DK154142B - Imidazo(1,5-a)quinoxaline compound, and preparation comprising it - Google Patents

Description

iin

DK 154142 BDK 154142 B

Opfindelsen angår hidtil ukendte terapeutisk aktive imidazo(l,5-a)-quinoxali nforbindelse og præparater indeholdende samme. De hidtil ukendte forbindelser er nyttige til psykofarmaceutiske anvendelser, f.eks. ved behandling af centralnervesystemssygdomme f.eks. som 5 krampehæmmende midler eller angstdæmpende midler.This invention relates to novel therapeutically active imidazo (1,5-a) -quinoxali compound and compositions containing the same. The novel compounds are useful for psychopharmaceutical applications, e.g. in the treatment of central nervous system diseases e.g. as 5 anticonvulsants or anxiety relievers.

Det er velkendt (Squires, R.F. og Bræstrup, C. Nature (London) 266 (1977) 732-4), at specifikke steder i centralnervesystemet hos pattedyr udviser en stor specifik affinitet for binding af 1,4- og 10 1,5-benzodiazepiner. Disse steder kaldes benzodiazepinreceptorer.It is well known (Squires, RF, and Bræstrup, C. Nature (London) 266 (1977) 732-4) that specific sites in the central nervous system of mammals exhibit a large specific affinity for binding of 1.4- and 1.5- benzodiazepines. These sites are called benzodiazepine receptors.

I US patentskrift nr. 4.440.929 er der omtalt imidazo(l,5-a)quinoxa-linforbindelser, som i 3-stillingen er substitueret med en COOEt-gruppe. Forbindelser af denne art har angiveligt cardiotonisk 15 aktivitet, men har ingen affinitet over for benzodiazepinreceptorer.U.S. Patent No. 4,440,929 discloses imidazo (1,5-a) quinoxaline compounds which at the 3-position are substituted by a COOEt group. Compounds of this kind reportedly have cardiotonic activity but have no affinity for benzodiazepine receptors.

Det har vist sig, at en hidtil ukendt gruppe af analoge imidazo(l,5--a)quinoxalinforbindelser har én stor affinitet for benzodiazepinreceptorerne, hvilket gør dem anvendelige i psykofarmaceutiske præpa-20 rater.It has been found that a novel group of analogous imidazo (1,5 - a) quinoxaline compounds has one great affinity for the benzodiazepine receptors, making them useful in psychopharmaceutical preparations.

Imidazo(l,5-a)quinoxalinforbindelserne ifølge opfindelsen har den almene formel " .ψΤ R6 0^ n ^ 30 hvor X betegner —<{ π eller —? —R' —R* hvor R' betegner C16-alkyl, C37-cycloalkyl eller C13-alkoxymethyl, R® og hver betegner hydrogen eller halogen ogThe imidazo (1,5-a) quinoxaline compounds of the invention have the general formula "RψΤO6 n n ^ where X represents - <{π or -? - R '- R * where R' represents C 16 -alkyl, C37- cycloalkyl or C13 alkoxymethyl, R® and each represents hydrogen or halogen and

^ V^ V

35 -A- betegner -N(R")-C(0)-, -N(R")-CH2, eller hvor R" betegner hydrogen, C3 y-cycloalkyl eller Cj g-alkyl.-A- represents -N (R ") - C (O) -, -N (R") - CH2, or wherein R "represents hydrogen, C3-6 cycloalkyl or C1-6 alkyl.

De omhandlede forbindelser kan fremstilles vedThe present compounds can be prepared by

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22

a) omsætning af en forbindelse med formlen II(a) reacting a compound of formula II

fofYfofY

5 (II) i6 6 75 (II) i6 6 7

hvor -A-, R og R har de ovenfor anførte betydninger og hvor Y betegner en fraspaltelig gruppe, med en forbindelse med formlen IIIwherein -A-, R and R have the above meanings and where Y represents a leaving group, with a compound of formula III

10 CN - CH2 - X (III) hvor X har den ovenfor anførte betydning ellerCN - CH2 - X (III) where X has the meaning given above or

15 b) omsætning af et reaktivt derivat af en forbindelse med den almene formel IVB) reacting a reactive derivative of a compound of general formula IV

20 R yv-» (IV) a6 6 7 hvor -A-, R og R har de ovenfor anførte betydninger, med en forbindelse med den almene formel V 25 R' - C (V) *^νη2 30 hvor R' har den ovenfor anførte betydning, til dannelse af en forbindelse med den almene formel I, hvor X betegner -Ol..Wherein R-A, R and R have the above meanings, with a compound of the general formula V 25 R '- C (V) * νη2 30 where R' has the above, to form a compound of the general formula I wherein X represents -O1.

35 hvor R' har den ovenfor anførte betydning.35 where R 'has the meaning given above.

Egnede fraspaltelige grupper, Y, er omtalt i US patentskrifterne nr.Suitable leaving groups, Y, are disclosed in U.S. Pat.

DK 154142 BDK 154142 B

3 4.031.079 eller 4.359.420. Eksempler på sådanne fraspaltelige grupper er halogen, alkylthio, f.eks. methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0P(0)(0R)2, hvor R betegner lavere al kyl eller -0P(0)(NR'R''), hvor R7 og R77 hver repræsenterer 5 lavere al kyl eller sammen med det nitrogenatom, til hvilket de er bundet, repræsenterer en heterocyklisk gruppe såsom morpholin, pyrrolidin, piperidin eller methylpiperazin. Omsætningen som beskrevet under a) gennemføres fortrinsvis under basiske betingelser, dvs. under tilstedeværelsen af en base, og foretrukne baser er 10 al kalimetal-, f.eks. kalium- eller natrium-, alkoxider eller hydrider. Omsætningen gennemføres fortrinsvis under tilstedeværelse af et organisk opløsningsmiddel, som ikke reagerer med reaktanterne og reaktionsprodukterne under reaktionsbetingelserne. Opløsningsmidlet er fortrinsvis vandfrit og særligt foretrukket er et vandfrit 15 aprotisk opløsningsmiddel såsom dimethyl formamid (DMF) eller lignende. Temperaturintervallet, der anvendes, bør være tilstrækkeligt højt til, at omsætningen kan forløbe i et rimeligt tempo og uden unødvenigt ophold eller dekomponering, og et interval på fra -40eC til stuetemperatur er derfor almindeligvis særlig egnet.3 4,031,079 or 4,359,420. Examples of such leaving groups are halogen, alkylthio, e.g. methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0P (0) (OR) 2, where R represents lower alkyl or -0P (0) (NR'R '') where R7 and R77 each represent 5 lower or all together with the nitrogen atom to which they are attached represents a heterocyclic group such as morpholine, pyrrolidine, piperidine or methylpiperazine. The reaction as described in (a) is preferably carried out under basic conditions, i.e. in the presence of a base, and preferred bases are 10 µm of potassium metal, e.g. potassium or sodium, alkoxides or hydrides. The reaction is preferably carried out in the presence of an organic solvent which does not react with the reactants and reaction products under the reaction conditions. The solvent is preferably anhydrous and particularly preferred is an anhydrous aprotic solvent such as dimethyl formamide (DMF) or the like. The temperature range used should be sufficiently high for the reaction to proceed at a reasonable pace and without unnecessary residence or decomposition, and a range of from -40 ° C to room temperature is therefore usually particularly suitable.

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Udgangsmaterialerne kan fremstilles ud fra kommercielt tilgængelige benzenderivater og ved anvendelse af velkendte syntesemetoder og som beskrevet i Synthesis, bind 10, s. 681-2.The starting materials can be prepared from commercially available benzene derivatives and using well known synthetic methods and as described in Synthesis, Vol. 10, pp. 681-2.

25 En forbindelse ifølge opfindelsen kan sammen med et sædvanligt hjælpestof, bærer eller fortyndingsmiddel og, om ønsket, i form af et farmaceutisk acceptabelt syreadditionssalt deraf, formuleres til et farmaceutisk præparat eller en enhedsdosis deraf og i sådan form anvendes i fast form som tabletter eller fyldte kapsler eller i 30 flydende form som opløsninger, suspensioner, emulsioner, eliksirer eller kapsler fyldt med væske, alle til oral brug; i form af suppositorier til rektal indgivelse; eller i form af sterile inji-cerbare opløsninger til parenteral (ink!. subkutan) brug. Sådanne farmaceutiske præparater og enhedsdosisformer deraf kan omfatte 35 sædvanlige bestanddele i sædvanlige mængder, med eller uden yderligere aktive forbindelser eller bestanddele og sådanne enhedsdosisformer bør indeholde en sådan til lindring af en lidelse i centralnervesystemet effektiv mængde af den aktive bestanddel, som står i rimeligt forhold til det beregnede daglige dosisområde, som 4A compound of the invention, together with a conventional adjuvant, carrier or diluent and, if desired, in the form of a pharmaceutically acceptable acid addition salt thereof, may be formulated into a pharmaceutical composition or unit dose thereof and in such form used in solid form as tablets or filled. capsules or in liquid form as solutions, suspensions, emulsions, elixirs or liquid-filled capsules, all for oral use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise 35 usual constituents in usual amounts, with or without additional active compounds or constituents, and such unit dosage forms should contain such as to relieve a central nervous system disorder effective amount of the active ingredient which is proportionate to the calculated daily dose range, as 4

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skal anvendes. Tabletter, som indeholder ti (10) mg aktiv bestanddel eller mere generelt ti (10) til tredive (30) mg per tablet, er passende repræsentative enhedsdosisformer.must be used. Tablets containing ten (10) mg of active ingredient or more generally ten (10) to thirty (30) mg per tablet are suitably representative unit dosage forms.

5 Forbindelserne ifølge opfindelsen kan således bruges til formulering af farmaceutiske præparater, f.eks. til oral eller parenteral indgivelse hos pattedyr inklusiv mennesker i overensstemmelse med sædvanlige galeniske farmaceutiske metoder.Thus, the compounds of the invention can be used to formulate pharmaceutical compositions, e.g. for oral or parenteral administration in mammals including humans in accordance with conventional galenic pharmaceutical methods.

10 Sædvanlige tilsætningsstoffer er sådanne farmaceutisk acceptable organiske eller uorganiske bærerstoffer, som er egnede til parenteral eller oral brug, og-som ikke på skadelig vis reagerer med den aktive forbindelse.Conventional additives are such pharmaceutically acceptable organic or inorganic carriers which are suitable for parenteral or oral use and which do not adversely react with the active compound.

15 Eksempler på sådanne bærerstoffer er vand, saltopløsninger, alkoholer, polyethylenglycoler, polyhydroxy-ethoxyleret ricinusolie, gelatine, lactose, amylose, magnesiumstearat, talkum, kiselsyre, fedtsyremonoglycerider og fedtsyrediglycerider, pentaerythritolfedtsyreestere, hydroxymethylcellulose og polyvinylpyrrolidon.Examples of such carriers are water, saline, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and fatty acid diglycerides, pentaerythritol fatty acid ester fatty acid ester, fatty acid ester fatty acid ester fatty acid ester fatty acid ester fatty acid ester fatty acid ethyl fatty acid ester

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De farmaceutiske præparater kan steriliseres og om ønsket blandes med sådanne hjælpemidler, såsom smøremidler, konserveringsmidler, stabiliseringsmidler, befugtningsmidler, emulgeringsmidler, salt til påvirkning af osmotisk tryk, puffere og/eller farvestoffer og 25 lignende, som ikke på skadelig vis reagerer med den aktive forbin-delse.The pharmaceutical compositions may be sterilized and, if desired, mixed with such adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, osmotic pressure salt, buffers and / or dyes, and the like, which do not adversely react with the active compound. -delse.

Injicerbare opløsninger eller suspensioner, fortrinsvis vandige opløsninger med den aktive forbindelse opløst i polyhydoxyleret 30 ricinusolie, er særligt egnede til parenteral anvendelse.Injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydoxylated castor oil, are particularly suitable for parenteral use.

Ampuller er hensigtsmæssige enhedsdoser.Ampoules are appropriate unit doses.

Til oral anvendelse er tabletter, drageer eller kapsler, der inde-35 holder talkum og/eller en kulhydratbærer eller binder eller lignende, specielt egnede, idet bæreren fortrinsvis er lactose og/eller majsstivise og/eller kartoffelstivelse. En sirup, eliksir eller lignende kan anvendes, når en sødet bærer kan bruges. I almindelighed dispenseres forbindelserne ifølge opfindelsen i enhedsdosisform,For oral use, tablets, dragees or capsules containing talc and / or a carbohydrate carrier or binder or the like are especially suitable, the carrier being preferably lactose and / or corn starch and / or potato starch. A syrup, elixir or the like can be used when a sweetened carrier can be used. In general, the compounds of the invention are dispensed in unit dosage form,

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5 hvor en enhedsdosis omfatter fra 0,05 til 100 mg aktiv forbindelsel i en farmaceutisk acceptabel bærer.5 wherein a unit dose comprises from 0.05 to 100 mg of active compound in a pharmaceutically acceptable carrier.

En typisk tablet, som kan fremstilles efter sædvanlige 5 tabletteringsmetoder, indeholder:A typical tablet which can be prepared according to the usual tableting methods contains:

Aktiv forbindelse 1,0 mgActive compound 1.0 mg

Lactosum 67,8 mg Ph.Eur.Lactosum 67.8 mg Ph.Eur.

Avicel® 31,4 mg 10 Amber!ite ® IRP 88 1,0 mgAvicel® 31.4 mg 10 Amber! Itte® IRP 88 1.0 mg

Magnesiumstearas 0,25 mg Ph.Eur.Magnesium stearase 0.25 mg Ph.Eur.

På grund af den store affinitet overfor benzodiazepinreceptorerne er forbindelserne ifølge opfindelsen meget anvendelige ved behandling 15 af centralnervesystemsygdomme eller -forstyrrelser, når de indgives i en mængde, der er effektiv til lindring, mildning eller fjernelse af sådann sygdomme eller lidelser. Den vigtige CNS-aktivitet af forbindelserne ifølge opfindelsen omfatter både krampehæmmende og angstdæmpende aktiviteter sammen med lav toksicitet, som sammen 1 20 giver et meget gunstigt terapeutisk indeks. Forbindelserne ifølge opfindelsen kan indgives i individer, f.eks. et menneske, der har behov for samme til behandling, lindring, mildning eller fjernelse af en indikation, som er forbundet med centralnervesystemet og benzodiazepinreceptorerne, og som gør sådan psykofarmaceutisk be-25 handling påkrævet, f.eks. personer, som lider af kramper og/eller som befinder sig i en angsttilstand. Om ønsket kan forbindelsen bruges i form af et farmaceutisk acceptabelt syreadditionssalt deraf (såsom hydrobromid, hydrochlorid eller sulfat), f.eks. fremstillet ved inddampning til tørhed af en opløsning af den frie base og 30 syren.Because of the high affinity for the benzodiazepine receptors, the compounds of the invention are very useful in the treatment of central nervous system disorders or disorders when administered in an amount effective to relieve, alleviate or remove such diseases or disorders. The important CNS activity of the compounds of the invention includes both anticonvulsant and anti-anxiety activities together with low toxicity, which together provide a very favorable therapeutic index. The compounds of the invention may be administered to individuals, e.g. a person in need of the same for treating, alleviating, alleviating or removing an indication associated with the central nervous system and benzodiazepine receptors and which makes such psychopharmaceutical treatment required, e.g. people who suffer from cramps and / or who are in an anxiety state. If desired, the compound can be used in the form of a pharmaceutically acceptable acid addition salt thereof (such as hydrobromide, hydrochloride or sulfate), e.g. prepared by evaporation to dryness of a solution of the free base and the acid.

De farmaceutiske egenskaber hos forbindelserne ifølge opfindelsen kan illustreres ved at bestemme deres evne til at fortrænge radioaktivt mærket flunitrazepam fra benzodiazepinreceptorer.The pharmaceutical properties of the compounds of the invention can be illustrated by determining their ability to displace radiolabeled flunitrazepam from benzodiazepine receptors.

3535

Fortrængningsaktiviteten for forbindelserne ifølge opfindelsen kan måles ved at bestemme ED^-værdien. EDgQ-værdi en repræsenterer den dosis (mg/kg) af en prøveforbindelse, hvormed den specifikke binding af flunitrazepam til benzodiazepinreceptorer i en levende hjerneThe displacement activity of the compounds of the invention can be measured by determining the ED The EDgQ value represents the dose (mg / kg) of a test compound by which the specific binding of flunitrazepam to benzodiazepine receptors in a living brain

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6 reduceres til 50% af kontrolværdien.6 is reduced to 50% of the control value.

En sådan in vivo bestemmelse udføres på følgende måde: 3 3 5 Princip. 20 minutter efter, at en dosis af H-flunitrazepam (H-FNM) (200 MCi/kg, i.v.) er blevet indgivet, når omfanget af specifik 3 H-FNM binding til hjernebenzodiazepinreceptorer den maximale værdi.Such an in vivo assay is performed as follows: 3 3 5 Principle. Twenty minutes after a dose of H-flunitrazepam (H-FNM) (200 MCi / kg, i.v.) has been administered, the extent of specific 3 H-FNM binding to brain benzodiazepine receptors reaches the maximum value.

3 H-FNMs specifikke binding kan delvis eller helt forhindres ved en samtidig eller forudgående indgivelse af farmakologiske aktive 10 benzodiazepiner og af nogle benzodiazepinlignende midler (Chang og Snyder, Eur. J. Pharmacol. 48» 212-218 (1978)).3 H-FNM specific binding may be partially or completely prevented by concomitant or prior administration of pharmacologically active benzodiazepines and some benzodiazepine-like agents (Chang and Snyder, Eur. J. Pharmacol. 48 »212-218 (1978)).

Bestemme!sesorocedure. Suspensioner af prøvestoffer (2mg/ml) fremstilles i 5% Duphasol®-X (ricinusolie-ethylenoxidderivat til emul-15 gering og opløsning af olie og andre vanduopløselige stoffer) ved lydbehandling i 10 minutter ved brug af en "Branson B15 microtip ultralydsapparat (indstilling 7). Grupper af 3 mus (hunmus af NMR-typen, der vejer 18-22 g) injiceres intraperitonealt med prøveforbindelsen i en mængde på 100 mg/kg. 15 minutter efter prøvestof-7 20 fets indgivelse tilføres musene intravenøst.4 øCi af 3H-FNM (70-90Determine! Sesorocedure. Suspensions of test substances (2mg / ml) are prepared in 5% Duphasol®-X (castor oil-ethylene oxide derivative for emulsification and solution of oil and other water-insoluble substances) by sonication for 10 minutes using a "Branson B15 microtip ultrasonic device (setting 7) Groups of 3 mice (NMR female weighing 18-22 g) are injected intraperitoneally with the test compound in an amount of 100 mg / kg 15 minutes after the test substance-7 20-fold administration, the mice are injected intravenously.4 oCi of 3H-FNM (70-90

Ci/mol) i 200 μΐ fysiologisk saltopløsning. 20 minutter efter 3 indgivelsen af H-FNM aflives musene ved halshugning, forhjernerne fjernes hurtigt (indenfor 30 sek.) og homogeniseres i 12 ml iskold 25 mM KH2P04, pH 7,1, ved hjælp af et Ultra-Turrax homogen i serings-25 apparat, som er forsynet med en N 10 aksel. To portioner på 1 ml filtreres straks gennem Whatman GF/C glasfiberfiltre og vaskes med 2 x 5 ml af ovennævnte puffer. Mængden af radioaktivitet på filtrene måles ved traditionel scintillationstælling. En gruppe af ubehandlede mus tjener som kontrolgruppe. 1-3 mus injiceres med 25 g/kg 30 clonazepam i.p 30 minutter før indgivelsen af H-FNM til bestemmelse af mængden af ikke-specifik H-FNM binding, som bør ligge på mellem 8-15% af den samlede binding. Når doser på 100 mg/kg inhiberer mere end 50% specifik 3H-flunitrazepambinding, indgives prøveforbindelserne i doser, som er en faktor på 3,16 gange mindre end den dosis, 35 som inhiberer mere end 50% specifik 3H-FNM binding. Som ovenfor nævnt defineres EDgQ-værdien som den dosis, der inhiberer 50% specifik 3H-FNM binding. Specifik binding defineres som mængden af binding i kontrol musene minus mængden af binding hos clonazepambe-handlede mus.Ci / mol) in 200 μΐ physiological saline. Twenty minutes after 3 administration of H-FNM, the mice are sacrificed by decapitation, the foreskins are rapidly removed (within 30 seconds) and homogenized in 12 ml of ice-cold 25 mM KH 2 PO 4, pH 7.1, using an Ultra-Turrax homogeneous apparatus fitted with an N 10 shaft. Two 1 ml portions are immediately filtered through Whatman GF / C fiberglass filters and washed with 2 x 5 ml of the above buffer. The amount of radioactivity on the filters is measured by traditional scintillation counting. A group of untreated mice serves as a control group. 1-3 mice are injected with 25 g / kg 30 clonazepam i.p 30 minutes prior to administration of H-FNM to determine the amount of non-specific H-FNM binding, which should be between 8-15% of the total binding. When doses of 100 mg / kg inhibit more than 50% specific 3H-flunitrazepam binding, the test compounds are administered at doses which are a factor of 3.16 times less than the dose which inhibits more than 50% specific 3H-FNM binding. As mentioned above, the EDgQ value is defined as the dose that inhibits 50% specific 3H-FNM binding. Specific binding is defined as the amount of binding in the control mice minus the amount of binding in clonazepam-treated mice.

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Resultater. EDgQ-værdien bestemmes ud fra dosisresponskurver. Hvis der kun indgives en dosis af prøvestoffet, beregnes ED50-værdien som følgende, forudsat at forhindringen af specifik binding ligger indenfor et interval på 25-75%: 5 ED,jq = (indgivet dosis) x_1_mg/kgResults. The EDgQ value is determined from dose-response curves. If only one dose of the test substance is administered, the ED50 value is calculated as follows, provided that the inhibition of specific binding is within a range of 25-75%: 5 ED, jq = (dose administered) x_1_mg / kg

Co - 1 10 cx hvor C. betegner specifik binding hos kontrolmusene og C betegnerCo - 1 10 cx where C represents specific binding in the control mice and C represents

O AO A

specifik binding hos mus, der er behandlet med prøvestoffet.specific binding in mice treated with the test substance.

15 De opnåede prøveresultater ved undersøgelse af nogle forbindelser ifølge opfindelsen vil fremgå af den efterfølgende tabel 1.The test results obtained when examining some compounds of the invention will be apparent from the following Table 1.

' 20 25 30 35'20 25 30 35

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s TABEL 1 rvxs TABLE 1 rvx

„£fS"£ fS

k6k6

Fortrængnings- 6 7 aktivitet in vivo R R__^__X _ ed50 (m9/k9) O-.Reproductive activity in vivo R R __ ^ __ X _ ed50 (m9 / k9) O-.

Η H -N(CH3)-CO- -( 0,69Η H -N (CH 3) -CO- - (0.69

Cl H -N(CH3)CO- 1,2 Η H -N(CH3J-C0- 3,4 " " tf tid Η H -N(CH3)CO- -I3,3 H H Cf u·3 Η H -N(CH3)-CH2- -\X4 6,9 Η H -N(-4)-0¾ 4-9Cl H -N (CH3) CO- 1.2 Η H -N (CH3J-CO- 3.4 "" tf time Η H -N (CH3) CO- -3.3 HH Cf u · 3 Η H -N (CH3) -CH2- - \ X4 6.9 Η H -N (-4) -0¾ 4-9

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Opfindelsen vil nu blive nærmere beskrevet under henvisning til de følgende eksempler:The invention will now be described in more detail with reference to the following examples:

Eksempel 1 5 A. 1.2.3.4-tetrahvdro-l-methv1-2.3-dioxo-auinoxalinExample 1 A. A. 1,2.3,4-Tetrahydro-1-methyl-2,3-dioxo-auinoxaline

En blanding af 12 g 98% oxalylchlorid i 19,5 ml triethylamin og 50 ml toluen tilsættes dråbevis en omrørt opløsning af 8,5 g o-N-10 methylaminoanilin i 80 ml toluen. Den derved fremkomne blanding opvarmes til tilbagesvaling i 1 time. Udfældningsproduktet vaskes med ether. Udvaskningsresten omrøres med vand og filtreres til dannelse af l,2,3,4-tetrahydro-l-methyl-2,3-dioxo-quinoxalin.A mixture of 12 g of 98% oxalyl chloride in 19.5 ml of triethylamine and 50 ml of toluene is added dropwise to a stirred solution of 8.5 g of o-N-10 methylaminoaniline in 80 ml of toluene. The resulting mixture is heated to reflux for 1 hour. The precipitate is washed with ether. The wash residue is stirred with water and filtered to give 1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline.

15 8-chlor-l,2,3,4-tetrahydro-l-methyl-2,3-dioxo-quinoxalin fremstilles på lignende måde ud fra 3-chlor-o-(N-methylamino)anilin.8-Chloro-1,2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline is similarly prepared from 3-chloro-o- (N-methylamino) aniline.

1,2,3,4-tetrahydro-1-cyclopropyl-2,3-di oxo-qui noxali n fremsti11es også på tilsvarende måde ud fra o-N-cyclopropylaminoanilin.1,2,3,4-Tetrahydro-1-cyclopropyl-2,3-dioxoquinoxalin is also prepared similarly from o-N-cyclopropylaminoaniline.

20 B. 1.2.3.3a.4.5-hexahvdro-4-oxo-Dvrrolf1.2-aloui noxalin 1,5 ml o-fluor-nitrobenzen og 8,2 g L-prolin omrøres i 50 ml DMSO ved 60eC i 3 timer. Blandingen inddampes derefter i vakuum til 25 dannelse af en gul olie. Denne olie opløses i 250 ml 96% ethanol og hydrogeneres ved normalt tryk ved stuetemperatur under anvendelse af 2 g Pd/C som katalysator. Efter hydrogenoptagelsens afslutning filtreres blandingen og inddampes i vakuum til dannelse af ovennævnte forbindelse. Smp. 169-72eC.B. 1.2.3.3a.4.5-Hexahydro-4-oxo-dihydrolph 1,2-alloxyxaline 1.5 ml o-fluoro-nitrobenzene and 8.2 g L-proline are stirred in 50 ml DMSO at 60 ° C for 3 hours. The mixture is then evaporated in vacuo to give a yellow oil. This oil is dissolved in 250 ml of 96% ethanol and hydrogenated at normal pressure at room temperature using 2 g of Pd / C as catalyst. After completion of the hydrogen uptake, the mixture is filtered and evaporated in vacuo to give the above compound. Mp. 169-72eC.

30 C. Ethvl 4.5-dihvdro-5-methv1-4-oxo-imidazo(1.5-alouinoxalin-3-car-boxvlat 6,2 ml diethylchlorphosphat tilsættes ved stuetemperatur en blanding 35 af 5,3 g l,2,3,4-tetrahydro-l-methyl-2,3-dioxo-quinoxalin og 4,5 g K-t-butoxId i 50 ml dimethyl formamid (DMF). Den derved fremkomne blanding opvarmes indtil den danner en opløsning og afkøles derefter til -30°C- En -30°C kold blanding af 4,8 g K-t-butoxid og 4,5 ml ethvl isocvanoacetat i 20 ml tør DMF tilsættes denne opløsnina. DenEthyl 4,5-dihydro-5-methyl-4-oxo-imidazo (1,5-aluminoxaline-3-carboxylate 6.2 ml of diethyl chlorophosphate at room temperature is added a mixture of 5.3 g, 2.3.4 tetrahydro-1-methyl-2,3-dioxo-quinoxaline and 4.5 g of Kt-butoxyl in 50 ml of dimethyl formamide (DMF) The resulting mixture is heated until it forms a solution and then cooled to -30 ° C. -30 ° C cold mixture of 4.8 g of Kt-butoxide and 4.5 ml of ethyl isocvanoacetate in 20 ml of dry DMF is added to this solution.

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ίο derved fremkomne blanding omrøres i 1 time ved stuetemperatur. Derefter tilsættes 100 ml vand og blandingen filtreres. Den derved fremkomne rest udkrystalliseres til dannelse af 2,5 g af ovennævnte forbindelse. Smp. 218,5-219,8eC.The resulting mixture is stirred for 1 hour at room temperature. Then add 100 ml of water and filter the mixture. The resulting residue is crystallized to give 2.5 g of the above compound. Mp. 218,5-219,8eC.

5 På lignende måde fremstilles ethyl 10,11,12,12a-tetrahydro-imidazo-(l,5-a)pyrrol(2,l-c)-quinoxalin-l-carboxylat, smp. 163,6-164,4eC, ud fra 1,2,3,3a,4,5-hexahydro-4-oxo-pyrrol(1,2-c)qui noxali n.Similarly, ethyl 10,11,12,12a-tetrahydro-imidazo- (1,5-a) pyrrole (2,1-c) -quinoxaline-1-carboxylate, m.p. 163.6-164.4 ° C, from 1,2,3,3a, 4,5-hexahydro-4-oxo-pyrrole (1,2-c) quinoxal n.

10 på lignende måde fremstilles ethyl 6-chlor-4,5-dihydro-5-methyl-4-oxo-imidazo(l,5-a)-quinoxalin-3-carboxylat, smp. 179*0, ud fra 8-chlor-1,2,3,4-tetrahydro-l-methyl-2,3-di oxo-qui noxali n.In a similar manner, ethyl 6-chloro-4,5-dihydro-5-methyl-4-oxo-imidazo (1,5-a) -quinoxaline-3-carboxylate is prepared, m.p. 179 * 0, from 8-chloro-1,2,3,4-tetrahydro-1-methyl-2,3-di oxo-quinoxyl n.

D. Methoxvacetamidoxim 15 2,3 g natrium i 33 ml tør methanol blandes med 6,55 g hydroxylaminhy-drochlorid i 66 ml tør methanol. Blandingen filtreres og filtratet tilsættes dråbevis 7,8 g methoxyacetonitril. Blandingen henstår i 48 timer ved stuetemperatur. Derefter afkøles blandingen til 4’C.D. Methoxacetamidoxim 15 Mix 2.3 g of sodium in 33 ml of dry methanol with 6.55 g of hydroxylamine hydrochloride in 66 ml of dry methanol. The mixture is filtered and the filtrate is added dropwise 7.8 g of methoxyacetonitrile. The mixture is left at room temperature for 48 hours. Then the mixture is cooled to 4 ° C.

20 Filtreringen og inddampningen af filtratet giver 8,7 g af ovennævnte forbindelse.The filtration and evaporation of the filtrate gives 8.7 g of the above compound.

På analog måde syntetiseres de følgende forbindelser ud fra passende nitriler: 25By analogy, the following compounds are synthesized from appropriate nitriles:

Propionamindoxim, cyclopropylcarboxami doxi m.Propionamindoxime, cyclopropylcarboxami doxi m.

E. 3-f3-cvcloDropvl-1.2.4-oxadiazo1-5-vll-4.5-dihvdro-5-methvl-4-oxo- 30 imidazon.5-alquinoxalin 50 mg natrium opløses i 25 ml tør ethanol indeholdende 3 g molekyl si (4Å), og 0,5 g cyclopropylcarboxamidoxim tilsættes denne blanding og derefter 0,6 g ethyl 4,5-dihydro-5-methyl-4-oxo-imidaxo(l,5-a)quinox-35 alin-3-carboxylat. Den derved fremkomne blanding tilbagesvales i 2 timer, hvorefter molekylesierne frafiltreres. Den ovennævnte forbindelse isoleres efter fordampning af opløsningsmidlet i vakuum efterfulgt af tilsætning af isvand og filtrering. Udbytte: 0,4 g af ovennævnte forbindelse. Smp. 224,7-225,6*0.E. 3- [3-Cyclo-Dropyl-1,2,4-oxadiazo-5-yl-4,5-dihydro-5-methyl-4-oxo-imidazone] 5-alquinoxaline 50 mg of sodium is dissolved in 25 ml of dry ethanol containing 3 g (4Å) and 0.5 g of cyclopropylcarboxamidoxime are added to this mixture and then 0.6 g of ethyl 4,5-dihydro-5-methyl-4-oxo-imidaxo (1,5-a) quinox-35-algin-3-carboxylate . The resulting mixture is refluxed for 2 hours, then the molecular sieves are filtered off. The above compound is isolated after evaporation of the solvent in vacuo followed by addition of ice water and filtration. Yield: 0.4 g of the above compound. Mp. 224.7 to 225.6 * 0th

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π På lignende måde syntetiseres de følgende forbindelser: 3-(3-methoxymethyl-1,2,4-oxadi azol-5-yl)-4,5-di hydro-5-methyl-4-oxo--imidazo(l,5-a)quinoxalin, smp. 184-90eC, ved omsætning af ethyl-4,5-5 -dihydro-5-methyl-4-oxo-imidazo(l,5-a)quinoxalin-3-carboxylat med methoxyacetami doxi m.π Similarly, the following compounds are synthesized: 3- (3-methoxymethyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5-methyl-4-oxo-imidazo (1, 5-a) quinoxaline, m.p. 184-90 ° C, by reacting ethyl 4,5-dihydro-5-methyl-4-oxo-imidazo (1,5-a) quinoxaline-3-carboxylate with methoxyacetamido doxi m.

3-(3-cyclopropyl-1,2,4-oxadi azol-5-yl)-4,5-di hydro-5-methyl-6-chlor--4-oxo-imidazo(l,5-a)quinoxalin, smp. 216,5-218,4*C, ved omsætning 10 af ethyl 6-chlor-4,5-dihydro-5-methyl-4-oxo-imidazo(l,5-a)quinoxalin--3-carboxylat med cyclopropylcarboxamidoxim.3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5-methyl-6-chloro-4-oxo-imidazo (1,5-a) quinoxaline , m.p. 216.5-218.4 ° C, by reaction of ethyl 6-chloro-4,5-dihydro-5-methyl-4-oxo-imidazo (1,5-a) quinoxaline-3-carboxylate with cyclopropylcarboxamidoxime.

1-(3-ethyl-1,2,4-oxadiazol-5-yl)-10,11,12,12a-tetrahydro-imidazo(l,- 5-a)pyrrol(2.,l-c)quinoxalin, smp. 123-124,9eC, ved omsætning af 15 ethyl 10,11,12,12a-tetrahydro-i mi dazo(1,5-a)pyrrol(2,1-c)qui noxali n med propionamidoxim.1- (3-Ethyl-1,2,4-oxadiazol-5-yl) -10,11,12,12a-tetrahydro-imidazo (1,5-a) pyrrole (2,1-c) quinoxaline, m.p. 123-124.9 ° C, by reacting 15 ethyl 10,11,12,12a-tetrahydro-i-mi dazo (1,5-a) pyrrole (2,1-c) qui noxali n with propionamidoxime.

l-(3-cycloprolyl-1,2,4-oxadiazol-5-yl)-10,11,12,12a-tetrahydro-imid-azo(l,5-a)pyrrol(2,l-c)quinoxalin, smp. 142,5eC, ved omsætning af / 20 ethyl 10,ll,12,12a-tetrahydro-imidazo(l,5-a)pyrrol(2,l-c)quinoxalin med cyclopropylcarboxamidoxim.1- (3-cycloprolyl-1,2,4-oxadiazol-5-yl) -10,11,12,12a-tetrahydro-imide-azo (1,5-a) pyrrole (2,1-c) quinoxaline, m.p. 142.5 ° C, by reacting ethyl 20,11,12,12a-tetrahydro-imidazo (1,5-a) pyrrole (2,1-c) quinoxaline with cyclopropylcarboxamidoxime.

Eksempel 2 25 A. 3-cvcloproDvl-5-isocvanomethvl-1.2.4-oxadiazol a. 3-cvclopropyl-5-formvlami nomethvl-1.2.4-oxadi azolExample 2 A. 3-Cyclopropyl-5-isocvanomethyl-1,2,4-oxadiazole a. 3-Cyclopropyl-5-formylamino-methyl-1,2,4-oxadiazole

En opløsning af ethyl formyl aminomethyl-carboxyl at (150 mmol) og 30 cyclopropylcarboxamidoxim (100 mmol) i 100% EtOH (100 ml) tilføres Na (200 mg,) og en knust molekylsi (4Å) (10 g). Den derved opnåede blanding omrøres og opvarmes til tilbagesvaling i 16 timer. Blandingen afkøles til stuetemperatur, filtreres gennem filter og filtratet inddampes i vakuum. Den olieagtige inddampningsrest deles 35 i en CHClg fase, som tørres med NagSO^ og inddampes til dannelse af ovennævnte forbindelse i form af en olie.A solution of ethyl formyl aminomethyl carboxyl at (150 mmol) and cyclopropylcarboxamidoxim (100 mmol) in 100% EtOH (100 ml) is added to Na (200 mg,) and a crushed molecular sieve (4 Å) (10 g). The resulting mixture is stirred and heated to reflux for 16 hours. The mixture is cooled to room temperature, filtered through filter and the filtrate is evaporated in vacuo. The oily residue is partitioned into a CHCl 3 phase which is dried over Na 2 SO 4 and evaporated to give the above compound as an oil.

b. 3-cvclopropvl-5-isocvanomethv1-1.2.4-oxadiazolb. 3-Cyclopropyl-5-isocvanomethyl-1,2,4-oxadiazole

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1212

En omrørt opløsning af 3-cyclopropyl-5-formylaminomethyl-l,2,4-oxa-diazol (60 mmol) og tri ethyl amin (176 mmol) i CHgClg (100 ml) tilføres dråbevis POClg (60 mmol) ved 0*C. Blandingen får derefter lov til at henstå i 30 minutter under omrøring ved 0eC, hvorefter en 5 opløsning af NagCO^ (60 mmol) i HgO (50 ml) tilsættes. Blandingen opvarmes til stuetemperatur, hvorefter den organiske fase fraskilles, tørres og inddampes i vakuum. Inddampningsresten behandles med ether, dekanteres og opløsningen inddampes til dannelse af ovennævnte forbindelse i form af en olie. Olien bruges uden yderligere 10 rensning. Forbindelsen karakteriseres ved dens IR absorptionsbånd ved 2160 cm-*.A stirred solution of 3-cyclopropyl-5-formylaminomethyl-1,2,4-oxa-diazole (60 mmol) and triethyl amine (176 mmol) in CH 2 Cl 2 (100 ml) is added dropwise POClg (60 mmol) at 0 ° C. . The mixture is then allowed to stand for 30 minutes with stirring at 0 ° C, after which a solution of NagCO 3 (60 mmol) in HgO (50 ml) is added. The mixture is warmed to room temperature, after which the organic phase is separated, dried and evaporated in vacuo. The evaporation residue is treated with ether, decanted and the solution is evaporated to give the above compound as an oil. The oil is used without further 10 cleaning. The compound is characterized by its IR absorption band at 2160 cm -1.

På lignende måde fremstilles 3-ethyl-5-isocyanomethyl-l,2,4-oxadia-zol ud fra 3-ethyl-5-formylaminomethyl-l,2,4-oxadiazol. IR: cm~*:-15 2170.Similarly, 3-ethyl-5-isocyanomethyl-1,2,4-oxadiazole is prepared from 3-ethyl-5-formylaminomethyl-1,2,4-oxadiazole. IR: cm ~ *: 2170.

B. 5-cvc1oDroDvl-3-isocvanomethvl-1.2.4-oxadiazol a. Formviaminomethvl-carboxamidoxlm 7 20 0,55 mmol nylig frigjort hydroxylamin opløst i 370 ml methanol sættes til 53,6 g (0,638 mmol) N-formylaminoacetonitril. Et isbad bruges til at holde temperaturen under 20eC under tilsætningen. Opløsningen får lov til at henstå natten over ved stuetemperatur, 25 hvorefter den inddampes til dannelse af ovennævnte forbindelse i form af blege krystaller. Dekomponering: 104-110eC.B. 5-Cyclodrodyl-3-isocvanomethyl-1,2,4-oxadiazole a. Formylaminomethyl-carboxamide oxime 7 0.55 mmol of newly released hydroxylamine dissolved in 370 ml of methanol is added to 53.6 g (0.638 mmol) of N-formylaminoacetonitrile. An ice bath is used to keep the temperature below 20 ° C during the addition. The solution is allowed to stand overnight at room temperature, after which it is evaporated to give the above compound in the form of pale crystals. Decomposition: 104-110eC.

b. 3-formvlaminomethvl-5-cvcloDroDvl-1.2.4-oxadiazol 30 En blanding af 35 ml ethyl cyclopropylcarboxyl at, 20 g formyl amino-methyl carboxamidoxim, 1 g natrium og 30 g af en knust molekylsi (4Å) tilbagesvales i 300 ml abs. EtOH i 8 timer, hvorefter yderligere 1 g natrium tilsættes.b. 3-Formylaminomethyl-5-cycloDroDyl-1,2,4-oxadiazole A mixture of 35 ml of ethyl cyclopropyl carboxyl, 20 g of formyl amino-methyl carboxamidoxim, 1 g of sodium and 30 g of a crushed molecular sieve (4Å) is refluxed in 300 ml abs. EtOH for 8 hours, then an additional 1 g of sodium is added.

35 Reaktionsblandingen filtreres og filtratet inddampes. Den derved fremkomne mørke olieagtige inddampningsrest suspenderes i 300 ml CHC13, filtreres og filtratet inddampes til dannelse af ovennævnte forbindelse i form af en olie. H-NMR (60 MHz, CDC13) (ppm): 1,2 (4H, m), 2,8 (IH, m), 4,5 (2H, d, J=6 Hz), 7,8 (IH, bred-NH), 8,2 (IH,The reaction mixture is filtered and the filtrate is evaporated. The resulting dark oily evaporation residue is suspended in 300 ml of CHCl 3, filtered and the filtrate is evaporated to give the above compound as an oil. H-NMR (60 MHz, CDCl 3) (ppm): 1.2 (4H, m), 2.8 (1H, m), 4.5 (2H, d, J = 6 Hz), 7.8 (1H) broad NH) 8.2 (1H,

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13 s).13 s).

På lignende måde syntetiseres de følgende forbindelser ud fra passende ethylestere: 5 3-formylami!nomethyl-5-ethyl-l,2,4-oxadiazol. H-NMR(60 MHz, CDC13) (ppm): 1,4 i(3H, t, J=8 Hz), 2,9 (2H, q, J=8 Hz), 4,55 (2H, s), 7,8 (IH, bred-NH), 8,25 (IH, s).Similarly, the following compounds are synthesized from appropriate ethyl esters: 3-formylaminomethyl-5-ethyl-1,2,4-oxadiazole. H-NMR (60 MHz, CDCl 3) (ppm): 1.4 i (3H, t, J = 8 Hz), 2.9 (2H, q, J = 8 Hz), 4.55 (2H, s) , 7.8 (1H, broad-NH), 8.25 (1H, s).

10 3-formylami,Tiomethyl-5-methyl-l,2,4-0xadiazol. H-NMR (60 MHz, DCD13) (ppm): 2,6 (3H, s), 4,6 (2H, d, J=3 Hz), 7,4 (IH, bred-NH), 8,25 (IH, s).3-Formylamide, Thiomethyl-5-methyl-1,2,4-oxadiazole. H-NMR (60 MHz, DCD13) (ppm): 2.6 (3H, s), 4.6 (2H, d, J = 3 Hz), 7.4 (1H, wide-NH), 8.25 (IH, s).

3-formyl ami noethyl-5-methoxymethyl-1,2,4-oxad i azol.3-formylaminoethyl-5-methoxymethyl-1,2,4-oxide in azole.

15 H-NMR (60 MHz, CDC13) (ppm): 3,5 (3H, s), 4,7 (4H, s+d, J=6 Hz), 7,8 (1H, bred-NH^,, 8,25 (H,s).1 H-NMR (60 MHz, CDCl 3) (ppm): 3.5 (3H, s), 4.7 (4H, s + d, J = 6 Hz), 7.8 (1H, broad-NH , 8.25 (H, s).

c. 6-cvcloDroDvl-3-isocvanomethvl-1.2.4-oxadiazol ' 20c. 6-CycloDroDyl-3-isocvanomethyl-1,2,4-oxadiazole

En omrørt opløsning af 5-cyclopropyl-3-formylamino-methyl-l,2,4-oxa-diazol (60 mmol) og triethylamin (176 mmol) i D^Clg (100 ml) tilføres dråbevis POCl3 (60 mmol) ved 0eC. Blandingen henstilles derefter i 3Ό minutter ved omrøring ved 0eC, hvorefter en opløsning 25 af Na2C03 (60 mmol) i H2O (50 ml) tilsættes. Blandingen opvarmes til stuetemperatur, hvorefter den organiske fase fraskilles, tørres og inddampes i vakuum. Inddampningsresten behandles med ether, dekanteres og opløsningen inddampes til dannelse af ovennævnte forbindelse i form af en olie. Olien bruges uden yderligere rensning. Forbindel-30 sen karakteriseres ved dens IR absorptionsbånd ved 2160 cm"*.A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxa-diazole (60 mmol) and triethylamine (176 mmol) in D 2 Clg (100 ml) is added dropwise POCl 3 (60 mmol) at 0 ° C. . The mixture is then allowed to stir for 3Ό minutes at 0 ° C, then a solution of Na 2 CO 3 (60 mmol) in H 2 O (50 ml) is added. The mixture is warmed to room temperature, after which the organic phase is separated, dried and evaporated in vacuo. The evaporation residue is treated with ether, decanted and the solution is evaporated to give the above compound as an oil. The oil is used without further purification. The compound is characterized by its IR absorption band at 2160 cm -1.

På samme måde fremstilles 5-ethyl-3-isocyanomethyl-l,2,4-oxadiazol, 5-methyl-3-isocyanomethyl-1,2,4-oxadiazol og 5-methoxy-methyl-3-iso-cyanomethyl-l,2,4-oxadiazol. Alle forbindelserne er 35 olier og karakteriseres ved deres IR strækbånd ved 2160 cm"*.Similarly, 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole, 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole and 5-methoxy-methyl-3-isocyanomethyl-1 are prepared. 2,4-oxadiazole. All the compounds are 35 oils and are characterized by their IR stretch bands at 2160 cm -1.

C. 1.2.3.4-tetrahvdro-l-methvl-3-oxo-ouinoxalin 5,2 g o-floor-nitrobenzen, 3,2 g sarcosin og 5,2 ml triethylaminC. 1.2.3.4-Tetrahydro-1-methyl-3-oxo-ouinoxaline 5.2 g of o-floor nitrobenzene, 3.2 g of sarcosine and 5.2 ml of triethylamine

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14 omrøres i 25 ml DMSO ved 70*C i 4 dage. Blandingen inddampes i vakuum og inddampningsresten deles mellem vand og methylenchlorid.14 is stirred in 25 ml of DMSO at 70 ° C for 4 days. The mixture is evaporated in vacuo and the residue is partitioned between water and methylene chloride.

Den organiske fase inddampes i vakuum. Inddampningsresten opløses i 100 ml 96% ethanol og hydrogeneres ved normalt tryk under anvendelse 5 af 0,5 g Pd/C som katalysator. Efter hydrogenoptagelsens afslutning filtreres blandingen og inddampes i vakuum. Inddampningsresten vaskes med vand med dinatriumcarbonat, ether og vand. Udbytte af ovennævnte forbindelse: 1,3 g, smp. 132eC.The organic phase is evaporated in vacuo. The residue is dissolved in 100 ml of 96% ethanol and hydrogenated at normal pressure using 5 g of Pd / C as catalyst. After the hydrogen uptake is complete, the mixture is filtered and evaporated in vacuo. The residue is washed with water with disodium carbonate, ether and water. Yield of the above compound: 1.3 g, m.p. 132eC.

10 D. 3-(5-cvclopropvl-1.2.4-oxadiazol-3-vl)-4.5-di hvdro-4-oxo-5-meth-vl-imidazofl.5-a)quinoxalin 1,7 ml di ethylchlorphosphat sættes ved stuetemperatur til en blanding af 1,8 g l,2,3,4-tetrahydro-l-methyl-2,3-dioxo-quinoxalin og 12 15 mmol natriumhydrid i 15 ml tør di methyl formamid (DMF). Den derved fremkomne blanding opvarmes indtil der dannes en klar opløsning.D. 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5-methyl-imidazofl-5-a) quinoxaline 1.7 ml of ethyl chlorophosphate is added at room temperature to a mixture of 1.8 g, 2,3,4-tetrahydro-1-methyl-2,3-dioxo-quinoxaline and 12 15 mmol sodium hydride in 15 ml dry di methyl formamide (DMF). The resulting mixture is heated until a clear solution is formed.

Derefter afkøles opløsningen til -30eG. En -30*C kold blanding af 1,35 g af K-t-butoxid og 1,8 g 3-isocyanomethyl-5-cyclopropyl-l,2,4-1 20 -oxadiazol i 10 ml DMF tilsættes denne opløsning ved -10 til -20eC.Then the solution is cooled to -30eG. A -30 ° C cold mixture of 1.35 g of Kt-butoxide and 1.8 g of 3-isocyanomethyl-5-cyclopropyl-1,2,4-120-oxadiazole in 10 ml of DMF is added at -10 to -20E C.

Den derved fremkomne blanding får lov til at henstå natten over ved 4eC. 3 ml iseddikesyre tilsættes og blandingen hældes i vand og filtreres derefter. Produktet vaskes med ethyl acetat, hvilket giver 150 mg af ovennævnte forbindelse, Smp. 284,2-288,2eC.The resulting mixture is allowed to stand overnight at 4 ° C. 3 ml of glacial acetic acid are added and the mixture is poured into water and then filtered. The product is washed with ethyl acetate to give 150 mg of the above compound, m.p. 284,2-288,2eC.

25 På samme måde fremstilles de følgende forbindelser: l-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-imid-azo(l,5-a)pyrrol(2,l-c)quinoxalin, smp. for hydrochloridet 190-200eC, 30 ved omsætning af l,2,3,3a,4,5-hexahydro-4-oxo-pyrrol(l,2-a)quinoxa-1 in med 5-cyclopropyl-3-isocyanomethyl-l,2,4-oxadiazol.Similarly, the following compounds are prepared: 1- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -10,11,12,12a-tetrahydro-imide-azo (1,5-a) pyrrole (2, lc) quinoxaline, m.p. for the hydrochloride 190-200 ° C, by reacting 1,2,3,3a, 4,5-hexahydro-4-oxo-pyrrole (1,2-a) quinoxa-1 in with 5-cyclopropyl-3-isocyanomethyl-1 , 2,4-oxadiazole.

1-(5-methyl-l,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-imidazo(l-,5-a)pyrrol(2,l-c)quinoxalin, smp. 146,4-148,5eC, ved omsætning af 35 l,2,3,3a,4,5-hexahydro-4-oxo-pyrrol(l,2-a)quinoxalin med 5-methyl-3--i socyanomethyl-1,2,4-oxadi azol.1- (5-methyl-1,2,4-oxadiazol-3-yl) -10,11,12,12a-tetrahydro-imidazo (1-, 5-a) pyrrole (2,1-c) quinoxaline, m.p. 146.4-148.5 ° C, by reacting 35 l, 2,3,3a, 4,5-hexahydro-4-oxo-pyrrole (1,2-a) quinoxaline with 5-methyl-3-in socyanomethyl 1,2,4-oxadi azole.

3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-methyl-imidazo-(l,5-a)quinoxalin, smp. for hydrochloridet 275-80oC, ved omsætning3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-methyl-imidazo- (1,5-a) quinoxaline, m.p. for the hydrochloride 275-80 ° C, by reaction

DK 154142 BDK 154142 B

15 af 1,2,3,4-itetrahydro-l-methyl-3-oxo-quinoxalin med 5-cyclopropyl-3--i socyanomethy1-1,2,4-oxad i azol.15 of 1,2,3,4-itetrahydro-1-methyl-3-oxo-quinoxaline with 5-cyclopropyl-3-in socyanomethyl-1,2,4-oxad in azole.

3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-cyclopropylimi-5 dazo(l,5-a)quinoxalin, smp. for hydrochloridet 290-300‘C, ved omsætning af l^jS^^tetrahydro-l-cyclopropyl-3-oxo-quinoxalin med 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazol.3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-cyclopropylimidazole (1,5-a) quinoxaline, m.p. for the hydrochloride 290-300 ° C, by reacting 1SS ^^ tetrahydro-1-cyclopropyl-3-oxo-quinoxaline with 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole.

10 15 7 20 25 30 3510 15 7 20 25 30 35

Claims (4)

1. Imidazol(l,5-a)quinoxalinforbindelse, kendetegnet ved, at den har den almene formel k5 hvor X betegner —π , eller ? 15 hvor R' betegner Cj_g-alkyl, Cgy-cycloalkyl eller Cj^-alkoxymeth-yl, R® og R^ hver betegner hydrogen eller halogen, og -A- betegner -N(R")-C(0)-, -N(R'7)-CH2— eller O 20 hvor R" betegner hydrogen, C^ j-cycloalkyl eller Cj_g-alkyl.1. Imidazole (1,5-a) quinoxaline compound, characterized in that it has the general formula k5 where X represents -π, or? Wherein R 'represents Cj_ alkyl alkyl, C-cyc cycloalkyl or Cj ^alkoxymethyl, R og and R ^ each represent hydrogen or halogen, and -A- represents -N (R)) - C (O) -, - N (R'7) -CH 2 - or O where R "represents hydrogen, C 1-6 cycloalkyl or C 1-6 alkyl. 2. Forbindelse ifølge krav 1, hvilken forbindelse er 3-(3-cyclopro-pyl-l,2,4-oxadiazol-5-yl)-4,5-dihydro-5-methyl-4-oxo-imidazo(l,5-a)- 25 -quinoxalin.A compound according to claim 1, which is 3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5-methyl-4-oxo-imidazo (1, 5-a) -25-quinoxaline. 3. Farmaceutisk præparat, som er egnet til brug ved behandling af en centralnervesystemssygdom, kendetegnet ved, at det omfatter en forbindelse ifølge et hvilket som helst af kravene 1-2 30 og en farmaceutisk acceptabel bærer eller fortyndingsmiddel.A pharmaceutical composition suitable for use in the treatment of a central nervous system disease, characterized in that it comprises a compound according to any one of claims 1-2 30 and a pharmaceutically acceptable carrier or diluent. 4. Farmaceutisk præparat ifølge krav 3, kendetegnet ved, at det er i form af en oral dosisenhed, som omfatter 1-100 mg af den aktive forbindelse. 35Pharmaceutical composition according to claim 3, characterized in that it is in the form of an oral dosage unit comprising 1-100 mg of the active compound. 35