DK155941B - Benzodiazepine derivatives and pharmaceutical preparations comprising them - Google Patents

Description

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DK 155941 BDK 155941 B

Opfindelsen angår hidtil ukendte terapeutisk aktive benzodiazepinderivater, og farmaceutiske præparater indeholdende forbindelserne. De hidtil ukendte forbindelser er nyttige til psykofarmaceutiske anvendelser, f.eks. ved behandling af 5 centralnervesystemssygdomme f.eks. som krampehæmmende midler eller angstdæmpende midler.The invention relates to novel therapeutically active benzodiazepine derivatives and pharmaceutical compositions containing the compounds. The novel compounds are useful for psychopharmaceutical applications, e.g. in the treatment of 5 central nervous system diseases e.g. as anticonvulsants or anxiety relievers.

Det er velkendt (Squires, R.F. og Bræstrup, C. Nature (London) 266 (1977) 732-734), at specifikke steder i centralnervesystemet hos pattedyr udviser en stor specifik affinitet 10 for binding af 1,4- og 1,5-benzodiazepiner. Disse steder kaldes benzodi azepi nreceptorer.It is well known (Squires, RF and Bræstrup, C. Nature (London) 266 (1977) 732-734) that specific sites in the central nervous system of mammals exhibit a large specific affinity 10 for binding of 1.4- and 1.5- benzodiazepines. These sites are called benzodi azepi nreceptors.

De europæiske patentansøgninger nr. 109.921 og 150.040 omtaler oxadiazolylderi vater af imidazobenzodiazepiner.European Patent Application Nos. 109,921 and 150,040 disclose oxadiazolylderate levels of imidazobenzodiazepines.

De hidtil ukendte forbindelser ifølge opfindelsen er 15 imidazobenzodiazepinderivater med den almene formel IThe novel compounds of the invention are 15 imidazobenzodiazepine derivatives of the general formula I

•fVx1 ^vN \ {I) 2° Uji } R4 ^R5 i 0 25 hvor 1 2 X og X hver for sig betegner• fVx1 ^ vN \ {I) 2 ° Uji} R4 ^ R5 in 0 25 where 1 2 X and X each represent

O—N N—OO — N N — O

30 ' Jl Λ—R1 eller C00R130 'J1 - R1 or C00R1

N. NN. N

hvor R^ betegner C-j_3-alkyl, C^.g-cycloalkyl, C.|_3-alkoxymethyl, C-|_3-hydroxyalkyl eller phenyl, 35 .wherein R 1 represents C 1-6 alkyl, C 1-6 cycloalkyl, C 1-3 alkoxymethyl, C 1-3 hydroxyalkyl or phenyl, 35.

4 R betegner hydrogen, 24 R represents hydrogen, 2

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5 Λ C5 Λ C

Κ betegner C^_g-alkyl eller hvor R og R tilsammen danner en 2-4 leddet alkylenkæde.Κ represents C ^gg alkyl or wherein R and R together form a 2-4 membered alkylene chain.

De omhandlede forbindelser kan fremstilles ved fremgangsmåder, der omfatter: 5The compounds of the present invention may be prepared by methods comprising:

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

PvC "" A o 4 5 2PvC "" A o 4 5 2

15 hvor R , R og X har de ovenfor anførte betydninger og hvor Y betegner en udskiftelig gruppe, med en forbindelse med formlen IIIWherein R, R and X have the meanings set forth above and wherein Y represents an interchangeable group, with a compound of formula III

CN - CH2 - X1 (III) 20 hvor X1 har den ovenfor anførte betydning, til dannelse af en forbindelse ifølge opfindelsen, ellerCN - CH2 - X1 (III) 20 wherein X1 has the meaning given above to form a compound of the invention, or

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

25 - C00H25 - C00H

yl hi r4 <iv>yl hi r4 <iv>

rfVRFV

30 . / O30. / O

X2 Λ c n hvor R , Ra og X har de ovenfor anførte betydninger, med en forbindelse med den almene formel V 35 r1-c(=noh)nh2 (V) 3X2 Λ c n where R, Ra and X have the meanings set forth above, with a compound of the general formula V 35 r1-c (= noh) nh2 (V) 3

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hvor R^ har den ovenfor anførte betydning, til dannelse af enwherein R 1 has the meaning given above to form one

O Λ CO Λ C

forbindelse med den almene formel I, hvor X , R og R har de ovenfor angivne betydninger og hvor X1 betegnercompound of the general formula I wherein X, R and R have the above meanings and wherein X 1

C O—NC O — N

hvor R^ har den ovenfor anførte betydning, eventuelt via et mellemprodukt med den almene formel VIwherein R 1 is as defined above, optionally via an intermediate of the general formula VI

10 -CC«0)-0-N=G(NH2)R1 r4 (vi) 15 II ^R5 X2 * / hvor X2, r\ R4 og R^ har de ovenfor angivne betydninger eller 2010 -CC (O) -O-N = G (NH 2) R1 r4 (vi) II ^ R5 X2 * / where X2, r \ R4 and R ^ have the above meanings or 20

c) omsætning af en forbindelse med den almene formel VII(c) reaction of a compound of general formula VII

/N\ Ϋ V-conh2 (Γ/Μ (VII) ^R5 4 0 * 30 2 4 5 -/ N \ Ϋ V-conh2 (Γ / Μ (VII) ^ R5 4 0 * 30 2 4 5 -

hvor X , R og R har de ovenfor anførte betydninger, med en forbindelse med den almene formel VIIIwherein X, R and R have the above meanings, with a compound of general formula VIII

r1-c(och3)2n(ch3)2 (VIII)r1-c (och3) 2n (ch3) 2 (VIII)

hvor R^ har den ovenfor anførte betydning, til dannelse af en forbindelse med den almene formel IXwherein R 1 is as defined above to form a compound of general formula IX

35 435 4

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— COH=CR1H(CH3)2 5 (IX)- COH = CR1H (CH3) 25 (IX)

FfVFFV

x2 ° 10 hvor X2, R4, R5 og R1 har de ovenfor anførte betydninger, og omsætning af formlen med den almene formel IX med NH^OH eller andet amineringsmiddel til dannelse af en forbindelse med den almene formel I, hvor X1 betegnerx2 ° 10 where X2, R4, R5 and R1 have the above meanings, and reacting the formula of the general formula IX with NH4 OH or other aminating agent to form a compound of the general formula I wherein X1 represents

O—NO-N

15 “4s15 “4s

NN

hvor R* har den ovenfor anførte betydning eller iwherein R * has the meaning given above or i

2o d) omsætning af en forbindelse med den almene formel X(D) reacting a compound of general formula X

_ CN_ CN

rfY ~~Vr4 (X) 25 \ 5rfY ~~ Vr4 (X) 25 \ 5

/ II R/ II R

hvor X2, R^ og R^ har de ovenfor anførte betydninger, med NH^OH til 30 dannelse af en forbindelse med den almene formel XIwherein X 2, R 2 and R 2 have the above meanings, with NH 2 OH to form a compound of general formula XI

fV~2 (XI) /TvfV ~ 2 (XI) / Tv

5 DK 155941B5 DK 155941B

2 4 5 hvor X , R og R har de.ovenfor anførte betydninger, og omsætning af forbindelsen med formlen XI med R1-C0C1 eller (R^COjgO, hvor R^ har den ovenfor anførte betydning, til dannelse af en forbindelse med formlen I, hvor X^ betegnerWhere X, R and R have the above meanings, and reacting the compound of formula XI with R 1 -COCl or (R 2 CO 2 O where R 1 has the meaning given above to form a compound of formula I) , where X ^ represents

NN

hvor R^ har den ovenfor anførte betydning, ellerwherein R 1 is as defined above, or

e) omsætning af et reaktivt derivat af en forbindelse med den almene formel XIIe) reacting a reactive derivative of a compound of general formula XII

O—* (xn)O— * (xn)

/ O R/ O R

COOHCOOH

4 5 1 hvor R , R og X har de ovenfor anførte betydninger, med en4 5 1 wherein R, R and X have the above meanings, with one

forbindelse med den almene formel XIIIcompound of general formula XIII

R]-C(=N0H)NH2 (XIII) hvor R^ har den ovenfor anførte betydning, til dannelse af en 14 5 forbindelse med den almene formel I, hvor X , R og R har de ovenfor ? angivne betydninger og hvor X betegnerR 1 -C (= NOH) NH 2 (XIII) wherein R 1 is as defined above to form a compound of general formula I wherein X, R and R have the above? given meanings and where X denotes

O—NO-N

hvor R^ har den ovenfor anførte betydning, eventuelt via etwherein R 1 has the meaning given above, optionally via a

mellemprodukt med formlen XIVintermediate of formula XIV

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6 /Nv i f>-x 5 j II (xiv) C(=0)-0-N=C(NH2)R1 hvor X*, R*, R^ og har de ovenfor angivne betydninger eller 106 / Nv in f> -x 5 j II (xiv) C (= O) -0-N = C (NH 2) R1 where X *, R *, R ^ and have the above meanings or 10

f) omsætning af en forbindelse med...dea almene formel XV(f) reacting a compound of ... general formula XV

fVfV

_.N—7 15 Kjf V"R4 (XV1_.N — 7 15 Kjf V "R4 (XV1

VV

/ conh2......... ./ conh2 ..........

14 5 2o hvor X , R og R har de ovenfor anførte betydninger, med en14 5 2o where X, R and R have the above meanings, with one

forbindelse med den almene formel XVIcompound of the general formula XVI

r1-c(och3)2n(ch3)2 (XVI) 2g hvor R^ har den ovenfor anførte betydning, til dannelse af enr1-c (och3) 2n (ch3) 2 (XVI) 2g where R 1 has the meaning given above to form a

forbindelse med den almene formel XVIIcompound of the general formula XVII

/Nv 1 O—x 30 K)f r^R4 ixvII) C0N=CR1H(CH3)2 *J v 1 il C i hvor X , R4, Rb og R har de ovenfor anførte betydninger, og omsætning af forbindelsen med formlen XVII med NH20H eller andet 35 7/ Nv 1 O-x 30 K) fr ^ R4 ixvII) CON = CR1H (CH3) 2 * J v 1 11 C in which X, R4, Rb and R have the above meanings, and reacting the compound of formula XVII with NH 2 OH or other 35 7

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amineringsmiddel til dannelse af en forbindelse med den almene formel 2 I, hvor X betegneramine agent to form a compound of general formula 2I wherein X represents

O—NO-N

5 ΑΛβ1 hvor R^ har den ovenfor angivne betydning, eller5 ΑΛβ1 where R 1 has the meaning given above, or

g) omsætning af en forbindelse med den almene formel XVIII(g) reaction of a compound of general formula XVIII

10 f>-x1 j{r4 (XVIII) 15 /^11 \ 5 / H Η10 f> -x1 j {r4 (XVIII) 15 / ^ 11 \ 5 / H Η

CNCN

i 14 5i 14 5

hvor X , R og R har de ovenfor anførte betydninger, med Nl^OH til 20 dannelse af en forbindelse med den almene formel XVIVwherein X, R and R have the meanings set forth above, with N 11 OH forming a compound of general formula XVIV

C(-=N0H)NH2 1 4 5 30 hvor X , R og R har de ovenfor anførte betydninger, og omsætning af forbindelsen med formlen XVIV med R^-COCl eller (R^COLO, hvor R1 har ^ 2 den ovenfor anførte betydning, til dannelse af formlen I, hvor X betegnerC (- = NOH) NH 2 1 4 5 30 wherein X, R and R have the above meanings and reacting the compound of formula XVIV with R 1 -COCl or (R 2 COLO where R 1 has ^ 2 the meaning given above) , to form the formula I, wherein X represents

N—ON-O

35 ^-R135 ^ -R1

NN

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OISLAND

hvor har <len ovenfor anførte betydning.where is the meaning given above.

Den udskiftelige gruppe, Y, kan være en hvilken som helst udskiftelig gruppe og f.eks. de i US patentskrifterne nr. 4.031.079 5 eller 4.359.420 omtalte f.eks. halogen, alkylthio, f.eks. methylthio, aralkylthio, N-ni trosoal kyl amino, alkoxy, mercapto, -OPiOMOR^s hvor R betegner lavere alkyl eller -OP(0)(NR1R"), hvor R‘ og R" hver betegner lavere al kyl eller phenyl, eller sammen med det nitrogenatom, til hvilket de er bundet, betegner en heterocyklisk gruppe, 10 såsom morpholin, pyrrol idin, piperidin eller methyl pi perazin.The interchangeable group, Y, can be any interchangeable group and e.g. those disclosed in U.S. Patent Nos. 4,031,079 or 4,359,420, e.g. halogen, alkylthio, e.g. methylthio, aralkylthio, N-ni trosoal cool amino, alkoxy, mercapto, -OPiOMOR ^ s where R represents lower alkyl or -OP (O) (NR 1 R "), where R 'and R" each represent lower alkyl or phenyl, or together with the nitrogen atom to which they are attached denotes a heterocyclic group, such as morpholine, pyrrolidine, piperidine or methyl pi perazine.

Omsætningen gennemføres fortrinsvis under basiske betingelser, d.v.s. under tilstedeværelsen af en base og foretrukne baser er alkalimetal-, f.eks. kalium- eller natrium-, alkoxider eller -hydrider. Omsætningen gennemføres fortrinsvis under tilstedeværelse 15 af et organisk opløsningsmiddel, som ikke reagerer med reaktanterne og reaktionsprodukterne under reaktionsbetingelserne, og specielt et vandfrit opløsningsmiddel og fortrinsvis et vandfrit aprotisk opløsningsmiddel såsom dimethylformamid (DMF) eller lignende. Temperaturintervallet, der anvendes, kan være et hvilket som helst 20 område, der er tilstrækkeligt højt til, at omsætningen kan forløbe i et rimeligt tempo og uden unødvendig forsinkelse eller dekomponering og et interval på fra -40°C til ca. stuetemperatur er derfor almindeligvis særligt egnet.The reaction is preferably carried out under basic conditions, i.e. in the presence of a base and preferred bases are alkali 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, and in particular an anhydrous solvent and preferably an anhydrous aprotic solvent such as dimethylformamide (DMF) or the like. The temperature range used may be any range sufficiently high for the reaction to proceed at a reasonable rate and without undue delay or decomposition and a range of from -40 ° C to approx. room temperature is therefore generally particularly suitable.

Udgangsmaterialerne kan fremstilles ud fra korranercielt 25 tilgængelige benzenderivater og ved anvendelse af velkendte syntesemetoder og som beskrevet i Synthesis, bind Kl, s. 681-682.The starting materials can be prepared from the commercially available benzene derivatives and using well-known synthetic methods and as described in Synthesis, Vol. K, pp. 681-682.

Forbindelserne ifølge opfindelsen har stort set samme evne til at fortrænge radioaktivt mærket flunitrazepam fra benzodiazepin-receptorer som de fra EP 109921 og EP.150040 kendte forbindelser, men 30 herudover har de overraskende forbedrede selektive benzodiazepinvirkninger, specielt hvad angår den sedative og anxiolytiske effekt.The compounds of the invention have substantially the same ability to displace radiolabeled flunitrazepam from benzodiazepine receptors as the compounds known from EP 109921 and EP.150040, but additionally have the surprisingly enhanced selective benzodiazepine effects, especially in terms of the sedative and anxiolytic effect.

Fortrængningsaktiviteten hos forbindelserne ifølge opfindelsen kan findes ved at bestemme EDgQ-værdien. EDg^-værdien repræsen-35 terer den dosis (mg/kg) af et prøvestof, hvormed den specifikke binding af flunitrazepam til benzodiazepinreceptorer i en levende hjerne reduceres til 50% af kontrolværdien.The displacement activity of the compounds of the invention can be found by determining the EDgQ value. The EDg value represents the dose (mg / kg) of a test substance by which the specific binding of flunitrazepam to benzodiazepine receptors in a living brain is reduced to 50% of the control value.

Et sådant in vivo forsøg udføres på følgende måde:Such an in vivo experiment is performed as follows:

9 DK 155941 B9 DK 155941 B

33

Princip. 20 minutter efter at en dosis af H-flunitrazepam (3H-FNM) (200 μ Ci/kg, i.v.) er blevet indgivet, når omfanget af specifik H-FNM binding til hjernebenzodiazepinreceptorer den maximale værdi. H-FNMs specifikke binding kan delvis eller helt 5 forhindres ved en samtidig eller forudgående indgivelse af farmakologisk aktive benzodiazepiner eller af nogle benzodiazepinlignende midler (Chang og Snyder, Eur. J. Pharmacol. 48, 212-218 (1978)).Principle. Twenty minutes after a dose of H-flunitrazepam (3H-FNM) (200 µ Ci / kg, i.v.) is administered, the extent of specific H-FNM binding to brain benzodiazepine receptors reaches the maximum value. The specific binding of H-FNM can be partially or completely prevented by the concomitant or prior administration of pharmacologically active benzodiazepines or by some benzodiazepine-like agents (Chang and Snyder, Eur. J. Pharmacol. 48, 212-218 (1978)).

Forsøgsprocedure. Suspensioner af prøvestoffer (2 mg/ml) 10 fremstilles i 5% Duphasol ®-X (ricinusolie-ethylenoxidderivat til emulgering og opløsning af olie og andre vanduopløselige stoffer) ved lydbehandling i 10 minutter ved brug af et Branson Bl5 microtip ultralydsapparat (indstilling 7). Grupper af 3 mus (hunmus af NMR-typen, der vejer 18-22 g) injiceres intraperitonealt med 15 prøveforbindelsen i en mængde på 100 mg/kg. 15 minutter efter 3 prøvestoffets indgivelse tilføres musene intravenøst 4 μ Ci af H-FNM (70-90 Ci/mol) i 200 μΐ fysiologisk saltopløsning. 20 minutter efter * ' o indgivelsen af H-FNM aflives musene ved halshugning og deres forhjerner fjernes hurtigt (indenfor 30 sek.) og homogeniseres i 12 20 ml iskold 25 mM K^PO^, pH 7,1 ved hjælp af et Ultra-TurraxExperimental procedure. Suspensions of test substances (2 mg / ml) 10 are prepared in 5% Duphasol ®-X (castor oil-ethylene oxide derivative for emulsifying and dissolving oil and other water-insoluble substances) by sound treatment for 10 minutes using a Branson Bl5 microtip ultrasonic device (setting 7) . Groups of 3 mice (NMR female mice weighing 18-22 g) are injected intraperitoneally with the test compound in an amount of 100 mg / kg. 15 minutes after administration of the 3 test substance, mice are intravenously fed 4 μ Ci of H-FNM (70-90 Ci / mol) in 200 μΐ physiological saline solution. Twenty minutes after the administration of H-FNM, the mice are sacrificed by decapitation and their foreskins are rapidly removed (within 30 seconds) and homogenized in 12 20 ml ice-cold 25 mM K 2 PO 2, pH 7.1 by an Ultra Turrax®

homogeniseringsapparat, som er forsynet med en N 10 aksel. To portioner på 1 ml filtreres straks gennem Whatman GF/Chomogenizer, which is provided with an N 10 shaft. Two 1 ml portions are immediately filtered through Whatman GF / C

glasfiberfiltre og vaskes med 2 x 5 ml af ovennævnte puffer. Mængden af radioaktivitet på filtrene måles ved traditionel 25 scintillationstælling. En gruppe af ubehandlede mus tjener som kontrolgruppe. 1-3 mus injiceres med 25 μ g/kg clonazepam i.p. 30 3 minutter før indgivelsen af H-FNM til bestemmelse af ikke-specifik 3 H-FNM binding, som bør ligge på mellem 8-15% af den totale binding.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 μg / kg clonazepam i.p. 3 minutes before the administration of H-FNM to determine non-specific 3 H-FNM binding, which should be between 8-15% of the total binding.

Når doser på 100 mg/kg inhiberer mere end 50% specifik 30 H-flunitrazepambinding, indgives prøveforbindelserne i doser, som er en faktor på 3,16 gange mindre end 100 mg/kg. EDgQ-værdien af en prøveforbindelse defineres som den dosis, som inhiberer 50% specifik 3 H-FNM binding. Specifik binding defineres som omfanget af binding i kontrolmusene minus omfanget af binding hos clonazepambehandlede mus.When doses of 100 mg / kg inhibit more than 50% specific 30 H flunitrazepam binding, the test compounds are administered at doses which are a factor of 3.16 times less than 100 mg / kg. The EDgQ value of a test compound is defined as the dose which inhibits 50% specific 3 H-FNM binding. Specific binding is defined as the extent of binding in the control mice minus the extent of binding in clonazepam-treated mice.

35 Resultater. ED5Q-værdien bestemmes ud fra dosis-responskur- ver. Hvis der kun indgives én dosis af prøvestoffet, beregnes EDgg-værdien som følger, forudsat at hæmningen af specifik binding35 results. The ED5Q value is determined from dose-response curves. If only one dose of the test substance is administered, the EDgg value is calculated as follows, provided that the inhibition of specific binding

10 DK 155941 B10 DK 155941 B

ligger indenfor et interval på 25-75%: 1 mg/kg ED50 = (indgivet dosis) * Cq \ V C / 5 N x 7 hvor C betegner specifik binding hos kontrolmusene og C betegner v Λ specifik binding hos mus, som er behandlet med prøvestoffet.is within a range of 25-75%: 1 mg / kg ED50 = (dose administered) * Cq \ VC / 5 N x 7 where C denotes specific binding in control mice and C denotes binding specific binding in mice treated with the test substance.

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

10 TABEL 1 gV* rVv Λ In vivo fortrang- Øningsaktivitet: E°so (rag/kg).TABLE 1 gV * rVv Λ In vivo displacement Activity: E ° so (rag / kg).

u« rS χ1u «rS χ1

O-NO-N

ΓοΤ « ch3 °·4 co2ch3 fol 30 JlChοΤ «ch3 ° · 4 co2ch3 fol 30 Jl

-CL-CL

“ øc X" « «3 -X>-C„3 0/-v- N 3“Ec X” «« 3 -X> -C „30 / -v- N 3

V NV N

..

1111

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ΤΠ bestemmelse af de selektive benzodiazepinvirkninger af forbindelser ifølge opfindelsen og et repræsentativt udvalg af de fra EP. 109921 og EP 150040 blev der gennemført følgende undersøgelser: 5 Mørkemotilitet hos musΤΠ determination of the selective benzodiazepine effects of compounds of the invention and a representative selection of those from EP. 109921 and EP 150040, the following studies were performed: 5 Dark motility in mice

Princip: Mus, der i 7 dage holdes under en omvendt dag/nat-cyclus, 10 ændrer fuldstændig døgnrytme, d.v.s. den aktive periode er om dagen (mørk periode). Ved at placere musene i undersøgelseskasse i 16 timer elimineres næsten al deres udforskende aktivitet. Hensigten med den omhandlede undersøgelse er at måle lægemiddel-induceret nedgang i bevægelsesaktivitet hos mus efter 16 timers tilvænning til undersø-15 gelseskassen og efter at de har været holdt under omvendt dag/nat-cyclus i 7 dage. Denne model anses at være prediktiv for sedativ effekt.Principle: Mice kept for 7 days during a reverse day / night cycle, 10 change complete circadian rhythm, i.e. the active period is during the day (dark period). By placing the mice in the study box for 16 hours, almost all their exploratory activity is eliminated. The purpose of the present study is to measure drug-induced decline in locomotor activity in mice after 16 hours of habituation to the study box and after being kept under the reverse day / night cycle for 7 days. This model is considered to be predictive of sedative effect.

Metoder: Aktiviteten hos 7 grupper af 4 hunmus af NMRI-typen (20-22 20 g), der i de sidste 16 timer har været holdt i transparente perspexbure, måles med et Animex motimeter (Columbus Instruments,Methods: The activity of 7 groups of 4 NMRI female mice (20-22 20 g), which have been kept in transparent perspex cages for the past 16 hours, is measured with an Animex motimeter (Columbus Instruments,

Ohio) efter 7 dage på en omvendt dag/nat-cyclus (mørke 6-18, lys 18-6) i undersøgelsesrummet. Temperaturen holdes på 21-22°C og aktiviteten i det kendte transparente perspexbur (36 X 22 X 20 cm) 25 måles i 8 timer, begyndende kl. 8.30 umiddelbart efter intraperitoneal injektion af lægemidlerne. Motilitetværdierne registreres hvert andet min. med en båndoptager og analyseres senere i fire 2 timers intervaller.Ohio) after 7 days on a reverse day / night cycle (darkness 6-18, light 18-6) in the study room. The temperature is maintained at 21-22 ° C and the activity of the known transparent perspex cage (36 X 22 X 20 cm) 25 is measured for 8 hours, starting at 10 am. 8.30 immediately after intraperitoneal injection of the drug. The motility values are recorded every two minutes. with a tape recorder and later analyzed in four 2 hour intervals.

30 Kontrolmus opnår motilitetværdier på ca. 6400 i de første to timer.30 Control mice achieve motility values of approx. 6400 in the first two hours.

Dette svarer omtrent til 3-4 gange mere end værdierne fra ikke-reverserede mus.This corresponds approximately to 3-4 times more than the values of non-reversed mice.

««

Tre eller fire doser indgives til 7 grupper af 4 mus med doser både 35 over og under ED^-værdien.Three or four doses are administered to 7 groups of 4 mice at doses both above and below the ED

Resultater: ED^-værdien er den dosis, der sænker resultatet af optællingen til 4000 for de første 2 timer efter indgivelse af lægemidlet beregnet på et computerprogram, der er baseret på Litchfield og Wilcoxon's metode (1949).Results: The ED ^ value is the dose that lowers the result of the count to 4000 for the first 2 hours after administration of the drug calculated on a computer program based on Litchfield and Wilcoxon's method (1949).

1212

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PENTAZOLINDUCEREDE CLONISKE KONVULSIONER HOS MUS (I.P.)PENTAZOLE-INDUCED CLONIC CONVULSIONS OF MICE (I.P.)

Princlp: Pentylentetrazol inducerer cloniske og toniske kramper hos 5 mus ved doser på 60-120 mg/kg s.c.. Mekanismen er ukendt, men synes at skyldes virkninger i forbindelse med GABA receptor/-benzodiazepin receptor/chlori di onforkomplexet. Antagonisme af kramper induceret ved maximale doser af pentylentetrazol anses at være prediktive for lægemidler, der er effektive overfor petit mal epilepsi og angst.Principle: Pentylenetetrazole induces clonic and tonic seizures in 5 mice at doses of 60-120 mg / kg s.c. The mechanism is unknown but appears to be due to effects associated with the GABA receptor / benzodiazepine receptor / chlori di onfor complex. Antagonism of seizures induced by maximal doses of pentylenetetrazole is considered to be predictive of drugs effective against petit mal epilepsy and anxiety.

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Metode: 150 mg/kg pentylentetrazol opløst i 0,9 % NaCl ingives subkutant i mængder af 15 ml/kg i han- eller hunmus af NMRI-typen, der vejer 20-25 g, 30 min. efter intraperitoneal injektion af det stof, der skal undersøges. Antallet af mus, der udviser kloniske 15 krampeanfald, noteres indenfor de næste 30 min. Mindst 3 doser af hver prøveforbindelse anvendes til 4 eller 8 mus pr. dosis, og med doser både over og under ED^-værdien.Method: 150 mg / kg pentylenetetrazole dissolved in 0.9% NaCl is administered subcutaneously in amounts of 15 ml / kg in male or female NMRI mice weighing 20-25 g, 30 min. after intraperitoneal injection of the drug to be examined. The number of mice exhibiting clonic seizures is noted within the next 30 min. At least 3 doses of each test compound are used in 4 or 8 mice per day. dose, and with doses both above and below the ED ^ value.

Resultater: EDgg-værdien beregnes som den dosis i pg/kg, ved hvilken 20 krampeanfald hæmmes hos 50% af dyrene, ved anvendelse af et computerprogram, der er baseret på Litchfield og Wilcoxon's metode (1949).Results: The EDgg value is calculated as the dose in pg / kg at which 20 seizures are inhibited in 50% of the animals using a computer program based on Litchfield and Wilcoxon's method (1949).

ATAXI HOS MUS (I.P.) 25ATAXI ON MUS (I.P.) 25

Princip: Lægemidlers indvirkning på bevægelseskoordinationen undersøges ved at undersøge, hvordan mus opfører sig på en roterende stav.Principle: The effect of drugs on movement coordination is investigated by examining how mice behave on a rotating rod.

30 Apparatur: Den roterende stav er en rå træstang med en diameter på 43 mm og opdelt i otte 60 mm sektioner ved hjælp af aluminiumskiver (diameter: 145 mm). Hver ende af stangen løber i et kugleleje.30 Apparatus: The rotary rod is a 43 mm diameter wooden bar and divided into eight 60 mm sections using aluminum washers (diameter: 145 mm). Each end of the rod runs in a ball bearing.

Stangen kobles via en 12.5:1-reduktionsgearkasse til en elektrisk vekselstrømsmotor (Heidolph, type D 73, 220 V) med trinløs 35 hastighedsregulering. Den øverste ende af stangen er 120 mm højere end den nederste, og denne anbringelse kan ikke ændres. Stangens hastighed: 6 omdr./min.The rod is coupled via a 12.5: 1 reduction gearbox to an electric AC motor (Heidolph, type D 73, 220 V) with infinitely variable speed control. The upper end of the bar is 120 mm higher than the lower one and this position cannot be changed. Rod speed: 6 rpm

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Metode: Grupper på fire han- eller hunmus af NMRI-typen (der vejer 20-22 g) trænes i ca. to min., hvorefter de normalt er bekendt med situationen. Derefter bevæger de sig kontinuerligt sammen med ® stangen, og forbliver i deres position nær den øverste ende.Method: Groups of four male or female NMRI-type mice (weighing 20-22 g) are trained for approx. two minutes, after which they are usually familiar with the situation. Then they move continuously together with the ® rod, and remain in their position near the upper end.

Det stof, der skal undersøges, indgives i.p. (0.2-0.4 ml/20 g) 30 min. inden undersøgelsen. Hver undersøgelse har en varighed på 2 min.The substance to be examined is administered i.p. (0.2-0.4 ml / 20 g) 30 min. before the investigation. Each study has a duration of 2 min.

Musene anses at være ataxi ske, hvis der sker mere end to fald fra stangen indenfor 2 min.The mice are considered to be ataxia if more than two falls from the rod occur within 2 min.

Tre eller fire doser indgives til 4 mus pr. dosis, med doser både over og under ED^Q-værdien.Three or four doses are administered to 4 mice per day. dose, with doses both above and below the ED ^ Q value.

^ Resultater: ED5Q-værdien er den dosis, der gør 50% af musene ataxi ske ; 1/2 time efter indgivelse af lægemidlet, beregnet på et computerprogram, der er baseret på Litchfield og Wilcoxon's metode (1949).^ Results: The ED5Q value is the dose that makes 50% of the mice ataxia happen; 1/2 hour after administration of the drug, calculated on a computer program based on Litchfield and Wilcoxon's method (1949).

VANDSLIKNINGSUNDERSØGELSEWATER licking STUDY

2020

Introduktion: Undertrykkelse af vand-sliknings adfærd hos rotter, der er frataget vand, med eletrisk stød, er blevet brugt til at studere anxiolytikas konfliktafledende egenskaber (Petersen og Buus Larsen, 1981) og de konfliktskabende egenskaber ved anxiogeni ske lægemidler 25 (Petersen og Jensen, 1984).Introduction: Suppression of water-licking behavior in water-deprived rats with electrical shock has been used to study the conflict-relieving properties of anxiolytics (Petersen and Buus Larsen, 1981) and the conflict-causing properties of anxiogenic drugs 25 (Petersen and Jensen , 1984).

Metode: Efter en kort træningsperiode undersøges rotter en gang om ugen efter forudgående berøvelse af vand i 48 timer.Method: After a short training period, rats are examined once a week after prior water deprivation for 48 hours.

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Apparatur: Apparaturet er en rustfri stålkasse (13 X 21 X 14 cm) med gulv og vægge af metal net. En vandflaske med glastud fastgøres til midten af ydersiden på en af de lange sider, således at tuden når 2 cm ind i kassen i en højde af 3 cm over gulvet. Et dri nkometer tilsluttes mellem drikkerøret (en sølvelektrode i vandet) og gulvet i ^ kassen.Apparatus: The apparatus is a stainless steel box (13 X 21 X 14 cm) with floors and walls of metal mesh. Attach a water bottle with glass spout to the center of the outside on one of the long sides so that the spout reaches 2 cm into the box at a height of 3 cm above the floor. A drain gauge is connected between the drinking pipe (a silver electrode in the water) and the floor of the box.

Stød gives ved hjælp af et drinkometer fra Columbus Instruments Inc.,Shock is provided with a Columbus Instruments Inc. drinkometer,

Ohio, Rotterne kan få stød for hver 20 slik (1 "slikkeperiode") eller 14Ohio, The Rats may be shocked for every 20 sweets (1 "licking period") or 14

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ved en konstant slikkeperiode svarende til 20 slik (ved hjælp af pulsgenerator, der producerer kunstig slikning med 7 stød pr. sekund, når rotten er i kontakt med vandet). Stødet er 50 Hz og 0.4 mA i 0.2 ® sek.at a constant licking period equal to 20 sweets (using pulse generator which produces artificial licking at 7 beats per second when the rat is in contact with the water). The shock is 50 Hz and 0.4 mA in 0.2 ® sec.

Hanrotter af Wistartypen (180-220 g) berøves vand i 24 timer forud for en 6 min. træningsperiode i undersøgelseskassen, uden at de får stød. Kun rotter, der slikker i løbet af denne tid, går videre til en ^ yderligere 24 timers prøve, hvorunder de berøves vand.Male Wistar rats (180-220 g) are deprived of water for 24 hours prior to a 6 min. training period in the examination box without being shocked. Only rats licking during this time go on to a ^ further 24 hour trial during which they are deprived of water.

24 timer efter første træningsperiode placeres rotten i kassen. En 6 min. undersøgelsesperiode starter automatisk, når rotten har foretaget 20 slik og modtager det første stød. Efter hvert 20 slik 15 gives et 0.4 mA stød mellem netgulvet og drikketuden.Twenty-four hours after the first training period, the rat is placed in the box. And 6 min. investigation period starts automatically when the rat has made 20 sweets and receives the first shock. After every 20 sweets 15, a 0.4 mA shock is given between the net floor and the drinking spout.

Salt (0.9% NaCl) injiceres i.p. straks efter den første straffeperiode, og 30 min. senere gentages straffeperioden.Salt (0.9% NaCl) is injected i.p. immediately after the first penalty period, and 30 min. later the penalty period is repeated.

Umiddelbart efter den ånden straffeperiode undersøges rotterne i 6 ·· ; ---Sø ' Λ · - ·. . . ·..··· min;, i et velkendt bur for ustraffet slikning. 'Immediately after that spirit penalty period, the rats are examined in 6 ··; --- Lake 'Λ · - ·. . . · .. ··· min ;, in a well-known cage for unpunished licking. '

Undersøgelse: Trænede rotter undersøges én gang ugentlig efter forudgående berøvelse af vand i 48 timer. Rotterne undersøges først ubehandlet i 6 min. og får stød efter hvert 20. slik. Kun rotter der 25 udfører 0-9 slikkeperioder under denne prodrugperiode med straf anvendes til undersøgelse af antikonflikt virkning hos den undersøgte forbindelse. Umiddelbart efter prodrugperioden med straf indgives den forbindelse, der skal undersøges i.p. og de undersøges 30 min. senere i 6 min. i undersøgelseskassen. Umiddelbart efter postdrugperioden 30 med straf er der en periode uden straf (6 min.) i et velkendt bur. I alle 3 perioder tælles slikke-perioderne. Sædvanligvis anvendes mellem 7-15 rotter pr. dosis.Study: Trained rats are examined once weekly after prior deprivation of water for 48 hours. The rats are first examined untreated for 6 min. and gets shock after every 20th candy. Only rats performing 0-9 licking periods during this prodrug period with punishment are used to investigate the anti-conflict effect of the compound studied. Immediately after the prodrug period with punishment, the compound to be examined i.p. and they are examined for 30 min. later for 6 min. in the examination box. Immediately after the post-drug period 30 with punishment, there is a period without punishment (6 min) in a well-known cage. In all 3 periods, the licking periods are counted. Usually between 7-15 rats are used per day. dosage.

**

Resultater: M.E.D.-værdien beregnes som den minimumsdosis, der tydeligt (p 0.05, Students t-test for parret observation) forhøjer postdrugstraffet respons sammenlignet med prædrugstraffet respons.Results: The M.E.D. value is calculated as the minimum dose that clearly (p 0.05, Student's t-test for paired observation) increases post-drug punishment response compared to pre-drug punishment response.

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Referencer: Petersen, E.N. og Buus*Larsen, J. (1981) A water lick conflict paradigm using drug experienced rats. Psychopharmacology 5 75:236-239.References: Petersen, E.N. and Buus * Larsen, J. (1981) A water lick conflict paradigm using drug experienced rats. Psychopharmacology 5 75: 236-239.

Petersen, E.N. og Jensen, L.H. (1984) Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function. European J. Pharmacol. 103:91-97.Petersen, E.N. and Jensen, L.H. (1984) Proconflict effect of benzodiazepine receptor inverse agonists and other inhibitors of GABA function. European J. Pharmacol. 103: 91-97.

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De ved de ovenfor omtalte undersøgelser opnåede resultater er angivet i tabel 2.The results obtained from the studies mentioned above are given in Table 2.

Det fremgår klart af tabel 2, at forbindelserne ifølge opfindelsen 15 besidder en udtalt selektivitet ved sedative undersøgelser (700) ©g anxiolytiske undersøgelser (500) sammenlignet med referencestoffer kendt fra EP 109921 og EP 150040. Dette fremgår klarest ved at betragte de "anxiolytiske" og "sedative" index. En anden metode til at beregne "anxTOlytiské" og "sedative" index ville være at beregne 20 forholdet mellem en standardbenzodiazepinvirkning, som f.eks. pentazolclonierne (400) med de sedative (700) pg anxiolytiske virkninger. En sådan beregning er ikke medtaget i tabellen, men et hurtigt blik på tabellen fortæller, at også ifølge en. sådan beregning vil stofferne ifølge denne opfindelse udvise en forbavsende 25 "anxiolytisk" eller "sedativ" selektivitet.It is clear from Table 2 that the compounds of the invention 15 have a pronounced selectivity in sedative studies (700) © anxiolytic studies (500) compared to reference substances known from EP 109921 and EP 150040. This is most clearly seen by considering the "anxiolytic" and "sedative" index. Another method of calculating "anxTOlytiské" and "sedative" index would be to calculate the ratio of a standard benzodiazepine effect, such as the pentazole clones (400) with the sedative (700) and anxiolytic effects. Such a calculation is not included in the table, but a quick look at the table tells that according to one. In such a calculation, the substances of this invention will exhibit an astonishing "anxiolytic" or "sedative" selectivity.

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Forbindelsen ifølge opfindelsen sammen med et sædvanligt hjælpestof, bærer eller fortyndingsmiddel og, om ønsket, i form af et farmaceutisk acceptabelt syreadditionssalt deraf, kan formuleres til ® farmaceutiske præparater og enhedsdoser deraf og kan i en sådan form bruges i faste stoffer, såsom tabletter eller fyldte kapsler, eller i væskeform, såsom opløsninger, suspensioner, emulsioner, eliksirer eller kapsler fyldt med samme, alle til oral anvendelse; i form af suppositorier til rektal indgivelse eller i form af sterile ^ injicerbare opløsninger til parenteral (herunder subkutan) brug. Sådanne farmaceutiske præparater og enhedsdosisformer heraf kan omfatte sædvanlige bestanddele i sædvanlige forhold, med eller uden yderligere aktive forbindelser eller principper, og 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 tilsigtede daglige dosisområde, som skal anvendes. Tabletter, som indeholder et (1) mg aktiv bestanddel eller mere generelt fra et (1) til hundrede (100) mg pr. tablet, er passende repræsentative enhedsdosisformer.The 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, may be formulated into pharmaceutical preparations and unit doses thereof and in such form may be used in solids 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 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 usual constituents in usual conditions, with or without additional active compounds or principles, and such unit dosage forms should contain an effective amount of the active ingredient that is proportionate to the central nervous system disorder. intended daily dose range to be used. Tablets containing one (1) mg of active ingredient or more generally from one (1) to one hundred (100) mg per day. tablet, are appropriately representative unit dosage forms.

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

Sædvanlige tilsætningsstoffer er sådanne farmaceutisk 25 acceptable organiske eller uorganiske bærestoffer, 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.

Eksempler på sådanne bærestoffer er vand, saltopløsninger, alkoholer, polyethylenglycoler, polyhydroxy-ethyleret ricinusolie, 30 gelatine, lactose, amylose, magnesiumstearat, talkum, kiselsyre, fedtsyremonoglycerider og fedtsyrediglycerider, pentaerythritolfedtsyreestere, hydroxymethylcellulose og polyvinyl pyrrol i don.Examples of such carriers are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and fatty acid diglyceryls, pentaerythritol fatty acid esters, hydroxy acid esters, hydroxyacetic acid esters, hydroxy acid esters,

De farmaceutiske præparater kan steriliseres og om ønsket blandes med sådanne hjælpemidler, såsom smøremidler, konserverings-35 . midler, stabiliseringsmidler, befugtningsmidler, emulgeringsmidler, salte til påvirkning af osmotisk tryk, puffere og/eller farvestoffer og lignende, som ikke på skadelig vis reagerer med den aktive forbindelse.The pharmaceutical compositions can be sterilized and, if desired, mixed with such adjuvants such as lubricants, preservatives. agents, stabilizers, wetting agents, emulsifiers, osmotic pressure salts, buffers and / or dyes, and the like, which do not adversely react with the active compound.

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Injicerbare opløsninger eller suspensioner, fortrinsvis vandige opløsninger med den aktive bestanddel opløst i polyhydroxyleret ricinusolie, er særligt foretrukne til parenteral 5 anvendelse.Injectable solutions or suspensions, preferably aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil, are particularly preferred for parenteral use.

Ampuller er hensigtsmæssige enhedsdosisformer.Ampoules are appropriate unit dosage forms.

Tabletter, drageer eller kapsler, der indeholder talkum og/eller en kulhydratbærer eller -binder eller lignende, er specielt egnede til oral anvendelse, idet bæreren fortrinsvis er lactose 1° og/eller majsstivelse og/eller kartoffelsstivelse. En sirup, eliksir eller lignende kan anvendes, når en sødet bærer kan bruges. I almindelighed dispenseres forbindelsen ifølge opfindelsen i enhedsdosisform, hvor en enhedsdosis omfatter 1-100 mg i en farmaceutisk acceptabel bærer.Tablets, dragons or capsules containing talc and / or a carbohydrate carrier or binder or the like are particularly suitable for oral use, the carrier being preferably lactose 1 ° 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 compound of the invention is dispensed in unit dosage form, wherein a unit dose comprises 1-100 mg in a pharmaceutically acceptable carrier.

En typisk tablet, som kan fremstilles efter sædvanlige tabletteringsmetoder, indeholder:A typical tablet which can be prepared by conventional tableting methods contains:

Aktiv forbindelse 1,0 mgActive compound 1.0 mg

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

20 AvicelR 31,4 mgAvicelR 31.4 mg

Amberi iteR IRP 88 1,0 mgAmberi iteR IRP 88 1.0 mg

Magnesii stearas 0,25 mg Ph.Eur.Magnesii stearas 0.25 mg Ph.Eur.

På grund af den store affinitet overfor benzodiazepinrecepto-25 rerne er forbindelserne ifølge opfindelsen meget anvendelige ved behandling af centralnervesystemssygdomme eller -forstyrrelser, når de indgives i en mængde, der er effektiv til lindring, mildning eller fjernelse af sygdommene eller forstyrrelserne. Den vigtige CNS-akti-vitet af forbindelsen ifølge opfindelsen omfatter både krampehæmmende 30 og angstdæmpende aktiviteter sammen med lav toksicitet, som tilsammen giver et meget gunstigt terapeutisk indeks. En forbindelse ifølge opfindelsen kan følgelig indgives i et individ, f.eks. et levende dyrisk legeme, herunder et menneske, som har behov for samme til behandling, lindring, mildning eller fjernelse af en indikation, som 35 er forbundet med centralnervesystemet og de såkaldte benzodiazepinreceptorer og som har behov for .psykofarmaceutisk behandling, f.eks. specielt krampe- og/eller angsttilstande. Om ønsket kan’forbi ndel sen bruges i form af et farmaceutisk acceptabelt syreadditionssalt derafBecause of the high affinity for the benzodiazepine receptors, the compounds of the invention are very useful in treating central nervous system disorders or disorders when administered in an amount effective for alleviating, alleviating or removing the diseases or disorders. The important CNS activity of the compound of the invention includes both anticonvulsant and anti-anxiety activities, together with low toxicity, which together provide a very favorable therapeutic index. Accordingly, a compound of the invention may be administered to a subject, e.g. a living animal body, including a human, in need of the same for treating, alleviating, alleviating or removing an indication associated with the central nervous system and so-called benzodiazepine receptors and in need of psychopharmaceutical treatment, e.g. especially cramp and / or anxiety conditions. If desired, the compound may be used in the form of a pharmaceutically acceptable acid addition salt thereof.

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19 (såsom hydrobromid, hydrochlorid eller sulfat, i alle tilfælde fremstillet på den almindelige eller sædvanlige måde, f.eks. ved inddampning til tørhed af en opløsning af den frie base og syren) 5 almindeligvis sideløbende med, samtidig med eller sammen med en. farmaceutisk acceptabel bærer eller fortyndingsmiddel og fortrinsvis i form af et farmaceutisk præparat hvad enten den indgives oralt, rektalt eller parenteralt (inkl. subkutant) i en til lindring af en lidelse i centralnervesystemet psykofarmaceutisk effektiv mængde, 10 f.eks. en mængde som virker krampehæmmende og/eller angstdæmpende, i alle tilfælde en mængde, som er effektiv til lindring af en sådan centralnervesystemslidelse som følge af benzodiazepinreceptoraffini-teten. Egnede daglige dosi sinterval ler er på 1-100 mg, fortrinsvis 1-30 mg og særligt 1-10 mg afhængig som sædvanlig af den eksakte 15 indgivelsesmåde, indgivelsesformen, indikationen som indgivelsen er rettet imod, individet der er involveret, og det involverede individs legemesvægt og den ansvarlige læge eller dyrlæges præference eller erfaring. Bredere dosisintervaller for forbindelserne ifølge opfindelsen er 0,1-100 mg/dag, fortrinsvis 1-30 mg/dag, når de 20 indgives i patienter, f.eks. mennesker, i form af et medikament.19 (such as hydrobromide, hydrochloride or sulphate, in all cases prepared in the usual or usual manner, for example by evaporation to dryness of a solution of the free base and the acid) 5, generally concurrent with, simultaneously with or with one. a pharmaceutically acceptable carrier or diluent and preferably in the form of a pharmaceutical composition, whether administered orally, rectally or parenterally (including subcutaneously) in a psycho-pharmaceutically effective amount to alleviate a disorder of the central nervous system, e.g. an amount that acts as an anticonvulsant and / or anesthetic, in any case an amount effective to relieve such central nervous system disorder as a result of the benzodiazepine receptor affinity. Suitable daily dosage intervals are 1-100 mg, preferably 1-30 mg and especially 1-10 mg, as is customary, as usual, for the exact mode of administration, the form of administration, the indication to which the administration is directed, the subject involved, and the subject involved. body weight and the physician or veterinarian's preference or experience. Broader dose ranges for the compounds of the invention are 0.1-100 mg / day, preferably 1-30 mg / day when administered to patients, e.g. humans, in the form of a drug.

Opfindelsen vil nu blive beskrevet nærmere under henvisning til de følgende eksempler: EKSEMPEL 1 25 5-Ethoxycarbony1 -1,2-dihydro-4H-3,1-benzoxazi n-2,4-di onThe invention will now be described in more detail with reference to the following examples: EXAMPLE 1 5-Ethoxycarbonyl-1,2-dihydro-4H-3,1-benzoxazi n-2,4-dione

En blanding af 6-ethoxycarbonyl-3-aminobenzoesyrehydrochlorid (25 g) og phosgen (70 mg, 30% opløsning i toluen) tilbagesvales i 2 timer i 300 ml tør dioxan. Opløsningen inddampes derefter i vakuum 30 til dannelse af ovennævnte forbindelse i form af et krystallinsk pulver. Smp. 188,5-189,6°C.A mixture of 6-ethoxycarbonyl-3-aminobenzoic acid hydrochloride (25 g) and phosgene (70 mg, 30% solution in toluene) is refluxed for 2 hours in 300 ml of dry dioxane. The solution is then evaporated in vacuum 30 to give the above compound as a crystalline powder. Mp. 188.5 to 189.6 ° C.

EKSEMPEL 2 35 6-Ethoxycarbony1-3,4-di hydro-4-methyl-3H-1,4-benzodi azepi n-2,5-(1H)- dionEXAMPLE 2 6-Ethoxycarbonyl-3,4-di hydro-4-methyl-3H-1,4-benzodi-azepine-2,5- (1H) -dione

En blanding af 5-ethoxycarbonyl-l,2-dihydro-4H-3,l-benzoxazin -2,4-di on (23,5 g) og sarcosin (9,5 g) i 200 ml di methyl sulf oxid 20A mixture of 5-ethoxycarbonyl-1,2-dihydro-4H-3,1-benzoxazine -2,4-dione (23.5 g) and sarcosine (9.5 g) in 200 ml of di-methyl sulfide 20

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(DMSO) opvarmes til 130°C under omrøring. Efter 4 timer afkøles opløsningen til stuetemperatur og opløsningsmidlet fjernes i vakuum.(DMSO) is heated to 130 ° C with stirring. After 4 hours, the solution is cooled to room temperature and the solvent removed in vacuo.

Resten behandles med ethyl acetat, hvorefter ovennævnte forbindelse 5 udfældes i form af lysegule krystaller. Krystallerne opsamles ved filtrering. Smp. 187,7-188,5°C.The residue is treated with ethyl acetate and the above compound 5 precipitates in the form of pale yellow crystals. The crystals are collected by filtration. Mp. 187.7 to 188.5 ° C.

EKSEMPEL 3 10 (S)-6-Ethoxycarbony1-l,2,3,lla-tetrahydro-5H-pyrrol(2,1-c)(1,4)-benzodi azepi n-5,11(1H)-di onExample 3 (S) -6-Ethoxycarbonyl-1,2,3,1a-tetrahydro-5H-pyrrole (2,1-c) (1,4) -benzodi-azepine-5,11 (1H) -dione

En blanding af 5-ethoxycarbonyl-l,2-dihydro-4H-3,l-benzoxazin -2,4-dion (5,5 g) og L-prolin opvarmes under omrøring til 140°C i 75 ml DMSO. Efter 4 1/2 time afkøles opløsningen til stuetemperatur og 15 inddampes i vakuum. Inddampningsresten deles i methylenchlorid og vand og den organiske fase fraskilles, tørres over MgSO^ og inddampes til dannelse af ovennævnte forbindelse i form af lysebrune krystaller. Smp. 188-188,2°C.A mixture of 5-ethoxycarbonyl-1,2-dihydro-4H-3,1-benzoxazine -2,4-dione (5.5 g) and L-proline is heated under stirring to 140 ° C in 75 ml of DMSO. After 4 1/2 hours, the solution is cooled to room temperature and evaporated in vacuo. The residue is partitioned into methylene chloride and water and the organic phase is separated, dried over MgSO4 and evaporated to give the above compound as light brown crystals. Mp. 188 to 188.2 ° C.

20 EKSEMPEL 4 3-Cycl opropy 1-5-i socyan'omethy 1-1,2,4-oxadiazol a. 3-Cyc1opropyl-5-formylaminomethyl-l,2,4-oxadiazol 2 5EXAMPLE 4 3-Cyclopropyl 1-5-i socyanomethyl 1-1,2,4-oxadiazole a. 3-Cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole

En opløsning af ethylformylami nomethyl carboxyl at (150 mmol) og cyclopropylcarboxamidoxim (100 mmol) i 100% EtOH (100 ml) tilsættes Na (200 mg) og knust molekyl si (4Å) (10 g). Den derved opnåede blanding omrøres og opvarmes under tilbagesvaling i 8 timer.A solution of ethylformylamethyl methyl carboxyl (150 mmol) and cyclopropylcarboxamidoxim (100 mmol) in 100% EtOH (100 ml) is added Na (200 mg) and crushed molecule si (4Å) (10 g). The resulting mixture is stirred and heated under reflux for 8 hours.

^ Blandingen afkøles til stuetemperatur-, filtreres gennem filterhjælpemiddel og filtratet inddampes i vakuum. Den olieagtige inddampningsrest deles i en CHC13 fase, som tørres med Na2S04 og inddampes.The mixture is cooled to room temperature, filtered through filter aid and the filtrate is evaporated in vacuo. The oily residue is partitioned into a CHCl 3 phase which is dried with Na 2 SO 4 and evaporated.

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21 henstå i 30 minutter med omrøring ved 0°C, hvorefter en opløsning afStir for 30 minutes with stirring at 0 ° C, then a solution of

Na,,C0g (60 mmol) i 1^0 (50 ml) tilsættes. Blandingen opvarmes til stuetemperatur, hvorefter den organiske fase fraskilles, tørres og 5 inddampes i vakuum. Inddampningsresten behandles med ether, dekanteres og opløsningen inddampes til dannelse af ovennævnte forbindelse i form af en olie. Olien viderebehandles uden yderligere rensning. Forbindelsen karakteriseres ved dens IR absorptionsbånd ved 2160cml.Na 2 CO 2 (60 mmol) in 100 µl (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 further processed without further purification. The compound is characterized by its IR absorption band at 2160cml.

^ På lignende måde fremstilles 3-ethyl-5-isocyanomethyl-l,2,4- oxadiazol ud fra 3-ethyl-5-formylaminomethyl-l,2,4-oxadiazoI. IR: 2170cm_1.Similarly, 3-ethyl-5-isocyanomethyl-1,2,4-oxadiazole is prepared from 3-ethyl-5-formylaminomethyl-1,2,4-oxadiazole. IR: 2170cm_1.

EKSEMPEL 5 15 5-Cyc1opropy1-3-i socyanomethyl-1,2,4-oxadi azol a. Formyl ami nomethyl-carboxami doxim 0,55 mmol af nylig frigjort hydroxylamin opløst i 370 ml 20 methanol sættes til 53,6 g (0,638 mmol) N-formylaminoacetonitril. Et isbad bruges til at holde temperaturen under 20°C under tilsætningen. Opløsningen får lov til at henstå natten over ved stuetemperatur, hvorefter den inddampes til dannelse af ovennævnte forbindelse i form af blege krystaller. Dekomponer!ng: 104-110°C.EXAMPLE 5 5-Cyclopropyl-3-i-socyanomethyl-1,2,4-oxadi azole a. Formyl aminomethyl-carboxamide dox 0.55 mmol of recently released hydroxylamine dissolved in 370 ml of methanol is added to 53.6 g (0.638 mmol) 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: 104-110 ° C.

25 JLl 3-Formyl ami nomethyl-5-cyc1opropyl-1,2,4-oxadi azol25 JL1 3-Formyl aminomethyl-5-cyclopropyl-1,2,4-oxadiazole

En blanding af 35 ml cyclopropylcarboxyl at, 20 g formylaminomethylcarboxamidoxim, 1 g natrium og 30 g knust molekylsi (4Å) tilbagesvales i 300 ml abs. EtOH i 8 timer, hvorefter yderligere 30 1 g natrium tilsættes. Reaktionsblandingen filtreres og filtratet inddampes. Den mørke olieagtige inddampningsrest suspenderes i 300 ml CHClg, filtreres og filtratet inddampes til dannelse af ovennævnte forbindelse i form af en olie. H-NMR (60 MHz, CDCl^) (ppm): 1,2 (4H, m), 2,8 (IH, m), 4,5 (2H, d, J=6Hz), 7,8 (IH, bred-NH), 8,2 (IH, s).A mixture of 35 ml of cyclopropylcarboxyl, 20 g of formylaminomethyl carboxamidoxime, 1 g of sodium and 30 g of crushed molecular sieve (4Å) is refluxed in 300 ml of abs. EtOH for 8 hours, then an additional 30 l of sodium is added. The reaction mixture is filtered and the filtrate is evaporated. The dark oily 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 = 6Hz), 7.8 (1H) , wide NH), 8.2 (1H, s).

På lignende måde syntetiseres de følgende forbindelser ud fra passende ethyl estere: 3-Formylaminomethyl-5-et.hyl-l,2,4-oxadiazol. H-NMR(60 MHz, CDClg) (ppm): 1,4 (3H, t, J=8 Hz), 2,9 (2H, q, J= 8Hz) 4,55 (2H, s), 22Similarly, 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 (3H, t, J = 8 Hz), 2.9 (2H, q, J = 8Hz) 4.55 (2H, s), 22

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7,8 (IH, bred-NH), 8,25 (IH, s).7.8 (1H, broad-NH), 8.25 (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), 5 8,25 (IH, s).3-Formylaminomethyl-5-methyl-l, 2,4-oxadiazole. 1 H-NMR (60 MHz, CDCl 3) (ppm); 2.6 (3H, s), 4.6 (2H, d, J = 3 Hz), 7.4 (1H, wide-NH), 8.25 (1H, s).

3-Formyl ami nomethyl-5-methoxymethyl-1,2,4-oxadi azol. H-NMR (60 MHz, CDC1.3) (ppm): 3,5 (3H, s), 4,7 (4H, s+d, J=6 Hz), 7,8 OH, bred-NH), 8,25 (H, s).3-Formyl aminomethyl-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 OH, wide-NH), 8.25 (H, s).

10 5-Cyclopropyl-3-isocyanomethyl-l,2,4-oxadiazol5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole

En omrørt opløsning af 5-cyclopropyl-3-formylamino-methyl-l, 2,4-oxadiazol (60 mmol) og tri ethyl amin (176 mmol) i CHgClg O 00 ml) tilføres dråbevis P0C13 (60 mmol) ved 0°C. Blandingen henstilles derefter i 30 minutter ved omrøring ved 0°C, hvorefter en opløsning 15 af Na3C03 (60 mmol) i ti^O (50ml) 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 viderebehandles uden yderligere 20 rensning. Forbindelsen karakteriseres ved dens IR absorptionsbånd ved 2160 cm"^.A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethyl amine (176 mmol) in CH 2 Cl 2 O (00 mL) is added dropwise PO 13 (60 mmol) at 0 ° C. . The mixture is then allowed to stir for 30 minutes by stirring at 0 ° C, then a solution of Na 3 CO 3 (60 mmol) in ti0 0 (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 continued without further cleaning. The compound is characterized by its IR absorption band at 2160 cm "^.

På lignende måde fremstilles 5-ethyl-3-isocyanomethyl-l,2,4-oxadiazol, 5-methyl-3-isocyanomethyl-l,2,4-oxadiazol og 5-methoxy-25 methyl-3-isocyanomethyl-l,2,4-oxadiazol. Alle forbindelserne er 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-1,2 are prepared. , 4-oxadiazole. All the compounds are oils and are characterized by their IR stretch bands at 2160 cm ~ ^.

EKSEMPEL 6 30 Methoxyacetami doxi m 2,3 g natrium i 33 ml tør methanol blandes med 6,55 g hydroxylaminhydrochlorid i 66 ml tør methanol. Blandingen filtreres og 7,8 g methoxyacetonitril sættes dråbevis til filtratet. Blandingen henstilles i 48 timer. Blandingen afkøles derefter til 4°C.Example 6 Methoxyacetam doxi m 2.3 g sodium in 33 ml dry methanol is mixed with 6.55 g hydroxylamine hydrochloride in 66 ml 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. The mixture is then cooled to 4 ° C.

35 Filtrering og inddampning af filtratet giver 8,7 g af ovennævnte forbindelse.Filtration and evaporation of the filtrate yields 8.7 g of the above compound.

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På analog måde syntetiseres de følgende forbindelser ud fra passende nitriler: 5By analogy, the following compounds are synthesized from appropriate nitriles:

Propionamidoxim cyclopropy1carboxamidoxi m i sopropy1carboxami doxi m acetamidoxim phenylcarboxamidoxim.Propionamidoxime cyclopropylcarboxamide oxime in sopropylcarboxamide doxi acetamidoxim phenylcarboxamide oxime.

EKSEMPEL 7EXAMPLE 7

Diethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo(l,5-a)(1,4)benzodia-,r zepin-3,7-dicarboxyl at i v 6- Ethoxycarbonyl-3,4-dihydro-4-methyl-2H-l,4-benzodiazepisn-2,5 (IH)-di on (10 mmol) opløses i 25 ml tør di methyl formamid (DMF). (Kinder omrøring tilsættes K-t-butoxid (12 mmol) og blandingen afkøles derefter til -20°C. En -30°C kold opløsning af K-t-butoxid (12 mmol) i tør DMF (15 ml) tilføres isocyanoeddikesyreethy1 ester (12 mmol).Diethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a) (1,4) benzodia-, r-zepine-3,7-dicarboxyl at iv 6- Ethoxycarbonyl-3,4 -dihydro-4-methyl-2H-1,4-benzodiazepisn-2,5 (1H) -dione (10 mmol) is dissolved in 25 ml of dry di methyl formamide (DMF). (Kidney stirring is added Kt-butoxide (12 mmol) and the mixture is then cooled to -20 ° C. A -30 ° C cold solution of Kt-butoxide (12 mmol) in dry DMF (15 ml) is added to isocyanoacetic acid ethyl ester (12 mmol) .

Denne opløsning tilsættes ovennævnte opløsning og den kombinerede opløsning omrøres ved stuetemperatur i 2 timer. 2 ml eddikesyre tilsættes, hvorefter opløsningen inddampes til tørhed. Den olieagtige inddampningsrest underkastes S^-rensning med acetone/chlorøform (1/3) som elueringsmiddel. Dette giver ovennævnte forbindelse i form af et krystallinsk pulver. Smp. 136,3-139,9°C.This solution is added to the above solution and the combined solution is stirred at room temperature for 2 hours. 2 ml of acetic acid is added and the solution is evaporated to dryness. The oily residue is subjected to S 2 purification with acetone / chloroform (1/3) as the eluent. This gives the above compound in the form of a crystalline powder. Mp. 136.3 to 139.9 ° C.

På lignende måde syntetiseres de følgende forbindelser ud fra de passende benzodiazepindi oner og isonitriler: (S)-l-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-8-ethoxycarbonyl-11,12,13,13a-tetrahydro-9-oxo-9H-i mi dazo(1,5-a) pyrrol (2,1-c)(1,4)benzo diazepin ved omsætning af (S)-6-ethoxycarbonyl-l,2,3,1la-tetrahydro-5H-pyrrol(2,1-c)(1,4)benzodi azepi n-5,11(1OH)-dion med 3-cyclopropyl-5 -isocyanomethyl-1,2,4-oxadiazol. Smp. 97,2-97,4°C.Similarly, the following compounds are synthesized from the appropriate benzodiazepines and isonitriles: (S) -1- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -8-ethoxycarbonyl-11,12,13, 13a-tetrahydro-9-oxo-9H-i-dazo (1,5-a) pyrrole (2,1-c) (1,4) benzo diazepine by reaction of (S) -6-ethoxycarbonyl-1,2, 3,1la-tetrahydro-5H-pyrrole (2,1-c) (1,4) benzodi-azepine-5,11 (1OH) -dione with 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole. Mp. 97.2 to 97.4 ° C.

7- Ethoxycarbonyl-5,6-di hydro-5-methyl-3-(5-methoxymethy1-1,2,4 3 5 . -oxadiazol-3-yl)-6-oxo-4H-imidazo(l,5-a)(l,4)benzodiazepin ved omsæt-ni ng af 6-ethoxycarbonyl-3,4-di hydro-4-methyl-2H-1,4-benzodi azepin-2,5(1H)-di on med 3-i socyanomethy 1-5-methoxymethy1-1,2,4-oxadi azol.7- Ethoxycarbonyl-5,6-dihydro-5-methyl-3- (5-methoxymethyl-1,2,4,3-oxadiazol-3-yl) -6-oxo-4H-imidazo (1,5 a) (1,4) benzodiazepine by reaction of 6-ethoxycarbonyl-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5 (1H) -dione with 3- in socyanomethyl 1-5-methoxymethyl1-1,2,4-oxadi azole.

Smp. 116,0-116,9°C.Mp. 116.0 to 116.9 ° C.

2424

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3-(3-Cyclopropy1-1,2,4-oxadi azol-5-yl)-7-ethoxycarbonyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodi azepin ved omsætning af 6-ethoxycarbony1-3,4-di hydro-4-methyl-2H-(1,4)-benzodiazepi n-5 2,5(lH)-dion med 3-cyclopropyl-5-isocyanomethyl-l,2,4-oxadiazol. Smp.3- (3-Cyclopropyl-1,2,2-oxadiazol-5-yl) -7-ethoxycarbonyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a) ( 1,4) benzodi azepine by reaction of 6-ethoxycarbonyl-3,4-di hydro-4-methyl-2H- (1,4) -benzodiazepine n-2,5 (1H) -dione with 3-cyclopropyl-5 -isocyanomethyl-l, 2,4-oxadiazole. Mp.

169,9-170,2°C.169.9 to 170.2 ° C.

3-(3-Cyclopropy 1-1,2,4-oxadi azol-5-yl)-5,6-di hydro-7-methoxy-carbonyl-5-methyl-6-oxo-4H-imidazo(l,5-a)(l,4)benzodiazepin ved om^ sætning af 3,4-dihydro-6-methoxycarbonyl-4-methyl-2H-(1,4)-benzo-10 diazepin-2,5(lH)dion med 3-cyclopropyl-5-isocyanomethyl-l,2,4-oxadia-zol. Smp. 199,4-199,5°C.3- (3-Cyclopropy-1, 1,2,4-oxadiazol-5-yl) -5,6-dihydro-7-methoxy-carbonyl-5-methyl-6-oxo-4H-imidazo (1,5 -a) (1,4) benzodiazepine by reacting 3,4-dihydro-6-methoxycarbonyl-4-methyl-2H- (1,4) -benzo-diazepine-2,5 (1H) dione with 3 cyclopropyl-5-isocyanomethyl-l, 2,4-oxadiazol-Zol. Mp. 199.4 to 199.5 ° C.

7-Ethoxycarbony1-5,6-di hydro-5-methy1-3-(5-methy1-1,2,4-oxadi azol-3-y1)-6-oxo-4H-i mi dazo(1,5-a)(1,4)benzodi azepi n ved omsætning af 6-ethoxycarbonyl-3,4-dihydro-4-methyl-2H-(l,4)-benzodiazepin-2,5(lH)-dion med 3-isocyanomethyl-5-methyl-l,2,4-oxadiazol. Smp.7-Ethoxycarbonyl-5,6-di hydro-5-methyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) -6-oxo-4H-imidazo (1,5 a) (1,4) Benzodi azepine n by reaction of 6-ethoxycarbonyl-3,4-dihydro-4-methyl-2H- (1,4) -benzodiazepine-2,5 (1H) -dione with 3-isocyanomethyl 5-methyl-l, 2,4-oxadiazole. Mp.

205,7-205,9°C.205.7 to 205.9 ° C.

3-(5-Cyclopropyl-l,2,4-oxadiazo1-3-yl)-5,6-dihydro-7-methoxy-carbonyl-5-methyl-6-oxo-4H-imidazo(l,5-a)(1,4)benzodiazepin ved omsætning af 3,4-dihydro-6-methoxycarbonyl-4-methyl-2H-l,4-benzodia-2° zepin-2,5(lH)-dion med 5-cyclopropy!-3-isocyanomethyl-l,2,4-oxadiazol Smp. 230,7-232,8°C. .3- (5-cyclopropyl-l, 2,4-oxadiazo1-3-yl) -5,6-dihydro-7-methoxy-carbonyl-5-methyl-6-oxo-4H-imidazo (l, 5-a) (1,4) benzodiazepine by reacting 3,4-dihydro-6-methoxycarbonyl-4-methyl-2H-1,4-benzodia-2 ° zepin-2,5 (1H) -dione with 5-cyclopropyl-3 -isocyanomethyl-1,2,4-oxadiazole m.p. 230.7 to 232.8 ° C. .

3-(5-Cyclopropyl-1,2,4-oxadi azol-3-yl)-5,6-di hydro-7-ethoxy-carbonyl-5-methyl-6-oxo-4H-imidazo(l,5-a)(1,4)benzodiazepin ved omsætning af 3,4-dihydro-6-ethoxyGarbonyl-4-methyl-2H-1,4-benzodia-25 zepin-2,5(lH)-dion med 3-isocyanomethyl-5-cyclopropy1-1,2,4-oxadia-zol. Smp.· 178,2-179,2°C.3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -5,6-dihydro-7-ethoxy-carbonyl-5-methyl-6-oxo-4H-imidazo (1,5 a) (1,4) benzodiazepine by reaction of 3,4-dihydro-6-ethoxyGarbonyl-4-methyl-2H-1,4-benzodiazepine-2,5 (1H) -dione with 3-isocyanomethyl-5 -cyclopropy1-1,2,4-oxadiazol-Zol. Mp · 178.2-179.2 ° C.

EKSEMPEL 8 50 3,7-Bi s-(3-ethy1-1,2,4-oxadi azol-5-yl)-5,6-di hydro-5-methyl-6-oxo-4H- imi dazo(1,5-a)(1,4)benzodi azepi nEXAMPLE 8 3,7-Bi 5 - (3-Ethyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1 , 5-a) (1,4) benzodi azepi n

En blanding af diethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a)(1,4)benzodiazepin-3,7-dicarboxyl at (500 mg), propionamidoxim . (500 mg), natriumethanolat (120 mg) og 5 g knust molekylsi (4Å) 55 tilbagesvales i 3 timer i 40 ml tør ethanol. Blandingen afkøles til stuetemperatur og den knuste molekylsi filtreres fra, hvorefter filtratet inddampes til dannelse af et olieagtigt inddampningspro-dukt, som udkrystalliseres i vand. Smp. 172,8-174,3°C.A mixture of diethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine-3,7-dicarboxyl at (500 mg), propionamidoxime. (500 mg), sodium ethanolate (120 mg) and 5 g of crushed molecular sieve (4Å) 55 are refluxed for 3 hours in 40 ml of dry ethanol. The mixture is cooled to room temperature and the crushed molecular sieve is filtered off, after which the filtrate is evaporated to give an oily evaporation product which is crystallized in water. Mp. 172.8 to 174.3 ° C.

DK 155941EDK 155941E

25 På_ lignende måde fremstilles de følgende forbindelser: 5,6-Di hydro-3-(5-methyl -1,2,4-oxadi azol-3-y1)-5-methyl-6-oxo-7 5 -(3-phenyl-l,2,4-oxadiazol-5-yl)-4H-imidazo(1,5-a)(1,4)benzodiazepin ' ved omsætning af 7-ethoxycarbonyl-5,6-dihydro-5-methyl-3(5-methyl- l,2,4-oxadiazol-3-yl)-6-oxo-4H-imidazo-(l,5-a)(l,4)benzodiazepin med phenylcarboxamidoxim. Smp. 244,6-246,2°C.Similarly, the following compounds are prepared: 5,6-Di hydro-3- (5-methyl-1,2,4-oxadiazol-3-yl) -5-methyl-6-oxo-7 - (3) -phenyl-1,2,4-oxadiazol-5-yl) -4H-imidazo (1,5-a) (1,4) benzodiazepine by reaction of 7-ethoxycarbonyl-5,6-dihydro-5-methyl 3 (5-methyl-1,2,4-oxadiazol-3-yl) -6-oxo-4H-imidazo- (1,5-a) (1,4) benzodiazepine with phenylcarboxamidoxime. Mp. 244.6 to 246.2 ° C.

7-(3-Cyclopropyl-l,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-3-*0 (5-methyl-1,2,4-oxadiazol-3-yl)-6-oxo-4H-imidazo(1,5-a)(l,4)benzodia- zepin ved omsætning af 7-ethoxycarbony1-5,6-dihydro-5-methy1-3-(5-methyl-1,2,4-oxadiazol-3-yl)-6-oxo-4H-imidazo(l,5-a)-(1,4)benzodiaze-pin med cyclopropylcarboxamidoxim. Smp. 249,6-250,8°C.7- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-5-methyl-3- (O-5-methyl-1,2,4-oxadiazol-3-yl) ) -6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine by reaction of 7-ethoxycarbonyl-5,6-dihydro-5-methyl-3- (5-methyl-1, 2,4-oxadiazol-3-yl) -6-oxo-4H-imidazo (1,5-a) - (1,4) benzodiazepine with cyclopropylcarboxamidoxime. Mp. 249.6 to 250.8 ° C.

3-(5-cyclopropy1-1,2,4-oxadiazol-3-yl)-7-(3-methyl-l,2,4-*5 oxadi azol -5-yl) -5,6-di hydro-5-methyl -6-oxo-4H-imidazo( 1,5-a) (1,4)ibenzo diazepin ved omsætning af 3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)-7-ethoxycarbonyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzo-diazepin med acetamidoxim. Smp. 246,4-246,5°C.3- (5-Cyclopropyl-1,2,2-oxadiazol-3-yl) -7- (3-methyl-1,2,4-oxadiazol-5-yl) -5,6-dihydro-2 5-Methyl-6-oxo-4H-imidazo (1,5-a) (1,4) ibenzo diazepine by reaction of 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -7- ethoxycarbonyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine with acetamidoxime. Mp. 246.4 to 246.5 ° C.

20 EKSEMPEL 9 5,6-Di hydro-7-(2-hydroxyethoxycarbonyl)-5-methyl-3-(5-methyl-1,2,4-oxadiazol-3-yl)-6-oxo-4H-imidazo(l,5-a)(l,4)benzodiazepin 7-Ethoxycarbony1-5,6-di hydro-5-methyl-3-(5-methyl-1,2,4-oxa-2® diazol-3-yl)-6-oxo-4H-imidazo(l,5-a)(l,4)benzodiazepin (500 mg) opløses i ethylenglycol (20 ml) og 3 dråber koncentreret svovlsyre tilsættes. Opløsningen omrøres derefter ved 130°C i 24 timer, afkøles og deles mellem vand (150 ml) og CHC13 (150 ml). Den organiske fase fraskilles, tørres over ^SO^ og inddampes til dannelse af 30 ovennævnte forbindelse i form af hvide krystaller.EXAMPLE 9 5,6-Di hydro-7- (2-hydroxyethoxycarbonyl) -5-methyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) -6-oxo-4H-imidazo ( 1,5-a) (1,4) benzodiazepine 7-Ethoxycarbonyl-5,6-dihydro-5-methyl-3- (5-methyl-1,2,4-oxa-2® diazol-3-yl) -6-oxo-4H-imidazo (1,5-a) (1,4) benzodiazepine (500 mg) is dissolved in ethylene glycol (20 ml) and 3 drops of concentrated sulfuric acid are added. The solution is then stirred at 130 ° C for 24 hours, cooled and partitioned between water (150 ml) and CHCl 3 (150 ml). The organic phase is separated, dried over 2 SO 2 and evaporated to give the above compound as white crystals.

Som konklusion på det foregående er det åbenlyst, at opfindelsen tilvejebringer hidtil ukendte neurologisk effektive benzodi azepi nreceptorbi ndende i mi dazobenzodi azepi nforbi ndel ser og 35 salte deraf, som har fordelagtige og uforudsigelige egenskaber såvel som hidtil ukendte farmaceutiske præparater deraf og en metode til behandling dermed, som alle besidder de foregående specielt opregnede karakteristika og fordele.In conclusion, it is obvious that the invention provides novel neurologically effective benzodi azepine receptor antagonists in dazobenzodi azepi compound and its salts, which have beneficial and unpredictable properties as well as novel pharmaceutical methods for treating and treating them. thus, all of which possess the preceding specially enumerated features and advantages.

Claims (5)

1. Benzodiazepinderivat kendetegnet ved, at det har formlen I 5 o-* X2 15 i 9 hvor X og X hver for sig betegner JN—O O—N ' -4¾ ^“R1 eller COOR1 N N 20 hvor R1 betegner C|_3-alkyl, C3_3-cycloalkyl, C-|_3-alkoxymethyl, C]_3-hydroxyalkyl eller phenyl, 4 R betegner hydrogen 25 5 4 5 R betegner Cj_g-alkyl eller hvor R og R tilsammen danner en 2-4 leddet alkylenkæde.1. Benzodiazepine derivative characterized in that it has the formula I 5 o - * X 2 15 wherein X and X are each independently JN-OO-N '-4¾ ^' R1 or COOR1 NN 20 where R1 represents C , C3-3 cycloalkyl, C1-3 alkoxymethyl, C1-3 hydroxyalkyl or phenyl, 4R represents hydrogen 25 5 4 5 R represents C1-6 alkyl or where R and R together form a 2-4 membered alkylene chain. 2. Forbindelse ifølge krav 1,kendetegnet ved, at forbi ndel sen er 7-ethoxycarbony1-5,6-di hydro-5-methy1-3-(3-cyclopro-30 pyl-1,2,4-oxadiazol-5-yl)-6-oxo-4H-imidazo(l,5-a)(1,4)benzodiazepin.Compound according to claim 1, characterized in that the compound is 7-ethoxycarbonyl-5,6-di hydro-5-methyl-3- (3-cyclopropyl-1,2,4-oxadiazole-5 yl) -6-oxo-4H-imidazo (l, 5-a) (1,4) benzodiazepine. 3. Forbindelse ifølge krav 1,kendetegnet ved, at forbi ndel sen er 7-ethoxycarbony1-5,6-di hydro-5-methyl-3-(5-methyl-1, 2,4-oxadi azol-3-y 1)-6-oxo-4H-i mi dazo(1,5-a)(1,4)benzodi azepi n.Compound according to claim 1, characterized in that the compound is 7-ethoxycarbonyl-5,6-di hydro-5-methyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) ) -6-oxo-4H-i dazo (1,5-a) (1,4) benzodi azepine. 4. Farmaceutisk præparat, som er egnet til brug ved 35 behandling af en centralnervesystemslidelse, kendetegnet ved, at det indeholder en forbindelse ifølge krav 1 i en mængde, som er effektiv til lindring af en sådan forstyrrelse sammen med en farmaceutisk acceptabel bærer eller fortyndingsmiddel.Pharmaceutical composition suitable for use in treating a central nervous system disorder, characterized in that it contains a compound according to claim 1 in an amount effective for relieving such a disorder together with a pharmaceutically acceptable carrier or diluent. 27 DK 155941 B t27 DK 155941 B t 5. Farmaceutisk præparat ifølge krav 4, kendetegnet ved, at det foreligger i form af en oral enhedsdosis, som indeholder 1-100 mg af den aktive forbindelse. 5 10 15 20 25 30 35 .Pharmaceutical composition according to claim 4, 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.