NO126085B

NO126085B -

Info

Publication number: NO126085B
Application number: NO4341/70A
Authority: NO
Inventors: K Meguro; Y Kuwada
Original assignee: Takeda Chemical Industries Ltd
Priority date: 1969-11-18
Filing date: 1970-11-13
Publication date: 1972-12-18
Also published as: ES385641A1; DE2064926A1; DE2056174A1; JPS5010659B1; AT311993B; DK141846C; GB1337737A; NL167697C; BE759099A; JPS4910958B1; SE363111B; ZA707644B; AT300816B; CH551432A; NL7016848A; GB1337736A; FI51701C; FI51701B; CH549588A; DK141846B

Description

Analogifremgangsmåte til fremstilling av Analogy method for the production of

terapeutisk aktive benzodiazepinderivater. therapeutically active benzodiazepine derivatives.

Foreliggende oppfinnelse angår en analogifremgangsmåte til fremstilling av nye, terapeutisk aktive 1-okso- eller 1-tiokso-s-tria-zolo [4 ,3-a] [T,il]benzodiazepinderivater med den generelle formel: The present invention relates to an analogue method for the preparation of new, therapeutically active 1-oxo- or 1-thioxo-s-triazolo [4,3-a] [T,yl]benzodiazepine derivatives with the general formula:

hvor PL er hydrogen, halogen, nitro, trifluormetyl, eller lavere alkyl, FL er hydrogen, halogen eller lavere alkoksy, X er oksygen eller svovel, og hvor nitrogenatomet i 5-stillingen kan være forbundet med et oksygenatom, samt farmasøytisk akseptable salter av ovennevnte derivater. 1-okso- eller 1-tiokso-s-triazolo[4,3-a][l,4]benzodiazepinderivater med formel (IV) fremstilles ifølge oppfinnelsen ved ring-slutning av 2-(4-substituert semikarbazido)- eller 2-(4-substituert tiosemikarbazido)-l,4-benzodiazepinderivater med formel III. Denne reaksjon samt fremstillingen av utgangsforbindelsene med formel III where PL is hydrogen, halogen, nitro, trifluoromethyl, or lower alkyl, FL is hydrogen, halogen or lower alkoxy, X is oxygen or sulfur, and where the nitrogen atom in the 5-position may be connected to an oxygen atom, as well as pharmaceutically acceptable salts of the above derivatives. 1-oxo- or 1-thioxo-s-triazolo[4,3-a][1,4]benzodiazepine derivatives of formula (IV) are prepared according to the invention by ring closure of 2-(4-substituted semicarbazido)- or 2- (4-Substituted thiosemicarbazido)-1,4-benzodiazepine derivatives of formula III. This reaction as well as the preparation of the starting compounds of formula III

hvor R^, og X har samme betydninger som angitt ovenfor, R' er en alkyl-, cykloalkyl-, aryl- eller aralkylgruppe, og hvor nitrogenatomet i 4-stillingen i formel I og III og i 5-stillingen i formel IV kan være forbundet med et oksygenatom. Når nitrogenatomet i 5-stillingen i det erholdte produkt er forbundet med et oksygenatom, kan where R^ and X have the same meanings as stated above, R' is an alkyl, cycloalkyl, aryl or aralkyl group, and where the nitrogen atom in the 4-position in formulas I and III and in the 5-position in formula IV can be connected to an oxygen atom. When the nitrogen atom in the 5-position in the product obtained is connected to an oxygen atom, can

produktet om ønsket behandles med et desoksygeneringsmiddel. Det erholdte produkt kan også om ønsket omdannes til terapeutisk akseptable salter derav. if desired, the product is treated with a deoxygenator. The product obtained can also, if desired, be converted into therapeutically acceptable salts thereof.

Trinn 1: Forbindelsen (I) omsettes med isocyansyreester eller en isotiocyansyreester med formel II. Vanligvis vil reaksjonen fordel-aktig skje i nærvær av et egnet oppløsningsmiddel, f.eks. aromatiske hydrokarboner, pyridin, tetrahydrofuran, kloroform, dimetylformamid og alkoholer (f.eks. metanol, etanol), ved romtemperatur eller under denne. Reaksjonen kan om ønsket utføres under oppvarming. Mengden av forbindelsen med formel II varierer vanligvis fra 1 til 1.5 mol i forhold til 1 mol av forbindelsen med formel I. Det resulterende 2-(4-substituerte semikarbazido)- eller 2-(4-substituerte tiosemi-karbazido)-l,4-benzodiazepinderivat (III) kan innvinnes i enhver ønsket renhet ved en i og for seg kjent metode (f.eks. destillasjon eller omkrystallisering). Step 1: The compound (I) is reacted with isocyanic acid ester or an isothiocyanic acid ester of formula II. Usually, the reaction will advantageously take place in the presence of a suitable solvent, e.g. aromatic hydrocarbons, pyridine, tetrahydrofuran, chloroform, dimethylformamide and alcohols (eg methanol, ethanol), at or below room temperature. If desired, the reaction can be carried out under heating. The amount of the compound of formula II usually varies from 1 to 1.5 mol relative to 1 mol of the compound of formula I. The resulting 2-(4-substituted semicarbazido)- or 2-(4-substituted thiosemicarbazido)-1,4 -benzodiazepine derivative (III) can be recovered in any desired purity by a method known per se (e.g. distillation or recrystallization).

Trinn 2: Forbindelsen med formel III fremstilt under trinn 1 blir så underkastet en ringslutningsreaksjon. Vanligvis skjer reaksjonen glatt ved oppvarming til ca. 120° til 250°C fulgt av en eliminering av et alkyl-, aralkyl- eller arylamin. Reaksjonen kan utføres ved å oppvarme forbindelsen III til dets smeltepunkt uten et nærvær av opp-løsningsmidler, eller ved en oppvarming i et egnet oppløsningsmiddel slik som pyridin, kollidin, dimetylformamid, xylen, tetralin eller di-fenyleter. Step 2: The compound of formula III prepared during step 1 is then subjected to a cyclization reaction. Usually, the reaction occurs smoothly when heated to approx. 120° to 250°C followed by an elimination of an alkyl, aralkyl or aryl amine. The reaction can be carried out by heating the compound III to its melting point without the presence of solvents, or by heating in a suitable solvent such as pyridine, collidine, dimethylformamide, xylene, tetralin or diphenyl ether.

Trinn 1 og trinn 2 kan utføres i rekkefølge med eller uten isolering av forbindelsen III. Således kan f.eks. reaksjonen mellom forbindelsene I og II utføres ved å oppvarme det hele i nærvær av et oppløsningsmiddel slik som pyridin, kollidin eller lignende, hvorved den ønskede forbindelse med formel IV oppnås med en gang. Step 1 and step 2 can be carried out in sequence with or without isolation of compound III. Thus, e.g. the reaction between compounds I and II is carried out by heating the whole in the presence of a solvent such as pyridine, collidine or the like, whereby the desired compound of formula IV is obtained at once.

I det tilfelle at nitrogenatomet i 5-stillingen er knyttet til et oksygenatom, så kan dette som nevnt, om ønsket, fjernes ved én reduksjon med et egnet deoksygenerende middel, f.eks. et fosfortri-halogenid (f.eks. fosfortriklorrd) eller ved katalytisk hydrogener-ingi Forbindelse IV fremstilt på ovennevnte måte kan innvinnes i In the event that the nitrogen atom in the 5-position is linked to an oxygen atom, as mentioned, this can, if desired, be removed by one reduction with a suitable deoxygenating agent, e.g. a phosphorus trihalide (e.g. phosphorus trichloride) or by catalytic hydrogenation Compound IV prepared in the above manner can be recovered in

ønsket renhet ved i og for seg kjent metode, f,.eks. ved omkrystallisering. desired purity by a method known per se, e.g. by recrystallization.

Forbindelsen.méd formel IV har basiske -nitrpgenatomer i molekylet og kan følgelig innvinnes i form av farmasøytisk akseptable syresalter (f„eks. hydroklorid, sxilfatj fosfat,, oks.alat, -malonat, succinat., tart ar at, eit rat, etc.). " The compound of formula IV has basic nitrogen atoms in the molecule and can therefore be recovered in the form of pharmaceutically acceptable acid salts (e.g. hydrochloride, xylfatj phosphate, oxalate, -malonate, succinate, tartar at, eit rat, etc .). "

Nevnte 1-okso- eller 1-tiokso-s-triazolo[4,3-a][1,4]-benzodi-azepinderivater med formel IV lean -danne tautomere med den generelle formel.: hvor ringene R^, R,, og X har samme betydning som angitt ovenfor, mens nitrogenatomet i 5-stillingen eventuelt kan være knyttet til et oksygenatom. Disse tautomere inngår også som fremstillingsprodukter i foreliggende oppfinnelse. Said 1-oxo- or 1-thioxo-s-triazolo[4,3-a][1,4]-benzodiazepine derivatives of formula IV lean -forming tautomers of the general formula.: where the rings R^, R,, and X has the same meaning as stated above, while the nitrogen atom in the 5-position may optionally be linked to an oxygen atom. These tautomers are also included as manufacturing products in the present invention.

Forbindelsene IV fremstilt ved foreliggende fremgangsmåte er nye og har bemerkelsesverdige farmakologiske virkninger >på sentral-nervesystemet, nemlig ved at de er muskelavslappende, antikrampemid-ler, sedativer og søvninduserende midler, og de kan følgelig brukes som legemidler for avslapning av muskler, mot kramper, som berolig-ende middel og som sovemiddel. Nevnte forbindelser og syresalter av disse kan anvendes oralt eller parenteralt som sådanne, eller kan om ønsket blandes med farmasøytisk akseptable bærere og opparbeides i en egnet farmasøytisk form, f.eks. som et pulver, som pellets, som tab-letter eller som injeksjonsoppløsninger. Den anvendte mengde for administrasjon vil være avhengig av forbindelsene, sykdommens type og natur, etc. , men vil vanligvis variere fra 1 til 30 mg per døgn for voksne pasienter ved oral administrasjon. The compounds IV produced by the present process are new and have remarkable pharmacological effects > on the central nervous system, namely in that they are muscle relaxants, anticonvulsants, sedatives and sleep-inducing agents, and they can consequently be used as drugs for muscle relaxation, against convulsions, as a sedative and as a sleeping aid. Said compounds and their acid salts can be used orally or parenterally as such, or can, if desired, be mixed with pharmaceutically acceptable carriers and processed into a suitable pharmaceutical form, e.g. as a powder, as pellets, as tablets or as injection solutions. The amount used for administration will depend on the compounds, the type and nature of the disease, etc., but will usually vary from 1 to 30 mg per day for adult patients by oral administration.

Følgende eksempler illustrerer oppfinnelsen. I disse eksempler betyr deler vektdeler hvis intet annet er angitt, og forholdet mellom vektdeler og volumdeler tilsvarer forholdet mellom gram og ml. The following examples illustrate the invention. In these examples, parts means parts by weight unless otherwise stated, and the ratio of parts by weight to parts by volume corresponds to the ratio of grams to ml.

Eksempel 1 Example 1

a) En oppløsning av 1H. 2 deler 7-klor-2-hydrazino-5-fenyl-3H-l,1J-benzodiazepin i 250 volumdeler tetrahydrofuran ble dråpevis a) A solution of 1H. 2 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,1J-benzodiazepine in 250 parts by volume of tetrahydrofuran were added dropwise

tilsatt 3.5 volumdeler metylisocyanat under isavkjøling og omrøring. Etter en times omrøring ble blandingen heilt over i 2000 volumdeler vann. Bunnfallet ble oppsamlet ved filtrering, vasket med vann og aceton og så tørket, hvorved man fikk fremstilt 7-klor-2-(4-metyl-semikarbazido,)-5-fenyl-3H-l,<i>J-benzodiazepin som krystaller. Omkrystallisering fra dimetylformamid-vann gir fargeløse nåler, smeltepunkt 2iJ7°C (dekomp.). added 3.5 parts by volume of methyl isocyanate under ice-cooling and stirring. After stirring for an hour, the mixture was completely poured into 2000 parts by volume of water. The precipitate was collected by filtration, washed with water and acetone and then dried, whereby 7-chloro-2-(4-methyl-semicarbazido,)-5-phenyl-3H-1,<i>J -benzodiazepine was prepared as crystals . Recrystallization from dimethylformamide-water gives colorless needles, melting point 2iJ7°C (decomp.).

Elementæranalyse: Elemental analysis:

Beregnet for C^H-^Clf^O: C 59.73; H 4.72; N 20.49 Calculated for C^H-^Clf^O: C 59.73; H 4.72; N 20.49

Funnet: C 59.53; H 4.62; N 20.80. Found: C 59.53; H 4.62; N 20.80.

b) 6.8 deler 7-klor-2-(4-mety.lsemikarbazido)-5-fenyl-3H-l,4-benzodiazepin fremstilt som angitt i eksempel 1 a) ble oppvarmet til b) 6.8 parts of 7-chloro-2-(4-methylsemicarbazido)-5-phenyl-3H-1,4-benzodiazepine prepared as indicated in example 1 a) were heated to

250°C under omrøring, hvorved utgangsmaterialet smelter under skumdannelse. Etter oppvarming i ca. 15 minutter inntil skumdannelsen stanset opp, ble det smeltede stoff behandlet med etylacetat, hvorved man oppnådde 8-klor-6-fenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]-benzodiazepin-l-on som krystaller. Omkrystallisering fra metanol gir fargeløse nåler, smeltepunkt 252° - 253°C. 250°C with stirring, whereby the starting material melts while foaming. After heating for approx. 15 minutes until foaming ceased, the molten material was treated with ethyl acetate, whereby 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]- benzodiazepine-l-one as crystals. Recrystallization from methanol gives colorless needles, melting point 252° - 253°C.

Elementæranalyse: Elemental analysis:

Beregnet for C-^H^CIN^O: C 61.84; H 3.57; N 18.03 Calculated for C-^H^CIN^O: C 61.84; H 3.57; N 18.03

Funnet: C 61.83; H 3.47; N 18.18. Found: C 61.83; H 3.47; N 18.18.

Eksempel 2 Example 2

En blanding av 5.1 deler 7-klor-2-(4-metylsemikarbazido)-5-fenyl-3H-l,4-benzodiazepin fremstilt som angitt i eksempel 1 a) og l80 volumdeler pyridin ble kokt under tilbakeløp i 35 timer inntil utviklingen av metylamin ikke kunne observeres. Oppløsningsmidlet ble fradestillert under redusert trykk, og residuet behandlet med etylacetat, hvorved man fikk fremstilt 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo[4,3-a][l,4]benzodiazepin-l-on som krystaller. Omkrystallisering fra metanol gir fargeløse nåler, som smelter ved 252° 253°C A mixture of 5.1 parts of 7-chloro-2-(4-methylsemicarbazido)-5-phenyl-3H-1,4-benzodiazepine prepared as indicated in Example 1 a) and 180 parts by volume of pyridine was refluxed for 35 hours until the development of methylamine could not be observed. The solvent was distilled off under reduced pressure, and the residue treated with ethyl acetate, whereby 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepine- l-on as crystals. Recrystallization from methanol gives colorless needles, melting at 252°-253°C

Dette produkt er identisk med forbindelsen oppnådd i eksempel lb). This product is identical to the compound obtained in example lb).

Eksempel 3 Example 3

En oppløsning av 2.8.5 deler 7-klor-2-hydrazino-5-fenyl-3H-1,4-benzodiazepin i 120 volumdeler pyridin ble tilsatt 0.7 volumdeler metylisocyanat under isavkjø.ling og omrøring, hvoretter blandingen ble holdt på romtemperatur i 30 minutter. Etter koking under tilbakeløp i 35 timer ble oppløsningsmidlet fradestillert under redusert trykk. Residuet ble behandlet med etylacetat, hvorved man fikk oppnådd 8-klor-6-f enyl-2,4-dihydro-lH-s-triazolo.[ 4,3-a] [ 1,4 ]-benzodiazepin-l-on som krystaller.. Omkrystallisering fra metanol gir fargeløse nåler, .smeltepunkt 252° - 253°C. A solution of 2.8.5 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 120 parts by volume of pyridine was added 0.7 parts by volume of methyl isocyanate under ice-cooling and stirring, after which the mixture was kept at room temperature for 30 minutes. After refluxing for 35 hours, the solvent was distilled off under reduced pressure. The residue was treated with ethyl acetate, whereby 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo.[4,3-a][1,4]-benzodiazepine-1-one was obtained as crystals.. Recrystallization from methanol gives colorless needles, m.p. 252° - 253°C.

Dette produkt er identisk med forbindelsen fremstilt som angitt i eksemplene lb) og 2. This product is identical to the compound prepared as indicated in examples 1b) and 2.

Eksempel 4 Example 4

a) En oppløsning av 1.4 deler 7-klor-2-hydrazino-5-fenyl-3H-l,4-benzodiazepin i 25 volumdeler tetrahydrofuran ble tilsatt 0.65 a) A solution of 1.4 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of tetrahydrofuran was added 0.65

volumdeler fenylisocyanat under isavkjøling og omrøring. Etter 1 times omrøring ble den dobbelte vannmengde tilsatt blandingen. De resulterende krystaller ble oppsamlet ved filtrering, vasket med vann og aceton og tørket, hvorved man fikk fremstilt 7-klor-5-fenyl-2-(4-fenylsemikarbazido)-3H-l,4-benzodiazepin som krystaller. Omkrystallisering fra dimetylformamid-vann gir fargeløse fine nåler, smeltepunkt 220° - 221°C (dekomp.). parts by volume phenyl isocyanate under ice-cooling and stirring. After stirring for 1 hour, twice the amount of water was added to the mixture. The resulting crystals were collected by filtration, washed with water and acetone and dried, whereby 7-chloro-5-phenyl-2-(4-phenylsemicarbazido)-3H-1,4-benzodiazepine was prepared as crystals. Recrystallization from dimethylformamide-water gives colorless fine needles, melting point 220° - 221°C (decomp.).

Elementæranalyse: Elemental analysis:

Beregnet for C^H^<C>l^O: C 65.42; H 4.49; N 17.34 Funnet:' C 65.6l; H 4.30; N 17.28. Calculated for C^H^<C>1^O: C 65.42; H 4.49; N 17.34 Found:' C 65.6l; H 4.30; N 17.28.

b) En oppløsning av 4 deler 7-klor-5-fenyl-2-(4-fenylsemi-karbazido)-3H-l,4-benzodiazepin fremstilt som angitt i eksempel 4 a) i b) A solution of 4 parts of 7-chloro-5-phenyl-2-(4-phenylsemi-carbazido)-3H-1,4-benzodiazepine prepared as indicated in example 4 a) in

120 volumdeler pyridin ble kokt under tilbakeløp i 5 timer. Oppløs-ningsmidlet ble fradestillert under redusert trykk. Residuet ble behandlet med etylacetat, hvorved man fikk fremstilt 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo [4,3-a][1,4]benzodiazepin-1-on som krystaller. Omkrystallisering fra metanol gir fargeløse nåler, smeltepunkt 252° - 253°C. 120 parts by volume of pyridine were refluxed for 5 hours. The solvent was distilled off under reduced pressure. The residue was treated with ethyl acetate, whereby 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo [4,3-a][1,4]benzodiazepine-1-one was produced as crystals. Recrystallization from methanol gives colorless needles, melting point 252° - 253°C.

Produktet er identisk med forbindelsen fremstilt som angitt i eksemplene lb), 2 og 3. The product is identical to the compound prepared as indicated in examples 1b), 2 and 3.

Eksempe1 5 Example 1 5

a) En oppløsning av 3.1 deler 7-klor-2-hydrazino-5-(p-met-oksyfenyl)-3H-l,4-benzodiazepin i 40 volumdeler pyridin ble dråpevis a) A solution of 3.1 parts of 7-chloro-2-hydrazino-5-(p-meth-oxyphenyl)-3H-1,4-benzodiazepine in 40 parts by volume of pyridine was added dropwise

tilsatt 0.7 volumdeler metylisocyanat under isavkjøling og omrøring. Etter ca. 30 minutters omrøring ble 100 volumdeler vann tilsatt blandingen. De resulterende krystaller ble oppsamlet ved filtrering, vasket med metanol og tørket, hvorved man fikk fremstilt 7-klor-5-(p-metoksyfenyl)-2-(4-metylsemikarbazido)-3H-l,4-benzodiazepin som krystaller. Omkrystallisering fra dimetylformamid-vann gir fargeløse, fine nåler, smeltepunkt 234° - 235°C (dekomp.). added 0.7 parts by volume of methyl isocyanate under ice-cooling and stirring. After approx. After 30 minutes of stirring, 100 parts by volume of water were added to the mixture. The resulting crystals were collected by filtration, washed with methanol and dried, whereby 7-chloro-5-(p-methoxyphenyl)-2-(4-methylsemicarbazido)-3H-1,4-benzodiazepine was prepared as crystals. Recrystallization from dimethylformamide-water gives colourless, fine needles, melting point 234° - 235°C (decomp.).

Elementæranalyse: Elemental analysis:

Beregnet for C^gH^ClN^: C 58.14; H 4.88; N 18.84 Funnet: C 57.83; H 4.74; N 19.17. Calculated for C^gH^ClN^: C 58.14; H 4.88; N 18.84 Found: C 57.83; H 4.74; N 19.17.

b) En oppløsning av 2.0 deler 7-klor-5- (p--metr'--*;f snyl )-2-(4-metylsemikarbazido)-3H-l,4-benzodiazepin, fremstilt som angitt i eksempel 5 a), i 70 volumdeler pyridin ble kokt under tilbakeløp i 36 timer. Oppløsningsmidlet ble fradestillert under redusert trykk. Residuet ble behandlet med etylacetat, hvorved man fikk fremstilt 8-klor-6- (p-metoksyfenyl")-2 ,4-dihydro- 1H-s-triazolo[4 ,3-a] [1,4 ]-benzo-'diazepin-l-on som krystaller. Omkrystallisering fra metanol gir farge-løse nåler, smeltepunkt 257° - 258°C. ;Elementæranalyse: ;Beregnet for C^H^CIN^: C 59.92; H 3.82; N l6."44 ;Funnet: C 60.16; H 3.77; N 16.-22. Eksempel 6 a) En blanding av 2.8 volumdeler 2-amino-7-nitro-5-fenyl-3H-1,4-benzodiazepin og-2 volumdeler hydrazinhydrat ble omrørt ved romtemperatur i 1 time og så heilt over i isvann. Kloroformlaget ble vasket med vann og tørket over vannfritt natriumsulfat. Oppløsnings-midlet ble fradestillert., hvorved man fikk fremstilt 2-hydrazino-7-nitro-5-fenyl-3H-l,4-bénzodiazepin som et viskøst, oljeaktig stoff. ;Det således fremstilte 2-hydrazinoderivat ble oppløst i ;20 volumdeler pyridin og så tilsatt 1.1 volumdeler metylisocyanat ved isavkjøling og omrøring. Etter 1 times omrøring blir blandingen tilsatt 80 volumdeler vann. Det frembragte bunnfall ble oppsamlet ved -filtrering, vasket med aceton og tørket, hvorved man fikk fremstilt 2-(4-metylsemikarbazido)-7-nitro-5-fenyl-3H-1,4-benzodiazepiri som krystaller. Omkrystallisering fra dimetylformamid-vann gir gule, ;fine plater-, smeltepunkt 239° - 240°C (dekomp.). Elementæranalyse: ;Beregnet for C^<H>^<N>gO^: -C .57.95; H 4.5S; N 23.85 ;Funnet: C 57.98; H 4.-47; N 24.14. ;b) En oppløsning av 4.2 deler 2-("4-métylsemikarbazido)-7-nitro-5-fenyl-3H-lJ4-benzodiazepin fremstilt som angitt i eksempel 6 a) ;i 150 volumdeler pyridin ble kokt under tilbakeløp i 25 timer, hvorpå oppløsningsmidlet hie fradestillert. Residuet "ble "blandet med vann. ;-Det resulterende trunnfall. ble oppsamlet ved filtrering og tørket, "hvorved man fikk fremstilt 8-nitro-6-fenyl-2-,4-dihydro-lH-s-tria-zolo~[4 ,3-al [l,:4-]benzbdiazepin-l-on som "krystaller. Omkrystallisering fra vandig aceton gir gule nåler, smeltepunkt 199°— 20O°G. Elementæranalyse: Beregnet for C^H^t^Oy C 59.81; H 3.45; N 2.1.80 Funnet: ' C 60.00; H 3.44; N 21.77. ;Eksempel 7 ;a) En oppløsning av 3 deler 7-klor-2-hydrazino-5-fenyl-3H-1,4-benzodiazepin-4N-oksyd i 60 volumdeler pyridin ble tilsatt 0.7 ;volumdeler metylisocyanat under isavkjøling og omrøring. Etter ca. 30 minutter ble krystallene oppsamlet ved filtrering, vasket med metanol og tørket, hvorved man fikk fremstilt 7-klor-2-(4-metylsemikarba-zido)-6-fenyl-3H-l,4-benzodiazepin-4N-oksyd som krystaller. Omkrystallisering fra dimetylformamid-vann gir fargeløse, fine nåler, smeltepunkt 251° - 252°C (dekomponering). ;Elementæranalyse: ;Beregnet for C-^H-^CIN^: C 57.06; H 4.51; N 19.58 ;Funnet: C 56.86; H 4.35; N 19.81. ;b) En blanding av 3 deler 7-klor-2-(4-metylsemikarbazido)-6-fenyl-3H-l,4-benzodiazepin-4N-oksyd, fremstilt som angitt i eksempel 7 a), 60 volumdeler pyridin og 140 volumdeler dimetylformamid ble kokt under tilbakeløp i 8.5 timer, hvorpå oppløsningsmidlet ble fradestillert under redusert trykk. Residuet ble behandlet med vandig etanol, hvorved man fikk fremstilt 8-klor-6-feny1-2,4-dihydro-lH-s-triazolo[4,3-a][l,4]benzodiazepin-l-on-5N-oksyd som krystaller. Omkrystallisering fra metanol gir gule prismer av monometanolatet, smeltepunkt 164° - l66°C (skumdannelse). ;Elementæranalyse: ;Beregnet for c16H11clNlj02 .CH^OH: . C 56.91; H 4.21; N 15.62 Funnet: C 56.77; H 4.02; N 15.88. ;En omkrystallisering fra vandig etanol gir gule prismer av monohydratet, smeltepunkt 173° - 174°C (mykning). Elementæranalyse: Beregnet for c16H11clNi402-^ 2°'' C 55.74; H 3.80; N 16.25 ;Funnet: C. 55.89; H 3.85; N 16.25. ;Eksempel 8 ;En oppløsning av 2.85 deler 7-klor-2-hydrazino-5-fenyl-3H-1,4-benzodiazepin i 25 volumdeler pyridin ble tilsatt 1.5 deler fenylisotiocyanat, og blandingen ble kokt under tilbakeløp. Etter 3.5 timer ble pyridin fradestillert under redusert trykk. Residuet ble behandlet med eter, hvorved man fikk fremstilt 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo[4,3-a][l,4]benzodiazepin-l-tion som krystaller. Omkrystallisering fra metanol gir fargeløse prismer, smeltepunkt 237° - 238°C. ;Elementæranalyse: ;Beregnet for C gH^ClN^S: C 58. 79; H 3.39; N 17.14 ;Funnet: C 58.94; H 3.29; N 17.24. Eksempel 9 ;a) En oppløsning av 2.85 deler 7-klor-2-hydrazino-5-fenyl-3H-l,4-benzodiazepin i 250 volumdeler etanol ble tilsatt 1.5 deler ;fenylisotiocyanat, og blandingen hensatt ved romtemperatur i ca. 3 timer. De utfelte krystaller ble oppsamlet ved filtrering, hvorved man fikk fremstilt 7-klor-5-fenyl-2-(4-fenyltiosemikarbazido)-3H-l,4-benzodiazepin som krystaller, Omkrystallisering fra aceton gir blek-gule nåler som smelter ved 199° - 205°C (dekomp.). ;Elementæranalyse: ;Beregnet for C22Hl8ClN5S: C 62.96; H 4.31; N 16.67 ;Funnet: C 62.51; H 4.31; N 16.65. b) En oppløsning av 3 deler 7-klor-5-fenyl-2-(4-fenyltiosemi-karbazido)-3H-l,4-benzodiazepin, fremstilt som angitt i eksempel 9 a), ;i 25 volumdeler pyridin ble kokt under tilbakeløp i 2 timer, hvorpå pyridinen ble fjernet ved destillasjon under redusert trykk. Residuet ble behandlet med eter. De resulterende krystaller ble oppsamlet ved filtrering og tørket, hvorved man fikk fremstilt 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo[4,3-a][1,4]benzodiazepin-l-tion som krystaller. Omkrystallisering fra metanol gir fargeløse prismer, smeltepunkt 237° - 238°C. ;Produktet er identisk med produktet fremstilt som angitt ;i eksempel 8.. ;Eksempel 10 ;En oppløsning av 3 deler 7-klor-2-hydrazino-5-fenyl-3H-l,4-benzodiazepin-4N-oksyd i 20 volumdeler pyridin ble tilsatt 1.5 deler fenylisotiocyanat, og blandingen ble kokt under tilbakeløp i 2.5 timer. Etter avkjøling ble uløselige stoffer fjernet ved filtrering. Filtratet ble konsentrert til tørrhet under redusert trykk. Omkrystallisering av residuet fra en blanding av etanol og aceton gir 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo[4 , >a] [l,4]-benzodiazepin-l-tion-5N-oksyd som gule prismer, smeltepunkt 243° - 244°C (dekomp.). Elementæranalyse: Beregnet for C^gH^ClN^OS. 1/4 C2H5OH: C 55.93; H 3.56; N 15.81 Funnet: C 56.09; H 3.74; N 15.79. ;Eksempel 11 ;En oppløsning av 1.8 deler 8-klor-6-feny1-2,4-dihydro-1H-s-triazolo[4.3-a] [l,4]benzodiazepin-l-on-5N-oksyd (metanolat) fremstilt som angitt i eksempel 7b), i 200 volumdeler kloroform ble tilsatt 2.1 volumdeler fosfortriklorid, og blandingen kokt under tilbake-løp i 5 timer. Etter avkjøling ble de utfelte krystaller oppsamlet ved filtrering. En behandling av krystallene med fortynnet vandig ammoniakk gir 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolol4,3-a][1,4]-benzodiazepin-l-on i fri form. Omkrystallisering fra metanol gir fargeløse nåler., smeltepunkt 252° - 253°C. ;Produktet er identisk med forbindelsen .fremstilt som an-.gitt i eksemplene 1 b), 2, 3 og 4 b). ;Eksempel 12 ;En blanding av 1.77 deler 7-klor-6-fenyl-2J4-dihydro-lH-s-triazolo ['4 ,3-a] [1,4 ]benzodiazepin-l-tion-5N-oksyd (1./4 etanolat), fremstilt som angitt i eksempel 10, 2.1 volumdeler fosfortriklorid og 200 volumdeler kloroform ble "kokt under tilbakeløp i ^ timer, hvorpå blandingen ble konsentrert. Residuet ble nøytralisert med fortynnet, vandig ammoniakk og ekstrahert med kloroform. Kloroformlaget ble vasket med vann, tørket over vannfri natriumsulfat og konsentrert. Residuet ble behandlet med etyleter, hvorved man fikk fremstilt 8-klor-6-fenyl-2,4-dihydro-lH-s-triazolo[4,3-a][1,4]benzodiazepin-l~ tion som krystaller. Omkrystallisering fra metanol gir fargeløse nåler, smeltepunkt 23^4° - 236°"C. ;Produktet er identisk med produktet fra eksemplene 8 og ;9 b). ;Følgende forbindelser ble fremstilt under anvendelse av ;.metoder i likhet med de ovenfor angitte. ;Eksempel. 1. 3 ;Omsetning av 7-klor-"5-(2-klorfenyl)-2-hydrazin-o-.3H-l,4-benzodiazepin med metylisocyanat ga 7—klor-5- (2-klorfenyl)-2- (^4-metyl-semikarbazido^-3H-JL,4-benzodiazepin (gule prismer fra vandig dimetylformamid), smeltepunkt 230° - 232°C (dekomp.), som ble kokt under til-bakeløp i pyridin-dimetylformamid hvilket ga 8~klor-6-(2-klorfenyl)-2 ,4-dihydro-lH-s-triazolo£4.,3-a]Il,4]benzodiazepin-l-on, i form av fargeløse nåler fra kloroform-metanol, smeltepunkt 205° - 208°C. Elementæranalyse: Beregnet for C^gH^ClgltyO: C 55.67"; H 2.92; "N 16.23 Purme-t:. C 55-77; « 2.76.-; H 1-6.30*b) A solution of 2.0 parts of 7-chloro-5-(p--metr'--*;f-synyl)-2-(4-methylsemicarbazido)-3H-1,4-benzodiazepine, prepared as indicated in example 5 a ), in 70 parts by volume of pyridine was refluxed for 36 hours. The solvent was distilled off under reduced pressure. The residue was treated with ethyl acetate, whereby 8-chloro-6-(p-methoxyphenyl")-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]-benzo-' diazepin-l-one as crystals. Recrystallization from methanol gives colorless needles, melting point 257° - 258° C. ;Elementary analysis: ;Calculated for C^H^CIN^: C 59.92; H 3.82; N l6."44 ; Found: C 60.16; H 3.77; N 16.-22. Example 6 a) A mixture of 2.8 parts by volume of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine and 2 parts by volume of hydrazine hydrate was stirred at room temperature for 1 hour and then completely poured into ice water. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, whereby 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine was produced as a viscous, oily substance. The 2-hydrazino derivative thus prepared was dissolved in 20 parts by volume of pyridine and then 1.1 parts by volume of methyl isocyanate was added with ice-cooling and stirring. After 1 hour of stirring, 80 parts by volume of water are added to the mixture. The resulting precipitate was collected by filtration, washed with acetone and dried, whereby 2-(4-methylsemicarbazido)-7-nitro-5-phenyl-3H-1,4-benzodiazepyri was produced as crystals. Recrystallization from dimethylformamide-water gives yellow, fine plates, melting point 239° - 240°C (decomp.). Elemental analysis: ;Calculated for C^<H>^<N>gO^: -C .57.95; H 4.5S; N 23.85 ;Found: C 57.98; H 4.-47; N 24.14. b) A solution of 4.2 parts of 2-((4-methylsemicarbazido)-7-nitro-5-phenyl-3H-1J4-benzodiazepine prepared as indicated in example 6 a) in 150 parts by volume of pyridine was refluxed for 25 hours , whereupon the solvent was distilled off. The residue was mixed with water. The resulting precipitate was collected by filtration and dried to give 8-nitro-6-phenyl-2-,4-dihydro-lH-s -tria-zolo~[4 ,3-al [l,:4-]benzbdiazepin-l-one as "crystals. Recrystallization from aqueous acetone gives yellow needles, mp 199°— 200°G. Elemental analysis: Calculated for C^H ^t^Oy C 59.81; H 3.45; N 2.1.80 Found: ' C 60.00; H 3.44; N 21.77. ;Example 7 ;a) A solution of 3 parts of 7-chloro-2-hydrazino-5-phenyl-3H -1,4-benzodiazepine-4N-oxide in 60 parts by volume of pyridine was added to 0.7 parts by volume of methyl isocyanate under ice-cooling and stirring. After about 30 minutes, the crystals were collected by filtration, washed with methanol and dried, whereby 7-chloro- 2-(4-methylsemicarbazido)-6-phen yl-3H-1,4-benzodiazepine-4N-oxide as crystals. Recrystallization from dimethylformamide-water gives colourless, fine needles, melting point 251° - 252°C (decomposition). ;Elementary analysis: ;Calculated for C-^H-^CIN^: C 57.06; H 4.51; N 19.58 ;Found: C 56.86; H 4.35; N 19.81. ;b) A mixture of 3 parts of 7-chloro-2-(4-methylsemicarbazido)-6-phenyl-3H-1,4-benzodiazepine-4N-oxide, prepared as indicated in example 7 a), 60 parts by volume of pyridine and 140 parts by volume of dimethylformamide was refluxed for 8.5 hours, after which the solvent was distilled off under reduced pressure. The residue was treated with aqueous ethanol, whereby 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepine-1-one-5N- oxide as crystals. Recrystallization from methanol gives yellow prisms of the monomethanolate, melting point 164° - 166°C (foaming). ;Elementary analysis: ;Calculated for c16H11clNlj02 .CH^OH: . C 56.91; H 4.21; N 15.62 Found: C 56.77; H 4.02; N 15.88. ;A recrystallization from aqueous ethanol gives yellow prisms of the monohydrate, melting point 173° - 174°C (softening). Elemental analysis: Calculated for c16H11clNi402-^ 2°'' C 55.74; H 3.80; N 16.25 ;Found: C. 55.89; H 3.85; Thu 16.25. ;Example 8 ;A solution of 2.85 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of pyridine was added with 1.5 parts of phenylisothiocyanate, and the mixture was boiled under reflux. After 3.5 hours, pyridine was distilled off under reduced pressure. The residue was treated with ether, whereby 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepine-1-thione was produced as crystals. Recrystallization from methanol gives colorless prisms, melting point 237° - 238°C. ;Elementary analysis: ;Calculated for C gH^ClN^S: C 58. 79; H 3.39; N 17.14 ;Found: C 58.94; H 3.29; N 17.24. Example 9 ;a) A solution of 2.85 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 250 parts by volume of ethanol was added with 1.5 parts of phenylisothiocyanate, and the mixture was left at room temperature for approx. 3 hours. The precipitated crystals were collected by filtration, whereby 7-chloro-5-phenyl-2-(4-phenylthiosemicarbazido)-3H-1,4-benzodiazepine was produced as crystals. Recrystallization from acetone gives pale yellow needles melting at 199 ° - 205°C (decomp.). ;Elementary analysis: ;Calculated for C22Hl8ClN5S: C 62.96; H 4.31; N 16.67 ;Found: C 62.51; H 4.31; N 16.65. b) A solution of 3 parts of 7-chloro-5-phenyl-2-(4-phenylthiosemi-carbazido)-3H-1,4-benzodiazepine, prepared as indicated in example 9 a), in 25 parts by volume of pyridine was boiled under refluxed for 2 hours, after which the pyridine was removed by distillation under reduced pressure. The residue was treated with ether. The resulting crystals were collected by filtration and dried to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepine-1-thione as crystals. Recrystallization from methanol gives colorless prisms, melting point 237° - 238°C. ;The product is identical to the product prepared as indicated ;in example 8.. ;Example 10 ;A solution of 3 parts 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 20 parts by volume pyridine was added to 1.5 parts of phenyl isothiocyanate, and the mixture was refluxed for 2.5 hours. After cooling, insoluble substances were removed by filtration. The filtrate was concentrated to dryness under reduced pressure. Recrystallization of the residue from a mixture of ethanol and acetone gives 8-chloro-6-phenyl-2,4-dihydro-lH-s-triazolo[4 , >a] [l,4]benzodiazepine-l-thione-5N- oxide as yellow prisms, melting point 243° - 244°C (decomp.). Elemental analysis: Calculated for C^gH^ClN^OS. 1/4 C 2 H 5 OH: C 55.93; H 3.56; N 15.81 Found: C 56.09; H 3.74; N 15.79. ;Example 11 ;A solution of 1.8 parts of 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4.3-a] [1,4]benzodiazepine-l-one-5N-oxide (methanolate) prepared as indicated in example 7b), in 200 parts by volume of chloroform, 2.1 parts by volume of phosphorus trichloride were added, and the mixture was boiled under reflux for 5 hours. After cooling, the precipitated crystals were collected by filtration. A treatment of the crystals with dilute aqueous ammonia gives 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolol4,3-a][1,4]-benzodiazepine-1-one in free form. Recrystallization from methanol gives colorless needles., melting point 252° - 253°C. The product is identical to the compound prepared as indicated in examples 1 b), 2, 3 and 4 b). ;Example 12 ;A mixture of 1.77 parts of 7-chloro-6-phenyl-2J4-dihydro-lH-s-triazolo ['4 ,3-a] [1,4 ]benzodiazepine-l-thione-5N-oxide (1 ./4 ethanolate), prepared as indicated in Example 10, 2.1 parts by volume of phosphorus trichloride and 200 parts by volume of chloroform were "refluxed for ^ hours, after which the mixture was concentrated. The residue was neutralized with dilute aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated.The residue was treated with ethyl ether to give 8-chloro-6-phenyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4 ]benzodiazepine-l~ tion as crystals. Recrystallization from methanol gives colorless needles, mp 23^4° - 236°"C. The product is identical to the product from examples 8 and 9 b). The following compounds were prepared using methods similar to those set forth above. ;Example. 1. 3 ;Reaction of 7-chloro-"5-(2-chlorophenyl)-2-hydrazine-o-.3H-1,4-benzodiazepine with methyl isocyanate gave 7-chloro-5-(2-chlorophenyl)-2- (^4-methyl-semicarbazido^-3H-JL,4-benzodiazepine (yellow prisms from aqueous dimethylformamide), mp 230° - 232°C (decomp.), which was refluxed in pyridine-dimethylformamide to give 8 ~chloro-6-(2-chlorophenyl)-2,4-dihydro-1H-s-triazolo£4,3-a]Il,4]benzodiazepine-1-one, in the form of colorless needles from chloroform-methanol, melting point 205° - 208° C. Elemental analysis: Calculated for C^gH^ClgltyO: C 55.67"; H 2.92; "N 16.23 Purme-t:. C 55-77; « 2.76.-; H 1-6.30*

Eksempel 14 Example 14

Omsetning av 2-hydrazino-5-fenyl-3H-l,4-benzodiazepin med metylisocyanat ga 2-(4-metylsemikarbazido)-5-fenyl-3H-l,4-benzodiaze-pin (fargeløse, pulverformige krystaller, smeltepunkt 233° - 234°C), som ble kokt under tilbakeløp i pyridin-dimetylformamid hvilket ga Reaction of 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine with methyl isocyanate gave 2-(4-methylsemicarbazido)-5-phenyl-3H-1,4-benzodiazepine (colorless, powdery crystals, m.p. 233° - 234°C), which was refluxed in pyridine-dimethylformamide which gave

6-fenyl-2,4-dihydro-lH-s-triazolo[4,3-a][l,4]benzodiazepin-l-on, i form av fargeløse nåler fra metanol, smeltepunkt 236° - 237°C. Elementæranalyse: 6-phenyl-2,4-dihydro-lH-s-triazolo[4,3-a][l,4]benzodiazepine-l-one, in the form of colorless needles from methanol, melting point 236° - 237°C. Elemental analysis:

Beregnet for C^H-^N^O: C 69.55; H- 4.37; N 20.28 Calculated for C^H-^N^O: C 69.55; H- 4.37; N 20.28

Funnet: C 69.39; H 4.27; N 20.12. Found: C 69.39; H 4.27; N 20.12.

Eksempel 15 Example 15

Omsetning av 2-hydrazino-7-metyl-5-fenyl-'3H-l,4-benzo-diazepin med metylisocyanat ga 7-metyl-2-(4-metylsemikarbazido)-5-fenyl-3H-l,4-benzodiazepin (lysegule prismer fra vandig dimetylformamid ) , smeltepunkt 229° - 231°C, som ble tilbakeløpskokt i pyridin-dimetylf ormamid og dette resulterte i oppnåelsen av 8-metyl-6-fenyl-2,4-dihydro-lH-s-triazolo[4,3-a]t1,4]benzodiazepin-l-on i form av fargeløse prismer (fra metanol), smeltepunkt 242° - 244°C. Elementæranalyse: Reaction of 2-hydrazino-7-methyl-5-phenyl-'3H-1,4-benzodiazepine with methyl isocyanate gave 7-methyl-2-(4-methylsemicarbazido)-5-phenyl-3H-1,4-benzodiazepine (light yellow prisms from aqueous dimethylformamide ), melting point 229° - 231°C, which was refluxed in pyridine-dimethylformamide and this resulted in obtaining 8-methyl-6-phenyl-2,4-dihydro-lH-s-triazolo[ 4,3-a]t1,4]benzodiazepine-l-one in the form of colorless prisms (from methanol), melting point 242° - 244°C. Elemental analysis:

Beregnet for C^H^<N>^<O:> C 70.33; H 4.86; N 19.30 Calculated for C^H^<N>^<O:> C 70.33; H 4.86; Thu 19.30

Funnet: C 70.18; H 4.81; N 19.36. Found: C 70.18; H 4.81; N 19.36.

Eksempel 16 Example 16

Omsetning av 7-klor-5-(^-klorfenyl)-2-hydrazino-3H-l,4-benzodiazepin-4N-oksyd med metylisocyanat ga 7~klor-5-(4-klorfenyl)-2-(4-metylsemikarbazido)-3H-l,4-benzodiazepin-4N-oksyd (fargeløse pulverformige krystaller, smeltepunkt 256° - 257°C), som ble tilbake-løpskokt i pyridin-dimetylformamid hvilket ga 8-klor-6-(4-klorfenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][l,4]benzodiazepin-l-on-5N-oksyd, fargeløse krystaller (fra metanol), smeltepunkt 188° - 190°C. Elementæranalyse: Beregnet for C16H10C12NH°2: C 53.20; H 2.79; N 15.51 Funnet: C 52.92; H 2.62; N 14.89. Reaction of 7-chloro-5-(^-chlorophenyl)-2-hydrazino-3H-1,4-benzodiazepine-4N-oxide with methyl isocyanate gave 7-chloro-5-(4-chlorophenyl)-2-(4-methylsemicarbazido )-3H-1,4-benzodiazepine-4N-oxide (colorless powdery crystals, mp 256°-257°C), which was refluxed in pyridine-dimethylformamide to give 8-chloro-6-(4-chlorophenyl)- 2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodiazepine-1-one-5N-oxide, colorless crystals (from methanol), melting point 188° - 190°C. Elemental analysis: Calculated for C16H10C12NH°2: C 53.20; H 2.79; N 15.51 Found: C 52.92; H 2.62; N 14.89.

Eksempel 17 Example 17

Omsetning av 2-hydrazino-7-nitro-5~fenyl-3H-l,4-benzo-diazepin-4N-oksyd med metylisocyanat ga 2-(4-metylsemikarbazido)-7-nitro-5-fenyl-3H-l,4-benzodiazepin-4N-oksyd (gule nåler fra vandig dimetylformamid, smeltepunkt 243° - 244°C (dekomp.)), som ble til-bakeløpskokt i pyridin og dette ga 8-nitro-6-fenyl-2,4-dihydro-lH-s-triazolo[4, 3-a] [1,4]benzodiazepin- 1-on-5N-oksyd, gule prismer (fra etylacetat), smeltepunkt 234° - 237°C. Reaction of 2-hydrazino-7-nitro-5~phenyl-3H-1,4-benzo-diazepine-4N-oxide with methyl isocyanate gave 2-(4-methylsemicarbazido)-7-nitro-5-phenyl-3H-1, 4-benzodiazepine-4N-oxide (yellow needles from aqueous dimethylformamide, mp 243° - 244°C (decomp.)), which was refluxed in pyridine to give 8-nitro-6-phenyl-2,4-dihydro -1H-s-triazolo[4, 3-a] [1,4]benzodiazepine-1-one-5N-oxide, yellow prisms (from ethyl acetate), mp 234° - 237°C.

Elementæranalyse: Elemental analysis:

Beregnet for C^H^N^: C 56.97; H 3.29; N 20.77 Calculated for C^H^N^: C 56.97; H 3.29; N 20.77

Funnet: C 57.00; H 3.20; N 20.83. Found: C 57.00; H 3.20; N 20.83.

Eksempel 18 Example 18

Omsetning av 2-hydrazino-5-fenyl-7-trifluormetyl-3H-1,4-benzodiazepin-4N-oksyd med metylisocyanat ga 2-(4-metylsemikarbazido)-5-fenyl-7-trifluormetyl-3H-1,4-benzodiazepin-4N-oksyd (fargeløse pul- Reaction of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine-4N-oxide with methyl isocyanate gave 2-(4-methylsemicarbazido)-5-phenyl-7-trifluoromethyl-3H-1,4- benzodiazepine-4N-oxide (colorless pul-

verformige krystaller fra vandig dimetylformamid, smeltepunkt 240° - vermiform crystals from aqueous dimethylformamide, melting point 240° -

242°C (dekomp.)), som ble tilbakeløpskokt i pyridin og dette ga 6-fenyl-8-trifluormetyl-2,4-dihydro-1H-s-triazolo[4,3-a][l,4]benzodia-zepin-l-on-5N-oksyd, fargeløse prismer (fra aceton-n-heksan), smelte- 242°C (decomp.)), which was refluxed in pyridine and this gave 6-phenyl-8-trifluoromethyl-2,4-dihydro-1H-s-triazolo[4,3-a][1,4]benzodia- zepin-l-one-5N-oxide, colorless prisms (from acetone-n-hexane), melt-

punkt 171° - 173°C point 171° - 173°C

Elementæranalyse: Elemental analysis:

Beregnet for c17^ 11F^ i^ 02: C 56.67; H 3.08; N 15.55 Calculated for c17^ 11F^ i^ 02: C 56.67; H 3.08; N 15.55

Funnet: C 56.74; H 3.27; N 15.65. Found: C 56.74; H 3.27; N 15.65.

Claims

Analogy method for the preparation of therapeutic

active 1-oxo- or l-thioxo-s-triazolo[4,3-a]|l,4]benzodiazepine derivatives of the general formula: where R^ is hydrogen, halogen, nitro, trifluoromethyl or lower alkyl, R2 is hydrogen, halogen or lower alkoxy, X is oxygen or sulphur, and where the nitrogen atom in the 5-position can be connected to an oxygen atom, as well as therapeutically acceptable salts thereof, characterized in that 2-(4-substituted semicarbazido)- or 2- (4-substituted thiosemicarbazido)-1,4-benzodiazepine derivatives of the general formula; where R 1 , R 2 and X have the meaning given above, R' is an alkyl, cycloalkyl, aryl or aralkyl group, and where the nitrogen atom in the bi-position may be connected to an oxygen atom, the ring is closed, and, if desired, when the nitrogen atom in the 5-position in the obtained product is connected with an oxygen atom, the product is treated with a deoxygenating agent, and further, if desired, conversion of the obtained product into therapeutically acceptable salts thereof.