HRP20171629T1 - Analozi cc-1065 i njihovi konjugati - Google Patents

Analozi cc-1065 i njihovi konjugati Download PDF

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HRP20171629T1
HRP20171629T1 HRP20171629TT HRP20171629T HRP20171629T1 HR P20171629 T1 HRP20171629 T1 HR P20171629T1 HR P20171629T T HRP20171629T T HR P20171629TT HR P20171629 T HRP20171629 T HR P20171629T HR P20171629 T1 HRP20171629 T1 HR P20171629T1
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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 (14)

1. Spoj formule (I) ili (II): [image] [image] , ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat, naznačen time što DB je ostatak koji se veže na DNA, koji je [image] , R1 je halogenid (fluorid, klorid bromid, te jodid), azid, sulfonat (primjerice izborno supstituirani C1-6 alkansulfonat, poput metansulfonata i trifluormetansulfonata, ili izborno supstituirani C7-12 alkilbenzensulfonat, poput p-toluensulfonata), sukcinimid-N-oksid, p-nitrofenoksid, pentafluorfenoksid, tetrafluorfenoksid, karboksilat, te aminokarboksilat (karbamat) ili alkoksikarboksilat (karbonat); R2, R2′, R3, R3′, R4, R4′, R12, te 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, te N(Ra)C(O)N(Rb)Rc, gdje Ra, Rb, te Rc se neovisno bira između H i izborno supstituiranog C1-3 alkila ili C1-3 heteroalkila, ili se R3 + R3′ i/ili R4 + R4′ neovisno bira između =O, =S, =NOR18, =C(R18)R18′, te =NR18, gdje se R18 i R18′ neovisno bira između H i izborno supstituiranog C1-3 alkila, a dva ili više R2, R2′, R3, R3′ R4, R4′, te R12 su 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′), te 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, te R7′ se neovisno bira između H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2, C(O)H, C(O)OH, halogena, 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, te N(Re)C(O)N(Rf)Rg, gdje Re, Rf, te Rg 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 se ee bira između 1 i 1000, X13 se bira između O, S, te NRf1, gdje se Rf1 i Re1 neovisno bira između H i C1-3 alkila, a dva ili više Re, Rf, te 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 bira između =O, =S, =NORe3, =C(Re3)Re4, te =NRe3, gdje se Re3 i Re4 neovisno bira 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 odgovarajuće nose R5′ i R6′, i/ili R6′ i R7′, i/ili R7′ i R14′, a dva ili više of R5, R5′, R6, R6′, R7, R7′, R14, te R14′ su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; X1 se bira između O, S, te NR13, gdje se R13 bira između H i izborno supstituiranog C1-8 alkila ili C1-8 heteroalkila i nije povezan niti sa jednim drugim supstituentom; 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, te NR15; X4 se bira između O, S, C(R16)R16′, NR16, N, te CR16 X5 se bira između O, S, C(R17)R17′, NOR17, te NR17, gdje se R17 i R17′ neovisno bira između H i izborno supstituiranog C1-8 alkila ili C1-8 heteroalkila i nisu povezani niti sa jednim drugim supstituentom; X6 se bira između CR11, CR11(R11′), N, NR11, O, te S; X7 se bira između CR8, CR8(R8′), N, NR8, O, te S; X8 se bira između CR9, CR9(R9′), N, NR9, O, te S; X9 se bira između CR10, CR10(R10′), N, NR10, O, te S; X11 se bira između C, CR21, te N; X12 se bira između C, CR22, te N; X34 se bira između C, CR23, te N; [image] 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′′, R15′′, R16, R16′, R21, R22, te 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, te N(Rh)C(O)N(Ri)Rj, gdje Rh, Ri, te 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, a dva ili više Rh, Ri, te Rj su izborno 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 neovisno bira između =O, =S, =NORh1, =C(Rh1)Rh2, te =NRh1, gdje se Rh1 i Rh2 neovisno bira između H i izborno supstituiranog C1-3 alkila, a dva ili više R8, R8′,R9 , R9′, R10, R10′, R11, R11′ R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, te R23 su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; 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, te R3′ i jedan od R5 i R5′ 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.
2. Spoj u skladu s patentnim zahtjevom 1, naznačen time što je DB [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] .
3. Spoj u skladu s patentnim zahtjevom 1 ili 2, naznačen time što je [image] .
4. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačrn time što se R5 bira između metila, etila, propila, izopropila, nitro, CF3, F, Cl, Br, cijano, metoksi, etoksi, propoksi, izopropoksi, amino (NH2), metilamino, formila, hidroksimetila, te dimetilamino.
5. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time što najmanje jedan od supstituenata R1, R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, te R23 sadrži ostatak X14(CH2CH2O)ffCH2CH2X14, gdje se ff bira između 1 i 1000, a svaki X14 se neovisno bira između [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] , koji je povezan s mjestom vezanja navedenog supstituenta bilo putem izravne veze ili putem ostatka koji je dio istog navedenog supstituenta, koji ne sadrži disulfid, hidrazon, hidrazid, ester, prirodnu aminokiselinu ili peptid koji sadrži najmanje jednu prirodnu aminokiselinu.
6. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 5, naznačen time što najmanje jedan od supstituenata R1, R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′, R16, R16′, R1, R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, te R23 sadrži triazolski ostatak.
7. Spoj formule (I′) ili (II′′): [image] [image] , naznačen time što navedeni spoj sadrži ciklopropilnu skupinu, gdje DB je ostatak koji se veže na DNA, koji je [image] , R2, R2′, R3, R3′, R4, R4′, R12, te 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, te N(Ra)C(O)N(Rb)Rc, gdje Ra, Rb, te Rc se neovisno bira između H i izborno supstituiranog C1-3 alkila ili C1-3 heteroalkila, ili se R3 + R3′ i/ili R4 + R4′ neovisno bira između =O, =S, =NOR18, =C(R18)R18′, te =NR18, gdje se R18 i R18′ neovisno bira između H i izborno supstituiranog C1-3 alkila, a dva ili više R2, R2′, R3, R3′, R4, R4′, te R12 su 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′), te 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, te R7′ se neovisno bira između H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2, C(O)H, C(O)OH, halogena, 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, te N(Re)C(O)N(Rf)Rg, gdje Re, Rf, te Rg 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 se ee bira između 1 i 1000, X13 se bira između O, S, te NRf1, gdje se Rf1 i Re1 neovisno bira između H i C1-3 alkila, a dva ili više Re, Rf, te 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 bira između =O, =S, =NORe3, =C(Re3)Re4, te =NRe3, gdje se Re3 i Re4 neovisno bira između H i izborno supstituiranog C1-3 alkila, ili R5′+ R6′ i/ili R6′ + R7 i/ili R7′ + R14′ su odsutni, što rezultira dvostrukom vezom između atoma predviđenih da odgovarajuće nose R5′ i R6′, i/ili R6′ i R7′, i/ili R7′ i R14′, dva ili više of R5, R5′, R6, R6, R7, R7′, R14, te R14′ su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; X1 se bira između O, S, te NR13, gdje se R13 bira između H i izborno supstituiranog C1-8 alkila ili C1-8 heteroalkila i nije povezan niti sa jednim drugim supstituentom; 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, te NR15; X4 se bira između O, S, C(R16)R16′, NR16, N, te CR16; X5 se bira između O, S, C(R17)R17′ NOR17, te NR17, gdje se R17 i R17′ neovisno bira između H i izborno supstituiranog C1-8 alkila ili C1-8 heteroalkila i nisu povezani niti sa jednim drugim supstituentom; X6 se bira između CR11, CR11(R11′), N, NR11, O, te S; X7 se bira između CR8, CR8(R8′), N, NR8, O, te S; X8 se bira između CR9, CR9(R9′), N, NR9, O, te S; X9 se bira između CR10, CR10(R10′), N, NR10, O, te S; X11 se bira između C, CR21, te N; X12 se bira između C, CR22, te N; X34 se bira između C, CR23, te N; [image] znači da naznačena veza može biti jednostruka veza ili nekumulirana, izborno delokalizirana, dvostruka veza; R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, te R23 svakog od 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, te N(Rh)C(O)N(Ri)Rj, gdje Rh, Ri, te 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, a dva ili više Rh, R1, i Rj su izborno 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 neovisno bira između =O, =S, =NORh1, =C(Rh1)Rh2, te =NRh1, gdje se Rh1 i Rh2 neovisno bira između H i izborno supstituiranog C1-3 alkila, a dva ili više R8, R8′,R9 ,R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, te R23 su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla; 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 R5′ 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] [image] [image] ; prsten B u DB1 je heterocikl.
8. Spoj formule (III): [image] , ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat, naznačen time što V2 je bilo odsutan ili protutijelo ili fragment protutijela; svaki L2 je neovisno odsutan ili je spojna skupina [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] , koja spaja V2 s L; svaki L je neovisno odsutan ili je spojna skupina, koja spaja L2 s jednim ili više V1 i/ili Y, te se bira između [image] i [image] i [image] , gdje je svaki od rr, rr′, te rr′′ neovisno u rasponu od 0 do 8, svaki X40 i X41 se neovisno bira između O, S, te NR135, gdje se R135 bira između H i C1-3 alkila, a svaki uu, uu′, te uu′′ se neovisno bira između 0 i 1; svaki V1 je neovisno odsutan ili je jedan aminokiselinski, dipeptidni, tripeptidni, tetrapeptidni ili oligopeptidni ostatak, koji se sastoji od prirodnih l-aminokiselina, neprirodnih d-aminokiselina ili sintetskih aminokiselina, ili je peptidomimetik, ili bilo koja njihova kombinacija; svaki Y je neovisno odsutan ili samouklanjajući sustav razmaknica, koji se bira između [image] i [image] i [image] i [image] i [image] i [image] , gdje se R117, R118, R119, te R120 neovisno bira između H, OH, SH, NH2, N3, NO2, NO, CF3, CN, C(O)NH2, C(O)H, C(O)OH, halogena, Rz, SRz, S(O)Rz, S(O)2Rz, S(O)ORz, S(O)2ORz, OS(O)Rz, OS(O)2Rz, OS(O)ORz, OS(O)2ORz, ORz, NHRz, N(Rz)Rz1, +N(Rz)(Rz1)Rz2, P(O)(ORz)(ORz1), OP(O)(ORz)(ORz1), C(O)Rz, C(O)ORz, C(O)N(Rz1)Rz, OC(O)Rz, OC(O)ORz, OC(O)N(Rz)Rz1, N(Rz1)C(O)Rz, N(Rz1)C(O)ORz, te N(Rz1)C(O)N(Rz2)Rz, gdje se Rz, Rz1, te Rz2 neovisno bira između H i izborno supstituiranog (CH2CH2O)eeCH2CH2X13Re1, C1-20 alkila, C1-20 heteroalkila, C3-20 cikloalkila, C1-20 heterocikloalkila, C5-20 arila ili C1-20 heteroarila, gdje se ee bira između 1 i 1000, X13 se bira između O, S, NRf1, gdje se Rf1 i Re1 neovisno bira između H i C1-3 alkila, dva ili više Rz, Rz1, te Rz2 su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla, a dva ili više supstituenata R117, R118, R119, te R120 su izborno povezani jednom ili više veza kako bi tvorili jedan ili više izborno supstituiranih karbocikla i/ili heterocikla, te je spojen s V1, izborno L, te jednim ili više Z; svaki p i q su brojevi koji predstavljaju stupanj grananja i svaki od 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 u skladu s bilo kojim od patentnih zahtjeva 1 do 6, gdje jedan ili više X1, R5, R5, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, te R23 mogu izborno biti dodatno supstituirani s ili biti supstituent formule (V): [image] , gdje svaki V2′, L2′, L′, V1′, Y′, Z′, p′, q′, te z′ ima isto značenje kao što je definirano za V2, L2, L, V1, Y, Z, p, q, odnosno z, te se neovisno bira, gdje je jedan ili više supstituenti formule (V) neovisno povezan putem Y′ s jednim ili više X1, R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, R23, i/ili s jednim ili više atoma koji nose te supstituente R; svaki Z je neovisno povezan s Y preko bilo X1, atoma u R5, R5′, R6, R6′, R7, R7′, R14, R14′, R8, R8′, R9, R9′, R10, R10′, R11, R11′, R15, R15′, R15′′, R15′′′, R16, R16′, R21, R22, R23, ili atoma koji nosi bilo koji od tih supstituenata R; i prisutan je u najmanju ruku V2 ili V1.
9. Spoj u skladu s patentnim zahtjevom 8, naznačen time što je X1 O, a Y je povezan s X1 putem ω-amino aminokarbonilne ciklizacijske razmaknice koja je dio Y.
10. Spoj u skladu s patentnim zahtjevom 8 ili 9, naznačen time što je [image] , gdje su R5, R6, R7, R14, te DB definirani kao u bilo kojem od patentnih zahtjeva 1 do 6, V1 se bira između valilcitrulina, valillizina, fenilalanillizina, alanilfenilalanillizina, te d-alanilfenilalanillizina, f je 1 ili 2, L se bira između [image] i [image] i [image] , q je u rasponu od 1 do 20, svaki od rr, rr′, te rr′′ je neovisno u rasponu od 0 do 8, svaki X40 i X41 se neovisno bira između O, S, te NR135, gdje se R135 bira između H i C1-3 alkila, svaki uu, uu′, te uu′′ se neovisno bira između 0 i 1, a Ab je protutijelo ili njegov fragment.
11. Spoj formule (IV): [image] , ili njegova farmaceutski prihvatljiva sol, hidrat ili solvat, naznačen time što RM je reaktivni ostatak, koji se bira između [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] ili [image] , gdje X35 se bira između halogenida, hidroksi, OC(O)Rdd, te OC(O)ORdd, ili je C(O)-X35 aktivni ester, X36 se bira između halogenida, mesiloksi, trifliloksi, te tosiloksi, a Rdd se bira između izborno supstituiranog C1-10 alkila, C1-10 heteroalkila, C3-10 cikloalkila, C1-10 heterocikloalkila, C5-10 arila, te C1-10 heteroarila; i L, V1, Y, Z, p, te z su definirani kao u patentnom zahtjevu 8, osim što L sada spaja RM s jednim ili više V1 i/ili Y, a jedan ili više ostataka V2′-L2′, izborno prisutnih u Z kao što su definirani gore, mogu umjesto toga izborno i neovisno biti RM′, koji je reaktivni ostatak, te gdje, ako je prisutno više reaktivnih ostataka u (IV), neki ili svi reaktivni ostaci su isti ili različiti.
12. Upotreba spoja u skladu s bilo kojim od patentnih zahtjeva 1 do 11, naznačena time što je spoj namijenjen proizvodnji farmaceutskog pripravka za liječenje ili sprječavanje tumora kod sisavca.
13. Farmaceutski pripravak, naznačen time što sadrži spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 11, kao i farmaceutski prihvatljivu podlogu.
14. Spoj u skladu s patentnim zahtjevom 1, naznačen time što ima bilo koju od sljedećih formula [image] [image] [image] [image] [image] [image]
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