HRP20220311T1 - Konjugati pirolobenzodiazepina - Google Patents

Konjugati pirolobenzodiazepina Download PDF

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HRP20220311T1
HRP20220311T1 HRP20220311TT HRP20220311T HRP20220311T1 HR P20220311 T1 HRP20220311 T1 HR P20220311T1 HR P20220311T T HRP20220311T T HR P20220311TT HR P20220311 T HRP20220311 T HR P20220311T HR P20220311 T1 HRP20220311 T1 HR P20220311T1
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conjugate according
alkenyl
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HRP20220311TT
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Nazzareno Dimasi
Philip Wilson Howard
Luke Masterson
Arnaud Charles Tiberghien
Balakumar VIJAYAKRISHNAN
Jason White
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Medimmune Limited
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
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    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Claims (23)

1. Konjugat, naznačen time, da je predstavljen formulom I: [image] u kojoj Ab je modificirano protutijelo koje ima najmanje jedno slobodno mjesto za konjugaciju na svakom teškom lancu, D predstavlja skupinu D1 ili D2: [image] ; crtkana linija označava opcionalnu prisutnost dvostruke veze između C2 i C3; kada je između C2 i C3 dvostruka veza, R2 se bira iz skupine koja se sastoji od sljedećih: (ia) C5-10 aril skupina, opcionalno supstituirana s jednim ili više supstituenata odabranih iz skupine koju čine: halogen, nitro, cijano, eter, karboksi, ester, C1-7 alkil, C3-7 heterociklil i bis-oksi-C1-3 alkilen; (ib) C1-5 zasićeni alifatski alkil; (ic) C3-6 zasićeni cikloalkil; (id) [image] , pri čemu se svaki od R11, R12 i R13 neovisno bira od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila, gdje ukupan broj atoma ugljika u skupini R2, nije veći od 5; (ie) [image] pri čemu jedan od R15a i R15b jest H i preostali se bira od: fenila, gdje je fenil opcionalno supstituiran sa skupinom odabranom od halogena, metila, metoksi; piridila; i tiofenila; i (if) [image] pri čemu se R14 bira od: H; C1-3 zasićenog alkila; C2-3 alkenila, C2-3 alkinila; ciklopropila; fenila, gdje je fenil opcionalno supstituiran sa skupinom odabranom od halogena, metila, metoksi; piridila; i tiofenila; kada je između C2 i C3 jednostruka veza, R2 se bira od H, OH, F, diF i [image] gdje se R16a i R16b neovisno biraju od H, F, C1-4 zasićenog alkila, C2-3 alkenila, pri čemu su alkil i alkenil skupine opcionalno supstituirane sa skupinom odabranom od sljedećih: C1-4 alkil amido i C1-4 alkil ester; ili kada jedan od R16a i R16b jest H, preostali se bira od nitrila i C1-4 alkil estera; D' predstavlja skupinu D'1 ili D'2: [image] pri čemu crtkana linija označava opcionalnu prisutnost dvostruke veze između C2' i C3'; kada je između C2' i C3' dvostruka veza, R22 se bira iz skupine koja se sastoji od sljedećih: (iia) C5-10 aril skupina, opcionalno supstituirana s jednim ili više supstituenata odabranih iz skupine koju čine: halogen, nitro, cijano, eter, karboksi, ester, C1-7 alkil, C3-7 heterociklil i bis-oksi-C1-3 alkilen; (iib) C1-5 zasićeni alifatski alkil; (iic) C3-6 zasićeni cikloalkil; (iid) [image] gdje se R31, R32 i R33 neovisno biraju od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila, gdje ukupni broj atoma ugljika u skupini R22, nije veći od 5; (iie) [image] pri čemu jedan od R25a i R25b jest H i preostali se bira od: fenila, gdje je fenil opcionalno supstituiran sa skupinom koja se bira od halogena, metila, metoksi; piridila; i tiofenila; i (iif) [image] gdje se R24 bira od: H; C1-3 zasićenog alkila; C2-3 alkenila; C2-3 alkinila; ciklopropila; fenila, gdje je fenil opcionalno supstituiran sa skupinom koja se bira od halogena, metila, metoksi; piridila; i tiofenila; kada je između C2' i C3' jednostruka veza, R22 se bira od H, OH, F, diF i [image] gdje se R26a i R26b neovisno biraju od: H, F, C1-4 zasićenog alkila, C2-3 alkenila, dok su alkil i alkenil skupine opcionalno supstituirane sa skupinom odabranom od sljedećih: C1-4 alkil amido i C1-4 alkil ester; ili kada jedan od R26a i R26b jest H, preostali se bira od nitrila i C1-4 alkil estera; R6 i R9 se neovisno biraju od H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn i halogena; pri čemu se R i R' neovisno biraju od opcionalno supstituiranih C1-12 alkila, C3-20 heterociklila i C5-20 aril skupina; R7 se bira od H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn i halogena; R'' je C3-12 alkilen skupina, čiji lanac može biti prekinut s jednim ili više heteroatoma, primjerice O, S, NRN2, gdje RN2 je H ili C1-4 alkil, i/ili aromatski prstenovi, primjerice benzen ili piridin; Y i Y' se biraju od O, S ili NH; R11a se bira od OH, ORA, gdje RA jest C1-4 alkil; R6', R7', R9' i R11a' se biraju iz istih skupina kao R6, R7, R9 i R11a, prema odgovarajućem poretku; i RLL1 i RLL2 su poveznici koji su spojeni s protutijelom na različitim mjestima i koji neovisno imaju formulu IIIa': [image] , u kojoj Q jest: [image] gdje QX je takav da Q je aminokiselinski ostatak, dipeptidni ostatak ili tripeptidni ostatak; X jest: [image] gdje a = 0 do 5, b = 0 do 16, c = 0 ili 1, d = 0 do 5; GLL se bira od: [image] gdje Ar predstavlja C5-6 arilen skupinu, primjerice fenilen i X predstavlja C1-4 alkil; gdje CBA predstavlja sredstvo za vezanje stanice koje je modificirano protutijelo s najmanje jednim slobodnim mjestom konjugacije na svakom teškom lancu; pri čemu izraz alkil uključuje podrazrede alkenila, alkinila i cikloalkila, izraz alkilen uključuje podrazrede alkenilena, alkinilena, cikloalkilena, izraz alkenil pripada u alkilnu skupinu koja ima jednu ili više dvostrukih veza ugljik-ugljik i izraz alkinil pripada u alkilnu skupinu koja ima jednu ili više trostrukih veza ugljik-ugljik.
2. Konjugat prema patentnom zahtjevu 1, naznačen time, da: a) Y i Y' su oba O; i/ili b) R'' je C3-7 alkilen ili skupina s formulom: [image] , gdje r je 1 ili 2; i/ili c) R9 je H; i/ili d) R6 je H; i/ili e) R7 se bira od H, OH, OR ili C1-4 alkiloksi skupine.
3. Konjugat prema patentnom zahtjevu 1 ili 2, naznačen time, da D je D1, između C2 i C3 je dvostruka veza, i R2 je: a) C5-7 aril skupina gdje R2 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili b) C8-10 aril skupina gdje R2 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili c) C1-5 zasićena alifatska alkil skupina, opcionalno gdje R2 je metil, etil ili propil; ili d) skupina s formulom: [image] , dok opcionalno pritom: i) ukupni broj atoma ugljika u skupini R2, nije veći od 4; ii) jedan od R11, R12 i R13 je H, s preostale dvije skupine koje se biraju od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili iii) dva od R11, R12 i R13 su H, s preostalom skupinom koja se bira od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili e) skupina s formulom: [image] ; ili f) skupina: [image] ; ili g) skupina s formulom: [image] ; ili h) C3-6 zasićena cikloalkil skupina, opcionalno pritom R2 je ciklopropil.
4. Konjugat prema patentnom zahtjevu 1 ili 2, naznačen time, da D je D1, između C2 i C3 je jednostruka veza, i R2 je: a) H; ili b) [image] i R16a i R16b su oba H; ili c) [image] , i R16a i R16b su oba metil; ili d) [image] , jedan od R16a i R16b je H, i preostali se bira od C1-4 zasićenog alkila, C2-3 alkenila, gdje su alkil i alkenil skupine opcionalno supstituirane.
5. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da D' je D'1, između C2' i C3' je dvostruka veza, i R22 je: a) C5-7 aril skupina gdje R22 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili b) C8-10 aril skupina gdje R22 opcionalno nosi jednu do tri supstituentske skupine odabrane od metoksi, etoksi, fluoro, kloro, cijano, bis-oksi-metilen, metil-piperazinil, morfolino i metil-tiofenil; ili c) C1-5 zasićena alifatska alkil skupina; ili d) C3-6 zasićena cikloalkil skupina; ili e) skupina s formulom: [image] u kojoj: i) ukupni broj atoma ugljika u skupini R22, nije veći od 4; ili ii) jedan od R31, R32 i R33 je H, s preostale dvije skupine koje se biraju od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili iii) dva od R31, R32 i R33 su H, s preostalom skupinom koja se bira od H, C1-3 zasićenog alkila, C2-3 alkenila, C2-3 alkinila i ciklopropila; ili f) skupina s formulom: [image] ; ili g) skupina: [image] ; ili h) skupina s formulom: [image] gdje se R24 bira od H, metila, etila, etenila i etinila.
6. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da D' je D'1, između C2' i C3' je jednostruka veza, i R22 je: a) H; ili b) [image] i oba R26a i R26b su H; ili c) [image] , i oba R26a i R26b su metil; ili d) [image] , jedan od R26a i R26b je H; i preostali se bira od C1-4 zasićenog alkila, C2-3 alkenila, gdje su alkil i alkenil skupine opcionalno supstituirane.
7. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da R11a je: a) OH; ili b) ORA, gdje RA jest C1-4 alkil.
8. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time, da: a) R6' se bira iz istih skupina kao R6, R7' se bira iz istih skupina kao R7, R9' se bira iz istih skupina kao R9, R11a' se bira iz istih skupina kao R11a i Y' se bira iz istih skupina kao Y; i/ili b) R6' je ista skupina kao R6, R7' je ista skupina kao R7, R9' je ista skupina kao R9, R11a' je ista skupina kao R11a i Y' je ista skupina kao Y; i/ili c) R22 je ista skupina kao R2.
9. Konjugat prema patentnom zahtjevu 1, naznačen time, da je predstavljen formulom Ia-1, Ia-2 ili Ia-3: [image] [image] [image] pri čemu su R2a i R22a isti i biraju se od: (a) [image] (b) [image] (c) [image] (d) [image] (e) [image] (f) [image] (g) [image] ; i (h) [image] R1a se bira od metila i benzila; RLL1, RLL2 i R11a su kao što su definirani u patentnom zahtjevu 1.
10. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da RLL1 je predstavljen formulom IIIa', i Qx je: a) aminokiselinski ostatak odabran od Phe, Lys, Val, Ala, Cit, Leu, Ile, Arg i Trp; ili b) dipeptidni ostatak odabran od: CO-Phe-Lys-NH, CO-Val-Ala-NH, CO-Val-Lys-NH, CO-Ala-Lys-NH, CO-Val-Cit-NH, CO-Phe-Cit-NH, CO-Leu-Cit-NH, CO-Ile-Cit-NH, CO-Phe-Arg-NH, i CO-Trp-Cit-NH; ili c) tripeptidni ostatak.
11. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time, da RLL1 je predstavljen formulom IIIa', i: a) a je 0 do 3; i/ili b) b je 0 do 12; i/ili c) d je 0 do 3.
12. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da RLL1 je predstavljen formulom IIIa', i a je 0, c je 1 i d je 2, i b je od 0 do 8, opcionalno b je 0, 4 ili 8.
13. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da RLL2 je predstavljen formulom IIIa', i Qx je: a) aminokiselinski ostatak odabran od Phe, Lys, Val, Ala, Cit, Leu, Ile, Arg i Trp; ili b) dipeptidni ostatak odabran od: CO-Phe-Lys-NH, CO-Val-Ala-NH, CO-Val-Lys-NH, CO-Ala-Lys-NH, CO-Val-Cit-NH, CO-Phe-Cit-NH, CO-Leu-Cit-NH, CO-Ile-Cit-NH, CO-Phe-Arg-NH, i CO-Trp-Cit-NH; ili c) tripeptidni ostatak.
14. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 13, naznačen time, da RLL2 je predstavljen formulom IIIa', i: a) a je 0 do 3; i/ili b) b je 0 do 12; i/ili c) d je 0 do 3.
15. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 13, naznačen time, da RLL2 je predstavljen formulom IIIa', i a je 0, c je 1 i d je 2, i b je od 0 do 8.
16. Konjugat prema patentnom zahtjevu 1, naznačen time, da je predstavljen formulom Id: [image] gdje je m cijeli broj od 2 do 8.
17. Konjugat prema bilo kojem od prethodnih patentnih zahtjeva, naznačen time, da: a) modificirano protutijelo koje ima najmanje jedno slobodno mjesto konjugacije na svakom teškom lancu, je IgG1, IgG2, IgG3 ili IgG4 protutijelo; i opcionalno b) modificirano protutijelo koje ima najmanje jedno slobodno mjesto konjugacije na svakom teškom lancu, jest ljudsko protutijelo; ili c) modificirano protutijelo koje ima najmanje jedno slobodno mjesto konjugacije na svakom teškom lancu, jest humanizirano protutijelo.
18. Konjugat prema patentnom zahtjevu 17, naznačen time, da: a) modificirano protutijelo je modificirano tako, da cisteinski ostaci prirodnog međulanca supstituiraju aminokiselinskeostatke kojima nedostaju tiol skupine; i/ili b) modificirano protutijelo sadrži najmanje jednu dodatnu supstituciju u svakom teškom lancu aminokiselinskog ostatka, pri čemu dodatno supstituirana aminokiselina je cistein ili neprirodna aminokiselina; i/ili c) modificirano protutijelo je modificirano tako, da ima najmanje jednu dodatnu supstituciju u svakom teškom lancu aminokiseline, gdje je pozicija koja se supstituira, odabrana iz onih koje su dolje prikazane: [image]
19. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 18, naznačen time, da je za uporabu u liječenju.
20. Farmaceutski pripravak, naznačen time, da sadrži konjugat prema bilo kojem od patentnih zahtjeva 1 do 18, i farmaceutski prihvatljiv razrjeđivač, nosač ili pomoćno sredstvo.
21. Konjugat prema bilo kojem od patentnih zahtjeva 1 do 18, ili farmaceutski pripravak prema patentnom zahtjevu 20, naznačen time, da je za uporabu u liječenju proliferativne bolesti kod pojedinca, opcionalno gdje bolest koja se liječi, jest rak.
22. Spoj, naznačen time, da je predstavljen formulom II: [image] i njegove soli i solvati, pri čemu su D, R2, R6, R7, R9, R11a, Y, R'', Y', D', R6', R7', R9', R11a' i R12 (uključujući prisutnost ili odsutnost dvostrukih veza između C2 i C3 odnosno C2' i C3'), kao što su definirani u bilo kojem od patentnih zahtjeva 1 do 9; RL1 i RL2 su poveznice za spajanje na sredstvo za vezanje stanice, gdje su neovisno predstavljeni formulom IIIa: [image] pri čemu su Q i X kao što su definirani u bilo kojem od patentnih zahtjeva 1, 10 do 12 i 13 do 15 i GL se bira od: [image] [image] gdje Ar predstavlja C5-6 arilen skupinu, primjerice fenilen, i X predstavlja C1-4 alkil.
23. Spoj prema patentnom zahtjevu 22, naznačen time, da je spoj predstavljen formulom Id': [image] u kojoj je m cijeli broj od 2 do 8.
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