HRP20170334T1 - Spojevi enedina, njihovi konjugati, primjene i metode - Google Patents

Spojevi enedina, njihovi konjugati, primjene i metode Download PDF

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HRP20170334T1
HRP20170334T1 HRP20170334TT HRP20170334T HRP20170334T1 HR P20170334 T1 HRP20170334 T1 HR P20170334T1 HR P20170334T T HRP20170334T T HR P20170334TT HR P20170334 T HRP20170334 T HR P20170334T HR P20170334 T1 HRP20170334 T1 HR P20170334T1
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Naidu S. Chowdari
Sanjeev Gangwar
Bilal Sufi
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Bristol-Myers Squibb Company
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • A61K47/50—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
    • A61K47/51—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
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • 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
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Peptides Or Proteins (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Claims (13)

1. Spoj koji ima strukturu predstavljenu formulom (I) [image] gdje R0 je NHR1a, NHC(=O)OR1b, NHC(=O)NHR1b, OC(=O)NHR1b, (CH2)1-4NHR1a, F, Cl, Br, OR1a, ili SR1b; R1a je H, C1-C6 alkil, (CH2)nNH2, C(=O)(CH2)nNH2, C(=O)CHR8NH2, ili C(=O)R9NH2; R1b je H, C1-C6 alkil, (CH2)nNH2, [image] R2 je H, R10, C(=O)R10, ili C(=O)OR10; R3 je H ili nesupstituirani ili supstituirani C1-C6 alkil; R4 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R5 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R6 je H ili nesupstituirani ili supstituirani C1-C6 alkil; ili R5 i R6 se kombiniraju da formiraju =O; R7 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b; OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R8 je ostatak bočnog lanca α-amino kiseline odabrane od grupe koja se sastoji od alanin, arginin, asparagin, asparaginska kiselina, γ-karboksiglutaminska kiselina, citrulin, cistein, glutaminska kiselina, glutamin, glicin, histidin, izoleucin, leucin, lizin, metionin, norleucin, norvalin, ornitin, fenilalanin, serin, treonin, triptofan, tirozin, i valin; R9 je nesupstituiran ili supstituiran arilen, nesupstituiran ili supstituiran heteroarilen, nesupstituiran ili supstituiran alkilarilen, nesupstituiran ili supstituiran cikloalkilen ili nesupstituiran ili supstituiran heterocikloalkilen; svako R10 je nezavisno nesupstituiran ili supstituiran C1-C6 alkil, nesupstituiran ili supstituiran cikloalkil, nesupstituiran ili supstituiran heterocikloalkil, nesupstituiran ili supstituiran arilalkil, nesupstituiran ili supstituiran aril; ili nesupstituiran ili supstituiran heteroaril; gdje supstituenti supstituiranih dijelova su nezavisno jedan od drugog odabrani od alkil, alkenil, alkinil, aril, heteroaril, cikloalifatik, heterocikloalifatik, halo, haloalkil, hidroksil, hidroksialkil, cijano, nitro, alkoksi, -O(hidroksialkil), -O(haloalkil), -O(cikloalkil), -O(heterocikloalkil), -O(aril), alkiltio, ariltio, =O, =NH, =N(alkil), =NOH, =NO(alkil), -C(=O)(alkil), -C(=O)H, -CO2H, -C(=O)NHOH, -C(=O)O(alkil), -C(=O)O(hidroksialkil), -C(=O)NH2, -C(=O)NH(alkil), -C(=O)N(alkil)2, -OC(=O)(alkil), -OC(=O)(hidroksialkil), -OC(=O)O(alkil), -OC(=O)O(hidroksialkil), -OC(=O)NH2, -OC(=O)NH(alkil), -OC(=O)N(alkil)2, azido, -NH2, -NH(alkil), -N(alkil)2, -NH(aril), -NH(hidroksialkil), -NHC(=O)(alkil), -NHC(=O)H, -NHC(=O)NH2, -NHC(=O)NH(alkil), -NHC(=O)N(alkil)2, -NHC(=NH)NH2, -OSO2(alkil), -SH, -S(alkil), -S(aril), -S(cikloalkil), -S(=O)alkil, -SO2(alkil), -SO2NH2, -SO2NH(alkil), i -SO2N(alkil)2; i n je 2, 3, 4, 5, ili 6; ili njegova farmaceutski prihvatljiva sol.
2. Spoj u skladu sa patentnim zahtjevom 1, koje ima strukturu predstavljenu formulom (Ia): [image]
3. Spoj u skladu sa patentnim zahtjevom 1, koje ima strukturu predstavljenu formulom (Ib): [image]
4. Spoj u skladu sa patentnim zahtjevom 3, gdje R1a je odabrano od grupe koja se sastoji od H, Me, [image] [image] i [image]
5. Konjugat, koji ima strukturu predstavljenu formulom (III) [D(XD)aC(XZ]b]mZ (III) gdje Z je ciljajući dio; XD je prvi dio koji razdvaja; XZ je drugi dio koji razdvaja; C je odvojiva grupa; indeksi a i b su nezavisno 0 ili 1; indeks m je l, 2, 3, 4, 5, 6, 7, 8, 9, ili 10; i D je odabrano iz grupe koja se sastoji od [image] [image] [image] [image] [image] ili [image] gdje R2 je H, R10, C(=O)R10, ili C(=O)OR10; R3 je H ili nesupstituiran ili supstituiran C1-C6 alkil; R4 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R5 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R6 je H ili nesupstituiran ili supstituiran C1-C6 alkil; ili R5 i R6 kombiniraju se da formiraju =O; R7 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R8 je bočni lanac ostatka α-amino kiseline odabran od grupe koja se sastoji od alanin, arginin, asparagin, asparaginska kiselina, γ-karboksiglutaminska kiselina, citrulin, cistein, glutaminska kiselina, glutamin, glicin, histidin, izoleucin, leucin, lizin, metionin, norleucin, norvalin, ornitin, fenilalanin, serin, treonin, triptofan, tirozin, i valin; R9 je nesupstituiran ili supstituiran arilen, nesupstituiran ili supstituiran heteroarilen, nesupstituiran ili supstituiran alkilarilen, nesupstituiran ili supstituiran cikloalkilen ili nesupstituiran ili supstituiran heterocikloalkilen; svako R10 je nezavisno nesupstituiran ili supstituiran C1-C6 alkil, nesupstituiran ili supstituiran cikloalkil, nesupstituiran ili supstituiran heterocikloalkil, nesupstituiran ili supstituiran arilalkil, nesupstituiran ili supstituiran aril; ili nesupstituiran ili supstituiran heteroaril; R12 je C1-C6 alkil; gdje supstituenti supstituiranih dijelova su nezavisno jedan od drugog odabrani od alkil, alkenil, alkinil, aril, heteroaril, cikloalifatik, heterocikloalifatik, halo, haloalkil, hidroksil, hidroksialkil, cijano, nitro, alkoksi, -O(hidroksialkil), -O(haloalkil), -O(cikloalkil), -O(heterocikloalkil), -O(aril), alkiltio, ariltio, =O, =NH, =N(alkil), =NOH, =NO(alkil), -C(=O)(alkil), -C(=O)H, -CO2H, -C(=O)NHOH, -C(=O)O(alkil), -C(=O)O(hidroksialkil), -C(=O)NH2, -C(=O)NH(alkil), -C(=O)N(alkil)2, -OC(=O)(alkil), -OC(=O)(hidroksialkil), -OC(=O)O(alkil), -OC(=O)O(hidroksialkil), -OC(=O)NH2, -OC(=O)NH(alkil), -OC(=O)N(alkil)2, azido, -NH2, -NH(alkil), -N(alkil)2, -NH(aril), -NH(hidroksialkil), -NHC(=O)(alkil), -NHC(=O)H, -NHC(=O)NH2, -NHC(=O)NH(alkil), -NHC(=O)N(alkil)2, -NHC(=NH)NH2, -OSO2(alkil), -SH, -S(alkil), -S(aril), -S(cikloalkil), -S(=O)alkil, -SO2(alkil), -SO2NH2, -SO2NH(alkil), i -SO2N(alkil)2; i n je 2, 3,4, 5, ili 6.
6. Kompozicija koja ima strukturu u skladu sa formulom (IV) D-(XD)aC(XZ)b-R31 (IV) gdje R31 je reaktivna funkcionalna grupa; XD je prvi dio koji razdvaja; XZ je drugi dio koji razdvaja; C je odvojiva grupa; indeksi a i b su nezavisno 0 ili 1; indeks m je l, 2, 3, 4, 5, 6, 7, 8, 9, ili 10; i D je odabrano od grupe koja se sastoji od [image] [image] [image] [image] [image] ili [image] gdje R2 je H, R10, C(=O)R10, ili C(=O)OR10; R3 je H ili nesupstituirani ili supstituirani C1-C6 alkil; R4 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R5 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R6 je H ili nesupstituiran ili supstituiran C1-C6 alkil; ili R5 i R6 koji se kombiniraju da formiraju =O; R7 je OH, SH, NH2, OR10, SR10, NHR10, N(R10)2, NHC(=O)OR10, OC(=O)NHR1b, OC(=O)R10, SC(=O)R10, ili NHC(=O)R10; R8 je ostatak bočnog lanca α-amino kiseline odabrane od grupe koja se sastoji od alanin, arginin, asparagin, asparaginska kiselina, γ-karboksiglutaminska kiselina, citrulin, cistein, glutaminska kiselina, glutamin, glicin, histidin, izoleucin, leucin, lizin, metionin, norleucin, norvalin, ornitin, fenilalanin, serin, treonin, triptofan, tirozin, i valin; R9 je nesupstituiran ili supstituiran arilen, nesupstituiran ili supstituiran heteroarilen, nesupstituiran ili supstituiran alkilarilen, nesupstituiran ili supstituiran cikloalkilen ili nesupstituiran ili supstituiran heterocikloalkilen; svaki R10 je nezavisno nesupstituiran ili supstituiran C1-C6 alkil, nesupstituiran ili supstituiran cikloalkil, nesupstituiran ili supstituiran heterocikloalkil, nesupstituiran ili supstituiran arilalkil, nesupstituiran ili supstituiran aril; ili nesupstituiran ili supstituiran heteroaril; R12 je C1-C6 alkil; gdje su susptituenti supstituiranih dijelova nezavisno jedan od drugog izabrani od alkil, alkenil, alkinil, aril, heteroaril, cikloalifatik, heterocikloalifatik, halo, haloalkil, hidroksil, hidroksialkil, cijano, nitro, alkoksi, -O(hidroksialkil), -O(haloalkil), -O(cikloalkil), -O(heterocikloalkil), -O(aril), alkiltio, ariltio, =O, =NH, =N(alkil), =NOH, =NO(alkil), -C(=O)(alkil), -C(=O)H, -CO2H, -C(=O)NHOH, -C(=O)O(alkil), -C(=O)O(hidroksialkil), -C(=O)NH2, -C(=O)NH(alkil), -C(=O)N(alkil)2, -OC(=O)(alkil), -OC(=O)(hidroksialkil), -OC(=O)O(alkil), -OC(=O)O(hidroksialkil), -OC(=O)NH2, -OC(=O)NH(alkil), -OC(=O)N(alkil)2, azido, -NH2, -NH(alkil), -N(alkil)2, -NH(aril), -NH(hidroksialkil), -NHC(=O)(alkil), -NHC(=O)H, -NHC(=O)NH2, -NHC(=O)NH(alkil), -NHC(=O)N(alkil)2, -NHC(=NH)NH2, -OSO2(alkil), -SH, -S(alkil), -S(aril), -S(cikloalkil), -S(=O)alkil, -SO2(alkil), -SO2NH2, -SO2NH(alkil), i -SO2N(alkil)2; i n je 2, 3, 4, 5, ili 6.
7. Kompozicija prema patentnom zahtjevu 6, gdje R31 je -NH2, -OH, -CO2H, -SH, maleimido, ciklooktin, azido, hidroksilamino, ili N-hidroksisukcinimido.
8. Kompozicija prema bilo kojem od patentnih zahtjeva 1 do 4 ili konjugat prema patentnom zahtjevu 5 za primjenu u metodi za liječenje raka kod subjekta koji je obolio od takvog raka.
9. Kompozicija prema bilo kojem od patentnih zahtjeva 1 do 4 za primjenu u metodi za liječenje raka prema patentnom zahtjevu 8, gdje je spoj konjugiran za ciljajući dio koji je antitijelo.
10. Kompozicija prema bilo kojem od patentnih zahtjeva 1 do 4 za primjenu u metodi za liječenje raka prema patentnom zahtjevu 9, gdje se antitijelo vezuje za antigen koji je prekomjerno eksprimiran ili jedinstveno eksprimiran pomoću raka.
11. Kompozicija prema bilo kojem od patentnih zahtjeva 1 do 4 ili konjugat prema patentnom zahtjevu 5 za primjenu u metodi za liječenje raka prema patentnom zahtjevu 8, gdje je rak odabran iz grupe koja se sastoji od leukemije, raka bubrega, raka jajnika, raka pluća, raka debelog crijeva, raka dojke, i raka prostate.
12. Farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 4 i farmaceutski prihvatljiv nosač.
13. Farmaceutska kompozicija koja sadrži konjugat prema patentnom zahtjevu 5 i farmaceutski prihvatljiv nosač.
HRP20170334TT 2012-02-13 2017-03-01 Spojevi enedina, njihovi konjugati, primjene i metode HRP20170334T1 (hr)

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US201261598143P 2012-02-13 2012-02-13
US201261653785P 2012-05-31 2012-05-31
PCT/US2013/025247 WO2013122823A1 (en) 2012-02-13 2013-02-08 Enediyne compounds, conjugates thereof, and uses and methods therefor
EP13704871.6A EP2814829B1 (en) 2012-02-13 2013-02-08 Enediyne compounds, conjugates thereof, and uses and methods therefor

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