl-1',2<1>,4'-oksadiazol)-yl)-6-diallylamino-Ø-karbolin, smp. 131-143°C, 3-(5'-(3<1->cyclopropyl-1',2<1>,4'-oxadiazol)-yl)-6-diallylamino-Ø-carboline, m.p. 131-143°C,

3-(5'-(3'-cyklopropyl-1',2',4<1->oksadiazol)-yl)-6-dimetyl-sulfamoyl-rø-karbolin, smp. 275-277°C, 3-(5'-(3'-cyclopropyl-1',2',4<1->oxadiazol)-yl)-6-dimethyl-sulfamoyl-rho-carboline, m.p. 275-277°C,

3-(5'-(3'-etyl-1',2',4'-oksadiazol)-yl)-4-metoksymetyl-Ø-karbolin, smp. 171-176°C, 3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-4-methoxymethyl-Ø-carboline, m.p. 171-176°C,

6-klor-3-(5'-(3<1->etyl-1<1>,2',4'-oksadiazol)-yl)-Ø-karbolin, smp. 300-312°C, 6-chloro-3-(5'-(3<1->ethyl-1<1>,2',4'-oxadiazol)-yl)-O-carboline, m.p. 300-312°C,

5- klor-3-(5'-(3'-etyl-1',2',4'-oksadiazol)-yl)-Ø-karbolin, smp.299-309°C, 5-chloro-3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-Ø-carboline, m.p. 299-309°C,

3-(5'-(3'-etyl-1',2',4'-oksadiazol)-yl)-6-nitro-Ø-karbolin, smp. 333-338°C, 3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-6-nitro-Ø-carboline, m.p. 333-338°C,

5- benzyloksy-3-(51 -(3'-etyl-1',2',4'-oksadiazol)-yl)-fi-kar bo lin, smp. 215-218°C, 5-benzyloxy-3-(51-(3'-ethyl-1',2',4'-oxadiazol)-yl)-ficarboline, m.p. 215-218°C,

6- benzyloksy-3-(5'-(3'-etyl-1',2',4'-oksadiazol)-yl)-0-karbolin, smp. 237-239°C, 6- benzyloxy-3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-O-carboline, m.p. 237-239°C,

3-(5'-(3'-etyl-1',2 *,4'-oksadiazol)-yl)-6-(4-metylpiperidino)-B-karbolin, smp. 195-198°C. 3-(5'-(3'-ethyl-1',2*,4'-oxadiazol)-yl)-6-(4-methylpiperidino)-B-carboline, m.p. 195-198°C.

3-(5'-(3'-etyl-1',2',4'-oksadiazol)-yl)-6-metylthio)-0-karbolin, smp. 193-198°C, 3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-6-methylthio)-O-carboline, m.p. 193-198°C,

6-(3-tetrahydropyran-2-yl-oksy-l-propynyl)-3-(5'-(3-etyl-1<1>,2',4'-oksadiazol)yl)-Ø-karbolin, smp. 211-214°C, 6-(3-tetrahydropyran-2-yl-oxy-1-propynyl)-3-(5'-(3-ethyl-1<1>,2',4'-oxadiazol)yl)-O-carboline, m.p. . 211-214°C,

6-cyano-3-(5 *-(3'-etyl-1',2',4'-oksadiazol)-yl)-Ø-karbolin, smp. 263-266°C, 6-cyano-3-(5*-(3'-ethyl-1',2',4'-oxadiazol)-yl)-O-carboline, m.p. 263-266°C,

6-metoksy-3- (5 ' - (3 ' -etyl-1', 2 ' ,4 ' -oksadiazol) -yl) -Ø-karbolin,. smp. 178-182°C, 6-Methoxy-3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-O-carboline,. m.p. 178-182°C,

5-metoksymetyl-3-(5'-(3'-etyl-1<1>,2',4<1->oksadiazol)-yl)-0-karbolin, smp. 207-211°C. 5-Methoxymethyl-3-(5'-(3'-ethyl-1<1>,2',4<1->oxadiazol)-yl)-O-carboline, m.p. 207-211°C.

Eksempel 16 Example 16

A. Ø- ka rbo1in- 3- karboks amidoks im A. Ø- ka rbo1in- 3- carbox amidox im

En blanding av 2,4 g 3-cyano-Ø-karbolin, 1,1 g hydroksylamin-hydroklorid, 20 0 ml 99% etanol og 5,2 ml 20% vandig kaliumkarbonatoppløsning ble kokt under tilbakeløp i 22 timer. Etter filtrering ble filtratet inndampet, hvorpå det ble tilsatt 100 ml vann. Det krystallinske stoff ble frafiltrert og vasket med vann. A mixture of 2.4 g of 3-cyano-O-carboline, 1.1 g of hydroxylamine hydrochloride, 200 ml of 99% ethanol and 5.2 ml of 20% aqueous potassium carbonate solution was refluxed for 22 hours. After filtration, the filtrate was evaporated, after which 100 ml of water was added. The crystalline substance was filtered off and washed with water.

Utbyttet ble 2,4 g Ø-karbolin-3-karboksamidoksim, smp. 159-163°C. The yield was 2.4 g of Ø-carboline-3-carboxamidoxime, m.p. 159-163°C.

B. 3-( 3'-( 5'- etyl- 1', 2', 4'- oksadiazol)- yl)- B- karbolin B. 3-(3'-(5'-ethyl-1',2',4'-oxadiazol)-yl)-B-carboline

En blanding av 1,2 g Ø-karbolin-3-karboksamid-oksim og 10 ml propionsyreanhydrid ble omrørt i 2 timer ved 20°C og derpå 5 timer ved 120°C. Etter inndampning ble det tilsatt 100 ml tetrahydrofuran og blandingen ble mettet med metylamingass. Etter henstand til neste dag ved værelsetemperatur ble blandingen inndampet. Det ble tilsatt 100 ml metylen-klorid og etter filtrering og inndampning av filtratet ble det tilsatt 10 ml etylacetat. A mixture of 1.2 g of β-carboline-3-carboxamide oxime and 10 ml of propionic anhydride was stirred for 2 hours at 20°C and then for 5 hours at 120°C. After evaporation, 100 ml of tetrahydrofuran was added and the mixture was saturated with methylamine gas. After standing until the next day at room temperature, the mixture was evaporated. 100 ml of methylene chloride was added and after filtration and evaporation of the filtrate, 10 ml of ethyl acetate was added.

Utbytte 0,4 g 3-(31 -(5'-etyl-11,2',4'-oksadiazol)-yl)-B-karbolin = FG 7287,smp. 214-216°C. Yield 0.4 g of 3-(31 -(5'-ethyl-11,2',4'-oxadiazol)-yl)-B-carboline = FG 7287, m.p. 214-216°C.

TLC: R_ = 0,48 CHC1,:CH0CN:CH.OH:Et0N = 18:4:2:1. TLC: R 1 = 0.48 CHCl 2 :CH0CN:CH.OH:Et0N = 18:4:2:1.

F 3 3 3 3 F 3 3 3 3

På samme måte, men ut fra eddiksyreanhydrid hen-holdsvis smørsyreanhydrid ble det fremstilt: In the same way, but from acetic anhydride or butyric anhydride respectively, the following was produced:

3-(3'-(5'-metyl-1<*>,2',4'-oksadiazol)-yl)-B-karbolin, 3-(3'-(5'-methyl-1<*>,2',4'-oxadiazol)-yl)-B-carboline,

smp. 279-287°C, m.p. 279-287°C,

3-(3'-(5'-propyl-l',2',4'-oksadiazol)-yl)-Ø-karbolin, 3-(3'-(5'-propyl-1',2',4'-oxadiazol)-yl)-O-carboline,

smp. 195-197°C. m.p. 195-197°C.

Eksempel 17 Example 17

3'-( 5'-( 3'- etyl- A2'- 11, 2'- 41- oksadiazolin)- yl)- p- karbolin 3'-( 5'-( 3'- ethyl- A2'- 11, 2'- 41- oxadiazolin)-yl)- p- carboline

Ø-karbolin-3-karboksaldehyd (2,0 g) og propionamidoksim (fremstilt av 2,3 g natrium) i 50 ml dimetylformamid ble omrørt i 2 timer ved værelsetemperatur og 2 timer ved 100°C. Inndampning og tilsetning av 25 ml H"20 ga 2,2 g 3'-(5'-(3<1->etyl-A<2>'-1',2',4'-oksadiazolin)-yl)-Ø-karbolin, β-Carboline-3-carboxaldehyde (2.0 g) and propionamidoxime (prepared from 2.3 g of sodium) in 50 ml of dimethylformamide were stirred for 2 hours at room temperature and 2 hours at 100°C. Evaporation and addition of 25 ml of H"20 gave 2.2 g of 3'-(5'-(3<1->ethyl-A<2>'-1',2',4'-oxadiazolin)-yl)- island-carboline,

smp. 208-211°C. m.p. 208-211°C.

TLC: R„= 0,24 CHC1-. :CH_CN:CH_.OH:Et-,N = 18:4:2:1. TLC: R 1 = 0.24 CHCl-. :CH_CN:CH_.OH:Et-,N = 18:4:2:1.

F 3 3 3 3 F 3 3 3 3

Eksempel 18 Example 18

3-( 5'-( 3'- metyl- isoksazol)- yl)- Ø- karbolin 3-(5'-(3'-methyl-isoxazol)-yl)-E-carboline

1,0 g 3-acetyl-Ø-karbolin og 3 ml dimetylacetamid-dimetylacetal ble oppvarmet i 20 timer i oljebad ved 110°C. Stoffet krystalliserte ved avkjøling, ble suget fra og vasket med eter. 1.0 g of 3-acetyl-Ø-carboline and 3 ml of dimethylacetamide-dimethylacetal were heated for 20 hours in an oil bath at 110°C. The substance crystallized on cooling, was sucked off and washed with ether.

Utbyttet ble 0,9 g 3-(3-dimetylaminocrotonoyl)-3-karbolin. The yield was 0.9 g of 3-(3-dimethylaminocrotonoyl)-3-carboline.

Til 0,9 g 3-(3-dimetylaminocrotonoyl)-3-karbolin To 0.9 g of 3-(3-dimethylaminocrotonoyl)-3-carboline

i 40 ml metanol ble det under isavkjøling satt 0,6 g hydroksylamin-O-sulfonsyre i 5 ml metanol. Etter omrøring i en halv time ble blandingen helt i 40 ml mettet natriumbikarbonat-oppløsning + 40 ml vann. Denne blanding ble.hensatt i kjøle-skap til neste dag. Ekstrahering med 5 x 100 ml eter ga 100 mg 3-(51 -(31-metyl-isoksazol)-yl)-3-karbolin, smp. 179-183°C. in 40 ml of methanol, 0.6 g of hydroxylamine-O-sulfonic acid was added to 5 ml of methanol under ice-cooling. After stirring for half an hour, the mixture was poured into 40 ml of saturated sodium bicarbonate solution + 40 ml of water. This mixture was stored in a refrigerator until the next day. Extraction with 5 x 100 ml of ether gave 100 mg of 3-(51 -(31-methyl-isoxazol)-yl)-3-carboline, m.p. 179-183°C.

TLC: RF = 1,46 x Rp • TLC: RF = 1.46 x Rp •

Eksempel 19 Example 19

6- dietoksyfosforyl- 3-( 5'-( 3'- etyl- 1', 2', 4'- oksadiazol)- yl)-3- karbolin 6- diethoxyphosphoryl- 3-( 5'-( 3'- ethyl- 1', 2', 4'- oxadiazol)- yl)-3- carboline

1,6 g 6-jod-3-(5'-(3'-etyl-l',2',4'-oksadiazol)-yl)-3-karbolin ble tilsatt under tørre betingelser til en blanding av 608 mg dietylfosfit, 448 mg trietylamin, 240 mg palladiumtetrakistrifenylfosfin og 60 ml N-metyl-2-pyrrolidon og ble omrørt i 12 timer ved 90°C. Etter inndampning ved oljepumpevakuum ble inndampningsresten kromatografert på 75 g kiselgel med metylenklorid/aceton = 1:1 som elueringsmiddel. De samlede fraksjoner ble kromatografert på 25 g kiselgel med metylenklorid/etanol = 10:2 som elueringsmiddel, hvorved det fremkom 425 mg 6-dietoksyfosforyl-3-(51 -(31-etyl-1',2',4<1->oksadiazol)-yl)-3-karbolin som en olje. 1.6 g of 6-iodo-3-(5'-(3'-ethyl-1',2',4'-oxadiazol)-yl)-3-carboline was added under dry conditions to a mixture of 608 mg of diethyl phosphite , 448 mg of triethylamine, 240 mg of palladium tetrakistriphenylphosphine and 60 ml of N-methyl-2-pyrrolidone and was stirred for 12 hours at 90°C. After evaporation by oil pump vacuum, the evaporation residue was chromatographed on 75 g of silica gel with methylene chloride/acetone = 1:1 as eluent. The combined fractions were chromatographed on 25 g of silica gel with methylene chloride/ethanol = 10:2 as eluent, whereby 425 mg of 6-diethoxyphosphoryl-3-(51 -(31-ethyl-1',2',4<1-> oxadiazol)-yl)-3-carboline as an oil.

På lignende måte ble det fremstilt: 6-dietoksyfosforyl-4-metyl-3-(5'-(3'-etyl-1',2<1>,4'-oksadiazol)-yl)-3-karbolin som en olje, In a similar manner was prepared: 6-diethoxyphosphoryl-4-methyl-3-(5'-(3'-ethyl-1',2<1>,4'-oxadiazol)-yl)-3-carboline as an oil ,

6-dietoksyfosforyl-4-metoksymetyl-3-(5'-(3'-etyl-1) 2',41-oksadiazol) -yl) -3-karbolin som en olje. 6-diethoxyphosphoryl-4-methoxymethyl-3-(5'-(3'-ethyl-1)2',41-oxadiazol)-yl)-3-carboline as an oil.

Eksempel 2 0 Example 2 0

3-( 2'-( 4'- fenylthiazol)- yl)- B- karbolin 3-(2'-(4'-phenylthiazol)-yl)-B-carboline

0-karbolinthiamid (1 g) ble oppløst i etanol O-carboline thiamide (1 g) was dissolved in ethanol

(50 ml) og tilsatt fenacylbromid (0,75 mg). Blandingen ble kokt under tilbakeløp i 20 timer. Etter avkjøling ble krystallene filtrert fra. Disse krystaller ble tilsatt trietylamin (600 yl) og omkrystallisert fra etanol:vann. Utbyttet var 0,6 g 3-(2'-(4<1->fenylthiazol)-yl)-B-karbolin. (50 ml) and added phenacyl bromide (0.75 mg). The mixture was refluxed for 20 hours. After cooling, the crystals were filtered off. These crystals were added to triethylamine (600 µl) and recrystallized from ethanol:water. The yield was 0.6 g of 3-(2'-(4<1->phenylthiazol)-yl)-B-carboline.

IR (KBr): 3400-3000 (m, flere brede signaler), 1630 (m), IR (KBr): 3400-3000 (m, several broad signals), 1630 (m),

1605 (m), 1580 (w), 1560 (w), 1510 (m), 1495 (m), 1475 (m), 1450 (s) cm"<1>. 1605 (m), 1580 (w), 1560 (w), 1510 (m), 1495 (m), 1475 (m), 1450 (s) cm"<1>.

På tilsvarende måte ble det fremstilt 3-(2'-(4'-metylthiazol)-yl)-3-karbolin. In a similar manner, 3-(2'-(4'-methylthiazol)-yl)-3-carboline was prepared.

IR (KBr): 3300-2900 (m, flere brede signaler), 1630 (m), IR (KBr): 3300-2900 (m, several broad signals), 1630 (m),

1600 (m), 1590 (w), 1560 (m), 1530 (m), 1505 (s), 1440 (s) cm<-1>. Rp = 0,66. 1600 (m), 1590 (w), 1560 (m), 1530 (m), 1505 (s), 1440 (s) cm<-1>. Rp = 0.66.

Eksempel 21 Example 21

3-( 2'- oksazolyl)- 3- karbolin 3-(2'-oxazolyl)-3-carboline

Fenyl 3_karbolin-3-karboksylat (0,5 g ) ble opp-slemmet i aminoacetaldehyddimetylacetat ( 5 ml) og oppvarmet til 110°C i 3 timer. Reaksjonsblandingen ble inndampet i vakuum og omkrystallisert fra etylacetat. Utbyttet ble 300 mg 3-karbolin-3-(2',2'-dimetoksyetylamid). Phenyl 3-carboline-3-carboxylate (0.5 g) was slurried in aminoacetaldehyde dimethyl acetate (5 ml) and heated to 110°C for 3 hours. The reaction mixture was evaporated in vacuo and recrystallized from ethyl acetate. The yield was 300 mg of 3-carboline-3-(2',2'-dimethoxyethylamide).

3-karbolin-3-(2<1>,2<1->dimetoksyetylamid) (200 mg) 3-carboline-3-(2<1>,2<1->dimethoxyethylamide) (200 mg)

ble oppløst i konsentrert svovelsyre (2 ml) og ble omrørt i 2 timer. Deretter ble reaksjonsblandingen nøytralisert med 10% natriumhydrogenkarbonat og ekstrahert med etylacetat, hvoretter de samlede etylacetatfaser ble inndampet. Utbyttet var 100 mg 3-(2<1->oksazolyl)-3-karbolin. 'HNMR (DMSO-d,) 6: 12,1 (IH,s), 9,0 (IH,s), 8,9 (IH,s), 8,4 (IH,d J 7,5 Hz), 7,8-7,8 (5H,m). was dissolved in concentrated sulfuric acid (2 ml) and was stirred for 2 hours. The reaction mixture was then neutralized with 10% sodium bicarbonate and extracted with ethyl acetate, after which the combined ethyl acetate phases were evaporated. The yield was 100 mg of 3-(2<1->oxazolyl)-3-carboline. HNMR (DMSO-d,) 6: 12.1 (1H,s), 9.0 (1H,s), 8.9 (1H,s), 8.4 (1H,d J 7.5 Hz) , 7.8-7.8 (5H,m).

Eksempel 2 2 Example 2 2

3-( 6'-!' , 2', 5'- oksadlazinyl)- 3- karbolin 3-( 6'-!' , 2', 5'- oxadlazinyl)- 3- carboline

3-(6' -1' ,2' , 5 '-oksad.iazinyl)-3-karbolin ble fremstilt fra 3-karbolin-3-(2',2<1->dimetoksyetylamid) ved hydrolyse av acetat og behandling med hydroksylamin. 3-(6'-1',2',5'-oxadziazinyl)-3-carboline was prepared from 3-carboline-3-(2',2<1->dimethoxyethylamide) by hydrolysis of acetate and treatment with hydroxylamine.

IR (KBr): 3400-2900 (s,flere brede bånd), 1660 (s), 1630 (s) , 1600 (s), 1540 (s), 1500 (s) cm"<1>. IR (KBr): 3400-2900 (s, several broad bands), 1660 (s), 1630 (s), 1600 (s), 1540 (s), 1500 (s) cm"<1>.

Claims

Analogous method to & prepare therapeutically active ø-carboline derivatives of the general formula in which Y denotes 0, NOR<1>, in which R<1> denotes hydrogen, lower alkyl, phenyl, CHC00R<3>, in which R<3> denotes hydrogen or lower alkyl;

wherein R<*> and R<5> are each hydrogen. lower alkyl, phenyl, or in which R<4> and R<5> together with the neighboring nitrogen atom form part of a 5- or 6-membered heterocyclic ring, consisting of triazolyl, piperidinyl, morpholinyl, N-methylpiperazinyl or pyrrolidlnyl, Z means hydrogen, a lower alkyl group, a group of formula

and in which Y and Z together with the neighboring C atom can form part of a 5- or 6-membered heterocyclic ring, consisting of pyrazolonyl, triazolyl, tetrazolyl, isoxazolyl, phenyltlazolyl, oxazolyl, oxadiazlnyl or oxadlazolyl, which is optionally substituted with a lower alkyl group, a cycloalkyl or phenyl group, allyl or lower alkoxyalkyl, RA denotes hydrogen, a halogen atom, NO2, CN, SCH3, lower alkoxyalkyl, NR16R1<7>, wherein R16 and R1<7> each means hydrogen or lower alkyl, allyl, propargyl or wherein R1^ and R17 together can form a plperldlnrlng, which ring is optionally substituted with a lower alkyl group with up to 3 carbon atoms, anOR<2>^, in which R<2>^ means lower alkyl or benzyl, SO2NR23R2<4>, in which R2<3>and R24 each means lower alkyl, the group

wherein R18 and R<19> each means lower alkyl, with up to 3 carbon atoms, or C=C-0-tetrahydropyranyl, in which each molecule may contain two or more identical or different RA groups, and R*" means hydrogen, a lower alkyl group, or lower alkoxyalkyl, characterized by a) a compound of formula II

in which rA and R^ have the meaning indicated above, is oxidized, or that a compound of formula III

wherein R<34>means OH or lower alkoxy or NR35R36, wherein R<35>and R<3>^ each means lower alkyl or aryl, and wherein RA and R<c>have the above meaning, is reduced to form the corresponding aldehyde of formula IV wherein RA and R<c> have the meaning stated above, and that the compound thus formed is reacted with 1) a compound of formula H2NOR<1>, in which R<1> has the meaning stated above to form a compound of formula I, in which Y means NOR<1>, Z means hydrogen and R^ and R<c> have the previously indicated meaning, 2) a compound of formula

wherein R<4> and R^ have the previously indicated meaning, forming a compound of formula I, wherein Y means

Z is hydrogen and R^ and R^ are as previously indicated, or 3) malonic acid or a malonic acid ester to form a compound of formula I, wherein Y is CHC00R<3>, wherein R<3> is as previously indicated, Z means hydrogen and R^ and R^ have the previously indicated meaning, or b) a compound of formula III, in which R<34> means a lower alkoxy group or NR35R<36>, in which R35 and R3<6> have the previously indicated meaning, is reacted with a compound of formula Z Mg Hal, in which Z has the previously indicated meaning and Hal means a halogen atom to obtain a compound of formula I, in which Y denotes 0, and E<*> and R^ have the previously indicated meaning, and that the compound thus prepared is optionally reacted with HgNOR<*>, in which R<1> has the previously indicated meaning, or with a compound of formula in which R<4> and R^ have the previously indicated meaning during the formation of a compound of formula I, in which Y means NOR<1>or

wherein RA and R<c>have the previously indicated meaning, or c) a compound of formula V

in which RA and r<C> have the previously indicated meaning, is reacted with a compound having the formula R<37>C(OR38)2N(CH3)2, in which R37 means hydrogen or lower alkyl, and R<38> means lower alkyl, forming a compound of formula I, in which Y means 0 and Z means N=CR<37>N(CH3)2 and that the thus produced compound is optionally reacted with guanldine, a compound of formula H2N0R<3>^fhvoriR3^ means hydrogen or lower alkyl, or with a compound of formula H2NNHR<40>, in which R<4>^ means hydrogen or lower alkyl, to form a compound of formula I, in which Y and Z together with the neighboring C atom form part of a 5-membered heterocyclic ring, and RA and R<c>have the previously indicated meaning or in which Y denotes 0, and R<*> and R^ have the previously indicated meaning, and that the compound thus prepared is optionally reacted with H-jNOR1, in which R<1> has the previously indicated meaning, or with a compound of formula

wherein R<4> and R^ have the previously indicated meaning during the formation of a compound of formula I, in which Y means NOR<1>or

wherein rA and R<c>have the previously stated meaning, or c) a compound of formula V

in which RA and R<c> have the previously stated meaning, is reacted with a compound having the formula R<37>C(OR38)2N(CH3)2, in which R3<7> denotes hydrogen or lower alkyl, and R<38> denotes lower alkyl, under formation of a compound of formula I, in which Y means 0 and Z means N=CR<37>N(CH3)2 and that the compound thus produced is optionally reacted with guanidine, a compound of formula H2N0R<39>, in which R<39> means hydrogen or lower alkyl, or with a compound of formula H2NNHR<40>, in which R<40> means hydrogen or lower alkyl, to form a compound of formula I, in which Y and Z together with the neighboring C atom form part of a 5-membered heterocyclic ring, and RA and R<c>have the previously indicated meaning or in which rA0g jjC has the above meaning, is reacted with hydroxylamine with the formation of a 3-carboline-3-carboxylic acid amide oxide which is then treated with the reactive acid anhydride with the formation of a compound of formula I, in which Y and Z represent an oxadiazole-3 ring system, in that a nitro group can be introduced into the A ring and hydrogenation of this to an amino group or the introduction of a dialkoxyphosphoryl group.