HUE027890T2 - Camptothecin derivatives with anti-tumor activity - Google Patents
Camptothecin derivatives with anti-tumor activity Download PDFInfo
- Publication number
- HUE027890T2 HUE027890T2 HUE07786063A HUE07786063A HUE027890T2 HU E027890 T2 HUE027890 T2 HU E027890T2 HU E07786063 A HUE07786063 A HU E07786063A HU E07786063 A HUE07786063 A HU E07786063A HU E027890 T2 HUE027890 T2 HU E027890T2
- Authority
- HU
- Hungary
- Prior art keywords
- mmols
- nmr
- mhz
- cdci3
- camptothecin
- Prior art date
Links
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title description 23
- 230000000259 anti-tumor effect Effects 0.000 title description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000003153 chemical reaction reagent Substances 0.000 claims description 38
- 150000001875 compounds Chemical class 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 229960000303 topotecan Drugs 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000002243 precursor Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 210000002784 stomach Anatomy 0.000 claims description 5
- 230000001684 chronic effect Effects 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 210000002966 serum Anatomy 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims 1
- 240000002871 Tectona grandis Species 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 239000013043 chemical agent Substances 0.000 claims 1
- 230000001086 cytosolic effect Effects 0.000 claims 1
- 210000004907 gland Anatomy 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 210000000936 intestine Anatomy 0.000 claims 1
- 210000001165 lymph node Anatomy 0.000 claims 1
- 230000001926 lymphatic effect Effects 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- 230000037390 scarring Effects 0.000 claims 1
- 230000028327 secretion Effects 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 150
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 229940127093 camptothecin Drugs 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- 239000007787 solid Substances 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 39
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 37
- 230000008034 disappearance Effects 0.000 description 34
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 238000012544 monitoring process Methods 0.000 description 29
- 238000003818 flash chromatography Methods 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 21
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 16
- 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 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 14
- 125000004103 aminoalkyl group Chemical group 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 12
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 12
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 12
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 8
- 108020004414 DNA Proteins 0.000 description 7
- -1 -N3 Inorganic materials 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 229950009073 gimatecan Drugs 0.000 description 6
- 210000001672 ovary Anatomy 0.000 description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- 230000002688 persistence Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- MISJXUDJCSZFAH-UHFFFAOYSA-N 1-sulfanylpyridin-2-one Chemical group SN1C=CC=CC1=O MISJXUDJCSZFAH-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 241001080024 Telles Species 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 208000005017 glioblastoma Diseases 0.000 description 4
- 150000002431 hydrogen Chemical group 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 210000003739 neck Anatomy 0.000 description 4
- WYURNTSHIVDZCO-SVYQBANQSA-N oxolane-d8 Chemical compound [2H]C1([2H])OC([2H])([2H])C([2H])([2H])C1([2H])[2H] WYURNTSHIVDZCO-SVYQBANQSA-N 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 210000002307 prostate Anatomy 0.000 description 4
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 3
- 102000003915 DNA Topoisomerases Human genes 0.000 description 3
- 108090000323 DNA Topoisomerases Proteins 0.000 description 3
- 230000005778 DNA damage Effects 0.000 description 3
- 231100000277 DNA damage Toxicity 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000003238 esophagus Anatomy 0.000 description 3
- UIVFUQKYVFCEKJ-OPTOVBNMSA-N gimatecan Chemical compound C1=CC=C2C(\C=N\OC(C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UIVFUQKYVFCEKJ-OPTOVBNMSA-N 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 3
- 229950002654 lurtotecan Drugs 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 150000002825 nitriles Chemical group 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 125000005353 silylalkyl group Chemical group 0.000 description 3
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- HAWSQZCWOQZXHI-UHFFFAOYSA-N CPT-OH Natural products C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000000006 cell growth inhibition assay Methods 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 2
- 229950009213 rubitecan Drugs 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- NDLIRBZKZSDGSO-UHFFFAOYSA-N tosyl azide Chemical compound CC1=CC=C(S(=O)(=O)[N-][N+]#N)C=C1 NDLIRBZKZSDGSO-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- AEELXMHQIJJMKP-QWWZWVQMSA-N (2r,3r)-3-sulfanylbutane-1,2,4-triol Chemical compound OC[C@@H](O)[C@H](S)CO AEELXMHQIJJMKP-QWWZWVQMSA-N 0.000 description 1
- PAEZRCINULFAGO-OAQYLSRUSA-N (R)-homocamptothecin Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC=CC=C3N=C21 PAEZRCINULFAGO-OAQYLSRUSA-N 0.000 description 1
- OSBLTNPMIGYQGY-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;boric acid Chemical compound OB(O)O.OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O OSBLTNPMIGYQGY-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- DZNNFZGDBUXWMV-ZUWDIFAMSA-N 581079-18-7 Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(OC(=O)[C@H](C)NC(=O)COCCOCC(=O)N[C@@H](C)C(=O)O[C@@]3(CC)C5=C(C(N6CC7=CC8=CC=CC=C8N=C7C6=C5)=O)COC3=O)CC)C4=NC2=C1 DZNNFZGDBUXWMV-ZUWDIFAMSA-N 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 241000759905 Camptotheca acuminata Species 0.000 description 1
- 206010011793 Cystitis haemorrhagic Diseases 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 230000007018 DNA scission Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 101710096438 DNA-binding protein Proteins 0.000 description 1
- 241000283715 Damaliscus lunatus Species 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 102100021888 Helix-loop-helix protein 1 Human genes 0.000 description 1
- 101000897691 Homo sapiens Helix-loop-helix protein 1 Proteins 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 241000209018 Nyssaceae Species 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000008051 TBE buffer Substances 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- SLOJCSGNHWIKIG-JNYZSSQASA-N afeletecan Chemical compound C([C@@H](C(=O)N[C@H](C(=O)O[C@@]1(CC)C2=C(C(N3CC4=CC5=CC=CC=C5N=C4C3=C2)=O)COC1=O)C(C)C)NC(=S)NC=1C=CC(O[C@@H]2[C@H]([C@H](OC)[C@H](O)[C@H](C)O2)O)=CC=1)C1=CNC=N1 SLOJCSGNHWIKIG-JNYZSSQASA-N 0.000 description 1
- 229950011393 afeletecan Drugs 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
- 229950011276 belotecan Drugs 0.000 description 1
- IRJKSAIGIYODAN-ISLYRVAYSA-N benzyl (ne)-n-phenylmethoxycarbonyliminocarbamate Chemical compound C=1C=CC=CC=1COC(=O)/N=N/C(=O)OCC1=CC=CC=C1 IRJKSAIGIYODAN-ISLYRVAYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- POADTFBBIXOWFJ-VWLOTQADSA-N cositecan Chemical compound C1=CC=C2C(CC[Si](C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 POADTFBBIXOWFJ-VWLOTQADSA-N 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000003297 denaturating effect Effects 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- LFQCJSBXBZRMTN-OAQYLSRUSA-N diflomotecan Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC(F)=C(F)C=C3N=C21 LFQCJSBXBZRMTN-OAQYLSRUSA-N 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 description 1
- 229950009429 exatecan Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000002802 hemorrhagic cystitis Diseases 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- VGIVLIHKENZQHQ-UHFFFAOYSA-N n,n,n',n'-tetramethylmethanediamine Chemical compound CN(C)CN(C)C VGIVLIHKENZQHQ-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229950009797 pegamotecan Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 229960002190 topotecan hydrochloride Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT001473A ITMI20061473A1 (it) | 2006-07-26 | 2006-07-26 | Derivati della camptotecina ad attivita antitumorale |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HUE027890T2 true HUE027890T2 (en) | 2016-11-28 |
Family
ID=38668829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HUE07786063A HUE027890T2 (en) | 2006-07-26 | 2007-07-13 | Camptothecin derivatives with anti-tumor activity |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US8217053B2 (https=) |
| EP (1) | EP2044079B1 (https=) |
| JP (1) | JP5313894B2 (https=) |
| KR (1) | KR101412157B1 (https=) |
| CN (1) | CN101495486B (https=) |
| AU (1) | AU2007278500B2 (https=) |
| BR (1) | BRPI0714553B8 (https=) |
| CA (1) | CA2658900C (https=) |
| DK (1) | DK2044079T3 (https=) |
| ES (1) | ES2561356T3 (https=) |
| HU (1) | HUE027890T2 (https=) |
| IL (1) | IL196653A (https=) |
| IT (1) | ITMI20061473A1 (https=) |
| MX (1) | MX2009000827A (https=) |
| NO (1) | NO341812B1 (https=) |
| PL (1) | PL2044079T3 (https=) |
| PT (1) | PT2044079E (https=) |
| RU (1) | RU2450008C2 (https=) |
| SI (1) | SI2044079T1 (https=) |
| WO (1) | WO2008011994A1 (https=) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK2907824T3 (en) * | 2012-10-11 | 2018-07-23 | Daiichi Sankyo Co Ltd | ANTIBODY-drug conjugate |
| EP2910573B1 (en) | 2012-10-19 | 2020-02-19 | Daiichi Sankyo Company, Limited | Antibody-drug conjugate produced by binding through linker having hydrophilic structure |
| KR101586030B1 (ko) * | 2014-01-22 | 2016-01-15 | 주식회사 엘지생활건강 | 캄프토테신을 유효성분으로 포함하는 체모 성장 억제용 조성물 |
| SI3466976T1 (sl) | 2014-01-31 | 2021-12-31 | Daiichi Sankyo Company, Limited | Anti-her2 konjugat protitelesa-zdravila |
| EP4180455A1 (en) | 2015-06-29 | 2023-05-17 | Daiichi Sankyo Company, Limited | Method for selectively manufacturing antibody-drug conjugate |
| BR112019011794A2 (pt) | 2016-12-12 | 2019-10-29 | Daiichi Sankyo Co Ltd | composição farmacêutica, e, método terapêutico. |
| CA3050668C (en) | 2017-01-17 | 2023-08-15 | Daiichi Sankyo Company, Limited | Anti-gpr20 antibody and anti-gpr20 antibody-drug conjugate |
| TW202532102A (zh) | 2017-05-15 | 2025-08-16 | 日商第一三共股份有限公司 | 抗體－藥物結合物及其用途 |
| BR112020003466B1 (pt) | 2017-08-31 | 2023-12-12 | Daiichi Sankyo Company, Limited | Métodos de produção de composto, e, composto |
| ES3057444T3 (en) | 2017-08-31 | 2026-03-02 | Daiichi Sankyo Co Ltd | Improved method for producing antibody-drug conjugate |
| HUE067382T2 (hu) | 2018-05-18 | 2024-10-28 | Daiichi Sankyo Co Ltd | Anti-MUC1-exatecan antitest-hatóanyag konjugátum |
| TWI846717B (zh) | 2018-07-27 | 2024-07-01 | 日商第一三共股份有限公司 | 辨識抗體-藥物結合物之藥物部位的蛋白質 |
| TW202537643A (zh) | 2018-07-31 | 2025-10-01 | 日商第一三共股份有限公司 | 抗體-藥物結合物之用途 |
| US10568873B1 (en) * | 2019-02-14 | 2020-02-25 | United Arab Emirates University | Safranal-sorafenib combination therapy for liver cancer |
| CN112225745B (zh) * | 2020-11-16 | 2021-10-12 | 烟台大学 | 一种具有抗肿瘤活性的异片螺素类化合物、制备方法及用途 |
| CN114805377A (zh) * | 2021-01-29 | 2022-07-29 | 明慧医药（杭州）有限公司 | 适用于抗体-药物偶联物的毒素分子 |
| JP2024523422A (ja) * | 2021-06-17 | 2024-06-28 | ミンフイ ファーマシューティカル （ハンチョウ） リミテッド | 抗腫瘍化合物およびその応用 |
| CN117510515A (zh) * | 2022-07-28 | 2024-02-06 | 明慧医药（杭州）有限公司 | 适用于抗体-药物偶联物的毒素分子 |
| CN121194979A (zh) * | 2023-05-08 | 2025-12-23 | 甘李药业股份有限公司 | 喜树碱衍生物、接头、配体-药物偶联物及其医药用途 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4391909A (en) * | 1979-03-28 | 1983-07-05 | Damon Corporation | Microcapsules containing viable tissue cells |
| US5972955A (en) * | 1995-06-06 | 1999-10-26 | Dr. Reddy's Research Foundation | Water soluble C-ring analogues of 20(S)-camptothecin |
| FR2757515B1 (fr) * | 1996-12-20 | 2000-05-05 | Sod Conseils Rech Applic | Formes prodrogues et nouveaux analogues de la camptothecine, leurs procedes de preparation, leur application comme medicaments et les compositions pharmaceutiques les contenant |
| US6881555B2 (en) * | 1999-03-19 | 2005-04-19 | Aventis Pharmaceuticals Inc. | AKT nucleic acids, polypeptides, and uses thereof |
| KR20040039404A (ko) * | 2001-09-25 | 2004-05-10 | 닥터 레디스 레보러터리즈 리미티드 | 20(에스)-캄포테신의 약제학적으로 수용가능한 염 |
| US20060084167A1 (en) * | 2004-10-16 | 2006-04-20 | Cohenford Menashi A | Formation of Hybrid Cells by Fusion of Lineage Committed Cells with Stem Cells |
-
2006
- 2006-07-26 IT IT001473A patent/ITMI20061473A1/it unknown
-
2007
- 2007-07-13 JP JP2009521137A patent/JP5313894B2/ja not_active Expired - Fee Related
- 2007-07-13 SI SI200731737T patent/SI2044079T1/sl unknown
- 2007-07-13 PL PL07786063T patent/PL2044079T3/pl unknown
- 2007-07-13 CA CA2658900A patent/CA2658900C/en not_active Expired - Fee Related
- 2007-07-13 CN CN2007800283564A patent/CN101495486B/zh not_active Expired - Fee Related
- 2007-07-13 ES ES07786063.3T patent/ES2561356T3/es active Active
- 2007-07-13 AU AU2007278500A patent/AU2007278500B2/en not_active Ceased
- 2007-07-13 DK DK07786063.3T patent/DK2044079T3/en active
- 2007-07-13 MX MX2009000827A patent/MX2009000827A/es active IP Right Grant
- 2007-07-13 HU HUE07786063A patent/HUE027890T2/en unknown
- 2007-07-13 US US12/374,963 patent/US8217053B2/en not_active Expired - Fee Related
- 2007-07-13 KR KR1020097001595A patent/KR101412157B1/ko not_active Expired - Fee Related
- 2007-07-13 EP EP07786063.3A patent/EP2044079B1/en active Active
- 2007-07-13 PT PT77860633T patent/PT2044079E/pt unknown
- 2007-07-13 RU RU2009102243/04A patent/RU2450008C2/ru active
- 2007-07-13 BR BRPI0714553A patent/BRPI0714553B8/pt not_active IP Right Cessation
- 2007-07-13 WO PCT/EP2007/006243 patent/WO2008011994A1/en not_active Ceased
-
2009
- 2009-01-16 NO NO20090251A patent/NO341812B1/no not_active IP Right Cessation
- 2009-01-22 IL IL196653A patent/IL196653A/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0714553B8 (pt) | 2021-05-25 |
| US8217053B2 (en) | 2012-07-10 |
| JP5313894B2 (ja) | 2013-10-09 |
| CN101495486A (zh) | 2009-07-29 |
| WO2008011994A1 (en) | 2008-01-31 |
| US20100120816A1 (en) | 2010-05-13 |
| SI2044079T1 (sl) | 2016-02-29 |
| DK2044079T3 (en) | 2016-02-29 |
| BRPI0714553A2 (pt) | 2013-03-26 |
| IL196653A0 (en) | 2009-11-18 |
| KR20090033456A (ko) | 2009-04-03 |
| MX2009000827A (es) | 2009-02-03 |
| NO20090251L (no) | 2009-01-16 |
| NO341812B1 (no) | 2018-01-29 |
| EP2044079A1 (en) | 2009-04-08 |
| IL196653A (en) | 2015-04-30 |
| CN101495486B (zh) | 2013-05-15 |
| PL2044079T3 (pl) | 2016-06-30 |
| KR101412157B1 (ko) | 2014-06-25 |
| BRPI0714553B1 (pt) | 2020-11-17 |
| RU2450008C2 (ru) | 2012-05-10 |
| PT2044079E (pt) | 2016-03-09 |
| AU2007278500A1 (en) | 2008-01-31 |
| ITMI20061473A1 (it) | 2008-01-27 |
| CA2658900A1 (en) | 2008-01-31 |
| JP2009544634A (ja) | 2009-12-17 |
| RU2009102243A (ru) | 2010-07-27 |
| AU2007278500B2 (en) | 2012-06-07 |
| ES2561356T3 (es) | 2016-02-25 |
| AU2007278500A2 (en) | 2010-09-09 |
| HK1135691A1 (en) | 2010-06-11 |
| EP2044079B1 (en) | 2015-12-09 |
| CA2658900C (en) | 2015-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| HUE027890T2 (en) | Camptothecin derivatives with anti-tumor activity | |
| CA2658902C (en) | Camptothecin derivatives with antitumor activity | |
| EP2044078B1 (en) | Camptothecin derivatives with antitumor activity | |
| HK1135693B (en) | Camptothecin derivatives with antitumor activity |