DK1966162T3 - Pyrimidinderivater - Google Patents

Pyrimidinderivater Download PDF

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DK1966162T3
DK1966162T3 DK06831747.8T DK06831747T DK1966162T3 DK 1966162 T3 DK1966162 T3 DK 1966162T3 DK 06831747 T DK06831747 T DK 06831747T DK 1966162 T3 DK1966162 T3 DK 1966162T3
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diamine
pyrimidine
methylamino
azetidin
inhibitors
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DK06831747.8T
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Andrew Simon Bell
Charlotte Alice Louise Lane
Charles Eric Mowbray
Matthew Duncan Selby
Nigel Alan Swain
David Howard Williams
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Ziarco Pharma Ltd
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Claims (13)

1. Forbindelse af formlen I:
eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, hvor: R1 er Ci-ealkyl, C3-7cycloalkyl-Co-6alkyl- eventuelt substitueret med methyl, alkoxyalkyl indeholdende 3 til 8 carbonatomer, het-Co-ealkyl-, CF3-Ci.6alkyl-, CF3OC2-3alkyl- eller Ci-6hydroxyalkyl; R3 og R2 danner sammen med det nitrogenatom, hvortil de er bundet, en 4 til 8 leddet ikke-aromatisk heterocyclisk gruppe, som eventuelt indeholder ét eller flere yderligere heteroatomer eller grupper uafhængigt valgt blandt N, O, S, S(O) og S(0)2, hvor den heterocycliske gruppe er eventuelt en forbundet bicyclisk gruppe, en spiro-bicyclisk gruppe eller er eventuelt forbundet med en 3-, 4-, 5- eller 6- leddet carbocyclisk gruppe eller en 4-, 5- eller 6-leddet heterocyclisk gruppe, som indeholder i det mindste ét ringelement uafhængigt valgt blandt N, O, S, S(O) og S(0)2, og hvor ringsystemet som helhed eventuelt er substitueret med én eller flere substituenter uafhængigt valgt blandt Ci^alkyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl indeholdende 2 til 8 carbonatomer, (CH2)bhet1, (CH2)cCF3, (CH2)yOCF3, (CH2)daryl og Ci-6hydroxyalkyl, forudsat at ringsystemet som helhed indeholder i det mindste to nitrogenatomer eller indeholder ét nitrogenatom og er substitueret med en gruppe, som indeholder i det mindste ét nitrogenatom; R4 er H; R5 er H eller NH2; R6 og R7 er hver uafhængigt valgt blandt H, Ci-6alkyl og (CH2)jC3-7cycloalkyl; eller R6 og R7 danner, sammen med det nitrogenatom, hvortil de er bundet, en 4, 5 eller 6 leddet heterocyclisk gruppe; R8 er H; aryl er phenyl eventuelt substitueret med én eller flere grupper uafhængigt valgt blandt Ci-salkyl, Ci-ealkoxy, OH, halogen, CF3, CHF2, OCF3, OCHF2, SCF3, hydroxy-Ci-6alkyl, Ci-4alkoxy-Ci-6alkyl, Ci^alkyl-S-Ci^alkyl, CF2CF3, CH2CF3, CF2CH3, C(0)NR13R14, C3-8cycloalkyl, C3-7cycloalkyl-Ci^alkyl, C3-7cycloalkyl-Ci-4alkoxy, R13 og R14 er hver især uafhængigt valgt blandt H, Ci-6alkyl og (CH2)mC3-7cycloalkyl; eller R13 og R14, sammen med det nitrogenatom, hvortil de er bundet, danner en 4, 5 eller 6 leddet heterocyclisk gruppe; a, b, c, d, j og m er hver især uafhængigt valgt blandt er hver især uafhængigt valgt blandt 0, 1,2 og 3; y er uafhængigt valgt blandt 1,2 og 3; het er 4 til 8 leddet ikke-aromatisk heterocyclisk gruppe, som indeholder i det mindste ét heteroatom eller heterogruppe uafhængigt valgt blandt N, O, S, S(O) og S(0)2, hvor den heterocycliske gruppe eventuelt er en forbundet bicyclisk gruppe eller eventuelt er forbundet med en 3-, 4-, 5- eller 6-leddet carbocyclisk gruppe eller en 4-, 5- eller 6-leddet heterocyclisk gruppe, som indeholder i det mindste ét ringelement uafhængigt valgt blandt N, O, S, S(O) og S(0)2, og hvor ringsystemet som helhed eventuelt er substitueret med én eller flere substituenter uafhængigt valgt blandt Ci-ealkyl, NR6R7, (CH2)aC3-7cycloalkyl, alkoxyalkyl indeholdende 2 til 8 carbonatomer, (CH2)bhet1, (CH2)cCF3, (CH2)yOCF3, (CH2)daryl og Ci-6hydroxyalkyl; og het1 er en aromatisk eller ikke-aromatisk 4-, 5- eller 6-leddet heterocyclus, som indeholder i det mindste ét N, O eller S heteroatom, eventuelt forbundet med en 4-, 5-eller 6-leddet carbocyclisk gruppe eller en anden 4-, 5- eller 6-leddet heterocyclus, som indeholder i det mindste ét N, O eller S heteroatom.
2. Forbindelse ifølge krav 1, eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, hvor R1 er C^cycloalkyl-Co-ealkyl-, eventuelt substitueret med methyl.
3. Forbindelse ifølge krav 1 eller krav 2, eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, hvor R2 og R3 sammen med det nitrogenatom, hvortil de er bundet, danner en gruppe valgt blandt følgende ringsystemer:
hvor ringsystemet som helhed kan være substitueret med én eller flere Ci^alkyl eller (CH2)aC3-7cycloalkylgrupper.
4. Forbindelse ifølge krav 3 eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, hvor R6 og R7 uafhængigt er valgt blandt H eller CH3.
5. Forbindelse ifølge krav 1, eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, hvilken forbindelse er valgt blandt /\/Mcyclopropylmethyl)-6-r(3R)-3-(methvlamino)DvnOlidin-1-vllDvrimidin-2,4-diamin, A/4-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin- tartrat, N4-isobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin, N4-(2,2-dimethylpropyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin, N-isobutyl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amin, N-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-4-amin, N4-(2,2-dimethylpropyl)-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6- yl]pyrimidin-2,4-diamin, N4-cyclopropyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2,4- diamin, N4-cyclobutyl-6-[(4aR*,7aR*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2,4- diamin, N4-(2,2-dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2,4-diamin, 6-(3-methylamino-azetidin-1-yl)-N4-(3,3,3-trifluor-propyl)-pyrimidin-2,4-diamin, N4-cyclopropylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidin-2,4-diamin, N4-(3,3-dimethyl-butyl)-6-(3-methylamino-azetidin-1-yl)-pyrimidin-2,4-diamin, N4-cyclopentylmethyl-6-(3-methylamino-azetidin-1-yl)-pyrimidin-2,4-diamin, N4-isobutyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2,4-diamin, 6-[3-(methylamino)azetidin-1-yl]-N4-propylpyrimidin-2,4-diamin, N4-(2,2-dimethylpropyl)-6-[(3R)-3-methylpiperazin-1-yl]pyrimidin-2,4-diamin, N4-ethyl-6-(4-methylpiperazin-1-yl)pyrimidin-2,4-diamin, N4-(cyclopropylmethyl)-6-(4-methylpiperazin-1-yl)pyrimidin-2,4-diamin, 6-[3-(methylamino)azetidin-1-yl]-N4-(2-methylbutyl)pyrimidin-2,4-diamin, N4-butyl-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2,4-diamin, 6-[(3R)-3-(methylamino)pyrrolidin-1-yl]-N4-(2-methylcyclopropyl)pyrimidin-2,4-diamin, N4-isobutyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidin-2,4-diamin, N4-(cyclopropylmethyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidin-2,4-diamin, N4-bicyclo[1.1.1]pent-1-yl-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin, 6-[3-methyl-3-(methylamino)azetidin-1-yl]-N4-propylpyrimidin-2,4-diamin, N4-(2,2-dimethylpropyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2,4- diamin, N4-(2,2-dimethylpropyl)-6-(3-pyrrolidin-1-ylazetidin-1-yl)pyrimidin-2,4-diamin, N4-(2,2-dimethylpropyl)-6-[3-(isopropylamino)azetidin-1-yl]pyrimidin-2,4-diamin, N4-(ferf-butyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin, 6-[(3R)-3-(methylamino)pyrrolidin-1-yl]-N4-(1-methylcyclopropyl)pyrimidin-2,4-diamin, N4-(ferf-butyl)-6-[(4aS*,7aS*)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2,4- diamin, N4-(2,2-dimethylpropyl)-6-piperazin-1-ylpyrimidin-2,4-diamin, N4-(2,2-dimethylpropyl)-6-[3-(methylamino)azetidin-1-yl]pyrimidin-2,4-diamin- hydrochlorid, N4-(2,2-dimethylpropyl)-6-[(3aR*,7aS*)-octahydro-5H-pyrrolo[3,2-c]pyridin-5- yl]pyrimidin-2,4-diamin, 6-piperazin-1-yl-N4-propylpyrimidin-2,4-diamin, N4-(cyclopropylmethyl)-6-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin- 2.4- diamin, N4-(2,2-dimethylpropyl)-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin- 2.4- diamin, N4-isopropyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2,4- diamin, 4-[3-(methylamino)azetidin-1-yl]-6-(4-methylpiperidin-1-yl)pyrimidin-2-amin, N4-(cyclopentylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin, N4-cyclobutyl-6-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]pyrimidin-2,4- diamin, 6-[(3R)-3-(methylamino)pyrrolidin-1-yl]-N4-propylpyrimidin-2,4-diamin, og N4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyrimidin-2,4-diamin.
6. Forbindelse ifølge krav 1, eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, hvilken forbindelse er A/*-(cyclopropylmethyl)-6-[(3R)-3-(methylamino)pyrrolidin-1-yl]pyrimidin-2,4-diamin.
7. Salt ifølge krav 6, hvilke salt er /^-(cyclopropylmethylJ-e-IXSRJ-S-imethylamino)-pyrrolidin-1-yl]pyrimidin-2,4-diamin-L-tartrat.
8. Farmaceutisk sammensætning omfattende en forbindelse ifølge ethvert af kravene 1 til 6, eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, eller saltet ifølge krav 7, sammen med et farmaceutisk acceptabelt excipiens.
9. Forbindelse ifølge ethvert af kravene 1 til 6 eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, eller saltet ifølge krav 7, til anvendelse som et medikament.
10. Anvendelse af en forbindelse ifølge ethvert af kravene 1 til 6 eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, eller saltet ifølge krav 7, til fremstilling af et medikament til behandling af en sygdom valgt blandt inflammatoriske sygdomme, respiratoriske sygdomme (eksempelvis voksen åndenødssyndrom, akut åndenødssyndrom, bronkitis, kronisk bronkitis, kronisk obstruktiv lungesygdom, cystisk fibrose, astma, emphysem, rhinitis, kronisk sinusitis), allergi; allergi-inducerede luftvejsreaktioner, allergisk rhinitis, viral rhinitis, ikke-allergisk rhinitis, vedvarende og årstidsbestemt rhinitis, nasal tilstopning, allergisk tilstopning, kvindelig og mandelig seksuel dysfunktion, hudsygdomme såsom dermatitis og psoriasis, hjertedysfunktioner såsom myokardial iskæmi og arrythmi, sygdomme i mave-tarmkanalen såsom inflammatorisk tarmsygdom, Crohn's sygdom og colitis ulcerosa, cancer, rheumatoid arthritis, hypotension, smerte og overaktive blæretilstande.
11. Forbindelse ifølge ethvert af kravene 1 til 6 eller et farmaceutisk og/eller veterinært acceptabelt salt eller solvat deraf, eller saltet ifølge krav 7, til anvendelse ved behandling af en sygdom valgt blandt inflammatoriske sygdomme, respiratoriske sygdomme (eksempelvis voksen åndenødssyndrom, akut åndenødssyndrom, bronkitis, kronisk bronkitis, kronisk obstruktiv lungesygdom, cystisk fibrose, astma, emphysem, rhinitis, kronisk sinusitis), allergi; allergi-inducerede luftvejsreaktioner, allergisk rhinitis, viral rhinitis, ikke-allergisk rhinitis, vedvarende og årstidsbestemt rhinitis, nasal tilstopning, allergisk tilstopning, kvindelig og mandelig seksuel dysfunktion, hudsygdomme såsom dermatitis og psoriasis, hjerte-dysfunktioner såsom myokardial iskæmi og arrythmi, sygdomme i mave-tarmkanalen såsom inflammatorisk tarmsygdom, Crohn's sygdom og colitis ulcerosa, cancer, rheumatoid arthritis, hypotension, smerte og overaktive blæretilstande.
12. Fremgangsmåde til fremstilling af en forbindelse ifølge ethvert af kravene 1 til 6, omfattende følgende trin: (a) omsætning afen forbindelse af formlen III
med en amin HN(R1)(R4) for tilvejebringelse af en forbindelse af formlen II
efterfulgt af omsætning med en amin HN(R2)(R3) for tilvejebringelse af en forbindelse af formlen I; eller (b) omsætning af en forbindelse af formlen III
med en amin HN(R2)(R3) for tilvejebringelse af en forbindelse af formlen IV
efterfulgt af omsætning med en amin HN(R1)(R4) for tilvejebringelse af en forbindelse af form len I; hvor X og Y er fraspaltelige grupper og R1, R2, R3, R4, R5 og R8 er som defineret i krav 1.
13. Kombination af en forbindelse ifølge ethvert af kravene 1 til 6, eller et farmaceutisk acceptable salt eller solvat deraf, eller saltet ifølge krav 7, med andre terapeutiske midler valgt blandt: • histamin Hi receptor-antagonister, især loratidin, desloratidin, fexofenadin og cetirizin • histamin H3 receptor-antagonister • histamin H2 receptor-antagonister • leukotrien-antagonister, inkl. antagonister for LTB4, LTC4, LTD4, og LTE4; eksempelvis montelukast • phosphodiesterase-inhibitorer, inkl. PDE3 inhibitorer, PDE4 inhibitorer, PDE5 inhibitorer, PDE7 inhibitorer og inhibitorer for to eller flere phosphodiesteraser, såsom duale PDE3/PDE4 inhibitorer • neurotransmitter-genoptagelses-inhibitorer, isærfluoxetin, setralin, paroxetin, ziprasidon • 5-lipoxygenaser (5-LO) inhibitorer eller 5-lipoxygenase-aktiverende protein (FLAP) antagonister • ar og a2-adrenoceptor-agonist-vasokonstriktor-sympathomimetiske midler til dekongestant anvendelse • muscarin M3 receptor-antagonister eller antikolinergiske midler • 32-adrenoceptor-agon ister • dobbeltvirkende β2/Μ3 midler • xanthiner, såsom theophyllin og aminophyllin • ikke-steroide anti-inflammatoriske midler, såsom natriumcromoglycat og nedocromil-natrium • ketotifen • COX-1 inhibitorer (NSAID'er) og COX-2 selektive inhibitorer • orale eller inhalerede glucocorticosteroider • monoklonale antistoffer, som er aktive imod endogene inflammatoriske elementer • anti-tumornecrosefaktor (anti-TNF-a)-midler • adhæsionsmolekyleinhibitorer, inkl. VLA-4-antagonister • kinin-Br og B2-receptor-antagonister • immunosuppressive midler • inhibitorer for matrix-metalloproteaser (MMP'er) • tachykinin ΝΚι, NK2 og NK3 receptor-antagonister • elastase-inhibitorer • adenosin A2a receptor-agonister • inhibitorer for urokinase • forbindelser, som fungerer på dopamin-receptorer, eksempelvis D2-agonister • modulatorerfor NFKb banen, eksempelvis IKK-inhibitorer • midler, som kan klassificeres som mucolytika eller anti-tussiva • antibiotika • modulatorerforcytokin-signaleringsveje, såsom p38 MAP kinase-inhibitorer, syk tyrosin-kinase-inhibitorer eller JAK kinase-inhibitorer • modulatorerfor prostaglandin-vejene, inkl. inhibitorer for H-PDGS og antagonister for DP-1 og CRTH2 • antagonister for kemokinreceptorer CXCR1 og CXCR2 • antagonister for kemokinreceptorer CCR3, CCR4 og CCR5 • inhibitorer for cytosolisk og opløselige phospholipaser A2 (CPLA2 og SPLA2) • prostaglandin D2 receptor-antagonister (DP1 og CRTH2) • inhibitorer for prostaglandin D syntase (PGDS) • inhibitorer for phosphoinositid-3-kinase, • HDAC inhibitorer, • p38 inhibitorer og/eller • CXCR2 antagonister.
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