NO330345B1 - Pyrimidine-4,6-dicarboxylic acid diamides, process for their preparation and composition containing at least one such compound - Google Patents

Pyrimidine-4,6-dicarboxylic acid diamides, process for their preparation and composition containing at least one such compound Download PDF

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NO330345B1
NO330345B1 NO20052628A NO20052628A NO330345B1 NO 330345 B1 NO330345 B1 NO 330345B1 NO 20052628 A NO20052628 A NO 20052628A NO 20052628 A NO20052628 A NO 20052628A NO 330345 B1 NO330345 B1 NO 330345B1
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alkyl
pyrimidine
dicarboxylic acid
benzylamide
substituted
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NO20052628D0 (en
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Klaus Ulrich Weithmann
Reinhard Kirsch
Otmar Klingler
Jorg Habermann
Christian Engel
Bernard Pirard
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Sanofi Aventis Deutschland
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Priority claimed from DE10254092A external-priority patent/DE10254092A1/en
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Abstract

Det beskrives pyrimidin-4,6-dikarboksamider med formel (1), der substituentene har de nærmere definerte betydninger. Forbindelsene med formel (I) er egnet for selektiv inhibering av kollagenase (MMP 13). Pyrimidin-4,6-dikarboksamidene kan således benyttes for behandling av degenerative leddsykdommer.Pyrimidine-4,6-dicarboxamides of formula (1) are described, the substituents having the defined meanings. The compounds of formula (I) are suitable for the selective inhibition of collagenase (MMP 13). The pyrimidine-4,6-dicarboxamides can thus be used for the treatment of degenerative joint diseases.

Description

Foreliggende oppfinnelse angår nye pyrirnidin-4,6-dikarboksylsyrediamider, fremgangsmåte for fremstilling samt farmasøytisk sammensetning inneholdende minst en slik forbindelse. Forbindelsene kan anvendes for selektiv inhibering av kollagenase (MMP 13), og de kan derfor anvendes for behandling av degenerative leddsykdommer. The present invention relates to new pyrrinidine-4,6-dicarboxylic acid diamides, a method for production and a pharmaceutical composition containing at least one such compound. The compounds can be used for selective inhibition of collagenase (MMP 13), and they can therefore be used for the treatment of degenerative joint diseases.

Det er kjent at pyrimidin-4,6-dikarboksylsyrediamider og 2,4-substituerte pyridin-N-oksider inhiberer enzymene prolin- og lysinhydroksylase og derved bevirker en inhibering av kollagenbiosyntese ved påvirkning av den kollagenspesifikke hydroksyleringsreaksjon (EP 0418797; EP 0463592). På grunn av denne inhibering av kollagenbiosyntesen dannes det et ikke-funksjonsdyktig, underhydroksylert kollagenmolekyl som kun i liten grad kan avgis fra cellene til det ekstracellulære rom. Det underhydroksylerte kollagen kan i tillegg ikke bygges inn i kollagenmatriksen og blir meget lett brutt ned proteolytisk. Som følge av denne virkning, reduseres totalt sett mengden av ekstracellulært avleiret kollagen. Fra WO 02/064571 og WO 02/064080 er det kjent at spesielle pyridin-2,4-dikarboksylsyrediamider og pyrimidin-4,6-dikarboksylsyrediamider kan være allosteriske inhibitorer av MMP 13. It is known that pyrimidine-4,6-dicarboxylic acid diamides and 2,4-substituted pyridine-N-oxides inhibit the enzymes proline and lysine hydroxylase and thereby cause an inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reaction (EP 0418797; EP 0463592). Due to this inhibition of collagen biosynthesis, a non-functional, underhydroxylated collagen molecule is formed which can only be released from the cells to the extracellular space to a small extent. In addition, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily broken down proteolytically. As a result of this effect, the overall amount of extracellularly deposited collagen is reduced. From WO 02/064571 and WO 02/064080 it is known that particular pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides can be allosteric inhibitors of MMP 13.

I sykdommer som osteoartritt og reumatiske sykdommer, skjer det en ødeleggelse av leddene, særlig betinget ved den proteolytiske nedbrytning av kollagen på grunn av kollagenaser. Kollagenaser tilhører superfamilien av metalloproteinasene (MP), hhv. matriksmetallproteinasene (MMP). MMP'ene spalter kollagen, laminin, proteoglykaner, elastin eller gelatin under fysiologiske betingelser og spiller derfor en viktig rolle i knokkel- og bindevev. Et stort antall forskjellige inhibitorer av MMP'er, hhv. kollagenasene, er kjent (EP 0 606 046; W094/28889). Mangler ved de kjente inhibitorer av MMP'er er ofte den manglende spesifisitet ved inhiberingen kun for en klasse MMP'er. Derfor hemmer de fleste MMP-inhibitorer flere MMP'er samtidig, fordi de katalytiske domener av MMP'ene oppviser en lik struktur. Som følge av dette virker inhibitorene på uønsket måte på flere enzymer, også slike med vitale funksjoner (I. Massova, et al., The FASEB journal (1998) 12, 1075-1095). In diseases such as osteoarthritis and rheumatic diseases, there is a destruction of the joints, particularly due to the proteolytic breakdown of collagen due to collagenases. Collagenases belong to the superfamily of the metalloproteinases (MP), respectively. the matrix metalloproteinases (MMP). The MMPs cleave collagen, laminin, proteoglycans, elastin or gelatin under physiological conditions and therefore play an important role in bone and connective tissue. A large number of different inhibitors of MMPs, resp. the collagenases, are known (EP 0 606 046; WO94/28889). Shortcomings of the known inhibitors of MMPs are often the lack of specificity of the inhibition for only one class of MMPs. Therefore, most MMP inhibitors inhibit several MMPs at the same time, because the catalytic domains of the MMPs have a similar structure. As a result, the inhibitors act in an undesirable manner on several enzymes, including those with vital functions (I. Massova, et al., The FASEB journal (1998) 12, 1075-1095).

I forsøket på å finne virksomme forbindelser for behandling av bindevevssykdommer er det nå funnet at forbindelsene som anvendes ved oppfinnelsen er sterke inhibitorer av matriksmetalloproteinase 13, mens de anvendte forbindelsene ifølge oppfinnelsen i det vesentlige er uvirksomme mot MMP'ene 3 og 8. In the attempt to find effective compounds for the treatment of connective tissue diseases, it has now been found that the compounds used in the invention are strong inhibitors of matrix metalloproteinase 13, while the compounds used according to the invention are essentially inactive against MMPs 3 and 8.

Gjenstand for foreliggende oppfinnelse er derfor en forbindelse med formel I The object of the present invention is therefore a compound of formula I

og/eller alle stereoisomere former av forbindelsen med formel I og/eller blandinger av disse former i et hvilket som helst forhold, og/eller et fysiologisk godtakbart salt av forbindelsene med formel I, hvorved and/or all stereoisomeric forms of the compound of formula I and/or mixtures of these forms in any ratio, and/or a physiologically acceptable salt of the compounds of formula I, whereby

RI er hydrogenatom eller -(Ci-C6)-alkyl, RI is hydrogen atom or -(Ci-C6)-alkyl,

R2 er -(Ci-C6)alkyl, hvor alkyl er substituert en, to eller tre ganger med R 2 is -(C 1 -C 6 )alkyl, wherein alkyl is substituted one, two or three times by

-(C6-Ci4)-aryl, hvori aryl er substituert en, to eller tre ganger, uavhengig av hverandre, med -(C 6 -C 14 )-aryl, wherein aryl is substituted one, two or three times, independently of each other, with

1) -(C0-C6)-alkyl-C(O)-N-(R9)-(R10), hvori R9 og RI 0 er like eller forskjellige og er, uavhengig av hverandre 1) -(C0-C6)-alkyl-C(O)-N-(R9)-(R10), wherein R9 and R10 are the same or different and are, independently of each other

i) hydrogenatom eller i) hydrogen atom or

ii) -(Ci-C6)-alkyl, eller ii) -(C 1 -C 6 )-alkyl, or

R9 og RIO danner, sammen med nitrogenatomet som de er bundet til, en 5-, 6- eller 7-leddet mettet ring, hvor ett heteroatom fra serien oksygen, svovel og nitrogen også kan erstatte ett eller to karbonatomer og, i tilfellet nitrogen, kan nitrogenatomene, uavhengig av hverandre, være usubstituerte eller substituerte med (Q-C^-alkyl, R9 and R10 form, together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated ring, where one heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, the nitrogen atoms may, independently of each other, be unsubstituted or substituted with (C 1 -C 4 -alkyl,

2) -(C0-C6)-alkyl-C(O)-NH-CN, 2) -(C0-C6)-alkyl-C(O)-NH-CN,

3) -O(C0-C6)-alkyl-C(O)-N(R9)-R( 10), hvori R9 og RI0 har den ovenfor angitte betydningen, 4) -0(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), hvori R8 er i) hydrogenatom 3) -O(C0-C6)-alkyl-C(O)-N(R9)-R( 10), in which R9 and R10 have the above meaning, 4) -O(Co-C6)-alkyl-C (O)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), wherein R8 is i) hydrogen atom

ii) -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med -NH2, -CN, -OH, -C(O)-NH-OH, N02, -C(0)-0(Ci-C6)-alkyl, eller halogen eller ii) -(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, independently, by -NH2, -CN, -OH, -C(O)-NH-OH, NO2, -C(O)-O(Ci-C6)-alkyl, or halogen or

iii) OH og iii) OH and

hvori R9 og RIO har den ovenfor angitte betydningen, wherein R 9 and RIO have the above meaning,

5) -(C0-C6)-alkyl-C(O)- N(R8)-(C0-C6)-alkyl-Het, hvor R8 har den ovenfor angitte betydningen og Het er et mettet eller umettet, monocyklisk eller bicyklisk, 3- til 10-leddet, heterocyklisk ringsystem som inneholder 1, 2 eller 3 like eller forskjellige ringheteroatomer fra rekken nitrogen, oksygen og svovel, og er usubstituert eller substituert en, to eller tre ganger uavhengig av hverandre med 5) -(C0-C6)-alkyl-C(O)- N(R8)-(C0-C6)-alkyl-Het, where R8 has the above meaning and Het is a saturated or unsaturated, monocyclic or bicyclic, 3- to 10-membered, heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms from the series nitrogen, oxygen and sulphur, and is unsubstituted or substituted one, two or three times independently of each other with

a) halogen, a) halogen,

b) cyano, b) cyano,

c) nitro, c) nitro,

d) hydroksy, d) hydroxy,

e) amino, e) amino,

f) -C(0)-0-(Ci-C6)-alkyl, f) -C(O)-O-(Ci-C6)-alkyl,

g) -C(0)-OH, g) -C(0)-OH,

h) -(Ci-C6)-alkyl, hvor alkyl er usubstituert eller substituert h) -(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted

en, to eller tre ganger med halogen, once, twice or three times with halogen,

i) -0-(Ci-C6)-alkyl, hvor alkyl er usubstituert eller substituert en, to eller tre ganger med halogen eller - N(R9)-(R10), eller i) -O-(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)-(R10), or

j) =0, j) =0,

k) -Het, k) -Hot,

1) -(C2-C6)-alkenyl, hvor alkenyl er usubstituert eller substituert en, to eller tre ganger med halogen eller 1) -(C2-C6)-alkenyl, where alkenyl is unsubstituted or substituted one, two or three times by halogen or

-N(R9)-(R10), eller -N(R9)-(R10), or

m) -(C2-C6)-alkynyl, hvor alkynyl er usubstituert eller substituert en, to eller tre ganger med halogen eller m) -(C2-C6)-alkynyl, where alkynyl is unsubstituted or substituted one, two or three times by halogen or

-N(R9)-(R10), eller -N(R9)-(R10), or

6) -(Co-C6)-alkyl-C(0)-N(R8)-(C6-Ci4)-aryl, hvor aryl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med de ovenfor nevnte restene a) til m), 6) -(Co-C6)-alkyl-C(0)-N(R8)-(C6-Ci4)-aryl, where aryl is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned the residues a) to m),

R3, R4, R5, R6 og R7 er like eller forskjellige og er, uavhengig hverandre, R3, R4, R5, R6 and R7 are the same or different and are, independently of each other,

1. hydrogenatom, 1. hydrogen atom,

2. halogen, 2. halogen,

3. -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, 4. -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger med halogen, eller 3. -(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, with halogen, 4. -O-(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times with halogen, or

5. -S-(Ci-C6)-alkyl eller 5. -S-(C1-C6)-alkyl or

R4 og R5 eller R5 og R6, danner sammen med karbonatomene som de i hvert tilfelle er bundet til, uavhengig av hverandre, en 5- eller 6-leddet ring som er aromatisk eller mettet og inneholder null, ett eller to heteroatomer fra rekken oksygen, nitrogen eller svovel, hvor ringen er usubstituert eller er substituert ved ett eller flere karbonatomer, en eller to ganger, med halogen og de andre restene R3, R6 og R7 eller R3, R4 og R7 har den ovenfor angitte betydningen ifølge 1. til 5.. R4 and R5 or R5 and R6, together with the carbon atoms to which they are attached in each case, independently form a 5- or 6-membered ring which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur, where the ring is unsubstituted or is substituted at one or more carbon atoms, once or twice, with halogen and the other residues R3, R6 and R7 or R3, R4 and R7 have the above-mentioned meaning according to 1. to 5. .

Michael Murray kunne vise at forbindelser som inneholder en usubstituert benzo[l,3]dioksolring som rest, hemmer de cytokrome P450 leverenzymer (Michael Murray, Current Drug Metabolism 2000, 67-84). Den nevnte rest gjøres ansvarlig for denne signifikante, toksikologiske effekt. Derfor er denne utelukket fra forbindelsene med formel I. Michael Murray was able to show that compounds containing an unsubstituted benzo[l,3]dioxole ring as a residue inhibit the cytochrome P450 liver enzymes (Michael Murray, Current Drug Metabolism 2000, 67-84). The aforementioned residue is made responsible for this significant, toxicological effect. This is therefore excluded from the compounds of formula I.

En ytterligere gjenstand for oppfinnelsen er en forbindelse med formel I, der A further object of the invention is a compound of formula I, wherein

RI er hydrogenatom eller -(Ci-C6)-alkyl, RI is hydrogen atom or -(Ci-C6)-alkyl,

R2 er -(Ci-C6)-alkyl, hvor alkyl er substituert en, to eller tre ganger med fenyl, hvori fenyl er substituert en, to eller tre ganger, uavhengig av hverandre, med R 2 is -(C 1 -C 6 )-alkyl, wherein alkyl is substituted one, two, or three times by phenyl, wherein phenyl is substituted one, two, or three times, independently, by

1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10) hvori R9 og RIO er like eller forskjellige og er uavhengig av hverandre 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10) wherein R9 and R10 are the same or different and are independent of each other

i) hydrogenatom eller, i) hydrogen atom or,

ii) -(Ci-C6)-alkyl, eller ii) -(C 1 -C 6 )-alkyl, or

R9 og RIO danner sammen med nitrogenatomet som de er bundet til en 5-, 6- eller 7-leddet, mettet ring, hvorved et heteroatom fra rekken oksygen, svovel og nitrogen også kan erstatte ett eller to karbonatomer og, i tilfellet nitrogen, kan nitrogenatomene, uavhengig av hverandre, være usubstituerte eller substituerte med (Ci-C6)-alkyl, R9 and R10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered, saturated ring, whereby a heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, can the nitrogen atoms, independently of each other, be unsubstituted or substituted with (Ci-C6)-alkyl,

2) -(C0-C6)-alkyl-C(O)-NH-CN, 2) -(C0-C6)-alkyl-C(O)-NH-CN,

3) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), hvor R9 og RIO har den ovenfor angitte 3) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 have the above

betydningen, the meaning,

4) -(Co-C6)-alkyl-C(0)-N(R8)-alkyl-N(R9)-(R10), hvori R8 er i) hydrogenatom 4) -(Co-C6)-alkyl-C(0)-N(R8)-alkyl-N(R9)-(R10), in which R8 is i) hydrogen atom

ii) -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med -NH2, -CN, -OH, -C(0)-OH, ii) -(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, independently of each other, with -NH2, -CN, -OH, -C(O)-OH,

-C(0)-OH, -C(0)-OH, C(0)-NH-OH, N02, -C(0)-0-(Ci-C6)-alkyl, eller halogen eller -C(0)-OH, -C(0)-OH, C(0)-NH-OH, NO2, -C(0)-0-(Ci-C6)-alkyl, or halogen or

iii) -OH, og hvori R9 og RIO har den ovenfor angitte betydningen, iii) -OH, and wherein R 9 and R 10 have the above meaning,

5) -(C0-C6)-alkyl-C(O)—N(R8)-(C0-C6)-alkyl-Het, hvori R8 har den ovenfor angitte betydningen og Het er en rest fra gruppen azepin, azetidin, aziridin, benzimidazol, benzofuran, benzo[l,4]dioksin, 1,3-benzodioksol, 4H-benzo[l,4]oksazin, benzoksazol, benzotiazol, benzotiofen, kinazolin, kinolin, kinoksalin, kroman, cinnolin, 1,2-diazepin, 1,3-diazepin, 1,4-diazepin, 1,4-dioksin, dioksol, furan, imidazol, indazol, indol, isokinolin, isokroman, isoindol, isotiazol, isoksazol, morfolin, 1,2-oksazin, 1,3-oksazin, 1,4-oksazin, oksazol, oksiran, piperazin, piperidin, ftalazin, pyran, pyrazin, pyrazol, pyridazin, pyridin, pyrimidin, pyridoimidazol, pyridopyridin, pyridopyrimidin, pyrrol, pyrrolidin, tetrazol, 1,2-tiazin, 1,3-tiazin, 1,4-tiazin, tiazol, tiomorfolin, tiofen, tiopyran, 1,2,3-triazin, 1,3,5-triazin, 1,2,4-triazin, 1,2,3-triazol eller 1,2,4-triazol og hvori Het er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med 5) -(C0-C6)-alkyl-C(O)—N(R8)-(C0-C6)-alkyl-Het, in which R8 has the above meaning and Het is a residue from the group azepine, azetidine, aziridine , benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine , 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3 -oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1 ,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole and wherein Het is unsubstituted or substituted one, two or three times, independently of each other, with

a) halogen, a) halogen,

b) cyano, b) cyano,

c) nitro, c) nitro,

d) hydroksy, d) hydroxy,

e) amino, e) amino,

f) -C(0)-0-(Ci-C6)-alkyl, f) -C(O)-O-(Ci-C6)-alkyl,

g) -C(0)-OH, g) -C(0)-OH,

h) -(Ci-C6)-alkyl, hvor alkyl er usubstituert eller substituert h) -(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted

en, to, eller tre ganger med halogen, once, twice, or three times with halogen,

i) -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen eller - N(R9)-(R10), i) -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, with halogen or - N(R9)-(R10),

j)<=>o, j)<=>o,

k) -Het, hvori Het er som definert ovenfor, k) -Het, in which Het is as defined above,

1) -(C2-C6)-alkenyl, hvor alkenyl er usubstituert eller substituert en, to eller tre ganger med halogen eller - N(R9)-(R10), eller 1) -(C2-C6)-alkenyl, where alkenyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)-(R10), or

m) -(C2-C6)-alkynyl, hvori alkynyl er usubstituert eller substituert en, to eller tre ganger med halogen eller m) -(C2-C6)-alkynyl, wherein alkynyl is unsubstituted or substituted one, two or three times by halogen or

-N(R9)-(R10), eller -N(R9)-(R10), or

6) -(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-(C6-Ci4)-fenyl, hvor fenyl 6) -(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-(C6-Ci4)-phenyl, where phenyl

er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med de ovenfor nevnte restene a) til m), is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned residues a) to m),

R3, R4, R5, R6 og R7 er like eller forskjellige og er, uavhengig av hverandre, R3, R4, R5, R6 and R7 are the same or different and are, independently of each other,

1. hydrogenatom, 1. hydrogen atom,

2. halogen, 2. halogen,

3. -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert, en, to eller tre ganger, med halogen, eller 4. -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert, en, to eller tre ganger, med halogen, eller 3. -(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted, one, two or three times, with halogen, or 4. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted, a , two or three times, with halogen, or

R4 og R5 eller R5 og R6 danner, sammen med karbonatomene som de i hvert tilfelle er bundet til, uavhengig av hverandre, en dioksan-, dioksol-, dihydrofuran- eller furanring, hvor ringen er usubstituert eller substituert, ved ett eller ved flere karbonatomer, en eller to ganger, med halogen og de andre restene R3, R6 og R7 eller R3, R4 og R7 har den ovenfor angitte betydningen for 1. til 4. R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached in each case, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring, where the ring is unsubstituted or substituted, at one or more carbon atoms , once or twice, with halogen and the other residues R 3 , R 6 and R 7 or R 3 , R 4 and R 7 have the meaning given above for 1. to 4.

En ytterligere gjenstand for oppfinnelsen er en forbindelse med formel I, der A further object of the invention is a compound of formula I, wherein

RI er hydrogenatom, RI is hydrogen atom,

R2 er -(Ci-C3)-alkyl, hvor alkyl er substituert med fenyl, hvori fenyl er substituert en, to eller tre ganger, uavhengig av hverandre, med 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10) hvori R9 og RIO er hydrogenatom, R 2 is -(C 1 -C 3 )-alkyl, wherein alkyl is substituted by phenyl, wherein phenyl is substituted one, two or three times, independently of each other, by 1) -(C 0 -C 6 )-alkyl-C(O)- N(R9)-(R10) in which R9 and R10 are hydrogen atoms,

metyl, etyl, propyl eller butyl, eller methyl, ethyl, propyl or butyl, or

R9 og RIO danner, sammen med nitrogenatomet som de er bundet til, en rest som kan avledes fra pyrrolidin, piperidin, pyrazolidin, pyrazin, tetrazin, imidazolidin, piperazin, isoksazolidin, morfolin, isotiazolidin og, i tilfellet nitrogen, kan nitrogenatomene uavhengig av hverandre være usubstituerte eller substituerte med (Ci-C4)-alkyl, R9 and R10 form, together with the nitrogen atom to which they are attached, a residue which may be derived from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, morpholine, isothiazolidine and, in the case of nitrogen, the nitrogen atoms may independently be unsubstituted or substituted with (Ci-C4)-alkyl,

2) -(C0-C4)-alkyl-C(O)-NH-CN, 2) -(C0-C4)-alkyl-C(O)-NH-CN,

3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10), hvori R9 og RIO har den ovenfor 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the above

angitte betydningen, state the meaning,

4) -(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), hvori R8 er 4) -(Co-C6)-alkyl-C(O)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), wherein R8 is

hydrogen, metyl, etyl, propyl eller butyl, og R9 og RIO har den ovenfor angitte betydningen, hydrogen, methyl, ethyl, propyl or butyl, and R9 and R10 have the meaning given above,

5) -C(O)-N(R8)-(C0-C2)-alkyl-Het, hvor R8 har den ovenfor angitte 5) -C(O)-N(R8)-(C0-C2)-alkyl-Het, where R8 has the above

betydningen og Het er azepin, azetidin, aziridin, benzimidazol, benzofuran, benzo[l,4]dioksin, 1,3-benzodioksol, 4H-benzo[l,4]oksazin, benzoksazol, benzotiazol, benzotiofen, kinazolin, kinolin, kinoksalin, kroman, cinnolin, 1,2-diazepin, 1,3-diazepin, 1,4-diazepin, 1,4-dioksin, dioksol, furan, imidazol, indazol, indol, isokinolin, isokroman, isoindol, isotiazol, isoksazol, morfolin, 1,2-oksazin, 1,3-oksazin, 1,4-oksazin, oksazol, oksiran, piperazin, piperidin, ftalazin, pyran, pyrazin, pyrazol, pyridazin, pyridin, pyrimidin, pyridoimidazol, pyridopyridin, pyridopyrimidin, pyrrol, pyrrolidin, tetrazol, 1,2-tiazin, 1,3-tiazin, 1,4-tiazin, tiazol, tiomorfolin, tiofen, tiopyran, 1,2,3-triazin, 1,3,5-triazin, 1,2,4-triazin, 1,2,3-triazol eller 1,2,4-triazol og Het er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med meaning and Het is azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochromane, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4- triazine, 1,2,3-triazole or 1,2,4-triazole and Het is unsubstituted or substituted one, two or three times, independently of each other, with

a) halogen, a) halogen,

b) cyano, b) cyano,

c) nitro, c) nitro,

d) hydroksy, d) hydroxy,

e) amino, e) amino,

f) -C(0)-0-(Ci-C4)-alkyl, f) -C(O)-O-(Ci-C4)-alkyl,

g) -C(0)-OH, g) -C(0)-OH,

h) -(Ci-C4)-alkyl, hvor alkyl er usubstituert eller substituert h) -(Ci-C4)-alkyl, where alkyl is unsubstituted or substituted

en, to eller tre ganger med halogen, once, twice or three times with halogen,

i) -0-(Ci-C4)-alkyl, hvor alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, eller 6) -C(0)-N(R8)-(Co-C4)-alkyl-fenyl, hvor fenyl er usubstituert eller i) -O-(Ci-C4)-alkyl, where alkyl is unsubstituted or substituted one, two or three times, with halogen, or 6) -C(0)-N(R8)-(Co-C4)-alkyl -phenyl, where phenyl is unsubstituted or

substituert en, to eller tre ganger uavhengig av hverandre med de ovenfor angitte rester a) til i), substituted one, two or three times independently of each other with the above stated residues a) to i),

R3, R4, R5, R6 og R7 er like eller forskjellige og er, uavhengig av hverandre, R3, R4, R5, R6 and R7 are the same or different and are, independently of each other,

1. hydrogenatom, 1. hydrogen atom,

2. halogen, 2. halogen,

3. -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, 4. -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, eller 3. -(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, with halogen, 4. -O-(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, with halogen, or

R4 og R5 eller R5 og R6 danner, sammen med karbonatomene som de er bundet til, uavhengig av hverandre, en dioksan-, dioksol-, dihydrofuran- eller furanring og de andre restene er R3, R6 og R7 eller R3, R4 og R7 har de ovenfor angitte betydningene ifølge 1. til 4. R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring and the other residues are R3, R6 and R7 or R3, R4 and R7 have the above meanings according to 1. to 4.

En ytterligere gjenstand for oppfinnelsen er en forbindelse med formel I som er valgt fra: pyrimidin-4,6-karboksylsyre 4-(4-dietylkarbamoylbenzylamid) 6-(3-metyloksybenzylamid), A further object of the invention is a compound of formula I which is selected from: pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methyloxybenzylamide),

pyrimidin-4,6-karboksylsyre 4-(3-metoksybenzylamid) 6-(4-propylkarbamoylbenzylamid), pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-(4-propylcarbamoylbenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(4-isopropylkarbamoylbenzylamid) 6-(3-metoksybenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(4-isopropylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-[(2-dimetylaminoetylkarbamoyl) benzylamid] 6-(3-metoksy-benzylamid), pyrimidine-4,6-dicarboxylic acid 4-[(2-dimethylaminoethylcarbamoyl)benzylamide] 6-(3-methoxy-benzylamide),

pyrimidin-4,6-dikarboksylsyre 4- [(2,3 -dihydrobenzo[ 1,4] dioksin-6-ylmetyl)amid] -6- [4-(2 -dimetylaminoetylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]-6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(2-dimetylaminoetylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6- {4-[2(4-metylpiperazin-1 -yl)-2-oksoetyl]benzylamid}, Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[2(4-methylpiperazin-1-yl)-2-oxoethyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4(2-morfolin-4-yl-2-oksoetoksy)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(2-morpholin-4-yl-2-oxoethoxy)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoylmetoksybenzylamid) 6- (4-fluor-3-metylbenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylmethoxybenzylamide) 6-(4-fluoro-3-methylbenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4(isopropylkarbamoylmetyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(isopropylcarbamoylmethyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6- {4-[(2-morfolin-4-yletylkarbamoyl)metyl]benzylamid}, pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[(2-morpholin-4-ylethylcarbamoyl)methyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoylmetylbenzylamid) 6-(4-fluor-3-metylbenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylmethylbenzylamide) 6-(4-fluoro-3-methylbenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(2-morfolin-4-yl-2-oksoetyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(isopropylkarbamoylmetoksy)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethoxy)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(2-morfolin-4-yletylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(2-pyrrolidin-1 -yl-etylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1 -yl-ethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(tiomorfolin-4-karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(tiomorfolin-4-karbonyl) benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-cyanokarbamoylbenzylamid) 6- (4-fluor-3-metylbenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(4-cyanocarbamoylbenzylamide) 6-(4-fluoro-3-methylbenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6- [4-(3 -morfolin-4-ylpropy lkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(3-morpholin-4-ylpropylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4(3-morfolin-4-yl-propyl-karbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4(3-morpholin-4-yl-propyl-carbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(4-metylpiperazin-1 -karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydrobenzofuran-5-ylmetyl)amid] 6- {4-[(pyridin-4-ylmetyl)karbamoyl]benzylamid}, pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6- {4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(4-N-cyanokarbamoylbenzylamid) 6-[(2,3-dihydrobenzofuran-5 -ylmetyl)amid], pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

pyrimidin-4,6-dikarboksylsyre 4-(4-N-cyanokarbamoylbenzylamid) 6- (3-metoksybenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-(3-methoxybenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(morfolin-4-karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4(2-piperazin-l-yletylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(2-piperazin-1-ylethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-tert-butylkarbamoylbenzylamid) 6-(3-metoksybenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(4-tert-butylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-{4-[metyl-(l - metylpiperidin-4-yl)karbamoyl]benzylamid}, pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(2-pyrrolidin- 1-yl-etylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[3-(2-morfolin-4-y letylkarbamoyl)benzy lamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(2-morfolin-4-yletylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

[4-( {[6-(4-fluor-3-metylbenzylkarbamoyl)-pyrimidin-4-karbonyl]-amino} -metyl)-benzoylamino]eddiksyremetylesterester, [4-( {[6-(4-fluoro-3-methylbenzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoylamino]acetic acid methyl ester ester,

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[3(morfolin-4-karbonyl)-benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3(morpholine-4-carbonyl)-benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6- {4-[(piperidin-4-ylmetyl)-karbamoyl]benzylamid}, pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- {4-[(piperidin-4-ylmethyl)-carbamoyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(3 -metoksybenzylamid) 6- [4-(piperidin-4-ylkarbamoyl)-benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)-benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(piperidin-4-ylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-{4-[metyl-(l-metylpiperidin-4-yl)karbamoyl]benzylamid}, pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6- {4-[(piperidin-4-ylmetyl)karbamoyl]benzylamid}, pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide},

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(4-metyl-piperazin-1 - karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-methyl-piperazine-1-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4-(morfolin-4-karbonyl)-benzylamid], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(morpholine-4-carbonyl)-benzylamide],

pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4-(4-metylpiperazin-1 -karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4-(2 - morfolin-4-yletylkarbamoyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3 -klor-4-fluorbenzylamid) 6- [4-(2 -pyrrolidin-1 - yletylkarbamoyl)benzylamid], Pyrimidin-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-pyrrolidin-1-ylethylcarbamoyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre4-(3-metoksybenzylamid) 6-[4-(morfolin-4-karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-{4-[(pyridin-4-ylmety l)karbamoyl]benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-(4-dietylkarbamoylbenzylamid), pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-diethylcarbamoylbenzylamide),

pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(morfolin-4-karbonyl)benzylamid], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(2-morfolin-4-yletylkarbamoyl)benzylamid], eller pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], or

pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoylbenzylamid) 6-(3-metoksybenzylamid). pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide).

Med "halogen" menes fluor, klor, brom eller jod. By "halogen" is meant fluorine, chlorine, bromine or iodine.

Med begrepet "-(C6-Ci4)-aryl" menes aromatiske hydrokarboner med 6 til 14 karbonatomer i ringen. -(C6-Ci4)-arylrester er f.eks. fenyl, naftyl, f.eks. 1-naftyl, 2-naftyl, bifenylyl, som f.eks. 2-bifenylyl, 3-bifenylyl og 4-bifenylyl, antryl eller fluorenyl. Bifenylylrester, naftylrester og særlig fenylrester er foretrukne arylrester. By the term "-(C6-C14)-aryl" is meant aromatic hydrocarbons with 6 to 14 carbon atoms in the ring. -(C6-C14)-aryl residues are e.g. phenyl, naphthyl, e.g. 1-naphthyl, 2-naphthyl, biphenylyl, such as e.g. 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl residues, naphthyl residues and especially phenyl residues are preferred aryl residues.

Med begrepet "-R4 og R5, eller R5 og R6, sammen med karbonatomene hvortil de er bundet, uavhengig av hverandre, danner en 5- eller 6-leddet ring, som er aromatisk eller mettet og inneholder null, et eller to heteroatomer fra rekken oksygen, nitrogen eller svovel", menes ringsystemer som kan avledes fra dioksol, pyrrol, pyrrolidin, pyridin, piperidin, dioksan, tetrahydropyridin, pyrazol, imidazol, pyrazolin, imidazolin, pyrazolidin, imidazolidin, pyridazin, pyrimidin, pyrazin, piperazin, pyran, furan, dihydrofuran, tetrahydrofuran, oksazol, isoksazol, 2-isoksazol, isoksazolidin, morfolin, oksotiolan, tiopyran, tiazol, isotiazol, 2-isotiazolin, isotiazolidin eller tiomorfolin. With the term "-R4 and R5, or R5 and R6, together with the carbon atoms to which they are attached, independently of each other, form a 5- or 6-membered ring, which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur", means ring systems that can be derived from dioxole, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran, furan , dihydrofuran, tetrahydrofuran, oxazole, isoxazole, 2-isoxazole, isoxazolidine, morpholine, oxothiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothiazolidine or thiomorpholine.

Med begrepet "Het" menes et mettet eller umettet, monocyklisk eller bicyklisk, 3- til 10-leddet, heterocyklisk ringsystem som inneholder 1,2 eller 3 like eller forskjellige ringheteroatomer fra rekken nitrogen, oksygen eller svovel. Het inneholder i det tilgrunnliggende monocykliske eller bicykliske, heterocykliske ringsystem 3, 4, 5, 6, 7, 8, 9 eller 10 ringatomer. Det monocykliske ringsystem kan være en 3-, 4-, 5-, 6- eller 7-leddet ring. I bicyklisk Het kan to ringer være forbundet med hverandre, hvorav en kan være en 5-leddet eller 6-leddet, heterocyklisk ring og den andre en 5- eller 6-leddet, heterocyklisk eller karbocyklisk ring. En bicyklisk Het-gruppe kan f.eks. bestå av 8, 9 eller 10 ringatomer. By the term "Het" is meant a saturated or unsaturated, monocyclic or bicyclic, 3- to 10-membered, heterocyclic ring system containing 1,2 or 3 identical or different ring heteroatoms from the nitrogen, oxygen or sulfur series. It contains in the underlying monocyclic or bicyclic, heterocyclic ring system 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. The monocyclic ring system can be a 3-, 4-, 5-, 6- or 7-membered ring. In bicyclic Het, two rings may be connected to each other, one of which may be a 5-membered or 6-membered heterocyclic ring and the other a 5- or 6-membered heterocyclic or carbocyclic ring. A bicyclic Het group can e.g. consist of 8, 9 or 10 ring atoms.

Het inneholder mettede, heterocykliske ringsystemer som ikke har noen dobbeltbinding i ringene og likeledes umettede, heterocykliske ringsystemer inkludert monoumettede og polyumettede, heterocykliske ringsystemer som har en eller flere dobbeltbindinger og danner et stabilt ringsystem. Umettede ringer kan være delvis umettet eller danne et aromatisk sysem. I Het-gruppen er det identiske eller forskjellige heteroatomer fra rekken nitrogen, oksygen eller svovel. Eksempler på heterocykler som kan avledes fra Het-gruppen er akridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzotiofuranyl, benzotiofenyl, benzoksazolyl, benztiazolyl, benztriazolyl, benztetrazolyl, benzisoksazolyl, benzisotiazolyl, benzimidazalinyl, karbazolyl, 4aH-karbazolyl, karbolinyl, kromanyl, kromenyl, cinnolyl, dekahydrokinolinyl, 2H,6H-l,5,2-ditiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isokromanyl, isoindazolyl, isoindolinyl, isoindolyl, isokinolinyl (benzimidazolyl), isotiazolyl, isoksazolyl, morfolinyl, naftyridinyl, oktahydroisokinolinyl, oksadiazolyl, 1,2,3-oksadiazolyl, 1,2,4-oksadiazolyl, 1,2,5-oksadiazolyl, 1,3,4-oksadiazolyl, oksazolidinyl, oksazolyl, oksazolidinyl, pyrimidinyl, fenantridinyl, fenantrolinyl, fenazinyl, fenotiazinyl, fenoksatiinyl, fenoksazinyl, ftalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyrozolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooksazol, pyridoimidazol, pyridotiazol, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, kinazolinyl, kinolinyl, 4H-kinolizinyl, kinoksalinyl, kinuklidinyl, tetrahydrofuranyl, tetrahydroisokinolinyl, tetrahydrokinolinyl, 6H-l,2,5-tiadiazinyl, 1,2,3-tiadiazolyl, 1,2,4-tiadiazolyl, 1,2,5-tiadiazolyl, 1,3,4-tiadiazolyl og xantenyl. Het contains saturated, heterocyclic ring systems that have no double bonds in the rings and likewise unsaturated, heterocyclic ring systems including monounsaturated and polyunsaturated, heterocyclic ring systems that have one or more double bonds and form a stable ring system. Unsaturated rings can be partially unsaturated or form an aromatic system. In the Het group there are identical or different heteroatoms from the series nitrogen, oxygen or sulphur. Examples of heterocycles that can be derived from the Het group are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, cromanyl, chromenyl, cinnolyl , decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isocromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl . l, pyrazinyl, pyrozolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl and xanthenyl.

Foretrukket er azepin, azetidin, aziridin, benzimidazol, benzofuran, benzo[l,4]dioksin, 1,3-benzodioksol, 4H-benzo[l,4]oksazin, benzoksazol, benzotiazol, benzotiofen, kinazolin, kinolin, kinoksalin, kroman, cinnolin, 1,2-diazepin, 1,3-diazepin, 1,4-diazepin, 1,4-dioksin, dioksol, furan, imidazol, indazol, indol, isokinolin, isokroman, isoindol, isotiazol, isoksazol, morfolin, 1,2-oksazin, 1,3-oksazin, 1,4-oksazin, oksazol, oksiran, piperazin, piperidin, ftalazin, pyran, pyrazin, pyrazol, pyridazin, pyridin, pyrimidin, pyridoimidazol, pyridopyridin, pyridopyrimidin, pyrrol, pyrrolidin, tetrazol, 1,2-tiazin, 1,3-tiazin, 1,4-tiazin, tiazol, tiomorfolin, tiofen, tiopyran, 1,2,3-triazin, 1,3,5-triazin, 1,2,4-triazin, 1,2,3-triazol eller 1,2,4-triazol osv. og likeledes ringsystemer som oppnås fra de ovenfor angitte heterocykler ved forbindelse eller påkondensering med en karbocyklisk ring som f.eks. benzoanellerte, cyklopentakondenserte, cykloheksakondenserte eller cykloheptakondenserte derivater av disse heterocykler. Egnede nitrogenheterocykler kan likeledes foreligge som N-oksider eller som kvaternære salter der et egnet nitrogenatom er alkylert med (Ci-C4)-alkylrester. Preferred are azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1, 2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole etc. and likewise ring systems which are obtained from the above-mentioned heterocycles by connection or condensation with a carbocyclic ring such as e.g. benzoanellated, cyclopentafused, cyclohexafused or cycloheptafused derivatives of these heterocycles. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts where a suitable nitrogen atom is alkylated with (Ci-C4) alkyl residues.

Het-gruppen kan være usubstituert eller være substituert i henhold til de ovenfor angitte definisjoner. The Het group may be unsubstituted or substituted according to the definitions given above.

Med begrepet "R9 og RIO eller R14 og R15, sammen med nitrogenatomet hvortil de er bundet, danner en 5-, 6- eller 7-leddet, mettet ring, hvor ett eller to karbonatomer kan være erstattet med et heteroatom fra rekken oksygen, svovel eller nitrogen", menes rester som lar seg avlede fra imidazolidin, isotiazolidin, isoksazolidin, morfolin, piperazin, piperidin, pyrazin, pyrazolidin, pyrrolidin, tetrazin eller tiomorfolin. Foreliggende oppfinnelse tilveiebringer videre en fremgangsmåte forfremstilling av en forbindelse med formel I, som omtalt ovenfor, kjennetegnet ved at en forbindelse med formel II With the term "R9 and R10 or R14 and R15, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered, saturated ring, where one or two carbon atoms may be replaced by a heteroatom from the series oxygen, sulfur or nitrogen", means residues that can be derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine. The present invention further provides a method for the preparation of a compound of formula I, as discussed above, characterized in that a compound of formula II

a) omsettes med en forbindelse Illa eller Illb der RI, R2, R3, R4, R5, R6 og R7 har den i formel I angitte betydning og Y er halogen, hydroksyl eller Ci-C4-alkoksy eller danner, sammen med karbonylgruppen, en aktiv ester eller et blandet anhydrid, idet forbindelse med formel I dannes, og reaksjonsproduktene omdannes, hvor aktuelt til de fysiologisk godtagbare saltene, eller b) en forbindelse med formel II omsettes med en forbindelse med formel Illa eller Illb til en forbindelse med formel IVa eller IVb. a) is reacted with a compound Illa or Illb where R1, R2, R3, R4, R5, R6 and R7 have the meaning given in formula I and Y is halogen, hydroxyl or C1-C4 alkoxy or forms, together with the carbonyl group, a active ester or a mixed anhydride, whereby a compound of formula I is formed, and the reaction products are converted, where relevant, into the physiologically acceptable salts, or b) a compound of formula II is reacted with a compound of formula Illa or Illb to a compound of formula IVa or IVb.

hvorved RI til R7 har den i formel I angitte betydning og Y er halogen, hydroksyl eller Ci-C4-alkoksy, eller danner sammen med karbonylgruppen en aktiv ester eller et blandet anhydrid, og forbindelsen med formel IVa eller IVb renses, om egnet, og omdannes deretter, med en forbindelse med formel Illa eller Illb, til en forbindelse med formel I whereby R1 to R7 has the meaning given in formula I and Y is halogen, hydroxyl or C1-C4 alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, and the compound of formula IVa or IVb is purified, if appropriate, and is then converted, with a compound of formula Illa or Illb, into a compound of formula I

I det følgende skal fremstillingen av forbindelsene ifølge formel I og fremstillingen av de for disse nødvendige utgangsprodukter, så sant de ikke er kommersielt tilgjengelige, beskrives nærmere. In the following, the preparation of the compounds according to formula I and the preparation of the starting products necessary for these, as long as they are not commercially available, will be described in more detail.

Fremstillingen av forbindelsene ifølge oppfinnelsen lykkes best ved at de to komponenter, pyridinderivatet ved formel II og aminet med formel Illa eller Illb, bringes sammen i ekvimolare mengder og omsettes ved temperaturer mellom -30°C og 150°C, fortrinnsvis fra 20°C til 100°C, til forbindelser med formel IVa eller IVb, og at forbindelsene med formel IVa eller IVb deretter omsettes på analog måte med opp til en ekvimolar mengde av aminet med formel Illb eller Illa. Betingelsene for reaksjonen kan bestemmes f.eks. ved hjelp av tynnsjiktkromatografi eller HPLC-MS. En variant av denne metode består i at man arbeider i et egnet oppløsningsmiddel, som dietyleter, dimetoksyetan eller tetrahydrofuran, klorerte hydrokarboner, som metylenklorid, kloroform, tri- eller tetrakloretylen, benzen, toluen eller også polare oppløsningsmidler , som dimetylformamid, aceton eller dimetylsulfoksid. Reaksjonstemperaturene ligger derved mellom romtemperatur og oppløsningsmidlets kokepunkt hvorved temperaturer i området romtemperatur til 130°C er spesielt foretrukket. The production of the compounds according to the invention is most successful when the two components, the pyridine derivative of formula II and the amine of formula Illa or Illb, are brought together in equimolar amounts and reacted at temperatures between -30°C and 150°C, preferably from 20°C to 100°C, to compounds of formula IVa or IVb, and that the compounds of formula IVa or IVb are then reacted in an analogous manner with up to an equimolar amount of the amine of formula Illb or Illa. The conditions for the reaction can be determined e.g. by means of thin-layer chromatography or HPLC-MS. A variant of this method consists in working in a suitable solvent, such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons, such as methylene chloride, chloroform, tri- or tetrachloroethylene, benzene, toluene or also polar solvents, such as dimethylformamide, acetone or dimethylsulfoxide. The reaction temperatures are therefore between room temperature and the boiling point of the solvent, whereby temperatures in the range of room temperature to 130°C are particularly preferred.

Likeledes kan omsetningen skje via et blandet anhydrid som klormaursyreetylester eller via en aktiv ester som paranitrofenylester (Y=ClCH2-COO eller NO2-C6H4-O). Tilsvarende metoder er kjente og beskrevet i litteraturen. Likewise, the reaction can take place via a mixed anhydride such as chloroformate ethyl ester or via an active ester such as paranitrophenyl ester (Y=ClCH2-COO or NO2-C6H4-O). Corresponding methods are known and described in the literature.

Likeledes kan omsetningen av en forbindelse med formel II eller en forbindelse med formel IVa eller IVb skje med et amin med formel Illa eller Illb hvis Y er OH og den tilsvarende karboksylsyre aktiveres in situ ved brukbare koblingsreagenser. Slike koblingsreagenser er f.eks. karbodiimider, som dicykloheksylkarbodiimid (DCC) eller diisopropylkarbodiimid (DCI) eller N,N'-karbonyldiazol, som N,N'-karbonyldiimidazol eller et uroniumsalt som 0-((cyano(etoksykarbonyl)metylen)-amino)-l,1,3,3-tetrametyluronium tetrafluorborat (TOTU) eller 0-(7-azabenzotriazol-l-yl)-l,1,3,3-tetrametyluronium heksafluorfosfat (HATU). Tilsvarende metoder er kjente. Hvis aminene med formel Illa eller Illb ikke er kommersielt tilgjengelige, kan de fremstilles fra de tilsvarende kommersielt tilgjengelige utgangsforbindelser i henhold til metoder som er kjente i litteraturen. Egnede utgangsforbindelser for aminer er f.eks. nitriler, nitroforbindelser, karboksylsyreamider, karboksylsyreestere, karboksylsyrer, aldehyder og bromider. Nitriler, nitroforbindelser og karboksylsyreamider kan i henhold til kjente metoder reduseres til aminer. Karboksylsyrer og karboksylsyreestere kan overføres til karboksylsyreamider. Aldehyder kan via en reduktiv aminering med NUtAc/NaBILtoverføres direkte til aminene eller først overføres til oksimer med hydroksylamin og så overføres til aminer ved reduksjon. Likewise, the reaction of a compound of formula II or a compound of formula IVa or IVb can take place with an amine of formula Illa or Illb if Y is OH and the corresponding carboxylic acid is activated in situ by usable coupling reagents. Such coupling reagents are e.g. carbodiimides, such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI) or N,N'-carbonyldiazole, such as N,N'-carbonyldiimidazole or a uronium salt such as O-((cyano(ethoxycarbonyl)methylene)-amino)-1,1,3 ,3-tetramethyluronium tetrafluoroborate (TOTU) or 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). Corresponding methods are known. If the amines of formula IIIa or IIIb are not commercially available, they can be prepared from the corresponding commercially available starting compounds according to methods known in the literature. Suitable starting compounds for amines are e.g. nitriles, nitro compounds, carboxylic acid amides, carboxylic acid esters, carboxylic acids, aldehydes and bromides. Nitriles, nitro compounds and carboxylic acid amides can be reduced to amines according to known methods. Carboxylic acids and carboxylic acid esters can be transferred to carboxylic acid amides. Aldehydes can via a reductive amination with NUtAc/NaBILt be transferred directly to the amines or first transferred to oximes with hydroxylamine and then transferred to amines by reduction.

Eventuelt kan omsetningen også foregå i nærvær av baser. Som ytterligere baser kan f.eks. nevnes karbonater eller hydrogenkarbonater, som natrium- eller kaliumkarbonat eller natrium- eller kaliumhydrogenkarbonat eller tertiære aminer, som trietylamin, tributylamin, etyldiisopropylamin eller heterocykliske aminer, som N-alkylmorfolin, pyridin, kinolin eller dialkylanilin. If necessary, turnover can also take place in the presence of bases. As additional bases, e.g. mention is made of carbonates or hydrogen carbonates, such as sodium or potassium carbonate or sodium or potassium hydrogen carbonate or tertiary amines, such as triethylamine, tributylamine, ethyldiisopropylamine or heterocyclic amines, such as N-alkylmorpholine, pyridine, quinoline or dialkylaniline.

Eventuelt kan opparbeidingen av produktene, særlig forbindelsene med formel IVa eller IVb, f.eks. skje ved ekstrahering eller kromatografi, f.eks. over kiselgel. Det isolerte produkt kan omkrystalliseres og eventuelt omsettes med egnede syrer til et fysiologisk godtagbart salt. Som egnede syrer kan f.eks. nevnes: mineralsyrer, som saltsyre eller bromhydrogensyre, samt svovel-, fosfor-, salpeter- eller perklorsyre, eller organiske syrer som maur-, eddik-, propion-, rav-, glykol-, melke-, eple-, vin-, sitron-, malein-, fumar-, fenyleddik-, benzo-, metansulfon-, toluensulfon-, oksal-, 4-aminobenzo-, naftalin-1,5-disulfon- eller askorbinsyre. Optionally, the processing of the products, especially the compounds of formula IVa or IVb, e.g. happen by extraction or chromatography, e.g. over silica gel. The isolated product can be recrystallized and optionally reacted with suitable acids to a physiologically acceptable salt. As suitable acids, e.g. mentioned: mineral acids, such as hydrochloric or hydrobromic acid, as well as sulphurous, phosphoric, nitric or perchloric acid, or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric -, maleic, fumaric, phenylacetic, benzoic, methanesulphonic, toluenesulphonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulphonic or ascorbic acid.

Utgangsforbindelsene med formel Illa eller Illb kan, i den grad de ikke er kommersielt tilgjengelige, også syntetiseres på enkel måte (se f.eks. "Organikum", Organische Chemisches Grundpraktikum, 15. opplag, VEG Deutscher Verlag der Wissenschaften, 1976; en oversikt over de forskjellige muligheter finnes i metoderegisteret, s. 822). The starting compounds of formula Illa or Illb can, to the extent that they are not commercially available, also be synthesized in a simple way (see, for example, "Organikum", Organische Chemisches Grundpraktikum, 15th edition, VEG Deutscher Verlag der Wissenschaften, 1976; an overview about the different possibilities can be found in the method register, p. 822).

Utgangsforbindelsene med formel (II) oppnås f.eks. ved omsetning av pyridin-4,6-dikarboksylsyre, til det tilsvarende pyridin-4,6-dikarboksylsyrehalogenid, fortrinnsvis -klorid (i henhold til metoder kjente fra litteraturen), fortrinnsvis i nærvær av en katalysator, som dimetylformamid. Dette syrehalogenid kan så f.eks. omsettes med en egnet alkohol, f.eks. paranitrobenzylalkohol til den tilsvarende aktive ester, eller også med lavere alkoholer, som metanol eller etanol, til de tilsvarende estere. Likeledes kan pyrimidin-4,6-dikarboksylsyren også først, under tilsetning av en egnet karboksylsyre eller en karboksylsyreester, som klormaursyreetyleser, overføres til et blandet anhydrid som så omsettes med aminer med formel Illa eller Illb og IVa eller IVb til produktet ifølge oppfinnelsen produkt. En tilsvarende metode er også beskrevet i litteraturen. The starting compounds of formula (II) are obtained, e.g. by reaction of pyridine-4,6-dicarboxylic acid, to the corresponding pyridine-4,6-dicarboxylic acid halide, preferably -chloride (according to methods known from the literature), preferably in the presence of a catalyst, such as dimethylformamide. This acid halide can then e.g. reacted with a suitable alcohol, e.g. paranitrobenzyl alcohol to the corresponding active ester, or also with lower alcohols, such as methanol or ethanol, to the corresponding esters. Likewise, the pyrimidine-4,6-dicarboxylic acid can also first, with the addition of a suitable carboxylic acid or a carboxylic acid ester, such as chloroformate ethylase, be transferred to a mixed anhydride which is then reacted with amines of formula Illa or Illb and IVa or IVb to the product according to the invention product. A similar method is also described in the literature.

Fremstillingen av pyrimidin-4,6-dikarboksylsyren skjer i henhold til metoder kjente fra litteraturen, f.eks. ved oksidasjon av 4,6-dimetylpyrimidin som i sin tur f.eks. kan oppnås ved katalytisk hydrering av kommersielt tilgjengelig 2-merkapto-4,6-dimetylpyrimidin. The preparation of the pyrimidine-4,6-dicarboxylic acid takes place according to methods known from the literature, e.g. by oxidation of 4,6-dimethylpyrimidine which in turn e.g. can be obtained by catalytic hydrogenation of commercially available 2-mercapto-4,6-dimethylpyrimidine.

I den grad forbindelsene med formel I tillater diastereoisomere eller enantiomere former og oppstår som blandinger av slike ved den valgte syntese, kan separeringen i de rene stereoisomerer skje enten ved kromatografi på et eventuelt kiralt bærermateriale eller, hvis den racemiske forbindelse med formel I er i stand til saltdannelse, ved fraksjonert krystallisering av de med en optisk aktiv base eller syre som hjelpestoffer, dannede, diasteromere salter. Som kirale stasjonære faser for tynnsjikt- eller søylekromatografisk separering av enantiomerer egner seg f.eks. modifiserte kiselgelbærere (såkalte Pirkle-faser) samt høymolekylære karbohydrater, som triacetylcellulose. For analytiske formål, kan man etter tilsvarende, for fagmannen kjente derivatiseringer, også anvende gasskromatografiske metoder på kirale, stasjonære faser. For enantiomerseparering av de racemiske karboksylsyrer dannes, med en optisk aktiv, og som regel kommersielt tilgjengelig base som (-)-nikotin, (+)- eller (-)-fenyletylamin, kininbaser, L-lysin eller L-eller D-arginin, de forskjellige oppløselige, diastereomere salter, den tyngre oppløselige komponent isolert som faststoff og den lettere oppløselige diastereomer separert fra moderluten og de således oppnådde, diastereomere salter utvunnet som rene enantiomerer. På prinsippielt samme måte kan man overføre de racemiske forbindelser med formel I, som inneholder en basisk gruppe som en aminogruppe, til de rene enantiomerer ved hjelp av optisk aktive syrer som (+)-kamfer-10-sulfonsyre, D- og L-vinsyre, D- og L-melkesyre samt (+)- og (-)-mandelsyre. Videre kan de kirale forbindelser som inneholder alkohol- eller aminfunksjoner, ved hjelp av tilsvarende aktiverte eller eventuelt N-beskyttede enantiomerrene aminosyrer, overføres til de tilsvarende estere eller amider eller eventuelt kan de kirale karboksylsyrer ved hjelp av karboksybeskyttede, enantiomerrene aminosyrer overføres til amidene eller, med enantiomerrene hydroksykarboksylsyrer som melkesyre, overføres til de tilsvarende kirale estere. Således kan kiraliteten for den i enantiomerren form innførte aminosyre-eller alkoholrest benyttes for separering av isomerene idet det foretas en separering av de nå foreliggende diastereomerer ved krystallisering eller kromatografi på egnede stasjonære faser og deretter spaltes den medførte, kirale molekyldel ved hjelp av egnede metoder. To the extent that the compounds of formula I allow diastereoisomeric or enantiomeric forms and occur as mixtures of such in the chosen synthesis, the separation into the pure stereoisomers can take place either by chromatography on an optional chiral support material or, if the racemic compound of formula I is capable of to salt formation, by fractional crystallization of those with an optically active base or acid as auxiliaries, formed, diastereomeric salts. As chiral stationary phases for thin-layer or column chromatographic separation of enantiomers, e.g. modified silica gel carriers (so-called Pirkle phases) as well as high-molecular carbohydrates, such as triacetyl cellulose. For analytical purposes, gas chromatographic methods can also be applied to chiral, stationary phases after corresponding derivatizations known to the person skilled in the art. For enantiomer separation of the racemic carboxylic acids, with an optically active, and usually commercially available base such as (-)-nicotine, (+)- or (-)-phenylethylamine, quinine bases, L-lysine or L-or D-arginine, the various soluble diastereomeric salts, the heavier soluble component isolated as a solid and the more easily soluble diastereomer separated from the mother liquor and the thus obtained diastereomeric salts recovered as pure enantiomers. In the same principle, the racemic compounds of formula I, which contain a basic group such as an amino group, can be converted to the pure enantiomers by means of optically active acids such as (+)-camphor-10-sulphonic acid, D- and L-tartaric acid , D- and L-lactic acid as well as (+)- and (-)-mandelic acid. Furthermore, the chiral compounds containing alcohol or amine functions can be transferred to the corresponding esters or amides by means of correspondingly activated or optionally N-protected enantiomeric amino acids or, optionally, the chiral carboxylic acids can be transferred to the amides by means of carboxy-protected, enantiomeric amino acids or, with enantiomerically pure hydroxycarboxylic acids such as lactic acid, are transferred to the corresponding chiral esters. Thus, the chirality of the amino acid or alcohol residue introduced in enantiomeric form can be used to separate the isomers, as the present diastereomers are separated by crystallization or chromatography on suitable stationary phases and then the entrained, chiral molecular part is cleaved using suitable methods.

Sure eller basiske produkter av forbindelsene med formel I kan foreligge i form av de respektive salter eller i fri form. Foretrukket er farmakologisk godtagbare salter, f.eks. alkali- eller jordalkalimetallsalter, som hydroklorider, hydrobromider, sulfater, hemisulfater, alle mulige fosfater samt salter av aminosyrer, naturlige baser eller karboksylsyrer. Acidic or basic products of the compounds of formula I can be present in the form of the respective salts or in free form. Pharmacologically acceptable salts are preferred, e.g. alkali or alkaline earth metal salts, such as hydrochlorides, hydrobromides, sulphates, hemisulphates, all possible phosphates as well as salts of amino acids, natural bases or carboxylic acids.

Fremstillingen av fysiologisk godtagbare salter fra forbindelser med formel I som er i stand til saltdannelse, inkludert deres stereoisomere former, skjer på i og for seg kjent måte. Karboksylsyrene danner med basiske reagenser, som hydroksyder, karbonater, hydrogenkarbonater, alkoholater samt ammoniakk eller organiske baser som trimetyl-eller trietylamin, etanol eller trietanolamin, eller også basiske aminosyrer som lysin, ornitin eller arginin, stabile alkali- eller jordalkalimetall- eller eventuelt substituerte ammoniumsalter. I den grad forbindelsene med formel I oppviser basiske grupper kan man med sterke syrer også fremstille stabile syreaddisjonssalter. For dette formålet kommer i betraktning både uorganiske og organiske syrer, som saltsyre, bromhydrogen-, svovel-, fosfor-, metansulfon-, benzen-, p-touensulfon-, 4-brombenzensulfon-, cykloheksylamidosulfon-, trifluormetylsulfon-, eddik-, oksal-, vin-, rav-, eller trifluoreddiksyre. The preparation of physiologically acceptable salts from compounds of formula I which are capable of salt formation, including their stereoisomeric forms, takes place in a manner known per se. The carboxylic acids form with basic reagents, such as hydroxides, carbonates, hydrogen carbonates, alcoholates as well as ammonia or organic bases such as trimethyl or triethylamine, ethanol or triethanolamine, or also basic amino acids such as lysine, ornithine or arginine, stable alkali or alkaline earth metal or optionally substituted ammonium salts . To the extent that the compounds of formula I exhibit basic groups, stable acid addition salts can also be prepared with strong acids. For this purpose, both inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid, acetic acid, oxal -, tartaric, succinic or trifluoroacetic acid.

På grunn av de farmakologiske egenskaper egner forbindelsene med formel I seg for profylakse og behandling av alle slike sykdommer ved hvis forløp en forsterket aktivitet av matriksmetalloproteinase 13 er involvert. Due to the pharmacological properties, the compounds of formula I are suitable for the prophylaxis and treatment of all such diseases in the course of which an enhanced activity of matrix metalloproteinase 13 is involved.

Dertil hører degenerative leddsykdommer, som osteoartroser, spondyloser, brusksvinn etter leddtrauma eller lengre tids leddro etter meniskus- eller patellaskader eller båndriss. Dertil hører også sykdommer i bindevev som kollagenoser, periodontalsykdommer, sårhelingsforstyrrelser og kroniske sykdommer i bevegelsesapparaturen som inflammatoriske, immunologiske eller stoffskiftebetingede akutte og kroniske artritider, artropatier, myalgier og forstyrrelser i knokkstoffskifte eller kreftsykdommer som brystkreft. These include degenerative joint diseases, such as osteoarthritis, spondylosis, cartilage loss after joint trauma or long-term joint stiffness after meniscus or patella injuries or torn ligaments. This also includes diseases in connective tissue such as collagenoses, periodontal diseases, wound healing disorders and chronic diseases of the musculoskeletal system such as inflammatory, immunological or metabolic acute and chronic arthritis, arthropathies, myalgias and disorders in bone metabolism or cancers such as breast cancer.

Foreliggende oppfinnelse tilveiebringer følgelig også en farmasøytisk sammensetning, kjennetegnet ved at den omfatter et effektivt innhold av minst en forbindelse med formel I, som omtalt ovenfor, sammen med et farmasøytisk egnet og fysiologisk godtakbart bærerstoff, additiv og/eller annen aktiv forbindelse og hjelpestoffer. The present invention consequently also provides a pharmaceutical composition, characterized in that it comprises an effective content of at least one compound of formula I, as discussed above, together with a pharmaceutically suitable and physiologically acceptable carrier substance, additive and/or other active compound and excipients.

Anvendelsen av den farmasøytiske sammensetningen ifølge oppfinnelsen kan skje subkutant, intraartikulært, intraperitonealt, eller intravenøst. Foretrukket er den intraartikulære injeksjon. Reaktal, oral, inhalativ, eller transdermal tilførsel er også mulig. The pharmaceutical composition according to the invention can be used subcutaneously, intra-articularly, intraperitoneally or intravenously. The intra-articular injection is preferred. Reactal, oral, inhalation, or transdermal delivery is also possible.

Den farmasøytiske sammensetningen ifølge oppfinnelsen kan fremstilles ved at minst en forbindelse med formel I, sammen med en farmasøytisk egnet og fysiologisk godtagbar bærer og eventuelt ytterligere aktiv bestanddel, tilsetnings- eller hjelpestoffer, bringes til en egnet administreringsform. The pharmaceutical composition according to the invention can be prepared by bringing at least one compound of formula I, together with a pharmaceutically suitable and physiologically acceptable carrier and any further active ingredient, additives or auxiliaries, into a suitable administration form.

Forbindelsene med formel I blandes med de egnede tilsetningsstoffer som bærere, stabilisatorer eller inerte fortynningsmidler og bringes ved egnede metoder til egnet administreringsform som tabletter, drageer, stikkapsler, vandige alkoholiske eller oljesuspensjoner eller vandige eller oljeoppløsninger. Som inerte bærere kan nevnes gummi arabikum, magnesiumoksid, magnesiumkarbonat, kaliumfosfat, melkesukker, glukose eller stivelse, særlig maisstivelse. Derved kan tilberedningen skje både som tørr- og fuktig granulat. Som oljeaktige bærere eller oppløsningsmidler kan nevnes vegetabilske eller animalske oljer, som solsikkeolje eller levertran. The compounds of formula I are mixed with the suitable additives such as carriers, stabilizers or inert diluents and brought by suitable methods into suitable administration form such as tablets, dragees, suppositories, aqueous alcoholic or oil suspensions or aqueous or oil solutions. Examples of inert carriers include gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. Thereby, the preparation can take place both as dry and moist granules. Vegetable or animal oils, such as sunflower oil or cod liver oil, can be mentioned as oily carriers or solvents.

For subkutan, intraartikulær, intraperitoneal eller intravenøs tilførsel blir de aktive bestanddeler, hvis ønskelig, brakt i oppløsning, suspensjon eller emulsjon med de for dette egnede substanser som oppløsningsformidlere, emulgatorer eller ytterligere hjelpestoffer. Som oppløsningsmiddel kan f.eks. nevnes fysiologisk koksaltoppløsning eller alkoholer som etanol, propanol, glyserin, i tillegg også sukkeroppløsninger som glukose- eller manittoppløsninger, eller også en blanding av de forskjellige, nevnte oppløsningsmidler. For subcutaneous, intra-articular, intraperitoneal or intravenous administration, the active ingredients are, if desired, brought into solution, suspension or emulsion with substances suitable for this purpose, such as dissolution agents, emulsifiers or further auxiliaries. As a solvent, e.g. mention is made of physiological saline solution or alcohols such as ethanol, propanol, glycerine, in addition also sugar solutions such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

Videre kan man anvende vanlige hjelpestoffer, som bærere, spreng-, binde-, overtrekks-, svelle-, glide- eller smøremidler, smaksstoffer, søtningsmidler og oppløsningsformidlere. Som hyppig anvendte hjelpestoffer skal nevnes magnesiumkarbonat, titandioksid, laktose, mannitt og andre sukkere, talkum, melkeeggehvite, gelatin, stivelse, cellulose og derivater derav, animalske og vegetabilske oljer som levertran, solsikke-, jordnøtt- eller sesamolje, polyetylenglykol og oppløsningsmidler, som f.eks. sterilt vann og en- eller flerverdige alkoholer som glyserin. You can also use common auxiliaries, such as carriers, blasting, binding, coating, swelling, sliding or lubricating agents, flavourings, sweeteners and solubilizing agents. Frequently used excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk egg white, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents, which e.g. sterile water and mono or polyhydric alcohols such as glycerin.

Forbindelsene med formel I fremstilles og administreres fortrinnsvis som farmasøytiske preparater i doseringsenheter hvorved hver enhet, som aktiv bestanddel, inneholder en spesiell dose av forbindelsene med formel I. De kan for dette formål f.eks. administreres oralt i doser fra 0,01 til 25,0 mg/kg/dag, fortrinnsvis 0,01 til 5,0 mg/kg/dag, eller parenteralt i doser på 0,001 til 5 mg/kg/dag og fortrinnsvis 0,001 til 2,5 mg/kg/dag. Doseringen kan i alvorlige tilfeller også økes. I de fleste tilfeller er det dog tilstrekkelig med lavere doser. Disse opplysninger angår behandling av voksne personer. The compounds of formula I are preferably prepared and administered as pharmaceutical preparations in dosage units whereby each unit, as active ingredient, contains a special dose of the compounds of formula I. For this purpose, they can e.g. administered orally in doses from 0.01 to 25.0 mg/kg/day, preferably 0.01 to 5.0 mg/kg/day, or parenterally in doses of 0.001 to 5 mg/kg/day and preferably 0.001 to 2 .5 mg/kg/day. In severe cases, the dosage can also be increased. In most cases, however, lower doses are sufficient. This information concerns the treatment of adults.

Oppfinnelsen skal forklares nærmere nedenfor ved hjelp av de følgende, illustrerende eksempler. The invention will be explained in more detail below with the help of the following illustrative examples.

Eksempel 1: Example 1:

[4-( {[6-(4-fluor-3-metyl-benzylkarbamoyl)-pyridin-4-karbonyl]-amino} -metyl)-fenyl]-eddiksyreetylester a) 6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karboksylsyremetylester 8,81 g (0,045 mol) pyrimidin-4,6-dikarboksylsyredimetylester oppløses i 200 ml DMF og det tilsettes 6,25 g (0,045 mol) 4-fluor-3-metyl-benzylamin og det hele omrøres i 48 timer ved 60°C. Oppløsningsmidlet fjernes under vakuum og resten tas opp i eddiksyreetylester. Den organiske fase vaskes med mettet natriumhydrogenkarbonatoppløsning og 0,5N HC1 og tørkes over MgS04. Etter avfiltrering og avdamping av oppløsningsmidlet under vakuum omrøres resten i isopropanol. Det oppnås 8,75 g produkt som benyttes videre uten ytterligere rensing. b) 6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karboksylsyre 8,75 g (0,02 mol) 6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karboksylsyremetylester (70%) tas opp i 150 ml etanol og det tilsettes 1,89 g (0,022 mol) NaOH i 6 ml vann. Etter 3 timer ved romtemperatur fjernes oppløsningsmidlet under redusert trykk, resten tilsettes vann og bringes til pH <2 med konsentrert HC1. Bunnfallet suges av og tørkes. Det oppnås 5,5 g (94%) 6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karboksylsyre. [4-( {[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyridine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester a) 6-(4-fluoro-3-methyl- benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester 8.81 g (0.045 mol) pyrimidine-4,6-dicarboxylic acid dimethyl ester are dissolved in 200 ml DMF and 6.25 g (0.045 mol) 4-fluoro-3-methyl-benzylamine are added and the the whole is stirred for 48 hours at 60°C. The solvent is removed under vacuum and the residue is taken up in ethyl acetate. The organic phase is washed with sat sodium bicarbonate solution and 0.5N HCl and dried over MgSO 4 . After filtering off and evaporating the solvent under vacuum, the residue is stirred in isopropanol. 8.75 g of product is obtained, which is used further without further purification. b) 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid 8.75 g (0.02 mol) 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester (70%) is taken up in 150 ml of ethanol and 1.89 g (0.022 mol) NaOH in 6 ml of water is added. After 3 hours at room temperature, the solvent is removed under reduced pressure, the residue is added to water and brought to pH <2 with concentrated HCl. The precipitate is sucked off and dried. 5.5 g (94%) of 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid is obtained.

MS (ES<+>): m/e = 289,09. MS (ES<+>): m/e = 289.09.

c) (4-aminometyl-fenyl)-eddiksyreetylester c) (4-aminomethyl-phenyl)-acetic acid ethyl ester

0,5 g (2,6 mmol) (4-cyano-fenyl)-eddiksyreetylester oppløses i 70 ml etanolisk ammoniakkoppløsning og hydreres ved Raney-nikkel ved romtemperatur og under normaltrykk. Etter 45 minutter filtreres det hele og dampes inn. Man oppår 0,42 g (82%) (4-aminometyl-fenyl)-eddiksyreetylester. 0.5 g (2.6 mmol) (4-cyano-phenyl)-acetic acid ethyl ester is dissolved in 70 ml of ethanolic ammonia solution and hydrated with Raney nickel at room temperature and under normal pressure. After 45 minutes, it is all filtered and evaporated. 0.42 g (82%) of (4-aminomethyl-phenyl)-acetic acid ethyl ester is obtained.

MS (ES+): m/e = 194,11. MS (ES+): m/e = 194.11.

d) [4-( {[6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino}-metyl)-fenyl] -eddiksyreetylester d) [4-( {[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester

1,3 g (4,5 mmol) 6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karboksylsyre og 1,042 g (5,4 mmol) (4-aminometyl-fenyl)-eddiksyreetylester oppløses i 30 ml DMF og det tilsettes 1,02 g (4,9 mmol) dicykloheksylkarbodiimid og 0,607 g (4,5 mmol) hydroksybenzotriazol ved 5°C. Det hele omrøres i 5 timer og suges av. Oppløsningsmidlet fjernes under vakuum, resten tas opp i eddiksyreetylester og vaskes med mettet, vandig NaHC03-oppløsning. Den organiske fase tørkes over MgS04, filtreres og dampes inn under redusert trykk. Man oppnår 2,66 g produkt, som opparbeides videre ved preparativ HPLC. 1.3 g (4.5 mmol) of 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid and 1.042 g (5.4 mmol) of (4-aminomethyl-phenyl)-acetic acid ethyl ester are dissolved in 30 ml of DMF and 1.02 g (4.9 mmol) of dicyclohexylcarbodiimide and 0.607 g (4.5 mmol) of hydroxybenzotriazole are added at 5°C. The whole thing is stirred for 5 hours and sucked off. The solvent is removed under vacuum, the residue is taken up in ethyl acetate and washed with saturated aqueous NaHCO 3 solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure. 2.66 g of product is obtained, which is further worked up by preparative HPLC.

MS (ES+): m/e = 464,19. MS (ES+): m/e = 464.19.

Eksempel 2: [4-( {[6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino} -metyl)-fenyl]-eddiksyre Example 2: [4-( {[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid

2,4 g (5,2 mmol) [4-({[6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino}-metyl)-fenyl]-eddiksyreetylester tas opp i 150 ml vann og tilsettes 10 ml vann og 0,227 g (5,7 mmol) NaOH. Etter 5 dagers omrøring ved romtemperatur fjernes oppløsningsmidlet under redusert trykk og resten omrøres med etanol og filtreres. Det oppnås 1,51 g (67%) [4-({[6-(4-fluor-3-metyl-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino}-metyl)-fenyl]-eddiksyre. 2.4 g (5.2 mmol) of [4-({[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester is taken up in 150 ml of water and add 10 ml of water and 0.227 g (5.7 mmol) of NaOH. After 5 days of stirring at room temperature, the solvent is removed under reduced pressure and the residue is stirred with ethanol and filtered. 1.51 g (67%) of [4-({[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid is obtained.

MS (ES+): m/e = 436,15. MS (ES+): m/e = 436.15.

Eksempel 3: Example 3:

Pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoyl-benzylamid) 6-(3-metoksybenzylamid) Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoyl-benzylamide) 6-(3-methoxybenzylamide)

a) Syntese av 6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karboksylsyre a) Synthesis of 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid

26 g (88 mmol) 6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karboksylsyremetylester 26 g (88 mmol) 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester

(fremstilt ved omsetning av pyrimidin-4,6-dikarboksylsyredimetylester med 3-metoksybenzylamin) oppløses i 100 ml tetrahydrofuran og det tilsettes 104 ml (1,2 ekvivalenter) av en 1 molar, vandig litiumhydroksidoppløsning hvoretter reaksjonsblandingen deretter omrøres i 18 timer ved romtemperatur. (prepared by reacting pyrimidine-4,6-dicarboxylic acid dimethyl ester with 3-methoxybenzylamine) is dissolved in 100 ml of tetrahydrofuran and 104 ml (1.2 equivalents) of a 1 molar aqueous lithium hydroxide solution is added, after which the reaction mixture is then stirred for 18 hours at room temperature.

Deretter ble mesteparten av det anvendte oppløsningsmiddel destillert av under redusert trykk, resten filtrert av fra uoppløselige biprodukter og filtratet surgjort med 10% vandig sitronsyreoppløsning. Deretter krystalliserte 6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karboksylsyre ut i form av lysegule krystaller som ble filtrert fra. Then most of the solvent used was distilled off under reduced pressure, the remainder filtered off from insoluble by-products and the filtrate acidified with a 10% aqueous citric acid solution. Then 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid crystallized out in the form of pale yellow crystals which were filtered off.

Man oppnådde 19 g (66,2 mmol) 6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karboksylsyre i et utbytte på 75% av det teoretiske. 19 g (66.2 mmol) of 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid were obtained in a yield of 75% of the theoretical.

MS (ES<+>): m/e = 287,8). MS (ES<+>): m/e = 287.8).

b) 4-({[6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino}-metyl)-benzosyremetylester b) 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester

4,3 g 6-(3-metksy-benzylkarbamoyl)-pyrimidin-4-karboksylsyre (15 mmol) fra a) ble oppløst i 50 ml absolutt N,N-dimetylformamid og under omrøring og ved 0°C, ble det etter hverandre tilsatt 3,3 g (16,5 mmol) metyl-4-(aminometyl)-benzoathydroklorid, 5,4 g (16,5 mmol) 0-[(cyanetoksykarbonylmetylen)-amino]-N,N,N',N'-tetrametyluronium-tetrafluorborat (TOTU) og 4,6 ml trietylamin (33 mmol). Reaksjonsblandingen ble deretter omrørt i 1 time ved 0°C og til slutt i 12 timer ved romtemperatur. 4.3 g of 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid (15 mmol) from a) was dissolved in 50 ml of absolute N,N-dimethylformamide and with stirring and at 0°C, it was successively added 3.3 g (16.5 mmol) methyl-4-(aminomethyl)-benzoate hydrochloride, 5.4 g (16.5 mmol) 0-[(cyanethoxycarbonylmethylene)-amino]-N,N,N',N' -tetramethyluronium tetrafluoroborate (TOTU) and 4.6 ml of triethylamine (33 mmol). The reaction mixture was then stirred for 1 hour at 0°C and finally for 12 hours at room temperature.

For opparbeiding ble oppløsningsmidlet destillert av under redusert trykk og resten tatt opp med 100 ml diklormetan. Den organiske fase ble vasket med 100 ml mettet, vandig natriumhydrogenkarbonatoppløsning og så med 3x100 ml vann. Etter tørking av den organiske fase ved hjelp av Na2S04ble oppløsningsmidlet destillert av under redusert trykk. Den oljeaktige rest ble gnidd med litt dietyleter hvorved det krystalliserte ut fargeløse krystaller. Etter frafiltrering av reaksjonsproduktet og vasking med n-pentan oppnådde man 6,6 g 4-({[6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino}-metyl)-benzosyremetylester i form av lysegule krystaller. Reaksjonsproduktet hadde en renhet på 88% i henhold til LC-MS-analyse. For work-up, the solvent was distilled off under reduced pressure and the residue taken up with 100 ml of dichloromethane. The organic phase was washed with 100 ml of saturated aqueous sodium bicarbonate solution and then with 3 x 100 ml of water. After drying the organic phase with Na 2 SO 4 , the solvent was distilled off under reduced pressure. The oily residue was rubbed with a little diethyl ether whereby colorless crystals crystallized out. After filtering off the reaction product and washing with n-pentane, 6.6 g of 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester were obtained in the form of pale yellow crystals . The reaction product had a purity of 88% according to LC-MS analysis.

MS (ES<+>): m/e = 435,2). MS (ES<+>): m/e = 435.2).

c) 4-( {[6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino} -metyl)-benzosyre c) 4-( {[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid

6,6 g av den under b) fremstilt metylester ble oppløst i 100 ml tetrahydrofuran og tilsatt 36 ml (2,4 ekvivalenter) av en 1 molar litiumhydroksidoppløsning hvoretter reaksjonsblandingen ble omrørt i 4 timer under tilbakeløp. 6.6 g of the methyl ester produced under b) was dissolved in 100 ml of tetrahydrofuran and 36 ml (2.4 equivalents) of a 1 molar lithium hydroxide solution was added, after which the reaction mixture was stirred for 4 hours under reflux.

Deretter ble oppløsningsmidlet destillert av under redusert trykk. Etter tilsetning av 50 ml vann ble det hele filtrert over celitt-filterhjelpemiddel og filtratet surgjort med 2N vandig saltsyre. Reaksjonsproduktet presipiterte ved surgjøring og ble frafiltrert. The solvent was then distilled off under reduced pressure. After adding 50 ml of water, the whole was filtered over celite filter aid and the filtrate acidified with 2N aqueous hydrochloric acid. The reaction product precipitated on acidification and was filtered off.

Man oppnådde 3,05 g 4-({[6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino}-metyl)-benzosyre i form av lysegule krystaller i et utbytte på 48% av det teoretiske. 3.05 g of 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid were obtained in the form of light yellow crystals in a yield of 48% of the theoretical.

MS (ES+): m/e = 421,31. MS (ES+): m/e = 421.31.

d) Pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoyl-benzylamid) 6-(3-metoksybenzylamid) d) Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoyl-benzylamide) 6-(3-methoxybenzylamide)

420 mg 4-({[6-(3-metoksy-benzylkarbamoyl)-pyrimidin-4-karbonyl]-amino} -metyl)-benzosyren fra c) ble oppløst i 5 ml absolutt N,N-dimetylformamid og under omrøring ved 0°C etter hverandre tilsatt 115 ul dietylamin, 361 mg 0-[(cyan-etoksykarbonylmetylen)-amino]-N,N,N',N'-tetrametyluroniumtetrafluorborat (TOTU) og 153 (il trietylamin, hvoretter reaksjonsblandingen ble omrørt i 1 time ved 0°C og deretter 12 timer ved romtemperatur. 420 mg of the 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid from c) was dissolved in 5 ml of absolute N,N-dimethylformamide and with stirring at 0 °C successively added 115 µl of diethylamine, 361 mg of O-[(cyano-ethoxycarbonylmethylene)-amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 153 µl of triethylamine, after which the reaction mixture was stirred for 1 hour at 0°C and then 12 hours at room temperature.

For opparbeiding ble oppløsningsmidlet avdestillert under redusert trykk og resten tatt opp i 100 ml diklormetan. Den organiske fase ble vasket med 30 ml mettet, vandig natriumhydrogenkarbonatoppløsning og så med 3x30 ml vann. Etter tørking av den organiske fase over Na2S04, ble oppløsningsmidlet destillert av under redusert trykk. Den oljeaktige rest ble renset ved hjelp av søylekromatografi på kiselgel (40-63 u) med etylacetat/n-heptan, 2:1 som mobil fase. Etter avdestillering av oppløsningsmidlet oppnådde man en oljeaktig rest som langsomt krystalliserte etter tilsetning av litt dietyleter. For work-up, the solvent was distilled off under reduced pressure and the residue taken up in 100 ml of dichloromethane. The organic phase was washed with 30 ml of saturated aqueous sodium bicarbonate solution and then with 3 x 30 ml of water. After drying the organic phase over Na 2 SO 4 , the solvent was distilled off under reduced pressure. The oily residue was purified by column chromatography on silica gel (40-63 u) with ethyl acetate/n-heptane, 2:1 as mobile phase. After distilling off the solvent, an oily residue was obtained which slowly crystallized after the addition of a little diethyl ether.

Man oppnådde 270 mg pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoyl-benzylamid) 6-(3-metoksy-benzyl)amid, i form av fargeløse krystaller i et utbytte på 57% av det teoretiske. 270 mg of pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoyl-benzylamide) 6-(3-methoxy-benzyl)amide were obtained in the form of colorless crystals in a yield of 57% of the theoretical.

MS (ES): m/e = 476,40. MS (ES): m/e = 476.40.

Eksempel 62: Example 62:

Pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydro-benzofuran-5-ylmetyl)-amid] 6-[(pyridin-4-ylmetyl)-amid] Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-amide] 6-[(pyridin-4-ylmethyl)-amide]

a) Syntese av 6-[(pyridin-4-ylmetyl)-karbamoyl]-pyrimidin-4-karboksylsyre 9,7 g (35,7 mmol) 6-[(pyridin-4-ylmetyl)-karbamoyl]-pyrimidin-4-karboksylsyre a) Synthesis of 6-[(pyridin-4-ylmethyl)-carbamoyl]-pyrimidine-4-carboxylic acid 9.7 g (35.7 mmol) 6-[(pyridin-4-ylmethyl)-carbamoyl]-pyrimidine-4 -carboxylic acid

metylester (oppnådd ved omsetning av pyrimidin-4,6-dikarboksylsyredimetylester med pyridin-4-yl-metylamin) ble oppløst i 80 ml tetrahydrofuran og 40 ml vann, tilsatt 40 ml av en 1 molar vandig NaOH-oppløsning, hvoretter reaksjonsblandingen ble omrørt i ytterligere 2 timer ved romtemperatur. methyl ester (obtained by reaction of pyrimidine-4,6-dicarboxylic acid dimethyl ester with pyridin-4-yl-methylamine) was dissolved in 80 ml of tetrahydrofuran and 40 ml of water, 40 ml of a 1 molar aqueous NaOH solution was added, after which the reaction mixture was stirred in a further 2 hours at room temperature.

For opparbeiding ble reaksjonsblandingen dampet inn på en rotasjonsfordamper under redusert trykk til halvparten av det opprinnelige volum. Deretter ble det surgjort med 22 ml vandig 2 n saltsyreoppløsning og reaksjonsblandingen dampet inn videre til tørr tilstand på en rotasjonsfordamper. For work-up, the reaction mixture was evaporated on a rotary evaporator under reduced pressure to half the original volume. It was then acidified with 22 ml of aqueous 2 N hydrochloric acid solution and the reaction mixture was further evaporated to dryness on a rotary evaporator.

Man oppnådde 12,2 g fargeløst faststoff, som ble direkte omsatt videre i henhold til 62 12.2 g of colorless solid was obtained, which was directly reacted further according to 62

b) . b).

b) Pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydro-benzofuran-5-ylmetyl)-amid] 6-[(pyridin-4-ylmetyl)-amid] b) Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-amide] 6-[(pyridin-4-ylmethyl)-amide]

12,2 g av den under 62a) fremstilte forbindelse ble oppløst i 15 ml absolutt DMF og under omrøring og ved 0°C (isavkjøling) etter hverandre tilsatt 6,63 g (35,7 mmol) 5-aminometyl-2,3-dihydrobenzofuranhydroklorid, 11,7 g (35,7 mmol) 0-[(cyan-etoksykarbonylmetylen)-amino]-N,N,N',N'-tetrametyluronium-tetrafluorborat (TOTU) og 20 ml trietylamin. Reaksjonsblandingen ble etter ferdig tilsetning omrørt i 1 time ved 0°C og 4 timer ved romtemperatur. 12.2 g of the compound prepared under 62a) was dissolved in 15 ml of absolute DMF and, with stirring and at 0°C (ice cooling), 6.63 g (35.7 mmol) of 5-aminomethyl-2,3- dihydrobenzofuran hydrochloride, 11.7 g (35.7 mmol) of O-[(cyano-ethoxycarbonylmethylene)-amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 20 ml of triethylamine. After the addition was complete, the reaction mixture was stirred for 1 hour at 0°C and 4 hours at room temperature.

For opparbeiding ble oppløsningsmidlet destillert av under redusert trykk og resten tatt opp med 200 ml diklormetan. Den organiske fase ble deretter vasket to ganger med mettet, vandig natriumhydrogenkarbonatoppløsning og en gang med vann, tørket over natriumsulfat, hvoretter oppløsningsmidlet ble fjernet under redusert trykk på en rotasjonsfordamper. Det som oljeaktig rest dannede reaksjonsprodukt krystalliserte etter tilsetning av litt dietyleter i form av rosafargede krystaller. For ytterligere rensing omkrystalliserte man ytterligere to ganger fra 200 ml isopropanol hver gang. For work-up, the solvent was distilled off under reduced pressure and the residue taken up with 200 ml of dichloromethane. The organic phase was then washed twice with saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate, after which the solvent was removed under reduced pressure on a rotary evaporator. The reaction product formed as an oily residue crystallized after the addition of a little diethyl ether in the form of pink crystals. For further purification, it was recrystallized twice more from 200 ml of isopropanol each time.

Man oppnådde 10 g (25,6 mmol) pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydrobenzofuran-5-ylmetyl)-amid] 6-[(pyridin-4-ylmetyl)-amid] i et utbytte på 72% av det teoretiske, beregnet på de to reaksjonstrinn. 10 g (25.6 mmol) of pyrimidin-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide] 6-[(pyridin-4-ylmethyl)-amide] were obtained in a yield of 72% of the theoretical, calculated for the two reaction steps.

MS (ES<+>): 390,08. MS (ES<+>): 390.08.

1H-NMR (400 MHz, d^-DMSO): 5 = 3.13 (t, J = 8.6 Hz,2H), 4.42 (d, J = 6.4 Hz, 2H), 4.48 (t, J = 8.6 Hz, 2 H), 4.54 (d, J = 6.4 Hz, 2 H), 6.69 (d, J = 8 Hz, 1 H), 7.07 (m, 1 H), 7.22 (m, 1 H), 7.31 (m, 2 H), 8.46 (m, 1 H), 8.50 (m 2 H), 9.47 (m, 1 H), 9.58 (t, J = 6.4 Hz, 1 H), 9.80 (t, J = 6.4 Hz, 1 H). 1H-NMR (400 MHz, d^-DMSO): δ = 3.13 (t, J = 8.6 Hz, 2H), 4.42 (d, J = 6.4 Hz, 2H), 4.48 (t, J = 8.6 Hz, 2H ), 4.54 (d, J = 6.4 Hz, 2 H), 6.69 (d, J = 8 Hz, 1 H), 7.07 (m, 1 H), 7.22 (m, 1 H), 7.31 (m, 2 H ), 8.46 (m, 1 H), 8.50 (m 2 H), 9.47 (m, 1 H), 9.58 (t, J = 6.4 Hz, 1 H), 9.80 (t, J = 6.4 Hz, 1 H) .

Eksempel 117: Example 117:

Pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydro-benzofuran-5-ylrnetyl)-arriid] 6-[4-(morfolin-4-karbonyl)-benzylamid] Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-aryl] 6-[4-(morpholine-4-carbonyl)-benzylamide]

a) Syntese av 6-[(2,3-dihydro-benzofuran-5-ylmetyl)-karbamoyl]-pyrimidin-4-karboksylsyre a) Synthesis of 6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carboxylic acid

16,1 g (51 mmol) 6-[(2,3-dihydro-benzofuran-5-ylmetyl)-karbamoyl]-pyrimidin-4-karboksylsyremetylester (fremstilt ved omsetning av pyrimidin-4,6-dikarboksylsyredimetylester med 5-aminometyl-2,3-dihydrobenzofuran) ble oppløst i 150 ml tetrahydrofuran, tilsatt 62 ml av en 1 molar vandig LiOH-oppløsning og deretter ble reaksjonsblandingen omrørt i ytterligere 2 timer ved romtemperatur. 16.1 g (51 mmol) 6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carboxylic acid methyl ester (prepared by reaction of pyrimidine-4,6-dicarboxylic acid dimethyl ester with 5-aminomethyl- 2,3-dihydrobenzofuran) was dissolved in 150 ml of tetrahydrofuran, 62 ml of a 1 molar aqueous LiOH solution was added and then the reaction mixture was stirred for a further 2 hours at room temperature.

For opparbeiding ble reaksjonsblandingen dampet inn på en rotasjonsfordamper under redusert trykk. Deretter ble råproduktet tatt opp i 100 ml vann og etter tilsetning av aktivt kull filtrert over celitt-klaringssjikt. Den oppnådde moderluten ble deretter surgjort ved tilsetning av 2N vandig HC1 hvorved reaksjonsproduktet langsomt presipiterte i form av fargeløse krystaller. For work-up, the reaction mixture was evaporated on a rotary evaporator under reduced pressure. The crude product was then taken up in 100 ml of water and, after adding activated charcoal, filtered over a celite clarification layer. The obtained mother liquor was then acidified by the addition of 2N aqueous HCl whereby the reaction product slowly precipitated in the form of colorless crystals.

Etter avfiltrering og tørking av reaksjonsproduktet oppnådde man 8,3 g (27 mmol) fargeløst faststoff som ble omsatt direkte videre til 117b). Utbytte var 53% av det teoretiske. After filtering off and drying the reaction product, 8.3 g (27 mmol) of colorless solid was obtained, which was reacted directly further to 117b). Yield was 53% of the theoretical.

MS(ES<+>): 300,1. MS(ES<+>): 300.1.

b) Syntese av 4-[({6-[(2,3-dihydro-benzofuran-5-ylmetyl)-karbamoyl]-pyrimidin-4-karbonyl}-amino)-metyl]-benzosyremetylester b) Synthesis of 4-[({6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidin-4-carbonyl}-amino)-methyl]-benzoic acid methyl ester

4,7 g (15,7 mmol) av den under a) fremstilte forbindelse ble oppløst i 30 ml absolutt DMF og under omrøring og ved 0°C etter hverandre tilsatt 3,5 g (17,3 mmol) 4-amino-metyl-benzosyre-metylester, 5,7 g (17,3 mmol) 0-[(cyan-etoksy-karbonyl-metylen)- 4.7 g (15.7 mmol) of the compound prepared under a) was dissolved in 30 ml of absolute DMF and, while stirring and at 0°C, 3.5 g (17.3 mmol) of 4-amino-methyl were successively added -benzoic acid methyl ester, 5.7 g (17.3 mmol) 0-[(cyano-ethoxy-carbonyl-methylene)-

amino]-N,N,N',N'-tetrametyluronium-tetrafluorborat (TOTU) og 4,8 ml trimetylamin. Reaksjonsblandingen ble omrørt videre 1 time ved 0°C og 8 timer ved romtemperatur etter ferdig tilsetning. amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 4.8 ml of trimethylamine. The reaction mixture was stirred for a further 1 hour at 0°C and 8 hours at room temperature after the addition was complete.

For opparbeiding, ble oppløsningsmidlet destillert av under redusert trykk og resten tatt opp i 100 ml diklormetan. Den organiske fase ble deretter vasket to ganger med mettet, vandig natriumhydrogenkarbonatoppløsning og en gang med vann, tørket over natriumsulfat og oppløsningsmidlet ble så fjernet under redusert trykk på en rotasjonsfordamper. Det som oljeaktig rest oppnådde reaksjonsprodukt, krystalliserte ut i form av lysegule krystaller etter tilsetning av litt dietyleter. For work-up, the solvent was distilled off under reduced pressure and the residue taken up in 100 ml of dichloromethane. The organic phase was then washed twice with saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate and the solvent was then removed under reduced pressure on a rotary evaporator. The resulting reaction product as an oily residue crystallized out in the form of pale yellow crystals after the addition of a little diethyl ether.

Man oppnådde 6,8 g (15,2 mmol) 4-[({6-[(2,3-dihydro-benzofuran-5-ylmetyl)-karbamoyl]-pyrimidin-4-karbonyl}-amino)-metyl]-benzosyremetylester, i et utbytte på 97% av det teoretiske. 6.8 g (15.2 mmol) of 4-[({6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carbonyl}-amino)-methyl]- benzoic acid methyl ester, in a yield of 97% of the theoretical.

MS (ES+): 447,1. MS (ES+): 447.1.

c) 4-[( {6-[(2,3-dihydro-benzofuran-5-ylmetyl)-karbamoyl]-pyrimidin-4-karbonyl} - amino)-metyl] -benzosyre c) 4-[( {6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid

6,28 g (14 mmol) 4-[({6-[(2,3-dihydro-benzofuran-5-ylmetyl)-karbamoyl]-pyrimidin-4-karbonyl}-amino)-metyl]-benzosyremetylester (se 117b)) ble suspendert i 150 ml tetrahydrofuran og 70 ml vann, det ble tilsatt 16,9 ml av en IN vandig NaOH-oppløsning og reaksjonsblandingen så omrørt i 24 timer ved romtemperatur. 6.28 g (14 mmol) 4-[({6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid methyl ester (see 117b )) was suspended in 150 ml of tetrahydrofuran and 70 ml of water, 16.9 ml of a 1N aqueous NaOH solution was added and the reaction mixture was then stirred for 24 hours at room temperature.

For opparbeiding ble reaksjonsblandingen dampet inn på en rotasjonsfordamper under redusert trykk til et volum på ca. 50 ml, hvoretter det ble tilsatt 100 ml isvann. Deretter ble det surgjort med 2N vandig saltsyreoppløsning, og reaksjonsproduktet presipiterte i form av lysegule krystaller. For work-up, the reaction mixture was evaporated on a rotary evaporator under reduced pressure to a volume of approx. 50 ml, after which 100 ml of ice water was added. It was then acidified with 2N aqueous hydrochloric acid solution, and the reaction product precipitated in the form of pale yellow crystals.

Etter filtrering, vasking med litt vann og tørking av reaksjonsproduktet, oppnådde man 5,4 g (12,5 mmol) fargeløst faststoff som ble brakt direkte videre til 117d). Utbytte var 89% av det teoretiske. After filtration, washing with a little water and drying of the reaction product, 5.4 g (12.5 mmol) of colorless solid was obtained, which was carried on directly to 117d). Yield was 89% of the theoretical.

MS (ES<+>): 433,2. MS (ES<+>): 433.2.

1H-NMR (400 MHz, dé-DMSO): 5 = 3.13 (t, J = 8.7 Hz, 2 H), 4.43 (d, J = 6.1 Hz, 2 H), 4.48 (t, J = 8.7 Hz, 2 H), 4.59 (d, J = 6.3 Hz, 2 H), 6,69 (d, J = 8.1 Hz, 1 H), 7.07 (m, 1 H), 7.22 (m, 1 H), 7.44 (m, 2 H), 7.88 (m, 1 H), 7.90 (m, 1 H), 8.47 (d, J = 1.5 Hz, 1 H), 9.46 (d, J = 1.3 Hz, 1 H), 9.56 (t, J = 6.3 Hz, 1 H), 9.76 (t, J = 6.3 Hz, 1 H), 12.90 (br s, 1H) 1H-NMR (400 MHz, dé-DMSO): δ = 3.13 (t, J = 8.7 Hz, 2 H), 4.43 (d, J = 6.1 Hz, 2 H), 4.48 (t, J = 8.7 Hz, 2 H), 4.59 (d, J = 6.3 Hz, 2 H), 6.69 (d, J = 8.1 Hz, 1 H), 7.07 (m, 1 H), 7.22 (m, 1 H), 7.44 (m , 2 H), 7.88 (m, 1 H), 7.90 (m, 1 H), 8.47 (d, J = 1.5 Hz, 1 H), 9.46 (d, J = 1.3 Hz, 1 H), 9.56 (t , J = 6.3 Hz, 1 H), 9.76 (t, J = 6.3 Hz, 1 H), 12.90 (br s, 1H)

d) Pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydro-benzofuran-5-ylmetyl)-amid] 6-[4-(morfolin-4-karbonyl)-benzylamid] d) Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-amide] 6-[4-(morpholine-4-carbonyl)-benzylamide]

432 mg (1 mmol) av den under c) fremstilte forbindelse ble oppløst i 5 ml absolutt DMF og under omrøring og ved 0°C etter hverandre tilsatt 96 ul (1,1 mmol) morfolin, 361 mg (1,1 mmol) O- [(cyan-etoksy-karbonyl-metylen)-amino]-N,N,N' ,N' -tetrametyluronium-tetrafluorborat (TOTU) og 155 (il trietylamin. Reaksjonsblandingen ble omrørt videre etter ferdig tilsetning i 1 time ved 0°C og 8 timer ved romtemperatur. 432 mg (1 mmol) of the compound prepared under c) was dissolved in 5 ml of absolute DMF and, with stirring and at 0°C, 96 µl (1.1 mmol) of morpholine, 361 mg (1.1 mmol) of O - [(cyano-ethoxy-carbonyl-methylene)-amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 155 (l of triethylamine. The reaction mixture was stirred further after the addition was complete for 1 hour at 0° C and 8 hours at room temperature.

For opparbeiding ble oppløsningsmidlet destillert av under redusert trykk og resten tatt opp i 30 ml diklormetan. Den organiske fase ble deretter vasket to ganger med mettet, vandig natriumhydrogenkarbonatoppløsning og en gang med vann, tørket over natriumsulfat og oppløsningsmidlet ble så fjernet under redusert trykk på en rotasjonsfordamper. Det som oljeaktig rest dannede råprodukt ble renset ved kromatografi på kiselgel (40-63 (i) og med etylacetat:metanol 20:1 som mobil fase. Etter fjerning av den mobile fase ved destillasjon under redusert trykk oppnådde man et oljeaktig reaksjonsprodukt som, etter tilsetning av dietyleter, krystalliserte ut i form av fargeløse krystaller. For work-up, the solvent was distilled off under reduced pressure and the residue taken up in 30 ml of dichloromethane. The organic phase was then washed twice with saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate and the solvent was then removed under reduced pressure on a rotary evaporator. The crude product formed as an oily residue was purified by chromatography on silica gel (40-63 (i) and with ethyl acetate:methanol 20:1 as mobile phase. After removal of the mobile phase by distillation under reduced pressure, an oily reaction product was obtained which, after addition of diethyl ether, crystallized out in the form of colorless crystals.

Man oppnådde 340 mg (0,68 mmol) fargeløse krystaller i et utbytte på 68% av det teoretiske. 340 mg (0.68 mmol) of colorless crystals were obtained in a yield of 68% of the theoretical.

MS (ES<+>): 502,27. MS (ES<+>): 502.27.

1H-NMR (500 MHz, dé-DMSO): 5 = 2.60 (m, 2 H), 3,4 - 3.6 (br m, 8 H), 4.42 (d, J = 6.5 Hz, 2 H), 4.48 (t, J = 8.6 Hz, 2 H), 4.56 (d, J = 6.5 Hz, 2 H), 6.68 (d, J = 8.3 Hz, 1 H), 7.07 (d, J = 6.5 Hz, 1 H), 7.22 (s, 1 H), 7.88 (m, 4 H), 8.46 (m, 1 H), 9.46 (m, 1 H), 9.57 (t, J = 6.5 Hz, 1 H), 9.75 (t, J = 6.5 Hz, 1 H). 1H-NMR (500 MHz, dé-DMSO): δ = 2.60 (m, 2 H), 3.4 - 3.6 (br m, 8 H), 4.42 (d, J = 6.5 Hz, 2 H), 4.48 ( t, J = 8.6 Hz, 2 H), 4.56 (d, J = 6.5 Hz, 2 H), 6.68 (d, J = 8.3 Hz, 1 H), 7.07 (d, J = 6.5 Hz, 1 H), 7.22 (s, 1 H), 7.88 (m, 4 H), 8.46 (m, 1 H), 9.46 (m, 1 H), 9.57 (t, J = 6.5 Hz, 1 H), 9.75 (t, J = 6.5 Hz, 1 H).

De følgende forbindelser ble fremstilt på sammenlignbar måte. The following compounds were prepared in a comparable manner.

Farmakologiske eksempler Pharmacological examples

Bestemmelse av den enzymatiske aktivitet for det katalytiske domenet av den humane kollagenase-3 (MMP-13). Determination of the enzymatic activity of the catalytic domain of the human collagenase-3 (MMP-13).

Dette protein ble oppnådd som inaktivt pro-enzym fra firma INVITEK, Berlin, (katalog nr. 30 100 803). Aktivering av protenzymet: 2 volumdeler proenzym ble inkubert med 1 volumdel APMA-oppløsning ved 37°C i 1,5 time. APMA-oppløsningen ble fremstilt fra en 10 mmol/1 p-aminofenylkvikksølvacetatoppløsning i 0,1 mmol/1 NaOH ved fortynnet med 3 volumdeler Tris/HCl-buffer pH 7,5 (se nedenfor). pH-verdien ble innstilt til 7,0 til 7,5 ved tilsetning av 1 mmol/1 HC1. Etter aktivering av enzymet ble dette fortynnet med Tris/HCl-bufferen til en konsentrasjon på 1,67 ug/ml. This protein was obtained as inactive pro-enzyme from the company INVITEK, Berlin, (catalog no. 30 100 803). Activation of the proenzyme: 2 volumes of proenzyme were incubated with 1 volume of APMA solution at 37°C for 1.5 hours. The APMA solution was prepared from a 10 mmol/l p-aminophenylmercuric acetate solution in 0.1 mmol/l NaOH diluted with 3 volumes of Tris/HCl buffer pH 7.5 (see below). The pH value was adjusted to 7.0 to 7.5 by the addition of 1 mmol/l HCl. After activation of the enzyme, this was diluted with the Tris/HCl buffer to a concentration of 1.67 µg/ml.

For måling av enzymaktivitet blir 10 ul enzymoppløsning inkubert med 10 ml av en 3 volum-%, bufret dimetylsulfoksidoppløsning (reaksjon 1) i 15 minutter. For måling av enzyminhibitoraktiviteten blir 10 (il enzymoppløsning inkubert med 10 (il av en 3 volum-% bufret dimetylsulfidoppløsning som inneholder enzyminhibitoren (reaksjon 2). For measurement of enzyme activity, 10 µl of enzyme solution is incubated with 10 ml of a 3% by volume, buffered dimethylsulfoxide solution (reaction 1) for 15 minutes. To measure the enzyme inhibitor activity, 10 µl of enzyme solution is incubated with 10 µl of a 3% by volume buffered dimethyl sulphide solution containing the enzyme inhibitor (reaction 2).

Både ved reaksjon 1 og ved reaksjon 2, blir enzymreaksjonen, etter tilsetning av 10 (il av en 3 volum-% vandig dimetylsulfoksidoppløsning som inneholder 0,75 mmol/1 av substratet, fulgt fluorescensspektroskopisk (ekstinksjon 328 nm/emisjon/393 nm). Both in reaction 1 and in reaction 2, the enzyme reaction, after the addition of 10 µl of a 3 volume-% aqueous dimethylsulfoxide solution containing 0.75 mmol/1 of the substrate, is followed fluorescence spectroscopically (extinction 328 nm/emission/393 nm).

Enzymaktiviteten angis som ekstinksjonsøkning pr. minutt. The enzyme activity is indicated as extinction increase per minute.

Inhibitorvirkningen beregnes som prosentvis inhibering i henhold til følgende formel: % inhibering = 100 - [(ekstinksjonsøkning/minutt i reaksjon The inhibitory effect is calculated as percentage inhibition according to the following formula: % inhibition = 100 - [(extinction increase/minute in reaction

2)/(ekstinksjonsøkning/minutt i reaksjon 1) x 100]. 2)/(extinction increase/minute in reaction 1) x 100].

IC50, dvs. den inhibitorkonsentrasjon som er nødvendig for en 50% inhibering av enzymaktiviteten, bestemmes grafisk ved oppføring av den prosentvise inhibering ved forskjellige inhibitorkonsentrasjoner. The IC50, i.e. the inhibitor concentration required for a 50% inhibition of the enzyme activity, is determined graphically by plotting the percentage inhibition at different inhibitor concentrations.

Bufferløsningen inneholder 0,05% Brij (Sigma, Deisenhofen, Tyskland) samt 0,1 mol/l Tris/HCl, 0,1 ml/l NaCl, 0,01 mol/l CaCl2(pH = 7,5). The buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) as well as 0.1 mol/l Tris/HCl, 0.1 ml/l NaCl, 0.01 mol/l CaCl2 (pH = 7.5).

Enzymoppløsningen inneholder 1,67 ug/ml av enzymdomenet. The enzyme solution contains 1.67 µg/ml of the enzyme domain.

Substratoppløsningen inneholder 0,75 mmol/1 av det fluorogene substrat (7-metoksykoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2',4'-dinitrofenyl)-L-2,3-diaminopropionyl-Ala-Arg-NH2(Bachem, Heidelberg, Tyskland). The substrate solution contains 0.75 mmol/1 of the fluorogenic substrate (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2',4'-dinitrophenyl)-L-2,3-diaminopropionyl -Ala-Arg-NH2 (Bachem, Heidelberg, Germany).

Den følgende tabell 2 viser resultatene. The following table 2 shows the results.

Bestemmelsen av den enzymatiske aktivitet for det katalytiske domenet av den humane neutrofilkollagenasen (MMP-8) og det humane stromelysin (MMP-3). The determination of the enzymatic activity of the catalytic domain of the human neutrophil collagenase (MMP-8) and the human stromelysin (MMP-3).

Enzymene human neutrofilkollagenase og human stromelysin ble gjennomført som beskrevet av Weithmann et al. i Inflamm. Res., 46 (1997), s. 246-252, som aktive, katalytiske domener. Målingen av enzymaktiviteten samt bestemmelsen av den inhibitoriske virkning av hemmerne på enzymaktiviteten skjedde likeledes som der beskrevet. The enzymes human neutrophil collagenase and human stromelysin were carried out as described by Weithmann et al. in Inflamm. Res., 46 (1997), pp. 246-252, as active, catalytic domains. The measurement of the enzyme activity as well as the determination of the inhibitory effect of the inhibitors on the enzyme activity took place in the same way as described there.

Forbindelsene i henhold til eksemplene ovenfor, viste ved bestemmelsen av den humane neutrofile kollagenasen og det humane stromelysin i hvert tilfelle IC50-verdier på mer enn 100 000 nm. Derved er disse forbindelser praktisk talt uvirksomme ved inhibering av MMP-3 og MMP-8. The compounds according to the above examples, in the determination of the human neutrophil collagenase and the human stromelysin, in each case showed IC 50 values of more than 100,000 nm. Thereby, these compounds are practically inactive when inhibiting MMP-3 and MMP-8.

Claims (6)

1. Forbindelse,karakterisert vedformell 1. Connection, characterized by formal og/eller alle stereoisomere former av forbindelsen med formel I og/eller blandinger av disse former i et hvilket som helst forhold, og/eller et fysiologisk godtagbart salt av forbindelsene med formel I, hvorved RI er hydrogenatom eller -(Ci-C6)-alkyl, R2 er -(Ci-C6)alkyl, hvor alkyl er substituert en, to eller tre ganger med -(C6-Ci4)-aryl, hvori aryl er substituert en, to eller tre ganger, uavhengig av hverandre, med 1) -(C0-C6)-alkyl-C(O)-N-(R9)-(R10), hvori R9 og RI 0 er like eller forskjellige og er, uavhengig av hverandre i) hydrogenatom eller ii) -(Ci-C6)-alkyl, eller R9 og RIO danner, sammen med nitrogenatomet som de er bundet til, en 5-, 6- eller 7-leddet mettet ring, hvor ett heteroatom fra serien oksygen, svovel og nitrogen også kan erstatte ett eller to karbonatomer og, i tilfellet nitrogen, kan nitrogenatomene, uavhengig av hverandre, være usubstituerte eller substituerte med (Ci-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-CN, 3) -O(C0-C6)-alkyl-C(O)-N(R9)-R(10), hvori R9 og RIO har den ovenfor angitte betydningen, 4) -0(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), hvori R8 er i) hydrogenatom ii) -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med -NH2, -CN, -OH, -C(O)-NH-OH, N02, -C(0)-0(Ci-C6)-alkyl, eller halogen eller iii) OH og hvori R9 og RIO har den ovenfor angitte betydningen, 5) -(Co-C6)-alkyl-C(0)- N(R8)-(C0-C6)-alkyl-Het, hvor R8 har den ovenfor angitte betydningen og Het er et mettet eller umettet, monocyklisk eller bicyklisk, 3- til 10-leddet, heterocyklisk ringsystem som inneholder 1, 2 eller 3 like eller forskjellige ringheteroatomer fra rekken nitrogen, oksygen og svovel, og er usubstituert eller substituert en, to eller tre ganger uavhengig av hverandre med a) halogen, b) cyano, c) nitro, d) hydroksy, e) amino, f) -CCOXMCrCéValkyl, g) -C(0)-OH, h) -(Ci-C6)-alkyl, hvor alkyl er usubstituert eller substituert en, to eller tre ganger med halogen, i) -0-(Ci-C6)-alkyl, hvor alkyl er usubstituert eller substituert en, to eller tre ganger med halogen eller - N(R9)-(R10), eller j)<=>o, k) -Het, 1) -(C2-C6)-alkenyl, hvor alkenyl er usubstituert eller substituert en, to eller tre ganger med halogen eller -N(R9)-(R10), eller m) -(C2-C6)-alkynyl, hvor alkynyl er usubstituert eller substituert en, to eller tre ganger med halogen eller -N(R9)-(R10), eller 6) -(Co-C6)-alkyl-C(0)-N(R8)-(C6-Ci4)-aryl, hvor aryl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med de ovenfor nevnte restene a) til m), R3, R4, R5, R6 og R7 er like eller forskjellige og er, uavhengig hverandre, 1. hydrogenatom, 2. halogen, 3. -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, 4. -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger med halogen, eller 5. -S-(Ci-C6)-alkyl eller R4 og R5 eller R5 og R6, danner sammen med karbonatomene som de i hvert tilfelle er bundet til, uavhengig av hverandre, en 5- eller 6-leddet ring som er aromatisk eller mettet og inneholder null, ett eller to heteroatomer fra rekken oksygen, nitrogen eller svovel, hvor ringen er usubstituert eller er substituert ved ett eller flere karbonatomer, en eller to ganger, med halogen og de andre restene R3, R6 og R7 eller R3, R4 og R7 har den ovenfor angitte betydningen ifølge 1. til 5..and/or all stereoisomeric forms of the compound of formula I and/or mixtures of these forms in any ratio, and/or a physiologically acceptable salt of the compounds of formula I, whereby RI is hydrogen atom or -(Ci-C6)-alkyl, R 2 is -(C 1 -C 6 )alkyl, wherein alkyl is substituted one, two or three times by -(C 6 -C 14 )-aryl, wherein aryl is substituted one, two or three times, independently of each other, by 1) -( C0-C6)-alkyl-C(O)-N-(R9)-(R10), wherein R9 and RI 0 are the same or different and are, independently of each other i) hydrogen atom or ii) -(Ci-C6)- alkyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated ring, where one heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted with (Ci-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-CN, 3) -O(C0-C6)- alkyl-C(O)-N(R9)-R(10), in which R9 and R10 have the above meaning, 4) -O(Co-C6)-alkyl-C(0)-N(R8)-( C 0 -C 6 )-alkyl-N(R 9 )-(R 10 ), in which R 8 is i) hydrogen atom ii) -(C 1 -C 6 )-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, independently of each other, with -NH2, -CN, -OH, -C(O)-NH-OH, NO2, -C(0)-O(Ci-C6)-alkyl, or halogen or iii) OH and wherein R 9 and R 10 have the above-mentioned meaning, 5) -(Co-C 6 )-alkyl-C(O)- N (R 8 )-(C 0-C 6 )-alkyl-Het, where R 8 has the above-mentioned meaning and Het is a saturated or unsaturated, monocyclic or bicyclic, 3- to 10-membered, heterocyclic ring system containing 1, 2, or 3 identical or different ring heteroatoms from the series nitrogen, oxygen, and sulfur, and is unsubstituted or substituted one, two, or three times independently of each other with a) halogen, b) cyano, c) nitro, d) hydroxy, e) amino, f) -CCOXMCrCéValkyl, g) -C(0)-OH, h) -(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted one, two or three times by halogen, i) -O-(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)-(R10 ), or j)<=>o, k) -Het, 1) -(C2-C6)-alkenyl, where alkenyl is unsubstituted or substituted one, two or three times by halogen or -N(R9)-(R10) , or m) -(C2-C6)-alkynyl, where alkynyl is unsubstituted or substituted one, two or three times with halogen or -N(R9)-(R10), or 6)-(Co-C6)-alkyl-C(0)-N(R8)-(C6-C14)-aryl, where aryl is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned residues a) to m), R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are, independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C 1 -C 6 )-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times , with halogen, 4. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by halogen, or 5. -S-(Ci-C6)-alkyl or R4 and R5 or R5 and R6, together with the carbon atoms to which they are attached in each case, independently form a 5- or 6-membered ring which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur, where the ring is unsubstituted or is substituted at one or more carbon atoms, once or twice, with halogen and the other residues R3, R6 and R7 or R3, R4 and R7 have the above-mentioned meaning according to 1. to 5. . 2. Forbindelse med formel I ifølge krav 1,karakterisertv e d at RI er hydrogenatom eller -(Ci-C6)-alkyl, R2 er -(Ci-C6)-alkyl, hvor alkyl er substituert en, to eller tre ganger med fenyl, hvori fenyl er substituert en, to eller tre ganger, uavhengig av hverandre, med 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10) hvori R9 og RIO er like eller forskjellige og er uavhengig av hverandre i) hydrogenatom eller, ii) -(Ci-C6)-alkyl, eller R9 og RIO danner sammen med nitrogenatomet som de er bundet til en 5-, 6- eller 7-leddet, mettet ring, hvorved et heteroatom fra rekken oksygen, svovel og nitrogen også kan erstatte ett eller to karbonatomer og, i tilfellet nitrogen, kan nitrogenatomene, uavhengig av hverandre, være usubstituerte eller substituerte med (Ci-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-CN, 3) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), hvor R9 og RIO har den ovenfor angitte betydningen, 4) -(C0-C6)-alkyl-C(O)-N(R8)-alkyl-N(R9)-(R10), hvori R8 er i) hydrogenatom ii) -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med -NH2, -CN, -OH, -C(0)-OH, -C(0)-OH, -C(0)-OH, C(0)-NH-OH, N02, -C(0)-0-(Ci-C6)-alkyl, eller halogen eller iii) -OH, og hvori R9 og RIO har den ovenfor angitte betydningen, 5) -(C0-C6)-alkyl-C(O)—N(R8)-(C0-C6)-alkyl-Het, hvori R8 har den ovenfor angitte betydningen og Het er en rest fra gruppen azepin, azetidin, aziridin, benzimidazol, benzofuran, benzo[l,4]dioksin, 1,3-benzodioksol, 4H-benzo[l,4]oksazin, benzoksazol, benzotiazol, benzotiofen, kinazolin, kinolin, kinoksalin, kroman, cinnolin, 1,2-diazepin, 1,3-diazepin, 1,4-diazepin, 1,4-dioksin, dioksol, furan, imidazol, indazol, indol, isokinolin, isokroman, isoindol, isotiazol, isoksazol, morfolin, 1,2-oksazin, 1,3-oksazin, 1,4-oksazin, oksazol, oksiran, piperazin, piperidin, ftalazin, pyran, pyrazin, pyrazol, pyridazin, pyridin, pyrimidin, pyridoimidazol, pyridopyridin, pyridopyrimidin, pyrrol, pyrrolidin, tetrazol, 1,2-tiazin, 1,3-tiazin, 1,4-tiazin, tiazol, tiomorfolin, tiofen, tiopyran, 1,2,3-triazin, 1,3,5-triazin, 1,2,4-triazin, 1,2,3-triazol eller 1,2,4-triazol og hvori Het er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med a) halogen, b) cyano, c) nitro, d) hydroksy, e) amino, f) -C(0)-0-(C1-C6)-alkyl, g) -C(0)-OH, h) -(Ci-C6)-alkyl, hvor alkyl er usubstituert eller substituert en, to, eller tre ganger med halogen, i) -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen eller - N(R9)-(R10), j)<=>o, k) -Het, hvori Het er som definert ovenfor, 1) -(C2-C6)-alkenyl, hvor alkenyl er usubstituert eller substituert en, to eller tre ganger med halogen eller - N(R9)-(R10), eller m) -(C2-C6)-alkynyl, hvori alkynyl er usubstituert eller substituert en, to eller tre ganger med halogen eller -N(R9)-(R10), eller 6) -(C0-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-(C6-Ci4)-fenyl, hvor fenyl er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med de ovenfor nevnte restene a) til m), R3, R4, R5, R6 og R7 er like eller forskjellige og er, uavhengig av hverandre, 5. hydrogenatom, 6. halogen, 7. -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert, en, to eller tre ganger, med halogen, eller 8. -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert, en, to eller tre ganger, med halogen, eller R4 og R5 eller R5 og R6 danner, sammen med karbonatomene som de i hvert tilfelle er bundet til, uavhengig av hverandre, en dioksan-, dioksol-, dihydrofuran- eller furanring, hvor ringen er usubstituert eller substituert, ved ett eller ved flere karbonatomer, en eller to ganger, med halogen og de andre restene R3, R6 og R7 eller R3, R4 og R7 har den ovenfor angitte betydningen for 1. til 4.2. Compound with formula I according to claim 1, characterized in that RI is hydrogen atom or -(Ci-C6)-alkyl, R 2 is -(C 1 -C 6 )-alkyl, wherein alkyl is substituted one, two or three times by phenyl, wherein phenyl is substituted one, two or three times, independently of each other, by 1) -(C 0 -C 6 )-alkyl -C(O)-N(R9)-(R10) in which R9 and R10 are the same or different and are independent of each other i) hydrogen atom or, ii) -(C1-C6)-alkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered, saturated ring, whereby a heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, can the nitrogen atoms, independently of each other, be unsubstituted or substituted with (Ci-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-CN, 3) -(C0-C6)-alkyl- C(O)-N(R9)-(R10), where R9 and R10 have the above meaning, 4) -(C0-C6)-alkyl-C(O)-N(R8)-alkyl-N(R9 )-(R10), in which R8 is i) hydrogen atom ii) -(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, independently of each other, with -NH2, -CN, -OH, -C(0)-OH, -C(0)-OH, -C(0)-OH, C(0)-NH-OH, NO2, -C(0)-0-(Ci-C6)-alkyl , or halogen or iii) -OH, and wherein R 9 and R 10 have the above meaning, 5) -(C0-C6)-alkyl-C(O)—N(R8)-(C0-C6)-alkyl-Het , in which R8 has the above meaning and Het is a residue from the group azepine, azetidine, aziridine, benzimidazole, benzofuran, be nzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochrome, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole and wherein Het is unsubstituted or substituted one, two or three times, independently of each other, with a) halogen, b) cyano, c) nitro, d) hydroxy, e) amino, f) -C(0)-0-(C1-C6)-alkyl, g) -C(0)-OH, h) -(C1-C6)-alkyl , wherein alkyl is unsubstituted or substituted one, two, or three times by halogen, i) -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two, or three times, by halogen or - N(R9 )-(R10), j)<=>o, k) -Het, wherein Het is as defined above, 1) -(C2-C6)-alkenyl, wherein alkenyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)- (R 10 ), or m) -(C 2 -C 6 )-alkynyl, wherein alkynyl is unsubstituted or substituted one, two or three times by halogen or -N(R 9 )-(R 10 ), or 6) -(C 0 -C 6 ) -alkyl-C(O)-N(R8)-(Co-C6)-alkyl-(C6-C14)-phenyl, where phenyl is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned the residues a) to m), R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are, independently of each other, 5. hydrogen atom, 6. halogen, 7. -(C 1 -C 6 )-alkyl, wherein alkyl is unsubstituted or substituted, one, two or three times, with halogen, or 8. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted, one, two or three times, with halogen, or R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached in each case, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring, where the ring is unsubstituted or substituted, at one or more carbon atoms , once or twice, with halogen and the other residues R 3 , R 6 and R 7 or R 3 , R 4 and R 7 have the meaning given above for 1. to 4. 3. Forbindelse av formel I ifølge krav 1 eller 2,karakterisertv e d at RI er hydrogenatom, R2 er -(Ci-C3)-alkyl, hvor alkyl er substituert med fenyl, hvori fenyl er substituert en, to eller tre ganger, uavhengig av hverandre, med 2) -(C0-C6)-alkyl-C(O)-N(R9)-(Rl0) hvori R9 og RI0 er hydrogenatom, metyl, etyl, propyl eller butyl, eller R9 og RIO danner, sammen med nitrogenatomet som de er bundet til, en rest som kan avledes fra pyrrolidin, piperidin, pyrazolidin, pyrazin, tetrazin, imidazolidin, piperazin, isoksazolidin, morfolin, isotiazolidin og, i tilfellet nitrogen, kan nitrogenatomene uavhengig av hverandre være usubstituerte eller substituerte med (Ci-C4)-alkyl, 2) -(C0-C4)-alkyl-C(O)-NH-CN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(Rl0), hvori R9 og RI0 har den ovenfor angitte betydningen, 4) -(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), hvori R8 er hydrogen, metyl, etyl, propyl eller butyl, og R9 og RIO har den ovenfor angitte betydningen, 5) -C(O)-N(R8)-(C0-C2)-alkyl-Het, hvor R8 har den ovenfor angitte betydningen og Het er azepin, azetidin, aziridin, benzimidazol, benzofuran, benzo[l,4]dioksin, 1,3-benzodioksol, 4H-benzo[l,4]oksazin, benzoksazol, benzotiazol, benzotiofen, kinazolin, kinolin, kinoksalin, kroman, cinnolin, 1,2-diazepin, 1,3-diazepin, 1,4-diazepin, 1,4-dioksin, dioksol, furan, imidazol, indazol, indol, isokinolin, isokroman, isoindol, isotiazol, isoksazol, morfolin, 1,2-oksazin, 1,3-oksazin, 1,4-oksazin, oksazol, oksiran, piperazin, piperidin, ftalazin, pyran, pyrazin, pyrazol, pyridazin, pyridin, pyrimidin, pyridoimidazol, pyridopyridin, pyridopyrimidin, pyrrol, pyrrolidin, tetrazol, 1,2-tiazin, 1,3-tiazin, 1,4-tiazin, tiazol, tiomorfolin, tiofen, tiopyran, 1,2,3-triazin, 1,3,5-triazin, 1,2,4-triazin, 1,2,3-triazol eller 1,2,4-triazol og Het er usubstituert eller substituert en, to eller tre ganger, uavhengig av hverandre, med a) halogen, b) cyano, c) nitro, d) hydroksy, e) amino, f) -C(0)-0-(Ci-C4)-alkyl, g) -C(0)-OH, h) -(Ci-C4)-alkyl, hvor alkyl er usubstituert eller substituert en, to eller tre ganger med halogen, i) -0-(Ci-C4)-alkyl, hvor alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, eller 6) -C(O)-N(R8)-(C0-C4)-alkyl-fenyl, hvor fenyl er usubstituert eller substituert en, to eller tre ganger uavhengig av hverandre med de ovenfor angitte rester a) til i), R3, R4, R5, R6 og R7 er like eller forskjellige og er, uavhengig av hverandre, 5. hydrogenatom, 6. halogen, 7. -(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, 8. -0-(Ci-C6)-alkyl, hvori alkyl er usubstituert eller substituert en, to eller tre ganger, med halogen, eller R4 og R5 eller R5 og R6 danner, sammen med karbonatomene som de er bundet til, uavhengig av hverandre, en dioksan-, dioksol-, dihydrofuran- eller furanring og de andre restene er R3, R6 og R7 eller R3, R4 og R7 har de ovenfor angitte betydningene ifølge 1. til 4.3. Compound of formula I according to claim 1 or 2, characterized in that RI is hydrogen atom, R 2 is -(C 1 -C 3 )-alkyl, wherein alkyl is substituted by phenyl, wherein phenyl is substituted one, two or three times, independently of each other, by 2) -(C 0 -C 6 )-alkyl-C(O)- N(R9)-(R10) in which R9 and R10 are hydrogen, methyl, ethyl, propyl or butyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a residue which may be derived from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, morpholine, isothiazolidine and, in the case of nitrogen, the nitrogen atoms may independently be unsubstituted or substituted with (Ci-C4)-alkyl, 2) -(C0-C4)-alkyl-C(O)-NH-CN, 3) -O-(C0-C6)-alkyl-C(O) -N(R 9 )-(R 10 ), wherein R 9 and R 10 have the meaning given above, 4) -(Co-C 6 )-alkyl-C(O)-N(R 8 )-(Co-C 6 )-alkyl-N (R 9 )-(R 10 ), wherein R 8 is hydrogen, methyl, ethyl, propyl or butyl, and R 9 and R 10 have the above meaning, 5) -C(O)-N(R 8 )-(C 0 -C 2 )- alkyl-Het, where R 8 has the above meaning and Het is azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole and Het is unsubstituted or substituted one, two or three times, independently of each other, with a ) halogen, b) cyano, c) nitro, d) hydroxy, e) amino, f) -C(0)-0-(Ci-C4)-alkyl, g) -C(0)-OH, h) - (Ci-C4)-alkyl, where alkyl is unsubstituted or substituted one, two or three times with halogen, i) -O-(Ci-C4)-alkyl, where alkyl is unsubstituted or substituted one, two or three times, with halogen, or 6) -C(O)-N(R8)-(C0-C4)-alkyl-phenyl, where phenyl is unsubstituted or substituted one, two or three times independently of each other with the above-mentioned residues a) to i), R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are, independently of each other, 5. hydrogen atom, 6. halogen, 7. -(C 1 -C 6 )-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, with halogen, 8. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, with halogen, or R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring and the other residues are R3, R6 and R7 or R3, R4 and R7 have the above meanings according to 1. to 4. 4. Forbindelser av formel I ifølge ett eller flere av kravene 1 til 3,karakterisert vedat én av de følgende forbindelsene er valgt: pyrimidin-4,6-karboksylsyre 4-(4-dietylkarbamoylbenzylamid) 6-(3-metyloksybenzylamid), pyrimidin-4,6-karboksylsyre 4-(3-metoksybenzylamid) 6-(4- propylkarbamoylbenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(4-isopropylkarbamoylbenzylamid) 6-(3-metoksybenzylamid), pyrimidin-4,6-dikarboksylsyre 4-[(2-dimetylaminoetylkarbamoyl) benzylamid] 6-(3-metoksy-benzylamid), pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydrobenzo[ 1,4]dioksin-6-ylmetyl)amid]-6-[4-(2 -dimetylaminoetylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(2-dimetylaminoetylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6- {4-[2(4-metylpiperazin-1 -yl)-2-oksoetyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4(2-morfolin-4-yl-2-oksoetoksy)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoylmetoksybenzylamid) 6- (4-fluor-3-metylbenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4(isopropylkarbamoylmetyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-{4-[(2-morfolin-4-yletylkarbamoyl)metyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoylmetylbenzylamid) 6-(4-fluor-3-metylbenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(2-morfolin-4-yl-2-oksoetyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(isopropylkarbamoylmetoksy)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(2-morfolin-4-yletylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(2-pyrrolidin-1 -yl-etylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(tiomorfolin-4-karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(tiomorfolin-4-karbonyl) benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-cyanokarbamoylbenzylamid) 6- (4-fluor-3-metylbenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(3 -metoksybenzylamid) 6- [4-(3 -morfolin-4-ylpropylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4(3-morfolin-4-yl-propyl-karbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(4-metylpiperazin-1 -karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-[(2,3-dihydrobenzofuran-5-ylmetyl)amid] 6- {4-[(pyridin-4-ylmetyl)karbamoyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(4-N-cyanokarbamoylbenzylamid) 6-[(2,3-dihydrobenzofuran-5 -ylmetyl)amid], pyrimidin-4,6-dikarboksylsyre 4-(4-N-cyanokarbamoylbenzylamid) 6- (3-metoksybenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(morfolin-4-karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4(2-piperazin-l-yletylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-tert-butylkarbamoylbenzylamid) 6-(3-metoksybenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-{4-[metyl-( 1 - metylpiperidin-4-yl)karbamoyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(2-pyrrolidin- 1-yl-etylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[3-(2-morfolin-4-yletylkarbamoyl)benzy lamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-[4-(2-morfolin-4-yletylkarbamoyl)benzylamid],4. Compounds of formula I according to one or more of claims 1 to 3, characterized in that one of the following compounds is selected: pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methyloxybenzylamide), pyrimidine-4, 6-carboxylic acid 4-(3-methoxybenzylamide) 6-(4-propylcarbamoylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-isopropylcarbamoylbenzylamide) 6-(3-methoxybenzylamide), pyrimidine-4,6-dicarboxylic acid 4-[ (2-dimethylaminoethylcarbamoyl)benzylamide] 6-(3-methoxy-benzylamide), pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzo[ 1,4]dioxin-6-ylmethyl)amide]-6-[ 4-(2-dimethylaminoethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4- (4-fluoro-3-methylbenzylamide) 6- {4-[2(4-methylpiperazin-1-yl)-2-oxoethyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide ) 6-[4(2-morpholin-4-yl-2-oxoethoxy)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoy lmethoxybenzylamide) 6-(4-fluoro-3-methylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(isopropylcarbamoylmethyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4 -(4-fluoro-3-methylbenzylamide) 6-{4-[(2-morpholin-4-ylethylcarbamoyl)methyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylmethylbenzylamide) 6-(4-fluoro -3-methylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethyl)benzylamide], pyrimidine-4,6 -dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethoxy)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholine-4- ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1 -yl-ethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4- fluoro-3-methylbenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide], pyrimidine-4,6-d icarboxylic acid 4-(4-cyanocarbamoylbenzylamide) 6-(4-fluoro-3-methylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- [4-(3-morpholin-4-ylpropylcarbamoyl)benzylamide] , pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4(3-morpholin-4-yl-propyl-carbamoyl)benzylamide], pyrimidine-4,6 -dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-methylpiperazin-1-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl )amide] 6- {4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-[(2,3-dihydrobenzofuran-5-ylmethyl )amide], pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-(3-methoxybenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4 -(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(2-piperazin-1-ylethylcarbamoyl)benzylamide], pyrimidine-4,6 -dicarboxylic acid 4-(4-tert-butylcarbamoylbe nzylamide) 6-(3-methoxybenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[methyl-( 1 -methylpiperidin-4-yl)carbamoyl]benzylamide}, pyrimidine-4, 6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[ 3-(2-morpholin-4-ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], [4-( {[6-(4-fluor-3-metylbenzylkarbamoyl)-pyrimidin-4-karbonyl]-amino} -metyl)-benzoylamino]eddiksyremetylesterester, pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[3(morfolin-4-karbonyl)-benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6- {4-[(piperidin-4-ylmetyl)-karbamoyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(3 -metoksybenzylamid) 6- [4-(piperidin-4-ylkarbamoyl)-benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6-[4-(piperidin-4-ylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(4-fluor-3-metylbenzylamid) 6-{4-[metyl-(l - metylpiperidin-4-yl)karbamoyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(4-fiuor-3-metylbenzylamid) 6- {4-[(piperidin-4-ylmetyl)karbamoyl]benzylamid}, pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6-[4-(4-metyl-piperazin-1 - karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4-(morfolin-4-karbonyl)-benzylamid], pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4-(4-metylpiperazin-1 -karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4- [(2,3-dihydrobenzofuran-5 -ylmety l)amid] 6- [4-(2 - morfolin-4-yletylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(2-pyrrolidin-l-yletylkarbamoyl)benzylamid], pyrimidin-4,6-dikarboksylsyre4-(3-metoksybenzylamid) 6-[4-(morfolin-4-karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-metoksybenzylamid) 6- {4-[(pyridin-4-ylmety l)karbamoyl]benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-(4-dietylkarbamoylbenzylamid), pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(morfolin-4-karbonyl)benzylamid], pyrimidin-4,6-dikarboksylsyre 4-(3-klor-4-fluorbenzylamid) 6-[4-(2-morfolin-4-yletylkarbamoyl)benzylamid], eller pyrimidin-4,6-dikarboksylsyre 4-(4-dietylkarbamoylbenzylamid) 6-(3-metoksybenzylamid).[4-( {[6-(4-fluoro-3-methylbenzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoylamino]acetic acid methyl ester ester, pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6 -[3(morpholine-4-carbonyl)-benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- {4-[(piperidin-4-ylmethyl)-carbamoyl]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- [4-(piperidin-4-ylcarbamoyl)-benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- [4-(piperidin-4-ylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide}, Pyrimidin-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-methyl-piperazine-1-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4- [(2,3-dihydrobenzofuran- 5-ylmethyl)amide] 6-[4-(morpholine-4-carbonyl)-benzylamide], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-pyrrolidin-1-ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- [4-(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- {4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-diethylcarbamoylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], or pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide). 5. Fremgangsmåte for fremstilling av forbindelsen av formel I ifølge ett eller flere av kravene 1 til 4,karakterisert vedat en forbindelse av formel II a) omsettes med en forbindelse av formel Illa eller Illb 5. Process for producing the compound of formula I according to one or more of claims 1 to 4, characterized in that a compound of formula II a) is reacted with a compound of formula Illa or Illb hvor RI, R2, R3, R4, R5, R6 og R7 har betydningen angitt i formel I og Y er halogen, hydroksyl eller Ci-C4-alkoksy eller danner, sammen med karbonylgruppen, en aktiv ester eller et blandet anhydrid, idet en forbindelse av formel I dannes, og reaksjonsproduktene omdannes, hvor aktuelt, til de fysiologisk godtagbare saltene, eller b) en forbindelse av formel II omsettes med en forbindelse av formel Illa eller Illb for å gi en forbindelse av formel IVa eller IVb where R1, R2, R3, R4, R5, R6 and R7 have the meaning given in formula I and Y is halogen, hydroxyl or C1-C4 alkoxy or forms, together with the carbonyl group, an active ester or a mixed anhydride, being a compound of formula I is formed, and the reaction products are converted, where appropriate, into the physiologically acceptable salts, or b) a compound of formula II is reacted with a compound of formula IIIa or IIIb to give a compound of formula IVa or IVb hvor RI til R7 har betydningen angitt i formel I og Y er halogen, hydroksyl eller C1-C4alkoksy, eller danner sammen med karbonylgruppen en aktiv ester eller et blandet anhydrid, og forbindelsen av formel IVa eller IVb renses, om egnet, og omdannes deretter, med en forbindelse av formel Illa eller Illb, til en forbindelse av formel I.where R1 to R7 have the meaning given in formula I and Y is halogen, hydroxyl or C1-C4 alkoxy, or forms together with the carbonyl group an active ester or a mixed anhydride, and the compound of formula IVa or IVb is purified, if appropriate, and then converted, with a compound of formula Illa or Illb, to a compound of formula I. 6. Farmasøytisk sammensetning,karakterisert vedat den omfatter et effektivt innhold av minst en forbindelse av formel I ifølge et hvilket som helst av krav 1 til 4, sammen med et farmasøytisk egnet og fysiologisk godtagbart bærerstoff, additiv og/eller annen aktiv forbindelse og hjelpestoffer.6. Pharmaceutical composition, characterized in that it comprises an effective content of at least one compound of formula I according to any one of claims 1 to 4, together with a pharmaceutically suitable and physiologically acceptable carrier substance, additive and/or other active compound and excipients.
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