WO2004050089A1 - Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives - Google Patents
Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives Download PDFInfo
- Publication number
- WO2004050089A1 WO2004050089A1 PCT/EP2003/013780 EP0313780W WO2004050089A1 WO 2004050089 A1 WO2004050089 A1 WO 2004050089A1 EP 0313780 W EP0313780 W EP 0313780W WO 2004050089 A1 WO2004050089 A1 WO 2004050089A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dione
- dihydroxy
- tetramethyl
- oxacyclohexadec
- methyl
- Prior art date
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- 230000002062 proliferating effect Effects 0.000 title claims abstract description 7
- 201000010099 disease Diseases 0.000 title claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 11
- 229930013356 epothilone Natural products 0.000 title abstract description 9
- 150000003883 epothilone derivatives Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000012636 effector Substances 0.000 claims abstract description 7
- 230000033115 angiogenesis Effects 0.000 claims abstract description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 155
- 239000001257 hydrogen Substances 0.000 claims description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- -1 heteroaromatic radical Chemical class 0.000 claims description 65
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- LZWPOLSJFGLQCE-UHFFFAOYSA-N heptadecane-5,9-dione Chemical compound CCCCCCCCC(=O)CCCC(=O)CCCC LZWPOLSJFGLQCE-UHFFFAOYSA-N 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 150000003254 radicals Chemical class 0.000 claims description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 13
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 239000007983 Tris buffer Substances 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 230000017074 necrotic cell death Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 5
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 4
- 125000006193 alkinyl group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 206010027476 Metastases Diseases 0.000 claims description 3
- 230000006907 apoptotic process Effects 0.000 claims description 3
- 230000030833 cell death Effects 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- KFZFCUIKKJNIKD-CULHHNCZSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzothiazol-5-yl]-4,8-dihydroxy-5,5,9,13-tetramethyl-7-propyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CN)=N2)C2=C1 KFZFCUIKKJNIKD-CULHHNCZSA-N 0.000 claims description 2
- ZIJCTROTGDFCCP-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzothiazol-5-yl]-7-butyl-4,8-dihydroxy-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CN)=N2)C2=C1 ZIJCTROTGDFCCP-HMDSJJHQSA-N 0.000 claims description 2
- BLMJENOMBPEWPQ-QXKFKBPZSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CN)=N2)C2=C1 BLMJENOMBPEWPQ-QXKFKBPZSA-N 0.000 claims description 2
- ZSVGCRQFJRLEIJ-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-7-but-3-enyl-4,8-dihydroxy-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC=C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CN)=N2)C2=C1 ZSVGCRQFJRLEIJ-HMDSJJHQSA-N 0.000 claims description 2
- VMPXAVYGUBPGCF-CULHHNCZSA-N (4s,7r,8s,9s,13z,16s)-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5,5,9,13-tetramethyl-7-propyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CO)=N2)C2=C1 VMPXAVYGUBPGCF-CULHHNCZSA-N 0.000 claims description 2
- JKMXYHWBYPSLER-MHSZFZGDSA-N (4s,7r,8s,9s,13z,16s)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl-1,3-benzothiazol-5-yl)-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(C)=N2)C2=C1 JKMXYHWBYPSLER-MHSZFZGDSA-N 0.000 claims description 2
- GDKQOJYYJDHHMA-MHSZFZGDSA-N (4s,7r,8s,9s,13z,16s)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl-1,3-benzoxazol-5-yl)-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(C)=N2)C2=C1 GDKQOJYYJDHHMA-MHSZFZGDSA-N 0.000 claims description 2
- ZEMGUFIRZSVXLM-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-7-but-3-enyl-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC=C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CO)=N2)C2=C1 ZEMGUFIRZSVXLM-HMDSJJHQSA-N 0.000 claims description 2
- ZFDBNVNNUAAWCX-TWLOFVPVSA-N (4s,7r,8s,9s,13z,16s)-7-but-3-enyl-4,8-dihydroxy-5,5,9,13-tetramethyl-16-(2-methyl-1,3-benzoxazol-5-yl)-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC=C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(C)=N2)C2=C1 ZFDBNVNNUAAWCX-TWLOFVPVSA-N 0.000 claims description 2
- BDYNGTSZFWPZDY-TWLOFVPVSA-N (4s,7r,8s,9s,13z,16s)-7-butyl-4,8-dihydroxy-5,5,9,13-tetramethyl-16-(2-methyl-1,3-benzoxazol-5-yl)-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(C)=N2)C2=C1 BDYNGTSZFWPZDY-TWLOFVPVSA-N 0.000 claims description 2
- BOGZLUKTLNBAPA-XTWHBGSHSA-N (4s,7r,8s,9s,13z,16s)-7-ethyl-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CO)=N2)C2=C1 BOGZLUKTLNBAPA-XTWHBGSHSA-N 0.000 claims description 2
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims description 2
- LHFMVIWZILZQHZ-DGFQIRGVSA-N [(2R,3S,4R,5S,6R)-3,4,5-triacetyloxy-6-[2-[carboxyoxy-(2,5-dioxopyrrolidin-1-yl)methyl]phenyl]oxan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@H]1C1=CC=CC=C1C(OC(O)=O)N1C(=O)CCC1=O LHFMVIWZILZQHZ-DGFQIRGVSA-N 0.000 claims description 2
- HPKPFIHCMIKXMU-OUUBHVDSSA-N [(2r,3r,4s,5r,6s)-3,4,5-triacetyloxy-6-phenoxyoxan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1OC1=CC=CC=C1 HPKPFIHCMIKXMU-OUUBHVDSSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical group C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000005004 perfluoroethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- OXORNNOPLOJTMY-BRVNTYEUSA-N (1s,3s,7s,10r,11s,12s,16r)-10-ethyl-7,11-dihydroxy-8,8,12,16-tetramethyl-3-(2-methyl-1,3-benzothiazol-5-yl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CC)[C@@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@H]1C1=CC=C(SC(C)=N2)C2=C1 OXORNNOPLOJTMY-BRVNTYEUSA-N 0.000 claims 1
- AHLOAHQGQPGLMH-QXKFKBPZSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzothiazol-5-yl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CN)=N2)C2=C1 AHLOAHQGQPGLMH-QXKFKBPZSA-N 0.000 claims 1
- BQQBYYWTWLUVGK-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzothiazol-5-yl]-7-but-3-enyl-4,8-dihydroxy-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC=C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CN)=N2)C2=C1 BQQBYYWTWLUVGK-HMDSJJHQSA-N 0.000 claims 1
- UARRINSJNAXRDE-XTWHBGSHSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzothiazol-5-yl]-7-ethyl-4,8-dihydroxy-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CN)=N2)C2=C1 UARRINSJNAXRDE-XTWHBGSHSA-N 0.000 claims 1
- MUDJNFXBMCAPNV-CULHHNCZSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-4,8-dihydroxy-5,5,9,13-tetramethyl-7-propyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CN)=N2)C2=C1 MUDJNFXBMCAPNV-CULHHNCZSA-N 0.000 claims 1
- DIHKXGZSYONZMX-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-7-butyl-4,8-dihydroxy-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CN)=N2)C2=C1 DIHKXGZSYONZMX-HMDSJJHQSA-N 0.000 claims 1
- UJZSACCLJJOCIN-XTWHBGSHSA-N (4s,7r,8s,9s,13z,16s)-16-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-7-ethyl-4,8-dihydroxy-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CN)=N2)C2=C1 UJZSACCLJJOCIN-XTWHBGSHSA-N 0.000 claims 1
- JBJCGBDMNXKJFN-QXKFKBPZSA-N (4s,7r,8s,9s,13z,16s)-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5,5,7,9,13-pentamethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CO)=N2)C2=C1 JBJCGBDMNXKJFN-QXKFKBPZSA-N 0.000 claims 1
- WCEWETIHGBVVAH-QXKFKBPZSA-N (4s,7r,8s,9s,13z,16s)-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]-5,5,7,9,13-pentamethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CO)=N2)C2=C1 WCEWETIHGBVVAH-QXKFKBPZSA-N 0.000 claims 1
- PQYYWKDRUMUOGD-CULHHNCZSA-N (4s,7r,8s,9s,13z,16s)-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]-5,5,9,13-tetramethyl-7-propyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CO)=N2)C2=C1 PQYYWKDRUMUOGD-CULHHNCZSA-N 0.000 claims 1
- MCEKFCIDYACSCS-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-7-butyl-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CO)=N2)C2=C1 MCEKFCIDYACSCS-HMDSJJHQSA-N 0.000 claims 1
- ITIHERWSPJBLHF-HMDSJJHQSA-N (4s,7r,8s,9s,13z,16s)-7-butyl-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzoxazol-5-yl]-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(OC(CO)=N2)C2=C1 ITIHERWSPJBLHF-HMDSJJHQSA-N 0.000 claims 1
- KVBYTOZLCMBYDU-TWLOFVPVSA-N (4s,7r,8s,9s,13z,16s)-7-butyl-4,8-dihydroxy-5,5,9,13-tetramethyl-16-(2-methyl-1,3-benzothiazol-5-yl)-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CCCC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(C)=N2)C2=C1 KVBYTOZLCMBYDU-TWLOFVPVSA-N 0.000 claims 1
- MQCFBAKJZYICEQ-XTWHBGSHSA-N (4s,7r,8s,9s,13z,16s)-7-ethyl-4,8-dihydroxy-16-[2-(hydroxymethyl)-1,3-benzothiazol-5-yl]-5,5,9,13-tetramethyl-1-oxacyclohexadec-13-ene-2,6-dione Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](CC)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C1=CC=C(SC(CO)=N2)C2=C1 MQCFBAKJZYICEQ-XTWHBGSHSA-N 0.000 claims 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 abstract description 6
- 150000001719 carbohydrate derivatives Chemical class 0.000 abstract description 2
- 150000001720 carbohydrates Chemical class 0.000 abstract description 2
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- ZTXSNMWLLINLIN-UHFFFAOYSA-N N1=C(C=CC=C1)C=CC12CCOC(CCCC(CCCCCCC2O1)=O)=O Chemical compound N1=C(C=CC=C1)C=CC12CCOC(CCCC(CCCCCCC2O1)=O)=O ZTXSNMWLLINLIN-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- QUVOXAIMVHJBPZ-DGFQIRGVSA-N [(2R,3S,4R,5S,6R)-3,4,5-triacetyloxy-6-[4-[carboxyoxy-(2,5-dioxopyrrolidin-1-yl)methyl]phenyl]oxan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@H]1C1=CC=C(C(OC(O)=O)N2C(CCC2=O)=O)C=C1 QUVOXAIMVHJBPZ-DGFQIRGVSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- ZUABWSWLOODFOS-BWMDDLPLSA-N methyl (2S,3S,4S,5R,6S)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-[4-tert-butyl-2-fluoro-5,6-dimethyl-3-(silyloxymethyl)phenoxy]oxane-2-carboxylate Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C(=O)OC)O[C@H]1OC1=C(C)C(C)=C(C(C)(C)C)C(CO[SiH3])=C1F ZUABWSWLOODFOS-BWMDDLPLSA-N 0.000 description 1
- XABUKQPQBWCUMJ-ATFNGGABSA-N methyl (2S,3S,4S,5R,6S)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-[4-tert-butyl-2-methoxy-5,6-dimethyl-3-(silyloxymethyl)phenoxy]oxane-2-carboxylate Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C(=O)OC)O[C@H]1OC1=C(C)C(C)=C(C(C)(C)C)C(CO[SiH3])=C1OC XABUKQPQBWCUMJ-ATFNGGABSA-N 0.000 description 1
- YMNPSXFLDNZXLH-BWMDDLPLSA-N methyl (2S,3S,4S,5R,6S)-3,4,5-tris[[tert-butyl(dimethyl)silyl]oxy]-6-[4-tert-butyl-3,5-dimethyl-2-(silyloxymethyl)phenoxy]oxane-2-carboxylate Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C(=O)OC)O[C@H]1OC1=CC(C)=C(C(C)(C)C)C(C)=C1CO[SiH3] YMNPSXFLDNZXLH-BWMDDLPLSA-N 0.000 description 1
- BLZJTNKQBYWXHJ-KVIJGQROSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-(2-fluoro-4-formylphenoxy)oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(C=O)C=C1F BLZJTNKQBYWXHJ-KVIJGQROSA-N 0.000 description 1
- LPLDMUGULFEJJK-KVIJGQROSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-(2-formyl-4-nitrophenoxy)oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C([N+]([O-])=O)C=C1C=O LPLDMUGULFEJJK-KVIJGQROSA-N 0.000 description 1
- QTHPZBHVIGLWPP-VDRZXAFZSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-(4-formyl-2-methoxyphenoxy)oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(C=O)C=C1OC QTHPZBHVIGLWPP-VDRZXAFZSA-N 0.000 description 1
- MHAQOFAFDHVKQE-KVIJGQROSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-(4-formyl-2-nitrophenoxy)oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(C=O)C=C1[N+]([O-])=O MHAQOFAFDHVKQE-KVIJGQROSA-N 0.000 description 1
- JKTPLNRSCRLVBF-KVIJGQROSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-(4-formylphenoxy)oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(C=O)C=C1 JKTPLNRSCRLVBF-KVIJGQROSA-N 0.000 description 1
- NZKIXPKPSQRAMN-KVIJGQROSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-[2-fluoro-4-(hydroxymethyl)phenoxy]oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(CO)C=C1F NZKIXPKPSQRAMN-KVIJGQROSA-N 0.000 description 1
- JGMZCRZQQBZLTC-VDRZXAFZSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-[4-(hydroxymethyl)-2-methoxyphenoxy]oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(CO)C=C1OC JGMZCRZQQBZLTC-VDRZXAFZSA-N 0.000 description 1
- AQTNRWKXMKQFCN-KVIJGQROSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-triacetyloxy-6-[4-(hydroxymethyl)phenoxy]oxane-2-carboxylate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(CO)C=C1 AQTNRWKXMKQFCN-KVIJGQROSA-N 0.000 description 1
- FRTHGZQGEXBEQG-DKBOKBLXSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)-2-methoxyphenoxy]oxane-2-carboxylate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(CO)C=C1OC FRTHGZQGEXBEQG-DKBOKBLXSA-N 0.000 description 1
- DTSWRSPRPSBVRT-BYNIDDHOSA-N methyl (2s,3s,4s,5r,6s)-3,4,5-trihydroxy-6-[4-(hydroxymethyl)phenoxy]oxane-2-carboxylate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(CO)C=C1 DTSWRSPRPSBVRT-BYNIDDHOSA-N 0.000 description 1
- MWDBJGOUZXUXSX-BYNIDDHOSA-N methyl (2s,3s,4s,5r,6s)-6-[2-fluoro-4-(hydroxymethyl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](C(=O)OC)O[C@H]1OC1=CC=C(CO)C=C1F MWDBJGOUZXUXSX-BYNIDDHOSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000004998 naphthylethyl group Chemical group C1(=CC=CC2=CC=CC=C12)CC* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- VFWRGKJLLYDFBY-UHFFFAOYSA-N silver;hydrate Chemical compound O.[Ag].[Ag] VFWRGKJLLYDFBY-UHFFFAOYSA-N 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- KPGNTWPHBLZNCH-UHFFFAOYSA-N sodium;prop-2-en-1-olate Chemical compound [Na+].[O-]CC=C KPGNTWPHBLZNCH-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
- A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
- A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
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- 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
- A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions
- the relatively low cytotoxicity of the chemotherapy agent doxorubicin that was used and that required a high dosage of the prodrug proved disadvantageous, and on the other hand, the relatively quick development of resistance against doxorubicin itself proved disadvantageous.
- the new structural class of the epothilones and analogs thereof primarily offers a possibility of avoiding these drawbacks.
- Most natural or synthetically modified compounds from their structural class exert their full antiproliferative activity against the most varied tumor cells that are resistant to other chemotherapy agents.
- the active strength relative to these cells can be up to 10,000 x greater, compared to chemotherapy agents that are used in clinical practice, such as, for example, taxol, doxorubicin, cis- platinum or camptothecin.
- the object of this invention is thus based on, i.a.,
- This invention correspondingly comprises conjugates of general formula I
- R ⁇ a , Rib independently of one another, are hydrogen, Ci -CJQ alkyl, aryl, aralkyl, or together a -(CH2) m group, in which m is 2 to 5, R-- a , j 2b ; independently of one another, are hydrogen, Ci -CJQ alkyl, aryl, aralkyl, or together a -(CH2) n group, in which n is 2 to 5, or C2-C10 alkenyl, or C2-C10 alkinyl, R3 is hydrogen, C ⁇ -C ⁇ Q alkyl, aryl or aralkyl, and R4 & 5 R4b ?
- R 5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH,
- Hal is a halogen atom, R6, R7. in each case, are hydrogen, or together an additional bond or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH2 group, and
- G is an oxygen atom or CH2,
- R ⁇ is hydrogen, C ⁇ -C ⁇ Q alkyl, aryl, aralkyl, halogen or CN, and
- R9 is hydrogen or a protective group PG ⁇
- RlO, Ri 1 in each case independently of one another, are hydrogen
- Z can represent oxygen or H/ORl2 5
- Ri 2 can represent hydrogen or a protective group PG ⁇ ,
- R can represent C ⁇ -C20 alkyl
- R 2 1 can represent a hydrogen atom or C 1 -C ⁇ Q alkyl
- L 1 , L,2, iA independently of one another, can represent hydrogen, a group
- R_22a 5 j ⁇ 22b ? independently of one another, can represent hydrogen, C1 -C20
- alkyl C1-C20 acyl, C1-C20 acyloxy, aryl, aralkyl, hydroxy, alkoxy, CO 2 H, CO 2 alkyl, halogen, CN, NO 2 , NH 2 , or N3,
- R 3 can represent hydrogen or C 1 -C 1 Q alkyl
- EG is a recognition unit of general formula IV
- R24 can represent a group CH2OPG or a group CO2R26, PGl, PG2, PG3, and PG4, independently of one another, can represent hydrogen or a protective group PG
- R26 can represent hydrogen, C ⁇ -C20 alkyl, C ⁇ -C20 alkenyl, C4-C7 cycloalkyl, which can contain an oxygen atom, aryl, aralkyl, tris(C ⁇ -C20 alkyl)silyl, bis(Cj-C20 alkyl)-arylsilyl, (C1-C20 alkyl)-diarylsilyl, or tris(aralkyl)-silyl
- PG ⁇ -, PG , and PG ⁇ can represent a protective group PG, as a uniform isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
- the above-mentioned conjugates can comprise one or more recognition units; in this case, the recognition units that are related to a conjugate can be identical or different. It is preferred that the recognition units of a conjugate be identical.
- the compounds of general formula I can be used in the form of their ⁇ -, ⁇ - or ⁇ -
- the conjugates according to the invention are preferably used for the treatment of diseases that are linked with proliferative processes.
- diseases that are linked with proliferative processes.
- the therapy of widely varying tumors the therapy of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, the therapy of angiogenesis-associated diseases, such as the growth of solid tumors, rheumatoid arthritis or diseases of the ocular fundus can be mentioned.
- conjugates according to the invention for the treatment of primary tumors and/or metastases that are not operatively accessible, either as monotherapy or in combination with substances that increasingly trigger cell death (apoptosis) and necrosis, so that when cells decompose, it results in an elevated release of normally intracellular, lysosomal enzymes, such as, e.g., glucuronidase, which results in a stronger reaction of the conjugates according to the invention.
- lysosomal enzymes such as, e.g., glucuronidase
- substances that are used for the so-called "vascular targeting” can be mentioned. These substances result in destruction in particular of the tumor endothelium, which subsequently results in an increased necrosis of the tumor because of the deficient nutrient supply.
- LI 9 constructs such as, for example, the EDB fibronectin or combrestatin A4-prodrugs
- the production of epothilones, their precursors and derivatives of general formula II is carried out according to the methods that are known to one skilled in the art, as they are described in, for example, DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927,
- R 26 g ⁇ R 27 straight-chain or branched-chain alkyl
- groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.
- R la , R lb , R 2a R2b R 3, R 4a R 4b R 5 ; R 8, R 10 ; R l l 5 R 20 5 R 21 3 R 22a ? 22b 5 R 25 ? R 26 and R 27 can a ⁇ so t ⁇ e perfluorinated or substituted by 1-5 halogen
- R 22b 5 R 26 an ⁇ R 27 substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl, benzoxazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C 2 o-alkyl, C ⁇ C20- ac yl .
- heteroatoms such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimi
- C ⁇ -C20 _ acyloxy groups are suitable.
- the heteroatoms can be oxidized if as a result the aromatic character is not lost, such as, for example, the oxidation of a pyridyl to a pyridyl-N-oxide.
- bi- and tricyclic aryl radicals W substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be substituted in one or more places by halogen, OH, O- alkyl, CO H, CO 2 -alkyl, -NH 2 , -NO , -N 3 , -CN, C ⁇ -C 2 o-alky
- R22 ? 22b ⁇ R 26 ⁇ d R 27 C an contain in the ring up to 14 C atoms, preferably 6 to 10 C
- aralkyl radicals for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are considered.
- the rings can be substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NO 2 , -N 3 , -CN, C ⁇ -C 2 o-alkyl. C 1 -C 2 o- a cyl . or C i -C20- yloxy groups.
- protective groups PG tris(Cj-C20 alkyl)silyl, bis(Cj-C20 alkyl)-arylsilyl, (C1 -C20 alkyl)-diarylsilyl, tris(aralkyl)-silyl, C ⁇ -C20 _ lkyl, C2-C20- alkenyl, C4-C7-cycloalkyl, which in addition can contain an oxygen atom in the ring, aryl, C7-C2()- ralkyl, Cj-C20- cyl, aroyl, C ⁇ -C20-alkoxycarbonyl, C1 -C20- alkylsulfonyl as well as arylsulfonyl can be mentioned.
- alkyl, silyl and acyl radicals for protective groups PG in particular the radicals that are known to one skilled in the art are considered.
- alkyoxycarbonyl radical e.g., trichloroethyloxycarbonyl (Troc) is suitable.
- acyl radicals e.g., formyl, acetyl, propionyl, isopropionyl, trichloromethylcarbonyl, pivalyl, and butyryl or benzoyl, which can be substituted with amino groups and/or hydroxy groups, are suitable.
- amino protective groups PG the radicals that are known to one skilled in the art are considered.
- Alloc, Boc, Z, benzyl, f-Moc, Troc, Stabase or benzostabase group can be mentioned.
- halogen atoms fluorine, chlorine, bromine or iodine is considered.
- the acyl groups can contain 1 to 20 carbon atoms, whereby formyl, acetyl, propionyl, isopropionyl and pivalyl groups are preferred.
- the C2-C ⁇ o-alkylene- ⁇ , ⁇ -dioxy group that is possible for X is preferably an ethyleneketal or neopentylketal group.
- preferred recognition units EG those are considered that, for example, by overexpression of suitable enzymes in proliferating tissues can be cleaved from the latter.
- suitable enzymes in proliferating tissues can be cleaved from the latter.
- glucuronidase can be mentioned here.
- Preferred compounds of general formula I are those in which A-Y represents O-
- G represents a CH2 group
- Z represents an oxygen atom
- Rla, Rlb i n each case represent C1-C10 alkyl or together a -(CH2)p group with p equal to 2 or 3 or 4
- R2a, R 2b ? independently of one another, represent hydrogen, C1 -CI Q alkyl, C2-C10 alkenyl, or C2-C10 alkinyl
- R3 represents hydrogen
- R ⁇ independently of one anotlier, represent hydrogen or C ⁇ -C ⁇ Q alkyl;
- R ⁇ represents hydrogen or C1 -C4 alkyl or CH2OH or CH2NH2 or CH2N(alkyl, acyl) ⁇ 2 or CH2Hal;
- X represents a CRI ⁇ RH group;
- R represents hydrogen or C1-C4 alkyl or a fluorine atom or a chlorine atom or a bromine atom;
- R10/R11 represent hydrogen/2 -methylthiazol-4-yl or hydrogen/2-pyridyl or hydrogen/2- methyloxazol-4-yl or hydrogen/2-amino
- radicals R22a g ⁇ R 22b ⁇ -Q selected from the group that consists of C ⁇ -Cg-alkyl, Cj-Cg-alkoxy, halogen, nitro, CN, N3, NH2 and CO2-(Ci-
- Cg-alkyl Especially preferred in this connection are the radicals methyl, ethyl, propyl, i-propyl, t-butyl, CF3, C 2 F 5 , F, CI, nitro, CN, N3, NH , CO2-methyl, CO2-ethyl, CO2- propyl and CO2-i-propyl.
- radical R ° is selected from the group that consists of C1 -Cg-alkyl and C2-Cg-alkenyl. Especially preferred in this connection are the radicals methyl, ethyl, propyl, i-propyl, t-butyl, CF3, propenyl and butenyl.
- radicals R2a and R b are selected such that one of radicals R2a or R2b represents hydrogen, while the other radical in each case is selected from the group that consists of C ⁇ -C7-alkyl, C2-C7-alkenyl and C2-C7-alkinyl.
- radicals methyl, ethyl, propyl, i-propyl, propenyl, butenyl, propinyl and butinyl are especially preferred in this connection.
- the invention also relates to linker-recognition units of general formula III 1 :
- RG2 represents an HO-CH2 group or an HNR 3-CH2 group; and R2 a 5 R 22b a ⁇ EQ nave me above-mentioned meanings;
- R27 is C ⁇ -C ⁇ o alkyl, aryl or aralkyl; and 22a 5 22b mc ⁇ JIQ h a ⁇ e t ne above-mentioned meanings;
- the invention also relates to processes
- a linker-recognition unit of general formula III 3 for reacting a linker-recognition unit of general formula III 3 with a compound of general formula I, in which the condition that at least one group 1-1, 1-2 or 1-4 represent a linker-recognition unit need not be met, and 1-1 and/or 1-2 and/or 1-4 have the meaning of a hydrogen atom, and free hydroxyl groups and/or amino groups that are not required for the reaction are optionally protected.
- the invention also relates to the use of a linker-recognition unit of general formula III 1 , III 2 or III 3 for the production of an effector-recognition unit conjugate, as described above.
- the invention also relates to the use of a linker-recognition unit of general formula III 1 , III 2 or III 3 in one of the processes according to the invention for the production of an effector-recognition unit conjugate as described above.
- the invention also relates to the conjugates according to the invention that contain effectors, linkers and recognition units for use as medications or for the production of a medication or a pharmaceutical composition.
- the invention also relates to the use of the conjugates according to the invention for the production of medications for the treatment of diseases that are linked with proliferative processes, such as tumors, inflammatory and/or neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or for the treatment of angiogenesis- associated diseases, such as the growth of solid tumors, rheumatoid arthritis, or diseases of the ocular fundus.
- diseases that are linked with proliferative processes such as tumors, inflammatory and/or neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or for the treatment of angiogenesis- associated diseases, such as the growth of solid tumors, rheumatoid arthritis, or diseases of the ocular fundus.
- the invention also relates to the use of the conjugates according to the invention for the production of medications for the treatment of primary tumors and/or metastases that are not operatively accessible, either as monotherapy or in combination with substances that increasingly trigger cell death (apoptosis) and necrosis, so that when tumor cells decompose, it results in an elevated release of normally intracellular, lysosomal enzymes, such as, e.g., glucuronidase, which results in a stronger reaction of the above-mentioned conjugates.
- normally intracellular, lysosomal enzymes such as, e.g., glucuronidase
- Treatment or administration in combination with the above-mentioned substances in this case comprises the simultaneous (both in the mixture and in separate doses) but also the respectively separate administration of the individual components of the combination, for example an alternating administration, as well as administration schemes, in which one component is given as a long-term medication, and the other component is administered in addition at regular or irregular intervals for shorter periods.
- the components of the combination can be fed via the same or via different administration paths.
- administrations in combination are preferably those in which the components of the combination achieve an additive action; especially preferred are those administration schemes in which a synergistic action is set.
- Example LEI a in a mixture that consists of 110 ml of tetrahydrofuran and 22 ml of methanol is mixed at 0°C with 224 mg of sodium borohydride, and it is stirred for 30 minutes. It is mixed with saturated ammonium chloride solution, diluted with water and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried on sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 5.62 g (11.6 mmol, 98%) of the title compound is isolated.
- (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-(2-[l,3]dioxolan-2-yl-4-nitro-phenoxy)- tetrahydro-pyran-2-carboxylic acid methyl ester 20.0 g (50.4 mmol) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6-bromo-tetrahydro- pyran-2-carboxylic acid methyl ester is reacted analogously to Example LEI a with the compound that is presented according to Example LE3a, and after working-up and purification, 21.9 g (41.5 mmol, 82%) of the title compound is isolated.
- Example LE3c in 560 ml of dichloromethane, is mixed with 22.9 ml of tert-butyl- dimethyl-silyltriflate as well as 23.8 ml of 2,6-lutidine, and it is stirred for 24 hours at 23 °C. It is poured into water, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel, and 9.90 g (13.3 mmol, 67%) of the title compound as well as 2.17 g (29.2 mmol, 15%) of a stereoisomer are isolated.
- Example LE3f in 2 ml of acetone is mixed with 12.9 mg of p-toluenesulfonic acid monohydrate, and it is stirred for 24 hours at 23 °C. It is poured into saturated sodium bicarbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel, and 25.9 mg (35.7 ⁇ mol, 58%) of the title compound is isolated.
- Example LE3g 720 mg (0.99 mmol) of the compound that is presented according to Example LE3g is reacted analogously to Example LEI, and after working-up, 710 mg (0.975 mmol, 98%) of the title compound, which is further reacted without purification, is isolated.
- Example LE3a Analogously to Example LE3a, 25 g (149.6 mmol) of 4-hydroxy-3- nitrobenzaldehyde is reacted, and after working-up, 27.6 g (131 mmol, 87%) of the title compound is isolated.
- Example LE4b 358 mg (679 ⁇ mol) of the compound that is presented according to Example LE4b is reacted analogously to Example LE3c, and after working-up, 270 mg (673 ⁇ mol, 99%o) of the title compound is isolated.
- Example LE4c 268 mg (668 ⁇ mol) of the compound that is presented according to Example LE4c is reacted analogously to Example LE3d, and after working-up and purification, 183 mg (246 ⁇ mol, 37%) of the title compound is isolated.
- Example LE4f 2.51 g (3.26 mmol) of the compound that is presented according to Example LE4f is reacted analogously to Example LE3g, and after working-up, 2.35 g (3.24 mmol, 99%) of the title compound, which is further reacted with purification, is isolated.
- Example LE5a is reacted analogously to Example LEI, and after working-up, 17.4 g (max. 37.7 mmol) of the title compound, which is further reacted without being purified, is isolated.
- Example LE5c is reacted analogously to Example LEI, and after working-up, 17.4 g (max. 37.7 mmol) of the title compound, which is further reacted without being purified, is isolated.
- Example LE5b 17.4 g (max. 37.7 mmol) of the compound that is presented according to Example LE5b is reacted analogously to Example LE3c, and after working-up, 13.9 g (max. 37.7 mmol) of the title compound, which is further reacted without being purified, is isolated.
- Example LE5c 13.9 g (max. 37.7 mmol) of the compound that is presented according to Example LE5c is reacted analogously to Example LE3d, and after working-up and purification, 21.5 g (27.9 mmol, 74%) of the title compound is isolated.
- Example LE6a 2-Chloro-4-[l,3]dioxolan-2-yl-phenol 25 g (160 mmol) of 3-chloro-4-hydroxybenzaldehyde is reacted analogously to Example LE3a, and after working-up, 26.1 g (130 mmol, 81%) of the title compound, which is further reacted without being purified, is isolated.
- Example LE6b is reacted analogously to Example LE3c, and after working-up, 17.2 g (44.0 mmol, 90%) of the title compound, which is further reacted without being purified, is isolated.
- Example LE6e is reacted analogously to Example LE3f, and after working-up and purification, 12.9 g (17.7 mmol, 100%) of the title compound is isolated.
- Example LE6g is reacted analogously to Example LE3f, and after working-up and purification, 12.9 g (17.7 mmol, 100%) of the title compound is isolated.
- Example LE6f 12.9 g (17.7 mmol) of the compound that is presented according to Example LE6f is reacted analogously to Example LE3g, and after working-up, 12.0 g (17.5 mmol, 99%) of the title compound, which is further reacted without being purified, is isolated.
- Example LE6f 12.0 g (17.5 mmol) of the compound, presented according to Example LE6f, is reacted analogously to Example LEI, and after working-up and purification, 11.4 g (16.6 mmol, 95%) of the title compound is isolated.
- Example LE7b is reacted analogously to Example LE3c, and after working-up, 4.64 g (max. 11.2 mmol) of the title compound, which is further reacted without being purified, is isolated.
- Example LE7c is reacted analogously to Example LE3d, and after working-up and purification, 8.43 g (10.5 mmol, 94%) of the title compound is isolated.
- Example LE7 8.43 g (10.5 mmol) of the compound that is presented according to Example LE7d is reacted analogously to Example LE5e, and after working-up, 8.38 g (10.1 mmol, 96%) of the title compound, which is further reacted without being purified, is isolated.
- Example LE7
- Example LE7e 8.38 g (10.1 mmol) of the compound that is presented according to Example LE7e is reacted analogously to Example LE5, and after working-up and purification, 5.92 g (8.3 mmol, 82%) of the title compound is isolated.
- Example LE8b is reacted analogously to Example LE3c, and after working-up, 11.2 g (max. 29.0 mmol) of the title compound, which is further reacted without being purified, is isolated.
- Example LE8c is reacted analogously to Example LE3d, and after working-up and purification, 18.5 g (23.4 mmol, 81%) of the title compound is isolated.
- Example ELEla in 20 ml of dichloromethane is mixed at 0°C with the solution of 285 mg of triphosgene in 6 ml of dichloromethane, 160 ⁇ l of pyridine, and it is stirred for 2.5 hours at 23°C. It is concentrated by evaporation, the residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution, and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 1.08 g (1.53 mmol, 98%) of the title compound is isolated.
- Example ELElc Analogously to Example ELElc, 265 mg (376 ⁇ mol) of the compound that is presented according to Example ELElb is reacted with the compound that is presented according to Example LEI, and after working-up and purification, 180 mg (156 ⁇ mol, 42%) of the title compound is isolated.
- Example ELE Analogously to Example ELE 1,173 mg (150 ⁇ mol) of the compound that is presented according to Example ELE3a is reacted, and after working-up and purification, 58 mg (55.8 ⁇ mol, 37%) of the title compound is isolated. -64-
- Example ELE2 Analogously to Example ELE2, 151 mg (145 ⁇ mol) of the compound that is presented according to Example ELE3 is reacted, and after working-up and purification, 75 mg (71.1 ⁇ mol, 49%) of the title compound as well as 28 mg (26.5 ⁇ mol, 18%) of (2S,3S,4S,5R,6S)-3,4,5-triacetoxy-6- ⁇ 2-[(lR,3S,7S,10R,llS,12S, 16S)-10-allyl-l l- hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4, 17-dioxa- bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-4-nitro-phenoxy ⁇ -tetrahydro- pyran-2-carboxylic acid methyl ester are isolated.
- Example ELElc Analogously to Example ELElc, 230 mg (312 ⁇ mol) of the compound that is presented according to Example ELElb is reacted with 1.32 g of the compound that is presented according to Example LE4, and after working-up and purification, 132 mg (95 ⁇ mol, 30%) of the title compound is isolated.
- Example ELE2 Analogously to Example ELE2, 50 mg (53 ⁇ mol) of the compound that is presented according to Example ELE5 is reacted, and after working-up and purification, 26 mg (27 ⁇ mol, 51%) of the title compound as well as 7 mg (7 ⁇ mol, 14%) of (2S,3S,4S,5R,6S)-6- ⁇ 4-[(lR,3S,7S,10R,l lS,12S,16S)-10-allyl-l l-hydroxy-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa- bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-nitro-phenoxy ⁇ -3,4,5- trihydroxy-tetrahydro-pyran-2-carboxylic acid allyl ester are isolated. -67-
- Example ELElb Analogously to Example ELElb, 1.0 g (1.56 mmol) of the compound that is presented according to Example ELE8a is reacted, and 1.05 g (1.49 mmol, 96%) of the title compound is isolated.
- Example ELE2 Analogously to Example ELE2, 766 mg (857 ⁇ mol) of the compound that is presented according to Example ELE 11 is reacted, and after working-up and purification, 616 mg (677 ⁇ mol, 79%) of the title compound is isolated.
- Example ELE10 Analogously to Example ELE10, 320 mg (352 ⁇ mol) of the compound that is presented according to Example ELE 12 is reacted, and after working-up and purification, 165 mg (190 ⁇ mol, 54%) of the title compound is isolated.
- Example ELE11 Analogously to Example ELE11, 2.78 g (2.06 mmol) of the compound that is presented according to Example ELE 14a is reacted, and after working-up and purification, 1.00 g (1.12 mmol, 54%) of the title compound is isolated.
- Example ELE 10 Analogously to Example ELE 10, 354 mg (389 ⁇ mol) of the compound that is presented according to Example ELE 15 is reacted, and after working-up and purification, 187 mg (215 ⁇ mol, 55%) of the title compound is isolated.
- Example ELE11 Analogously to Example ELE11, 1.54 g (1.14 mmol) of the compound that is presented according to Example ELE 17a is reacted, and after working-up and purification, 612 mg (659 ⁇ mol, 58%) of the title compound is isolated.
- Example ELE2 Analogously to Example ELE2, 610 mg (657 ⁇ mol) of the compound that is presented according to Example ELE 17 is reacted, and after working-up and purification, 517 g (547 ⁇ mol, 83%) of the title compound is isolated.
- Example ELE17a Analogously to Example ELE17a, 2.13 g (3.02 mmol) of the compound that is presented according to Example ELE8b is reacted with the compound that is presented according to Example LE6, and after working-up and purification, 1.71 g (1.26 mmol, 42%) of the title compound is isolated.
- Example ELE11 Analogously to Example ELE11, 930 mg (686 ⁇ mol) of the compound that is presented according to Example ELE20a is reacted, and after working-up and purification, 460 mg (495 ⁇ mol, 72%>) of the title compound is isolated.
- Example ELE2 Analogously to Example ELE2, 610 mg (657 ⁇ mol) of the compound that is presented according to Example ELE20 is reacted, and after working-up and purification, 601 mg (636 ⁇ mol, 97%) of the title compound is isolated.
- Example ELE 10 Analogously to Example ELE 10, 302 mg (320 ⁇ mol) of the compound that is presented according to Example ELE21 is reacted, and after working-up and purification, 178 mg (197 ⁇ mol, 62%>) of the title compound is isolated.
- Example ELElc Analogously to Example ELElc, 1.15 g (1.63 mmol) of the compound that is presented according to Example ELElb is reacted with the compound that is presented according to Example LE7, and after working-up and purification, 1.44 g (1.04 mmol, 64%o) of the title compound is isolated.
- Example ELE11 Analogously to Example ELE11, 1.44 g (1.04 mmol) of the compound that is presented according to Example ELE23a is reacted, and after working-up and purification, 386 mg (418 ⁇ mol, 40%) of the title compound is isolated.
- Example ELE2 Analogously to Example ELE2, 384 mg (416 ⁇ mol) of the compound that is presented according to Example ELE23 is reacted, and after working-up and purification, 278 mg (296 ⁇ mol, 71%) of the title compound is isolated.
- Example ELE10 100 mg (106 ⁇ mol) of the compound that is presented according to Example ELE24 is reacted, and after working-up and purification, 64 mg (71 ⁇ mol, 67%) of the title compound is isolated.
- Example ELElc Analogously to Example ELElc, 2.0 g (2.84 mmol) of the compound that is presented according to Example ELElb is reacted with the compound that is presented according to Example LE8, and after working-up and purification, 2.06 g (1.50 mmol, 53%) of the title compound is isolated.
- Example ELE11 Analogously to Example ELE11, 2.06 g (1.50 mmol) of the compound that is presented according to Example ELE26a is reacted, and after working-up and purification, 1.01 g (l.l l mmol, 74%>) of the title compound is isolated.
- Example ELE2 Analogously to Example ELE2, 1.01 g (1.11 mmol) of the compound that is presented according to Example ELE26 is reacted, and after working-up and purification, 657 mg (708 ⁇ mol, 64%) of the title compound is isolated.
- Example ELE 10 Analogously to Example ELE 10, 350 mg (377 ⁇ mol) of the compound that is presented according to Example ELE27 is reacted, and after working-up and purification, 234 mg (264 ⁇ mol, 70%») of the title compound is isolated.
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Abstract
Priority Applications (3)
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JP2004556300A JP2006510626A (ja) | 2002-12-05 | 2003-12-05 | 増殖疾患の処理における部位特異的供給のためのエポチロン類似体 |
EP03785751A EP1581218A1 (fr) | 2002-12-05 | 2003-12-05 | Analogues d'epothilone permettant l'administration specifique d'un site dans le traitement de maladies proliferatives |
AU2003294796A AU2003294796A1 (en) | 2002-12-05 | 2003-12-05 | Epothilone analogs for site specific delivery in the treatment of proliferative diseases |
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DE10256982A DE10256982A1 (de) | 2002-12-05 | 2002-12-05 | Neue Effektor-Konjugate, Verfahren zu Ihrer Herstellung und Ihre Pharmazeutische Verwendung |
DE10256982.7 | 2002-12-05 | ||
US43119702P | 2002-12-06 | 2002-12-06 | |
US60/431,197 | 2002-12-06 |
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JP (1) | JP2006510626A (fr) |
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Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005074901A2 (fr) * | 2004-01-30 | 2005-08-18 | Schering Ag | Nouveaux conjugues d'effecteurs, leurs procedes de production et leur utilisation pharmaceutique |
WO2006032537A2 (fr) * | 2004-09-24 | 2006-03-30 | Bayer Schering Pharma Aktiengesellschaft | Utilisation d'epothilones dans le traitement de metastase osseuse |
US7759374B2 (en) | 2002-08-23 | 2010-07-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US7875638B2 (en) | 2002-08-23 | 2011-01-25 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US20160184451A1 (en) * | 2014-05-28 | 2016-06-30 | Legochem Biosciences, Inc. | Compounds comprising self-immolative group |
US10118965B2 (en) | 2015-09-25 | 2018-11-06 | Legochem Biosciences, Inc. | Compositions and methods related to anti-EGFR antibody drug conjugates |
US10183997B2 (en) | 2015-09-25 | 2019-01-22 | Legochem Biosciences, Inc. | Compositions and methods related to anti-CD19 antibody drug conjugates |
CN111138444A (zh) * | 2020-01-08 | 2020-05-12 | 山东大学 | 一组埃博霉素b葡萄糖苷类化合物及其酶法制备与应用 |
CN111205343A (zh) * | 2020-01-08 | 2020-05-29 | 山东大学 | 埃博霉素b的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用 |
US11167040B2 (en) | 2015-11-25 | 2021-11-09 | Legochem Biosciences, Inc. | Conjugates comprising peptide groups and methods related thereto |
US11173214B2 (en) | 2015-11-25 | 2021-11-16 | Legochem Biosciences, Inc. | Antibody-drug conjugates comprising branched linkers and methods related thereto |
US11413353B2 (en) | 2015-11-25 | 2022-08-16 | Legochem Biosciences, Inc. | Conjugates comprising self-immolative groups and methods related thereto |
US11654197B2 (en) | 2017-03-29 | 2023-05-23 | Legochem Biosciences, Inc. | Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same |
US11707533B2 (en) | 2019-09-04 | 2023-07-25 | Legochem Biosciences, Inc. | Antibody-drug conjugate comprising antibody against human ROR1 and use for the same |
US11827703B2 (en) | 2018-05-09 | 2023-11-28 | Legochem Biosciences, Inc. | Compositions and methods related to anti-CD19 antibody drug conjugates |
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EP0595133A2 (fr) * | 1992-10-27 | 1994-05-04 | BEHRINGWERKE Aktiengesellschaft | Prodroques, leur préparation, et utilisation comme médicaments |
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2003
- 2003-12-05 WO PCT/EP2003/013780 patent/WO2004050089A1/fr active Application Filing
- 2003-12-05 EP EP03785751A patent/EP1581218A1/fr not_active Withdrawn
- 2003-12-05 AU AU2003294796A patent/AU2003294796A1/en not_active Abandoned
- 2003-12-05 JP JP2004556300A patent/JP2006510626A/ja not_active Withdrawn
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EP0595133A2 (fr) * | 1992-10-27 | 1994-05-04 | BEHRINGWERKE Aktiengesellschaft | Prodroques, leur préparation, et utilisation comme médicaments |
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Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
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US7875638B2 (en) | 2002-08-23 | 2011-01-25 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US8513429B2 (en) | 2002-08-23 | 2013-08-20 | Sloan-Kettering Insitute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US8110590B2 (en) | 2002-08-23 | 2012-02-07 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US7759374B2 (en) | 2002-08-23 | 2010-07-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
WO2005074901A2 (fr) * | 2004-01-30 | 2005-08-18 | Schering Ag | Nouveaux conjugues d'effecteurs, leurs procedes de production et leur utilisation pharmaceutique |
WO2005074901A3 (fr) * | 2004-01-30 | 2006-03-30 | Schering Ag | Nouveaux conjugues d'effecteurs, leurs procedes de production et leur utilisation pharmaceutique |
WO2006032537A3 (fr) * | 2004-09-24 | 2006-05-04 | Schering Ag | Utilisation d'epothilones dans le traitement de metastase osseuse |
JP2008514569A (ja) * | 2004-09-24 | 2008-05-08 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | 骨転移の治療へのエポチロンの使用 |
WO2006032537A2 (fr) * | 2004-09-24 | 2006-03-30 | Bayer Schering Pharma Aktiengesellschaft | Utilisation d'epothilones dans le traitement de metastase osseuse |
US10383949B2 (en) | 2014-05-28 | 2019-08-20 | Legochem Biosciences, Inc. | Compounds comprising self-immolative group |
US20160184451A1 (en) * | 2014-05-28 | 2016-06-30 | Legochem Biosciences, Inc. | Compounds comprising self-immolative group |
US9919057B2 (en) * | 2014-05-28 | 2018-03-20 | Legochem Biosciences, Inc. | Compounds comprising self-immolative group |
US9993568B2 (en) | 2014-05-28 | 2018-06-12 | Legochem Biosciences, Inc. | Compounds comprising self-immolative group |
US10980890B2 (en) | 2014-05-28 | 2021-04-20 | Legochem Biosciences, Inc. | Compounds comprising self-immolative group |
US10118965B2 (en) | 2015-09-25 | 2018-11-06 | Legochem Biosciences, Inc. | Compositions and methods related to anti-EGFR antibody drug conjugates |
US10183997B2 (en) | 2015-09-25 | 2019-01-22 | Legochem Biosciences, Inc. | Compositions and methods related to anti-CD19 antibody drug conjugates |
US11167040B2 (en) | 2015-11-25 | 2021-11-09 | Legochem Biosciences, Inc. | Conjugates comprising peptide groups and methods related thereto |
US11173214B2 (en) | 2015-11-25 | 2021-11-16 | Legochem Biosciences, Inc. | Antibody-drug conjugates comprising branched linkers and methods related thereto |
US11413353B2 (en) | 2015-11-25 | 2022-08-16 | Legochem Biosciences, Inc. | Conjugates comprising self-immolative groups and methods related thereto |
US11975076B2 (en) | 2015-11-25 | 2024-05-07 | Legochem Biosciences, Inc. | Antibody-drug conjugates comprising branched linkers and methods related thereto |
US11654197B2 (en) | 2017-03-29 | 2023-05-23 | Legochem Biosciences, Inc. | Pyrrolobenzodiazepine dimer prodrug and ligand-linker conjugate compound of the same |
US11827703B2 (en) | 2018-05-09 | 2023-11-28 | Legochem Biosciences, Inc. | Compositions and methods related to anti-CD19 antibody drug conjugates |
US11707533B2 (en) | 2019-09-04 | 2023-07-25 | Legochem Biosciences, Inc. | Antibody-drug conjugate comprising antibody against human ROR1 and use for the same |
CN111138444A (zh) * | 2020-01-08 | 2020-05-12 | 山东大学 | 一组埃博霉素b葡萄糖苷类化合物及其酶法制备与应用 |
CN111205343A (zh) * | 2020-01-08 | 2020-05-29 | 山东大学 | 埃博霉素b的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用 |
CN111205343B (zh) * | 2020-01-08 | 2022-06-14 | 山东大学 | 埃博霉素b的氮乙酰葡萄糖苷或半乳糖苷化合物及其酶法制备与应用 |
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AU2003294796A1 (en) | 2004-06-23 |
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