USRE41911E1 - Epothilone derivatives - Google Patents
Epothilone derivatives Download PDFInfo
- Publication number
- USRE41911E1 USRE41911E1 US12/539,492 US53949209A USRE41911E US RE41911 E1 USRE41911 E1 US RE41911E1 US 53949209 A US53949209 A US 53949209A US RE41911 E USRE41911 E US RE41911E
- Authority
- US
- United States
- Prior art keywords
- cancer
- methyl
- compound
- patient
- alkyl
- 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, expires
Links
- 150000003883 epothilone derivatives Chemical class 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims description 336
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 77
- 125000000217 alkyl group Chemical group 0.000 claims description 58
- 229910052760 oxygen Inorganic materials 0.000 claims description 52
- 238000011282 treatment Methods 0.000 claims description 52
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 46
- 239000001301 oxygen Chemical group 0.000 claims description 44
- LZWPOLSJFGLQCE-UHFFFAOYSA-N heptadecane-5,9-dione Chemical compound CCCCCCCCC(=O)CCCC(=O)CCCC LZWPOLSJFGLQCE-UHFFFAOYSA-N 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 229920006395 saturated elastomer Polymers 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 34
- -1 1-methyl-2-(substituted-4-thiazolyl)ethenyl Chemical group 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- 201000011510 cancer Diseases 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000003107 substituted aryl group Chemical group 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004122 cyclic group Chemical group 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 11
- 125000002950 monocyclic group Chemical group 0.000 claims description 11
- 210000001672 ovary Anatomy 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 10
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 10
- 210000001072 colon Anatomy 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- 201000001441 melanoma Diseases 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 229910052717 sulfur Chemical group 0.000 claims description 10
- 239000011593 sulfur Chemical group 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 6
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 claims description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 230000001093 anti-cancer Effects 0.000 claims description 4
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 4
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 4
- 125000004476 heterocycloamino group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 102000003915 DNA Topoisomerases Human genes 0.000 claims description 3
- 108090000323 DNA Topoisomerases Proteins 0.000 claims description 3
- 239000012624 DNA alkylating agent Substances 0.000 claims description 3
- 230000000970 DNA cross-linking effect Effects 0.000 claims description 3
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 claims description 3
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000001769 aryl amino group Chemical group 0.000 claims description 3
- 230000022131 cell cycle Effects 0.000 claims description 3
- 239000003431 cross linking reagent Substances 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 239000003145 cytotoxic factor Substances 0.000 claims description 3
- 239000003102 growth factor Substances 0.000 claims description 3
- 125000004470 heterocyclooxy group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 2
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 18
- 206010033128 Ovarian cancer Diseases 0.000 claims 18
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 18
- 208000029742 colonic neoplasm Diseases 0.000 claims 18
- 206010005003 Bladder cancer Diseases 0.000 claims 9
- 208000003174 Brain Neoplasms Diseases 0.000 claims 9
- 206010006187 Breast cancer Diseases 0.000 claims 9
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 9
- 208000034578 Multiple myelomas Diseases 0.000 claims 9
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 claims 9
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims 9
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 9
- 206010035226 Plasma cell myeloma Diseases 0.000 claims 9
- 206010060862 Prostate cancer Diseases 0.000 claims 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 9
- 206010039491 Sarcoma Diseases 0.000 claims 9
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 9
- 201000004101 esophageal cancer Diseases 0.000 claims 9
- 201000003115 germ cell cancer Diseases 0.000 claims 9
- 201000010536 head and neck cancer Diseases 0.000 claims 9
- 208000014829 head and neck neoplasm Diseases 0.000 claims 9
- 201000005202 lung cancer Diseases 0.000 claims 9
- 208000020816 lung neoplasm Diseases 0.000 claims 9
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 9
- 230000012106 negative regulation of microtubule depolymerization Effects 0.000 claims 9
- 201000002528 pancreatic cancer Diseases 0.000 claims 9
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 9
- 206010044412 transitional cell carcinoma Diseases 0.000 claims 9
- 201000005112 urinary bladder cancer Diseases 0.000 claims 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 229940126161 DNA alkylating agent Drugs 0.000 claims 2
- 229940123934 Reductase inhibitor Drugs 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 2
- 150000004982 aromatic amines Chemical group 0.000 claims 1
- 238000001959 radiotherapy Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 52
- 239000011541 reaction mixture Substances 0.000 description 50
- 0 [1*]C1([2*])C(=C)[W]C([7*])(C)CCCCCC([6*])C(BB)C([5*])C(=[Y])C([3*])([4*])C1B Chemical compound [1*]C1([2*])C(=C)[W]C([7*])(C)CCCCCC([6*])C(BB)C([5*])C(=[Y])C([3*])([4*])C1B 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000377 silicon dioxide Substances 0.000 description 24
- 229910052681 coesite Inorganic materials 0.000 description 22
- 229910052906 cristobalite Inorganic materials 0.000 description 22
- 229910052682 stishovite Inorganic materials 0.000 description 22
- 229910052905 tridymite Inorganic materials 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 17
- 239000000284 extract Substances 0.000 description 17
- 238000010828 elution Methods 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 229940126062 Compound A Drugs 0.000 description 12
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 12
- 239000003638 chemical reducing agent Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000003039 volatile agent Substances 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000007822 coupling agent Substances 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 150000001336 alkenes Chemical class 0.000 description 5
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 5
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 5
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 5
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 4
- 239000012448 Lithium borohydride Substances 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 4
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229930013356 epothilone Natural products 0.000 description 4
- 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 4
- 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 4
- 238000006735 epoxidation reaction Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 125000000466 oxiranyl group Chemical group 0.000 description 4
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- 229910019020 PtO2 Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000037906 ischaemic injury Diseases 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003971 isoxazolinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- OKGGRXMKBJLXHI-UHFFFAOYSA-N lithium;triethoxyalumane Chemical compound [Li].CCO[Al](OCC)OCC OKGGRXMKBJLXHI-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- 229960003908 pseudoephedrine Drugs 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000004276 retinal vascularization Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000002342 ribonucleoside Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
- 125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000001730 thiiranyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- ZCAGUOCUDGWENZ-UHFFFAOYSA-N thiomorpholinyl sulfoxide group Chemical group N1(CCSCC1)S(=O)N1CCSCC1 ZCAGUOCUDGWENZ-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- KPGXUAIFQMJJFB-UHFFFAOYSA-H tungsten hexachloride Chemical compound Cl[W](Cl)(Cl)(Cl)(Cl)Cl KPGXUAIFQMJJFB-UHFFFAOYSA-H 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
- C07D225/02—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/28—Radicals substituted by nitrogen atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
Description
have been found to exert microtubule-stabilizing effects similar to TAXOL and hence cytotoxic activity against rapidly proliferating cells, such as, tumor cells or other hyperproliferative cellular disease, see Angew. Chem. Int. Ed. Engl., 1996, 35, No. 13/14.
-
- Q is selected from the group consisting of
- G is selected from the group consisting of alkyl, substituted alkyl, substituted or unsubstituted aryl, heterocyclo,
- W is O or NR15;
- X is O or H, H;
- Y is selected from the group consisting of O; H, OR16; OR17, OR17; NOR18; H, NOR19; H, NR20R21; H, H; or CHR22; OR17 OR17 can be a cyclic ketal;
- Z1, and Z2 are selected from the group consisting of CH2, O, NR23, S, or SO2, wherein only one of Z1 and Z2 can be a heteroatom;
- B1 and B2 are selected from the group consisting of OR24, or OCOR25, or O2CNR26R27; when B1 is OH and Y is OH, H they can form a six-membered ring ketal or acetal;
- D is selected from the group consisting of NR28R29, NR30COR31 or saturated heterocycle;
- R1, R2, R3, R4, R5, R6, R7, R13, R14, R18, R19, R20, R21, R22, R26, and R27 are selected from the group H, alkyl, substituted alkyl, or aryl and when R1 and R2 are alkyl can be joined to form a cycloalkyl; R3 and R4 are alkyl can be joined to form a cycloalkyl;
- R9, R10, R16, R17, R24, R25, and R31 are selected from the group H, alkyl, or substituted alkyl;
- R8, R11, R12, R28, R30, R32, R33, and R30 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or heterocyclo;
- R15, R23 and R29 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R32C═O, R33SO2, hydroxy, O-alkyl or O-substituted alkyl;
- and any salts, solvates or hydrates thereof.
Proviso
- Q is selected from the group consisting of
-
- W and X are both O; and
- R1, R2, R7, are H; and
- R3, R4, R6, are methyl; and
- R8, is H or methyl; and
- Z1, and Z2, are CH2; and
- G is 1-methyl-2-(substituted-4-thiazolyl)ethenyl;
- Q is as defined above.
-
- a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Acamedic Press, 1985);
- b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs,” by H. Bundgaard, p. 113-191 (1991);
- c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
- d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
- e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984).
-
- carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma;
- hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burketts lymphoma;
- hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia;
- tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas;
- tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and
- other tumors including melanoma, xenoderma, pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma.
-
- Q is
- X is O
- Y is O
- Z1 and Z2 are CH2 and
- W is NR15.
Method of Preparation
- Q is
wherein R3, R4, R5, R6, R8 and R15 are as above and P1 is an oxygen protecting group.
and D is selected from the group consisting of NR28R29, NR30COR31, and saturated heterocycle (i.e., piperidinyl, morpholinyl, piperazinyl, etc.) can be prepared as shown in Scheme 9. A compound of formula LI can be prepared from a compound of formula XXXII by reductive amination using a primary or secondary amine and a reducing agent such as sodium triacetoxyborohydride. Compounds of formula LIII, LIV, and V can then be prepared following methods described above in Scheme 1.
and D is selected from the group consisting of NR28R29, NR30COR31, and saturated heterocycle (i.e., piperidinyl, morpholinyl, piperazinyl, etc.) can be prepared from a compound of formula V as shown in Scheme 10. A compound of formula V can be converted to a compound of formula LV by protection of the hydroxyl groups with suitable protecting groups such as t-butyldimethylsilyl. A compound of formula LVI can be prepared from a compound of formula LV by ozonolysis. Treatment of a compound of formula LVI with an amine and a reducing agent such as sodium triacetoxyboro-hydride provides a compound of formula LVII. Removal of the protecting groups from a compound of formula LVII, with for example hydrogen fluoride, provides a compound of formula V where X is oxygen, W is NR15 or oxygen, and G is
can be prepared as outline d in Scheme 11. A compound of formula LVIII can be prepared from a compound of formula XXX by treatment with an amine and standard amide bond coupling agents such as EDCI and HOBT. A compound of formula LX can be prepared from a compound of formula LVIII by N-deprotection, using for example trifluoroacetic acid when P2 is a t-butyloxycarbonyl group, followed by coupling of compounds of formula LIX and XIII using standard amide bond coupling agents such as EDCI and HOBT. A compound of formula LXI can be prepared from a compound of formula LX by ring-closing metathesis. A compound of formula V can be prepared from a compound of formula LXI following methods described in Scheme 1.
can be prepared as outlined in Scheme 12. A compound of formula LXII can be prepared from allylglycine by treatment with nitrous acid. A compound of formula LXIII can be prepared from a compound of formula LXII by treatment with an amine and standard amide bond coupling agents such as EDCI and HOBT. A compound of formula LXIV can be prepared from compounds of formula LXIII and XIII using standard amide bond coupling agents such as EDCI and HOBT. A compound of formula LXV can be prepared from a compound of formula LXIV by ring-closing metathesis. A compound of formula V can be prepared from a compound of formula LXV following methods described in Scheme 1.
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4thiazolyl)ethenyl]-1-aza-13(E)-cyclohexadecene-2,6-dione
A. N-[(2-Methyl)-1-propenyl]morpholine.
J. (S)-2[N-[(tert-Butyloxy)carbonyl]amino]-4pentenoic acid.
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [1S[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,13,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,10-dioxa-13-cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;]
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,14,17-trioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclobexadecene-2,6-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E))]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1,11-dioxa-13-cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;
- 1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-9-one;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13,16-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,16-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-oxa-13-cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-6,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-6,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-4,8,8,10,12,16-hexamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;]
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-4,8,8,10,12-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-1,5,5,7,9,13-hexamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-1,5,5,7,9-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13-cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-13-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13-cyclohexadecene-2,6-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-10-aza-1-oxa-13- cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-14-aza-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;
- [4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-11-aza-1-oxa-13-cyclohexadecene-2,6-dione;
- [1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-Phenyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;
- [1S-[1R*,3R*,7R*,10S*,11R*,12R*,16S*]]-N-Phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecane-3-carboxamide;
- [4S-[4R*,7S*,8R*,9R*,15R*]]-N-Phenyl-4,8-dihydroxy-5,5,7,9,13-pentamethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide;
- [4S-[4R*,7S*,8R*,9R*,15R*]]-N-Phenyl-4,8-dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide.
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.
- [1S-[R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)cyclopropyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.
A. (3S,6R,7S,8S,12R,13S,15S)-15-Azido-3,7-dihydroxy-12,13-epoxy-4,4,6,8,16-pentamethyl-17-(2-methyl-4-thiazolyl)oxo-16(E)-heptadecenoic acid.
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6dione.
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-hydroxymethyl-4-thiazolyl)ethenyl]-1-aza-13(Z)-cyclohexadecene-2,6-dione.
Claims (62)
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US11/512,623 Expired - Lifetime US7241755B2 (en) | 1997-07-08 | 2006-08-30 | Epothilone derivatives |
US11/763,636 Expired - Fee Related US8536327B2 (en) | 1997-07-08 | 2007-06-15 | Epothilone derivatives |
US12/539,498 Expired - Lifetime USRE41893E1 (en) | 1997-07-08 | 2009-08-11 | Epothilone derivatives |
US12/539,492 Expired - Lifetime USRE41911E1 (en) | 1997-07-08 | 2009-08-11 | Epothilone derivatives |
US12/539,496 Expired - Lifetime USRE41895E1 (en) | 1997-07-08 | 2009-08-11 | Epothilone derivatives |
US12/882,769 Expired - Fee Related USRE43003E1 (en) | 1997-07-08 | 2010-09-15 | Epothilone derivatives |
US13/966,613 Expired - Fee Related US8921542B2 (en) | 1997-07-08 | 2013-08-14 | Epothilone derivatives |
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US11/512,623 Expired - Lifetime US7241755B2 (en) | 1997-07-08 | 2006-08-30 | Epothilone derivatives |
US11/763,636 Expired - Fee Related US8536327B2 (en) | 1997-07-08 | 2007-06-15 | Epothilone derivatives |
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US13/966,613 Expired - Fee Related US8921542B2 (en) | 1997-07-08 | 2013-08-14 | Epothilone derivatives |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021142202A1 (en) | 2020-01-10 | 2021-07-15 | R-Pharm Us Operating Llc | Compositions of ixabepilone |
Families Citing this family (160)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5969145A (en) * | 1996-08-30 | 1999-10-19 | Novartis Ag | Process for the production of epothilones and intermediate products within the process |
ATE408612T1 (en) | 1996-11-18 | 2008-10-15 | Biotechnolog Forschung Gmbh | EPOTHILONES E AND F |
CA2273083C (en) * | 1996-12-03 | 2012-09-18 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US20050043376A1 (en) * | 1996-12-03 | 2005-02-24 | Danishefsky Samuel J. | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6867305B2 (en) | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US6380394B1 (en) | 1996-12-13 | 2002-04-30 | The Scripps Research Institute | Epothilone analogs |
US6660758B1 (en) | 1996-12-13 | 2003-12-09 | The Scripps Research Institute | Epothilone analogs |
US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
US6605599B1 (en) * | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
DE59814067D1 (en) | 1997-08-09 | 2007-09-06 | Bayer Schering Pharma Ag | NEW EPOTHILON DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR PHARMACEUTICAL USE |
US6365749B1 (en) * | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
US6683100B2 (en) | 1999-01-19 | 2004-01-27 | Novartis Ag | Organic compounds |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
US6302838B1 (en) | 1998-02-25 | 2001-10-16 | Novartis Ag | Cancer treatment with epothilones |
FR2775187B1 (en) | 1998-02-25 | 2003-02-21 | Novartis Ag | USE OF EPOTHILONE B FOR THE MANUFACTURE OF AN ANTIPROLIFERATIVE PHARMACEUTICAL PREPARATION AND A COMPOSITION COMPRISING EPOTHILONE B AS AN IN VIVO ANTIPROLIFERATIVE AGENT |
US6498257B1 (en) * | 1998-04-21 | 2002-12-24 | Bristol-Myers Squibb Company | 2,3-olefinic epothilone derivatives |
US6399638B1 (en) * | 1998-04-21 | 2002-06-04 | Bristol-Myers Squibb Company | 12,13-modified epothilone derivatives |
DE19826988A1 (en) * | 1998-06-18 | 1999-12-23 | Biotechnolog Forschung Gmbh | Epothilone minor components |
KR20070087132A (en) | 1998-11-20 | 2007-08-27 | 코산 바이오사이언시즈, 인코포레이티드 | Recombinant methods and materials for producing epothilone and epothilone derivatives |
US6410301B1 (en) | 1998-11-20 | 2002-06-25 | Kosan Biosciences, Inc. | Myxococcus host cells for the production of epothilones |
EP1140944B1 (en) * | 1998-12-22 | 2003-08-27 | Novartis AG | Epothilone derivatives and their use as antitumor agents |
US6780620B1 (en) * | 1998-12-23 | 2004-08-24 | Bristol-Myers Squibb Company | Microbial transformation method for the preparation of an epothilone |
SK11452001A3 (en) * | 1999-02-11 | 2002-04-04 | Schering Aktiengesellschaft | Epothilon derivatives, method for the production and the use thereof as pharmaceuticals |
PL215901B1 (en) | 1999-04-15 | 2014-02-28 | Bristol Myers Squibb Co | Cyclic protein tyrosine kinase inhibitors |
US7125875B2 (en) | 1999-04-15 | 2006-10-24 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
AU772750C (en) | 1999-04-30 | 2005-02-24 | Schering Aktiengesellschaft | 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6518421B1 (en) | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
DE10020899A1 (en) * | 2000-04-20 | 2001-10-25 | Schering Ag | New 9-oxa-epothilone derivatives, are phase-specific cell division regulators useful for treating malignant tumors, angiogenesis or inflammatory disease |
US6489314B1 (en) | 2001-04-03 | 2002-12-03 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
WO2001092255A2 (en) * | 2000-05-26 | 2001-12-06 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
UA75365C2 (en) | 2000-08-16 | 2006-04-17 | Bristol Myers Squibb Co | Epothilone analog polymorph modifications, a method for obtaining thereof (variants), a pharmaceutical composition based thereon |
US6989450B2 (en) | 2000-10-13 | 2006-01-24 | The University Of Mississippi | Synthesis of epothilones and related analogs |
CN1489466A (en) * | 2001-01-25 | 2004-04-14 | ����˹�ж�-����˹˹������˾ | Parenteral dosage containing epothilones |
JP4633331B2 (en) * | 2001-01-25 | 2011-02-16 | ブリストル−マイヤーズ スクイブ カンパニー | Methods of administering epothilone analogs for cancer treatment |
WO2002058699A1 (en) | 2001-01-25 | 2002-08-01 | Bristol-Myers Squibb Company | Pharmaceutical forms of epothilones for oral administration |
EP1938821B1 (en) | 2001-01-25 | 2016-03-30 | Bristol-Myers Squibb Company | Dosage forms of an epothilone analogue for the treatment of cancer |
US6893859B2 (en) | 2001-02-13 | 2005-05-17 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
BR0207487A (en) | 2001-02-20 | 2004-08-10 | Brystol Myers Squibb Company | Method of treating tumors in mammals and using epothilone compounds |
EP1368030A1 (en) | 2001-02-20 | 2003-12-10 | Bristol-Myers Squibb Company | Epothilone derivatives for the treatment of refractory tumors |
ATE335746T1 (en) | 2001-02-27 | 2006-09-15 | Biotechnolog Forschung Gmbh | METHOD FOR PRODUCING EPOTHILONES |
ATE554756T1 (en) | 2001-03-14 | 2012-05-15 | Bristol Myers Squibb Co | COMBINATION OF EPOTHILONE ANALOG AND CHEMOTHERAPEUTICS FOR THE TREATMENT OF PROLIFERATIVE DISEASES |
MXPA03010909A (en) | 2001-06-01 | 2004-02-17 | Bristol Myers Squibb Co | Epothilone derivatives. |
TWI315982B (en) * | 2001-07-19 | 2009-10-21 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
CA2471509A1 (en) | 2002-01-14 | 2003-07-17 | Novartis Ag | Combinations comprising epothilones and anti-metabolites |
EP1340498A1 (en) * | 2002-03-01 | 2003-09-03 | Schering Aktiengesellschaft | Use of epothilones in the treatment of brain diseases associated with proliferative processes |
US7211593B2 (en) * | 2002-03-12 | 2007-05-01 | Bristol-Myers Squibb Co. | C12-cyano epothilone derivatives |
ATE452896T1 (en) | 2002-03-12 | 2010-01-15 | Bristol Myers Squibb Co | C3-CYANOEPOTHILONE DERIVATIVES |
TW200403994A (en) | 2002-04-04 | 2004-03-16 | Bristol Myers Squibb Co | Oral administration of EPOTHILONES |
TW200400191A (en) * | 2002-05-15 | 2004-01-01 | Bristol Myers Squibb Co | Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives |
US7405234B2 (en) | 2002-05-17 | 2008-07-29 | Bristol-Myers Squibb Company | Bicyclic modulators of androgen receptor function |
US7008936B2 (en) | 2002-06-14 | 2006-03-07 | Bristol-Myers Squibb Company | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
DE10232094A1 (en) * | 2002-07-15 | 2004-02-05 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | 5-thiaepothilones and 15-disubstituted epothilones |
US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
MXPA05002113A (en) | 2002-08-23 | 2005-06-03 | Sloan Kettering Inst Cancer | Synthesis of epothilones, intermediates thereto, analogues and uses thereof. |
EP2280014B1 (en) | 2002-09-23 | 2013-10-23 | Bristol-Myers Squibb Company | Methods for the preparation, isolation and purification of epothilone B |
AU2003264822A1 (en) * | 2002-10-11 | 2004-05-04 | Dana-Farber Cancer Institute Inc | Epothilone derivatives for the treatment of multiple myeloma |
EP1567487A4 (en) | 2002-11-15 | 2005-11-16 | Bristol Myers Squibb Co | Open chain prolyl urea-related modulators of androgen receptor function |
DK1567524T3 (en) * | 2002-11-28 | 2009-11-16 | Wolfgang Richter | Thia-epothilone derivatives for the treatment of cancer |
CA2510610A1 (en) * | 2002-12-09 | 2004-06-24 | Novartis Ag | Microtubule stabilisers for treating stenosis in stents |
GB0230024D0 (en) * | 2002-12-23 | 2003-01-29 | Novartis Ag | Organic compounds |
CN101177425B (en) * | 2003-01-28 | 2012-07-18 | 北京华昊中天生物技术有限公司 | Novel epothilones compound as well as preparation method and use thereof |
ATE479667T1 (en) | 2003-02-06 | 2010-09-15 | Bristol Myers Squibb Co | THIAZOLYL-BASED COMPOUNDS SUITABLE AS KINASE INHIBITORS |
AU2008200555C1 (en) * | 2003-03-14 | 2011-12-15 | Novartis Ag | Treatment of proliferative diseases with epothilone derivatives and radiation |
GB0305928D0 (en) * | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
US7371759B2 (en) | 2003-09-25 | 2008-05-13 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
DE10344882A1 (en) * | 2003-09-26 | 2005-04-21 | Morphochem Ag Komb Chemie | New macrocycles for the treatment of cancer |
US20050171167A1 (en) * | 2003-11-04 | 2005-08-04 | Haby Thomas A. | Process and formulation containing epothilones and analogs thereof |
WO2005054429A2 (en) * | 2003-11-19 | 2005-06-16 | The University Of Mississippi | Synthesis of the c1-c6 keto-acid synthon of the epothilones |
US7420059B2 (en) | 2003-11-20 | 2008-09-02 | Bristol-Myers Squibb Company | HMG-CoA reductase inhibitors and method |
EP1559447A1 (en) | 2004-01-30 | 2005-08-03 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism |
US7820702B2 (en) | 2004-02-04 | 2010-10-26 | Bristol-Myers Squibb Company | Sulfonylpyrrolidine modulators of androgen receptor function and method |
US7378426B2 (en) | 2004-03-01 | 2008-05-27 | Bristol-Myers Squibb Company | Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
US7625923B2 (en) | 2004-03-04 | 2009-12-01 | Bristol-Myers Squibb Company | Bicyclic modulators of androgen receptor function |
US7696241B2 (en) | 2004-03-04 | 2010-04-13 | Bristol-Myers Squibb Company | Bicyclic compounds as modulators of androgen receptor function and method |
US7459562B2 (en) | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
TW200538453A (en) | 2004-04-26 | 2005-12-01 | Bristol Myers Squibb Co | Bicyclic heterocycles as kinase inhibitors |
US20090004277A1 (en) * | 2004-05-18 | 2009-01-01 | Franchini Miriam K | Nanoparticle dispersion containing lactam compound |
US7439246B2 (en) | 2004-06-28 | 2008-10-21 | Bristol-Myers Squibb Company | Fused heterocyclic kinase inhibitors |
US7432373B2 (en) | 2004-06-28 | 2008-10-07 | Bristol-Meyers Squibb Company | Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors |
US20050288290A1 (en) | 2004-06-28 | 2005-12-29 | Borzilleri Robert M | Fused heterocyclic kinase inhibitors |
WO2006017761A2 (en) * | 2004-08-05 | 2006-02-16 | Emory University | Epothilone analogues as therapeutic agents |
EP1640004A1 (en) * | 2004-09-24 | 2006-03-29 | Schering Aktiengesellschaft | Use of epothilones in the treatment of bone metastases and bone tumors or cancers |
AU2005306464A1 (en) * | 2004-11-18 | 2006-05-26 | Bristol-Myers Squibb Company | Enteric coated bead comprising Ixabepilone, and preparation thereof |
EP1824458A1 (en) * | 2004-11-18 | 2007-08-29 | Bristol-Myers Squibb Company | Enteric coated bead comprising epothilone or an epothilone analog, and preparation and administration thereof |
US20060121511A1 (en) | 2004-11-30 | 2006-06-08 | Hyerim Lee | Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents |
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 |
US7754850B2 (en) | 2005-02-11 | 2010-07-13 | University Of Southern California | Chimeric disintegrin domain |
EP1883627B1 (en) | 2005-05-18 | 2018-04-18 | Pharmascience Inc. | Bir domain binding compounds |
US7348325B2 (en) | 2005-11-30 | 2008-03-25 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
JP2009532035A (en) | 2006-03-31 | 2009-09-10 | ブリストル−マイヤーズ スクイブ カンパニー | Biomarkers and methods for determining sensitivity to microtubule stabilizers |
EP2029156A4 (en) * | 2006-05-01 | 2010-07-21 | Univ Southern California | Combination therapy for treatment of cancer |
EP2024362A4 (en) | 2006-05-16 | 2012-01-25 | Pharmascience Inc | Iap bir domain binding compounds |
JP2010511408A (en) | 2006-12-04 | 2010-04-15 | ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・イリノイ | Compositions and methods for treating cancer with CpG rich DNA and cupredoxins |
WO2008098216A2 (en) | 2007-02-08 | 2008-08-14 | The Board Of Trustees Of The University Of Illinois | Compositions and methods to prevent cancer with cupredoxins |
WO2008147941A1 (en) * | 2007-05-25 | 2008-12-04 | Bristol-Myers Squibb Company | Processes for making epothilone compounds and analogs |
US20090076099A1 (en) * | 2007-09-14 | 2009-03-19 | Protia, Llc | Deuterium-enriched ixabepilone |
EP2065054A1 (en) | 2007-11-29 | 2009-06-03 | Bayer Schering Pharma Aktiengesellschaft | Combinations comprising a prostaglandin and uses thereof |
DE102007059752A1 (en) | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Functionalized solid polymer nanoparticles containing epothilones |
EP2070521A1 (en) | 2007-12-10 | 2009-06-17 | Bayer Schering Pharma Aktiengesellschaft | Surface-modified nanoparticles |
CN101909693A (en) * | 2008-01-08 | 2010-12-08 | 百时美施贵宝公司 | Combination of anti-CTLA4 antibody with tubulin modulating agents for the treatment of proliferative diseases |
PL2276485T3 (en) * | 2008-04-24 | 2014-12-31 | Bristol Myers Squibb Co | Use of epothilone d in treating tau-associated diseases including alzheimer's disease |
WO2010056901A2 (en) | 2008-11-13 | 2010-05-20 | University Of Southern California | Method of expressing proteins with disulfide bridges with enhanced yields and activity |
EP2210584A1 (en) | 2009-01-27 | 2010-07-28 | Bayer Schering Pharma Aktiengesellschaft | Stable polymeric composition comprising an epothilone and an amphiphilic block copolymer |
JP4500951B1 (en) * | 2009-08-07 | 2010-07-14 | 学校法人神戸学院 | DNA synthase inhibitors |
WO2011049625A1 (en) | 2009-10-20 | 2011-04-28 | Mansour Samadpour | Method for aflatoxin screening of products |
AU2010316780B2 (en) | 2009-11-05 | 2015-07-16 | Rhizen Pharmaceuticals Sa | Novel benzopyran kinase modulators |
AU2011214057B2 (en) | 2010-02-12 | 2016-11-17 | Pharmascience Inc. | IAP BIR domain binding compounds |
EP3450432A1 (en) | 2010-05-17 | 2019-03-06 | Incozen Therapeutics Pvt. Ltd. | Novel 3,5-disubstitued-3h-imidazo[4,5-b]pyridine and 3,5- disubstitued - 3h-[1,2,3]triazolo[4,5-b] pyridine compounds as modulators of protein kinases |
CA2799202C (en) | 2010-05-18 | 2016-07-05 | Cerulean Pharma Inc. | Compositions and methods for treatment of autoimmune and other diseases |
JP2013527239A (en) | 2010-06-01 | 2013-06-27 | プラス・ケミカルス・エスアー | Ixabepilone solid form |
CN101906099A (en) * | 2010-07-16 | 2010-12-08 | 泰州市今朝伟业精细化工有限公司 | Method for biochemically synthesizing epothilone D-lactam derivatives |
CA2824521C (en) | 2011-01-20 | 2016-06-28 | Board Of Regents, The University Of Texas System | Mri markers, delivery and extraction systems, and related methods |
WO2012135286A2 (en) * | 2011-04-01 | 2012-10-04 | The Research Foundation Of State University Of New York | Stabilized acid amplifiers |
WO2012135278A2 (en) * | 2011-04-01 | 2012-10-04 | The Research Foundation Of State University Of New York | Olefin-triggered acid amplifiers |
MY168757A (en) | 2011-05-04 | 2018-12-04 | Rhizen Pharmaceuticals S A | Novel compounds as modulators of protein kinases |
CA2838387A1 (en) | 2011-06-06 | 2012-12-13 | Chevron Phillips Chemical Company Lp | Use of metallocene compounds for cancer treatment |
TWI597065B (en) | 2011-06-10 | 2017-09-01 | 梅爾莎納醫療公司 | Protein-polymer-drug conjugates |
CN102863474A (en) | 2011-07-09 | 2013-01-09 | 陈小平 | Platinum compounds for treating cell proliferative diseases and preparation method and application thereof |
WO2013008091A1 (en) * | 2011-07-13 | 2013-01-17 | Xellia Pharmaceuticals Aps | Manufacturing of epothilone derivatives and the use thereof |
ES2458220T3 (en) | 2011-09-12 | 2014-04-30 | Agfa-Gevaert | Methods for color laser marking of security document precursors |
CN102993239A (en) | 2011-09-19 | 2013-03-27 | 陈小平 | Platinum compound of succinic acid derivative with leaving group containing amino or alkylamino |
AU2012356894B2 (en) | 2011-12-23 | 2018-01-18 | Innate Pharma | Enzymatic conjugation of polypeptides |
US9815831B2 (en) | 2012-03-30 | 2017-11-14 | Rhizen Pharmaceuticals Sa | 3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of c-Met protein kinases |
WO2014009426A2 (en) | 2012-07-13 | 2014-01-16 | Innate Pharma | Screening of conjugated antibodies |
EP2916872B1 (en) | 2012-11-09 | 2019-02-27 | Innate Pharma | Recognition tags for tgase-mediated conjugation |
WO2014075391A1 (en) | 2012-11-17 | 2014-05-22 | 北京市丰硕维康技术开发有限责任公司 | Platinum compound of malonic acid derivative having leaving group containing amino or alkylamino |
WO2014089177A2 (en) | 2012-12-04 | 2014-06-12 | Massachusetts Institute Of Technology | Compounds, conjugates and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines |
WO2014093394A1 (en) | 2012-12-10 | 2014-06-19 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
EP2931316B1 (en) | 2012-12-12 | 2019-02-20 | Mersana Therapeutics, Inc. | Hydroxyl-polymer-drug-protein conjugates |
TWI520956B (en) | 2013-03-08 | 2016-02-11 | 台灣神隆股份有限公司 | Process for ixabepilone, and intermediates thereof |
AU2014228822A1 (en) | 2013-03-15 | 2015-10-01 | Memorial Sloan-Kettering Cancer Center | HSP90-targeted cardiac imaging and therapy |
WO2014140300A1 (en) | 2013-03-15 | 2014-09-18 | Innate Pharma | Solid phase tgase-mediated conjugation of antibodies |
CN105283178A (en) | 2013-06-11 | 2016-01-27 | 拜耳制药股份公司 | Combinations for the treatment of cancer comprising an MPS-1 kinase inhibitor and a mitotic inhibitor |
US10071169B2 (en) | 2013-06-20 | 2018-09-11 | Innate Pharma | Enzymatic conjugation of polypeptides |
JP6744212B2 (en) | 2013-06-21 | 2020-08-19 | イナート・ファルマ・ソシエテ・アノニムInnate Pharma Pharma S.A. | Enzymatic binding of polypeptides |
WO2015054659A1 (en) | 2013-10-11 | 2015-04-16 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
WO2015054669A1 (en) | 2013-10-11 | 2015-04-16 | Asana Biosciences, Llc | Protein-polymer-drug conjugates |
US10341459B2 (en) | 2015-09-18 | 2019-07-02 | International Business Machines Corporation | Personalized content and services based on profile information |
WO2017197045A1 (en) | 2016-05-11 | 2017-11-16 | Movassaghi Mohammad | Convergent and enantioselective total synthesis of communesin analogs |
WO2018004338A1 (en) | 2016-06-27 | 2018-01-04 | Tagworks Pharmaceuticals B.V. | Cleavable tetrazine used in bio-orthogonal drug activation |
US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
US11932650B2 (en) | 2017-05-11 | 2024-03-19 | Massachusetts Institute Of Technology | Potent agelastatin derivatives as modulators for cancer invasion and metastasis |
TW201905037A (en) | 2017-06-22 | 2019-02-01 | 美商梅爾莎納醫療公司 | Drug-carrying polymer scaffold and method for producing protein polymer drug conjugate |
US10640508B2 (en) | 2017-10-13 | 2020-05-05 | Massachusetts Institute Of Technology | Diazene directed modular synthesis of compounds with quaternary carbon centers |
WO2019092148A1 (en) | 2017-11-10 | 2019-05-16 | Innate Pharma | Antibodies with functionalized glutamine residues |
WO2019212356A1 (en) | 2018-05-04 | 2019-11-07 | Tagworks Pharmaceuticals B .V. | Tetrazines for high click conjugation yield in vivo and high click release yield |
EP3788032B1 (en) | 2018-05-04 | 2024-01-24 | Tagworks Pharmaceuticals B.V. | Compounds comprising a linker for increasing transcyclooctene stability |
EP3873534A1 (en) | 2018-10-29 | 2021-09-08 | Mersana Therapeutics, Inc. | Cysteine engineered antibody-drug conjugates with peptide-containing linkers |
US11535634B2 (en) | 2019-06-05 | 2022-12-27 | Massachusetts Institute Of Technology | Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof |
JP2022537543A (en) | 2019-06-17 | 2022-08-26 | タグワークス ファーマシューティカルス ビー.ブイ. | Compounds for fast and efficient click release |
IL289094A (en) | 2019-06-17 | 2022-02-01 | Tagworks Pharmaceuticals B V | Tetrazines for high click release speed and yield |
WO2023031445A2 (en) | 2021-09-06 | 2023-03-09 | Veraxa Biotech Gmbh | Novel aminoacyl-trna synthetase variants for genetic code expansion in eukaryotes |
WO2023094525A1 (en) | 2021-11-25 | 2023-06-01 | Veraxa Biotech Gmbh | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
EP4186529A1 (en) | 2021-11-25 | 2023-05-31 | Veraxa Biotech GmbH | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
WO2023104941A1 (en) | 2021-12-08 | 2023-06-15 | European Molecular Biology Laboratory | Hydrophilic tetrazine-functionalized payloads for preparation of targeting conjugates |
WO2023158305A1 (en) | 2022-02-15 | 2023-08-24 | Tagworks Pharmaceuticals B.V. | Masked il12 protein |
WO2024013723A1 (en) | 2022-07-15 | 2024-01-18 | Pheon Therapeutics Ltd | Antibody drug conjugates that bind cdcp1 and uses thereof |
WO2024080872A1 (en) | 2022-10-12 | 2024-04-18 | Tagworks Pharmaceuticals B.V. | Strained bicyclononenes |
Citations (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4272525A (en) | 1978-10-23 | 1981-06-09 | Schering Corporation | Derivatives of polyene macrolide antibiotics containing an amino sugar moiety, process for the preparation thereof, and pharmaceutical compositions containing them |
EP0103465A1 (en) | 1982-09-13 | 1984-03-21 | Eli Lilly And Company | 20-Amino macrolide derivatives |
US4820695A (en) | 1982-09-13 | 1989-04-11 | Eli Lilly And Company | C-20-dihydro-deoxy-(cyclic amino)-derivatives of macrolide antibiotics |
JPH03101679A (en) | 1989-09-14 | 1991-04-26 | Sankyo Co Ltd | Rhizoxin derivative |
EP0512779A1 (en) | 1991-05-02 | 1992-11-11 | Eli Lilly And Company | Tilmicosine and related compounds for the production of a medicament for the treatment of mastitis |
WO1992019247A1 (en) | 1991-05-03 | 1992-11-12 | Abbott Laboratories | Erythromycin derivatives |
WO1993010121A1 (en) | 1991-11-19 | 1993-05-27 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents |
EP0586738A1 (en) | 1992-09-11 | 1994-03-16 | Boehringer Ingelheim Vetmedica Gmbh | Enhanced chemotherapeutic compositions against microbial infections in fish containing a benzylamine derivative and an antimicrobial substance |
WO1994013324A1 (en) | 1992-12-16 | 1994-06-23 | Vestar, Inc. | Lipid prodrugs for oral administration |
EP0606747A1 (en) | 1992-12-21 | 1994-07-20 | Eli Lilly And Company | Tilmicosin and derivatives for treating gram-positive diseases of aquatic species |
WO1994021657A1 (en) | 1993-03-18 | 1994-09-29 | Pfizer Inc. | Antibacterial 16-membered ring macrolides containing olefins at c-20 |
DE4316836A1 (en) | 1993-05-19 | 1994-11-24 | Knoell Hans Forschung Ev | Tetrahydrofuranylpropionic acid, a process for its preparation and use thereof |
WO1995002594A1 (en) | 1993-07-15 | 1995-01-26 | Pfizer Inc. | Amide derivatives of 16-membered ring antibiotic macrolides |
WO1996009312A1 (en) | 1994-09-22 | 1996-03-28 | Pfizer Inc. | Antibiotic macrolides |
WO1996011398A1 (en) | 1994-10-07 | 1996-04-18 | Merck & Co., Inc. | Process for assessing tubulin protein polymerization |
US5545624A (en) | 1992-07-15 | 1996-08-13 | Pfizer Inc. | Derivatives of 16-membered ring antibiotic macrolides |
WO1996026182A1 (en) | 1995-02-21 | 1996-08-29 | Schering Aktiengesellschaft | Substituted dtpa monoamides of central carboxylic acids and metal complexes thereof, pharmaceuticals containing these complexes, diagnostic and therapeutic uses thereof and methods for preparing the complexes and pharmaceuticals |
US5610178A (en) | 1993-08-16 | 1997-03-11 | Ciba-Geigy Corporation | Macrolides and the use thereof |
DE19542986A1 (en) | 1995-11-17 | 1997-05-22 | Biotechnolog Forschung Gmbh | New epothilone derivatives useful as cytostatics |
WO1997019088A1 (en) | 1995-11-21 | 1997-05-29 | Hoechst Celanese Corporation | Novel nonlinear optical molecules and polymers incorporating them |
WO1997019086A1 (en) | 1995-11-17 | 1997-05-29 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone derivatives, preparation and use |
EP0778283A2 (en) | 1995-12-05 | 1997-06-11 | Pfizer Inc. | Antibiotic macrolides |
DE19636343C1 (en) | 1996-08-30 | 1997-10-23 | Schering Ag | New (di:methyl)-dioxanyl-methyl-pentanone and related compounds |
WO1998008849A1 (en) | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Method for producing epothilones, and intermediate products obtained during the production process |
DE19639456A1 (en) | 1996-09-25 | 1998-03-26 | Biotechnolog Forschung Gmbh | New epothilone derivatives |
DE19645361A1 (en) | 1996-08-30 | 1998-04-30 | Ciba Geigy Ag | Production of epothilone compounds with taxol-like activity |
DE19645362A1 (en) | 1996-10-28 | 1998-04-30 | Ciba Geigy Ag | Production of epothilone compounds with taxol-like activity |
WO1998022461A1 (en) | 1996-11-18 | 1998-05-28 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents |
WO1998022462A1 (en) | 1996-11-15 | 1998-05-28 | Zeneca Limited | 8-azabicyclo[3.2.1]octane-, 8-azabicyclo[3.2.1]oct-6-ene-, 9-azabicyclo[3.3.1]nonane-, 9-aza-3-oxabicyclo[3.3.1]nonane-, 9-aza-3-thiabicyclo[3.3.1]nonane derivatives, their preparation and their use as insecticides |
US5763429A (en) | 1993-09-10 | 1998-06-09 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
WO1998024427A2 (en) | 1996-12-02 | 1998-06-11 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating or preventing inflammatory diseases |
WO1998025929A1 (en) | 1996-12-13 | 1998-06-18 | Novartis Ag | Epothilone analogs |
DE19701758A1 (en) | 1997-01-20 | 1998-07-23 | Wessjohann Ludgar A Dr | New beta-keto-alcohol derivatives |
US5786348A (en) | 1991-01-08 | 1998-07-28 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxy vitamin D2 |
US5795882A (en) | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
US5798345A (en) | 1990-09-21 | 1998-08-25 | Bone Care International, Inc. | Method of inhibiting the hyperproliferation of malignant cells |
WO1998038192A1 (en) | 1997-02-25 | 1998-09-03 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilones with a modified side chain |
DE19713970A1 (en) | 1997-04-04 | 1998-10-08 | Ludger A Dr Wessjohann | New structural elements which include prenyl derivatives |
WO1998047891A1 (en) | 1997-04-18 | 1998-10-29 | Studiengesellschaft Kohle Mbh | Selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide as reaction medium |
DE19821954A1 (en) | 1997-05-15 | 1998-11-19 | Biotechnolog Forschung Gmbh | Preparation of epothilone derivatives |
DE19720312A1 (en) | 1997-05-15 | 1998-11-19 | Hoechst Ag | Preparation with increased in vivo tolerance |
DE19726627A1 (en) | 1997-06-17 | 1998-12-24 | Schering Ag | New intermediates for epothilone |
WO1999001124A1 (en) | 1996-12-03 | 1999-01-14 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
WO1999003848A1 (en) | 1997-07-16 | 1999-01-28 | Schering Aktiengesellschaft | Thiazole derivatives, method for their production and use |
WO1999007692A2 (en) | 1997-08-09 | 1999-02-18 | Schering Aktiengesellschaft | New epothilone derivatives, method for producing same and their pharmaceutical use |
WO1999039694A2 (en) | 1998-02-05 | 1999-08-12 | Novartis Ag | Compositions containing organic compounds |
WO1999042602A2 (en) | 1998-02-19 | 1999-08-26 | Novartis Ag | Fermentative preparation process for cytostatics and crystal forms thereof |
WO1999043320A1 (en) | 1998-02-25 | 1999-09-02 | Novartis Ag | Use of epothilones for the treatment of cancer |
WO1999043653A1 (en) | 1998-02-25 | 1999-09-02 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues therof |
WO1999067252A2 (en) | 1998-06-22 | 1999-12-29 | Novartis Ag | Epothilone derivatives and their synthesis and use |
WO2000000485A1 (en) | 1998-06-30 | 2000-01-06 | Schering Aktiengesellschaft | Epothilon derivatives, their preparation process, intermediate products and their pharmaceutical use |
WO2000031247A2 (en) | 1998-11-20 | 2000-06-02 | Kosan Biosciences, Inc. | Recombinant methods and materials for producing epothilone and epothilone derivatives |
WO2000037473A1 (en) | 1998-12-22 | 2000-06-29 | Novartis Ag | Epothilone derivatives and their use as antitumor agents |
WO2000049021A2 (en) | 1999-02-18 | 2000-08-24 | Schering Aktiengesellschaft | 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use |
US6124453A (en) | 1995-07-04 | 2000-09-26 | Novartis Ag | Macrolides |
JP3101679B2 (en) | 1991-07-02 | 2000-10-23 | 株式会社ニチレイ | Serum-free medium for cryopreservation of animal cells and storage method |
WO2000066589A1 (en) | 1999-04-30 | 2000-11-09 | Schering Aktiengesellschaft | 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations |
US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US6211412B1 (en) | 1999-03-29 | 2001-04-03 | The University Of Kansas | Synthesis of epothilones |
US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
US6518421B1 (en) | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
US20030073677A1 (en) | 2001-03-14 | 2003-04-17 | Lee Francis Y.F. | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
US6576651B2 (en) | 2001-01-25 | 2003-06-10 | Bristol-Myers Squibb Company | Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones |
US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
US6670384B2 (en) | 2001-01-25 | 2003-12-30 | Bristol-Myers Squibb Company | Methods of administering epothilone analogs for the treatment of cancer |
US6686380B2 (en) | 2001-02-20 | 2004-02-03 | Bristol-Myers Squibb Company | Treatment of refractory tumors using epothilone derivatives |
US6689802B2 (en) | 2000-08-16 | 2004-02-10 | Bristol-Myers Squibb Company | Polymorphs of an epothilone analog |
US6867305B2 (en) | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US7022330B2 (en) | 2001-01-25 | 2006-04-04 | Bristol-Myers Squibb Company | Parenteral formulation for epothilone analogs |
US7125893B1 (en) | 1999-04-30 | 2006-10-24 | Schering Ag | 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5515936A (en) * | 1995-07-10 | 1996-05-14 | Vehicules Ts Bellechasse Ltee | Track tensioning system for endless track propelled vehicle |
AT404477B (en) | 1997-01-15 | 1998-11-25 | Thal Hermann Dipl Ing | BUNDLED TENSION AND METHOD FOR PRODUCING THE SAME |
US6136630A (en) * | 1998-06-04 | 2000-10-24 | The Regents Of The University Of Michigan | Method of making a micromechanical device from a single crystal semiconductor substrate and monolithic sensor formed thereby |
US7026362B2 (en) | 2001-10-09 | 2006-04-11 | Simax Technologies, Inc. | Sol-gel process utilizing reduced mixing temperatures |
-
1998
- 1998-05-26 US US09/084,542 patent/US6605599B1/en not_active Ceased
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Patent Citations (85)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4272525A (en) | 1978-10-23 | 1981-06-09 | Schering Corporation | Derivatives of polyene macrolide antibiotics containing an amino sugar moiety, process for the preparation thereof, and pharmaceutical compositions containing them |
EP0103465A1 (en) | 1982-09-13 | 1984-03-21 | Eli Lilly And Company | 20-Amino macrolide derivatives |
US4820695A (en) | 1982-09-13 | 1989-04-11 | Eli Lilly And Company | C-20-dihydro-deoxy-(cyclic amino)-derivatives of macrolide antibiotics |
JPH03101679A (en) | 1989-09-14 | 1991-04-26 | Sankyo Co Ltd | Rhizoxin derivative |
US5798345A (en) | 1990-09-21 | 1998-08-25 | Bone Care International, Inc. | Method of inhibiting the hyperproliferation of malignant cells |
US5786348A (en) | 1991-01-08 | 1998-07-28 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxy vitamin D2 |
EP0512779A1 (en) | 1991-05-02 | 1992-11-11 | Eli Lilly And Company | Tilmicosine and related compounds for the production of a medicament for the treatment of mastitis |
WO1992019247A1 (en) | 1991-05-03 | 1992-11-12 | Abbott Laboratories | Erythromycin derivatives |
JP3101679B2 (en) | 1991-07-02 | 2000-10-23 | 株式会社ニチレイ | Serum-free medium for cryopreservation of animal cells and storage method |
WO1993010121A1 (en) | 1991-11-19 | 1993-05-27 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilones, process for preparing the same and their use as medicaments and as plant protecting agents |
DE4138042A1 (en) | 1991-11-19 | 1993-05-27 | Biotechnolog Forschung Gmbh | EPOTHILONES, THEIR PRODUCTION PROCESS AND MEANS CONTAINING THEM |
US5795882A (en) | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
US5545624A (en) | 1992-07-15 | 1996-08-13 | Pfizer Inc. | Derivatives of 16-membered ring antibiotic macrolides |
EP0586738A1 (en) | 1992-09-11 | 1994-03-16 | Boehringer Ingelheim Vetmedica Gmbh | Enhanced chemotherapeutic compositions against microbial infections in fish containing a benzylamine derivative and an antimicrobial substance |
WO1994013324A1 (en) | 1992-12-16 | 1994-06-23 | Vestar, Inc. | Lipid prodrugs for oral administration |
EP0606747A1 (en) | 1992-12-21 | 1994-07-20 | Eli Lilly And Company | Tilmicosin and derivatives for treating gram-positive diseases of aquatic species |
WO1994021657A1 (en) | 1993-03-18 | 1994-09-29 | Pfizer Inc. | Antibacterial 16-membered ring macrolides containing olefins at c-20 |
DE4316836A1 (en) | 1993-05-19 | 1994-11-24 | Knoell Hans Forschung Ev | Tetrahydrofuranylpropionic acid, a process for its preparation and use thereof |
WO1995002594A1 (en) | 1993-07-15 | 1995-01-26 | Pfizer Inc. | Amide derivatives of 16-membered ring antibiotic macrolides |
US5716939A (en) | 1993-07-15 | 1998-02-10 | Pfizer Inc. | Amide derivatives of 16-membered ring antibiotic macrolides |
US5610178A (en) | 1993-08-16 | 1997-03-11 | Ciba-Geigy Corporation | Macrolides and the use thereof |
US5763429A (en) | 1993-09-10 | 1998-06-09 | Bone Care International, Inc. | Method of treating prostatic diseases using active vitamin D analogues |
WO1996009312A1 (en) | 1994-09-22 | 1996-03-28 | Pfizer Inc. | Antibiotic macrolides |
WO1996011398A1 (en) | 1994-10-07 | 1996-04-18 | Merck & Co., Inc. | Process for assessing tubulin protein polymerization |
WO1996026182A1 (en) | 1995-02-21 | 1996-08-29 | Schering Aktiengesellschaft | Substituted dtpa monoamides of central carboxylic acids and metal complexes thereof, pharmaceuticals containing these complexes, diagnostic and therapeutic uses thereof and methods for preparing the complexes and pharmaceuticals |
US6124453A (en) | 1995-07-04 | 2000-09-26 | Novartis Ag | Macrolides |
WO1997019086A1 (en) | 1995-11-17 | 1997-05-29 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone derivatives, preparation and use |
DE19542986A1 (en) | 1995-11-17 | 1997-05-22 | Biotechnolog Forschung Gmbh | New epothilone derivatives useful as cytostatics |
WO1997019088A1 (en) | 1995-11-21 | 1997-05-29 | Hoechst Celanese Corporation | Novel nonlinear optical molecules and polymers incorporating them |
US5760011A (en) | 1995-12-05 | 1998-06-02 | Pfizer Inc. | Antibiotic macrolides |
EP0778283A2 (en) | 1995-12-05 | 1997-06-11 | Pfizer Inc. | Antibiotic macrolides |
DE19645361A1 (en) | 1996-08-30 | 1998-04-30 | Ciba Geigy Ag | Production of epothilone compounds with taxol-like activity |
WO1998008849A1 (en) | 1996-08-30 | 1998-03-05 | Novartis Aktiengesellschaft | Method for producing epothilones, and intermediate products obtained during the production process |
DE19636343C1 (en) | 1996-08-30 | 1997-10-23 | Schering Ag | New (di:methyl)-dioxanyl-methyl-pentanone and related compounds |
DE19639456A1 (en) | 1996-09-25 | 1998-03-26 | Biotechnolog Forschung Gmbh | New epothilone derivatives |
DE19645362A1 (en) | 1996-10-28 | 1998-04-30 | Ciba Geigy Ag | Production of epothilone compounds with taxol-like activity |
WO1998022462A1 (en) | 1996-11-15 | 1998-05-28 | Zeneca Limited | 8-azabicyclo[3.2.1]octane-, 8-azabicyclo[3.2.1]oct-6-ene-, 9-azabicyclo[3.3.1]nonane-, 9-aza-3-oxabicyclo[3.3.1]nonane-, 9-aza-3-thiabicyclo[3.3.1]nonane derivatives, their preparation and their use as insecticides |
WO1998022461A1 (en) | 1996-11-18 | 1998-05-28 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone c, d, e and f, production process, and their use as cytostatic as well as phytosanitary agents |
WO1998024427A2 (en) | 1996-12-02 | 1998-06-11 | Angiotech Pharmaceuticals, Inc. | Compositions and methods for treating or preventing inflammatory diseases |
US6242469B1 (en) | 1996-12-03 | 2001-06-05 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6867305B2 (en) | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US6316630B1 (en) | 1996-12-03 | 2001-11-13 | Sloan Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
WO1999001124A1 (en) | 1996-12-03 | 1999-01-14 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6369234B1 (en) | 1996-12-03 | 2002-04-09 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
US6656961B2 (en) | 1996-12-03 | 2003-12-02 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
WO1998025929A1 (en) | 1996-12-13 | 1998-06-18 | Novartis Ag | Epothilone analogs |
US6380394B1 (en) | 1996-12-13 | 2002-04-30 | The Scripps Research Institute | Epothilone analogs |
US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
DE19701758A1 (en) | 1997-01-20 | 1998-07-23 | Wessjohann Ludgar A Dr | New beta-keto-alcohol derivatives |
WO1998038192A1 (en) | 1997-02-25 | 1998-09-03 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilones with a modified side chain |
DE19713970A1 (en) | 1997-04-04 | 1998-10-08 | Ludger A Dr Wessjohann | New structural elements which include prenyl derivatives |
WO1998047891A1 (en) | 1997-04-18 | 1998-10-29 | Studiengesellschaft Kohle Mbh | Selective olefin metathesis of bifunctional or polyfunctional substrates in compressed carbon dioxide as reaction medium |
EP0879605A2 (en) | 1997-05-15 | 1998-11-25 | Hoechst Aktiengesellschaft | Glycosyl prodrug conjugate with enhanced tolerance |
DE19821954A1 (en) | 1997-05-15 | 1998-11-19 | Biotechnolog Forschung Gmbh | Preparation of epothilone derivatives |
DE19720312A1 (en) | 1997-05-15 | 1998-11-19 | Hoechst Ag | Preparation with increased in vivo tolerance |
DE19726627A1 (en) | 1997-06-17 | 1998-12-24 | Schering Ag | New intermediates for epothilone |
US20070255055A1 (en) | 1997-07-08 | 2007-11-01 | Vite Gregory D | Epothilone derivatives |
US7241755B2 (en) | 1997-07-08 | 2007-07-10 | Bristol-Myers Squibb Company | Epothilone derivatives |
US7125899B2 (en) | 1997-07-08 | 2006-10-24 | Bristol-Myers Squibb Company | Epothilone derivatives |
US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
WO1999003848A1 (en) | 1997-07-16 | 1999-01-28 | Schering Aktiengesellschaft | Thiazole derivatives, method for their production and use |
WO1999007692A2 (en) | 1997-08-09 | 1999-02-18 | Schering Aktiengesellschaft | New epothilone derivatives, method for producing same and their pharmaceutical use |
US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
WO1999039694A2 (en) | 1998-02-05 | 1999-08-12 | Novartis Ag | Compositions containing organic compounds |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
WO1999042602A2 (en) | 1998-02-19 | 1999-08-26 | Novartis Ag | Fermentative preparation process for cytostatics and crystal forms thereof |
WO1999043320A1 (en) | 1998-02-25 | 1999-09-02 | Novartis Ag | Use of epothilones for the treatment of cancer |
WO1999043653A1 (en) | 1998-02-25 | 1999-09-02 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues therof |
WO1999067252A2 (en) | 1998-06-22 | 1999-12-29 | Novartis Ag | Epothilone derivatives and their synthesis and use |
WO2000000485A1 (en) | 1998-06-30 | 2000-01-06 | Schering Aktiengesellschaft | Epothilon derivatives, their preparation process, intermediate products and their pharmaceutical use |
WO2000031247A2 (en) | 1998-11-20 | 2000-06-02 | Kosan Biosciences, Inc. | Recombinant methods and materials for producing epothilone and epothilone derivatives |
US6387927B1 (en) | 1998-12-22 | 2002-05-14 | Novatis Ag | Epothilone derivatives and their use as antitumor agents |
WO2000037473A1 (en) | 1998-12-22 | 2000-06-29 | Novartis Ag | Epothilone derivatives and their use as antitumor agents |
WO2000049021A2 (en) | 1999-02-18 | 2000-08-24 | Schering Aktiengesellschaft | 16-halogen-epothilone derivatives, method for producing them and their pharmaceutical use |
US6211412B1 (en) | 1999-03-29 | 2001-04-03 | The University Of Kansas | Synthesis of epothilones |
WO2000066589A1 (en) | 1999-04-30 | 2000-11-09 | Schering Aktiengesellschaft | 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations |
US7125893B1 (en) | 1999-04-30 | 2006-10-24 | Schering Ag | 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations |
US6518421B1 (en) | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
US6689802B2 (en) | 2000-08-16 | 2004-02-10 | Bristol-Myers Squibb Company | Polymorphs of an epothilone analog |
US7022330B2 (en) | 2001-01-25 | 2006-04-04 | Bristol-Myers Squibb Company | Parenteral formulation for epothilone analogs |
US6670384B2 (en) | 2001-01-25 | 2003-12-30 | Bristol-Myers Squibb Company | Methods of administering epothilone analogs for the treatment of cancer |
US6576651B2 (en) | 2001-01-25 | 2003-06-10 | Bristol-Myers Squibb Company | Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones |
US6686380B2 (en) | 2001-02-20 | 2004-02-03 | Bristol-Myers Squibb Company | Treatment of refractory tumors using epothilone derivatives |
US20030073677A1 (en) | 2001-03-14 | 2003-04-17 | Lee Francis Y.F. | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
Non-Patent Citations (76)
Title |
---|
"Partial Synthesis of Soraphen Analogs in the ring segment C-3/O-17", Dissertation of Thorsten Jahn of Schleswig, 1995, (English translation and original German dissertation enclosed). |
Altmann et al., "Epothilones and Related Structures-A New Class of Microtubule Inhibitors With Patent In Vivo Antitumor Activity," Biochim. Biophys Acta,, 1470:M79-M81 (2000). |
Balasubramanian et al., Recent Developments in Cancer Cytotoxics, Annual Reports in Medicinal Chemistry, vol. 33, pp. 151-162, 1998. |
Balog et al., 1996, "Total Synthesis of (-)-Epothilone A", Angew. Chem. Int. Ed. Engl., 35(23-24):2801-2803. |
Balog et al., 1996, "Total Synthesis of (−)-Epothilone A", Angew. Chem. Int. Ed. Engl., 35(23-24):2801-2803. |
Balog, et al., Stereoselective Synthesis and Evaluation of Compounds in the 8-Desmethylepothilone A Series: Some Surprisng Observations Regarding Their Chemical and Biological Properties, Tetrahedron Letters, vol. 38, No. 26, pp. 4529-4532, (1997). |
Banker et al., Modern Pharmaceutics, Third Edition, Revised and Expanded, p. 908, 1996. |
Bennett et al., Cecil Textbook of Medicine, 20th Edition, Index, 1996. |
Bertinato P., et al., 1996, "Studies Toward a Synthesis of Epothilone A; Stereocontrolled Assembly of the Acyl Region and Models for Macrocycilization", J. Org. Chem., 61(23):8000-8001. |
Bertini et al., 1970, "Alkenes from Expoxides by Reductive Elimination with Magnesium Bromide-Magnesium Amaigam", Chem. Commun., 144. |
Bollag D., 1997, "Epothilones: Novel Microtubule-Stabilising Agents," Expert Opin. Invest. Drugs, 6(7):867-873. |
Bollag D., et al., 1995, "Epothilone, A New Structural Class of Microtubule Stablizer", Abstract, Proc Am. Assoc. Cancer Res., 36(86): Meet. 454. |
Bollag et al., 1995, "Epothilones, A New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action", Cancer Res., 55, No. 11, 2325-2333. |
Borzilleri, et al., "A Novel Application of a Pd(0)-Catalyzed Nucleophilic Substitution Reaction to the Regio- and Stereoselective Synthesis of Lactam Analogues of the Epothilone Natural Products", J. Am. Chem. Soc., 2000, 122:8890-8897. |
Chemical & Engineering News, 1996, "Epothilone Epiphany: Total Synthesis", 74( 52):24-26. |
Chemical & Engineering News, 1997, "First Total Synthesis of Epothilone B", 75(13):23. |
Chemical & Engineering News, 1997, "Solid-Phase Epothilone Synthesis Used to Create Analog Library", 75(20):33. |
Claus et al., 1997, "Synthesis of the C1-C9 Segment of Epothilons", Tetrahedron Lett., 38(8):1359-1362. |
De Brabander et al., 1997 "Iowards a Synthesis of Epothilone A: Rapid Assembly of the C1-C6 and C7-C12 Fragments", Synlett, 7: 824-826. |
Fujisawa et al., 1974, "Deoxygenation of Epoxides to Olefins with FeCl3-BuLi System", Chem. Lett., 883-886. |
Fujisawa et al., 1978, "Reductive Coupling of Carbonyl Compounds to Olefins by Tungsten Hexachloride-Lithium Aluminum Hydride and Some Tungsten and Molybdenum Carbonyls", J. Org. Chem., 43(12): 2477-2479. |
Gabriel T. and Wessjohann, L., 1997, "The Chromium-Reformatsky Reaction; Asymmetric Synthesis of the Aldol Fragment of the Cytotoxic Epothilons from 3-(2-Bromoacyl)-2-Oxazolidinones", Tetrahedron Lett., 38(8):1363-1366. |
Gerth K., et al., 1996, "Epothilons A and B: Antifungal and Cytotoxic Compounds from Sorangiusm celluiosum (Myxobacteria) Production Physico-chemical and Biological Properties", J. Antibiotics, 49(6): 560-563. |
Gerth, et al., "The Soraphens: A Family of Novel Antifungal Compounds From Sorangium callulosum (Myxobacteria)", The Journal of Antibiotics, 1993, vol. 47, No. 1, pp. 23-31. |
Gladysz et al., 1976, "Deoxygenation of Epoxides by Metal Atom Cocondensation", J. Org. Chem., 41(22): 3647-3648. |
Hofle et al., 1996, "Epothilone A and B-Novel 16-Membered Macrolides and Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution", Angew. Chem. Int. Ed Engl., 35(13-14):1567-1569. |
Hofle et al., 1999, "N-Oxidation of Epothilone A-C and O-Acyl Rearrangement to C-19 and C-21 -Substituted Epothilones", Angew. Chem. Int. Ed., 38(13/14):1971-1974. |
Hunt, "Discovery of Ixabepilone", Mol. Cancer ther., Feb. 2009, 8(2):275-281. |
Information concerning inactivities of certain compounds dated Mar. 26, 1998. |
Information concerning inactivity of certain compounds dated 1998 and 1999. |
Inokuchi et al., 1992, "Opening of Epoxides to Olefins or Halohydrins with Vanadium(II)-Tetrahydrofuran or Vanadium(III)-Tetrahydrofuran Complexes", Synlett, No. 6, 510-512. |
Kowalski et al., 1997, "Activities of the Microtubule-stabilizing Agents Epothilones A and B with Purified Tubulin and in Cells Resistant to Paclitaxel (Taxol®)" J. Bio, Chem., 272(4):2534-2541. |
Kupchan et al., 1971, "Reductive Elimination of Epoxides to Olefins with Zinc-Copper Couple", J. Org. Chem., 36(9):1187-1190. |
Marshall A., "Total Synthesis of Epothilone", Nature Biotechnology, vol. 15, No. 3, 205 (1997). |
Martin et al., 1984, "Epoxides as Alkene Protecting Groups. A Mild and Efficient Deoxygenation", Tetrahedron Letters, 25(3):251-254. |
McMurry et al, 1975, "Reduction of Epoxides to Olefins with Low Valent Titanium", J. Org. Chem., 40(17):2555-2556. |
McMurry et al., 1978, "Some Deoxygenation Reactions with Low-Valent Titanium (TiC3/LiAIH4)", J. Org. Chem., 43(17):3249-3254. |
Meng D., et al., "Remote Effects in Macrolide Formation Through Ring-Forming Olefin Metathesis: An Application to the Synthesis of Fully Active Epothilone Congeners", J. Am. Chem. Soc., vol. 119, No. 11, 2733-2734 (1997). |
Meng D., et al., "Studies Toward a Synthesis of Epothilone A: Use of Hydropyran Templates for the Managment of Acyclic Stereochemical Relationships", J. Org. Chem., vol. 61, No. 23, 7998-7999 (1996). |
Meng D., et al., "Total Syntheses of Epothilones A and B", J. Am. Chem. Soc., vol. 119, No. 42, 10073-10092 (1997). |
Mensching, S. and Kalesse, M., "Generation of Thiazoles by Column Dehydrogenation of Thiazolidines with MnO2", J. Prakat. Chem., vol. 339, No. 1, 96-97 (1997). |
Mulzer, J. and Mantoulidis, A., "Synthesis of the C(1)-C(9) Segment of the Cytotoxic Macrolides Epothilon A and B", Tetrahedron Lett., vol. 37 No. 51, 9179-9182 (1996). |
Nicolaou et al., "Chemistry and Biology of Epothilones", Angew. Chem. Int. Ed., 37, pp. 2014-2045, 1998. |
Nicolaou et al., "Designed Epothilones: Combinatorial Synthesis, Tubulin Assembly Properties, and Cytotoxic Action Against Taxol-Resistant Tumor Cells", Angew. Chem. Int. Ed. Engl., vol. 36, No. 19, 2097-2103 (1997). |
Nicolaou et al., "Total Synthesis of Epothilone E and Analogs with Modified Side Chains Through the Stille Coupling Reaction", Angew Chem. Int. Ed., 37, pp. 84-87, 1998. |
Nicolaou K. C., et al., 1996, "An Approach to Epothilones Based on Olefin Metathesis", Angew. Chem. Int. Ed. Engl., 35(20):2399-2401. |
Nicolaou K. C., et al., 1998, "Synthesis and Biological Properties of C12, 13-Cyclopropylepothilone A and Related Epothilones", Chemistry & Biology, 5(7): 365-372. |
Nicolaou K., et al., 1997, "Total Synthesis of Epothilone E and Related Side -chain Modified Analogues Via a Stille Coupling Based Strategy", Bloorg. Med. Chem., 7(5): 665-697. |
Nicolaou K., et al., 1999, "Chemistry, Biology and Medicine of Selected Tubulin Polymerizing Agents", Pure Appl. Chem., 71(6):989-997. |
Nicolaou K.C. et al., 1997, "Synthesis of Epothilones A and B in Solid and Solution Phase" (Correction to Nature 387, 268-272 (1997)), Nature 390, 100. |
Nicolaou K.C. et al., 1997, "Synthesis of Epothilones A and B in Solid and Solution Phase", Nature, 387: 268-272. |
Nicolaou K.C. et al., 1997, "The Olefin Metathesis Approach to Epothilone A and its Analogues", J. Am. Chem. Soc., 119(34): 7960-7973. |
Nicolaou K.C. et al., 1997, "Total Syntheses of Epothillones A and B via a Macrolactonization-Based Strategy", J. Am. Chem. Soc., 119(34): 7974-7991. |
Nicolaou K.C. et al., 1997, "Total Synthesis of Epothilone A: The Macrolactonization Approach", Angew. Chem. Int. Ed. Engl., 36(5): 525-527. |
Raucher, S., et al., 1986, "Total Synthesis of (+)-Dihydrocostunolide via Tandem Cope-Claisen Rearrangement", J. Org. Chem., 51(26): 5503-5505. |
Sato M. et al., 1982, "Reduction of Organic Compounds with Low-Valent Nioblum (NbCL5/NaAIH4)", Chem. Letters, 157-160. |
Schinzer D. et al., 1997, "Total Synthesis of (31)-Epothilone A", Angew. Chem. Int. Ed. Engl., 36(5):523-524. |
Schinzer D., et al., "Syntheses of (-)-Epothilone B", Chem. Eur. J., 5(9): 2492-2500, (1999) |
Schinzer D., et al., "Total Synthesis of (-)-Epothilone A", Chem. Eur. J., 5(9): 2483-2491, (1999). |
Schinzer D., et al., "Syntheses of (−)-Epothilone B", Chem. Eur. J., 5(9): 2492-2500, (1999) |
Schinzer D., et al., "Total Synthesis of (−)-Epothilone A", Chem. Eur. J., 5(9): 2483-2491, (1999). |
Schinzer D., et al., 1996, "Studies Towards the Synthesis of Epothilones: Asymmetric Synthesis of the Key Fragments", Chem. Eur. J., 2(22): 1477-1482. |
Schobert R., et al., 1990, "Reduction and Isomerization of Oxiranes and-Diazoketones by Various Early Transition Metallocenes", Synlett, 8: 465-466. |
Schummer, et al., "Chemical Modification of the Antifungal Macolide Soraphen A1alpha: Cleavage and Reconstruction of the Lactone Bond: Chemical Modification of SoraphenA," in Antibiotics and Antiviral Compounds-Chemical Synthesis and Modifications, Krohn et al. (Eds.), VCH Verlagsgesellschaft, 1993, pp. 133-141. |
Schummer, et al., "Chemical Modification of the Antifungal Macolide Soraphen A1α: Cleavage and Reconstruction of the Lactone Bond: Chemical Modification of SoraphenA," in Antibiotics and Antiviral Compounds—Chemical Synthesis and Modifications, Krohn et al. (Eds.), VCH Verlagsgesellschaft, 1993, pp. 133-141. |
Sharpless K.B., et al., 1972, "Lower Valent Tungsten Halides. A New Class of Reagents for Deoxygenation of Organic Molecules", J. Amer. Chem. Soc., 94(18): 6538-6540. |
Su D.-S. et al., 1997, "Total Synthesis of (-)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure-Activity Realationships of the Epothilones", Angew. Chem. Int. Ed. Engl., 36(7): 757-759. |
Su D.-S. et al., 1997, "Total Synthesis of (−)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure-Activity Realationships of the Epothilones", Angew. Chem. Int. Ed. Engl., 36(7): 757-759. |
Su D.-S., et al., 1997, "Structure-Activity Relationships of the Epothilones and the First In Vivo Comparison with Paclitaxel", Angew. Chem. Int. Ed. Engl., 36(19):2093-2096. |
Taylor and Haley, J., 1997, "Towards the Synthesis of Epothilone A: Enantioselective Preparation of the Thiazole Sidechain and Macrocyclic Ring Closure", Tetrahedron Lett., 38(12):2061-2064. |
U.S. Appl. No. 08/856,533, filed May 14, 1997, Nicolaou et al. |
U.S. Appl. No. 08/923,869, Nicolaou et al., filed Sep. 4, 1997. * |
U.S. Appl. No. 60/032,864, filed Dec. 12, 1996, Nicolaou et al. |
Victory, S.F., et al., 1996, "Relative Stereochemistry and Solution Conformation of the Novel Pacilitaxel-Like Antimitotic Agent Epothilone A", Bloorg. Med. Chem. Letts., 6(7):893-898. |
Winkler J. D. et al., 1996, "A Model For The Taxol (Pacitaxel)/Epothilone Pharmacophore", Bloorg. Med. Chem. Letts., 6(24): 2963-2966. |
Yang Z., et al., 1997, "Total Synthesis of Epothilone A: The Olefin Metathesis Approach", Angew. Chem. Int. Ed. Engl., 36(1/2): 166-168. |
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