ES2436296T3 - Trans-9,10-dehidroepotilona C y trans-9,10-dehidroepotilona D, sus análogos y procedimientos de fabricación de las mismas - Google Patents
Trans-9,10-dehidroepotilona C y trans-9,10-dehidroepotilona D, sus análogos y procedimientos de fabricación de las mismas Download PDFInfo
- Publication number
- ES2436296T3 ES2436296T3 ES09012671T ES09012671T ES2436296T3 ES 2436296 T3 ES2436296 T3 ES 2436296T3 ES 09012671 T ES09012671 T ES 09012671T ES 09012671 T ES09012671 T ES 09012671T ES 2436296 T3 ES2436296 T3 ES 2436296T3
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- Prior art keywords
- compound
- dehydroepotilone
- alkyl
- compounds
- trans
- 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.)
- Expired - Lifetime
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- 238000004519 manufacturing process Methods 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 154
- 239000000203 mixture Substances 0.000 claims description 78
- -1 = C1-4 N-alkoxy Chemical group 0.000 claims description 76
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 201000011510 cancer Diseases 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 238000011282 treatment Methods 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001475 halogen functional group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 230000001413 cellular effect Effects 0.000 claims description 8
- 230000003463 hyperproliferative effect Effects 0.000 claims description 8
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 7
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 125000004945 acylaminoalkyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 3
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- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 229940127557 pharmaceutical product Drugs 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 239000000243 solution Substances 0.000 description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- 238000000034 method Methods 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 40
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 37
- 239000000047 product Substances 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 30
- 239000000543 intermediate Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 229930013356 epothilone Natural products 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 22
- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 21
- 239000012267 brine Substances 0.000 description 21
- 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 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 20
- 235000019341 magnesium sulphate Nutrition 0.000 description 20
- 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 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 235000017557 sodium bicarbonate Nutrition 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 18
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 18
- 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 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 150000003883 epothilone derivatives Chemical class 0.000 description 15
- 230000009467 reduction Effects 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
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- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 229920000858 Cyclodextrin Polymers 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- VDDXQSUSMHZCLS-UHFFFAOYSA-N ethenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC=C VDDXQSUSMHZCLS-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000008389 polyethoxylated castor oil Substances 0.000 description 9
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- 230000008030 elimination Effects 0.000 description 8
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- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 7
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 6
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- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 6
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Landscapes
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| CN1330648C (zh) * | 2002-11-07 | 2007-08-08 | 科桑生物科学公司 | 反式－9,10－脱氢埃坡霉素c和d,其类似物以及制备这些化合物的方法 |
| SI1562941T1 (sl) * | 2002-11-07 | 2010-05-31 | Kosan Biosciences Inc | Trans dehidroepotilon c in d njihovi analogi in postopek za izdelavo le teh |
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| CN104086641A (zh) * | 2007-02-23 | 2014-10-08 | 爱勒让治疗公司 | 三唑大环系统 |
| CA2682174C (en) | 2007-03-28 | 2021-04-06 | President And Fellows Of Harvard College | Stitched polypeptides |
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| US9175047B2 (en) | 2009-01-14 | 2015-11-03 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
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| WO2012021875A1 (en) | 2010-08-13 | 2012-02-16 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles with triazole linkers |
| CN108929375A (zh) | 2011-10-18 | 2018-12-04 | 爱勒让治疗公司 | 拟肽大环化合物 |
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| US10905739B2 (en) | 2014-09-24 | 2021-02-02 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and formulations thereof |
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| US5415869A (en) | 1993-11-12 | 1995-05-16 | The Research Foundation Of State University Of New York | Taxol formulation |
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| US5534270A (en) | 1995-02-09 | 1996-07-09 | Nanosystems Llc | Method of preparing stable drug nanoparticles |
| US5510118A (en) | 1995-02-14 | 1996-04-23 | Nanosystems Llc | Process for preparing therapeutic compositions containing nanoparticles |
| WO1997033552A1 (en) | 1996-03-12 | 1997-09-18 | Pg-Txl Company, L.P. | Water soluble paclitaxel prodrugs |
| US6458373B1 (en) | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| PL201329B1 (pl) | 1998-02-05 | 2009-03-31 | Novartis Ag | Preparat farmaceutyczny w postaci koncentratu infuzyjnego |
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| DE19954229A1 (de) * | 1999-11-04 | 2001-05-10 | Schering Ag | Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung |
| DE19907480A1 (de) * | 1999-02-11 | 2000-08-17 | Schering Ag | Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung |
| US6156373A (en) | 1999-05-03 | 2000-12-05 | Scimed Life Systems, Inc. | Medical device coating methods and devices |
| MXPA01011981A (es) | 1999-05-24 | 2003-09-04 | Sonus Pharma Inc | Vehiculo de emulsion para farmacos poco solubles. |
| GB9918429D0 (en) | 1999-08-04 | 1999-10-06 | Novartis Ag | Organic compounds |
| CN100480389C (zh) | 2000-04-28 | 2009-04-22 | 科塞生物科学有限公司 | 聚酮化合物的制备 |
| AU2001266583A1 (en) * | 2000-05-26 | 2001-12-11 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
| US6906188B2 (en) * | 2001-04-30 | 2005-06-14 | State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University | Method for synthesizing epothilones and epothilone analogs |
| US20030176368A1 (en) * | 2001-09-06 | 2003-09-18 | Danishefsky Samuel J. | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US7649006B2 (en) * | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6921769B2 (en) * | 2002-08-23 | 2005-07-26 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| DK1767535T3 (da) * | 2002-08-23 | 2010-04-12 | Sloan Kettering Inst Cancer | Syntese af epothiloner, mellemprodukter deraf, analoge og deres anvendelse |
| SI1562941T1 (sl) * | 2002-11-07 | 2010-05-31 | Kosan Biosciences Inc | Trans dehidroepotilon c in d njihovi analogi in postopek za izdelavo le teh |
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2003
- 2003-11-07 SI SI200331732T patent/SI1562941T1/sl unknown
- 2003-11-07 JP JP2005507102A patent/JP4641941B2/ja not_active Expired - Fee Related
- 2003-11-07 EP EP09012671.5A patent/EP2135867B1/en not_active Expired - Lifetime
- 2003-11-07 ES ES09012671T patent/ES2436296T3/es not_active Expired - Lifetime
- 2003-11-07 KR KR1020057008039A patent/KR100966667B1/ko not_active Expired - Fee Related
- 2003-11-07 KR KR1020107000780A patent/KR100996996B1/ko not_active Expired - Fee Related
- 2003-11-07 ES ES03768730T patent/ES2336911T3/es not_active Expired - Lifetime
- 2003-11-07 WO PCT/US2003/035411 patent/WO2004043954A2/en not_active Ceased
- 2003-11-07 EP EP09012860A patent/EP2135868A1/en not_active Withdrawn
- 2003-11-07 PT PT03768730T patent/PT1562941E/pt unknown
- 2003-11-07 AT AT03768730T patent/ATE452888T1/de active
- 2003-11-07 EP EP03768730A patent/EP1562941B1/en not_active Expired - Lifetime
- 2003-11-07 CA CA2505368A patent/CA2505368C/en not_active Expired - Fee Related
- 2003-11-07 DK DK03768730.8T patent/DK1562941T3/da active
- 2003-11-07 DE DE60330703T patent/DE60330703D1/de not_active Expired - Lifetime
- 2003-11-07 AU AU2003291337A patent/AU2003291337B2/en not_active Ceased
- 2003-11-07 US US10/703,404 patent/US20040152708A1/en not_active Abandoned
-
2008
- 2008-07-11 US US12/172,174 patent/US20090186927A1/en not_active Abandoned
-
2010
- 2010-03-19 CY CY20101100250T patent/CY1110295T1/el unknown
- 2010-10-08 JP JP2010228356A patent/JP5679757B2/ja not_active Expired - Fee Related
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2013
- 2013-07-16 JP JP2013147528A patent/JP2013213054A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| KR100966667B1 (ko) | 2010-06-29 |
| KR20050084959A (ko) | 2005-08-29 |
| US20090186927A1 (en) | 2009-07-23 |
| PT1562941E (pt) | 2010-01-25 |
| US20040152708A1 (en) | 2004-08-05 |
| CA2505368C (en) | 2011-09-20 |
| WO2004043954A3 (en) | 2004-11-18 |
| WO2004043954A2 (en) | 2004-05-27 |
| JP4641941B2 (ja) | 2011-03-02 |
| JP2011006480A (ja) | 2011-01-13 |
| ATE452888T1 (de) | 2010-01-15 |
| EP2135867A1 (en) | 2009-12-23 |
| KR20100018075A (ko) | 2010-02-16 |
| SI1562941T1 (sl) | 2010-05-31 |
| CY1110295T1 (el) | 2015-01-14 |
| JP5679757B2 (ja) | 2015-03-04 |
| AU2003291337A1 (en) | 2004-06-03 |
| JP2006510743A (ja) | 2006-03-30 |
| EP2135867B1 (en) | 2013-09-25 |
| ES2336911T3 (es) | 2010-04-19 |
| JP2013213054A (ja) | 2013-10-17 |
| EP1562941A2 (en) | 2005-08-17 |
| EP1562941B1 (en) | 2009-12-23 |
| AU2003291337B2 (en) | 2010-09-09 |
| EP2135868A1 (en) | 2009-12-23 |
| KR100996996B1 (ko) | 2010-11-25 |
| DE60330703D1 (de) | 2010-02-04 |
| DK1562941T3 (da) | 2010-04-19 |
| CA2505368A1 (en) | 2004-05-27 |
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