EP1259490A2 - Synthesis of epothilones, intermediates thereto and analogues thereof - Google Patents
Synthesis of epothilones, intermediates thereto and analogues thereofInfo
- Publication number
- EP1259490A2 EP1259490A2 EP01916335A EP01916335A EP1259490A2 EP 1259490 A2 EP1259490 A2 EP 1259490A2 EP 01916335 A EP01916335 A EP 01916335A EP 01916335 A EP01916335 A EP 01916335A EP 1259490 A2 EP1259490 A2 EP 1259490A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- substituted
- aryl
- linear
- unsubstituted
- cyclic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 229930013356 epothilone Natural products 0.000 title abstract description 82
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title abstract description 44
- 230000015572 biosynthetic process Effects 0.000 title description 93
- 238000003786 synthesis reaction Methods 0.000 title description 85
- 239000000543 intermediate Substances 0.000 title description 12
- 238000000034 method Methods 0.000 claims abstract description 144
- 239000000203 mixture Substances 0.000 claims abstract description 91
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 40
- 201000011510 cancer Diseases 0.000 claims abstract description 20
- 229930184531 desoxyepothilone Natural products 0.000 claims abstract description 6
- -1 heteroaliphatic Chemical group 0.000 claims description 308
- 150000001875 compounds Chemical class 0.000 claims description 239
- 125000003118 aryl group Chemical group 0.000 claims description 183
- 229910052739 hydrogen Inorganic materials 0.000 claims description 171
- 239000001257 hydrogen Substances 0.000 claims description 171
- 125000001931 aliphatic group Chemical group 0.000 claims description 162
- 125000001072 heteroaryl group Chemical group 0.000 claims description 143
- 125000004122 cyclic group Chemical group 0.000 claims description 137
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 131
- 125000002015 acyclic group Chemical group 0.000 claims description 126
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 229910052736 halogen Inorganic materials 0.000 claims description 60
- 150000002367 halogens Chemical class 0.000 claims description 60
- 229920000642 polymer Polymers 0.000 claims description 56
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 49
- 230000000694 effects Effects 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
- 150000001299 aldehydes Chemical class 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 33
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 239000007856 photoaffinity label Substances 0.000 claims description 32
- 239000002243 precursor Substances 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 31
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 31
- 239000003153 chemical reaction reagent Substances 0.000 claims description 30
- 150000001720 carbohydrates Chemical class 0.000 claims description 29
- 150000002576 ketones Chemical class 0.000 claims description 29
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims description 28
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 25
- 125000002252 acyl group Chemical group 0.000 claims description 25
- 238000005575 aldol reaction Methods 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 23
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 22
- 150000001540 azides Chemical class 0.000 claims description 22
- 150000002148 esters Chemical class 0.000 claims description 22
- 239000002246 antineoplastic agent Substances 0.000 claims description 21
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 claims description 19
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 150000001412 amines Chemical class 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 230000003197 catalytic effect Effects 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 229930012538 Paclitaxel Natural products 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- 238000005859 coupling reaction Methods 0.000 claims description 15
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 15
- 229960001592 paclitaxel Drugs 0.000 claims description 15
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 15
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical group 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 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 238000010511 deprotection reaction Methods 0.000 claims description 14
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 14
- MBVFRSJFKMJRHA-UHFFFAOYSA-N 4-fluoro-1-benzofuran-7-carbaldehyde Chemical compound FC1=CC=C(C=O)C2=C1C=CO2 MBVFRSJFKMJRHA-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000005283 haloketone group Chemical group 0.000 claims description 12
- 125000003435 aroyl group Chemical group 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 10
- 238000009833 condensation Methods 0.000 claims description 10
- 230000005494 condensation Effects 0.000 claims description 10
- 239000000412 dendrimer Substances 0.000 claims description 10
- 229920000736 dendritic polymer Polymers 0.000 claims description 10
- 230000000640 hydroxylating effect Effects 0.000 claims description 10
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 10
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 9
- 229920002988 biodegradable polymer Polymers 0.000 claims description 9
- 239000004621 biodegradable polymer Substances 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 8
- 238000006256 asymmetric dihydroxylation reaction Methods 0.000 claims description 8
- 150000002084 enol ethers Chemical class 0.000 claims description 8
- 239000010936 titanium Substances 0.000 claims description 8
- 229910052719 titanium Inorganic materials 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000001769 aryl amino group Chemical group 0.000 claims description 7
- 125000005110 aryl thio group Chemical group 0.000 claims description 7
- 230000037396 body weight Effects 0.000 claims description 7
- 238000005710 macrocyclization reaction Methods 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine 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-CFWMRBGOSA-N 0.000 claims description 7
- 229960003048 vinblastine Drugs 0.000 claims description 7
- 125000004036 acetal group Chemical group 0.000 claims description 6
- 229940009456 adriamycin Drugs 0.000 claims description 6
- 150000001261 hydroxy acids Chemical class 0.000 claims description 6
- 125000002524 organometallic group Chemical group 0.000 claims description 6
- YUCBLVFHJWOYDN-PPIALRKJSA-N 4-[(r)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]-1-[(r)-[(2r,4r,5s)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@@H](OC=3C4=CC=CC=C4C(O[C@@H]([C@@H]4N5CC[C@@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-PPIALRKJSA-N 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 229940127089 cytotoxic agent Drugs 0.000 claims description 5
- 239000002254 cytotoxic agent Substances 0.000 claims description 5
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 5
- 239000011982 enantioselective catalyst Substances 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 3
- 229910052770 Uranium Inorganic materials 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 150000004795 grignard reagents Chemical group 0.000 claims description 3
- 150000002443 hydroxylamines Chemical class 0.000 claims description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 20
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 229910052727 yttrium Inorganic materials 0.000 claims 3
- 125000000676 alkoxyimino group Chemical group 0.000 claims 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims 2
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 2
- 239000007801 affinity label Substances 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 27
- 239000003814 drug Substances 0.000 abstract description 26
- 229940079593 drug Drugs 0.000 abstract description 16
- 230000008569 process Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 167
- 239000000243 solution Substances 0.000 description 145
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 128
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 115
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 81
- 235000019439 ethyl acetate Nutrition 0.000 description 66
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
- 238000006243 chemical reaction Methods 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 48
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 47
- 239000003921 oil Substances 0.000 description 47
- 235000019198 oils Nutrition 0.000 description 47
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 43
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 43
- 239000000741 silica gel Substances 0.000 description 41
- 229910002027 silica gel Inorganic materials 0.000 description 41
- 150000003883 epothilone derivatives Chemical class 0.000 description 40
- 239000012267 brine Substances 0.000 description 39
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 37
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 235000019441 ethanol Nutrition 0.000 description 31
- 238000003756 stirring Methods 0.000 description 31
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- 239000010408 film Substances 0.000 description 27
- 239000002904 solvent Substances 0.000 description 24
- 238000000746 purification Methods 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- 235000014633 carbohydrates Nutrition 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000011734 sodium Substances 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000012634 fragment Substances 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 16
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
- 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 15
- 230000008901 benefit Effects 0.000 description 15
- 238000001727 in vivo Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B 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 14
- 230000002829 reductive effect Effects 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 14
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- 239000000284 extract Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 238000006257 total synthesis reaction Methods 0.000 description 12
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 11
- 150000002009 diols Chemical class 0.000 description 11
- GHXZPUGJZVBLGC-UHFFFAOYSA-N iodoethene Chemical compound IC=C GHXZPUGJZVBLGC-UHFFFAOYSA-N 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 230000009467 reduction Effects 0.000 description 11
- 238000006722 reduction reaction Methods 0.000 description 11
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 10
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 10
- 241000699660 Mus musculus Species 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000011324 bead Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 238000011580 nude mouse model Methods 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229910052740 iodine Inorganic materials 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 239000003937 drug carrier Substances 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 125000002346 iodo group Chemical group I* 0.000 description 8
- 208000032839 leukemia Diseases 0.000 description 8
- 230000001404 mediated effect Effects 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- 102000029749 Microtubule Human genes 0.000 description 7
- 108091022875 Microtubule Proteins 0.000 description 7
- 238000003428 Staudinger Azide reduction reaction Methods 0.000 description 7
- 102000004243 Tubulin Human genes 0.000 description 7
- 108090000704 Tubulin Proteins 0.000 description 7
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- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])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
- 238000011915 stereoselective alkylation Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- JYRWUSXRTGACLY-UHFFFAOYSA-N tert-butyl 4-[[3-(4-methylsulfonylphenyl)-[1,2]oxazolo[4,5-d]pyrimidin-7-yl]oxy]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1OC1=NC=NC2=C1ON=C2C1=CC=C(S(C)(=O)=O)C=C1 JYRWUSXRTGACLY-UHFFFAOYSA-N 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
- RFQWLOQXMJIJBR-UHFFFAOYSA-N tert-butyl-[tert-butyl(diethyl)silyl]oxy-diethylsilane Chemical compound CC[Si](CC)(C(C)(C)C)O[Si](CC)(CC)C(C)(C)C RFQWLOQXMJIJBR-UHFFFAOYSA-N 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 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
- 229960000303 topotecan Drugs 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-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-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the epothilones ire a family of naturally occurring cytotoxic macrolides that were isolated from the mycobacterium Sorangium cellulosum. Though possessing a vastly different structure than that of taxoids, the epothilones, similarly to paclitaxel (Taxol®), apparently function through a simile mechanism involving inliibition of cellule division by stabilization of microtubule assemblies, thereby leading to cell death (Bollag et al. Cancer Res. 1995, 55, 2325). Paclitaxel is currently employed as a first-line chemotherapeutic agent; however, concerns for its therapeutic index and formulation difficulties, due to its insolubility in water, are a liability.
- this feature is particul> rly useful in that die additional hydroxy would provide a chemotherapeutic having enhanced aqueous solubility, which could result in a major improvement in formulation capabilities.
- the 21 -hydroxyl group represents a readily accessible primary alcohol, it could be utilized as a molecular handle for further elaboration.
- the present invention provides novel analogues of epothilones and methods for the synthesis thereof.
- nd R D are each independently hydrogen, phenyl, benzyl, linear or branched chain alkyl; wherein R 6 is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CONHR A ; N 2 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; nitrogen protecting group; carbon protecting group; oxygen protecting group; sulfur protecting group; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; polymer; carbohydrate; photoaffinity label; or radiolabel; wherein Z is O, N(OR E ) or N-NR F RQ; wherein R E , R F , -
- CY is phenyl, 4-thiazolyl, 2-furanyl- 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4- oxazolyl, 3-indolyl or 6-indolyl.
- CY is a 4-thiazolyl or 4-oxazolyl moiety substituted with one or two methyl groups, and in certain embodiments the methyl groups are substituted at the 2- or 5- position.
- C Y is 4-thiazolyl; m is 1 ; and n is 3.
- R 2 ⁇ md R 3 are each hydrogen; R 4 is methyl and R 5 is hydrogen; and Z is O.
- R 6 is methyl or ediyl.
- CY is 4-thi£izolyl or 4-oxazolyl and R 6 is methyl or ethyl. In certain other embodiments, R 6 is ethyl.
- R 6 is ethyl, n-propyl, n-butyl, n-hexyl, or (CH 2 ) p -OH, wherein p is 1-6.
- thiazolinyl and oxazolinyl compounds are of interest.
- compounds are provided having the general structure:
- stereoisomers and double bond isomers are provided, and the present invention additionally includes all possible stereoisomers and double bond isomers.
- isomers of interest include compounds, as defined above and herein, having the following structures:
- Ri is OR and R is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic aliphatic or heteroaliphatic, or substimted or unsubstituted aryl or heteroaryl; W is -CH 2 -; and m is 1.
- Rj is NR A R A , and R A is hydrogen, a nitrogen protecting group, or lower alkyl; m is 1; and W is -CH 2 -.
- R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- R ⁇ is H, methyl, ethyl, n-propyl, n-butyl, n-
- R 6 is ethyl, n-propyl, n-butyl, n-hexyl, or (CH 2 ) p -OH, wherein p is 1-6.
- R 6 is methyl and the compound has the structure:
- inventive compounds are provided wherein the inventive compounds, as described herein, are linked to polymers, carbohydrates, photoaffinity labels, or radiolabels.
- inventive compounds have the general structure:
- the peptide is made from 5 to about 25 amino acids.
- R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- compositions wherein epothilone compounds, as described in detail herein, are multiply presented.
- inventive compositions comprise a polymeric backbone, wherein the polymeric backbone is a biopolymer or a synthetic polymer; and two or more compounds as described above and herein, wherein the two or more compounds are the same or different, whereby said two or more compounds are linked to the polymeric backbone directly or through a linker, and wherein the two or more compounds are linked through the 12-position, the 20- position or the 21 -position of the compound.
- the polymeric backbone is a dendrimer, a peptide, or a biodegradable polymer.
- EPO has the structure:
- R 6 is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ;
- R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- X is methylene, Y is NH, and Z is absent.
- pharmaceutical compositions are provided comprising any one of the inventive compounds as described above and herein, and a pharmaceutically acceptable carrier.
- the present invention provides a method of treating cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of any one of the compounds as described above and herein.
- the method is used to treat cancer wherein the cancer is a solid tumor.
- the metiiod is used to treat cancer wherein the cancer is breast cancer.
- the present invention additionally provides a composition comprising an amount of any one of d e compounds as described above and herein, effective to inhibit the growth of multidrug resistant cells.
- the present invention further provides methods of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of any one of the compounds as described above and herein, effective to inhibit the growth of multidrug resistant cells.
- the composition further comprises a pharmaceutically acceptable carrier or diluent.
- the composition further comprises an amount of a cytotoxic agent, including, but not limited to, an anticancer agent.
- the anticancer agent is adriamycin, vinblastin or paclitaxel, or any combination thereof.
- the effective amount of the compound is between about 0.01 mg/kg to about 50 mg/kg of body weight. In certain other embodiments, the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.
- the present invention provides a method of preparing a compound having the structure:
- P is an oxygen protecting group; wherein Hal is a halogen; and wherein Rg is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CON_HR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; polymer; nitrogen protecting group; carbon protecting group; sulfur protecting group; or oxygen protecting group; which method comprises the steps of: a) providing a haloketone having die structure:
- the step of hydroxylating comprises reacting the haloketone using asymmetric catalyst to effect asymmetric dihydroxylation, to generate a compound having the structure:
- the step of hydroxylating is conducted in the presence of Os0 and AD- mix- .
- the step of hydroxylating comprises reacting the haloketone using asymmetric catalyst to effect asymmetric dihydroxylation, to generate a compound having the structure:
- the step of hydroxylating is conducted in the presence of OsO 4 and AD-mix- ⁇ .
- P is -SIR H R J R K _.
- R H , R J , and R K are each ethyl.
- R 6 linear or branched, cyclic or acyclic, substituted or unsubstituted aliphatic or heteroaliphatic.
- R 5 is methyl, ethyl, n— or wo-propyl, phenyl or benzyl.
- Hal' is iodo.
- the present invention provides a method of preparing a compound having the structure:
- P is an oxygen protecting group; wherein Hal is a halogen; and wherein R 6 is independently hydrogen; OR A ; SR A ; NR A RA; C(0)OR A ; C(0)R A ; CONHRA; N 3 ; NR A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; comprising the steps of a) preparing a glycolimide having the structure:
- a substituted hydroxylamine selected from the group consisting of N.O-(linear or branched chain C ⁇ - 8 alkyl,aryl)hydroxylamine, N,0-di-(linear or branched chain C 1 _g)alkylhydroxylamine and N,0-aryl,arylhydroxylamine under suitable conditions to fo ⁇ n an amide having the structure:
- R' and R" are each independently linear or branched chain C ⁇ - 8 alkyl or aryl; and c) reacting the amide with a substituted organometallic reagent under suitable conditions to form the compound.
- P is SIR H RJRK and wherein RH, RJ and RK are each ethyl.
- Re is methyl, ethyl, n— or /sO-propyl, phenyl or benzyl.
- Hal is iodo.
- the substituted organometallic reagent is a Grignard reagent, including, but not limited to, MeMgBr or
- the present invention provides a method of preparing a compound having the structure:
- ⁇ is hydrogen, or is substituted or unsubstituted, linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substitued aliphatic, or aryl substituted heteroaliphatic;
- Z A is OP; wherein P is an oxygen protecting group; wherein Hal is a halogen; wherein R 6 is independently hydrogen; OR A ; SRA; NR A RA; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 RA; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroary
- R' and R" are independently Ci-s linear or branched chain alkyl, or a substituted or unsubstituted phenyl; aryloxy; or alkoxy; b) condensing the phosphine oxide with a ketone having the structure:
- step b) optionally reducing the ester formed in step b) under suitable conditions to form the compound.
- P is SiR H RjR ⁇ and R H , R J and R ⁇ are each ethyl.
- R 6 is linear or branched, cyclic or acyclic, substituted or unsubstituted aliphatic or heteroaliphatic.
- R ⁇ is methyl, ethyl, n— or /so-propyl, phenyl or benzyl.
- Hal is iodo.
- Ri is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl.
- Rj is substituted or unsubstituted 4-thiazolyl.
- 4-thiazolyl is substituted with one or two methyl groups in the -2 or-5 positions.
- the present invention provides a method for preparing a compound having the structure:
- R t is hydrogen, or is substituted or unsubstituted, linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substitued aliphatic, or aryl substituted heteroaliphatic; wherein Z is N 3 or NHP; wherein P is a nitrogen protecting group; wherein Hal is a halogen; wherein R 6 is independently hydrogen; ORA; SR A ; NRARA; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, ary
- R' and R" are independently -8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl; aryloxy; or alkoxy; b) condensing the phosphine oxide with a ketone having the structure:
- step b) reacting the compound formed in step b) under suitable conditions to effect inversion to generate an azide, and optionally further treating the azide to generate a protected amine.
- Ri is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl.
- Rj is substimted or unsubstituted 4-d ⁇ iazolyl.
- the present invention provides a method of preparing a compound having the structure:
- P is a nitrogen protecting group; wherein Hal is a halogen; wherem Rg is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(O)R A ; CONFIR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or imsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of A is independently hydrogen; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; which comprises the steps of : a) preparing a phosphine oxide having the structure:
- RQ, R' and R" are independently C ⁇ - 8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl; alkoxy; or aryloxy; b) condensing the phosphine oxide with a ketone having the structure:
- step b) reducing the ester formed in step b) under suitable conditions to form the compound.
- P is SIRHR J K and RH, RJ and
- RK are each ethyl.
- R 6 is linear or branched, cyclic or acyclic, substituted or unsubstituted aliphatic or heteroaliphatic.
- Re is methyl, ethyl, n— or zs ⁇ -propyl or phenyl or benzyl.
- Hal is iodo.
- the present invention provides a method preparing a compound having the structure:
- ZB is CO2R 9 or COSR 9 , wherein R 9 is hydrogen or an. oxygen or sulfur protecting group, wherein R 2 and R 3 are each independently hydrogen, substituted or unsubstituted aliphatic, heteroaliphatic, aryl, or heteroaryl; linear or branched, substituted or unsubstituted acyl, aroyl or benzoyl; or Si(R ⁇ ) 3 , wherein each occurrence of R B is independently substituted or unsubstituted aliphatic, heteroaliphatic, aryl or heteroaryl; and wherein R4 and R 5 are each independently hydrogen, linear or branched chain alkyl, optionally substituted by hydroxy, alkoxy, carboxy, carboxaldehyde, linear or branched alkyl or cyclic acetal, fluorine, NR C R D , N- hydroxyimino, or N-alkoxyimino, wherein Rc and R D are each independently hydrogen, phenyl, benz
- ketoaldehyde having the structure:
- the step of reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction comprises reacting said ketoaldehyde under stoichiometric conditions with a chiral titanium enolate.
- the step of reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction comprises reacting said ketoaldehyde with a catalytic reagent.
- the catalytic reagent employed is the Carreira catalyst.
- the catalytic reagent employed is Mikami's chiral aldol catalyst.
- the present invention provides a method for preparing a compoimd having the structure:
- R ⁇ -R 6 are as defined above;
- Z A is OR 7 , NFIR 8 , or N 3 , and
- Z B is C0 2 R or COSR wherein each occurrence of R 7 , R 8 , R 9 , R 10 , or Ru is independently hydrogen, an oxygen protecting group or a nitrogen protecting group; and wherein the step of providing die precursor further comprises: reacting a first compound having the structure
- the method includes a step of deprotection to generate a compoimd wherein R 2 and R 3 are hydrogen.
- Ri is -CY ⁇ CHX or hydrogen, substituted or unsubstituted, linear or branched, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4- oxazolyl, 3-indolyl or 6-indolyl, wherein X is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4- furanyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, imidazolyl, 4-
- the aliphatic, heteroaliphatic, aryl or heteroaryl group is further substimted with a photoactivatable group or with one or more of hydroxy, thio, amino, substituted amino, aldehyde, carboxylic acid, alkenyl, iminio, or diazo.
- X is 4-thiazolyl substituted at the 2- and 5- positions by methyl.
- M is NH or O
- R 6 is a substituted or imsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- ketoaldehyde having the structure:
- Y is hydrogen or alkyl
- X is 4-thiazolyl substituted at the 2-position by linear or branched alkyl or substituted by -(CH 2 ) resortOH
- n is 0-5
- R 6 is independently hydrogen; ORA; SR A ; NRARA; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occuixence of R A is independently hydrogen; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl.
- M is NH or O
- R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- Z A is N 3
- the method optionally fiirther comprising a step of reacting the azide under suitable conditions to generate a protected amine.
- the method further comprises a step of deprotecting the precursor compound to generate a free hydroxy acid precursor, or an amino acid precursor.
- Figure 1 depicts a modular plan for the synthesis of epothilones .and analogues thereof using .an aldol coupling reaction for the synthesis of the acyl sector.
- Figure 2 depicts the synthesis of desoxyepothilone F via Suzuki coupling, Noyori reduction and niacrolactonization.
- Figure 3 depicts a catalytic asymmetric route to ketone 11: Reagents and conditions: (a) i) 9-BBN-I, Hexanes, ii) methyl vinyl ketone, iii) 3 N NaOH, Toluene, 100 °C, 65%; (b) TMSI- HMDS, CH 2 C1 2 , -20 °C to rt; (c) 1 mol% Os0 4 , AD-mix- , MeS0 2 NH 2 , t-BuOH-H 2 0 (1 :1), 55% for two steps; (d) TESCl, imidazole, DMF, 85%.
- Figure 4 depicts the stereoselective alkylation route to ketone 11 : Reagents and conditions: (a) i) TiCl 4 , CH 2 C1 2 , DIPEA, 87%, ii) TESCl, Imidazole, DMF, 84%; (b) i) Glycolic acid, TESCl, NaH-TEA, ether, 0 °C, then r-BuCOCl, -78 °C, ii) /?-BuLi, -78 °C to rt, 38-41%;
- Figure 5 depicts the synthesis and utilization of certain functionalized epothilone analogues.
- Figure 6 depicts the conversion of 21-hydroxy-desoxyepothilone B to 21-oxo- desoxyepothilone B.
- Figure 7 depicts the synthesis of certain 21-fimctionalized 12,13-desoxyepothilone B ⁇ analogues.
- Figure 8 depicts the synthesis of certain zwitter ions providing enhanced water solubility.
- Figure 9 depicts the conjugation of certain inventive compounds to peptides.
- Figure 10 depicts the synthesis of certain carbohydrate-epothilone conjugates.
- Figure 11 depicts the synthesis of certain carbohydrate-epothilone conjugates attached via direct C-C linkage, and depicts certain other epothilone analogues.
- Figure 12 depicts the synthesis of certain epothilone dimers.
- Figure 13 depicts the multiple presentation of inventive epothilones on dendrimers and polymers.
- Figure 14 depicts the synthesis of certain inventive epothilones bound to a biodegradable polymer.
- Figure 15 depicts the synthesis of certain inventive water soluble epothilone derivatives.
- Figure 16 depicts the synthesis of thiazolyl moiety 7G.
- Figure 17 depicts the synthesis of protected cyclization precursor 13Gc.
- Figure 18 depicts the synthesis of dEpoF (2Gd).
- Figure 19 depicts the synthetic plan for the O-Acyl Wing by sequential aldol reactions.
- Figure 20 depicts the synthesis of the O-Alkyl wing via Homer Condensation. Reagents and conditions: (a) Toluene, 110 °C, 2 h, 96%; (b) HOPPh 2 , Cs 2 C0 3 , cat.
- Figure 21 depicts the aldol condensation of TES ether antipodes 38.
- Figure 22 depicts a novel synthetic route to the O-Acyl Wing. Reagents and conditions:
- Figure 23 depicts the total synthesis of dEpoB. Reagents and conditions: (a) i) 9-BBN-H, THF (ii) PdCl 2 (dppfj, AsPh 3 , DMF-THF-H 2 0, rt, 2 h, 72%; (b) TESOTf, 2,6-lutidine, CH 2 C1 2 , - 78 °C to rt, 8 h, (ii) HCl-CH 3 OH, THF, 0 °C, 69%.
- Figure 24 depicts the completion of the total synthesis of dEpoF. Reagents and conditions: (a) i) 9-BBN-H, THF (ii) PdCl 2 (dppf), AsPh 3 , DMF-THF-H 2 0, rt, 8 h, 89%; (b)
- Figure 25 depicts the synthesis of EpoF and photoaffinity labeled dEpoF.
- Figure 26 depicts certain aza-analogues
- Figure 27 depicts a synthetic pathway to prepare C15-epi-aza-desoxyepothilone B.
- Figure 28 depicts the synthesis of Aza-dEpoB via Suzuki coupling, Noyori
- Figure 30 depicts Suzuki coupling with Azide fragment.
- Figure 31 depicts Suzuki coupling of azido vinyl-iodide 17 with methyl enol ether 21.
- Figure 34 depicts mmor size in nude mice bearing human leukemia K526 tumor following 6 mg/kg C-15-Aza-EpoB, Q2D x 6 and 30 mg/kg dEpoF, Q2D x 6 (i.v. infusion 6 hr).
- Figure 37 depicts therapeutic effects of dEpoB and Taxol in nude mice bearing human leukemia K562 xenograft.
- Figure 39 depicts body weight in nude mice bearing CCRF-CEM tumor following 15- Aza-EpoB or dEpoF treatment (i.v. infusion 6 hr.)
- Figure 40 depicts tumor size in nude mice bearing MX-1 following dEpoF (i.v. 6 hr. infusion (Q2D x 5).
- Figure 41 depicts tumor size in nude mice bearing MX-1 tumor following C-15-Aza-
- EpoB or dEpoB treatment EpoB or dEpoB treatment.
- Figure 42 depicts body weight in nude mice bearing MX-1 tumor following C-15-Aza- EpoB or dEpoB treatment.
- Figure 43 depicts resistance to human lung carcinoma A549.
- Figure 44 depicts stability in plasma (mouse vs. human).
- Figure 45 depicts pharmacokinetics of dEpoB in dog following 6 mg/kg, i.v. infusion (10 minutes).
- Figure 47 depicts the synthesis of C12 cyclic acetal using novel methodologies as described herein. Definitions
- the present invention provides a novel class of compounds useful for the treatment of cancer and other proliferative conditions related thereto.
- Compounds of tiiis invention comprise those, as set forth above and described herein, and are illustrated in part by the various classes, subgenera and species disclosed elsewhere herein.
- inventive compounds and pharmaceutical compositions thereof may be in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers. Additionally, in certain preferred embodiments, as detailed herein, the method of the present invention provides improved methods for the efficient synthesis of epothilones and analogues thereof.
- the present invention provides pharmaceutically acceptable derivatives of the foregoing compounds, and methods of treating a subject using these compounds, pharmaceutical compositions thereof, or either of these in combination with one or more additional ' therapeutic agents.
- pharmaceutically acceptable derivative denotes any pharmaceutically acceptable salt, ester, or salt of such ester, of such compoimd, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.
- Pharmaceutically acceptable derivatives thus include among others pro-drugs.
- a pro-drug is a derivative of a compound, usually witii significantly reduced pharmacological activity, which contains an additional moiety which is susceptible to removal in vivo yielding the parent molecule as the pharmacologically active species.
- An example of a pro-drug is an ester which is cleaved in vivo to yield a compound of interest.
- Pro-drugs of a vmety of compounds, and materials and methods for derivatizing the parent compounds to create the pro-drugs are known and may be adapted to the present invention. Certain exemplary pharmaceutical compositions and pharmaceutically acceptable derivatives will be discussed in more detail herein below.
- protecting group By the term “protecting group”, has used herein, it is meant that a particular functional moiety, e.g., O, S, or N, is temporarily blocked so that a reaction can be carried out selectively at anouier reactive site in a multifunctional compound.
- a protecting group reacts selectively in good yield to give a protected substrate that is stable to die projected reactions; the protecting group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the other funcational groups; the protecting group forms an easily separable derivative (more preferably without the generation of new stereogenic centers); and the protecting group has a minimum of additional functionality to avoid further sites of reaction.
- oxygen, sulfur, nitrogen and carbon protecting groups may be utilized.
- protecting groups are detailed herein, however, it will be appreciated that the present invention is not intended to be limited to these protecting groups; rather, a variety of additional equivalent protecting groups can be readily identified using the above criteria and utilized in the method of the present invention. Additionally, a variety of protecting groups are described in "Protective Groups in Organic Synthesis” Third Ed. Greene, T.W. and Wuts, P.G., Eds., John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
- the permissible substituents include acyclic and cyclic, branched and unbrEinched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
- heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
- this invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
- Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful in the treatment of cancer and/or the inhibition of the growth of or die killing of cancer cells.
- stable preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein.
- aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
- aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
- alkyl includes both straight, branched and cyclic alkyl groups.
- An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like.
- alkyl alkenyl, “alkynyl” and the like encompass both substituted and imsubstituted groups.
- alkyl and other aliphatic groups preferably contain 1-6, or 1- 3, contiguous aliphatic carbon atoms.
- Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CH 2 -cyclopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclobutyl, -CH -cyclobutyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, cyclopentyl, -CH 2 -cyclopentyl, n-hexyl, sec-hexyl, cyclohexyl, -CH 2 - cyclohexyl moieties and the like, which again, may bear one or more substituents.
- Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten- 1-yl, and the like.
- Representative alkynyl groups include, but are not limited to, ethynyl, 2- propynyl (propargyl), 1-propynyl and the like.
- alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom or through a sulfur atom.
- alkoxy include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
- tliioalkyl include, but are not limited to methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
- alkylamino refers to a group having the structure -NHR' wherein R' is alkyl, as defined herein.
- alkylamino include, but are not limited to, methylamino, ethylamino, iso-propylamino and the like.
- substituents of the above-described aliphatic (and other) moieties of compounds of the invention include, but are not limited to: F, Cl, Br, I, OH, N0 2 , CN, C(O)- alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 -aryl, C0 2 -heteroaryl, CONH 2 , CONH-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-alkyl, OC(0)-aryl, OC(0)-heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(0)-alkyl, NHC(0)-aryl, NFIC(0)-heteroaryl, NHC0 2 -alkyl,
- aryl and heteroaryl refer to stable mono- or polycyclic, heterocyclic, polycyclic, and polyheterocyclic unsaturated moieties having preferably 3-14 carbon atoms, each of which may be substituted or unsubstituted.
- Substituents include, but are not limited to, any of the previously mentioned substitutents, i.e., the substituents recited for aliphatic moieties, or for other moieties as disclosed herein, resulting in the formation of a stable compound.
- aryl refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings mcluding, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.
- heteroaryl refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, tliiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
- cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in die case of other aliphatic, heteroaliphatic or hetercyclic moieties, may optionally be substituted.
- heteroaliphatic refers to aliphatic moieties which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms, e.g., m place of carbon atoms. Heteroaliphatic moieties may be branched, unbranched or cyclic and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc.
- heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more moieties including, but not limited to: F, Cl, Br, I, OH, N0 2 , CN, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 -aryl, C0 2 -heteroaryl, CONH 2 , CONH-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-alkyl, OC(0)-aryl, OC(O)- heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(0)-alkyl, NHC(0)-aryl, NHC(0)-heteroaryl, NHC0
- haloalkyl denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromediyl, and die like.
- heterocycloalkyl refers to a non-aromatic 5-, 6- or 7- membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring.
- heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, diiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
- a "substituted heterocycloalkyl or heterocycle” group refers to a heterocycloalkyl or heterocycle group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with but are not limited to: F, Cl, Br, I, OH, N0 2 , CN, C(0)-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 - aryl, C0 2 -heteroaryl, CONH 2 , CONH-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-alkyl, OC(0)-aryl, OC(0)-heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH- alkyl, OCONH-aryl, OCON
- labels As used herein, the term “labeled” is intended to mean that a compound has at least one element, isotope or chemical compound attached to enable the detection of the compound.
- labels fall into three classes: a) isotopic labels, which may be radioactive or heavy isotopes, including, but not limited to, 7 Ga, 99m Tc (Tc-99m), m In, 123 1, m I, 169 Yb and 1 Re; b) immune labels, which may be antibodies or antigens; and c) colored or fluorescent dyes. It will be appreciated that the labels may be incorporated into the compoimd at any position tiiat does not interfere with the biological activity or characteristic of the compound which is being detected.
- photoaffinity labeling is utilized for the direct elucidation of intermolecular interactions in biological systems (e.g., to probe the epothilone binding site in a tubulin dimer).
- a variety of known photophores can be employed, most relying on photoconversion of diazo compounds, azides, or diazirines to nitrenes or carbenes (See, Bayley, H., Photogenerated Reagents in Biochemistry and Molecular Biology (1983), Elsevier, Amsterdam.), the entire contents of which are hereby incorporated by reference.
- Polymer The term “polymer”, as used herein, refers to a composition comprising chains that may be open, closed, linear, branched or cross-linked of repeating units (monomers) that may be the same or different.
- polymer refers to biopolymers, which, as used herein, is intended to refer to polymeric materials found in nature or based upon those materials found in nature, including, but not limited to nucleic acids, peptides, and mimetics thereof.
- polymer refers to synthetic polymers, such as biodegradable polymers or other polymeric materials.
- polymeric solid supports are also encompassed by the polymers of the present invention. Inventive compounds can be attached to polymeric supports and thus certain synthetic modifications can be conducted on the solid phase.
- solid support is meant to include, but is not limited to, pellets, disks, capillaries, hollow fibers, needles, pins, solid fibers, cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross- linked with divinylbenzene, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamiiie, and glass particles coated with a hydrophobic polymer.
- solid support is meant to include, but is not limited to, pellets, disks, capillaries, hollow fibers, needles, pins, solid fibers, cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross- linked with divinylbenzene, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally crosslinked with N-N'-bis-acryloylethylenediamii
- An exemplary solid support is a Tentagel amino resin, a composite of 1) a polystyrene bead crosslinked with divinylbenzene and 2) PEG (polyethylene glycol).
- Tentagel is a particularly useful solid support because it provides a versatile support for use in on-bead or off-bead assays, and it also undergoes excellent swelling in solvents ranging from toluene to water.
- the present invention provides novel epothilone analogues and methods for the synthesis thereof.
- the present invention provides 20- or 21- and 12-substituted epothilones and aza-analogues, pharmaceutical compositions, and methods of use of the epothilone analogues in the treatment of cancer.
- certain epothilones have been found to be effective not only in reversing multi-drug resistance in cancer cells, both in vitro and in vivo, but have been determined to be active as collateral sensitive agents, which are more cytotoxic towards MDR cells than normal cells, and as synergistic agents, which are more active in combination with other cytotoxic agents, such as vinblastin, than the individual drugs would be alone at the same concentrations.
- the desoxyepothilones of the invention have exceptionally high specificity as tumor cytotoxic agents in vivo, more effective and less toxic to normal cells than the principal chemotherapeutics currently in use, including Taxol®, vinblastin, adriamycin and camptothecin.
- the present invention provides novel compounds and mediodology that enables the efficient synthesis of epothilones and analogues thereof.
- the invention provides novel compounds having the structure:
- each occurrence of V is independently hydrogen; halogen; -OH; -SH; amino; or substituted or imsubstituted alkyl, heteroalkyl, aryl or heteroaryl; wherein each occurrence of m is independently 1-5; wherein the bond W — R t represents a single bond or a double bond; wherein each occurrence of Ri is independently hydrogen; OR A ; SR A ; R A RA; C(0)ORA; C(0)R A ; CONHR A ; N 3 ; N 2 ; N 2 R A ; halogen; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; polymer; carbohydrate; photoaffinity label; or radiolabel; wherein each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphaphaphaphatic,
- X is S; Y is N; m is 1 ; and n is 3. In certain other embodiments,
- Re is methyl or ethyl.
- M is O.
- the present invention includes those compounds wherein R 6 is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl,
- Re is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- Re is ethyl
- Rj is a photoaffinity label
- the photoaffinity label is the photoactivatable group 0-, m- or p- azidobenzoyl, substituted by one or more halogen moieties.
- the photoactivatable group is 4-azido-2,3,5,6-tetrafluorophenylacyl.
- isomers having the following structure are provided:
- isomers having the following structure are provided:
- 21-hydroxylated compounds which compounds have the following structure:
- R 6 is independently hydrogen; ORA; SRA; NRARA; C(0)OR A ; C(0)RA; CONHR A ; N 3 ; N 2 RA; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; polymer; carbohydrate; photoaffinity label; or radiolabel.
- R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more cai'bon atoms.
- R 6 is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl, or (CH ) p -OH, wherein p is 1-6.
- compounds are provided in which R 6 is H, methyl, ethyl, n-propyl, n-butyl, n-hexyl, or (CH ) p -OH, wherein p is 1-6.
- R 6 is ethyl, n-propyl, n-butyl, n-hexyl,. or (CH 2 ) p -OH, wherein p is 1-6.
- Re is methyl and the compound has the structure:
- is ethyl and inventive compounds have the structure:
- inventive compounds have the structure:
- R 6 is independently hydrogen; OR A ; SR A ; NR A RA; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; polymer; carbohydrate; photoaffinity label; or radiolabel.
- the present invention provides compounds having die general structure:
- R 6 is independently hydrogen; OR A ; SR A ; NR A RA; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; nitrogen protecting group; polymer; carbohydrate; photoaffinity label; or radiolabel.
- the present invention contemplates the attachment of the compounds as described herein to polymers; carbohydrates; photoaffinity labels; or radiolabels.
- compounds having the following formula are provided:
- the present invention provides multiply presented compounds, and in one embodiment the present invention provides a composition comprising a polymeric backbone; and two or inventive compounds, wherein the two or inventive compounds are the same or different, whereby said two or more compounds are linked to the polymeric backbone directly or tlirough a linker, and wherein the two or more compounds are linked through the 12-position, the 20- position or the 21 -position of the compound.
- the polymeric backbone is a dendrimer, a peptide, or a biodegradable polymer.
- a dimeric desoxyepothilone having the following structure is provided:
- EPO has the structure:
- R 6 is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CONHRA; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherem each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; polymer; carbohydrate; photoaffinity label; or radiolabel.
- R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- the present invention provides novel methodology by which the necessary acyl and alkyl sectors for macrocyclization can be provided in significant quantities, representing improved methods from previously reported synthetic methodologies as disclosed in 08/986,025 and 09/257,072 , die entire contents of which are hereby incorporated by reference.
- the present invention provides, in one aspect, a novel synthesis for epothilones and analogues thereof.
- This approach involves the use of an acyl sector, as described herein, wherein the C3 in die acyl sector is already reduced and poised for coupling with the alkyl sector. Additionally, a more convenient and modular approach to the alkyl sector is provided.
- the two fragments can then be coupled, in certain embodiments by a B-alkyl Suzuki coupling reaction, and then advanced to macrolactone or macrolactam by a macrocyclization reaction.
- a Yamaguclii macrocyclization is utilized similarly to the reaction employed for previous syntheses of dEpoB (as described in pending patent applications 08/986,025 and 09/257,072, the entire contents of which are hereby incorporated by reference) and dEpoF (as described in Example 1, and as shown in Figure 2).
- efficient methods for preparing an intermediate for the O-Alkyl segment which intermediate compound has the structure: wherein P is an oxygen protecting group; wherein Hal is a halogen; and wherein Re is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of RA is independently hydrogen; polymer; nitrogen protecting group; oxygen protecting group; sulfur protecting group or carbon protecting group; or linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl.
- asymmetric catalytic oxygenation see, Figure 3 for the synthesis of one isomer.
- an asymmetric catalytic oxygenation method is employed to install the Cl 5 center and iodoboration of an alkyne is effected to implement the (Z)-alkene geometry.
- the method of the invention comprises: a) providing a haloketone having the structure:
- the step of hydroxylating comprises reacting the haloketone using asymmetric catalyst to effect asymmetric dihydroxylation, preferably in the presence of Os0 4 and AD-mix- ⁇ ,to generate a compound having the structure:
- the step of hydroxylating comprises reacting the haloketone using asymmetric catalyst to effect asymmetric dihydroxylation, preferably conducted in the presence of Os0 and AD-mix- ⁇ , to generate a compound having the structure: which compound is particularly useful for the synthesis of lactam derivatives, as described in more detail herein. It will also be appreciated tiiat the present invention additionally contemplates those methods wherein the silyl enol ether is first provided.
- P is -SiR H RjR ⁇ , wherein R H , R J , and R K are each ethyl.
- R 6 linear or branched, cyclic or acyclic, substituted or unsubstituted aliphatic or heteroaliphatic.
- R 6 is methyl, ethyl, n- or ⁇ -propyl, phenyl or benzyl.
- Hal is iodo.
- this approach involves reacting propyne (17) with B-iodo-9-BBN and adding the resulting vinyl borant to methyl vinyl ketone to furnish ketone (18). Subsequent treatment of this compound with a reagent such as TMSI/HMDS afforded a 88:12 mixture of two silyl ether regioisomers 19 and 20. Asymmetric dihydroxylation of the mixture, using AD-mix- ⁇ , generated hydroxyketone 21. Significantiy, it is possible using this procedure, to sustain the potentially vulnerable iodoalkene functionality during the osmium mediated dihydroxylation. Finally, triethylsilylation of 25 produced 18, completing the sequence in only 4 steps.
- the ketone can also be generated using an asymmetric alkylation reaction to establish the Cl 5 configuration, as depicted in one embodiment, in Figure 4.
- the method of the invention comprises the steps of: a) preparing a glycolimide having the structure:
- a substituted hydroxylamine selected from the group consisting of N,0-(linear or branched chain C ⁇ - 8 alkyl,aryl)hydroxyl. n ⁇ ine, N,0-di-(linear or branched chain C ⁇ - 8 )alkylhydroxylamine and N,0-aryl,arylhydroxylamine under suitable conditions to form an amide having the structure:
- R' and R" are each independently linear or branched chain -s alkyl or aryl; and c) reacting the amide with a substituted organometallic reagent under suitable conditions to form the compound.
- P is SIR H R J R K and wherein R H , R J and R are each ethyl.
- R 6 linear or branched, cyclic or acyclic, substituted or imsubstituted aliphatic or heteroaliphatic.
- R 6 is methyl, ethyl, n- or ⁇ -propyl, phenyl or benzyl.
- Hal is iodo.
- the substituted organometallic reagent is a Grignard reagent, including, but not limited to MeMgBr or MeMgCl.
- ketone 18 was provided using asymmetric alkylation starting with the synthesis of the silylated glycolate from a known PMB derivative 24b which was obtained from 23 in 3 steps.
- 23 can be converted to 24a in multi-gram scales by a one flask procedure involving in situ formation of a mixed anhydride.
- Subsequent treatment of lithio 24a with diiodide 22 at -78°C affords the desired 25a as a single isomer.
- formation of Weinreb amide 26a is effected by simultaneous detachment of the chiral auxiliary, and subsequent protection and Grignard addition affords 11.
- Ri is hydrogen, or is substituted or unsubstituted, linear or branched, cyclic or acyclic, aliphatic, heteroaliphatic, aryl, heteroaryl, aryl substitued aliphatic, or aryl substituted heteroaliphatic; wherein Z A is OP, SP, N 3 or NHP; wherein P is an oxygen, sulfur, or nitrogen protecting group; wherein Hal is a halogen; wherein R 6 is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CONHR ⁇ ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic,
- R' and R" are independently C ⁇ - 8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl; aryloxy; alkoxy; b) condensing die phosphine oxide with a ketone having the structure:
- step b) optionally reducing the ester formed in step b) under suitable conditions to form the compound.
- the method of the invention comprises : a) preparing a phosphine oxide having the structure:
- R' and R" are independently - 8 linear or branched chain alkyl, or a substituted or unsubstituted phenyl; alkoxy; or aryloxy; b) condensing the phosphine oxide with a ketone having the structure:
- step b) reacting the compound formed in step b) under suitable conditions to effect inversion to generate .an azide, and optionally further treating the azide to generate a protected amine.
- the inversion is effected using Thompson's procedure.
- the azide is reduced by Staudinger reduction to generate a protected amine.
- R t is hydrogen, linear or branched, substituted or unsubstituted, cyclic or acyclic, alkyl, heteroalkyl, phenyl, 4-thiazolyl, 2-furanyl, 3-furanyl, 4-furanyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, imidazolyl, 4-oxazolyl, 3-indolyl or 6-indolyl.
- Ri is substituted or unsubstituted 4-thiazolyl, and in certain embodiments, includes thiazolyl moieties substituted with one or two methyl functionalities at one or both of the 2- or 5- positions.
- P is a nitrogen protecting group; wherein Hal is a halogen; wherem R 6 is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substimted or unsubstituted, cyclic or acyclic, linear or branched aliphatic, heteroaliphatic, aryl, or heteroaryl; wherein each occurrence of R A is independently hydrogen; linear or branched, substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; or polymer.
- the method comprises the steps of : a) preparing a phosphine oxide having the structure:
- R o , R' and R" are independently -g linear or branched chain alkyl, or a substituted or unsubstituted phenyl; aryloxy; alkoxy; b) condensing the phosphine oxide with a ketone having the structure:
- P is SIRHR J R K and RH
- R J and R are each ethyl.
- R 6 is linear or branched, cyclic or acyclic, substituted or unsubstimted aliphatic or heteroaliphatic.
- R 5 is metiiyl, ethyl, n- or ⁇ o-propyl, phenyl or benzyl.
- Flal is iodo.
- ketoaldehyde having the structure:
- the step of reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction comprises reacting said ketoaldehyde under stoichiometric conditions with a chiral titanium enolate. In certain other embodiments, the step of reacting said ketoaldehyde under suitable conditions to effect a second aldol reaction comprises reacting said ketoaldehyde with a catalytic reagent. It will be appreciated that a variety of catalytic reagents can be employed, including, but not limited to the Carreira catalyst and Mikami's chiral aldol catalyst. For example, an asymmetric aldol reaction can be utilized for construction of the right wing sector. (Duthaler, R.
- the first scheme below represents a catalytic Mukaiyama-type aldol reaction employing the Carreira catalyst (Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837).
- EE's are generally high with this method using silyl ketene acetals with low catalyst loading (2-5 mol%). In this case a methyl ester will be produced which can be hydrolzed after the subsequent Suzuki coupling with aqueous base.
- novel methodologies are described herein with reference to dEpoB and dEpoF and certain analogues thereof, the novel methodologies can also be employed for the synthesis of a wide range of other analogues including, but not limited to, oxazolinyl, pyridyl, and phenyl analogues and substituted derivatives thereof.
- phosphine oxide as described herein for the dEpoB and dEpoF precursor compounds, can also be prepared utilizing the appropriate oxazolinyl, pyridyl or phenyl starting materials, or materials for other analogues, as described herein.
- phosphine oxides can be reacted with the ketone, as described herein, which ketone can also be diversified to generate 12- modified analogues.
- the present invention provides efficient and modular syntheses of the ketone moiety and the acyl sector which can then be employed, utilizing appropriate phosphine oxides, for the syntheis of the macrocyclization precursor (via Suzuki coupling).
- the ability to easily generate the modular ketone enables the synthesis of a variety of C12 analogues and thus the method enables the simultaneous modification of the 12- position and the aryl or heteroaryl sector during the course of the synthesis.
- novel methodologies as described herein can be utilized to synthesize compounds having the following general structure:
- nched 3 substituted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; or polymer; wherein n is 0, 1, 2 or 3; wherein Z is OR , NHRg, or N 3 , and Z B is CO2R9 or COSR9 wherein each occurrence of R 7 , R 8 , R , Rio, or R ⁇ is independently hydrogen, an oxygen protecting group or a nitrogen protecting group, is generally prepared by: providing a first sector having the structure:
- R 2 , R 3 , R), and R 5 are as defined above, and wherein Z B is C0 2 R 9 or COSR 9 ; and reacting said first and second sectors under suitable conditions to effect coupling to generate the precursor.
- Y is hydrogen or alkyl
- X is 4-thiazolyl substituted at die 2-position, 5-position or both the 2- and 5- position by linear or branched alkyl or substituted by -(CH 2 ) n OH, wherein 11 is 0-5; and R 6 is independently hydrogen; OR A ; SR A ; NR A R A ; C(0)OR A ; C(0)R A ; CONHR A ; N 3 ; N 2 R A ; halogen; cyclic acetal; substituted or unsubstituted, cyclic or acyclic, linear or.
- R A is independently hydrogen; linear or branched, substimted or unsubstituted, cyclic or acyclic, aliphatic, heteroaliphatic, aryl or heteroaryl; or polymer.
- M is NH
- R 6 is a substimted or unsubstimted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- M is O, and wherein R 6 is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, having 2 or more carbon atoms.
- the present invention further contemplates subjecting the cyclized compounds to steps of deprotecting and optionally further contemplates reacting the cyclized compounds under suitable conditions to generate the photoaffinity labeled, radiolabeled, carbohydrate-linked or polymer-linked compounds as described in more detail herein.
- labeled compounds are provided, and in certain embodiments, photoaffinity labeled or radiolabeled compounds are provided.
- photoaffinity radioactive reagents can be utilized.
- condensation of unprotected dEpoF with 4-azido-2,3,5,6- tetrafluorobenzoic acid is performed under the agency of DCC to afford photoaffinity labeled dEpoF 3 (as depicted in Figure 5) which can be utilized to probe the epothilone binding site in a tubulin dimer.
- the coupling reaction furnishes novel epothilone 4 containing a fluorophore.
- novel epothilone is particularly useful for binding studies and monitoring of subcelluar distribution of epothilone.
- a radio-labeled epothilone (7, T-dEpoB) can be readily produced if a corresponding tritium reducing agent (e.g., NaBT 3 CN, or r ⁇ -Bu 3 SnT) is employed as the hydride source.
- a corresponding tritium reducing agent e.g., NaBT 3 CN, or r ⁇ -Bu 3 SnT
- nucleopliiles can be introduced to C21 position by simple substitution reactions using tosylate 5 or iodide 6.
- the selective functionalization at C21 is not limited to acylation or sulfonylation.
- direct subjection of unprotected dEpoF (2d) to Mn0 2 mediated oxidation conditions results in the formation of 21-oxo-epothilone B (8) in high yield as shown in Figure 6, which is a useful analogue for further functionalization as depicted in Figure 7
- epothilone derivatives can be accessed from the 21-oxo system as shown in figure 7.
- Wittig type olefination reactions generate 21-alkylidene-eopti ⁇ ilo ⁇ e 10 which can then be chemoselectively hydrogenated or dihydroxylated to give 11 and 12, respectively.
- an ally! unit can be readily added to unprotected aldehyde 8 in aqueous media to furnish 12b by the agency of an allylindium reagent.
- a terminal alkene function such as 10 and 12b
- its ability to participate in subsequent addition reactions can be utilized to produce more elaborated epothilone derivatives.
- selective hydrogenation furnishes 11, which constitutes a "desoxy" analog of naturally occurring epothilone B ⁇ . Isotopic labeling witii tritium is also possible by employing T 2 instead of using hydrogen gas.
- 12a (or dihydroxylated 12b) is a water-soluble analog that provides advantages in formulation.
- a new epothilone with a carboxylic acid moiety, 13 is generated tlirough the oxidation of aldehyde 8 by sodium chlorite.
- aldehyde 8 is reacted with an amine, and the ' corresponding
- Schiff base 14 is readily generated via dehydration.
- Schiff base 14 represents 21-imino- epothilone analogs, whose biological activity remains unreported.
- derived form the reaction with hydrazine are another stable form of 21-imino- epothilones.
- Subsequent reduction with NaBH 3 CN readily converts imine 14 into 21-amino- epothilone 15.
- N-dEpoB-Gly methyl ester is formed as the product in good yield.
- the present invention additionally contemplates the formulation and/or funtionalization of the inventive compounds to permit more effective delivery of the therapeutic agent.
- One major problem in taxol chemotherapy arises from the hydrophobicity. Its marginal aqueous solubility necessitates recourse to formulation vehicles such as cremophores that pose their own risks and management issues.
- formulation vehicles such as cremophores that pose their own risks and management issues.
- the relatively higher aqueous solubility imparted in epothilones and the additional increase by the hydroxy substitution at C21 have shown some promises. However, it would be more desirable if the aqueous solubility of epothilone is further enhanced to the extent that formulation epothilone in an aqueous medium is possible.
- the present invention provides novel compounds prepared by reacting dEpoF with N,N-dimethylglycine followed by hydrochloride salt formation as shown in Figure 8.
- the C21 functional groups lend tiiemselves as a staging point for introduction of various ⁇ -amino acids or peptides containing hydrophilic side chains to increase the aqueous solubility.
- an ⁇ -protected oligopeptide can be attached to the epothilone domain through the C- terminal coupling.
- reductive amination and peptide coupling allow for the ⁇ - terminal coupling of carboxy-protected peptides to aldehyde 8 and acid 13, respectively.
- the peptide-epothilone conjugate may provide an additional advantage of targeting tumor cells. Since tumors cells often over-express certain receptors to peptide ligands, the peptide attached to epothilone can be utilized as the recognition element. Thus, the ligand-receptor interaction can guide the peptide-epothilone to the tumor cells and facilitate endocytosis. For example, a segment of somatostatin can be used to deliver epothilone to the somatostatin receptor over-expressing cells, which are frequently found in several tumor types.
- the present invention contemplates the formation of a polyvalent array.
- the low affinity binding of extracellular ligands can be significantly improved by covalently tethering many ligands together to form a polyvalent array. Since the initiating event of epothilone' s anticancer activity involves noncovalent binding to microtubules, the formation of a dimer may enhance binding of the ligand (epothilone) to the biopolymer (microtubules). While the validity of polyvalency in an intracellular context is open to question, the multiple binding sites presented by microtubules offer a possibility of such advantage.
- the concept of polyvalency in the context of a small molecule ligand (epothilone) and an intracellular receptor (microtubule) can be better tested by the multiple presentation of epothilones on a dendrimer or a polymer backbone.
- the interactions between the multiple binding sites located in microtubule and multiply presented epothilones can create a favorable situation of polyvalency, thereby ultimately leading to enhancement in antitumor activity.
- multiply presented epothilones can be readily synthesized using available functional groups on the backbone of a dendrimer or a polymer.
- Illustrated in Figure 12 is presentation of eight epothilones on a commercially available PAMAM (Starburst ® ) dendrimer (X - C0 2 or NH) and an octapeptide (e.g., glutamate, lysine).
- PAMAM Starburst ®
- X - C0 2 or NH an octapeptide
- the present invention additionally contemplates the administration of epothilones via polymers such as biopolymers or biocompatible (synthetic or naturally occuring) polymers.
- Biocompatible polymers can be categorized as biodegradable and non-biodegradable. Biodegradable polymers degrade in vivo as a function of chemical composition, method of manufacture, and implant structure. Synthetic and natural polymers can be used although synthetic polymers are preferred due to more uniform and reproducible degradation and other physical properties. Examples of synthetic polymers include polyanhydrides, polyhydroxyacids such as polylactic acid, polyglycolic acids and copolymers thereof, polyesters, polyamides, polyorthoesters, and some polyphosphazenes.
- Naturally occurring polymers include proteins and polysaccharides such as collagen, hyaluronic acid, albumin and gelatin.
- epothilone is administered via biopolymers or .artificial functional polymers, it is possible to exploit the biological advantages of large molecule therapeutics.
- the ideal polymeric matrix would combine the characteristics of hydrophobicity, stability, organic solubility, low melting point, and suitable degradation profile.
- the polymer additionally is also preferably hydrophobic so that it retains its integrity for a suitable period of time when placed in an aqueous environment, such as the body, and be stable enough to be stored for an extended period before use.
- the ideal polymer must also be strong, yet flexible enough so that it does not crumble or fragment during use.
- biodegradable polymers can be used in the present invention, inter alia, containing a fashionable functional group, such as N-(hydroxypropyl)- methacrylamide (HPMA), glutamate, and lactide-lysine copolymers, (as shown in Figure 14) can serve as an efficient vehicle.
- a fashionable functional group such as N-(hydroxypropyl)- methacrylamide (HPMA), glutamate, and lactide-lysine copolymers, (as shown in Figure 14) can serve as an efficient vehicle.
- HPMA N-(hydroxypropyl)- methacrylamide
- glutamate glutamate
- lactide-lysine copolymers as shown in Figure 14
- polypeptides bearing a charged side chain are inherently water soluble, .an engineered peptide linker as the solubility enhancer may be covalently incorporated between the polymer backbone and the epothilone analog in the case of nonpolar polymers.
- the compounds as described herein may be conjugated via suitable functionality to a water soluble chelator, or water soluble polymer, such as polyethylene glycol, poly(l-glutamic acid) or poly (1-aspartic acid), as described in U.S. Patent No.: 5,977,163, the entire contents of which are hereby incorporated by reference.
- a water soluble chelator such as polyethylene glycol, poly(l-glutamic acid) or poly (1-aspartic acid
- a strategy of multiply presenting epothilone on the sphere of a dendritic center is illustrated in Figure 15.
- the 3, 4-diprotected glucal is attached to the terminal carboxy groups.
- the number (4, 8, 16, 32, etc.) and nature (C0 2 Na, NH ) of die terminal group can be changed.
- compositions As discussed above, the present invention provides novel compounds having antitumor and antiproliferative activity, and thus the inventive compounds are useful for die treatment of cancer. Accordingly, in another aspect of the present invention, pharmaceutical compositions are provided, wherein these compositions comprise any one of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier. In certain preferred embodiments, tiiese compositions optionally further comprise one or more additional therapeutic agents. In certain other embodiments, the additional therapeutic agent is an anticancer agent, as discussed in more detail herein.
- a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof, e.g., a prodrug.
- the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the ait. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference.
- the salts can be prepared in situ during the final isolation and purification of die compounds of the invention, or separately by reacth g the free base function with a suitable organic acid.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, bydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in die art such as ion exchange.
- inorganic acids such as hydrochloric acid, bydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in die art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, alate, maleate, malonate, metiianesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
- alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
- Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
- Examples of particular esters includes formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
- prodrugs refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compoimds of the invention.
- prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of die above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
- compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable carrier includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as
- tumor cells are killed, or their growth is inhibited by contacting said tumor cells witii an inventive compound or composition, as described herein.
- a method for the treatment of cancer comprising administering a therapeutically effective amount of an inventive compound, or a pharmaceutical composition comprising an inventive compound to a subject in need thereof, in such amounts and for such time as is necessary to achieve the desired result.
- a "therapeutically effective amount" of the inventive compound or pharmaceutical composition is that amount effective for killing or inhibiting the growth of tumor cells.
- the compounds and compositions, according to the method of the present invention may be administered using any amount and any route of administration effective for killing or inhibiting the growth of tumor cells.
- the expression "amount effective to kill or inhibit the growth of tumor cells”, as used herein, refers to a sufficient amount of agent to kill or inhibit the growth of tumor cells. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular anticancer agent, its mode of administration, and the like.
- the anticancer compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
- the expression “dosage unit form” as used herein refers to a physically discrete unit of anticancer agent appropriate for the patient to be treated.
- the pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
- the inventive compounds as described herein are formulated by conjugating with water soluble chelators, or water soluble polymers such as polyethylene glycol as poly (1-glutamic acid), or poly (1-aspartic acid), as described hi U.S. Patent 5,977,163, the entire contents of which are hereby incorporated by reference.
- the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylform.amide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures ti ereof.
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium cldoride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtiation through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing die compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, .and granules.
- the active compoimd is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar— agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cety
- Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition tiiat they release the active ingredient(s) only, or preferentially, in a certain part of die intestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- embedding compositions which can be used include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within die scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing conu-olled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing the compound in die proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin.
- the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the compounds of the present invention are useful as anticancer agents, and thus may be useful in the treatment of cancer, by effecting tumor cell death or inhibiting the growth of tumor cells.
- the inventive anticancer agents are useful in the treatment of cancers and other proliferative disorders, including, but not limited to breast cancer, cervical cancer, colon and rectal cancer, leukemia, lung cancer, melanoma, multiple myeloma, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer, to name a few.
- the inventive anticancer agents are active against leukemia cells and melanoma cells, and thus are useful for the treatment of leukemias (e.g., myeloid, lymphocytic, myelocytic and lymphoblastic leukemias) and malignant melanomas.
- the inventive anticancer agents are active against solid tumors and also kill and/or inhibit the growth of multidrug resistant cells (MDR cells).
- MDR cells multidrug resistant cells
- the compounds and pharmaceutical compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more otiier desired therapeutics or medical procedures.
- the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into accoimt compatibility of die desired therapeutics and/or procedures and the desired therapeutic effect to be achieved.
- the tiierapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another anticancer agent), or they may achieve different effects (e.g., control of any adverse effects).
- inventive anticancer agents include surgery, radiotherapy (in but a few examples, ⁇ -radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes, to name a few), endocrine therapy, biologic response modifiers (interferons, interleukins, .and tumor necrosis factor (TNF) to name a few), hyperthermia and cryotherapy, agents to attenuate any adverse effects (e.g., antiemetics), and odier approved chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, Cyclophos
- the present invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, and in certain embodiments, includes an additional approved therapeutic agent for use as a combination tiierapy.
- a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention, and in certain embodiments, includes an additional approved therapeutic agent for use as a combination tiierapy.
- Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
- a new epothilone analogue 12,13- desoxy epothilone F (dEpoF, 21 -hydroxy- 12, 13 -desoxyepothilone B; Fig. 2), was synthesized using the convergent strategy previously used for the practical synthesis of 12, 13 -desoxyepothilone B (dEpoB), the synthesis of which is described in Figures 16-18..
- dEpoB 12, 13 -desoxyepothilone B
- the new analogue containing an additional hydroxyl group provides certain advantages over other epothilones since it is more soluble in water and is readily functionalized for pertinent biological studies.
- a method was utilized for the synthesis of dEpoF similar to the mediod used to prepare dEpoB as taught herein, in which two fragments of roughly equal complexity served as key building blocks (Fig. 2).
- methodology was developed for the de novo construction of the thiazole moiety, and the right wing utilized in the previous synthesis of dEpoB was employed for the polypropionate domain for the synthesis of dEpoF.
- the synthesis of the left wing was started from the protection of the known 2-substituted thiazole (Ciufolini, M. A.; Shen, Y. C. J Org. Chem. 1997, 62, 3804) with Troc group which was removed simultaneously with the C7 hydroxy protection at a late stage of the synthesis (Fig. 16).
- the ethyl ester was reduced witii Dibal-H to aldehyde which was then homologated to aldehyde.
- Asymmetric addition of the allyl unit was accomplished by the Brown protocol (Racherla, U. S.; Brown, H. C. J. Org. Chem.
- Procedure B To a mixture of the alcohol (8.50 g, 25.0 mmol) and imidazole (3.40 g, 50.0 mmol) in DMF (50 mL) were added TBSC1 (4.72 g, 31.3 mmol) and 4-DMAP (30 mg, 0.25 mmol). After stirring at room temperature for 8 h, the mixture was diluted with ether (250 mL) and washed successively with 2 N HCl (50 mL), aqueous NaHC ⁇ 3 (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgS04 and concentrated. Flash chromatography on
- glycolimide lOHa (5.5 g, 87%) as a clear oil. Glycolimide 11H.
- glycolimide X (4.75 g, 20.2 mmol) in DMF
- TES-protected glycolimide 11H (1.11 g, 3.18 mmol) was dissolved in THF (20 mL) and cooled to -78°C.
- LHMDS 1.0M THF solution, 3.50 mmol
- l,3-diiodo-3-butene (1.08 g, 3.5 mmol) in THF (5 mL) was added to the cooled enolate via cannula aftewhich the solution was slowly warmed to room temperature over 12 h.
- the solution was quenched with a sat. NaC0 3 solution and extracted with EtOAc (3 x 30 mL).
- Alkylated TES-Protected N-O-dimethamide (12Ha) Alkylated TES-Protected N-O-dimethamide 12Ha was dissolved in HOAc:THF:H 2 0 (3: 1 :1, 150 mL) and stirred at room temperature for 4 h. The solvent was then removed in vacuo. The oily residue was dissolved in EtOAc (100 mL) and washed with sat. NaC0 3 (2 x 50 mL), and brine (50 mL). The organic layer was dried over MgS0 , filtered, and concentrated in vacuo. This material was used for the subsequent reaction without further purification.
- N,0-Dimethyl hydroxylamine hydrochloride (4.87 g, 50.0 mmol) was suspended in THF (60 mL) and cooled to 0°C.
- a 1.0 M solution of AlMe 3 in toluene 25 mL, 50 mmol was added dropwise. After the addition was complete the ice bath was remove and the solution was stirred at room temperature for 2 h. This solution was then cannulated into a solution of the crude alkylated glycolimide (prepare above) in THF (100 mL) at 0°C. After the addition was complete the ice bath was remove and the mixture was stirred at room temperature for 6 h.
- N,0-dimethylamide 12Ha (2.53 g, 8.47mmol) in DMF (15 mL) was added imidazole (0.69 g, 10.2 mmol) followed by TESCl (1.40 g, 9.32 mmol). The solution was stirred at room temperature for 5 h. The solution was then poured into H 2 0 (150 mL) and extracted with EtOAc (4 x 100 mL). The combined organic layers were washed with H 2 0 (2 x 100 mL) and dried over MgS0 . The solution was then filtered and concentrated in vacuo.
- Example 2 Synthesis of desoxyepothilone F via presentation of acyl sector for coupling in reduced form and novel methodologies for the synthesis of right and left wings:
- the total synthesis of dEpoF was accomplished, as shown in Figure 1, and as detailed herein.
- dEpoF was developed utilizing an acyl sector for Suzuki coupling with C3 already reduced (rather than performing the Noyori reduction after Suzuki coupling).
- C3 already reduced
- a more convergent and modular route to both the acyl and alkyl sectors was developed.
- the new synthesis features a convergent and modular nature strategy with strong stereoselectivities at each step.
- the conciseness of the syntheses of the key intermediates readily allow for large scale preparation and easy structural variation in each synthetic segment.
- the Horner-like condensation conveniently conjoined the thiazole moiety and the segment possessing the critical C15 stereochemistry and (Z)-12,13-alkene function.
- the stereoselective aldol reactions en route to the O-acyl wing were investigated in some detail. As depicted hi Figure 19, it was demonstrated that a subtle variation in factors affecting the transition state has remarkable influence on the long range transmission of stereochemical information. In these studies (see also Wu et al, Angew. Chem. Int. Ed.
- the new O-acyl wing fragment may serve as a widely applicable intermediate for accessing various analogues.
- the present invention additionally provides novel methods for the preparation of methyl ketone 11 by two independent sequences.
- the first approach involves an asymmetric catalytic oxygenation method to install the C15 center and iodoboration of an alkyne to implement the (Z)-alkene geometry ( Figure 3).
- Figure 3 in one embodiment of the invention, propyne (17) reacted with 5-iodo-9- BBN and the resultant vinyl borane was added to methyl vinyl ketone to furnish ketone 18.
- Subsequent treatment of this compound with TMSI/HMDS afforded an 88:12 mixture of two silyl ether regioisomers 19 and 20.
- silyl protected 24 in these alkylations was examined.
- Synthesis of the silylated glycolate began with the known PMB derivative 24b which was obtained from 23 in 3 steps.
- 23 could be converted to 24a in multi-gram scales by a one flask procedure involving in situ formation of a mixed anhydride.
- ethyl thiooxamate (31) was condensed with 1,3-dichloroacetone (32) to provide 2,4-disubstituted thiazole 33 in excellent yield.
- 35 can then be effected, in certain embodiments via Arbuzov reaction using Ph 2 POEt or direct -alkylation with HOPPI1 3 .
- thiazole 34 and ketone 11 condensed smoothly to furnish 35 as a single geometric isomer.
- stereocontrol was achieved by the reaction of a chiral titanium enolate derived from t-butyl acetate.
- literature protocol (Dunthaler et al. Angew. Chem. Int. Ed. Engl. 1989, 28, 495)
- both enantiomers of ⁇ -hydroxy t-butyl ester 37 were prepared in good yields with high enantioselectivity (entries 4 and 5).
- the ee and sense of the absolute stereoselectivity was determined by derivatization of 37 to the corresponding Mosher's ester, and corroborated by certain events in our program (see, Dale et al. J. Am. Chem. Soc. 1973, 95, 512).
- ketoaldehyde 13 was protected as a diisopropyl acetal, and the resultant ketone 49 was subjected to an aldol reaction with 14.
- smooth condensation gave rise to a 4:1 mixture of aldol adducts 50 and 51.
- the major diastereomer 50 was very easily separated by flash chromatography and protected as a Troc group. Indeed, there was a significant advantage in this route in that the aldol condensation, unlike our earlier cases where C3 corresponded to an enol ether, went to completion.
- the reaction conditions are much less demanding technologically, since now die coupling is conducted at -78 °C rather than at -120 °C in the previous synthesis.
- Newly prepared 9 was then utilized in the formal total synthesis of dEpoB as illustrated in Figure 23.
- the 5-alkyl Suzuki coupling witii the O-alkyl segment for EpoB series 58 proceeded to yield 59.
- treatment of 59 with TESOTf followed by selective desilylation afforded hydoxyacid 60 which had been advanced to dEpoB (2b) and EpoB (lb) in our previous syntheses. Accordingly, these studies unambiguously established the stereochemical outcomes of the various aldol reactions and constitute an alternate total synthesis of dEpoB.
- fragments 8 and 9 were conjoined via the 5-alkyl Suzuki protocol to provide the seco ester 62.
- Conversion of the t-butyl ester 62 to the TES ester followed by acid catalyzed selective desilylation provided 63, which awaited macrolactonization.
- detailed spectral correlatons of 63 confirmed its identity with the previously syntiiesized intermediate.
- hydroxyacid 63 was cyclized to the fully protected macrolactone 64.
- sequential- removal of the Troc and TES groups afforded 12,13-desoxyepothilone (2d, dEpoF) which again proved identical in all respects with the previously synthesized dEpoF.
- dEpoF The fully synthetic dEpoF was first tested against various cell types to evaluate its antitumor potential. As shown in Table 2, dEpoF showed high cytotoxic activities against a broad range of sensitive and resistant tumor cell lines. In particular, dEpoF retained high potency and low cross-resistances against MDR cell lines and consistently outperformed other non-epothilone anticancer agents such as paclitaxel, vinblastine, etoposide, actinomycin, and adriamycin. These properties of dEpoF are closely comparable to those of the highly promising antitumor agent, dEpoB.
- Procedure B In a 2 L three necked flask equipped with a mechanical stirrer and a nitrogen inlet were added sodium hydride (60% dispersion, 8.0 g, 0.200 mol) and ether (400 mL). To this suspension was added in several portions glycolic acid (15.21 g. 0.200 mol) at 0 °C. After 20 min, triethylamine (30 mL, 0.215 mol) and TESCl (30.15 g, 0.200 mol) were added, and the mixture was stirred at rt for 2 h.
- sodium hydride 50% dispersion, 8.0 g, 0.200 mol
- ether 400 mL
- glycolic acid 15.21 g. 0.200 mol
- TESCl 30.15 g, 0.200 mol
- reaction mixture was then poured into a separatory fuimel containing saturated aqueous NaHS0 (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated aqueous NaHC0 3 (50 mL) and brine, dried over anhydrous Na 2 S0 4 , and concentrated in vacuo.
- keto aldehyde 19 (6.40 g, 50 mmol) in isopropanol (100 mL) was added triisopropyl orthoformate (16.7 mL, 75 mmol) and -TsOH (951 mg, 5.0 mmol). After the mixture was stirred for 3 h, it was poured into brine (100 mL) and extracted with ether (3 x 100 mL).
- Titanium complex D-41 (0.0715 mmol) and aldehyde 55 (22 mg, 0.055 mmol): IR (neat) 3514,
- the crude TES derivative was then dissolved in THF (5 mL) and treated with a solution of 0.1 NHC1 in MeOH (0.5 mL) at 0 °C. Additional methanolic HCl was added in small portions, and approximately 1.5 mL of 0.1 N HCl was required for completion.
- Epothilone F (Id, EpoF).
- dEpoF 2d, 7.1 mg, 0.014 mmol
- 2,2-dimethyldioxirane -0.04 M in CH 2 C1 2
- the reaction mixture was warmed to -40 °C and stirred for 1 h.
- the reaction mixture was diluted with EtOAc (10 mL) and washed with 10% Na 2 S 2 0 3 (2 mL) and brine.
- the organic layer was dried (Na 2 S0 ), filtered and concentrated.
- EpoF (Id) as a thin film (4.4 mg, 60%): [ ⁇ ]o -26.5 (c 0.35, CH 3 OH); IR (film) 3420, 2967, 2935, 2876, 1734, 1685, 1451, 1381, 1252, 1148, 1063, 980, 913, 732 cm "1 ; !
- aza-epothilones are prepared using methodology as described herein, and in more detail below. The results pertaining to a total synthesis of aza-dEpoB (4a) were recently communicated. Herein, we report the total synthesis of aza-EpoB (2) and provide indications of its likely value as an antitumor agent based on our own in vivo comparison.
- a ruthenium mediated asymmetric hydrogenation would provide highly selective access to the desired stereochemistiy at C-3. Deprotection followed by macrolactamization would then lead to aza-dEpoB in short order. As will be seen, implementation of these ideas proved to be anything but straightforward in the lactam series.
- the ⁇ -keto ester 18 was then subjected to a ruthenium-mediated asymmetric hydrogenation reaction in methanol using a modified Noyori catalyst ( Figure 32). Indeed, the desired diol 24 was produced as a single diastereomer in 78% yield. However, the necessity of acid in the hydrogenation medium (for protonation of the thiazole moiety) resulted in minor amounts of deprotected amine products. This undesired hydrolysis was circumvented by employing re-crystallized catalyst which results in an increased reaction rate, thus minimizing the time of exposure to the acidic solution.
- aza-epothilone B (2, aza-EpoB), 12,13,15-desoxy-15(S)-aza-epothilone B(4a, aza-dEpoB), and the epimeric 12,13, 15-desoxy-15(R)-aza-epothilone B (4b, 15-epi-aza- dEpoB) have been evaluated in the context of a variety of cell types to evaluate their antitumor potential.
- Table 3 direct comparison of aza-EpoB with dEpoB showed that aza- EpoB was slightly more potent in vitro in our base leukemia cell line (CCRF-CEM), 0.0021 and 0.0095 ⁇ M respectively.
- aza-EpoB had markedly reduced activity in our multi- drug resistant cell lines (CCRF-CEM/ V BLIOO, CCRM-CEM/VMI, ⁇ CCRF-CEM/ Taxo ⁇ ) as compared with dEpoB. Additionally, as we have noted with epothilone B (containing a C12,13 epoxide) compaied with dEpoB (without epoxide), aza-dEpoB was about 10 fold less potent than the epoxide containing aza-EpoB. Also, 15-epi-aza-dEpoB displayed even further reduced activity in all cell lines tested.
- aza-dEpoB has been produced ti rough total chemical synthesis, using the strategy based on the convergent merger of the two key fragments by 5-alkyl Suzuki coupling and subsequent macrolactamization.
- aza-dEpoB was also successfully oxidized to aza-EpoB to study the in vitro activity. The synthesis has proven efficient and amenable to larger scale production to facilitate animal studies. As such, aza-dEpoB was shown to exhibit similar activity to dEpoB, but was not effective towards resistant cell lines. Whereas, aza-EpoB was more active than dEpoB in non-resistant cell lines, it proved ineffective when extended to in vivo models.
- Example 3 Experimental Section General Procedures. All commercial materials were used without fiirther purification unless otherwise noted. The following solvents were obtained from a dry solvent system and used without further drying: THF, diethyl ether, methylene chloride, toluene, and benzene. All reactions were performed under a positive pressure of prepurified dry argon gas. H and C NMR spectra were recorded in CDCI 3 solution at 400 and 100 MHz, respectively. Analytical thin layer chromatography was performed on E. Merck silica gel 60 F254 plates, and flash chromatography was performed using the indicated solvent on E. Merck silica gel 60 (40 — 63 ⁇ m) or Sigma H-type silica gel (10 - 40 ⁇ m).
- TES-protected alcohol 15 (2.28 g, 4.92 mmol) was dissolved in HO Ac: THF: H 2 0 (3: 1 : 1, 50 mL) and stirred at room temperature for 8 h. The solvent was then removed in vacuo. The oily residue was dissolved in EtOAc (100 mL) and excess acid was neutralized by the addition of sat. NaHC ⁇ 3 (50 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with sat. NaFIC ⁇ 3 (1 x 50 mL), brine (1 x 50 mL), and then dried (MgS0 ).
- reaction mixture was diluted with ethyl acetate (300 mL), washed with H 2 0 (1 x 250 mL), brine (1 x 100 mL), dried over MgS0 , filtered, and concentrated in vacuo.
- Taxol® is by far the most well known, extensively studied, and widely used front-line cancer chemotherapeutic agent, especially for treating solid tumors (Landino, L.M. & MacDonald, T.L. (1995) in: The Chemistry and Pharmacology of Taxol and Its Derivatives, ed. Favin, V. (Elsevier, New York ) Chap. 7.; Rose, W.C. (1992) Anti. Cancer Drugs 3, 311-321 ; Rowinsky, E.K., Eisenliauser, E.A., Chaudliry, V., Arbuck, S.G. & Doiiehower, R.C. (1993) Semin, Oncol, 20, 1-15).
- Therapeutic efficacy of cancer chemotherapeutic agents varies with various factors including the tumor models used and the dosage of drug and schedules and routes of administration.
- human colon carcinoma HCT-116 xenografts in nude mice dEpoB, dEpoF, paclitaxel and CPT-11 virtually showed similar curative effects against this tumor xenograft (Fig. 35).
- dEpoB, dEpoF, paclitaxel and CPT-11 virtually showed similar curative effects against this tumor xenograft (Fig. 35).
- dEpoB was particularly effective against naive non-MDR human chronic myelocytic leukemia K562 xenografts in nude mice. Complete remission was achieved for dEpoB, whereas Adriamycin, paclitaxel and vinblastine showed only partial curative or remissive effects. This is in contrast with our earlier reports (19,27,28) that dEpoB showed superior therapeutic effects than paclitaxel in a broad range of drug-resistant tumors (e.g., tumors resistant to VBL, Adr, or paclitaxel), but had similar efficacy as paclitaxel, in non-drug resistant tumors. b.
- drug-resistant tumors e.g., tumors resistant to VBL, Adr, or paclitaxel
- Nude mice bearing well established CCRF-CEM tumor xenografts were treated with 30 mg/kg of dEpoB or with 6 mg/kg of 15-azaEpoB, 6 In- - i.v. infusion Q2Dx6 as shown in Fig. 37. Moderate suppression of tumor growth by 15-azaEpoB was observed. However, dEpoF shrank tumor gradually and on day 28 (the 6 l dose) one of three mice was tumor free and the other two mice had only residual tumors (Fig. 38). In this experiment, the control mice continued to gain body-weight whereas dEpoF or 15-azaEpoB treated mice reduced body-weight about 10% on day 28 (Fig. 39). Comparison of Therapeutic Effect of dEpoB and 15 AzaEpoB against MX-1 Xenografts.
- Body-weight decreased about 3.5 gm on day 22 after dEpoB 30 mg/kg Q2D (day 10-20), but recovered to the near control body-weight on day 26.
- the body -weight dropped about 4.1 gm on day 36 and then gained about 2 gm body-weight during day 36-40, when tumor disappearance occurred. (Fig. 41 & 42).
- dEpoB 30-40 mg/kg and paclitaxel (Taxol ® ) 15- 24 mg/kg botii in Cremophor: EtOH (1:1) formulations were used for 6-hr i.v. infusion with the treatment schedules as indicated in Table 5. These doses of treatment led to 10-20% body- weight decrease without lethality. Depending on the tumor type, treatment started on day 10 to day 21 when subcutaneous tumor size reached 35-200 mm 3 , except otherwise indicated. Tumor size and body-weight were recorded every other day (Q2D) and, for humane reasons, the animals were sacrificed when tumor size reached > 10% of body-weight. Each group, including untreated control, consisted of 3-5 animals unless otherwise indicated.
- dEpoB showed the broadest and most efficacious therapeutic effects, followed by taxol, and then followed by other cancer chemotherapeutic agents tested.
- dEpoF has a similar therapeutic effect as dEpoB but had not yet been compared directly with other established cancer chemotherapeutic agents.
- EpoB and azaEpoB showed moderate .antitumor effect but appeared to have n.arrow therapeutic windows as indicated by the death at moderate decreases in body-weight (Ref. 19, tables 3 and 4 and this report Fig.38 and 39).
- dEpoB Toxicity and Pharmacokinetics of dEpoB in Beagle Dogs.
- dEpoB was formulated in Cremophor 3%, ethanol 3%, propyleneglycol
- the animal was pretreated at - 30 min with Benadryl 5mg/kg, i.v.; cimetidine 5mg/kg i.m.; and dexamethasone l g/kg, i.e. to minimize allergic reactions due to Cremophor administration.
- dEpoB Pharmacokinetic studies were also carried out for of dEpoB in beagle dogs at 6 mg/kg (120mg/m 2 body surface), with 10-min i.v. infusion. Serial blood samples were collected in 5 ml heparinized tubes intermittently from-15 min to 24 hours. Plasma concentrations of dEpoB were determined by HPLC as described in methods. The ⁇ -phase of ty- was 1.9 hrs .and the ⁇ -phase, 21 hrs (Fig. 45).
- epothiolones e.g., EpoA
- EpoB and dEpoB are distinct from taxanes (e.g., paclitaxel) in terms of their natural source, chemical structure, water solubility, Pgp-MDR profile, tolerance to structural modifications, difficulty in total synthesis, and anticancer spectrum. Results cumulated so far indicate that dEpoB has more favorable pharmacological features than paclitaxel both in vitro and in vivo, especially in terms of efficacy against drug-resistant cells or tumors (19, 29, Table 4).
- taxanes e.g., paclitaxel
- EpoB although more potent than EpoA, paclitaxel, and dEpoB, was shown to be highly toxic in nude mice and showed little therapeutic effect in mice bearing human tumor xenografts even at highly toxic doses when compared with dEpoB or paclitaxel (19).
- paclitaxel is a good substrate for Pgp-MDR and is ineffective against multiple-drug resistant tumors hi which dEpoB achieved curative effect (19, 20, 28 and Figs. 35 and 36).
- dEpoB and dEpoF were superior than taxol ® (Figs. 36, and 37) or 15-aza-EpoB (Figs. 38 and 39, 41 and 42), and some currently widely used cancer therapeutic agents such as dexombicm, vinblastine or CPT-11 (Fig. 35).
- the six-hour i.v. infusion of dEpoB to nude mice may have compensated the short half-life situations.
- the long half-life of dEpoB hi human plasma (Fig. 44) and in beagle dog (Fig. 45) may reduce the necessity for i.v. infusion in humans and in dogs.
- Essential features of useful cancer therapeutic agent involve not only high efficiency against cancer but also low toxicity toward the host, especially toward vital organs or functions [i.e. wide therapeutic window or high therapeutic index (LD50/ED50)].
- One important toxicological finding is that dEpoF and dEpoB may render 23-29% drop in body- weight in nude mice during treaUnent without causing lethality whereas only 14-20% drop in body- weight due to EpoB or azaEpoB led to lethality.
- Furthermore complete tumor disappearances were achieved for dEpoB and dEpoF in the absence of lethality (Figs. 36-42); whereas EpoB (19) or azaEpoB (Fig. 41-42) caused lethality when only marginal therapeutic effects were achieved.
- dEpoB (NSC-703147) (10,14), dEpoF (21) and aza EpoB (BMS 247550) (22) used in this study were obtained in our Bio-Organic Chemistry Laboratory through total synthesis as described.
- paclitaxel (Taxol®), etoposide (VP-16), teniposide (VM-26) camptothecin (CPT), actinomycin D (AD) and vinblastine sulfate (NBL) were purchased from Sigma. All stock solutions of the above (except VBL in saline) were prepared by using dimethyl sulfoxide (DMSO) solvent and were further diluted to desired concentrations for experimental use.
- DMSO dimethyl sulfoxide
- DMSO DMSO
- Cremophor/EtOH 1:1 vehicle
- Cremophor EL was purchased from Sigma.
- Paclitaxel in Cremophor/EtOH formulation was obtained commercially from clinical preparation (Bristol-Myers Squibb).
- Solubility in water for paclitaxel, dEpoB and dEpoF was approximately 0.6 mg/ml, lOmg/ml and 25mg/ml, respectively.
- Vinblastine sulfate VBL, Velban; Eli Lilly
- etoposide VP-16, Vepisid, Bristol- Myers Squibb
- Camptosar Irinotecan or CPT-11; pharmacia & Upjohn
- DX or Adr Doxorubiane-HCl; Astra Pharmaceutical
- CCRF-CEM human T cells acute lymphoblastic leukemic cells acute lymphoblastic leukemic cells
- CCRF-CEM/VMi teniposide- resistant subline
- CCRF-CEM/VBLioo vinblastine-resistaiit subline
- the resistant cells lines exhibited 4308- fold resistance to vinblastine (IC 5 0: 0.9743 ⁇ M), 282-fold resistance to paclitaxel (IC 50 : 0.339 ⁇ M), and 69-fold resistant to VP-16 (IC 50. 19.8 ⁇ M), respectively, when compared with the original CCRF-CEM cells at the beginning of the experiment (see Table 1). Similar procedure was used for the time-course of the development of drug-resistance to VBL, taxol, Adr and dEpoB in A549 human lung carcinoma cells (see Fig. 43). In each case ,the drug-exposed cells were resuspended in fresh media for a minimum of 4 days before the experiments for the cell- growth inhibition was carried out.
- Ovarian adenocarcinoma UL3-C, UL3-B/taxol, hamster lung fibroblasts and its sublines DC-3F, DC-3F/ADII and DC-3F/ADX were obtained from the cell bank of this institution.
- mammary carcinoma MX-1
- mammary adenocarcinoma MCF-7
- ovarian adenocarcinoma SK-OV-3
- lung carcinoma A549
- colon adenocarcinoma HT-29
- colon carcinoma PICT- 116
- prostate adenocarcinoma PC-3
- chronic myeloblastic leukemia
- the cells were cultured at an initial density of 2-5x10 4 cells per ml. They were maintained iii a 5% C0 2 -humidified atmosphere at 37°C in RPMI medium 1640 (GIBCO/BRL) containing penicillin (100 units/ml), streptomycin (100 ⁇ g/ml) (GIBCO/BRL), and 5% heat- inactivated fetal bovine serum.
- RPMI medium 1640 containing penicillin (100 units/ml), streptomycin (100 ⁇ g/ml)
- 5% heat- inactivated fetal bovine serum For solid tumor cells growing in a monolayer (such as MCF-
- HCT-116 dEpoB 30mg/kg Q2Dx5,x3 0 1/2 ⁇ Fig. 2
- CCRF/CEM dEpoB 40mg/kg Q2Dx4 0 2/2 Leukemia Taxol 20mg/kg Q2Dx4 0 2/2 #
- Cremophor-EtOH (1:1) was used as a solvent for both dEpoB and taxol for 6-hr infusion with doses and schedules as indicated.
- the therapeutic effects were compared with the tumor size reduction or disappearance of the maximally tolerated doses as measured by body weight decreases and lack of lethality.
- the relative therapeutic effects are indicated by: >, greater: » much greater: >», very much greater; «, almost equal; > equal; or slightly greater; ⁇ _, equal or slightly less. # Chou, T.-C, (unpublished results)
- Table 6 Comparison of chemotherapeutic effect among dEpoB, dEpoF, EpoB, 15-aza-EpoB, paclitaxel (Taxol®) and/or other cancer therapeutic agents in murine B 16 melanoma or in nude mice bearing human tumor xenografts.
- the therapeutic effects were compared with the tumor size reduction or disappearance at the maximal tolerated doses as measured by body weight decreases and lack of lethality.
- the relative therapeutic effects are indicated by: >, greater; » much greater; >» very much greater; » almost equal; > equal; or slightly greater. + 10
- Murine melanoma all others are human tumor xenografts.
- DMSO was used as solvent for i.p. injection whereas Cremophor-EtOH (1:1) was used for i.v. infusion for all dEpoB or EpoB studies.
- Clinical preparations were used for taxol, vinblastine, Adriamycin, VP-16 and camptothecin. # Chou, T.-C, et al (unpublished results)
- Example 5 Additional biological data and synthesis of analogues
- dEpoF Stability of dEpoF in animal plasmas.
- a HPLC method is setup using a ovaPak C18, 3.9 x 300 mm column with a mobile phase of 50% acetonitrile in 50 mM potassium dihydrogen phosphate with 0.01% triethylamine at a flow rate of 0.8ml/min.
- dEpoF is monitored at a wavelength of 260 nm and has a retention time of about 10 min.
- the plasma stability is performed with mouse plasma and dog plasma purchased from Pel-Freeze and human plasma from the blood center in MSKCC. A small amount of dEpoF was dissolved in 50% methanol/water at a concentration of 500 ⁇ g/mL.
- Tosylate (5) Tosylate (5). To a solution of dEpoF (4.2 mg, 0.0083 mmol) and pyridine (0.1 mL) in CH 2 C1 2 (0.2 mL) was added j_ toluenesulfonyl chloride (2.4 mg, 0.013 mmol) at 0 °C. The resulting solution was stirred for 1 h at which point TLC analysis indicated a small progress of the reaction. An additional amount of ? toluenesulfonyl chloride (1.0 mg) and 4- dimethylaminopyridine (0.1 mg) were further added, and the stirring was continued for 0.5 h.
- dEpoB The identity of dEpoB was verified by chromatographic and spectroscopic comparison of the sample with previously obtained data.
- Aldehyde (8) To a solution of dEpoF (10.0 mg, 0.0197mmol) in CH 2 C1 2 (0.5 mL) was added manganese dioxide (pre-activated, 14 mg, 0.16 mmol). After stirring at rt for 2 h, the mixture was filtered through a short pad of silica gel column. The filtrate was concentrated to give aldehyde 8 (8.9 mg, 89%) as a viscous, colorless oil.
- dEpoF is slightly less potent than dEpoB and 21-oxo-dEpoB is about 3.7 x less potent than dEpoB and shows a similar degree of low drug resistance as dEpoB.
- dEpoF is 4.5 x less potent than dEpoB and 21-oxo-dEpoB is 5.1 x less potent than dEpoB.
- dEpoB is 8.6 x resistant
- 21-oxo-dEpoB is 11.9 x resistant
- dEpoF is 33.6 x resistant.
- C12-Diox-dEpoB C12-Diox-dEpoB
- TBDPS protected alkyne 1 Compound 1 undergoes .an iodo-boration with B-Iodo-9- BBN.
- the resulting vinyl borane adds to methyl vinyl ketone in a 1,4 manner to provide ketone 2 in 78% yield.
- the silyl group is removed by treatment with HF-pyridine to afford primary alcohol 3. This proved to be necessary as the TBDPS ether is not compatible with the synthesis at a latter stage.
- thermodynamic enol ether is generated in approximately a 9:1 ratio (thermo:kinetic) witii TMSI and HMDS in 95 % yield.
- the primary alcohol is simultaneously protected as the TMS ether during the reaction.
- Asymmetric installation of the hydroxyl group is accomplished by using the Slwpless dihydroxylation methodology to provide, following hydrolysis of the primary silyl group and protection of the resulting diol as the bis TES derivative, compound 4 in 56% overall yield.
- An efficient Horner olefination with phosphine oxide 5 and ketone 4 (86%) forms the final carbon-carbon bond in the vinyl iodide segment.
- the primary TES is removed under carefully controlled conditions using 2% acetic acid in methanol at 0 °C and the resulting alcohol is reprotected as the Troc carbonate to provide compound 8.
- a crucial step in the synthesis involves the ligation of vinyl iodide 8 and polypropionate 9 to form the fully elaborated carbon skeleton. This is accomplished by using a Suzuki cross- coupling which provides compound 10 in 77% yield.
- the tert-Butyl ester is subsequently deprotected through treatment with TESOTf, and the resulting silyl ester and die C15 silyl ether .are simult. neously hydrolyzed by treatment with dilute HCl in methanol.
- the resulting seco- acid undergoes a Yamaguichi cyclization to afford macrolactone 12 in 71% yield.
- Both Troc carbonates are removed with zinc metal in acetic acid to provide diol 13 in 68 % yield.
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Application Number | Priority Date | Filing Date | Title |
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US18596800P | 2000-03-01 | 2000-03-01 | |
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PCT/US2001/006643 WO2001064650A2 (en) | 2000-03-01 | 2001-03-01 | Synthesis of epothilones, intermediates thereto and analogues thereof |
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Publication Number | Publication Date |
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EP1259490A2 true EP1259490A2 (en) | 2002-11-27 |
Family
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Family Applications (1)
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EP01916335A Withdrawn EP1259490A2 (en) | 2000-03-01 | 2001-03-01 | Synthesis of epothilones, intermediates thereto and analogues thereof |
Country Status (5)
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EP (1) | EP1259490A2 (en) |
JP (1) | JP2004500388A (en) |
AU (1) | AU2001243372A1 (en) |
CA (1) | CA2401800A1 (en) |
WO (1) | WO2001064650A2 (en) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0977563B1 (en) | 1996-12-03 | 2005-10-12 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
EP1383490B1 (en) | 2001-03-14 | 2012-04-25 | Bristol-Myers Squibb Company | Combination of an epothilone analog and chemotherapeutic agents for the treatment of proliferative diseases |
KR20050043796A (en) * | 2002-05-20 | 2005-05-11 | 코산 바이오사이언시즈, 인코포레이티드 | Methods to administer epothilone d |
CA2487147A1 (en) * | 2002-06-10 | 2003-12-18 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
WO2004007492A1 (en) * | 2002-07-15 | 2004-01-22 | Gesellschaft Fuer Biotechnolgische Forschung Mbh (Gbf) | Novel macrocycles for the treatment of cancer |
AR040956A1 (en) | 2002-07-31 | 2005-04-27 | Schering Ag | NEW CONJUGATES OF EFFECTORS, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL USE |
JP2006505627A (en) * | 2002-07-31 | 2006-02-16 | シエーリング アクチエンゲゼルシャフト | Novel effector conjugates, methods for their production and their pharmaceutical use |
EP1767535B1 (en) | 2002-08-23 | 2009-12-02 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US7384964B2 (en) * | 2002-08-23 | 2008-06-10 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
AU2003264822A1 (en) * | 2002-10-11 | 2004-05-04 | Dana-Farber Cancer Institute Inc | Epothilone derivatives for the treatment of multiple myeloma |
JP2005095152A (en) * | 2003-08-29 | 2005-04-14 | Japan Tissue Engineering:Kk | Method for preserving cultured tissue |
EP1674098A1 (en) | 2004-12-23 | 2006-06-28 | Schering Aktiengesellschaft | Stable and tolerable parental formulations of highly reactive organic drug substances with low or no solubility in water |
WO2008083491A1 (en) | 2007-01-11 | 2008-07-17 | Critical Outcome Technologies Inc. | Compounds and method for treatment of cancer |
EP2065054A1 (en) | 2007-11-29 | 2009-06-03 | Bayer Schering Pharma Aktiengesellschaft | Combinations comprising a prostaglandin and uses thereof |
EP2070521A1 (en) | 2007-12-10 | 2009-06-17 | Bayer Schering Pharma Aktiengesellschaft | Surface-modified nanoparticles |
DE102007059752A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Functionalized solid polymer nanoparticles containing epothilones |
WO2009079797A1 (en) | 2007-12-26 | 2009-07-02 | Critical Outcome Technologies, Inc. | Compounds and method for treatment of cancer |
EP3023426A1 (en) | 2008-07-17 | 2016-05-25 | Critical Outcome Technologies, Inc. | Thiosemicarbazone inhibitor compounds and cancer treatment methods |
EP2210584A1 (en) | 2009-01-27 | 2010-07-28 | Bayer Schering Pharma Aktiengesellschaft | Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer |
EP3235818A3 (en) | 2010-04-01 | 2018-03-14 | Critical Outcome Technologies, Inc. | Compounds for the treatment of hiv |
EP2793949B1 (en) | 2011-12-23 | 2018-08-22 | Innate Pharma | Enzymatic conjugation of antibodies |
EP2872894B1 (en) | 2012-07-13 | 2019-04-17 | Innate Pharma | Screening of conjugated antibodies |
EP2916872B1 (en) | 2012-11-09 | 2019-02-27 | Innate Pharma | Recognition tags for tgase-mediated conjugation |
US9309259B2 (en) | 2013-03-08 | 2016-04-12 | Scinopharm Taiwan, Ltd. | Process for ixabepilone, and intermediates thereof |
US10611824B2 (en) | 2013-03-15 | 2020-04-07 | Innate Pharma | Solid phase TGase-mediated conjugation of antibodies |
EP3010547B1 (en) | 2013-06-20 | 2021-04-21 | Innate Pharma | Enzymatic conjugation of polypeptides |
CA2914189C (en) | 2013-06-21 | 2023-03-14 | Innate Pharma | Enzymatic conjugation of polypeptides |
WO2019092148A1 (en) | 2017-11-10 | 2019-05-16 | Innate Pharma | Antibodies with functionalized glutamine residues |
KR20210150496A (en) * | 2019-04-05 | 2021-12-10 | 프로린크스 엘엘시 | Improved conjugation linker |
-
2001
- 2001-03-01 AU AU2001243372A patent/AU2001243372A1/en not_active Abandoned
- 2001-03-01 EP EP01916335A patent/EP1259490A2/en not_active Withdrawn
- 2001-03-01 CA CA002401800A patent/CA2401800A1/en not_active Abandoned
- 2001-03-01 JP JP2001563492A patent/JP2004500388A/en not_active Withdrawn
- 2001-03-01 WO PCT/US2001/006643 patent/WO2001064650A2/en active Application Filing
Non-Patent Citations (1)
Title |
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See references of WO0164650A2 * |
Also Published As
Publication number | Publication date |
---|---|
AU2001243372A1 (en) | 2001-09-12 |
JP2004500388A (en) | 2004-01-08 |
WO2001064650A3 (en) | 2002-05-10 |
WO2001064650A2 (en) | 2001-09-07 |
CA2401800A1 (en) | 2001-09-07 |
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