DK2785706T3 - Substituerede 4-phenyl-pyridiner til behandling af nk-1-receptor-relaterede sygdomme - Google Patents

Substituerede 4-phenyl-pyridiner til behandling af nk-1-receptor-relaterede sygdomme Download PDF

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DK2785706T3
DK2785706T3 DK12798549.7T DK12798549T DK2785706T3 DK 2785706 T3 DK2785706 T3 DK 2785706T3 DK 12798549 T DK12798549 T DK 12798549T DK 2785706 T3 DK2785706 T3 DK 2785706T3
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compound
formula
group
substituents
nr101r102
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Luca Fadini
Peter Manini
Claudio Pietra
Claudio Giuliano
Emanuela Lovati
Roberta Cannella
Alessio Venturini
Valentino J Stella
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Helsinn Healthcare Sa
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Claims (19)

1. Forbindelse valgt fra gruppen bestående af:
eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifølge krav 1 til anvendelse i en fremgangsmåde til behandling af emesis, blæredysfunktion, depression eller angst hos en patient med behov derfor.
3. Forbindelse til anvendelse ifølge krav 2, hvor nævnte emesis omfatter kemoterapiinduceret kvalme og opkastning (CINV), strålebehandlingsinduceret kvalme og opkastning (RINV) eller postoperativ kvalme og opkastning (PONV).
4. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-3, hvor nævnte emesis er induceret af moderat eller svært emetogen kemoterapi.
5. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-4, hvor emesis er akut og forsinket emesis induceret af moderat eller svært emetogen kemoterapi.
6. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-5, hvor nævnte blæredysfunktion er valgt blandt urgency, frekvens, pollakiuri, nykturi, lav udsættelsestid, suboptimal volumentærskel og neurogen blære eller en kombination deraf.
7. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-6, hvor nævnte forbindelse eller et farmaceutisk acceptabelt salt eller addukt deraf administreres ad en eller flere veje valgt fra gruppen bestående af rektal, bukkal, sublingual, intravenøs, subkutan, intradermal, transdermal, intraperitoneal, oral, øjendråbe-, parenteral og topisk administration.
8. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-7, hvor nævnte forbindelse eller et farmaceutisk acceptabelt salt eller addukt deraf administreres intravenøst i en dosis på fra 10 mg til 200 mg.
9. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-8, hvor nævnte emesis er akut og forsinket emesis induceret af moderat eller svært emetogen kemoterapi, hvilken fremgangsmåde yderligere omfatter administration af en 5-HT3- antagonist og kortikosteroid.
10. Forbindelse til anvendelse ifølge krav 9, hvor nævnte 5-Fnyantagonist er ondansetron, palonosetron, granisetron eller tropisetron eller et farmaceutisk acceptabelt salt deraf.
11. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-10, som yderligere omfatter administration af 2-(3,5-bis(trifluormethyl)phenyl)-N,2-dimethyl-N-(6-(4-methylpiperazin-l-yl)-4-(o-tolyl)pyridin-3-yl)-propanamid (netupitant).
12. Forbindelse til anvendelse ifølge et hvilket som helst af kravene 2-11, hvor individet er et menneske.
13. Farmaceutisk præparat, der omfatter en terapeutisk effektiv mængde af en forbindelse ifølge krav 1 og en eller flere farmaceutisk acceptable hjælpestoffer.
14. Forbindelse ifølge krav 1 som et chloridhydrochloridsalt med følgende kemiske formel:
15. Proces til fremstilling af en forbindelse ifølge formel (I):
Formel (I) hvor: R er valgt fra gruppen bestående af hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR101, -NR101R102, -NR101C(O)R102, -C(0)R101, -C(0)OR101, -C(O)NR101R102, -alkylNR101R102, -S(0)2R102, -SR101, -S(O)2NR101R102, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl og heteroarylalkyl, hver især eventuelt 103 uafhængigt af hinanden substitueret med en eller flere uafhængige R -substituenter; Ri og R2 uafhængigt af hinanden er valgt fra gruppen bestående af hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR101, -NR101R102, -NR101C(O)R102, -C(0)R101, -C(0)OR101, -C(O)NR101R102, -alkylNR101R102, -S(0)2R102, -SR101, -S(O)2NR101R102, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl og heteroarylalkyl, hver især eventuelt uafhængigt af hinanden substitueret med 103 en eller flere uafhængige R -substituenter; eller Ri sammen med atomerne og/eller anden/andre substituent(er) på samme phenylring danner en fusioneret eller ikke-fusioneret mono-, bicyklisk eller tricyklisk heterocyklisk eller carbocyklisk ring, som eventuelt er uafhængigt substitueret med en eller 103 flere R -substituenter; eller R2 sammen med atomerne og/eller anden/andre substituent(er) på samme phenylring danner en fusioneret eller ikke-fusioneret mono-, bicyklisk eller tricyklisk heterocyklisk eller carbocyklisk ring, som eventuelt er uafhængigt substitueret med en eller flere R103-substituenter; R3 og R4 uafhængigt af hinanden er valgt fra gruppen bestående af hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR101, -NR101R102, -NR101C(O)R102, -C(0)R101, -C(0)OR101, -C(O)NR101R102, -alkylNR101R102, -S(0)2R102, -SR101, -S(O)2NR101R102, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl og heteroarylalkyl, hver især eventuelt uafhængigt af hinanden substitueret med 103 en eller flere uafhængige R -substituenter; eller R3 og R4, sammen med de atomer, som forbinder samme, danner en fusioneret eller ikke-fusioneret mono-, bicyklisk eller tricyklisk heterocyklisk eller carbocyklisk ring, som eventuelt er uafhængigt substitueret med en eller flere R -substituenter; R5 og R6 uafhængigt af hinanden er valgt fra gruppen bestående af hydrogen, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxyalkyl, -OR101, -NR101R102, -NR101C(O)R102, -C(0)R101, -C(0)OR101, -C(O)NR101R102, -alkylNR101R102, -S(0)2R102, -SR101, -S(O)2NR101R102, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl og heteroarylalkyl, hver især eventuelt uafhængigt af hinanden substitueret med 103 en eller flere uafhængige R -substituenter; X er valgt fra gruppen bestående af -C(O)NR101R102, -alkylO, -alkylNR101R102, -NR101C(O) og -NR101alkyl, hver især eventuelt uafhængigt af hinanden substitueret med en eller flere uafhængige R -substituenter; Y er valgt fra gruppen bestående af -NR101R102, -NR101alkylOH, -NR101S(O)2alkyl, -NR101S(O)2phenyl, -N=CH-NR101R102, heterocycloalkyl og heterocycloalkylalkyl, hver især eventuelt uafhængigt af hinanden 103 substitueret med en eller flere uafhængige R -substituenter; Z er en strukturformel, der er valgt fra gruppen bestående af
hvor formel (la) henviser til et oxid, Ri00, R100 , R101, R102 og R103 er hver især valgt uafhængigt af hinanden fra gruppen bestående af hydrogen, cyano, NO2, -OR104, oxid, hydroxy, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, -C(0)R104, -C(0)OR104, -C(O)NR104R105, -NR104R105, -NR104S(O)2R105, -NR104C(O)R105, -S(0)2R104, SR104 og -S(O)2NR104R105, hver især eventuelt uafhængigt af hinanden substitueret med en eller flere uafhængige R -substituenter; eller R101, R102, sammen med de atomer, som forbinder samme, danner en fusioneret eller ikke-fusioneret mono-, bicyklisk eller tricyklisk heterocyklisk eller carbocyklisk ring, som eventuelt er uafhængigt substitueret med en eller flere R103-substituenter; eller R100, R100 , sammen med de atomer, som forbinder samme, danner en fusioneret eller ikke-fusioneret mono-, bicyklisk eller tricyklisk heterocyklisk eller carbocyklisk 103 ring, som eventuelt er uafhængigt substitueret med en eller flere R -substituenter; R104 og R105 hver især er valgt uafhængigt af hinanden fra gruppen bestående af hydrogen, cyano, -N02, hydroxy, oxid, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl, halogen, alkoxy, alkoxyalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl og heteroarylalkyl; m er 0, 1, 2, 3 eller 4; n er Ο, 1, 2, 3, 4 eller 5; ρ er Ο eller 1; og med det forbehold, at hvis et ikke-pyridin-N-oxid (N~—>0+) er til stede på forbindelsen ifølge formel (I), er det samlede antal N-oxid på forbindelsen ifølge formel (I) mere end én, hvilken proces omfatter: a) tilvejebringelse af en forbindelse ifølge formel (I), hvor Y er en 4-N-methylpiperazingruppe, og Z ikke er til stede, b) tilvejebringelse af et dialkyl(halogenmethyl)phosphat, c) omsætning af et N-atom af piperazingruppen med dialkyl(halogenmethyl)phosphatet for at opnå en kvatemær ammoniummethylenphosphatforbindelse, hvor nævnte proces udføres for at opnå forbindelsen GA1 ifølge krav 1.
16. Proces ifølge krav 15, hvor reaktionen udføres i nærværelse af et iodidsalt og i fravær af en proton-scavenger.
17. Proces ifølge et hvilket som helst af kravene 15-16, hvor reaktionen udføres i det væsentlige i fravær af luft og dioxygen.
18. Proces ifølge et hvilket som helst af kravene 15-17, hvor den kvatemære ammoniummethylenphosphatforbindelse opnås med en (phosphooxy)methylgruppe i dealkyleret form uden forsuring af reaktionen eller produktet.
19. Proces til fremstilling af en forbindelse ifølge formel (V):
Formel (V) hvor p uafhængigt er 0 eller 1, R7 er valgt fra den gruppe, der er valgt blandt hydrogen, alkoxy, alkoxyalkyl, -OR101, hydroxy, hydroxyalkyl, amino, alkyl, alkenyl, cycloalkyl og halogen, hver især eventuelt uafhængigt af hinanden substitueret med en eller flere 103 uafhængige R -substituenter; s er 0, 1, 2, 3 eller 4, og alle andre radikaler er defineret ifølge formel (I) i krav 15, hvilken proces omfatter: etablering af kontakt mellem en forbindelse ifølge formel (V), hvor p er 0 for piperazinylringens methylerede 4-N-atom, og en forbindelse ifølge formel (VII) i nærværelse af et iodidsalt, i et tidsrum, der er tilstrækkeligt til funktionalisering af det methylerede 4-N-atom på forbindelsen ifølge formel (V) med forbindelsen ifølge formel (VII) og til dealkylering af forbindelsen ifølge formel (VII):
Formel (VII) hvor nævnte proces udføres for at opnå forbindelsen GA1 ifølge krav 1.
DK12798549.7T 2011-11-29 2012-11-28 Substituerede 4-phenyl-pyridiner til behandling af nk-1-receptor-relaterede sygdomme DK2785706T3 (da)

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