HRP20231642T1 - Konjugati polimer-lijek koji se mogu cijepati - Google Patents

Konjugati polimer-lijek koji se mogu cijepati Download PDF

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HRP20231642T1
HRP20231642T1 HRP20231642TT HRP20231642T HRP20231642T1 HR P20231642 T1 HRP20231642 T1 HR P20231642T1 HR P20231642T T HRP20231642T T HR P20231642TT HR P20231642 T HRP20231642 T HR P20231642T HR P20231642 T1 HRP20231642 T1 HR P20231642T1
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formula
polymer
natural number
drug conjugate
meth
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HRP20231642TT
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Rana SANYAL
Amitav SANYAL
Mehmet Arslan
Burcu SUMER BOLU
Ozgul GOK
Merve KARACIVI
Sadik KAGA
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Rs Arastirma Egitim Danismanlik Ilac Sanayi Ticaret Anonim Sirketi
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Claims (13)

1. Konjugat polimer-lijek formule I [image] naznačen time što • R1 i R2 su neovisno odabrani između H ili -CH3; R3 je odabran između -H ili -CH3; • x je prirodni broj između 1-100; • y je prirodni broj između 1-100; • n je prirodni broj između 1-200 i • L je poveznica koja se može cijepati i • D je najmanje jedno terapeutsko sredstvo; • Z je odabran između -O ili -NH; • A je krajnja skupina koja je izborno inicijator polimerizacije ili njezin fragment; • B je krajnja skupina koja je izborno inicijator polimerizacije ili njezin fragment.
2. Konjugat polimer-lijek prema zahtjevu 1, naznačen time što je poveznica odabrana iz skupine koja sadrži poli(etilen glikol), amino kiselinu, poli(amino kiselinu), polipeptid i kratke peptide.
3. Konjugat polimer-lijek prema zahtjevu 2, naznačen time što je poveznica kratki peptid koji je labilan na katepsin B.
4. Konjugat polimer-lijek prema zahtjevu 3, naznačen time što je kratki peptid odabran iz skupine koja sadrži Gly-Phe-Leu-Gly (SEQ ID NO: 1), Val-Cit (SEQ ID NO: 2), Phe-Lys (SEQ ID NO: 3), Val-Ala (SEQ ID NO: 4), Ala-Leu-Ala-Leu (SEQ ID NO: 5).
5. Konjugat polimer-lijek prema zahtjevu 1, naznačen time što je poveznica C1-C10 ugljikovodik ili C1-C10 supstituirani ili hetero supstituirani ugljikovodik, koji sadrži funkcionalnu skupinu koja disocira pod fiziološkim uvjetima, poželjno je navedena funkcionalna skupina odabrana od acetala, estera, imina, amida, disulfida, karbonata, hidrazina, karbamata.
6. Konjugat polimer-lijek prema bilo kojem od zahtjeva 1-5, naznačen time što je terapeutsko sredstvo odabrano iz skupine koja sadrži analoge nukleozida, antifolate, druge metabolite, inhibitore topoizomeraze I, antracikline, podofilotoksine, taksane, vinka alkaloide, alkilirajuća sredstva, spojeve platine, antihormone, radiofarmaceutike, monoklonska protutijela, inhibitore tirozin kinaze, inhibitore rapamicina (mTOR) kod sisavaca, retinoide, imunomodulacijska sredstva, inhibitore histonske deacetilaze i druga sredstva.
7. Konjugat polimer-lijek prema zahtjevu 6, naznačen time što je terapeutsko sredstvo odabrano iz skupine koja sadrži docetaksel, pemetreksed, klorokin, kombretastatin, gemcitabin, doksorubicin, 5-FU, 5'-Deoksi 5-fluorocitidin (5'-DFCR), lapatinib.
8. Postupak za pripremu konjugata polimer-lijek s formulom I prema zahtjevu 1, naznačen time što uključuje polimerizaciju PEG (met)akrilatnog monomera (formula II) [image] i najmanje jednog tipa (met)akrilat-L-D monomera (formula IIIa) [image] pri čemu su R1 i R2 neovisno odabrani između H ili -CH3; R3 je odabran između -H ili - CH3; L je poveznica koja se može cijepati; D je terapeutsko sredstvo i n je prirodni broj između 1-200 da bi se dobila formula I.
9. Postupak za pripremu konjugata polimer-lijek s formulom I prema zahtjevu 1, naznačen time što uključuje (i) polimerizaciju PEG (met)akrilatnog monomera (formula II) prema zahtjevu 8 i (met)akrilatnog monomera (Formula IIIb) [image] pri čemu su R1 i R2 neovisno odabrani između H ili -CH3; R3 je odabran između -H ili -CH3; L je poveznica koja se može cijepati i n je prirodni broj između 1-200 da bi se dobio kopolimer formule IV [image] pri čemu je x prirodni broj između 1-100 i y je prirodni broj između 1-100, Z je odabran između O ili -NH, A je krajnja skupina koja je izborno inicijator polimerizacije ili njezin fragment, B je krajnja skupina koja je izborno inicijator polimerizacije ili njezin fragment i zatim (ii) reakciju formule IV s najmanje jednim terapijskim sredstvom (D) da bi se dobila formula I.
10. Postupak za pripremu konjugata polimer-lijek formule I prema zahtjevu 1, naznačen time što uključuje (i) polimerizaciju PEG (met)akrilatnog monomera (Formula II) prema zahtjevu 8 i (met)akrilatnog monomera (formula IIIc) [image] pri čemu R1 i R2 su neovisno odabrani između H ili -CH3; R3 je odabran između -H ili - CH3; R4 je odabran između karbonilnih aktivirajućih skupina kao što su perfluorofenoksi, maleimid, karbonat, tiazolidon-2-tion, N-oksibenzotriazol, imidazolil, o/p-nitrofenoksi, pentaklor-fenoksi, N-hidroksisukcinimid, acetati, formijati, 2,3,5-triklorfenol, 8-hidroksikinolin, i -OH, -OCH3, -OCH2CH3, Cl, F, Br, H, -SH, -NH2, -NHR5 ili -OR5, R5 je C1-C10 zasićeni ili nezasićeni ugljikovodik i n je prirodni broj između 1-200 da bi se dobio kopolimer formule V [image] • pri čemu je x prirodni broj između 1-100 i y je prirodni broj između 1-100, Z je odabran između -O ili -NH, A je krajnja skupina koja je po izboru inicijator polimerizacije ili njezin fragment, B je krajnja skupina koja je po izboru inicijator polimerizacije ili njezin fragment i zatim (ii) reakciju formule V s najmanje jednom vrstom terapeutskog sredstva vezanog na poveznicu (L-D) da bi se dobila formula I.
11. Postupak za pripremu konjugata polimer-lijek formule I prema zahtjevu 1, naznačen time što obuhvaća (i) polimerizaciju PEG (met)akrilatnog monomera (Formula II) prema zahtjevu 8 i (met)akrilatnog monomera (Formula IIIc) [image] pri čemu R1 i R2 su neovisno odabrani između H ili -CH3; R3 je odabran između -H ili - CH3 ili -CH2CH3; R4 je odabran između karbonilnih aktivirajućih skupina kao što su perfluorofenoksi, maleimid, karbonat, tiazolidon-2-tion, N-oksibenzotriazol, imidazolil, o/p-nitrofenoksi, pentaklor-fenoksi, N-hidroksisukcinimid, acetati, formijati, 2,3,5-triklorfenol, 8-hidroksikinolin i -OH, -OCH3, -OCH2CH3, Cl, F, Br, H, -SH, -NH2, -NHR5 ili -OR5, R5 je C1-C10 zasićeni ili nezasićeni ugljikovodik i n je prirodni broj između 1-200 da bi se dobio kopolimer formule V • pri čemu je x prirodni broj između 1-100 i y je prirodni broj između 1-100, A je krajnja skupina koja je izborno inicijator polimerizacije ili njezin fragment, B je krajnja skupina koja je izborno inicijator polimerizacije ili njezin fragment i zatim (ii) reakciju formule V s poveznicom (L) da bi se dobio kopolimer formule IV i (iii) reakciju formule IV s najmanje jednom vrstom terapeutskog sredstva (D) da bi se dobio polimerni konjugat formule I.
12. Farmaceutski pripravak, naznačen time što sadrži konjugat polimer-lijek formule I prema bilo kojem od zahtjeva 1-7.
13. Konjugat polimer-lijek formule I prema bilo kojem od zahtjeva 1-7, naznačen time što se koristi kao lijek za liječenje i/ili profilaksu raka.
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