DK2265589T3 - Arylsulfonylpyrazolincarboxamidinderivater som 5-ht6-antagonister - Google Patents

Arylsulfonylpyrazolincarboxamidinderivater som 5-ht6-antagonister Download PDF

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DK2265589T3
DK2265589T3 DK09721279.9T DK09721279T DK2265589T3 DK 2265589 T3 DK2265589 T3 DK 2265589T3 DK 09721279 T DK09721279 T DK 09721279T DK 2265589 T3 DK2265589 T3 DK 2265589T3
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compound
mixture
alkyl
optionally substituted
formula
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Loevezijn Arnold Van
Bakker Wouter I Iwema
Axel Stoit
Agatha A M Rensink
Jennifer Venhorst
Der Neut Martina A W Van
Haan Martin De
Cornelis G Kruse
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Abbvie Bahamas Ltd
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Claims (17)

1. Forbindelse med formlen (1):
eller tautomer, stereoisomer, N-oxid eller farmakologisk acceptabelt salt ifølge et hvilket som helst af de foregående, hvori: Ri er udvalgt fra hydrogen eller en alkyl(Ci_4)-gruppe, eventuelt substitueret med et eller flere halogenatomer eller en hydroxylgruppe, R2 og R3 uafhængigt er udvalgt fra hydrogen, en hydroxylgruppe eller en alkyl(Ci_4)-gruppe eventuelt substitueret med en eller flere substituenter Q, uafhængigt udvalgt fra: halogen, alkyl(Ci-4), alkenyl(Ci_4), alkynyl(Ci-4), CF3, NFb, NHalkyl(C'M), N[alkyl(Ci-4)]2, OH, =0, 0-alkyl(Ci-4) eller OCF3 eller Ri og R2, sammen med carbonatomeme mærket ”a” og ”b” danner en Cs-s-cycloalkylring, eventuelt substitueret med et eller flere halogenatomer, en hydroxylgruppe eller en alkyl(Ci_4)-gruppe eller R2 og R3, sammen med carbonatomet mærket ”b” danner en C3_8-cycloalkyl- eller en C4-8-heterocycloalkylring, eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, R4 og R5 uafhængigt er udvalgt fra hydrogen eller en alkyl(Ci_4)-gruppe eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, eller, R4 og R5 uafhængigt er udvalgt fra en monocyklisk eller kondenseret bicyklisk aromatisk eller heteroaromatisk gruppe, eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, forudsat at Q ikke kan være =0 (keto) på aromatiske ringe, eller R3 og R4, sammen med carbonatomeme mærket ”b” og ”c” danner en C3-8-cycloalkyl- eller en C5-8-heterocycloalkylring, eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, R6 og R7 uafhængigt er udvalgt fra hydrogen, eller en alkyl(Ci-4)-gruppe eventuelt substitueret med et eller flere halogenatomer eller en hydroxylgruppe, eller en dialkyl(Ci-3)-amino-alkyl(Ci-3)-gruppe, eller Ri og R7 uafhængigt er udvalgt fra en monocyklisk eller kondenseret bicyklisk aromatisk eller hetero-aromatisk gruppe eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, eller Ri og R7 uafhængigt er en Cs-s-cycloalkylgruppe eller en Cs-s-heterocycloalkylgruppe eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, eller, R6 og R7, sammen med det nitrogenatom, hvortil de er bundet, danner en Cs-s-heterocycloalkylgruppe eventuelt substitueret med en eller flere substituenter Q, som defineret ovenfor, R§ er 4-aminophenyl, Forudsat, når Ri, R3, R4, Rs og R6 er hydrogen, og R2 og R7 er ethyl, at forbindelsen ikke er en racemisk blanding men en ren enantiomer.
2. Forbindelse ifølge krav 1 med formlen (1), eller tautomer, stereoisomer, N-oxid eller farmakologisk acceptabelt salt ifølge et hvilket som helst af de foregående, hvori: Ri, R4 og R6 er hydrogen R2 og R3 uafhængigt er udvalgt fra hydrogen, en hydroxylgruppe eller en alkyl(Ci-4)-gruppe, eventuelt substitueret med en eller flere substituenter Q*, uafhængigt udvalgt fra: halogen, alkylfC m), NFF, NHalkyl(Ci-4), N[alkyl(Ci-4)]2 eller OH, eller R2 og R3, sammen med det carbonatom, hvortil de er bundet, danner en C3-8-cycloalkyl eller en C5-8-heterocycloalkylring eventuelt substitueret med en eller flere substituenter Q* som defineret ovenfor, Rs er udvalgt fra hydrogen eller en alkyl(Ci-4)-gruppe, eventuelt substitueret med en eller flere substituenter Q* som defineret ovenfor, eller en monocyklisk aromatisk eller heteroaromatisk gruppe eventuelt substitueret med en eller flere substituenter Q* som defineret ovenfor, R7 er udvalgt fra hydrogen, eller en usubstitueret alkyl(Ci_4)-gruppe, eventuelt substitueret med et eller flere halogenatomer eller en hydroxylgruppe, Rs er 4-aminophenyl, Forudsat, når R3 og R5 er hydrogen, og R2 og R7 er ethyl, at forbindelsen ikke er en racemisk blanding men en ren enantiomer.
3. Forbindelse ifølge krav 1 eller krav 2, eller tautomer, stereoisomer, N-oxid eller farmakologisk acceptabelt salt ifølge et hvilket som helst af de foregående, hvor forbindelsen er en optisk aktiv enantiomer.
4. Forbindelse ifølge et hvilket som helst af kravene 1-3 udvalgt fra:
forbindelse 1, (+)-enantiomer, forbindelse 2, (-)-enantiomer, forbindelse 5, forbindelse 8, forbindelse 9, forbindelse 10, eller et farmaceutisk acceptabelt salt ifølge et hvilket som helst af de foregående forbindelser.
5. Forbindelse ifølge et hvilket som helst af kravene 1-3 med formlen
6. Forbindelse ifølge et hvilket som helst af kravene 1-3 med formlen
7. Forbindelse ifølge et hvilket som helst af kravene 1-3 med formlen
8. Forbindelse ifølge et hvilket som helst af kravene 1-3 med formlen
9. Forbindelse ifølge et hvilket som helst af kravene 1-3 med formlen
10. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1-9 eller et farmakologisk acceptabelt salt deraf, og en farmaceutisk acceptabel bærer.
11. Medikament, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 -9, eller et farmakologisk acceptabelt salt deraf.
12. Medikament ifølge krav 11, der endvidere omfatter: mindst ét yderligere terapeutisk middel.
13. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1-9 til fremstilling af en farmaceutisk sammensætning til behandling eller profylakse af Parkinsons sygdom, Huntingtons chorea, skizofreni, angst, depression, manisk depression, psykoser, epilepsi, obsessive-kompulsive tilstande, stemningsforstyrrelser, migræne, Alzheimers sygdom, aldersrelateret kognitiv tilbagegang, mild kognitiv svækkelse, søvnforstyrrelser, spiseforstyrrelser, anoreksi, bulimi, overspisning, panikanfald, akatisi, ADHD, ADD, afvænning fra misbrug af kokain, ethanol, nikotin eller benzodiazepiner, smerte, forstyrrelser forbundet med rygradstraumer eller hovedlæsion, hydrocefali, funktionel tarmsygdom, irritable tarmsyndrom, fedme eller type-2 diabetes.
14. Forbindelser med den almene formel (lx):
hvori A enten repræsenterer halogen eller S-alkyl(Ci_4), og de andre symboler har betydninger som anført i krav 1, og tautomer og stereoisomerer deraf, hvor sådanne forbindelser er anvendelige i syntesen af forbindelser med den almene formel (1).
15. Fremgangsmåde til fremstilling af forbindelser ifølge krav 1 med formlen (1), hvori R7 er hydrogen, der dermed har formlen (Γ), hvori alle symboler har betydningen som anført i krav 1, hvilken fremgangsmåde omfatter følgende trin: (i) etablering af kontakt mellem en forbindelse med formlen (X), opnået ved etablering af en reaktion mellem en forbindelse med formlen (IX) og et alkylhalogenid, eksempelvis methyliodid, med et pyrazolin i nærvær af en base for at give en forbindelse med formlen (n (ii) etablering af kontakt mellem en forbindelse med formlen (P) og et sulfonylhalogenid med formlen Rs-SCp-X, hvori X er Br, Cl eller F, i et aprotisk opløsningsmiddel, såsom dichlormethan, i nærvær af en base, såsom diisopropylethyl-amin,
16. Forbindelse ifølge et hvilket som helst af kravene 1-9 til anvendelse som et medikament.
17. Forbindelse ifølge et hvilket som helst af kravene 1-9 til anvendelse i en fremgangsmåde til behandling eller profylakse af Parkinsons sygdom, Huntingtons chorea, skizofreni, angst, depression, manisk depression, psykoser, epilepsi, obsessive-kompulsive tilstande, humørforstyrrelser, migræne, Alzheimers sygdom, aldersrelateret kognitiv tilbagegang, mild kognitiv svækkelse, søvnforstyrrelser, spiseforstyrrelser, anoreksi, bulimi, overspisning, panikanfald, akatisi, ADHD, ADD, afvænning fra misbrug af kokain, ethanol, nikotin eller benzodiazepiner, smerte, forstyrrelser forbundet med rygradstraumer eller hovedlæsion, hydrocefali, funktionel tarmsygdom, irritabel tarmsyndrom, fedme eller type-2 diabetes.
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