DK2498609T3 - Selektive heterocykliske sphingosin-1-phosphatreceptormodulatorer - Google Patents

Selektive heterocykliske sphingosin-1-phosphatreceptormodulatorer Download PDF

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DK2498609T3
DK2498609T3 DK10830879.2T DK10830879T DK2498609T3 DK 2498609 T3 DK2498609 T3 DK 2498609T3 DK 10830879 T DK10830879 T DK 10830879T DK 2498609 T3 DK2498609 T3 DK 2498609T3
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inden
dihydro
compound
mmol
cyano
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Marcus F Boehm
Esther Martinborough
Enugurthi Brahmachary
Manisha Moorjani
Junko Tamiya
Liming Huang
Adam Richard Yeager
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Celgene Int Ii Sarl
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Claims (10)

1. Forbindelse med formel (I) eller et farmaceutisk acceptabelt salt, en tautomer, en stereoisomer eller et hydrat eller et solvat deraf: .1
_ a2 5 0) hvor en stiplet linje betyder, at en en enkeltbinding eller en dobbeltbinding kan vaere til stede, forudsat at der er to dobbeltbindinger og tre enkeltbindinger i ringen omfattende A1, A2 og A3; I0 A1, A2 og A3 hver uafhaengigt er C eller S eller N; forudsat at en af A1, A2 og A3 er S; R1 er
R3 er C2-4-alkyl; og Y er -CN, -Cl, I, -O-R3, -COOH, -COOR3 eller -CF3; I5 R2 er _
_ eller
XerNR'R" eller -OR'"; >0 R' er H, Ci-4-alkyl, n-hydroxy Ci-4-alkyl, -SO2-R3 eller -CO-R3; R" er H, -SO2-R5, Ci-4-alkyl, eventuelt substitueret med 1 eller fiere R4, eller en ringdel, eventuelt substitueret med R6, hvor en sadan ringdel er piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl eller phenyl; R'" er H, Ci-4-alkyl eller -CO-R3 hvert R4 uafhaengigt er H, halo, OH, oxo, =NH, NH2, -COOH, F, -NHR3, -N(R7R7), -SO2-R3, -S02-N(R7R7), -N(R3)-S02-R3, -COOR3, -OCO-R3, -CO-N(R7R7), -N(R3)-COR3, Ci-3-alkyl, Ci-3-alkoxy og en ringdel, eventuelt substitueret med R6, hvor en sadan ringdel er piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutinyl eller phenyl; hvert R5 uafhaengigt er R4, Ci-4-alkyl, C3-6-cycloalkyl eller Ci-4-alkyl, eventuelt substitueret med 1 eller fiere R4; hvert R6 uafhaengigt er halo, OH, -NH2, -NHR3, -N(R3R3), -COOH, -COOR3, -NHCO-R3; hvert R6 uafhaengigt er Ci-4-alkyl eller H, eller to R6 sammen med det nitrogenatom, hvortil de er bundet, danner en 4-, 5- eller 6-leddet maettet heterocyklisk ring indeholdende 0 eller 1 yderligere heteroatom, hvor et sadant yderligere heteroatom er O eller N, hvor en sadan heterocyklus eventuelt er substitueret med -OH, -NH2, -N(R3R3), n-hydroxy Ci-4-alkyl, -(CH2)m-COOH, -(CH2)m-COOR3; hvert m uafhaengigt er 0, 1,2 eller 3, hvor strukturen af formel I er udvalgt fra gruppen bestaende af formlerne a-i til og med a-x:
2. Forbindelse if0lge krav 1, hvor forbindelsen i det vaesentlige er enantiome-risk ren.
3. Forbindelse ifolge krav 1 og 2, hvor X er NR'R".
4. Forbindelse ifolge krav 1, hvor forbindelsen er udvalgt blandt forbindel-serne 1-227: .. .κι N—
/=s\
eller et hvilket som helst acceptabelt salt, tautomer, stereoisomer eller hydrat eller solvat deraf.
5. Farmaceutisk sammensaetning omfattende en forbindelse ifolge et hvilket som helst af kravene 1-4.
6. Forbindelse ifolge et hvilket som helst af kravene 1-4 eller sammensaetning ifolge krav 5 til anvendelse til behandling af multipel sklerose, transplantataf-stodning, akut respiratorisk distress-syndrom, ulceros kolitis, influenza, Crohns sygdom eller respiratorisk distress-syndrom hos voksne.
7. Fremgangsmade til syntese af en forbindelse med formel I ifolge krav 1 til 4, omfattende en indandel med et chiralt carbon i den femleddede ring af indandelen, hvor forbindelsen er enantiomerisk beriget med hensyn til det chi-rale carbon, hvilken fremgangsmade omfatter trinnene (i) at tilvejebringe en forbindelse omfattende en indandel, hvor ringcarbonet af den femleddede ring af indandelen, hvor chiral substitution er onsket, er oxo-substitueret ved sadant carbon, og hvor et carbon af phenylringen er halogen-substitueret; (ii) at omsaette en sadan forbindelse med et chiralt reagens udvalgt fra gruppen bestaende af en Corey Bakshita Shibata-oxazaborolidin og en chiral sulfi-namid med formen RS(=0)NFl2, hvor R er udvalgt fra gruppen bestaende af t-butyl, forgrenet C2-6-alkyl og C3-8-cycloalkyl; og (iii) at danne det chirale center ved det indandel-carbon, der tidligere var bun-det til oxo-gruppen, ved enten at omsaette en sadan forbindelse med et egnet reduktionsmiddel sammen med det chirale reagens i trin (ii) eller at omsaette resultatet af omsaetningen af en sadan forbindelse med et egnet reduktionsmiddel.
8. Fremgangsmade ifolge krav 7, hvor forbindelsen omfattende en indandel, der tilvejebringes i trin (i), bringes i kontakt med det chirale reagens til dannelse i trin (iii) af formel Vl-R eller Vl-S:
VI-R
VI-S hvor Z er Cl, Br eller I.
9. Fremgangsmade ifolge krav 8, hvor fremgangsmaden yderligere omfatter trinnet at beskytte hydroxygruppen med formel Vl-R eller Vl-S ved at behandle formel Vl-R eller Vl-S med et beskyttelsesmiddel til dannelse af formel Vla-R ellerVla-S:
Vla-R Vla-S hvor PG er en beskyttelsesgruppe; og trinnet med at omsaette Vla-R eller Vla-S med borsyre eller bis(pinacolato)diboron til dannelse af en borsyre eller bo-ronatester med formel Vlb-R eller Vlb-S:
VIb-R
VIb-S.
10. Fremgangsmade ifolge krav 7, hvor en forbindelse med formel Vlll-R eller Vlll-S dannes i trin (iii):
VIII-R
VIII-S.
DK10830879.2T 2009-11-13 2010-11-15 Selektive heterocykliske sphingosin-1-phosphatreceptormodulatorer DK2498609T3 (da)

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EP3868377A1 (en) 2009-11-13 2021-08-25 Receptos Llc Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
BR112012011430A8 (pt) 2009-11-13 2017-12-26 Celgene Int Ii Sarl Compostos moduladores de receptor de esfingosina 1 fosfato e composições farmacêuticas
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