NO313126B1 - Forbedrede promedikamenter for enzym-formidlet aktivering og farmasöytiske preparater inneholdende disse - Google Patents
Forbedrede promedikamenter for enzym-formidlet aktivering og farmasöytiske preparater inneholdende disse Download PDFInfo
- Publication number
- NO313126B1 NO313126B1 NO19943319A NO943319A NO313126B1 NO 313126 B1 NO313126 B1 NO 313126B1 NO 19943319 A NO19943319 A NO 19943319A NO 943319 A NO943319 A NO 943319A NO 313126 B1 NO313126 B1 NO 313126B1
- Authority
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- Norway
- Prior art keywords
- solution
- mmol
- prodrug
- compound
- prodrugs
- Prior art date
Links
- 102000004190 Enzymes Human genes 0.000 title claims description 16
- 108090000790 Enzymes Proteins 0.000 title claims description 16
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 6
- 239000000651 prodrug Substances 0.000 title abstract description 31
- 229940002612 prodrug Drugs 0.000 title abstract description 31
- 230000004913 activation Effects 0.000 title description 4
- 230000001404 mediated effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 17
- 230000003197 catalytic effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000002502 liposome Substances 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 229940127121 immunoconjugate Drugs 0.000 claims 1
- 229940051026 immunotoxin Drugs 0.000 claims 1
- 230000002637 immunotoxin Effects 0.000 claims 1
- 239000002596 immunotoxin Substances 0.000 claims 1
- 231100000608 immunotoxin Toxicity 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 40
- 239000000243 solution Substances 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 229910004298 SiO 2 Inorganic materials 0.000 description 14
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 8
- 102000037865 fusion proteins Human genes 0.000 description 8
- 108020001507 fusion proteins Proteins 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PSGQCCSGKGJLRL-UHFFFAOYSA-N 4-methyl-2h-chromen-2-one Chemical group C1=CC=CC2=C1OC(=O)C=C2C PSGQCCSGKGJLRL-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 2
- HSHNITRMYYLLCV-UHFFFAOYSA-N 4-methylumbelliferone Chemical compound C1=C(O)C=CC2=C1OC(=O)C=C2C HSHNITRMYYLLCV-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- -1 Prop-1-enyl Chemical group 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000005571 anion exchange chromatography Methods 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229950002441 glucurolactone Drugs 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YTHJCZRFJGXPTL-UHFFFAOYSA-N 4-hydroxy-3-nitrobenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1[N+]([O-])=O YTHJCZRFJGXPTL-UHFFFAOYSA-N 0.000 description 1
- XECPAIJNBXCOBO-MMPJQOAZSA-N D-glucaro-1,4-lactone Chemical compound OC(=O)[C@@H](O)[C@H]1OC(=O)[C@H](O)[C@H]1O XECPAIJNBXCOBO-MMPJQOAZSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-M D-glucopyranuronate Chemical compound OC1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-M 0.000 description 1
- 101000933465 Homo sapiens Beta-glucuronidase Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 229910003691 SiBr Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000002708 random mutagenesis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
- A61K47/6899—Antibody-Directed Enzyme Prodrug Therapy [ADEPT]
-
- 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
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93114475A EP0647450A1 (fr) | 1993-09-09 | 1993-09-09 | Prodrogues améliorées pour activation médiée par enzyme |
Publications (3)
Publication Number | Publication Date |
---|---|
NO943319D0 NO943319D0 (no) | 1994-09-08 |
NO943319L NO943319L (no) | 1995-03-10 |
NO313126B1 true NO313126B1 (no) | 2002-08-19 |
Family
ID=8213248
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO19943319A NO313126B1 (no) | 1993-09-09 | 1994-09-08 | Forbedrede promedikamenter for enzym-formidlet aktivering og farmasöytiske preparater inneholdende disse |
Country Status (13)
Country | Link |
---|---|
US (1) | US5621002A (fr) |
EP (2) | EP0647450A1 (fr) |
JP (1) | JP3773120B2 (fr) |
KR (1) | KR100385830B1 (fr) |
AT (1) | ATE208213T1 (fr) |
AU (1) | AU678494B2 (fr) |
CA (1) | CA2131662C (fr) |
DE (1) | DE69428957T2 (fr) |
DK (1) | DK0642799T3 (fr) |
ES (1) | ES2167343T3 (fr) |
NO (1) | NO313126B1 (fr) |
PT (1) | PT642799E (fr) |
ZA (1) | ZA946920B (fr) |
Families Citing this family (143)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5525606A (en) | 1994-08-01 | 1996-06-11 | The United States Of America As Represented By The Department Of Health And Human Services | Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines |
DE19512484A1 (de) | 1995-04-04 | 1996-10-17 | Bayer Ag | Kohlenhydratmodifizierte Cytostatika |
ES2257756T3 (es) * | 1996-03-12 | 2006-08-01 | Sanofi-Aventis Deutschland Gmbh | Nuevos profarmacos para la terapia de tumores y enfermedades inflamatorias. |
ATE365562T1 (de) * | 1996-05-03 | 2007-07-15 | Immunomedics Inc | Zielgerichtete kombinations-immuntherapie für krebs |
DE19631288A1 (de) * | 1996-08-02 | 1998-02-05 | Hoechst Ag | Neue Inhibitoren der ß-Glucuronidase |
JP2001501601A (ja) * | 1996-09-12 | 2001-02-06 | メルク エンド カンパニー インコーポレーテッド | 前立腺ガンの治療において有用な共役体 |
DE19720312A1 (de) * | 1997-05-15 | 1998-11-19 | Hoechst Ag | Zubereitung mit erhöhter in vivo Verträglichkeit |
US6127333A (en) * | 1997-07-10 | 2000-10-03 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
US6391305B1 (en) | 1997-09-10 | 2002-05-21 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
ZA9810974B (en) * | 1997-12-02 | 1999-06-03 | Merck & Co Inc | Conjugates useful in the treatment of prostate cancer |
US20040081659A1 (en) * | 1997-12-02 | 2004-04-29 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
NZ504615A (en) * | 1997-12-02 | 2003-05-30 | Merck & Co Inc | Conjugates useful in the treatment of prostate cancer |
CA2319836C (fr) | 1998-02-06 | 2010-11-23 | De Montfort University | Promedicaments actives par hydroxylation |
GB2334256A (en) | 1998-02-12 | 1999-08-18 | Univ Montfort | Hydroxylation activated prodrugs |
AU2531599A (en) * | 1998-02-12 | 1999-08-30 | De Montfort University | Hydroxylation activated drug release |
US6043367A (en) * | 1998-09-30 | 2000-03-28 | Roffler; Steve | Proactive antitumor compounds |
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AU678494B2 (en) | 1997-05-29 |
JP3773120B2 (ja) | 2006-05-10 |
DE69428957D1 (de) | 2001-12-13 |
CA2131662A1 (fr) | 1995-03-10 |
AU7169994A (en) | 1995-03-23 |
JPH07149667A (ja) | 1995-06-13 |
ZA946920B (en) | 1995-04-12 |
DK0642799T3 (da) | 2002-02-25 |
KR100385830B1 (ko) | 2003-08-19 |
NO943319D0 (no) | 1994-09-08 |
CA2131662C (fr) | 2008-09-02 |
KR950007874A (ko) | 1995-04-15 |
NO943319L (no) | 1995-03-10 |
DE69428957T2 (de) | 2002-06-06 |
US5621002A (en) | 1997-04-15 |
EP0642799B1 (fr) | 2001-11-07 |
ES2167343T3 (es) | 2002-05-16 |
EP0647450A1 (fr) | 1995-04-12 |
ATE208213T1 (de) | 2001-11-15 |
PT642799E (pt) | 2002-04-29 |
EP0642799A1 (fr) | 1995-03-15 |
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