NO853853L

NO853853L - PROCEDURE FOR PREPARATION OF PYRIMIDINE DERIVATIVES.

Info

Publication number: NO853853L
Application number: NO853853A
Authority: NO
Inventors: Takao Takaya; Hisashi Takasugi; Atsushi Kuno; Yoshie Sugiyama
Original assignee: Fujisawa Pharmaceutical Co
Priority date: 1984-10-01
Filing date: 1985-09-30
Publication date: 1986-04-02

Description

Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av hittil ukjente pyrimidinderivater. Mer spesifikt angår oppfinnelsen fremstilling av pyrimidinderivater og farma-søytisk akseptable salter derav, som er nyttige til behandling av cerebrovaskulære sykdommer. The present invention relates to a method for the production of hitherto unknown pyrimidine derivatives. More specifically, the invention relates to the production of pyrimidine derivatives and pharmaceutically acceptable salts thereof, which are useful in the treatment of cerebrovascular diseases.

Pyrimidinderivatene fremstilt ifølge foreliggende oppfinnelse har nedenstående generelle formel I The pyrimidine derivatives produced according to the present invention have the following general formula I

hvor where

Ar betyr aryl-substituert med 1-3 substituenter valgt blant nitro, halogen-lavere-alkyl, lavere alkoksy og en gruppe med den generelle formel II Ar means aryl-substituted with 1-3 substituents selected from nitro, halo-lower-alkyl, lower alkoxy and a group of the general formula II

4 5 6 4 5 6

(hvor &, R , R og R har den nedenfor angitte betydning), (where &, R , R and R have the meanings given below),

R 1 betyr forestret karboksy, lavere alkanoyl, hydroksy-lavere alkyl eller en gruppe med den generelle formel III eller IV R 1 means esterified carboxy, lower alkanoyl, hydroxy-lower alkyl or a group of the general formula III or IV

(hvor R 7 , R 8 og A har den nedenfor angitte betydning), R 2betyr hydrogen, lavere alkyl eller en gruppe med den generelle formel V (where R 7 , R 8 and A have the meanings given below), R 2 means hydrogen, lower alkyl or a group of the general formula V

(hvor B, R 7 og R 8 har den nedenfor angitte betydning), (where B, R 7 and R 8 have the meanings given below),

3 3

R betyr lavere alkyl eller aryl, R means lower alkyl or aryl,

J2 er et helt tall 0 eller 1-6, J2 is an integer 0 or 1-6,

4 S 6 4 S 6

R , R og R hver betyr hydrogen eller halogen, R , R , and R each mean hydrogen or halogen,

R<7>og Ru ° hver betyr hydrogen, en eventuelt substituert N-holdig heterocyklisk gruppe eller lavere alkyl eventuelt substituert med 1-3 substituenter valgt blant mono- eller di-(lavere alkyl Jaitiino og eventuelt substituerte N-holdige heterocykliske grupper, eller R<7> and Ru ° each means hydrogen, an optionally substituted N-containing heterocyclic group or lower alkyl optionally substituted with 1-3 substituents selected from mono- or di-(lower alkyl Jaitiino and optionally substituted N-containing heterocyclic groups, or

7 8 7 8

R og R til sammen danner en eventuelt, substituert N-holdig R and R together form an optionally substituted N-containing

heterocyklisk gruppe sammen med det nabostilte nitrogenatom, A og B hver betyr lineær eller forgrenet lavere alkylen, som heterocyclic group together with the adjacent nitrogen atom, A and B each means linear or branched lower alkylene, which

kan være substituert med lavere alkyliden, may be substituted with lower alkylidene,

med det forbehold, at R betyr en gruppe med den generelle formel with the proviso that R means a group with the general formula

IV IV

(hvor R 7 , R 8og A har den ovenfor angitte betydning) (where R 7 , R 8 and A have the meaning stated above)

når R<2>betyr hydrogen eller lavere alkyl, when R<2> means hydrogen or lower alkyl,

og farmasøytisk akseptable salter derav. and pharmaceutically acceptable salts thereof.

Nærmere opplysninger om de i foreliggende beskrivelse og krav nevnte definisjoner og foretrukne eksempler på disse er angitt i det følgende. More detailed information about the definitions mentioned in the present description and claims and preferred examples of these are given below.

I foreliggende beskrivelse og krav betyr uttrykket "lavere" en gruppe med 1-6 karbonatomer, med mindre annet er angitt. In the present description and claims, the term "lower" means a group with 1-6 carbon atoms, unless otherwise indicated.

"Aryl" omfatter hensiktsmessig brom, fluor, klor og jod. "Halogen" omfatter hensiktsmessig brom, fluor, klor og jod. "Aryl" suitably includes bromine, fluorine, chlorine and iodine. "Halogen" conveniently includes bromine, fluorine, chlorine and iodine.

"Lavere alkyl" omfatter hensiktsmessig lineære eller forgrenete grupper såsom metyl, etyl, propyl, isopropyl, butyl, tert.butyl, pentyl, heksyl og lignende. "Lower alkyl" suitably includes linear or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

"Halogen-lavere alkyl" omfatter hensiktsmessig klormetyl, trifluormetyl, brometyl, 1-brometyl, dikloretyl, jodpropyl, triklor-tert.butyl, fluorpentyl, klorheksyl og lignende. "Halogen-lower alkyl" conveniently includes chloromethyl, trifluoromethyl, bromomethyl, 1-bromomethyl, dichloroethyl, iodopropyl, trichloro-tert.butyl, fluoropentyl, chlorohexyl and the like.

"Lavere alkoksy" omfatter hensiktsmessig lineære eller forgrenete grupper såsom metoksy, etoksy, propoksy, isopropoksy, butoksy, tert.butoksy, pentyloksy, heksyloksy og lignende. "Lower alkoxy" suitably includes linear or branched groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert.butoxy, pentyloxy, hexyloxy and the like.

Foretrukne eksempler på en gruppe med den generelle formel Preferred examples of a group with the general formula

II II

kan omfatte fenoksy, fenyl-lavere alkoksy (for eksempel benzyl-oksy, fenetyloksy, osv.), halogenfenyl-lavere alkoksy (for eksempel klorbenzyloksy, diklorfenetyloksy, fluorfenylbutoksy, bromfenylheksyloksy, osv.) og lignende. may include phenoxy, phenyl-lower alkoxy (for example, benzyloxy, phenethyloxy, etc.), halophenyl-lower alkoxy (for example, chlorobenzyloxy, dichlorophenethyloxy, fluorophenylbutoxy, bromophenylhexyloxy, etc.) and the like.

Esterdelen i "forestret karboksy" kan hensiktsmessig omfatte lavere alkylestere (for eksempel metylester, etylester, propyl-ester, isopropylester, butylester, tert.butylester, pentylester, heksylester, osv.), mono-(di- eller tri-)halogen-lavere alkylestere (for eksempel jodetylester, dikloretylester, trikloretyl-ester, trifluormetylester, osv.), hydroksy-lavere alkylestere (for eksempel hydroksymetylester, hydroksyetylester, hydroksy-propylester, hydroksybutylester, osv.), ar-lavere alkylestere The ester part in "esterified carboxy" may suitably comprise lower alkyl esters (for example methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, tert.butyl ester, pentyl ester, hexyl ester, etc.), mono-(di- or tri-)halo-lower alkyl esters (for example, iodoethyl ester, dichloroethyl ester, trichloroethyl ester, trifluoromethyl ester, etc.), hydroxy-lower alkyl esters (for example, hydroxymethyl ester, hydroxyethyl ester, hydroxypropyl ester, hydroxybutyl ester, etc.), ar-lower alkyl esters

(for eksempel benzylester, 4-nitrobenzylester, tritylester, osv.) (eg benzyl ester, 4-nitrobenzyl ester, trityl ester, etc.)

og lignende. and such.

"Lavere alkanoyl" kan hensiktsmessig omfatte lineære eller forgrenete grupper såsom formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl og lignende. "Lower alkanoyl" may suitably include linear or branched groups such as formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl and the like.

"Hydroksy-lavere alkyl" kan hensiktsmessig omfatte hydroksy-metyl, 1-hydroksyetyl, 2-hydroksyetyl, 1-hydroksypropyl, 3-hydroksypropyl, 2-hydroksybutyl, 4-hydroksybutyl, 5-hydroksy-pentyl, 6-hydroksyheksyl og lignende. "Hydroxy-lower alkyl" may suitably include hydroxy-methyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like.

"N-holdige heterocykliske grupper" kan hensiktsmessig omfatte en umettet 5- eller 6-leddet heteromonocyklisk gruppe inneholdende 1 eller 2 nitrogenatomer, for eksempel pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, 1,2,3,6-tetrahydropyridyl, osv.; "N-containing heterocyclic groups" may conveniently include an unsaturated 5- or 6-membered heteromonocyclic group containing 1 or 2 nitrogen atoms, for example pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, 1,2,3,6-tetrahydropyridyl, etc.;

en mettet 5- eller 6-leddet heteromonocyklisk gruppe inneholdende 1 eller 2 nitrogenatomer og/eller 1 eller 2 oksygenatomer, for eksempel pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morfolinyl, osv.; a saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 nitrogen atoms and/or 1 or 2 oxygen atoms, for example pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholinyl, etc.;

en mettet 5- eller 6-leddet heteromonocyklisk gruppe inneholdende 1 eller 2 nitrogenatomer og 1 eller 2 svovelatomer, for eksempel tiazolidinyl, tiomorfoliny1, osv. og lignende. a saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 nitrogen atoms and 1 or 2 sulfur atoms, for example thiazolidinyl, thiomorpholiny1, etc. and the like.

Den "N-holdige heterocykliske gruppe" kan ha 1-3 substituenter såsom lavere alkyl som eksemplifisert ovenfor. The "N-containing heterocyclic group" may have 1-3 substituents such as lower alkyl as exemplified above.

Foretrukne eksempler på "substituerte N-holdige heterocykliske grupper" kan omfatte lavere alkylpyrrolidinyl (for eksempel 1-etylpyrrolidinyl, 2-metylpyrrolidinyl, 3-isopropyl-pyrrolidinyl, 1-tert.butylpyrrolidinyl, 1-heksylpyrrolidinyl, osv.), lavere alkylimidaz.olidinyl (for eksempel 3-metylimida-zolidinyl, osv.), lavere alkylpiperidyl (for eksempel 1-metyl-piperidyl, 1-etylpiperidyl, 2-tert.butylpiperidyl, 3-heksyl-piperidyl, osv.), lavere alkylpiperazinyl (for eksempel 1-metyl-piperazinyl, 2-etylpiperazinyl, 3-isopropylpiperazinyl, 1-heksyl-piperazinyl, osv.), lavere alkylpyridyl (for eksempel 1-metyl-pyridyl, 2-etylpyridy.l, 3-tert. butylpyridyl, 1-heksylpyridyl, osv.) og lignende. Preferred examples of "substituted N-containing heterocyclic groups" may include lower alkylpyrrolidinyl (eg, 1-ethylpyrrolidinyl, 2-methylpyrrolidinyl, 3-isopropyl-pyrrolidinyl, 1-tert.butylpyrrolidinyl, 1-hexylpyrrolidinyl, etc.), lower alkylimidaz.olidinyl (for example, 3-methylimidazolidinyl, etc.), lower alkylpiperidyl (for example, 1-methyl-piperidyl, 1-ethylpiperidyl, 2-tert.butylpiperidyl, 3-hexyl-piperidyl, etc.), lower alkylpiperazinyl (for example, 1 -methyl-piperazinyl, 2-ethylpiperazinyl, 3-isopropylpiperazinyl, 1-hexyl-piperazinyl, etc.), lower alkylpyridyl (for example 1-methyl-pyridyl, 2-ethylpyridyl, 3-tert.butylpyridyl, 1-hexylpyridyl, etc.) and the like.

"Mono- eller di(lavere alkyl)amino" kan hensiktsmessig omfatte metylamino, etylamino, isopropylamino, heksylamino, dimetylamino, dietylamino, dipropylamino, metyletylamino og lignende. "Mono- or di(lower alkyl)amino" can suitably include methylamino, ethylamino, isopropylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino and the like.

Foretrukne eksempler på substituerte lavere alkylgrupper R<7>og R Q kan omfatte mono- eller di-(lavere alkyl)amino-lavere alkyl (for eksempel metylaminometyl, dimetylaminoetyl, dietylaminoetyl, dipropylaminoetyl, dimetylaminopropyl, dietylaminopropyl, dimetylaminobutyl, dimetylaminoheksyl, osv.), morfolinyl-lavere alkyl (for eksempel morfolinylmetyl, morfolinoetyl, morfolinyl-etyl, morfolinylpropyl, morfolinylbutyl, osv.), piperazinyl-lavere alkyl, hvor piperazinyl eventuelt er substituert med lavere alkyl (for eksempel piperazinylmetyl, piperazinyletyl, piperazinylpropyl, metylpiperazinyletyl, etylpiperazinyletyl, isopropylpiperazinylheksyl, osv.), piperidyl-lavere alkyl, hvor piperidyl eventuelt er substituert med lavere alkyl (for eksempel piperidylmetyl, piperidyletyl, piperidylpropyl, etylpiperidyl-etyl, etylpiperidylheksyl, osv.), tiomorfolinyl-lavere alkyl (for eksempel tiomorfolinylmetyl, tiomorfolinyletyl, tiomorfolinyl-propyl, osv.), pyrrolidinyl-lavere alkyl, hvor pyrrolidinyl eventuelt er substituert med lavere alkyl (for eksempel pyrroli- dinylmetyl, pyrrolidinyletyl, N-etylpyrrolidinylmetyl, metyl-pyrrolidinylpropyl, isoproylpyrrolidinylheksyl, osv.) og lignende. Preferred examples of substituted lower alkyl groups R<7> and R Q may include mono- or di-(lower alkyl)amino-lower alkyl (for example, methylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl, dimethylaminopropyl, diethylaminopropyl, dimethylaminobutyl, dimethylaminohexyl, etc.), morpholinyl-lower alkyl (for example, morpholinylmethyl, morpholinoethyl, morpholinyl-ethyl, morpholinylpropyl, morpholinylbutyl, etc.), piperazinyl-lower alkyl, where piperazinyl is optionally substituted with lower alkyl (for example, piperazinylmethyl, piperazinylethyl, piperazinylpropyl, methylpiperazinylethyl, ethylpiperazinylethyl, isopropylpiperazinylhexyl ) propyl, etc.), pyrrolidinyl-lower alkyl, where pyrrolidine yl is optionally substituted with lower alkyl (for example pyrrolidinylmethyl, pyrrolidinylethyl, N-ethylpyrrolidinylmethyl, methylpyrrolidinylpropyl, isoproylpyrrolidinylhexyl, etc.) and the like.

"N-holdige heterocykliske grupper, som er dannet ved konjugasjon av R , R og det nabostilte nitrogenatom", kan hensiktsmessig omfatte "N-containing heterocyclic groups, which are formed by conjugation of R , R and the adjacent nitrogen atom", may conveniently include

en 5- eller 6-leddet umettet heteromonocyklisk gruppe inneholdende 1 eller 2 nitrogenatomer, for eksempel 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, pyridinio, pyrimidinio, 1,2,3,6-tetra-hydropyridin-1-yl, osv.; a 5- or 6-membered unsaturated heteromonocyclic group containing 1 or 2 nitrogen atoms, for example 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, pyridinio, pyrimidinio, 1,2,3,6-tetra-hydropyridin-1-yl, etc.;

en mettet 5-, 6- eller 7-leddet heteromonocyklisk gruppe inneholdende 1 eller 2 nitrogenatomer og/eller 1 eller 2 oksygenatomer, for eksempel 1-pyrrolidinyl, 1-imidazolidinyl, piperi-dino, 1-piperazinyl, 1-homopiperazinyl, morfolino, osv.; a saturated 5-, 6- or 7-membered heteromonocyclic group containing 1 or 2 nitrogen atoms and/or 1 or 2 oxygen atoms, for example 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-homopiperazinyl, morpholino, etc.;

en mettet aza- eller diazabicyklo-hydrokarbongruppe såsom et 6-5-ringsystem (for eksempel 1,4-diazabicyklo[4.3.0]nonan-4-yl, 2,5-diazabicyklo[4. 3.0]nonan-2-yl, 3-azabicykloC 4.3.0]nonan-3-yl, osv.), et 6-6-ringsystem (for eksempel 1,4-diazabicyklo[4 . 4.0]-dekan-4-yl, osv.), osv.; a saturated aza or diazabicyclo hydrocarbon group such as a 6-5 ring system (for example 1,4-diazabicyclo[4.3.0]nonan-4-yl, 2,5-diazabicyclo[4.3.0]nonan-2-yl, 3-azabicyclo[4.3.0]nonan-3-yl, etc.), a 6-6 ring system (for example, 1,4-diazabicyclo[4.4.0]-decan-4-yl, etc.), etc.;

en mettet 5- eller 6-leddet heteromonocyklisk gruppe inneholdende 1 eller 2 nitrogenatomer og 1 eller 2 svovelatomer, for eksempel 3-tiazolidinyl, tiomorfolino, osv., a saturated 5- or 6-membered heteromonocyclic group containing 1 or 2 nitrogen atoms and 1 or 2 sulfur atoms, for example 3-thiazolidinyl, thiomorpholino, etc.,

og ftalimido, osv. and phthalimido, etc.

Den "N-holdige heterocykliske gruppe, som er dannet ved konjugasjon av R 7 , R 8 og det nabostilte nitrogenatom" kan ha 1-3 substituenter valgt blant hydroksy, lavere alkyl, lavere alkoksy, mono- eller di-(lavere alkyl)amino-lavere alkyl, hydroksy-lavere alkyl, forestret karboksy-lavere alkyl, cyklo-lavere alkyl-lavere alkyl, acyl, acyl-lavere alkyl, fenylsulfonyl eventuelt substituert med halogen, fenyl-lavere alkenyl og en gruppe med den generelle formel VI The "N-containing heterocyclic group, which is formed by conjugation of R 7 , R 8 and the adjacent nitrogen atom" can have 1-3 substituents selected from hydroxy, lower alkyl, lower alkoxy, mono- or di-(lower alkyl)amino -lower alkyl, hydroxy-lower alkyl, esterified carboxy-lower alkyl, cyclo-lower alkyl-lower alkyl, acyl, acyl-lower alkyl, phenylsulfonyl optionally substituted with halogen, phenyl-lower alkenyl and a group of the general formula VI

9 10 11 (hvor & har den ovenfor angitte betydning, og R , R og R hver betyr hydrogen eller lavere alkoksy). 9 10 11 (where & has the meaning given above, and R , R , and R each mean hydrogen or lower alkoxy).

"Mono- eller di-(lavere alkylamino", "lavere alkyl" og "forestret karboksy" i mono- eller di-(lavere alkyl)amino-lavere alkyl- og forestret karboksy-lavere alkylgruppene er hensiktsmessig de samme som eksemplifisert ovenfor. "Mono- or di-(lower alkylamino", "lower alkyl" and "esterified carboxy" in the mono- or di-(lower alkyl)amino-lower alkyl and esterified carboxy-lower alkyl groups are conveniently the same as exemplified above.

"Mono- eller di-(lavere alkyl)amino-lavere alkyl" kan mere foretrukket omfatte metylaminometyl, dimetylaminometyl, etylaminometyl, dietylaminometyl, N-metyl-N-etylaminometyl, dimetylaminoetyl, dietylaminoetyl, propylaminometyl, isopropylaminoetyl og lignende. "Mono- or di-(lower alkyl)amino-lower alkyl" can more preferably include methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, diethylaminomethyl, N-methyl-N-ethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, propylaminomethyl, isopropylaminoethyl and the like.

"Forestret karboksy-lavere alkyl" kan mer foretrukket omfatte metoksykarbonylmetyl, metoksykarbonyletyl, etoksykarbo-nylmetyl, etoksykarbonyletyl og lignende. "Esterified carboxy-lower alkyl" may more preferably include methoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl and the like.

"Cyklo-lavere alkyl-lavere alkyl" kan hensiktsmessig omfatte cyklopropylmetyl, 2-cyklopropyletyl, 3-cyklopropylpropyl, 2-cyklopropylbutyl, 5-cyklopropylpentyl, 6-cyklopropylheksyl, cyklobutylmetyl, 2-cyklopentyletyl, cykloheksylmetyl og lignende. "Cyclo-lower alkyl-lower alkyl" may suitably include cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylpropyl, 2-cyclopropylbutyl, 5-cyclopropylpentyl, 6-cyclopropylhexyl, cyclobutylmethyl, 2-cyclopentylethyl, cyclohexylmethyl and the like.

"Acyl" og "acyl"-delen i "acyl-lavere alkyl" kan hensiktsmessig omfatte lavere alkanoyl som eksemplifisert ovenfor, lavere alkylkarbamoyl (for eksempel metylkarbamoyl, etylkarbamoyl, iso-propylkarbamoyl, tert.butylkarbamoyl, pentylkarbamoyl, heksyl-karbamoyl, osv.), aroyl (for eksempel benzoyl, naftoyl, osv.), furoyl, tenoyl og lignende. "Acyl" and the "acyl" portion of "acyl-lower alkyl" may conveniently include lower alkanoyl as exemplified above, lower alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, tert.butylcarbamoyl, pentylcarbamoyl, hexylcarbamoyl, etc. ), aroyl (for example, benzoyl, naphthoyl, etc.), furoyl, thenoyl, and the like.

Foretrukne eksempler på "acyl-lavere alkyl" kan omfatte lavere alkyl-karbamoyl-lavere alkyl såsom metylkarbamoylmetyl, isopropylkarbamoylmetyl og lignende. Preferred examples of "acyl-lower alkyl" may include lower alkyl-carbamoyl-lower alkyl such as methylcarbamoylmethyl, isopropylcarbamoylmethyl and the like.

"Fenylsulfonyl eventuelt substituert med halogen" kan hensiktsmessig omfatte fenylsulfonyl, klorfenylsulfonyl, brom-fenylsulfonyl, fluorfenylsulfonyl, diklorfenylsulfonyl og lignende. "Phenylsulfonyl optionally substituted with halogen" can conveniently include phenylsulfonyl, chlorophenylsulfonyl, bromophenylsulfonyl, fluorophenylsulfonyl, dichlorophenylsulfonyl and the like.

"Fenyl-lavere alkenyl" kan hensiktsmessig omfatte styryl, cinnamyl og lignende. "Phenyl-lower alkenyl" may suitably include styryl, cinnamyl and the like.

Hensiktsmessige grupper med den generelle formel VI Appropriate groups of the general formula VI

9 10 11 9 10 11

(hvor £, R , R og R har den ovenfor angitte betydning) kan omfatte fenyl, metoksyfenyl, dimetoksyfenyl, trimetoksyfenyl, (where £, R , R and R have the meaning given above) may include phenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl,

etoksyfenyl, benzyl, metoksybenzy1, dimetoksybenzyl, trimetoksy-benzyl, dietoksybenzy] og lignende. ethoxyphenyl, benzyl, methoxybenzyl, dimethoxybenzyl, trimethoxybenzyl, diethoxybenzyl] and the like.

"Lavere alkylen" kasn hensiktsmessig omfatte lineære eller forgrenete grupper såsom metylen, etylen, metylmetylen, metyl-etylen, trimetylen, pentametylen, heksametylen, etyletylen, propylen og lignende. "Lower alkylene" can suitably include linear or branched groups such as methylene, ethylene, methylmethylene, methyl-ethylene, trimethylene, pentamethylene, hexamethylene, ethylethylene, propylene and the like.

"Lavere alkylen" kan være substituert med lavere alkyliden såsom metylen, estyliden, propyliden, butyliden og lignende. "Lower alkylene" may be substituted with lower alkylidene such as methylene, ethylidene, propylidene, butylidene and the like.

"Lavere alkylen substituert med lavere alkyliden" kan hensiktsmessig omfatte metylenetylen, etylidenetylen, metylen-propylen og lignende. "Lower alkylene substituted with lower alkylidene" may suitably include methyleneethylene, ethylideneethylene, methylene-propylene and the like.

Hensiktsmessige farmasøytisk akseptable salter av de frem-stilte forbindelser med den generelle formel I er konvensjonelle ikke-toksiske salter og kan omfatte et salt med en organisk eller uorganisk syre såsom maleinsyre, fumarsyre, vinsyre, sitronsyre, eddiksyre, benzoesyre, saltsyre, svovelsyre, salpetersyre, jod-hydrogensyre, fosforsyre og lignende. Suitable pharmaceutically acceptable salts of the prepared compounds of the general formula I are conventional non-toxic salts and may comprise a salt with an organic or inorganic acid such as maleic acid, fumaric acid, tartaric acid, citric acid, acetic acid, benzoic acid, hydrochloric acid, sulfuric acid, nitric acid , hydroiodic acid, phosphoric acid and the like.

De nye forbindelser med den generelle formel I kan ifølge oppfinnelsen fremstilles ved nedenstående fremgangsmåter. According to the invention, the new compounds with the general formula I can be prepared by the following methods.

hvor where

1 2 7<8>1 2 7<8>

Ar, R , R , R , R , R , A og B hver har den ovenfor angitte betydning, Ar, R , R , R , R , R , A and B each have the above meaning,

R<1>betyr lavere alkanoyl eller forestret karboksy, R<1> means lower alkanoyl or esterified carboxy,

cl cl

Rk 1 betyr hydroksy-lavere alkyl, Rk 1 means hydroxy-lower alkyl,

2 2

R betyr hydrogen eller lavere alkyl, R means hydrogen or lower alkyl,

a a

7 8 7 8

R og R til sammen danner ftalimido eller 4-(lavere alkanoyl)-a a R and R together form phthalimido or 4-(lower alkanoyl)-a a

piperazin-1-yl, piperazin-1-yl,

7 8 7 8

Rk og R^ begge betyr hydrogen eller til sammen danner piperazin-1-yl, Rk and R^ both represent hydrogen or together form piperazin-1-yl,

1 2 1 2

R betyr lavere alkyl, hydroksy-lavere alkyl, cyklo-lavere alkyl-lavere alkyl, acyl, acyl-lavere alkyl, fenylsulfonyl eventuelt substituert med halogen eller en gruppe med den generelle formel VI R means lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl-lower alkyl, acyl, acyl-lower alkyl, phenylsulfonyl optionally substituted with halogen or a group of the general formula VI

SL har den ovenfor angitte betydning, SL has the meaning set out above,

9 10 11 9 10 11

R , R og R hver betyr hydrogen eller lavere alkoksy, A^ betyr en valensbinding eller lavere alkylen, R , R , and R each mean hydrogen or lower alkoxy, A^ means a valence bond or lower alkylene,

A2betyr etylen eller metylenetylen, og A2 means ethylene or methylene ethylene, and

X betyr en syrerest. X means an acid residue.

Hver av definisjonesne ovenfor er den samme som eksemplifisert ovenfor. Each of the above definitions is the same as exemplified above.

Foretrukne eksempler på en "syrerest" kan omfatte halogen som nevnt ovenfor, acyloksy (for eksempel mesyloksy, benzen-sulfonyloksy, tosyloksy, osv.) og lignende. Preferred examples of an "acid residue" may include halogen as mentioned above, acyloxy (for example, mesyloxy, benzenesulfonyloxy, tosyloxy, etc.) and the like.

Fremgangsmåtene til fremstilling av de nye forbindelser med den generelle formel I forklares nærmere i det følgende. The methods for preparing the new compounds with the general formula I are explained in more detail below.

Fremgangsmåtevariant 1 Method variant 1

Forbindelsen med den generelle formel Ia eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel VII eller et salt derav med en forbindelse med den generelle formel VIII eller et salt derav. The compound of the general formula Ia or a salt thereof can be prepared by reacting a compound of the general formula VII or a salt thereof with a compound of the general formula VIII or a salt thereof.

Egnede salter av forbindelsene med de generelle formler VII og VIII er de samme som de, som er eksemplifisert for forbindelsen med den generelle formel I. Suitable salts of the compounds of general formulas VII and VIII are the same as those exemplified for the compound of general formula I.

Denne reaksjon kan utføres på vanlig måte til aminering av halogenerende hydrokarboner. This reaction can be carried out in the usual way for the amination of halogenating hydrocarbons.

Reaksjonen utføres typisk i et konvensjonelt oppløsnings-middel såsom vann, metanol, etanol, isopropylalkohol, dioksan, tetrahydrofuran, N,N-dimetylformamid, metylenklorid, kloroform eller et hvilket som helst annet organisk oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. The reaction is typically carried out in a conventional solvent such as water, methanol, ethanol, isopropyl alcohol, dioxane, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, chloroform or any other organic solvent, which does not adversely affect the reaction.

Reaksjonstemperaturen er ikke kritisk, og reaksjonen kan ut-føres under temperaturbetingelser varierende fra vkjøling til oppvarmning. The reaction temperature is not critical, and the reaction can be carried out under temperature conditions varying from cooling to heating.

Reaksjonen kan også utføres i nærvær av en uorganisk base såsom et alkalimetallhydrid (for eksempel natriumhydrid, kalium-hydrid, osv.), et jordalkalimetallhydrid (for eksempel kalsium-hydrid, magnesiumhydrid, osv.), et alkalimetallhydroksy (for eksempel natriumhydrksyd, kaliumhydroksyd, osv.), et alkali-metallkarbonat eller -hydrogenkarbonat (for eksempel natrium-karbonat, kaliumkarbonat, natriumhydrogenkarbonat, kalium-hydrogenkarbonat, osv.) eller en organisk base såsom tertiære aminer (for eksempel trietylamin, pyridin, N,N-dimetyl-anilin, osv.) eller lignende. The reaction can also be carried out in the presence of an inorganic base such as an alkali metal hydride (for example, sodium hydride, potassium hydride, etc.), an alkaline earth metal hydride (for example, calcium hydride, magnesium hydride, etc.), an alkali metal hydroxy (for example, sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate or hydrogen carbonate (for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) or an organic base such as tertiary amines (for example, triethylamine, pyridine, N,N-dimethylaniline , etc.) or similar.

Denne reaksjon kan også utføres i nærvær av et alkalimetall-halogenid (for eksempel natriumjodid, kaliumjodid, osv.) eller lignende. This reaction can also be carried out in the presence of an alkali metal halide (eg sodium iodide, potassium iodide, etc.) or the like.

Fremgangsmåtevariant 2 Method variant 2

Forbindelsen med den generelle formel Ib eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel IX eller et salt derav med en forbindelse med den generelle formel VIII eller et salt derav. The compound of the general formula Ib or a salt thereof can be prepared by reacting a compound of the general formula IX or a salt thereof with a compound of the general formula VIII or a salt thereof.

Egnede salter av forbindelsene med de generelle formler VIII og IX er de samme som de, som er eksemplifisert for forbindelsen med den generelle formel I. Suitable salts of the compounds of the general formulas VIII and IX are the same as those exemplified for the compound of the general formula I.

Reaksjonen kan utføres på i det vesentlige samme måte som beskrevet under fremgangsmåtevariant 1. Følgelig henvises det til reaksjonsmåten og -betingelsene beskrevet der. The reaction can be carried out in essentially the same way as described under method variant 1. Accordingly, reference is made to the reaction method and conditions described there.

F r e m g a n g s m å t e v a r i a n t 3 How to proceed 3

Forbindelsen med den generelle formel Id eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel Ic eller et salt derav med formaldehyd og en forbindelse med den generelle formel VIII eller et salt derav. The compound of the general formula Id or a salt thereof can be prepared by reacting a compound of the general formula Ic or a salt thereof with formaldehyde and a compound of the general formula VIII or a salt thereof.

Egnede salter av forbindelsen med den generelle formel VIII er de samme som de, som er eksemplifisert for forbindelsen med den generelle formel I. Suitable salts of the compound of general formula VIII are the same as those exemplified for the compound of general formula I.

Reaksjonen kan utføres på samme måte som den velkjente Mannich-reaksjon. The reaction can be carried out in the same way as the well-known Mannich reaction.

Denne reaksjon utføres typisk i et oppløsningsmiddel under oppvarmning. This reaction is typically carried out in a solvent under heating.

Egnede oppløsningsmidler kan omfatte alkohol (for eksempel metanol, etanol, isopropylalkohol, osv.), eddiksyre, halogenerte hydrokarboner (for eksempel diklormetan, dikloretan, kloroform, karbontetraklorid, osv.), vann, acetonitril, eter (for eksempel dietyleter, dioksan, osv.), N,N-dimetylformamid eller et hvilket som helst annet oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. Suitable solvents may include alcohol (for example, methanol, ethanol, isopropyl alcohol, etc.), acetic acid, halogenated hydrocarbons (for example, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.), water, acetonitrile, ether (for example, diethyl ether, dioxane, etc. .), N,N-dimethylformamide or any other solvent, which does not adversely affect the reaction.

Reaksjonen kan fortrinnsvis utføres under sure betingelser under anvendelse av eddiksyre, saltsyre, svovelsyre, en kationisk ionebytterharpiks eller lignende. The reaction can preferably be carried out under acidic conditions using acetic acid, hydrochloric acid, sulfuric acid, a cationic ion exchange resin or the like.

Fremgangsmåtevariant 4 Method variant 4

Forbindelsen med den generelle formel If eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel le eller et salt derav med en forbindelse med den generelle formel VIII eller et salt derav, hvorefter den resulterende forbindelse reduseres. The compound of the general formula If or a salt thereof can be prepared by reacting a compound of the general formula Ie or a salt thereof with a compound of the general formula VIII or a salt thereof, after which the resulting compound is reduced.

Det første trinn i reaksjonen utføres vanligvis i et konvensjonelt oppløsningsmiddel såsom vann, metanol, etanol, propanol, tetralin, tetrahydrofuran, dioksan, kloroform, benzen, toluen, dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. The first step of the reaction is usually carried out in a conventional solvent such as water, methanol, ethanol, propanol, tetralin, tetrahydrofuran, dioxane, chloroform, benzene, toluene, dimethylformamide, dimethylsulfoxide or any other organic solvent, which does not adversely affect the reaction direction.

Reaksjonen utføres fortrinnsvis i nærvær av en syre såsom en uorganisk syre (for eksempel saltsyre, svovelsyre, polyfosfor-syre, osv.), en organisk syre (for eksempel trifluoreddiksyre, benzensulfonsyre, toluensulfonsyre, osv.) eller lignende. The reaction is preferably carried out in the presence of an acid such as an inorganic acid (for example hydrochloric acid, sulfuric acid, polyphosphoric acid, etc.), an organic acid (for example trifluoroacetic acid, benzenesulfonic acid, toluenesulfonic acid, etc.) or the like.

Reaksjonen kan også utføres under dehydratiseringsbeting-elser såsom azeotrop dehydratisering i nærvær av et dehydrati-seringsmiddel (for eksempel magnesiumsulfat, vannfritt sink-klorid, fosforpentoksyd, zeolitt, silikagel, osv.) eller lignende. The reaction can also be carried out under dehydration conditions such as azeotropic dehydration in the presence of a dehydrating agent (for example magnesium sulfate, anhydrous zinc chloride, phosphorus pentoxide, zeolite, silica gel, etc.) or the like.

Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved omgivelsestemperatur eller under oppvarmning. The reaction temperature is not critical, and the reaction is usually carried out at ambient temperature or under heating.

Reduksjonen i det annet trinn kan utføres ved en konvensjonell metode, for eksempel ved kjemisk eller katalytisk reduksjon. The reduction in the second step can be carried out by a conventional method, for example by chemical or catalytic reduction.

Foretrukne eksempler på reduksjonsmidler til anvendelse ved den kjemiske reduksjon er litiumaluminiumhydrid, diboran, natriumborhydrid, bortetrahydrofuran og lignende. Preferred examples of reducing agents for use in the chemical reduction are lithium aluminum hydride, diborane, sodium borohydride, boron tetrahydrofuran and the like.

Foretrukne eksempler på katalysatorer til anvendelse ved den katalytiske reduksjon er vanlige katalysatorer såsom platina-katalysatorer (for eksempel platinaplate, platinasvamp, platina-sort, kolloidalt, platina, platinaoksyd, osv.), palladiumkata-lysatorer (for eksempel palladiumsvamp, palladiumsort, palladium-oksyd, palladium/kull, kolloidalt palladium, osv.) eller lignende. Preferred examples of catalysts for use in the catalytic reduction are common catalysts such as platinum catalysts (for example, platinum plate, platinum sponge, platinum black, colloidal, platinum, platinum oxide, etc.), palladium catalysts (for example, palladium sponge, palladium black, palladium- oxide, palladium/charcoal, colloidal palladium, etc.) or the like.

Reduksjonen utføres vanligvis i et oppløsningsmiddel såsom vann, alkohol (for eksempel metanol, etanol, osv.), tetrahydro furan eller lignende og fortrinnsvis under noe mildere betingelser såsom under avkjøling, ved romtemperatur eller under oppvarmning. The reduction is usually carried out in a solvent such as water, alcohol (for example methanol, ethanol, etc.), tetrahydrofuran or the like and preferably under somewhat milder conditions such as under cooling, at room temperature or under heating.

Fremgangsmåtevariant 5 Method variant 5

Forbindelsen med den generelle formel Ih eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel lg eller et salt derav med en forbindelse med den generelle formel XI. The compound of the general formula Ih or a salt thereof can be prepared by reacting a compound of the general formula Ig or a salt thereof with a compound of the general formula XI.

Reaksjonen utføres typisk i et konvensjonelt oppløsnings-middel såsom acetonitril, halogenert hydrokarbon som eksemplifisert ovenfor, alkohol som eksemplifisert ovenfor eller et hvilket som helst annet oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning, og fortrinnsvis i nærvær av en uorganisk eller organisk base som eksemplifisert under fremgangsmåtevariant 1, et salt av en oranisk syre (for eksempel natriumacetat, osv.) eller lignende. The reaction is typically carried out in a conventional solvent such as acetonitrile, halogenated hydrocarbon as exemplified above, alcohol as exemplified above or any other solvent which does not adversely affect the reaction, and preferably in the presence of an inorganic or organic base as exemplified under process variant 1, a salt of an oranic acid (for example sodium acetate, etc.) or the like.

Reaksjonstemperaturen er ikke kritisk, og reaksjonen kan ut-føres under temperaturbetingelser varierende fra avkjøling til oppvarmning. The reaction temperature is not critical, and the reaction can be carried out under temperature conditions varying from cooling to heating.

Fremgangsmåtevariant 6 Method variant 6

Forbindelsen med den generelle formel Ij er et salt derav kan fremstilles ved å underkaste en forbindelse med den generelle formel li eller et salt derav solvolyse. The compound of the general formula Ij is a salt thereof can be prepared by subjecting a compound of the general formula li or a salt thereof to solvolysis.

Solvolysen kan utføres ved en konvensjonell metode såsom hydrolyse, aminolyse, alkoholyse eller lignende. The solvolysis can be carried out by a conventional method such as hydrolysis, aminolysis, alcoholysis or the like.

Blant disse metoder foretrekkes aminolyse og hydrolyse. Among these methods, aminolysis and hydrolysis are preferred.

Aminolysen utføres typisk i et konvensjonelt oppløsnings-middel (for eksempel vann, alkohol som eksemplifisert ovenfor, halogenert hydrokarbon som eksemplifisert ovenfor eller lignende) under anvendelse av hydrazin eller ammoniakk eller lignende. The aminolysis is typically carried out in a conventional solvent (for example water, alcohol as exemplified above, halogenated hydrocarbon as exemplified above or the like) using hydrazine or ammonia or the like.

Hydrolysen utføres typisk i nærvær av en syre (for eksempel saltsyre, svovelsyre, eddiksyre, trifluoreddiksyre, p-toluensulfonsyre, osv.) eller en base (for eksempel natriumhydroksyd, natriumetoksyd, trietylamin, osv.) i et oppløsningsmiddel såsom alkohol som eksemplifisert ovenfor, benzen eller et hvilket som helst annet oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. The hydrolysis is typically carried out in the presence of an acid (for example, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, etc.) or a base (for example, sodium hydroxide, sodium ethoxide, triethylamine, etc.) in a solvent such as alcohol as exemplified above, benzene or any other solvent which does not adversely affect the reaction.

Reaksjonstemperaturen er ikke kritisk, og reaksjonen kan ut-føres ved en hvilken som helst temperatur varierende fra av-kjøling til oppvarmning. The reaction temperature is not critical, and the reaction can be carried out at any temperature varying from cooling to heating.

Fremgangsmåtevariant 7 Method variant 7

Forbindelsen med den generelle formel Im eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel Ik eller et salt derav med en forbindelse med den generelle formel XII The compound of the general formula Im or a salt thereof can be prepared by reacting a compound of the general formula Ik or a salt thereof with a compound of the general formula XII

hvor X har den ovenfor angitte betydning, og R 1 3 betyr lavere alkyl, hvorefter det omsettes med etylendiamin eller et salt derav. where X has the meaning given above, and R 1 3 means lower alkyl, after which it is reacted with ethylenediamine or a salt thereof.

Egnede salter av forbindelsen med den generelle formel XII og etylendiamin er de samme som de, som er eksemplifisert for forbindelsen med den generelle formel I. Suitable salts of the compound of general formula XII and ethylenediamine are the same as those exemplified for the compound of general formula I.

Det første trinn i reaksjonen utføres vanligvis i et opp-løsningsmiddel såsom metanol, etanol eller et hvilket som helst annet oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. The first step of the reaction is usually carried out in a solvent such as methanol, ethanol or any other solvent which does not adversely affect the reaction.

Denne reaksjon kan utføres i nærvær av en base som nevnt ovenfor. This reaction can be carried out in the presence of a base as mentioned above.

Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres fortrinnsvis ved omgivelsestemperatur eller under oppvarmning. The reaction temperature is not critical, and the reaction is preferably carried out at ambient temperature or under heating.

Det utvundne produkt kan omsettes med etylendiamin uten isolering. The recovered product can be reacted with ethylenediamine without isolation.

Omsetningen mellom den ovenfor utvundne forbindelse og etylendiamin eller et salt derav utføres vanligvis i et opp-løsningsmiddel såsom metanol, etanol eller et hvilket som helst annet oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. The reaction between the above-derived compound and ethylenediamine or a salt thereof is usually carried out in a solvent such as methanol, ethanol or any other solvent which does not adversely affect the reaction.

Fremgangsmåtevariant 8 Method variant 8

Forbindelsen med den generelle formel lp eller et saltderav kan fremstilles ved å redusere en forbindelse med den generelle formel In eller et salt derav. The compound of the general formula Ip or a salt thereof can be prepared by reducing a compound of the general formula In or a salt thereof.

Reduksjonen kan utføres på samme måte som beskrevet for det annet trinn i fremgangsmåtevariant 4. The reduction can be carried out in the same way as described for the second step in method variant 4.

De nye forbindelser og salter derav, som er fremstilt ved de ovenfor beskrevne fremgangsmåtederivanter, kan isoleres fra reaksjonsblandingen og renses på konvensjonell måte. The new compounds and their salts, which are prepared by the process derivatives described above, can be isolated from the reaction mixture and purified in a conventional manner.

Alle forbindelsene Ia-Ip ligger innenfor omfanget av den generelle formel I, og med hensyn til saltene av forbindelsene Ia-Ip henvises som til saltene av forbindelsene med den generelle formel I. All the compounds Ia-Ip are within the scope of the general formula I, and with regard to the salts of the compounds Ia-Ip are referred to as the salts of the compounds of the general formula I.

Noen av de i de ovenfor beskrevne fremgangsmåtederivanter anvendte utgangsforbindelser er hittil ukjente og kan fremstilles ifølge nedenstående fremgangsmåte A, fremstilling 1-7 eller en kjemisk ekvivalent derav. Some of the starting compounds used in the process derivatives described above are hitherto unknown and can be prepared according to the following process A, preparation 1-7 or a chemical equivalent thereof.

hvor where

Ar, R 3 og B hver har den ovenfor angitte betydning, Ar, R 3 and B each have the meaning indicated above,

1 1

Rc betyr forestret karboksy, Rc means esterified carboxy,

2 2

Rk betyr lavere alkyl, og Rk means lower alkyl, and

Ha£ betyr halogen. Ha£ means halogen.

Fremgangsmåten til fremstilling av utgangsforbindelsene med den generelle formel XIV ifølge oppfinnelsen forklares nærmere i det følgende. The process for preparing the starting compounds with the general formula XIV according to the invention is explained in more detail below.

Fremgangsmåte A Procedure A

Forbindelsen med den generelle formel XIV eller et salt derav kan fremstilles ved å omsette en forbindelse med den generelle formel XIII eller et salt derav med et halogenerings-middel. The compound of the general formula XIV or a salt thereof can be prepared by reacting a compound of the general formula XIII or a salt thereof with a halogenating agent.

Egnede salter av forbindelsene med de generelle formler XIII og XIV er de samme som de, som er eksemplifisert for forbindelsen med den generelle formel I. Suitable salts of the compounds of the general formulas XIII and XIV are the same as those exemplified for the compound of the general formula I.

Hensiktsmessige eksempler på de halogeneringsmidler, som kan anvendes ved denne fremgangsmåte, kan omfatte konvensjonelle halogeneringsmidler såsom fosforoksyhalogenid (for eksempel fos-foroksybromid, fos foroksyklorid, osv.), fosforpentahalogenid (for eksempel fosforpentabromid, fosforpentaklorid, fosforpenta-fluorid, osv.), fosfortrihalogenid (for eksempel fosfortribromid, fosfortriklorid, fosfortrifluorid, osv.), tionylhalogenid (for eksempel tionylklorid, tionylbromid, osv.), trifenylfosfin-dihalogenid (for eksempel trifenylfosfindiklorid, trifenylfosfin-dibtromid, osv.) eller lignende. Appropriate examples of the halogenating agents which can be used in this method may include conventional halogenating agents such as phosphorus oxyhalide (for example phosphorus oxybromide, phosphorus oxychloride, etc.), phosphorus pentahalide (for example phosphorus pentabromide, phosphorus pentachloride, phosphorus pentafluoride, etc.), phosphorus trihalide (for example, phosphorus tribromide, phosphorus trichloride, phosphorus trifluoride, etc.), thionyl halide (for example, thionyl chloride, thionyl bromide, etc.), triphenylphosphine dihalide (for example, triphenylphosphine dichloride, triphenylphosphine dibromide, etc.) or the like.

Reaksjonen utføres vanligvis i et konvensjonelt oppløsnings-middel såsom metylenklorid, kloroform, karbontetraklorid, benzen, tetrahydrofuran, dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløsningsmiddel, som ikke påvirker reaksjonen i ugunstig retning. Hvis halogeneringsmidlet er flytende, kan det også anvendes som oppløsningsmiddel. The reaction is usually carried out in a conventional solvent such as methylene chloride, chloroform, carbon tetrachloride, benzene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or any other organic solvent which does not adversely affect the reaction. If the halogenating agent is liquid, it can also be used as a solvent.

Det skal videre bemerkes, at utgangsforbindelsene med den generelle formel XIV også er nyttige til behandling av cerebrovaskulære sykdommer. It should further be noted that the starting compounds of the general formula XIV are also useful for the treatment of cerebrovascular diseases.

Pyrimidinderivatene med den generelle formel I og farma-søytisk akseptable salter derav har vist seg å være nyttige til behandling av cerebrovaskulære sykdommer såsom cerebral apopleksi (for eksempel hjerneblødning, hjerneinfarkt, forbigående cerebrale ischæmiske anfall) eller lignende. The pyrimidine derivatives of the general formula I and pharmaceutically acceptable salts thereof have been found to be useful in the treatment of cerebrovascular diseases such as cerebral apoplexy (eg cerebral haemorrhage, cerebral infarction, transient cerebral ischemic attacks) or the like.

Til påvisning av anvendeligheten av forbindelser med den genrelle formel I er farmakologiske testdata angitt i det følgende. In order to demonstrate the usefulness of compounds of the general formula I, pharmacological test data are given below.

Test 1. Virkning på lipidperoksydproduksjonen i rottehjernemitokondrier Test 1. Effect on lipid peroxide production in rat brain mitochondria

Metode Method

Hjernemitokondrier fraWistar-hannrotter ble inkubert med 100 uM askorbinsyre, 20 pM FeSO^og testlegemiddel i 1 time ved 37°C. Det malondialdehyd, som ble dannet i inkubasjonsbland-ingen, ble målt ved tiobarbitursyre-metoden i henhold til Shimada et al. (Biochem. Biophys. Acta 489, 1977, s. 163-172). Brain mitochondria from male Wistar rats were incubated with 100 µM ascorbic acid, 20 µM FeSO 4 and test drug for 1 hour at 37°C. The malondialdehyde formed in the incubation mixture was measured by the thiobarbituric acid method according to Shimada et al. (Biochem. Biophys. Acta 489, 1977, pp. 163-172).

Testforbindelser Test connections

Følgende testforbindelser ble oppløst i vann: The following test compounds were dissolved in water:

De i tabellen angitte forbindelser inhiberte signifikant malondialdehyd-dannelsen i rottehjernemitokondrier ved en dose på 10~<4>g/ml. The compounds listed in the table significantly inhibited malondialdehyde formation in rat brain mitochondria at a dose of 10~<4>g/ml.

Test 2. Virkning på overlevelsestiden hos mus, som ble utsatt Test 2. Effect on survival time in mice, which were exposed

for anoksi (100 % N2) for anoxia (100% N2)

Metode Method

Et par ICR-hannmus på samme alder ble holdt i et tett glass-kammer, hvori det sirkulerte en strøm av nitrogengass, og overlevelsestiden ble målt. En mus ble forbehandlet intraperitonealt med testforbindelsen og en annen med bæreren 30 minutter før for-søket . A pair of ICR male mice of the same age were kept in a sealed glass chamber, in which a stream of nitrogen gas circulated, and the survival time was measured. One mouse was pretreated intraperitoneally with the test compound and another with the vehicle 30 minutes before the experiment.

Testforbindelser Test connections

Testforbindelsene ble oppløst i saltvann. The test compounds were dissolved in saline.

De nye forbindelser med den generelle formel I og farmasøy-tisk akseptable salter derav fremstilles ifølge foreliggende oppfinnelse kan anvendes i form av et konvensjonelt farmasøytisk preparat, for eksempel i en fast, halvfast eller flytende form, som inneholder et aktivt stoff ifølge oppfinnelsen i blanding med en organisk eller uorganisk bærer eller eksipiens, som er egnet til ekstern, enteral eller parenteral anvendelse. Den aktive bestanddel kan for eksempel være blandet med de vanlige ikke-toksiske, farmasøytisk akseptable bærere for tabletter, pelleter, kapsler, suppositorier, oppløsninger, emkulsjoner, suspensjoner og en hvilken som helst annen form, som er egnet til anvendelse. De bærere, som kan anvendes, er vann, glukose, laktose, acacia-gummi, gelatin, mannitol, stivelsespasta, magnesimtrisilikat, talkum, maisstivelse, keratin, kolloidalt silisiumdioksyd, potet-stivelse, urinstoff og andre bærere, som er egnet til anvendelse ved fremstilling av preparater i fast, halvfast eller flytende form, og dessuten kan hjelpemidler, stabiliseringsmidler, for-tykningsmidler og farvestoffer og parfymer anvendes. De farma-søytiske preparater kan også inneholde konserveringsmidler eller bakteriostatiske midler for å holde den aktive bestanddel i de ønskede preparater stabile i deres virkning. Den aktive forbindelse fremstilt ifølge oppfinnelsen er inkorporert i det farmasøytiske preparat i en mengde, som er tilstrekkelig til å gi den ønskede terapeutiske virkning på prosessen eller tilstanden av lidelsene. The new compounds with the general formula I and pharmaceutically acceptable salts thereof prepared according to the present invention can be used in the form of a conventional pharmaceutical preparation, for example in a solid, semi-solid or liquid form, which contains an active substance according to the invention in mixture with an organic or inorganic carrier or excipient, which is suitable for external, enteral or parenteral use. For example, the active ingredient may be mixed with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions and any other form suitable for use. The carriers that can be used are water, glucose, lactose, acacia gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silicon dioxide, potato starch, urea and other carriers suitable for use in production of preparations in solid, semi-solid or liquid form, and in addition auxiliaries, stabilizers, thickeners and dyes and perfumes can be used. The pharmaceutical preparations may also contain preservatives or bacteriostatic agents to keep the active ingredient in the desired preparations stable in their effect. The active compound produced according to the invention is incorporated into the pharmaceutical preparation in an amount sufficient to provide the desired therapeutic effect on the process or state of the disorders.

Mens en dose eller en terapeutisk virksom mengde av den nye forbindelse med den generelle formel I fremstilt ifølge den foreliggende oppfinnelse varierer efter alderen og tilstanden av hver enkelt pasient, som skal behandles, gies det generelt en daglig dose på ca. 0,1-100 mg/kg aktiv bestanddel til behandling av sykdommer. While a dose or a therapeutically effective amount of the novel compound of general formula I prepared according to the present invention varies according to the age and condition of each individual patient to be treated, a daily dose of approx. 0.1-100 mg/kg active ingredient for the treatment of diseases.

Oppfinnelsen belyses nærmere ved nedenstående fremstillinger og eksempler. The invention is explained in more detail by the representations and examples below.

FREMSTILLING 1 MANUFACTURE 1

1) Til en oppløsning av 475 g metyl-4-metyl-2-fenyl-6-(3-nitrofenyl)-1,6-dihydro-5-pyrimidinkarboksylat i 5 1 kloroform ble satt 1,9 kg aktivert mangandioksyd, og blandingen ble kokt' under tilbakeløpskjøling i 2 timer under kraftig omrøring. Efter avkjøling til romtemperatur ble mangandioksydet frafiltrert. Filtratet ble inndampet under vakuum, og det resterende bunnfall ble omkrystallisert fra 500 ml diisopropyleter. Krystallene ble frafiltrert, vasket med diisopropyleter og tørret under vakuum, hvilket ga 320 g metyl-6-metyl-4-(3-nitrofenyl)-2-fenyl-5-pyri-midinkarboksylat, smeltepunkt 128-130°C. 1) 1.9 kg of activated manganese dioxide was added to a solution of 475 g of methyl-4-methyl-2-phenyl-6-(3-nitrophenyl)-1,6-dihydro-5-pyrimidine carboxylate in 5 1 of chloroform, and the mixture was boiled under reflux for 2 hours with vigorous stirring. After cooling to room temperature, the manganese dioxide was filtered off. The filtrate was evaporated under vacuum, and the remaining precipitate was recrystallized from 500 ml of diisopropyl ether. The crystals were filtered off, washed with diisopropyl ether and dried under vacuum, which gave 320 g of methyl-6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate, melting point 128-130°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1725, 1590 og 1270 cm""<1.>IR spectrum (Nujo<l>)<:><v>max = 1725, 1590 and 1270 cm""<1.>

NMR-spektrum (dimetylsulfoksyd -dg): 5 (ppm) = 2,63 (3H, s), 3,77 (3H, s), 7,4-8,7 (9H, m). NMR spectrum (dimethylsulfoxide -dg): δ (ppm) = 2.63 (3H, s), 3.77 (3H, s), 7.4-8.7 (9H, m).

Massespektrum: 349 (M+). Mass spectrum: 349 (M+).

2) Til en suspensjon av 12,24 g 1itiumaluminiumhydrid i en blanding av 180 ml tørt tetrahydrofuran og 360 ml dietyleter ble det dråpevis satt en oppløsning av 45 g metyl-6-metyl-4-(3-nitrof enyl)-2-f enyl-5-pyrimidinkarboksylat. i 180 ml tørt tetrahydrofuran under avkjøling ved -50°C * -40°C. Overskytende litiumaluminiumhydrid ble nedbrutt ved forsiktig tilsetning til isvann. Den fraskilte organiske fase ble vasket med 400 ml 15 % ig svovelsyre og ekstrahert med 1 liter etylacetat. Den organiske fase ble suksessivt vasket med mettet vandig natriumhydrogenkarbonat og vandig natriumklorid og konsentrert under vakuum. Residuet ble omkrystallisert fra dietyleter, hvilket ga 30 g 5-hydroksy-metyl-6-met.yl-2-f enyl-4- ( 3-nitrof enyl) pyrimidin, smeltepunkt 1 77-178°C. 2) A solution of 45 g of methyl-6-methyl-4-(3-nitrophenyl)-2-f enyl-5-pyrimidine carboxylate. in 180 ml of dry tetrahydrofuran under cooling at -50°C * -40°C. Excess lithium aluminum hydride was decomposed by careful addition to ice water. The separated organic phase was washed with 400 ml of 15% sulfuric acid and extracted with 1 liter of ethyl acetate. The organic phase was successively washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride and concentrated under vacuum. The residue was recrystallized from diethyl ether, yielding 30 g of 5-hydroxy-methyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine, mp 177-178°C.

-1 IR-spektrum (Nujo<l>)<:><v>maks = 1590, 1360 og 1025 cm -1 IR spectrum (Nujo<l>)<:><v>max = 1590, 1360 and 1025 cm

NMR-spektrum (dimety1sul foksyd -dg): 5 (ppm) = 2,66 NMR spectrum (dimethylsulfoxide -dg): δ (ppm) = 2.66

(3H, s), 4,55 (2H, d, J=4Hz), 5,50 (1H, t, J=4Hz), 7,3-7,67 (3H, s), 4.55 (2H, d, J=4Hz), 5.50 (1H, t, J=4Hz), 7.3-7.67

(3H, m), 7,80 (1H, dd, J=8Hzog 8Hz), 8,1-8,6 (4H, ra), 8,67 (1H, dd, J=2Hz og 2Hz). (3H, m), 7.80 (1H, dd, J=8Hz and 8Hz), 8.1-8.6 (4H, ra), 8.67 (1H, dd, J=2Hz and 2Hz).

Massespektrum: 321 (M<+>). Mass spectrum: 321 (M<+>).

3) Til en oppløsning av 16,85 g fosfortribromid i en blanding av 150 ml benzen og 150 ml tetrahydrofuran ble det dråpevis satt en oppløsning av 30 g 5-hydroksymetyl-6-metyl-2-fenyl-4-(3-nitro-fenyl)pyrimidin i 150 ml tetrahydrofuran under avkjøling ved 7-10°C. Efter omrøring i 4 timer ved samme temperatur ble reaksjonsblandingen helt i 200 ml isvann, innstilt på pH 9,5 med mettet kaliumkarbonat og ekstrahert med 300 ml etylacetat. Efter frafiltrering av uoppløselig materiale ble den organiske fase vasket med mettet vandig natriumklorid, tørret over magnesiumsulfat og inndampet under vakuum. Residuet ble omkrystallisert fra dietyleter, hvilket ga 29,08 g 5-brommetyl-6-metyl-2-fenyl-4-(3-nitrofenyl)pyrimidin, smeltepunkt 163-164°C. 3) A solution of 30 g of 5-hydroxymethyl-6-methyl-2-phenyl-4-(3-nitro- phenyl)pyrimidine in 150 ml of tetrahydrofuran while cooling at 7-10°C. After stirring for 4 hours at the same temperature, the reaction mixture was poured into 200 ml of ice water, adjusted to pH 9.5 with saturated potassium carbonate and extracted with 300 ml of ethyl acetate. After filtering off insoluble material, the organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The residue was recrystallized from diethyl ether, yielding 29.08 g of 5-bromomethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine, mp 163-164°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1550, 1530 og 1350 cm"1. IR spectrum (Nujo<l>)<:><v>max = 1550, 1530 and 1350 cm"1.

NMR-spektrum (CDClg): 6 (ppm) = 2,80 (3H, s), 4,47 (2H, s), 7,35-7,55 (3H, m), 7,73 (1H, dd, J=8Hz og 8Hz), 8,17 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,3-8,6 (4H, m), 8,80 (1H, dd, J=2Hz og 2Hz). NMR spectrum (CDClg): δ (ppm) = 2.80 (3H, s), 4.47 (2H, s), 7.35-7.55 (3H, m), 7.73 (1H, dd , J=8Hz and 8Hz), 8.17 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.3-8.6 (4H, m), 8.80 (1H, dd, J=2Hz and 2Hz).

Massespektrum: 383, 385 (M<+>). Mass spectrum: 383, 385 (M<+>).

FREMSTILLING 2 MANUFACTURE 2

1) En blanding av 20 g 3-nitrobenzaldehyd, 13,25 g acetyl-aceton, 1,58 g eddiksyre og 0,45 g piperidin i 20 ml benzen ble kokt under tilbakeløpskjøling i 1 time under azeotrop dehydratisering. Til reaksjonsblandingen ble det satt 100 ml dietyleter. Blandingen ble suksessivt vasket med 50 ml vann og 50 ml av en mettet vandig oppløsning av natriumklorid, tørret over magnesiumsulfat og inndampet under vakuum. Det resterende stoff ble omkrystallisert fra eter, hvilket ga 16,5 g 1-acetyl-1-(3-nitro-benzyliden)aceton, smeltepunkt 92-95°C. 1) A mixture of 20 g of 3-nitrobenzaldehyde, 13.25 g of acetyl-acetone, 1.58 g of acetic acid and 0.45 g of piperidine in 20 ml of benzene was refluxed for 1 hour under azeotropic dehydration. 100 ml of diethyl ether was added to the reaction mixture. The mixture was successively washed with 50 ml of water and 50 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The residue was recrystallized from ether, yielding 16.5 g of 1-acetyl-1-(3-nitro-benzylidene)acetone, mp 92-95°C.

-1 IR-spektrum (Nujo<l>)<:>v ks = 1705, 1620, 915 og 810 cm -1 IR spectrum (Nujo<l>)<:>v ks = 1705, 1620, 915 and 810 cm

NMR-spektrum (dimety1sulfoksyd -dg): 5 (ppm) - 2,25 NMR spectrum (dimethylsulfoxide -dg): δ (ppm) - 2.25

(3H, s), 2,47 (3H, s), 7,5-8,0 (3H, m), 8,1-8,5 (2H, m). 2) En blanding av 10 g 1-acetyl-1-(3-nitrobenzyliden)aceton, 8,06 g benzamidin-hydroklorid ogh 8,4 ml trietylamin i 100 ml n-butanol ble kokt under tilbakeløpskjøling i 2 timer. Til reaksjonsblandingen ble det satt 100 ml etylacetat, hvorefter det suksessivt ble vasket med 100 ml vann og 100 ml 5 %ig saltsyre. Oppløsningsmidlet ble avdampet, og residuet ble omrørt med 100 ml etylacetat i 1 time. Krystallene ble oppsamlet ved filtrering, det ble tilsatt en blanding av 100 ml kloroform og 100 ml vann, og det hele ble instilt på pH 8,5 med mettet kaliumkarbonat. Den organiske fase ble inndampet under vakuum, hvilket ga 4,46 g 5-acetyl-4-metyl-6-(3-nitrofenyl)-2-fenyl-1,6-dihydropyrimidin, smeltepunkt 154-155°C. (3H, s), 2.47 (3H, s), 7.5-8.0 (3H, m), 8.1-8.5 (2H, m). 2) A mixture of 10 g of 1-acetyl-1-(3-nitrobenzylidene)acetone, 8.06 g of benzamidine hydrochloride and 8.4 ml of triethylamine in 100 ml of n-butanol was refluxed for 2 hours. 100 ml of ethyl acetate was added to the reaction mixture, after which it was successively washed with 100 ml of water and 100 ml of 5% hydrochloric acid. The solvent was evaporated and the residue was stirred with 100 ml of ethyl acetate for 1 hour. The crystals were collected by filtration, a mixture of 100 ml chloroform and 100 ml water was added, and the whole was adjusted to pH 8.5 with saturated potassium carbonate. The organic phase was evaporated under vacuum, giving 4.46 g of 5-acetyl-4-methyl-6-(3-nitrophenyl)-2-phenyl-1,6-dihydropyrimidine, melting point 154-155°C.

IR-spektrum (Nujol)<:><v>maks = 1655, 1590, 1530, 1340 og IR spectrum (Nujol)<:><v>max = 1655, 1590, 1530, 1340 and

1245 cm~<1.>1245 cm~<1.>

NMR-spektrum (dimetylsulfoksyd -dg): 5 (ppm) = 2,23 NMR spectrum (dimethylsulfoxide -dg): δ (ppm) = 2.23

(3H, s), 2,50 (3H, s), 5,93 (1H, s), 7,3-8,2 (9H, m), 9,60 (1H, s) . (3H, s), 2.50 (3H, s), 5.93 (1H, s), 7.3-8.2 (9H, m), 9.60 (1H, s).

Massespektrum: 335 (M<+>). Mass spectrum: 335 (M<+>).

3) 1,25 g 5-acetyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin ble utvundet fra 3,43 g 5-acetyl-4-metyl-6-(3-nitrofenyl)-2-fenyl-1,6-dihydropyrimidin på samme måte som beskrevet under fremstilling 1(1), smeltepunkt 131-132°C. 3) 1.25 g of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine was recovered from 3.43 g of 5-acetyl-4-methyl-6-(3-nitrophenyl)-2- phenyl-1,6-dihydropyrimidine in the same way as described under preparation 1(1), melting point 131-132°C.

IR-spektrum (Nujo<l>)<:>vmak,- = 1770, 1530, 1348 og 1245 cm 1. IR spectrum (Nujo<l>)<:>vmak,- = 1770, 1530, 1348 and 1245 cm 1.

NMR-spektrum (dime t yl sul f oksyd - årb) 5 (ppm)~2,28 NMR spectrum (dimethyl sulfoxide - yrb) δ (ppm)~2.28

(3H, s), 2,60 (3H, s), 7,50-8,70 (9H, m). (3H, s), 2.60 (3H, s), 7.50-8.70 (9H, m).

Massespektrum: 334 (M+1). Mass spectrum: 334 (M+1).

4) En blanding av 3 g 5-acetyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin og 0,34 g natriumborhydrid i 110 ml metanol ble omrørt ved romtemperatur i 4 timer. Reaksjonsblandingen ble inndampet under vakuum, og residuet ble holdt i en blanding av etylacetat og vann. Den fraskilte organiske fase ble tørret over magnesiumsulfat og inndampet under vakuum. Det krystallinske residuum ble omkrystallisert fra en blanding av n-heksan og dietyleter, hvilket ga 2,3 g 5-(1-hydroksyetyl)-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 119-121°C. 4) A mixture of 3 g of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine and 0.34 g of sodium borohydride in 110 ml of methanol was stirred at room temperature for 4 hours. The reaction mixture was evaporated under vacuum, and the residue was kept in a mixture of ethyl acetate and water. The separated organic phase was dried over magnesium sulfate and evaporated under vacuum. The crystalline residue was recrystallized from a mixture of n-hexane and diethyl ether, yielding 2.3 g of 5-(1-hydroxyethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 119-121° C.

IR-spektrum (Nujol): vk<s= 3350, 1 585, 1535 og 1350 cm"<1.>IR spectrum (Nujol): vk<s= 3350, 1585, 1535 and 1350 cm"<1.>

NMR-spektrum (CDCl.^): 6 (ppm) - 1,62 (3H, d, J=7Hz), 1,96 (1H, bred), 2,88 (3H, s), 5,11 (1H, q, J=7Hz)f7,3-8,5 (9H, m). NMR spectrum (CDCl.^): δ (ppm) - 1.62 (3H, d, J=7Hz), 1.96 (1H, broad), 2.88 (3H, s), 5.11 (1H , q, J=7Hz)f7.3-8.5 (9H, m).

Massespektrum: 334 (M-1). Mass spectrum: 334 (M-1).

5) En oppløsning av 1,8 g 5-(1-hydrksyetyl)-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin i 10 ml tetrahydrofuran ble dryppet til en oppløsning av 0,34 ml fosfortribromid i 20 ml tetrahydrofuran under isavkjøling. Reaksjonsblandingen ble omrørt i 5 timer under samme betingelser og holdt i isvann og ekstrahert med etylacetat. Den organiske fase ble inndampet under vakuum. Residuet ble kromatografert på silikagel under eluering med kloroform. Fraksjonene inneholdende det ønskede prdukt ble kombinert og inndampet under vakuum. Residuet ble krystallisert fra diisopropyleter, hvilket ga 0,3 g 5-(1-brometyl)-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 133-134°C. 5) A solution of 1.8 g of 5-(1-hydroxyethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine in 10 ml of tetrahydrofuran was added dropwise to a solution of 0.34 ml of phosphorus tribromide in 20 ml tetrahydrofuran under ice-cooling. The reaction mixture was stirred for 5 hours under the same conditions and kept in ice water and extracted with ethyl acetate. The organic phase was evaporated under vacuum. The residue was chromatographed on silica gel eluting with chloroform. The fractions containing the desired product were combined and evaporated under vacuum. The residue was crystallized from diisopropyl ether, giving 0.3 g of 5-(1-bromomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 133-134°C.

-1 -1

IR-spektrum (Nudo<I>)<:><v>maks = 1530 og 1350 cm IR spectrum (Nudo<I>)<:><v>max = 1530 and 1350 cm

NMR-spektrum (CDC13): 5 (ppm) = 2,01 (3H, d, J=7Hz), 2,98 (3H, s), 5,4 (1H, q, J=7Hz), 7,3-8,2 (5H, m), 8,2-8,7 (4H, m) . NMR spectrum (CDCl 3 ): δ (ppm) = 2.01 (3H, d, J=7Hz), 2.98 (3H, s), 5.4 (1H, q, J=7Hz), 7.3 -8.2 (5H, m), 8.2-8.7 (4H, m).

Massespektrum: 397 (M<+>), 399. Mass spectrum: 397 (M<+>), 399.

FREMSTILLING 3 MANUFACTURE 3

1) En oppløsning av 25.2 g etyl-(2-(3,4-dimetoksybenzoy1)acetat og 17,9 g N,N-dimetylformamid-dimetylacetal i 100 ml tetrahydrofuran ble kokt under tilbakeløpskjøling i 18 timer under om-røring. Reaksjonsblandingen ble inndampet under vakuum, hvilket ga 31,09 g etyl-2-(3,4-dimetoksybenzoyl)-2-(dimetylaminometylen)-acetat i form av en olje. 1) A solution of 25.2 g of ethyl-(2-(3,4-dimethoxybenzoyl)acetate and 17.9 g of N,N-dimethylformamide-dimethylacetal in 100 ml of tetrahydrofuran was refluxed for 18 hours with stirring. The reaction mixture was evaporated under vacuum to give 31.09 g of ethyl 2-(3,4-dimethoxybenzoyl)-2-(dimethylaminomethylene)-acetate as an oil.

NMR-spektrum (dimetylsulfoksyd -dcb):5 (ppm) = 1,95 (3H, t, J=7Hz), 2,90 (6H, s), 3,7 9 (3H, s), 3,8 3 (3H, s), 3,9 2 (2H, q, J=7Hz), 7,02 (1H, d, J=7Hz), 7,30 (1H, d, J=2Hz), 7,3 5 (1H, dd, J=2 og 9Hz), 7,64 (1H, s). 2) En oppløsning av 31 g etyl 2-(3,4-dimetoksybenzoyl)-2-(dimetylaminometylen)acetat, 13,3 g acetoamidin-hydroklorid og 16,2 g trietylamin i 200 ml etanol ble kokt under tilbakeløps-kjøling i 10 timer under omrøring. Reaksjonsblandingen ble inndampet under vakuum, og residuet ble oppløst i en blanding av etylacetat og vann. Den fraskilte organiske fase vasket med saltvann, tørret over magnesiumsulfat og inndampet under vakuum. Residuet ble krystallisert fra etyleter, hvilket ga 14 g etyl-2-metyl-4-(3,4-dimetoksyfenyl)-5-pyrimidinkarboksylat, smeltepunkt 98-100°C. NMR spectrum (dimethyl sulfoxide -dcb): δ (ppm) = 1.95 (3H, t, J=7Hz), 2.90 (6H, s), 3.7 9 (3H, s), 3.8 3 (3H, s), 3.9 2 (2H, q, J=7Hz), 7.02 (1H, d, J=7Hz), 7.30 (1H, d, J=2Hz), 7.3 5 (1H, dd, J=2 and 9Hz), 7.64 (1H, s). 2) A solution of 31 g of ethyl 2-(3,4-dimethoxybenzoyl)-2-(dimethylaminomethylene)acetate, 13.3 g of acetoamidine hydrochloride and 16.2 g of triethylamine in 200 ml of ethanol was boiled under reflux for 10 hours while stirring. The reaction mixture was evaporated under vacuum, and the residue was dissolved in a mixture of ethyl acetate and water. The separated organic phase was washed with brine, dried over magnesium sulfate and evaporated under vacuum. The residue was crystallized from ethyl ether, giving 14 g of ethyl 2-methyl-4-(3,4-dimethoxyphenyl)-5-pyrimidine carboxylate, mp 98-100°C.

IR-spektrum (Nujol): vmaks = 1710, 1603, 1572, 1535 og 1510 cm"1. IR spectrum (Nujol): vmax = 1710, 1603, 1572, 1535 and 1510 cm"1.

NMR-spektrum (dimetylsulfoksyd -dg): 5 (ppm) = 1,17 (3H, t, J=7Hz), 2,72 (3H, s), 3,87 (6H,s), 4,25 (2H, q, J=7Hz), 6,92-7,33 (3H, m), 8,85 (1H, s). 3) 1,1 g 4-(3,4-dimetoksyfenyl)-5-hydroksymetyl-2-metylpyri-midin ble vunnet ut fra 7,6 g etyl-2-metyl-4-(3,4-dimetoksyfenyl)-5-pyrimidinkarboksylat på samme måte som beskrevet under fremstilling 2(4). NMR spectrum (dimethylsulfoxide -dg): δ (ppm) = 1.17 (3H, t, J=7Hz), 2.72 (3H, s), 3.87 (6H,s), 4.25 (2H , q, J=7Hz), 6.92-7.33 (3H, m), 8.85 (1H, s). 3) 1.1 g of 4-(3,4-dimethoxyphenyl)-5-hydroxymethyl-2-methylpyrimidine was obtained from 7.6 g of ethyl-2-methyl-4-(3,4-dimethoxyphenyl)-5 -pyrimidine carboxylate in the same way as described under preparation 2(4).

NMR-spektrum (dimetylsulfoksyd - dcb): 5 (ppm) = 2,65 (3H, s), 4,17 (6H, s), 4,52 (2H, d, J=5Hz), 5,47 (1H, t, J=5Hz), 6,93-7,20 (3H, m), 8,70 (1H, s). 4) 0,9 g 5-brommetyl-4-(3,4-dimetoksyfenyl)-2-metylpyrimidin ble utvundet fra 1,0 g 4-(3,4-dimetoksyfenyl)-5-hydroksymetyl-2-metylpyrimidin på samme måte som beskrevet under fremstilling 1(3). NMR spectrum (dimethyl sulfoxide - dcb): δ (ppm) = 2.65 (3H, s), 4.17 (6H, s), 4.52 (2H, d, J=5Hz), 5.47 (1H , t, J=5Hz), 6.93-7.20 (3H, m), 8.70 (1H, s). 4) 0.9 g of 5-bromomethyl-4-(3,4-dimethoxyphenyl)-2-methylpyrimidine was recovered from 1.0 g of 4-(3,4-dimethoxyphenyl)-5-hydroxymethyl-2-methylpyrimidine in the same manner as described under preparation 1(3).

IR-spektrum (Nujo<l>)<:>v k 1625, 1590 og 1515 cm"<1.>Massespektrum: 322, 324 (M<+>). IR spectrum (Nujo<l>)<:>v k 1625, 1590 and 1515 cm"<1.>Mass spectrum: 322, 324 (M<+>).

FREMSTILLING 4 MANUFACTURE 4

1) 17,4 g 2-(4-metylpiperazin-1-ylkarbonyl)-1-(3-nitrofenyl)-1 - buten-3-on ble utvundet fra 10 g 3-nitrobenzaldehyd og 20,4 g 1-acetoacetyl-4-metylpiperazin på samme måte som beskrevet under fremstilling 2(1). 1) 17.4 g of 2-(4-methylpiperazin-1-ylcarbonyl)-1-(3-nitrophenyl)-1-buten-3-one was recovered from 10 g of 3-nitrobenzaldehyde and 20.4 g of 1-acetoacetyl- 4-methylpiperazine in the same way as described under preparation 2(1).

IR-spektrum (Nujo<l>)<:><v>maks = 1630 og 1530 cm"<1>. Massespektrum: 317 (M+). 2) En blanding av 20 g 2-(4-metylpiperazin-1-ylkarbonyl)-1-(3-nitrofenyl)-1-buten-3-on, 9,9 g benzamidin-hydroklorid og 11,4 ml trietylamin i 200 ml n-butanol ble kokt under tilbakeløpskjøling i 2 timer. Efter avdampning av oppløsningsmidlet ble residuet oppløst i en suspensjon av 200 ml vann og 200 ml kloroform. Den fraskilte organiske fase ble vasket med mettet vandig natriumklorid og tørret over magnesiumsulfat. Til denne oppløsning ble satt 120 g aktivert mangandioksyd, og blandingen ble kokt under tilbakeløpskjøling i 1 time under kraftig omrøring. Efter avkjøling til romtemperatur ble mangandioksydet frafiltrert. Filtratet ble inndampet under vakuum, og residuet ble underkastet kolonnekromatografi på 200 g aluminiumoksyd under eluering med kloroform. Fraksjonene inneholdende den ønskede forbindelse ble kombinert og konsentrert under redusert trykk. Krystallene ble omkrystallisert fr dietyleter, hvilket ga 6-metyl-5-(4-metyl-piperazin- 1 -ylkarbonyl) -4- ( 3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 153-155°C. IR spectrum (Nujo<l>)<:><v>max = 1630 and 1530 cm"<1>. Mass spectrum: 317 (M+). 2) A mixture of 20 g of 2-(4-methylpiperazin-1-ylcarbonyl )-1-(3-nitrophenyl)-1-buten-3-one, 9.9 g of benzamidine hydrochloride and 11.4 ml of triethylamine in 200 ml of n-butanol were boiled under reflux for 2 hours. After evaporation of the solvent, the residue dissolved in a suspension of 200 ml of water and 200 ml of chloroform. The separated organic phase was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. To this solution was added 120 g of activated manganese dioxide, and the mixture was refluxed for 1 hour under vigorous stirring. After cooling to room temperature, the manganese dioxide was filtered off. The filtrate was evaporated under vacuum, and the residue was subjected to column chromatography on 200 g of alumina eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. The crystals were recrystallized from diethyl ether, which t gave 6-methyl-5-(4-methyl-piperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 153-155°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1634, 1530 og 1345 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1634, 1530 and 1345 cm"<1.>

FREMSTILLING 5 MANUFACTURE 5

Følgende forbindelser ble utvundet på samme måte som beskrevet under fremstilling 1, 2, 3 eller 4. 1 ) 5 --bremme ty.1-4-[ 2- (4- klorbenzyloksy) f enyl ]-2 , 6-dimety Ipyrimi - din, smeltepunkt 119 -121°C. The following compounds were recovered in the same manner as described under preparation 1, 2, 3 or 4. 1 ) 5 --bremme ty.1-4-[ 2-(4-chlorobenzyloxy)phenyl]-2 , 6-dimethyl Ipyrimi - din, melting point 119 -121°C.

IR-spektrum (Nujol): vmak,- 1600, 1585, 1550, 1240 og IR spectrum (Nujol): vmak,- 1600, 1585, 1550, 1240 and

12 20 cm" 1. 12 20 cm" 1.

NMR-spektrum (CDCl ) : 5 (ppm) 2,58 (3H, s), 2,7 (3H, s), 4,26 (2H, s), 4,97 (2H, s), 6,85-7,5 (8H, m). NMR spectrum (CDCl ) : δ (ppm) 2.58 (3H, s), 2.7 (3H, s), 4.26 (2H, s), 4.97 (2H, s), 6.85 -7.5 (8H, m).

Massespektrum: 417 (M<4>). Mass spectrum: 417 (M<4>).

2) 5-brommetyl-6 -metyl- 4 -(4-nitrofenyl)-2-fenylpyrimidin. IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1515, 1415 og 1350 cm""<1.>2) 5-bromomethyl-6-methyl-4-(4-nitrophenyl)-2-phenylpyrimidine. IR spectrum (Nujo<l>)<:><v>max = 1545, 1515, 1415 and 1350 cm""<1.>

NMR-spektrum (CDC1.J: 5 (ppm) = 2,78 (3H, s), 4,45 (2H, s), 7,35-7,6 (3 H, m) , 7,85 -3,65 ( 6 H, m) . 3) 5-brommetyl-6-metyl- 4 -(2-nitrofenyl)-2-fenylpyrimidin. IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1530, 1 395 og 1360 cm""<1.>NMR spectrum (CDC1.J: δ (ppm) = 2.78 (3H, s), 4.45 (2H, s), 7.35-7.6 (3H, m) , 7.85 -3 .65 ( 6 H, m). 3) 5-bromomethyl-6-methyl-4-(2-nitrophenyl)-2-phenylpyrimidine. IR spectrum (Nujo<l>)<:><v>max = 1545, 1530, 1395 and 1360 cm""<1.>

NMR-spektrum (CDC13): 5 (ppm) = 2,78 (3H, s), 4,36 (2H, s), 7,25-7,9 (6H, m) , 8,0-8,6 (3H, m). 4) 5-brommetyl-4-(3-trifluormetylfenyl)-6-metyl-2-fenylpyrimidin . NMR spectrum (CDCl 3 ): δ (ppm) = 2.78 (3H, s), 4.36 (2H, s), 7.25-7.9 (6H, m), 8.0-8.6 (3H, m). 4) 5-bromomethyl-4-(3-trifluoromethylphenyl)-6-methyl-2-phenylpyrimidine.

IR-spektrum (Nujo<l>)<:>v rn 3. K. s = 1610, 1545 og 1330 cm""<1.>IR spectrum (Nujo<l>)<:>v rn 3. K. s = 1610, 1545 and 1330 cm""<1.>

NMR-spektrum (CDC10): 5 (ppm) = 3,16 (3H, s), 4,51 (2H, s), 7,35-8,9 (9H, m). 5) 5-(brommetyl)-4-(4-nitrofenyl)-2-fenylpyrimidin. IR-spektrum (Nujol): vmaks = 1565, 1535, 1520, 1430 og 13 60 cm""1 . NMR spectrum (CDCl 0 ): δ (ppm) = 3.16 (3H, s), 4.51 (2H, s), 7.35-8.9 (9H, m). 5) 5-(bromomethyl)-4-(4-nitrophenyl)-2-phenylpyrimidine. IR spectrum (Nujol): vmax = 1565, 1535, 1520, 1430 and 13 60 cm""1 .

NMR-spektrum (CDC13): 5 (ppm) = 4,47 (2H, s), 7,3-8,72 (9H, m), 8,93 (1H, s). NMR spectrum (CDCl 3 ): δ (ppm) = 4.47 (2H, s), 7.3-8.72 (9H, m), 8.93 (1H, s).

FREMSTILLING 6 MANUFACTURE 6

Til en oppløsning av 0,3 g 5-hydroksymetyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin i 10 ml etylacetat ble satt 2,4 g aktivert mangandioksyd, og blandingen ble kokt under tilbake-løpsk jøling i 2 timer under kraftig omrøring. Efter henstand ved romtemperatur ble mangandioksydet frafiltrert. Filtratet ble inndampet under vakuum, og det resterende bunnfall ble omkrystallisert fra dietyleter, hvilket ga 0,15 g 5-formyl-6-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 154-155°C. To a solution of 0.3 g of 5-hydroxymethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine in 10 ml of ethyl acetate was added 2.4 g of activated manganese dioxide, and the mixture was boiled under reflux in 2 hours under vigorous stirring. After standing at room temperature, the manganese dioxide was filtered off. The filtrate was evaporated under vacuum, and the remaining precipitate was recrystallized from diethyl ether, yielding 0.15 g of 5-formyl-6-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 154-155°C.

IR-spektrum (Nuno<l>)<:><v>maks = 1700 og 1535 cm<-1>IR spectrum (Nuno<l>)<:><v>max = 1700 and 1535 cm<-1>

NMR-spektrum (CDC13): (ppm) = 2,97 (3H, s), 7,5-8,8 NMR spectrum (CDCl 3 ): (ppm) = 2.97 (3H, s), 7.5-8.8

(9H, m), 10,13 (1H, s). (9H, m), 10.13 (1H, s).

Massespektrum: 319 (M+). Mass spectrum: 319 (M+).

FREMSTILLING 7 MANUFACTURE 7

En blanding av 5 g metyl-6-metyl-4-(3-nitrofenyl)-2-fenyl-5-pyrimidinkarboksylat, 5,6 g pyridiniumbromid-perbromid og 5 ml 25 %ig hydrogenbromid-eddiksyre i 200 ml eddiksyre ble omrørt i 2 timer ved romtemperatur. Reaksjonsblandingen ble holdt i 200 ml isvann og omrørt i 10 minutter. Det resulterende bunnfall ble oppsamlet og oppløst i en blanding av 50 ml kloroform og 50 ml vann. Den fraskilte organiske fase ble vasket suksessivt med metet vandig natriumhydrogenkarbonat og mettet vandig natriura-klorid og tørret over magnesiumsulfat. Oppløsningsmidlet ble avdampet under vakuum, og den resterende krystall ble omkrystallisert fra etanol, hvilket ga 4,07 g metyl-6-brommetyl-4-(3-nitrofenyl)-2-fenyl-5-pyrimidinkarboksylat, smeltepunkt 103-104°C. A mixture of 5 g of methyl-6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate, 5.6 g of pyridinium bromide-perbromide and 5 ml of 25% hydrogen bromide-acetic acid in 200 ml of acetic acid was stirred in 2 hours at room temperature. The reaction mixture was kept in 200 ml of ice water and stirred for 10 minutes. The resulting precipitate was collected and dissolved in a mixture of 50 ml of chloroform and 50 ml of water. The separated organic phase was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under vacuum, and the remaining crystal was recrystallized from ethanol, yielding 4.07 g of methyl 6-bromomethyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidine carboxylate, mp 103-104°C.

IR-spektrum (Nujo<l>)<:><v>maks 1730, 1525 og 1352 cm"<1.>IR spectrum (Nujo<l>)<:><v>max 1730, 1525 and 1352 cm"<1.>

NMR-spektrum (CDC13): 6 (ppm) = 3,83 (3H, s), 4,78 (2H, s), 7,4-7,6 (3H, m), 7,70 (1H, dd, J=8Hzog 8Hz), 8,05 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,35 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,45-8,7 (3H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 3.83 (3H, s), 4.78 (2H, s), 7.4-7.6 (3H, m), 7.70 (1H, dd , J=8Hz and 8Hz), 8.05 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.35 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.45-8.7 (3H , m).

Massespektrum: 427, 429 (M<+>). Mass spectrum: 427, 429 (M<+>).

EKSEMPEL 1 EXAMPLE 1

En blanding av 1,5 g 5-brommetyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin og 1,17 g N-metylpiperazin i 15 ml isopropylalkohol ble kokt under tilbakeløpskjølling i 6 timer. Efter avdampning av oppløsningsmidlet ble residuet oppløst i kloroform, vasket med mettet vandig natriumklorid og tørret over magnesiumsulfat. Filtratet ble inndampet under redusert trykk, og residuet ble underkastet kolonnekromatografi på 100 g aluminiumoksyd under eluering med kloroform. Fraksjonene inneholdende den ønskede forbindelse ble kombinert og konsentrert under redusert trykk. Residuet ble omkrystallisert fra dietyleter, hvilket ga 0,30 g 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 138-140°C. A mixture of 1.5 g of 5-bromomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine and 1.17 g of N-methylpiperazine in 15 ml of isopropyl alcohol was refluxed for 6 hours. After evaporation of the solvent, the residue was dissolved in chloroform, washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography on 100 g of alumina eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether, yielding 0.30 g of 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 138-140°C.

IR-spektrum (Nujo<l>)<:><v>maks 1525°91348 cm"1. IR spectrum (Nujo<l>)<:><v>max 1525°91348 cm"1.

NMR-spektrum (CDC1?):6 (ppm) = 2,27 (3H, s), 3,50 (2H, s), 8,8-9,0 (1H, m), 2,43 (8H, s), 7,3-7,8 (4H, m), 2,77 (3H, s), 8,0-8,6 (4H, m). NMR spectrum (CDC1?):6 (ppm) = 2.27 (3H, s), 3.50 (2H, s), 8.8-9.0 (1H, m), 2.43 (8H, s), 7.3-7.8 (4H, m), 2.77 (3H, s), 8.0-8.6 (4H, m).

Massespektrum: 403 (M<+>). Mass spectrum: 403 (M<+>).

EKSEMPEL 2 EXAMPLE 2

Følgende forbindelser ble utvundet ved å omsette 5-brom-met.yl-6-met.yl-4-(substituert f enyl)-2-f enylpyrimidin med tilsvarende aminforbindelser på lignende måte som beskrevet i eksempel 1. 1) 6-metyl-4-(3-nitrofenyl)-5-ftalimidometyl-2-fenylpyrimidin, smeltepunkt 194-195°C. The following compounds were recovered by reacting 5-bromo-methyl-6-methyl-4-(substituted phenyl)-2-phenylpyrimidine with corresponding amine compounds in a similar manner as described in Example 1. 1) 6-methyl -4-(3-nitrophenyl)-5-phthalimidomethyl-2-phenylpyrimidine, melting point 194-195°C.

IR-spektrum (Nujo<l>)<:>vmak,- 1775 0<3 1705 cm"<1>. IR spectrum (Nujo<l>)<:>vmak,- 1775 0<3 1705 cm"<1>.

NMR-spektrum (CDC13): 5 (ppm) = 2,70 (3H, s), 4,93 (2H, s), 7,7 (4H, s), 7,25-3,7 (9H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 2.70 (3H, s), 4.93 (2H, s), 7.7 (4H, s), 7.25-3.7 (9H, m ).

Massespektrum: 450 (M<+>). Mass spectrum: 450 (M<+>).

2 ) 5- (dietylaminometyl) - 6-metyl - 4 - (.3 -ni tr of enyl) - 2-f enylpyrimidin, smeltepunkt 101-103°C. 2 ) 5-(diethylaminomethyl)-6-methyl-4-(.3-nitrofenyl)-2-phenylpyrimidine, melting point 101-103°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1530 0<3 1200 cm"<1>. IR spectrum (Nujo<l>)<:><v>max = 1530 0<3 1200 cm"<1>.

NMR-spektrum (CDC13): 6 (ppm) = 0,83 (6H, 7, J=8Hz), 2,30 (4H, q, J=8Hz), .3,58 (2H, s), 7,5-8,7 (9H, m) . NMR spectrum (CDCl 3 ): δ (ppm) = 0.83 (6H, 7, J=8Hz), 2.30 (4H, q, J=8Hz), .3.58 (2H, s), 7, 5-8.7 (9H, m) .

Massespektrum: 376 (M<+>). Mass spectrum: 376 (M<+>).

.3 ) 6-metyl-5- [ 4 - ( 2-hydroksyetyl) piperazin- 1 -ylmetyl ] - 4- ( 3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 89°C. .3 ) 6-methyl-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 89°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1610, 1580, 1530, 1435 og IR spectrum (Nujo<l>)<:><v>max = 1610, 1580, 1530, 1435 and

1.3 5 5 cm""1 . 1.3 5 5 cm""1 .

NMR-spektrum (CDCl-j): 5 (ppm) = 2,48 (H, s), 2,52 (2H, t, J=6Hz), 3,51 (2H, s), 3,58 (2H, t, J=6Hz), 7,33-9,0 (9H, m). NMR spectrum (CDCl-j): δ (ppm) = 2.48 (H, s), 2.52 (2H, t, J=6Hz), 3.51 (2H, s), 3.58 (2H , t, J=6Hz), 7.33-9.0 (9H, m).

Massespektrum: 433 (M<+>). Mass spectrum: 433 (M<+>).

4) 6-metyl-5-(4-metylhomopiperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-dihydroklorid, fusjonspunkt 170°C, klaringspunkt 180°C. 4) 6-methyl-5-(4-methylhomopiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride, melting point 170°C, clearing point 180°C.

IR-spektrum (Nujol): vmaks = 1530 og 1360 cm . IR spectrum (Nujol): vmax = 1530 and 1360 cm.

IR-spektrum (Nujo<l>)<:>v 1530 og 1360 _ i IR spectrum (Nujo<l>)<:>v 1530 and 1360 _ i

NMR-spektrum (dimetylsulfoksyd -dg): 5 (ppm) = 1,7-4,0 (10H, m), 2,67 (3H, s), 2,97 (3H, s), 4,45 (2H, bred s), 7,4-8,75 (9H, m). NMR spectrum (dimethyl sulfoxide -dg): δ (ppm) = 1.7-4.0 (10H, m), 2.67 (3H, s), 2.97 (3H, s), 4.45 (2H , wide s), 7.4-8.75 (9H, m).

Massespektrum: 417 (M ). Mass spectrum: 417 (M ).

5) 6-mety1-5-[(6-R,S)- 1,4-diazabicyklo[4.3.0]nonan-4-ylmetyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 64-68°C. IR-spektrum (Nujol): vmak-= 1525°51350 cm"<1.>5) 6-methyl-5-[(6-R,S)-1,4-diazabicyclo[4.3.0]nonan-4-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 64-68 °C. IR spectrum (Nujol): vmak-= 1525°51350 cm"<1.>

NMR-spektrum (CDC13): 6 (ppm) - 1,0-3-4 (13H, m), 2,78 NMR spectrum (CDCl 3 ): 6 (ppm) - 1.0-3-4 (13H, m), 2.78

(3H, s), 3,55 (2H, s), 7,2-7,8 (4H, m), 7,9-8,7 (4H, m), 8,8-9,05 (1H, m). (3H, s), 3.55 (2H, s), 7.2-7.8 (4H, m), 7.9-8.7 (4H, m), 8.8-9.05 (1H , m).

Massespektrum: 429 (M<+>). Mass spectrum: 429 (M<+>).

6) 6-metyl-5-[4-(2-metoksyfenyl)piperazin-1-ylmetyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 177,5-179°C. IR-spektrum (Nujo<l>)<:><v>raaks = 1530, 1500 og 1350 cm""1. 6) 6-methyl-5-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 177.5-179°C. IR spectrum (Nujo<l>)<:><v>raaks = 1530, 1500 and 1350 cm""1.

NMR-spesktrum (CDCl^): 6 (ppm) = 2,4-2,9 (4H, m), 2,82 NMR spectrum (CDCl 2 ): δ (ppm) = 2.4-2.9 (4H, m), 2.82

(3H, s), 2,85-3,23 (4H, m), 3,59 (2H, s), 3,85 (3H, s), 6,92 (3H, s), 2.85-3.23 (4H, m), 3.59 (2H, s), 3.85 (3H, s), 6.92

(4H, s), 7,3-7,83 <84H, m), 8,0-8,7 (4H, m), 8,9-9,1 (1H, m). (4H, s), 7.3-7.83 <84H, m), 8.0-8.7 (4H, m), 8.9-9.1 (1H, m).

Massespektrum: 495 (M<+>). Mass spectrum: 495 (M<+>).

Analyse: Analysis:

Beregnet for C29<H>29<N>5°3■<3/>4H2°: c 68,42 H 6'04 N 13,75 Funnet : C 68,33 H 6,29 N 13,75 7) 6-metyl-5-[4-(3,4,5-trimetoksybenzyl)piperazin-1-ylmetyl]-4-(3-nitrofenyl)-2-fenylpyrimidin-dihydroklorid, smeltepunkt 216°C (dekomponerng). Calculated for C29<H>29<N>5°3■<3/>4H2°: c 68.42 H 6'04 N 13.75 Found: C 68.33 H 6.29 N 13.75 7) 6 -methyl-5-[4-(3,4,5-trimethoxybenzyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride, melting point 216°C (decomposition).

IR-spektrum (Nujo<l>)<:><v>maks = 1590, 1530, 1510, 1430 og IR spectrum (Nujo<l>)<:><v>max = 1590, 1530, 1510, 1430 and

13 50 cm<-1>. 13 50 cm<-1>.

NMR-spektrum (dimetylsulfoksyd -db,):6 (ppm) = 2,6-3,3 NMR spectrum (dimethylsulfoxide -db,):6 (ppm) = 2.6-3.3

(4H, m), 2,81 (3H, s), 3,66 (3H, s), 3,75-4,2 (4H, m), 3,77 (4H, m), 2.81 (3H, s), 3.66 (3H, s), 3.75-4.2 (4H, m), 3.77

(8H, s), 4,17 (2H, s), 7,0 (2H, s), 7,4-7,63 (3H, m) , 7,7-7,94 (1H, m), 8,03-8,72 (5H, m). (8H, s), 4.17 (2H, s), 7.0 (2H, s), 7.4-7.63 (3H, m), 7.7-7.94 (1H, m), 8.03-8.72 (5H, m).

Massespektrum: 570 (M+1). Mass spectrum: 570 (M+1).

8) 5-(4-isopropylkarbamoylmetylpiperazin--1-ylmetyl)-6-metyl-4~(3-nitrofenyl)-2 fenylpyrimidin, smeltepunkt 172-173°C. IR-spektrum (NujJ ol): v mak, s<=><3>490 og 1665 cm"<1.>8) 5-(4-isopropylcarbamoylmethylpiperazin--1-ylmethyl)-6-methyl-4~(3-nitrophenyl)-2-phenylpyrimidine, melting point 172-173°C. IR spectrum (NujJ ol): v mak, s<=><3>490 and 1665 cm"<1.>

NMR-spektrum (CDC13): 5 (ppm) =1,15 (6H, d, J=7Hz), 2,46 (8H, s), 2,78 (3H, s), 2,94 (2H, s), 3,54 (2H, s), 4,08 (1H, m); 6,85 (1H, bred s), 7,35-7,60 (3H, m), 7,67 (1H, dd, J=8Hz og 8Hz), 8,11 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,34 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,5-8,7 (2H, m), 8,88 (1H, dd, J=2Hz og 2Hz). NMR spectrum (CDCl 3 ): δ (ppm) = 1.15 (6H, d, J=7Hz), 2.46 (8H, s), 2.78 (3H, s), 2.94 (2H, s ), 3.54 (2H, s), 4.08 (1H, m); 6.85 (1H, wide s), 7.35-7.60 (3H, m), 7.67 (1H, dd, J=8Hz and 8Hz), 8.11 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.34 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.5-8.7 (2H, m), 8.88 (1H, dd, J=2Hz and 2Hz).

Massespektrum: 488 (M<+>). Mass spectrum: 488 (M<+>).

9) 6-metyl-5-[N-metyl-N-(2,2-dimetylaminoetyl)aminometyl]-4-(3-nitrofenyl)-2-fenylpyrimidin-dihydroklorid, smeltepunkt 214-216°C (dekomponering). 9) 6-methyl-5-[N-methyl-N-(2,2-dimethylaminoethyl)aminomethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride, melting point 214-216°C (decomposition).

IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1530, 1400 og 1350 cm"<1>. IR spectrum (Nujo<l>)<:><v>max = 1545, 1530, 1400 and 1350 cm"<1>.

NMR-spektrum (dimetylsulfoksyd~dg); 5 (ppm) = 2,32 NMR spectrum (dimethylsulfoxide~dg); 5 (ppm) = 2.32

(3H, s), 2,7 (6H, s), 2,92 (3H, s), 3,1-3,7 (4H, m), 4,3 (2H, bred s), 7,4-3,6 (9H, m). (3H, s), 2.7 (6H, s), 2.92 (3H, s), 3.1-3.7 (4H, m), 4.3 (2H, wide s), 7.4 -3.6 (9H, m).

Massespektrum: 405 (M4). Mass spectrum: 405 (M4).

10) 6 - met.yl-5 - [N - ( 2-morf olinoetyl) aminometyl ] - 4- ( 3-nitrof enyl) - 2-fenylpyrimidin, smeltepunkt 110-114°C. 10) 6-methyl-5-[N-(2-morpholinoethyl)aminomethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 110-114°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1580, 1535, 1400 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1580, 1535, 1400 and 1350 cm"<1.>

NMR-spektrum (CDC13): 5 (ppm) = 2,3-2,95 (8H, m), 2,79 (3H, s), 3,55-3,8 (4H, m), 3,76 (2H, s), 7,33-7,8 (4H, m), 8.2- 8,6 (4H, m), 9,07 (1H, dd, J=2Hz og 2Hz). NMR spectrum (CDCl 3 ): δ (ppm) = 2.3-2.95 (8H, m), 2.79 (3H, s), 3.55-3.8 (4H, m), 3.76 (2H, s), 7.33-7.8 (4H, m), 8.2- 8.6 (4H, m), 9.07 (1H, dd, J=2Hz and 2Hz).

Massespektrum: 434 (M<+>1). Mass spectrum: 434 (M<+>1).

Analyse: Analysis:

Beregnet for C24<H>27N5°3<:>C 66'50 H 5 >28 N 16,15 Calculated for C24<H>27N5°3<:>C 66'50 H 5 >28 N 16.15

Funnet C 66,53 H 6,10 N 16,19 11) 5-[N-(1-etylpyrrolidin-2-ylmetyl)aminometyl]-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 91-94°C. IR-spektrum (Nujo<l>)<:><v>maks = 1535, 1400 og 1350 cm"<1.>Found C 66.53 H 6.10 N 16.19 11) 5-[N-(1-ethylpyrrolidin-2-ylmethyl)aminomethyl]-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 91 -94°C. IR spectrum (Nujo<l>)<:><v>max = 1535, 1400 and 1350 cm"<1.>

NMR-spektrum (CDC13): 6 (ppm) - 1,11 (3H, t, J=7Hz), 1.3- 3,3 (11H, m), 2,78 (3H, s), 3,74 (2H, s), 7,3-7,83 (4H, m), 8,2-8,64 (4H, m), 8,93-9,12 (1H,m). NMR spectrum (CDCl 3 ): 6 (ppm) - 1.11 (3H, t, J=7Hz), 1.3 - 3.3 (11H, m), 2.78 (3H, s), 3.74 (2H , s), 7.3-7.83 (4H, m), 8.2-8.64 (4H, m), 8.93-9.12 (1H, m).

Massespektrum: 432 (M<+>1). Mass spectrum: 432 (M<+>1).

Analyse -. Analysis -.

Beregnet, for C^H^N^O,-, : C 69,58 H 6,77 N 16,23 Calculated, for C^H^N^O,-, : C 69.58 H 6.77 N 16.23

Funnet : C 69,56 H 6,47 N 16,06 12) 5 - [N- ( 1 -etyl pipe r id in- 3-yl) aminometyl ] - 6-met.yl-4 - ( 3-nitro-fenyl)-2-fenylpyrimidin-dihydroklorid, smesltepunkt 267°C (dekomponering). Found : C 69.56 H 6.47 N 16.06 12) 5-[N-(1-ethyl piperidin-3-yl)aminomethyl]-6-methyl-4-(3-nitro- phenyl)-2-phenylpyrimidine dihydrochloride, melting point 267°C (decomposition).

IR-spektrum (Nujo<l>)<:>v k = 1575, 1535, 1400 og 1360 cm"<1.>IR spectrum (Nujo<l>)<:>v k = 1575, 1535, 1400 and 1360 cm"<1.>

NMR-spektrum (CF3C00D): 5 (ppm) = 1,44 (3H, t, J=7Hz), 1,65-2,55 (4H, m), 2,8-4,5 (7H, m), 3,38 (3H, s), 5,23 (2H, s), 7,5-9 (9H, m). NMR spectrum (CF3CO0D): δ (ppm) = 1.44 (3H, t, J=7Hz), 1.65-2.55 (4H, m), 2.8-4.5 (7H, m) , 3.38 (3H, s), 5.23 (2H, s), 7.5-9 (9H, m).

Massespektrum: 431 (M ). Mass spectrum: 431 (M ).

13) 5 -[2-(dietylaminometyl)imidazol-1-ylmetyl]-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 107-109°C. IR-spektrum (Nujo<l>)<:><v>maks = 1580, 1545, 1530 og 1350 cm"<1.>13) 5-[2-(diethylaminomethyl)imidazol-1-ylmethyl]-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 107-109°C. IR spectrum (Nujo<l>)<:><v>max = 1580, 1545, 1530 and 1350 cm"<1.>

NMR-spektrum (CDC13): 5 (ppm) = 0,95 (6H, t, J=7Hz), 2,5 (4H, q, J=7Hz), 2,58 (3H, s), 3,62 (2H, s), 5,3 (2H, s), 6,57 (1H, d, J=2Hz), 6,95 (1H, d, J=2Hz), 7,4-7,895 (5H, m), 8,2-8,7 (4H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 0.95 (6H, t, J=7Hz), 2.5 (4H, q, J=7Hz), 2.58 (3H, s), 3.62 (2H, s), 5.3 (2H, s), 6.57 (1H, d, J=2Hz), 6.95 (1H, d, J=2Hz), 7.4-7.895 (5H, m ), 8.2-8.7 (4H, m).

Massespektrum: 456 (M<+>). Mass spectrum: 456 (M<+>).

14) 6-metyl-4-(3-nitrofenyl)-2-fenyl-5-(piperidinometyl)pyri-midin, smeltepunkt 140-141°C. 14) 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-(piperidinomethyl)pyrimidine, melting point 140-141°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1590, 1530 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1590, 1530 and 1350 cm"<1.>

NMR-spektrum (CDC13): 5 (ppm) = 1,2-1,6 (6H, m), 2,15-2,4 (4H, m), 2,75 (3H, s), .3,41 (2H, s), 7,35-7,50 (3H, m), 7,62 (1H, dd, J=8Hz og 8Hz), 8,11 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,21 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,40-8,60 (2H, m), 8,91 (1H, dd, J=2Hz og 2Hz). NMR spectrum (CDCl 3 ): δ (ppm) = 1.2-1.6 (6H, m), 2.15-2.4 (4H, m), 2.75 (3H, s), .3, 41 (2H, s), 7.35-7.50 (3H, m), 7.62 (1H, dd, J=8Hz and 8Hz), 8.11 (1H, ddd, J=8Hz, 2Hz and 2Hz ), 8.21 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.40-8.60 (2H, m), 8.91 (1H, dd, J=2Hz and 2Hz).

Massespektrum: 388 (M<+>). Mass spectrum: 388 (M<+>).

15) 6-metyl-5-(4-hydroksypiperidinometyl)-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 154-164°C. 15) 6-methyl-5-(4-hydroxypiperidinomethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 154-164°C.

-1 IR-spektrum (Nujol): vraaks = 1535, 1520 og 1345 cm -1 IR spectrum (Nujol): vraaks = 1535, 1520 and 1345 cm

NMR-spektrum (CDC13): 6 (ppm) = 1,15-2,8 (8H, m), 2,79 NMR spectrum (CDCl 3 ): δ (ppm) = 1.15-2.8 (8H, m), 2.79

(3H, s), 3,51 (2H, s), 3,5.3-3,9 (1H, m) , 7,35-7,85 (4H, m) , 8,03-8,7 (4H, m), 8,84-9,04 (1H, m). (3H, s), 3.51 (2H, s), 3.5.3-3.9 (1H, m) , 7.35-7.85 (4H, m) , 8.03-8.7 (4H , m), 8.84-9.04 (1H, m).

Massespektrum: 404 (M<+>). Mass spectrum: 404 (M<+>).

1 6 ) 6--metyl-5- ( 4-cyk] opropylmetylpiperazin-1 -ylmetyl) - 4- ( 3-nitrofenyl)-2-fenylpyrimidin, smesltepunkt 180°C. IR-spektrum (Nujo<l>)<:>v k = 1530, 1350 og 1300 cm"<1.>16) 6-methyl-5-(4-cyclopropylmethylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 180°C. IR spectrum (Nujo<l>)<:>v k = 1530, 1350 and 1300 cm"<1.>

NMR-spektrum (CDCl.,):5 (ppm) = 0,1-0,34 (2H, m), 0,45-0,75 (2H, m), 0,8-1,37 (1H, m), 2,3-3,2 (8H, m), 2,51 (2H, d, J=6Hz), 2,78 (3H, s), 3,58 (2H, s), 7,35-7,86 (4H, m), 7,95-8,66 (4H, m), 8,9-9,15 (1H, m). NMR spectrum (CDCl.,): δ (ppm) = 0.1-0.34 (2H, m), 0.45-0.75 (2H, m), 0.8-1.37 (1H, m), 2.3-3.2 (8H, m), 2.51 (2H, d, J=6Hz), 2.78 (3H, s), 3.58 (2H, s), 7.35 -7.86 (4H, m), 7.95-8.66 (4H, m), 8.9-9.15 (1H, m).

Massespektrum: 443 (M<+>). Mass spectrum: 443 (M<+>).

17) 6-metyl-4-(3-nitrofenyl)-2-fenyl-5-tiomorfolinometylpyri - midin, smeltepunkt 162-164°C. 17) 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-thiomorpholinomethylpyrimidine, melting point 162-164°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1525 og 1350 cm IR spectrum (Nujo<l>)<:><v>max = 1525 and 1350 cm

NMR-spektrum (CDC13): 5 (ppm) - 2,63 (3H, s), 2,77 (3H, s), 3,55 (2H, s), 7,4-7,56 (3H, m), 7,69 (1H, dd, J=7Hz), 8,12 (1H, ddd, J=2Hz, 2Hz og 7Hz), 8,2-8,6 (3H, m), 8,85 (1H, dd, J=2Hz og 2Hz) . 18) 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(4-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 138-142°C. NMR spectrum (CDCl 3 ): δ (ppm) - 2.63 (3H, s), 2.77 (3H, s), 3.55 (2H, s), 7.4-7.56 (3H, m ), 7.69 (1H, dd, J=7Hz), 8.12 (1H, ddd, J=2Hz, 2Hz and 7Hz), 8.2-8.6 (3H, m), 8.85 (1H , dd, J=2Hz and 2Hz) . 18) 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(4-nitrophenyl)-2-phenylpyrimidine, melting point 138-142°C.

IR-spektrum (Nujol): v kg = 1605, 1540, 1525, 1495, 1410 og 13 50 cm<1.>IR spectrum (Nujol): v kg = 1605, 1540, 1525, 1495, 1410 and 13 50 cm<1.>

NMR-spektrum (CDC13): 5 (ppm) =2,27 (3H, s), 2,38 (8H, s), 2,80 (3H, s), 3,53 (2H, s), 7,3-8,7 (9H, m) . NMR spectrum (CDCl 3 ): δ (ppm) =2.27 (3H, s), 2.38 (8H, s), 2.80 (3H, s), 3.53 (2H, s), 7, 3-8.7 (9H, m) .

Massespektrum: 403 (M ). Mass spectrum: 403 (M ).

19) 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(2-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 117-119°C. 19) 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(2-nitrophenyl)-2-phenylpyrimidine, melting point 117-119°C.

IR-spektrum (Nujol): vmaks= 1545, 1530, 1350 og 1300 cirf1 . IR spectrum (Nujol): vmax= 1545, 1530, 1350 and 1300 cirf1 .

NMR-spektrum (CDC13): 6 (ppm) = 2,22 (3H, s), 2,24 (8H, s), 3,27 (2H, s), 7,32-7,85 ( 6H, m), 8,13-8,57 (3H, m) . NMR spectrum (CDCl 3 ): δ (ppm) = 2.22 (3H, s), 2.24 (8H, s), 3.27 (2H, s), 7.32-7.85 ( 6H, m ), 8.13-8.57 (3H, m).

Massespektrum: 403 (M<+>). Mass spectrum: 403 (M<+>).

20) 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(3-trifluormetyl-fenyl)-2-fenylpyrimidin, smeltepunkt 159-162°C. 20) 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-trifluoromethyl-phenyl)-2-phenylpyrimidine, melting point 159-162°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1330 og 1320 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1545, 1330 and 1320 cm"<1.>

NMR-spektrum (CDC13): 5 (ppm) = 2,26 (3H, s), 2,39 (8H, s), 2,76 (3H, s), 3,5 (2H, s), 7,35-8,0 (6H, m), 8,21 (1H, bred s), 8,37-8,64 (2H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 2.26 (3H, s), 2.39 (8H, s), 2.76 (3H, s), 3.5 (2H, s), 7, 35-8.0 (6H, m), 8.21 (1H, wide s), 8.37-8.64 (2H, m).

Massespektrum: 426 (M<h>). Mass spectrum: 426 (M<h>).

21) 6~metyl-5-[N-(2-pyrroIidin-1-yletyl)aminometyl]-4-(3-nitro-fenyl)-2-fenylpyrimidin, fusjonspunkt 60°C, klaringspunkt 70°C. 21) 6-methyl-5-[N-(2-pyrrolidin-1-ylethyl)aminomethyl]-4-(3-nitro-phenyl)-2-phenylpyrimidine, melting point 60°C, clearing point 70°C.

IR~spekt.rum (Nujo<l>)<:><v>maks'~ z 1545, 1535, 1400 og 1350 cm""<1.>IR~spekt.rum (Nujo<l>)<:><v>max'~ z 1545, 1535, 1400 and 1350 cm""<1.>

NMR-spektrum (CDCl..,): 5 (ppm) = 1,6-1,9 (4H, m), 2,3-2,95 (3H, m), 2,78 (3H, s), 3,77 (2H, s), 7,33-7,8 (4H, m), 3,2-3,63 (4H, m) , 8,97-9,14 ( 1H, rn) . NMR spectrum (CDCl..,): δ (ppm) = 1.6-1.9 (4H, m), 2.3-2.95 (3H, m), 2.78 (3H, s), 3.77 (2H, s), 7.33-7.8 (4H, m), 3.2-3.63 (4H, m), 8.97-9.14 (1H, rn).

Massespektrum: 417 (M<*>). Mass spectrum: 417 (M<*>).

22 ) 4 - [ 2 - ( 4-klor benzyl ok sy) f enyl ] -2 , 6-d. imet yl--5- ( 4 -me tyl piperazin- 1-ylmetyl)pyrimidin ble fremstilt fra 5-brommetyl-4-[2-(4-klorbenzyloksy)fenyl]-2,6-dimetylpyrimidin, smelte-punkr 110-111°C. 22 ) 4 - [ 2 - ( 4-chloro benzyl oxy) phenyl ] -2 , 6-d. Imethyl-5-(4-methylpiperazin-1-ylmethyl)pyrimidine was prepared from 5-bromomethyl-4-[2-(4-chlorobenzyloxy)phenyl]-2,6-dimethylpyrimidine, mp 110-111 °C.

IR-spektrum (Nujo<l>)<:><v>raajcs = 1600, 1550 og 1300 cm""<1.>IR spectrum (Nujo<l>)<:><v>raajcs = 1600, 1550 and 1300 cm""<1.>

NMR-spektrum (CDC13): 5 (ppm) = 2,17 (11H, s), 2,63 NMR spectrum (CDCl 3 ): δ (ppm) = 2.17 (11H, s), 2.63

(3H, s), 2,7 2 (3H, s), 3,2-3,36 (2H, m), 4,97 (2H, s), 6,9-7,5 (8H, m). (3H, s), 2.7 2 (3H, s), 3.2-3.36 (2H, m), 4.97 (2H, s), 6.9-7.5 (8H, m) .

Massespektrum: 436, 438 (M ). Mass spectrum: 436, 438 (M ).

23) 5-(4-metylpiperazin-1-ylmetyl)-4-(4-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 194-196°C. 23) 5-(4-methylpiperazin-1-ylmethyl)-4-(4-nitrophenyl)-2-phenylpyrimidine, melting point 194-196°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1565, 1535, 1520, 1425 og 13 50 cm<_1.>IR spectrum (Nujo<l>)<:><v>max = 1565, 1535, 1520, 1425 and 13 50 cm<_1.>

NMR-spektrum (CDC13): 6 (ppm) = 2,3 (3H, s), 2,5 (8H, s), 3,48 (2H, s), 7,4-7,63 (3H, m), 8,22 (2H, d, J=9Hz), 8,40 (2H, d, J=9Hz), 8,37-8,67 (2H, m), 8,85 (1H, s). NMR spectrum (CDCl 3 ): δ (ppm) = 2.3 (3H, s), 2.5 (8H, s), 3.48 (2H, s), 7.4-7.63 (3H, m ), 8.22 (2H, d, J=9Hz), 8.40 (2H, d, J=9Hz), 8.37-8.67 (2H, m), 8.85 (1H, s).

Massespektrum: 389 (M ). Mass spectrum: 389 (M ).

24) 4-(3,4-dimetoksyfenyl)-2-metyl-5-(4-metylpiperazin-1-yl-metylpyrimidin. 24) 4-(3,4-dimethoxyphenyl)-2-methyl-5-(4-methylpiperazin-1-yl-methylpyrimidine).

IR-spektrum (Nujo<l>)<:>%aks<=>1605, 1570, 1330 og 1265 cm"<1.>NMR-spektrum (CDCl-j); 6 (ppm) = 2,3 (3H, s), 2,49 (8H, s), 2,77 (3H, s), 3,45 (2H, s), 3,96 (6H, s), 6,95 (1H, d, J=8Hz), 7,36-7, 6 (2H, ra), 8,61 (1H, s) . IR spectrum (Nujo<l>)<:>%aks<=>1605, 1570, 1330 and 1265 cm"<1.>NMR spectrum (CDCl-j); 6 (ppm) = 2.3 (3H, s), 2.49 (8H, s), 2.77 (3H, s), 3.45 (2H, s), 3.96 (6H, s), 6.95 (1H, d, J=8Hz ), 7.36-7.6 (2H, ra), 8.61 (1H, s).

Massespektrum: 342 (M ). Mass spectrum: 342 (M ).

25) 6-metyl-5-[2-(N,N-dimetylamino)etylaminometyl]-4-(3-nitro-fenyl)-2-fenylpyr imidin-fumarat, smeltepunkt 104-106°C. IR-spektrum (Nujo<l>)<:><v>maks = 1705 og 1530 cm<-1>2 6) 6-metyl-5-[4 -(2-fuxoy1)piperazin-1-ylmetyl)-4-(3-nitro-fenyl)-2-fenylpyrimidin. 25) 6-methyl-5-[2-(N,N-dimethylamino)ethylaminomethyl]-4-(3-nitro-phenyl)-2-phenylpyr imidine fumarate, melting point 104-106°C. IR spectrum (Nujo<l>)<:><v>max = 1705 and 1530 cm<-1>2 6) 6-methyl-5-[4-(2-fuxoyl1)piperazin-1-ylmethyl)-4 -(3-nitro-phenyl)-2-phenylpyrimidine.

IR-spektrum (Nujol: v k_.. = 1630, 1530 og 1350 cm Massespektrum: 483 (M ). 27) 6-metyl-5 -[4-(4-fluorfenylsulfonyl)piperazin-1-ylmetyl]-4-(3-nitrofenyl)-2-fenylpyrimidin. IR spectrum (Nujol: v k_.. = 1630, 1530 and 1350 cm Mass spectrum: 483 (M ). 27) 6-methyl-5-[4-(4-fluorophenylsulfonyl)piperazin-1-ylmethyl]-4-( 3-nitrophenyl)-2-phenylpyrimidine.

MIaRs-sspeeskptekrutm rum(N: ujo54l7 ):(M^vm)a.ks1595, 1525, 1495 og 1355 cm"<1.>28) 6-metyl-5-(1-piperazinylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-dihydroklorid, smeltepunkt 174°C (dekomponering). MIRas-sspeeskptekrutm rum(N: ujo38l9 ):(M+vm)a.ks= 1530, 1400 og 1355 cm" . 29) 5-aminometyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 145-147°C. MIaRs-sspeeskptekrutm rum(N: ujo54l7 ):(M^vm)a.ks1595, 1525, 1495 and 1355 cm"<1.>28) 6-methyl-5-(1-piperazinylmethyl)-4-(3-nitrophenyl) )-2-phenylpyrimidine dihydrochloride, melting point 174°C (decomposition). 29) 5-aminomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 145-147°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1520 og 1360 cm"<1.>Massespektrum: 320 (M+). 30) 6-metyl-5-(4-formylpiperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-hydroklorid, smeltepunkt 212-214oC (dekomponering ) . IR spectrum (Nujo<l>)<:><v>max = 1545, 1520 and 1360 cm"<1.>Mass spectrum: 320 (M+). 30) 6-methyl-5-(4-formylpiperazine-1- ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine hydrochloride, melting point 212-214oC (decomposition).

MIaRs-sspeeskpetkrutm rum(N: ujo4l17 ):(M+vm)a.ks= 1675, 1545, 1525 og 1350 cm"<1.>MIaRs-sspeeskpetkrutm rum(N: ujo4l17 ):(M+vm)a.ks= 1675, 1545, 1525 and 1350 cm"<1.>

EKSEMPEL 3 EXAMPLE 3

En blanding av 1,5 g 5-(1-brometyl)-6-metyl-4-(3-nitro-fenyl)-2-fenylpyrimidin og 1,13 g N-metylpiperazin i 15 ml isopropylalkohol ble kokt under tilbakeløpskjøling i 1,5 timer. Reaksjonsblandingen ble inndampet under vakuum. Residuet ble kromatografert på aluminiumoksyd under eluering med en blanding av etylacetat og n-heksan (1:20). Fraksjonene inneholdende det ønskede produkt ble kombinert og konsentrert under vakuum. Residuet ble krystallisert fra en blanding av n-heksan og dietyleter, hvilket ga 0,51 g 6-metyl-5-[1-(4-metyl-piperazin-1-yl)etyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 130-131°C. A mixture of 1.5 g of 5-(1-bromomethyl)-6-methyl-4-(3-nitro-phenyl)-2-phenylpyrimidine and 1.13 g of N-methylpiperazine in 15 ml of isopropyl alcohol was refluxed for 1 .5 hours. The reaction mixture was evaporated under vacuum. The residue was chromatographed on alumina eluting with a mixture of ethyl acetate and n-hexane (1:20). The fractions containing the desired product were combined and concentrated under vacuum. The residue was crystallized from a mixture of n-hexane and diethyl ether, yielding 0.51 g of 6-methyl-5-[1-(4-methyl-piperazin-1-yl)ethyl]-4-(3-nitrophenyl)- 2-phenylpyrimidine, melting point 130-131°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1528 0<3 1360 cm<-1>IR spectrum (Nujo<l>)<:><v>max = 1528 0<3 1360 cm<-1>

NMR-spektrum (CDC13): 5 (ppm) = 1,42 (3H, d, J=7Hz), 2,27 (3H, s), 2,3-2,8 (8H, m), 2,94 (3H, s), 3,57 (1H, q, J=7Hz), 7,4-7,9 (5H, m), 8,2-8,6 (4H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 1.42 (3H, d, J=7Hz), 2.27 (3H, s), 2.3-2.8 (8H, m), 2.94 (3H, s), 3.57 (1H, q, J=7Hz), 7.4-7.9 (5H, m), 8.2-8.6 (4H, m).

Massespektrum : 4 17 (M *") . Mass spectrum : 4 17 (M *") .

EKSEMPEL 4 EXAMPLE 4

1) En blanding zlv 0,2 5 g ammoniumtiocyanat og 0,41 g benzoyl-klorid i 20 ml aceton ble kokt under tilbakeløpskjøling i 2 timer, og det ble tilsatt 0,9 g 5-aminometyl-6-metyl-4-(3-nitro-fenyl)-2-fenylpyrimidin i 5 ml aceton. Etter tilbakeløpskjøling i 2 timer ble reaksjonsblcindingen holdt i en blanding av 100 ml kloroform og 50 ml vann. Den organiske fase ble skit fra, vasket med mettet vandig natriumklorid og tørret over magnesiumsulfat. Oppløsningsmidlet ble fradestillert, og den resulterende krystall ble omkrystallisert fra diisopropyleter, hvilket ga 1,1 g 5-(3-benzoyltioureidometyl)-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 182-187°C. 1) A mixture of 0.25 g of ammonium thiocyanate and 0.41 g of benzoyl chloride in 20 ml of acetone was boiled under reflux for 2 hours, and 0.9 g of 5-aminomethyl-6-methyl-4-( 3-nitro-phenyl)-2-phenylpyrimidine in 5 ml of acetone. After refluxing for 2 hours, the reaction mixture was kept in a mixture of 100 ml of chloroform and 50 ml of water. The organic phase was skimmed off, washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled off, and the resulting crystal was recrystallized from diisopropyl ether to give 1.1 g of 5-(3-benzoylthioureidomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 182-187°C.

IR-spektrum (Nujol)<:><v>maks = 1680°91250 cm"<1>. IR spectrum (Nujol)<:><v>max = 1680°91250 cm"<1>.

NMR-spektrum (CDC13): 6 (ppm) = 2,83 (3H, s), 4,91 (2H, d, J=5Hz), 7,2-8,1 (10H, m), 8,2-8,6 (4H, m), 9,02 (1H, s), 10,85 (1H, bred s) . NMR spectrum (CDCl 3 ): δ (ppm) = 2.83 (3H, s), 4.91 (2H, d, J=5Hz), 7.2-8.1 (10H, m), 8.2 -8.6 (4H, m), 9.02 (1H, s), 10.85 (1H, wide s) .

2) En blanding av 1,0 g 5-(3-benzoyltioureidometyl)-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin og 0,089 g natriumhydroksyd i 20 ml metanol og 10 ml vann ble omrørt i 1 time ved romtemperatur. Efter avdampning av oppløsningsmidlet ble 20 ml vann tilsatt, hvorefter det ble omrørt i 30 minutter. Den resulterende bunnfall ble oppsamlet ved filtrering, vasket med vann og tørret over fosforpentoksyd, hvilket ga 0,75 g 6-metyl-4-(3- nitrofenyl)-2-fenyl-5-tioureidometylpyrimidin, smeltepunkt 227-229°C. 2) A mixture of 1.0 g of 5-(3-benzoylthioureidomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine and 0.089 g of sodium hydroxide in 20 ml of methanol and 10 ml of water was stirred for 1 hour at room temperature. After evaporation of the solvent, 20 ml of water was added, after which it was stirred for 30 minutes. The resulting precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide to give 0.75 g of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-thioureidomethylpyrimidine, mp 227-229°C.

IR-spektrum (Nujo<l>)<:><v>maks = 3380, 1630 og 1530 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 3380, 1630 and 1530 cm"<1.>

3) En blanding av 0,7 g 6-metyl-4-(3-nitrofenyl)-2-fenyl-5-tioureidometylpyrimidin og 0,31 g metyljodid i 20 ml N,N-dimetylformamid ble omrørt i 7 timer ved romtempertur. Efter avdampning av oppløsningsmidlet under vakuum ble det resterende produkt oppløst i 14 ml etanol. 0,33 g etylendiamin ble tilsatt, og blandingen ble kokt under tilbakeløpskjøling i 2 timer. Efter avkjøling ble reaksjonsblandingen holdt i en blanding av 50 ml koroform og 100 ml vann og innstilt på pH 11,0 med 10 % ig vandig kaliumkarbonat. Den organiske fase ble skilt fra, vasket med metet vandig natriumklorid, tørret over magnesiumsulfat og inndampet under vakuum. Det resterende produkt ble underkastet kolonnekromatografi på aluminiumoksyd under eluering med en blanding av kloroform og metanol (50:1). Fraksjonene inneholdende den ønskede forbindelse ble kombinert og konsentrert under vakuum. Residuet ble omkrystallisert fra etanol, hvilket ga 0,06 g 5-(1-imidazolin-2-ylaminometyl)-6-metyl-4-(3-nitro-fenyl)-2-fenylpyrimidin, smeltepunkt 220°C (dekomponering). 3) A mixture of 0.7 g of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-thioureidomethylpyrimidine and 0.31 g of methyl iodide in 20 ml of N,N-dimethylformamide was stirred for 7 hours at room temperature. After evaporation of the solvent under vacuum, the remaining product was dissolved in 14 ml of ethanol. 0.33 g of ethylenediamine was added and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was kept in a mixture of 50 ml of coroform and 100 ml of water and adjusted to pH 11.0 with 10% aqueous potassium carbonate. The organic phase was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The remaining product was subjected to column chromatography on alumina eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired compound were combined and concentrated under vacuum. The residue was recrystallized from ethanol to give 0.06 g of 5-(1-imidazolin-2-ylaminomethyl)-6-methyl-4-(3-nitro-phenyl)-2-phenylpyrimidine, mp 220°C (decomposition).

IR-spektrum (Nujol)<:><v>makr-= 1530 og 1350 cm 1 . IR spectrum (Nujol) <:><v>makr-= 1530 and 1350 cm 1 .

NMR-spektrum (CDC13): 5 (ppm) = 2,70 (3H, s), 3,48 (4H, s), 4,15 (2H, s), 7,3-7,8 (4H, m), 8,0-8,75 (5H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 2.70 (3H, s), 3.48 (4H, s), 4.15 (2H, s), 7.3-7.8 (4H, m ), 8.0-8.75 (5H, m).

Massespektrum: 388 (M<+>). Mass spectrum: 388 (M<+>).

EKSEMPEL 5 EXAMPLE 5

Til en suspensjon av 1,5 g metyl-6-brommetyl-4-(3-nitro-fenyl)-2-fenyl-5-pyrimidinkarboksylat i 15 ml isopropylalkohol ble satt 0,88 g N-metylpiperazin ved 70°C. Reaksjonsblandingen ble omrørt i 10 minutter ved samme temperatur. Efter avdampning av oppløsningsmidlet ble residuet oppløst i en blanding av 50 ml kloroform og 50 ml vann. Den organiske fase ble skilt fra, tørret over magnesiumsulfat og inndampet under vakuum. Residuet ble underkastet kolonnekromatografi på 100 g aluminiumoksyd under eluering med kloroform. Fraksjonene inneholdende den ønskede forbindelse ble kombinert og konsentrert under redusert trykk. Den resterende krystall ble omkrystallisert for en blanding av dietyleter og etanol, hvilket ga 0,37 g metyl-6-(4-metylpiperazin- 1-ylmetyl)-4-(3-nitrofenyl)-2-fenyl-5-pyrimidinkarboksylat, fusjonspunkt 120°C, klaringspunkt 126°C. To a suspension of 1.5 g of methyl-6-bromomethyl-4-(3-nitro-phenyl)-2-phenyl-5-pyrimidinecarboxylate in 15 ml of isopropyl alcohol was added 0.88 g of N-methylpiperazine at 70°C. The reaction mixture was stirred for 10 minutes at the same temperature. After evaporation of the solvent, the residue was dissolved in a mixture of 50 ml of chloroform and 50 ml of water. The organic phase was separated, dried over magnesium sulfate and evaporated under vacuum. The residue was subjected to column chromatography on 100 g of alumina eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. The remaining crystal was recrystallized from a mixture of diethyl ether and ethanol to give 0.37 g of methyl 6-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate, m.p. 120°C, clearing point 126°C.

IR-spektrum (Nujo<l>)<:><v>maks 1723, 1585, 1525 og 1355 cm"<1.>IR spectrum (Nujo<l>)<:><v>max 1723, 1585, 1525 and 1355 cm"<1.>

NMR-spektrum (CDC1?): 5 (ppm) = 2,27 (3H, s), 2,25-2,65 (8H, m), 3,33 (3H, s), 3,94 (2H, s), 7,4-7,6 (3H, m), 7,69 (1H, dd, J=8Hz og 8Hz), 3,12 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,3 7 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,45-8,75 (3H, m). NMR spectrum (CDCl?): δ (ppm) = 2.27 (3H, s), 2.25-2.65 (8H, m), 3.33 (3H, s), 3.94 (2H, s), 7.4-7.6 (3H, m), 7.69 (1H, dd, J=8Hz and 8Hz), 3.12 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8, 3 7 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.45-8.75 (3H, m).

Massespektrum: 447 (M<+>). Mass spectrum: 447 (M<+>).

EKSEMPEL 6 EXAMPLE 6

Følgende forbindelser ble utvunnet fra metyl-6-brommetyl-4-(3-nitrofenyl)-2-fenyl-5-pyrimidinkarboksylat og de tilsvarende aminforbindelser på samme måte som beskrevet i eksempel 5. 1 ) Metyl-6-morf olinomet.yl-4- ( 3-nitrof enyl) - 2-f enyl-5-pyrimidin-karboksylat, smeltepunkt 125-126°C. The following compounds were recovered from methyl-6-bromomethyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidine carboxylate and the corresponding amine compounds in the same manner as described in example 5. 1 ) Methyl-6-morpholinomet.yl- 4-(3-nitrophenyl)-2-phenyl-5-pyrimidine carboxylate, melting point 125-126°C.

IR--spektrun (Nujo<l>)<:><v>maks = 1718, 1585, 1530, 1350 og 12 65 cm"<1>. IR spectrum (Nujo<l>)<:><v>max = 1718, 1585, 1530, 1350 and 12 65 cm"<1>.

NMR-spektrum (CDC13): 5 (ppm) = 2,4-2,6 (4H, m), 3,5-3,75 (4H, m), 3,82 (3H, s), 3,93 (2H, s), 7,4-7,6 (3H, m), 7,67 (1H, dd, J=7Hz og 7Hz), 8,13 (1H, ddd, J=2Hz, 2Hz og 7Hz), 8,39 (1H, ddd, J=2Hz, 2Hz og 7Hz), 8,5-8,7 (3H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 2.4-2.6 (4H, m), 3.5-3.75 (4H, m), 3.82 (3H, s), 3.93 (2H, s), 7.4-7.6 (3H, m), 7.67 (1H, dd, J=7Hz and 7Hz), 8.13 (1H, ddd, J=2Hz, 2Hz and 7Hz) , 8.39 (1H, ddd, J=2Hz, 2Hz and 7Hz), 8.5-8.7 (3H, m).

Massespektrum: 434 (M<+>). Mass spectrum: 434 (M<+>).

2) Metyl-6-dietylaminometyl-4-(3-nitrofenyl)-2-fenyl-5-pyrimi-dinkarboksylat-hydroklorid, smeltepunkt 149°C (dekomponering) . 2) Methyl 6-diethylaminomethyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate hydrochloride, melting point 149°C (decomposition).

IR-spektrum (Nujo<l>)<:><v>maks = 1730, 1545, 1535, 1410 og 13 50 cm"<1>. IR spectrum (Nujo<l>)<:><v>max = 1730, 1545, 1535, 1410 and 13 50 cm"<1>.

NMR-spektrum (CDC13): 5 (ppm) = 1,5 8 (6H, t, J=8Hz), 3,2-3,9 (4H, m), 3,81 (3H, s), 4,64 (2H, bred s), 7,4-8,75 (9H, m) . NMR spectrum (CDCl 3 ): δ (ppm) = 1.5 8 (6H, t, J=8Hz), 3.2-3.9 (4H, m), 3.81 (3H, s), 4, 64 (2H, wide s), 7.4-8.75 (9H, m) .

Massespektrum: 421 (M+1). Mass spectrum: 421 (M+1).

3) Metyl-4-(3-nitrofenyl)-2-fenyl-6-ftalimidomety1-5-pyrimi-dinkarboksylat , smeltepunkt 176-179°C. 3) Methyl 4-(3-nitrophenyl)-2-phenyl-6-phthalimidomethyl-1-5-pyrimidinecarboxylate, melting point 176-179°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1770, 1735 og 1710 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1770, 1735 and 1710 cm"<1.>

NMR-spektrum (CDC13):5 (ppm) = 3,82 (3H, s), 5,30 (2H, s), 7.2- 8,7 (13H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 3.82 (3H, s), 5.30 (2H, s), 7.2-8.7 (13H, m).

EKSEMPEL 7 EXAMPLE 7

En blanding av 2,5 g 5-acetyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, 1,3 g N-metylpiperazin-dihydroklorid og 0,3 g 9 5 %ig rent paraformaIdehyd i 15 ml eddiksyre ble kokt under tilbakeløpskjøling i 6 timer. Reaksjonsblandingen ble inndampet under vakuum, og residuet ble holdt i en blanding av etylacetat og vann. Blandingen ble surgjort til pH 1,0 med 10 % ig vandig saltsyre. Den vandige fase ble skilt fra, innstilt på pH 9 med mettet kaliumkarbonat og ekstrahert med kloroform. Ekstrakten ble tørret, over magnesiumsulf at og inndampet under vakuum. Residuet ble kromatografert på silikagel under eluering med en blanding av kloroform og metanol (50:1). Fraksjonene inneholdende det ønskede produkt ble kombinert og konsentrert under vakuum. Den resulterende krystall ble omkrystallisert fra dietyleter, hvilket ga 0,13 g 5-acetyl-6-[2-(4-metylpiperazin-1-yl)etyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 88-91°C. A mixture of 2.5 g of 5-acetyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, 1.3 g of N-methylpiperazine dihydrochloride and 0.3 g of 95% pure paraformaldehyde in 15 ml acetic acid was boiled under reflux for 6 hours. The reaction mixture was evaporated under vacuum, and the residue was kept in a mixture of ethyl acetate and water. The mixture was acidified to pH 1.0 with 10% aqueous hydrochloric acid. The aqueous phase was separated, adjusted to pH 9 with saturated potassium carbonate and extracted with chloroform. The extract was dried, over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired product were combined and concentrated under vacuum. The resulting crystal was recrystallized from diethyl ether to give 0.13 g of 5-acetyl-6-[2-(4-methylpiperazin-1-yl)ethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, mp 88- 91°C.

-1 IR-spektrum (Nujo<l>)<:><v>maks = 1685, 1530 og 1350 cm -1 IR spectrum (Nujo<l>)<:><v>max = 1685, 1530 and 1350 cm

NMR-spektrum (CDC13): 5 (ppm) = 2,17 (3H, s), 2,30 (3H, s), 2.3- 2,7 (8H, m), 3,0 (4H, s), 7,4-8,0 (5H, m), 8,2-8,8 (4H, m). NMR spectrum (CDCl 3 ): δ (ppm) = 2.17 (3H, s), 2.30 (3H, s), 2.3- 2.7 (8H, m), 3.0 (4H, s), 7.4-8.0 (5H, m), 8.2-8.8 (4H, m).

Massespektrum: 445 (M<+>). Mass spectrum: 445 (M<+>).

EKSEMPEL 8 EXAMPLE 8

1) 0,15 g metyl-6-[2-(4-metylpiperazin-1-yl)etyl]-4-(3-nitro-fenyl ) -2-f enyl-5-pyrimidinkarboksylat ble utvunnet fra 3 g 6-metyl-4-(3-nitrofenyl)-2-fenyl-5-pyrimidinkarboksylat, 1,49 g 4-metyl-piperazin-dihydroklorid og 0,33 g paraformaldehyd på samme måte som beskrevet i eksempel 7, smeltepunkt 99-101°C. 1) 0.15 g of methyl 6-[2-(4-methylpiperazin-1-yl)ethyl]-4-(3-nitro-phenyl)-2-phenyl-5-pyrimidine carboxylate was recovered from 3 g of 6- methyl 4-(3-nitrophenyl)-2-phenyl-5-pyrimidine carboxylate, 1.49 g of 4-methyl-piperazine dihydrochloride and 0.33 g of paraformaldehyde in the same manner as described in example 7, melting point 99-101°C .

IR-spektrum (Nujo<l>)<:><n>maks = 1720, 1530 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:><n>max = 1720, 1530 and 1350 cm"<1.>

NMR-spektrum (CDC13): 6 (ppm) = 2,3 (3H, s), 2,4-2,8 NMR spectrum (CDCl 3 ): δ (ppm) = 2.3 (3H, s), 2.4-2.8

(8H, m), 2,8-3,3 (4H, m) , 7,4-7,6 (3H, m), 7,67 (1H, dd, J=8Hz), 8,08 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,35 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,4-8,7 (3H, m). (8H, m), 2.8-3.3 (4H, m), 7.4-7.6 (3H, m), 7.67 (1H, dd, J=8Hz), 8.08 (1H , ddd, J=8Hz, 2Hz and 2Hz), 8.35 (1H, ddd, J=8Hz, 2Hz and 2Hz), 8.4-8.7 (3H, m).

Massespektrum: 461 (M<+>). Mass spectrum: 461 (M<+>).

2) 0,95 g met.yl-6" ( 2-dimetylaminoety1)-4-( 3-nitrof enyl)-2-fenyl-5-pyrimidinkarboksylat ble utvunndet fra 3 g metyl-6-metyl-4-(3-nitrofenyl)-2-fenyl-5-pyrimidinkarboksylat, 0,325 g para-formaldebyd og 0,7 g dirnetylamin-hydroklorid på samme måte som beskrevet i eksempel 7, smeltepunkt 124-126°C. 2) 0.95 g of methyl-6" (2-dimethylaminoethyl)-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate was recovered from 3 g of methyl-6-methyl-4-(3- nitrophenyl)-2-phenyl-5-pyrimidine carboxylate, 0.325 g of paraformaldehyde and 0.7 g of dirnetylamine hydrochloride in the same manner as described in Example 7, melting point 124-126°C.

IR-spektrum (Nujo<l>)<:><v>maks - 1720, 1580, 1530 og 1350 cm""<1.>IR spectrum (Nujo<l>)<:><v>max - 1720, 1580, 1530 and 1350 cm""<1.>

NMR-spektrum (CDCl^): 5 (ppm) = 2,35 (6H, s), 2,8-3,3 NMR spectrum (CDCl 2 ): δ (ppm) = 2.35 (6H, s), 2.8-3.3

(4H, m), 3,8 (3H, s), 7,4-7,6 (3H, s), 7,65 (1H, dd, J=8Hz), 8,09 (1H, ddd, J=8Hz, 2Hz og 2Hz), 8,3 5 (1H, ddd, j=8Hz, 2Hz og 2Hz), 8,45-8,7 (3H, m). (4H, m), 3.8 (3H, s), 7.4-7.6 (3H, s), 7.65 (1H, dd, J=8Hz), 8.09 (1H, ddd, J =8Hz, 2Hz and 2Hz), 8.3 5 (1H, ddd, j=8Hz, 2Hz and 2Hz), 8.45-8.7 (3H, m).

Massespektrum: 406 (M<+>). Mass spectrum: 406 (M<+>).

3) 0,7 g 5-acetyl-6-(2-dimetylaminoetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-hydroklorid ble utvunnet fra 3 g 5-acetyl-6-memtyl-4-(3-nitrofenyl)-2-fenylpyrimidin, 0,36 g paraformaldehyd og 0,73 g dirnetylamin-hydroklorid på samme måte som beskrevet i eksempel 7, smeltepunkt 138-140°C. 3) 0.7 g of 5-acetyl-6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine hydrochloride was recovered from 3 g of 5-acetyl-6-memthyl-4-(3-nitrophenyl )-2-phenylpyrimidine, 0.36 g paraformaldehyde and 0.73 g dirnetylamine hydrochloride in the same way as described in example 7, melting point 138-140°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1690, 1530 og 1355 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1690, 1530 and 1355 cm"<1.>

NMR-spektrum (CDC13): 5 (ppm) = 2,33 (3H, s), 2,93 (3H, s), 2,97 (3H, s), 3,4-3,9 (4H, m), 7,4-8,1 (5H, m), 8,23-8,80 NMR spectrum (CDCl 3 ): δ (ppm) = 2.33 (3H, s), 2.93 (3H, s), 2.97 (3H, s), 3.4-3.9 (4H, m ), 7.4-8.1 (5H, m), 8.23-8.80

(4H, m). (4H, m).

4) 0,45 g 6-(2-dimetylaminoetyl)-5-(4-metylpiperazin-1-yl-karbonyl ) -4- ( 3-nitrof enyl ) -2-f enylpyrimidin (forbindelse A) og 0,01 g 6-( 2-dimet.ylamino-1-metylenetyl)-5-(4-metylpiperazin-1-ylkarbonyl)-4-(3-nitrofenyl)-2-fenylpyrimidin (forbindelse B) ble utvunnet fra 3 g 6-metyl-5-(4-metylpiperazin-1-ylkarbonyl)-4-(3-nitrofenyl)-2-fenylpyrimidin, 0,29 g paraformaldehyd og 0,7 g dirnetylamin-hydroklorid på samme måte som beskrevet i eksempel 7. 4) 0.45 g of 6-(2-dimethylaminoethyl)-5-(4-methylpiperazin-1-yl-carbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine (compound A) and 0.01 g 6-(2-dimethylamino-1-methyleneethyl)-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine (compound B) was recovered from 3 g of 6-methyl- 5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl)-2-phenylpyrimidine, 0.29 g paraformaldehyde and 0.7 g dirnetylamine hydrochloride in the same manner as described in Example 7.

Forbindelse A: Compound A:

Smeltepunkt: 119-120°C. Melting point: 119-120°C.

IR-spektrum (Nujo<l>)<:><v>maks= 1628, 1525 og 1345 cm"<1>. IR spectrum (Nujo<l>)<:><v>max= 1628, 1525 and 1345 cm"<1>.

NMR-spektrum (CDC13): 6 (ppm) - 1,3-2,3 (4H, m), 2,13 NMR spectrum (CDCl 3 ): δ (ppm) - 1.3-2.3 (4H, m), 2.13

(3H, s), 2,39 (6H, s), 3,02 (2H, t, J=3Hz), 3,07 (2H, t, J=3Hz), 2,75-3,2 (2H, m), 3,72 (2H, t, J=6Hz), 7,4-7,8 (4H, m), 8,1-8,9 (5H, m). (3H, s), 2.39 (6H, s), 3.02 (2H, t, J=3Hz), 3.07 (2H, t, J=3Hz), 2.75-3.2 (2H , m), 3.72 (2H, t, J=6Hz), 7.4-7.8 (4H, m), 8.1-8.9 (5H, m).

Massespektrum: 474 (M<+>). Mass spectrum: 474 (M<+>).

Forbindelse B: Compound B:

NMR-spektrum (CDC1 ): 5 (ppm) = 1,2-2,4 (4H, m), 2,1 NMR spectrum (CDC1 ): δ (ppm) = 1.2-2.4 (4H, m), 2.1

(3H, s), 2,27 (6H, s), 2,7-4,0 (4H, m), 3,5 (2H, s), 5,6-5,8 (2H, m), 7,4-7,8 (4H, m), 8,2-8,9 (5H, m). (3H, s), 2.27 (6H, s), 2.7-4.0 (4H, m), 3.5 (2H, s), 5.6-5.8 (2H, m), 7.4-7.8 (4H, m), 8.2-8.9 (5H, m).

Massespektrum: 486 (Mf). Mass spectrum: 486 (Mf).

EKSEMPEL 9 EXAMPLE 9

En blanding av 3 g 5-formyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin, 0,83 g 2 -dimetylaminoetylamin og en katalytisk mengde p-toluensulfonsyre i 30 ml benzen ble kokt under tilbake-løpsk jøling i 2 timer under azeotrop dehydratisering. Efter fjernelse, av oppløsningsmidlet ble residuet oppløst i 30 ml etanol, det ble tilsatt 360 mg natriumborhydrid, og blandingen ble omrørt i 1 time ved romtemperatur. Reaksjonsblandingen ble satt. til en suspensjon av 100 ml kloroform og 100 ml vann og innstilt på pH 8. Den fraskilte organiske fase ble vasket med mettet vandig natriumklorid, tørret over magnesiumsulfat og inndampet under vakuum. Residuet ble underkastet kolonnekromato-graf i på 100 g aluminiumoksyd og eluert. med kloroform. Fraksjonene inneholdende den ønskede forbindelse ble kombinert og konsentrert under redusert trykk. Residuet og 0,4 g fumarsyre ble oppløst i 30 ml etanol. Den fraskilte krystall ble filtrert og tørret under vakuum, hvilket ga 0,69 g 5-[N-(2-dimetylamino-ety 1 ) aminometyl]-6-mety1-4-(3-nitrofenyl)-2-fenylpyrimidin-fumarat, smeltepunkt 104-106°C. A mixture of 3 g of 5-formyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, 0.83 g of 2-dimethylaminoethylamine and a catalytic amount of p-toluenesulfonic acid in 30 ml of benzene was refluxed. for 2 hours under azeotropic dehydration. After removal of the solvent, the residue was dissolved in 30 ml of ethanol, 360 mg of sodium borohydride was added, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was set. to a suspension of 100 ml chloroform and 100 ml water and adjusted to pH 8. The separated organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The residue was subjected to column chromatography on 100 g of alumina and eluted. with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue and 0.4 g of fumaric acid were dissolved in 30 ml of ethanol. The separated crystal was filtered and dried under vacuum to give 0.69 g of 5-[N-(2-dimethylamino-ethyl)aminomethyl]-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine fumarate, melting point 104-106°C.

-1 -1

IR-spektrum (Nujo<l>)<:>vma]Cr- 1705 og 1530 cm IR spectrum (Nujo<l>)<:>vma]Cr- 1705 and 1530 cm

NMR-spesktrum (dimetylsulfoksyd _dg): 5 (ppm) = 2,50 NMR spectrum (dimethyl sulfoxide _dg): δ (ppm) = 2.50

(6H, s), 2,76 (3H, s), 2,897 (4H, s), 3,67 (2H, s), 6,53 (2H, s), 7,3-7,6 (3H, m), 7,80 (1H, dd, J=8Hz og 8Hz), 8,2-8,5 (4H, m), 8,83 (1H, dd, J=2Hz og 2Hz). (6H, s), 2.76 (3H, s), 2.897 (4H, s), 3.67 (2H, s), 6.53 (2H, s), 7.3-7.6 (3H, m), 7.80 (1H, dd, J=8Hz and 8Hz), 8.2-8.5 (4H, m), 8.83 (1H, dd, J=2Hz and 2Hz).

EKSEMPEL 10 EXAMPLE 10

Følgende forbindelser fåes ut fra 5-formyl-6-metyl-4-(3-nitrofenyl)-2-fenylpyrimidin og tilsvarende aminforbindelser. 1) 6-metyl-5-[N-(2-morfolinoetyl)aminometyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 110-114°C. The following compounds are obtained from 5-formyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine and corresponding amine compounds. 1) 6-methyl-5-[N-(2-morpholinoethyl)aminomethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 110-114°C.

IR-spektrum (Nujo<l>)<:>^ maikG = 1580, 1535, 1400 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:>^ maikG = 1580, 1535, 1400 and 1350 cm"<1.>

Massespektrum: 434 (Mh1). Mass spectrum: 434 (Mh1).

2 ) 5 - [N- ( 1 -etylpyrro.l idin-2-ylmetyl) aminometyl ] -6-metyl-4- ( 3-nitrofenyl) -2-fenylpyrimidin, smeltepunkt 91-94°C. IR-spektrum (Nujo<l>)<:>vfflaks = 1535, 1400 og 1350 cm"<1.>Massespektrum: 432 (M<+>1). 3) 5-[N-(1-etylpiperidin-3-yl)aminometyl]-6-metyl-4-(3-nitro-fenyl) -2-fenylpyrLmidin-dihydroklorid, smeltepunkt 267°C (dekomponering). 2) 5-[N-(1-ethylpyrrolidin-2-ylmethyl)aminomethyl]-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 91-94°C. IR spectrum (Nujo<l>)<:>vflax = 1535, 1400 and 1350 cm"<1.>Mass spectrum: 432 (M<+>1). 3) 5-[N-(1-ethylpiperidine-3- yl)aminomethyl]-6-methyl-4-(3-nitro-phenyl)-2-phenylpyrimidine dihydrochloride, m.p. 267°C (decomposition).

IR-spektrum (Nujol): v k = 1575, 1535, 1400 og 1360 cm"1. Massespektrum: 431 (Mf). IR spectrum (Nujol): v k = 1575, 1535, 1400 and 1360 cm"1. Mass spectrum: 431 (Mf).

EKSEMPEL 11 EXAMPLE 11

Til en blanding av 1 g 6-metyl-5-(1-piperazinylmetyl)-4-(3-nitrofenyl)-2-fenyIpyrimidin-dihydroklorid, 10 ml diklormetan og 0,48 g trietylamin ble satt 0,31 g 2-furoylklorid ved 5°C og under isavkjøling. Efter omrøring i 1 time ved samme temperatur ble reaksjonsblandingen konsentrert under redusert trykk. Residuet ble suspendert i vann og innstilt på pH 9 med vandig mettet natriumhydrogenkarbonat. Bunnfallet ble oppsamlet ved filtrering, vasket med vann og tørret under vakuum, hvilket ga 1,02 g 6-metyl-5-[4-(2-furoyl)piperazin-1-ylmetyl]-4-(3-nitro-fenyl ) -2-f enylpyrimidin, fusjonspunkt 178°C, klaringspunkt 188°C. To a mixture of 1 g of 6-methyl-5-(1-piperazinylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride, 10 ml of dichloromethane and 0.48 g of triethylamine was added 0.31 g of 2-furoyl chloride at 5°C and under ice cooling. After stirring for 1 hour at the same temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water and adjusted to pH 9 with aqueous saturated sodium bicarbonate. The precipitate was collected by filtration, washed with water and dried under vacuum to give 1.02 g of 6-methyl-5-[4-(2-furoyl)piperazin-1-ylmethyl]-4-(3-nitro-phenyl) -2-phenylpyrimidine, melting point 178°C, clearing point 188°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1630, 1530 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1630, 1530 and 1350 cm"<1.>

NMR-spektrum (dimetylsulfoksyd - dcb) ■. 6 (ppm) = 2,2-4,0 NMR spectrum (dimethylsulfoxide - dcb) ■. 6 (ppm) = 2.2-4.0

(8H, m), 2,83 (3H, s), 3,57 (2H, s), 6,6 (1H, dd, J=2Hz og 3Hz), 6,96 (1H, d, J=3Hz), 7,35-8,8 (10H, m). (8H, m), 2.83 (3H, s), 3.57 (2H, s), 6.6 (1H, dd, J=2Hz and 3Hz), 6.96 (1H, d, J=3Hz ), 7.35-8.8 (10H, m).

Massespektrum: 483 (M ). Mass spectrum: 483 (M ).

EKSEMPEL 12 EXAMPLE 12

Følgende forbindelser ble utvunnet på samme måte som beskrevet i eksempel 11. The following compounds were recovered in the same manner as described in Example 11.

1) 1,03 g 6-metyl-5-[4-(4-fluorfenylsulfonyl)piperazin-1-ylmetyl ] -4- ( 3-nitrof enyl ) -2-f enylpyrimidin ble utvunnet fra 1 g 6-metyl-5-(piperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimi din-dihydroklorid og 0,46 g 4-fluorfenylsulfonyl, smeltepunkt 19 6-2 20°C. 1) 1.03 g of 6-methyl-5-[4-(4-fluorophenylsulfonyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine was recovered from 1 g of 6-methyl-5 -(piperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride and 0.46 g of 4-fluorophenylsulfonyl, melting point 19 6-2 20°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1595, 1525, 1495 og 1355 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1595, 1525, 1495 and 1355 cm"<1.>

NMR-spektrum (CDCl.^):b (ppm) = 2,35-2,6 (4H, m), 2,72 NMR spectrum (CDCl 2 ): b (ppm) = 2.35-2.6 (4H, m), 2.72

(3H, s), 2,85-3,1 (4H, m), 3,54 (2H, s), 7,15-3,9 (13H, m). (3H, s), 2.85-3.1 (4H, m), 3.54 (2H, s), 7.15-3.9 (13H, m).

Ma sse spektrum: 5 47 (M+) - Mass spectrum: 5 47 (M+) -

2) 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(3-nitrofenyl)- 2-fenylpyrimidin fåes ut fra 6-metyl-5-(piperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-dihydroklorid og metyljodid, smeltepunkt. 138-140°C. 2) 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine is obtained from 6-methyl-5-(piperazin-1-ylmethyl)-4-(3 -nitrophenyl)-2-phenylpyrimidine dihydrochloride and methyl iodide, m.p. 138-140°C.

-1 -1

IR-spektrum (Nujo<l>)<:><v>maks~1525 og 1348 cm Massespektrum: 403 (M<+>). 3) 6-metyl-5-[4-(2-hydroksyetyl)piperazin-1-ylmetyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 89°C. IR spectrum (Nujo<l>)<:><v>max~1525 and 1348 cm Mass spectrum: 403 (M<+>). 3) 6-methyl-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 89°C.

1.355 cm"<1>. 1.355 cm"<1>.

Massespektrum: 433 (M<+>). Mass spectrum: 433 (M<+>).

4) 6-metyl-5-[1-(4-metylpiperazin-1-yl)etyl]-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 130-131°C. 4) 6-methyl-5-[1-(4-methylpiperazin-1-yl)ethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 130-131°C.

IR-spektrum (Nujo<l>)<:><v>maks = 1528°?I360 cm"<1>. Massespektrum: 417 (M+). 5) 6-metyl-5-[4-(3,4,5-trimetoksybenzyl)piperazin-1-ylmetyl]-4-(3-nitrofenyl)-2-fenylpyrimidin-dihydroklorid, smeltepunkt 216°C (dekomponering). IR spectrum (Nujo<l>)<:><v>max = 1528°?I360 cm"<1>. Mass spectrum: 417 (M+). 5) 6-methyl-5-[4-(3,4, 5-trimethoxybenzyl)piperazin-1-ylmethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine dihydrochloride, melting point 216°C (decomposition).

IR-spektrum (Nujo<l>)<:><v>maks = 1590, 1530, 1510, 1430 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1590, 1530, 1510, 1430 and 1350 cm"<1.>

Massespektrum: 570 (M<+>). Mass spectrum: 570 (M<+>).

6) 5-(4-isopropylkarbamoylmetylpiperazin-1-ylmetyl)-6-mety1-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 172-173°C. 6) 5-(4-isopropylcarbamoylmethylpiperazin-1-ylmethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 172-173°C.

-1 -1

IR-spektrum (Nujo<l>)<:><v>maks = 3490 og 1665 cm<-1>Massespektrum: 488 (M<+>). 7) 6-metyl-5-(4-cyklopropylmetylpiperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 180°C. IR-spektrum (Nujo<l>)<:>v mak, s -■ 1530, 1350 og 1300 cm"1. Massespektrum: 443 (M ). 8) 6-metyl-5-(4-me tylpiperazin-1-ylmetyl)-4-(4-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 138-142°C. IR spectrum (Nujo<l>)<:><v>max = 3490 and 1665 cm<-1>Mass spectrum: 488 (M<+>). 7) 6-methyl-5-(4-cyclopropylmethylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine, melting point 180°C. IR spectrum (Nujo<l>)<:>v mak, s -■ 1530, 1350 and 1300 cm"1. Mass spectrum: 443 (M ). 8) 6-methyl-5-(4-methylpiperazine-1- ylmethyl)-4-(4-nitrophenyl)-2-phenylpyrimidine, melting point 138-142°C.

IR-spektrum (Nujo<l>)<:>^ mak3 = 1605, 1540, 1525, 1495, 1410 og 1350 cm<1>. IR spectrum (Nujo<l>)<:>^ mak3 = 1605, 1540, 1525, 1495, 1410 and 1350 cm<1>.

Massespektrum: .403 (M<+>). Mass spectrum: .403 (M<+>).

9) 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(2-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 117-119°C. 9) 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(2-nitrophenyl)-2-phenylpyrimidine, melting point 117-119°C.

IR-spektrum (Nujol): v k - 1545, 1530, 1350 og 1300 cm<-1>. Massespektrum: 403 (M<+>). 10) 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(3-trifluormetyl-fenyl)-2-fenylpyrimidin, smeltepunkt 159-162°C. IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1330 og 1320 cm"<1.>MassespektruM: 426 (M<+>). 11) 4-[2-(4-klorbenzyloksy)fenyl]-2,6-dimetyl-5-(4-metylpiperazin- 1 -ylmetyl ) pyrimidin , smeltepunkt 110-111°C. IR-spektrum (Nujo<l>)<:><v>maks = 1600, 1550 og 1300 cm"1. Massespektrum: 4.36, 438 (M+) . 12) 5-(4-metylpiperazin-1-ylmetyl)-4-(4-nitrofenyl)-2-fenylpyrimidin, smeltepunkt 194-196°C. IR spectrum (Nujol): v k - 1545, 1530, 1350 and 1300 cm<-1>. Mass spectrum: 403 (M<+>). 10) 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-trifluoromethyl-phenyl)-2-phenylpyrimidine, melting point 159-162°C. IR spectrum (Nujo<l>)<:><v>max = 1545, 1330 and 1320 cm"<1.>Mass spectrum: 426 (M<+>). 11) 4-[2-(4-Chlorobenzyloxy) phenyl]-2,6-dimethyl-5-(4-methylpiperazin-1-ylmethyl)pyrimidine, melting point 110-111° C. IR spectrum (Nujo<l>)<:><v>max = 1600, 1550 and 1300 cm"1. Mass spectrum: 4.36, 438 (M+). 12) 5-(4-methylpiperazin-1-ylmethyl)-4-(4-nitrophenyl)-2-phenylpyrimidine, melting point 194-196°C.

IR-spektrum (Nujol): v k = 1565, 1535, 1520, 1425 og 1350 cm"<1>. IR spectrum (Nujol): v k = 1565, 1535, 1520, 1425 and 1350 cm"<1>.

Massespektrum: 389 (M<+>). Mass spectrum: 389 (M<+>).

EKSEMPEL 13 EXAMPLE 13

En blanding av 3 g 6-metyl-5-(4-formylpiperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-hydroklorid, 30 ml metylalkohol, 10 ml vann og 6 ml konsentrert saltsyre ble omrørt ved 70°C i 2 timer. Det resulterende bunnfall ble oppsamlet ved filtrering, vasket med metylalkohol og tørret under vakuum, hvilket ga 2.86 g 6-metyl-5-(1-piperazinylmetyl)-4-(3-nitro-fenyl )-2-fenylpyrimidindihydroklorid, smeltepunkt 17 4°C (dekomponering ) . -1 IR-spektrum (Nujol): vmakc- = 1530, 1400 og 1355 cm NMR-spesktrum (dimetylsulfoksyd -do,):5 (ppm) = 2,5-3,3 (8H, m), 2,32 (3H, s), 4,17 (2H, bred s), 7,4-3,75 (9H, m). A mixture of 3 g of 6-methyl-5-(4-formylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine hydrochloride, 30 ml of methyl alcohol, 10 ml of water and 6 ml of concentrated hydrochloric acid was stirred at 70°C for 2 hours. The resulting precipitate was collected by filtration, washed with methyl alcohol and dried under vacuum to give 2.86 g of 6-methyl-5-(1-piperazinylmethyl)-4-(3-nitro-phenyl)-2-phenylpyrimidine dihydrochloride, mp 174° C (decomposition). -1 IR spectrum (Nujol): vmakc- = 1530, 1400 and 1355 cm NMR spectrum (dimethyl sulfoxide -do,):5 (ppm) = 2.5-3.3 (8H, m), 2.32 ( 3H, s), 4.17 (2H, wide s), 7.4-3.75 (9H, m).

Massespektrum: 389 (Mf). Mass spectrum: 389 (Mf).

EKSEMPEL 14 EXAMPLE 14

En suspensjon av 6,9 g 6-metyl-4-(3-nitrofenyl)-5-ftalimido-metyl-2-fenylpyrimidin og 0,8 g hydrazin-monohydrat i 140 ml etanol ble kokt under tilbakeløpskjøling i 6 timer. Efter frafiltrering av uoppløselig materiale ble filtratet under omrøring holdt i en suspensjon av 200 ml kloroform og 300 ml vann. Den oraniske fase ble skilt fra, vasket med vandig natriumklorid og tørret over magnesiumsulfat. Oppløsningsmidlet ble avdampet under vakuum, og de resulterende krystaller ble omkrystallisert av etanol, hvilket ga 1,12 g 5-amino-metyl-6-metyl-4-(3-nitro-fenyl )-2-fenylpyrimidin, smeltepunkt 145-147°C. A suspension of 6.9 g of 6-methyl-4-(3-nitrophenyl)-5-phthalimido-methyl-2-phenylpyrimidine and 0.8 g of hydrazine monohydrate in 140 ml of ethanol was refluxed for 6 hours. After filtering off insoluble material, the filtrate was kept under stirring in a suspension of 200 ml of chloroform and 300 ml of water. The orange phase was separated, washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under vacuum and the resulting crystals were recrystallized from ethanol to give 1.12 g of 5-amino-methyl-6-methyl-4-(3-nitro-phenyl)-2-phenylpyrimidine, mp 145-147° C.

IR-spektrum (Nujo<l>)<:><v>maks = 1545, 1520 og 1360 cm"<1>. IR spectrum (Nujo<l>)<:><v>max = 1545, 1520 and 1360 cm"<1>.

NMR-spektrum (CDC13): 5 (ppm) = 2,80 (3H, s), 3,93 (2H, s), 7,4-7,6 (3H, m), 7,69 (1H, dd, J=8Hzog 8Hz), 8,15-8,6 (4H, m), 8,80 (1H, dd, J=2Hz og 2Hz). NMR spectrum (CDCl 3 ): δ (ppm) = 2.80 (3H, s), 3.93 (2H, s), 7.4-7.6 (3H, m), 7.69 (1H, dd , J=8Hz and 8Hz), 8.15-8.6 (4H, m), 8.80 (1H, dd, J=2Hz and 2Hz).

Massespektrum: 320 (M<+>). Mass spectrum: 320 (M<+>).

EKSEMPEL 15 EXAMPLE 15

En blanding av 1 g 5-acet.yl-6-( 2-dimetylaminoetyl)-4-( 3-nitrofenyl)-2-fenylpyrimidin og 0,1 g natriumborhydrid i 40 ml metanol ble omrørt i 1 time. Reaksjonsblandingen ble holdt i en blanding av vann og kloroform og innstilt på pH 9. Ekstrakten ble tørret over magnesiumsulfat og inndampet under vakuum. Residuet ble kromatografert på silikagel under eluering med en blanding av kloroform og metanol (20:1). Fraksjonene inneholdende det ønskede produkt ble kombinert og konsentrert under vakuum. Residuet ble omkrystallisert fra dietyleter, hvilket ga 0,2 g 6-(2-dimetylaminoetyl)-5-(1-hydroksyetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin. A mixture of 1 g of 5-acetyl-6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine and 0.1 g of sodium borohydride in 40 ml of methanol was stirred for 1 hour. The reaction mixture was kept in a mixture of water and chloroform and adjusted to pH 9. The extract was dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired product were combined and concentrated under vacuum. The residue was recrystallized from diethyl ether to give 0.2 g of 6-(2-dimethylaminoethyl)-5-(1-hydroxyethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine.

IR-spektrum (Nujo<l>)<:><v>maks= 3320, 1530 og 1350 cm"<1>. IR spectrum (Nujo<l>)<:><v>max= 3320, 1530 and 1350 cm"<1>.

NMR-spektrum (CDCl^):6 (ppm) = 1,52 (3H, d, J=6Hz), 2,86 (6H, s), 3,0-4,2 (4H, m), 5,1 (1H, q, J=6Hz), 7,3-7,8 (4H, m) , 7,8 5-8,55 (5H, m). NMR spectrum (CDCl 2 ): 6 (ppm) = 1.52 (3H, d, J=6Hz), 2.86 (6H, s), 3.0-4.2 (4H, m), 5, 1 (1H, q, J=6Hz), 7.3-7.8 (4H, m), 7.8 5-8.55 (5H, m).

Massespektrum: 392 (M+). Mass spectrum: 392 (M+).

EKSEMPEL 16 EXAMPLE 16

En. blanding av 4,5 g 6~metyl-5-( 4 f ormylpipera zin- 1 -ylmetyl )-4-(3-nitrofenyl)-2 - fenylpyrimidin og 2 ml saltsyre i 45 ml metylaIkohol ble omrørt ved 10^C i 2 timer. Det resulterende bunnfall ble oppsamlet ved filtrering, vasket med metylalkohol og tørret under vakuum, hvilket ga 4,14 g 6-metyl-5-(4-formyl-piperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin-hydroklorid, smeltepunkt 212-214°C (dekomponerng). One. mixture of 4.5 g of 6-methyl-5-(4-formylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine and 2 ml of hydrochloric acid in 45 ml of methyl alcohol was stirred at 10 °C for 2 hours. The resulting precipitate was collected by filtration, washed with methyl alcohol and dried under vacuum to give 4.14 g of 6-methyl-5-(4-formyl-piperazin-1-ylmethyl)-4-(3-nitrophenyl)-2- phenylpyrimidine hydrochloride, melting point 212-214°C (decomposition).

IR-spektrum (Nujo<l>)<:><v>maks = 1675, 1545, 1525 og 1350 cm"<1.>IR spectrum (Nujo<l>)<:><v>max = 1675, 1545, 1525 and 1350 cm"<1.>

NMR-spektrum (dimetylsulfoksyd -dg): 5 (ppm) = 2,5-4,0 NMR spectrum (dimethylsulfoxide -dg): δ (ppm) = 2.5-4.0

(4H, m), 2,9 8 (3H, s), 4,4 2 (2H, s), 7,4-8,7 (10H, m). (4H, m), 2.9 8 (3H, s), 4.4 2 (2H, s), 7.4-8.7 (10H, m).

Massespektrum: 417 (M+). Mass spectrum: 417 (M+).

Claims

1. Fremgangsmåte til fremstilling av pyrimidinderivater med den generelle formel I 1. Process for the preparation of pyrimidine derivatives of the general formula I

hvor Ar betyr aryl substituert med 1-3 substituenter valgt blant nitro, halogen-lavere alkyl, lavere alkoksy og en gruppe med den generelle formel II (456 hvor Æ, R , R og R har den nedenfor angxtte betydning), R 1 betyr forestret karboksy, lavere alkanoyl, hydroksy-lavere alkyl eller en gruppe med den generelle formel III eller IV where Ar means aryl substituted with 1-3 substituents selected from nitro, halogen-lower alkyl, lower alkoxy and a group of the general formula II (456 where Æ, R , R and R have the following meaning), R 1 means esterified carboxy, lower alkanoyl, hydroxy-lower alkyl or a group of the general formula III or IV

(hvor R 7 , R 8 og A har den nedenfor angitte betydning), R 2betyr hydrogen, lavere alkyl eller en gruppe med den generelle formel V (where R 7 , R 8 and A have the meanings given below), R 2 means hydrogen, lower alkyl or a group with the general formula V

(hvor B, R 7 og R 8har den nedenfor angitte betydning), R 3 betyr lavere alkyl eller aryl, SL er et helt tall 0 eller 1-6, 4 5 G R , R og R hver betyr hydrogen eller halogen, R 7 og R 8 hver betyr hydrogen, en eventuelt substituert N-holdig heterocyklisk gruppe eller lavere alkyl eventuelt substituert med 1-3 substituenter valgt blant mono- eller di-(lavere alkyl)amino og eventuelt substituerte N-holdige heterocykliske grupper, eller R^ og R^ til sammen danner en eventuelt substituert N-holdig heterocyklisk gruppe sammen med det nabostilte nitrogenatom, A og B hver betyr lineær eller forgrenet lavere alkylen, som kan være substituert med lavere alkyliden, med det forbehold, at R<1>betyr en gruppe med den generelle formel IV 7 8 (hvor R , R og A har den ovenfor angitte betydning) når R 2betyr hydrogen eller lavere alkyl, og farmasøytisk akseptable salter derav,karakterisert vedat 1) en forbindelse med den generelle formel VII (where B, R 7 and R 8 have the meanings given below), R 3 means lower alkyl or aryl, SL is an integer 0 or 1-6, 4 5 G R , R , and R each mean hydrogen or halogen, R 7 and R 8 each mean hydrogen, an optionally substituted N-containing heterocyclic group or lower alkyl optionally substituted with 1-3 substituents selected from mono- or di-(lower alkyl)amino and optionally substituted N-containing heterocyclic groups, or R^ and R^ together form an optionally substituted N-containing heterocyclic group together with the adjacent nitrogen atom, A and B each means linear or branched lower alkylene, which may be substituted with lower alkylidene, with the proviso that R<1> means a group with the general formula IV 7 8 (where R , R and A have the meaning given above) when R 2 means hydrogen or lower alkyl, and pharmaceutically acceptable salts thereof, characterized in that 1) a compound of the general formula VII

eller et salt derav omsettes med en forbindelse med den generelle formel VIII or a salt thereof is reacted with a compound of the general formula VIII

eller et salt derav, hvilket gir en forbindelse med den generelle formel Ia or a salt thereof, giving a compound of the general formula Ia

eller et salt derav, elleror a salt thereof, or

2) en forbindelse med den generelle formel IX 2) a compound of the general formula IX

eller et salt derav, hvilket gir en forbindelse med den generelle formel Ib or a salt thereof, giving a compound of the general formula Ib

eller et salt derav, elleror a salt thereof, or

3) en forbindelse med den generelle formel Ic 3) a compound of the general formula Ic

eller et salt derav omsettes med formaldehyd og en forbindelse med den generelle formel VIII or a salt thereof is reacted with formaldehyde and a compound of the general formula VIII

eller et salt derav, hvilket, gir en forbindelse med den generelle formel Id or a salt thereof, which gives a compound of the general formula Id

eller et salt derav, elleror a salt thereof, or

4) en forbindelse med den generelle formel le 4) a compound of the general formula le

eller et salt derav, hvorefter den resulterende forbindelse reduseres, hvilket gir en forbindelse med den generelle formel If or a salt thereof, after which the resulting compound is reduced to give a compound of the general formula If

eller et salt derav,or a salt thereof,

5) en forbindelse med den generelle formel lg 5) a compound of the general formula lg

eller et salt derav omsettes med en forbindelse med den generelle formel XI 1 "> R -X XI hvilket, gir en forbindelse med den generelle formel Ih or a salt thereof is reacted with a compound of the general formula XI 1 "> R-X XI which gives a compound of the general formula Ih

eller et salt derav, elleror a salt thereof, or

6) en forbindelse, med den generelle formel li 6) a compound, with the general formula li

eller et salt derav underkastes solvolyse, hvilket gir en. forbindelse med den generelle formel Ij or a salt thereof is subjected to solvolysis, giving a connection with the general formula Ij

eller et salt derav, elleror a salt thereof, or

7) en forbindelse med den generelle formel Ik 7) a compound of the general formula Ik

eller et salt derav omsettes med en forbindelse med den generelle formel XII or a salt thereof is reacted with a compound of the general formula XII

hvorefter det omsettes med etylendiamin eller et salt derav, hvilket gir en forbindelse med den generelle formel Im eller et salt derav, ellerafter which it is reacted with ethylenediamine or a salt thereof, giving a compound of the general formula Im or a salt thereof, or

8) en forbindelse med den generelle formel In 8) a compound of the general formula In

eller et salt derav reduseres, hvilket gir en forbindelse med den generelle formel lp or a salt thereof is reduced, giving a compound of the general formula lp

eller et salt derav, idet symbolene i ovenstående formler har følgende betydning: Ar, R 1 , R 2 , R 3 , R 7 , R 8, A og B hver har den ovenfor angitte betydning, R betyr lavere alkanoyl eller forestret karboksy, a Rk 1 betyr hydroksy-lavere alkyl, R<2>betyr hydrogen eller lavere alkyl, aor a salt thereof, in that the symbols in the above formulas have the following meaning: Ar, R 1 , R 2 , R 3 , R 7 , R 8 , A and B each have the above meaning, R means lower alkanoyl or esterified carboxy, and Rk 1 means hydroxy lower alkyl, R<2>means hydrogen or lower alkyl, a

7 8 R og R til sammen danner ftalimido eller 4-(lavere alkanoyl)-3. cl piperazin-1-yl, 7 8 Rk og Rtø begge betyr hydrogen eller til sammen danner piperazin-1-yl,7 8 R and R together form phthalimido or 4-(lower alkanoyl)-3. cl piperazin-1-yl, 7 8 Rk and Rtø both mean hydrogen or together form piperazin-1-yl,

1 2 R betyr lavere alkyl, hydroksy-lavere alkyl, cyklo-lavere alkyl-lavere alkyl, acyl, acyl-lavere alkyl, fenylsulfonyl eventuelt substituert med halogen eller en gruppe med den generelle formel VI 1 2 R means lower alkyl, hydroxy-lower alkyl, cyclo-lower alkyl-lower alkyl, acyl, acyl-lower alkyl, phenylsulfonyl optionally substituted with halogen or a group of the general formula VI

& har den ovenfor angitte betydning,& has the above meaning,

9 10 11 R', R og R hver betyr hydrogen eller lavere alkoksy,9 10 11 R', R and R each represent hydrogen or lower alkoxy,

1 3 R betyr lavere alkyl, A. betyr en valensbinding eller lavere alkylen, A2betyr etylen eller metylenetylen, og X betyr en syrerest. 2. Fremgangsmåte ifølge krav 1,karakterisertved at det fremstilles en forbindelse med formel I hvor R1 betyr en gruppe med den generelle formel IV 7 8 hvor R , R og A har den i krav 1 angitte betydning. 3. Fremgangsmåte ifølge krav 2,karakterisertved at det fremstilles en forbindelse med formel I hvor R 7 og R gtil sammen danner en eventuelt substituert N-holdig heterocyklisk gruppe med det nabostilte nitrogenatom. 4. Fremgangsmåte ifølge krav 3,karakterisertved at det fremstillen en forbindelse med formel I hvor R 7 og R Qtil sammen danner en mettet 5-, 6- eller 7-leddet heteromonocyklisk gruppe, som inneholder 1 eller 2 nitrogenatomer og/eller 1 eller 2 oksygenatomer, med det nabostilte nitrogenatom, og som kan ha 1-3 substituenter valgt blant hydroksy, lavere alkyl, lavere alkoksy, mono- eller di-(lavere alkyl)amino-lavere alkyl, hydroksy-lavere alkyl, forestret karboksy-lavere alkyl, cyklo-lavere alkyl-lavere alkyl, acyl, acyl-lavere alkyl, fenylsulfonyl, som eventuelt er substituert med halogen, fenyl-lavere alkenyl og en gruppe med den generelle formel VI 9 10 11 hvor .2 har den x krav 1 angitte betydning, og R , R og R h v e r b e tyr hyd r o g e n e .1.1 e r 1 a v e r e alk o ksy . 5. Fremgangraåte ifølge krav 4, k a r a k t e r j. s e r t ved at det fremstiller en forbindelse med formel I hvor R 7 og R^ til sammen danner en piperazinring med det nabostilte nitrogenatom, og som kan være substituert med lavere alkyl. 6. Fremgangsmåte ifølge krav 5,karakterisertved at det fremstilles en forbindelse med formel I hvor Ar betyr aryl substituert med nitro. 7. Fremgangsmåte ifølge krav 6,karakterisertved at det fremstilles en forbindelse med formel I hvor R<2>betyr hydrogen eller lavere alkyl. 8. Fremgangsmåte ifølge krav 7,karakterisertved at det fremstilles 6-metyl-5-(4-metylpiperazin-1-ylmetyl)-4-(3-nitrofenyl)-2-fenylpyrimidin eller et salt derav. 1 3 R means lower alkyl, A. means a valence bond or lower alkylene, A2 means ethylene or methylene ethylene, and X means an acid residue. 2. Method according to claim 1, characterized in that a compound of formula I is prepared where R1 means a group of the general formula IV 7 8 where R , R and A have the meaning specified in claim 1. 3. Method according to claim 2, characterized in that a compound of formula I is prepared where R 7 and R g together form an optionally substituted N-containing heterocyclic group with the adjacent nitrogen atom. 4. Method according to claim 3, characterized in that a compound of formula I is prepared where R 7 and R Q together form a saturated 5-, 6- or 7-membered heteromonocyclic group, which contains 1 or 2 nitrogen atoms and/or 1 or 2 oxygen atoms, with the adjacent nitrogen atom, and which may have 1-3 substituents selected from hydroxy, lower alkyl, lower alkoxy, mono- or di-(lower alkyl)amino-lower alkyl, hydroxy-lower alkyl, esterified carboxy-lower alkyl, cyclo-lower alkyl-lower alkyl, acyl, acyl-lower alkyl, phenylsulfonyl, which is optionally substituted with halogen, phenyl-lower alkenyl and a group of the general formula VI 9 10 11 where .2 has the meaning given in claim 1, and R , R and R w h e r b e ty r hy d r o g e n e .1.1 e r 1 a v e r e alk o ksy . 5. Method according to claim 4, character j. especially in that it produces a compound of formula I where R 7 and R^ together form a piperazine ring with the adjacent nitrogen atom, and which can be substituted with lower alkyl. 6. Process according to claim 5, characterized in that a compound of formula I is prepared where Ar means aryl substituted with nitro. 7. Process according to claim 6, characterized in that a compound of formula I is prepared where R<2> means hydrogen or lower alkyl. 8. Process according to claim 7, characterized in that 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine or a salt thereof is prepared.

9. Fremgangsmåte ifølge krav 1,karakterisertved at det fremstilles en forbindelse med formel I hvor R1 betyr forestret karboksy, lavere alkanoyl, hydroksy-lavere alkyl eller en gruppe med den generelle formel III 9. Method according to claim 1, characterized in that a compound of formula I is prepared where R1 means esterified carboxy, lower alkanoyl, hydroxy-lower alkyl or a group with the general formula III

hvor R 7 og R 8 har deni krav 1 angitte betydning, og R 2 betyr en gruppe med den generelle formel V 7 8 hvor R , R og B har den i krav 1 angitte betydning.where R 7 and R 8 have the meaning stated in claim 1, and R 2 means a group with the general formula V 7 8 where R , R and B have the meaning specified in claim 1.