HRP20110955T1 - Citotoksična sredstva koja sadrže nove derivate tomamicina - Google Patents

Citotoksična sredstva koja sadrže nove derivate tomamicina Download PDF

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HRP20110955T1
HRP20110955T1 HR20110955T HRP20110955T HRP20110955T1 HR P20110955 T1 HRP20110955 T1 HR P20110955T1 HR 20110955 T HR20110955 T HR 20110955T HR P20110955 T HRP20110955 T HR P20110955T HR P20110955 T1 HRP20110955 T1 HR P20110955T1
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qsz
cr13r14
cr15r16
och2ch2
ysz
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HR20110955T
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Gauzy Laurence
Zhao Robert
Deng Yonghong
Li Wei
Bouchard Herv
V.J. Chari Ravi
Commercon Alain
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Sanofi
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    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis

Abstract

Spojevi formule (I): naznačeni time što: predstavlja izbornu jednostruku vezu; predstavlja bilo jednostruku vezu ili dvostruku vezu; uz uvjet da kada predstavlja jednostruku vezu, U i U', isti ili različiti, neovisno predstavljaju H, a W i W', iste ili različite, se neovisno bira iz skupine koju čine OH, -OR, -OCOR, -OCOOR, -OCONRR', ciklički karbamat u kojem N10 i C11 čine dio prstena, -NRCONRR', -OCSNHR, ciklički tiokarbamat u kojem N10 i C11 čine dio prstena, -SH, -SR, -SOR, -SOOR, -SO3, -OSO3, -NRSOOR, -NRR', izborno ciklički amin u kojem N10 i C11 čine dio prstena, -NROR', -NRCOR, -N3, cijano, halogen, trialkil ili triarilfosfonij; a kada predstavlja dvostruku vezu, U i U' su odsutni, a W i W' predstavljaju H; • R1, R2, R1', R2' su isti ili različiti i neovisno ih se bira između halogenida ili alkila, izborno supstituiranog s jednim ili više Hal, CN, NRR', CF3, OR, arila, Het, S(O)qR, ili R1, R2, R1' i R2' zajedno tvore skupinu koja sadrži dvostruku vezu, =B odnosno =B'; • B i B' su isti ili različiti i neovisno ih se bira između alkila koji je izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, arila, Het; • A i A' su isti ili različiti i neovisno ih se bira između alkila ili alkenila, od kojih je svaki izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, arila, Het, alkila, alkenil; • Y i Y' su isti ili različiti i neovisno ih se bira između H, OR; • q je 0, 1 ili 2; • n, n' su isti ili različiti i jesu 0 ili 1; • R i R' su isti ili različiti i neovisno ih se bira između H, alkila, arila, od kojih je svaki izborno supstituiran s Hal, CN, NRR', CF3, OR, arilom, Het; • T je -NR- ili 4- do 10-eročlani aril ili heteroaril, od kojih je svaki izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, alkila i supstituiran s jednim ili više supstituenata koji sadrže tiol, sulfid ili disulfid formule: -(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CR17=CR18)(CR15R16)y(OCH2CH2)ySZ'; -(CR13R14)t(NR19CO)(CR15R18)u(OCH2CH2)ySZ'; -(CR13R14)t(OCO)(R15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CO)(CR15R16)u(OCH2CH2)ySZ': -(CR13R14)t(CONR19)(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t-fenil-CO(CR15R16)uSZ'; -(CR13R14)t-furil-CO(CR15R16)uSZ'; -(CR13R14)t-oksazolil-CO(CR15R16)uSZ'; -(CR13R14)t-tiazolil-CO(CR15R16)uSZ'; -(CR13R14)t-tienil-CO(CR15R16)uSZ'; -(CR13R14)t-imidazolil-CO(CR15R16)uSZ', -(CR13R14)t-morfolino-CO(CR15R16)uSZ'; -(CR13R14)t-piperazino-CO(CR15R16)uSZ'; -(CR13R14)t-N-metilpiperazino-CO(CR15R16)uSZ'; -(CR13R14)t-fenil-QSZ'; -(CR13R14)t-furil-QSZ'; -(CR13R14)t-oksazolil-QSZ'; -(CR13R14)t-tiazolil-QSZ'; -(CR13R14)t-tienil-QSZ'; -(CR13R14)t-imidazolil-QSZ'; -(CR13R14)t-morfolino-QSZ'; -(CR13R14)t-piperazino-QSZ'; -(CR13R14)t-N-metilpiperazino-QSZ'; -O(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -O(CR13R14)t-NR19CO)(CR15R16)u(OCH2CH2)ySZ'; -O(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -O-fenil-OSZ'; -O-furil-QSZ'; -O-oksazolil-QSZ'; -O-tiazolil-QSZ'; -O-tienil-QSZ'; -O-i

Claims (26)

1. Spojevi formule (I): [image] naznačeni time što: [image] predstavlja izbornu jednostruku vezu; [image] predstavlja bilo jednostruku vezu ili dvostruku vezu; uz uvjet da kada [image] predstavlja jednostruku vezu, U i U', isti ili različiti, neovisno predstavljaju H, a W i W', iste ili različite, se neovisno bira iz skupine koju čine OH, -OR, -OCOR, -OCOOR, -OCONRR', ciklički karbamat u kojem N10 i C11 čine dio prstena, -NRCONRR', -OCSNHR, ciklički tiokarbamat u kojem N10 i C11 čine dio prstena, -SH, -SR, -SOR, -SOOR, -SO3, -OSO3, -NRSOOR, -NRR', izborno ciklički amin u kojem N10 i C11 čine dio prstena, -NROR', -NRCOR, -N3, cijano, halogen, trialkil ili triarilfosfonij; a kada [image] predstavlja dvostruku vezu, U i U' su odsutni, a W i W' predstavljaju H; • R1, R2, R1', R2' su isti ili različiti i neovisno ih se bira između halogenida ili alkila, izborno supstituiranog s jednim ili više Hal, CN, NRR', CF3, OR, arila, Het, S(O)qR, ili R1, R2, R1' i R2' zajedno tvore skupinu koja sadrži dvostruku vezu, =B odnosno =B'; • B i B' su isti ili različiti i neovisno ih se bira između alkila koji je izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, arila, Het; • A i A' su isti ili različiti i neovisno ih se bira između alkila ili alkenila, od kojih je svaki izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, arila, Het, alkila, alkenil; • Y i Y' su isti ili različiti i neovisno ih se bira između H, OR; • q je 0, 1 ili 2; • n, n' su isti ili različiti i jesu 0 ili 1; • R i R' su isti ili različiti i neovisno ih se bira između H, alkila, arila, od kojih je svaki izborno supstituiran s Hal, CN, NRR', CF3, OR, arilom, Het; • T je -NR- ili 4- do 10-eročlani aril ili heteroaril, od kojih je svaki izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, alkila i supstituiran s jednim ili više supstituenata koji sadrže tiol, sulfid ili disulfid formule: -(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CR17=CR18)(CR15R16)y(OCH2CH2)ySZ'; -(CR13R14)t(NR19CO)(CR15R18)u(OCH2CH2)ySZ'; -(CR13R14)t(OCO)(R15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CO)(CR15R16)u(OCH2CH2)ySZ': -(CR13R14)t(CONR19)(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t-fenil-CO(CR15R16)uSZ'; -(CR13R14)t-furil-CO(CR15R16)uSZ'; -(CR13R14)t-oksazolil-CO(CR15R16)uSZ'; -(CR13R14)t-tiazolil-CO(CR15R16)uSZ'; -(CR13R14)t-tienil-CO(CR15R16)uSZ'; -(CR13R14)t-imidazolil-CO(CR15R16)uSZ', -(CR13R14)t-morfolino-CO(CR15R16)uSZ'; -(CR13R14)t-piperazino-CO(CR15R16)uSZ'; -(CR13R14)t-N-metilpiperazino-CO(CR15R16)uSZ'; -(CR13R14)t-fenil-QSZ'; -(CR13R14)t-furil-QSZ'; -(CR13R14)t-oksazolil-QSZ'; -(CR13R14)t-tiazolil-QSZ'; -(CR13R14)t-tienil-QSZ'; -(CR13R14)t-imidazolil-QSZ'; -(CR13R14)t-morfolino-QSZ'; -(CR13R14)t-piperazino-QSZ'; -(CR13R14)t-N-metilpiperazino-QSZ'; -O(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -O(CR13R14)t-NR19CO)(CR15R16)u(OCH2CH2)ySZ'; -O(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -O-fenil-OSZ'; -O-furil-QSZ'; -O-oksazolil-QSZ'; -O-tiazolil-QSZ'; -O-tienil-QSZ'; -O-imidazolil-QSZ'; -O-morfolino-QSZ'; -O-piperazino-QSZ'; -O-N-metilpiperazino-QSZ'; -OCO-(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)ySZ'; -OCONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -OCO-fenil-QSZ'; -OCO-furil-QSZ'; -OCO-oksazolil-QSZ'; -OCO-tiazolil-QSZ'; -OCO-tienil-QSZ'; -OCO-imidazolil-QSZ'; -OCO-morfolino-QSZ'; -OCO-piperazino-QSZ'; -OCO-N-metilpiperazino-QSZ'; -CO(CR13R14)t(CR15R16)u(OCH2CH2)y SZ'; -CO-(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)ySZ'; -CONR12(CR13R14)t(R15R16)u(OCH2CH2)ySZ'; -CO-fenil-QSZ'; -CO-furil-QSZ'; -CO-oksazolil-QSZ'; -CO-tiazolil-QSZ'; -CO-tienil-QSZ'; -CO-imidazolil-QSZ'; -CO-morfolino-QSZ'; -CO-piperazino-QSZ'; -CO-piperidino-QSZ'; -CO-N-metilpiperazino-QSZ'; -NR19(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -NR19CO(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -NR19(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -NR19CO(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -NR19CONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -NR19CONR12(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -NR19CO-fenil-QSZ'; -NR19CO-furil-OSZ'; -NR19CO-oksazolil-QSZ'; -NR19CO-tiazolil-QSZ'; -NR19CO-tianil-QSZ'; -NR19CO-imidazolil-QSZ'; -NR19CO-morfolino-QSZ'; -NR19CO-piperazino-QSZ'; -NR19CO-piperidino-QSZ'; -NR19CO-N-metilpiperazino-QSZ'; -NR19-fenil-QSZ'; -NR19-furil-QSZ'; -NR19-oksazolil-QSZ'; -NR19-tiazolil-QSZ'; -NR19-tienil-QSZ'; -NR19-imidazolil-QSZ'; -NR19-morfolino-QSZ'; -NR19-piperazino-QSZ'; -NR19-piperidino-QSZ'; -NR19-N-metilpiperazino-QSZ'; -NR19CO-NR12-fenil-QSZ'; -NR19CO-NR12-oksazolil-QSZ'; -NR19CO-NR12-tiazolil-QSZ'; -NR19CO-NR12-tienil-QSZ'; -NR19CO-NR12-piperidino-QSZ'; -S(O)q(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -S(O)q(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -SCONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -SCO-morfolino-QSZ'; -SCO-piperazino-QSZ'; -SCO-piperidino-QSZ'; -SCO-N-metilpiperazino-QSZ' gdje: • Z' je H, Ac, R19' ili SR19'; • Q je izravna veza ili nerazgranati alkil ili razgranati alkil s 1-10 atoma ugljika ili polietilen-glikolna razmaknica s 2 do 20 ponavljajućih etilenoksi jedinica; • R19' i R12 su isti ili različiti i jesu nerazgranati alkil, razgranati alkil ili ciklički alkil s 1 do 10 atoma ugljika, ili nesupstituirani ili supstituirani aril ili heterocikl, a R12 dodatno može biti H; • R13, R14, R15 i R16 su isti ili različiti i jesu H ili nerazgranati ili razgranati alkil s 1 do 4 atoma ugljika; • R17, R18 i R19 su H ili alkil; • u je cijeli broj od 1 do 10, a također može biti i 0; • t je cijeli broj od 1 do 10, a također može biti i 0; • y je cijeli broj od 1 do 20, a također može biti i 0; ili njihove farmaceutski prihvatljive soli, hidrati ili hidratirane soli, ili polimorfne kristalne strukture tih spojeva ili njihovi optički izomeri, racemati, dijastereomeri ili enantiomeri.
2. Spojevi u skladu s patentnim zahtjevom 1, naznačeni time što n = n' = 1.
3. Spojevi u skladu s patentnim zahtjevom 1 ili 2, naznačeni time što su spojevi formule (II): [image]
4. Spojevi u skladu s patentnim zahtjevima 1 do 3, naznačeni time što W i W' su isti ili različiti i jesu OH, OMe, OEt, NHCONH2, SMe.
5. Spojevi u skladu s patentnim zahtjevom 1 ili 2, naznačeni time što su spojevi formule: [image] ili [image]
6. Spojevi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što A = A'.
7. Spojevi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što A = A' = nerazgranati nesupstituirani alkil.
8. Spojevi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što Y = Y'.
9. Spojevi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što Y = Y' = OAlkil.
10. Spojevi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što Y = Y' = OMe.
11. Spojevi u skladu s bilo kojim od prethodnih patentnih zahtjeva, naznačeni time što T je fenil ili piridil.
12. Konjugat, naznačen time što sadrži najmanje jedan spoj formule: [image] gdje: [image] predstavlja izbornu jednostruku vezu; [image] predstavlja bilo jednostruku vezu ili dvostruku vezu; uz uvjet da kada [image] predstavlja jednostruku vezu, U i U', isti ili različiti, neovisno predstavljaju H, a W i W', iste ili različite, se neovisno bira iz skupine koju čine OH, -OR, -OCOR, -OCOOR, -OCONRR', ciklički karbamat u kojem N10 i C11 čine dio prstena, -NRCONRR', -OCS-NHR, ciklički tiokarbamat u kojem N10 i C11 čine dio prstena, -SH, -SR, -SOR, -SOOR, -SO3, -OSO3, -NRSOOR, -NRR', izborno ciklički amin u kojem N10 i C11 čine dio prstena, -NROR', -NRCOR, -N3, cijano, halogen, trialkil ili triarilfosfonij; a kada [image] predstavlja dvostruku vezu, U i U' su odsutni, a W i W' predstavljaju H; • R1, R2, R1', R2' su isti ili različiti i neovisno ih se bira između halogenida ili alkila, izborno supstituiranog s jednim ili više Hal, CN, NRR', CF3, OR, arila, Het, S(O)qR, ili R1, R2, R1' i R2' zajedno tvore skupinu koja sadrži dvostruku vezu, =B odnosno =B'; • B i B' su isti ili različiti i neovisno ih se bira između alkila koji je izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, arila, Het; • A i A' su isti ili različiti i neovisno ih se bira između alkila ili alkenila, od kojih je svaki izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, arila, Het, alkila, alkenil; • Y i Y' su isti ili različiti i neovisno ih se bira između H, OR; • q je 0, 1 ili 2; • n, n' su isti ili različiti i jesu 0 ili 1; • R i R' su isti ili različiti i neovisno ih se bira između H, alkila, arila, od kojih je svaki izborno supstituiran s Hal, CN, NRR', CF3, OR, arilom, Het; • T je -NR- ili 4- do 10-eročlani aril ili heteroaril, od kojih je svaki izborno supstituiran s jednim ili više Hal, CN, NRR', CF3, OR, S(O)qR, alkila i supstituiran s jednom ili više spojnica koje sadrže tiol, sulfid ili disulfid formule: -(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CR17=CR18)(CR15R16)y(OCH2CH2)ySZ'; -(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(OCO)(R15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CO)(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t(CONR19)(CR15R16)u(OCH2CH2)ySZ'; -(CR13R14)t-fenil-CO(CR15R16)uSZ'; -(CR13R14)t-furil-CO(CR15R16)uSZ'; -(CR13R14)t-oksazolil-CO(CR15R16)uSZ'; -(CR13R14)t-tiazolil-CO(CR15R16)uSZ'; -(CR13R14)t-tienil-CO(CR15R16)uSZ'; -(CR13R14)t-imidazolil-CO(CR15R16)uSZ', -(CR13R14)t-morfolino-CO(CR15R16)uSZ'; -(CR13R14)t-piperazino-CO(CR15R16)uSZ'; -(CR13R14)t-N-metilpiperazino-CO(CR15R16)uSZ'; -(CR13R14)t-fenil-QSZ'; -(CR13R14)t-furil-QSZ'; -(CR13R14)t-oksazolil-QSZ'; -(CR13R14)t-tiazolil-QSZ'; -(CR13R14)t-tienil-QSZ'; -(CR13R14)t-imidazolil-QSZ'; -(CR13R14)t-morfolino-QSZ'; -(CR13R14)t-piperazino-QSZ'; -(CR13R14)t-metilpiperazino-QSZ'; -O(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -O(CR13R14)t(NR19CO)(CR15R16)u(OCH2CH2)ySZ'; -O(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -O-fenil-QSZ'; -O-furil-QSZ'; -O-oksazolil-QSZ'; -O-tiazolil-QSZ'; -O-tienil-OSZ'; -O-imidazolil-QSZ'; -O-morfolino-OSZ'; -O-piperazino-QSZ'; -O-N-metilpiperazino-QSZ'; -OCO-(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)ySZ'; -OCONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -OCO-fenil-QSZ'; -OCO-furil-QSZ'; -OCO-oksazolil-QSZ'; -OCO-tiazolil-OSZ'; -OCO-tienil-QSZ'; -OCO-imidazolil-QSZ'; -OCO-morfolino-QSZ'; -OCO-piperazino-QSZ'; -OCO-N-metilpiperazino-QSZ'; -CO(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -CO-(CR13R14)t(CR17=CR18)(CR15R16)u(OCH2CH2)ySZ'; -CONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -CO-fenil-QSZ'; -CO-furil-QSZ'; -CO-oksazolil-QSZ'; -CO-tiazolil-QSZ'; -CO-tienil-QSZ'; -CO-imidazolil-QSZ'; -CO-morfolino-QSZ'; -CO-piperazino-OSZ'; -CO-piperidino-QSZ'; -CO-N-metilpiperazino-QSZ'; -NR19(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -NR19CO(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -NR19(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -NR19CO(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -NR19CONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -NR19CONR12(CR13R14)t(CR17=CR18)(CR15R18)t(OCH2CH2)ySZ'; -NR19CO-fenil-QSZ'; -NR19CO-furil-QSZ'; -NR19CO-oksazolil-QSZ'; -NR19CO-tiazolil-QSZ'; -NR18CO-tienil-QSZ'; -NR19CO-imidazolil-QSZ'; -NR19CO-morfolino-QSZ'; -NR19CO-piperazino-QSZ'; -NR19CO-piperidino-QSZ'; -NR19CO-N-metilpiperazino-QSZ'; -NR19-fenil-QSZ'; -NR19-furil-QSZ'; -NR19-oksazolil-QSZ'; -NR19-tiazolil-QSZ'; -NR19-tienil-QSZ'; -NR19-imidazolil-QSZ'; -NR19-morfolino-QSZ'; -NR19-piperazino-QSZ'; -NR19-piperidino-QSZ'; -NR19-N-metilpiperazino-QSZ'; -NR19CO-NR12-fenil-QSZ'; -NR19CO-NR12-oksazolil-QSZ'; -NR19CO-NR12-tiazolil-QSZ'; -NR19CO-NR12-tienil-QSZ'; -NR19CO-NR12-piperidino-QSZ'; -S(O)q(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -S(O)q(CR13R14)t(CR17=CR18)(CR15R16)t(OCH2CH2)ySZ'; -SCONR12(CR13R14)t(CR15R16)u(OCH2CH2)ySZ'; -SCO-morfolino-QSZ'; -SCO-piperazino-QSZ'; -SCO-piperidino-QSZ'; -SCO-N-metilpiperazino-QSZ' gdje: • Z' je H, Ac, R19' ili SR19'; • Q je izravna veza ili nerazgranati alkil ili razgranati alkil s 1-10 atoma ugljika ili polietilen-glikolna razmaknica s 2 do 20 ponavljajućih etilenoksi jedinica; • R19' i R12 su isti ili različiti i jesu nerazgranati alkil, razgranati alkil ili ciklički alkil s 1 do 10 atoma ugljika, ili nesupstituirani ili supstituirani aril ili heterocikl, a R12 dodatno može biti H; • R13, R14, R15 i R16 su isti ili različiti i jesu H ili nerazgranati ili razgranati alkil s 1 do 4 atoma ugljika; • R17, R18 i R19 su H ili alkil; • u je cijeli broj od 1 do 10, a također može biti i 0, • t je cijeli broj od 1 do 10, a također može biti i 0, • y je cijeli broj od 1 do 20, a također može biti i 0; ili njihove farmaceutski prihvatljive soli, hidrati ili hidratirane soli, ili polimorfne kristalne strukture tih spojeva ili njihovi optički izomeri, racemati, dijastereomeri ili enantiomeri, gdje je navedeni spoj kovalentno vezan na sredstvo za vezanje na stanicu preko navedene spojnice.
13. Konjugat u skladu s patentnim zahtjevom 12, naznačen time što U, U', W, W, T, R1, R2, R1', R2', Y, Y', A, A', n, n', [image] , [image] 13. su definirani kao u patentnim zahtjevima 2 do 11.
14. Konjugat u skladu s patentnim zahtjevom 12 ili 13, naznačen time što navedeno sredstvo za vezanje na stanicu se bira između protutijela, fragmenta protutijela koji sadrži najmanje jedno mjesto vezanja, limfokina, hormona, čimbenika rasta, molekula za transport nutricijenata.
15. Konjugat u skladu s patentnim zahtjevima 12 do 14, naznačen time što sredstvo za vezanje na stanicu se bira između monoklonskih protutijela; jednolančanih protutijela; Fab, Fab', F(ab')2 i Fv, interferona; peptida; IL-2, IL-3, IL-4, IL-6; inzulina, TRH (tireotropin-otpuštajućih hormona), MSH (melanocitno-stimulirajućeg hormona), steroidnih hormona, androgena, estrogena; EGF, TGFα, inzulinu sličnog čimbenika rasta (IGF-I, IGF-II) G-CSF, M-CSF, GM-CSF; folata, transferin.
16. Farmaceutski pripravak, naznačen time što sadrži konjugat u skladu s patentnim zahtjevima 12 do 15 ili spoj u skladu s patentnim zahtjevima 1 do 11, zajedno s farmaceutski prihvatljivom podlogom.
17. Postupak dobivanja konjugata u skladu s patentnim zahtjevima 12 do 15, naznačen time što se sastoji u koraku u kojem spoj formule (I) u skladu s patentnim zahtjevom 1, u kojem T sadrži sulfidnu, disulfidnu ili tiolnu skupinu, ili njegov preteča, reagira sa sredstvom za vezanje na stanicu, koje sadrži funkcionalnu skupinu koja reagira s disulfidom ili tiolom, tako da se spoj i sredstvo za vezanje na stanicu vežu zajedno kovalentnom vezom.
18. Postupak dobivanja konjugata, naznačen time što slobodno ili zaštićeno sredstvo za vezanje na stanicu koje sadrži tiol reagira sa spojem koji sadrži disulfid ili tiol, u skladu s bilo kojim od patentnih zahtjeva 1 do 11, gdje je sredstvo za vezanje na stanicu peptid ili protutijelo modificirano umrežujućim reagensom.
19. Postupak u skladu s patentnim zahtjevom 18, naznačen time što umrežujući reagens je N-sukcinimidil-3-(2-piridilditio)propionat, N-sukcinimidil-4-(2-piridilditio)pentanoat, 4-sukcinimidiloksikarbonil-α-metil-α-(2-piridilditio)toluen, N-sukcinimidil-3-(2-piridilditio)butirat, N-sulfosukcinimidil-3-(2-(5-nitropiridilditio)butirat, 2-iminotiolan ili S-acetilsukcinanhidrid.
20. Postupak u skladu s patentnim zahtjevom 17, naznačen time što: – tiopiridilnu skupinu u monoklonskom protutijelu modificiranom sukcinimidil-piridilditiopropionatom se zamijenjuje obradom spojem koji sadrži tiol, u skladu s bilo kojim od patentnih zahtjeva 1 do 11, kako bi se dobilo disulfidno vezani konjugat; – aril-tiolnu skupinu u spoju u skladu s bilo kojim od patentnih zahtjeva 1 do 11 se zamjenjuje sulfhidrilnim skupinama, uvedenim ranije u protutijelo, kako bi se dobilo disulfidno vezani konjugat.
21. Postupak u skladu s patentnim zahtjevom 17, naznačen time što spoj koji sadrži tiol u skladu s bilo kojim od patentnih zahtjeva 1 do 11 je vezan tioeterskom vezom s protutijelom ili sredstvom za vezanje na stanicu modificiranim N-sukcinimidil-4-(maleimidometil)cikloheksankarboksilatom, N-sukcinimidil-4-(N-maleimidometil)cikloheksan-1-karboksi-(6-amidokaproatom).
22. Postupak u skladu s patentnim zahtjevom 17, naznačen time što umrežujući reagens sadrži ostatak na bazi halogenacetila i bira ga se između sukcinimidil-4-(jodacetil)aminobenzoata, N-sukcinimidil-jodacetata, N-sukcinimidil-bromacetata ili N-sukcinimidil-3-(bromacetamido)propionata.
23. Postupak u skladu s patentnim zahtjevima 17 do 22, naznačen time što konjugat se pročišćuje: • standardnim kromatografskim tehnikama, koje se bira između HPLC-a, gel-permeacijske kromatografije, adsorpcijske kromatografije, ionsko-izmjenjivačke kromatografije, kromatografije s hidrofobnim međudjelovanjem ili afinitetne kromatografije, kromatografije na keramičkom hidroapatitu; • ili dijalizom; • ili dijafiltracijom.
24. Upotreba djelotvotne količine konjugata u skladu s bilo kojim od patentnih zahtjeva 12 do 15 ili spoja u skladu s bilo kojim od patentnih zahtjeva 1 do 11, naznačena time što su navedeni konjugat ili spoj namijenjeni pripravi medikamenta za liječenje raka.
25. Spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 11 do, naznačen time što je namijenjen upotrebi kao sredstvo protiv raka.
26. Konjugat u skladu s bilo kojim od patentnih zahtjeva 12 do 15, naznačen time što je namijenjen upotrebi kao sredstvo protiv raka.
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