DK3102573T3 - Substitueret thiazol eller oxazol P2X7-receptorantagonister - Google Patents

Substitueret thiazol eller oxazol P2X7-receptorantagonister Download PDF

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DK3102573T3
DK3102573T3 DK15705523.7T DK15705523T DK3102573T3 DK 3102573 T3 DK3102573 T3 DK 3102573T3 DK 15705523 T DK15705523 T DK 15705523T DK 3102573 T3 DK3102573 T3 DK 3102573T3
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formula
compound
mmol
yield
hydrogen
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DK15705523.7T
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Paolo Pevarello
Stefan Lohmer
Chiara Liberati
Pierfausto Seneci
Cristina Pesenti
Adolfo Prandi
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Axxam Spa
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Claims (12)

1. Forbindelse med den folgende formel (I) eller et farmaceutisk acceptabelt salt deraf:
(i) herunder en hvilken som helst stereokemisk isomerform deraf, hvor n er 1 eller 2; Y repraesenterer oxygen eller svovl; hvert af R1 og R2 uafhaengigt er valgt fra gruppen bestaende af hydrogen, deuterium, halogen, C1-C4-alkyl, eventuelt substitueret med hydroxy eller halogen, sasom hydroxymethyl, fluormethyl, difluormethyl, trifluormethyl, C3-C6-cycloalkyl, eventuelt substitueret med hydroxy eller halogen eller C1-C4-al-kyloxy; hvert af R3 og R4 uafhaengigt er valgt fra gruppen bestaende af hydrogen, halogen, C1-C4-alkyl, difluormethyl, trifluormethyl, C1-C4-alkyloxy, NR9R10, hvor R9 og R10 uafhaengigt er hydrogen eller C1-C4-alkyl eller 2-thi-azolidin-1,1-dion; eller de to R3-grupper eller R3- og R4-grupperne sammen danner en seksleddet heterocyklisk ring indeholdende et nitrogenatom; R5 er valgt blandt hydrogen, halogen eller er en heterocyklisk ring, der er valgt blandt pyrimidin-2-yl, pyridin-2-yl eller pyrazin-2-yl, eventuelt substitueret med halogen, C1-C4-alkyl, fluormethyl, difluormethyl, trifluormethyl eller C1-C4-al-kyloxy; R7 er hydrogen eller C1-C4-alkyl; rad i kal et
repraesenterer en eventuelt substitueret azetidin-, pyrrolidin-, piperidin-, morp-holin-, oxazepan- eller 1,2,3,4-tetrahydroisoquinolinring, hvor hvert af R6 uafhaengigt er valgt fra gruppen bestaende af hydrogen, halogen, C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-spirocycloalkyl, difluormethyl, trifluormethyl, C1-C4-alkyloxy, aryl, heteroaryl, C1-C4-aryloxy eller C1-C4-arylalkoxy, hvor arylgrup-pen eller heteroarylgruppen eventuelt er substitueret med halogen, C1-C4-al-kyl, fluormethyl, difluormethyl, trifluormethyl eller C1-C4-alkyloxy.
2. Forbindelse med formlen (I) ifolge krav 1, hvor R7 er hydrogen, og n er 1.
3. Forbindelse med formlen (I) ifolge krav 1 eller 2, hvor bade R1 og R2 er hydrogen eller den ene er hydrogen og den anden er methyl, ethyl, propyl, tert-butyl, eventuelt substitueret med hydroxy eller fluorin, C3-C6-cycloalkyl, eventuelt substitueret med hydroxy eller fluorin.
4. Forbindelse med formlen (I) ifolge et hvilket som helst af de foregaende krav, hvor R5 er hydrogen og hvert af R3 og R4 uafhaengigt er hydrogen, halogen, C1-C4-alkyl, C1-C4-alkyloxy, NR9R10, hvor R9 og R10 uafhaengigt er hydrogen eller C1-C4-alkyl eller 2-thiazolidin-1,1-dion; eller de to R3-grupper eller R3- og R4-grupperne sammen danner en seksleddet heterocyklisk ring inde-holdende et nitrogenatom.
5. Forbindelse med formlen (I) ifolge krav 1-4, hvor R4 er hydrogen, R3 i me-taposition er hydrogen, og R3 i orthoposition er valgt fra gruppen bestaende af halogen eller C1-C4-alkyl, og R5 er en heterocyklisk ring, der er valgt blandt pyrimidin-2-yl, pyridin-2-yl eller pyrazin-2-yl, eventuelt substitueret med halogen.
6. Forbindelse med formlen (I) ifolge et hvilket som helst af de foregaende krav, hvor ring A er valgt fra gruppen bestaende af
hvor R6 er hydrogen, halogen, benzyloxy eller phenoxy, phenyl, pyrazol, C3-C6-cycloalkyl, eventuelt substitueret med halogen, fortrinsvis substitueret med fluor.
7. Forbindelse med formlen (I) if0lge krav 1, der er valgt fra gruppen bestaende af:
8. Fremgangsmade til fremstilling af en forbindelse med formlen (I) som defi-neret i krav 1, omfattende trinnet med at omsaette en forbindelse med formlen (II):
(II) hvor betydningen af η, Y, A og R1, R2 og R6 er som defineret i krav 1, med en forbindelse med formlen (III)
(lil) hvor betydningen af R3, R4 og R5 er som defineret i krav 1; eller med en forbindelse med formlen (lila):
hvor betydningen af R3, R4 og R5 er som defineret i krav 1, og W er en egnet fraspaltelig enhed og eventuelt at omdanne den opnaede forbindelse med formlen (I) til et additionssalt deraf og/eller fremstilling af stereokemiske iso-merformer deraf.
9. Farmaceutisk sammensaetning omfattende en forbindelse med formlen (I) ifolge krav 1-7 og et farmaceutisk acceptabelt fortyndingsmiddel og/eller bae-rer.
10. Forbindelse med formlen (I) ifolge krav 1-7 til anvendelse som et medika-ment.
11. Forbindelse med formlen (I) ifolge krav 1-7 til anvendelse ved behandling af tilstande eller sygdomme, der er valgt blandt P2X7-receptormedierede til-stande eller sygdomme.
12. Forbindelse med formlen (I) ifolge krav 1-7 til anvendelse ved forebyggelse og/eller behandling af neurodegenerative, kognitive, psykiatriske lidelser, neu-ropatisk smerte, kronisk smerte, FllV-induceret neuroinflammation og CNS-be-skadigelse, epilepsi, inflammatoriske processer i det muskuloskeletale system, leverfibrose, mave-tarmsygdomme, sygdomme i urogenitalkanalen, oftalmiske sygdomme, kronisk obstruktiv lungesygdom (COPD), cancer og proliferative sygdomme.
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EP3290416A1 (en) * 2016-08-31 2018-03-07 AXXAM S.p.A. Substituted n-[2-(4-phenoxypiperidin-1-yl)-2-(1,3-thiazol-5-yl)ethyl]benzamide and n-[2-(4-benzyloxypiperidin-1-yl)-2-(1,3-thiazol-5-yl)ethyl]benzamide derivatives and their use as p2x7 receptor antagonist
EP3290417A1 (en) 2016-08-31 2018-03-07 AXXAM S.p.A. 2-chloro-n-[2-(1,3-thiazol-5-yl)ethyl]-5-(5-fluoropyrimidin-2-yl)-benzamides and their use as p2x7 receptor antagonists
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