DK2542084T3 - Catechol-o-methyltransferasehæmmere og deres anvendelse ved behandling af psykotiske lidelser - Google Patents

Catechol-o-methyltransferasehæmmere og deres anvendelse ved behandling af psykotiske lidelser Download PDF

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DK2542084T3
DK2542084T3 DK11751129.5T DK11751129T DK2542084T3 DK 2542084 T3 DK2542084 T3 DK 2542084T3 DK 11751129 T DK11751129 T DK 11751129T DK 2542084 T3 DK2542084 T3 DK 2542084T3
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alkyl
aryl
hydroxy
heterocyclyl
groups
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Scott Wolkenberg
Scott T Harrison
James C Barrow
Zhijian Zhao
Nathan Kett
Amy Zartman
Jeffrey Melamed
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Merck Sharp & Dohme
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Claims (24)

1. Forbindelse med strukturformlen I:
herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor: A betegner hydrogen eller C1-6 alkyl, hvor alkyl eventuelt er substitueret med 1 til 3 grupper af halogen, OH eller O-alkyl; X betegner hydrogen, OH, halogen, OC1-6 alkyl, NR2R3 eller (CH2)nC6-10 aryl, hvor alkyl og aryl eventuelt er substitueret med 1 til 3 grupper af Ra; R1 betegner C6-10 aryl eller (CH2)nC5-10 heterocyclyl, hvor aryl og heterocyclyl er substitueret med 1 til 3 grupper af Ra; R2 og R3 betegner uafhængigt H, OH, Cl-6 alkyl, N(CH3)2, (CH2)nC5-10 heterocyclyl eller (CH2)nC6-10 aryl, hvor aryl og heterocyclyl eventuelt er substitueret med 1 til 3 grupper af Ra; eller R2 og R3 sammen med det nitrogenatom, de er bundet til, danner en 5-1 O-leddet ring, der eventuelt er substitueret med 1 til 3 grupper af halogen, OH, C2-6 alkenyl, (CH2)nC5-10 heterocyclyl eller (CH2)nC6-10 aryl; Ra betegner Cl-6 alkyl, halogen, hydroxyl, C2-4 alkynyl, (CH2)nCF3, OCHF2, OCF3, C3-6 cycloalkyl, 0(CH2)nC3-6 cycloalkyl, NR2C(0)R2, C(0)N(R2)2, C(R2)20R2, C(0)R2, N02, CN, N(R2)2, (CH2)nC(0)0R2, S02R2, NHS02R2, OC1-6 alkyl, O(CH2)nC5-10 heterocyclyl, NH(CH2)nC5-10 heterocyclyl, (CH2)nC6-10 aryl, O(CH2)nC6-10 aryl eller O(CH2)nC5-10 heterocyclyl, idet alkyl-, alkynyl-, cycloalkyl-, heterocyclyl- og arylgruppeme eventuelt er substitueret med 1 til 3 grupper af Rb; Rb betegner C1-6 alkyl, 0C1-6 alkyl, halogen, CHF2, OCHF2, -O-, N(R2)2, CH20H, S(0)2NR2R3, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, C(O)(CH2)nC5-10 heterocyclyl, NH(CH2)nC5-10 heterocyclyl, C(0)NHC3-6 cycloalkyl, OR2, C3-6 cycloalkyl, (CH2)nCF3 eller CN, idet heterocyclylgruppen eventuelt er substitueret med 1 eller flere af C1-6 alkyl; og n betegner 0 til 5.
2. Forbindelse ifølge krav 1, hvor R1 er phenyl eller pyridyl, idet begge er substitueret med 1 til 3 grupper af Ra.
3. Forbindelse ifølge krav 1, hvor Ra-substituenten på R1 er valgt fra gruppen bestående af NHS02R2, halogen, CN, (CH2)nC6-10 aryl, C5-10 heterocyclyl, C2-4 alkynyl, OC1-6 alkyl og OC6-10 aryl, idet alkyl-, alkynyl-, aryl- og heterocyclylgruppeme eventuelt er substitueret med 1 til 3 grupper af Rb.
4. Forbindelse ifølge krav 1, hvor Rb-substituenten på Ra i R1 er valgt fra gruppen bestående af halogen, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, Cl-6 alkyl, OC1-6 alkyl, OCHF2 og CF3.
5. Forbindelse ifølge krav 1, hvor X betegner hydrogen, OH, halogen, OC1-6 alkyl, NR2R3 eller (CH2)nC6-10 aryl, idet alkyl- og arylgrupperne eventuelt er substitueret med 1 til 3 grupper af Ra.
6. Forbindelse ifølge krav 1, der er repræsenteret af strukturformlen la:
herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor A og X begge er hydrogen, og Ra er mindst en til tre substituenter, som er uafhængigt valgt fra gruppen bestående af NHS02R2, halogen, CN, (CH2)nC6-10 aryl, C5-10 heterocyclyl, C2-4 alkynyl, OC1-6 alkyl og OC6-10 aryl, idet alkyl-, alkynyl-, aryl- og heterocyclylgrupperne eventuelt er substitueret med 1 til 3 grupper af Rb, og Rb er valgt fra gruppen bestående af halogen, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, Cl-6 alkyl, OC1-6 alkyl, OCHF2 og CF3.
7. Forbindelse ifølge krav 1, der er repræsenteret af strukturformlen Ib:
herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor en af Y1, Y2, Y3 og Y4 er N, mens de øvrige er CH, A og X begge er hydrogen, og Ra er valgt fra gruppen bestående af NHS02R2, halogen, CN, (CH2)nC6-10 aryl, C5-10 heterocyclyl, C2-4 alkynyl, OC1-6 alkyl og OC6-10 aryl, idet alkyl-, alkynyl-, aryl- og heterocyclylgrupperne eventuelt er substitueret med 1 til 3 grupper af Rb, og Rb er valgt fra gruppen bestående af halogen, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, Cl-6 alkyl, OC1-6 alkyl, OCHF2 og CF3.
8. Forbindelse ifølge krav 1, der er repræsenteret af strukturformlen Ila:
herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor Ra er valgt fra gruppen bestående af NHS02R2, halogen, CN, (CH2)nC6-10 aryl, C5-10 heterocyclyl, C2-4 alkynyl, OC1-6 alkyl og OC6-10 aryl, idet alkyl-, alkynyl-, aryl- og heterocyclylgruppeme eventuelt er substitueret med 1 til 3 grupper af Rb, og Rb er valgt fra gruppen bestående af halogen, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, Cl-6 alkyl, OC1-6 alkyl, OCHF2 og CF3.
9. Forbindelse ifølge krav 1, der er repræsenteret af strukturformlen Ilb:
herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor en af Y1, Y2, Y3 og Y4 er N, mens de øvrige er CH, Ra er valgt fra gruppen bestående af NHS02R2, halogen, CN, (CH2)nC6-10 aryl, C5-10 heterocyclyl, C2-4 alkynyl, OC1-6 alkyl og OC6-10 aryl, idet alkyl-, alkynyl-, aryl- og heterocyclylgruppeme eventuelt er substitueret med 1 til 3 grupper af Rb, og Rb er valgt fra gruppen bestående af halogen, (CH2)nC6-10 aryl, (CH2)nC5-10 heterocyclyl, Cl-6 alkyl, OC1-6 alkyl, OCHF2 og CF3.
10. Forbindelse ifølge krav 7 eller 9, hvor Y2 er N, og Y1, Y3 og Y4 alle er CH.
11. Forbindelse ifølge krav 1, som er: N-[3-(5-hydroxy-6-oxo-l,6-dihydropyrimidin-2-yl)phenyl]methansulfonamid, 2-(3,4-dichlorphenyl)-5-hydroxypyrimidin-4(3//)-on, 2-fluor-5-(5-hydroxy-6-oxo-l,6-dihydropyrimidin-2-yl)benzonitril, 2-(2’,4’-dichlorbiphenyl-3-yl)-5-hydroxypyrimidin-4(3//)-on, 2-[3-(l-benzofuran-2-yl)phenyl]-5-hydroxypyrimidin-4(3//)-on, 5-hydroxy-2-[3-(pyridin-3-yl)phenyl]pyrimidin-4(3//)-on, 5-hydroxy-2-[3-(phenylethynyl)phenyl]pyrimidin-4(3//)-on, 5-hydroxy-2-[3-(prop-l-yn-l-yl)phenyl]pyrimidin-4(3//)-on, 5-hydroxy-2-[3-(6-methoxypyrazin-2-yl)phenyl]pyrimidin-4(3//)-on, 5-hydroxy-2-[3-(2-methoxy-l,3-thiazol-5-yl)phenyl]pyrimidin-4(3//)-on, 5-hydroxy-2-[3-(l,3-thiazol-4-yl)phenyl]pyrimidin-4(3//)-on, 5-hydroxy-2-[3-(pyridazin-3-yl)phenyl]pyrimidin-4(3//)-on, 2-[2-(l-benzyl-lH-pyrazol-4-yl)pyridin-4-yl]-5-hydroxypyrimidin-4(3H)-on, 5-hydroxy-2-{2-[l-(3-methylbutyl)-lH-pyrazol-4-yl]pyridin-4-yl}pyrimidin-4(3H)-on, 2-{2-[3-(difluormethoxy)phenyl]pyridin-4-yl}-5-hydroxypyrimidin-4(3H)-on, 2-[2-(2-fluorbiphenyl-4-yl)pyridin-4-yl]-54iydroxy-3-methylpyrimidin-4(3H)-on, 5-hydroxy-3-methyl-2-[2-(lH-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl]pyrimidin-4(3H)-on, 2-[2-(4-chlor-lH-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl]-5-hydroxy-3-methylpyrimidin-4(3H)-on, 2-[2-(4-chlor-lH-pyrrolo[2,3-b]pyridin-5-yl)pyridin-4-yl]-5-hydroxy-3-methylpyrimidin-4(3H)-on, 2-[4-(benzyloxy)phenyl]-5-hydroxy-3-methylpyrimidin-4(3H)-on, 5-hydroxy-3-methyl-2-{3-[3-(trifluormethyl)phenoxy]phenyl}pyrimidin-4(3H)-on, 2-{3-[2-brom-4-(trifluormethyl)phenoxy]phenyl}-5-hydroxy-3-methylpyrimidin-4(3H)-on, 2-(2’-chlorbiphenyl-3-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-on, 5-hydroxy-3-methyl-2-[3’-(5-methyl-l,3,4-oxadiazol-2-yl)biphenyl-3-yl]pyrimidin-4(3H)-on, 2-[3-(l-benzothiophen-3-yl)phenyl]-5-hydroxy-3-methylpyrimidin-4(3H)-on, 5-hydroxy-3-methyl-2-[3-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazin-7- yl)phenyl]pyrimidin-4(3H)-on, 5-hydroxy-2-[3-(lH-indol-4-yl)phenyl]-3-methylpyrimidin-4(3H)-on, 2-[3-(lH-benzimidazol-5-yl)phenyl]-5-hydroxy-3-methylpyrimidin-4(3H)-on, 5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3//)-on, 5- hydroxy-3-methyl-2-(3-phenoxyphenyl)pyrimidin-4(3//)-on, 2-[4-chlor-3-(trifluormethyl)phenyl]-5-hydroxy-3-methylpyrimidin-4(3//)-on, 6- chlor-5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3//)-on, 2-biphenyl-3-yl-5-hydroxy-3-methylpyrimidin-4(3//)-on, 2-(3-isoquinolin-5-ylphenyl)-5-hydroxy-3-methylpyrimidin-4(3//)-on, 5-hydroxy-2-[3-(4-methoxyphenoxy)phenyl]-3-methylpyrimidin-4(3//)-on, 5-Hydroxy-2-(4-trifluormethyl-phenyl)-3//-pyrimidin-4-on, 5-Hydroxy-2-[2-(lH-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3i0-on, 5-Hydroxy-2-[2-(l//-indol-4-yl)pyridin-4-yl]-3-methylpyrimidin-4(3i0-on, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf.
12. Farmaceutisk sammensætning, der omfatter en inert bærer og en virkningsfuld mængde af en sammensætning ifølge et hvilket som helst af kravene 1 til 11 og 16 til 22.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 og 16 til 22 til anvendelse ved behandling og/eller forebyggelse af neurologiske og psykiatriske forstyrrelser og lidelser.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 og 16 til 22 til anvendelse til forøgelse af virkningen af antipsykotika ved behandling af skizofreni, eller til anvendelse ved behandling og/eller forebyggelse af skizofreni, svær depressiv lidelse, bipolar sygdom, angstsygdom, obsessiv-kompulsiv tilstand, dopaminmangelrelaterede sygdomme, ADD, ADHD, stofafhængighed, vægtforøgelse eller madtrang forbundet med rygestop eller brug af antipsykotika, demens, Parkinsons sygdom, Huntingtons sygdom, Picks sygdom, Creutzfeldt-Jacobs sygdom, perinatal hypoxi, kognitiv forstyrrelse eller kognitiv deficiens i forbindelse med en hvilken som helst af forstyrrelserne eller lidelserne.
15. Sammensætning ifølge krav 12, der endvidere omfatter en eller flere terapeutisk aktive forbindelser valgt fra gruppen bestående af opiatagonister eller -antagonister, calciumkanalantagonister, agonister eller antagonister for komplet eller delvis 5HT-, 5-HT1A-receptor, natriumkanalantagonister, N-methyl-D-aspartat (NMDA)-receptoragonister eller - antagonister, COX-2-selektive hæmmere, neurokininreceptor 1 (NKl)-antagonister, non-steroide antiinflammatoriske lægemidler (NSAID), selektiv-serotonin-geoptagelseshæmmere (SSRI) og/eller selektiv-serotonin-og-norepinephrin-genoptagelseshæmmere (SSNRI), tricykliske antidepressiva, norepinephrin-modulatorer, lithium, valproat, norepinephrin-genoptalgelseshæmmere, monoamin-oxidasehæmmere (MAOI), reversible monoamin-oxidasehæmmere (RIMAs), alfa-adrenoreceptor-antagonister, atypiske antidepressiva, benzodiazepiner, corticotropinfrigivelsesfaktor (CRF)-antagonister, neurontin (gabapentin) og pregabalin.
16. Forbindelse ifølge krav 1, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor: A betegner C1-6 alkyl, idet alkylgruppen eventuelt er substitueret med 1 til 3 grupper af halogen, OH eller Oalkyl; og X betegner hydrogen, OH, halogen, OC1-6 alkyl eller NR2R3, eventuelt substitueret med 1 til 3 grupper af Ra.
17. Forbindelse ifølge krav 1, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor: A betegner hydrogen; og X betegner OH, halogen, Cl-6 alkyl, OC1-6 alkyl, NR2R3, (CH2)nC6-10 aryl, CH2C5-10 heterocyclyl, (CH2)2C5-10 heterocyclyl, (CH2)3C5-10 heterocyclyl, (CH2)4C5-10 heterocyclyl, (CH2)5C5-10 heterocyclyl, idet alkyl-, aryl- og heterocyclylgruppeme eventuelt er substitueret med 1 til 3 grupper af Ra.
18. Forbindelse ifølge krav 1, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf, hvor: A betegner hydrogen; X betegner hydrogen; og R1 betegner C6-10 aryl, idet arylgruppen er substitueret med 1 til 3 grupper af Ra.
19. Forbindelse ifølge krav 1, som er N-[3-(5-hydroxy-6-oxo-l,6-dihydropyrimidin-2-yl)phenyl]methansulfonamid, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf.
20. Forbindelse ifølge krav 1, som er 2-(3,4-dichlorphenyl)-5-hydroxypyrimidin-4(3H)-on, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf.
21. Forbindelse ifølge krav 1, som er -5-hydroxy-2-(4-trifluormethyl-phenyl)-3H-pyrimidin-4-on, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf.
22. Forbindelse ifølge krav 1, som er 2-[4-chlor-3-(trifluormethyl)phenyl]-5-hydroxy-3-methylpyrimidin-4(3H)-on, herunder tautomerer eller farmaceutisk acceptable salte og individuelle enantiomerer og diastereoisomerer deraf.
23. Sammensætning ifølge et hvilket som helst af kravene 12 og 15, hvor sammensætningen er til anvendelse i kombination med et antidepressivum, og sammensætningen og antidepressivummet indgives adskilt eller sammen.
24. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1 til 11 og 16 til 22 til fremstilling af et lægemiddel til forøgelse af virkningen af antipsykotika ved behandling af skizofreni, eller til anvendelse ved behandling og/eller forebyggelse af skizofreni, svær depressiv lidelse, bipolar sygdom, angstsygdom, obsessiv-kompulsiv tilstand, dopaminmangelrelaterede sygdomme, ADD, ADHD, stofafhængighed, demens, Parkinsons sygdom, Huntingtons sygdom, Picks sygdom, Creutzfeldt-Jacobs sygdom, perinatal hypoxi, kognitiv forstyrrelse, vægtforøgelse eller madtrang forbundet med rygestop eller brug af antipsykotika, eller kognitiv deficiens i forbindelse med en hvilken som helst af forstyrrelserne eller lidelserne.
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