HRP20201158T1 - Derivati indolin-2-ona - Google Patents

Derivati indolin-2-ona Download PDF

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HRP20201158T1
HRP20201158T1 HRP20201158TT HRP20201158T HRP20201158T1 HR P20201158 T1 HRP20201158 T1 HR P20201158T1 HR P20201158T T HRP20201158T T HR P20201158TT HR P20201158 T HRP20201158 T HR P20201158T HR P20201158 T1 HRP20201158 T1 HR P20201158T1
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dimethyl
methylpyrimidin
oxoindolin
compound
formula
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HRP20201158TT
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Delphine Gaufreteau
Sabine Kolczewski
Jean-Marc Plancher
Theodor Stoll
Remy HALM
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F. Hoffmann - La Roche Ag
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Claims (28)

1. Spoj, naznačen time, da je predstavljen formulom [image] u kojoj A je fenil ili petero- ili šesteročlana heteroarilna skupina, koja sadrži jedan ili dva N atoma, odabrana od [image] ili amidne skupine −C(O)-NR1R2 koja može zajedno s dva susjedna ugljikova atoma iz skupine A, tvoriti dodatno staljeni prsten, odabran od [image] R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1−C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
2. Spoj formule IA prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstutuiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1−C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
3. Spoj formule IA prema patentnom zahtjevu 2, naznačen time, da je to spoj kako slijedi: 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilpirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilpirazin-2-karboksamid 1-(6-(azetidin-1-karbonil)pirazin-2-il)-3,3-dimetil-6-(2-metilpirimidin-5-il)indolin-2-on 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metil-N-(2,2,2-trifluoroetil)pirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-(2-metoksietil)-N-metilpirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-(2-hidroksietil)pirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-(2-metoksietil)pirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-2,2,2-trifluoroetil) pirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-izopropilpirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pirazin-2-karboksamid 5-[3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindol-1-il]-dimetilpirazin-2-karboksamid N-(terc-butil)-5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilpirazin-2-karboksamid 1-(5-(azetidin-1-karbonil)pirazin-2-il)-3,3-dimetil-6-(2-metilpirimidin-5-il)indolin-2-on 5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-(2-metoksietil)-N-metilpirazin-2-karboksamid 5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pirazin-2-karboksamid N-ciklopropil-6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pirazin-2-karboksamid N-(3,3-difluorociklobutil)-6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pirazin-2-karboksamid N-ciklobutil-6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pirazin-2-karboksamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-(oksetan-3-il)pirazin-2-karboksamid ili N-(terc-butil)-6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pirazin-2-karboksamid.
4. Spoj formule IB prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1-C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
5. Spoj formule IB prema patentnom zahtjevu 4, naznačen time, da je to spoj kako slijedi: 2-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilpirimidin-4-karboksamid 2-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilpirimidin-4-karboksamid ili 2-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,5-dimetil-pirimidin-4-karboksamid.
6. Spoj formule IC prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1−C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
7. Spoj formule IC prema patentnom zahtjevu 6, naznačen time, da je to spoj kako slijedi: 4-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilpirimidin-2-karboksamid ili 4-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilpirimidin-2-karboksamid.
8. Spoj formule ID prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1-C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
9. Spoj ID formule prema patentnom zahtjevu 8, naznačen time, da je to spoj 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilpiridazin-3-karboksamida.
10. Spoj formule IE prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1-C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
11. Spoj formule IE prema patentnom zahtjevu 10, naznačen time, da je to spoj kako slijedi: 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilpikolinamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilpikolinamid N-ciklopropil-6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pikolinamid N-(ciklopropilmetil)-6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pikolinamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)pikolinamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,3-dimetilpikolinamid 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N,3-trimetilpikolinamid ili 6-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilnikotinamid.
12. Spoj formule IF prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1-C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
13. Spoj formule IF prema patentnom zahtjevu 12, naznačen time, da je to spoj kako slijedi: 5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N-dimetilnikotinamid-1-(5-(azetidin-1-karbonil)piridin-3-il)-3,3-dimetil-6-(2-metilpirimidin-5-il)indolin-2-on 5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-(2,2,2-trifluoroetil)nikotinamid 5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilnikotinamid ili 5-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,2-dimetilnikotinamid.
14. Spoj formule IG prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1−C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
15. Spoj formule IG prema patentnom zahtjevu 1, naznačen time, da je to spoj kako slijedi: 4-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,6-dimetilpikolinamid ili 4-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N-metilpikolinamid.
16. Spoj formule IH prema patentnom zahtjevu 1, [image] naznačen time, da R1/R2 su neovisno jedan od drugoga vodik, C1-C7 alkil, C1-C7 alkil supstituiran s halogenom, C1-C7 alkil supstituiran s hidroksi, -(CH2)2-C1-C7 alkoksi, oksetanil, cikloalkil, CH2-cikloalkil, gdje su cikloalkilni prsteni opcijski supstituirani s halogenom; ili R1 i R2 zajedno s N atomom s kojim su spojeni, mogu tvoriti skupinu [image] ; R3 je vodik ili C1-C7 alkil; kao i s njihovom farmaceutski prihvatljivom soli, s racemičnom smjesom ili s njihovim odgovarajućim enantiomerom i/ili optičkim izomerom i/ili stereoizomerom.
17. Spoj formule IH prema patentnom zahtjevu 16, naznačen time, da je to spoj kako slijedi: 4-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-l-il)-N,l-dimetil-1H-imidazol-2-karboksamid ili 4-(3,3-dimetil-6-(2-metilpirimidin-5-il)-2-oksoindolin-1-il)-N,N,1-trimetil-1H-imidazol-2-karboksamid.
18. Spoj formula Ii prema patentnom zahtjevu 1, naznačen time, da A je fenil ili petero- ili šesteročlana heteroarilna skupina, koja sadrži jedan ili dva N atoma, i amidna skupina −C(O)-NR1R2 koja zajedno s dva susjedna ugljikova atoma iz skupine A, tvori dodatno staljeni prsten.
19. Spoj formule Ii prema patentnom zahtjevu 1, naznačen time, da je to spoj kako slijedi: [image] .
20. Kombinacija, naznačena time, da se sastoji od spoja formule I prema bilo kojem od patentnih zahtjeva 1 do 19, zajedno s tržišno poznatim antipsihotikom, antidepresivom, anksiolitikom ili stabilizatorom raspoloženja.
21. Kombinacija u skladu s patentnim zahtjevom 20, naznačena time, da je na tržištu antipsihotički lijek olanzapin, klozapin, risperidon, aripiprazol ili ziprasidon.
22. Kombinacija u skladu s patentnim zahtjevom 20, naznačena time, da je na tržištu antidepresivni lijek citalopram, escitalopram, paroksetin, fluoksetin, sertralin, duloksetin, milnacipran, venlafaksin ili mirtazapin.
23. Kombinacija u skladu s patentnim zahtjevom 20, naznačena time, da je na tržištu anksiolitički lijek alprazolam, klordijazepoksid, klonazepam, diazepam, estazolam, eszopiklon, zaleplon, zolpidem, pregabalin ili gabapentin.
24. Kombinacija u skladu s patentnim zahtjevom 20, naznačena time, da je na tržištu stabilizator raspoloženja karbamazepin, lamotrigin, litij i valprojska kiselina.
25. Postupak proizvodnje spoja formule I, prema opisu u bilo kojem od patentnih zahtjeva 1 do 19, naznačen time, da obuhvaća: a) reakciju spoja formule [image] sa spojem formule Y-A(R3)-C(O)-NR1R2 2 za tvorbu spoja formule [image] gdje Y je Cl, Br ili I, a ostale skupine imaju značenje kao što je opisano gore, i prema želji, pretvaranje dobivenih spojeva u farmaceutski prihvatljive kiselinske adicijske soli; ili b) reakciju spoja formule [image] s HNR1R2 aminokarbonilacijom u prisutnosti katalizatora ferocena-paladija, s izvorom ugljičnog monoksida, ponajprije molibden-heksakarbonilom ili s CO gaz (50 bara), za tvorbu spoja formule [image] pri čemu X je Cl ili Br, a ostale skupine imaju gore opisano značenje i, prema želji, pretvaranje dobivenih spojeva u farmaceutski prihvatljive kiselinske adicijske soli; ili c) amidaciju spoja formule [image] s HNR1R2 upotrebom aktivacijskog sredstva, poželjno je to HATU ili TBTU, da se dobiju spojevi formule I [image] pri čemu skupine imaju gore opisano značenje, i prema želji, pretvaranje dobivenih spojeva u farmaceutski prihvatljive kiselinske adicijske soli.
26. Spoj prema bilo kojem od patentnih zahtjeva 1 do 19, naznačen time, da se upotrebljava kao terapeutski aktivna tvar.
27. Farmaceutski pripravak, naznačen time, da sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 19 i terapeutski aktivan nosač za liječenje bolesti SŽS-a povezanih s pozitivnim (psihoza) i negativnim simptomima shizofrenije, zlouporabe tvari, ovisnosti o alkoholu i drogama, opsesivno-kompulzivnih poremećaja, oštećenja kognitivnih sposobnosti, bipolarnih poremećaja, poremećaja raspoloženja, velike depresije, depresije otporne na liječenje, anksioznih poremećaja, Alzheimerove bolesti, autizma, Parkinsonove bolesti, kronične boli, graničnog poremećaja ličnosti, neurodegenerativne bolesti, poremećaja spavanja, sindroma kroničnog umora, ukočenosti, upalne bolesti, astme, Huntingtonove bolesti, ADHD-a, amiotrofne lateralne skleroze, učinaka u artritisu, autoimune bolesti, virusnih i gljivičnih infekcija, kardiovaskularnih bolesti, u oftalmologiji za liječenje upalnih bolesti mrežnice te za liječenje problema s ravnotežom, epilepsije i neurorazvojnih poremećaja s komorbidnom epilepsijom.
28. Spoj prema bilo kojem od patentnih zahtjeva 1 do 19, naznačen time, da se upotrebljava u liječenju bolesti SŽS-a povezanih s pozitivnim (psihoza) i negativnim simptomima shizofrenije, zlouporabe tvari, ovisnosti o alkoholu i drogama, opsesivno-kompulzivnih poremećaja, oštećenja kognitivnih sposobnosti, bipolarnih poremećaja, poremećaja raspoloženja, velike depresije, depresije otporne na liječenje, anksioznih poremećaja, Alzheimerove bolesti, autizma, Parkinsonove bolesti, kronične boli, graničnog poremećaja ličnosti, neurodegenerativne bolesti, poremećaja spavanja, sindroma kroničnog umora, ukočenosti, upalne bolesti, astme, Huntingtonove bolesti, ADHD-a, amiotrofne lateralne skleroze, učinaka u artritisu, autoimune bolesti, virusnih i gljivičnih infekcija, kardiovaskularnih bolesti, u oftalmologiji za liječenje upalnih bolesti mrežnice te za liječenje problema s ravnotežom, epilepsije i neurorazvojnih poremećaja s komorbidnom epilepsijom.
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