HRP20160625T1 - Novi inhibitori stat3 signalnog puta i inhibitori matičnih stanica raka - Google Patents
Novi inhibitori stat3 signalnog puta i inhibitori matičnih stanica raka Download PDFInfo
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- HRP20160625T1 HRP20160625T1 HRP20160625TT HRP20160625T HRP20160625T1 HR P20160625 T1 HRP20160625 T1 HR P20160625T1 HR P20160625T T HRP20160625T T HR P20160625TT HR P20160625 T HRP20160625 T HR P20160625T HR P20160625 T1 HRP20160625 T1 HR P20160625T1
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- Prior art keywords
- substituted
- cancer
- aryl
- alkyl
- cycloalkyl
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- 206010028980 Neoplasm Diseases 0.000 title claims 28
- 201000011510 cancer Diseases 0.000 title claims 28
- 210000000130 stem cell Anatomy 0.000 title claims 5
- 239000003112 inhibitor Substances 0.000 title 2
- 101100311214 Xenopus laevis stat3.1 gene Proteins 0.000 title 1
- 230000037361 pathway Effects 0.000 title 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 37
- 125000003118 aryl group Chemical group 0.000 claims 33
- 125000000217 alkyl group Chemical group 0.000 claims 32
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims 30
- 229910052739 hydrogen Inorganic materials 0.000 claims 29
- 239000001257 hydrogen Substances 0.000 claims 29
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 29
- 125000003342 alkenyl group Chemical group 0.000 claims 28
- 150000001875 compounds Chemical class 0.000 claims 26
- 125000000304 alkynyl group Chemical group 0.000 claims 25
- 125000004432 carbon atom Chemical group C* 0.000 claims 20
- 229910052736 halogen Inorganic materials 0.000 claims 14
- 150000002367 halogens Chemical class 0.000 claims 14
- 125000002877 alkyl aryl group Chemical group 0.000 claims 11
- MPVDXIMFBOLMNW-UHFFFAOYSA-N chembl1615565 Chemical group OC1=CC=C2C=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=C1N=NC1=CC=CC=C1 MPVDXIMFBOLMNW-UHFFFAOYSA-N 0.000 claims 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 9
- 238000011282 treatment Methods 0.000 claims 9
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 8
- 229910052760 oxygen Inorganic materials 0.000 claims 8
- 125000005017 substituted alkenyl group Chemical group 0.000 claims 8
- 125000000547 substituted alkyl group Chemical group 0.000 claims 8
- 125000003107 substituted aryl group Chemical group 0.000 claims 8
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 8
- 150000003839 salts Chemical class 0.000 claims 7
- 101150099493 STAT3 gene Proteins 0.000 claims 6
- 125000004426 substituted alkynyl group Chemical group 0.000 claims 6
- 229910052717 sulfur Inorganic materials 0.000 claims 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 4
- 235000010290 biphenyl Nutrition 0.000 claims 4
- 239000004305 biphenyl Substances 0.000 claims 4
- 238000002512 chemotherapy Methods 0.000 claims 4
- 125000005842 heteroatom Chemical group 0.000 claims 4
- 201000001441 melanoma Diseases 0.000 claims 4
- 125000002950 monocyclic group Chemical group 0.000 claims 4
- 125000001624 naphthyl group Chemical group 0.000 claims 4
- 229910052757 nitrogen Inorganic materials 0.000 claims 4
- 239000001301 oxygen Substances 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- 230000019491 signal transduction Effects 0.000 claims 4
- 238000011272 standard treatment Methods 0.000 claims 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims 3
- 206010006187 Breast cancer Diseases 0.000 claims 3
- 208000026310 Breast neoplasm Diseases 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 3
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 3
- 208000034578 Multiple myelomas Diseases 0.000 claims 3
- 206010033128 Ovarian cancer Diseases 0.000 claims 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 3
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 3
- 206010060862 Prostate cancer Diseases 0.000 claims 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 3
- 239000005864 Sulphur Substances 0.000 claims 3
- 206010017758 gastric cancer Diseases 0.000 claims 3
- 201000010536 head and neck cancer Diseases 0.000 claims 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims 3
- 230000002401 inhibitory effect Effects 0.000 claims 3
- 208000032839 leukemia Diseases 0.000 claims 3
- 201000005202 lung cancer Diseases 0.000 claims 3
- 208000020816 lung neoplasm Diseases 0.000 claims 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 3
- 201000002528 pancreatic cancer Diseases 0.000 claims 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 3
- 201000011549 stomach cancer Diseases 0.000 claims 3
- 238000001356 surgical procedure Methods 0.000 claims 3
- 230000004083 survival effect Effects 0.000 claims 3
- SAXKEWRSGLPYPB-UHFFFAOYSA-N 2-(1-hydroxyethyl)benzo[f][1]benzofuran-4,9-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1OC(C(O)C)=C2 SAXKEWRSGLPYPB-UHFFFAOYSA-N 0.000 claims 2
- RPCXZIRGAHYOKZ-UHFFFAOYSA-N 2-acetyl-7-fluorobenzo[f][1]benzofuran-4,9-dione Chemical compound O=C1C2=CC(F)=CC=C2C(=O)C2=C1OC(C(=O)C)=C2 RPCXZIRGAHYOKZ-UHFFFAOYSA-N 0.000 claims 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 2
- 208000006168 Ewing Sarcoma Diseases 0.000 claims 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 2
- 208000000172 Medulloblastoma Diseases 0.000 claims 2
- 206010027476 Metastases Diseases 0.000 claims 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims 2
- 206010039491 Sarcoma Diseases 0.000 claims 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 2
- 230000002159 abnormal effect Effects 0.000 claims 2
- 238000009098 adjuvant therapy Methods 0.000 claims 2
- 201000010881 cervical cancer Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 2
- 238000001727 in vivo Methods 0.000 claims 2
- 201000007270 liver cancer Diseases 0.000 claims 2
- 208000014018 liver neoplasm Diseases 0.000 claims 2
- DPHUWDIXHNQOSY-UHFFFAOYSA-N napabucasin Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1OC(C(=O)C)=C2 DPHUWDIXHNQOSY-UHFFFAOYSA-N 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 230000005855 radiation Effects 0.000 claims 2
- MOMFXATYAINJML-UHFFFAOYSA-N 2-Acetylthiazole Chemical group CC(=O)C1=NC=CS1 MOMFXATYAINJML-UHFFFAOYSA-N 0.000 claims 1
- RVIUPSHRLLQFOH-UHFFFAOYSA-N 2-acetyl-7-chlorobenzo[f][1]benzofuran-4,9-dione Chemical compound O=C1C2=CC(Cl)=CC=C2C(=O)C2=C1OC(C(=O)C)=C2 RVIUPSHRLLQFOH-UHFFFAOYSA-N 0.000 claims 1
- QORFLTDEUGKOSZ-UHFFFAOYSA-N 2-ethylbenzo[f][1]benzofuran-4,9-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1OC(CC)=C2 QORFLTDEUGKOSZ-UHFFFAOYSA-N 0.000 claims 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 239000000945 filler Substances 0.000 claims 1
- 201000011587 gastric lymphoma Diseases 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 230000001394 metastastic effect Effects 0.000 claims 1
- 206010061289 metastatic neoplasm Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000026731 phosphorylation Effects 0.000 claims 1
- 238000006366 phosphorylation reaction Methods 0.000 claims 1
- 239000012453 solvate Substances 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- 238000011144 upstream manufacturing Methods 0.000 claims 1
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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Claims (13)
1. Spoj, gdje se spoj odabire iz skupine koju čine:
[image]
[image]
i
[image]
.
2. Spoj formule II,
[image]
ili njegova farmaceutski prikladna sol, gdje simboli imaju sljedeća značenja i, za svako pojavljivanje, se biraju nezavisno:
X je O ili S;
svaki R1 je nezavisno vodik, halogen, cijano, nitro, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ili SRa;
R4 je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, alkilaril;
R5 je vodik, alkil, cikloalkil, aril, alkilaril; po izboru, R4 i R5 mogu biti spojeni da formiraju alkenil;
R7 je vodik, halogen, cijano, nitro, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, ili SRa;
Ra je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, ili aril; i
n je 1-4,
uz uvjet da je barem jedan od R1 i R7 halogen; ili je barem jedan od R1, R4, R5 i R7 aril;
gdje svaki alkil sadrži 1 do 6 atoma ugljika,
alkenil sadrži 2 do 12 atoma ugljika i barem jednu dvostruku vezu ugljik-ugljik,
alkinil sadrži 2 do 12 atoma ugljika i barem jednu trostruku vezu ugljik-ugljik,
cikloalkil sadrži 3 do 8 atoma ugljika,
cikloalkenil sadrži 3 do 8 atoma ugljika,
aril je fenil, bifenil ili naftil, i
heterocikl je 4 do 7-eročlani monociklički prsten s 1, 2, 3 ili 4 heteroatoma izabrana između dušika, kisika i sumpora.
3. Spoj prema zahtjevu 2, izabran iz skupine koju čine:
[image]
i
[image]
.
4. Spoj formule III,
[image]
ili njegova farmaceutski prikladna sol, gdje simboli imaju sljedeća značenja i, za svako pojavljivanje, se biraju nezavisno:
X je O ili S;
R1 je halogen;
R4 je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, alkilaril;
R5 je vodik, alkil, cikloalkil, aril, alkilaril; po izboru, R4 i R5 mogu biti spojeni da formiraju alkenil ili supstituirani alkenil;
R6 je vodik, alkil, ORa, OC(=O)Ra, ili SRa;
R7 je vodik, halogen, cijano, nitro, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, ili SRa;
Ra je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, ili aril ili; i
n je 1-4
gdje svaki alkil sadrži 1 do 6 atoma ugljika,
alkenil sadrži 2 do 12 atoma ugljika i barem jednu dvostruku vezu ugljik-ugljik,
alkinil sadrži 2 do 12 atoma ugljika i barem jednu trostruku vezu ugljik-ugljik,
cikloalkil sadrži 3 do 8 atoma ugljika,
cikloalkenil sadrži 3 do 8 atoma ugljika,
aril je fenil, bifenil ili naftil, i
heterocikl je 4 do 7-eročlani monociklički prsten s 1, 2, 3 ili 4 heteroatoma izabrana između dušika, kisika i sumpora.
5. Spoj prema zahtjevu 4, čije je struktura:
[image]
ili
[image]
.
6. Spoj izabran iz skupine koju čine:
[image]
i
[image]
.
7. Spoj formule V,
[image]
ili njegova farmaceutski prikladna sol, gdje simboli imaju sljedeća značenja i, za svako pojavljivanje, se biraju nezavisno:
X je O ili S;
svaki R1 je nezavisno vodik, halogen, cijano, nitro, CF3, OCF3, alkil , alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, ili SRa;
R7 je vodik, halogen, cijano, nitro, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, ili SRa;
R11 je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, alkilaril, alkilheteroaril;
Ra je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, ili aril;
n je 1-4, gdje
svaki alkil sadrži 1 do 6 atoma ugljika,
alkenil sadrži 2 do 12 atoma ugljika i barem jednu dvostruku vezu ugljik-ugljik,
alkinil sadrži 2 do 12 atoma ugljika i barem jednu trostruku vezu ugljik-ugljik,
cikloalkil sadrži 3 do 8 atoma ugljika,
cikloalkenil sadrži 3 do 8 atoma ugljika,
aril je fenil, bifenil ili naftil, i
heterocikl je a 4 do 7-eročlani monociklički prsten s 1, 2, 3 ili 4 heteroatoma izabrana između dušika, kisika i sumpora.
8. Spoj formule VI,
[image]
ili njegova farmaceutski prikladna sol, gdje simboli imaju sljedeća značenja i, za svako pojavljivanje, se biraju nezavisno:
X je O;
svaki R1, je nezavisno vodik, halogen, cijano, nitro, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, ili SRa;
R3 je vodik, cijano, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, SRa, ili NRbRc;
R7 je vodik, halogen, cijano, nitro, CF3, OCF3, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, aril, ORa, ili SRa;
Ra je vodik, alkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterocikl, ili aril;
Rb i Rc su nezavisno vodik, alkil, cikloalkil, heterocikl, ili aril, ili ti Rb i Rc zajedno s N s kojim su spojeni po izboru formiraju heterocikl;
gdje svaki alkil sadrži 1 do 6 atoma ugljika,
alkenil sadrži 2 do 12 atoma ugljika i barem jednu dvostruku vezu ugljik-ugljik,
alkinil sadrži 2 do 12 atoma ugljika i barem jednu trostruku vezu ugljik-ugljik,
cikloalkil sadrži 3 do 8 atoma ugljika,
cikloalkenil sadrži 3 do 8 atoma ugljika,
aril je fenil, bifenil ili naftil, i
heterocikl je 4 do 7-eročlani monociklički prsten s 1, 2, 3 ili 4 heteroatoma izabrana između dušika, kisika i sumpora,
i uz uvjet ako je R3 hidroksil, alkil, onda je R1 halogen, aril; i dalje uz uvjet ako je R3 aril, onda R7 nije vodik, i dalje uz uvjet da su isključeni 2-acetil-7-kloro-nafto[2,3-b]furan-4,9-dion i 2-acetil-7-fluoro-nafto[2,3-b]furan-4,9-dion; i
(1) barem jedan od R1 je halogen; ili
(2) jedan od R1 je halogen, i drugi R1 je vodik.
9. Farmaceutski pripravak koji sadrži spoj ili njegovu farmaceutski prikladnu sol prema bilo kojem od zahtjeva 1-8, i farmaceutski prikladnu pomoćnu tvar, nosač ili punilo.
10. Spoj ili njegova farmaceutski prikladna sol prema bilo kojem od zahtjeva 1-8 za liječenje raka u subjekta, koje obuhvaća primjenu terapijski učinkovite količine spoja subjektu.
11. Spoj prema zahtjevu 10, gdje
(1) rak se odabire iz skupine koju čine rak dojke, rak glave i vrata, rak pluća, rak jajnika, rak gušterače, multipli mijelom, kolorektalni rak, rak prostate, melanom, Kaposijev sarkom, Ewingov sarkom, rak jetre, rak želuca, meduloblastom, tumori mozga i leukemija;
(2) rak se odabire iz skupine koju čine karcinom renalnih stanica, melanom, hepatocelularni karcinomi, rak cerviksa, sarkomi, rakovi želuca i limfomi.
12. Spoj formule VIII:
[image]
ili njegov enantiomer, dijastereomer, tautomer, ili njegova farmaceutski prikladna sol ili solvat, gdje simboli imaju sljedeća značenja i, za svako pojavljivanje, se biraju nezavisno:
X je O ili S;
svaki R1, je nezavisno vodik, halogen, cijano, nitro, CF3, OCF3, alkil ili supstituirani alkil, alkenil ili supstituirani alkenil, alkinil ili supstituirani alkinil, cikloalkil ili supstituirani cikloalkil, cikloalkenil ili supstituirani cikloalkenil, heterocikl ili supstituirani heterocikl, aril ili supstituirani aril, ORa, ili SRa;
R7 je vodik, halogen, cijano, nitro, CF3, OCF3, alkil ili supstituirani alkil, alkenil ili supstituirani alkenil, alkinil ili supstituirani alkinil, cikloalkil ili supstituirani cikloalkil, cikloalkenil ili supstituirani cikloalkenil, heterocikl ili supstituirani heterocikl, aril ili supstituirani aril, ORa, ili SRa;
R12 je vodik, alkil ili supstituirani alkil, alkenil ili supstituirani alkenil, alkinil ili supstituirani alkinil, cikloalkil ili supstituirani cikloalkil, cikloalkenil ili supstituirani cikloalkenil, heterocikl ili supstituirani heterocikl, aril ili supstituirani aril, alkilaril ili supstituirani alkilaril, -C(=O)R3, ili -C(OH)R4R5;
R3 je vodik, cijano, CF3, OCF3, alkil ili supstituirani alkil, alkenil ili supstituirani alkenil, alkinil ili supstituirani alkinil, cikloalkil ili supstituirani cikloalkil, cikloalkenil ili supstituirani cikloalkenil, heterocikl ili supstituirani heterocikl, aril ili supstituirani aril, ORa, SRa, ili NRbRc;
R4 je vodik, alkil ili supstituirani alkil, alkenil ili supstituirani alkenil, alkinil ili supstituirani alkinil, cikloalkil ili supstituirani cikloalkil, cikloalkenil ili supstituirani cikloalkenil, heterocikl ili supstituirani heterocikl, aril ili supstituirani aril, alkilaril ili supstituirani alkilaril;
R5 je vodik, alkil ili supstituirani alkil, cikloalkil ili supstituirani cikloalkil, aril ili supstituirani aril, alkilaril ili supstituirani alkilaril; po izboru, R4 i R5 mogu biti spojeni da formiraju alkenil ili supstituirani alkenil;
Ra je vodik, alkil ili supstituirani alkil, alkenil ili supstituirani alkenil, alkinil ili supstituirani alkinil, cikloalkil ili supstituirani cikloalkil, cikloalkenil ili supstituirani cikloalkenil, heterocikl ili supstituirani heterocikl, ili aril ili supstituirani aril;
Rb i Rc su nezavisno vodik, alkil ili supstituirani alkil, cikloalkil ili supstituirani cikloalkil, heterocikl ili supstituirani heterocikl, ili aril ili supstituirani aril, ili ti Rb i Rc zajedno s N s kojim su spojeni po izboru formiraju heterocikl ili supstituirani heterocikl; i
n je 1-4;
uz uvjet da su isključeni 2-(1-hidroksietil)-nafto[2,3-b]furan-4,9-dion, 2-acetil 1-7-kloro-nafto[2,3-b]furan-4,9-dion, 2-acetil-7-fluoro-nafto[2,3-b]furan-4,9-dion, 2-acetilnafto[2,3-b]furan-4,9-dion, i 2-etil-nafto[2,3-b]furan-4,9-dion; za uporabu u:
(1) liječenju raka u bolesnika, koje obuhvaća korake:
odabir bolesnika s neprirodnom aktivnošću signalnog puta Stat3; i primjenu terapijski učinkovite količine spoja formule VIII bolesniku;
(2) liječenju raka u bolesnika za kojeg je ispitano da ima rak koji pokazuje neprirodnu aktivnost signalnog puta Stat3 preko primjene terapijski učinkovite količine spoja formule VIII bolesniku;
(3) liječenju raka u subjekta inhibicijom preživljavanja matičnih stanica raka i/ili samo-obnove, koje obuhvaća primjenu učinkovite količine spoja formule VIII na matične stanice raka;
(4) liječenju raka u subjekta čiji je rak refraktoran na standarni režim liječenja, koje obuhvaća primjenu terapijski učinkovite količine spoja formule VIII subjektu;
(5) liječenju relapsa raka u subjekta, koje obuhvaća primjenu terapijski učinkovite količine spoja formule VIII subjektu; ili
(6) liječenju ili prevenciju metastaza raka u subjekta, koje obuhvaća primjenu terapijski učinkovite količine spoja formule VIII subjektu.
13. Spoj prema zahtjevu 12 gdje je u slučaju (1) spoj za liječenje poremećaja povezanog s neprirodnom aktivnošću signalnog puta Stat3 u subjekta i gdje se neprirodna aktivnost signalnog puta Stat3 može odrediti ekspresijom fosforiliranog Stat3 ili surogatom uzvodnog ili nizvodnog regulatora Stat3 fosforilacije i gdje je poremećaj (i) rak izabran iz skupine koju čine rak dojke, rak glave i vrata, rak pluća, rak jajnika, rak gušterače, kolorektalni karcinom, rak prostate, karcinom renalnih stanica, melanom, hepatocelularni karcinomi, rak cerviksa, sarkomi, tumori mozga, rakovi želuca, multipli mijelom, leukemija, limfomi;
u slučaju (3) spoj je za inhibiciju preživljavanja matičnih stanica raka i/ili samo-obnove in vivo za liječenje raka u subjekta;
u slučaju (3) spoj je za inhibiciju preživljavanja matičnih stanica raka i/ili samo-obnove in vivo za liječenje raka u subjekta (i) rak je izabran iz skupine koju čine rak dojke, rak glave i vrata, rak pluća, rak jajnika, rak gušterače, multipli mijelom, kolorektalni karcinom, rak prostate, melanom, Kaposijev sarkom, Ewingov sarkom, rak jetre, rak želuca, meduloblastom, tumori mozga, leukemija; (ii) rak je metastatski; (iii) rak je refraktoran na kemoterapiju ili zračenje; (iv) rak je sam po sebi otporan na kemoterapiju; ili (v) subjekt ima relaps raka nakon prethodnog liječenja;
u slučaju (4) spoj je za liječenje subjekta s rakom koji je refraktoran na standardni režim liječenja i gdje (i) standardni režim liječenja obuhvaća konvencionalni standardni režim kemoterapije i/ili zračenja; (ii) standardni režim liječenja obuhvaća operaciju; ili (iii) rak je sam po sebi otporan na kemoterapiju;
u slučaju (5) spoj je za liječenje relapsa raka u subjekta i koristi se kao adjuvansa terapija nakon operacije; ili
u slučaju (6) spoj je za liječenje ili prevenciju metastaza raka u subjekta i koristi se kao adjuvansa terapija nakon operacije.
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