DE1795763C3 - Verfahren zur Herstellung von Vincaleukoblastin- und Leurocristinderivaten - Google Patents
Verfahren zur Herstellung von Vincaleukoblastin- und LeurocristinderivatenInfo
- Publication number
- DE1795763C3 DE1795763C3 DE1795763A DE1795763A DE1795763C3 DE 1795763 C3 DE1795763 C3 DE 1795763C3 DE 1795763 A DE1795763 A DE 1795763A DE 1795763 A DE1795763 A DE 1795763A DE 1795763 C3 DE1795763 C3 DE 1795763C3
- Authority
- DE
- Germany
- Prior art keywords
- general formula
- methanol
- compound
- denotes
- vincaleukoblastin
- 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
Links
- 238000000034 method Methods 0.000 title claims description 18
- 238000002360 preparation method Methods 0.000 title claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 150000008064 anhydrides Chemical class 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- NDMPLJNOPCLANR-XQLDGQACSA-N methyl (1R,9R,10S,11R,12R,19R)-12-ethyl-4-[(13S,15R,17S)-17-ethyl-17-hydroxy-13-methoxycarbonyl-1,11-diazatetracyclo[13.3.1.04,12.05,10]nonadeca-4(12),5,7,9-tetraen-13-yl]-10,11-dihydroxy-5-methoxy-8-methyl-8,16-diazapentacyclo[10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,13-tetraene-10-carboxylate Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 NDMPLJNOPCLANR-XQLDGQACSA-N 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 16
- 230000008020 evaporation Effects 0.000 description 15
- -1 alkyl radicals Chemical class 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000000908 ammonium hydroxide Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000012458 free base Substances 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 229960003048 vinblastine Drugs 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine Chemical group C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-CFWMRBGOSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 3
- 229940089960 chloroacetate Drugs 0.000 description 3
- 229940120124 dichloroacetate Drugs 0.000 description 3
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229940066528 trichloroacetate Drugs 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000174 oncolytic effect Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229940049953 phenylacetate Drugs 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- RQHMQURGSQBBJY-UHFFFAOYSA-N (2,2-dichloroacetyl) 2,2-dichloroacetate Chemical compound ClC(Cl)C(=O)OC(=O)C(Cl)Cl RQHMQURGSQBBJY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- MGKBJNVLJBEDCF-UHFFFAOYSA-N benzene;ethanol;hydrate Chemical compound O.CCO.C1=CC=CC=C1 MGKBJNVLJBEDCF-UHFFFAOYSA-N 0.000 description 1
- VEFXTGTZJOWDOF-UHFFFAOYSA-N benzene;hydrate Chemical compound O.C1=CC=CC=C1 VEFXTGTZJOWDOF-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FUSVYSIRZDZAGP-UHFFFAOYSA-N butanoic acid;sulfuric acid Chemical compound OS(O)(=O)=O.CCCC(O)=O FUSVYSIRZDZAGP-UHFFFAOYSA-N 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1795763A DE1795763C3 (de) | 1964-03-09 | 1965-03-08 | Verfahren zur Herstellung von Vincaleukoblastin- und Leurocristinderivaten |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US350519A US3392173A (en) | 1964-03-09 | 1964-03-09 | Novel acyl derivatives of desacetyl-vincaleukoblastine and processes for their preparation |
| DE1795763A DE1795763C3 (de) | 1964-03-09 | 1965-03-08 | Verfahren zur Herstellung von Vincaleukoblastin- und Leurocristinderivaten |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1795763A1 DE1795763A1 (de) | 1974-11-21 |
| DE1795763B2 DE1795763B2 (de) | 1977-11-10 |
| DE1795763C3 true DE1795763C3 (de) | 1978-06-29 |
Family
ID=23377073
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1795763A Expired DE1795763C3 (de) | 1964-03-09 | 1965-03-08 | Verfahren zur Herstellung von Vincaleukoblastin- und Leurocristinderivaten |
| DE1545760A Expired DE1545760C3 (de) | 1964-03-09 | 1965-03-08 | Vincaleukoblastinderivate |
| DE1795823A Expired DE1795823C3 (de) | 1964-03-09 | 1965-03-08 | Desacetylvincaleukoblastin und seine Salze mit Säuren |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE1545760A Expired DE1545760C3 (de) | 1964-03-09 | 1965-03-08 | Vincaleukoblastinderivate |
| DE1795823A Expired DE1795823C3 (de) | 1964-03-09 | 1965-03-08 | Desacetylvincaleukoblastin und seine Salze mit Säuren |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US3392173A (enExample) |
| BE (1) | BE660843A (enExample) |
| CH (1) | CH507970A (enExample) |
| DE (3) | DE1795763C3 (enExample) |
| ES (1) | ES310240A1 (enExample) |
| FR (2) | FR1449628A (enExample) |
| GB (1) | GB1095833A (enExample) |
| NL (1) | NL6502977A (enExample) |
| SE (1) | SE330700B (enExample) |
Families Citing this family (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3899493A (en) * | 1972-12-29 | 1975-08-12 | Richter Gedeon Vegyeszet | Chromic acid oxidation of vinblastine sulfate to form vincristine |
| HU165986B (enExample) * | 1973-02-16 | 1974-12-28 | ||
| US4012390A (en) * | 1974-10-16 | 1977-03-15 | Eli Lilly And Company | Vinblastinoic acid |
| US3954773A (en) * | 1974-11-21 | 1976-05-04 | Eli Lilly And Company | 4-Desacetoxyvinblastine |
| US3944554A (en) * | 1975-01-09 | 1976-03-16 | Eli Lilly And Company | 4-Desacetoxy-3-hydroxyvinblastine |
| US4029663A (en) * | 1975-07-10 | 1977-06-14 | Eli Lilly And Company | Dimeric anhydro-vinca derivatives |
| US4209443A (en) * | 1976-02-13 | 1980-06-24 | Richter Gedeon Vegyeszeti Gyar Rt. | Process for separating pharmaceutically active diindole alkaloids |
| US4143041A (en) * | 1977-01-19 | 1979-03-06 | Eli Lilly And Company | 4'-Deoxyvincristine and related compounds |
| HU178084B (en) * | 1977-05-31 | 1982-03-28 | Richter Gedeon Vegyeszet | New process for the extraction of native vindoline,catharantine,3',4'-anhydrovinblastine,leurosine and,if desired,of other diinodle alkaloids from vinca rosea l.drogue |
| US4195022A (en) * | 1978-03-27 | 1980-03-25 | Eli Lilly And Company | 4-Desacetoxy-4α-hydroxyvinblastine and related compounds |
| US4166810A (en) * | 1978-04-20 | 1979-09-04 | Eli Lilly And Company | Derivatives of 4-desacetyl VLB C-3 carboxyhydrazide |
| HU178706B (en) * | 1979-04-23 | 1982-06-28 | Richter Gedeon Vegyeszet | Process for preparing bis-indole alkaloids and acid addition salts thereof |
| FR2461714A1 (fr) | 1979-07-17 | 1981-02-06 | Anvar | Nouvelle classe de composes bis-indoliques utiles comme medicaments et procede pour leur preparation |
| GR79898B (enExample) * | 1983-03-30 | 1984-10-31 | Lilly Industries Ltd | |
| US4522750A (en) * | 1984-02-21 | 1985-06-11 | Eli Lilly And Company | Cytotoxic compositions of transferrin coupled to vinca alkaloids |
| HU198074B (en) * | 1985-06-12 | 1989-07-28 | Richter Gedeon Vegyeszet | Process for producing new bis-indole derivatives and pharmaceutical compositions comprising these compounds |
| HU193318B (en) * | 1985-06-12 | 1987-09-28 | Richter Gedeon Vegyeszet | Process for producing new bis- indol derivatives |
| US4667030A (en) * | 1985-06-17 | 1987-05-19 | Eli Lilly And Company | Hydrazide succinimide derivatives of antineoplastic indole-dihydroindole alkaloids |
| US4801688A (en) * | 1986-05-27 | 1989-01-31 | Eli Lilly And Company | Hydrazone immunoglobulin conjugates |
| HUT76925A (hu) * | 1995-04-04 | 1998-01-28 | MTA Enzimológiai Intézet | Bisz-indol-származékok, eljárás előállításukra és az azokat tartalmazó gyógyszerkészítmények |
| US6326402B1 (en) | 1998-08-12 | 2001-12-04 | Octamer, Inc. | Methods for treating viral infections using a compound capable of inhibiting microtubules |
| DE60231868D1 (de) * | 2001-04-24 | 2009-05-20 | Purdue Research Foundation | Folat-mimetika und deren folatrezeptorbindende konjugate |
| DE60326833D1 (de) * | 2002-05-15 | 2009-05-07 | Endocyte Inc | Vitamin-mitomycin-konjugate |
| TWI367096B (en) | 2003-01-27 | 2012-07-01 | Endocyte Inc | Vitamin-receptor binding drug delivery conjugates and pharmaceutical compositions |
| WO2006012527A1 (en) | 2004-07-23 | 2006-02-02 | Endocyte, Inc. | Bivalent linkers and conjugates thereof |
| CN101175757B (zh) * | 2005-03-16 | 2012-11-14 | 恩多塞特公司 | 蝶酸及其缀合物的合成和纯化 |
| WO2007022493A2 (en) | 2005-08-19 | 2007-02-22 | Endocyte, Inc. | Ligand conjugates of vinca alkaloids, analogs, and derivatives |
| US8465724B2 (en) | 2005-08-19 | 2013-06-18 | Endocyte, Inc. | Multi-drug ligand conjugates |
| WO2008101231A2 (en) | 2007-02-16 | 2008-08-21 | Endocyte, Inc. | Methods and compositions for treating and diagnosing kidney disease |
| EP2489372A3 (en) * | 2007-03-14 | 2013-01-02 | Endocyte, Inc. | Binding ligand linked drug delivery conjugates of tubulysins |
| US9877965B2 (en) | 2007-06-25 | 2018-01-30 | Endocyte, Inc. | Vitamin receptor drug delivery conjugates for treating inflammation |
| RU2523909C2 (ru) * | 2007-06-25 | 2014-07-27 | Эндосайт, Инк. | Конъюгаты, содержащие гидрофильные спейсеры линкеров |
| CN101909441B (zh) * | 2007-10-25 | 2015-05-13 | 恩多塞特公司 | 微管蛋白抑制剂及其制备方法 |
| WO2013126797A1 (en) | 2012-02-24 | 2013-08-29 | Purdue Research Foundation | Cholecystokinin b receptor targeting for imaging and therapy |
| US20140080175A1 (en) | 2012-03-29 | 2014-03-20 | Endocyte, Inc. | Processes for preparing tubulysin derivatives and conjugates thereof |
| IN2015DN04147A (enExample) | 2012-10-16 | 2015-10-16 | Endocyte Inc |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3097137A (en) * | 1960-05-19 | 1963-07-09 | Canadian Patents Dev | Vincaleukoblastine |
| US3169968A (en) * | 1962-05-08 | 1965-02-16 | Ciba Geigy Corp | Esters of ajmaline and related compounds |
| US3225053A (en) * | 1963-01-10 | 1965-12-21 | Lilly Co Eli | Quebrachidine and derivatives |
-
1964
- 1964-03-09 US US350519A patent/US3392173A/en not_active Expired - Lifetime
-
1965
- 1965-03-04 CH CH304165A patent/CH507970A/de not_active IP Right Cessation
- 1965-03-05 GB GB9516/65A patent/GB1095833A/en not_active Expired
- 1965-03-08 DE DE1795763A patent/DE1795763C3/de not_active Expired
- 1965-03-08 ES ES0310240A patent/ES310240A1/es not_active Expired
- 1965-03-08 DE DE1545760A patent/DE1545760C3/de not_active Expired
- 1965-03-08 DE DE1795823A patent/DE1795823C3/de not_active Expired
- 1965-03-09 BE BE660843A patent/BE660843A/xx unknown
- 1965-03-09 NL NL6502977A patent/NL6502977A/xx unknown
- 1965-03-09 SE SE03033/65A patent/SE330700B/xx unknown
- 1965-03-09 FR FR8509A patent/FR1449628A/fr not_active Expired
- 1965-06-09 FR FR20098A patent/FR6668M/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES310240A1 (es) | 1965-10-16 |
| DE1795763B2 (de) | 1977-11-10 |
| DE1795823B2 (de) | 1981-04-30 |
| SE330700B (enExample) | 1970-11-30 |
| DE1795823A1 (de) | 1976-02-05 |
| DE1795823C3 (de) | 1982-04-15 |
| FR6668M (enExample) | 1969-02-03 |
| DE1545760B2 (de) | 1978-02-09 |
| GB1095833A (en) | 1967-12-20 |
| BE660843A (enExample) | 1965-09-09 |
| FR1449628A (fr) | 1966-08-19 |
| NL6502977A (enExample) | 1965-09-10 |
| CH507970A (de) | 1971-05-31 |
| DE1545760A1 (de) | 1969-11-27 |
| DE1795763A1 (de) | 1974-11-21 |
| US3392173A (en) | 1968-07-09 |
| DE1545760C3 (de) | 1978-10-05 |
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| Date | Code | Title | Description |
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| C3 | Grant after two publication steps (3rd publication) | ||
| 8339 | Ceased/non-payment of the annual fee |