HRP20161339T1 - Konjugati analoga cc-1065 s bifunkcionalnim spojnicama - Google Patents

Konjugati analoga cc-1065 s bifunkcionalnim spojnicama Download PDF

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HRP20161339T1
HRP20161339T1 HRP20161339TT HRP20161339T HRP20161339T1 HR P20161339 T1 HRP20161339 T1 HR P20161339T1 HR P20161339T T HRP20161339T T HR P20161339TT HR P20161339 T HRP20161339 T HR P20161339T HR P20161339 T1 HRP20161339 T1 HR P20161339T1
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image
ring
optionally substituted
antibody
linked
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HRP20161339TT
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Patrick Henry Beusker
Rudy Gerardus Elisabeth Coumans
Ronald Christiaan Elgersma
Wiro Michaël Petrus Bernardus MENGE
Johannes Albertus Frederikus Joosten
Henri Johannes Spijker
Franciscus Marinus Hendrikus De Groot
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Syntarga B.V.
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Claims (17)

1. Spoj formule (III): [image] , ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat, naznačen time što V2 je bilo odsutan ili je funkcionalni ostatak; svaki L2 je neovisno odsutan ili je povezujuća skupina koja povezuje V2 s L; svaki L je neovisno odsutan ili je povezujuća skupina koja povezuje L2 s jednim ili više V1 i/ili Y; svaki V1 je neovisno odsutan ili uvjetno odcjepljiv ili uvjetno transformabilan ostatak, kojeg se može odcijepiti ili transformirati kemijskim, fotokemijskim, fizičkim, biološkim ili enzimskim postupkom; svaki Y je samouklonjiv sustav razmaknica kojeg čini 1 ili više samouklonjivih razmaknica i povezan je s V1, izborno s L, te s jednim ili više Z; svaki od p i q je broj koji predstavlja stupanj grananja i svaki je neovisno pozitivni cijeli broj; z je pozitivni cijeli broj jednak ili manji od ukupnog broja mjesta vezanja za Z; svaki Z je neovisno spoj formule (I) ili (II): [image] [image] , ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat, gdje je DB ostatak koji se veže na DNA i bira se iz skupine koju čine [image] R1 je izlazna skupina; R2, R2′, R3, R3′, R4, R4′, R12 i R19 se neovisno bira između H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2 C(O)H, C(O)OH, halogena, Ra, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, OS(O)Ra, OS(O)2Ra, OS(O)ORa, OS(O)2ORa, ORa, NHRa, N(Ra)Rb, +N(Ra)(Rb)Rc, P(O)(ORa)(ORb), OP(O)(ORa)(ORb), SiRaRbRc, C(O)Ra, C(O)ORa, C(O)N(Ra)Rb, OC(O)Ra, OC(O)ORa, OC(O)N(Ra)Rb, N(Ra)C(O)Rb, N(Ra)C(O)ORb i N(Ra)C(O)N(Rb)Rc, gdje Ra, Rb i Rc se neovisno bira između H i izborno supstituiranog C1-3 alkila ili C1-3 heteroalkila, ili R3 + R3 i/ili R4 + R4′ se neovisno bira između =O, =S, =NOR18, =C(R18)R18′ i =NR18, R18, gdje se R18′ neovisno bira između H i izborno supstituiranog C1-3 alkila, gdje su dva ili više od R2, R, R3, R3′, R4, R i R izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; X2 se bira između O, C(R14)(R14′) i NR14′, gdje R14 i R14′ imaju isto značenje kao što je definirano za R7 i neovisno ih se bira, ili su R14′ i R7′ odsutni, što rezultira dvostrukom vezom između atoma predviđenih da nose R7′ i R14′; R5, R5′, R6, R6′, R7 i R7′ se neovisno bira između H, OH, SH, NH2, N3, NO2 NO, CF3, CN, C(O)NH2C(O)H, C(O)OH, halogen, Re, SRe, S(O)Re, S(O)2Re, S(O)ORe, S(O)2ORe, OS(O)Re, OS(O)2Re, OS(O)ORe, OS(O)2ORe, ORe, NHRe, N(Re)Rf, +N(Re)(Rf)Rg, P(O)(ORe)(ORf), OP(O)(ORe)(ORf), SiReRfRg, C(O)Re, C(O)ORe, C(O)N(Re)Rf, OC(O)Re, OC(O)ORe, OC(O)N(Re)Rf, N(Re)C(O)Rf, N(Re)C(O)ORf, N(Re)C(O)N(Rf)Rg i skupine topljive u vodi, gdje Re, Rf i Rg se neovisno bira između H i izborno supstituiranog (CH2CH2O)eeCH2CH2X13Re1, C1-15 alkil, C1-15 heteroalkila, C3-15 cikloalkila, C1-15 heterocikloalkila, C5-15 arila ili C1-15 heteroarila, gdje se ee bira između 1 do 1000, X13 se bira između O, S i NRf1, a Rf1 i Re1 se neovisno bira između H i C1-3 alkila, gdje jedan ili više izbornih supstituenata u Re, Rf i/ili Rg može biti skupina topljiva u vodi, dva ili više od Re, Rf i Rg su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla, ili se R5 + R5′ i/ili R6 + R6′ i/ili R7 + R7′ neovisno biraju između =O, =S, =NORe3, =C(Re3)Re4 i =NRe3, Re3 i Re4 se neovisno biraju između H i izborno supstituiranog C1-3 alkila, ili su R5′ + R6′ i/ili R6′ + R7′ i/ili R7′ + R14′ odsutni, što rezultira dvostrukom vezom između atoma predviđenih da nose R5′ i R, i/ili R i R7′, odnosno R7′ i R14′, dva ili više od R5, R5′, R6, R6′, R7, R7′, R14 i R14′ su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; X1 je O, a Y je povezan s X1 preko ω-amino-aminokarbonilne ciklizacijske razmaknice koja je dio Y; X3 se bira između O, S, C(R15)R15′, -C(R15)(R15′)-C(R15′′)(R15′′′)-, -N(R15)-N(R15′)-, -C(R15)(R15′)-N(R15")-, -N(R15′′)-C(R15)(R15′)-, -C(R15)(R15′)-O-, -O-C(R15)(R15′)-, -C(R15)(R15′)-S-, -S-C(R15)(R15′)-, -C(R15)=C(R15′)-, =C(R15)-C(R15′)=, -N=C(R15′)-, =N-C(R15′)=, -C(R15)=N-, =C(R15)-N=, -N=N-, =N-N=, CR15, N i NR15, ili u DB1 i DB2 -X3- predstavlja -X3a i X3b-, gdje je X3a povezan s X34, dvostruka veza je prisutna između X34 i X4, a X3b je povezan s X11, gdje se X3a neovisno bira između H i izborno supstituiranog (CH2CH2O)eeCH2CH2X13Re1, C1-8 alkila ili C1-8 heteroalkila i nije povezan s bilo kojim drugim supstituentom; X4 se bira između O, S, C(R16)R16′, NR16, N i CR16; X5 se bira između O, S, C(R17)R17′, NOR17 i NR17, gdje se R17 i R17′ neovisno biraju između H i izborno supstituiranog C1-8 alkila ili C1-8 heteroalkila i nisu povezani s bilo kojim drugim supstituentom; X6 se bira između CR11, CR11(R11′), N, NR11, O i S; X7 se bira između CR8, CR8(R8′), N, NR8, O i S; X8 se bira između CR9, CR9(R9′), N, NR9, O i S; X9 se bira između CR10, CR10(R10′), N, NR10, O i S; X10 se bira između CR20, CR20(R20′), N, NR20, O i S; X11 se bira između C, CR21 i N, ili se X11-X3b bira između CR21, CR21(R21′), N, NR21, O i S; X12 se bira između C, CR22 i N; X6*, X7*, X8*, X9*, X10* i X11* imaju isto značenje kao što je definirano za X6, X7, X8, X9, X10 odnosno X11, te se neovisno biraju; X34 se bira između C, CR23 i N; atom X11* u prstenu B u DB6 i DB7 je povezan s atomom u prstenu u prstenu A, tako da su prsten A i prsten B u DB6 i DB7 izravno povezani jednostrukom vezom; --- znači da naznačena veza može biti jednostruka veza ili nekumulirana, izborno delokalizirana, dvostruka veza; svakog od R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′′, R15′′′, R16, R16′, R20, R20′, R21, R21′, R22 i R23 se neovisno bira između H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2, C(O)H, C(O)OH, halogena, Rh, SRh, S(O)Rh, S(O)2Rh, S(O)ORh, S(O)2ORh, OS(O)Rh, OS(O)2Rh, OS(O)ORh, OS(O)2ORh, ORh, NHRh, N(Rh)Ri, +N(Rh)(Ri)Rj, P(O)(ORh)(ORi), OP(O)(ORh)(ORi), SiRhRiRj, C(O)Rh, C(O)ORh, C(O)N(Rh)Ri, OC(O)Rh, OC(O)ORh, OC(O)N(Rh)Ri, N(Rh)C(O)Ri, N(Rh)C(O)ORi, N(Rh)C(O)N(Ri)Rj i skupine topljive u vodi, gdje Rh, Ri i Rj se neovisno bira između H i izborno supstituiranog (CH2CH2O)eeCH2CH2X13Re1, C1-15 alkila, C1-15 heteroalkila, C3-15 cikloalkila, C1-15 heterocikloalkila, C5-15 arila ili C1-15 heteroarila, gdje jedan ili više izbornih supstituenata u Rh, R1, i/ili Rj može biti skupina topljiva u vodi, dva ili više od Rh, R1 i Rj izborno su povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla, ili se R8 + R8′ i/ili R9 + R9′ i/ili R10 + R10′ i/ili R11 + R11′ i/ili R15 + R15′ i/ili R15′′ + R15′′′ i/ili R16 + R16′ i/ili R20 + R20′ i/ili R21 + R21′ se neovisno biraju između =O, =S, =NORh1, =C(Rh1)Rh2 i =NRh1, Rh1 i Rh2 se neovisno biraju između H i izborno supstituiranog C1-3 alkila, dva ili više od R8, R8, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R20, R20′, R21, R21′, R22 i R23 su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; R8b i R9b se neovisno biraju i imaju isto značenje kao R8, osim što ne mogu biti povezani s bilo kojim drugim supstituentom; jedan od R4 i R4′ i jedan od R16 i R16′ mogu izborno biti povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; jedan od R2, R2′, R3 i R3′ i jedan od R5 i R mogu izborno biti povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; a i b se neovisno bira između 0 i 1; ostatak DB ne sadrži ostatak DA1, DA2, DA1′ ili DA2′ [image] [image] ; prsten B u DB1 je heterocikl; ako X3 u DB1 predstavlja -X3a i X3b-, a prsten B je aromatski, dva vicinalna supstituenta na navedenom prstenu B su povezani kako bi tvorili izborno supstituirani karbocikl ili heterocikl kondenziran s navedenim prstenom B; ako X3 u DB2 predstavlja -X3a i X3b-, a prsten B je aromatski, dva vicinalna supstituenta na navedenom prstenu B su povezani kako bi tvorili izborno supstituirani heterocikl kondenziran s navedenim prstenom B, izborno supstituirani nearomatski karbocikl kondenziran s navedenim prstenom B ili supstituirani aromatski karbocikl kondenziran s navedenim prstenom B i s kojim je vezan najmanje jedan supstituent koji sadrži hidroksi skupinu, primarnu amino skupinu ili sekundarnu amino skupinu, gdje primarni ili sekundarni amin nije atom u prstenu u sustavu aromatskih prstena niti je dio amida; ako je prsten A u DB2 6-eročlani aromatski prsten, supstituenti na prstenu B nisu povezani kako bi tvorili prsten kondenziran s prstenom B; dva vicinalna supstituenta na prstenu A u DB8 su povezani kako bi tvorili izborno supstituirani karbocikl ili heterocikl kondenziran s navedenim prstenom A kako bi tvorili biciklički ostatak s kojim nisu kondenzirani nikakvi dodatni prsteni ; prsten A u DB9 zajedno s bilo kojim prstenima kondenziranim s navedenim prstenom A sadrži najmanje dva heteroatoma u prstenu; i jedan ili više od R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R20, R20′, R21, R21′, R22 i R23 mogu izborno u biti dodatno supstituirani s ili biti supstituent formule (V): [image] , gdje svaki V2′, L2′, L′, V1′, Y′, Z′, p′, q′ i z′ ima isto značenje kao što je definirano za V2, L2, L, V1, Y, Z, p, q odnosno z i neovisno se bira, gdje su jedan ili više supstituenata formule (V) neovisno povezani preko Y′ s jednim ili više od R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R20, R20′, R21, R21′, R22, R23, i/ili s jednim ili više atoma koji nose te R supstituente; svaki Z je povezan s Y preko X1; i u najmanju ruku je prisutan V2 ili V1; gdje je ω-amino-aminokarbonilna ciklizacijska razmaknica koja je dio Y [image] [image]
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je DB DB1.
3. Spoj u skladu s patentnim zahtjevom 1 ili 2, naznačen time što se DB bira između [image]
4. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time što se DB bira između [image]
5. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time što se DB bira između [image]
6. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time što je Z [image] ili izomer jednog od navedenih, ili smjesa izomera.
7. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 6, naznačen time što je Z [image] [image] ili izomer jednog od navedenih, ili smjesa izomera.
8. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time što se L bira između [image]
9. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 8, naznačen time što je L2 [image]
10. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 9, naznačen time što je [image] , ili izomer, ili smjesa izomera, gdje se R5 bira između H, metila i metoksi, R6, R7 i R14 su H, DB je DB1, V1 se bira između valilcitrulina, valillizina, fenilalanillizina, alanilfenilalanillizina i d-alanilfenilalanillizina, f je 1 ili 2, CL se bira između: [image] L se bira između [image] q je u rasponu od 1 do 4, a Ab je protutijelo, ili njegov fragment ili derivat.
11. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 10, naznačen time što je ostatak V2 protutijelo koje se bira između protutijela protiv CD19, protutijela protiv CD22, protutijela protiv CD30, protutijela protiv CD33, protutijela protiv CD56, protutijela protiv CD70, protutijela protiv CD74, protutijela protiv CD138, protutijela protiv CLL-1, protutijela protiv 5T4, protutijela protiv CD303, protutijela protiv Tag 72, protutijela protiv ugljikohidrata sličnog Lewis A, protutijela protiv EphB3, protutijela protiv HMW-MAA, protutijela protiv CD38, protutijela protiv Cripto, protutijela protiv EphA2, protutijela protiv GPNMB, protutijela protiv integrin, protutijela protiv MN, protutijela protiv Her2 i protutijela protiv PSMA, ili između epitopno vežućeg funkcionalnog fragmenta ili derivata bilo kojeg od navedenih, osobito protutijela protiv Her2, trastuzumaba.
12. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je [image] , gdje je DB [image] , V1 je valilcitrulin, CL je [image] L je [image] , q je u rasponu od 1 do 4, a Ab je trastuzumab.
13. Spoj formule (IV): [image] , ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat, naznačen time što RM je reaktivni ostatak, a L, V1, Y, Z, p i z su definirani kao u patentnom zahtjevu 1, osim što L sada povezuje RM s jednim ili više V1 i/ili Y, a V1, Y i Z mogu sadržavati zaštitne skupine, gdje jedan ili više ostataka V2′-L2′ koji mogu biti prisutni u Z kao što je definirano gore u ovom dokumentu mogu umjesto toga izborno i neovisno biti RM′, koji je reaktivni ostatak, te gdje su, ako je u (IV) prisutno više od 1 reaktivnog ostatka, neki ili svi reaktivni ostaci isti ili različiti.
14. Spoj u skladu s patentnim zahtjevom 13, naznačen time što je reaktivni ostatak RM [image] gdje X35 se bira između halogenida, hidroksi, OC(O)Rdd i OC(O)ORdd, ili je C(O)-X35 aktivni ester, X36 se bira između halogenida, mesiloksi, trifliloksi i tosiloksi, a Rdd se bira između izborno supstituiranog C1-10 alkila, C1-10 heteroalkila, C3-10 cikloalkila, C1-10 heterocikloalkila, C5-10 arila i C1-10 heteroarila.
15. Spoj u skladu s patentnim zahtjevom 13 ili 14, naznačen time što je [image] , ili izomer, ili smjesa izomera, gdje se R5a bira između H, metila i metoksi, AZ je [image] [image] V1 se bira između valilcitrulina, valillizina, fenilalanillizina, alanilfenilalanillizina i d-alanilfenilalanillizina, CL je [image] a L se bira između [image]
16. Spoj u skladu s bilo kojim od patentnih zahtjeva 13 do 15, naznačen time što ga se bira između [image] [image] [image] .
17. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 16, naznačen time što je namijenjen upotrebi kao medikament, osobito u liječenju ili sprječavanju tumora kod sisavca.
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