NO128962B

NO128962B -

Info

Publication number: NO128962B
Application number: NO00603/69A
Authority: NO
Inventors: H Ott
Original assignee: Sandoz Ag
Priority date: 1968-02-26
Filing date: 1969-02-14
Publication date: 1974-02-04
Also published as: DK128564B; BG17592A3; RO57857A; DK127187B; IE33434L; OA03389A; RO55407A; BG17595A3; BG17596A3; BG17597A3; PL70441B1; IL31683A0; SE353911B; IL31683A; PL79534B1; IE33434B1; DK128007B; ES364005A1

Description

hvori R står for fluor, klor eller brom, en alkylgruppe,'med. ,1-5 karbonatomer, en alkoksygruppe med 1 - h karbonatomer, en alkyMo-gruppe med 1- k karbonatomer, hydroksy-, nitro-, amino-, cyano-, acetamido-, trifluormetyl- 'eller merkapto-gruppen og n står for 1 eller 2 idet, in which R stands for fluorine, chlorine or bromine, an alkyl group,'med. ,1-5 carbon atoms, an alkoxy group with 1-h carbon atoms, an alkyMo group with 1-k carbon atoms, the hydroxy-, nitro-, amino-, cyano-, acetamido-, trifluoromethyl-' or mercapto group and n stands for 1 or 2 while,

1) hvis n står for 1, har R en annen betydning enn fluor,' 1) if n stands for 1, R has a meaning other than fluorine,'

klor eller brom, og chlorine or bromine, and

2) hvis n står for 2, er begge.R like eller forskjellige og 2) if n stands for 2, both.R are equal or different and

står for en alkylgruppe med 1-5 karbonatomer, en alkoksygruppe med 1 - U- karbonatomer eller for fluor, klor eller brom, stands for an alkyl group with 1-5 carbon atoms, an alkoxy group with 1 - U carbon atoms or for fluorine, chlorine or bromine,

R^ betyr en:alkylgruppe med 1-5 karbonatomer, allyl- eller proparyl-gruppen, idet R^ bare står for isopropyl-gruppen når n = 1 og R betyr hydroksy-, amino-, cyano-, acetamido- eiler merkaptogruppen og R2 står for fenyl eller en gruppe med den alminnelige formel II R^ means an alkyl group with 1-5 carbon atoms, the allyl or proparyl group, R^ only standing for the isopropyl group when n = 1 and R means hydroxy, amino, cyano, acetamido, or the mercapto group and R2 stands for phenyl or a group of the general formula II

hvor Y betyr fluor, klor eller brom, en alkylgruppe med 1- h karbonatomer, en alkoksygruppe med 1karbonatomer eller trifluormetylgruppen og Y1 betyr hydrogen, fluor, klor eller brom, where Y means fluorine, chlorine or bromine, an alkyl group with 1-h carbon atoms, an alkoxy group with 1 carbon atoms or the trifluoromethyl group and Y1 means hydrogen, fluorine, chlorine or bromine,

en alkylgruppe med 1- k karbonatomer eller en alkoksygruppe med 1- h karbonatomer, idet Y og Y^ ikke står for alkoksygruppen når R betyr hydroksy-eler merkapto-gruppen, an alkyl group with 1-k carbon atoms or an alkoxy group with 1-h carbon atoms, where Y and Y^ do not stand for the alkoxy group when R means the hydroxy or mercapto group,

Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at The peculiarity of the method according to the invention is that

for fremstilling av forbindelser med den alminnelige formel Ia , for the preparation of compounds of the general formula Ia,

hvori R' står for fluor, klor eller brom, en alkylgruppe med 1-5 karbonatomer, en alkoksygruppe med 1- h karbonatomer, en alkyltiogruppe med 1-V karbonatomer, nitro-, cyano-, acetamid-, eller trifluormetyl-gruppen og n står for 1 eller 2 idet, in which R' stands for fluorine, chlorine or bromine, an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-h carbon atoms, an alkylthio group with 1-V carbon atoms, the nitro-, cyano-, acetamide, or trifluoromethyl group and n stands for 1 or 2 as,

1) hvis n står for 1 har R' en annen betydning enn fluor, 1) if n stands for 1, R' has a different meaning than fluorine,

klor eller brom, og chlorine or bromine, and

2) hvis n står for 2 er begge R' like eller forskjellige og betyr en alkylgruppe med 1-5 karbonatomer, en alkoksygruppe me'd 1-<!>+ karbonatomer eller fluor, klor eller bro:n, 2) if n stands for 2, both R' are the same or different and mean an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-<!>+ carbon atoms or fluorine, chlorine or bro:n,

R.j betyr en alkylgruppe med 1-5 karbonatomer, allyl-eller propargylgruppen, idet betydningen av alkylgruppe med 1-5 karbonatomer ikke medomfatter tert. alkylgrupper hvori det tert. karbonatom er bundet til ringnitrogenatomet, idet R' bare stå" for isopropylgruppen når n = 1 og R' beiyr cyan- eller acetamid-grupperi og Rp har den ovennevnte betydning, R.j means an alkyl group with 1-5 carbon atoms, the allyl or propargyl group, the meaning of alkyl group with 1-5 carbon atoms not including tert. alkyl groups in which the tert. carbon atom is bound to the ring nitrogen atom, with R' only standing for the isopropyl group when n = 1 and R' belonging to the cyano or acetamide group and Rp having the above meaning,

(1 ) omsettes forbindelser med den alminnelige formel III (1 ) compounds with the general formula III are reacted

hvori R', R.j , R 2 og n har den ovennevnte betydning, i nærvær av en katalytisk mengde Lewis-syre med et alkyl-karbonat, hvori alkylgruppen har 1-5 karbonatomer, eller (2) forbindelser med den alminnelige formel IV hvori R', R2 og n har den ovennevnte betydning og Me står for et alkalimetall, omsettes i et under reaksjonsbetingelsene inert organisk løsningsmiddel med forbindelser med den alminnelige formel V hvori R.<j> har den ovennevnte betydning og X står for klor, brom eller jod, eller b) for fremstilling av forbindelser med den alminnelige formel Ic hvori R^ og B.^ ^ar ^en ovennevnte betydning, og acetamido-derivater derav, reduseres forbindelser med den alminnelige formel Id hvori R^ og R^ har den ovennevnte betydning, overfores aminogruppen i forbindelser med den alminnelige formel Ih in which R', R.j , R 2 and n have the above meaning, in the presence of a catalytic amount of Lewis acid with an alkyl carbonate, in which the alkyl group has 1-5 carbon atoms, or (2) compounds of the general formula IV in which R ', R2 and n have the above meaning and Me stands for an alkali metal, is reacted in an organic solvent inert under the reaction conditions with compounds of the general formula V in which R.<j> has the above meaning and X stands for chlorine, bromine or iodine . , the amino group is transferred in compounds of the general formula Ih

hvori R^ og Rp har den ovennevnte betydning, i cyanogruppen etter Sandmeyer. in which R^ and Rp have the above meaning, in the cyano group according to Sandmeyer.

De to under avsnitt a) angitte fremgangsmåter for fremstilling The two manufacturing methods specified under section a).

av forbindelser med den alminnelige formel Ia kan gjennomføres, f. eks. som beskrevet i det følgende: of compounds with the general formula Ia can be carried out, e.g. as described in the following:

(1) Forbindelsene med den alminnelige formel III omsettes med alkylkarbamater, fortrinnsvis etylkarbamat, i nærvær av katalyt-tiske mengder av en Lewis-syre, f.eks. zinl&Lorid, ved temperaturer mellom 1<!>+0 og 230°C i 30 min. til 20 timer. Omsetningen kan g,jennorafores i nærvær av et under reaks jonsbetiingelsene inert organisk løsningsmiddel, f.eks. o-diklorbenzen, eller uten løsningsmiddel, idet i det siste tilfelle et overskudd av kar-bamat overtar funksjonen som løsningsmiddel. Etter avsluttet omsetning avkjøles reaksjonsblandingen til romtemperatur og behandles med an blanding bestående av et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. metylenklorid og vann. Etter fraskilling, tørring og inndamping av den organiske fase erholdes etter omkrystallisering de rene forbindelser med den alminnelige formel Ia. (2) Forbindelser med den alminnelige formel IV, fortrinnsvis deres natrium eller kaliumforbindelser, omsettes med forbindelser med den alminnelige formel V, fortrinnsvis deres jodider, i et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. dimetylacetamid, dietylacetamid, dimetylformamid, dimetylsulfoksyd eller dioksan. Omsetningen gjennomføres ved temperaturer mellom 20 og 100°C, idet omsetningen fortrinnsvis igangsettes ved romtemperatur i 1 - h timer og avsluttes ved koketemperaturen. Etter avsluttet omsetning inndampes reaksjonsblandingen og den herved erholdte rest blandes med is. Det dannede bunnfall frafiltreres og loses så i et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. i metylenklorid. Etter avdamping av løsningsmidlet og omkrystallisering erholdes de ønskede forbindelser med den alminnelige formel Ia i ren tilstand. (1) The compounds with the general formula III react with alkyl carbamates, preferably ethyl carbamate, in the presence of catalytic amounts of a Lewis acid, e.g. zinl&Lorid, at temperatures between 1<!>+0 and 230°C for 30 min. to 20 hours. The reaction can be carried out in the presence of an organic solvent inert under the reaction conditions, e.g. o-dichlorobenzene, or without solvent, in the latter case an excess of carbamate takes over the function as solvent. After completion of the reaction, the reaction mixture is cooled to room temperature and treated with a mixture consisting of an organic solvent inert under the reaction conditions, e.g. methylene chloride and water. After separation, drying and evaporation of the organic phase, the pure compounds with the general formula Ia are obtained after recrystallization. (2) Compounds of the general formula IV, preferably their sodium or potassium compounds, are reacted with compounds of the general formula V, preferably their iodides, in an organic solvent inert under the reaction conditions, e.g. dimethylacetamide, diethylacetamide, dimethylformamide, dimethylsulfoxide or dioxane. The reaction is carried out at temperatures between 20 and 100°C, with the reaction preferably being initiated at room temperature for 1 - h hours and ending at the boiling temperature. After completion of the reaction, the reaction mixture is evaporated and the resulting residue is mixed with ice. The formed precipitate is filtered off and then dissolved in an organic solvent that is inert under the reaction conditions, e.g. in methylene chloride. After evaporation of the solvent and recrystallization, the desired compounds with the general formula Ia are obtained in a pure state.

Hvis man tar sikte på fremstilling av forbindelser med den alminnelige formel Ia hvori ringnitrogenatomet i stilling 1 for chinazolinonringen er substituert med en forgrenet alkylgruppe, If one aims at producing compounds with the general formula Ia in which the ring nitrogen atom in position 1 of the quinazolinone ring is substituted with a branched alkyl group,

og forgreningen begynner på det karbonatom som er bundet til nitrogenatomet, f.eks. isopropyl eller sec. butyl, er det fordelaktig å benytte den under (1) beskrevne fremgangsmåte da denne fører til bedre utbytter. and the branching begins on the carbon atom that is bound to the nitrogen atom, e.g. isopropyl or sec. butyl, it is advantageous to use the method described under (1) as this leads to better yields.

Den under b) beskrevne fremgangsmåte for fremstilling av forbindelser med den alminnelige formel Ic kan gjennomføres som beskrevet i det følgende: The method described under b) for the preparation of compounds with the general formula Ic can be carried out as described in the following:

Forbindelser med den alminnelige formel Id løses hensiktsmessig Compounds with the general formula Id are resolved appropriately

i et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. etanol, og den erholdte løsning oppvarmes til koking. in an organic solvent inert under the reaction conditions, e.g. ethanol, and the resulting solution is heated to boiling.

Etter tilsetting av elementært metall, f.eks. jern (jernspon) tildryppes ved koketemperatur en mineralsyre, f.eks. saltsyre, Herved dannede forbindelser med den alminnelige formel Ic After addition of elemental metal, e.g. iron (iron filings) is dripped at boiling temperature with a mineral acid, e.g. hydrochloric acid, Hereby formed compounds with the general formula Ic

isoleres deretter på i og for seg kjent måte ved inndamping av is then isolated in a manner known per se by evaporation of

reaksjonsblandingen, oppløsning av resten i et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. etylacetat, the reaction mixture, dissolving the residue in an organic solvent inert under the reaction conditions, e.g. ethyl acetate,

sur ekstraksjon, alkalisk innstilling av ekstrakten, etc. og renses på i og for seg kjent måte, f.eks. ved omkrystallisering. De således erholdte forbindelser med den alminnelige formel Ic kan deretter eventuelt, hensiktsmessig løst i et egnet organisk løsningsmiddel, f.eks. pyridin, ved hjelp av behandling med egnede acetyleringsmidler, f.eks. eddiksyreanhydrid, overføres i de tilsvarende acetamidoderivater, som f.eks. kan isoleres ved inndamping av reaksjonsblandingen og renses ved omkrystallisering, f.eks. fra etylacetat. acid extraction, alkaline adjustment of the extract, etc. and purified in a manner known per se, e.g. by recrystallization. The thus obtained compounds with the general formula Ic can then optionally, appropriately, be dissolved in a suitable organic solvent, e.g. pyridine, by means of treatment with suitable acetylating agents, e.g. acetic anhydride, is transferred in the corresponding acetamido derivatives, which e.g. can be isolated by evaporation of the reaction mixture and purified by recrystallization, e.g. from ethyl acetate.

Den under avsnitt c) beskrevne fremgangsmåte for fremstilling The manufacturing method described under section c)

av forbindelser med den alminnelige formel le kan gjennomføres som bedrevet i det følgende: Forbindelser med den alminnelige formel If oppvarmes sammen med vandig bromhydrogensyre eller en løsning av hydrogenbromid i eddiksyre ved temperaturer mellom 60 ogHO°C, fortrinnsvis ved koketemperatur. Etter avsluttet omsetning innstilles reaksjonsblandingen ved tilsetning av et egnet alkalisk middel, f.eks. en vandig natriumhydroksydløsning, alkalisk og ekstraheres ved hjelp av et passende' under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. etylacetat. De herved ekstraherte forbindelser med den alminnelige formel le isoleres deretter ved avdamping av løsningsmidlet og renses ved omkrystallisering. of compounds with the general formula le can be carried out as carried out in the following: Compounds with the general formula If are heated together with aqueous hydrobromic acid or a solution of hydrogen bromide in acetic acid at temperatures between 60 and HO°C, preferably at boiling temperature. After completion of the reaction, the reaction mixture is adjusted by adding a suitable alkaline agent, e.g. an aqueous sodium hydroxide solution, alkaline and extracted by means of a suitable organic solvent inert under the reaction conditions, e.g. ethyl acetate. The thus extracted compounds with the general formula 1e are then isolated by evaporation of the solvent and purified by recrystallization.

Den under avsnitt d) beskrevne fremgangsmåte for fremstilling av forbindelser med den alminnelige formel lg kan gjennomføres som beskrevet i det følgende: Forbindelser med den alminnelige formel Ih løses henholdsvis oppslemmes i et surt medium, f.eks. vandig saltsyre, og den således erholdte løsning henholdsvis oppslemning tilsettes en vandig løsning av alkalimetallnitrit, fortrinnsvis natriumnitrit-løsnirig. Den erholdte løsning av det tilsvarende diazoniumsalt tilsettes deretter en vandig løsning av et alkalimetallcyanid, fortrinnsvis natriumcyanid såvel som koppercyanid, og oppvarmes deretter ved en temperatur på 90 - 100°C. De erholdte forbindelser med den alminnelige formel lg isoleres deretter fra reaksjonsblandingen på i og for seg kjent måte, f.eks. ved ekstraksjon med et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. kloroform, og renses på i og for seg kjent måte, f.eks. ved kromatografering og omkrystallisering, f.eks. The method described under section d) for producing compounds with the general formula Ig can be carried out as described in the following: Compounds with the general formula Ih are dissolved or suspended in an acidic medium, e.g. aqueous hydrochloric acid, and the thus obtained solution or slurry is added to an aqueous solution of alkali metal nitrite, preferably sodium nitrite-solvent. The resulting solution of the corresponding diazonium salt is then added to an aqueous solution of an alkali metal cyanide, preferably sodium cyanide as well as copper cyanide, and then heated at a temperature of 90 - 100°C. The obtained compounds with the general formula Ig are then isolated from the reaction mixture in a manner known per se, e.g. by extraction with an organic solvent inert under the reaction conditions, e.g. chloroform, and purified in a manner known per se, e.g. by chromatography and recrystallization, e.g.

fra etanol/dietyleter. from ethanol/diethyl ether.

De ved fremgangsmåten 1) under avsnitt a) som utgangsforbindelser anvendte forbindelser med den alminnelige formel III er enten kjent eller kan fremstilles på i og for seg kjent måte. Hvis det skal fremstilles forbindelser med den alminnelige formel III som i 5-stillingen er substituert med en nitro-eller trifluor-metylgruppe, anbefales det å omsette et tilsvarende 5-(nitro-eller trifluormetyl )-2-klor-benzofenon med et egnet amin (R-jOT^ hvori R.J ' har den ovennevnte betydning) i nærvær av en egnet katalysator, f.eks. en blanding av kopper og kopperklorid. Hvis det skal fremstilles forbindelser med den alminnelige formel III, hvori aminogruppen er substituert med en forgrenet alkylrest, hvor forgreningen går ut fra det karbonatom som er bundet til nitrogenatomet, særlig med isopropylresten, er det gunstig å anvende en omsetning mellom tilsvarende o-aminobenzofenon og et sec. alkylbromid eller jodid. The compounds of the general formula III used as starting compounds in method 1) under section a) are either known or can be prepared in a manner known per se. If compounds with the general formula III are to be prepared which are substituted in the 5-position with a nitro- or trifluoromethyl group, it is recommended to react a corresponding 5-(nitro- or trifluoromethyl)-2-chloro-benzophenone with a suitable amine (R-jOT^ wherein R.J' has the above meaning) in the presence of a suitable catalyst, e.g. a mixture of copper and copper chloride. If compounds with the general formula III are to be prepared, in which the amino group is substituted with a branched alkyl residue, where the branching starts from the carbon atom that is bound to the nitrogen atom, in particular with the isopropyl residue, it is advantageous to use a reaction between the corresponding o-aminobenzophenone and a second alkyl bromide or iodide.

De ved fremgangsmåte 2) under avsnitt a) som utgangsforbindelser anvendte forbindelser med den alminnelige formel IV kan fremstilles ved at tilsvarende 1-stillingen usubstituerte chinazolin-oner omsettes med alkalimetallforbindelser, f.eks. natriumhydrid eller med et alkalimetalloksyd som f.eks. natriummetoksyd, natriumotoksyd, kaliummetoksyd eller kalium-atoksyd, i et under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. dimetylacetamid, dietylacetamid, dimetylformamid, dimetylsulfoksyd eller dioksan, ved romtemperatur. Med fordel anvendes for denne omsetning et under reaksjonsbetingelsene inert organisk løsnings-middel, som deretter også kan anvendes for fremstilling av forbindelser med den alminnelige formel Ia. The compounds of the general formula IV used as starting compounds in method 2) under section a) can be prepared by reacting unsubstituted quinazolinones corresponding to the 1-position with alkali metal compounds, e.g. sodium hydride or with an alkali metal oxide such as e.g. sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide, in an organic solvent inert under the reaction conditions, e.g. dimethylacetamide, diethylacetamide, dimethylformamide, dimethylsulfoxide or dioxane, at room temperature. An organic solvent which is inert under the reaction conditions is advantageously used for this reaction, which can then also be used for the preparation of compounds with the general formula Ia.

De for den ovennevnte fremgangsmåte som utgangsforbindelser anvendte, i 1-stillingen usubstituerte cliinazolinoner er enten kjent (japansk patentskrift 20 865/65)eller kan fremstilles på i og for seg kjent måte fra kjente utgangsforbindelser. F.eks. kan for dette tilsvarende substituerte 2-amino-benzofenoner etter fremgangsmåten 1) under avsnitt a) underkastes en ringslutnings-reaks jon. The cliinazolinones unsubstituted in the 1-position used as starting compounds for the above-mentioned process are either known (Japanese patent document 20 865/65) or can be prepared in a manner known per se from known starting compounds. E.g. for this, correspondingly substituted 2-amino-benzophenones can be subjected to a cyclization reaction according to method 1) under section a).

De under avsnittene b) henholdsvis c) som utgangsforbindelser anvendte forbindelser med den alminnelige formel Id henholdsvis If kan fremstilles fra tilsvarende utgangsforbindelser under anvendelse av de i avsnitt a) henholdsvis e) beskrevne fremgangsmåter, idet det må påsees at fremgangsmåten 1) avsnitt a) særlig er egnet for fremstilling av i 1-stillingen med forgrenede alkylgruppe r (sec. alkylgrupper) substituerte sluttforbindelser, og at fremgangsmåten under avsnitt e) særlig er egnet for fremstilling av i 1-stillingen med tert. alkylgrupper substituerte sluttforbindelser. The compounds with the general formula Id and If used as starting compounds under sections b) and c) respectively can be prepared from corresponding starting compounds using the methods described in sections a) and e) respectively, as it must be ensured that the method 1) section a) in particular is suitable for the preparation of final compounds substituted in the 1-position with branched alkyl groups r (sec. alkyl groups), and that the method under section e) is particularly suitable for the preparation of in the 1-position with tert. alkyl groups substituted end compounds.

De under avsnitt d) som utgangsforbindelser anvendte forbindelser mad den alminnelige formel Ih kan fremstilles fra tilsvarende utgangsforbindelser etter fremgangsmåten i avsnitt b). The compounds of the general formula Ih used as starting compounds under section d) can be prepared from corresponding starting compounds according to the procedure in section b).

De ved fremgangsmåten i henhold til oppfinnelsen erholdbare forbindelser med den alminnelige formel I besitter overorgentlig gunstige farmakodynamiske egenskaper. Særlig har disse forbindelser, hvilket kan sluttes fra resultatene ved Carragen-indusert Odem-test ved rotter, en gunstig betennelseshindrende virkning. Den daglig administrerbare dose skal utgjore mellom 10 og 1000 mg, som fortrinnsvis tilfores i flere (2-^) daglige doser på 3~500 mg eller i retardert form. Forbindelsene med den alminnelige formel I besitter utover dette analgetisk, antipyretisk og antibradykinin-virkning. De for den analgetiske eller antipyretiske anvendelse nødvendige doser tilsvarer de som kreves for den betennelseshemmende anvendelse. The compounds of the general formula I obtainable by the method according to the invention possess extremely favorable pharmacodynamic properties. In particular, these compounds, which can be concluded from the results of the Carrageen-induced Oedema test in rats, have a beneficial anti-inflammatory effect. The daily administrable dose should be between 10 and 1000 mg, which is preferably administered in several (2-^) daily doses of 3~500 mg or in delayed form. The compounds of the general formula I also possess analgesic, antipyretic and antibradykinin action. The doses required for the analgesic or antipyretic use correspond to those required for the anti-inflammatory use.

For anvendelsen som betennelseshemmende middel har på grunnlag For its use as an anti-inflammatory agent

av de ovennevnte prover de forbindelser med den alminnelige formel I vist seg spesielt brukbare, hvori R^ betyr metyl, etyl, isopropyl, tert. butyl, allyl eller propargyl, fortrinnsvis dog etyl, isopropyl og tert. butyl særlig da isopropyl, og R2 betyr of the above, the compounds with the general formula I prove to be particularly useful, in which R 1 means methyl, ethyl, isopropyl, tert. butyl, allyl or propargyl, preferably, however, ethyl, isopropyl and tert. butyl especially as isopropyl, and R 2 means

en usubstituert fenylgruppe. Hvis R, Y eller Y^ står for -en alkylgruppe, skal disse fortrinnsvis inneholde 1-3 karbonatomer og, hvis R, Y eller Y1 står for en alkoksygruppe skal disse fortrinnsvis inneholde 1 eller 2 karbonatomer, Hvis R står for en alkyltiogruppe bor denne fortrinnsvis inneholde 1 eller 2 karbonatomer. an unsubstituted phenyl group. If R, Y or Y^ represents an alkyl group, these should preferably contain 1-3 carbon atoms and, if R, Y or Y1 represents an alkoxy group, these should preferably contain 1 or 2 carbon atoms. If R represents an alkylthio group, this preferably contain 1 or 2 carbon atoms.

En gunstig virkning har imidlertid også forbindelser hvori n står for 2. Forbindelser, hvori n står for 1 og R betyr en alkylgruppe, en alkoksygruppe, en tioalkylgruppe eller trifluormetyl-gruppen, såvel som hvori R betyr hydroksygruppen, aminogruppen, cyanogruppen, nitrogruppen (særlig når R^ står for den teit. butyl-gruppe), acetamidogruppen eller merkaptogruppen. However, compounds in which n stands for 2 also have a beneficial effect. Compounds in which n stands for 1 and R means an alkyl group, an alkoxy group, a thioalkyl group or the trifluoromethyl group, as well as in which R means the hydroxy group, the amino group, the cyano group, the nitro group (especially when R 1 stands for the tert. butyl group), the acetamido group or the mercapto group.

De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser eller deres salter kan anvendes som legemiddel i seg selv eller i tilsvarende preparatformer for oral eller paren-teral tilførsel. For fremstilling av egnede preparatformer for-arbeides forbindelsene med uorganiske eller organiske, farmako-logisk indifferente hjelpestoffer. The compounds or their salts which can be prepared by the method according to the invention can be used as medicine in themselves or in corresponding preparation forms for oral or parenteral administration. For the production of suitable preparation forms, the compounds are prepared with inorganic or organic, pharmacologically indifferent excipients.

Som hjelpestoffer anvendes f.eks.: Excipients are used, for example:

for tabletter og drageer anvendes således melkesukker, stivelse, for tablets and dragees, therefore, milk sugar, starch,

talkum, stearinsyre etc., talc, stearic acid etc.,

for siruper anvendes f.eks. rorsukker-, invertsukker-, glukose-losninger etc., for syrups, e.g. cane sugar, invert sugar, glucose solutions etc.,

for injeksjonspreparater anvendes f.eks. vann, alkoholer, for injection preparations are used e.g. water, alcohols,

glycerol, planteoljer og lignende. glycerol, vegetable oils and the like.

Videre kan preparatene inneholde egnede konserverings-, stabiliserings-, fukte-midler, losningsformidlere, stotnings- og fargestoffer, aromabestanddeler etc. Furthermore, the preparations may contain suitable preservatives, stabilisers, wetting agents, release agents, thickeners and colourants, aroma components etc.

I de etterfølgende eksempler, som skal illustrere utførelsen av fremgangsmåten samt fremstilling av de anvendte utgangsforbindelser, er alle temperaturangivelser i °C og er korrigert. In the following examples, which shall illustrate the execution of the method and the preparation of the starting compounds used, all temperature indications are in °C and have been corrected.

Eksempel 1: 6, 7- dimetyl- l- etyl-^- feny1- 2( 1H)- chinazolinon Example 1: 6,7-Dimethyl-1-ethyl-^-phenyl-2(1H)-quinazolinone

a) §iZl^i5<®>t<y>il^ll!22<y>Il2(1H)-ch<ln>azolinon a) §iZl^i5<®>t<y>il^ll!22<y>Il2(1H)-ch<ln>azolinone

En blanding av 10 g <1>+,5-dimetyl-2-aminobenzofenon, 20 g uretan A mixture of 10 g <1>+,5-dimethyl-2-aminobenzophenone, 20 g urethane

og 2 g sinkklorid holdes i 2 timer ved 180 - 200°C (oljebadtemperatur) avkjoles deretter til romtemperatur og tilsettes 100 ml av en blanding av metylenklorid/vann (1:). Den organiske fase fraskilles, torres over vannfritt natriumsulfat, filtreres og losningsmidlet avdampes. Etter omkrystallisering av. resten fra etylacetat erholdes 6 ,7-dimetyl-l+-f enyl-2 (1H)-chinazolinon som beige-fargede krystaller. Smeltepunktet ligger over 280°C. and 2 g of zinc chloride are held for 2 hours at 180 - 200°C (oil bath temperature), then cooled to room temperature and 100 ml of a mixture of methylene chloride/water (1:) is added. The organic phase is separated, dried over anhydrous sodium sulphate, filtered and the solvent evaporated. After recrystallization of. the residue from ethyl acetate, 6,7-dimethyl-1+-phenyl-2(1H)-quinazolinone is obtained as beige-coloured crystals. The melting point is above 280°C.

) §aZl^i52i2ililf:iZil^l£§5<y>.il<2>(<1>^ ) §aZl^i52i2ililf:iZil^l£§5<y>.il<2>(<1>^

1 g natriumhydrid ( 50% suspensjon i mineralolje) tilsettes 1 g of sodium hydride (50% suspension in mineral oil) is added

ved romtemperatur en losning av K£ g 6,7-dimetyl-*+-f enyl-2(1H)-chinazolinon i 100 ml dietylacetamid. Den erholdte blanding, som inneholder natriumforbindelsen av 6,7-dimetyl-l+-fenyl-2(1H)-chinazolinon, rores i 15 min. ved romtemperatur og tilsettes deretter 10 ml etyljodid. Deretter rores i 30 min. ved romtemperatur og for å gjore omsetningen fullstendig oppvarmes i 30 min. ved 6o°C. Blandingen'inndampes i vakuum hvorved losningsmidlet stort sett fjernes, og resten blandes med 100 g is. Deretter frafUtreres, resten loses i 50 ml metylenklorid og den erholdte losning torres over natriumsulfat. Etter inndamping i vakuum og omkrystallisering av den oljeaktige rest fra etanol/dietyleter (1 :1) erholdes 6 ,7-dimetyl-1-etyl-l+-fenyl-2(1H)-chinazolinon med smeltepunkt 176-180°C. at room temperature a solution of K£ g 6,7-dimethyl-*+-phenyl-2(1H)-quinazolinone in 100 ml of diethylacetamide. The resulting mixture, which contains the sodium compound of 6,7-dimethyl-1+-phenyl-2(1H)-quinazolinone, is stirred for 15 minutes. at room temperature and then add 10 ml of ethyl iodide. Then stir for 30 min. at room temperature and to make the turnover complete is heated for 30 min. at 6o°C. The mixture is evaporated in a vacuum whereby the solvent is mostly removed, and the residue is mixed with 100 g of ice. It is then filtered off, the residue is dissolved in 50 ml of methylene chloride and the resulting solution is dried over sodium sulphate. After evaporation in vacuum and recrystallization of the oily residue from ethanol/diethyl ether (1:1), 6,7-dimethyl-1-ethyl-1+-phenyl-2(1H)-quinazolinone with a melting point of 176-180°C is obtained.

Eksempel 2:' ^ f- fenyl- 1, 6, 7- trimetyl~ 2( 1H)- chihazolinon Example 2:' ^f-phenyl-1,6,7-trimethyl~ 2(1H)-chihazolinone

0,75 g natriumhydrid (50$ suspensjon i mineralolje) tilsettes 0.75 g of sodium hydride (50% suspension in mineral oil) is added

ved romtemperatur en losning av <*>+,5 g 6,7-dimetyl-^-f enyl-2(1H)-chinazolinon (fremstilt... etter<->den i eksempel. 1a) beskrevene fremgangsmåte) i 100 ml dimetylformamid. Den erholdte . blanding som inneholder natriumforbindelsen av 6,7-dimetyl-^t—f enyl-2(1 H)-chinazolinon, rores i 15 min. og tilsettes deretter *f ml metyljodid. Deretter rores i 30 min. at room temperature a solution of <*>+.5 g of 6,7-dimethyl-^-phenyl-2(1H)-quinazolinone (prepared... according to<->the method described in example. 1a) in 100 ml dimethylformamide. It obtained . mixture containing the sodium compound of 6,7-dimethyl-[t-phenyl-2(1H)-quinazolinone, is stirred for 15 min. and then *f ml of methyl iodide is added. Then stir for 30 min.

ved romtemperatur, for vidtgående fjernelse av losningsmidlet inndampes i vakuum og resten blandes med 100 ,g is. Det utfelte bunnfall frafiltreres, loses i 50 ml metylenklorid, den erholdte losning torres over natriumsulfat og losningsmidlet inndampes i vakuum. Etter omkrystallisering fra dietyl- at room temperature, for extensive removal of the solvent is evaporated in vacuum and the residue is mixed with 100 g of ice. The precipitate that precipitates is filtered off, dissolved in 50 ml of methylene chloride, the solution obtained is dried over sodium sulphate and the solvent is evaporated in vacuo. After recrystallization from diethyl

eter erholdes ^--fenyl-1,6,7-trimetyl-2(1H)-chinazolinon som hvite krystaller med smeltepunkt 20If-206oC. ether, ^--phenyl-1,6,7-trimethyl-2(1H)-quinazolinone is obtained as white crystals with a melting point of 20If-206oC.

Eksempel 3; 6 ^-dimetyl-^-fenyl-1-propargyl-2(1H)-chinazolinon Example 3; 6 ^-Dimethyl-^-phenyl-1-propargyl-2(1H)-quinazolinone

0,75 g natriumhydid ( 50% suspensjon i mineralolje) tilsettes ved romtemperatur en losning av ^,5 g 6,7-dimetyl-1+-f enyl-2(1H)-chinazolinon i 100 ml dimetylformamid. Den erholdte blanding, som inneholder natriumforbindelsen av 6,7-dimetyl-<l>+-fenyl-2(1H)-chinazolinon, rores i 15 min. ved romtemperatur og tilsettes deretter <*>f ml propargylbromid. Deretter rores i 30 min. ved romtemperatur, inndampes for vidtgående fjerning av losningsmidlet i vakuum og resten blandes med 100 g is. 0.75 g of sodium hydride (50% suspension in mineral oil) is added at room temperature to a solution of .5 g of 6,7-dimethyl-1+-phenyl-2(1H)-quinazolinone in 100 ml of dimethylformamide. The resulting mixture, which contains the sodium compound of 6,7-dimethyl-<1>+-phenyl-2(1H)-quinazolinone, is stirred for 15 min. at room temperature and then <*>f ml of propargyl bromide is added. Then stir for 30 min. at room temperature, is evaporated to remove the solvent extensively in vacuum and the residue is mixed with 100 g of ice.

Det utfallende bunnfall frafiltreres, loses i 50 ml metylen-klorid, den erholdte losning torres over natriumsulfat og losningsmidlet inndampes i vakuum. Etter omkrystallisering fra dietyleter erholdes 6,7-dimetyl-^-fenyl-1-propargyl-2(1H)-chinazolinon som hvite krystaller med smeltepunkt fra 202-205°C The resulting precipitate is filtered off, dissolved in 50 ml of methylene chloride, the solution obtained is dried over sodium sulphate and the solvent is evaporated in vacuo. After recrystallization from diethyl ether, 6,7-dimethyl-^-phenyl-1-propargyl-2(1H)-quinazolinone is obtained as white crystals with a melting point of 202-205°C

Eksempel h: 1 -etyl-^f-f enyl-6-trifluormetyl-2(1H)-chinazolinon Example h: 1-ethyl-[f-phenyl-6-trifluoromethyl-2(1H)-quinazolinone

a) 5-trifluormetyl-2-etylaminobenzofenon a) 5-trifluoromethyl-2-ethylaminobenzophenone

En blanding av 10 g 5-trifluormetyl-2-klorbenzofenon, 500 A mixture of 10 g of 5-trifluoromethyl-2-chlorobenzophenone, 500

mg kopperpulver, 500 mg kopperklorid og 100 ml flytende- etylamin oppvarmes i 2 timer i autoklav ved 130 - 1<1>+0°C. Deretter helles reaksjonsblandingen ut i 200 ml etylacetat og ekstraheres 2 ganger med vann. Den organiske fase fraskilles, torres over vannfritt natriumsulfat, filtreres og inndampes til tbrrhet i vakuum. Resten oppvarmes i 20 ml dioksan og 30 ml 6N saltsyre, den erholdte losning innstilles alkalisk med natriumhydroksyd og ekstraheres 2 ganger med 100 ml etylacetat. De forente organiske faser torres over vannfritt natriumsulfat og inndampes til torrhet i vakuum. Etter omkrystallisering av resten fra etanol erholdes 5-trifluormetyl-2-etyl-aminobeno-fenon som gule prismer med smeltepunkt 78-80°C. mg copper powder, 500 mg copper chloride and 100 ml liquid ethylamine are heated for 2 hours in an autoclave at 130 - 1<1>+0°C. The reaction mixture is then poured into 200 ml of ethyl acetate and extracted twice with water. The organic phase is separated, dried over anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo. The residue is heated in 20 ml of dioxane and 30 ml of 6N hydrochloric acid, the resulting solution is made alkaline with sodium hydroxide and extracted twice with 100 ml of ethyl acetate. The combined organic phases are dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from ethanol, 5-trifluoromethyl-2-ethylaminobenophenone is obtained as yellow prisms with a melting point of 78-80°C.

b) 1-ety.il1*-^ eny_l-6-trif luormety_l-2 (1_H) -chinazolinon b) 1-Ethy.yl1*-^enyl-1-6-trifluoromethyl-1-2 (1_H)-quinazolinone

En blanding av 6,5 g 5-trifluormetyl-2-etylaminobenzofenon, A mixture of 6.5 g of 5-trifluoromethyl-2-ethylaminobenzophenone,

2 g uretan og 20 mg zinkklorid holdes i 20 timer ved l<!>+0- 2 g of urethane and 20 mg of zinc chloride are kept for 20 hours at l<!>+0-

150aC (oljebadtemperatur), deretter avkjoles til romtemperatur og tilsettes 100 ml av en blanding av metylenklorid/ 150aC (oil bath temperature), then cool to room temperature and add 100 ml of a mixture of methylene chloride/

vann (1:). Den organiske fase fraskilles, torres over vannfritt natriumsulfat, filtreres og losningsmidlet avdampes. Etter omkrystallisering av resten fra dietyleter erholdes 1-etyl-V-fenyl-6-trifluormetyl-2(1H)-chinazolinon som gule prismer som sublimerer ved 180°C. water (1:). The organic phase is separated, dried over anhydrous sodium sulphate, filtered and the solvent evaporated. After recrystallization of the residue from diethyl ether, 1-ethyl-V-phenyl-6-trifluoromethyl-2(1H)-quinazolinone is obtained as yellow prisms which sublime at 180°C.

Eksempel 5: 1 - etyl- 6- nitro- 1+- fenyl- 2( 1H)- chinazolinon Example 5: 1-ethyl-6-nitro-1+-phenyl-2(1H)-quinazolinone

a) 5-nitro-2-etylaminobenzofenon a) 5-nitro-2-ethylaminobenzophenone

En blanding av 15 g 5-nitro-2-klorbenzofenon, 700 mg kopperpulver, 700 mg kopperklorid, 15 ml etanol og 15 ml flytende etylamin oppvarmes i 7 timer til koking under tilbakelop. Det herved erholdte krystalline material frafiltreres, loses i 200 ml metylenklorid, behandles med trekull og , filtreres. Filtratet inndampes til torrhet i vakuum og resten omkrystalliseres fra etanol, idet 5~ni"tro-2-etyl-aminobenzofenon erholdes som gule prismer med smeltepunkt 132-133°C. A mixture of 15 g of 5-nitro-2-chlorobenzophenone, 700 mg of copper powder, 700 mg of copper chloride, 15 ml of ethanol and 15 ml of liquid ethylamine is heated to reflux for 7 hours. The crystalline material thus obtained is filtered off, dissolved in 200 ml of methylene chloride, treated with charcoal and filtered. The filtrate is evaporated to dryness in vacuo and the residue is recrystallized from ethanol, 5-nitro-2-ethyl-aminobenzophenone being obtained as yellow prisms with a melting point of 132-133°C.

b) 1-etyl-6-nitro-^-fenyl-2(1H)-chinazolinon b) 1-ethyl-6-nitro-^-phenyl-2(1H)-quinazolinone

En blanding av 37 g 5-nitro-2-etylaminobenzofenon, ho g uretan A mixture of 37 g of 5-nitro-2-ethylaminobenzophenone, high urethane

og 1,5 g zinkklorid holdes i h timer ved 180-200°C (oljebadtemperatur), avkjoles deretter til romtemperatur og tilsettes 200 ml metylenklorid. Den erholdte blanding filtreres og filtratet ekstraheres 2 ganger med hver gang 100 ml vann. Den organiske fase torres over vannfritt natriumsulfat og inndampes i vakuum. Etter omkrystallisering av resten fra metanol erholdes 1-etyl-6-nitro-1+-fenyl-2(1H)-chinazolinon i form av gule prismer med smeltepunkt 21^-215°C. and 1.5 g of zinc chloride are held for h hours at 180-200°C (oil bath temperature), then cooled to room temperature and 200 ml of methylene chloride are added. The resulting mixture is filtered and the filtrate is extracted twice with 100 ml of water each time. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. After recrystallization of the residue from methanol, 1-ethyl-6-nitro-1+-phenyl-2(1H)-quinazolinone is obtained in the form of yellow prisms with a melting point of 21^-215°C.

Eksempel 6: 6-amino-1 -isopropyl->+-fenyl-2(1H)-chinazolinon Example 6: 6-amino-1-isopropyl->+-phenyl-2(1H)-quinazolinone

a) 5l2it£o=2-isogrcp_y_laminobenzof 2322 a) 5l2it£o=2-isogrcp_y_laminobenzof 2322

En blanding av 15 g 5-nitro-2-klorbenzofenon, 700 mg kopperpulver, 700 mg kopperklorid, 15 ml etanol og 15 ml flytende isopropylamin oppvarmes i 20 timer til koking under tilbakelop. Det herved erholdte krystalline material frafiltreres, loses i 200 ml metylen-klorid, behandles med trekull og filtreres. Filtratet inndampes til torrhet i vakuum og resten omkrystalliseres fra etanol, idet 5-nitro-2-isopropyl-aminobenzofenon erholdes i form av gule prismer med smeltepunkt 155°C A mixture of 15 g of 5-nitro-2-chlorobenzophenone, 700 mg of copper powder, 700 mg of copper chloride, 15 ml of ethanol and 15 ml of liquid isopropylamine is heated to reflux for 20 hours. The crystalline material thus obtained is filtered off, dissolved in 200 ml of methylene chloride, treated with charcoal and filtered. The filtrate is evaporated to dryness in vacuo and the residue is recrystallized from ethanol, 5-nitro-2-isopropyl-aminobenzophenone being obtained in the form of yellow prisms with a melting point of 155°C

<k>) §lSit£°zlzi22EE2E^Il'±z£§^il2 (1 H)-chinazolinon <k>) §lSit£°zlzi22EE2E^Il'±z£§^il2 (1 H)-quinazolinone

En blanding. av 37 g 5-nitro-2-isopropylaminobenzofenon, k- 0 g uretan og 1,5 g zinkklorid holdes i k timer ved 180-200°C (oljebadtemperatur), avkjoles deretter til romtemperatur og tilsettes 200 ml metylenklorid. Den erholdte blanding filtreres og filtratet ekstraheres 2 ganger med hver gang 100 ml vann. Den organiske fase torres over vannfritt natriumsulfat og inndampes i vakuum. Etter omkrystallisering av resten fra etylacetat erholdes 6-nitro-1 -isopropyl-^f-feny.1-2(1H)-chinazolinon i form av gule prismer med smeltepunkt 190-192°C. A mixture. of 37 g of 5-nitro-2-isopropylaminobenzophenone, k-0 g of urethane and 1.5 g of zinc chloride are kept for k hours at 180-200°C (oil bath temperature), then cooled to room temperature and 200 ml of methylene chloride are added. The resulting mixture is filtered and the filtrate is extracted twice with 100 ml of water each time. The organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. After recrystallization of the residue from ethyl acetate, 6-nitro-1-isopropyl-3-phenyl-1-2(1H)-quinazolinone is obtained in the form of yellow prisms with a melting point of 190-192°C.

c) §-amino^=iso£r^y_l-^-f^n^c) §-amino^=iso£r^y_l-^-f^n^

En blanding av 1 2 g 6-nitro-1 -isopropyl-^-fenyl-2'(1H)-chinazolinon A mixture of 1 2 g of 6-nitro-1-isopropyl-^-phenyl-2'(1H)-quinazolinone

lost i 2^0 ml varm etanol, oppvarmes til koking og tilsettes under roring forst 80 ml vann og deretter 16 g jernspon. Deretter tilsettes dråpevis under roring en losning fremstilt av 80 ml etanol, 20 ml vann og k- ml 2N saltsyre, i lopet av ^0 min. Den erholdte blanding oppvarmes i 3 timer under tilbakelop, den dissolved in 2^0 ml of hot ethanol, heated to boiling and, while stirring, first 80 ml of water and then 16 g of iron filings are added. A solution prepared from 80 ml of ethanol, 20 ml of water and 100 ml of 2N hydrochloric acid is then added dropwise with stirring over the course of 10 min. The resulting mixture is heated for 3 hours under reflux

varme losning tilsettes k- ml av en vandig 2N natriumhydroksydlosning, filtreres og inndampes for vidtgående fjernelse av etanol i vakuum. Etter tilsetting av 100 ml etylacetat ekstraheres den organiske fase 3 ganger med hver gang 50 ml fortynnet saltsyre. De forente vandige faser innstilles alkalisk med vandig natriumhydroksydlosning og ekstraheres 2 ganger med hver gang 100 ml metylenklorid.- De organiske faser forenes, torres: over vannfritt natriumsulfat, filtreres og inndampes til torrhet i vakuum. Etter omkrystallisering av resten fra etylacetat erholdes 6-amino-1-isopropyl-if-fenyl-2(1H)-chinazolinon i form av gule prismer med smeltepunkt 210-215°C. warm solution, k-ml of an aqueous 2N sodium hydroxide solution is added, filtered and evaporated for extensive removal of ethanol in vacuum. After adding 100 ml of ethyl acetate, the organic phase is extracted 3 times with 50 ml of dilute hydrochloric acid each time. The combined aqueous phases are made alkaline with aqueous sodium hydroxide solution and extracted twice with 100 ml of methylene chloride each time.- The organic phases are combined, dried: over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. After recrystallization of the residue from ethyl acetate, 6-amino-1-isopropyl-if-phenyl-2(1H)-quinazolinone is obtained in the form of yellow prisms with a melting point of 210-215°C.

Eksempel 7: 6-acetamido-1 -isopropyl-^f-fenyl-2(1 H)-22i2§3°iin2S Example 7: 6-acetamido-1-isopropyl-β-phenyl-2(1H)-22i2§3°iin2S

En losning av 2,65 g 6-amino-1-isopropyl-^--fenyl-2(1H)-chinazolinon (fremstilt etter den i eksempel' 6 beskrevne fremgangsmåte) i 25 ml pyridin og 25 ml eddiksyreanhydrid, oppvarmes i 3jr time ved 70°C. Den erholdte klare losning inndampes til torrhet i vakuum og resten omkrystalliseres fra etylacetat, idet 6-acetamido-1-isopropyl-^-fenyl-2(1H)-chinazolinon erholdes i A solution of 2.65 g of 6-amino-1-isopropyl-^--phenyl-2(1H)-quinazolinone (prepared according to the method described in Example 6) in 25 ml of pyridine and 25 ml of acetic anhydride is heated for 3 hours at 70°C. The clear solution obtained is evaporated to dryness in vacuo and the residue is recrystallized from ethyl acetate, 6-acetamido-1-isopropyl-^-phenyl-2(1H)-quinazolinone being obtained in

form av gule prismer med smeltepunkt 278-280°C. form of yellow prisms with melting point 278-280°C.

Eksempel 8: 6- cyano- 1 - isopropyl-^ f- fenyl- 2( 1H)- chinazolinon Example 8: 6-cyano-1-isopropyl-^f-phenyl-2(1H)-quinazolinone

En blanding av M-,2 g 6-amino-1-isopropyl-^-fenyl-2(1 H)-chinazolinon (fremstilt etter den i eksempel 6 beskrevne fremgangsmåte) og fortynnet saltsyre diazoteres ved en temperatur på 0-5°C med 15 ml av en vandig 1N natriumnitrit-losning. Den erholdte losning tilsettes uten opphold (i lopet av 5 min) til en losning av 12 g natriumcyanid og 22 g koppercyanid i 500 ml vann ved romtemperatur og oppvarmes deretter i <*>+5 min. ved en temperatur på 90-100°C (vannbad). Den erholdte blanding avkjoles til romtemperatur, tilsettes 200 ml kloroform og uopplost material frafiltreres. Den organiske fase fraskilles og ekstraheres en gang med 100 ml 1N saltsyre og en gang med 50 ml fortynnet vandig natriumbikarbonatlosning. Den organiske fase torres over vannfritt natriumsulfat, filtreres og inndampes til torrhet i vakuum. Det rå reaksjonsprodukt loses i metylenklorid og renses ved filtrering over en kort kolonne med aluminiumoksyd. Filtratet omkrystalliseres etter fjernelse av losningsmidlet fra etanol/ dietyleter (1 :1 ). A mixture of M-.2 g of 6-amino-1-isopropyl-^-phenyl-2(1 H)-quinazolinone (prepared according to the method described in example 6) and dilute hydrochloric acid is diazotized at a temperature of 0-5°C with 15 ml of an aqueous 1N sodium nitrite solution. The obtained solution is added without delay (in the course of 5 min) to a solution of 12 g of sodium cyanide and 22 g of copper cyanide in 500 ml of water at room temperature and is then heated for <*>+5 min. at a temperature of 90-100°C (water bath). The resulting mixture is cooled to room temperature, 200 ml of chloroform is added and undissolved material is filtered off. The organic phase is separated and extracted once with 100 ml of 1N hydrochloric acid and once with 50 ml of dilute aqueous sodium bicarbonate solution. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The crude reaction product is dissolved in methylene chloride and purified by filtration over a short column of aluminum oxide. The filtrate is recrystallized after removing the solvent from ethanol/diethyl ether (1:1).

Herved erholdes 6-cyano-1-isopropyl-^-fenyl-2(1H)-chinazolinon This gives 6-cyano-1-isopropyl-3-phenyl-2(1H)-quinazolinone

i form av krystalline prismer med smeltepunkt 125-128°C. in the form of crystalline prisms with a melting point of 125-128°C.

Eksempel 9: 1 - etyl- 6- metyl-^ f- fenyl- 2( 1H)- chinazolinon Example 9: 1-ethyl-6-methyl-^f-phenyl-2(1H)-quinazolinone

a) 6-metyl-^--f enyl-2(^H)-chinazolinon a) 6-Methyl-^--phenyl-2(^H)-quinazolinone

En blanding av 5 g 5-metyl-2-aminobenzofenon og h g urinstoff A mixture of 5 g of 5-methyl-2-aminobenzophenone and 1 g of urea

oppvarmes i 2 timer ved en temperatur på 180-200°C. Den faste rest behandles med 100 ml av en 50% vandig etanollosning og filtreres, idet 6-metyl-<l>+-fenyl-2(1H)-chinazolinon erholdes som krystalline beige fargede krystaller med smeltepunkt 280-281°C. heated for 2 hours at a temperature of 180-200°C. The solid residue is treated with 100 ml of a 50% aqueous ethanol solution and filtered, whereby 6-methyl-<1>+-phenyl-2(1H)-quinazolinone is obtained as crystalline beige colored crystals with a melting point of 280-281°C.

il§tXil§z5§^iz^ll!§52iliI15}l22i2§ZOiinon il§tXil§z5§^iz^ll!§52iliI15}l22i2§ZOiinon

Analogt den i eksempel 1 beskrevne fremgangsmåte erholdes ved erstatning av det deri anvendte 6,7-dimetyl-W-fenyl-2(1H)-chinazolinon med en ekvivalent mengde 6-metyl-^-fenyl-2(1H)-chinazolinon og omkrystallisering av resten fra etyleter den .onskede forbindelse 1-etyl-6-metyl-^-fenyl-2(1H)-chinazolinon i form av gule nåler med smeltepunkt 180°C. Analogously to the method described in example 1, it is obtained by replacing the 6,7-dimethyl-N-phenyl-2(1H)-quinazolinone used therein with an equivalent amount of 6-methyl-^-phenyl-2(1H)-quinazolinone and recrystallization of the residue from ethyl ether the desired compound 1-ethyl-6-methyl-^-phenyl-2(1H)-quinazolinone in the form of yellow needles with melting point 180°C.

Eksempel 10: 6- metyltio- 1- etyl-^- fenyl- 2( 1H)- chinazolinon Example 10: 6-methylthio-1-ethyl-^-phenyl-2(1H)-quinazolinone

a) éi^st^ltio^^-f eny_l = 2(1_H)=chinazolinon a) éi^st^ltio^^-f eny_l = 2(1_H)=quinazolinone

Analogt den i eksempel 9 a) beskrevne fremgangsmåte erholdes ved Analogous to the method described in example 9 a) is obtained by

erstatning av det deri anvendte 5-metyl-2-aminobenzofenon med en ekvivalent mengde 5-metyltio-2-aminobenzofenon den onskede forbindelse 6-metyltio-^-fenyl-2(1H)-chinazolinon med smeltepunkt 219-221°C. replacement of the 5-methyl-2-aminobenzophenone used therein with an equivalent amount of 5-methylthio-2-aminobenzophenone the desired compound 6-methylthio-^-phenyl-2(1H)-quinazolinone with melting point 219-221°C.

b) 6:mety_ltio=;[=ety_l^-f eny_l-2 (15 ):chinazolinon Analogt den i eksempel 1 beskrevne fremgangsmåte erholdes ved b) 6:methy_ltio=;[=ety_l^-f eny_l-2 (15 ):quinazolinone Analogous to the method described in example 1 is obtained by

erstatning av det deri anvendte 6,7-dimetyl-<!>+-fenyl-2(1H)-chinazolinon med en ekvivalent mengde é-metyltio-^-fenyl-2(1H)-chinazolinon og omkrystallisering av resten fra etylacetat den onskede forbindelse 6-metyltio-1 -etyl-lf-fenyl-2(1H)-chinazolinon - med smeltepunkt 1 50-151°C. replacement of the 6,7-dimethyl-<!>+-phenyl-2(1H)-quinazolinone used therein with an equivalent amount of ε-methylthio-^-phenyl-2(1H)-quinazolinone and recrystallization of the residue from ethyl acetate the desired compound 6-methylthio-1-ethyl-1f-phenyl-2(1H)-quinazolinone - with melting point 1 50-151°C.

Eksempel 11 : 1 - isopropyl- 7- hydroksy-^- feny1- 2( 1H)- chinazolinon Example 11: 1-isopropyl-7-hydroxy-^-phenyl-2(1H)-quinazolinone

a) ^l^stoks^-g-isoprog^laminobenzofenon a) ^l^stox^-g-isoprog^laminobenzophenone

En blanding av 9 g 2-amino-^-metoksybenzofenon, 15 g vannfritt A mixture of 9 g of 2-amino-^-methoxybenzophenone, 15 g anhydrous

kaliumkarbonat og ho ml 2-jodpropan oppvarmes i h dogn til koking under tilbakelop. Etter avkjoling av reaksjonsblandingen fortynnes med 200 ml benzen og vaskes med vann 2 ganger og 2 ganger med saltvann. Den organiske fase fraskilles, torres over v vannfritt natriumsulfat og inndampes i vakuum for vidtgående fjerning av benzen. Den erholdte olje loses i ca. 10 ml metylen-klorid og underkastes en kolonnekromatografering på ca. h- 00 g aluminiumoksyd, idet metylenklorid anvendes som elueringsmiddel. Den forste fraksjon inndampes i vakuum for fjernelse av metylen-klorid idet ^-metoksy-2-isopropylaminobenzofenon erholdes som en olje. potassium carbonate and 10 ml of 2-iodopropane are heated for 1 h to boiling under reflux. After cooling, the reaction mixture is diluted with 200 ml of benzene and washed twice with water and twice with salt water. The organic phase is separated, dried over v anhydrous sodium sulfate and evaporated in a vacuum for extensive removal of benzene. The obtained oil is unloaded for approx. 10 ml of methylene chloride and subjected to a column chromatography of approx. h- 00 g aluminum oxide, methylene chloride being used as eluent. The first fraction is evaporated in vacuo to remove methylene chloride, yielding ^-methoxy-2-isopropylaminobenzophenone as an oil.

k) ili§°EE2EY/ilZlm2t2ksy_-^-f^ny_l-2 0 H)=chinazolinon k) ili§°EE2EY/ilZlm2t2ksy_-^-f^ny_l-2 0 H)=quinazolinone

En blanding av 5?9 g M—metoksy-2-isopropylaminobenzofenon (erholdt etter den i eksempel 11 a) beskevne fremgangsmåte), 20 g uretan og 1,2 g zinkklorid oppvarmes i <*>f0 min. ved en temperatur på 200-215°C. Deretter tilsettes ca. 10 g uretan og 600 mg zinkklorid og oppvarmes på nytt ved en temperatur på 200-215°C i 1 time. Den erholdte blanding avkjoles til omtrent 100°C og fortynnes med kloroform. Deretter filtreres og filtratet vaskes forst med vann og deretter med saltvann. Den organiske fase fraskilles, torres over vannfritt natriumsulfat og inndampes i vakuum for vidtgående fjernelse av kloroform, idet det erholdes en oljeaktig rest som loses i en liten mengde på omtrent 10 ml metylenklorid. Etter fortynning med omtrent ho ml etylacetat og inndamping i vakuum erholdes 1-isopropyl-7-metoksy-!+-f enyl-2(1H)-chinazolinon med smeltepunkt 133-137°C. c) liiS°E£°EYilZ~5Z^E°^§^i^l?22Zil2(lH)=chinazolinon En blanding av 1 g 1-isopropyl-7-metoksy-^-fenyl-2(1H)-chinazolinon og 5 ml K8% bromhydrogensyre oppvarmes til koking under tilbakelop i 20 timer. Deretter fortynnes med 100 ml vann, innstilles alkalisk med vandig 2N natriumhydroksyd-lbsning (pH ^ 10) og ekstraheres 2 ganger med hver gang 50 ml etylacetat for fjernelse av ikke sure produkter. Den vandige fase fraskilles, behandles med 2N saltsyre og det dannede bunnfall frafiltreres. Etter omkrystallisering fra etanol erholdes 7-hydroksy-1-isopropyl-^-fenyl-2(1H)-chinazolinon med smeltepunkt 266-267°C. A mixture of 5.9 g of N-methoxy-2-isopropylaminobenzophenone (obtained according to the method described in example 11 a), 20 g of urethane and 1.2 g of zinc chloride is heated for <*>f0 min. at a temperature of 200-215°C. Then add approx. 10 g of urethane and 600 mg of zinc chloride and reheated at a temperature of 200-215°C for 1 hour. The resulting mixture is cooled to approximately 100°C and diluted with chloroform. It is then filtered and the filtrate is washed first with water and then with salt water. The organic phase is separated, dried over anhydrous sodium sulfate and evaporated in a vacuum for extensive removal of chloroform, obtaining an oily residue which is dissolved in a small amount of approximately 10 ml of methylene chloride. After dilution with approximately 100 ml of ethyl acetate and evaporation in a vacuum, 1-isopropyl-7-methoxy-!+-phenyl-2(1H)-quinazolinone with a melting point of 133-137°C is obtained. c) liiS°E£°EYilZ~5Z^E°^§^i^l?22Zil2(1H)=quinazolinone A mixture of 1 g of 1-isopropyl-7-methoxy-^-phenyl-2(1H)-quinazolinone and 5 ml K8% hydrobromic acid is heated to boiling under reflux for 20 hours. It is then diluted with 100 ml of water, made alkaline with aqueous 2N sodium hydroxide solution (pH ^ 10) and extracted twice with 50 ml of ethyl acetate each time to remove non-acidic products. The aqueous phase is separated, treated with 2N hydrochloric acid and the precipitate formed is filtered off. After recrystallization from ethanol, 7-hydroxy-1-isopropyl-^-phenyl-2(1H)-quinazolinone with melting point 266-267°C is obtained.

Eksempel 12: 1- etyl- 6- merkapto-^- feny1- 2( 1H)- chinazolinon Example 12: 1-ethyl-6-mercapto-^-phenyl-2(1H)-quinazolinone

En blanding av 3 g 6-metyltio-1-etyl-^--fenyl-2(1 H)-chinazolinon (fremstilt etter den i eksempel 10 beskrevne fremgangsmåte) og 25 ml h8% bromhydrogensyre oppvarmes i k dogn under tilbakelop. Deretter nøytraliseres med vandig 2N natriumhydroksydlosning og ekstraheres 2 ganger med hver gang 100 ml etylacetat. De organiske faser forenes, torres over vannfritt natriumsulfat, filtreres og inndampes i vakuum. Etter omkrystallisering av resten fra etylacetat erholdes 1-etyl-6-merkapto->+-fenyl-2(1H)-chinazolinon med smeltepunkt 200-20<1>+°C. A mixture of 3 g of 6-methylthio-1-ethyl-^--phenyl-2(1H)-quinazolinone (prepared according to the method described in example 10) and 25 ml of h8% hydrobromic acid is heated for 2 days under reflux. It is then neutralized with an aqueous 2N sodium hydroxide solution and extracted twice with 100 ml of ethyl acetate each time. The organic phases are combined, dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. After recrystallization of the residue from ethyl acetate, 1-ethyl-6-mercapto->+-phenyl-2(1H)-quinazolinone with melting point 200-20<1>+°C is obtained.

Eksempel 13: 7- klor- 1- etyl- 6- metyl-^- fenyl- 2( 1H)- chinazolinon Example 13: 7-chloro-1-ethyl-6-methyl-^-phenyl-2(1H)-quinazolinone

a) 2=amino-*f-klor=5imety_lbenzofenon a) 2=amino-*f-chloro=5imethy_lbenzophenone

Til 1*4-2 g benzoylklorid tilsettes i lbpet av -§- time i små To 1*4-2 g of benzoyl chloride is added over the course of -§- hour in small increments

pors.j.oner til sammen 57 g 3-klor-<!>+-metylanilin ved 110°C. Den erholdte blanding oppvarmes 180°C, 1<>>+0 g zinkklorid tilsettes i fleres porsjoner i lopet av 1 time og det oppvarmes ved en temperatur på 225 - 230°C videre i 1^ time. Den erholdte blanding avkjoles til en temperatur på 120 - 130°C og en blanding portions to a total of 57 g of 3-chloro-<!>+-methylaniline at 110°C. The resulting mixture is heated to 180°C, 1<>>+0 g of zinc chloride is added in several portions over the course of 1 hour and it is heated at a temperature of 225 - 230°C for a further 1^ hours. The resulting mixture is cooled to a temperature of 120 - 130°C and a mixture

•av 150 ml eddiksyre, 100 ml vann og 150 ml konsentrert svovel-syre tilsettes. Deretter oppvarmes i 3 timer under tilbake- • of 150 ml of acetic acid, 100 ml of water and 150 ml of concentrated sulfuric acid are added. Then heated for 3 hours under reflux

lop, blandingen helles ut på 2 liter isblandet vann og ekstraheres 3 ganger med hver gang 300 ml metylenklorid. De organiske faser forenes, torres over vannfritt natriumsulfat, filtreres og inndampes I vakuum. Den erholdte oljeaktige rest fordeles mellom et av 500 ml 2N vandig natriumhydroksyd-ldsning og 300 lop, the mixture is poured into 2 liters of ice-cold water and extracted 3 times with 300 ml of methylene chloride each time. The organic phases are combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The oily residue obtained is distributed between one of 500 ml of 2N aqueous sodium hydroxide solution and 300

ml metylenklorid sammensatt flytende system og den organiske fase vaskes forst med vann og deretter med saltvann. Deretter torres, filtreres og inndampes i vakuum, idet det erholdes et råprodukt. Dette renses ved omkrystallisering fra dietyleter/ pentan (1:2). Det herved erholdte 2-amino-<1>+-klor-5-metyl-benzofenon smelter ved 95 - 96°C. ml methylene chloride compound liquid system and the organic phase is washed first with water and then with salt water. It is then dried, filtered and evaporated in a vacuum, whereby a crude product is obtained. This is purified by recrystallization from diethyl ether/pentane (1:2). The 2-amino-<1>+-chloro-5-methyl-benzophenone thus obtained melts at 95 - 96°C.

b) 7-klor-6-metyl^^-fenyl-2(^H)-chinazolinon En blanding av 10 g 2-amino-<1>+-klor-5-metylbenzofenon og 10 g b) 7-chloro-6-methyl^^-phenyl-2(^H)-quinazolinone A mixture of 10 g of 2-amino-<1>+-chloro-5-methylbenzophenone and 10 g

urinstoff oppvarmes i 32" timer ved omtrent 180-200°C. Etter omkrystallisering av den faste rest fra dimetylsulfamid/vann (1:1) erholdes 7-klor-6-metyl-Lf-fenyl-2(1H)-chinazolinon som krystaller med smeltepunkt 310-315°C urea is heated for 32 hours at approximately 180-200°C. After recrystallization of the solid residue from dimethylsulfamide/water (1:1), 7-chloro-6-methyl-Lf-phenyl-2(1H)-quinazolinone is obtained as crystals with melting point 310-315°C

c) Zl^I°Elll!:5yil§I?§tyil^l£2nyiz2 (IH)-chinazolinon. c) Zl^I°Elll!:5yil§I?§tyil^l£2nyiz2 (1H)-quinazolinone.

1 ,1+ g natriumhydrid ( 50% suspensjon i mineralolje) tilsettes ved 1.1+ g of sodium hydride (50% suspension in mineral oil) is added by

romtemperatur en losning av 7 g 7-klor-6-metyl-<l>+-fenyl-2(1H)-chinazolinon i 200 ml dimetylsulfamid. Den erholdte blanding som inneholder natriumf orbindelsen av 7-klor-6-metyl-1+-f enyl-2 (1H)-chinazolinon, rores i 30 min. ved romtemperatur og tilsettes deretter 20 ml etyljodid. Deretter rores i 20 timer ved romtemperatur, room temperature a solution of 7 g of 7-chloro-6-methyl-<l>+-phenyl-2(1H)-quinazolinone in 200 ml of dimethylsulfamide. The resulting mixture containing the sodium compound of 7-chloro-6-methyl-1+-phenyl-2(1H)-quinazolinone is stirred for 30 min. at room temperature and then add 20 ml of ethyl iodide. Then stir for 20 hours at room temperature,

blandingen uthelles i 1 liter isblandet vann, det utfallende bunnfall frafiltreres, torres og omkrystalliseres fra metylen-klorid/eter (1:5). Det herved erholdte 7-klor-1-etyl-6-metyl-<l>+-fenyl-2(1H)-chinazolinon smelter ved 1 85°C~1 87°C. the mixture is poured into 1 liter of ice-cold water, the resulting precipitate is filtered off, dried and recrystallized from methylene chloride/ether (1:5). The 7-chloro-1-ethyl-6-methyl-<l>+-phenyl-2(1H)-quinazolinone thus obtained melts at 1 85°C~1 87°C.

Eksempel 1*+ : Example 1*+ :

Analogt den i eksempel 1 b) beskrevne fremgangsmåte erholdes ved omsetning av ekvivalente mengder av natriumforbindelsene av de i det folgende beskrevne utgangsforbindelser med etyljodid de folgende sluttforbindelser: Utgangsforbindelser Sluttforbindelser Natriumforbindelser av a) 7-metyl->+-fenyl-2(1H)- 1 -etyl-7-metyl-^-fenyl-2(1H)-chinazolinon chinazolinon med smp. 160-162 C (omkrystallisering fra etylacetat. ) b) 7-nitro-<l>+-fenyl-2(1H)- 1-etyl-7-nitro-)+-fenyl-2(1H)-chinazolinon chinazolinon med smp. 200-203°C (omkrystallisering fra etylacetat) c) 6 ,7-dimetoksy-^-f enyl- 1-etyl-6 ,7-dimetoksy-!+-f enyl-2(1H)-chinazolinon 2(1H)-chinazolinon med smp. 175 C. (omkrystallisering fra dietyleter) Ved omsetningen med metyljodid kommer man frem til Utgangsforbindelser Sluttforbindelser Natriumforbindelser av d) 7-metyl-4--fenyl-2(1H)- 1 ,7-dimetyl-*4--fenyl-2(1H)-chinazolinon chinazolinon med smp. 171-172 C (omkrystallisering fra etylacetat) e) 6,7-dimetoksy-^-fenyl- 1-metyl-6,7-dimetoksy-^-fenyl 2(1H)-chinazolinon -2(1H)-chinazolinon med smp. Analogous to the method described in example 1 b), the following end compounds are obtained by reacting equivalent amounts of the sodium compounds of the starting compounds described below with ethyl iodide: Starting compounds End compounds Sodium compounds of a) 7-methyl->+-phenyl-2(1H)- 1 -ethyl-7-methyl-^-phenyl-2(1H)-quinazolinone quinazolinone with m.p. 160-162 C (recrystallization from ethyl acetate. ) b) 7-nitro-<l>+-phenyl-2(1H)- 1-ethyl-7-nitro-)+-phenyl-2(1H)-quinazolinone quinazolinone with m.p. . 200-203°C (recrystallization from ethyl acetate) c) 6,7-dimethoxy-^-phenyl-1-ethyl-6,7-dimethoxy-!+-phenyl-2(1H)-quinazolinone 2(1H)- quinazolinone with m.p. 175 C. (recrystallization from diethyl ether) The reaction with methyl iodide leads to Starting compounds Final compounds Sodium compounds of d) 7-methyl-4--phenyl-2(1H)- 1 ,7-dimethyl-*4--phenyl -2(1H)-quinazolinone quinazolinone with m.p. 171-172 C (recrystallization from ethyl acetate) e) 6,7-dimethoxy-^-phenyl-1-methyl-6,7-dimethoxy-^-phenyl 2(1H)-quinazolinone -2(1H)-quinazolinone with m.p.

197-198 C (omkrystallisering fra etylacetat) 197-198 C (recrystallization from ethyl acetate)

Eksempel 15: Example 15:

Analogt de eksempåA b) eller 5 b) beskrevne fremgangsmåter fås Analogous to the methods described in example A b) or 5 b) are obtained

ved omsetning av ekvivalente mengder av de i det folgende beskrevne utgangsforbindelser med uretan de folgende sluttforbindelser: by reacting equivalent quantities of the starting compounds described below with urethane the following final compounds:

Utgangsforbindelser Sluttforbindelser Output connections End connections

a) 5-metoksy-2-etylamino- 1 -etyl-é-metoksy-^-fenyl-benzofenon 2(1H)-chinazolinon med smp. a) 5-methoxy-2-ethylamino-1-ethyl-é-methoxy-^-phenyl-benzophenone 2(1H)-quinazolinone with m.p.

138-1*f20C 138-1*f20C

b) If-klor-5-metyl-2-etyl- 1-etyl-6-metyl-7-klor-If-aminobenzofenon fenyl-2(1H)-chinazolinon b) If-chloro-5-methyl-2-ethyl-1-ethyl-6-methyl-7-chloro-If-aminobenzophenone phenyl-2(1H)-quinazolinone

med smp. 185-187 C with m.p. 185-187C

c) h,5-dimetyl-2-etylamino- 1-etyl-6,7-dimetyl-^-fenyl-benzofenon 2(1H)-chinazolinon med smp. c) h,5-dimethyl-2-ethylamino-1-ethyl-6,7-dimethyl-^-phenyl-benzophenone 2(1H)-quinazolinone with m.p.

176-1809C. 176-1809C.

Claims

Analogous method as indicated in patent no. 125-929 for the preparation of new, therapeutically active quinazolinone derivatives of the general formula I

in which R stands for fluorine, chlorine or bromine, an alkyl group with 1-5 carbon atoms, an alkoxy group with 1 carbon atom, an alkylthio group with 1 carbon atom, hydroxy-, nitro-, amino-, cyano-, acetamido-, trifluoromethyl or mercapto- the group and n stands for 1 or 2 where, 1) if n stands for 1, R has a meaning other than fluorine, chlorine or bromine, and 2) if n stands for 2, both R are the same or different and stand for an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-<*>+ carbon atoms or for fluorine, chlorine or bromine, FL means an alkyl group with 1-5 carbon atoms, the allyl or propargyl group, where R^ only stands for the isopropyl group when n = 1 and R means the hydroxy, amino, cyano, acetamido or mercapto group and R~ stands for phenyl or a group of the general formula II in which Y means fluorine, chlorine or bromine, an alkyl group with 1-<*>f carbon atoms, an alkoxy group with 1-<*>f carbon atoms or the trifluoromethyl group and Y^ means hydrogen, fluorine, chlorine or bromine, an alkyl group with 1-* + carbon atoms, or an alkoxy group with 1-k carbon atoms, where Y and Y^ do not stand for the alkoxy group when R means the hydroxy or mercapto group, characterized in that a) for the preparation of compounds with the general formula Ia in which R' stands for fluorine, chlorine or bromine, an alkyl group with 1-5 carbon atoms, an alkoxy group with 1-h carbon atoms, an alkylthio group with 1-k carbon atoms, the nitro-, cyano-, acetamido- or trifluoromethyl group and n stands for for 1 or 2 at a time in which R.J has the meaning mentioned above and X stands for chlorine, bromine or iodine, or b) for the preparation of compounds with the general formula Ic in which R.y, and R.sup. have the above meaning, and acetamido derivatives thereof, compounds of the general formula Id are reduced in which R^ and R.^ have the above-mentioned meaning, and the thus obtained compounds of the general formula Ic are then optionally transferred with the aid of an acetylating agent into their acetamido derivatives or c) to produce compounds of the general formula le in which R.J and R^ have the above meaning and G stands for the hydroxy or mercapto group, compounds with the general formula If in which R^ and R^ have the above meaning and J stands for an alkoxy group with 1-*f carbon atoms respectively an alkyltLo group with 1-*+ carbon atoms, an acid hydrolysis, or d) for the preparation of compounds with the general formula lg in which R.j and R.sup. have the above-mentioned meaning, the amino group is transferred in compounds of the general formula Ih in which FL and R.sup. have the above-mentioned meaning, in the cyano group according to Sandmeyer.