NZ617430B2 - Taxane and abeo-taxane analogs - Google Patents
Taxane and abeo-taxane analogs Download PDFInfo
- Publication number
- NZ617430B2 NZ617430B2 NZ617430A NZ61743012A NZ617430B2 NZ 617430 B2 NZ617430 B2 NZ 617430B2 NZ 617430 A NZ617430 A NZ 617430A NZ 61743012 A NZ61743012 A NZ 61743012A NZ 617430 B2 NZ617430 B2 NZ 617430B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- inhibitors
- alkyl
- group
- cancer
- compound
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 172
- -1 benzylidene acetal Chemical class 0.000 claims abstract description 88
- 201000011510 cancer Diseases 0.000 claims abstract description 52
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 165
- 239000000203 mixture Substances 0.000 claims description 131
- 239000003112 inhibitor Substances 0.000 claims description 74
- 230000002401 inhibitory effect Effects 0.000 claims description 74
- 229910052739 hydrogen Inorganic materials 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 70
- 125000003118 aryl group Chemical group 0.000 claims description 68
- 229910052799 carbon Inorganic materials 0.000 claims description 60
- 125000003342 alkenyl group Chemical group 0.000 claims description 57
- 239000003795 chemical substances by application Substances 0.000 claims description 56
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000000304 alkynyl group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 108090001123 antibodies Proteins 0.000 claims description 22
- 102000004965 antibodies Human genes 0.000 claims description 22
- 239000000556 agonist Substances 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 102000004243 Tubulin Human genes 0.000 claims description 17
- 108090000704 Tubulin Proteins 0.000 claims description 17
- 150000002431 hydrogen Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 239000011780 sodium chloride Substances 0.000 claims description 17
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temodal Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 15
- 239000002168 alkylating agent Substances 0.000 claims description 15
- 229960004964 temozolomide Drugs 0.000 claims description 15
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 claims description 14
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 claims description 14
- 230000000340 anti-metabolite Effects 0.000 claims description 14
- 239000002256 antimetabolite Substances 0.000 claims description 14
- 239000002246 antineoplastic agent Substances 0.000 claims description 14
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 claims description 14
- 230000037361 pathway Effects 0.000 claims description 14
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 14
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 102000017256 epidermal growth factor-activated receptor activity proteins Human genes 0.000 claims description 13
- 108040009258 epidermal growth factor-activated receptor activity proteins Proteins 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 11
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 9
- 229960003668 docetaxel Drugs 0.000 claims description 9
- 102000004169 proteins and genes Human genes 0.000 claims description 9
- 108090000623 proteins and genes Proteins 0.000 claims description 9
- 125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 8
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 8
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 8
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 8
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 8
- 229940100198 ALKYLATING AGENTS Drugs 0.000 claims description 8
- 208000005017 Glioblastoma Diseases 0.000 claims description 8
- 206010029260 Neuroblastoma Diseases 0.000 claims description 8
- 230000001772 anti-angiogenic Effects 0.000 claims description 8
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 8
- 230000003054 hormonal Effects 0.000 claims description 8
- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 8
- 229940100197 ANTIMETABOLITES Drugs 0.000 claims description 7
- 229940034982 ANTINEOPLASTIC AGENTS Drugs 0.000 claims description 7
- 102000004400 Aminopeptidases Human genes 0.000 claims description 7
- 108090000915 Aminopeptidases Proteins 0.000 claims description 7
- 102000014654 Aromatase Human genes 0.000 claims description 7
- 108010078554 Aromatase Proteins 0.000 claims description 7
- 229940046844 Aromatase inhibitors Drugs 0.000 claims description 7
- 108060001001 BRK1 Proteins 0.000 claims description 7
- QXZGBUJJYSLZLT-FDISYFBBSA-N Bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 claims description 7
- 101710040446 CD40 Proteins 0.000 claims description 7
- 102100013137 CD40 Human genes 0.000 claims description 7
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 claims description 7
- 229960001334 Corticosteroids Drugs 0.000 claims description 7
- 102100013714 DIABLO Human genes 0.000 claims description 7
- 101710002761 DIABLO Proteins 0.000 claims description 7
- 102100008645 FGF3 Human genes 0.000 claims description 7
- 102400000932 Gonadoliberin-1 Human genes 0.000 claims description 7
- 108010084340 Gonadotropin-Releasing Hormone Proteins 0.000 claims description 7
- 102100003684 HPSE Human genes 0.000 claims description 7
- 239000003458 I kappa b kinase inhibitor Substances 0.000 claims description 7
- 101710004181 INTS2 Proteins 0.000 claims description 7
- 102000004218 Insulin-like growth factor I Human genes 0.000 claims description 7
- 108090000723 Insulin-like growth factor I Proteins 0.000 claims description 7
- 102100011311 KNG1 Human genes 0.000 claims description 7
- 102000028664 Microtubules Human genes 0.000 claims description 7
- 108091022031 Microtubules Proteins 0.000 claims description 7
- 210000004688 Microtubules Anatomy 0.000 claims description 7
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 7
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 7
- 102000001708 Protein Isoforms Human genes 0.000 claims description 7
- 108010029485 Protein Isoforms Proteins 0.000 claims description 7
- QFJCIRLUMZQUOT-HPLJOQBZSA-N Sirolimus Chemical class C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 7
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 7
- 230000002280 anti-androgenic Effects 0.000 claims description 7
- 230000002424 anti-apoptotic Effects 0.000 claims description 7
- 230000001833 anti-estrogenic Effects 0.000 claims description 7
- 239000000051 antiandrogen Substances 0.000 claims description 7
- 230000001640 apoptogenic Effects 0.000 claims description 7
- 239000003886 aromatase inhibitor Substances 0.000 claims description 7
- 230000024245 cell differentiation Effects 0.000 claims description 7
- 229960004316 cisplatin Drugs 0.000 claims description 7
- 239000003246 corticosteroid Substances 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000000328 estrogen antagonist Substances 0.000 claims description 7
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims description 7
- 229960001442 gonadorelin Drugs 0.000 claims description 7
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 claims description 7
- 108010037536 heparanase Proteins 0.000 claims description 7
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 7
- 238000001794 hormone therapy Methods 0.000 claims description 7
- 150000002632 lipids Chemical class 0.000 claims description 7
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 7
- 239000003475 metalloproteinase inhibitor Substances 0.000 claims description 7
- 230000000051 modifying Effects 0.000 claims description 7
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 claims description 7
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 claims description 7
- 239000003197 protein kinase b inhibitor Substances 0.000 claims description 7
- 239000002464 receptor antagonist Substances 0.000 claims description 7
- 230000019491 signal transduction Effects 0.000 claims description 7
- 239000003277 telomerase inhibitor Substances 0.000 claims description 7
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 claims description 7
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 claims description 7
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 6
- 229940063683 Taxotere Drugs 0.000 claims description 6
- 239000000824 cytostatic agent Substances 0.000 claims description 6
- 239000002254 cytotoxic agent Substances 0.000 claims description 6
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 6
- 229960005277 gemcitabine Drugs 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 239000000546 pharmaceutic aid Substances 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 230000000240 adjuvant Effects 0.000 claims description 5
- 238000001959 radiotherapy Methods 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 229940120638 Avastin Drugs 0.000 claims description 4
- 210000000481 Breast Anatomy 0.000 claims description 4
- 206010024324 Leukaemias Diseases 0.000 claims description 4
- 210000004072 Lung Anatomy 0.000 claims description 4
- 206010025650 Malignant melanoma Diseases 0.000 claims description 4
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 4
- 210000002307 Prostate Anatomy 0.000 claims description 4
- 230000000973 chemotherapeutic Effects 0.000 claims description 4
- 201000011231 colorectal cancer Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 230000002611 ovarian Effects 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 230000000268 renotropic Effects 0.000 claims description 4
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 3
- 102100000129 CHURC1 Human genes 0.000 claims description 3
- 101710014631 CHURC1 Proteins 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 description 89
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 58
- 239000000243 solution Substances 0.000 description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 50
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- 238000004128 high performance liquid chromatography Methods 0.000 description 34
- 239000007787 solid Substances 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 29
- 210000004027 cells Anatomy 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 239000000047 product Substances 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 150000001241 acetals Chemical class 0.000 description 24
- 239000010410 layer Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 22
- 239000000377 silicon dioxide Substances 0.000 description 21
- 239000002253 acid Substances 0.000 description 20
- 238000000034 method Methods 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 229940079593 drugs Drugs 0.000 description 19
- 125000004432 carbon atoms Chemical group C* 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- RCINICONZNJXQF-MZXODVADSA-N Intaxel 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 16
- 229940045698 antineoplastic Taxanes Drugs 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 238000005859 coupling reaction Methods 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
- 229960001592 Paclitaxel Drugs 0.000 description 14
- 238000007792 addition Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 229960001866 silicon dioxide Drugs 0.000 description 14
- 239000007858 starting material Substances 0.000 description 14
- 229930003347 taxol Natural products 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 230000036457 multidrug resistance Effects 0.000 description 11
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- 239000006260 foam Substances 0.000 description 10
- 238000007363 ring formation reaction Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 230000001808 coupling Effects 0.000 description 9
- 238000010168 coupling process Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 230000000875 corresponding Effects 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- 238000006462 rearrangement reaction Methods 0.000 description 8
- MCIPQLOKVXSHTD-UHFFFAOYSA-N 3,3-diethoxyprop-1-ene Chemical compound CCOC(C=C)OCC MCIPQLOKVXSHTD-UHFFFAOYSA-N 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000005755 formation reaction Methods 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000006640 acetylation reaction Methods 0.000 description 6
- 125000004429 atoms Chemical group 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000004927 clay Substances 0.000 description 6
- 229910052570 clay Inorganic materials 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 5
- 230000002378 acidificating Effects 0.000 description 5
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrugs Drugs 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 10-deacetylbaccatin III Natural products O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- 102100014001 ABCB1 Human genes 0.000 description 4
- IAKHMKGGTNLKSZ-INIZCTEOSA-N Colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 4
- 229960002949 Fluorouracil Drugs 0.000 description 4
- 101710021184 PAPOLB Proteins 0.000 description 4
- NQSIKKSFBQCBSI-UHFFFAOYSA-N Tetrapropylammonium perruthenate Chemical compound [O-][Ru](=O)(=O)=O.CCC[N+](CCC)(CCC)CCC NQSIKKSFBQCBSI-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- KARVSHNNUWMXFO-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane;hydrate Chemical compound O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Al]O[Al]=O KARVSHNNUWMXFO-UHFFFAOYSA-N 0.000 description 4
- 229950010514 misonidazole Drugs 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229910052901 montmorillonite Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000001681 protective Effects 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- OBBCSXFCDPPXOL-UHFFFAOYSA-N α-(methoxymethyl)-2-nitro-1H-Imidazole-1-ethanol Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 4
- YWLXLRUDGLRYDR-YLPZXOTFSA-N 10-DAB III Chemical compound O([C@H]1[C@@H]2[C@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@H](O)C[C@H]1OC[C@@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-YLPZXOTFSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005420 Etoposide Drugs 0.000 description 3
- 102100002485 MAPT Human genes 0.000 description 3
- 206010034133 Pathogen resistance Diseases 0.000 description 3
- 229960002340 Pentostatin Drugs 0.000 description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N Pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 3
- 206010039491 Sarcoma Diseases 0.000 description 3
- 229960003048 Vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 241000863480 Vinca Species 0.000 description 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 229930013930 alkaloids Natural products 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 230000003197 catalytic Effects 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- YEMWINDXAKRPBK-UHFFFAOYSA-N heptane;2-methoxy-2-methylpropane Chemical compound COC(C)(C)C.CCCCCCC YEMWINDXAKRPBK-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006011 modification reaction Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 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 3
- 108060008687 tus Proteins 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- HONKEGXLWUDTCF-YFKPBYRVSA-N (2S)-2-amino-2-methyl-4-phosphonobutanoic acid Chemical compound OC(=O)[C@](N)(C)CCP(O)(O)=O HONKEGXLWUDTCF-YFKPBYRVSA-N 0.000 description 2
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 description 2
- XYIPZQCDLAFBSX-CMPLNLGQSA-N (4aR,9bR)-8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole Chemical compound C1CNC[C@H]2C3=CC(C)=CC=C3N[C@@H]21 XYIPZQCDLAFBSX-CMPLNLGQSA-N 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical group COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- OEWYWFJWBZNJJG-UHFFFAOYSA-N 1-(aziridin-1-yl)-3-(2-nitroimidazol-1-yl)propan-2-ol Chemical compound C1=CN=C([N+]([O-])=O)N1CC(O)CN1CC1 OEWYWFJWBZNJJG-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- RMIODHQZRUFFFF-UHFFFAOYSA-M 2-methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- OBWGMYALGNDUNM-UHFFFAOYSA-N 3,3-dimethoxyprop-1-ene Chemical compound COC(OC)C=C OBWGMYALGNDUNM-UHFFFAOYSA-N 0.000 description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 102100017860 ABCC1 Human genes 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N Altretamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229960001561 Bleomycin Drugs 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 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 2
- 229960004630 Chlorambucil Drugs 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N Chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N Chlormethine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 229960000640 Dactinomycin Drugs 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 229960000975 Daunorubicin Drugs 0.000 description 2
- 229960004679 Doxorubicin Drugs 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 229960004338 Leuprorelin Drugs 0.000 description 2
- 101700017358 MAP2 Proteins 0.000 description 2
- 102100013127 MAP4 Human genes 0.000 description 2
- 101700050767 MAP4 Proteins 0.000 description 2
- 101710039852 METAP1 Proteins 0.000 description 2
- 102100016477 METAP2 Human genes 0.000 description 2
- 101710012506 METAP2 Proteins 0.000 description 2
- 102100007141 MOAP1 Human genes 0.000 description 2
- 101700056220 MOAP1 Proteins 0.000 description 2
- 101700059931 MPK4 Proteins 0.000 description 2
- 229960004961 Mechlorethamine Drugs 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960004857 Mitomycin Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 229960001156 Mitoxantrone Drugs 0.000 description 2
- 206010048723 Multiple-drug resistance Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-Methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 229940026778 Other chemotherapeutics in ATC Drugs 0.000 description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N Phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 2
- 229960003171 Plicamycin Drugs 0.000 description 2
- 229960004029 Silicic Acid Drugs 0.000 description 2
- 210000002356 Skeleton Anatomy 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 241000202349 Taxus brevifolia Species 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229960001278 Teniposide Drugs 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 2
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 2
- UHTHHESEBZOYNR-UHFFFAOYSA-N Vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 2
- 229960004528 Vincristine Drugs 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229960000473 altretamine Drugs 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 229960001338 colchicine Drugs 0.000 description 2
- 230000001143 conditioned Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000001963 growth media Substances 0.000 description 2
- 125000005842 heteroatoms Chemical group 0.000 description 2
- 239000008079 hexane Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 125000004430 oxygen atoms Chemical group O* 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-M phenoxyacetate Chemical compound [O-]C(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-M 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 2
- 229940049953 phenylacetate Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 2
- 125000006000 trichloroethyl group Chemical group 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229960000241 vandetanib Drugs 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- ZROHGHOFXNOHSO-BNTLRKBRSA-L (1R,2R)-cyclohexane-1,2-diamine;oxalate;platinum(2+) Chemical compound [H][N]([C@@H]1CCCC[C@H]1[N]1([H])[H])([H])[Pt]11OC(=O)C(=O)O1 ZROHGHOFXNOHSO-BNTLRKBRSA-L 0.000 description 1
- QXRSDHAAWVKZLJ-PVYNADRNSA-N (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[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 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 1
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-[(2S)-2-(ethylcarbamoyl)pyrrolidin-1-yl]-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hy Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N (3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1H-indol-2-one Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- YJGVMLPVUAXIQN-LGWHJFRWSA-N (5S,5aR,8aR,9R)-5-hydroxy-9-(3,4,5-trimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-LGWHJFRWSA-N 0.000 description 1
- OMJKFYKNWZZKTK-POHAHGRESA-N (5Z)-5-(dimethylaminohydrazinylidene)imidazole-4-carboxamide Chemical compound CN(C)N\N=C1/N=CN=C1C(N)=O OMJKFYKNWZZKTK-POHAHGRESA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- IGERFAHWSHDDHX-UHFFFAOYSA-N 1,3-dioxanyl Chemical group [CH]1OCCCO1 IGERFAHWSHDDHX-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- GPAAEZIXSQCCES-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxymethoxymethoxy)ethane Chemical compound COCCOCOCOCCOC GPAAEZIXSQCCES-UHFFFAOYSA-N 0.000 description 1
- DEEULBIVHZVMHX-UHFFFAOYSA-N 1-nitroacridine Chemical compound C1=CC=C2C=C3C([N+](=O)[O-])=CC=CC3=NC2=C1 DEEULBIVHZVMHX-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- KUFRQPKVAWMTJO-LMZWQJSESA-N 17-Dimethylaminoethylamino-17-demethoxygeldanamycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCCN(C)C)C(=O)C=C1C2=O KUFRQPKVAWMTJO-LMZWQJSESA-N 0.000 description 1
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 1
- 150000000307 17β-estradiols Chemical class 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-Dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- XPBJPGMCFKYBBV-UHFFFAOYSA-N 2-bromoethyl-[2-hydroxy-3-(2-nitroimidazol-1-yl)propyl]azanium;bromide Chemical compound Br.BrCCNCC(O)CN1C=CN=C1[N+]([O-])=O XPBJPGMCFKYBBV-UHFFFAOYSA-N 0.000 description 1
- SYNHCENRCUAUNM-UHFFFAOYSA-N 2-chloro-N-(2-chloroethyl)-N-methylethanamine oxide;hydron;chloride Chemical compound Cl.ClCC[N+]([O-])(C)CCCl SYNHCENRCUAUNM-UHFFFAOYSA-N 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N 2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 125000000094 2-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
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- HXHAJRMTJXHJJZ-UHFFFAOYSA-N 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-(4-pyrrolidin-1-ylbutylcarbamoylamino)-1,2-thiazole-4-carboxamide Chemical compound S1N=C(OCC=2C(=CC(Br)=CC=2F)F)C(C(=O)N)=C1NC(=O)NCCCCN1CCCC1 HXHAJRMTJXHJJZ-UHFFFAOYSA-N 0.000 description 1
- HOJZAHQWDXAPDJ-UHFFFAOYSA-N 3-anilino-2-hydroxypropanoic acid Chemical group OC(=O)C(O)CNC1=CC=CC=C1 HOJZAHQWDXAPDJ-UHFFFAOYSA-N 0.000 description 1
- 125000002103 4,4'-dimethoxytriphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)(C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H])C1=C([H])C([H])=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- MMURVNDSFNJHAM-OWOJBTEDSA-N 4-[(E)-2-(4-carbamimidoylphenyl)ethenyl]benzenecarboximidamide Chemical compound C1=CC(C(=N)N)=CC=C1\C=C\C1=CC=C(C(N)=N)C=C1 MMURVNDSFNJHAM-OWOJBTEDSA-N 0.000 description 1
- ADHLSOGCYJHJBG-UHFFFAOYSA-N 4-[5-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1,3-dihydrobenzimidazol-2-ylidene]cyclohexa-2,5-dien-1-one Chemical compound C1CN(C)CCN1C1=CC=C(N=C(N2)C=3C=C4NC(NC4=CC=3)=C3C=CC(=O)C=C3)C2=C1 ADHLSOGCYJHJBG-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2R)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- 101700002015 ABCB1 Proteins 0.000 description 1
- 101700012269 ABCC1 Proteins 0.000 description 1
- 229960003272 ASPARAGINASE Drugs 0.000 description 1
- 101710031223 Abcb1b Proteins 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229960003437 Aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N Aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003896 Aminopterin Drugs 0.000 description 1
- 229960001220 Amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N Amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N Anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N Anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 229950003145 Apolizumab Drugs 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- MOTJMGVDPWRKOC-QPVYNBJUSA-N Atrasentan Chemical compound C1([C@H]2[C@@H]([C@H](CN2CC(=O)N(CCCC)CCCC)C=2C=C3OCOC3=CC=2)C(O)=O)=CC=C(OC)C=C1 MOTJMGVDPWRKOC-QPVYNBJUSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Belustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N Benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N Benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N Benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 108010005144 Bevacizumab Proteins 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N Bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 229960004117 Capecitabine Drugs 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229960004562 Carboplatin Drugs 0.000 description 1
- 229940097647 Casodex Drugs 0.000 description 1
- 108010022830 Cetuximab Proteins 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- 229960002559 Chlorotrianisene Drugs 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N Chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 229960000579 Clodronate Disodium Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N Clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M Copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229960004397 Cyclophosphamide Drugs 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 229960000978 Cyproterone Acetate Drugs 0.000 description 1
- UWFYSQMTEOIJJG-FDTZYFLXSA-N Cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 description 1
- 229960000684 Cytarabine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 230000000970 DNA cross-linking Effects 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- 229940057307 Dihydrate Calcium Sulfate Drugs 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N Disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N Dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 229950004203 Droloxifene Drugs 0.000 description 1
- NOTIQUSPUUHHEH-UXOVVSIBSA-N Drostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VQNATVDKACXKTF-XELLLNAOSA-N Duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 description 1
- 229960001904 EPIRUBICIN Drugs 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N EPIRUBICIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 230000035695 Efflux Effects 0.000 description 1
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 1
- 229960001433 Erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001842 Estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N Estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- ISVXIZFUEUVXPG-UHFFFAOYSA-N Etiopurpurin Chemical compound CC1C2(CC)C(C(=O)OCC)=CC(C3=NC(C(=C3C)CC)=C3)=C2N=C1C=C(N1)C(CC)=C(C)C1=CC1=C(CC)C(C)=C3N1 ISVXIZFUEUVXPG-UHFFFAOYSA-N 0.000 description 1
- 229950011548 FADROZOLE Drugs 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N Fadrozole Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- 241000272184 Falconiformes Species 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N Finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 Floxuridine Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N Fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 Fluoxymesterone Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N Flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- OSVMTWJCGUFAOD-KZQROQTASA-N Formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
- 229960002258 Fulvestrant Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N Gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 108010091266 Gemtuzumab Proteins 0.000 description 1
- 229940074045 Glyceryl Distearate Drugs 0.000 description 1
- 229960002913 Goserelin Drugs 0.000 description 1
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 229940022353 Herceptin Drugs 0.000 description 1
- JARKCYVAAOWBJS-UHFFFAOYSA-N Hexanal Natural products CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 1
- 229960000908 Idarubicin Drugs 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- 229960001101 Ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N Ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N Imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N Indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- 102000003996 Interferon beta Human genes 0.000 description 1
- 108090000467 Interferon beta Proteins 0.000 description 1
- 229960001388 Interferon-beta Drugs 0.000 description 1
- 229940047124 Interferons Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 229950010897 Iproplatin Drugs 0.000 description 1
- 229940084651 Iressa Drugs 0.000 description 1
- 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 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N Isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- UHEBDUAFKQHUBV-UHFFFAOYSA-N JSPY-st000261 Chemical compound C1=CC=C2C3=C(C(=O)NC4)C4=C(C=4C(=CC=C(C=4)COC(C)C)N4CCCOC(=O)CN(C)C)C4=C3CC2=C1 UHEBDUAFKQHUBV-UHFFFAOYSA-N 0.000 description 1
- 102100013180 KDR Human genes 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N Lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N Letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229940008250 Leuprolide Drugs 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levotetramisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- KYYQSAMPTLGNIQ-CIGKBZFWSA-N Liblomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN(C)CCCN(CC=1C=C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)=CC=1)CC=1C=C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C KYYQSAMPTLGNIQ-CIGKBZFWSA-N 0.000 description 1
- HJYYPODYNSCCOU-ODRIEIDWSA-N MDL-62769 Chemical compound OC1=C(C(O)=C2C)C3=C(O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O HJYYPODYNSCCOU-ODRIEIDWSA-N 0.000 description 1
- WKPWGQKGSOKKOO-RSFHAFMBSA-N Maitansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N Marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 Marimastat Drugs 0.000 description 1
- 229960003951 Masoprocol Drugs 0.000 description 1
- HCZKYJDFEPMADG-TXEJJXNPSA-N Masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 1
- 229960004296 Megestrol Acetate Drugs 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 241001108995 Messa Species 0.000 description 1
- 108020004999 Messenger RNA Proteins 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- VMMKGHQPQIEGSQ-UHFFFAOYSA-N Minodronic acid Chemical compound C1=CC=CN2C(CC(O)(P(O)(O)=O)P(O)(O)=O)=CN=C21 VMMKGHQPQIEGSQ-UHFFFAOYSA-N 0.000 description 1
- 229960000350 Mitotane Drugs 0.000 description 1
- 229950003063 Mitumomab Drugs 0.000 description 1
- 241000918728 Monotes Species 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide;(2S)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- BYQPDMUOXXCZOV-UHFFFAOYSA-N N-[3-(2-nitroimidazol-1-yl)propyl]acridin-9-amine;hydrochloride Chemical compound Cl.[O-][N+](=O)C1=NC=CN1CCCNC1=C(C=CC=C2)C2=NC2=CC=CC=C12 BYQPDMUOXXCZOV-UHFFFAOYSA-N 0.000 description 1
- UPBAOYRENQEPJO-UHFFFAOYSA-N N-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical compound CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229940086322 Navelbine Drugs 0.000 description 1
- 108010042309 Netropsin Proteins 0.000 description 1
- IDBIFFKSXLYUOT-UHFFFAOYSA-N Netropsin Chemical compound C1=C(C(=O)NCCC(N)=N)N(C)C=C1NC(=O)C1=CC(NC(=O)CN=C(N)N)=CN1C IDBIFFKSXLYUOT-UHFFFAOYSA-N 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N Nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N Nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- MDJFHRLTPRPZLY-UHFFFAOYSA-N Nimorazole Chemical compound [O-][N+](=O)C1=CN=CN1CCN1CCOCC1 MDJFHRLTPRPZLY-UHFFFAOYSA-N 0.000 description 1
- 229960004918 Nimorazole Drugs 0.000 description 1
- MSHZHSPISPJWHW-UHFFFAOYSA-N O-(chloroacetylcarbamoyl)fumagillol Chemical compound O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)NC(=O)CCl)CCC21CO2 MSHZHSPISPJWHW-UHFFFAOYSA-N 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N OLIVOMYCIN Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 OLIVOMYCIN Drugs 0.000 description 1
- 229950007283 Oregovomab Drugs 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108010061219 Panitumumab Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229940109328 Photofrin Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N Pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N Procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- WTFXJFJYEJZMFO-UHFFFAOYSA-N Propamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCOC1=CC=C(C(N)=N)C=C1 WTFXJFJYEJZMFO-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N Quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N Raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 Raloxifene Drugs 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N Rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 108010001645 Rituximab Proteins 0.000 description 1
- 229950003647 Semaxanib Drugs 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M Sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- 229950001248 Squalamine Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- XJTXBUKLGQCZHC-GCKMJXCFSA-N Steganacin Chemical compound C1=C2C=3C(OC)=C(OC)C(OC)=CC=3C[C@@H]3C(=O)OC[C@H]3[C@H](OC(C)=O)C2=CC2=C1OCO2 XJTXBUKLGQCZHC-GCKMJXCFSA-N 0.000 description 1
- 229960001052 Streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 102000018075 Subfamily B ATP Binding Cassette Transporter Human genes 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N Sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N THP Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 102100002607 TIMP1 Human genes 0.000 description 1
- 102100006014 TIMP2 Human genes 0.000 description 1
- 229950000212 TRIOXIFENE Drugs 0.000 description 1
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 1
- 229960001603 Tamoxifen Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N Tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229950007866 Tanespimycin Drugs 0.000 description 1
- 229940120982 Tarceva Drugs 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- 229960005353 Testolactone Drugs 0.000 description 1
- 229960003604 Testosterone Drugs 0.000 description 1
- 229960003433 Thalidomide Drugs 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N Thalidomide Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N ThioTEPA Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 229960005454 Thioguanine Drugs 0.000 description 1
- 229960001196 Thiotepa Drugs 0.000 description 1
- 108010031374 Tissue Inhibitor of Metalloproteinase-1 Proteins 0.000 description 1
- 108010031372 Tissue Inhibitor of Metalloproteinase-2 Proteins 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- 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 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N Toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 108010010691 Trastuzumab Proteins 0.000 description 1
- 229960001727 Tretinoin Drugs 0.000 description 1
- SHGAZHPCJJPHSC-NWVFGJFESA-N Tretinoin Chemical compound OC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NWVFGJFESA-N 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N Triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N Trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- GCPXMJHSNVMWNM-UHFFFAOYSA-N Trihydroxyarsenite(Iii) Chemical compound O[As](O)O GCPXMJHSNVMWNM-UHFFFAOYSA-N 0.000 description 1
- 229960004824 Triptorelin Drugs 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N Trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N Uramustine Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- 229950008158 Uramustine Drugs 0.000 description 1
- 108091007928 VEGF receptors Proteins 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N Valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N Verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 Verteporfin Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N Vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 Vindesine Drugs 0.000 description 1
- KSZGVNZSUJHOJA-UHFFFAOYSA-N Zindoxifene Chemical compound CC=1C2=CC(OC(C)=O)=CC=C2N(CC)C=1C1=CC=C(OC(C)=O)C=C1 KSZGVNZSUJHOJA-UHFFFAOYSA-N 0.000 description 1
- 229950006514 Zindoxifene Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N Zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N [(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- ZYVSOIYQKUDENJ-MNGCYDFMSA-N [6-[[(6S,7S)-6-[4-[4-(5-acetyloxy-4-hydroxy-4,6-dimethyloxan-2-yl)oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-7-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-4,10-dihydroxy-3-methyl-5-oxo-7,8-dihydro-6H-anthracen-2-yl]oxy]-4-(4- Chemical compound C([C@H]([C@@H](C(=O)C1=C(O)C2=C(O)C=3C)OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(OC(C)=O)C(C)(O)C6)C5)C4)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)C1=CC2=CC=3OC(OC(C)C1OC(C)=O)CC1OC1CC(O)C(OC)C(C)O1 ZYVSOIYQKUDENJ-MNGCYDFMSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000006359 acetalization reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- HGINCPLSRVDWNT-UHFFFAOYSA-N acrylaldehyde Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 1
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 125000006241 alcohol protecting group Chemical group 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000005466 alkylenyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N aminolevulinic acid Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 108010062611 apolizumab Proteins 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960002594 arsenic trioxide Drugs 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004350 aryl cycloalkyl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 229950010993 atrasentan Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000002051 biphasic Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- PASHVRUKOFIRIK-UHFFFAOYSA-L calcium sulfate dihydrate Chemical compound O.O.[Ca+2].[O-]S([O-])(=O)=O PASHVRUKOFIRIK-UHFFFAOYSA-L 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-N calcium;sulfuric acid Chemical compound [Ca+2].OS(O)(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-N 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- OKTJSMMVPCPJKN-YPZZEJLDSA-N carbon-10 atom Chemical compound [10C] OKTJSMMVPCPJKN-YPZZEJLDSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000024881 catalytic activity Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229960001411 chlormethine Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000006448 cycloalkyl cycloalkyl group Chemical group 0.000 description 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001472 cytotoxic Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 239000003145 cytotoxic factor Substances 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 238000005828 desilylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 229930004069 diterpenes Natural products 0.000 description 1
- 229940017743 dromostanolone propionate Drugs 0.000 description 1
- 229950004683 drostanolone propionate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 229930013349 epothilone B Natural products 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 230000001747 exhibiting Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 229960004421 formestane Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 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
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 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
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229960002899 hydroxyprogesterone Drugs 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 media Substances 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229920002106 messenger RNA Polymers 0.000 description 1
- YUUAYBAIHCDHHD-UHFFFAOYSA-N methyl 5-aminolevulinate Chemical compound COC(=O)CCC(=O)CN YUUAYBAIHCDHHD-UHFFFAOYSA-N 0.000 description 1
- 229960005033 methyl aminolevulinate Drugs 0.000 description 1
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229950011129 minodronic acid Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000000394 mitotic Effects 0.000 description 1
- 108010066052 multidrug resistance-associated protein 1 Proteins 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000005445 natural product Substances 0.000 description 1
- 229930014626 natural products Natural products 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
- 229960001346 nilotinib Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 229960000435 oblimersen Drugs 0.000 description 1
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 108010060422 oregovomab Proteins 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- FXSKHQLAUMGYJK-UHFFFAOYSA-J platinum(4+);propan-2-amine;dichloride;dihydroxide Chemical compound [OH-].[OH-].[Cl-].[Cl-].[Pt+4].CC(C)N.CC(C)N FXSKHQLAUMGYJK-UHFFFAOYSA-J 0.000 description 1
- 230000004983 pleiotropic Effects 0.000 description 1
- 125000005592 polycycloalkyl group Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229960003761 propamidine Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 229960003292 rifamycin Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- CKNPWBAXEKSCRG-UHFFFAOYSA-J satraplatin Chemical compound CC(=O)O[Pt-2]([NH3+])(Cl)(Cl)(OC(C)=O)[NH2+]C1CCCCC1 CKNPWBAXEKSCRG-UHFFFAOYSA-J 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 231100000197 serious side effect Toxicity 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VBDRTGFACFYFCT-UHFFFAOYSA-M sodium;hydroxy-[(1R)-1-hydroxy-3-[methyl(pentyl)amino]-1-phosphonopropyl]phosphinate;hydrate Chemical compound O.[Na+].CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)([O-])=O VBDRTGFACFYFCT-UHFFFAOYSA-M 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 230000000087 stabilizing Effects 0.000 description 1
- 108010042747 stallimycin Proteins 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 229960002812 sunitinib malate Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 description 1
- RMFNGLHOFHJMHN-UHFFFAOYSA-L triplatin tetranitrate Chemical compound [O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[NH3+][Pt-2]([NH3+])(Cl)[NH2+]CCCCCC[NH2+][Pt-2]([NH3+])([NH3+])[NH2+]CCCCCC[NH2+][Pt-2]([NH3+])([NH3+])Cl RMFNGLHOFHJMHN-UHFFFAOYSA-L 0.000 description 1
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- CILBMBUYJCWATM-IJDPFCGHSA-N vinorelbine L-tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-IJDPFCGHSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N α-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/06—Peri-condensed systems
Abstract
The disclosure relates to abeo-taxane derivatives of general formula I and II, wherein the unspecified groups are defined in the specification. The disclosure also relates to pharmaceutical compositions comprising these compounds and their use in the treatment of cancer. Example compounds include: 10-alpha abeo-taxane-2-methylpropenyl acetal. 10-alpha abeo-taxane-2,6-dimethyl-1,5-heptadienyl acetal. 10-alpha abeo-taxane benzylidene acetal. The disclosure also relates to taxane derivates. 10-alpha abeo-taxane-2-methylpropenyl acetal. 10-alpha abeo-taxane-2,6-dimethyl-1,5-heptadienyl acetal. 10-alpha abeo-taxane benzylidene acetal. The disclosure also relates to taxane derivates.
Description
Taxane and Abeo-Taxane Analogs
Field of the Invention
The present invention generally relates to chemical compounds for use in treating cancer
patients. More particularly, the present invention is directed to new and useful taxane analogs
and further to methods for producing them. The present application is also directed to
pharmaceutical formulations comprising the disclosed taxanes, abeo-taxanes and methods of
treating cancer with the disclosed taxanes, abeo-taxanes and their pharmaceutical formulations.
In addition, the present application discloses 9α,10β- and 9α,10α- taxane and abeo-taxane analog
syntheses and their applications in cancer treatment. Specifically, the present invention relates to
taxane and abeo-taxane analogs, intermediates and their synthesis.
Background of the Invention
Taxanes such as paclitaxel are diterpene natural product drug molecules that have been
used to treat cancer in the clinic for many years. Synthetic analogs of paclitaxel such as
docetaxel have been developed and also used in the clinic to treat various cancers. The taxanes
act by binding to tubulin and stabilizing the mitotic spindle thereby halting mitosis and leading
cells into apoptosis. However the taxanes and other drug molecules have been found to be
ineffective in treating multidrug resistant cancers and cancers with mutant tubulins. Therefore a
continuing need exists for compounds that are effective therapeutic agents for cancers that are
multidrug resistant.
One approach in developing new anti-cancer drugs is the identification of superior
analogs and derivatives of biologically active compounds. Modifications of various portions of a
complex molecule may lead to new and better drugs having improved properties such as
increased biological activity, effectiveness against cancer cells that have developed multi-drug
resistance (MDR), fewer or less serious side effects, improved solubility characteristics, better
therapeutic profile and the like.
Zamir et al, Tetrahedron Letters, 37, 6435-6438 (1996) discloses taxane analogues
containing a five membered A-ring and a position 1 -C(CH ) OH group. These analogues were
abeo-taxanes lacking the four membered oxatane ring. Zamir et al, Tetrahedron Letters, 53.
15991-16008 (1997) discloses abeo-taxane analogues and also trapped intermediates containing
a 5 membered A-ring and a position 1 -C(CH ) OH group. Wahl et al, Tetrahedron, 48, 6965-
6974 (1992) discloses a wide range of modified taxane analogues including one which had a 5
membered A-ring and a 1 position -C(CH ) OH group.
US Patent No 5,352,806 discloses 10β- substituted taxanes which may have bridges
between the 7- and 9- hydroxyl groups of the formula:
11 12
wherein R and R are as defined in the patent.
Summary of the Invention:
In view of the promising anti-tumor activity of the taxane family, it is desirable to
investigate new and improved taxane analogs and derivatives for use in cancer treatment. One
particularly important area is the development of drugs having improved MDR reversal
properties. Accordingly, there is a need to provide new taxane compounds having improved
biological activity for use in treating cancer. There is also a need to provide methods for forming
such compounds. Finally, there is a need for methods of treating patients with such compounds
in cancer treatment regimens. It is an object of the present invention to go some way towards
meeting these needs; and/or to provide the public with a useful choice.
In one embodiment, the present application describes compounds that have an affinity to
bind with tubulin and are potential drugs in the treatment of cancer and other disease conditions
related to dysfunction of proteins associated with tubulin such as tau, MAP1, MAP2 and MAP4.
Embodiments and Aspects of the Application:
The following embodiments, aspects and variations thereof are exemplary and illustrative
and not intended to be limiting in scope.
[0008a] In a first embodiment, there is provided a compound of the formula II:
wherein:
R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl,
1-6 1-6 2-6 6-10
C arylC alkyl and C arylC alkoxy;
6-10 1-3 6-10 1-3
R is hydrogen or R'CO-, wherein R' is selected from the group consisting of C alkyl,
1 1-6
C aryl and arylC alkyl-;
6-10 1-3
R is selected from the group consisting of optionally substituted C alkyl, optionally
2 1-6
substituted phenyl and optionally substituted heteroaryl wherein the substituents are selected
from the group consisting of halo, nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy,
-NH , -OH, -SH, -NHCH , -N(CH ) , -SMe and -CN;
2 3 3 2
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
R' is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
provided that when one of R or R' is hydrogen, then the other is not a) a C alkyl
3 3 1-2
optionally substituted with 1 or 2 –OH, -NR°R°°or mixture thereof, b) a C alkenyl optionally
substituted with –OH or -NR°R°°, or c) C alkynyl optionally substituted with –OH or -NR°R°°,
wherein R° and R°° are each independently selected from the group consisting of hydrogen, C
alkyl- and wherein R° and R°° together with the nitrogen to which they attach form a 1-
morpholinyl group or a 4, 5, 6 or 7 membered heterocyclic ring; as a single diastereomer or a
mixture of diastereomers;
and pharmaceutically acceptable salts thereof;
provided that, when one of R or R' is –CH=CH , then R is not CH CO-.
3 3 2 1 3
Also described is a compound of the formula I:
wherein:
R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl,
1-6 1-6 2-6 6-10
C arylC alkyl and C arylC alkoxy;
6-10 1-3 6-10 1-3
R is hydrogen or R'CO-, wherein R' is selected from the group consisting of C alkyl,
1 1-6
C aryl and arylC alkyl-;
6-10 1-3
R is selected from the group consisting of optionally substituted C alkyl, optionally
2 1-6
substituted phenyl and optionally substituted heteroaryl wherein the substituents are selected
from the group consisting of halo, nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy,
-NH , -OH, -SH, -NHCH , -N(CH ) , -SMe and -CN;
2 3 3 2
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
R' is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
provided that when one of R or R' is hydrogen, then the other is not a) a C alkyl
3 3 1-2
optionally substituted with 1 or 2 –OH, -NR°R°°or mixture thereof, b) a C alkenyl optionally
substituted with –OH or -NR°R°°, or c) C alkynyl optionally substituted with –OH or -NR°R°°,
wherein R° and R°° are each independently selected from the group consisting of hydrogen, C
alkyl- and wherein R° and R°° together with the nitrogen to which they attach form a 1-
morpholinyl group or a 4, 5, 6 or 7 membered heterocyclic ring; as a single diastereomer or a
mixture of diastereomers;
and pharmaceutically acceptable salts thereof.
[0009A] Also described are compounds of the formula III or formula IV:
wherein:
R is selected from the group consisting of C1-6alkyl, C1-6alkoxy-, C2-6alkenyl, C6-10aryl,
C arylC alkyl and C arylC alkoxy;
6-10 1-3 6-10 1-3
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, R'CO-,
1 1-6 2-6
C aryl and C arylC alkyl, wherein R' is selected from the group consisting of C alkyl, C
6-10 6-10 1-3 1-6 6-
aryl and arylC alkyl-;
1-3
R is selected from the group consisting of optionally substituted C alkyl, optionally
2 1-6
substituted phenyl and optionally substituted heteroaryl;
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
R' is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
provided that when one of R or R' is hydrogen, then the other is not a) a C alkyl
3 3 1-2
optionally substituted with 1 or 2 –OH, -NR°R°°or mixture thereof, b) a C alkenyl optionally
substituted with –OH or -NR°R°°, or c) C alkynyl optionally substituted with –OH or -NR°R°°,
wherein R° and R°° are each independently selected from the group consisting of hydrogen, C
alkyl- and wherein R° and R°° together with the nitrogen to which they attach form a 1-
morpholinyl group or a 4, 5, 6 or 7 membered heterocyclic ring;
as a single diastereomer or a mixture of diastereomers;
and pharmaceutically acceptable salts thereof;
provided that for formula IV, when one of R or R' is –CH=CH , then R is not CH CO-.
3 3 2 1 3
[0009B] In a second embodiment, the invention provides a pharmaceutical composition
comprising:
a) a therapeutically effective amount of a compound of the invention, in the form of a
single diastereoisomer; and
b) at least one pharmaceutically acceptable excipient, diluent or adjuvant.
[0009C] In a third embodiment, the invention provides a use of a compound of the invention in
the manufacture of a medicament.
[0009D] In a fourth embodiment, the invention provides a use of a compound of the invention in
the manufacture of a medicament for the treatment of a cancer in a patient in need of such
treatment.
[0009E] Also described is a process for the preparation of compound of formula I:
wherein:
R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl
1-6 1-6 2-6 6-10
and C arylC alkyl;
6-10 1-3
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, R'CO-,
1 1-6 2-6
C aryl and C arylC alkyl, wherein R' is selected from the group consisting of C alkyl, C
6-10 6-10 1-3 1-6 6-
aryl and arylC alkyl-;
1-3
R is selected from the group consisting of C alkyl, optionally substituted phenyl and
2 1-6
optionally substituted heteroaryl wherein the substituents are selected from the group consisting
of halo, nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, -NH , -OH, -SH, -NHCH ,
-N(CH ) , -SMe and -CN;
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
R' is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl;
6 6-10 6-10 1-3
provided that when one of R or R' is hydrogen, then the other is not a) a C alkyl
3 3 1-2
optionally substituted with 1 or 2 –OH, -NR°R°°or mixture thereof, b) a C alkenyl optionally
substituted with –OH or -NR°R°°, or c) C alkynyl optionally substituted with –OH or -NR°R°°,
wherein R° and R°° are each independently selected from the group consisting of hydrogen, C
alkyl- and wherein R° and R°° together with the nitrogen to which they attach form a 1-
morpholinyl group or a 4, 5, 6 or 7 membered heterocyclic ring;
and P is a protecting group;
the process comprising the steps of treating a compound of the formula 5 under condition
sufficient to effect a rearrangement reaction to form a compound of the formula 6;
ring formation to form an acetal or ketal of the formula 7;
selective de-acetylation of the C-13 acetate to form a compound of the formula 8;
coupling of the compound of the formula 8 with a side chain of the formula 9 or 10;
and deprotecting the protecting group P to form the compound of the formula 10.
[0009G] Also described is a compound of formula I prepared by the method described above.
[009F] Also described are compounds of the formula I or II:
wherein: R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl,
1-6 1-6 2-6 6-10
C arylC alkyl and C arylC alkoxy; R is hydrogen or is selected from the group
6-10 1-3 6-10 1-3 1
consisting of C alkyl, C alkenyl, R'CO-, C aryl and C arylC alkyl, wherein R' is
1-6 2-6 6-10 6-10 1-3
selected from the group consisting of C alkyl, C aryl and arylC alkyl-; R is selected from
1-6 6-10 1-3 2
the group consisting of optionally substituted C alkyl, optionally substituted phenyl and
optionally substituted heteroaryl; R3 is hydrogen or is selected from the group consisting of C1-
alkyl, C alkenyl, C alkynyl, C aryl and C arylC alkyl, wherein each C alkyl, C
18 2-6 2-6 6-10 6-10 1-3 1-18 3-
alkenyl and C alkynyl are optionally substituted by 1 or 2 –OH, NH , –NHC alkyl or –N(C
6 3-6 2 1-3 1-
alkyl) and wherein each C aryl is unsubstituted or substituted with 1, 2 or 3 –OCH ; R' is
3 2 6-10 3 3
hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C alkynyl, C
1-18 2-6 2-6 6-
aryl and C arylC alkyl, wherein each C alkyl, C alkenyl and C alkynyl are optionally
6-10 1-3 1-18 3-6 3-6
substituted by 1 or 2 –OH, NH , –NHC alkyl or –N(C alkyl) and wherein each C aryl is
2 1-3 1-3 2 6-10
unsubstituted or substituted with 1, 2 or 3 –OCH3; provided that when one of R3 or R'3 is
hydrogen, then the other is not a) a C alkyl optionally substituted with 1 or 2 –OH, -NR°R°°or
mixture thereof, b) a C alkenyl optionally substituted with –OH or -NR°R°°, or c) C alkynyl
optionally substituted with –OH or -NR°R°°, wherein R° and R°° are each independently
selected from the group consisting of hydrogen, C alkyl- and wherein R° and R°° together with
the nitrogen to which they attach form a 1-morpholinyl group or a 4, 5, 6 or 7 membered
heterocyclic ring; as a single diastereomer or a mixture of diastereomers; prodrugs and
pharmaceutically acceptable salts thereof; provided that for formula II, when one of R or R' is –
CH=CH , then R is not CH CO-. In one aspect of the above compounds, R and R' are each
2 1 3 3 3
independently hydrogen and C alkyl or C alkyl. In another aspect, R and R' are each
1-6 7-9 3 3
independently hydrogen and C alkyl.
-18
In one aspect of the above, R is selected from the group consisting of C alkyl, C
1-6 1-
alkoxy- and C arylC alkoxy; R is hydrogen or R'CO-, wherein R' is selected from the group
6 6-10 1-3 1
consisting of C alkyl, C aryl and arylC alkyl-; R is selected from the group consisting of
1-6 6-10 1-3 3
C1-6alkyl and optionally substituted C2-6alkenyl; and R'3 is hydrogen. In another aspect, R2 is
selected from the group consisting of (CH ) CHCH -, t-butyl, optionally substituted phenyl, and
3 2 2
optionally substituted heteroaryl, R is t-butoxy, R is CH CO-, R is beta CH =CH- and R' is
1 3 3 2 3
hydrogen.
Also described is a compound of the formula III or formula IV:
wherein R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C
1-6 1-6 2-6 6-
aryl, C arylC alkyl and C arylC alkoxy; R is hydrogen or is selected from the group
6-10 1-3 6-10 1-3 1
consisting of C alkyl, C alkenyl, R'CO-, C aryl and C arylC alkyl, wherein R' is
1-6 2-6 6-10 6-10 1-3
selected from the group consisting of C alkyl, C aryl and arylC alkyl-; R is selected from
1-6 6-10 1-3 2
the group consisting of optionally substituted C1-6alkyl, optionally substituted phenyl and
optionally substituted heteroaryl; R is hydrogen or is selected from the group consisting of C
3 1-
alkyl, C alkenyl, C alkynyl, C aryl and C arylC alkyl, wherein each C alkyl, C
18 2-6 2-6 6-10 6-10 1-3 1-18 3-
alkenyl and C alkynyl are optionally substituted by 1 or 2 –OH, NH , –NHC alkyl or –N(C
6 3-6 2 1-3 1-
alkyl) and wherein each C aryl is unsubstituted or substituted with 1, 2 or 3 –OCH ; R' is
3 2 6-10 3 3
hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C alkynyl, C
1-18 2-6 2-6 6-
aryl and C arylC alkyl, wherein each C alkyl, C alkenyl and C alkynyl are optionally
6-10 1-3 1-18 3-6 3-6
substituted by 1 or 2 –OH, NH , –NHC alkyl or –N(C alkyl) and wherein each C aryl is
2 1-3 1-3 2 6-10
unsubstituted or substituted with 1, 2 or 3 –OCH ; provided that when one of R or R' is
3 3 3
hydrogen, then the other is not a) a C alkyl optionally substituted with 1 or 2 –OH, -NR°R°°or
mixture thereof, b) a C alkenyl optionally substituted with –OH or -NR°R°°, or c) C alkynyl
optionally substituted with –OH or -NR°R°°, wherein R° and R°° are each independently
selected from the group consisting of hydrogen, C alkyl- and wherein R° and R°° together with
the nitrogen to which they attach form a 1-morpholinyl group or a 4, 5, 6 or 7 membered
heterocyclic ring; as a single diastereomer or a mixture of diastereomers; prodrugs and
pharmaceutically acceptable salts thereof; provided that for formula IV, when one of R or R' is
–CH=CH2, then R1 is not CH3CO-. In one aspect of the above compound, R is selected from the
group consisting of C alkyl, C alkoxy- and C arylC alkoxy; R is hydrogen or R'CO-,
1-6 1-6 6-10 1-3 1
wherein R' is selected from the group consisting of C alkyl, C aryl and arylC alkyl-; R is
1-6 6-10 1-3 3
selected from the group consisting of C alkyl and optionally substituted C alkenyl; and R' is
1-6 2-6 3
hydrogen. In another aspect of the above, R is selected from the group consisting of
(CH ) CHCH -, t-butyl, optionally substituted phenyl and optionally substituted heteroaryl, R is
3 2 2
tert-butoxy, R is CH CO-, R is beta CH =CH- and R' is hydrogen. In one aspect of the above
1 3 3 2 3
compounds, R and R' are each independently hydrogen and C alkyl or C alkyl. In another
3 3 1-6 7-9
aspect, R and R' are each independently hydrogen and C alkyl. In another aspect of the
3 3 10-18
above, R' is hydrogen and the stereochemistry of R at the 7,9- bridge ring is selected from the
group consisting of:
(beta configuration) and (alpha configuration), or a mixture of the alpha
and beta isomers. In another aspect of the above, the stereochemistry of R at the 7,9- bridge
ring is:
In another aspect of each of the above compounds, after isolation using the
chromatographic methods described herein, the compound is greater than 95% pure, greater than
97% pure or greater than 99% pure.
Also described is a pharmaceutical composition comprising: a) a therapeutically effective
amount of a compound of each of the above compounds, in the form of a single diastereoisomer;
and b) at least one pharmaceutically acceptable excipient, diluent or adjuvant. In another aspect,
the composition further comprises temozolomide and/or Avastin. In another aspect, the above
compositions further comprise one or more therapeutic agent selected from the group consisting
of aromatase inhibitors, antiestrogen, anti-androgen, a gonadorelin agonists, topoisomerase 1
inhibitors, topoisomerase 2 inhibitors, microtubule active agents, alkylating agents,
anthracyclines, corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40 antibodies,
Smac mimetics, FGF3 modulators, mTOR inhibitors, HDAC inhibitors, IKK inhibitors,
P38MAPK inhibitors, HSP90 inhibitors, akt inhibitors, antineoplastic agents, antimetabolites,
platin containing compounds, lipid- or protein kinase-targeting agents, protein- or lipid
phosphatase-targeting agents, anti-angiogentic agents, agents that induce cell differentiation,
bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase inhibitors,
heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, bisphosphanates, rapamycin
derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists,
inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors
and aminopeptidase inhibitors, cytostatic agent, cytotoxic agent, taxane, topoisomerase II
inhibitor, topoisomerase I inhibitor, tubulin interacting agent, antibodies, antiangiogenics, COX-
2 inhibitors, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating agent,
farnesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor,
antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination and aromatase
combination.
Also described is a method for the treatment of cancer in a patient comprising
administering to the patient a therapeutically effective amount of a compound or composition of
each of the above to a patient in need of such treatment. In one aspect of the method, the cancer
is selected from the group consisting of leukemia, neuroblastoma, glioblastoma, cervical,
colorectal, pancreatic, renal and melanoma. In another aspect, the cancer is selected from the
group consisting of lung, breast, prostate, ovarian and head and neck. In one aspect, the cancer is
colorectal cancer. In another aspect, the cancer is pancreatic cancer. In another aspect, the
cancer is neuroblastoma or a glioblastoma.
In one aspect of the above methods, the compound is administered simultaneously,
separately or sequentially with a chemotherapeutical agent selected from temozolomide,
cisplatin, 5-flurouracil, taxotere or gemcitabine, preferably temozolomide. In another aspect, the
compound is administered simultaneously, separately or sequentially with temozolomide. In
another aspect of the above, the methods further comprise administering radiation therapy. In
another aspect, the method is used in combination with surgical removal of a cancer. In another
aspect, the composition is administered simultaneously separately or sequentially with aromatase
inhibitors, antiestrogen, anti-androgen, a gonadorelin agonists, topoisomerase 1 inhibitors,
topoisomerase 2 inhibitors, microtubule active agents, alkylating agents, anthracyclines,
corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40 antibodies, Smac mimetics,
FGF3 modulators, mTOR inhibitors, HDAC inhibitors, IKK inhibitors, P38MAPK inhibitors,
HSP90 inhibitors, akt inhibitors, antineoplastic agents, antimetabolites, platin containing
compounds, lipid- or protein kinase-targeting agents, protein- or lipid phosphatase-targeting
agents, anti-angiogentic agents, agents that induce cell differentiation, bradykinin 1 receptor
antagonists, angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors,
lymphokine inhibitors, cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-
apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, inhibitors of Ras
isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors and
aminopeptidase inhibitors, cytostatic agent, cytotoxic agent, taxane, topoisomerase II inhibitor,
topoisomerase I inhibitor, tubulin interacting agent, antibodies, antiangiogenics, COX-2
inhibitors, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating agent,
farnesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor,
antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination and aromatase
combination.
Also described is a pharmaceutical composition for oral administration comprising: a) a
therapeutically effective amount of a compound as described above in the form of a single
diastereoisomer; and b) at least one pharmaceutically acceptable excipient, diluent or adjuvant.
In one aspect, the composition further comprises temozolomide and/or Avastin. In another
aspect, the composition further comprise one or more therapeutic agents selected from the group
consisting of aromatase inhibitors, antiestrogen, anti-androgen, a gonadorelin agonists,
topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, microtubule active agents, alkylating
agents, anthracyclines, corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40
antibodies, Smac mimetics, FGF3 modulators, mTOR inhibitors, HDAC inhibitors, IKK
inhibitors, P38MAPK inhibitors, HSP90 inhibitors, akt inhibitors, antineoplastic agents,
antimetabolites, platin containing compounds, lipid- or protein kinase-targeting agents, protein-
or lipid phosphatase-targeting agents, anti-angiogentic agents, agents that induce cell
differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase
inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, bisphosphanates,
rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR
agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase
inhibitors and aminopeptidase inhibitors, cytostatic agent, cytotoxic agent, taxane, topoisomerase
II inhibitor, topoisomerase I inhibitor, tubulin interacting agent, antibodies, antiangiogenics,
COX-2 inhibitors, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating
agent, farnesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor,
antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination and aromatase
combination.
Also described is a method for the treatment of cancer in a patient comprising oral
administration to the patient of a therapeutically effective amount of a compound as described
above to a patient in need of such treatment. In one aspect of the above method, the cancer is
selected from the group consisting of leukemia, neuroblastoma, glioblastoma, cervical,
colorectal, pancreatic, renal and melanoma. In another aspect of the method, the cancer is
selected from the group consisting of lung, breast, prostate, ovarian and head and neck. In
another aspect, the cancer is colorectal cancer, pancreatic cancer, neuroblastoma or a
glioblastoma. In another aspect of the above method, the compound is administered
simultaneously, separately or sequentially with a chemotherapeutical agent selected from
temozolomide, cisplatin, 5-flurouracil, taxotere or gemcitabine, preferably temozolomide. In
another aspect of the above method, the compound is administered simultaneously, separately or
sequentially temozolomide. In another aspect of the above, the methods further comprise
administering radiation therapy. In another aspect of the above, the method is used in
combination with surgical removal of a cancer. In another aspect of the above methods, the
composition is administered simultaneously, separately or sequentially with aromatase inhibitors,
antiestrogen, anti-androgen, a gonadorelin agonists, topoisomerase 1 inhibitors, topoisomerase 2
inhibitors, microtubule active agents, alkylating agents, anthracyclines, corticosteroids, IMiDs,
protease inhibitors, IGF-1 inhibitors, CD40 antibodies, Smac mimetics, FGF3 modulators,
mTOR inhibitors, HDAC inhibitors, IKK inhibitors, P38MAPK inhibitors, HSP90 inhibitors, akt
inhibitors, antineoplastic agents, antimetabolites, platin containing compounds, lipid- or protein
kinase-targeting agents, protein- or lipid phosphatase-targeting agents, anti-angiogentic agents,
agents that induce cell differentiation, bradykinin 1 receptor antagonists, angiotensin II
antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine
inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic
pathway agonists, PPAR agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease
inhibitors, metalloproteinase inhibitors and aminopeptidase inhibitors, cytostatic agent, cytotoxic
agent, taxane, topoisomerase II inhibitor, topoisomerase I inhibitor, tubulin interacting agent,
antibodies, antiangiogenics, COX-2 inhibitors, hormonal agent, thymidilate synthase inhibitor,
anti-metabolite, alkylating agent, farnesyl protein transferase inhibitor, signal transduction
inhibitor, EGFR kinase inhibitor, antibody to EGFR, C-abl kinase inhibitor, hormonal therapy
combination and aromatase combination.
Also described is a process for the preparation of compound of formula I: (See Figure 1)
wherein: R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl
1-6 1-6 2-6 6-10
and C arylC alkyl; R is hydrogen or is selected from the group consisting of C alkyl, C
6-10 1-3 1 1-6 2-
alkenyl, R'CO-, C aryl and C arylC alkyl, wherein R' is selected from the group consisting
6 6-10 6-10 1-3
of C alkyl, C aryl and arylC alkyl-; R is selected from the group consisting of C alkyl,
1-6 6-10 1-3 2 1-6
optionally substituted phenyl and optionally substituted heteroaryl; R is hydrogen or is selected
from the group consisting of C alkyl, C alkenyl, C alkynyl, C aryl and C arylC alkyl,
1-18 2-6 2-6 6-10 6-10 1-3
wherein each C alkyl, C alkenyl and C alkynyl are optionally substituted by 1 or 2 –OH,
1-18 3-6 3-6
NH , –NHC alkyl or –N(C alkyl) and wherein each C aryl is unsubstituted or substituted
2 1-3 1-3 2 6-10
with 1, 2 or 3 –OCH ; R' is hydrogen or is selected from the group consisting of C alkyl, C
3 3 1-18 2-
alkenyl, C alkynyl, C aryl and C arylC alkyl, wherein each C alkyl, C alkenyl and
6 2-6 6-10 6-10 1-3 1-18 3-6
C alkynyl are optionally substituted by 1 or 2 –OH, NH , –NHC alkyl or –N(C alkyl) and
3-6 2 1-3 1-3 2
wherein each C aryl is unsubstituted or substituted with 1, 2 or 3 –OCH ; provided that when
6-10 3
one of R or R' is hydrogen, then the other is not a) a C alkyl optionally substituted with 1 or 2
3 3 1-2
–OH, -NR°R°°or mixture thereof, b) a C alkenyl optionally substituted with –OH or -NR°R°°, or
c) C alkynyl optionally substituted with –OH or -NR°R°°, wherein R° and R°° are each
independently selected from the group consisting of hydrogen, C alkyl- and wherein R° and
R°° together with the nitrogen to which they attach form a 1-morpholinyl group or a 4, 5, 6 or 7
membered heterocyclic ring; and P is a protecting group;
the process comprising the steps of treating a compound of the formula 5 under condition
sufficient to effect a rearrangement reaction to form a compound of the formula 6;
ring formation to form an acetal or ketal of the formula 7;
selective de-acetylation of the C-13 acetate to form a compound of the formula 8;
coupling of the compound of the formula 8 with a side chain of the formula 9 or 10;
and deprotecting the protecting group P or Ar to form the compound of the formula I. In one
aspect, of the above process, the condition sufficient to effect a rearrangement reaction of the
compound of the formula 5 is wet acid in an organic solvent. In another aspect of the above
process, the acid is selected from the group consisting of CSA, TFA, p-TsOH, Montmorillonite
clay and polymer supported acidic catalysts.
The compounds described herein may be mixtures of the stereoisomers of the 7,9- bridge,
for example as diastereomeric mixtures, or they may be single isomers with respect to a
particular stereocenter as provided herein. Also described are pharmaceutical compositions
comprising a diastereoisomer of the above formula, in which the diastereomer is greater than
90% pure, greater than 95% pure, greater than 97% pure or greater than 99% pure. In certain
aspects of the above compounds, the purity is determined by HPLC or by isolation of the
compound using novel methods described herein.
In certain embodiments, the
stereochemistry of the 7,9- bridge in such
compounds is: O O
In another embodiment, the stereochemistry of the 7,9- bridge is:
In another embodiment of each of the above compounds having the stereochemistry at
the 7,9- bridge as beta, alpha or a mixture thereof, the compounds also have a stereochemistry at
C-10 that is alpha, beta or mixtures thereof:
Representative processes for the preparation of the compounds described herein are also
illustrated in Figure 6. In one embodiment, the compound of the formula V, which may be
obtained from the de-acetylation of the C-13 acetate of 9-DHB (5b.1, where C-10 is beta -OAc),
and placing a protecting group P on the 13 hydroxyl, may undergo a rearrangement reaction (or
an isomerization reaction) to the corresponding abeo-taxane structure VI under acidic conditions.
In one aspect, the –OR group at C-10 is alpha or beta, or a mixture thereof. In another aspect,
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, R'CO-, C aryl
1 1-6 2-6 6-10
and C arylC alkyl, wherein R' is selected from the group consisting of C alkyl, C aryl and
6-10 1-3 1-6 6-10
arylC1-3alkyl-. In one variation, R1 is acetyl. The acidic condition may include a sulfonic acid,
such as camphorsulfonic acid (CSA), p-toluene sulfonic acid (p-TsOH), trifluoroacetic acid
(TFA) or an organic acid such as acetic acid, or mixtures thereof, in a protic solvent such as
methanol, ethanol, propanol, isopropanol and mixtures thereof. Alternatively, the solvent may
be a water wet aprotic solvent such as dichloromethane (DCM), toluene, MTBE or mixtures
thereof. The water wet aprotic solvent may be a water saturated solvent. Depending on the acid,
solvent or solvent mixture, the reaction may be conducted at about 20-25 °C, 25-35 °C or 35-55
°C, or starting from about 20-25 °C and slowly heating the reaction to refluxing temperatures for
a sufficient period of time for substantially complete rearrangement to VI. The rearrangement
reaction results in the abeo-taxane that retains the stereochemistry of the taxane (or baccatin)
starting material, such as at C-7, C-9, C-10 and C-13 etc. For example, starting with the baccatin
structure of the formula V wherein C-10 is beta, the resulting rearranged compound of formula
VI will also have the chiral center where C-10 beta.
The coupling reaction at the C-13 hydroxy group of VI with a protected side chain (see
Figure 6, compounds 9 or 10a to 10f) may be performed as an acylation reaction using an
activated acid known in the art, such as using acid halides, anhydrides, mixed anhydrides, beta
lactams and an activated acid (e.g., using DCC/DMAP), or acid catalyzed esterification reactions
using an acid such as HCl, H SO , CSA, p-TSOH, polymeric sulfonic acids etc., in a protic or
aprotic organic solvent, to form VII. In one aspect, the coupling or acylating agent is 9
RCONHCHR CH(OP )C(O)X, wherein R is selected from the group consisting of C alkyl, C
2 1 1-6 2-
alkenyl, R'O-, C aryl, C arylC alkyl and C arylC alkoxy, wherein R' is selected from
6 6-10 6-10 1-3 6-10 1-3
the group consisting of C alkyl, C aryl and arylC alkyl-, R is C alkyl, optionally
1-6 6-10 1-3 2 1-6
substituted phenyl or optionally substituted heteroaryl, and X is selected from –OH, -OCOC
6alkyl, -F, -Cl, -Br and -I. In another aspect, the coupling agent is 10e or 10f, wherein R is C1-
alkyl, C alkoxy-, C alkenyl, C aryl or C arylC alkyl; R is C alkyl, phenyl, or
6 1-6 2-6 6-10 6-10 1-3 2 1-6
heteroaryl. In one aspect, Ar is phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,6-
dimethoxyphenyl or 2,4,6-trimethoxyphenyl. In one aspect of the compound VII, R is t-BuO
and R is –CH CH(CH ) .
2 2 3 2
The 7,9-bridge ring formation reaction for the conversion of VII having a 7,9-diol to the
corresponding 7,9-bridged compound VIII may be performed with the reaction of VII with an
aldehyde, R CHO, a dialkyl acetal (R -CH(OC alkyl) wherein R is selected from the group
3 3 1-4 2 3
consisting of C alkyl, optionally substituted C alkenyl, C alkynyl, optionally substituted C
1-18 2-6 2-6 6-
aryl, optionally substituted heteroaryl and C arylC alkyl; or with a dialkyl ketal
6-10 1-3
(R R' C(OC alkyl) ), wherein R is selected from the group consisting of C alkyl, optionally
3 3 1-4 2 3 1-18
substituted C alkenyl, C alkynyl, optionally substituted C aryl, optionally substituted
2-6 2-6 6-10
heteroaryl and C arylC alkyl; and R' is selected from the group consisting of optionally
6-10 1-3 3
substituted C alkyl, C alkenyl, C alkynyl, optionally substituted C aryl, optionally
1-18 2-6 2-6 6-10
substituted heteroaryl and C6-10arylC1-3alkyl. In one aspect of the compound VIII, R'3 is
hydrogen and R is –CH=CH . In another aspect, R is beta –CH=CH . In another aspect, R is
3 2 3 2 3
an optionally substituted C alkenyl. In one aspect, the 7,9-ring formation reaction may be
performed in the presence of an acid, such as a sulphonic acid. The acid may be used in a
catalytic amount, and the acid may be camphorsulphonic acid or p-toluenesulfonic acid. In
another aspect, the acid catalysts include montmorillonite clay and polymer supported acidic
catalysts. The 7,9-ring formation may be performed in an organic solvent, such as acetonitrile,
DCM (CH Cl ), THFor toluene, at about room temperatures (20 - 25 °C).
Where the 7,9-ring formation reaction to form VIII, wherein R' is hydrogen and the 7,9-
ring is an acetal, the resulting diastereomer of the 7,9-bridge may also be obtained as a single
isomer by separating mixtures of alpha and beta isomers. In one aspect, the separation may be
performed using chromatography to provide the desired mixture of isomers or single isomer,
such as the beta isomer of R , where R' is hydrogen. In one aspect, chromatographic separation
may be performed using silica, such as spherical silica. As provided herein, normal phase
purification at differing scales were carried out on various sizes of columns packed with YMC
silica (Silica gel S50 µm 120 Å) or Kromasil silica (100 Å, 10µm Kromasil silica gel) and
with solvent mixtures, such as solvents prepared from n-Heptane/waIBAc (1% water and 1%
acetic acid in isobutyl acetate) or n-Heptane/waMTBE (1% water and 1% acetic acid in Methyl-
t-butyl ether), that provided the single isomer (e.g., the beta isomer or the alpha isomer) in
greater than 95%, 97% and greater than about 99% isomeric purity. Using the purification
methods disclosed herein the specific compounds were also obtained in greater than 95%, greater
than 97%, greater than 98% and greater than 99% chemical purity.
In another embodiment, the compound of the formula VIII may be prepared starting with
V with the 7,9-ring formation to form IX, followed by addition of the protected side chain to
form X, in turn followed by a rearrangement reaction to form VIII. Alternatively, the coupling
reaction with the side chain may be performed before the rearrangement reaction to form VIII.
IX may be prepared from the reaction of V with an aldehyde, R CHO, a dialkyl acetal (R -
CH(OC alkyl) wherein R is selected from the group consisting of C alkyl, optionally
1-4 2 3 1-18
substituted C alkenyl, C alkynyl, C aryl and C arylC alkyl; or with a dialkyl ketal
2-6 2-6 6-10 6-10 1-3
(R R' C(OC alkyl) ), wherein R is selected from the group consisting of C alkyl, optionally
3 3 1-4 2 3 1-18
substituted C2-6alkenyl, C2-6alkynyl, C6-10aryl and C6-10arylC1-3alkyl; and R'3 is selected from the
group consisting of C alkyl, C alkenyl, C alkynyl, C aryl and C arylC alkyl. In one
1-18 2-6 2-6 6-10 6-10 1-3
aspect of the compound IX, R' is hydrogen and R is –CH=CH . In another aspect, R is beta –
3 3 2 3
CH=CH . In another aspect, R is an optionally substituted C alkenyl. In one aspect, the 7,9-
2 3 2-6
ring formation reaction may be performed in the presence of an acid, such as a sulphonic acid.
The acid may be used in a catalytic amount, and the acid may be camphorsulphonic acid or p-
toluenesulfonic acid. In another aspect, the acid catalysts include montmorillonite clay and
polymer supported acidic catalysts. The 7,9-ring formation may be performed in an organic
solvent, such as acetonitrile, DCM (CH Cl ), THF or toluene, at about room temperatures (20 °-
°C). In one aspect, the separation of the diastereomers may be performed using
chromatography, as described above, to provide the desired mixture of isomers or a single
isomer, such as the beta isomer of R , where R' is hydrogen. Rearrangement of X to VIII may
be performed under the same reaction conditions as described for the reaction of V to VI. In one
aspect, there is provided a product obtained from the process of rearrangement of the compound
of the formula X under the rearrangement conditions described above.
Alternatively, the compound of formula VIII may be prepared from the rearrangement
reaction of the compound of the formula IX under the same reaction conditions as described for
the reaction of V to VI followed by coupling of a protected side chain as in the conversion of
compound VI to compound VII. In one aspect, there is provided a product obtained from the
process of rearrangement of the compound of the formula IX under the rearrangement conditions
described above followed by coupling of a protected side chain to the 13 hydroxyl to provide the
compound of the formula VIII.
The compound of the formula X may be prepared by the coupling reaction of IX with a
coupling agent (9 or 10a to 10f) under standard coupling conditions known in the art, or under
the similar conditions as described above for the coupling reaction of VI to form VII.
Optionally, in any of the above reaction processes, depending on the reaction conditions,
any unprotected reactive hydroxyl groups or amine group (such as C-7, C-9, C-10, C-13 or the
nitrogen on the coupling reagent) may be protected with a hydroxyl protecting group and/or an
amine protecting group. The selection of a particular hydroxyl or amine protecting group will
depend on the subsequent reaction conditions and reaction sequence to provide the desired
product, as disclosed herein. In one aspect, a selected protecting group may be removed after the
7,9-ring formation reaction to form VIII. In another aspect of the above compounds VII and
VIII, R is -COCH . In one aspect of the compound VIII, R' is hydrogen, and the configuration
1 3 3
of the 7,9- bridge is beta:
A selected single diastereomer of the compounds of Figure 6, including the compounds
of the formulae VII, IX or X may be isolated with the chromatographic separation methods of
using silica, such as spherical silica, as described above. The selected single diastereomers may
be obtained as a single isomer in greater than 95%, 97% and greater than about 99% isomeric
purity.
The variables of the compounds defined herein and in Figures 1-6, unless noted
otherwise, are as follows:
R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl,
1-6 1-6 2-6 6-10
C arylC alkyl and C arylC alkoxy;
6-10 1-3 6-10 1-3
R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, R'CO-,
1 1-6 2-6
C6-10aryl and C6-10arylC1-3alkyl, wherein R' is selected from the group consisting of C1-6alkyl, C6-
aryl and arylC alkyl-;
1-3
R is selected from the group consisting of C alkyl, phenyl and heteroaryl;
2 1-6
R is hydrogen or is selected from the group consisting of C alkyl, optionally
3 1-18
substituted C alkenyl, C alkynyl, C aryl and C arylC alkyl, and wherein each C aryl
2-6 2-6 6-10 6-10 1-3 6-10
is unsubstituted or substituted with 1, 2 or 3-OCH ;
R' is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C
3 1-18 2-6 2-
alkynyl, C aryl and C arylC alkyl, and wherein each C aryl is unsubstituted or
6 6-10 6-10 1-3 6-10
substituted with 1, 2 or 3-OCH ;
Ar is phenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl or 2,4,6-
trimethoxyphenyl;
P is an alcohol protecting group selected from the group consisting of TBS, CBz, Bn,
BOM, Troc, trichloroethyl, allyl, alloc, phenoxyacetate, methoxyacetate, phenylacetate,
ethoxyethyl, acetyl, benzoyl, benzyl, TMS (trimethyl silyl), MEM (beta-methoxyethoxymethyl
ether), DMT, MMT, PMB, methylthiomethyl ether, NDMS (2-norbornyldimethylsilyl), TES
(triethylsilyl), TBDMS, THP, Trityl, Piv and MOM; and
X is selected from –OH, -OCOC alkyl, -F, -Cl, -Br and –I.
DETAILED DESCRIPTION:
Unless specifically noted otherwise herein, the definitions of the terms used are standard
definitions used in the art of organic synthesis and pharmaceutical sciences. Exemplary
embodiments, aspects and variations are illustrative in the figures and drawings, and it is
intended that the embodiments, aspects and variations, and the figures and drawings disclosed
herein are to be considered illustrative and not limiting.
DEFINITIONS
As used herein, the term "alkyl", alone or in combination, refers to an optionally
substituted straight chain or branched chain alkyl radical having from 1 to 20 carbon atoms (e.g.
C alkyl), from 1 to 10 carbon atoms or form 1 to 6 carbon atoms. Optionally, an "alkyl" group
1-20
may have oxygen, nitrogen or sulfur atoms inserted between the carbon atoms in the chain or as
indicated. A C alkyl, for example, includes alkyl groups that have a chain of between 1 and 20
1-20
carbon atoms, and include, for example, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl,
1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl, 1,3-butadienyl, penta-1,3-dienyl,
penta-1,4-dienyl, hexa-1,3-dienyl, hexa-1,3,5-trienyl and the like. An alkyl group may also be
represented, for example, as a -(CR R ) - group where R and R are independently hydrogen or
1 2 m 1 2
are independently absent, and for example, m is 1 to 8, and such representation is also intended
to cover both saturated and unsaturated alkyl groups. Lower alkyl groups include groups of 1, 2,
3, 4, 5, 6, 7 or 8 carbon atoms (i.e., C alkyl or C alkyl etc.,) and can be straight or branched
1-4 1-8
and can optionally be substituted with one or more cyclic moieties of 3, 4, 5, 6, 7 or 8 carbon
atoms. Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-
butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl, heptyl and octyl. Examples of cyclic groups
include cyclopropyl, cyclobutylmethyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. In
an embodiment, lower alkyl groups are straight or branched alkyl groups of up to 6 carbon
atoms.
An alkyl as noted with another group such as an aryl group, represented as "arylalkyl" for
example, is intended to be a straight, branched, saturated or unsaturated aliphatic divalent group
with the number of atoms indicated in the alkyl group (as in C alkyl, for example) and/or aryl
1-20
group (as in C5-14aryl, for example) or when no atoms are indicated means a bond between the
aryl and the alkyl group. Nonexclusive examples of such group include benzyl, phenethyl and
the like.
An "alkylene" or “alkylenyl” group is a straight, branched, saturated or unsaturated
aliphatic divalent group with the number of atoms indicated in the alkyl group; for example, a
-C alkylene- or -C alkylenyl-.
1-3 1-3
The term "alkenyl", alone or in combination, refers to an optionally substituted straight-
chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds
and having from 2 to about 18 carbon atoms. Examples of alkenyl radicals include ethenyl,
propenyl, 1,4-butadienyl and the like. Lower alkenyl groups include groups having 2, 3, 4, 5, 6,
7 or 8 carbon atoms and can be straight or branched and can optionally be substituted with one or
more cyclic moieties of 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of lower alkenyl groups
include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and examples of cyclic
moieties include cyclohexenylmethyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl
and the like.
The term "alkoxy" refers to an alkyl ether radical wherein the term alkyl is defined as
above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy and the like. The term “lower alkoxy” is an oxygen atom
substituted by a lower alkyl group. In one aspect, a lower alkoxy group is the tert-butyloxy
group.
The term "aryl", alone or in combination, refers to an optionally substituted aromatic
ring. The term aryl includes monocyclic aromatic rings, polyaromatic rings and polycyclic ring
systems. The polyaromatic and polycyclic rings systems may contain from two to four, more
preferably two to three, and most preferably two rings. Examples of aryl groups include six-
membered aromatic ring systems, including, without limitation, phenyl, biphenyl, naphthyl and
anthryl ring systems. The aryl groups of the present application generally contain from five to
six carbon atoms.
A "cyclyl" such as a monocyclyl or polycyclyl group includes monocyclic, or linearly
fused, angularly fused or bridged polycycloalkyl, or combinations thereof. Such cyclyl group is
intended to include the heterocyclyl analogs. A cyclyl group may be saturated, partially
saturated or aromatic.
The term “diastereoisomer” refers to any group of four or more isomers occurring in
compounds containing two or more asymmetric carbon atoms. Compounds that are
stereoisomers of one another, but are not enantiomers are called diastereosiomers.
"Halogen" or "halo" means fluorine, chlorine, bromine or iodine.
A "heterocyclyl" or "heterocycle" is a cycloalkyl wherein one or more of the atoms
forming the ring is a heteroatom that is a N, O or S. Non-exclusive examples of heterocyclyl
include piperidyl, 4-morpholyl, 4-piperazinyl, pyrrolidinyl, 1,4-diazaperhydroepinyl, 1,3-
dioxanyl, and the like.
"Heteroaryl" means a cyclic aromatic group with at least five or six ring atoms, wherein
at least one ring atom is a heteroatom and the remaining are carbon atoms. Heteroaryl groups
may include, for example, furan, imidazole, isoxazole, oxazole, pyrazine, pyridine, pyrimidine,
triazole and tetrazole. Heteroaryl also includes, for example, bicyclic or tricyclic heteroaryl
rings. These bicyclic or tricyclic heteroaryl rings include benzo[b]furan, benzimidazole,
quinazoline, quinoline, isoquinoline, naphthyridine, quinolizine, indole, indazole, benzoxazole,
benzopyrazole and indolizine. The bicyclic or tricyclic heteroaryl rings can be attached (or
substituted) to a particular group or compound through either the heteroaryl group itself or the
aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl group to which it is fused. The heteroaryl
groups can be substituted or unsubstituted.
The groups, substituents or functional groups described in the present application,
including for example, C alkyl, alkoxy, alkenyl, aryl, heteroaryl and the like, may be
1-10
unsubstituted or may be further substituted by one or two substituents. The specific substituents
may include, for example, amino, halo (bromo, chloro, fluoro and iodo), oxo, hydroxyl, nitro, C
alkyl, C alkoxy, C alkylCO- and the like.
1-10 1-10
The term “baccatin” or “baccatin derivatives” means the taxane derivatives in which the
side chain at the 13-position of the taxane skeleton is a hydroxy group and these derivatives are
often referred to in the literature as a baccatin or “baccatin I-VII” or the like depending, on the
nature of the substituents on the tricyclic rings of the taxane skeleton.
The terms "taxanes," "taxane derivatives," and "taxane analogs" etc., are used
interchangeably to mean compounds relating to a class of antitumor agents derived directly or
semi-synthetically from Taxus brevifolia, the Pacific yew. Examples of such taxanes include
paclitaxel and docetaxel and their natural as well as their synthetic or semi-synthetic derivatives.
The term “abeo-taxane(s)” or “abeo-taxane analog(s)” etc., are used interchangeably to
mean compounds that are directly or indirectly derived from the taxanes, and having an 5-
membered (pentacylic) A-ring. Such abeo-taxane may be synthetic derivatives or semi-synthetic
derivatives of the taxanes or other abeo-taxanes. Representative abeo-taxanes having the
particular ring structures that are distinct from the taxanes ring structures are disclosed herein.
An "alpha" or "α" designation for a substituent on a molecular structure means that the
substituent is attached below the plane of the paper, or shown as a dashed line.
A "beta" or "β" designation for a substituent on a molecular structure means that the
substituent is attached above the plane of the paper, or shown as a wedge line.
Where a chiral center, such as a chiral carbon, is illustrated as a straight line (bond) that is
neither a dashed line nor a wedge line, the chiral center represents 1) a racemic center having a
mixture of both diastereomers, 2) a single alpha stereoisomer or 3) a single alpha stereoisomer.
In the absence of a designation, the structure shown with a straight line is intended to cover all
three permutations. An example of such a straight line designation is illustrated in Figure 6, at
C-10 bearing the –OR group of formula V, and compounds prepared from V. Similarly, where
the bond is represented by line that is a wiggly line , the line designates that the compound has
a mixture of both alpha and beta stereoisomers.
"Pharmaceutically acceptable excipient” or “pharmaceutically acceptable salts" as used
herein, means the excipient or salts of the compounds disclosed herein, that are pharmaceutically
acceptable and provides the desired pharmacological activity. These excipients and salts include
acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
phosphoric acid and the like. The salt may also be formed with organic acids such as acetic acid,
propionic acid, hexanoic acid, glycolic acid, lactic acid, succinic acid, malic acid, citric acid,
benzoic acid and the like.
The phrase "protecting group" as used herein means temporary substituents which protect
a potentially reactive functional group from undesired chemical transformations. In some
aspects, the protecting group may be part of the compound of the present application. Examples
of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals
and ketals of aldehydes and ketones, respectively. Representative protecting groups and their
applications are provided in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 4 ed.; Wiley: New York, 2007. Specific hydroxyl protecting groups that may be
employed in the compound disclosed in the present application include TBS, CBz, Bn, BOM,
PMB, Troc, trichloroethyl, allyl, alloc, phenoxyacetate, methoxyacetate, phenylacetate,
ethoxyethyl, butoxyethyl THP other cyclic and acyclic acetals and ortho esters. Exemplary silyl
groups for protection of hydroxyl groups include TBDMS (tert-butyldimethylsilyl), NDMS (2-
norbornyldimethylsilyl), TMS (trimethylsilyl) and TES (triethylsilyl). Exemplary NH-protecting
groups include benzyloxycarbonyl, t-butoxycarbonyl and triphenylmethyl. Because of the
sensitive nature of certain compounds and certain protecting groups toward hydrolysis or toward
particular reaction conditions, the judicious selection of the particular protecting group that may
be used in any particular compound for any particular reaction process or processing steps is
required. Additional, representative hydroxyl protecting groups also include acetyl, tert-butyl,
benzoyl, benzyl, benzyloxymethyl, tetrahydropyranyl, 1-ethoxyethyl, allyl, formyl and the like.
"Substituted or unsubstituted" or “optionally substituted” means that a group such as, for
example, alkyl, aryl, heterocyclyl, (C - )cycloalkyl, hetrocyclyl(C - )alkyl, aryl(C - )alkyl,
1 8 1 8 1 8
heteroaryl, heteroaryl(C - )alkyl, and the like, unless specifically noted otherwise, may be
unsubstituted or, may substituted by 1, 2 or 3 substituents selected from the group such as halo,
nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, -NH2, -OH, -SH, -NHCH3,
-N(CH ) , -SMe, -CN and the like.
"Therapeutically effective amount" means a drug amount that elicits any of the biological
effects listed in the specification.
The term “7,9- bridge” as used herein with respect to the taxane ring structure, refers to
the carbon atoms at position 7- and position 9-, along with the representative stereochemistry as
designated at position 7 and position 9, that forms an acetal or ketal, such as a 6-membered
acetal or ketal ring as depicted in the “Taxane Ring Structure” in the figure below. Similarly, for
the convenience of nomenclature for discussions and for comparison purposes between the
taxane ring structure and the abeo ring structure depicted in the figure below, recognizing that
the Abeo-Taxane Ring has a different IUPAC numbering of the ring carbon atoms, the
“corresponding” ring carbon atoms at the same position in the “Abeo-Taxane Ring Structure” are
also referred to as being the carbon atoms at position 7- and position 9- that also form a 6-
membered acetal (where one of R or R' is a hydrogen) or ketal ring (where both R and R' are
3 3 3 3
not hydrogen. Similarly, the position carbon number 10 that is substituted with an acetate group,
and the position carbon number 13 that bears a hydroxy group (that may be linked with the side
chain) are referred to the same positions (i.e. carbon 10 or carbon 13) in the taxane ring structure
and the abeo ring structure.
The term “abeo-taxane” means a taxane derivative in which the baccatin ring portion of
the taxane has been rearranged such that a new multi-ring structure is produced - the abeo-taxane
ring structure as depicted above. The representative taxane ring structure and the abeo-taxane
ring structure shown above have both the 7,9-bridge ring and the C-13 acylated side chain. In
this application a particular abeo-taxane ring structure is the basis of the new taxane analogs- the
11(15--->1) abeo-taxane ring structure.
Structure of 11(15--->1) abeo-taxane without a side chain at position C-13.
[0057A] The term “comprising” as used in this specification means “consisting at least in part
of”. When interpreting each statement in this specification that includes the term “comprising”,
features other than that or those prefaced by the term may also be present. Related terms such as
“comprise” and “comprises” are to be interpreted in the same manner.
Also included in the above embodiments, aspects and variations are prodrugs and their
salts such as prodrugs of amino acids such as arginate and the like, gluconate, and galacturonate.
Some of the compounds described herein may form inner salts or Zwitterions. Certain of the
compounds described herein can exist in unsolvated forms as well as solvated forms, including
hydrated forms, and are intended to be within the scope of the present disclosure. Certain of the
above compounds may also exist in one or more solid or crystalline phases or polymorphs, the
variable biological activities of such polymorphs or mixtures of such polymorphs are also
included in the scope of this disclosure. Also described are pharmaceutical compositions
comprising pharmaceutically acceptable excipients and a therapeutically effective amount of at
least one compound of this application.
Pharmaceutical compositions of the compounds of this application, or derivatives thereof,
may be formulated as solutions or lyophilized powders for parenteral administration. Powders
may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable
carrier prior to use. The liquid formulation is generally a buffered, isotonic, aqueous solution.
Examples of suitable diluents are normal isotonic saline solution, 5% dextrose in water or
buffered sodium or ammonium acetate solution. Such formulations are especially suitable for
parenteral administration but may also be used for oral administration. Excipients, such as
polyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium
chloride, or sodium citrate, may also be added. Alternatively, these compounds may be
encapsulated, tableted, or prepared in an emulsion or syrup for oral administration.
Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the
composition, or to facilitate preparation of the composition. Liquid carriers include syrup,
peanut oil, olive oil, glycerin, saline, alcohols or water. Solid carriers include starch, lactose,
calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia,
agar, or gelatin. The carrier may also include a sustained release material such as glyceryl
monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies but,
preferably, will be between about 20 mg to about 1 g per dosage unit. The pharmaceutical
preparations are made following the conventional techniques of pharmacy involving milling,
mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing, and
filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the
form of a syrup, elixir, emulsion, or an aqueous or non-aqueous suspension. Such a liquid
formulation may be administered directly p.o. or filled into a soft gelatin capsule. Suitable
formulations for each of these methods of administration may be found in, for example,
Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott,
Williams & Wilkins, Philadelphia, Pa.
In one variation, there is described the above compound, or a pharmaceutically
acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of
stereoisomers thereof.
Also described are compounds which have an affinity to bind with tubulin and are
potential drugs in the treatment of cancer and other disease conditions related to dysfunction of
proteins associated with tubulin such as tau, MAP1, MAP2 and MAP4. The compounds
described herein may be useful in the treatment of diseases when used alone or in combination
with other therapies. For example, when used for the treatment of cancer, the compounds
described herein be administered alone or in combination with radiotherapy, surgical removal,
hormonal agents, antibodies, antiangiogenics, COX-2 inhibitors, and/or other chemotherapeutic
agents such as taxanes, temozolomide, cisplatin, 5-fluorouracil, taxotere, gemcitabine,
topoisomerase II inhibitor, topoisomerase I inhibitor, tubulin interacting agent, antibodies,
antiangiogenics, COX-2 inhibitors, hormonal agent, thymidilate synthase inhibitor, anti-
metabolite, alkylating agent, farnesyl protein transferase inhibitor, signal transduction inhibitor,
EGFR kinase inhibitor, antibody to VEGFR, C-abl kinase inhibitor, hormonal therapy
combination and aromatase combination.
The compounds described herein may be useful in the treatment of diseases when used
alone or in combination with other chemotherapeutics. For example, when used for the
treatment of cancer, the compounds described herein may be administered alone or in
combination with aromatase inhibitors, antiestrogen, anti-androgen, a gonadorelin agonists,
topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, microtubule active agents, alkylating
agents, anthracyclines, corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40
antibodies, Smac mimetics, FGF3 modulators, mTOR inhibitors, HDAC inhibitors, IKK
inhibitors, P38MAPK inhibitors, HSP90 inhibitors, akt inhibitors, antineoplastic agents,
antimetabolites, platinum containing compounds, lipid- or protein kinase-targeting agents,
protein- or lipid phosphatase-targeting agents, anti-angiogentic agents, agents that induce cell
differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase
inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, bisphosphanates,
rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR
agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase
inhibitors, aminopeptidase inhibitors, thymidilate synthase inhibitors, a DNA cross linking
agents, topoisomerase I or II inhibitors, DNA alkylating agents, ribonuclase reductase inhibitors,
cytotoxic factors, and growth factor inhibitors.
The compounds described herein may be useful in the treatment of diseases when used
alone or in combination with other chemotherapeutics. For example, when used for the
treatment of cancer, the compounds described herein may be administered alone or in
combination with one or more pharmaceutically acceptable, inert or physiologically active
diluents, adjuvants or chemotherapeutic agents selected from the group consisting of phomopsin,
dolastatin, Avastin, steganacin, paclitaxel, taxotere, vinblastine, vincristine, vindesine,
vinorelbine, navelbine, colchicine, maytansine, ansamitocin, Iressa, Tarceva, Herceptin,
lapatinib, vandetanib, Sorafenib, BAY9006, bevacizumab, cetuximab, gemtuzumab,
panitumumab, rituximab, tositumomab, trastuzumab, apolizumab, oregovomab, mitumomab,
alembuzumab, ibritumomab, vitaxin, SU-6668, semaxanib, sunitinib malate, SU-14813,
vandetanib, Recentin, CP-547632, CEP-7055, AG-013736, pazopanib, combretastatin,
squalamine, combrestatin A4 phosphate, TNP-470, neovastat, dasatinib, imatinib, nilotinib,
sorafenib, sunitinib, triethylenethiophosphoramine, alitretinoin, altretamine, arsenic trioxide,
asparaginase, bexarotene, denileukin diftitox, hydroxycarbamide, masoprocol, mitotane,
pegaspargase, tretinoin, raltitrexed, IL-10, IL-12, bortezomib, leuprolide, interferon β, pegylated
interferons, atrasentan, melphalan, cyclophosphamide, chlormethine, chlorambucil, trofosfamide,
ifosfamide, nitromin, busulfan, thiotepa, chlorambucil, CC-1065, temozolomide, pipobroman,
dacarbazine, mechlorethamine, procarbazine, uramustine, RSU-1069, CB-1954,
hexamethylmelamine, cisplatin, carboplatin, oxaliplatin, BBR3464, satraplatin, tetraplatin,
iproplatin, amsacrine, netropsin, pibenzimol, mitomycin, duocarmycin, dactinomycin,
distamycin, mithramycin, chromomycin, olivomycin, anthramycin, bleomycin, liblomycin,
rifamycin, actinomycin, adramycin, trichostatin A, propamidine, stilbamidine, rhizoxin,
nitroacridine, geldamycin, 17-AAG, 17-DMAG, plicamycin, deoxycoformycin, levamisole,
daunorubicin, doxorubicin, epirubicin, idarubicin, mitroxantrone, valrubicin, carmustine,
fotemustine, lomustine, streptozocin, gemcitabine, 5-fluorouracil (5-FU), fludarabine, cytarabine,
capecitabine, mercaptopurine, cladribine, clofarabine, thioguanine, pentostatin, floxuridine,
pentostatin, aminopterin, methotrexate, pemetrexed, camptothecin, irinotecan, topotecan,
epipodophyllotoxin, etoposide, teniposide, aminogluthetimide, anastrozole, exemestane
formestane, letrozole, fadrozole, aminoglutethimide, leuprorelin, buserelin, goserelin, triptorelin,
abarelix, estramustine, megestro1, flutamide, casodex, anandron, cyproterone acetate, finasteride,
bicalutamide, tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene or zindoxifene, a
derivative of 17-β-estradiol such as ICI 164, ICI 384, ICI 182, ICI 780, testolactone, fulvestrant,
toremifene, testosterone, fluoxymesterone, dexamethasone, triamcinolone, dromostanolone
propionate, megestrol acetate, methyltestosterone, chlorotrianisene, hydroxyprogesterone,
medroxyprogesterone acetate, reloxafine, etanercept, thalidomide, revimid (CC-5013),
aziridoquinones, misonidazole, NLA-1, RB-6145, misonidazole, nimorazole, RSU-1069, SR-
4233, porfimer, photofrin, verteporfin, merocyanin 540, tin etiopurpurin, PUVA, aminolevulinic
acid, methyl aminolevulinate, minodronate, zoledronic acid, ibandronate sodium hydrate or
clodronate disodium, misonidazole, misonidazole, amifostene, oblimersen, TIMP-1 or TIMP-2,
marimastat, TLK-286 and mixtures thereof.
In addition to the exemplary embodiments, aspects and variations described above,
further embodiments, aspects and variations will become apparent by reference to the drawings
and figures and by examination of the following descriptions.
Brief Description of the Drawings:
Figure 1 depicts a representative process for preparing 10 beta abeo-taxane compounds of
the present application.
Figure 2 depicts a representative process for preparing 10 beta taxane and abeo-taxane
compounds of the present application.
Figure 3 depicts a representative process for preparing a 10-beta taxane and abeo-taxane
derivative from a 9-DHB derivative. Figure 4 depicts a representative process for preparing a
-alpha abeo-taxane derivative from a baccatin derivative.
Figure 5 depicts a representative process for preparing a 10-alpha taxane and abeo-taxane
derivative from a baccatin derivative.
Figure 6 depicts a general synthetic scheme illustrating representative processes for the
preparation of the compounds of the present application.
Figure 7 depicts a representative process for preparing a 10-beta abeo-taxane compound.
Experimental:
The following procedures may be employed for the preparation of the compounds
described herein. The starting materials and reagents used in preparing these compounds are
either available from commercial suppliers such as the Aldrich Chemical Company (Milwaukee,
Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well
known to a person of ordinary skill in the art, following procedures described in such references
as Fieser and Fieser's Reagents for Organic Synthesis, vols. 1-17, John Wiley and Sons, New
York, N.Y., 1991; Rodd's Chemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier
Science Publishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons, New York, N.Y.,
1991; March J.: Advanced Organic Chemistry, 4th ed., John Wiley and Sons, New York, N.Y.;
and Larock: Comprehensive Organic Transformations, VCH Publishers, New York, 1989.
In some cases, protective groups may be introduced and finally removed. Suitable
protective groups for amino, hydroxy and carboxy groups are described in Greene et al.,
Protective Groups in Organic Synthesis, Second Edition, John Wiley and Sons, New York, 1991.
Standard organic chemical reactions can be achieved by using a number of different reagents, for
examples, as described in Larock: Comprehensive Organic Transformations, VCH Publishers,
New York, 1989.
Example 1
In one variation, the 10-beta compounds of the present application can be prepared by the
steps as outlined below. See also Figures 2 and 3.
9-DHB 7,9-Ketal:
630 mg of 5b.1 9-DHB (13-acetyldihydrobaccatin III, 1 mmol) was weighed into a 25
ml RB flask, 7 ml of ACN was added at room temperature and the resulting mixture was stirred.
2.44 ml (~20 mmol) of 2,2-dimethoxypropane was added followed by 126 mg of
montmorrilonite clay. Stirring was continued under nitrogen. The reaction progress was
monitored by TLC (15:85 acetone:DCM) after about 135 minutes; which suggested that reaction
was about 50% complete. The reaction had not progressed after another 2 hours of stirring. 15
mg of camphorsulfonic acid was added and stirring was continued. After 45 minutes, TLC
indicated all starting material was consumed. The reaction was quenched by adding 450 mg of
solid K CO and the resulting mixture was stirred for 15 minutes. 3 ml of water was added and
stirring continued for another 10 minutes. The slurry was filtered on a sintered funnel and the
filtrate evaporated on the rotavapor. The water was azeotroped with acetonitrile and the
resulting product dried in an oven overnight. The crude product was purified on a flash column
with 1:9 acetone:DCM to give 550 mg of product 11.
13-Deacetylation:
450 mg (0.67 mmol) of 7,9-acetonideDHB, 11 was added to a RB flask, and 15 ml of
THF was added and the solution stirred under nitrogen and cooled to -50 C. 1.6 ml of (1.8 M)
phenyl lithium was added dropwise over a period of 8 minutes. TLC of the reaction with 4:6
EtOAc, heptanes after 10 minutes indicated the reaction was complete. The reaction mixture
was poured into a 50 ml solution of saturated aqueous ammonium chloride and allowed to rise to
room temperature. The layers were partitioned and the mixture was extracted thrice with 20 ml
of isopropyl acetate. The organic layers were combined, washed with brine, dried over Na SO
and concentrated. The crude product was dried in the oven overnight. Purification by silica gel
chromatography using 40:60 EtOAc, Heptanes with 1% AcOH and 1% water gave purified
product (11b.1) which was taken into the next step.
Coupling Reaction:
In a RB flask 469 mg (1 mmol) of protected side chain for coupling, 10, 630 mg (1
mmol) of protected 13-hydroxybeta acetyl baccatin derivative (11b.1), 61 mg (0.5 mmol) of
DMAP were weighed and the flask capped with a septum. 15 ml of dry EtOAc were added and
the mixture stirred under N at room temperature and 206 mg (1 mmol) of DCC were added.
The reaction was stirred for 45 minutes and checked with TLC indicating it was about 60%
complete. After another 1 hour, TLC indicated little change. Another 50 mg of DCC and 200
mg of the protected side chain, 10, was added and stirring continued for 2 more hours. TLC
showed the reaction complete (complete conversion of 11b.1). The reaction was quenched by
adding 5 ml of water and 20 ml of ammonium chloride and partitioned and the organic layer
separated, washed with 25 ml of brine, dried over sodium sulfate and concentrated on the
rotavapor. The crude product was purified by flash chromatography with 1:3 EtOAc/heptanes to
give purified coupled ester, 12b.1.
Acetal Deprotection:
1.5 gm of the coupled ester (1.39 mmol) was weighed into a 100 ml RB flask with a
reflux condenser, and 30 ml of MeOH were added and the mixture stirred under nitrogen. The
flask warmed to 45 C and 10 ml of 0.1 N HCl were added dropwise over a period of 10 minutes.
Stirring was continued after the addition and the reaction monitored by TLC until the starting
material was converted to slower spot on TLC. The reaction was cooled to room temperature
and quenched with aqueous sodium bicarbonate until the pH was about 9. MeOH was
evaporated on a rotary evaporator and 50 ml of EtOAc was added to the flask. The mixture was
partitioned and the EtOAc removed. The aqueous layer was extracted twice more with 50 ml
EtOAc. The organic layers were combined, washed with 50 ml brine and concentrated to give
crude product which was purified by flash chromatography using 1:1 EtOAc : Heptanes. 900 mg
of product 13b.1 was obtained.
Clay Catalyzed Acrolein Acetalization Reaction:
0.16 gm of 13b.1 (0.192 mmol) and 42 mg of acrolein dimethyl acetal (0.41 mmol) were
weighed into a 25 ml RB flask followed by addition of 40 mg of Montmorillonite clay, the flask
was capped with a septum and 3 ml of ACN were added under nitrogen. The pH of the reaction
was determined to be about 6. About 3 microliters of TFA were added. After additional stirring,
the pH was found to be 3.5. After 30 minutes, 0.15 ml of acrolein dimethyl acetal was added and
stirring continued at room temperature. The reaction was monitored by TLC and HPLC. The
reaction was quenched after stirring for 5 hours with 2 ml of aqueous sodium bicarbonate and the
solution was filtered over a bed of celite. The celite bed was washed with 20 ml of ACN, and the
filtrates combined and concentrated on the rotavapor. The crude product was purified by reverse
phase chromatography using methanol/water 4:1 to give 150 mg of acrolein acetal product,
14b.1.
NH OH 10
Acid
O 13
R NH OH
2 13
H R H
Acrolein Acetal 14b.1 15b.1
Abeo-Taxane
Abeo-Taxane Formation:
To 0.125 gm of acrolein acetal starting material, 14b.1, contained in a RB flask was
added 5 ml of wet toluene (toluene stored in a bottle containing 2 ml of water at the bottom so
the solvent was saturated with water). The contents of the flask were stirred and cooled to 14 C
in a water bath containing some ice. 5 ml of 2% TFA in toluene were added over a minute to the
flask and stirring continued. The reaction was monitored by HPLC by the taxane method which
indicated the starting material conversion to product with retention time of 10.7 minutes. The
reaction was quenched after 120 minutes with 5 ml of aqueous sodium bicarbonate. The toluene
layer was separated and the bicarbonate layer separated with 20 ml of EtOAc. The organic
layers were combined washed with 20 ml of brine, dried over sodium sulfate and concentrated on
the rotavapor. The crude product was dried in the oven overnight and purified by reverse phase
chromatography with 4:1 MeOH, water to give 58 mg of abeo-taxane rearranged product, 15b.1.
Example 2:
In one variation, the 10-alpha compounds of the present application can be prepared by
the steps as outlined below. See also Figure 4.
Oxidation of 10 DAB III 16:
A 4 L reaction flask, rinsed with 300 mL dried EtOAc and held under N , was charged
with 1250 mL dried EtOAc. The resulting mixture was stirred, and dried 16 (100 g, 0.184 mol)
was added. The addition of 800 mL USP EtOH followed and the reaction mixture was cooled to
–1.3 ºC. Anhydrous CuCl (86.4 g, 3.5 eq.) was added and solids were washed into the mixture
with 450 mL anhydrous EtOH. The reaction mixture was cooled to ≤ –13 ºC and anhydrous
TEA (90 mL, 3.5 eq.) was added slowly. The reaction was monitored by HPLC /TLC. At 1 h
the reaction was judged complete (< 5% starting material). 36 mL TFA was added to quench the
reaction and stirring continued for 15 min. The reaction mixture was transferred to a 10 L
rotovap flask. 500 mL EtOAc and 300 mL EtOH were added to the reaction flask, stirred for 2
min and the rinse added to the contents of the rotovap flask, which was evaporated on the
rotovap at 40 ºC until no further distillation occurred (80 min). Acidified ethanol (1% acetic
acid, 300 mL) was added to the residue and the resulting slurry was transferred to a 2 L rotovap
flask. The first rotovap flask was rinsed into the second with 400 mL acidified EtOH. The
mixture was evaporated on the rotovap at 40 ºC. Acidified ethanol (305 mL) was added to the
rotovap flask and the mixture was stirred at 40 ºC for 10 min. The flask were then cooled to 5 ºC
and filtered. The rotovap flask was rinsed 2X 300 mL cold (2 ºC) acidified ethanol and the rinse
was transferred completely to the filter to wash the solids. The solids were dried in the vacuum
oven overnight at 45 ºC to give 17. HPLC Area % = 91.3%. Yield = 96.7 g.
Silylation of 17 to form 19:
To 17 (96.72 g, 0.1783 mmol) in a 10 L rotovap flask was added ethyl acetate (3000 mL,
mL/g). The solution was evaporated on the rotovap at 40 ºC to approximately half the
original volume (distilled volume = 1680 mL). 1000 mL toluene (10 mL/g) was added to the
remaining solution and rotovaped at 40 ºC until solids were obtained (45 min). The solids were
suspended in toluene (1000 mL, 10 mL/g) and the suspension was rotoevaporated at 40 ºC (~1 h)
to dry solids. The solids were transferred to a 2 L flask under N stream. The solids were rinsed
into the reaction flask with anhydrous pyridine (292 mL, 3 mL/g) and the resulting mixture was
stirred. Upon dissolution, the contents were cooled to –20 ºC. Triethylsilyl
trifluoromethanesulfonate (TES-OTf, 120.9 mL, 3.0 eq.) was slowly added to the reaction
mixture to maintain at ≤ –10 ºC. After the addition of TES-OTf, the mixture was allowed to
warm to –5.8 ºC. 30 mins. after the addition of TES-OTf, sampling was begun at thirty-minute
intervals for HPLC/TLC. The reaction was judged complete at 2 h when HPLC/TLC indicated <
2% mono-TES derivative remaining. The mixture was cooled to –17.5 ºC, methanol (19.3 mL,
0.2 mL/g) was added and stirred for 5 min. The mixture was warmed to room temperature, 500
mL MTBE was slowly added and then transferred to a separatory funnel. Residues in the
reaction flask were washed into the separatory funnel with MTBE (200 mL, 2 mL/g), then water
(250 mL, 2.5 mL/g) and saturated NH Cl solution (250 mL, 2.5 mL/g) were added. The organic
layer was transferred to a clean container. MTBE (250 mL, 2 mL/g) was added to the aqueous
layer. It was agitated and the layers were separated. The second organic layer was washed with
100 mL MTBE and water (200 mL, 2 mL/g) was added to the combined layers. The organic
layer was transferred to a 2 L rotovap flask and evaporated to a residue at 40 ºC. n-Heptane (500
mL, 5 mL/g) was added and the solution was evaporated to a residue at 40 ºC. n-Heptane (1000
mL, ~10 mL/g) was added and the solution was evaporated to one-half of its volume (distilled
volume = 375 mL). n-Heptane (300 mL, ~2.5 mL/g) was added and stirred on a rotovap at 40
ºC. The solution was then cooled to –15.7 ºC while stirring was continued for ~2.5 h and then
filtered. The solids were rinsed into the filtration funnel with cold (<5 ºC) n-heptane (100 mL)
and collected and dried in the vacuum oven to give 111 g 19. HPLC Area % purity = 93.4%.
Reduction of 19 to prepare 20:
To a stirred solution of THF (560 mL, 5 mL/g) under N in a 4 L reaction flask, was
added 19 (111 g, 0.144 mol,) followed by anhydrous ethanol (560 mL, 5 mL/g). The mixture
was stirred to dissolve the solids and then cooled to –12 ºC. 2 M LiBH in 72 mL THF was
added to control the reaction temperature (temp = –11.9 to –9.7 ºC). The reaction was sampled
for HPLC / TLC at 30 min intervals. Additional 2 M LiBH in THF was added (72 mL, 1.0 eq.)
to the reaction flask (temp = –9.6 ºC to –7.1 ºC) and stirred for 30 min. A third addition of 2 M
LiBH in THF (36 mL, 0.5 eq.) was made as before (temp = –7.6 ºC to –6.7 ºC), but with the
bath temperature adjusted to 15 ºC following the addition of the LiBH solution and to 12.5 ºC
ten minutes later. At 1 hr after LiBH addition, the reaction was complete (mono reduced
product ≤3% relative to 20). The mixture was cooled to –10.8 ºC and 10% ammonium acetate in
560 mL EtOH was added to allow the foam to settle and to control the temperature of the
solution ≤ -3 ºC. The mixture was transferred to a 2 L rotovap flask and residues were rinsed
into the rotovap flask with 250 mL EtOH and content were evaporated on the rotovap at 40 ºC to
an oil, and 560 mL Methanol was added. 1700 mL water was added to a 5 L flask and was
vigorously agitated. To precipitate the product, the methanol reaction mixture (748 mL) was
added to the flask containing water. The mixture was filtered and the solids were washed with
650 mL water. The solids were vacuum dried overnight at 45 ºC to give 140 g of slightly wet
non-homogeneous product, 20. HPLC area % purity = 92.8%.
Acetylation/Deprotection of 20 to prepare 22:
Acetylation: To 20 (138 g, 0.178 mol) in a 2 L rotovap flask was added IPA (isopropyl
acetate, 1400 mL, 10 mL/g). The solution was rotoevaporated at 40 ºC to an oil. The procedure
was repeated. 550 mL dried IPA was then added to the oil and the contents were transferred to a
1 L reaction flask under N . The rotovap flask was washed into the reaction flask with 140 mL
IPAc. DMAP (8.72 g, 0.4 eq.), anhydrous TEA (170 mL, 7 eq.) and acetic anhydride (100.6 mL,
6 eq.) were added and the mixture was stirred and heated to 35 ºC. The mixture was heated to 35
ºC, the reaction was monitored by HPLC /TLC. Upon completion of the reaction, as indicated
by the absence of 20 (3 h total time), the mixture was cooled to 19.7 ºC and saturated ammonium
chloride solution (552 mL) was added. After stirring for 15 min, the mixture was transferred to a
separatory funnel, the layers were separated. 280 mL water was added to the organic layer and
the mixture was stirred for 4 min. and the layers were separated. The organic layer was
transferred to a 2 L rotovap flask and the remaining content of the separatory funnel was washed
into the rotovap flask with 200 mL IPA. The mixture was evaporated to dryness at 40 ºC to give
~124 g 21 as pale yellow oily foam.
Deprotection: To the rotovap flask containing 21 (124 g) was added methanol (970 mL,
7 mL/g). Sampling for HPLC/TLC was begun and continued at 1-hour intervals. The 21
/methanol solution was transferred to a 3 L reaction flask and agitation was begun. The
remaining content of the rotovap flask was washed with 400 mL methanol. Acetic acid (410 mL,
3 mL/g) and water (275 mL, 2 mL/g) were added and the reaction mixture was heated to 50 ºC to
and 55 ºC, and the reaction was monitored by HPLC / TLC at 1-hour intervals for formation of
the product, 22. Upon completion (~9 h), the mixture was cooled to rt and transferred to a 10 L
rotovap flask. Solvent exchanges to n-heptane (2 X 1370 mL, 1 X 1000 mL) and IPA (2 X 1370
mL, 1 X 1500 mL) were performed. IPA (280 mL, 2 mL/g) and silica (140 g, 1 g/g) were added
and the contents rotoevaporated at 40 ºC until free flowing solids were obtained. The dry silica
mixture was loaded onto a silica pad (7 cm column, 280 g silica), conditioned with 2:1 n-
heptane/IPA (500 mL, 2 mL/g silica) and washed (4X) with 2:1 n-heptane/IPA, 2 mL/g silica,
3400 mL total) and (4X) with 1:1 n-heptane/IPA (3020 mL total, 2 mL/g silica) until all
impurities were removed as indicated by TLC. Each wash (~840 mL) was collected as a separate
fraction and analyzed by TLC. The silica pad was then washed (5X) with waEtOAc (1% water,
1% AcOH in EtOAc) (3950 mL total, 2 mL/g silica) and with 1:1 MeOH/EtOAc and each wash
(~840 mL) was collected. The fractions containing 22 as indicated by HPLC/TLC were
combined and rotoevaporated to dryness at 40 ºC. The residue in the flask was dissolved and
evaporated to dryness: first with 1055 mL IPA and 550 mL n-heptane and a second time with
830 mL IPA and 410 mL n-heptane. 500 mL IPA was then added to the residue, the solution
was transferred to a 2 L round bottom flask and 140 mL n-heptane was added. The resulting
solution was rotoevaporated at 40 ºC to give 22 as foam. 160 mL IPA was added to the flask
followed by 800 mL toluene. The solution was rotoevaporated under vacuum at 50 ºC until half
of the solvent was removed. The flask was stirred and cooled to 21 ºC for 1.5 h. The solids were
filtered and were washed with 165 mL toluene and dried at 40 ºC to give 62.6 g of 22. HPLC
area % = 96.9%
Acetal Formation: Compound 22 to 23
To a 3 L reaction flask containing 22 (25 g, 42.4 mmol) was added 375 mL toluene and
the reaction was cooled to ~ –15 ºC. TFA (9.8 mL, 3.0 eq.) was slowly added, followed by the
addition of acrolein diethyl acetal (8.7 g) and the reaction was monitored by HPLC until <3% of
22 remained. Hydrated silica was prepared by mixing silica (25 g) and water (25%) and a
“basified silica” mixture was prepared by mixing a solution of K CO (17.6 g, 3.0 eq.) in water
(1 mL/g 22) with 50 g silica. Upon reaction completion, the hydrated silica was added to the
reaction mixture and it was stirred for 30-45 min at ≤5 ºC. The basified silica was then added to
the mixture at ≤5 ºC and the pH >5. After stirring for ~15 min, the mixture was filtered. The
silica was washed with ~20 mL/g toluene and the filtrates were combined and concentrated. The
residue was digested with 1 mL/g toluene for ~4 h. The resultant solids were filtered and washed
with 80:20 toluene/heptane to give 25 g of 23. HPLC area % = 98%. Mass yield = 66%.
Preparation of Compound 15a.2 from 23:
To THF (300 mL, 8 mL/g) stirring in a 1 L reaction flask (rinsed with 500 mL THF) was
added 23 (35.7 g, 0.0570 mol). Purified coupling agent 10a (30.9 g, 1.25 eq.) was added to the
reaction mixture followed by the addition of NMM (11.5 mL, 1.8 eq.), DMAP (2.77 g, 0.4 eq.)
and THF (75 mL, 2 mL/g). The mixture was stirred while N was bubbled from the bottom of
the flask to mix and dissolve the solids. Pivaloyl chloride (11.5 mL, 1.6 eq.) was then added the
reaction mixture. The reaction mixture was warmed to 38 ºC ± 4 ºC. After 1 h the reaction was
cooled to 2 ºC. 0.5 N HCl in MeOH (280 mL, ~20 mL/mL NMM) was added to maintain the pH
= 1.5-1.9. The mixture was stirred at 2 ºC ± 2 ºC and monitored by HPLC/TLC at 30 min
intervals for formation of 15a.2 and the acrolein acetal hydrolyzed by-product. After 2 hr 300
mL 5% aqueous sodium bicarbonate and IPAc (185 mL, 5 mL/g) was added. The reaction
mixture was transferred to a 2 L rotovap flask and rinsed with 2X with 60 mL IPAc. The
mixture was evaporated at 40 ºC to an oil and water was obtained. 200 mL IPAc was added and
the contents were transferred to a separatory funnel. The reaction flask was rinsed with 100 mL
IPAc and the layers were separated. 70 mL water was added to the organic layer and the layers
were separated. The organic layer was rotoevaporated at 40 ºC to a foam, and dried in the
vacuum oven to give 64.8 g crude 15a.2. HPLC area % = 45.5%.
Purification Procedures:
Normal Phase Chromatography: The 6" Varian DAC column was packed with Kromasil
(5 Kg, 10µm, 100 Å normal phase silica gel). The 50-cm bed length provided a 9 L empty
column volume (eCV). The column had been regenerated (1 eCV 80:20 waMTBE:MeOH) and
re-equilibrated(1 eCV waMTBE, 1 eCV 65:35 n-heptane:waMTBE). The crude 15a.2 (64.7 g),
was dissolved in MTBE (180 mL) and heated to ~ 40 C. 280 mL n-Heptane was added to the
solution, and was pumped onto the column. The column was then eluted with 65:35 n-
heptane:waMTBE at 800 mL/min. A 34 L forerun (~3.8 eCV) was collected followed by 24
fractions (500 mL each). Fractions 1 through 23 were combined and concentrated to dryness on
a rotovapor. The residue was dried in the vacuum oven overnight to provide 41.7 g 15a.2.
HPLC area % = 99.4%.
Final Purification: The normal phase pool was dissolved in USP EtOH (6 mL/g) and
concentrated to dryness three times. The residue was dissolved in USP EtOH (2 mL/g). This
ethanolic solution was slowly added drop-wise to water (deionized, 20 mL/g) with stirring. The
solids were vacuum filtered and washed with cold DI water, and dried in the vacuum oven at 40
C overnight to give 38.9 g 15a.2. HPLC area % = 99.5%.
Separation of diastereoisomers of formula 15a.2 by Normal Phase Chromatography
The compound of formula15a.2, (570 mg) which comprises a mixture of
diastereoisomers is dissolved in 35:65 MTBE/n-heptane. The solution is loaded onto a flash
chromatography column packed with spherical silica (YMC-1701, 56 g), which has been
conditioned with 35:65 MTBE/n-heptane. The column is eluted with 35:65 MTBE/n-heptane
and fractions (25 mL) collected. Fractions containing the pure product are collected, pooled and
concentrated to the diastereoisomer of 15a.2 as a white solid.
Example 3
In one variation, the 10-alpha compounds of the present application can be prepared by
the steps as outlined below. See also Figure 5.
7,10-di-CBZ protection of 10-DAB III:
10-Deacetylbaccatin III (10-DAB III), which has formula 16 as shown in Figure
, (Sigma-Aldrich) was used as an intermediate in the preparation of various taxanes. 10-DAB
III, formula 16, is first protected at both the C-7 and C-10 positions to form the C7, C10 di-CBZ
derivative of formula 25. 10-Deacetylbaccatin III of formula 16 (50 g, 91. mmol) was dissolved
in THF (2L, 40 ml/g) by warming to 40 ºC. The solution was cooled to -41 ºC and
benzylchloroformate (46 mL, 3.2 eq, 294 mmol) was added followed by further cooling to -44
ºC. 2.3M hexyl lithium solution (130 mL, 3.3 eq, 303 mmol) was added over 45 min at ≤ -39 ºC,
and stirred for 45 minutes. After two hours, 1N HCl (400mL) and IPAc (1L) was added and
warmed to 10 ºC. The layers were separated and the IPAc layer was washed with H O (500
mL), saturated NaHCO (200 mL) and H O (4x500 mL) and then filtered through a silica gel
pad. The filtrate was concentrated until solids started to form. IPAc (850 mL) was added and
the mixture was heated to 60 ºC. Heptanes (800 mL) were added and the solution was cooled
and filtered. The solids collected by the filtration were washed with heptanes and dried under
vacuum at 45 ºC to give formula 25.
Coupling of compound 25 and 9a.1:
Next, the compound of formula 25 was coupled with a side chain to form the
compound of formula 26. Here, the side chain of the compound of formula 9a.1, (38 g,
99.6mmol) was dissolved in toluene to 0.095 g/mL. This solution was added to the compound of
formula 25 (54.0 g, 66.4 mmol). The solution was heated in a warm-water bath and DMAP
(8.13 g, 66.4 mmol) and DCC (25.3 g, 120 mmol) in toluene (540 mL) were added. After 3
hours, additional DCC (13.0 g) in toluene (140 mL) was added. After about 25.25 hrs, MTBE
(450 mL) was added and the mixture was filtered through a pad of silica gel, washed with
MTBE, ethyl acetate, and concentrated to give the compound of formula 26 as 61.8 g of an oil.
Deprotection of 7,10-benzoyl groups:
The compound of formula 26 was then deprotected at both the C7 and C10 to give
the compound of formula 27. A solution of THF (300 mL) and conc. HCl (22 mL) was added to
a solution of the compound of formula 26 (61.8 g, 52.5 mmol) in THF (15 mL/g, 920 mL) under
nitrogen. A catalyst (10% Pd/C with 50% water, 99.1 g) was added and the flask was flushed
with nitrogen three times and then with hydrogen three times. The reaction mixture was stirred
under a hydrogen balloon for 21 hours. HPLC indicated that 38% by area of starting material
still remained. Water (10 mL) was added and stirring continued. Twenty hours later, HPLC
indicated the same amount of starting material still remaining. The reaction mixture was filtered
through celite and washed with THF. Excess THF was removed; fresh catalyst (101 g) was
added and the reaction mixture was re-charged. After another 24 hours, more catalyst (20 g) was
added. After another hour, the reaction mixture was filtered through celite and washed through
with IPAc. The combined filtrate was washed with NH Cl solution (500 mL), water (500 mL),
% NaHCO (500 mL), H O (300 mL), and brine (300 mL). The organic layer was dried,
filtered, and concentrated to give a foam of the compound of formula 27 (42.5 g).
Disilylation of compound 27:
The compound of formula 27 was then converted to the compound of formula 28.
Formula 27 (41.4 g, 52.5 mmol) was dissolved in DCM (500 mL) at room temperature. In the
case that the impurity was water, Na SO was added to the solution, and the solution was filtered
through filter paper into to a 2L flask. The solids were collected and washed with DCM (250
mL) and the washings transferred into the flask. TEA (35 mL) followed by DMAP (1.28 g) and
TES-Cl (~30 mL, 3.5 eq) were added to the solution and stirred. Additional TES-Cl (15 mL) and
TEA (20 mL) were added, and after 6 hours HPLC indicated the reaction had gone to
completion. The reaction was then quenched with ethanol (25 mL). The layers were separated
and the organic layer was washed with saturated NH Cl (~500 mL), and dried over Na SO and
4 2 4
concentrated. A flash column was packed with silica gel and wet with 8:2 heptane/IPAc (1.5L).
The solids were dissolved in 8:2 heptane/IPAc (250 mL) and filtered to remove solids. This
solution was concentrated to ~100 mL and applied to the column. The column was eluted with
8:2 heptane/IPAc. Fractions with product were pooled and concentrated to give foam of formula
28 (24.5 g).
Oxidation of compound 28:
The compound of formula 28 was then oxidized to form the compound of formula
29. Solid Na SO was added to a solution of formula 28 (24.5 g, 24.0 mmol) and 4-methyl
morpholine N-oxide (10.1 g, 84 mmol) in DCM (340 mL). The mixture was stirred for 1 hour
and then filtered through 24 cm fluted filter paper into a flask. The Na2SO4 solids were washed
with DCM (100 mL) and the washings transferred into the flask. Molecular sieves (6.1 g, 0.15
g/g) were added to the solution and stirring was begun. TPAP (1.38 g) was added and the
reaction was allowed to stir under a N blanket and monitored by HPLC. Additional TPAP (0.62
g) was added after 2 hours and again (0.8 g) after 15 hours. The reaction mixture was applied to
a pad of silica gel (86 g), wet with 8:2 heptane/IPAc and eluted with IPAc. The fractions were
collected and concentrated to an oil. 4-Methyl morpholine N-oxide (5.0 g) and DCM (100 mL)
were added and stirred. Na SO (13 g) was added to the mixture and it was filtered through filter
paper. The Na SO solids were washed with DCM (45 mL). Molecular sieves (5 g) and TPAP
(1.03 g) were added to the solution and after 45 minutes, more TPAP (1.05 g) was added. A pad
of silica gel was prepared and wet with 80:20 Heptane/IPAc. The reaction mixture was applied
to the pad and eluted with IPAc. Fractions with product were collected and pooled and
concentrated to give an oil product of formula 29 (21.8 g).
Reduction on diketone 29:
The compound of formula 29 was reduced to form the compound of formula 30.
NaBH (365 mg, 6 eq) was added to a stirred solution of formula 29 (1.6 g) in ethanol (19 mL)
and methanol (6.5 mL) cooled in an ice-water bath. After 1 hour, the mixture was removed from
the ice-water bath and at 2 hours, the reaction was complete. The mixture was cooled in an ice-
water bath and a solution of NH OAc in methanol (15 mL) was added followed by the addition
of IPAc (50 mL) and H O (20 mL), and separated. The organic layer was washed with water (20
mL) and brine (10 mL), with water (15 mL) and brine (10 mL), and then twice with water (2x15
mL). It was dried over Na SO and placed in the freezer overnight. A sample was taken for
HPLC and the reaction was dried and the organic layer was concentrated on the rotary
evaporator. It was placed in the vacuum oven to give a foam product of formula 30 (1.45 g).
Regioselective acetylation of compound 30:
The compound of formula 30 was then acylated to form the compound of formula
31. TEA (5.8 mL, 41.5 mmol), Ac O (2.62 mL, 27.7 mmol) and DMAP (724 mg, 5.5 mmol)
were added to a solution of formula (11) (14.1 g. 13.8 mmol)) in DCM (50 mL). The reaction
was stirred and sampled for HPLC. After 18.5 hours, additional TEA (1.5 mL) and Ac O (1 mL)
were added. At 19 hours, the reaction mixture was diluted with IPAc (300 mL) and poured into
% NaHCO (100 ml). It was then stirred, separated, and the organic layer was washed with
water (100 mL), saturated NH4Cl (2x100 mL), water (3x50 mL) and brine (50 mL) and then
filtered through Na SO . The mixture was concentrated to give a foam product of formula 31
(14.6 g).
Desilylation of compound 31:
The compound of formula 31 was converted to the compound of formula 13a.2. A
quantity of formula 31 (3.0 g, 2.83 mmol) was weighed into a 100 mL flask. DCM (24 mL)
followed by methanol (6 mL) were added to the flask, and camphorsulfonic acid (CSA) (0.0394
g, 0.17 mmol) was added. After 4 hours, 5% NaHCO (15 mL) was added, and the mixture was
shaken and transferred to a separatory funnel. The reaction flask was washed with 5% NaHCO
(25 mL) and the layers were separated. The organic layer was washed with brine, dried over
Na SO , and concentrated. MTBE (3x25 mL) was added and the reaction mixture was
concentrated to dryness to give 3.71 g foam. The foam was dissolved in MTBE (10 mL) and
stirred. Heptane (50 mL) was added to the reaction solution. The solids were vacuum filtered
and rinsed with heptane (720 mL). The solids were collected and dried in a vacuum oven at 40
ºC to give the compound of formula 13a.2 (2.18 g).
Synthesis of 14a.2 and 15a.2:
The compound of formula 13a.2 was converted to the compound of formula 14a.2
and then to the compound of formula 15a.2 using the experimental conditions as described for
the conversion of 13b.1 to 14b.1 and then to 15b.1
Example 4
In another variation, the 10-beta compounds of the present application can be
prepared more efficiently by the steps as outlined below. See also Figure 7.
9-DHB-7,9-PMB Acetal:
10.1 g of 5b.1 (9-DHB, 16 mmol) was weighed into a 250 ml RB flask, 40 ml of
ACN was added at room temperature and the resulting mixture was stirred (9-DHB was not
completely soluble at this concentration). 8.17 ml (48 mmol) of 4-methoxybenzyledene acetal
was added followed by 149 mg of camphorsulfonic acid and stirred for 15 min. After 20
minutes, the mixture was poured into a 100 ml saturated sodium bicarbonate solution, and
extracted with EtOAc (2x100 ml). The organic layers were combined, washed with brine, dried
over Na SO and concentrated. The crude product was purified on a flash column with 7:3 to 4:6
heptanes:EtOAc to give 11.9 of product 5b.2 in 92% yield.
Abeo-Taxane Formation:
To 12.2 g of compound 5b.2 (PMB acetal of 9-DHB, 16.3 mmol), contained in a
RB flask was added 163 ml (0.1molar concentration) of wet toluene (toluene stored in a bottle
containing 5 ml of water at the bottom so the solvent was saturated with water). The contents of
the flask were stirred and cooled to 14 C in a water bath containing some ice. 163 ml of 2%
TFA in toluene were added over a minute to the flask and stirring continued. The reaction
progress was monitored by HPLC by the taxane_MKG10 method (Synergy column, ACN 60%
min, 2 min 100% CAN, 230 nm, 1.5 ml/min, 30 C) which indicated the starting material
retention time at 5.58 minutes and the product retention time at 5.80 minutes. The reaction was
quenched after 4 hr 45 minutes (at this point HPLC analysis showed 5% starting material, 60%
product and three side products at 3.70 (7%), 3.89 (26%) and 9.5 (2%) retention time) by pouring
in 200 ml of saturated aqueous sodium bicarbonate solution. The toluene layer was separated
and the bicarbonate layer was re-extracted twice with 100 ml EtOAc. The organic layers were
combined, washed with 100 ml of brine, dried over sodium sulfate and concentrated on the
rotavapor. The crude product was dried in the oven overnight and purified by normal phase
chromatography using Kromasil normal phase silica gel (10µm, 100 Å) in 6:4 heptane:EtOAc
(EtOAc was saturated with 2% H O and 1% AcOH) to give 9.2 g (60%) abeo-taxane rearranged
product 7b.1.
13-Deacetylation:
8.23 g (11 mmol) of 9-DHB-7,9-PMB acetal 7b.1 was dissolved in 220 ml (0.05
M) of anhydrous THF (HPLC grade THF over 4A molecular sieves) was added and the solution
stirred under nitrogen and cooled to ‒60 C (by acetone-dry ice mixture). 37 ml of (66 mmol,
1.8 M solution in di-n-butylether) phenyl lithium was added dropwise over a period of 10
minutes. TLC of the reaction with 6:4 EtOAc:heptanes after 10 minutes indicated the reaction
was complete. The reaction mixture was poured into a 150 ml solution of saturated aqueous
ammonium chloride. The layers were partitioned and the mixture was extracted thrice with 100
ml of ethyl acetate. The organic layers were combined, washed with brine, dried over Na SO
and concentrated. The crude product was purified by flash chromatography using silica gel in
1:4 and 1:1 EtOAc, heptanes to give 5.4 g of 13-deacetyl product 8b.1 in 70% yield.
Coupling Reaction:
2.6 g of 2,6-dimethoxybenzylidene acetal protected side chain sodium salt 10a.2a
was dissolved in EtOAc (25 ml) and poured into a of saturated sodium bisulfate solution (50 ml).
The biphasic layers were mixed well in a separatory funnel for 5 minutes and the organic layer
was separated, and washed twice with brine (20 ml). Organic layer was dried over sodium
sulfate, evaporated under reduced pressure to obtain 2.5 g of the free acid 10a.2. 2.5 g (6.1
mmol) of acid 10a.2, 2.4 g (3.4 mmol) of PMB protected 13-hydroxy-abeo-taxane 8b.1, 200 mg
(1.7 mmol) of DMAP were weighed and the flask capped with a septum. 23 ml of dry THF and
1 ml (9.5 mmol) of N-methylmorpholine (NMM) was added and the mixture stirred under N
atmosphere. Reaction mixture was warmed to 35 ± 4 ºC and 1 ml (8.1 mmol) of trimethylacetyl
chloride was added in 3 portions. The reaction was stirred for 30 minutes. THF was evaporated
and the reaction mixture was poured in saturated sodium bicarbonate solution (25 ml) and
extracted with EtOAc (2x20 ml). The combined organic layers were washed with brine (25 ml),
dried over sodium sulfate and concentrated. The crude product was dried under high vacuum
and purified by silica gel chromatography using 4:1 to 7:3 heptane:EtOAc to give 3.3 g of
purified coupled ester 32 in 89% yield.
MeO OMe
AcO O
AcO O
BocHN OH
BocN O
0.2NHCl
HO OAc
15b.2
Ketal Deprotection:
0.22 g of the coupled ester 32 (0.2 mmol) was weighed into a 100 ml RB flask
with a reflux condenser, and 6.6 ml (0.03 M) of MeOH was added and the mixture stirred under
nitrogen. The flask warmed to 35 ºC ± 4 ºC and 2.2 ml of 0.1 N HCl was added dropwise over a
period of 5 minutes. Stirring was continued until the starting material was completely consumed.
The reaction was cooled to room temperature and quenched with aqueous sodium bicarbonate
until the pH was about 9. MeOH was evaporated on a rotary evaporator and 15 ml of EtOAc
was added to the flask. The reaction mixture was partitioned and the EtOAc layer was separated.
The aqueous layer was extracted twice more with 15 ml EtOAc. The organic layers were
combined, washed with 15 ml brine and concentrated to give crude product which was purified
by flash chromatography using 7:3 hexanes:EtOAc to give 0.11 g of 15b.2 in 70% yield.
Example 5:
In one variation, the process comprising the synthesis of various abeo-taxanes can
be prepared efficiently from the corresponding taxanes as outlined below. See also Figure 1.
AcO OH
1%TFA
wettoluene,56%
OH OBz
OBz OAc HO
9-DHB 5b.1
Direct conversion of 9-DHB to abeo-taxane:
0.946 g of 9-DHB (1.5 mmol) was dissolved in 65 ml (0.0225 M) of wet toluene
and the reaction flask was cooled to 15 C in a water bath containing some ice. 65 ml of 2%
TFA in wet toluene was added in one portion and the reaction was continued to stir at 15 C. The
reaction progress was monitored in 15 minute time intervals by HPLC using taxane_MKG5
method (Synergy column, ACN:H O 40:60 9 min, 2 min 100% ACN, 230 nm, 1.5 ml/min, 30
C), which indicated the starting material retention time at 5.02 minutes and the desired product
retention time at 5.98 minutes. The reaction was quenched after 1 hr 50 minutes (at this point
HPLC analysis showed 10% starting material, 57% product and four side products with retention
times 4.79 (9%), 4.09 (13%), 3.71 (7%) and 7.16 (4%) respectively) by pouring in 20 ml of
saturated aqueous sodium bicarbonate solution. The toluene layer was separated and the
bicarbonate layer was re-extracted twice with 10 ml EtOAc. The organic layers were combined,
washed with 10 ml of brine, dried over sodium sulfate and concentrated on the rotavapor. The
crude product was dried in the oven overnight and purified by normal phase chromatography
using Kromasil normal phase silica gel (10µm, 100 Å) in 45:55 heptane:EtOAc (EtOAc was
saturated with 2% H O and 1% AcOH) to give 0.52 g (56%) of rearranged product 6b.
Example 6:
In one variation, 7,9-acetal/ketal analogs of the 10-beta taxanes can be prepared
from the corresponding diol 13b.2 following the general procedure as outlined below.
Acid catalyzed acetal/ketal formation of 10-beta taxanes:
25 mg of 13b.2 (0.03 mmol), 5 mg montmorillonite-K10 and 0.4 mmol of the
corresponding dimethyl/diethyl acetal were weighed in an oven dried reaction flask equipped
with a septa or a 4 ml vial with a Teflon cap. 1 ml of acetonitrile was added and the reaction
mixture was stirred under nitrogen atmosphere at room temperature. The pH of the reaction was
about 6. 1 to 2 microliters of TFA was added to bring the reaction pH to about 3-3.5. The
reaction mixture was stirred about 2 to 5 hours and then quenched with 2 ml of aqueous sodium
bicarbonate and the solution was filtered over a bed of celite, washed with 3x5 ml of ACN, and
the filtrates were concentrated on the rotavapor. The crude product was purified by flash column
chromatography on silica gel, using heptanes/EtOAc. The following acetals/ketals 14b have
been prepared employing the above procedure in good yields (60-90%). All the compounds
were characterized by the 1H NMR and HRMS and their purity was determined by HPLC.
10-beta taxane acrolein acetal (14b.2)
+TOF MS: m/z 870.4162 [M+H]
10-beta taxane -2,2-dimethylketal (14b.3)
BocHN OH
O OH
+TOF MS: m/z 872.4307 [M+H]
10-beta taxanemethylpropenyl acetal (14b.4)
+TOF MS: m/z 898.4468 [M+H]
10-beta taxane 2,6-dimehtyl-1,5-hepadienyl acetal (14b.5)
+TOF MS: m/z 966.5098 [M+H]
10-alpha taxane hexanal acetal (14b.6)
+TOF MS: m/z 914.4696 [M+H]
10-beta taxane benzylidene acetal (14b.7)
+TOF MS: m/z 920.4224 [M+H]
Example 7:
7,9-acetal/ketal analogs of the 10-alpha abeo-taxanes can be prepared from the
corresponding diol 15a.0 which was prepared by acetal deprotection of compound 15a.2 as
outlined below.
Acetal deprotection of 10-alpha abeo-taxane:
2.2 g of the acrolein acetal 15a.2 (2.53 mmol) was weighed into a 250 ml RB
flask with a reflux condenser, and 50 ml (0.05 M) of MeOH was added and the mixture stirred
under nitrogen. The flask warmed to 35 ºC ± 4 ºC and 16.6 ml (1/3 of MeOH volume) 0.1 N
HCl was added dropwise over a period of 5 minutes and stirred over night to complete the
reaction. MeOH was evaporated on a rotary evaporator and the reaction mixture was poured in
saturated NaHCO (50 ml) and extracted twice with 40 ml of EtOAc. The organic layers were
combined, washed with 30 ml of brine and concentrated to give crude product which was
purified by flash chromatography on silica gel using 3:7 hexanes:EtOAc to give 1.74 g of 15a.0
in 83% yield.
Acid catalyzed acetal/ketal formation of 10-alpha abeo-taxanes:
25 mg of 15a.0 (0.03 mmol), 5 mg montmorillonite-K10 and 0.4 mmol of the
corresponding dimethyl/diethyl acetal were weighed in an oven dried reaction flask equipped
with a septa or a 4 ml vial with a Teflon cap. 1 ml of acetonitrile was added and the reaction
mixture was stirred under nitrogen. The pH of the reaction was about 6. 1 to 2 microliters of
TFA was added to bring the reaction pH to 3-3.5. The reaction mixture was stirred about 2 to 5
hours and then quenched with 2 ml of aqueous sodium bicarbonate and the solution was filtered
over a bed of celite, and washed with 3x5 ml of ACN, and the filtrates combined and
concentrated on the rotavapor. The crude product was purified by flash column chromatography
on silica gel using heptanes/EtOAc solvent system. The following acetals/ketals 15a have been
prepared employing the above general procedure in good yields (60-90%). All the compounds
were characterized by the H NMR and HRMS and their purity was determined by HPLC.
10-alpha abeo-taxanemethylpropenyl acetal (15a.3)
+TOF MS: m/z 915.4571 [M+18]
10-alpha abeo-taxane-2,6-dimethyl-1,5-heptadienyl acetal (15a.4)
+TOF MS: m/z 983.5178 [M+18]
10-alpha abeo-taxane benzylidene acetal (15a.5)
+TOF MS: m/z 937.4593 [M+18]
The MTT proliferation assay:
The purpose of these experiments was to compare the cytotoxicity of the abeo-
taxane analogs and their normal taxane analogs listed below in multidrug resistant cells and their
parental susceptible lines to show that a subset of these compounds would exhibit a similar level
of toxicity in the drug resistant lines as that observed in the parent susceptible cell line.
Methods
MTT-based cytotoxicity assays were performed using human cancer cell lines and
paired sublines exhibiting multidrug resistance. These lines included a uterine sarcoma line,
MES-SA. (Harker, W. G.; MacKintosh, F. R.; Sikic, B. I., Development and characterization of
a human sarcoma cell line, MES-SA, sensitive to multiple drugs. Cancer Res. 1983, 43, 4943-
4950), and its doxorubicin-resistant subline, MES-SA/Dx5. (Harker, W. G.; Sikic, B. I.,
Multidrug (pleiotropic) resistance in doxorubicin-selected variants of the human sarcoma cell
line MES-SA. Cancer Res. 1985, 45, 4091-4096). MES-SA/Dx5 exhibits a marked cross
resistance to a number of chemotherapeutic agents including vinblastine, taxol, colchicine,
vincristine, etoposide, dactinomycin, mitoxantrone and daunorubicin and moderate cross
resistance to mitomycin C and melphalan. However, resistance to bleomycin, cisplatin,
carmustine, 5-fluorouracil or methotrexate is not observed. MES-SA/Dx5 cells express high
levels of ABCB1 (MDR1) mRNA and its gene product, the P-glycoprotein. MES-SA and MES-
SA/Dx5 were purchased from the American Type Culture Collection (ATCC, Manassas, VA).
The second set of cells tested, CCRF-CEM or simply CEM, were derived from
the blood of a patient with acute lymphoblastic leukemia. (Foley, G. E.; Lazarus, H.; Farber, S.;
Uzman, B. G.; Boone, B. A.; McCarthy, R. E., Continuous Culture of Human Lymphoblasts
from Peripheral Blood of a Child with Acute Leukemia. Cancer 1965, 18, 522-529). The subline
CEM/VLB was developed to be resistant to up to vinblastine at 100 ng/ml. (Beck, W. T.;
Mueller, T. J.; Tanzer, L. R., Altered surface membrane glycoproteins in Vinca alkaloid-resistant
human leukemic lymphoblasts. Cancer Res. 1979, 39, 2070-2076). Drug resistance is achieved
by overexpression of the MDR1 gene. Resistance in the CEM subline designated CEM/VM5,
however, is “atypical.” (Danks, M. K.; Yalowich, J. C.; Beck, W. T., Atypical multiple drug
resistance in a human leukemic cell line selected for resistance to teniposide (VM-26). Cancer
Res. 1987, 47, 1297-1301). The classes of drugs included in the "classic" multiple drug
resistance phenotype are Vinca alkaloids, anthracyclines, epipodophyllotoxins and antibiotics.
However, CEM/VM5 cells retain sensitivity to the Vinca alkaloids despite resistance and
cross-resistance to etoposide, anthracyclines and mitoxantrone. (Danks, M. K.; Schmidt, C. A.;
Cirtain, M. C.; Suttle, D. P.; Beck, W. T., Altered catalytic activity of and DNA cleavage by
DNA topoisomerase II from human leukemic cells selected for resistance to VM-26.
Biochemistry 1988, 27, 8861-8869). Resistance in CEM/VM5 cells is effected by over
expression of the ABCC1 (MRP1) gene. CEM, CEM/VLB and CEM/VM5 cells were
obtained from Dr. WT Beck, University of Illinois at Chicago.
Summary of Test Compounds at Different Concentrations:
Compound Test Concentrations (ng/ml)
Paclitaxel 25,000, 5,000, 1,000, 200, 40, 8
-βTX (14b.2) 1,000, 200, 40, 8, 1.6, 0.32
-βAT (15b.2) 25,000, 5,000, 1,000, 200, 40, 8, 1.6
-αAT (15a.2) 1,000, 200, 40, 8, 1.6, 0.32
-DAB III (16) 25,000, 5,000, 1,000, 200, 40, 8
-αTX (14a.2) 1,000, 200, 40, 8, 1.6, 0.32
Results
IC50 (nM)
Compound MES- MES- Degree of CEM CEM/VLB Degree of CEM/ Degree of
SA SA/Dx resistance resistance VM resistance
<11/2 3029/1295 >275/648 <11/8 4
Paclitaxel 9±7 19398± 3105±2416
-βTX 28±16 36±34 1.2±0.5 7.5± 22±11 3±1 9±1 1.2±0.3
(14b.2)
-βAT 432±261 328± 0.75±0.07 112± 453±293 4±0.3 77±6 0.9±0.5
173 60
(15b.2)
9.5±0.7 15±8 1.6±0.8 5±3 19±9 4±0 5±4 1.3±1.4
-αAT
(15a.2)
N/A N/A N/A N/A N/A N/A N/A N/A
-DAB III
(16)
<0.3/15 <0.02/1.5
-αTX 30±14 34±24 1.1±0.3 14±5 43±23 3±0.6
(14a.2)
Vinblastine 1.1±0.3 43±12 38.5±0.7 1±0.8 227±77 255±127 1.3±0.9 1.2±0.07
2 97 49 14 2100 150 3060 219
Doxorubicin
Data are expressed as IC values (nM). N/A means not active.
Calculated by dividing the IC50 of the resistant lines by the IC50 of the sensitive MES-SA cells.
Calculated by dividing the IC of the resistant lines by the IC of the sensitive CEM cells.
50 50
The MTS Proliferation Assay:
Day 1: Cells were plated in appropriate growth medium at 5x10 per well in 100
μL in 96 well tissue culture plates, Falcon, one plate for each drug to be tested. Column 1 was
blank; it contained medium, but no cells. The plates were incubated overnight at 37 ºC in 5%
CO to allow attachment. Day 2: Drug diluted in culture media was added to the cells at a
concentration of 0.005 nM to 10 μM in quadruplicate. After 48-72 hours of drug exposure, the
MTS agent was added to all wells and incubated 1-6 hrs (37 ºC, 5% CO ), depending on cell
type, as per CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay (MTS), Promega.
Plates were processed using a Bio-Tek Synergy HT Multi-detection microtiter plate reader at 490
nanometer wavelength and data were processed with KC4V.3 software. Data plots of drug
concentration vs. absorbance were plotted and IC values were extrapolated for each of the
tested compounds.
As summarized below, the IC value for each tested compound in each of the
various cell lines was determined. The clinical comparator drug, paclitaxel, was included in the
experiment to allow comparison of the results of the candidate compounds to a clinically relevant
standard in the taxane class.
The results of all the compounds tested gave a wide range of IC values, some of
which were extrapolated from outside the actual range of drug tested and are thus represented as
<0.002 nM. The MDR negative cell lines KB, SKNAS, DU145, MDAMB435s, and the HT29
are all cell lines sensitive to paclitaxel with IC <0.002 nM, while the MDR positive cell lines,
KBV, MV522/Mdr1, MESSA/DOX are much less sensitive to paclitaxel and have IC values of
500 nM and higher.
These results are consistent with published studies where paclitaxel has been
shown to be a good substrate for the MDR1 drug efflux pump, thus requiring significantly higher
drug levels to reach equivalent cell cytotoxicity in MDR positive cell lines as compared to MDR-
cell lines. As shown by the results for the abeo-taxane 15a.2, the compounds of the present
application provide similar cytotocity to cancer cell lines, both MDR expressing and non-MDR
expressing, with IC ’s of less than 1 micromolar. Accordingly, the compounds of the present
application are shown to be active anticancer agents.
Cytotoxicity Data:
MTS-6: 72 hr proliferation IC nM
Cell type 10alphaAT Paclitaxel 10betaAT
(15a.2) (15b.2)
A2780-A5 0.282 <0.002 *
A2680-DXR1 (MDR+) 15 3582 *
HCT-15 (MDR+) 2.4 311 *
MDAH2774 0.18 0.015 *
MV522 3.5 1.71 *
22Rv1 5.7 1.7 *
* IC50 nM Cytotoxic data for 10betaAT are determined to be in the similar magnitude s those
obtained from 10alphaAT.
Example 4
In one embodiment, the tubulin protein assembly assay was conducted according
to the procedures as described by Mathew AE, Mejillano MR, Nath JP, Himes RH, Stella VJ,
“Synthesis and Evaluation of Some Water-Soluble Prodrugs and Derivatives of Taxol with
Antitumor Activity”, J. Med. Chem., 35, 145-151 (1992) and Georg GI, Cheruvallath ZS, Himes
RH, Mejillano, MR, Burke CT “Synhtesis of Biologically Active Taxol Analogs with Modified
Phenylisoserine Side Chain”, J. Med. Chem., 35, 4230 (1992).
The data are provided below:
Compound ED50, µM ED50/ED50 (Paclitaxel)
Paclitaxel 2.97 ± 0.50 1.00
Docetaxel 3.18± 0.45 1.07
Epothilone B 3.31± 0.51 1.11
10alphaAT (15a.2) 1.58± 0.46 0.53
10betaAT (15b.2) * *
10alphaTX (14a.2) * *
10betaTX (14b.2) * *
* ED50 and ED50/ED50 (Paclitaxel) data for 10betaAT, 10alphaTX and 10betaTX are
determined to be in the magnitude of 10alphaAT.
As in the case of the cytotoxicity results, the abeo-taxane analog 15a.2
demonstrates surprisingly great affinity for tubulin in this binding assay protocol compared to
several recognized tubulin binding agents. The additional compounds of the present application
similarly are expected to show high affinity for tubulin making them potentially useful as
anticancer drugs like paclitaxel or as prospective drugs for treating other tau and tubulin
associated disorders.
While a number of exemplary embodiments, aspects and variations have been
provided herein, those of skill in the art will recognize certain modifications, permutations,
additions and combinations and certain sub-combinations of the embodiments, aspects and
variations. It is intended that the following claims are interpreted to include all such
modifications, permutations, additions and combinations and certain sub-combinations of the
embodiments, aspects and variations are within their scope.
The entire disclosures of all documents cited throughout this application are
incorporated herein by reference.
Claims (35)
1. A compound of the formula II: wherein: R is selected from the group consisting of C alkyl, C alkoxy-, C alkenyl, C aryl, 1-6 1-6 2-6 6-10 C arylC alkyl and C arylC alkoxy; 6-10 1-3 6-10 1-3 R1 is hydrogen or R'CO-, wherein R' is selected from the group consisting of C1-6alkyl, C aryl and arylC alkyl-; 6-10 1-3 R is selected from the group consisting of optionally substituted C alkyl, optionally 2 1-6 substituted phenyl and optionally substituted heteroaryl wherein the substituents are selected from the group consisting of halo, nitro, trifluoromethyl, trifluoromethoxy, methoxy, carboxy, -NH , -OH, -SH, -NHCH , -N(CH ) , -SMe and -CN; 2 3 3 2 R is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C 3 1-18 2-6 2- alkynyl, C aryl and C arylC alkyl,; 6 6-10 6-10 1-3 R' is hydrogen or is selected from the group consisting of C alkyl, C alkenyl, C 3 1-18 2-6 2- alkynyl, C aryl and C arylC alkyl; 6 6-10 6-10 1-3 provided that when one of R or R' is hydrogen, then the other is not a) a C alkyl 3 3 1-2 optionally substituted with 1 or 2 –OH, -NR°R°°or mixture thereof, b) a C alkenyl optionally substituted with –OH or -NR°R°°, or c) C alkynyl optionally substituted with –OH or -NR°R°°, wherein R° and R°° are each independently selected from the group consisting of hydrogen, C alkyl- and wherein R° and R°° together with the nitrogen to which they attach form a 1- morpholinyl group or a 4, 5, 6 or 7 membered heterocyclic ring; as a single diastereomer or a mixture of diastereomers; and pharmaceutically acceptable salts thereof; provided that, when one of R or R' is –CH=CH , then R is not CH CO-. 3 3 2 1 3
2. The compound of Claim 1, wherein: R is selected from the group consisting of C alkyl, C alkoxy- and C arylC alkoxy; 1-6 1-6 6-10 1-3 R is hydrogen or R'CO-, wherein R' is selected from the group consisting of C alkyl, 1 1-6 C aryl and arylC alkyl-; 6-10 1-3 R is selected from the group consisting of C alkyl and C alkenyl; and 3 1-18 2-6 R' is hydrogen.
3. The compound of Claim 1, wherein R is selected from the group consisting of (CH ) CHCH -, (CH ) CH-, t-butyl, optionally substituted phenyl, and optionally substituted 3 2 2 3 2 heteroaryl, R is t-butoxy, R1 is CH3CO-, R3 is beta CH2=CH- and R'3 is hydrogen.
4. The compound of Claim 1, wherein R' is hydrogen and the stereochemistry of R at the 7,9- bridge ring is selected from the group consisting of: (beta configuration) and (alpha configuration), or a mixture of the alpha and beta isomers.
5. The compound of Claim 4, wherein the stereochemistry of R at the 7,9- bridge ring is:
6. The compound of any one of Claims 1 to 5, wherein the compound is greater than 95% pure or greater than 99% pure.
7. A pharmaceutical composition comprising: a) a therapeutically effective amount of a compound of any one of Claims 1 to 5, in the form of a single diastereoisomer; and b) at least one pharmaceutically acceptable excipient, diluent or adjuvant.
8. The composition of Claim 7 further comprising temozolomide and/or Avastin.
9. The composition of Claim 7 or Claim 8, further comprising one or more therapeutic agent selected from the group consisting of aromatase inhibitors, antiestrogen, anti-androgen, a gonadorelin agonists, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, microtubule active agents, alkylating agents, anthracyclines, corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40 antibodies, Smac mimetics, FGF3 modulators, mTOR inhibitors, HDAC inhibitors, IKK inhibitors, P38MAPK inhibitors, HSP90 inhibitors, akt inhibitors, antineoplastic agents, antimetabolites, platin containing compounds, lipid- or protein kinase-targeting agents, protein- or lipid phosphatase-targeting agents, anti-angiogentic agents, agents that induce cell differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors and aminopeptidase inhibitors, cytostatic agent, cytotoxic agent, taxane, topoisomerase II inhibitor, topoisomerase I inhibitor, tubulin interacting agent, antibodies, antiangiogenics, COX-2 inhibitors, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating agent, farnesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor, antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination and aromatase combination.
10. A composition as claimed in any one of Claims 7 to 9 formulated for oral administration.
11. A use of a compound according to any one of Claims 1 to 5 in the manufacture of a medicament.
12. A use of a compound of any one of Claims 1 to 5 in the manufacture of a medicament for the treatment of a cancer in a patient in need of such treatment.
13. The use of Claim 12, wherein the cancer is selected from the group consisting of leukemia, neuroblastoma, glioblastoma, cervical, colorectal, pancreatic, renal and melanoma.
14. The use of Claim 12, wherein the cancer is selected from the group consisting of lung, breast, prostate, ovarian and head and neck.
15. The use of Claim 13, wherein the cancer is colorectal cancer.
16. The use of Claim 13, wherein the cancer is pancreatic cancer.
17. The use of Claim 13, wherein the cancer is neuroblastoma or a glioblastoma.
18. The use of any one of Claims 12 to 17 wherein the medicament is to be administered simultaneously, separately or sequentially with a chemotherapeutical agent selected from temozolomide, cisplatin, 5-flurouracil, taxotere or gemcitabine.
19. The use of Claim 18 wherein the medicament is to be administered simultaneously, separately or sequentially with temozolomide.
20. The use of any one of Claims 12 to 19 wherein the medicament is to be administered to a patient in combination with radiation therapy.
21. The use of any one of Claims 12 to 20 wherein the medicament is to be administered to a patient in combination with surgical removal of a cancer.
22. The use of any one of Claims 11 to 20 wherein the medicament is to be administered simultaneously, separately or sequentially with one or more therapeutic agents selected from the group consisting of aromatase inhibitors, antiestrogen, anti-androgen, a gonadorelin agonists, topoisomerase 1 inhibitors, topoisomerase 2 inhibitors, microtubule active agents, alkylating agents, anthracyclines, corticosteroids, IMiDs, protease inhibitors, IGF-1 inhibitors, CD40 antibodies, Smac mimetics, FGF3 modulators, mTOR inhibitors, HDAC inhibitors, IKK inhibitors, P38MAPK inhibitors, HSP90 inhibitors, akt inhibitors, antineoplastic agents, antimetabolites, platin containing compounds, lipid- or protein kinase-targeting agents, protein- or lipid phosphatase-targeting agents, anti-angiogentic agents, agents that induce cell differentiation, bradykinin 1 receptor antagonists, angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokine inhibitors, cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors and aminopeptidase inhibitors, cytostatic agent, cytotoxic agent, taxane, topoisomerase II inhibitor, topoisomerase I inhibitor, tubulin interacting agent, antibodies, antiangiogenics, COX-2 inhibitors, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating agent, farnesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor, antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination and aromatase combination.
23. A use of a composition as claimed in Claim 10 in the manufacture of a medicament for treating cancer in a patient in need thereof.
24. A use as claimed in Claim 23, wherein the cancer is selected from the group consistenting of leukemia, neuroblastoma, glioblastoma, cervical, colorectal, pancreatic, renal and melanoma.
25. A use as claimed in Claim 23, wherein the cancer is selected from the group consisting of lung, breast, prostate, ovarian and head and neck.
26. A use as claimed in Claim 23, wherein the cancer is colorectal cancer.
27. A use as claimed in Claim 23, wherein the cancer is pancreatic cancer.
28. A use as claimed in Claim 23, wherein the cancer is neuroblastoma or a glioblastoma.
29. A use as claimed in Claim 23, wherein the medicament is to be administered simultaneously, separately or sequentially with a chemotherapeutical agent selected from temozolomide, cisplatin, 5-flurouracil, taxotere or gemcitabine.
30. A use as claimed in Claim 23, wherein the medicament is to be administered simultaneously, separately or sequentially with temozolomide.
31. A use as claimed in Claim 23, wherein the medicament is to be administered to a patient in combination with radiation therapy.
32. A use as claimed in Claim 23, wherein the medicament is to be administered to a patient in combination with surgical removal of a cancer.
33. A compound as claimed in Claim 1 substantially as herein described, and with or without reference to the accompanying drawings.
34. A pharmaceutical composition as claimed in Claim 7, substantially as herein described, and with or without reference to the accompanying drawings.
35. A use as claimed in Claim 11 or Claim 12 substantially as herein described, and with or without reference to the accompanying drawings.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161472968P | 2011-04-07 | 2011-04-07 | |
US61/472,968 | 2011-04-07 | ||
PCT/US2012/032568 WO2013106029A1 (en) | 2011-04-07 | 2012-04-06 | Taxane and abeo-taxane analogs |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ617430A NZ617430A (en) | 2016-05-27 |
NZ617430B2 true NZ617430B2 (en) | 2016-08-30 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11220512B2 (en) | Biologically active taxane analogs and methods of treatment by oral administration | |
JP7264060B2 (en) | Bicyclic compounds and their use in treating cancer | |
EP3858835A1 (en) | Pyrimidine-based antiproliferative agents | |
CN114401952A (en) | Substituted cycloalkyl compounds as modulators of integrated stress pathways | |
US8912229B2 (en) | Taxane and abeo-taxane analogs | |
JP2008500366A (en) | Migrastatin analogues in the treatment of cancer | |
JP2022522694A (en) | Compounds with ferrotosis-inducing activity and how to use them | |
JP2011105766A (en) | Migrastatin analog composition and use thereof | |
WO2008106621A1 (en) | Taxane analogs for the treatment of brain cancer | |
JP2019531295A (en) | BRIOSTATIN COMPOUND AND METHOD FOR PREPARING THE SAME | |
US9340530B2 (en) | Preparation and use of bicyclic himbacine derivatives as PAR-1 receptor antagonists | |
JP7436630B2 (en) | Adenosine receptor antagonist | |
US9227983B2 (en) | Taxane and abeo-taxane analogs | |
NZ617430B2 (en) | Taxane and abeo-taxane analogs | |
JP7299411B2 (en) | adenosine receptor antagonist | |
US11873308B2 (en) | Biologically active taxane analogs and methods of treatment by oral administration | |
KR20180110134A (en) | Cortistatin analog | |
WO2016058144A1 (en) | Preparation and use of cyclic sulfonamide derivatives as par-1 receptor antagonists | |
EP3206687A1 (en) | Preparation and use of cyclic sulfonamide derivatives as par-1 receptor antagonists |