NO127971B

NO127971B -

Info

Publication number: NO127971B
Application number: NO135870A
Authority: NO
Inventors: H Yamamoto; S Inaba; T Hirohashi; M Yamamoto; K Ishizumi; M Akatsu; I Maruyama; Y Kume; K Mori; T Izumi
Original assignee: Sumitomo Chemical Co
Priority date: 1969-04-18
Filing date: 1970-04-13
Publication date: 1973-09-10
Also published as: DK131675C; PL80606B1; FI49966C; IL34333A0; FI49966B; DK131675B; IL34333A

Description

Fremgangsmåte til fremstilling av benzodiazepinderivater. Process for the preparation of benzodiazepine derivatives.

Foreliggende oppfinnelse angår en ny fremgangsmåte til fremstilling av benzodiazepinderivater med den generelle formel: og syreaddisjonssalter derav* hvor R-^ betyr hydrogen, ^-alkyl, C2_^-alkenyl, C^_^-alkynyl, eller en gruppe med formelen -cnH2n'R5' hvor n er et helt tall på 1 - 4 og R^ betyr halo gan, trifluormetyl, cyan, C-^y-cykloalkyl, C-^-alkoksy, C-^-alkyltio, C2_^-alkenyl-oksy, karbamoyl, C-L_Zf-alkyl-karbamoyl, acyloksy, C-L_^-alkylkarbonyl, fenyl eller fenyl substituert med halogen, nitro, trifluormetyl, C1_^-alkoksy, C-L_^-alkyl eller sulfamoyl, eller R^ betyr en gruppe med formelen: hvor Rg betyr hydrogen eller ^-alkyl og Ry betyr ^-alkyl, forutsatt at Rg og R^ sammen med det tilstbtende nitrogenatom kan danne en eventuelt med alkyl, hydroksyalkyl, alkoksyalkyl eller alkenyloksyalkyl substituert pyrrolidino-, piperidino-, piperazino-, alkylpiperazino-, alkyloksyalkyl-piperazino- eller morfolino-gruppe; R2 betyr hydrogen, halogen, C-^^-alkyl, ni tro, cyano, trifluormetyl, trifluormetoksy, di-(C1_Zf-alkyl)amino, piperidino, C-^^-alkoksy, C1_ ^-alkyl ti o, C-L_^-alkylsulfonyl, C-L_^-alkylsulfinyl, karbamoyl eller sulfamoyl; R^ betyr hydrogen, ni tro, C-^^-alkyl eller halogen; R^ betyr C-^^-alkyl, C^_y-cykloalkyl, cykloalkenyl, fenyl, fenyl substituert med halogen, nitro, trifluormetyl, C-^ ^-alkoksy, C1_^-alkyl eller sulfamoyl, fenyl-C-j_ ^-alkyl eller en pyridyl-, pyrimidyl-, pyridazinyl-, pyrazinyl-, tienyl-, furyl-, tiazol-, oksazoyl- eller indolylgruppe, hvilke grupper kan være substituert med halogen eller alkyl; Rg betyr hydrogen, C-^_^-alkyl, C1_^-alkoksy-C1_^-alkyl, C1_z+-alkyltio-C1_^-alkyl, fenyl, fenyl substituert med halogen eller C-^ 2-alkoksy, benzyl eller hydroksybenzyl, samt syreaddisjonssalter derav. The present invention relates to a new process for the preparation of benzodiazepine derivatives with the general formula: and acid addition salts thereof* where R-^ means hydrogen, ^-alkyl, C2_^-alkenyl, C^_^-alkynyl, or a group with the formula -cnH2n' R5' where n is an integer from 1 to 4 and R^ means halogen, trifluoromethyl, cyano, C1-4-cycloalkyl, C-1-4-alkoxy, C-1-4-alkylthio, C2-4-alkenyl-oxy, carbamoyl . the formula: where Rg means hydrogen or ^-alkyl and Ry means ^-alkyl, provided that Rg and R^ together with the corresponding nitrogen atom can form a pyrrolidino-, piperidino-, piperazino-, alkylpiperazino, alkyloxyalkylpiperazino or morpholino group; R 2 means hydrogen, halogen, C 1-3 -alkyl, ni tro, cyano, trifluoromethyl, trifluoromethoxy, di-(C 1-2 -alkyl)amino, piperidino, C 1-3 -alkyl, C 1-3 -alkyl thio, C-L- 3-alkylsulfonyl, C-L-4-alkylsulfinyl, carbamoyl or sulfamoyl; R 1 means hydrogen, Ni tro, C 1-3 alkyl or halogen; R 1 means C 1 -alkyl, C 1 -cycloalkyl, cycloalkenyl, phenyl, phenyl substituted with halogen, nitro, trifluoromethyl, C 1 -alkyl, C 1 -alkyl or sulfamoyl, phenyl-C 1 - alkyl or a pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, thiazole, oxazoyl or indolyl group, which groups may be substituted with halogen or alkyl; Rg means hydrogen, C-^_^-alkyl, C 1-^-alkyl-C 1_^-alkyl, C 1_z+-alkylthio-C 1-^-alkyl, phenyl, phenyl substituted with halogen or C-^ 2- alkoxy, benzyl or hydroxybenzyl, as well as acid addition salts thereof.

I forbindelser med formel I kan C-L_^-alkylgruppen f.eks. være metyl, etyl, n-propyl, isopropyl, n-butyl, isobutyl og ter-tiær butyl, nevnte C2_^-alkenylgrupper kan være grupper såsom allyl, butenyl (heri innbefattet forskjellige isomere) og lignende. Nevnte ^-alkynylgrupper er fortrinnsvis propargyl. C^-Cy-cykloalkyl-grupper innbefatter f.eks. cyklopropyl, cyklobutyl, cykloentyl, cykloheksyl og cykloheptyl, mens nevnte C-L_ ^-alkoksy gruppe r innbefatter f.eks. metoksy, etoksy, n-propoksy, isopropoksy, n-butoksy og tertiære butoksygrupper, mens nevnte halogenatom innbefatter In compounds of formula I, the C-L-alkyl group can e.g. be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tertiary butyl, said C 2 -alkenyl groups can be groups such as allyl, butenyl (including various isomers) and the like. Said 3-alkynyl groups are preferably propargyl. C₁-Cy-cycloalkyl groups include e.g. cyclopropyl, cyclobutyl, cycloentyl, cyclohexyl and cycloheptyl, while the said C-L- 4 -alkyl group includes e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tertiary butoxy groups, while said halogen atom includes

klor, brom, jod bg fluor. chlorine, bromine, iodine bg fluorine.

Gruppen med formelen -^H^- representerer en rettkjedet eller forgrenet alkylengruppe med opptil 4 karbonatomer og innbefatter f.eks. metylen, etylen, 1-metyletylen, 2-metyletylen, tri-metylen, 1-metyltrimetylen og 2-metyltrimetylengrupper. The group with the formula -^H^- represents a straight-chain or branched alkylene group with up to 4 carbon atoms and includes e.g. methylene, ethylene, 1-methylethylene, 2-methylethylene, tri-methylene, 1-methyltrimethylene and 2-methyltrimethylene groups.

Når Rc representerer en acyloksygruppe, så innbefatter dette acetyloksy, propionyloksy, benzoyloksy, halogenbenzoyloksy, metoksybenzoyloksy, dimetoksybenzoyloksy, trimetoksybenzoyloksy, fenylacetyloksy,nlkotinoyloksy, isonikotinoyloksy eller lignende. When Rc represents an acyloxy group, this includes acetyloxy, propionyloxy, benzoyloxy, halobenzoyloxy, methoxybenzoyloxy, dimethoxybenzoyloxy, trimethoxybenzoyloxy, phenylacetyloxy, nilcotinoyloxy, isonicotinoyloxy or the like.

Når R^ og/eller R^ representerer en substituert fenyl-gruppe eller en substituert benzyloksygruppe, så kan substituentene på fenylringen være halogen, f.eks. fluor, klor, brom eller jod, ni tro, trifluormetyl, C-^^-alkoksy, C1_^+-alkyl eller sulfamoyl. When R^ and/or R^ represents a substituted phenyl group or a substituted benzyloxy group, then the substituents on the phenyl ring can be halogen, e.g. fluorine, chlorine, bromine or iodo, ni tro, trifluoromethyl, C 1-3 -alkyl, C 1-4 -alkyl or sulfamoyl.

R^ og/eller R^ kan således som substituerte fenylgrupper innbefat-te 2-fluorfenyl, 2-klorfenyl, 4-klorfenyl, 2-bromfenyl, 4-bromfenyl, 2-metoksyfenyl, 4-metoksyfenyl, 3-metoksyfenyl, 4-tolyl, 2-nitro-fenyl, 4-trifluormetylfenyl, 2-trifluormetylfenyl, 2,6-diklorfenyl, 2,4-diklorfenyl, 2,3-diklorfenyl, 2,4-difluorfenyl, 2,6-difluorfenyl, 3,4-dimetoksyfenyl, 2-klor-4-metylfenyl, 2-metyl-4-klorfenyl, 2-metyl-4-bromfenyl, 2-klor-5-sulfamoylfenyl, 2,4,6-triklorfenyl, 3,4,5-trimetoksyfenyl og lignende. Andre substituenter i tillegg til de som er nevnt ovenfor kan eventuelt være tilstede i fenyl-gruppen uten at man derved kvalitativt forandrer egenskapene ved den foreliggende forbindelse. R^ and/or R^ may thus include, as substituted phenyl groups, 2-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 4-tolyl , 2-nitro-phenyl, 4-trifluoromethylphenyl, 2-trifluoromethylphenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 3,4-dimethoxyphenyl , 2-chloro-4-methylphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4-bromophenyl, 2-chloro-5-sulfamoylphenyl, 2,4,6-trichlorophenyl, 3,4,5-trimethoxyphenyl and the like . Other substituents in addition to those mentioned above may optionally be present in the phenyl group without thereby qualitatively changing the properties of the present compound.

Benzodiazepinderivater med formel (i) har utpregede effekter som beroligende midler, muskelavslappende midler, som antispasme- og antikrampemidler foruten som hypnotisk middel, og er fblgelig av stor viktighet, som medisiner. Benzodiazepine derivatives of formula (i) have pronounced effects as sedatives, muscle relaxants, as antispasmodics and anticonvulsants in addition to as hypnotics, and are obviously of great importance as medicines.

Det er hittil blitt beskrevet flere framgangsmåter for fremstilling av disse benzodiazepinderivater. Det er f.eks. kjent hvordan man kan fremstille nevnte benzodiazepinderivater ved å oppvarme et o-aminofenylketon med et overskudd av glycinetylester-hydroklorid av pyridin, og hvis det er bnskelig, alkylere det re-sulterende 1-usubstituerte benzodiazepinderivat. ^L.H. Sternbach, et al.: Journal of Organic Chemistry, 27, 3788 (1962), Journal of Medicinal Chemistry, 8, 815 (1965^7- Denne fremgangsmåte krever imidlertid åt man oppvarmer reaksjonsblandingén til temperaturer med meget nær opplosningsmidiets kokepunkt, og det er ytterligere meget vanskelig å oppnå hoyt utbytte, og den er fplgelig ikke særlig godt egnet for kommersiell anvendelse i stor skala. Several procedures for the production of these benzodiazepine derivatives have so far been described. It is e.g. known how to prepare said benzodiazepine derivatives by heating an o-aminophenyl ketone with an excess of glycine ethyl ester hydrochloride of pyridine and, if desired, alkylating the resulting 1-unsubstituted benzodiazepine derivative. ^L.H. Sternbach, et al.: Journal of Organic Chemistry, 27, 3788 (1962), Journal of Medicinal Chemistry, 8, 815 (1965^7- This method, however, requires heating the reaction mixture to temperatures very close to the boiling point of the solvent, and it is furthermore very difficult to achieve a high yield, and it is obviously not very well suited for large-scale commercial use.

I motsetning til denne kjente fremgangsmåte har man nå relativt uventet funnet at benzodiazepinderivater med formel (I) lett og okonomisk kan fremstilles i meget hoyt utbytte.og med hby renhet ved å omsette et Orraminofenylketonderivat med formel (II) med et 2,5-dionderivat med formel (III). Foreliggende fremgangsmåte kan videre utfores ved romtemperatur eller under denne temperatur, og gir de foronskede benzodiazepinderivater i nesten kvanti-tative utbytter. In contrast to this known method, it has now been relatively unexpectedly found that benzodiazepine derivatives of formula (I) can be easily and economically prepared in very high yield and with high purity by reacting an Orraminophenylketone derivative of formula (II) with a 2,5-dione derivative with formula (III). The present method can further be carried out at room temperature or below this temperature, and gives the desired benzodiazepine derivatives in almost quantitative yields.

Det er en hensikt ved foreliggende oppfinnelse å til-veiebringe en ny fremgangsmåte for fremstilling av benzodiazepinderivater . It is an aim of the present invention to provide a new method for the production of benzodiazepine derivatives.

Foreliggende oppfinnelse tilveiebringer en fremgangsmåte for fremstilling av benzodiazepinderivater og salter av disse med forannevnte formel (i), og denne fremgangsmåte er kjennetegnet ved at man behandler et aminofenylketonderivat med formelen The present invention provides a method for the production of benzodiazepine derivatives and their salts with the aforementioned formula (i), and this method is characterized by treating an aminophenylketone derivative with the formula

hvor R-p R2, R^ og R4 er som definert ovenfor, med et 2,5-dionderivat med formelen: where R-p R 2 , R 4 and R 4 are as defined above, with a 2,5-dione derivative of the formula:

hvor Rg er som definert ovenfor, og X representerer oksygen eller svovel. where Rg is as defined above, and X represents oxygen or sulfur.

Ved fremstilling av benzodiazepinderivater ifblge foreliggende oppfinnelse kan aminofenylketonderivater med formel (II) behandles met et 2,5-dionderivat med formel (III) i et opplbsningsmiddel eller i en blanding av opplosningsmidler. Egnede opplosningsmidler innbefatter f.eks. kloroform, karbontetraklorid, metylenklorid, etylenklorid, eter,' diisopropyleter, tetrahydrofuran, dioksan, vann, metanol, etanol, dimetylformamid, dimetylsulfoksyd, eller blandinger av disse. Reaksjonen utfores vanligvis i nærvær av en syre. Som nevnte syre kan man i dette henseende anvende saltsyre, hydrogenbromid, svovelsyre, fosforsyre, polyfosforsyrer, bortrifluorid eller paratoluensulfonsyre. Reaksjonen utfores ved temperaturer fra -25 til +120°C, fortrinnsvis fra ca. 0 til ca. 30°C. Man kan hvis det er onskelig også anvende temperaturer uten-for det forannevnte området, men dette er mindre foretrukket. I de fleste tilfeller kan reaksjonen utfores ved romtemperatur eller lavere. Trykk er ikke kritisk, og fremgangsmåten kan utfores ved atmosfærisk trykk, subatmosfærisk eller overatmosfærisk trykk. Hvis det er onskelig, kan fremgangsmåten utfores i en inert atmosfære, f.eks. i en atmosfære av nitrogen, argon eller lignende. When producing benzodiazepine derivatives according to the present invention, aminophenylketone derivatives of formula (II) can be treated with a 2,5-dione derivative of formula (III) in a solvent or in a mixture of solvents. Suitable solvents include e.g. chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, ether, diisopropyl ether, tetrahydrofuran, dioxane, water, methanol, ethanol, dimethylformamide, dimethyl sulfoxide, or mixtures thereof. The reaction is usually carried out in the presence of an acid. As said acid, hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, polyphosphoric acids, boron trifluoride or paratoluenesulfonic acid can be used in this respect. The reaction is carried out at temperatures from -25 to +120°C, preferably from approx. 0 to approx. 30°C. If desired, temperatures outside the aforementioned range can also be used, but this is less preferred. In most cases, the reaction can be carried out at room temperature or lower. Pressure is not critical, and the process can be carried out at atmospheric pressure, subatmospheric or superatmospheric pressure. If desired, the process can be carried out in an inert atmosphere, e.g. in an atmosphere of nitrogen, argon or the like.

Skjbnt molforholdet mellom 2,5-dionderivatet og amino-fenylketonderivatet ikke er kritisk, så er det foretrukket å anvende minst stbkiometriske mengder av reaktantene. I de fleste tilfeller er det foretrukket å anvende et overskudd av 2,5-dionderivatet. Although the molar ratio between the 2,5-dione derivative and the amino-phenylketone derivative is not critical, it is preferred to use at least stoichiometric amounts of the reactants. In most cases it is preferred to use an excess of the 2,5-dione derivative.

Hvis det er onskelig, kan reaktantene oppvarmes i et egnet opplbsningsmiddel, f.eks. dimetylsulfoksyd,dimetylformamid eller lignende, for derved å fullfore reaksjonen. If desired, the reactants can be heated in a suitable solvent, e.g. dimethylsulfoxide, dimethylformamide or the like, thereby completing the reaction.

Benzodiazepinderivater fremstilt ifblge forannevnte fremgangsmåte'kan dessuten isoleres i form av et syreaddisjonssalt ved en behandling med en syre, f.eks. en mineralsyre såsom saltsyre, svovelsyre, salpetersyre eller fosforsyre, eller en organisk syre, såsom maleinsyre, fumarsyre, ravsyre, maursyre eller eddiksyre. Benzodiazepine derivatives produced according to the aforementioned method can also be isolated in the form of an acid addition salt by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, or an organic acid such as maleic acid, fumaric acid, succinic acid, formic acid or acetic acid.

Fblgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.

Eksempel 1 Example 1

Én opplosning av 0,2 g 2-metylamino-5-klorbenzofenon i 20 ml tbrr metylenklorid ble tilsatt 0,2 g oksazolid-2,5-dion. Blandingen ble så tilsatt 20 ml eter mettet med hydrogenklorid under avkjbling. Blandingen ble hensatt ved romtemperatur under periodevis rbring. Reaksjonsblandingen ble helt over i vann, gjort alkalisk med vandig ammoniakk og ekstrahert med metylenklorid. To a solution of 0.2 g of 2-methylamino-5-chlorobenzophenone in 20 ml of tbr methylene chloride was added 0.2 g of oxazolidin-2,5-dione. The mixture was then added with 20 ml of ether saturated with hydrogen chloride under cooling. The mixture was left at room temperature with periodic stirring. The reaction mixture was poured into water, made alkaline with aqueous ammonia and extracted with methylene chloride.

Ekstraktene "ble slått sammen og tbrket over natriumsulfat, hvoretter opplbsningsmidlet ble fjernet under redusert trykk. Residuet ble utkrystallisert fra isopropylalkohol, hvorved man fikk 1-metyl-5-fenyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra isopropylalkohol ga 0,22 g av prismer med sirip. på 129 - 131°C. Utbytte 90%. The extracts were combined and dried over sodium sulfate, after which the solvent was removed under reduced pressure. The residue was crystallized from isopropyl alcohol to give 1-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4 -benzodiazepine-2-one Recrystallization from isopropyl alcohol gave 0.22 g of prisms with syrup at 129 - 131° C. Yield 90%.

Eksempel 2 Example 2

Ved å anvende samme fremgangsmåte som i eksempel 1, men ved å erstatte 2-metylamino-5-klorbenzofenon med 2-((3, |3, p-trifluor-etyl)-amino-5-klorbenzofenon, fikk man fremstilt 1-(p,p,p-trifluor-etyl)-5-fenyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 164 - 166°C. By using the same procedure as in example 1, but by replacing 2-methylamino-5-chlorobenzophenone with 2-((3,|3,p-trifluoro-ethyl)-amino-5-chlorobenzophenone, 1-( p,p,p-trifluoroethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, mp 164-166°C.

Eksempel 3 Example 3

Ved å anvende samme fremgangsmåte som i eksempel 1, men ved å erstatte 2-metylamino-5-klorbenzofenon med 2-metylamino-5-klor-2'-fluorbenzofenon, fikk man fremstilt l-metyl-5-(o-fluorfenyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on. By using the same procedure as in example 1, but by replacing 2-methylamino-5-chlorobenzophenone with 2-methylamino-5-chloro-2'-fluorobenzophenone, 1-methyl-5-(o-fluorophenyl)- 7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one.

Denne forbindelse ble behandlet med etanolisk hydrogenklorid, hvorved man fikk hydrokloridet i et kvantitativt utbytte. Omkrystallisasjon fra etanol gir krystaller som dekompnerte ved 2A8,5 - 219°C This compound was treated with ethanolic hydrogen chloride, whereby the hydrochloride was obtained in quantitative yield. Recrystallization from ethanol gives crystals that decomp at 2A8.5 - 219°C

Eksempel 4 Example 4

Ved å anvende samme fremgangsmåte som i eksempel 1, men ved å erstatte 2-metylamino-5-klorbenzofenon med 2-metylamino-5,2'-diklor-benzofenon, fikk man fremstilt l-metyl-5-(o-klorfenyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 136 - 138°C. By using the same procedure as in example 1, but by replacing 2-methylamino-5-chlorobenzophenone with 2-methylamino-5,2'-dichloro-benzophenone, 1-methyl-5-(o-chlorophenyl)- 7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 136 - 138°C.

Eksempel 5 Example 5

Ved å anvende samme fremgangsmåte som i eksempel 1, men ved å erstatte 2-metylamino-5-klorbenzofenon med 2-metylamino-5,4'-diklorbenzofenon, fikk man fremstilt l-metyl-5-(p-klorfenyl)-7-klor-1,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 154 - 156°C. By using the same procedure as in example 1, but by replacing 2-methylamino-5-chlorobenzophenone with 2-methylamino-5,4'-dichlorobenzophenone, 1-methyl-5-(p-chlorophenyl)-7- chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 154 - 156°C.

Eksempel 6 Example 6

Ved å anvende samme fremgangsmåte som i eksempel 1, men ved å erstatte oksazolid-2,5-dion med tiazolid-2,5-dion, fikk man fremstilt l-metyl-5-fenyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 129 - 131°C. By using the same procedure as in example 1, but by replacing oxazolidin-2,5-dione with thiazolidin-2,5-dione, 1-methyl-5-phenyl-7-chloro-1,3-dihydro was produced -2H-1,4-benzodiazepine-2-one, m.p. 129 - 131°C.

Eksempel 7 Example 7

En opplbsning av 0,2 g 2-metylamino-5-nitro-benzofenon A solution of 0.2 g of 2-methylamino-5-nitro-benzophenone

i 20 ml torr metylenklorid ble tilsatt 0,2 g oksazolid-2,5-dion. 0.2 g of oxazolidin-2,5-dione was added to 20 ml of dry methylene chloride.

Blandingen ble så dråpevis tilsatt 10 ml eter mettet med hydrogenklorid under avkjbling. Blandingen ble så rort ved romtemperatur. Den ble deretter helt over i vann, gjort alkalisk med vandig ammoniakk og ekstrahert med metylenklorid. Metylenkloridekstraktene ble slått sammen og tbrket over natriumsulfat, hvoretter opplos-ningsmidlet ble fjernet under redusert trykk. Residuet ble omkrystallisert fra etanol, hvorved man fikk l-metyl-5-fenyl-7-nitro-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 157 - 159°C. The mixture was then added dropwise to 10 ml of ether saturated with hydrogen chloride under cooling. The mixture was then stirred at room temperature. It was then poured into water, made alkaline with aqueous ammonia and extracted with methylene chloride. The methylene chloride extracts were combined and triturated over sodium sulfate, after which the solvent was removed under reduced pressure. The residue was recrystallized from ethanol, whereby 1-methyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained, m.p. 157 - 159°C.

Eksempel 8 Example 8

Ved å anvende samme fremgangsmåte som i eksempel 7, men ved å erstatte 2-metylamino-5-nitrobenzofenon med 2-metylamino-2'-fluorr-5-nitrobenzofenon, fikk man fremstilt 1-mety 1-5- (o-fluorfenyl)-7-nitro-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 170 - .'7 Eksempel 9 En opplbsning ar 0,2 g 2-amino-5-klor-benzofenon i 15 ml tbrr metylenklorid ble tilsatt 0,15 g oksazolid-2,5-dion. Blandingen ble., så .. tilsatt 5 ml eter mettet med hydrogeriklorid under avkjbling. Blandingen ble hensatt ved romtemperatur under rbring. Den ble så helt over i vann, gjort basisk med vandig ammoniakk og ekstrahert med metylenklorid. Metylenkloridekstraktene ble slått sammen, tbrket over natriumsulf at og konsentrert. Residuet ble opplost i 4 ml dimetylsulfoksyd, og opplbsningen oppvarmet til 50 - 60 C og konsentrert under redusert trykk. Residuet ble utkrystallisert fra metanol og deretter omkrystallisert fra samme opplbsningsmiddel, hvorved man fikk 0,22 g (91,9%) 5-fenyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 213 - 215°C. By using the same procedure as in example 7, but by replacing 2-methylamino-5-nitrobenzophenone with 2-methylamino-2'-fluoror-5-nitrobenzophenone, 1-methyl 1-5-(o-fluorophenyl) -7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 170 - .'7 Example 9 To a solution of 0.2 g of 2-amino-5-chloro-benzophenone in 15 ml of dry methylene chloride was added 0.15 g of oxazolid-2,5-dione. The mixture was.. then .. added 5 ml of ether saturated with hydrogen chloride under cooling. The mixture was left at room temperature under stirring. It was then poured into water, basified with aqueous ammonia and extracted with methylene chloride. The methylene chloride extracts were combined, triturated over sodium sulfate and concentrated. The residue was dissolved in 4 ml of dimethylsulfoxide, and the solution heated to 50-60°C and concentrated under reduced pressure. The residue was crystallized from methanol and then recrystallized from the same solvent, whereby 0.22 g (91.9%) of 5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained , m.p. 213 - 215°C.

Eksempel 10 Example 10

Ved å anvende samme fremgangsmåte som i eksempel 9,.men ved å erstatte 2-amino-5-klorbenzofenon med 2-amino-5-brom-benzofenon, fikk man fremstilt 5-fenyl-7-brom-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra aceton gir krystaller med et smp. på 220 - 221°C. By using the same procedure as in example 9, but by replacing 2-amino-5-chlorobenzophenone with 2-amino-5-bromo-benzophenone, 5-phenyl-7-bromo-1,3-dihydro- 2H-1,4-benzodiazepine-2-one. Recrystallization from acetone gives crystals with a m.p. at 220 - 221°C.

Eksempel 11 Example 11

Ved å anvende samme fremgangsmåte som i eksempel 9, men ved å erstatte 2-amino-5-klorbenzofenon med 2-amino-5-trifluormetyl-benzofenon,.fikk man fremstilt 5-fenyl-7-trifluormetyl-1,3-dihydro-2H-1,4-benzodlazepin-2-on. Omkrystallisasjon fra benzen-heksan gir krystaller- med et smp. på 204 - 205°C By using the same procedure as in example 9, but by replacing 2-amino-5-chlorobenzophenone with 2-amino-5-trifluoromethyl-benzophenone, 5-phenyl-7-trifluoromethyl-1,3-dihydro- 2H-1,4-benzodlazepin-2-one. Recrystallization from benzene-hexane gives crystals- with a m.p. at 204 - 205°C

Eksempel 12 Example 12

Ved å anvende samme fremgangsmåte som i eksempel 9, men ved å erstatte 2-amino-5-klorbenzofenon med 2-amino-benzofenon, fikk man fremstilt 5-fenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra aceton gir krystaller med et smp. på 180 - 181°C. By using the same procedure as in example 9, but by replacing 2-amino-5-chlorobenzophenone with 2-amino-benzophenone, 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2 was produced -on. Recrystallization from acetone gives crystals with a m.p. at 180 - 181°C.

Eksempel 13 Example 13

Ved å anvende samme fremgangsmåte som i eksempel 9, men ved å erstatte 2-amino-5-klorbenzofenon med 2-amino-5-klor-2'-fluorbenzofenon, fikk man fremstilt 5-(o-fluorfenyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra isopropylalkohol gir krystaller med et smp. på 203 - 205°C, utbytte: 93%. By using the same procedure as in example 9, but by replacing 2-amino-5-chlorobenzophenone with 2-amino-5-chloro-2'-fluorobenzophenone, 5-(o-fluorophenyl)-7-chloro- 1,3-dihydro-2H-1,4-benzodiazepine-2-one. Recrystallization from isopropyl alcohol gives crystals with a m.p. at 203 - 205°C, yield: 93%.

Eksempel 14 Example 14

Ved å anvende samme fremgangsmåte som i eksempel 9, men ved å erstatte 2-amino-5-klorbenzofenon med 2-amino-5,2'-diklor-benzofenon, fikk man fremstilt 5-(o-klor-fenyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra etanol gir krystaller med et smp. på 199 - 201°C, utbytte 82,6%. By using the same procedure as in example 9, but by replacing 2-amino-5-chlorobenzophenone with 2-amino-5,2'-dichloro-benzophenone, 5-(o-chloro-phenyl)-7- chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one. Recrystallization from ethanol gives crystals with a m.p. at 199 - 201°C, yield 82.6%.

Eksempel 15 Example 15

Ved å anvende samme fremgangsmåte som i eksempel 9, men ved å erstatte 2-amino-5-klorbenzofenon med 2-amino-5,4'-diklor-benzofenon, fikk man fremstilt 5-(p-klorfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on. Omkrystallisasjon fra etanol gir krystaller med et smp. på 246 - 247°C By using the same procedure as in example 9, but by replacing 2-amino-5-chlorobenzophenone with 2-amino-5,4'-dichloro-benzophenone, 5-(p-chlorophenyl)-7-chloro- 1,3-dihydro-2H-1,4-benzodiazepine-2-one. Recrystallization from ethanol gives crystals with a m.p. at 246 - 247°C

Eksempel 16 Example 16

Ved å anvende samme fremgangsmåte som i eksempel 9, men ved å erstatte oksazolid-2,5-dion med 4-metyl-oksazolid-2,5-dion, fikk man fremstilt 3-metyl-5-fenyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra benzen-petroleter gir krystaller med et smp. på 219 - 221°C. By using the same procedure as in example 9, but by replacing oxazolidin-2,5-dione with 4-methyl-oxazolidin-2,5-dione, 3-methyl-5-phenyl-7-chloro-1 was produced ,3-dihydro-2H-1,4-benzodiazepine-2-one. Recrystallization from benzene-petroleum ether gives crystals with a m.p. at 219 - 221°C.

Eksempel 17 Example 17

En opplbsning av 0,2 g 2-amino-5-nitro«benzofenon i 15 ml tbrr metylenklorid ble tilsatt 0,2 g oksazolid-2,5-dion. Blandingen ble så tilsatt 10 ml eter mettet med hydrogenklorid under isavkjbling. " Blandingen ble hensatt ved romtemperatur under rbring. Den ble så helt over i vann, gjort basisk med vandig ammoniakk og ekstrahert med metylenklorid. Metylenkloridekstraktene ble slått sammen og tbrket over natriumsulfat, hvoretter opplbsningsmidlet ble fjernet. Residuet ble opplost i 10 ml dimetylsulfoksyd og opplbsningen oppvarmet ved 50 - 60°C og så konsentrert under redusert trykk. Residuet ble utkrystallisert fra etanol og omkrystallisert fra samme opplbsningsmiddel-, hvorved man fikk 0,2 g (88%) 5-fenyl-7-nitro-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 223 - 225°C. A solution of 0.2 g of 2-amino-5-nitrobenzophenone in 15 ml of dry methylene chloride was added with 0.2 g of oxazolidin-2,5-dione. The mixture was then added with 10 ml of ether saturated with hydrogen chloride under ice-cooling. " The mixture was left at room temperature with stirring. It was then poured into water, made basic with aqueous ammonia and extracted with methylene chloride. The methylene chloride extracts were combined and dried over sodium sulfate, after which the solvent was removed. The residue was dissolved in 10 ml of dimethyl sulfoxide and the solution heated at 50 - 60° C. and then concentrated under reduced pressure. The residue was crystallized from ethanol and recrystallized from the same solvent to give 0.2 g (88%) of 5-phenyl-7-nitro-1,3-dihydro -2H-1,4-benzodiazepine-2-one, mp 223 - 225°C.

Eksempel 18 Example 18

Ved å anvende samme fremgangsmåte som i eksempel 17, men : ved å erstatte 2-amino-5-nitrobenzofenon med: 2-amino-2'-fluor-5-nitrobenzofenon, fikk man fremstilt 5-(o-fluorfenyl)-7-nitro-l,3-dihydro-2H-l,4-benzodiazepin-2-on', smp. 223 — 225°C. By using the same procedure as in example 17, but: by replacing 2-amino-5-nitrobenzophenone with: 2-amino-2'-fluoro-5-nitrobenzophenone, 5-(o-fluorophenyl)-7- nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one', m.p. 223 — 225°C.

Eksempel 19 Example 19

Ved'å anvende samme fremgangsmåte som i eksempel 17, men ved å erstatte 2-amino-5-nitrobenzofenon med 2-amino-2'-klor-5-nitrobenzofenon, fikk man fremstilt 5-(o-klorfenyl)-7-nitro-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 236,5 - 238°C. By using the same method as in example 17, but by replacing 2-amino-5-nitrobenzophenone with 2-amino-2'-chloro-5-nitrobenzophenone, 5-(o-chlorophenyl)-7-nitro was produced -1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 236.5 - 238°C.

Eksempel 20 Example 20

Ved å anvende samme fremgangsmåte som i eksempel 17, men ved å erstatte 2-amino-5-nitrobenzofenon med 2-amino-2'-trifluormetyl-5-nitrobenzofenon, fikk man fremstilt 5-(o-trifluormetylfenyl)-7-nitro-1,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 233 - 234°C. By using the same procedure as in example 17, but by replacing 2-amino-5-nitrobenzophenone with 2-amino-2'-trifluoromethyl-5-nitrobenzophenone, 5-(o-trifluoromethylphenyl)-7-nitro- 1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 233 - 234°C.

Eksempel 21 Example 21

En opplbsning av 2 g 2-amino-5-klor-2'-metylbenzofenon A solution of 2 g of 2-amino-5-chloro-2'-methylbenzophenone

i 100 ml tbrr metylenklorid ble tilsatt 2 g oksazolid-2,5-dion. Blandingen ble dråpevis tilsatt 20 ml eter mettet med hydrogenklorid idet temperaturen ble holdt under 5°C med isavkjbling og rbring. Blandingen ble rbrt ved romtemperatur, helt over i isvann, gjort alkalisk méd vandig ammoniakk og ekstrahert med metylenklorid. De samlede metylenkloridekstrakter ble tbrket over 2 g of oxazolidin-2,5-dione were added to 100 ml of tbrr methylene chloride. The mixture was added dropwise to 20 ml of ether saturated with hydrogen chloride, keeping the temperature below 5°C with ice cooling and stirring. The mixture was stirred at room temperature, poured into ice water, made alkaline with aqueous ammonia and extracted with methylene chloride. The combined methylene chloride extracts were concentrated

natriumsulfat, hvoretter opplbsningsmidlet ble fjernet. Residuet ble oppvarmet med 30 ml dimetylsulfoksyd ved 65 - 70°C, hvoretter opplbsningsmidlet ble fjernet under redusert trykk. Residuet ble opplost i metylenklorid, vasket méd vann og tbrket over natrium-<* >sulfat, hvoretter opplbsningsmidlet ble fjernet. Residuet som stivnet ved henstand, ble omkrystallisert fra isopropylalkohol, hvorved man fikk 2,1 g 5-(o-tolyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 179 - 180°C, utbytte: 90,5% sodium sulfate, after which the solvent was removed. The residue was heated with 30 ml of dimethylsulfoxide at 65-70°C, after which the solvent was removed under reduced pressure. The residue was dissolved in methylene chloride, washed with water and washed over sodium sulfate, after which the solvent was removed. The residue, which solidified on standing, was recrystallized from isopropyl alcohol, whereby 2.1 g of 5-(o-tolyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained, m.p. 179 - 180°C, yield: 90.5%

Eksempel 22 Example 22

Ved å anvende samme fremgangsmåte som i eksempel 21, men ved å erstatte 2-amino-5-klor-2'-metylbenzofenon med 2-metylamino-5-klor-2'-metylbenzofenon, fikk man fremstilt l-metyl-5-(o-tolyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on. Omkrystallisasjon fra isopropylalkohol gir krystaller med et smp. 138 - 139°C. By using the same procedure as in example 21, but by replacing 2-amino-5-chloro-2'-methylbenzophenone with 2-methylamino-5-chloro-2'-methylbenzophenone, 1-methyl-5-( o-tolyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one. Recrystallization from isopropyl alcohol gives crystals with a m.p. 138 - 139°C.

Eksempel 23 Example 23

Ved hjelp av de fremgangsmåter som er beskrevet i eksempel 1-22, ble fblgende forbindelser fremstilt. 5-fenyl-6-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, Using the methods described in examples 1-22, the following compounds were prepared. 5-phenyl-6-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 243 - 245°C. m.p. 243 - 245°C.

5-fenyl-8-klor-1,3-dihydro-2H-1,4-benzodi azepin-2-on, 5-phenyl-8-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one,

smp. 214 - 215°C. m.p. 214 - 215°C.

5-fenyl-9-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, • 5-phenyl-9-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, •

smp. 174 - 176°C. m.p. 174 - 176°C.

5-fenyl-8-nitro-l,3-dihydro-2H-l,4-benzodiazepin-2-on, 5-phenyl-8-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 252°C (dekomp.). m.p. 252°C (decomp.).

5-fenyl-9-nitro-1,3-dihydro-2H-1,4-benzodi azepin-2-on, 5-phenyl-9-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one,

smp. 146 - 147°C m.p. 146 - 147°C

7-metyl-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 7-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 209 - 210°C. m.p. 209 - 210°C.

7- metoksy-5-fenyl-1,3-dihydro-2H-1,4-benzodi azepin-2-on, 7- methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one,

smp. 216 - 218°C. m.p. 216 - 218°C.

8- metoksy-5-fenyl-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 8- methoxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 186 - 188°C. m.p. 186 - 188°C.

8-metoksy-7-brom-5-fenyl-1,3-dihydro-2H-l,4-benzodiazepin^2-on, smp. 260 - 26l°C, 8-Methoxy-7-bromo-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine^2-one, m.p. 260 - 26l°C,

8-trifluormetyl-5-feny1-1,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 216 - 218°C. 8-trifluoromethyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 216 - 218°C.

7-metylsulfonyl-5-fenyl-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 256 - 258°C. 7-methylsulfonyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 256 - 258°C.

7- metylsulfinyl-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 254°C (dekomp.). 7- methylsulfinyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 254°C (decomp.).

7-cyano-5-fenyl-1,3-dihydro-2H-l,4-benzodiazepin-2-on, 7-cyano-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp<*.> 238°C (dekomp.). 7-dimetylamino-5-fenyl-1,3-dihydro-2H-1,4- benz od iazepin-2-on, • smp. 245 - 247°C. mp<*.> 238°C (decomp.). 7-dimethylamino-5-phenyl-1,3-dihydro-2H-1,4-benz od iazepin-2-one, • m.p. 245 - 247°C.

7-piperidino-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 7-piperidino-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 250 - 252°C. m.p. 250 - 252°C.

5-(p-klorfenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 253 - 254°C. 5-(p-chlorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 253 - 254°C.

5-(p-klorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-(p-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 262 - 263°C. m.p. 262 - 263°C.

5-(o-metoksyfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 205 - 207°C 5-(o-methoxyphenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 205 - 207°C

5-(m-metoksyfenyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 220 - 222°C. 5-(m-methoxyphenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 220 - 222°C.

5-(o-klorfenyl)-7,8-dimetyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 259 - 260°C. 5-(o-chlorophenyl)-7,8-dimethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 259 - 260°C.

5-(o-klorfenyl)-7-dimetylamino-1,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 245 - 248°C. 5-(o-chlorophenyl)-7-dimethylamino-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 245 - 248°C.

5-fenyl-7-brom-8-metoksy-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 260 - 26l°C. 5-phenyl-7-bromo-8-methoxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 260 - 261°C.

5-(o-trifluormetylfenyl)-7-trifluormetyl-1,3-dihydro-2H-l,4-benzodiazepin- 2- on, smp. 226 - 227°C. 5-(o-trifluoromethylphenyl)-7-trifluoromethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 226 - 227°C.

7,8-dimetyl-5-fenyl-1,3-dihydro-2H-1,4-benzodi azepin-2-on, 7,8-dimethyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one,

smp. 255 - 256°C. m.p. 255 - 256°C.

7-klor-9-metyltio-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 189 - 191°C. 7-chloro-9-methylthio-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 189 - 191°C.

l-metyl-5-fenyl-7-trifluormetoksy-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 234 - 236°C. 1-methyl-5-phenyl-7-trifluoromethoxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 234 - 236°C.

l-metyl-5-fenyl-7-cyano-l,3-dihydro-2H-1,4-benzodiazepin-2-on,, smp. 158 - 160°C. l-/propy1-(2)-yl7-5-(o-klorfenyl)-7-klor-1,3-dihydro-2H-1,4-benzodiazepih-2-on, smp. 140 - 142°C. 1-methyl-5-phenyl-7-cyano-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 158 - 160°C. 1-(propy1-(2)-yl7-5-(o-chlorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepih-2-one, m.p. 140 - 142°C.

1- metyl-5-(o-fluorfenyl)-7-brom-l,3-dihydro-2H-1,4-benzodiazepin-2- on, smp. 132 - 133°C 1-methyl-5-(o-fluorophenyl)-7-bromo-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 132 - 133°C

1- etyl-5-(p-klorfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2- on, smp. 129 - 130°C. 1-ethyl-5-(p-chlorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 129 - 130°C.

1-isopropy1-5-(o-klorfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 145 - 150°C. 1-isopropyl-5-(o-chlorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 145 - 150°C.

l-etyl-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 1-ethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 132 - 133°C. l-allyl-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin--2-on, smp. 105 - 106°C. m.p. 132 - 133°C. 1-allyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 105 - 106°C.

1-benzyl-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 105 - 106°C. 1-benzyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 105 - 106°C.

5-(o-klorfenyl)-7-dimetylamino-l-mety1-1,3-dihydro-2H-l,4-benzodiazepin- 2- on, smp. 112 - 114°C. 5-(o-chlorophenyl)-7-dimethylamino-1-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 112 - 114°C.

7-dimetylamino-l-metyl-5-(o-trifluormetylfenyl)-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 111 - 114°C. 7-dimethylamino-1-methyl-5-(o-trifluoromethylphenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 111 - 114°C.

7-klor-3-isopropyl-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 226 - 227°C. 7-chloro-3-isopropyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 226 - 227°C.

7-klor-. 3-metoksymety1-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-• 2-on, smp. 166 - 167°C. 7-chloro-. 3-methoxymethyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-• 2-one, m.p. 166 - 167°C.

7-klor-5-fenyl-3-isobutyl-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 213 - 214°C. 7-klor-5-fenyl-3- (3-metyltioetyl-l, 3-dihydro^2H-1, 4-benzodiazepin-2-on, smp. 179 - 180°C. 7-chloro-5-phenyl-3-isobutyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 213 - 214°C. 7-chloro-5-phenyl-3-(3-methylthioethyl-1,3-dihydro^2H-1,4-benzodiazepine-2-one, m.p. 179 - 180°C.

7-klor-5-fenyl-3-(p-hydroksybenzyl)-l,3-dihydro-2H-l,4-benzodiazepin- 2- on, smp. 217 - 218°C. 7-chloro-5-phenyl-3-(p-hydroxybenzyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 217 - 218°C.

7-klor-3-(p-metoksyfenyl)-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin- 2-on, smp. 237 - 238°C. 7-chloro-3-(p-methoxyphenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 237 - 238°C.

l-metyl-7-klor-5-fenyl-3-(p-klorfenyl)-l,3-dihydro-2H-1,4-benzodiazepin- 2- on, smp. 200 - 201°C. 1-methyl-7-chloro-5-phenyl-3-(p-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 200 - 201°C.

7-klor-3,5-difenyl-1-metyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 217 - 218°C. 7-chloro-3,5-diphenyl-1-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 217 - 218°C.

7-klor-l-metyl-3-(p-metoksyfenyl)-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 177 - 178°C. 5-(o-nitrofenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 7-chloro-1-methyl-3-(p-methoxyphenyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 177 - 178°C. 5-(o-nitrophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 206 - 208°C. m.p. 206 - 208°C.

5-(o-nitrofenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 226 - 228°C. 5-(o-nitrophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 226 - 228°C.

5-(m-sulfamoylfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, l-metyl-5-(2',6'-diklorfenyl)-7-klor-1,3-d ihydro-2H-1,4-benzodiazepin-2-on, 5-(m-sulfamoylphenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, 1-methyl-5-(2',6'-dichlorophenyl)-7-chloro- 1,3-dihydro-2H-1,4-benzodiazepine-2-one,

1- metyl-5-(o-nitrofenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2- on, smp. 209 - 212°C. 1- methyl-5-(o-nitrophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 209 - 212°C.

l-metyl-5-(3',4',5'-trimetoksy-fenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 140 - 142°C. 1-methyl-5-(3',4',5'-trimethoxy-phenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 140 - 142°C.

l-metyl-5-(2'-klor-5'-sulfamoyl-fenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 1-methyl-5-(2'-chloro-5'-sulfamoyl-phenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

5-(2'-pyridyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-(2'-pyridyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 231 - 232°C (dekomp..). m.p. 231 - 232°C (decomp..).

5-(2<*->pyridyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-(2<*->pyridyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 224 - 226°C (dekomp.). m.p. 224 - 226°C (decomp.).

5-(2'-pyridyl)-7-brom-l,3-dihydro-2H-l,4-benzodiazepin-2-on," smp. 238 - 240°C. 5-(2'-pyridyl)-7-bromo-1,3-dihydro-2H-1,4-benzodiazepine-2-one," mp 238-240°C.

5-(2'-pyridyl)-l-metyl-7-brom-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 135 - 137°C 5-(2'-pyridyl)-1-methyl-7-bromo-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 135 - 137°C

5-(2'-pyridyl)-3-metyl-7-hrom-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 228 - 229°C (dekomp.). ' 5-(2'-pyridyl)-3-methyl-7-chromo-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 228 - 229°C (decomp.). '

5-(2' pyridyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-(2' pyridyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 253 f 255°C (dekomp.). m.p. 253 f 255°C (decomp.).

l-metyl-5-(2'-tienyl)-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 1-methyl-5-(2'-thienyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 107 - 109°C m.p. 107 - 109°C

5-(2'-tienyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-(2'-thienyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 212 - 214°C. m.p. 212 - 214°C.

1- metyl-5-(2*-pyridyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 1- methyl-5-(2*-pyridyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 199 - 200°C. m.p. 199 - 200°C.

5-(2•-pyrrolyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-(2•-pyrrolyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 262 - 263°C. m.p. 262 - 263°C.

Eksempel 24 Example 24

En opplbsning av 0,2 g 2-amino-5-klor-acetofenon i 30 A solution of 0.2 g of 2-amino-5-chloro-acetophenone in 30

ml tbrr metylenklorid ble tilsatt 0,2 g oksazolid-2,5-dlon. Blandingen ble så tilsatt 10 ml eter mettet med hydrogenklorid. Blandingen ble hensatt ved romtemperatur under rbring, ble så helt over i vann og gjort alkalisk med vandig ammoniakk og ekstrahert med metylenklorid. Metylenkloridekstraktene ble slått sammen og tbrket over natriumsulfat, hvoretter opplbsningsmidlet ble fjernet under redusert trykk. Residuet ble omkrystallisert fra etylacetat, hvorved man fikk 5-<-metyl-7-klor-l, 3-dihydro-2H-1, 4-benzodiazepin-2- on som fargelbse nåler, smp. 221 - 222°C. ml of tbr methylene chloride was added to 0.2 g of oxazolidin-2,5-dlone. To the mixture was then added 10 ml of ether saturated with hydrogen chloride. The mixture was allowed to stand at room temperature under stirring, then poured into water and made alkaline with aqueous ammonia and extracted with methylene chloride. The methylene chloride extracts were combined and dried over sodium sulfate, after which the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate, whereby 5-<-methyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained as colorless needles, m.p. 221 - 222°C.

Eksempel 25 Example 25

Ved å anvende samme fremgangsmåte som i eksempel 24, men ved å erstatte 2-amino-5-klor-acetofenon med 2-metylamino-5-kloracetofenon, fikk man fremstilt 1,5-dimetyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on som ble omkrystallisert fra cykloheksan, smp. 141 - 143°C By using the same procedure as in example 24, but by replacing 2-amino-5-chloro-acetophenone with 2-methylamino-5-chloroacetophenone, 1,5-dimethyl-7-chloro-1,3-dihydro was produced -2H-1,4-benzodiazepine-2-one which was recrystallized from cyclohexane, m.p. 141 - 143°C

Eksempel 26 Example 26

Ved å anvende samme fremgangsmåte som i eksempel 24, men ved å erstatte 2-amino-5-kloracetofenon med (2-amino-5-klorfenyl)-cykloheksyl-keton, fikk man fremstilt 5-cykloheksyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, som ble omkrystallisert fra etylacetat, smp. 210 - 212°C. By using the same procedure as in example 24, but by replacing 2-amino-5-chloroacetophenone with (2-amino-5-chlorophenyl)-cyclohexyl ketone, 5-cyclohexyl-7-chloro-1,3 -dihydro-2H-1,4-benzodiazepine-2-one, which was recrystallized from ethyl acetate, m.p. 210 - 212°C.

På lignende måte ble fblgende forbindelser fremstilt: In a similar manner, the following compounds were prepared:

1-metyl-5-etyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 1-methyl-5-ethyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 97°C m.p. 97°C

l-metyl-5-isopropyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 108°C. 1-methyl-5-isopropyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 108°C.

5-benzy1-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-Benzy1-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 156 - 159°C. m.p. 156 - 159°C.

l-metyl-5-benzyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on, hydroklorid, smp. 214 - 2l6°C (dekomp.). 1-methyl-5-benzyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, hydrochloride, m.p. 214 - 2l6°C (decomp.).

1-cyklopropylmetyl-5-benzyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin- 2- on, smp. 195°C (dekomp.). 1-cyclopropylmethyl-5-benzyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 195°C (decomp.).

5-cyklopentyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin- 2-on, 5-cyclopentyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 175 - 176°C. m.p. 175 - 176°C.

5-cykloheksy1-1,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-cyclohexy1-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 199 - 201°C. 5-cykloheksyl-7-klor-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 212°C. 5-cykloheksyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-on, m.p. 199 - 201°C. 5-cyclohexyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 212°C. 5-cyclohexyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 232- 233°C. 1- metyl-5-cykloheksyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2- on, smp. 149 - 150°C. 5-cykloheptyl-l,3-dihydro-2H-1,4-benzodiazepin-2-on, m.p. 232-233°C. 1-methyl-5-cyclohexyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 149 - 150°C. 5-cycloheptyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 158 - 160°C. m.p. 158 - 160°C.

5-cykloheptyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, 5-cycloheptyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one,

smp. 159 - 161°C. m.p. 159 - 161°C.

l-metyl-5-(1'-cykloheksenyl)-7-klor-l,3-dihydro-2H-1,4-benzo-di azepin- 2- on, smp. 144°C. 1-methyl-5-(1'-cyclohexenyl)-7-chloro-1,3-dihydro-2H-1,4-benzo-diazepin-2-one, m.p. 144°C.

l-metyl-5-(1'-cykloheksenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin- 2-on, smp. l63°C. 1-methyl-5-(1'-cyclohexenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 163°C.

Eksempel 27 Example 27

En opplbsning av 0,1 g 2-cyklopropylmetyl-amino-5-klor-benzofenon i 20 ml tbrr metylenklorid ble tilsatt 0,1 g oksazolid-2,5-dion. Blandingen ble så tilsatt 9 ml eter mettet med hydrogenklorid, hvoretter blandingen ble hensatt under periodevis rbring. Den ble deretter helt over i vann, gjort alkalisk med vandig ammoniakk og ekstrahert med metylenklorid. De samlede metylenkloridekstrakter ble tbrket over natriumsulfat, hvoretter opplbsningsmidlet ble fjernet under redusert trykk. Residuet ble utkrystallisert fra isopropylalkohol og omkrystallisert fra samme opplbsningsmiddel, hvorved man fikk l-cykloprbpylmetyl-5-fenyl-7-klor-1.3- dihydro-2H-1,4-benzodiazepin-2-on i et utbytte på 80 %, smp. 142 - 144°C. To a solution of 0.1 g of 2-cyclopropylmethyl-amino-5-chloro-benzophenone in 20 ml of dry methylene chloride was added 0.1 g of oxazolidin-2,5-dione. The mixture was then added with 9 ml of ether saturated with hydrogen chloride, after which the mixture was allowed to stand under periodic stirring. It was then poured into water, made alkaline with aqueous ammonia and extracted with methylene chloride. The combined methylene chloride extracts were washed over sodium sulfate, after which the solvent was removed under reduced pressure. The residue was crystallized from isopropyl alcohol and recrystallized from the same solvent, whereby 1-cyclopropylmethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained in a yield of 80%, m.p. 142 - 144°C.

Eksempel 28 Example 28

Ved å anvende samme fremgangsmåte som i eksempel 27, Using the same procedure as in Example 27,

men ved å erstatte 2-cyklopropylmetylamino-5-klorbenzofenon med 2-cyklopropylmetylamino-2'-fluor-5-klorbenzofenon, fikk man fremstilt 1-cyklopropylmetyl-(o-fluorfenyl)-7-klor-1,3-dihydro-2H-1.4- benzodiazepin-2-on. Denne frie base ble behandlet med eta-nolLsk hydrogenklorid, hvoretter opplbsningsmidlet ble fjernet. Residuet ble omkrystallisert fra isopropylalkohol-isopropyleter, hvorved man fikk hydrokloridet med et smp. på 195°C (dekomp.). but by replacing 2-cyclopropylmethylamino-5-chlorobenzophenone with 2-cyclopropylmethylamino-2'-fluoro-5-chlorobenzophenone, 1-cyclopropylmethyl-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H- 1.4- benzodiazepine-2-one. This free base was treated with ethanolic hydrogen chloride, after which the solvent was removed. The residue was recrystallized from isopropyl alcohol-isopropyl ether, whereby the hydrochloride was obtained with a m.p. at 195°C (decomp.).

Eksempel 29 Example 29

men ved å erstatte 2-cyklopropylmetylamino-5-klor-benzofenon med 2-cyklopropylmetylamino-benzofenon, fikk man fremstilt 1-cyklo-propylmetyl-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on som en olje. Denne frie base ble opplost i eter og behandlet med meta-nolisk hydrogenklorid for fremstilling av hydrokloridet, som hadde et smp. på 204°C (dekomp.). but by replacing 2-cyclopropylmethylamino-5-chloro-benzophenone with 2-cyclopropylmethylamino-benzophenone, 1-cyclopropylmethyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one was produced like an oil. This free base was dissolved in ether and treated with methanolic hydrogen chloride to produce the hydrochloride, which had a m.p. at 204°C (decomp.).

Eksempel 30 Example 30

En opplbsning av 0,2 g 2-(P-dietylamino-etylamino)-5-klor-2'-fluorbenzofenon hydroklorid i 20 ml tbrr metylenklorid ble tilsatt 0,2 g oksazolid-2,5-dion. Blandingen ble tilsatt 9 ml eter mettet med hydrogenklorid under avkjbling. Blandingen ble så hensatt ved romtemperatur under periodevis rysting, ble deretter helt over i vann, gjort alkalisk med vandig ammoniakk og ek*ra-hert med metylenklorid. De samlede metylenkloridekstrakter ble tbrket over natriumsulfat, hvoretter opplbsningsmidlet ble fjernet under redusert trykk. Residuet ble behandlet med etanolisk hydrogenklorid., hvorved man fikk 1-(P-dietylamino-etyl)-5-(o-fluorfenyl)-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on dihydroklorid, som ble omkrystallisert fra isopropylalkohol til fargelbse krystaller med et smp. på 211 - 212°C (dekomp.). To a solution of 0.2 g of 2-(P-diethylamino-ethylamino)-5-chloro-2'-fluorobenzophenone hydrochloride in 20 ml of dry methylene chloride was added 0.2 g of oxazolidin-2,5-dione. The mixture was added with 9 ml of ether saturated with hydrogen chloride under cooling. The mixture was then allowed to stand at room temperature with periodic shaking, then poured into water, made alkaline with aqueous ammonia and concentrated with methylene chloride. The combined methylene chloride extracts were washed over sodium sulfate, after which the solvent was removed under reduced pressure. The residue was treated with ethanolic hydrogen chloride, whereby 1-(P-diethylamino-ethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained dihydrochloride, which was recrystallized from isopropyl alcohol to colorless crystals with a m.p. at 211 - 212°C (decomp.).

Eksempel 31 Example 31

Ved å anvende samme fremgangsmåte som i eksempel 30, Using the same procedure as in Example 30,

men ved å erstatte 2-(P-dietylaminoetylamino)-5-klor-2'-fluorbenzo-fenon hydroklorid med 2-(P-dietylaminoetylamino)-5,2<*->diklorbenzo- but by replacing 2-(P-diethylaminoethylamino)-5-chloro-2'-fluorobenzophenone hydrochloride with 2-(P-diethylaminoethylamino)-5,2<*->dichlorobenzo-

fenon hydroklorid, fikk man fremstilt 1-(£-dietylaminbetyl)-5-(o-klorfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, som ble omkrystallisert fra heksan og fikk da -et smp. på 68 - 70°C. phenone hydrochloride, 1-(£-diethylaminobutyl)-5-(o-chlorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was prepared, which was recrystallized from hexane and then got -a smp. at 68 - 70°C.

Eksempel 32 Example 32

men ved å erstatte 2-(f3-dietylaminoetylamino)-5-klor-2'-fluorbenzo-fenon hydroklorid med 2- ((3-dietylaminoetylamino)-5-nitrobenzo- but by replacing 2-(f3-diethylaminoethylamino)-5-chloro-2'-fluorobenzophenone hydrochloride with 2-((3-diethylaminoethylamino)-5-nitrobenzo-

fenon hydroklorid, fikk man fremstilt 1-((3-dietylaminoetyl)-5-fenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-on, dihydro- phenone hydrochloride, 1-((3-diethylaminoethyl)-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, dihydro-

klorid, som ble omkrystallisert fra metanol-eter, smp. 232 - 233°C dekomp.). chloride, which was recrystallized from methanol-ether, m.p. 232 - 233°C decomp.).

Eksempel 33 Example 33

Ved å anvende den fremgangsmåte som er angitt i eksem- By applying the procedure indicated in ex-

pel 30, men ved å erstatte 2-(P-dietylaminoetylamino)-5-klorbenzo-fenon hydroklorid med 2-(|3-dietylaminoetylamino)-5-trifluormetyl-benzofenon hydroklorid, fikk man fremstilt 1-(p-dietylaminoetyl)-5-fenyl-7-trifluormetyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on dihydroklorid, som ble omkrystallisert fra metanol-eter og fikk da et smp. på 218 - 221°C. pel 30, but by replacing 2-(P-diethylaminoethylamino)-5-chlorobenzophenone hydrochloride with 2-(|3-diethylaminoethylamino)-5-trifluoromethyl-benzophenone hydrochloride, 1-(p-diethylaminoethyl)-5 -phenyl-7-trifluoromethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride, which was recrystallized from methanol-ether and then obtained a m.p. at 218 - 221°C.

Eksempel 34 Example 34

pel 30, men ved å erstatte 2- (|3-dietylaminoetylamino)-5-klor-21 - fluorbenzofenon hydroklorid med 2-(y-dimetylaminopropylamino)-5-klor-2'-fluorbenzofenon hydroklorid, fikk man fremstilt 1-(y-dimetyl-aminopropy1)-5-(o-fluorfenyl)-7-klor-1,3-dihydro-2H-1,4-b enzo diaz e-pin-2-on dihydroklorid, som ble omkrystallisert fra metanol-eter, pel 30, but by replacing 2-(|3-diethylaminoethylamino)-5-chloro-21-fluorobenzophenone hydrochloride with 2-(y-dimethylaminopropylamino)-5-chloro-2'-fluorobenzophenone hydrochloride, 1-(y -dimethyl-aminopropyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride, which was recrystallized from methanol-ether,

smp. 202- 207°C/(dekomp.). m.p. 202- 207°C/(decomp.).

Eksempel 35 Example 35

Ved å anvende samme fremgangsmåte som angitt i eksempel By applying the same procedure as indicated in the example

30, men ved å erstatte 2-(|3-dietylaminoetylamino)-5-klor-2'-fluor-benzofenon med 2-/2-()f-dimetylaminopropylamino)- 5-brombenzoyl7-pyridin, fikk man fremstilt l-( "2f-dimetylaminopropyl)-5-(2'-pyridyl)-7-brom-l,3-dihydro-2H-1,4-benzodiazepin-2-on dihydroklorid, smp. 181 - 183°C (dekomp.). 30, but by replacing 2-(|3-diethylaminoethylamino)-5-chloro-2'-fluoro-benzophenone with 2-/2-((f-dimethylaminopropylamino)-5-bromobenzoyl7-pyridine, 1-( "2f-dimethylaminopropyl)-5-(2'-pyridyl)-7-bromo-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride, m.p. 181 - 183°C (decomp.).

På lignende måte ble fblgende forbindelser fremstilt: 1-(3'-mety laminopr opy 1) - 5-(o-f luorf eny 1) - 7-klor-1,3-dihydro-2H-r 1,4-benzodiazepin- -2-on dihydroklorid, smp. 193 - 196°C. 1-(3'-dimetylaminopropyl)-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin- 2- on, smp. 90 -r 92°C. In a similar manner, the following compounds were prepared: 1-(3'-methyl laminopropy 1)-5-(o-fluoropheny 1)-7-chloro-1,3-dihydro-2H-r 1,4-benzodiazepine-2 -one dihydrochloride, m.p. 193 - 196°C. 1-(3'-dimethylaminopropyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 90 -r 92°C.

1-(2<1->dimetylåmino-l'-metyletyl)-5-feriyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-bn, dihydroklorid, smp. 165 - 168°C. 1- C2-,-pyrrolidlnoetyl)-5-fenyl-7-klbr-l, 3-dihydro-2H-1, 4-benzodiazepin-2-on maleat, smp. 157- 159°C. 1-(2'-piperidinoetyl)-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on maleat, smp. 172 - 173°C. 1-(2'-morfolinoetyl)-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin- 2- on. smp. 144 - 146°C. 1-/2'-(4"-metyl-lM<->piperazinyl)etyl7-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 159 - 160°C. 1- /3'-(4"-/2"-etoksyetyl7-lM-piperazinyl)-propyl7-5-(o-fluorfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on trimaleat, smp. 1-(2<1->dimethylamino-1'-methylethyl)-5-ferryyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-bn, dihydrochloride, m.p. 165 - 168°C. 1-C2-,-pyrrolidlnoethyl)-5-phenyl-7-klbr-1,3-dihydro-2H-1,4-benzodiazepine-2-one maleate, m.p. 157-159°C. 1-(2'-piperidinoethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one maleate, m.p. 172 - 173°C. 1-(2'-morpholinoethyl)-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one. m.p. 144 - 146°C. 1-(2'-(4"-methyl-1N<->piperazinyl)ethyl7-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 159 - 160° C. 1- /3'-(4"-/2"-ethoxyethyl7-1N-piperazinyl)-propyl7-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4 -benzodiazepine-2-one trimaleate, m.p.

129 - 132°C. 7-klor-5-fenyl-1-(p-metyltioetyl)-l,3-dihydro-2H-1,4-benzodiazepin-2-on hydroklorid, smp. 165 - 167°C (dekomp.). 7-klor-5-fenyl-1-(p-etoksyetyl)-l,3-dihydro-2H-1,4-benzodiazepin-2- on, smp. 156 - 158°C. 129 - 132°C. 7-chloro-5-phenyl-1-(p-methylthioethyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, m.p. 165 - 167°C (decomp.). 7-chloro-5-phenyl-1-(p-ethoxyethyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 156 - 158°C.

7-klor-5-fenyl-l-(p-vinyloksyetyl)-l,3-dihydro-2H-l,4-benzodiazepin-2-on hydroklorid, smp. 216 - 218°C (dekomp.). 7-chloro-5-phenyl-1-(p-vinyloxyethyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one hydrochloride, m.p. 216 - 218°C (decomp.).

7-klor-5-fenyl-l-(etoksykarbonylmetyl)-l,3-dihydro-2H-1,4-benzodiazepin- 2- on, smp. 116 - 117°C. 7-chloro-5-phenyl-1-(ethoxycarbonylmethyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 116 - 117°C.

7-klor-5-fenyl-1-(P-acetoksyetyl)-l,3-dihydro-2H-1,4-benzodiazepin- 2-on, smp. 102 - 103°C 1- ((3- ace toksye tyl) - 5- (o- fluor f enyl) - 7-klor-1,3- dihydro- 2H-1,4-benzodiazepin-2-on, smp. 103 - 105°C. 7-chloro-5-phenyl-1-(P-acetoxyethyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 102 - 103°C 1- ((3-acetoxyethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 103 - 105°C.

1-(P-acetoksyetyl)-5-(o-fluorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin- 2-on, smp. 135 - 137°C. 1-(P-acetoxyethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 135 - 137°C.

l-p(3',4',5'-trimetoksybenzoyloksyetyl)-5-(o-fluorfenyl)-7-klor-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 161 - 163°C. l-(P-etoksyacetoksyetyl)-5-(o-fluorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 154 - 158°C. 1- ( p-nikotinoyloksyetyl)-5-(o-fluorf enyl) - 7-klor-l, 3-dihydro-2H-1, 4-benzodiazepin-2-on, smp. 138 - 140°C. l-(p-isonikotinoyloksyetyl)-5-(o-fluorfenyl)-7-klor-l,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 139 - 142°C. 1-p(3',4',5'-trimethoxybenzoyloxyethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 161 - 163°C. 1-(P-ethoxyacetoxyethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 154 - 158°C. 1-(p-nicotinoyloxyethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 138 - 140°C. 1-(p-isonicotinoyloxyethyl)-5-(o-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 139 - 142°C.

Eksempel 36 Example 36

En opplbsning av 0,7 g 2-(cyanometylamino)-5--klorbenzo-fenon i tbrr metylenklorid ble tilsatt 0,7 g oksazolid-2»5-dion. To a solution of 0.7 g of 2-(cyanomethylamino)-5-chlorobenzophenone in dry methylene chloride was added 0.7 g of oxazolidin-2,5-dione.

Blandingen ble så tilsatt 7 ml eter mettet med hydrogenklorid To the mixture was then added 7 ml of ether saturated with hydrogen chloride

ved en temperatur under ca. 5°C Blandingen ble rort ved; 0 - 5°C og deretter ved romtemperatur. Den ble deretter helt over i isvann, at a temperature below approx. 5°C The mixture was stirred at; 0 - 5°C and then at room temperature. It was then poured into ice water,

nøytralisert med vandig ammoniakk og ekstrahert med metylenklorid. neutralized with aqueous ammonia and extracted with methylene chloride.

De samlede metylenkloridekstrakter ble torket over natriumsulfat, opplbsningsmidlet ble så fjernet, hvorved man fikk et residuum bestående av l-cyanometyl-5-fenyl-7-klor-l,3-dihydro-2H-1,4-benzodiazepin- 2-on. Dette residuum ble opplost i eter og behandlet med eter mettet med hydrogenklorid for fremstilling av hydrokloridet. Omkrystallisasjon fra kloroform-isopropylalkohol gir 1-cyanometyl-5-fenyl-7-klor-l,3-dihydro-2H-l,4-benzodiazepin-2-on dihydroklorid, The combined methylene chloride extracts were dried over sodium sulfate, the solvent was then removed, whereby a residue consisting of 1-cyanomethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one was obtained. This residue was dissolved in ether and treated with ether saturated with hydrogen chloride to produce the hydrochloride. Recrystallization from chloroform-isopropyl alcohol gives 1-cyanomethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride,

som fargelose prismer, smp. 219 - 221°C (dekomp.). as colorless prisms, m.p. 219 - 221°C (decomp.).

Eksempel 37 Example 37

Ved å anvende samme fremgangsmåte som i eksempel 36, Using the same procedure as in Example 36,

men ved å erstatte 2-(eyanometylamino)-5-klor-benzofenon med 2-(cyanometylamino)-5-nitrobenzofenon, fikk man fremstilt 1-cyanometyl-5-fenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-on. Omkry- but by replacing 2-(cyanomethylamino)-5-chloro-benzophenone with 2-(cyanomethylamino)-5-nitrobenzophenone, 1-cyanomethyl-5-phenyl-7-nitro-1,3-dihydro-2H-1 was produced ,4-benzodiazepine-2-one. Circum-

stallisas jon fra etanol gir krystaller med et smp. på 207 - 208°C. Stallisation from ethanol gives crystals with a m.p. at 207 - 208°C.

På lignende måte ble fblgende forbindelser fremstilt: 7- klor-1- (N, N- di e ty lkarbamoy Ime ty 1) - 5- f enyl-1, 3- dihydro- 2H-1,4-benzodiazepin-2-on, smp. 146 - 148°C. In a similar manner, the following compounds were prepared: 7-chloro-1-(N,N-diethylcarbamoy Ime ty 1)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one , m.p. 146 - 148°C.

7-klor-l-(N,N-dimetylkarbamoylmetyl)-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 178 - 180°C. 7-chloro-1-(N,N-dimethylcarbamoylmethyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 178 - 180°C.

7-klor-l-(N-metylkarbamoyImetyl)-5-(o-fluorfenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-on, smp. 212 - 214°C. 7-chloro-1-(N-methylcarbamoylmethyl)-5-(o-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 212 - 214°C.

7-klor-l-(N-etylkarbamoylmetyl)-5-fenyl-1,3-dihydro-2H-l,4-benzo- 7-chloro-1-(N-ethylcarbamoylmethyl)-5-phenyl-1,3-dihydro-2H-1,4-benzo-

diazepin- 2-on, smp. 210 - 212°C. diazepin-2-one, m.p. 210 - 212°C.

7-klor-l-(N-metylkarbamoylmetyl)-5-fenyl-1,3-dihydro-2H-l,4-benzodiazepin-2-on, smp. 253 - 254°C. 7-chloro-1-(N-methylcarbamoylmethyl)-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, m.p. 253 - 254°C.

1- karbamoylmetyl-7-klor-5-fenyl-1,3-dihydro-2H-1,4-benzodiazepin- 1- carbamoylmethyl-7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-

2- on, smp. 234 -235°C. 2- on, m.p. 234 -235°C.

Claims

Fremgangsmåte til fremstilling av benzodiazepinderivater med den generelle formel:Process for the preparation of benzodiazepine derivatives with the general formula:

og syreaddisjonssalter derav, hvor R, betyr hydrogen, C^_^-alkyl, C2 ^-alkenyl, C^_^-alkynyl eller en gruppe med formelen -CnH2n'R5' hvor n er et helt tall på 1 - 4 og R^ betyr halogen, trifluormetyl, cyan, C-^y-cy klo alkyl, C-L_^-alkoksy, C1_^-alkyltio, C2_^-alkenyl-oksy, karbamoyl, C-L_^-alkyl-karbamoyl, acyloksy, C-L_Zf-alkylkarbonyl, fenyl eller fenyl substituert med halogen, nitro, trifluormetyl, C-^ ^-alkoksy, C-^ ^-alkyl eller sulfamoyl, eller R^ betyr en gruppe med formelen: hvor Rg betyr hydrogen eller C-^^-alkyl °6 betyr C-^ ^-alkyl, forutsatt at Rg og Ry sammen med det tilstotende nitrogenatom kan danne en eventuelt med alkyl, hydroksyalkyl, alkoksyalkyl eller alkenyloksyalkyl subsituert pyrrolidono-, piperidino-, piperazino-, alkylpiperazino-, alkyloksyalkyl-piperazino- eller morfolino-gruppe; R2 betyr hydrogen, halogen, C^_^-alkyl, nitro, cyano, trifluormetyl, trifluormetoksy, di-(C-^ ^-alkyl)amino, piperidino, C-L_^-alkoksy, C-^ ^ alkyl ti o, C1_Zf-alkylsulfonyl, C-^^-alkylsulfi-nyl, karbamoyl eller sulfamoyl; R^ betyr hydrogen, nitro, C-L_^-alkyl eller halogen; R^ betyr C^^-alkyl, C^_y-cykloalkyl, cykloalkenyl, fenyl, fenyl substituert med halogen, nitro, trifluormetyl, C-^ ^-alkoksy, C-^^-alkyl eller sulfamoyl, fenyl-C-L_^-alkyl eller en pyridyl-, pyrimidyl-, pyridazinyl-, pyrazinyl-, tienyl-, furyl-, tiazol-, oksazoyl- eller indolylgruppe, hvilke grupper kan være substituert med halogen eller alkyl; Rg betyr hydrogen, C^_^-. alkyl, C-L_^-alkoksy-C-L_z+-alkyl, C-L_ ^-alkyltio-C-^_^-alkyl, fenyl, feriyl substituert med halogen eller C-^_2-alkoksy, benzyl eller hydroksybenzyl, samt syreaddisjonssalter derav, karakter i- sert ved. at et aminofenylketonderivat med formelen: hvor R-p R2, R^ og R^ har den ovenfor angitte betydning, omsettes med et 2,5-dionderivat med formelen: hvor Rg har den ovenfor angitte betydning, og hvor X betyr oksygen eller svovel, og, om bnsket, omdannelse av det erholdte produkt til dets syreaddisjonssalt ved å omsette det med en uorganisk eller organisk syre. Anførte publikasjoner: Elderfield :"Heterocyelic, Compounds, New York, vol. 5, 1957, p. 406and acid addition salts thereof, where R, means hydrogen, C^_^-alkyl, C2 ^-alkenyl, C^_^-alkynyl or a group with the formula -CnH2n'R5' where n is an integer from 1 to 4 and R ^ means halogen, trifluoromethyl, cyan, C-^y-cyclo alkyl, C-L_^- alkoxy, C 1_^-alkylthio, C 2_^-alkenyl-oxy, carbamoyl, C-L_^-alkyl-carbamoyl, acyloxy, C -L_Zf-alkylcarbonyl, phenyl or phenyl substituted with halogen, nitro, trifluoromethyl, C-1-4-alkyl, C-1-4-alkyl or sulfamoyl, or R^ means a group of the formula: where Rg means hydrogen or C-^^ -alkyl °6 means C-^^-alkyl, provided that Rg and Ry together with the adjacent nitrogen atom can form a pyrrolidone-, piperidino-, piperazino-, alkylpiperazino-, alkyloxyalkyl-piperazino optionally substituted with alkyl, hydroxyalkyl, alkoxyalkyl or alkenyloxyalkyl - or morpholino group; R 2 means hydrogen, halogen, C^_^-alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, di-(C-^^-alkyl)amino, piperidino, C-L_^-alkyl, C-^^ alkyl ti o, C 1 -Z 6 -alkylsulfonyl, C 1-3 -alkylsulfinyl, carbamoyl or sulfamoyl; R 1 is hydrogen, nitro, C 1-4 alkyl or halogen; R 1 means C 1 -alkyl, C 1 -cycloalkyl, cycloalkenyl, phenyl, phenyl substituted with halogen, nitro, trifluoromethyl, C 1 - 4 -alkyl, C 1 -3 -alkyl or sulfamoyl, phenyl-C 1 -L -alkyl or a pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thienyl, furyl, thiazole, oxazoyl or indolyl group, which groups may be substituted with halogen or alkyl; Rg means hydrogen, C^_^-. alkyl, C-L_^-Alkoxy-C-L_z+-alkyl, C-L_^-alkylthio-C-^_^-alkyl, phenyl, ferriyl substituted with halogen or C-^_2-Alkoxy, benzyl or hydroxybenzyl, as well as acid addition salts hence, grade i- sert wood. that an aminophenylketone derivative of the formula: where R-p R2, R^ and R^ have the meaning given above, is reacted with a 2,5-dione derivative with the formula: where Rg has the meaning given above, and where X means oxygen or sulphur, and, if desired, converting the product obtained into its acid addition salt by reacting it with an inorganic or organic acid. Publications cited: Elderfield: "Heterocyelic, Compounds, New York, vol. 5, 1957, p. 406