DK2344157T3 - Nye inhibitorer - Google Patents

Nye inhibitorer Download PDF

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DK2344157T3
DK2344157T3 DK09782605.1T DK09782605T DK2344157T3 DK 2344157 T3 DK2344157 T3 DK 2344157T3 DK 09782605 T DK09782605 T DK 09782605T DK 2344157 T3 DK2344157 T3 DK 2344157T3
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imidazol
dione
benzo
compound
inhibitors
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DK09782605.1T
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Michael Almstetter
Hans-Ulrich Demuth
Antje Hamann
Ulrich Heiser
Torsten Hoffmann
Robert Sommer
Michael Thormann
Andreas Treml
Ulf-Torsten Gaertner
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Probiodrug Ag
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Claims (17)

1. Forbindelse ifølge formel (I):
(I) eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, omfattende alle tautome-rer og stereoisomerer deraf hvor: R1 repræsenterer 1 H-benzimidazolyl eller
hvor A repræsenterer en uforgrenet eller forgrenet Ci-6-alkylenkæde; og R11, R12 og R13 uafhængigt repræsenterer H eller Ci-2-alkyl; R2 repræsenterer aryl, heteroaryl, phenyl substitueret med phenyl, phenyl splejset til hete-rocyclyl eller R2 og R3 er forbundne for at danne en carbocyclylring, hvilken er splejset til phenyl; hvilke aryl, heteroaryl, phenyl, heterocyclyl og carbocyclyl eventuelt er substitueret med én eller flere grupper valgt blandt Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Ci-6-halogenalkyl, -Ci-6-thioalkyl, -SOCi-4-alkyl, -S02-Ci-4-alkyl, Ci-6-alkoxy-, -0-C3-8-cycloalkyl, C3.8-cycloalkyl, -S02-C3.8-cycloalkyl, -SOC3-6-cycloalkyl, C3-6-alkenyloxy-, C3-6-alkynyloxy-, -C(0)Ci-6-alkyl, -C(0)OCi-6-alkyl, Ci-6-alkoxy-Ci-6-alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)0H, -NH2, -NHCx-4-alkyl, -NtC^-alkylXC^-alkyl), -CCOjNtC^-alkylXC^-alkyl), -C(0)NH2, -C(O)NH(Cx_4-alkyl) og -C(O)NH(C3_10-cycloalkyl); R3 repræsenterer H, eller R2 og R3 er forbundne for at danne en carbocyclylring, hvilken er splejset til phenyl; R4 repræsenterer H; X repræsenterer O eller S; og Y repræsenterer O eller S.
2. Forbindelse ifølge krav 1, hvor R1 repræsenterer:
3. Forbindelse ifølge krav 1, hvor R1 repræsenterer:
hvor A repræsenterer en uforgrenet eller forgrenet Ci-6-alkylenkæde og R11, R12 og R13 uafhængigt repræsenterer H eller Ci-2-alkyl.
4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3 repræsenteret ved formlen:
eller
hvor R2, R3, R4, X og Y er som defineret i krav 1.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R2 repræsenterer phenyl substitueret med phenyl, hvilke phenylgrupper eventuelt er substitueret med én eller flere substituenter, hvilke kan være de samme eller forskellige og er valgt blandt halogen, OH, Ci-3-alkyl, Ci_3-halogenalkyl, Ci_3-alkoxy, Ci_3-halogenalkoxy; eller hvor R2 er -biphenyl-4-yl; eller hvor R2 repræsenterer phenyl eventuelt substitueret med én, to eller tre substituenter, hvilke kan være de samme eller forskellige og er valgt blandt halogen, OH, Ci_3-alkyl, Ci_3-halogenalkyl, Ci_3-alkoxy, Ci_3-halogenalkoxy; eller hvor R2 er phenyl substitueret med n-propyloxy.
6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor R3 repræsenterer H.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor R2 og R3 er forbundne for at danne en carbocyclylring, hvilken er splejset til phenyl.
8. Forbindelse ifølge et hvilket som helst af kravene 1 til 7, hvor X repræsenterer O.
9. Forbindelse ifølge et hvilket som helst af kravene 1 til 8, hvor Y repræsenterer O.
10. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor forbindelsen ifølge formel (I) er repræsenteret ved
eller
hvor R2 og R3 er som defineret i krav 1.
11. Forbindelse ifølge formel (I) valgt blandt: l-(lH-benzo[d]imidazol-5-yl)-5-phenylimidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(2-hydroxy-5-methylphenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(2-fluor-5-trifluormethyl)phenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(2-brom-5-fluorphenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(4-chlor-3-trifluormethyl)phenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(3-fluor-4(trifluormethyl)phenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(3-hydroxy-4-methoxyphenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(2-hydroxy-3-methoxyphenyl)imidazolidin-2,4-dion; l-(lH-benzimidazol-5-yl)-5-(l,l'-biphenyl-4-yl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(3-chlorphenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(4-chlorphenyl)imidazolidin-2,4-dion; 1 -(1 H-hpn7nrHlimirla7nl-ci-vn-ci-(,?-rhlnrnhpnvhimiHa7nliHin-? 4-Hinrv l-(lH-benzo[d]imidazol-5-yl)-5-(4-fluorphenyl)imidazolidin-2,4-dion; l-(lH-benzo[d]imidazol-5-yl)-5-(2,3-dihydrobenzo[b][l,4]dioxin-7-yl)imidazolidin-2,4- dion; l-(3-(lH-imidazol-l-yl)propyl)-5-phenylimidazolidin-2,4-dion; l-(3-(lH-imidazol-l-yl)propyl)-5-(2-brom-4-fluorphenyl)imidazolidin-2,4-dion; l-(3-(lH-imidazol-l-yl)propyl)-5-(4-propoxyphenyl)imidazolidin-2,4-dion; l-(3-(lH-imidazol-l-yl)propyl)-5-(3-fluor-4-(trifluormethyl)phenyl) imidazolidin-2,4-dion; l-[3-(lH-imidazol-l-yl)propyl]-5-(4-biphenyl)imidazolidin-2,4-dion; l-(3-(lH-imidazol-l-yl)propyl)-5-(3-chlorphenyl)imidazolidin-2,4-dion; l-(3-(lH-imidazol-l-yl)propyl)-5-(2-chlorphenyl)imidazolidin-2,4-dion; l-(3-(5-methyl-lH-imidazol-l-yl)propyl)-5-phenylimidazolidin-2,4-dion; 5-(2-brom-5-fluorphenyl)-l-(3-(5-methyl-lH-imidazol-l-yl)propyl)imidazolidin-2,4-dion; l-(3-(5-methyl-lH-imidazol-l-yl)propyl)-5-(4-propoxyphenyl)imidazolidin-2,4-dion; l-[3-(5-methyl-lH-imidazol-l-yl)propyl]-5-(4-phenylphenyl)imidazolidin-2,4-dion; 5-(3-chlorphenyl)-l-(3-(5-methyl-lH-imidazol-l-yl)propyl)imidazolidin-2,4-dion; l-(3-(4-methyl-lH-imidazol-l-yl)propyl)-5-phenylimidazolidin-2,4-dion; l-[3-(4-methyl-lH-imidazol-l-yl)propyl]-5-(4-biphenyl)imidazolidin-2,4-dion; 5-(3-chlorphenyl)-l-(3-(4-methyl-lH-imidazol-l-yl)propyl)imidazolidin-2,4-dion; 3-(lH-benzimidazol-5-yl)-l',3'-dihydro-2H,5H-spiro[imidazolidin-4,2’-inden]-2,5-dion; 5-(benzo[c][l,2,5]thiadiazol-6-yl)-l-(lH-benzo[d]imidazol-5-yl)-2-thioxoimidazolidin-4- on; l-(lH-benzo[d]imidazol-5-yl)-5-phenyl-2-thioxoimidazolidin-4-on; l-(lH-benzimidazol-5-yl)-5-(l,l'-biphenyl-4-yl)-2-thioxoimidazolidin-4-on; l-(lH-benzo[d]imidazol-5-yl)-5-(3-hydroxy-4-methoxyphenyl)-2-thioxoimidazolidin-4-on; l-(lH-benzo[d]imidazol-5-yl)-5-phenyl-4-thioxoimidazolidin-2-on; l-(lH-benzimidazol-5-yl)-5-(l,l'-biphenyl-4-yl)-4-thioxoimidazolidin-2-on; 3-(lH-benzimidazol-5-yl)-5-thioxo-l',3'-dihydro-2H-spiro[imidazolidin-4,2,-inden]-2-on; l-(lH-benzo[d]imidazol-5-yl)-5-(4-chlorphenyl)-4-thioxoimidazolidin-2-on; l-(lH-benzo[d]imidazol-5-yl)-5-(2,3,4-trifluorphenyl)-4-thioxoimidazolidin-2-on; l-(lH-benzo[d]imidazol-6-yl)-5-(4-brom-2-fluorphenyl)-4-thioxoimidazolidin-2-on; l-(lH-benzo[d]imidazol-5-yl)-5-(2,3-difluor-4-methylphenyl)-4-thioxoimidazolidin-2-on; l-(lH-benzo[d]imidazol-5-yl)-5-(4-chlor-3-methylphenyl)-4-thioxoimidazolidin-2-on; og l-(lH-benzo[d]imidazol-5-yl)-3-methyl-5-phenylimida4zolidin-2,4-dion; eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, omfattende alle tautome- rer og stereoisomerer deraf.
12. Fremgangsmåde til fremstilling af en forbindelse ifølge formel (I) ifølge et hvilket som helst af kravene 1 til 11, hvilken fremgangsmåde omfatter enten: a) reaktion af en forbindelse ifølge formel (II) (II)
hvor R1, R2, R3 og Y er som defineret i krav 1, og R repræsenterer alkyl (f.eks. butyl) ved omdannelse af iminen til en carbonyl under vandige betingelser (f.eks. vandig trifluoreddi-kesyre) for at give en forbindelse ifølge formel (I), hvor X er O, og R4 er H; eller b) reaktion af en forbindelse ifølge formel (II) som defineret ovenfor med en kilde af sulfidioner, f.eks. natriumsulfid, for at give en forbindelse ifølge formel (I), hvor X er S, og R4 er H; eller c) reaktion af en forbindelse ifølge formel (VIII)
(VIN) hvor R1 og R4 er som defineret i krav 1; med en forbindelse ifølge formel (IX):
(IX) hvor R2 er som defineret i krav 1; for at give en forbindelse ifølge formel (I), hvor R1, R2 og Y er som defineret i krav 1, R3 repræsenterer H, R4 repræsenterer H, og X repræsenterer O; eller d) Reaktion af en forbindelse ifølge formel (XIII)
(XIII) hvor R1, R2 og R3 er som defineret i krav 1; med en forbindelse ifølge formel (XIV) (XIV)
hvor enten J og K begge repræsenterer H, eller J og K begge repræsenterer leaving-grupper (f.eks. repræsenterer J og K begge imidazolyl, eller J repræsenterer alkoxy (såsom ethoxy), og K repræsenterer halogen (f.eks. chlor); for at give en forbindelse ifølge formel (I) hvor R1, R2 R3, R4 og Y er som defineret ovenfor, og X repræsenterer O.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 til anvendelse som et medikament.
14. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af kravene 1 til 11 i kombination med ét eller flere farmaceutisk acceptable fortyndingsmidler eller bærestoffer.
15. Farmaceutisk sammensætning ifølge krav 14, hvilken yderligere omfatter mindst én forbindelse valgt fra gruppen bestående af neuroprotektanter, antiparkinson-lægemidler, inhibitorer af deponering af amyloid protein, inhibitorer af beta-amyloid-syntese, antidepressive midler, angstdæmpende lægemidler, a nti psykotiske lægemidler og anti-multipel sclerose-lægemidler.
16. Farmaceutisk sammensætning ifølge krav 14 eller krav 15, hvilken yderligere omfatter mindst én forbindelse valgt fra gruppen bestående af PEP-inhibitorer, LiCI, inhibitorer af inhibitorer af DP IV eller DP IV-lignende enzymer, acetylcholinesterase (ACE)-inhibitorer, PIMT-enhancere, inhibitorer af beta-secretaser, inhibitorer af gamma-secretaser, inhibitorer af neutral endopeptidase, inhibitorer af Phosphodiesterase-4 (PDE-4), TNFalpha-inhibitorer, muscarin Ml-receptorantagonister, NMDA-receptorantagonister, sigma-l-receptorinhibitorer, histamin H3-antagonister, immunmodu-latoriske midler, immunundertrykkende midler eller et middel valgt fra gruppen bestående af antegren (natalizumab), Neurelan (fampridin-SR), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (tiplimotid), paclitaxel, Anergix.MS (AG 284), SH636, Differin (CD 271, adapalen), BAY 361677 (interleukin-4), matrix-metalloproteinase-inhibitorer, interfe-ron-tau (trophoblastin) og SAIK-MS.
17. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 eller en farmaceutisk sammensætning ifølge et hvilket som helst af kravene 14 til 16 til anvendelse i behandling af en sygdom valgt fra gruppen bestående af Kennedys sygdom, duodenalcancer med eller uden Helicobacter pylori-infectioner, colorectalcancer, Zolliger-Ellison-syndrom, gastrisk cancer med eller uden Helicobacter pylori-infectioner, patogene psykotiske betingelser, skizofreni, infertilitet, neoplasi, inflammatoriske værtsresponser, cancer, malign metastase, melanom, psoriasis, svækkede humorale og cellemedierede immunresponser, leuko-cytadhæsions- og migrationsprocesser i endotelet, svækket fødevareindtag, svækket søvn- vågenhed, svækket homeostatisk regulering af energimetabolisme, svækket autonom funktion, svækket hormonbalance eller svækket regulering af legemsvæsker, multipel sele-rose, Guillain-Barré-syndrom, kronisk inflammatorisk demyeliniserende polyradikuloneuro-pati, mild kognitiv svækkelse, Alzheimers sygdom. Arvelig Britisk Demens, Arvelig Dansk Demens, neurodegeneration i Downs Syndrom, Huntingtons sygdom, reumatoid arthrit, atherosclerose, pancreatitis og restenose.
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