HRP20191189T1 - Pirimido[4,5-b]indol derivati i njihova primjena u ekspanziji hematopoetskih matičnih stanica - Google Patents

Pirimido[4,5-b]indol derivati i njihova primjena u ekspanziji hematopoetskih matičnih stanica Download PDF

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HRP20191189T1
HRP20191189T1 HRP20191189TT HRP20191189T HRP20191189T1 HR P20191189 T1 HRP20191189 T1 HR P20191189T1 HR P20191189T T HRP20191189T T HR P20191189TT HR P20191189 T HRP20191189 T HR P20191189T HR P20191189 T1 HRP20191189 T1 HR P20191189T1
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optionally substituted
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heterocyclyl
heteroaryl
aryl
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Guy Sauvageau
Yves Gareau
Réjean RUEL
Stéphane GINGRAS
Iman FARES
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Université de Montréal
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0647—Haematopoietic stem cells; Uncommitted or multipotent progenitors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components

Claims (15)

1. Spoj je formule IIA, formule IIB ili formule IIC ili njegova sol, Het je 3 do 7-člani heterocikl, po izboru supstituiran sa jednim ili više R1 ili RA; R5 i R6 su isti ili različiti i svako je nezavisno L, ili se udružuju zajedno sa C da se formira 5-člani prsten koji po izboru uključuje jedan ili više heteroatoma odabrana od N, O i S, po izboru prsten je supstituiran sa jednim ili više R1 ili RA; W je 74) -(N(R1)-L)n-N(R1)R1, Ili W je 1) -H, 2) -halogen, 3) -OR1, 4) -L-OH, 5) -L-OR1, 6) -SR1, 7) -CN, 8) -P(O)(OR1)(OR1), 9) -NHR1, 10) -N(R1)R1, 11) -L-NH2, 12) -L-NHR1, 13) -L-N(R1)R1, 14) -L-SR1, 15) -L-S(O)R1, 16) -L-S(O)2R1, 17) -L-P(O)(OR1)(OR1), 18) -C(O)OR1, 19) -C(O)NH2, 20) -C(O)NHR1, 21) -C(O)N(R1)R1, 22) -NHC(O)R1, 23) -NR1C(O)R1, 24) -NHC(O)OR1, 25) -NR1C(O)OR1, 26) -OC(O)NH2, 27) -OC(O)NHR1, 28) -OC(O)N(R1)R1, 29) -OC(O)R1, 30) -C(O)R1, 31) -NHC(O)NH2, 32) -NHC(O)NHR1, 33) -NHC(O)N(R1)R1, 34) -NR1C(O)NH2, 35) -NR1C(O)NHR1, 36) -NR1C(O)N(R1)R1, 37) -NHS(O)2R1, 38) -NR1S(O)2R1, 39) -S(O)2NH2, 40) -S(O)2NHR1, 41) -S(O)2N(R1)R1, 42) -S(O)R1, 43) -S(O)2R1, 44) -OS(O)2R1, 45) -S(O)2OR1, 46) -benzil po izboru supstituiran sa 1, 2 ili 3 RA ili R1 supstituenta, 47) -L-heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heteroaril grupi, 48) -L-heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heterociklil grupi, 49) -L-aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na aril grupi, 50) -L-NR1(R1), 51) -L-)2NR1, 52) -L-(N(R1)-L)n-N(R1)R1, 53) -L-(N(R1)-L)n - heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heteroaril grupi, 54) -L-(N(R1)-L)n - heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heterociklil grupi, 55) -L-(N(R1)-L)n - aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na aril grupi, 56) -O-L-N(R1)R1, 57) -O-L- heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heteroaril grupi, 58) -O-L- heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heterociklil grupi, 59) -O-L- aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na aril grupi, 60) -O-L)2-NR1, 61) -O-L-(N(R1)-L)n - N(R1)R1, 62) -O-L-(N(R1)-L)n - heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heteroaril grupi, 63) -O-L-(N(R1)-L)n - heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heterociklil grupi, 64) -O-L-(N(R1)-L)n- aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata, 65) -S-L- heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata, 66) -S-L- heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata, 67) -S-L- aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na aril grupi, 68) -S-L)2NR1, 69) -S-L-(N(R1)-L)n - N(R1)R1, 70) -S-L-(N(R1)-L)n - heteroaril po izboru supstituiran sa jednim ili više RA supstituenata, 71) -S-L-(N(R1)-L)n - heterociklil po izboru supstituiran sa jednim ili više RA supstituenata, 72) -S-L-(N(R1)-L)n - aril po izboru supstituiran sa jednim ili više RA supstituenata, 73) -NR1(R1), 75) -N(R1)L)2-NR1, 76) -(N(R1)-L)n - N(R1)RA, 77) -(N(R1)-L)n - heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata, 78) -(N(R1)-L)n - heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata, 79) -(N(R1)-L)n - aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata, 80) -heteroaril po izboru supstituiran sa jednim ili više RA supstituenata, ili 81) -aril po izboru supstituiran sa jednim ili više RA supstituenata, i gdje svaki supstituent je po izboru vezan za L grupu ukoliko nije već prisutan, i gdje kada su dva R1 supstituenta prisutna na istom atomu dušika, tada svaki R1 supstituent je nezavisno odabran sa liste R1 vrijednosti opisane kasnije, i gdje n je cijeli broj jednak sa bilo 0, 1, 2, 3, 4, ili 5, i gdje, kada (R1) i R1 su vezani za atom dušika, po izboru oni se udružuju zajedno sa atomom dušika da se formira 3 do 7-člani prsten koji po izboru uključuje jedan ili više drugih heteroatoma odabranih od N, O i S, po izboru prsten je supstituiran sa jednim ili više R1 ili RA; L je 4) -C3-7 cikloalkil ili 1) -C1-6 alkil, ili L je 2) -C2-6 alkenil, 3) -C2-6 alkinil, 5) -C3-7 cikloalkenil, 6) heterociklil, 7) -C1-6 alkil-C3-7 cikloalkil, 8) -C1-6 alkil-heterociklil, 9) aril, ili 10) heteroaril, i gdje alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterociklil, aril i heteroaril grupe su svaka nezavisno po izboru supstituirana sa jednim ili dva RA supstituenta; R1 je 1) -H, 2) -C1-6 alkil, 3) -C2-6 alkenil, 4) -C2-6 alkinil, 5) -C3-7 cikloalkil, 6) -C3-7 cikloalkenil, 7) -C1-5 perfluorovan, 8) -heterociklil, 9) -aril, 10) -heteroaril, 11) -benzil, ili 12) 5-[(3aS,4S,6aR)-2-oksoheksahidro-1H-tieno[3,4-d]imidazol-4-il]pentanoil, i gdje alkil, alkenil, alkinil, cikloalkenil, perfluorovan alkil, heterociklil, aril, heteroaril i benzil grupe su svaka nezavisno po izboru supstituirana sa 1, 2 ili 3 RA ili R1 supstituenta; R2 je 7) benzil po izboru supstituiran sa 1, 2 ili 3 RA ili R1 supstituenta; ili 1) -H, Ili R2 je 2) -C1-6 alkil, 3) -SR1, 4) -C(O)R1, 5) -S(O)R1, 6) -S(O)2R1, 8) -L-heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heteroaril grupi, 9) -L-heterociklil po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na heterociklil grupi, 10) -L-aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenata vezanih na jednoj ili i na L i na aril grupi, 11) -heteroaril po izboru supstituiran sa jednim ili više RA ili R1 supstituenta, ili 12) -aril po izboru supstituiran sa jednim ili više RA ili R1 supstituenta, i gdje svaki supstituent je po izboru vezan za L grupu ukoliko nije već prisutan; RA je 1) -halogen, 2) -CF3, 3) -OH, 4) -OR1, 5) -L-OH, 6) -L-OR1, 7) -OCF3, 8) -SH, 9) -SR1, 10) -CN, 11) -NO2, 12) -NH2, 13) -NHR1, 14) -NR1R1, 15) -L-NH2, 16) -L-NHR1, 17) -L-NR4R1, 18) -L-SR1, 19) -L-S(O)R1, 20) -L-S(O)2R1, 21) -C(O)OH, 22) -C(O)OR1, 23) -C(O)NH2, 24) -C(O)NHR1, 25) -C(O)N(R1)R1, 26) -NHC(O)R1, 27) -NR1C(O)R1, 28) -NHC(O)OR1, 29) -NR1C(O)OR1, 30) -OC(O)NH2, 31) -OC(O)NHR1, 32) -OC(O)N(R1)R1, 33) -OC(O)R1, 34) -C(O)R1, 35) -NHC(O)NH2, 36) -NHC(O)NHR1, 37) -NHC(O)N(R1)R1, 38) -NR1C(O)NH2, 39) -NR1C(O)NHR1, 40) -NR1C(O)N(R1)R1, 41) -NHS(O)2R1, 42) -NR1S(O)2R1, 43) -S(O)2NH2, 44) -S(O)2NHR1, 45) -S(O)2N(R1)R1, 46) -S(O)R1, 47) -S(O)2R1, 48) -OS(O)2R1, 49) -S(O)2OR1, 50) -benzil, 51) -N3, ili 52) -C(-N=N-)(CF3), i gdje benzil grupa je po izboru supstituirana sa 1, 2 ili 3 RA ili R1 supstituenta, pod uvjetom da Spoj formule IIA, formule IIB ili formule IIC je različit od
2. Spoj prema patentnom zahtjevu 1, gdje heteroatom je N u 5-članom prstenu formiranom pomoću R5 i R6 zajedno.
3. Spoj prema patentnom zahtjevu 1 ili 2, gdje navedeni spoj ima formulu IIC i R2 je benzil.
4. Spoj prema patentnom zahtjevu 1, gdje: u formuli IIA, je CO2Me i u formuli IIC, R5 i R6 se udružuju zajedno sa C da se formira 2-metil-2H-tetrazol-5-il; R2 je benzil, 3-tienilmetil ili 3-piridinil metil; i W je NH-L-N(R1)R1 gdje L je C2-4 alkil i R1 je C1-4 alkil ili (R1) i R1 se udružuju zajedno sa atomom dušika za koji su vezani da se formira 3 do 7-člani prsten, koji po izboru uključuje jedan ili više drugih heteroatoma odabranih od N, O i S, po izboru prsten je supstituiran sa jednim ili više R1 ili RA.
5. Spoj koje je:
Ili njegova sol.
6. Spoj prema patentnom zahtjevu 1 koje je ili farmaceutski prihvatljiva sol istog.
7. Spoj prema patentnom zahtjevu 1 gdje spoj je ili farmaceutski prihvatljiva sol istog.
8. Spoj prema patentnom zahtjevu 1 gdje spoj je ili farmaceutski prihvatljiva sol istog.
9. Metoda povećanja matičnih i progenitorskih stanica, metoda koja obuhvata: kultiviranje in vitro ili ex vivo polazne stanice populacije koja sadrži hematopoetske matične stanice sa agensom koji sadrži spoj ili njegovu sol kao što je definirano u bilo kojem od patentnih zahtjeva 1 do 8, po izboru zajedno sa najmanje jednim faktorom za staničnu ekspanziju koji je biološki ili druga mala molekula.
10. Metoda iz patentnog zahtjeva 9, u kojoj polazna stanična populacija uključuje CD34+ stanice prikupljene iz mobilizirane periferne krvi (mPB), koštane srži (BM) ili krvi pupčane vrpce (UCB).
11. Farmaceutska kompozicija koja sadrži spoj kao što je definirano u bilo kojem od patentnih zahtjeva 1 do 8 ili njegovu sol, i farmaceutski prihvatljiv nosač.
12. Spoj kao što je definirano u bilo kojem od patentnih zahtjeva 1 do 8 ili njegova sol za primjenu u liječenju hematopoetskog poremećaja/maligniteta, autoimune bolesti i/ili nasljedne imunodeficijentne bolesti kod subjekta.
13. Spoj kao što je definirano u patentnom zahtjevu 12 gdje navedeni hematopoetski poremećaj/malignitet, autoimuna bolest i/ili nasljedna imunodeficijentna bolest obuhvaćaju stanja insuficijencije koštane srži, razne kongenitalne bolesti općeg značaja (npr. anemiju srpastih stanica i talasemiju), lupus, akutnu mijeloidnu leukemiju, akutnu limfoblastnu leukemiju, kroničnu mijeloidnu leukemiju, kroničnu limfocitnu leukemiju, mijeloproliferativne poremećaje, mijelodisplastične sindrome, multipli mijelom, ne-Hodgkin-ov limfom, Hodgkin-ovu bolest, aplastičnu anemiju, čistu aplaziju eritrocita, hemoglobinuriju, Fanconi anemiju, talasemiju, anemiju srpastih stanica, Wiskott-Aldrich-ov sindrom, urođene greške u metabolizmu (kao što je Gaucher-ova bolest).
14. Farmaceutska kompozicija prema patentnom zahtjevu 11, koja je pogodna za intravensku infuziju.
15. Komplet za primjenu u ekspandiranju hematopoetskih matičnih stanica, koji sadrži spoj kao što je definirano u bilo kojem od patentnih zahtjeva 1 do 8, ili njegovu sol, i uputstva za primjenu, po izboru, komplet sadrži najmanje jedan faktor za ekspanziju stanica koji je biološki ili druga mala molekula.
HRP20191189TT 2012-01-27 2019-07-02 Pirimido[4,5-b]indol derivati i njihova primjena u ekspanziji hematopoetskih matičnih stanica HRP20191189T1 (hr)

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US9409906B2 (en) 2012-01-27 2016-08-09 Universite De Montreal Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells
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