NO750978L - - Google Patents

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Publication number
NO750978L
NO750978L NO750978A NO750978A NO750978L NO 750978 L NO750978 L NO 750978L NO 750978 A NO750978 A NO 750978A NO 750978 A NO750978 A NO 750978A NO 750978 L NO750978 L NO 750978L
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Norway
Prior art keywords
formula
compounds
carbon atoms
stands
diazepine
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NO750978A
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Norwegian (no)
Inventor
W R J Simpson
Original Assignee
Sandoz Ag
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Priority claimed from US456017A external-priority patent/US3929884A/en
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of NO750978L publication Critical patent/NO750978L/no

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D243/00Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye 5~amino-7-fenyl-2,3-dihydro-1H-1,^-diazepiner med formel I The present invention relates to a process for the production of new 5-amino-7-phenyl-2,3-dihydro-1H-1,^-diazepines of formula I

hvori enten R^ står for hydrogen, en alkylgruppe med 1-6 karbon-' in which either R^ stands for hydrogen, an alkyl group with 1-6 carbon-'

atomer eller en aminogruppe,atoms or an amino group,

og R2står for hydrogen eller en alkylgruppe med 1-6 and R 2 stands for hydrogen or an alkyl group with 1-6

karbonatomer,carbon atoms,

med den begrensning at (1) R 1 og R2ikke samtidig betyr t-alkylgrupper og (2) hvis R^står for en aminogruppe, betyr R^hydrogen, with the restriction that (1) R 1 and R 2 do not simultaneously mean t-alkyl groups and (2) if R^ stands for an amino group, R^ means hydrogen,

eller R^og R2står sammen for gruppeneor R^ and R 2 together stand for the groups

og R^, Rk og R^står uavhengig av hverandre for hydrogen, and R^, Rk and R^ independently stand for hydrogen,

en alkylgruppe med. 1-<*>+ karbonatomer, en alkqksygruppe med 1-<*>+ karbonatomer, fluor, klor eller brom, idet to av substituentene R^, R^og R^, som er knyttet til nabokarbonatomer, står for en metylendioksygruppe. an alkyl group with. 1-<*>+ carbon atoms, an alkyl group with 1-<*>+ carbon atoms, fluorine, chlorine or bromine, two of the substituents R^, R^ and R^, which are attached to neighboring carbon atoms, represent a methylenedioxy group.

Forbindelsene med formel I kan opptre i form av frie baser såvel som i form av syreaddisjonssalter. The compounds of formula I can appear in the form of free bases as well as in the form of acid addition salts.

Forbindelsene med formel I kan likeledes opptre i form av deres tautomerer med formel I', og hvis R2betyr hydrogen, i form av formel I". The compounds of formula I can likewise appear in the form of their tautomers of formula I', and if R2 is hydrogen, in the form of formula I".

De tautomere former er gjenstand for en gjensidig omvandling i nærvær av syre. For enkelhets skyld, omhandles i det folgende imidlertid, bare formen med formel I, henholdsvis dennes kjemiske betegnelse, men oppfinnelsen omfatter ikke bare fremstilling av denne tautomere form. The tautomeric forms are subject to an interconversion in the presence of acid. For the sake of simplicity, in the following, however, only the form with formula I, respectively its chemical designation, is dealt with, but the invention does not only cover the production of this tautomeric form.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen for fremstilling av forbindelsene med, formel I, er at forbindelser med. formel II The peculiarity of the method according to the invention for the production of the compounds with, formula I, is that compounds with. formula II

hvori R^, R^_ og R^har den ovennevnte betydning, wherein R^, R^_ and R^ have the above meaning,

og R' står for en primær eller sekundær alkylgruppe med, 1-<*>+ karbonatomer, foretrukket metyl eller etyl, omsettes med aminer med formel and R' stands for a primary or secondary alkyl group with, 1-<*>+ carbon atoms, preferably methyl or ethyl, is reacted with amines of formula

III III

hvori R^og R2har den ovennevnte betydning, eller b). for fremstilling av forbindelser med formel Ia, in which R1 and R2 have the above meaning, or b). for the preparation of compounds of formula Ia,

hvori R^5R^og R^ har den ovennevnte betydning, wherein R^5R^ and R^ have the above meaning,

og R^'.står for en alkylgruppe med 1-6 karbonatomer, fremstilles ved, at forbindelser med formel IV, and R^' stands for an alkyl group with 1-6 carbon atoms, are produced by compounds of formula IV,

hvori R-jR^? R^°§R5har den ovennevnte betydning, ringsluttes under sterkt sure betingelser i nærvær av inert organisk løsnings-middel og i en inert atmosfære, eller c) forbindelser med formel Ib • in which R-jR^? R^°§R5 has the above meaning, is ring-closed under strongly acidic conditions in the presence of an inert organic solvent and in an inert atmosphere, or c) compounds of formula Ib •

hvori R^, R^_ og R^har den ovennevnte betydning, fremstilles ved in which R^, R^_ and R^ have the above meaning, is prepared by

at forbindelser med, formel Ia, hvori R^ 1 står for t-butyl, oppvarmes i nærvær av fri syre eller that compounds of formula Ia, in which R^ 1 stands for t-butyl, are heated in the presence of free acid or

d) for fremstilling av forbindelser med formel Icd) for the preparation of compounds of formula Ic

hvori R^, R^_ og R^har den ovennevnte betydning, omsettes forbindelser med formel Ia eller Ib med, hydrazin i en inert atmosfære. in which R^, R^_ and R^ have the above meaning, compounds of formula Ia or Ib are reacted with hydrazine in an inert atmosphere.

Fremgangsmåten a) kan gjennomføres i nærvær av et inert løsnings-middel, idet man i dette tilfellet anvender 1,05 til 10 mol av forbindelsen med, formel III pr. mol av forbindelsen med formel II. Foretrukket tjener imidlertid et større overskudd, av aminet med The method a) can be carried out in the presence of an inert solvent, in which case one uses 1.05 to 10 mol of the compound with, formula III per moles of the compound of formula II. Preferably, however, a greater surplus is earned, of the amine with

formel III, f. eks. fra 2 - 1000 mol pr. mol av forbindelsen med, formel II som løsningsmiddel. Hvis ammoniak eller et flyktig amin med, et kokepunkt under 60°C anvendes, gj.ennomfores omsetningen foretrukket i en forseglet reaksjons.beholder. Egnede reaksjonstemperaturer utgjor 20 til 115°C, foretrukket 60 til 115°C. Koker forbindelsen med, formel III i det sistnevnte området, arbeider man hensiktsmessig ved, tilbakeløpstemperatur for reaksjonsblandingen og foretrukket i en inert atmosfære, f.eks. nitrogen. Reaksjonstidene ligger mellom 5 min. og 3 timer, foretrukket fra 10 min. til 2 timer. formula III, e.g. from 2 - 1000 mol per moles of the compound with formula II as solvent. If ammonia or a volatile amine with a boiling point below 60°C is used, the reaction is preferably carried out in a sealed reaction container. Suitable reaction temperatures are 20 to 115°C, preferably 60 to 115°C. If the compound with formula III is boiled in the latter range, one conveniently works at the reflux temperature of the reaction mixture and preferably in an inert atmosphere, e.g. nitrogen. Reaction times are between 5 min. and 3 hours, preferably from 10 min. to 2 hours.

Som løsningsmiddel i fremgangsmåten b) egner seg lavere alkanoler, f.eks. etanol, n-propanol, isopropanol, n-butanol, sek.-butanol og isobutanol, foretrukket etanol, n-propanol eller isopropanol, halogenerte lavere alkaner, f.eks. 1,1,2-trikloretan eller 1,2-diklor-etan, cycliske etere som p-dioksan, acycl iske etere, foretrukket med. 5-10 karbonatomer og maur syreamider,'f.eks. formamid og dets mono- eller di-lavere alkyl-derivater, f.eks. n-etylformamid, n,n-dimetyl- eller dietylformamid eller n-etyl-n-metylformamid. De foretrukne løsningsmiddeler er lavere alkanoler. De i fremgangsmåt.en b) anvendte syrer omfatter sterke mineralsyrer, f.eks. perkldsyre, bromhydrogensyre, saltsyre eller svovelsyre, og sterke organiske syrer, som metansulfonsyre, etansulfonsyre, benzensulfonsyre eller p-toluensulfonsyre. Syren anvendes hensiktsmessig som konsentrert vanndig løsning, som løsning i et organisk løsningsmiddel, f.eks. Lower alkanols, e.g. ethanol, n-propanol, isopropanol, n-butanol, sec.-butanol and isobutanol, preferably ethanol, n-propanol or isopropanol, halogenated lower alkanes, e.g. 1,1,2-trichloroethane or 1,2-dichloroethane, cyclic ethers such as p-dioxane, acyclic ethers, preferably with. 5-10 carbon atoms and ant acid amides,' e.g. formamide and its mono- or di-lower alkyl derivatives, e.g. n-ethylformamide, n,n-dimethyl- or diethylformamide or n-ethyl-n-methylformamide. The preferred solvents are lower alkanols. The acids used in method b) include strong mineral acids, e.g. perchloric acid, hydrobromic acid, hydrochloric acid or sulfuric acid, and strong organic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. The acid is suitably used as a concentrated aqueous solution, as a solution in an organic solvent, e.g.

en lavere alkanol, som etanol, n-propanol eller isopropanol, eller i ufortynnet form..F.eks. anvendes perklorsyren hensiktsmessig som- 70% vanndig losning, saltsyren og bromhydrogensyren som mettede a lower alkanol, such as ethanol, n-propanol or isopropanol, or in undiluted form..E.g. the perchloric acid is used appropriately as a 70% aqueous solution, the hydrochloric acid and hydrobromic acid as saturated

■ løsninger av gassformet hydrogenklorid eller hydrogenbromid i en lavere alkanol, svovelsyren som konsentrert losning og sulfonsyrene-hensiktsmessig som faststoffer. Man anvender så meget syre at pH-verdien i mediet utgjor 0,6 - 6, foretrukket. 1- h, spesielt 2-3. Som inert atmosfære anvendes hensiktsmessig nitrogen. Fremgangsmåten gjennomføres hensiktsmessig ved. temperaturer på ^5 - 120°C, foretrukket 55 - 100°C. Reaksjonstidene utgjor hensiktsmessig 30 - ■ solutions of gaseous hydrogen chloride or hydrogen bromide in a lower alkanol, the sulfuric acid as a concentrated solution and the sulphonic acids-appropriately as solids. So much acid is used that the pH value in the medium is 0.6 - 6, preferably. 1-h, especially 2-3. Nitrogen is suitably used as an inert atmosphere. The procedure is carried out appropriately by. temperatures of ^5 - 120°C, preferably 55 - 100°C. The reaction times are appropriately 30 -

180 min., foretrukket 60 - 120 min.180 min., preferred 60 - 120 min.

I fremgangsmåten c) oppvarmes forbindelsene med formel Ia, hvori R^' betyr t-butyl, hensiktsmessig over deres smeltepunkter i nærvær av fri syre så lenge inntil gassblæreutviklingen er avsluttet. An-vendelsen av syre-addisjonssalter, hvis anioner ved forhøyet temperatur har tendens til spalting, bør unngås. Fortrinnsvis er forbindelsen i form av metansulfonat-syreaddisjonssaltet. Syreaddisjons-salt kan anvendes som sådant eller kan fremstilles in situ fra den fri base ved tilsetning av minst omtrent mer enn 1 equivalent, f.ek»s 1.01 til 5 equivalenter av en syre. Egnede reaksjonstemperaturer ligger fra 150 til 210°C, og egnede reaksjonstider utgjør mellom 5 og ^5 min. Reaksjonen gjennomføres fortrinnsvis uten løsningsmiddel. In method c), the compounds of formula Ia, in which R^' means t-butyl, are suitably heated above their melting points in the presence of free acid until gas bubble development has ended. The use of acid addition salts, whose anions tend to split at elevated temperatures, should be avoided. Preferably, the compound is in the form of the methanesulfonate acid addition salt. Acid addition salt can be used as such or can be prepared in situ from the free base by adding at least approximately more than 1 equivalent, e.g. 1.01 to 5 equivalents of an acid. Suitable reaction temperatures are from 150 to 210°C, and suitable reaction times are between 5 and 5 minutes. The reaction is preferably carried out without solvent.

Om ønsket kan imidlertid høytkokende inerte organiske løsningsmidler anvendes. However, if desired, high-boiling inert organic solvents can be used.

I fremgangsmåten d) anvendes hydrazinet foretrukket i vannfri form. Fortrinnsvis anvendes et overskudd av hydrazin, f.eks. et 10 - 1000-dobbelt overskudd., som tjener som løsningsmiddel. Egnede reaksjonstemperaturer ligger mellom 80°C og tilbakeløpstemperaturen for hydrazinet, idet den siste temperatur foretrekkes. Reaksjonen kan om ønsket gjennomføres i nærvær av et inert organisk løsningsmiddel hvis kokepunkt ligger over 80°C. I dette tilfellet anvendes hensiktsmessig 1 - 2 mol hydrazin pr. mol av forbindelsene med. formel Ia eller Ib. Egnede reaksjonstider utgjør mellom 20 og'180 min, foretrukket 30 til 60 min. Reaksjonen gjennomføres i inert atmosfære, f.eks. nitrogen. In method d), the hydrazine is preferably used in anhydrous form. Preferably, an excess of hydrazine is used, e.g. a 10 - 1000-fold excess., which serves as a solvent. Suitable reaction temperatures are between 80°C and the reflux temperature for the hydrazine, the latter temperature being preferred. If desired, the reaction can be carried out in the presence of an inert organic solvent whose boiling point is above 80°C. In this case, 1 - 2 mol of hydrazine per moles of the compounds with. formula Ia or Ib. Suitable reaction times are between 20 and 180 min, preferably 30 to 60 min. The reaction is carried out in an inert atmosphere, e.g. nitrogen.

De ved, fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser med formel I, kan isoleres og renses på i og for seg kjent måte. Forbindelsene med formel I kan på i og for seg kjent måte overfores i sine syreaddisjonssalter og omvendt. The compounds of formula I which can be prepared by the method according to the invention can be isolated and purified in a manner known per se. The compounds of formula I can be converted in a manner known per se into their acid addition salts and vice versa.

De i fremgangsmåten a) som utgangsforbindelser anvendte forbindelser med formel II kan fremstilles ved at forbindelser med formel V The compounds of formula II used as starting compounds in method a) can be prepared by compounds of formula V

hvori R^, R^ og R^har den ovennevnte betydning, omsettes med trialkyloksoniumtetrafluoroborat i et inert organisk løsnings-middel. Av tetrafluoroboratene foretrekkes trimetyloksonium og trietyloksoniumtetrafluoroboratene. Som inerte organiske løs-ningsmidler er halogenerte lavere alkaner foretrukket metylendiklorid egnet. Reaksjonen kan gjennomføres ved temperaturer fra 0 til 30°C, foretrukket ved 20 til 25°C. Reaksjonstiden ut-gjør hensiktsmessig 25 til 120 min. Reaksjonen gjennomføres foretrukket i inert atmosfære, f.eks. nitrogen. Forbindelsene med formel II kan isoleres og renses på i og for seg kjent måte. in which R^, R^ and R^ have the above meaning, is reacted with trialkyloxonium tetrafluoroborate in an inert organic solvent. Of the tetrafluoroborates, the trimethyloxonium and triethyloxonium tetrafluoroborates are preferred. Halogenated lower alkanes preferably methylene dichloride are suitable as inert organic solvents. The reaction can be carried out at temperatures from 0 to 30°C, preferably at 20 to 25°C. The reaction time is suitably 25 to 120 min. The reaction is preferably carried out in an inert atmosphere, e.g. nitrogen. The compounds of formula II can be isolated and purified in a manner known per se.

De i fremgangsmåten b) som utgangsforbindelser anvendte forbindelser med formel IV kan fremstilles ved at forbindelser med. formel The compounds of formula IV used as starting compounds in method b) can be prepared by compounds with formula

VI WE

hvori R1', R , R^og R^har den ovennevnte betydning, wherein R 1', R , R^ and R^ have the above meaning,

og A betyr et anion som ikke deltar i reaksjonen,.and A means an anion that does not participate in the reaction.

omsettes med etylendiamin i et inert organisk løsningsmiddel.is reacted with ethylenediamine in an inert organic solvent.

Egnede anioner A er perklorat, tetrafluoroborat, metylsulfat, etylsulfat, bisulfat, klorid, bromid og jodid. Som inerte organiske løsningsmidler egner seg halogenerte alkaner, f.eks. metylendiklorid, eter, f.eks. p-dioksan, lavere alkylnitriler, f.eks. acetonitril og substituerte amider, f.eks. N,N-dimetylformamid, foretrukket metylendiklorid.' Molforholdet mellom etylendiamin og forbindelsen med formel VI utgjør foretrukket minst 1,5:4, spesielt anvendes dog et større molart overskudd, f.eks. fra 2 til 10 mol etylendiamin pr..mol forbindelse med formel VI. Suitable anions A are perchlorate, tetrafluoroborate, methyl sulphate, ethyl sulphate, bisulphate, chloride, bromide and iodide. Suitable inert organic solvents are halogenated alkanes, e.g. methylene dichloride, ether, e.g. p-dioxane, lower alkylnitriles, e.g. acetonitrile and substituted amides, e.g. N,N-dimethylformamide, preferably methylene dichloride.' The molar ratio between ethylenediamine and the compound of formula VI is preferably at least 1.5:4, but in particular a larger molar excess is used, e.g. from 2 to 10 moles of ethylenediamine per mole of compound of formula VI.

Reaksjonen gjennomføres hensiktsmessig ved temperaturer fra -10 til +<1>+0°C, foretrukket fra +10 til +35°C, iløpet av en tid mellom 20 og 120 min., foretrukket 30 - 90 min. Reaksjonen gjennomføres foretrukket i inert atmosfære, f.eks. nitrogen. The reaction is conveniently carried out at temperatures from -10 to +<1>+0°C, preferably from +10 to +35°C, during a time between 20 and 120 min., preferably 30 - 90 min. The reaction is preferably carried out in an inert atmosphere, e.g. nitrogen.

Forbindelsene med formel IV kan isoleres og renses på i og for seg kjent måte men de kan dog uten isolering videreforarbeid.es i henhold til fremgangsmåten b). The compounds with formula IV can be isolated and purified in a manner known per se, but they can, however, be further processed without isolation according to method b).

Forbindelsene med. formel V og VI er enten kjente eller kan fremstilles på i og for seg kjent måte. The connections with. formulas V and VI are either known or can be prepared in a manner known per se.

Forbindelsene med formel I utmerker seg ved, pharmakodynamiske egen-skaper. De virker spesielt mot fedme og har antidiabetisk virkning, slik at de egner seg for behandling av fedme og diabetes. The compounds of formula I are distinguished by their pharmacodynamic properties. They work particularly against obesity and have antidiabetic effects, so that they are suitable for the treatment of obesity and diabetes.

Den daglig tilførte dose utgjør mellom 75 og 2000 mg, hensiktsmessig tilført i flere delmengder mellom omtrent 20 og 1000 mg, 2- h ganger daglig eller i retardform. The daily administered dose is between 75 and 2,000 mg, suitably administered in several sub-quantities of between approximately 20 and 1,000 mg, 2-hourly times a day or in slow-release form.

Forbindelsene med formel I kan anvendes i form av de fri baser eller i form av pharmasøytisk tålbare syreaddisjonssalter, idet saltene størrelsesordenmessig har den samme virkning som de tilsvarende fri baser. Egnede syreaddisjonssalter er perkloratene, hydrokloridene, The compounds of formula I can be used in the form of the free bases or in the form of pharmaceutically acceptable acid addition salts, the salts having in terms of order of magnitude the same effect as the corresponding free bases. Suitable acid addition salts are the perchlorates, the hydrochlorides,

metansulfonatene og tetrafluoroboratene.the methanesulfonates and the tetrafluoroborates.

Forbindelsene med. formel I kan blandes med. vanlige, pharmasoytisk tålbare fortynnings- eller bærermidler og tilfores i form av The connections with. formula I can be mixed with. usual, pharmazoytically acceptable diluents or carriers and are supplied in the form of

tabletter eller kapsler.tablets or capsules.

I forbindelsene med formel I foretrekkes de folgende substituenter Ri - v In the compounds of formula I, the following substituents Ri - v are preferred

R^= hydrogen eller alkyl, spesielt t-butyl,R^= hydrogen or alkyl, especially t-butyl,

R2= hydrogen,R2= hydrogen,

R^= hydrogen, p-metyl, p-metoksy, p-etyl eller p-etoksy, spesielt R 1 = hydrogen, p-methyl, p-methoxy, p-ethyl or p-ethoxy, in particular

hydrogen, p-metyl eller p-metoksy,hydrogen, p-methyl or p-methoxy,

R^= hydrogen eller m-metyl,R^= hydrogen or m-methyl,

R^= hydrogen.R 1 = hydrogen.

Av forbindelsene med. formel I foretrekkes dem hvori R^- R^ har de ovenfor som foretrukket nevnte betydninger. Spesielt foretrukket er 5~amino-7-fenyl-2,3-dihydro-1H-1,^-diazepin, helt spesielt som metansulfonat. Of the connections with. formula I are preferred those in which R^-R^ have the meanings mentioned above as preferred. Particularly preferred is 5-amino-7-phenyl-2,3-dihydro-1H-1,3-diazepine, especially as methanesulfonate.

Oppfinnelsen skal nærmere illustreres ved hjelp av folgende eksempler. The invention shall be further illustrated by means of the following examples.

EKSEMPEL 1: 5- metylamino- 7- fenvl- 2. Vdihydro- 1H- 1A- diazepin ( VII) EXAMPLE 1: 5-methylamino-7-phenyl-2.Vdihydro-1H-1A-diazepine (VII)

A) ^-.e.toksy-7-f en^l=2j3-dih^dro-1H-1 ,^-diazepin_A) ^-.e.toxy-7-f en^l=2j3-dih^dro-1H-1 ,^-diazepine_

10,0 g (53jO mMol) 7-fenyl-1 ,2,3,^,-tetrahydro-1 ,If-diazepin-5-ohm suspenderes under nitrogen i 100 ml tort metylenklorid. Til den omrorte suspensjon tilsettes ilopet av 20 min. 10,1 g (53>0 mMol) trietyloksonium-tetrafluoroborat slik at reaksjonsblandingen holder seg ved. en temperatur på 20 - 25°C (reaksjonen er svakt eksoterm). Etter avsluttet tilsetning omrores reaksjonsblandingen videre i 30 min. ved, romtemperatur. Deretter inndampes blandingen hvorved. 10.0 g (53jO mmol) of 7-phenyl-1,2,3,^,-tetrahydro-1,If-diazepin-5-ohm are suspended under nitrogen in 100 ml of dry methylene chloride. To the stirred suspension is added the ilope of 20 min. 10.1 g (53>0 mmol) of triethyloxonium tetrafluoroborate so that the reaction mixture remains. a temperature of 20 - 25°C (the reaction is slightly exothermic). After the addition is complete, the reaction mixture is stirred further for 30 min. wood, room temperature. The mixture is then evaporated whereby

16,6 g oljeaktige krystaller erholdes. Ved utgnidning av rfast-stoffet i etylacetat og omkrystallisering fra kloroform erholdes 5-etoksy-7-f enyl-2,3-dihyd,ro-1H-1 ,^-diazepinet som tetraf luoroborat med, smeltepunkt 1^7,5 - 158,5°C. 16.6 g of oily crystals are obtained. By trituration of the solid in ethyl acetate and recrystallization from chloroform, 5-ethoxy-7-phenyl-2,3-dihydro-1H-1,^-diazepine is obtained as tetrafluoroborate with, melting point 1^7.5 - 158 .5°C.

B) ^-metylamino-7zf enY;l=2j3-dihy;dro-1H-1 ,H~diazepin_ (VII)B) β-methylamino-7zf enY;l=2j;dro;dro-1H-1 ,H~diazepine_ (VII)

3,20 g 5-e"toksy-7-fenyl-2,3-dihydro-1H-1 ,^-diazepin-tetrafluoroborat og 15 - 20 ml metylamin bringes i en autoklav og får stå i 1-g- time. -Reaksjonsblandingen oppvarmes deretter for fullstendiggjoring av reaksjonen i 1 1A time i ^-0 til 50°C. Overskudd av metylamin avdampes, den erholdte olje loses i kloroform, losningen filtreres og inndampes. Resten krystalliseres fra isopropanol/eter, loses deretter i 5% metanol/kloroform, filtreres gjennom silicagel og omkrystalliseres fra isopropanol/eter, idet 5-metylamino-7-fenyl-2,3-dihydro-1H-1,^-diazepin-tetrafluoroborat med smeltepunkt 121,5-123°C erholdes. 3.20 g of 5-e"toxy-7-phenyl-2,3-dihydro-1H-1,^-diazepine tetrafluoroborate and 15 - 20 ml of methylamine are placed in an autoclave and allowed to stand for 1 hour. - The reaction mixture is then heated to complete the reaction for 1 1A hours at ^-0 to 50°C. Excess methylamine is evaporated, the resulting oil is dissolved in chloroform, the solution is filtered and evaporated. The residue is crystallized from isopropanol/ether, then dissolved in 5% methanol /chloroform, filtered through silica gel and recrystallized from isopropanol/ether, whereby 5-methylamino-7-phenyl-2,3-dihydro-1H-1,^-diazepine tetrafluoroborate with melting point 121.5-123°C is obtained.

EKSEMPEL 2; 5- n- butylamino- 7- fenvl- 2. Vdihvdro- 1H- 1A- diazepin (VIII) EXAMPLE 2; 5- n- butylamino- 7- phenyl- 2. Hydro- 1H- 1A- diazepine (VIII)

(Fremgangsmåten a))(Procedure a))

2 g (6,07 mMol) av den i eksempel t A) erholdte forbindelse og2 g (6.07 mmol) of the compound obtained in example t A) and

10,0 ml n-butylamin oppvarmes under nitrogen i 5 min. til koking (tilbakelop) og overskudd av n-butylamin avdampes under redusert trykk. Den herved erholdte olje loses i 50 ml kloroform, losningen vaskes med 50 ml vann og tilsettes 50 ml kald. 2N vanndig natriumhydroksyd-losning. Kloroform-losningen torres med vannfritt magnesiumsulfat og syres med en 70% perklorsyre-losning i isopropanol. Losningsmidlet avdampes. Ved utgnidning med vann (1,8 g) erholdes krystaller av et biprodukt. Moderluten inndampes til en olje og ved. utgnidning med eter under avkjøling erholdes 5-n-butylamino-7-fenyl-2,3-dihydro-1H-1,^-diazepin-perklorat med smeltepunkt 59 - 6<I>f°C. 10.0 ml of n-butylamine is heated under nitrogen for 5 min. to boiling (reflux) and excess n-butylamine is evaporated under reduced pressure. The oil thus obtained is dissolved in 50 ml of chloroform, the solution is washed with 50 ml of water and 50 ml is added cold. 2N aqueous sodium hydroxide solution. The chloroform solution is dried with anhydrous magnesium sulfate and acidified with a 70% perchloric acid solution in isopropanol. The solvent is evaporated. Upon trituration with water (1.8 g), crystals of a by-product are obtained. The mother liquor is evaporated to an oil and wood. trituration with ether while cooling yields 5-n-butylamino-7-phenyl-2,3-dihydro-1H-1,^-diazepine perchlorate with melting point 59 - 6<I>f°C.

EKSEMPEL ^: 5- dimetylamino- 7- fenvl- 2.^- dihydro- 1H- 1A- diazepin (IX) EXAMPLE ^: 5- dimethylamino- 7- phenyl- 2.^- dihydro- 1H- 1A- diazepine (IX)

(fremgangsmåten a))(method a))

Analogt med, eksempel 1B) og under anvendelse av tilsvarende utgangsforbindelser, som oppvarmes ved 100°C i 20 min. i en autoklav, erholdes 5-dimetylamino-7-fenyl-2,3-dihydro-1H-1,^—diazepin-tetrafluoroborat med smeltepunkt 126,5 - 128,5°C. Analogous to, example 1B) and using corresponding starting compounds, which are heated at 100°C for 20 min. in an autoclave, 5-dimethylamino-7-phenyl-2,3-dihydro-1H-1,^-diazepine tetrafluoroborate with melting point 126.5 - 128.5°C is obtained.

EKSEMPEL hi 5- pyrrolidino- 7- fenyl- 2. Vdihydro- 1H- 1A- diazepin (X) EXAMPLE hi 5- pyrrolidino- 7- phenyl- 2. Vdihydro- 1H- 1A- diazepine (X)

(fremgangsmåten a))(method a))

3,8 g av den i eksempel 1A) erholdte forbindelse loses i 10 ml pyrrolidin og losningen oppvarmes under nitrogen i 10 min. til koking (tilbakelop). Overskudd av pyrrolidin avdampes og den erholdte olje loses i omtrent 10 ml isopropanol. Losningen tilsettes omtrent 20 ml torr eter og de erholdte krystaller omkrystalliseres fra isopropanol, hvorved 5-pyrrolidino-7-fenyl-2,3-dihydro-1H-1 ,^-diazepin-tetrafluoroborat med smeltepunkt 139,5 - 1<1>+0,5°C erholdes. 3.8 g of the compound obtained in example 1A) is dissolved in 10 ml of pyrrolidine and the solution is heated under nitrogen for 10 min. to boil (reverse). Excess pyrrolidine is evaporated and the oil obtained is dissolved in approximately 10 ml of isopropanol. About 20 ml of dry ether is added to the solution and the crystals obtained are recrystallized from isopropanol, whereby 5-pyrrolidino-7-phenyl-2,3-dihydro-1H-1,^-diazepine-tetrafluoroborate with melting point 139.5 - 1<1>+ 0.5°C is obtained.

EKSEMPEL" 5; 5- ( N'- 2- hydroksvetylpjperazino)- 7- fenyl- 2. Vdihydro-1H- 1A- diazepin (XI) (fremgangsmåten a)) EXAMPLE" 5; 5-( N'- 2- Hydroxvethylpiperazino)- 7- phenyl- 2. Vdihydro-1H- 1A-diazepine (XI) (Procedure a))

3,1 g av den i eksempel 1A) erholdte forbindelse og 2,1 g nydestil-lert N-(2-hydroksyetyl)piperazin oppvarmes i 1 time ved 100°C. Etter avkjøling kromatograferes reaksjonsproduktet på 100 ml silicagel under anvendelse av forskjellige metanol/kloroform-blandinger som elueringsmiddel. Den fraksjon som inneholder reaksjonsp.roduktet omkrystalliseres fra isopropanol, hvorved 5-(N'-2-hydroksyetyl-piperazino)-7-f enyl-2,3~ dihydr o-1 H-1 ,^-diazepin-tetraf luoroborat med smeltepunkt 120 - 121,5°C'erholdes. 3.1 g of the compound obtained in example 1A) and 2.1 g of freshly distilled N-(2-hydroxyethyl)piperazine are heated for 1 hour at 100°C. After cooling, the reaction product is chromatographed on 100 ml of silica gel using different methanol/chloroform mixtures as eluent. The fraction containing the reaction product is recrystallized from isopropanol, whereby 5-(N'-2-hydroxyethyl-piperazino)-7-phenyl-2,3~ dihydro-1H-1,^-diazepine-tetrafluoroborate with melting point 120 - 121.5°C is obtained.

EKSEMPEL 6; 5- t- butvlamino- 7- f envl- 2. Vdihvdrb- 1H- 1A- diazepinEXAMPLE 6; 5- t- butvlamino- 7- f envl- 2. Vdihvdrb- 1H- 1A- diazepine

(XII) (fremgangsmåten b))(XII) (method b))

A) g-(22aminoet^lamino)-P-(1,1-dimetyletylamino2vin^l-fen^lketon.A) γ-(22aminoethylamino)-β-(1,1-dimethylethylamino2vinyl-1-phenylketone).

i) Til en omrort losning av 50,0 ml (750 mMol) etylendiamin ii) To a stirred solution of 50.0 ml (750 mmol) ethylenediamine in

700 ml metylenklorid tilsettes ilopet av 20 min. 30,0 g (100 mMol) 700 ml of methylene chloride is added over a period of 20 min. 30.0 g (100 mmol)

fast 2-t-butyl-5-fenylisoxazolium-perklorat (J.Org. Chem. 31, solid 2-t-butyl-5-phenylisoxazolium perchlorate (J.Org. Chem. 31,

2039 (1966)) i* små porsjoner. Temperaturen i reaksjonsblandingen holdes ved. kjoling på 20 - 30°G. Etter avsluttet tilsetning fortsettes omrøringen i 1 time. Reaksjonsblandingen fortynnes ved tilsetning av metylenklorid til 1 liter, vaskes så to ganger 2039 (1966)) in* small portions. The temperature of the reaction mixture is maintained. dressing at 20 - 30°G. After the addition is complete, stirring is continued for 1 hour. The reaction mixture is diluted by adding methylene chloride to 1 liter, then washed twice

med hver gang 300 ml vann og torres med vannfritt magnesiumsulfat. Metylenkloridet avdampes under redusert trykk, hvorved, en olje erholdes. Oljen loses i 300 ml vannfri eter og frafUtreres with each time 300 ml of water and dried with anhydrous magnesium sulphate. The methylene chloride is evaporated under reduced pressure, whereby an oil is obtained. The oil is dissolved in 300 ml of anhydrous ether and filtered

fra hvite faststoffer. De hvite faststoffer vaskes med. en liten mengde vannfri eter, vaskeeteren forenes med filtratet, inndampes under redusert trykk, hvorved. (3-(2-amino-etylamino)-8- (1 ,1 -dimetyletylamino)vinylf enylketon erholdes som fargeløs olje. from white solids. The white solids are washed with a small amount of anhydrous ether, the washing ether is combined with the filtrate, evaporated under reduced pressure, whereby. (3-(2-amino-ethylamino)-8-(1,1-dimethylethylamino)vinylphenylketone is obtained as a colorless oil.

ii) Til en energisk omrort losning av 1^0 ml etylendiamin i 2 liter metylenklorid tilsettes under nitrogen 100 g 2-t-butyl-^-fenyl-isoxazolum-perklorat. Temperaturen i reaksjonsblandingen holdes ved tilsvarende dosering av tilsetningen og ved kjø- ii) To a vigorously stirred solution of 1^0 ml of ethylenediamine in 2 liters of methylene chloride, 100 g of 2-t-butyl-^-phenyl-isoxazolum perchlorate is added under nitrogen. The temperature in the reaction mixture is maintained by corresponding dosage of the additive and by cooling

ling på 20 - 25°C. Etter avsluttet tilsetning fortsettes omrøringen i 1 time. Deretter ekstraheres reaksjonsblandingen 2 ganger med hver gang 1 liter vann og tørres med,vannfritt ling at 20 - 25°C. After the addition is complete, stirring is continued for 1 hour. The reaction mixture is then extracted twice with 1 liter of water each time and dried with anhydrous

magnesiumsulfat. Metylenkloridet av suges under redusert trykk og den erholdte olje loses i 1 liter eter. De erholdte faststoffer fjernes ved filtrering, eteren avdampes under redusert trykk hvorved (3-(2-aminoetylamino)-(3-(1 ,1 -dimetyletylamino)vi-nylfenylketon erholdes som en olje. magnesium sulfate. The methylene chloride is sucked off under reduced pressure and the oil obtained is dissolved in 1 liter of ether. The solids obtained are removed by filtration, the ether is evaporated under reduced pressure whereby (3-(2-aminoethylamino)-(3-(1,1-dimethylethylamino)vinylphenylketone) is obtained as an oil.

Forbindelsen kan overfores i sitt dihydroklorid med. smeltepunkt 175°C (spalting) ved tilsetning av gassformet hydrogenklorid til dens losning. The compound can be transferred in its dihydrochloride with. melting point 175°C (decomposition) by adding gaseous hydrogen chloride to its solution.

B) ^-t-butylamino-y^f enYl2 2^3zdih^dro-1H-1 ,j+-diazepin_ (XII)B) t-butylamino-y^f enYl2 2^3zdih^dro-1H-1 ,j+-diazepine_ (XII)

i) En losning av 2^,0 g (92,0 mMol) |3-(2-aminoetyl-amino)-B-(1 ,1-dimetyletylamino)vinylfenylketon i 200 ml absolutt etanol bringes med 70% perklorsyre til en pH-verdi på omtrent 1 og oppvarmes under nitrogen i 1 time til koking (tilbakelop). i) A solution of 2^.0 g (92.0 mmol) |3-(2-aminoethyl-amino)-B-(1,1-dimethylethylamino)vinylphenylketone in 200 ml of absolute ethanol is brought with 70% perchloric acid to a pH -value of about 1 and heated under nitrogen for 1 hour to boiling (reflux).

Deretter tilsettes den til romtemperatur avkjølte blandingThe mixture cooled to room temperature is then added

500 ml vannfri eter, idet 5~'t-butylamino-7-f>enyl-2,3-dihydro-1H-1,^-diazepin-perkloratet erholdes som hvite krystaller, som etter omkrystallisering fra etano.l/eter har et smeltepunkt på 169-171°C (spalting). 500 ml of anhydrous ether, whereby the 5-t-butylamino-7-phenyl-2,3-dihydro-1H-1,5-diazepine perchlorate is obtained as white crystals, which after recrystallization from ethanol/ether have a melting point of 169-171°C (decomposition).

ii) Den ovenfor beskrevne fremgangsmåte gjentas med følgende endringe Reaksjonsblandingen syres til en pH-verdi på 1:2 og oppvarmes til koking (tilbakeløp) i ^fO min. Reaks jonsproduktet utkrystal-liseres ved. tilsetning av 500 ml vannfri eter og avkjøling. ii) The procedure described above is repeated with the following changes. The reaction mixture is acidified to a pH value of 1:2 and heated to boiling (reflux) for ^fO min. The ion product of the reaction is crystallized by addition of 500 ml of anhydrous ether and cooling.

Moderluten inndampes under redusert trykk til et volum på 200 ml, oppvarmes under nitrogen til koking i 1-jjr time '(tilbakelop) og inndampes under redusert trykk til et volum på 50 ml. Ved tilsetning av 100 ml vann erholdes ytterligere krystaller som for-enet med de forst erholdte krystaller omkrystalliseres fra absolutt etanol/eter, idet 5-p-t>utylamino-7-fenyl-2,3^ dihyd.ro-1H-1,^-diåzepin-perklorat med smeltepunkt 169 - 171°C (spalting) erholdes. The mother liquor is evaporated under reduced pressure to a volume of 200 ml, heated under nitrogen to boiling for 1-jjr hour (reflux) and evaporated under reduced pressure to a volume of 50 ml. By adding 100 ml of water, further crystals are obtained which, together with the crystals obtained first, are recrystallized from absolute ethanol/ether, whereby 5-p-t>utilamino-7-phenyl-2,3^ dihydro-1H-1,^- Diazepine perchlorate with melting point 169 - 171°C (decomposition) is obtained.

EKSEMPEL 7: 5- t- butylamino- 7- f enyl- 2. Vdihvdro- 1H- 1. tøiazepin (XII) EXAMPLE 7: 5- t-butylamino- 7- phenyl- 2. Vdihdro- 1H- 1. thoiazepine (XII)

(fremgangsmåten b))(method b))

En losning av 2,5 g (955mMol) (3-(2-aminoetylamino)-B-(1 ,1-dimetylamino) vinylf enylketon i 50 ml absolutt etanol tilsettes 1,0 g (10,0 mMol) metansulf onsyre og reaks jonsblandingen oppvarmes i 20 min til koking (tilbakelop). Etter avkjøling av blandingen fjernes etanol under redusert trykk. Den erholdte olje utgnis med vannfri eter og de derved erholdte krystaller omkrystalliseres fra isopropanol/ eter, idet 5_t-butylamino-7-fenyl-2,3-dihydro-1H-1,^-diazepin-metansulfonatet med smeltepunkt 159_162°C erholdes. A solution of 2.5 g (955 mmol) (3-(2-aminoethylamino)-B-(1,1-dimethylamino) vinylphenylketone in 50 ml of absolute ethanol is added with 1.0 g (10.0 mmol) of methanesulfonic acid and reacted the ionic mixture is heated for 20 min to boiling (reflux). After cooling the mixture, ethanol is removed under reduced pressure. The oil obtained is triturated with anhydrous ether and the crystals thus obtained are recrystallized from isopropanol/ether, as 5_t-butylamino-7-phenyl-2, The 3-dihydro-1H-1,3-diazepine methanesulfonate with a melting point of 159-162°C is obtained.

10,0 g (29,5 mMol) av den ovennevnte forbindelse loses i 50 ml vann, losningen avkjøles i isblandet vann og tilsettes 50 ml vanndig 2N natoumhydroksyd-løsning. Blandingen ekstraheres to ganger med hver gang 150 ml kloroform. Kloroformekstraktene forenes og tørres med vannfritt magnesiumsulfat. Kloroform avdampes under redusert trykk, hvorved en olje erholdes. Ved tilsetning av 50 ml vannfri eter, 10.0 g (29.5 mmol) of the above-mentioned compound are dissolved in 50 ml of water, the solution is cooled in ice-mixed water and 50 ml of aqueous 2N sodium hydroxide solution is added. The mixture is extracted twice with 150 ml of chloroform each time. The chloroform extracts are combined and dried with anhydrous magnesium sulfate. Chloroform is evaporated under reduced pressure, whereby an oil is obtained. By adding 50 ml of anhydrous ether,

går den største del av oljen i løsning og etterlater noen hvite faststoffer som frafiltreres. Filtratet inndampes under redusert trykk til det minste mulige volum. Ved en .langsom tilsetning av he.ptan og kjøling erholdes 5-t-butylamino-7-f enyl-2,3-dihyd.ro-1H-1 ,^-d.iazepinei med.smeltepunkt 102-103.5 :°C i form av den fri base. Ytterligere fri base med smeltepunkt 93 97°C ble likeledes erholdt. most of the oil goes into solution and leaves behind some white solids which are filtered off. The filtrate is evaporated under reduced pressure to the smallest possible volume. By slow addition of heptane and cooling, 5-t-butylamino-7-phenyl-2,3-dihydro-1H-1,^-diazepine is obtained with melting point 102-103.5 :°C in form of the free base. Further free base with melting point 93 97°C was likewise obtained.

EKSEMPEL 8: 5- t- butylamino- 7-( V- metoksvfenvl)- 2. Vdihvdro- 1H-EXAMPLE 8: 5-t-butylamino-7-(V-methoxyphenyl)-2.Vdihydro-1H-

1 A-^ iazeiDi- n-C-XIII) . f fremgang små ten b))1 A-^ iazeiDi- n-C-XIII) . f progress small ten b))

A> j3- (2-aminoety;lamino) -B- (1 ,1-dimetylamino)viny;l-V-metoksy;-_ A> j3-(2-aminoethyl;lamino)-B-(1,1-dimethylamino)vinyl;1-V-methoxy;-_

fenylketon_phenylketone_

Analogt med. eksempel 6A) il) og under anvendelse av 6. 6k g (20,0 mMol) 2-t-butyl-5-(<1>+,-metoksyfenyl)is':OXazolium-perklorat og 10 ml etylendiamin erholdes B- (2-aminoetylamino)-B- (1 ,1-d.imetyletylaminoV vinyl-V-metoksy-f enylketon i form av en olje. Analogous to. example 6A) 11) and using 6.6k g (20.0 mmol) of 2-t-butyl-5-(<1>+,-methoxyphenyl)is':OXazolium perchlorate and 10 ml of ethylenediamine is obtained B- ( 2-aminoethylamino)-B-(1,1-dimethylethylaminoV vinyl-V-methoxy-phenylketone in the form of an oil.

B) ^-t-butylamin.o-7- (^'-metoksyf enyl):2j3-dihYdro-1H-1 ,|+-d.iazepin_ B) ^-t-butylamine.o-7-(^'-methoxy enyl):2j3-dihydro-1H-1 ,|+-d.iazepine_

Det oljeaktige produkt fra eksempel 8 A) loses i 100 ml absolutt etanol og losningen innstilles svakt sur (pH omtrent 5) ved. tilsetning av en hydrogenkloridlosning i absolutt etanol. Losningen oppvarmes under nitrogen i 1-g- time til koking (tilbakelop) og etanol fjernes deretter under redusert trykk. Den erholdte The oily product from example 8 A) is dissolved in 100 ml of absolute ethanol and the solution is made slightly acidic (pH approximately 5) by addition of a hydrogen chloride solution in absolute ethanol. The solution is heated under nitrogen for 1-g-hr to boiling (reflux) and ethanol is then removed under reduced pressure. It obtained

olje loses i 150 ml vann og nøytraliseres med, vanndig 2N natrium-hyd.roksydlosning. Den fri base ekstraheres 2 ganger med hver gang 150 ml kloroform, de forenede ekstrakter torres med, vannfritt magnesiumsulfat og inndampes under"redusert trykk til en olje. Ved tilsetning av isopropanol og 70% perklorsyrelosning oil is dissolved in 150 ml of water and neutralized with aqueous 2N sodium hydroxide solution. The free base is extracted twice with 150 ml of chloroform each time, the combined extracts are dried with anhydrous magnesium sulfate and evaporated under reduced pressure to an oil. By adding isopropanol and 70% perchloric acid solution

i isopropanol erholdes 5-t-butylamino-7~(<!>+,-metoksyfenyl)-2,3-dihydro-1H-1,^-diazepin-perklorat som etter omkrystallisering fra isopropanol smelter ved, 151 - 152,5°C. in isopropanol yields 5-t-butylamino-7~(<!>+,-methoxyphenyl)-2,3-dihydro-1H-1,^-diazepine perchlorate which, after recrystallization from isopropanol, melts at, 151 - 152.5° C.

EKSEMPEL 9: (fremgangsmåten b))EXAMPLE 9: (method b))

Analogt med. eksempel 6 og under anvendelse av egnede utgangsprodukter i omtrent equivalente mengder erholdes folgende forbindelse med formel I: a) 5-t-butylamino-7-(^'-metoksyfenyl)-2,3-dihydro-1H-1,^-diazepin-perklorat med. smeltepunkt 151 - 152>5°C.. b) 5-metylamino-7-fenyl-2,3-dihydro-1H-1,^-diazepin-perklorat (VII), c) (under anvendelse av en hydrogenklorid-losning i etanol istedet Analogous to. example 6 and using suitable starting products in roughly equivalent amounts, the following compound of formula I is obtained: a) 5-t-butylamino-7-(^'-methoxyphenyl)-2,3-dihydro-1H-1,^-diazepine- perchlorate with. melting point 151 - 152>5°C.. b) 5-methylamino-7-phenyl-2,3-dihydro-1H-1,^-diazepine perchlorate (VII), c) (using a hydrogen chloride solution in ethanol instead

for perklorsyre) for perchloric acid)

5-t-butylamino-7-(2<1->klorfenyl)-2,3-dihydro-1H-1,^-diazepin-hydroklorid med smeltepunkt 1^2 - 155°C (XIV). 5-t-Butylamino-7-(2<1->chlorophenyl)-2,3-dihydro-1H-1,^-diazepine hydrochloride with melting point 1^2 - 155°C (XIV).

EKSEMPEL 10: (fremgangsmåten b))EXAMPLE 10: (Procedure b))

Analogt med eksempel 7 og under anvendelse av egnede utgangsprodukter 1 omtrent equivalente mengder erholdes over de tilsvarende forbindelser med formel IV folgende forbindelser med formel I: a) 5-t-butylamino-7- A-met<y>lfen<y>l)-2,3-dihydro-1H-1 ,^-diazepin-metansulfonat med smeltepunkt 17<>>+ - 177°C (spalting) (XV) , b) 5_"t-butylamino-7-(3 1 ,^.'-d,imetylf enyl)-2-, 3-dihydro-i H-1 ,^-diazepin-. metansulfonat med smeltepunkt 200 - 202°C (spalting) (XVI), c) - 5-etylamino-7-fenyl-2,3-dihydro-1H-1, h-diazepin-metansulfonat Analogously to example 7 and using suitable starting products 1 approximately equivalent amounts are obtained over the corresponding compounds of formula IV the following compounds of formula I: a) 5-t-butylamino-7-A-meth<y>lfen<y>l) -2,3-dihydro-1H-1,3-diazepine methanesulfonate with melting point 17<>>+ - 177°C (decomposition) (XV) , b) 5_"t-butylamino-7-(3 1,^). (-dimethylphenyl)-2-, 3-dihydro-in H-1,^-diazepine-. methanesulfonate with melting point 200 - 202°C (decomposition) (XVI), c) - 5-ethylamino-7-phenyl-2,3-dihydro-1H-1, h-diazepine methanesulfonate

(XVII). (XVII).

EKSEMPEL . 11: " 5- amino- 7- f envl- 2. 3- dihvdro- 1H- 1. l+- diazepin (XVIII) EXAMPLE . 11: " 5- amino- 7- f envl- 2. 3- dihydro- 1H- 1. l+- diazepine (XVIII)

(fremgangsmåten c))(method c))

2 g 5-"t-butylamino-7-fenyl-2,3-dihyd.ro-1H-1 ,^-diazepin-metansulfonat 2 g of 5-"t-butylamino-7-phenyl-2,3-dihydro-1H-1,3-diazepine-methanesulfonate

oppvarmes i 15 min. med en dråpe metansulfonsyre i et oljebad ved 160 - 165°C. Etter at smeiten ikke lenger danner noen blærer, loses den varme rest i den minst mulige mengde isopropanol og- utfelling av 5-amino-7-;rfenyl-2,3-dihydro-1H-1 ,^-diazepin-metansulfonatet med smeltepunkt 176 - 17755°C bevirkes ved tilsetning av eter. Den fri base kan erholdes analogt med. eksempel 7. heated for 15 min. with a drop of methanesulfonic acid in an oil bath at 160 - 165°C. After the melt no longer forms any bubbles, the hot residue is dissolved in the smallest possible amount of isopropanol and precipitation of the 5-amino-7-;rphenyl-2,3-dihydro-1H-1,^-diazepine-methanesulfonate with a melting point of 176 - 17755°C is effected by the addition of ether. The free base can be obtained analogously to example 7.

EKSEMPEL 12: (fremgangsmåten c))EXAMPLE 12: (Procedure c))

Analogt med eksempel 11 og under anvendelse av egnede utgangsforbindelser i omtrent equivalente mengder kommer man frem til folgende forbindelse med formel I: a) ' 5-amino-7-(V-metylfenyl)-2,3-dihyd.ro- 1H-1 ,^-diazepin-metansul-V 'f onat med .smeltepunkt 200 - 210°C (XIX) b) 5-amino~7- (3 1 A'-dimetylfenyl)-2,3-dihydro-1H-1 , ^~ di a-z ep in-metansulfonat med smeltepunkt 180 - 181,5°V (XX) Analogous to example 11 and using suitable starting compounds in roughly equivalent amounts, the following compound with formula I is arrived at: a) '5-amino-7-(V-methylphenyl)-2,3-dihydro-1H-1 ,^-diazepine-methanesul-V 'fonate with melting point 200 - 210°C (XIX) b) 5-amino~7-(3 1 A'-dimethylphenyl)-2,3-dihydro-1H-1 , ^ ~ di a-z ep in-methanesulfonate with melting point 180 - 181.5°V (XX)

EKSEMPEL H; 5- hvdrazino- 7- fenvl- 2.^- dihvdro- 1H- 1A- diazepinEXAMPLE H; 5- hvdrazino- 7- phenvl- 2.^- dihvdro- 1H- 1A- diazepine

(XXI) (fremgangsmåten d))(XXI) (method d))

25 ml vannfritt hydrazin tilsettes 550 g 5-"t-butyl-amino-7-fenyl-2,3-dihydro-1H-1,^-diazepin-metansulfonat og blandingen oppvarmes under nitrogen i 30 min. til koking (tilbakelop). Overskudd av hydrazin avdampes under redusert trykk. Den erholdte olje tilsettes 50 ml isopropanol og deretter 50 ml vannfri eter, hvorved krystaller med smeltepunkt 139?5- Al,5°C erholdes, som vaskes med isopropanol/eter (1:1). Vaskevæsken forenes med moderluten og blandingen inndampes til en olje, som kromatograferes på 125 ml silicagel under anvendelse av kloroform, 2% metanollosning i kloroform, 10% metanollosning i kloroform og 50% metanollosning i kloroform som elueringsmiddel. 50% metanol/kloroformfraksjonen inndampes under redusert trykk til en olje som etter utgnidning i torr eter krystalliserer til 5~hydrazino-7-fenyl-2,-3-dihydro-1H-1,^-diazepin i form av den fri base med smeltepunkt 85 - 88°C. 25 ml of anhydrous hydrazine are added to 550 g of 5-"t-butyl-amino-7-phenyl-2,3-dihydro-1H-1,3-diazepine methanesulfonate and the mixture is heated under nitrogen for 30 min. to boiling (reflux). Excess hydrazine is evaporated under reduced pressure. 50 ml of isopropanol and then 50 ml of anhydrous ether are added to the oil obtained, whereby crystals with a melting point of 139?5-Al.5°C are obtained, which are washed with isopropanol/ether (1:1). The washing liquid combine with the mother liquor and the mixture is evaporated to an oil, which is chromatographed on 125 ml silica gel using chloroform, 2% methanol solution in chloroform, 10% methanol solution in chloroform and 50% methanol solution in chloroform as eluent. The 50% methanol/chloroform fraction is evaporated under reduced pressure to an oil which, after rubbing in dry ether, crystallizes into 5~hydrazino-7-phenyl-2,-3-dihydro-1H-1,^-diazepine in the form of the free base with melting point 85 - 88°C.

Den fri base' overfores i metansulfonatsaltet, idet en losning av omtrent 1,3 'g av den rå fri base i 25 ml isopropanol under kjoling tilsettes 0,5 g metansulfonsyre i 10 ml isopropanol. Etter noen minutter dannes krystaller og 50 ml vannfri eter tilsettes. Krystal-lene frafUtreres, vaskes med vann og omkrystalliseres fra absolutt etanol/eter, idet man erholder 1 , h g 5-hyd,razino-7-fenyl-2,3-dihydro-1H-1 ,^-diazepin-metansulfonatet med smeltepunkt 190,5 - '191 ?5°C The free base is transferred to the methanesulfonate salt, whereby a solution of approximately 1.3 g of the crude free base in 25 ml of isopropanol is added while cooling to 0.5 g of methanesulfonic acid in 10 ml of isopropanol. After a few minutes, crystals form and 50 ml of anhydrous ether is added. The crystals are filtered off, washed with water and recrystallized from absolute ethanol/ether, obtaining 1, h g of the 5-hydr,razino-7-phenyl-2,3-dihydro-1H-1,^-diazepine-methanesulfonate with a melting point of 190 .5 - '191 ?5°C

i form av hvite krystaller.in the form of white crystals.

EKSEMPEL A:EXAMPLE A:

I den etterfølgende tabell er de spektroskopiske data for forbindelser med formel I, hvori B.^ betyr hydrogen, angitt. UV-spektra er opptatt i metanol, for IR- og NMR-spektra er mediene angitt i tabellen. Alle NMR-spektra er opptatt ved romtemperatur med et 60 MHz NMR-spektrum, de kjemiske forskyvninger er i p.p.m. ( S ) målt i sammenligning med tetrametylsilan. Hvis i tabellen en eneste- (J)-verdi er angitt for en ikke-singulett, så vedrorer denne sen-tralpunktet. Tallene i parenteser etter d-verdiene.betyr antallet av protoner i"toppen. s = singulett, /= dublett, m = multiplett, x = utbyttbar med D^O, b bred. In the following table, the spectroscopic data for compounds of formula I, in which B.sub.1 means hydrogen, are given. UV spectra are recorded in methanol, for IR and NMR spectra the media are indicated in the table. All NMR spectra were taken at room temperature with a 60 MHz NMR spectrum, the chemical shifts are in p.p.m. ( S ) measured in comparison with tetramethylsilane. If in the table a single (J) value is indicated for a non-singlet, then this relates to the central point. The numbers in parentheses after the d values mean the number of protons in the peak. s = singlet, /= doublet, m = multiplet, x = exchangeable with D^O, b broad.

Claims (1)

Fremgangsmåte -for fremstilling av nye 5~ amino-7-fenyl-2,3~ dihydro- 1H-1,^-diazepiner med formel I, Process - for the preparation of new 5~ amino-7-phenyl-2,3~ dihydro- 1H-1,^-diazepines of formula I, hvori enten R. står for hydrogen, en alkylgruppe med. 1-6 karbonatomer eller en aminogruppe, og R^ står for hydrogen eller en alkylgruppe med 1-6 karbonatomer, med den begrensning at (1) R., og-R^ ikke samtidig betyr t-alkylgrupper, og (2) hvis R1 står for en aminogruppe, betyr R^ hydrogen, eller R^ og R2 står sammen for gruppene in which either R. stands for hydrogen, an alkyl group with. 1-6 carbon atoms or an amino group, and R^ stands for hydrogen or an alkyl group with 1-6 carbon atoms, with the restriction that (1) R 1 and -R 2 do not simultaneously mean t-alkyl groups, and (2) if R 1 stands for an amino group, R 2 means hydrogen, or R^ and R2 together stand for the groups og R^ , R^ og R^ uavhengig av hverandre står for hydrogen, en alkylgruppe med 1-H- karbonatomer, en alkoksygruppe med 1- <*> + karbonatomer, fluor, klor eller brom, eller to av substituentene R^ , R^ og R^ , som er knyttet til nabokarbonatomer, står for en metylendioksygruppe, karakterisert ved at a) for fremstilling av forbindelser med formel I, omsettes forbindelser med formel II and R^ , R^ and R^ independently of each other stand for hydrogen, an alkyl group with 1-H- carbon atoms, an alkoxy group with 1- <*> + carbon atoms, fluorine, chlorine or bromine, or two of the substituents R^ , R ^ and R^ , which are attached to neighboring carbon atoms, represent a methylenedioxy group, characterized by that a) for the preparation of compounds of formula I, compounds of formula II are reacted hvori R^ , R^ og R^ har den ovennevnte betydning, og R <1> står for en primær -eller sekundær alkylgruppe med 1-H- karbonatomer, foretrukket metyl eller etyl, med, aminer med, formel III wherein R^ , R^ and R^ have the above meaning, and R <1> stands for a primary - or secondary alkyl group with 1-H- carbon atoms, preferably methyl or ethyl, with, amines with, formula III hvori R^ og R2 har den ovennevnte betydning, ellerb) for fremstilling av forbindelser med formel Ia in which R 1 and R 2 have the above meaning, orb) for the preparation of compounds of formula Ia hvori R^ , R^ og R^ har den ovennevnte betydning, og R1<1> står for en alkylgruppe med 1-6 karbonatomer, ringsluttet forbindelser med formel IV wherein R^ , R^ and R^ have the above meaning, and R1<1> stands for an alkyl group with 1-6 carbon atoms, ring-closed compounds of formula IV hvori R^<1> , R^ , R^ og R^ har den ovennevnte betydning, under sterkt sure betingelser i nærvær av et inert organisk løsningsmiddel og i en inert atmosfære, eller c) for fremstilling av forbindelser med formel Ib in which R^<1> , R^ , R^ and R^ have the above meaning, under strongly acidic conditions in the presence of an inert organic solvent and in an inert atmosphere, or c) for the preparation of compounds of formula Ib hvori R^ , R^og R^ har den ovennevnte betydning, oppvarmes forbindelser med formel Ia, hvori R ' står for t-butyl i nærvær av fri syre, ellerd.) for fremstilling av forbindelser med formel Ic, in which R^ , R^ and R^ have the above meaning, compounds of formula Ia are heated, in which R' stands for t-butyl in the presence of free acid, ord.) for the preparation of compounds of formula Ic, hvori R^ , R^ og R^ har den ovennevnte betydning, omsettes forbindelser med formal Ia eller Ib med hydrazin i inert atmosfære.in which R^ , R^ and R^ have the above meaning, compounds with formal Ia or Ib are reacted with hydrazine in an inert atmosphere.
NO750978A 1974-03-29 1975-03-21 NO750978L (en)

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US52834474A 1974-11-29 1974-11-29

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