DK2948443T3 - Nye pyrimidinderivater som phosphodiesterase 10-inhibitorer (PDE-10) - Google Patents

Nye pyrimidinderivater som phosphodiesterase 10-inhibitorer (PDE-10) Download PDF

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DK2948443T3
DK2948443T3 DK14703553.9T DK14703553T DK2948443T3 DK 2948443 T3 DK2948443 T3 DK 2948443T3 DK 14703553 T DK14703553 T DK 14703553T DK 2948443 T3 DK2948443 T3 DK 2948443T3
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diamine
pyrimidine
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pyrazol
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Gómez Juan Camacho
Palomino Laria Julio Castro
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Palobiofarma Sl
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Claims (22)

1. Forbindelse med formlen (I):
hvor: - R1 er valgt fra gruppen bestående af hydrogen, halogen, cycloalkyl og alkyl med tre eller fire carbonatomer, ligekædet eller forgrenet; - Y er valgt fra gruppen bestående af C-R2 og et nitrogenatom; - R2 er valgt fra gruppen bestående af: (a) en aryl- eller heteroarylgruppe, som eventuelt er substitueret med ét eller flere halogenatomer eller med én eller flere cycloalkyl-, hydroxy-, (CrCe) alk-oxy-, (CrC8) alkylthio-, amino-, mono- eller dialkylamino-, alkoxyalkyl-, hydroxy-carbonyl- og alkoxycarbonylgrupper, (b) en alkoxycarbonylgruppe med formlen (-CO(R7), hvor R7 betegner en hy-droxylgruppe eller en [-N(R8)(R9)]-gruppe; R8 og R9 er uafhængigt valgt fra gruppen bestående af et hydrogenatom, cycloalkyl og alkyl med tre eller fire carbonatomer, ligekædet eller forgrenet og eventuelt substitueret med halogen eller en aryl- eller heterocyklisk gruppe; eller R8 og R9 sammen med det nitrogenatom, til hvilket de er bundet, danner en mættet fem- eller seksleddet ring, som eventuelt omfatter et yderligere heteroatom, der er valgt fra gruppen bestående af oxygen og nitrogen, som eventuelt er substitueret med en (CrCe) alkylgruppe; - R3 er valgt fra gruppen bestående af hydrogen, halogen, en cycloalkylgruppe og en (Ci-C8) alkylgruppe, ligekædet eller forgrenet, som eventuelt er substitueret med halogenatomer; eller R2 og R3 sammen med de carbonatomer, til hvilke de er bundet, danner en seksleddet aryl- eller heteroarylring, som eventuelt er substitueret med ét eller flere halogenatomer eller med én eller flere grupper, som er valgt blandt cyclo-alkyl, hydroxy, (CrC8) alkoxy, (CrC8) alkylthio, amino, mono- eller dialkylamino, alkoxyalkyl, hydroxycarbonyl og alkoxycarbonyl; - X er valgt fra gruppen bestående af et halogenatom og en cyanogruppe; - R4, R5 og R6 er uafhængigt valgt fra gruppen bestående af: (a) et hydrogenatom; (b) en alkyl-, cycloalkyl- eller cycloalkylalkylgruppe, som maksimalt har fem carbonatomer, ligekædet eller forgrenet, og som eventuelt er substitueret med ét eller flere halogenatomer, methoxygrupper eller en heteroarylgruppe, hvilken heteroarylgruppe eventuelt er substitueret med halogenatomer eller (CrC8) al-kylgrupper; (c) en allyl- eller propargylgruppe, som eventuelt er substitueret med ét eller flere halogenatomer eller med én eller flere grupper, som er valgt fra gruppen bestående af cycloalkyl, hydroxy, (CrC8) alkoxy, (CrC8) alkylthio, amino, monoeller dialkylamino, alkoxyalkyl, hydroxycarbonyl og alkoxycarbonyl; og (d) en tetrahydropyranylgruppe; eller R5 og R6 sammen med det nitrogenatom, til hvilket de er bundet, kan danne en pyrazol- eller triazolring, som eventuelt er substitueret med halogenatomer, og farmaceutisk acceptable salte deraf.
2. Forbindelse ifølge krav 1, hvor R4 betegner et hydrogenatom.
3. Forbindelse ifølge krav 2, hvor R1, R3 og R5 betegner et hydrogenatom, X betegner et bromatom, og Y betegner et nitrogenatom.
4. Forbindelse ifølge krav 3, hvor R6 er valgt fra gruppen bestående af alkyl, cycloalkyl-alkyl og alkylcycloalkyl, som eventuelt er substitueret med en methoxygruppe eller en heteroaryl, som på sin side eventuelt kan være substitueret med en (Ci-C8) alkylgrup-pe.
5. Forbindelse ifølge krav 4, hvor R6 er valgt fra gruppen bestående af ethyl, propyl og cyclopropyl methyl, som alle eventuelt er substitueret med en methoxygruppe eller en femleddet heteroarylgruppe, som på sin side eventuelt er substitueret med én eller flere methylgrupper.
6. Forbindelse ifølge krav 3, hvor R6 er valgt fra gruppen bestående af allyl, propargyl og tetrahydropyranyl, som alle eventuelt er substitueret med en alkylgruppe, ligekædet eller forgrenet, som maksimalt har tre carbonatomer.
7. Forbindelse ifølge krav 2, hvor R1, R3 og R5 betegner et hydrogenatom, X betegner et bromatom, Y betegner en C-R2-del, og R2 betegner en heteroarylgruppe, som eventuelt er substitueret med halogenatomer.
8. Forbindelse ifølge krav 7, hvor R2 er valgt blandt pyridin, quinolin, pyrimidin eller py-razin, som eventuelt er substitueret med halogenatomer.
9. Forbindelse ifølge krav 8, hvor R6 er valgt fra gruppen bestående af alkyl-, cyclo-alkylalkyl- og alkylcycloalkylgrupper, som alle eventuelt er substitueret med en methoxygruppe eller med en heteroarylgruppe, som på sin side eventuelt er substitueret med en (CrCs) alkylgruppe.
10. Forbindelse ifølge krav 8, hvor R6 er valgt fra gruppen bestående af ethyl, propyl, og cyclopropylmethyl, som eventuelt er substitueret med en methoxygruppe eller med en femleddet heteroarylgruppe, som eventuelt er substitueret med én eller flere methylgrupper.
11. Forbindelse ifølge krav 8, hvor R6 er valgt fra gruppen bestående af allyl-, prop-argyl- og tetrahydropyranylgrupper, som eventuelt er substitueret med halogenatomer.
12. Forbindelse ifølge krav 2, hvor R1 og R5 betegner et hydrogenatom, X betegner et bromatom, Y betegner et carbonatom, og R2 og R3 sammen med de carbonatomer, til hvilke de er bundet, danner en eventuelt substitueret aryl- eller heteroarylgruppe.
13. Forbindelse ifølge krav 12, hvor R2 og R3 sammen med de carbonatomer, til hvilke de er bundet, danner en phenyl- eller pyridinring, som eventuelt er substitueret med halogenatomer.
14. Forbindelse ifølge krav 13, hvor R6 er valgt fra gruppen bestående af alkyl, cyclo-alkylalkyl og alkylcycloalkyl, som eventuelt er substitueret med en methoxygruppe eller en heteroarylgruppe, som på sin side eventuelt er substitueret med en (Ci-C8) alkyl-gruppe.
15. Forbindelse ifølge krav 14, hvor R6 er valgt fra gruppen bestående af ethyl, propyl og cyclopropylmethyl, som eventuelt er substitueret med en methoxygruppe eller med en femleddet heteroarylgruppe, som eventuelt er substitueret med én eller flere methyl-grupper.
16. Forbindelse ifølge krav 13, hvor R6 er valgt fra gruppen bestående af eventuelt substitueret allyl, propargyl og tetrahydropyranyl.
17. Forbindelse ifølge krav 2, hvor R1 og R5 betegner et hydrogenatom, X betegner et bromatom, Y betegner en CR2-del, R2 og R3 sammen med de carbonatomer, til hvilke de er bundet, danner en phenyl- eller pyridinring, og R6 er valgt fra gruppen bestående af ethyl, propyl og cyclopropylmethyl, som eventuelt er substitueret med en thiazolring, som eventuelt er substitueret med én eller flere methylgrupper.
18. Forbindelse ifølge krav 2, hvor R1, R3 og R5 betegner et hydrogenatom, X betegner et bromatom, Y betegner et nitrogenatom, og R6 er valgt fra gruppen bestående af ethyl, propyl, propargyl og cyclopropylmethyl, som eventuelt er substitueret med en thiazolring, som på sin side eventuelt er substitueret med én eller flere methylgrupper.
19. Forbindelse ifølge krav 1, som er valgt fra gruppen bestående af: 5-brom-N4-(cyclopropylmethyl)-2-(1 H-indazol-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-ethyl-2-(1 H-indazol-1 -yl)pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1-yl)-N4-(prop-2-ynyl)pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1-yl)-6-(1H-pyrazol-1-yl)pyrimidin-4-amin; N4-[(1 H-benzo[d]imidazol-2-yl)methyl]-5-brom-2-(1 H-indazol-1 -yl)pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1-yl)-N4-[(2-methylthiazol-4-yl)methyl]pyrirnidin-4,6-diamin; 5-brom-N4-(tetrahydro-2H-pyran-4-yl)-2-(1 H-indazol-1-yl)pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1 -yl)-N4-[(1-methyl-1 H-pyrazol-4-yl)methyl]pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1-yl)-N4-[(thiazol-5-yl)methyl]pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1-yl)-N4-[(4-methylthiazol-5-yl)methyl]pyrimidin-4,6-diamin; 5-brom-2-(1 H-indazol-1-yl)-N4-(2-methoxyethyl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(1 H-pyrazol-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-(2-methoxyethyl)-2-(1 H-pyrazol-1-yl)pyrimidin-4,6-diamin; N4-[(1 H-benzo[d]imidazol-2-yl)methyl]-5-brom-2-(1 H-pyrazol-1 -yl)pyrimidin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-[4-(pyridin-4-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-2-(4-(pyridin-4-yl)-1 H-pyrazol-1-yl)-N4-[(thiazol-5-yl)methyl]pyrimidin- 4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-(cyclopropylmethyl)-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(4-(pyridin-2-yl)-1 H-pyrazol-1-yl)-pyrimidin-4,6-diamin; 5-brom-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]-N4-[(thiazol-5-yl)methyl]pyrimidin-4,6-diamin; 5-brom-N4-(2-methoxyethyl)-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-[4-(quinolin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-(tetrahydro-2H-pyran-4-yl)-2-[4-(quinolin-2-yl)-1 H-pyrazol-1-yl]-pyrimidin-4,6-diamin; 5-brom-N4-[(2-methylthiazol-4-yl)methyl]-2-[4-(quinolin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-[4-(quinolin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-ethyl-2-(4-phenyl-1 H-pyrazol-1-yl)pyrimidin-4,6-diamin; 5-brom-2-[4-(4-chlorphenyl)-1 H-pyrazol-1-yl]-N4-ethylpyrimidin-4,6-diamin; 5-brom-2-[4-(4-chlorphenyl)-1 H-pyrazol-1-yl]-N4-(prop-2-ynyl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-[4-(pyrazin-2-yl)-1 H-pyrazol-1-yl]-pyrimidin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-[4-(pyrazin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(1 H-pyrazolo[3,4-b]pyridin-1-yl)pyri-midin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-(1H-pyrazolo[3,4-c]pyndin-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(1 H-pyrazolo[3,4-c]pyridin-1-yl)pyri-midin-4,6-diamin; 5-brom-N4-(cyclopropylmethyl)-2-(1H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidin-4,6- diamin; 5-brom-2-(1 H-pyrazolo[3,4-c]pyridin-1-yl)-N4-[(thiazol-5-yl)methyl]pyrimidiri-4,6-diamin; 5-brom-N4-(2-methoxyethyl)-2-(1 H-pyrazolo[3,4-c]pyridin-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-(1 H-pyrazolo[4,3-c]pyridin-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(1 H-pyrazolo[4,3-c]pyridin-1-yl)-pyrimidin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-(1 H-pyrazolo[4,3-b]pyridin-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(1 H-pyrazolo[4,3-b]pyridin-1-yl)pyri-midin-4,6-diamin; 5-brom-N4-(prop-2-ynyl)-2-(1H-1,2,4-triazol-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-[(4-methylthiazol-5-yl)methyl]-2-(1 H-1,2,4-triazol-1 -yl)pyrimidin-4,6-diamin; 5-brom-N4-(2-methoxyethyl)-2-(1H-1,2,4-tnazol-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-[(thiazol-5-yl)methyl]-2-(1H-1,2,4-triazol-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-(cyclopropylmethyl)-2-(1 H-1,2,4-triazol-1 -yl)pyrimidin-4,6-diamin; 1-[4-amino-5-brom-6-(prop-2-ynylamino)pyrimidin-2-yl]-1 H-pyrazol-4-carboxylsyre; 1-[4-amino-5-brom-6-(ethylamino)pyrimidin-2-yl]-1H-pyrazol-4-carboxylsyre; 1-{4-[(4-methylthiazol-5-yl)methylamino]-6-amino-5-brompyrimidin-2-yl}-1 H-pyrazol-4-carboxylsyre; {1-[4-amino-5-brom-6-(ethylamino)pyrimidin-2-yl]-1 H-pyrazol-4-yl}(morpho-lino)methanon; 5-brom-6-(1 H-pyrazol-1 -yl)-2-[4-(pyridin-4-yl)-1 H-pyrazol-1-yl]pyrimidin-4-amin; 5-brom-6-(1 H-pyrazol-1 -yl)-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4-amin; 5-brom-2-[4-(pyrazin-2-yl)-1 H-pyrazol-1-yl)-6-(1 H-pyrazol-1-yl]pyrimidin-4-amin; 5-brom-6-(1 H-pyrazol-1-yl)-2-(1 H-1,2,4-triazol-1-yl)pyrimidin-4-amin; 1-[4-(2-methoxyethylamino)-6-amino-5-brompyrimidin-2-yl]-1 H-pyrazol-4-carboxylsyre; 1-[4-amino-5-brom-6-(cyclopropylmethylamino)pyrimidin-2-yl]-1 H-pyrazol-4-carboxylsyre; 1-[4-amino-5-brom-6-(isopropylamino)pyrimidin-2-yl]-1 H-pyrazol-4-carboxyl-syre; 5-brom-N4-ethyl-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-ethyl-2-[4-(pyrimidin-4-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-brom-N4-ethyl-2-[4-(quinolin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-chlor-N4-ethyl-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin-4,6-diamin; 5-chlor-N4-ethyl-2-(1 H-indazol-1 -yl)pyrimidin-4,6-diamin; 5-chlor-N4-ethyl-2-(5-fluor-1H-indazol-1-yl)pyrimidin-4,6-diamin; 5-brom-N4-ethyl-2-(1 H-indazol-1-yl)-N6-(prop-2-ynyl)pyrimidin-4,6-diamin; 5-brom-N4-(cyclopropylmethyl)-2-(1 H-indazol-1-yl)-N6-(prop-2-ynyl)pyrimidin- 4.6- diamin; 5-brom-N4-(tetrahydro-2H-pyran-4-yl)-2-(1 H-indazol-1-yl)-N6-(prop-2-ynyl)-pyrimidin-4,6-diamin; N4-[(1 H-benzo[d]imidazol-2-yl)methyl]-5-brom-2-(1 H-indazol-1 -yl)-N6-(prop-2-ynyl)pyrimidin-4,6-diamin; 5-brom-N4-ethyl-N6-(prop-2-ynyl)-2-[4-(pyridin-2-yl)-1 H-pyrazol-1-yl]pyrimidin- 4.6- diamin; 5-brom-N4-(cyclopropylmethyl)-N6-(prop-2-ynyl)-2-[4-(pyridin-2-yl)-1H-pyrazol-1- yl]pyrimidin-4,6-diamin; 5-brom-N4-(tetrahydro-2H-pyran-4-yl)-N6-(prop-2-ynyl)-2-[4-(pyridin-2-yl)-1H- pyrazol-1-yl]pyrimidin-4,6-diamin; N4-[(1 H-benzo[d]imidazol-2-yl)methyl]-5-brom-N6-(prop-2-ynyl)-2-[4-(pyridin-2-yl)-1 H-pyrazol-1 -yl]pyrimidin-4,6-diamin; 5-brom-N4-ethyl-N6-(prop-2-ynyl)-2-[4-(pyrimidin-4-yl)-1 H-pyrazol-1-yl]pyrimidin- 4.6- diamin; 5-brom-N4-(cyclopropylmethyl)-N6-ethyl-2-[4-(pyrimidin-4-yl)-1 H-pyrazol-1-yl]-pyrimidin-4,6-diamin; 5-brom-N4-ethyl-N6-(tetrahydro-2H-pyran-4-yl)-2-[4-(pyrimidin-4-yl)-1H-pyrazol-1-yl]pyrimidin-4,6-diamin; og N4-[(1H-benzo[d]imidazol-2-yl)methyl]-5-brom-N6-ethyl-2-[4-(pyrimidin-4-yl)-1H- pyrazol-1-yl]pyrimidin-4,6-diamin.
20. Farmaceutisk præparat, som omfatter en forbindelse som defineret i et hvilket som helst af kravene 1 til 19 sammen med en farmaceutisk acceptabel excipiens.
21. Forbindelse ifølge et hvilket som helst af kravene 1 til 19 til anvendelse til behandling af en sygdom eller patologisk tilstand, som kan forbedres ved inhibering af Phosphodiesterase 10, hvor den sygdom eller patologiske tilstand, som kan forbedres ved inhibering af Phosphodiesterase 10, er valgt fra gruppen bestående af sygdomme og patologiske tilstande i centralnervesystemet såsom skizofreni, Huntingtons sygdom, Parkinsons sygdom, Alzheimers sygdom og depression samt respiratoriske lidelser såsom pulmonal hypertension, astma og KOL.
22. Kombinationsprodukt, som omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 19 og i det mindste et andet lægemiddel, hvilket lægemiddel er valgt blandt lægemidler, som er nyttige til behandling af sygdomme i centralnervesystemet såsom skizofreni, Parkinsons sygdom, Huntingtons sygdom, Alzheimers sygdom og depression samt respiratoriske lidelser såsom pulmonal hypertension, astma og KOL.
DK14703553.9T 2013-01-24 2014-01-23 Nye pyrimidinderivater som phosphodiesterase 10-inhibitorer (PDE-10) DK2948443T3 (da)

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