HRP20220227T1 - Postupak priprave tricikličnih spojeva inhibitora p13k i postupci upotrebe navedenih spojeva u liječenju raka - Google Patents

Postupak priprave tricikličnih spojeva inhibitora p13k i postupci upotrebe navedenih spojeva u liječenju raka Download PDF

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HRP20220227T1
HRP20220227T1 HRP20220227TT HRP20220227T HRP20220227T1 HR P20220227 T1 HRP20220227 T1 HR P20220227T1 HR P20220227T T HRP20220227T T HR P20220227TT HR P20220227 T HRP20220227 T HR P20220227T HR P20220227 T1 HRP20220227 T1 HR P20220227T1
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palladium
compound
alkylene
ch2ch3
process according
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HRP20220227TT
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Andreas Stumpf
Remy Angelaud
Andrew MCCLORY
Herbert Yajima
Chudi Ndubaku
Alan Olivero
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Genentech, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Claims (15)

1. Postupak priprave spoja Formule III iz spoja Formule II u reakcijskoj smjesi prema sljedećoj reakcijskoj shemi: [image] gdje se postupak sastoji u: (i) pripravi reakcijske smjese koja sadrži spoj Formule II, organobor-R4, sustav otapala koji sadrži najmanje 5 vol./vol.% vode, bazu i katalizator; (ii) reagiranju reakcijske smjese na temperaturi ispod 100 °C kako bi se dobilo smjesu produkata reakcije koja sadrži spoj Formule III; i (iii) izdvajanju spoja Formule III, njegovog stereoizomera, geometrijskog izomera, tautomera ili farmaceutski prihvatljive soli, iz smjese produkata reakcije, gdje postupak dodatno uključuje korake pročišćavanja, gdje se navedeni koraci sastoje u: (I) miješanju spoja Formule III s hvatačem metala u sustavu otapala koji sadrži najmanje jedno polarno protonsko otapalo; (II) grijanju smjese kako bi se otopilo spoj Formule III; (III) filtriranju zagrijane smjese; (IV) snižavanju temperature filtrata i miješanju kristala spoja Formule III za zasijavanje s ohlađenim filtratom; (V) snižavanju temperature smjese filtrata i kristala za zasijavanje kako bi se potaklo kristalizaciju pročišćenog spoja Formule III; i (VI) prikupljanju kristala pročišćenog spoja Formule III, pri čemu: (a) sustav otapala sadrži vodu i octenu kiselinu ili uglavnom se sastoji od vode i octene kiseline, pri čemu se volumni omjer između octene kiseline i vode kreće od 1:1 do 10:1; (b) hvatač metala je silika-tiol; i (c) temperatura otapanja se kreće od 80 °C do 100 °C, kristale za zasijavanje se kombinira s filtratom na temperaturi od 70 °C do 80 °C, a temperatura kristalizacije se kreće od 0 °C do 10 °C, te pri čemu: katalizator sadrži paladij, a reakcijska smjesa sadrži manje od 0,05 ekvivalenata katalizatora po ekvivalentu spoja Formule II; X1 je S, O, N, NR6, CR1, C(R1)2 ili -C(R1)2O-; X2 je C, CR2 ili N; X3 je C, CR3 ili N; X4 je halogen; A je 5, 6 ili 7-eročlani karbociklilni ili heterociklilni prsten kondenziran s X2 i X3, koji može biti supstituiran s jednom ili više skupina R5, R10 ili R15; R6 je H, C1-C12 alkil, C2-C8 alkenil, C2-C8 alkinil, -(C1-C12 alkilen)-(C3-C12 karbociklil), -(C1-C12 alkilen)(-C2-C20 heterociklil), -(C1-C12 alkilen)-C(=O)-(C2-C20 heterociklil), (C1-C12 alkilen)-(C6-C20 aril), te -(C1-C12 alkilen)-(C1-C20 heteroaril), gdje alkil, alkenil, alkinil, alkilen, karbociklil, heterociklil, aril, te heteroaril mogu biti supstituirani s jednom ili više skupina koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -(CH3)2OH, -CH2OCH3, -CN, -CO2H, -COCH3, -COC(CH3)3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, ciklopropila, ciklobutila, oksetanila, morfolino, te 1,1-dioksotiopiran-4-ila; R1, R2, te R3 se neovisno bira između H, F, Cl, Br, I, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH2OCH3, -CN, -CF3, -CO2H, -COCH3, -COC(CH3)3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2, -CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCOCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, ciklopropila, ciklobutila, oksetanila, morfolino, te 1,1-dioksotiopiran-4-ila; R4 se bira između C6-C20 arila, C2-C20 heterociklila i C1-C20 heteroarila, od kojih svaki može biti supstituiran s jednom ili više skupina koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH2CH3, -CH2CN, -CN, -CF3, -CH2OH, -CO2H, -CONH2, CONH(CH3), -CON(CH3)2, -NO2, -NH2, -NHCH3, -NHCOCH3, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -NHS(O)2CH3, -N(CH3)C(O)OC(CH3)3, -S(O)2CH3, benzila, benziloksi, morfolinila, morfolinometila, te 4-metilpiperazin-1-ila; svakog R5, R10 i R15 se neovisno bira između C1-C12 alkila, C2-C8 alkenila, C2-C8 alkinila, -(C1-C12 alkilen)-(C3-C12 karbociklila), -(C1-C12 alkilen)-(C2-C20 heterociklila), -(C1-C12 alkilen)-C(O)-(C2-C20 heterociklila), -(C1-C12 alkilen)-(C6-C20 arila), te -(C1-C12 alkilen)-(C1-C20 heteroarila); ili dvije geminalne skupine R5, R10 i/ili R15 tvore 3, 4, 5, ili 6-eročlani karbociklilni ili heterociklilni prsten, gdje alkil, alkenil, alkinil, alkilen, karbociklil, heterociklil, aril, te heteroaril mogu biti supstituirani s jednom ili više skupina koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -C(CH3)3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH2OCH3, -CN, -CH2F, -CHF2, -CF3, -CO2H, -COCH3, -COC(CH3)3, -CO2CH3, -CONH2, -CONHCH3, -CON(CH3)2, -C(CH3)2CONH2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NH-COCH3, -NHS(O)2CH3, -N(CH3)C(CH3)2CONH2, -N(CH3)CH2CH2S(O)2CH3, =O, -OH, -OCH3, -S(O)2N(CH3)2, -SCH3, -S(O)2CH3, ciklopropila, ciklobutila, oksetanila, morfolino, te 1,1-dioksotiopiran-4-ila; i mor se bira između: [image] [image] , pri čemu mor može biti supstituiran s jednom ili više skupina R7 koje se neovisno bira između F, Cl, Br, I, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2OCH3, -CHF2, -CN, -CF3, -CH2OH, -CH2OCH3, -CH2CH2OH, -CH2C(CH3)2OH, -CH(CH3)OH, -CH(CH2CH3)OH, -CH2CH(OH)CH3, -C(CH3)2OH, -C(CH3)2OCH3, -CH(CH3)F, -C(CH3)F2, -CH(CH2CH3)F, -C(CH2CH3)2F, -CO2H, -CONH2, -CON(CH2CH3)2, -COCH3, -CON(CH3)2, -NO2, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3, -NHCH(CH3)2, -NHCH2CH2OH, -NHCH2CH2OCH3, -NHCOCH3, -NHCOCH2CH3, -NHCOCH2OH, -NHS(O)2CH3, -N(CH3)S(O)2CH3, =O, -OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -SH, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -S(O)CH3, -S(O)CH2CH3, -S(O)2CH3, -S(O)2NH2, -S(O)2NHCH3, -S(O)2N(CH3)2, te -CH2S(O)2CH3.
2. Postupak u skladu s patentnim zahtjevom 1, pri čemu sustav otapala dodatno sadrži najmanje jedno polarno neprotonsko otapalo kojeg se bira između N-metilpirolidona, metil-izobutil-ketona, metil-etil-ketona, tetrahidrofurana, diklormetana, etil-acetata, acetona, N,N-dimetilformamida, acetonitrila i dimetil-sulfoksida.
3. Postupak u skladu s patentnim zahtjevom 2, pri čemu se omjer između vode i najmanje jednog polarnog neprotonskog otapala kreće od 1:10 vol./vol. i 5:1 vol./vol.
4. Postupak u skladu s patentnim zahtjevom 2 ili patentnim zahtjevom 3, pri čemu se sustav otapala uglavnom sastoji od vode i najmanje jednog polarnog neprotonskog otapala.
5. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 4, pri čemu je organobor-R4 5-(4,4,5,5-tetrametil-1,3,2-dioksaborolan-2 il)-R4.
6. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 5, pri čemu se bazu bira između K3PO4, Cs2CO3 i KOH.
7. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 6, pri čemu se katalizator koji sadrži paladij bira između klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-aminoetil)fenil)]paladija(II) ("Pd Xphos"); kompleksa 1,1′-bis(difenilfosfino)ferocen]dikloropaladija(II) s diklormetanom ("PdCl2 dppf CH2Cl2"); bis(di-tert-butil(4-dimetilaminofenil)fosfin)dikloropaladija(II) ("Pd(amphos)Cl2"); diklorbis(di-tert-butilfenilfosfin)paladija(II) ("Pd 122"); PdCl2(PPh3)2; Pd(t-Bu)3; Pd(PPh3)4; Pd(Oac)/PPh3; Cl2Pd[(Pet3)]2; Pd(DIPHOS)2; Cl2Pd(Bipy); [PdCl(Ph2PCH2PPh2)]2; Cl2Pd[P(o-tol)3]2; Pd2(dba)3/P(o-tol)3; Pd2(dba)/P(furil)3; Cl2Pd[P(furil)3]2; Cl2Pd(PmePh2)2; Cl2Pd[P(4-F-Ph)3]2; Cl2Pd[P(C6F6)3]2; Cl2Pd[P(2-COOH-Ph)(Ph)2]2; Cl2Pd[P(4-COOH-Ph)(Ph)2]2; paladijevog acetata, mikroinkapsuliranog u matriks od poliuree, koji sadrži 0,4 mmol/g Pd; paladijevog acetata i trifenilfosfina, mikroinkapsuliranog u matriks od poliuree, koji sadrži 0,4 mmol/g Pd i 0,3 mmol/g fosfora; paladijevog acetata i BINAP, mikroinkapsuliranog u matriks od poliuree, koji sadrži 0,4 mmol/g Pd; i klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-amino-1,1′-bifenil)]paladija(II) ("XPhos PdG2").
8. Postupak u skladu s patentnim zahtjevom 7, pri čemu se katalizator koji sadrži paladij bira između: klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-aminoetil)fenil)]paladij(II), kompleks 1,1′-bis(difenilfosfino)ferocen]dikloropaladija(II) s diklormetanom, te klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-amino-1,1′-bifenil)]paladij(II) ("XPhos PdG2").
9. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 8, pri čemu je ekvivalentni omjer između katalizatora koji sadrži paladij i spoja Formule II između 0,003:1 i 0,05:1.
10. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 9, pri čemu je temperatura reakcije između 40 °C i 100 °C.
11. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 10, koji se dodatno sastoji u dodavanju polarnog protonskog otapala u smjesu produkata reakcije kako bi se dobilo smjesu koja sadrži više od 25 vol./vol.% vode i izdvajanju spoja Formule III iz smjese produkata reakcije odvajanjem krutine od tekućine.
12. Postupak u skladu s patentnim zahtjevom 11, pri čemu se polarno protonsko otapalo bira između vode, metanola, etanola, izopropanola, n-propanola, te octene kiseline.
13. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 12, pri čemu se volumni omjer između octene kiseline i vode kreće (i) od 1:1 do 5:1 ili (ii) od 1:1 do 3:1, ili (iii) 3:1.
14. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 13, pri čemu je spoj Formule III: [image] .
15. Postupak u skladu s bilo kojim od patentnih zahtjeva 1 do 14, pri čemu je katalizator koji sadrži paladij klor(2-dicikloheksilfosfino-2′,4′,6′-triizopropil-1,1′-bifenil)[2-(2-amino-1,1′-bifenil)]paladij(II) ("Xphos PdG2").
HRP20220227TT 2015-12-16 2016-12-16 Postupak priprave tricikličnih spojeva inhibitora p13k i postupci upotrebe navedenih spojeva u liječenju raka HRP20220227T1 (hr)

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EP16876773.9A EP3389662B1 (en) 2015-12-16 2016-12-16 Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer
PCT/US2016/067174 WO2017106647A1 (en) 2015-12-16 2016-12-16 Process for the preparation of tricyclic pi3k inhibitor compounds and methods for using the same for the treatment of cancer

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