DK2686313T3 - Benzimidazolderivater som inhibitorer af glutaminylcyclase - Google Patents

Benzimidazolderivater som inhibitorer af glutaminylcyclase Download PDF

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DK2686313T3
DK2686313T3 DK12709323.5T DK12709323T DK2686313T3 DK 2686313 T3 DK2686313 T3 DK 2686313T3 DK 12709323 T DK12709323 T DK 12709323T DK 2686313 T3 DK2686313 T3 DK 2686313T3
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phenyl
substituted
cycloalkyl
alkyl
inhibitors
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DK12709323.5T
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Ulrich Heiser
Daniel Ramsbeck
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Probiodrug Ag
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Claims (16)

1. Forbindelse ifølge formel (I):
eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, herunder alle tau-tomerer og stereoisomerer deraf, hvor: R1 repræsenterer hydrogen, halogen, -Ci-6-alkyl, C2.6-alkenyl, C2-6-alkynyl, -aryl, -Ci-6-alkylaryl, -cycloalkyl, -Ci-6-alkylcycloalkyl, -heteroaryl, -Ci-6-alkylheteroaryl, heterocyclyl, -Ci-6-alkylheterocyclyl, -cycloalkyl substitueret med phenyl, -cycloalkyl substitueret med phenoxy, -phenyl substitueret med cycloalkyl, -phenyl substitueret med phe-noxy, -phenyl substitueret med phenyl, heterocyclyl substitueret med phenyl, heteroaryl substitueret med phenyl, phenyl substitueret med heterocyclyl, phenyl substitueret med heteroaryl, phenyl substitueret med -O-cycloalkyl, phenyl substitueret med -heterocyclyl-phenyl eller phenyl substitueret med -cycloalkyl-heterocyclyl; og hvor en hvilken som helst af førnævnte aryl-, cycloalkyl-, heterocyclyl-, heteroaryl-, phenyl- eller phenoxygrupper eventuelt kan være substitueret med én eller flere Rb-grupper valgt blandt Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, Ci-5-haloalkyl, -Ci-6-thioalkyl, -SOCi-4-alkyl, -S02Ci-4-alkyl, Q-6-alkoxy-, Ci-6-haloalkoxy, -0-C3-8-cycloalkyl, C3-8-cycloalkyl, -S02C3.8-cycloalkyl, -SOC3.5-cycloalkyl, C3.5-alkenyloxy-, C3.5-alkynyloxy-, -C(0)Ci-5-alkyl, -C(0)OCi-5-alkyl, Ci-5-alkoxy-Ci-6-alkyl-, nitro, halogen, cyano, hydroxyl, =0, -C(0)0H, -NH2, -NHCi-4-alkyl, -N(Ci_4-alkyl)(Ci_4-alkyl), -C(0)N(Ci-4-alkyl)(Ci-4-alkyl), -C(0)NH2, -C(0)NH(Ci-4-alkyl) og -C(O)NH(C3-i0-cycloalkyl); R2 repræsenterer -0-Ci-6-alkyl, -NR3R4 eller -0-Ci-6-haloalkyl; R3 og R4 uafhængigt af hinanden repræsenterer hydrogen, Ci_5-alkyl eller C3.8-cycloalkyl; eller R3 og R4 sammen med nitrogenatomet, til hvilket de er bundet, kan danne en heterocyclylgruppe eventuelt substitueret med én eller flere Rb grupper; n repræsenterer et heltal valgt blandt O til 3; og Ra repræsenterer Ci-5-alkyl, C2.5-alkenyl, C2.5-alkynyl, Ci_5-haloalkyl, -Ci-5-thioalkyl, -S0Ci-4-alkyl, -S02Ci-4-alkyl, Ci-5-alkoxy-, -0-C3-8-cycloalkyl, C3.8-cycloalkyl, -S02C3-8-cycloalkyl, -SOC3-5-cycloalkyl, C3-5-alkenyloxy-, C3.5-alkynyloxy-, -C(0)Ci.5-alkyl, -C(0)0Ci-s-alkyl, Ci-5-alkoxy-Ci-5-alkyl-, nitro, halogen, cyano, hydroxyl, -C(0)0H, -NH2, -NHCi.4-alkyl, -N(Ci-4-alkyl)(Ci-4-alkyl), -C(0)N(Ci-4-alkyl)(Ci-4-alkyl), -C(0)NH2, -C(0)NH(Ci-4- alkyl) og -C(0)NH(C3-io-cycloalkyl).
2. Forbindelse ifølge krav 1, hvor R1 repræsenterer -Ci_6-alkyl, -aryl, -cycloalkyl, -heteroaryl, -heterocyclyl, -cycloalkyl substitueret med phenyl, -cycloalkyl substitueret med phenoxy, -phenyl substitueret med cycloalkyl, -phenyl substitueret med phenoxy, -phenyl substitueret med phenyl, heterocyclyl substitueret med phenyl, heteroaryl substitueret med phenyl, phenyl substitueret med heterocyclyl, phenyl substitueret med heteroaryl, phenyl substitueret med -O-cycloalkyl, phenyl substitueret med -heterocyclyl-phenyl eller phenyl substitueret med -cycloalkyl-heterocyclyl.
3. Forbindelse ifølge krav 2, hvor R1 repræsenterer -Ci-6-alkyl, -aryl, -cycloalkyl, -heteroaryl, -cycloalkyl substitueret med phenyl, -cycloalkyl substitueret med phenoxy, -phenyl substitueret med cycloalkyl, -phenyl substitueret med phenyl, heterocyclyl substitueret med phenyl, phenyl substitueret med heterocyclyl, phenyl substitueret med -0-cycloalkyl, phenyl substitueret med -heterocyclyl-phenyl eller phenyl substitueret med -cycloalkyl-heterocyclyl.
4. Forbindelse ifølge krav 3, hvor R1 repræsenterer -Ci-6-alkyl, -aryl, -cycloalkyl, -heteroaryl, -phenyl substitueret med cycloalkyl, -phenyl substitueret med phenyl, phenyl substitueret med heterocyclyl, phenyl substitueret med -heterocyclyl-phenyl eller phenyl substitueret med -O-cycloalkyl, hvor phenylgruppen eventuelt er substitueret med én eller flere halogen-, Ci-6-alkoxy- eller Ci-6-haloalkoxygrupper, hvor nævnte heterocyclylgruppe eventuelt er substitueret med én eller flere Ci-6-alkyl-, halogen-, C3-8-cycloalkyl-, hydroxyl-eller =0-grupper og hvor cycloalkylgruppen eventuelt er substitueret med én eller flere halogen- eller =0-grupper.
5. Forbindelse ifølge krav 4, hvor R1 repræsenterer -aryl (f.eks. phenyl), -phenyl substitueret med cycloalkyl (f.eks. -phenyl-cyclohexyl), phenyl substitueret med heterocyclyl (f.eks.-phenyl-pyrrolidinyl, -phenyl-morpholinyl, -phenyl-thiomorpholinyl, -phenyl-piperidinyl,-phenyl-piperazinyl, -phenyl-tetrahydrothiopyranyl eller -phenyl-tetrahydropyranyl) eller phenyl substitueret med -heterocyclyl-phenyl (f.eks. -phenyl-piperazinyl-phenyl);, hvor phenylgruppen eventuelt er substitueret med én eller flere halogen- (f.eks. fluor, brom eller chlor), Ci-6-alkoxy- (f.eks. butoxy) eller Ci-6-haloalkoxy-(f.eks. difluorobutoxy)-grupper; hvor heterocyclylgruppen eventuelt er substitueret med én eller flere Ci-6-alkyl- (f.eks. methyl), halogen- (f.eks. fluor), C3.8-cycloalkyl- (f.eks. cyclopropyl), hydroxyl- eller =0-grupper; og hvor cycloalkylgruppen eventuelt er substitueret med én eller flere halogen- (f.eks. fluor) eller =0-grupper.
6. Forbindelse ifølge et hvilket som helst af krav 1 til 5, hvor R2 repræsenterer -O-Ci-6-alkyl (f.eks. methoxy) eller NR3R4 (f.eks. -NHMe, -N(Me)2), -NH-cyclohexyl eller en hete-rocyklisk gruppe såsom piperidinyl, piperazinyl eller morpholinyl, hvor den heterocykliske gruppe eventuelt er substitueret med én eller flere Rb-grupper såsom halogen (f.eks. fluor) eller Ci-6-alkyl (f.eks. methyl).
7. Forbindelse ifølge et hvilket som helst af krav 1 til 6, hvor n repræsenterer 0.
8. Forbindelse ifølge krav 1, som er valgt fra gruppen bestående af:
eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, herunder alle tau- tomerer og stereoisomerer.
9. Forbindelse, som er valgt fra gruppen bestående af:
eller et farmaceutisk acceptabelt salt, solvat eller polymorf deraf, herunder alle tau-tomerer og stereoisomerer.
10. Forbindelse ifølge krav 1 til 9, til anvendelse som et lægemiddel.
11. Farmaceutisk sammensætning omfattende en forbindelse ifølge et hvilket som helst af krav 1 til 9, eventuelt i kombination med ét eller flere terapeutisk acceptable fortyndingsmidler eller bærestoffer.
12. Farmaceutisk sammensætning ifølge krav 11, som omfatter yderligere mindst én forbindelse, valgt fra gruppen bestående af neurobeskyttende midler, antiparkinson lægemidler, inhibitorer af amyloidproteindeponering, inhibitorer af beta-amyloidsyntese, anti-depressiver, angstdæmpende lægemidler, antipsykotiske lægemidler og anti-multipel sklerose lægemidler.
13. Farmaceutisk sammensætning ifølge krav 11 eller 12, som omfatter yderligere mindst én forbindelse, valgt fra gruppen bestående af PEP-inhibitorer, LiCI, inhibitorer af inhibitorer af DP-IV eller DP-IV-lignende (ENG: DP-IV-like) enzymer, acetylcholinesterase (ACE) inhibitorer, PIMT-enhancere, inhibitorer af beta-sekretaser, inhibitorer af gamma-sekretaser, inhibitorer af neutral endopeptidase, inhibitorer af Phosphodiesterase-4 (PDE-4), TNF-alfa inhibitorer, muskarin-Ml receptor-antagonister, NMDA receptor-antagonister, sigma-1 receptor inhibitorer, histamin-H3-antagonister, immunmodulerende midler, immunsuppressive midler eller et middel valgt fra gruppen bestående af antegren (natalizu-mab), 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, interferon-tau (trophoblastin) og SAIK-MS.
14. Forbindelse ifølge et hvilket som helst af krav 1 til 9, eller en farmaceutisk sammensætning ifølge et hvilket som helst af krav 11 til 13 til anvendelse i behandling af en sygdom valgt fra gruppen bestående af Kennedys sygdom, duodenalcancer med eller uden Helicobacter pylori-infektioner, kolo-rektalcancer, Zolliger-Ellison-syndrom, mavecancer med eller uden Helicobacter pylori-infektioner, patogene psykotiske tilstande, skizofreni, ufrugtbarhed, neoplasi, inflammatoriske værtsresponser, cancer, malign metastase, mela-nom, psoriasis, hæmmede humorale og celle-medierede immunresponser, leukocytadhæ-sion- og migrationsprocesser i endothelet, hæmmet fødemiddel indtag, hæmmet søvn-vågenhed, hæmmet homeostatisk regulation af energimetabolisme, hæmmet autonom funktion, hæmmet hormonalbalance eller hæmmet regulation af kropsvæsker, multipel sklerose, Guillain-Barré syndrom og kronisk inflammatorisk demyeliniserende polyradiculo-neuropati.
15. Forbindelse ifølge et hvilket som helst af krav 1 til 9, eller en farmaceutisk sammensætning ifølge et hvilket som helst af krav 11 til 13 til anvendelse i behandling af en sygdom valgt fra gruppen bestående af mild kognitiv funktionsnedsættelse, Alzheimers sygdom, familiær britisk demens, familiær dansk demens, neurodegeneration i Downs Syndrom og Huntingtons sygdom eller af en sygdom valgt fra gruppen bestående af rheumatoid arthrit, aterosklerose, pancreatit og restenose.
16. Fremgangsmåde til fremstilling af en forbindelse ifølge formel (I) ifølge et hvilket som helst af krav 1 til 9, som omfatter at: (a) fremstille en forbindelse ifølge formel (I) hvor R2 repræsenterer =0 fra en forbindelse ifølge formel (II)
(II) hvor Ra, n og R1 er som defineret ifølge krav 1 og Alk repræsenterer en ethyl- eller butylgruppe, derefter efterfulgt af en afbeskyttelsesreaktion; eller (b) indbyrdes omdanne forbindelser ifølge formel (I); og/eller (c) afbeskytte en forbindelse ifølge formel (I) som er beskyttet.
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