DK155006B

DK155006B - Fused imidazole derivatives, and pharmaceutical preparation comprising such a compound

Info

Publication number: DK155006B
Application number: DK499486A
Authority: DK
Inventors: Frank Waetjen; Mogens Engelstoft
Original assignee: Ferrosan As
Priority date: 1985-10-17
Filing date: 1986-10-17
Publication date: 1989-01-23
Also published as: DK499486A; DK155006C; DK499486D0

Description

1 DK 155006 B1 DK 155006 B

Opfindelsen angår hidtil ukendte terapeutisk aktive kondenserede imidazolderi vater og farmaceutiske præparater indeholdende disse.This invention relates to novel therapeutically active condensed imidazole derivatives and pharmaceutical compositions containing them.

De hidtil ukendte forbindelser er anvendelige til 5 psykofarmaceutisk brug, f.eks. til behandling af centralnervesystemssygdomme, f.eks. som krampehæmmende midler eller angstdæmpende midler. De hidtil ukendte forbindelser ifølge opfindelsen er endvidere anvendelige som anthelmintika, ekto- og endoparasiti cider, insekticider og acaricider til behandling af mennesker og dyr.The novel compounds are useful for psychopharmaceutical use, e.g. for the treatment of central nervous system diseases, e.g. as anticonvulsants or anxiety relievers. The novel compounds of the invention are further useful as anthelmintics, ecto- and endoparasitic ciders, insecticides and acaricides for the treatment of humans and animals.

Det er velkendt (M. Nielsen et al., Biochem. Pharmacol., Bind 34, 3633-42(1985)), at centralnervesystemsundertrykkende midler, såsom etomidat, etazolat (SQ 20.009) og carbazolat påvirker t-butylbicyclophosphorthionatbindingen til aniongatingmekanismen i GABA/benzodi azepi nreceptor chloridkanalkomplekset.It is well-known (M. Nielsen et al., Biochem. Pharmacol., Vol. 34 benzodi azepi nreceptor chloride channel complex.

Herudover kendes fra EP patentpublikationerne 027214, 0059386, 0059391, 0109921 og 0150040 imidazodiazepinderivater, som udviser affinitet over for de centrale benzodiazepinreceptorer.In addition, from EP patent publications 027214, 0059386, 0059391, 0109921 and 0150040 are known imidazodiazepine derivatives which exhibit affinity for the central benzodiazepine receptors.

Endvidere er det velkendt, at ivermectins ormefordri vende 20 aktivitet formidles gennem dets binding til chloridionkanalen.Furthermore, it is well known that ivermectin's worm-disperse activity is mediated through its binding to the chloride ion channel.

Det har vist sig, at en hidtil ukendt gruppe af kondenserede imidazolderi vater udviser en så stor affinitet overfor TBPS bindingsstedet, at de er i stand til at fortrænge radioaktivt mærket TBPS fra sådanne bindingssteder. Denne egenskab gør de hidtil ukendte forbindelser brugbare i psykofarmaceutiske præparater, såsom krampehæmmende midler, angstdæmpende midler, hypnotiske midler, beroligende midler, nootropiske midler og som anthelmintika, ekto- og endoparasiticider, insekticider og acaricider.It has been found that a novel group of condensed imidazole veins exhibit such an affinity for the TBPS binding site that they are capable of displacing radiolabeled TBPS from such binding sites. This property makes the novel compounds useful in psychopharmaceuticals, such as anticonvulsants, anxiety relievers, hypnotic agents, sedatives, nootropic agents and as anthelmintics, ecto- and endoparasiticides, insecticides and acaricides.

De hidtil ukendte forbindelser ifølge opfindelsen er 30The novel compounds of the invention are 30

kondenserede imidazolderivater med den almene formel Icondensed imidazole derivatives of the general formula I

ry x ω 35 /V"/ @urow x ω 35 / V ”/ @u

2 DK 155006 B2 DK 155006 B

hvor o-- Ν'- _/ N -4 ? X betegner v —R« —R* eller COgR1 5 hvor R1 betegner C-|_g-alkyl, C^.y-cycloalkyl eller C-j^-alkoxymethyl og - A - betegner 10 hvor n og m hver betegner 0 eller 1 og -Y- betegner -0-, -S-, -CHg-, eller -NR"-, hvor R" betegner hydrogen eller C-j_g-alkyl.where o-- Ν'- _ / N -4? X represents v -R «-R * or COgR1 where R R1 represents C- |g alkyl, C ^yy cycloalkyl or Cj ^alkoxymethyl and - A - represents 10 wherein n and m each represent 0 or 1 and - Y- represents -O-, -S-, -CHg-, or -NR "-, where R" represents hydrogen or C1-6 alkyl.

De omhandlede forbindelser fremstilles ved:The present compounds are prepared by:

jg a) omsætning af en forbindelse med den almene formel IIand (a) reaction of a compound of the general formula II

@ΓΎ* 20 (11) hvor -A- har den ovenfor anførte betydning og Z betegner en 25 fraspaltelig gruppe, med en forbindelse med den almene formel m under basiske betingelser, til dannelse af en forbindelse med den 3q almene formel I, hvor X og -A- har de ovenfor anførte betydninger eller@ ΓΎ * 20 (11) where -A- has the meaning given above and Z represents a leaving group, with a compound of the general formula m under basic conditions, to form a compound of the 3q of general formula I, where X and -A- have the above meanings or

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

/ \ (III)/ \ (III)

isCTisCT

DK 155006 BDK 155006 B

hvor -A- har den ovenfor anførte betydning, med en forbindelse med den almene formel IVwherein -A- has the meaning set forth above, with a compound of general formula IV

-NOH-NOH

R'-C^ 5 R C\ NH2 hvor R' har den ovenfor angivne betydning, til dannelse af en forbindelse med den almene formel I, hvor -A- har den ovenfor anførte jq betydning og hvor X betegner 25 hvor R' har den ovenfor angivne betydning.Wherein R 'has the meaning given above to form a compound of general formula I wherein -A- is as defined above and where X represents 25 wherein R' is the above meaning given.

Egnede fraspaltelige grupper (Z) er omtalt i USSuitable leaving groups (Z) are disclosed in the US

patentskrifterne nr. 4.031.079 eller 4.359.420. Eksempler på sådanne fraspaltelige grupper er halogen, alkylthio, f.eks. methylthio, 2o aralkylthio, N-nitrosoal kyl amino, alkoxy, mercapto, -OP-iOMOR^» hvor R betegner lavere al kyl og fortrinsvis ethyl, -OP(0)(NR'R" ), hvor R'og R" hver repræsenterer lavere alkyl eller phenyl eller sammen med det nitrogenatom, som de er bundet til, danner en heterocyklisk gruppe såsom morpholin, pyrrol i din, piperidin eller 25 methyl piperazin.U.S. Patent Nos. 4,031,079 or 4,359,420. Examples of such leaving groups are halogen, alkylthio, e.g. methylthio, 2-aralkylthio, N-nitrosoalkyl amino, alkoxy, mercapto, -OP-iOMOR 2, where R represents lower alkyl and preferably ethyl, -OP (O) (NR'R "), where R'and R represents lower alkyl or phenyl or together with the nitrogen atom to which they are attached form a heterocyclic group such as morpholine, pyrrole in your, piperidine or methyl piperazine.

Omsætningen udføres fortrinsvis under tilstedeværelse af en base og foretrukne baser er alkalimetal- f.eks. kalium- eller natrium-, alkoxider eller hydrider. Omsætningen som beskrevet under a) udføres fortrinsvis under tilstedeværelse af et organisk 30 opløsningsmiddel, som ikke reagerer med reaktanterne og reaktionsprodukterne under reaktionsbetingelserne. Opløsningsmidlet er fortrinsvis vandfrit og særligt foretrukket er brugen af et vandfrit aprotisk opløsningsmiddel, såsom dimethylformamid (DMF) eller lignende. Reaktionstemperaturen bør være tilstrækkelig høj til, 35 at omsætningen kan forløbe i et rimeligt tempo og uden unødvendigt ophold eller dekomponering, og et interval, der ligger fra -40°C til ca. stuetemperatur, er normalt særligt egnet.The reaction is preferably carried out in the presence of a base and preferred bases are alkali metal - e.g. potassium or sodium, alkoxides or hydrides. The reaction as described in (a) 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 the use of an anhydrous aprotic solvent such as dimethylformamide (DMF) or the like. The reaction temperature should be sufficiently high to allow the reaction to proceed at a reasonable rate and without undue delay or decomposition, and a range ranging from -40 ° C to approx. room temperature is usually particularly suitable.

Udgangsmaterialerne kan fremstilles ved velkendteThe starting materials can be prepared by well known ones

4 DK 155006 B4 DK 155006 B

fremgangsmåder og ud fra kommercielt tilgængelige forbindelser.methods and from commercially available compounds.

En forbindelse ifølge opfindelsen kan sammen med et sædvanligt hjælpestof, bærer eller fortyndingsmiddel, og om ønsket i g form af et farmaceutisk acceptabelt syreadditionssalt deraf, formuleres til et farmaceutisk præparat eller en enhedsdosis deraf og i sådan form bruges i fast form, såsom tabletter eller fyldte kapsler, eller i flydende form, såsom opløsninger, suspensioner, emulsioner, eliksirer eller kapsler fyldt med samme, alle til oral jq anvendelse; i form af suppositorier til rektal indgivelse; eller i form af sterile injicerbare opløsninger til parenteral (ink!. subkutan) brug. Sådanne farmaceutiske præparater og enhedsdosisformer heraf kan omfatte sædvanlige bestanddele i sædvanlige mængder, med eller uden yderligere aktive forbindelser eller bestanddele og j5 sådanne enhedsdosisformer bør indeholde en til lindring af en lidelse i centralnervesystemet effektiv mængde af den aktive bestanddel, der står i rimeligt forhold til det beregnede daglige dosisområde, som skal anvendes. Tabletter, som indeholder ca. ti (10) mg aktiv bestanddel eller mere generelt fra ca. ti (10) til tredive (30) mg 2Q per tablet, er passende repræsentative enhedsdosisformer.A compound of the invention, together with a conventional excipient, carrier or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, can be formulated into a pharmaceutical composition or unit dose thereof and in such form used in solid form such as tablets or filled capsules. or in liquid form, such as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral and use; in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (inc. subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise usual constituents in the usual amounts, with or without additional active compounds or constituents, and such unit dosage forms should contain an effective amount of the active ingredient which is proportionate to the disorder of the central nervous system. calculated daily dose range to be used. Tablets containing approx. ten (10) mg of active ingredient or more generally from ca. ten (10) to thirty (30) mg 2Q per tablet are suitably representative unit dosage forms.

Forbindelserne ifølge opfindelsen kan således bruges til formulering af farmaceutiske præparater, f.eks. til oral og parenteral indgivelse hos pattedyr herunder 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 and parenteral administration in mammals including humans in accordance with conventional galenic pharmaceutical methods.

25 Sædvanlige tilsætningsstoffer er sådanne farmaceutisk acceptable organiske eller uorganiske bærestoffer, som er egnede til parenteral eller enteral brug, og som ikke på skadelig vis reagerer med de aktive forbindelser.Usual additives are such pharmaceutically acceptable organic or inorganic carriers which are suitable for parenteral or enteral use and which do not adversely react with the active compounds.

Eksempler på sådanne bærere er vand, saltopløsninger, 3Q alkoholer, polyethylenglycoler, polyhydroxy-ethoxyleret ricinusolie, gelatine, lactose, amylose, magnesiumstearat, talkum, kiselsyre, fedtsyremonoglycerider og fedtsyrediglycerider, pentaerythritolfedt-syreestere, hydroxymethylcellulose og polyvinylpyrrolidon.Examples of such carriers are water, saline solutions, 3Q alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and fatty acid glycerides, pentaerythritol fatty acid acid fatty acid and fatty acid

De farmaceutiske præparater kan steriliseres og om ønsket 35 blandes med sådanne hjælpemidler, såsom emulgeringsmidler, salt til påvirkning af osmotisk tryk, puffere og/eller farvestoffer og lignende, som ikke på skadelig vis reagerer med de aktive forbindelser.The pharmaceutical compositions may be sterilized and, if desired, mixed with such adjuvants such as emulsifiers, osmotic pressure salt, buffers and / or dyes and the like, which do not adversely react with the active compounds.

5 DK 155006 B5 DK 155006 B

Injicerbare opløsninger eller suspensioner, fortrinsvis vandige opløsninger med den aktive forbindelse opløst i polyhydroxyleret ricinusolie, er særligt egnede til parenteral g anvendelse.Injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated 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 indeholder talkum og/eller en kulhydratbærer eller binder eller lignende, specielt egnede, idet bæreren fortrinsvis er lactose 10 og/eller majsstivelse og/eller kartoffelstivelse. En sirup, eliksir eller lignende kan anvendes, når en sødet bærer kan bruges.For oral use, tablets, dragees or capsules containing talc and / or a carbohydrate carrier or binder or the like are particularly suitable, the carrier being preferably lactose 10 and / or corn starch and / or potato starch. A syrup, elixir or the like can be used when a sweetened carrier can be used.

I almindelighed dispenseres forbindelserne ifølge opfindelsen i enhedsdosisform, hvor en enhedsdosis omfatter fra 0,05-100 mg aktiv forbindelse i en farmaceutisk acceptabel bærer.In general, the compounds of the invention are dispensed in unit dosage form, wherein a unit dose comprises from 0.05 to 100 mg of active compound in a pharmaceutically acceptable carrier.

Dosis af forbindelserne ifølge opfindelsen er 0,1-300 mg/dag, når de indgives i patienter, f.eks. mennesker, i form af et medikament.The dose of the compounds of the invention is 0.1-300 mg / day when administered to patients, e.g. humans, in the form of a drug.

En typisk tablet, som kan fremstilles efter sædvanlige tabletteri ngsmetoder, i ndeholder: 2Q Aktiv forbindelse 1,0 mgA typical tablet, which can be prepared by conventional tableting methods, in holder: 2Q Active Compound 1.0 mg

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

Avicef^ 31,4 mgAvicef ^ 31.4 mg

Amberi itJ^ IRP 88 1,0 mgAmberi itJ ^ IRP 88 1.0 mg

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

2g På grund af deres store affinitet overfor TBPS bindingsstedet er forbindelserne ifølge opfindelsen meget anvendelige til behandling af centralnervesystemssygdomme eller -forstyrrelser, når de indgives i en mængde, der er effektiv til lindring, mildning eller fjernelse af sådanne sygdomme eller forstyrrelser. Den vigtige CNS-aktivitet 30 for forbindelserne ifølge opfindelsen omfatter både krampehæmmende og angstdæmpende aktiviteter sammen med lav toksicitet, og frembyder derved et meget gunstigt terapeutisk indeks. Forbindelserne ifølge opfindelsen kan følgelig indgives i individer, f.eks. et menneske, som har behov for samme til behandling, lindring, mildning eller 35 fjernelse af en indikation, som er forbundet med centralnervesystemet og det såkaldte TBPS-bindingssted, og som kræver sådan psykofarmaceutisk behandling , f.eks. personer, som befinder sig i krampe eller angsttilstande. Om ønsket kan forbindelsen ifølge2g Because of their high affinity for the TBPS binding site, 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 comprises both anticonvulsant and anxiety-reducing activities, together with low toxicity, thereby providing a very favorable therapeutic index. Accordingly, 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 the so-called TBPS binding site and requiring such psychopharmaceutical treatment, e.g. people who are in convulsions or states of anxiety. If desired, the compound of

6 DK 155006 B6 DK 155006 B

opfindelsen bruges i form af et farmaceutisk acceptabelt syreadditionssalt (såsom hydrobromid, hydrochlorid eller sulfat), f.eks. fremstillet ved inddampning til tørhed af en opløsning af den frie base og syren.the invention is used in the form of a pharmaceutically acceptable acid addition salt (such as hydrobromide, hydrochloride or sulfate), e.g. prepared by evaporation to dryness of a solution of the free base and the acid.

55

De farmakologiske egenskaber hos forbindelserne ifølge opfindelsen kan illustreres ved at bestemme deres evne til atThe pharmacological properties of the compounds of the invention can be illustrated by determining their ability to

OCOC

fortrænge (S)-TBPS fra aniongatingbindingsstedet.displacing (S) -TBPS from the anion gate binding site.

Fortrængningsaktiviteten af forbindelserne ifølge opfindelsen kan måles ved at bestemme ICcn-værdi en.The displacement activity of the compounds of the invention can be measured by determining the ICcn value.

10 50 ICgQ-værdien repræsenterer den koncentration (ng/ml), som forårsager fortrængning af 50% af den specifikke binding af 35(S)TBPS.The 50 ICgQ value represents the concentration (ng / ml) causing displacement of 50% of the specific binding of 35 (S) TBPS.

Cerebral cortex (0,1-1 g) fra hanrotter af typen Wistar ( der vejer 200-300 g) homogeniseres i 5-10 sek. med et Ultra-Turrax 15 homogeniseringsapparat i 10 ml Triscitrat (50 mM), pH 7,1. Homogenisatet skylles med 10 ml puffer og de forenede suspensioner centrifugeres i 10 minutter ved 27.000 X 6. Den derved fremkomne pellet homogeniseres som før i 2 X 10 ml puffer og centrifugeres i 10 minutter ved 27.000 X G. Pel leten nedfryses derefter natten over (ved 20 -70°C), optøs og vaskes to gange. Ved hver vask homogeniseres pel leten i 2 X 10 ml af 50 mM Triscitrat og centrifugeres ved 27.000 X G i 10 minutter. Pelleten nedfryses igen natten over (ved -70°C) optøs og vaskes to gange. Ved hver vask homogeniseres pelleten igen i 2 X 10 ml af 50 mM Triscitrat og centifugeres ved 27.000 X G i 10 minutter. Den endelige pellet homogeniseres i Triscitrat (50 mM),Cerebral cortex (0.1-1 g) from male Wistar rats (weighing 200-300 g) is homogenized for 5-10 sec. with an Ultra-Turrax 15 homogenizer in 10 ml Triscitrate (50 mM), pH 7.1. The homogenate is rinsed with 10 ml of buffer and the combined suspensions centrifuged for 10 minutes at 27,000 X 6. The resulting pellet is homogenized as before in 2 X 10 ml of buffer and centrifuged for 10 minutes at 27,000 X G. The pellet is then frozen overnight (at 20 -70 ° C), thaw and wash twice. At each wash, the pellet is homogenized in 2 X 10 ml of 50 mM Triscitrate and centrifuged at 27,000 X G for 10 minutes. The pellet is frozen again overnight (at -70 ° C) thawed and washed twice. At each wash, the pellet is again homogenized in 2 X 10 ml of 50 mM Triscitrate and centrifuged at 27,000 X G for 10 minutes. The final pellet is homogenized in Triscitrate (50 mM),

NaCl (1 M) (100 ml per g oprindelig væv) og bruges til bindingsanalyser.NaCl (1 M) (100 ml per g of original tissue) and used for binding assays.

25 μΐ af prøveopløsningen og 25 μΐ af 35S-TBPS (1 nM, slutkoncentration) tilsættes 2 portioner af 0,5 ml vævssuspension og 30 blandingen omrøres og inkuberes derefter i 60 minutter ved 25°C. Ikke-specifik binding bestemmes ved dobbeltbestemmelse ved brug af picrotoxinin (10 pg/ml, slutkoncentation) som prøveforbindelse. Efter inkubation tilsættes 10 ml iskold puffer (Triscitrat (50 mM), NaCl (1 M)) og blandingen hældes direkte på Whatman GF/C glasfiberfiltre under sug og vaskes straks igen med 10 ml iskold puffer. Mængden af radioaktivitet på filtrene måles ved sædvanlig væskescinti 11ationstælling. Den specifikke binding er den samlede binding minus den25 µ 25 of the sample solution and 25 µΐ of 35S-TBPS (1 nM, final concentration) are added 2 portions of 0.5 ml of tissue suspension and the mixture is stirred and then incubated for 60 minutes at 25 ° C. Non-specific binding is determined by double determination using picrotoxinin (10 pg / ml, final concentration) as the test compound. After incubation, add 10 ml of ice-cold buffer (Triscitrate (50 mM), NaCl (1 M)) and pour the mixture directly onto Whatman GF / C fiberglass filters under suction and immediately wash again with 10 ml of ice-cold buffer. The amount of radioactivity on the filters is measured by usual liquid scintillation counting. The specific bond is the total bond minus it

7 DK 155006 B7 DK 155006 B

ikke-specifikke binding.non-specific binding.

Prøveforbindelserne opløses i 10 ml vand (om nødvendigt syrnet med 25 pi 1 N HC1 og opvarmet i et dampbad i mindre end 5 5 minutter) ved en koncentration på 0,22 mg/ml. Fortyndingerne laves i vand.The test compounds are dissolved in 10 ml of water (acidified with 25 µl of 1 N HCl, if necessary, and heated in a steam bath for less than 5 minutes) at a concentration of 0.22 mg / ml. The dilutions are made in water.

Prøver med koncentrationer på 10, 100, 1000 ng/ml (slutkoncentration) tilsættes duplikatprøver. 25-75% inhibering af specifik binding skal opnås før beregning af IC^q.Samples with concentrations of 10, 100, 1000 ng / ml (final concentration) are added to duplicate samples. 25-75% inhibition of specific binding must be achieved before calculating IC

1q Prøveværdien angives som IC^q (den koncentration (ng/ml) af prøveforbindelsen, som inhiberer 50% af den specifikke binding af 3 H-flunitrazepam).The sample value is given as IC IC q (the concentration (ng / ml) of the test compound that inhibits 50% of the specific binding of 3 H-flunitrazepam).

___ ng/ml ICgg = (Koncentration af anvendt prøveforbindelse) x i Cq λ 15 l c~ / v x hvor C betegner specifik binding ved kontrol analyser og C betegner___ ng / ml ICgg = (Concentration of test compound used) x in Cq λ 15 l c ~ / v x where C represents specific binding by control assays and C represents

O XO X

den specifikke binding ved prøveanalysen.the specific binding in the sample analysis.

2o De resultater, som opnåedes ved undersøgelse af visse forbindelser ifølge opfindelsen, vil fremgå af den efterfølgende tabel.The results obtained by examining certain compounds of the invention will appear in the following table.

25 30 35 825 30 35 8

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TABELTABLE

@CT@CT

Fortrængnings-aktivitet, 10 in vitro - A - x IC,_q -ch2-s-ch2- -ζ\νί 350In vitro displacement activity - A - x IC, _q -ch2-s-ch2- -ζ \ νί 350

15 Q-NQ-N

-ch2ch2ch2- -4 360-ch2ch2ch2- -4 360

o_No_N

-CH0CH0CH-- / \\ / 110 20 2 2 2-CH0CH0CH-- / \\ / 110 20 2 2 2

CL-NCL N

-CH2CH2CH2- 590-CH2CH2CH2- 590

NN

25 -CH2CH2CH2- -C02C2H5 350 -CH2-0-CH2- -C02C2H5 850 30 -S-CH2- -C02C2H5 2704 35 -0-CH2- -C02C2H5 8519-CH2CH2CH2- -CO2C2H5 350 -CH2-O-CH2- -CO2C2H5 850 30 -S-CH2- -CO2C2H5 2704 -0-CH2- -CO2C2H5 8519

Etazolat 3500Etazolate 3500

9 DK 155006 B9 DK 155006 B

Opfindelsen vil nu blive nærmere beskrevet under henvisning til de følgende eksempler: 5 EKSEMPEL 1 A. l,2,3,4-tetrahydro-2-oxo-4,l-benzothiazepin a. Methyl (o-nitrobenzylthi o)-acetat jq En blanding af o-nitrobenzylchlorid (17,2 g), methyl mercaptoacetat og kaliumkarbonat (27,6 g) tilbagesvales under omrøring i acetone (200 ml) i 6 timer. Reaktionsblandingen filtreres og inddampes til dannelse af ovennævnte forbindelse i form af en olie.The invention will now be described in greater detail with reference to the following examples: EXAMPLE 1 A. 1,2,3,4-Tetrahydro-2-oxo-4,1-benzothiazepine a. Methyl (o-nitrobenzylthio) acetate mixture of o-nitrobenzyl chloride (17.2 g), methyl mercaptoacetate and potassium carbonate (27.6 g) is refluxed with stirring in acetone (200 ml) for 6 hours. The reaction mixture is filtered and evaporated to give the above compound as an oil.

15 b. Methyl (o-aminobenzylthi o)-acetatB. Methyl (o-aminobenzylthio) acetate

Methyl (o-nitrobenzylthio)-acetat (24,4 g) opløses i ethanol (500 ml). Raney nikkel tilsættes og blandingen hydrogeneres ved stuetemperatur og ved 1 atmosfæres tryk. Ovennævnte forbindelse opnås 2Q i form af en olie efter filtrering og inddampning af reaktionsblandingen.Methyl (o-nitrobenzylthio) acetate (24.4 g) is dissolved in ethanol (500 ml). Raney nickel is added and the mixture is hydrogenated at room temperature and at 1 atmospheric pressure. The above compound is obtained 2Q in the form of an oil after filtration and evaporation of the reaction mixture.

c^ 1,2,3,4-tetrahydro-2-oxo-4,1-benzothiazepinc, 1,2,3,4-tetrahydro-2-oxo-4,1-benzothiazepine

Methyl (o-aminobenzylthio)-acetat opvarmes over et dampbad i 2jj 40 ml 4N NaOH i 30 minutter til dannelse af en klar opløsning. Efter afkøling af opløsningen til stuetemperatur neutraliseres den (4N HC1) og ekstraheres to gange med ethyl acetat. Den kombinerede organiske fase tørres over MgSO^ og inddampes. Den olieagtige inddampningsrest opløses derefter i polyphosphorsyre (100 g) og opløsningen opvarmes 20 til 150°C i 6 timer, hvorefter den hældes ned i isvand (500 ml).Methyl (o-aminobenzylthio) acetate is heated over a steam bath in 2 µg 40 ml of 4N NaOH for 30 minutes to form a clear solution. After cooling the solution to room temperature, it is neutralized (4N HCl) and extracted twice with ethyl acetate. The combined organic phase is dried over MgSO4 and evaporated. The oily residue is then dissolved in polyphosphoric acid (100 g) and the solution is heated at 20 to 150 ° C for 6 hours, then poured into ice water (500 ml).

Ovennævnte udfældede forbindelse opsamles ved filtrering. Smp. 213-217°C.The above precipitated compound is collected by filtration. Mp. 213-217 ° C.

B. 1,2,3,4-tetrahydro-2-oxo-4,l-benzoxazepin 20 g o-nitrobenzylal kohol og 21,7 ml ethyl bromacetat opløses i 250 ml tør DMF. Portioner af 55-60¾ natriumhydrid tilsættes denne opløsning under omrøring gennem 1 time indtil en samlet mængde på 8,5 g er blevet tilsat. Blandingen henstilles natten over vedB. 1,2,3,4-Tetrahydro-2-oxo-4,1-benzoxazepine 20 g of o-nitrobenzylal alcohol and 21.7 ml of ethyl bromoacetate are dissolved in 250 ml of dry DMF. Portions of 55-60¾ sodium hydride are added to this solution with stirring for 1 hour until a total amount of 8.5 g has been added. The mixture is left to stand overnight

10 DK 155006 BDK 155006 B

stuetemperatur og opvarmes derefter til 150°C under omrøring i 2 timer. Blandingen inddampes derefter og inddampningsresten deles mellem diethyl ether og vand. Den organiske fase inddampes til _ dannelse af 14 g ethyl (o-nitrobenzyloxy)-acetat i form af en olie.room temperature and then heated to 150 ° C with stirring for 2 hours. The mixture is then evaporated and the residue is partitioned between diethyl ether and water. The organic phase is evaporated to give 14 g of ethyl (o-nitrobenzyloxy) acetate as an oil.

14 g ethyl (o-nitrobenzyloxy)acetat opløses i 300 ml 96% ethanol og 1,5 g Pd på kulstof tilsættes. Blandingen hydrogeneres ved normalt tryk og ved stuetemperatur. Efter afslutningen af reaktionen filtreres blandingen og filtratet sættes til 50 ml 4N NaOH og den jQ derved fremkomne opløsning henstilles i 2 timer ved stuetemperatur, hvorefter 50 ml 4N HC1 tilsættes. Blandingen inddampes og inddampningsresten omrøres med 200 ml acetone. Blandingen filtreres. Filtratet inddampes til dannelse af o-aminobenzyloxyeddikesyre i form af en olie.Dissolve 14 g of ethyl (o-nitrobenzyloxy) acetate in 300 ml of 96% ethanol and add 1.5 g of Pd on carbon. The mixture is hydrogenated at normal pressure and at room temperature. After completion of the reaction, the mixture is filtered and the filtrate is added to 50 ml of 4N NaOH and the resulting solution is left to stand for 2 hours at room temperature, after which 50 ml of 4N HCl is added. The mixture is evaporated and the residue is stirred with 200 ml of acetone. The mixture is filtered. The filtrate is evaporated to give o-aminobenzyloxyacetic acid in the form of an oil.

1 g o-aminobenzyloxyeddikesyre og 1,1 g dicyclohexylcarbodi-15 imid omrøres i 15 ml til bagesval ende methanol i 8 timer. Blandingen inddampes og inddampningsresten omrøres med 50 ml acetone og filtreres, hvorefter filtratet inddampes til dannelse af ovennævnte forbindelse. Smp. 160-165°C: 20 C. 2,3,4,5-tetrahydro-4-methyl-2-oxo-1H-l,4-benzodiazepin1 g o-aminobenzyloxyacetic acid and 1.1 g dicyclohexylcarbodiimide are stirred in 15 ml to reflux methanol for 8 hours. The mixture is evaporated and the residue is stirred with 50 ml of acetone and filtered, then the filtrate is evaporated to give the above compound. Mp. 160-165 ° C: 20 C. 2,3,4,5-tetrahydro-4-methyl-2-oxo-1H-1,4-benzodiazepine

En blanding af 8,6 g o-nitrobenzylchlorid, 7,6 g sarcosinethylesterhydrochlorid og 13,8 g I^COg tilbagesvales i 300 ml acetone i 16 timer, hvorefter blandingen filtreres og inddampes. Den 25 olieagtige inddampningsrest deles mellem ether og IN HC1. Den vandholdige fase fraskilles og pH justeres til 10 med fortyndet NaOH opløsning, hvorefter den ekstraheres med dichlormethan. Den organiske fase tørres over Na^SO^ og inddampes. Den derved fremkomne olie hydrogeneres ved hjælp af en standard procedure og 5% Pd/C til 2Q dannelse af N-(o-aminobenzyl)sarcosinethyl ester i form af en olie.A mixture of 8.6 g of o-nitrobenzyl chloride, 7.6 g of sarcosinethyl ester hydrochloride and 13.8 g of 1 CO 2 is refluxed in 300 ml of acetone for 16 hours, after which the mixture is filtered and evaporated. The 25 oily residue is partitioned between ether and 1N HCl. The aqueous phase is separated and the pH is adjusted to 10 with dilute NaOH solution, then extracted with dichloromethane. The organic phase is dried over Na 2 SO 4 and evaporated. The resulting oil is hydrogenated by a standard procedure and 5% Pd / C to give 2Q of N- (o-aminobenzyl) sarcosinethyl ester in the form of an oil.

2,0 g N-(o-aminobenzyl)sarcosinethylester opløses i 40 g polyphosphorsyre og blandingen opvarmes til 150°C i 2 timer, hvorefter den afkøles og tilsættes 300 ml isvand. pH justeres til 8 med 50% NaOH og blandingen ekstraheres med dichlormethan. Den 25 organiske fase tørres over NagSO^ og inddampes til dannelse af ovennævnte forbindelse. Smp. 113-114°C.Dissolve 2.0 g of N- (o-aminobenzyl) sarcosine ethyl ester in 40 g of polyphosphoric acid and heat the mixture to 150 ° C for 2 hours, then cool and add 300 ml of ice water. The pH is adjusted to 8 with 50% NaOH and the mixture is extracted with dichloromethane. The organic phase is dried over NagSO 4 and evaporated to give the above compound. Mp. 113-114 ° C.

11 DK 155006 B11 DK 155006 B

D. 3,4-dihydro-3-oxo-2H-l,4-benzothiazinD. 3,4-dihydro-3-oxo-2H-1,4-benzothiazine

En opløsning af bromacetyl bromid i toluen (20 ml) tilsættes dråbevis en iskold omrørt opløsning af o-mercaptoanilin (10 mmol, 2,5 g) i en blanding af pyridin og toluen (50 ml, 30 ml). Blandingen får 5 lov til at opvarme til stuetemperatur og omrøring fortsættes i 2 timer efterfulgt af tilbagesvaling i 30 minutter, hvorefter vand (100 ml) tilsættes. Den organiske fase fraskilles, tørres (MgSO^) og inddampes til dannelse af 3,4-dihydro-3-oxo-2H-l,4-benzothiazepin.A solution of bromoacetyl bromide in toluene (20 ml) is added dropwise to an ice-cold stirred solution of o-mercaptoaniline (10 mmol, 2.5 g) in a mixture of pyridine and toluene (50 ml, 30 ml). The mixture is allowed to warm to room temperature and stirring is continued for 2 hours followed by reflux for 30 minutes, then water (100 ml) is added. The organic phase is separated, dried (MgSO4) and evaporated to give 3,4-dihydro-3-oxo-2H-1,4-benzothiazepine.

Smp. 170-171°C.Mp. 170-171 ° C.

På samme måde syntetiseres den følgende forbindelse ud fra det passende anilin: 3,4-dihydro-3-oxo-2H-l,4-benzoxazin. Smp. 150,5°C.Similarly, the following compound is synthesized from the appropriate aniline: 3,4-dihydro-3-oxo-2H-1,4-benzoxazine. Mp. 150.5 ° C.

j5 2,3,4,5-tetrahydro-2-oxo-lH-1-benzazepin2,3,4,5-Tetrahydro-2-oxo-1H-1-benzazepine

En blanding af 4,0 g 1-tetralonoxim og 50 g polyphosphorsyre omrøres i 3 timer ved 120°C. Blandingen afkøles derefter og tilsættes 200 ml isvand. Ved filtrering opnås ovennævnte forbindelse. Smp. 135-6°C.A mixture of 4.0 g of 1-tetralone oxime and 50 g of polyphosphoric acid is stirred for 3 hours at 120 ° C. The mixture is then cooled and 200 ml of ice water is added. By filtration, the above compound is obtained. Mp. 135-6 ° C.

20 F. 3-cyclopropyl-5-isocyanomethy1-l,2,4-oxadiazol a. 3-cyclopropy1-5-formylaminomethyl-l,2,4-oxadiazol 25 En opløsning af ethyl formyl ami nomethyl carboxyl at (150 mmol) og cyclopropylcarboxamidoxim (100 mmol) i 100% EtOH (100 ml) tilsættes Na (200 mg) og knust molekylsi (4Å) (10 g). Den omrørte reaktionsblanding opvarmes til tilbagesvaling i 8 timer. Blandingen afkøles til stuetemperatur, filtreres gennem et filterhjælpemiddel og 30 filtratet inddampes i vakuum. Den olieagtige inddampningsrest deles i en CHC12 fase, tørres med ^SO^ og inddampes.20 F. 3-Cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole a. 3-Cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole A solution of ethyl formyl aminomethyl carboxyl at (150 mmol) and cyclopropylcarboxamidoxime (100 mmol) in 100% EtOH (100 mL) is added Na (200 mg) and crushed molecular sieve (4Å) (10 g). The stirred reaction mixture is heated to reflux for 8 hours. The mixture is cooled to room temperature, filtered through a filter aid and the filtrate is evaporated in vacuo. The oily residue is partitioned into a CHCl 2 phase, dried with 2 SO 2 and evaporated.

b^_ 3“Cyclopropyl-5-isocyanomethyl-l,2,4-oxadiazol3 Cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole

En omrørt opløsning af 3-cyclopropyl-5-formylaminomethyl-l,2, 35 4-oxadiazol (50 mmol) og triethylamin (176 mmol) i CH^l^ (100 ml) tilsættes dråbevis P0C1^ (60 mmol) ved 0°C. Blandingen henstilles derefter i 30 minutter under omrøring ved 0°C, hvorefter en opløsningA stirred solution of 3-cyclopropyl-5-formylaminomethyl-1,2,3,4-oxadiazole (50 mmol) and triethylamine (176 mmol) in CH₂ l (100 ml) is added dropwise POC1 (60 mmol) at 0 ° C. The mixture is then left for 30 minutes with stirring at 0 ° C, followed by a solution

12 DK 155006 B12 DK 155006 B

af NaC03 (60 mmol) i H20 (50 ml) tilsættes. Blandingen opvarmes til stuetemperatur, hvorefter den organiske fase fraskilles, tørres og inddampes i vakuum. Inddampningsresten behandles med ether, 5 dekanteres og opløsningen inddampes til dannelse af ovennævnte forbindelse i form af en olie. Olien anvendes uden yderligere behandling. Forbindelsen karakteriseres ved dens IR absorption ved 2160 cm-1.of NaCO 3 (60 mmol) in H2 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 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 treatment. The compound is characterized by its IR absorption at 2160 cm -1.

3-ethyl-5-isocyanomethyl-l,2,4-oxadiazol fremstilles ud fra 10 3-ethyl-5-formylaminomethyl-l,2,4-oxadiazol på lignende måde. IR: 2170 cm-1.3-Ethyl-5-isocyanomethyl-1,2,4-oxadiazole is prepared from 3-ethyl-5-formylaminomethyl-1,2,4-oxadiazole in a similar manner. IR: 2170 cm -1.

5-cyclopropyl-3-isocyanomethyl-l,2,4-oxadiazol 15 a^_ Formyl ami nomethyl -carboxami doxi m 0,55 m nylig frigjort hydroxylamin opløst i 370 ml methanol sættes til 53,6 g (0,638 mol) N-formylamino-acetonitril. Et isbad anvendes til at holde temperaturen under 20°C under tilsætningen. Opløsningen får lov til at stå natten over ved stuetemperatur, 20 hvorefter den inddampes til dannelse af ovennævnte forbindelse i form af blege krystaller. Dekomponering 104-110°C.5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole 15 A Formyl aminomethyl-carboxamido doxi m 0.55 m recently released hydroxylamine dissolved in 370 ml of methanol is added to 53.6 g (0.638 mole) of N- formylamino-acetonitrile. 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 104-110 ° C.

b. 3-formylaminomethyl-5-ethyl-l,2,4-oxadiazolb. 3-Formylaminomethyl-5-ethyl-1,2,4-oxadiazole

En blanding af 70 ml ethylpropionat, 20 g formyl ami nomethyl -25 carboxamidoxim, 1 g natrium og 30 g knust molekyl sier (4Å) tilbagesvales i 300 ml abs. EtOH i 5 timer. Reaktionsblandingen filtreres og filtratet inddampes. Den olieagtige inddampningsrest suspenderes i 300 ml CHClg, filtreres og filtratet inddampes til dannelse af ovennævnte forbindelse i form af en olie.A mixture of 70 ml of ethyl propionate, 20 g of formyl aminomethyl-25 carboxamidoxime, 1 g of sodium and 30 g of crushed molecules (4Å) is refluxed in 300 ml of abs. EtOH for 5 hours. The reaction mixture is filtered and the filtrate is evaporated. The oily residue is suspended in 300 ml of CHCl 3, filtered and the filtrate is evaporated to give the above compound as an oil.

30 H-NMR (60 HMz, CDC13) (ppm): 1,4 (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).1 H-NMR (60 HMz, CDCl 3) (ppm): 1.4 (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).

De følgende forbindelser syntetiseres ud fra de passende ethyl estere: 3-formylaminomethyl-5-cyclopropyl-l,2,4-oxadiazol. H-NMR (60 35 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, s).The following compounds are synthesized from the appropriate ethyl esters: 3-formylaminomethyl-5-cyclopropyl-1,2,4-oxadiazole. 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, wide NH), 8.2 (1H, s).

3-formylaminomethyl-5-methyl-l,2,4-oxadiazol. H-NMR (60 MHz, CDC13) (ppm): 2,6 (3H, s), 4,6 (2H, d, J=3 Hz), 7,4 (IH, bred-NH),3-formylaminomethyl-5-methyl-l, 2,4-oxadiazole. H-NMR (60 MHz, CDCl 3) (ppm): 2.6 (3H, s), 4.6 (2H, d, J = 3 Hz), 7.4 (1H, broad-NH),

13 DK 155006 B13 DK 155006 B

8,25 (IH, s).8.25 (1H, s).

3-formylaminomethyl-5-methoxymethyl-1,2,4-oxadiazol. H-NMR (60 MHz, CDCT3) (ppm): 3,5 (3H, s), 4,7 (4H, s+d, J=6 Hz), 7,8 (IH, 5 bred=NH), 8,25 (IH, s).3-formylaminomethyl-5-methoxymethyl-1,2,4-oxadiazole. H-NMR (60 MHz, CDCl3) (ppm): 3.5 (3H, s), 4.7 (4H, s + d, J = 6 Hz), 7.8 (1H, 5 broad = NH), 8.25 (1H, s).

c- 5-cyclopropyl-3-isocyanomethyl-l,2,4-oxadiazolc-5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole

En omrørt opløsning af 5-cyclopropyl-3-formylaminomethyl- 1.2.4- oxadiazol (60 mmol) og tri ethylamin (176 mmol) i CH^Clg (100 10 ml) tilsættes dråbevis P0C13 (60 mmol) ved 0°C. Blandingen får lov til at stå i 30 minutter under omrøring ved 0°C, hvorefter en opløsning af ^COg (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, 15 dekanteres og opløsningen inddampes til dannelse of ovennævnte forbindelse i form af en olie. Olien anvendes uden yderligere rensning. Forbindelsen karakteriseres ved dens IR strækbånd ved 2160 cm 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazol, 5-methyl-3-20 isocyanomethyl-1,2,4-oxadiazol og 5-methoxymethyl-3-isocyanomethyl- 1.2.4- oxadiazol fremstilles på lignende måde. Alle forbindelserne er olier og karakteriseres ved deres IR strækbånd ved 2160 cnf\ ϋ· 3-(5-ethyl-l,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo(l,5-a)(1) 25 benzazepin 2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin (10 mmol) opløses i tør DMF (15 ml) og tilsættes natriumhydrid (13 mmol). Den derved fremkomne opløsning afkøles under ^ til -20°C, hvorefter chlordiethylphosphat (13 mmol) tilsættes. Reaktionsblandingen holdes 30 under ^ under omrøring ved -20°C og tilsættes en -30°C kold opløsning af 5-ethyl-3-isocyano-methyl-l,2,4-oxadiazol (13 mmol) og K-t-butylat (13 mmol) i tør DMF (10 ml). Den derved fremkomne reaktionsblanding får lov til at opvarme til stuetemperatur, hvorefter 5 ml iseddikesyre tilsættes. Den derved fremkomne blanding 35 filtreres, hvilket giver 0,36 g af ovennævnte forbindelse. Smp.A stirred solution of 5-cyclopropyl-3-formylaminomethyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH 2 Cl 2 (100 10 ml) is added dropwise POC13 (60 mmol) at 0 ° C. The mixture is allowed to stand for 30 minutes with stirring at 0 ° C, then a solution of 2 COg (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 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 stretch band at 2160 cm @ -1 of 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole, 5-methyl-3-20 isocyanomethyl-1,2,4-oxadiazole and 5-methoxymethyl-3-isocyanomethyl 1.2.4-Oxadiazole is prepared in a similar manner. All of the compounds are oils and are characterized by their IR stretch bands at 2160 cm³ of 3- (5-ethyl-1,2,4-oxadiazol-3-yl) -5,6-dihydro-4H-imidazo (1,5 a) (1) Benzazepine 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (10 mmol) is dissolved in dry DMF (15 ml) and sodium hydride (13 mmol) is added. The resulting solution is cooled below 3 to -20 ° C and then chlorinated diethyl phosphate (13 mmol) is added. The reaction mixture is kept under stirring at -20 ° C and a -30 ° C cold solution of 5-ethyl-3-isocyano-methyl-1,2,4-oxadiazole (13 mmol) and K-butylate (13 mmol) is added. ) in dry DMF (10 ml). The resulting reaction mixture is allowed to warm to room temperature, after which 5 ml of glacial acetic acid are added. The resulting mixture is filtered to give 0.36 g of the above compound. Mp.

150,7-150,8°C.150.7 to 150.8 ° C.

På analog vis syntetiseres de følgende forbindelser:By analogy, the following compounds are synthesized:

Ethyl 4H-imidazo(5,l-c)(1,4)benzothiazin-3-carboxylat (smp.Ethyl 4H-imidazo (5,1-c) (1,4) benzothiazine-3-carboxylate (m.p.

14 DK 155006 B14 DK 155006 B

135,0°C) ved omsætning af ethyl isocyanoacetat med 3,4-dihydro-3-oxo-2H-l,4-benzothiazin.135.0 ° C) by reacting ethyl isocyanoacetate with 3,4-dihydro-3-oxo-2H-1,4-benzothiazine.

Ethyl 4H-imidazo(5,l-c)(1,4)benzoxazin-3-carboxylat (smp.Ethyl 4H-imidazo (5,1-c) (1,4) benzoxazine-3-carboxylate (m.p.

5 138,0°C) ved omsætning af ethyl isocyanoacetat med 3,4-dihydro-3-oxo- 2H-l,4-benzoxazin.5 138.0 ° C) by reacting ethyl isocyanoacetate with 3,4-dihydro-3-oxo-2H-1,4-benzoxazine.

Ethyl 5,6-dihydro-4H-imidazo(1,5-a)(1)benzazepi n-3-carboxy1 at (smp. 157,4-159,6°C) ved omsætning af ethyl isocyanoacetat med 2,3,4,5-tetrahydro-2-oxo-lH-l-benzazepin.Ethyl 5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine n-3-carboxylate (mp 157.4-159.6 ° C) by reacting ethyl isocyanoacetate with 2.3, 4,5-tetrahydro-2-oxo-lH-l-benzazepine.

20 Ethyl 5,6-dihydro-5-methyl-4H-imidazo(l,5-a)(1,4)benzodiaze- pin-3-carboxylat (smp. 114,3-116,7°C) ved omsætning af ethyl isocyanoacetat med 2,3,4,5-tetrahydro-4-methyl-2-oxo-lH-l,4 -benzodiazepin.Ethyl 5,6-dihydro-5-methyl-4H-imidazo (1,5-a) (1,4) benzodiazepine-3-carboxylate (mp 114.3-116.7 ° C) by reaction of ethyl isocyanoacetate with 2,3,4,5-tetrahydro-4-methyl-2-oxo-1H-1,4-benzodiazepine.

Ethyl 4H,6H-imidazo(5,l-c)(4,l)-benzoxazepin-3-carboxylat 25 (smp. 142,0-142,6°C) ved omsætning af ethyl isocyanoacetat med 1.2.3.4- tetrahydro-2-oxo-4,1-benzoxazepi n.Ethyl 4H, 6H-imidazo (5,1c) (4,1) -benzoxazepine-3-carboxylate (mp 142.0-142.6 ° C) by reaction of ethyl isocyanoacetate with 1.2.3.4-tetrahydro-2 oxo-4,1-benzoxazepine n.

Ethyl 4H,6H-imidazo(5,l-c)(4,l)benzthiazepin-3-carboxylat (smp. 17194-171,7°C) ved omsætning af ethyl isocyanoacetat med 1.2.3.4- tetrahydro-2-oxo-4,1-benzthi azepi n.Ethyl 4H, 6H-imidazo (5,1c) (4,1) benzthiazepine-3-carboxylate (mp 17194-171.7 ° C) by reaction of ethyl isocyanoacetate with 1.2.3.4-tetrahydro-2-oxo-4, 1-benzthi azepi n.

20 EKSEMPEL 2 A. Methoxyacetamidoxim 2,3 g natrium i 30 ml tør methanol blandes med 6,55 g 25 hydroxylaminhydrochlorid i 66 ml tør methanol. Blandingen filtreres og 7,8 g methoxyacetonitril sættes dråbevis til filtratet. Blandingen henstilles i 48 timer ved stuetemperatur. Blandingen afkøles derefter til 4°C. Filtrering og inddampning giver ovennævnte forbindelse.EXAMPLE 2 A. Methoxyacetamidoxime 2.3 g of sodium in 30 ml of dry methanol are mixed with 6.55 g of hydroxylamine hydrochloride in 66 ml of dry methanol. The mixture is filtered and 7.8 g of methoxyacetonitrile are added dropwise to the filtrate. The mixture is allowed to stand for 48 hours at room temperature. The mixture is then cooled to 4 ° C. Filtration and evaporation give the above compound.

På analog måde syntetiseres følgende forbindelser ud fra 20 passende nitri ler:By analogy, the following compounds are synthesized from 20 suitable nitriles:

Propionamidoxim, cyclopropylcarboxami doxim, i sopropylcarboxami doxi m, acetamidoxim, 25 benzamidoxim.Propionamidoxime, cyclopropylcarboxamide dox, in sopropylcarboxamide doxi, acetamidoxime, benzamidoxime.

15 DK 155006 BDK 155006 B

B. 3-(3-methoxymethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-4H-imidazo (1,5-a)(1)benzazepin 50 mg natrium opløses i 20 ml tør ethanol, der indeholder 3 g 5 molekylsier (4Å), og 0,5 g methoxyacetamidoxim tilsættes denne blanding og dernæst tilsættes 0,5 g ethyl 5,6-dihydro-4H-imidazo(l,5- a)(1)benzazepin-3-carboxylat. Den derved fremkomne blanding tilbagesvales i 12 timer, hvorefter den afkøles og molekylsierne fjernes ved filtrering. Ovennævnte forbindelse isoleres ved 10 inddampning af opløsningsmidlet i vakuum efterfulgt af en tilsætning af isvand og filtrering. Smp. 115,6-115,8°C.B. 3- (3-Methoxymethyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine 50 mg of sodium is dissolved in 20 ml of dry ethanol containing 3 g of 5 molecular sieves (4Å) and 0.5 g of methoxyacetamidoxime are added to this mixture and then 0.5 g of ethyl 5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine is added. 3-carboxylate. The resulting mixture is refluxed for 12 hours, then cooled and the molecular sieves removed by filtration. The above compound is isolated by evaporation of the solvent in vacuo followed by the addition of ice water and filtration. Mp. 115.6 to 115.8 ° C.

På samme måde fremstilles de følgende forbindelser: 3-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)-4H, 6H-imidazo(5,l-c) (4,1Ibenzthiazepin (smp. 165,5-162,0°C) ved omsætning af cyclopropyl-15 carboxamidoxim med ethyl 4H, 6H-imidazo(5,l-c)(4,1)benzthiazepin-3-carboxylat.Similarly, the following compounds are prepared: 3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4H, 6H-imidazo (5,1c) (4,1-benzthiazepine (mp 165.5-162) (0 ° C) by reacting cyclopropyl-carboxamidoxime with ethyl 4H, 6H-imidazo (5,1c) (4,1) benzthiazepine-3-carboxylate.

3-(3-ethyl-l,2,4-oxadiazol-5-yl)-5,6-dihydro-4H-imidazo-(l,5-a)(l)benzazepin (smp. 166,1°G) ved omsætning af propionamidoxim med ethyl 5,6-di hydro-4H-imi dazo(1,5-a)(1)benzazepi n-3-carboxylat.3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-4H-imidazo- (1,5-a) (1) benzazepine (m.p. 166.1 ° G) by reaction of propionamidoxime with ethyl 5,6-di hydro-4H-imidazo (1,5-a) (1) benzazepine n-3-carboxylate.

20 3-(3-ethyl-1,2,4-oxadi azol-5-yl)-4H-i mi dazo(5,1-c)(1,4)- benzoxazin (smp. 133,7°C) ved omsætning af propionamidoxim med ethyl 4H-i mi dazo(5,1-c)(1,4)benzoxazi n-3-carboxy1 at.3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -4H-imidazo (5,1-c) (1,4) -benzoxazine (mp 133.7 ° C) by reaction of propionamidoxim with ethyl 4H-i-mi dazo (5,1-c) (1,4) benzoxazi n-3-carboxy1 at.

3-(3-ethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo(5,l-c)(1,4)-benzothiazin (smp. 144,0°C) ved omsætning af propionamidoxim med 25 ethyl 4H-imidazo(5,l-c)(l,4)benzothiazin-3-carboxylat.3- (3-Ethyl-1,2,4-oxadiazol-5-yl) -4H-imidazo (5,1c) (1,4) -benzothiazine (mp 144.0 ° C) by reaction of propionamidoxim with 25 ethyl 4H-imidazo (5, 1c) (1,4) benzothiazine-3-carboxylate.

3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-di hydro-4H-imidazo (1,5-a)(1)benzazepin (smp. 169-171°C) ved omsætning af benzamidoxim med ethyl 5,6-dihydro-4H-imidazo(1,5-a)(1)benzazepi n-3-carboxylat.3- (3-Phenyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine (mp 169-171 ° C) by reacting benzamidoxime with ethyl 5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine n-3-carboxylate.

3-(3-methy1-1,2,4-oxadi azol-5-yl)-5,6-di hydro-4H-imi dazo 30 (l,5-a)(l)benzazepin (smp. 173,5-174,2°C) ved omsætning af acetamidoxim med ethyl 5,6-dihydro-4H-imidazo(l,5-a)(l)benzazepin-3-carboxylat.3- (3-Methyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine (mp 173.5 -174.2 ° C) by reacting acetamidoxime with ethyl 5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine-3-carboxylate.

3-(3-cyclopropy1-1,2,4-oxadi azol-5-yl)-5,6-di hydro-4H-i mi dazo (l,5-a)(l)benzazepin (smp. 147,2-147,3°C) ved omsætning af 35 cyclopropylcarboxamidoxim med ethyl 5,6-dihydro-4H-imidazo(l,5-a)(l) benzazepi n-3-carboxylat.3- (3-Cyclopropyl-1,2,2-oxadiazol-5-yl) -5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine (mp 147.2 -147.3 ° C) by reacting cyclopropylcarboxamidoxime with ethyl 5,6-dihydro-4H-imidazo (1,5-a) (1) benzazepine n-3-carboxylate.

Claims

16 DK 155006B

1. Condensed imidazole derivatives characterized in that they have the general formula 5 ry * 10 where o ^ N / N "~ o X represents H JUR. 'R * or CO 2 R ·

N where R 1 represents C 1-6 alkyl, C 1-4 cycloalkyl or C 1-6 alkoxymethyl and - A - represents "(C 1 -N 2 'nf' 20 where n and m are 0 or 1 and -Y- -O-, -S-, -Ch 2 -, or -NR "-, where R" represents hydrogen or C 1-6 alkyl.

Compound according to claim 1, characterized in that the compound is 3- (3-ethyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-4H- in dazoO, 5-a) ( 1 Jbenzazepine.

Compound according to claim 1, characterized in that the compound is 3- (5-ethyl-1,2,4-oxadiazol-3-yl) -5,6-di hydro-4H-i-dazo (1 , 5-a) (1) benzazepi n.

Compound according to claim 1, characterized in that the compound is ethyl 4H, 6H-imidazo (5,1-c) (4,1) benzoxazepine-3-carboxyl at.

Compound according to claim 1, characterized in that the compound is 3- (3-cyclopropyl-1,2,4-oxadiazole) -4H, 6H-imidazo (5,1-c) (4,1) benzthiazepine.

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 1-5 and a pharmaceutically acceptable carrier or diluent.

Pharmaceutical composition according to claim 6, characterized in that it is in the form of an oral unit dose containing 1-100 mg of the active compound. 5 10 15 20 25 30 35