SI2498611T1 - Modulatorji receptorja sfingozin-1-fosfata in postopki za kiralno sintezo - Google Patents

Modulatorji receptorja sfingozin-1-fosfata in postopki za kiralno sintezo Download PDF

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SI2498611T1
SI2498611T1 SI201031665T SI201031665T SI2498611T1 SI 2498611 T1 SI2498611 T1 SI 2498611T1 SI 201031665 T SI201031665 T SI 201031665T SI 201031665 T SI201031665 T SI 201031665T SI 2498611 T1 SI2498611 T1 SI 2498611T1
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compound
chiral
tetrahydronaphthalene
moiety
carbon
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Esther Martinborough
Marcus F. Boehm
Adam Richard Yeager
Junko Tamiya
Liming Huang
Enugurthi Brahmachary
Manisha Moorjani
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Celgene International Ii Sarl
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Claims (14)

  1. Modulatorji receptorja sfingozin-1 -fosfata in postopki za kiralno sintezo Patentni zahtevki
    1. Spojina, ki ima strukturo s formulo l-R ali l-S ali njena farmacevtsko sprejemljiva sol, hidrat ali solvat:
    v kateri X je -NR'R" ali -ORm; Y je -CN, -Cl, -CF3, I, -COOH ali -COOR1; R' je H, Ci-4-alkil, n-hidroksi-Ci^-alkil, -S02-R1 ali -CO-R1; R" je H, -S02-R3, Ci-4-alkil, ki je po izbiri substituiran z 1 ali več R2 ali obročni del, ki je po izbiri substituiran z R4, pri čemer je tak obročni del piperidinil, cikloheksil, morfolinil, tiazolil, pirazolil, pirolidinil, imidazolil ali fenil; ali R' in R" vzeta skupaj z atomom dušika, na katerega sta vezana, tvorita 4-, 5-ali 6-členski nasičen heterociklični obroč, ki vsebuje 0 ali 1 dodaten heteroatom, kjer je tak dodaten heteroatom O ali N, pri čemer je tak heterocikel po izbiri enkrat ali večkrat substituiran s substituenti, neodvisno izbranimi iz skupine, ki sestoji iz -OH, okso, -NH2, n-hidroksi-CM-alkila, -COOH, -(CH2)m-COOH, -(CH2)m-COOR1, -N(R1R1) in -(CH2)m-CO-N(R5R5); R"' je H, Ci_4-alkil ali -CO-R1; vsak R1 je neodvisno C^-alkil ali H; vsak R2 je neodvisno H, halo, OH, okso, =NH, NH2, -COOH, F, -NHR1, -N(RSR5), -S02-R1, -S02-N(R5Rs), -N(R1)-S02-R1, -COOR1, -OCO-R1, -CO-N(R5R5), -N(R1)-COR1, Ci-3-alkil, Ci-3-alkoksi in obročni del, ki je po izbiri substituiran z R4, pri čemer je tak obročni del piperazinil, piperidinil, morfolinil, pirolidinil, pirazolil, imidazolil, benzimidazolil, azetidinil, ciklobutinil ali fenil; vsak R3 je neodvisno R2, Ci_4-alkil, C3-6-cikloalkil ali Ci^-alkil, po izbiri substituiran z 1 ali več R2; vsak R4 je neodvisno halo, OH, -NH2, -NHR1, -N(R1R1), -COOH, -COOR1, -NHCO-R1; vsak R5 je neodvisno Ci.4-alkil ali H ali dva R5 vzeta skupaj z atomom dušika, na katerega sta vezana, tvorita 4-, 5- ali 6-členski nasičen heterociklični obroč, ki vsebuje 0 ali 1 dodaten heteroatom, kjer je tak dodaten heteroatom O ali N, pri čemer je tak heterocikel po izbiri substituiran z -OH, -NH2, -N(R1R1), n-hidroksi-Ci-4-alkilom, -(CH2)m-COOH,-(CH2)m-COOR1; in vsak m je neodvisno 0,1,2 ali 3.
  2. 2. Spojina po zahtevku 1, pri čemer je spojina v bistvu enantiomerno čista.
  3. 3. Spojina po zahtevkih 1-2, pri čemer je X -NR'R".
  4. 4. Spojina po zahtevkih 1-2, pri čemer je spojina izbrana izmed spojin 1-55:
    >
    ali farmacevtsko sprejemljiva sol, hidrat ali solvat le-teh.
  5. 5. Farmacevtski sestavek, ki obsega spojino po katerem koli od zahtevkov 1-4.
  6. 6. Spojina po katerem koli od zahtevkov 1-4 ali sestavek po zahtevku 5 za uporabo pri zdravljenju multiple skleroze, zavrnitve presajenega organa, sindroma akutne dihalne stiske, ulceroznega kolitisa, gripe, Crohnove bolezni ali sindroma dihalne stiske pri odraslem.
  7. 7. Postopek za sintezo spojine s formulo l-R ali l-S po zahtevkih 1-4, ki obsega tetrahidronaftalenski del, ki ima kiralni ogljik v šestčlenskem nasičenem obroču tetrahidronaftalenskega dela, kjer je spojina enantiomerno obogatena glede na kiralni ogljik, pri čemer postopek obsega koraka (i) zagotavljanje spojine, ki obsega tetrahidronaftalenski del, kjer je obročni ogljik šestčlenskega nasičenega obroča tetrahidronaftalenskega dela, kjer je želena kiralna substitucija, okso-substituiran pri takem ogljiku; (ii) reagiranje takšne spojine s kiralnim reagentom, da nastane kiralni center pri ogljiku v tetrahidronaftalenskem delu, ki je bil predhodno vezan na skupino okso.
  8. 8. Postopek po zahtevku 7, pri katerem se spojina, ki obsega tetrahidronaftalenski del, zagotovljen v koraku (i), da v stik s kiralnim reagentom, da se v koraku (ii) tvori formula Vl-R ali Vl-S:
    v kateri je Z -CN, -Cl ali -CF3.
  9. 9. Postopek po zahtevku 8, pri čemer postopek dalje obsega korak obračanja kiralne konfiguracije kiralnega ogljika v šestčlenskem nasičenem obroču tetrahidronaftalenskega dela, ki je bil prej vezan na okso skupino, z obdelavo formule Vl-R ali Vl-S z difenilfosforil azidom (DPPA), da nastane azido tetrahidronaftalen s formulo Vll-S ali Vll-R:
    kjer ima substituent azido v šestčlenskem nasičenem obroču tetrahidronaftalenskega dela, ki nadomešča substituent hidroksi in kiralni ogljik, ki je vezan na substituent azido, obratno kiralno konfiguracijo kiralnega ogljika kot prej, ko je bil vezan na substituent hidroksi.
  10. 10. Postopek po zahtevku 9, pri čemer je Z -CN in postopek dalje obsega korak tvorjenja substituiranega 1,2,4-oksadiazola na tetrahidronaftalenskem delu z (a) reagiranjem intermediata Vll-R ali Vll-S z zaščitnim sredstvom in potem reagiranjem dobljene zaščitene oblike intermediata Vll-R ali Vll-S s hidroksilaminom ali hidroksilamin hidrokloridom, da nastane hidroksiamidin na fenilnem ogljiku, na katerega je bil prej vezan Z, pri čemer ima dobljena spojina formulo Vlll-R ali Vlll-S:
    in (b) kontaktiranjem intermediata s formulo Vlll-R ali Vlll-S s substituirano benzojsko kislino in reagentom za spajanje, da nastane spojine s formulo IX-R ali IX-S:
    v kateri je X OH, N3, NH-PG, NH2 ali NR'R"; PG je zaščitna skupina; R' je H, C1-4-alkil, n-hidroksi-Ci-4-alkil, -SO2-R1 ali -CO-R1; R" je H, -S02-R3, Ci^-alkil, ki je po izbiri substituiran z 1 ali več R2 ali obročni del, ki je po izbiri substituiran z R4, pri čemer je tak obročni del piperidinil, cikloheksil, morfolinil, tiazolil, pirazolil, pirolidinil, imidazolil ali fenil; Ra je nižji alkil in R1, R2, R3 in R4 so takšni, ko je bilo definirano v zahtevku 1.
  11. 11. Postopek po zahtevku 10, pri čemer ima spojina s formulo IX-R ali IX-S spodnji strukturi:
  12. 12. Postopek po zahtevkih 7-11, pri čemer je dobljena spojina, ki obsega tetrahidronaftalenski del, ki ima kiralni ogljik v šestčlenskem nasičenem obroču tetrahidronaftalenskega dela, enantiomerno obogatena vsaj 90 %.
  13. 13. Spojina, izbrana iz skupine, ki sestoji iz:
  14. 14. Postopek za sintezo spojine s formulo l-R ali l-S po zahtevku 1, ki obsega tetrahidronaftalenski del, ki ima kiralni ogljik v šestčlenskem nasičenem obroču tetrahidronaftalenskega dela, kjer je spojina enantiomerno obogatena glede na kiralni ogljik, pri čemer postopek obsega koraka (i) zagotavljanje spojine, ki obsega tetrahidronaftalenski del, kjer je obročni ogljik šestčlenskega nasičenega obroča tetrahidronaftalenskega dela, kjer je želena kiralna substitucija, okso-substituiran pri takem ogljiku; (ii) reagiranje takšne spojine s kiralnim reagentom, da nastane kiralni center pri ogljiku v tetrahidronaftalenskem delu, ki je bil predhodno vezan na skupino okso.
SI201031665T 2009-11-13 2010-11-15 Modulatorji receptorja sfingozin-1-fosfata in postopki za kiralno sintezo SI2498611T1 (sl)

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US26128209P 2009-11-13 2009-11-13
US26247409P 2009-11-18 2009-11-18
PCT/US2010/056757 WO2011060389A1 (en) 2009-11-13 2010-11-15 Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis
EP10830877.6A EP2498611B1 (en) 2009-11-13 2010-11-15 Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis

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