CA2501388C - Nitroaniline-based alkylating agents and their use as prodrugs - Google Patents
Nitroaniline-based alkylating agents and their use as prodrugs Download PDFInfo
- Publication number
- CA2501388C CA2501388C CA2501388A CA2501388A CA2501388C CA 2501388 C CA2501388 C CA 2501388C CA 2501388 A CA2501388 A CA 2501388A CA 2501388 A CA2501388 A CA 2501388A CA 2501388 C CA2501388 C CA 2501388C
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- Canada
- Prior art keywords
- amino
- etoac
- formula
- nmr
- dinitroanilino
- 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.)
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- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229940002612 prodrug Drugs 0.000 title abstract description 23
- 239000000651 prodrug Substances 0.000 title abstract description 23
- 239000002168 alkylating agent Substances 0.000 title description 2
- 229940100198 alkylating agent Drugs 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 32
- 235000003351 Brassica cretica Nutrition 0.000 claims abstract description 30
- 235000003343 Brassica rupestris Nutrition 0.000 claims abstract description 30
- 235000010460 mustard Nutrition 0.000 claims abstract description 30
- 238000010317 ablation therapy Methods 0.000 claims abstract description 9
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 63
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 56
- 150000001875 compounds Chemical class 0.000 claims description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 24
- 241000219198 Brassica Species 0.000 claims description 20
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 claims description 16
- -1 carrier Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 11
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000002798 polar solvent Substances 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 5
- 150000008045 alkali metal halides Chemical class 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000000565 sulfonamide group Chemical group 0.000 claims description 5
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 229910013470 LiC1 Inorganic materials 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- TVGZVOAGMXONFJ-UHFFFAOYSA-N 2-[2-(2-hydroxyethylcarbamoyl)-n-(2-iodoethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCI)C1=C(C(=O)NCCO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O TVGZVOAGMXONFJ-UHFFFAOYSA-N 0.000 claims description 2
- BLCMUMHBRDDXAM-UHFFFAOYSA-N 2-[2-carbamoyl-n-(2-chloroethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCCl)C1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O BLCMUMHBRDDXAM-UHFFFAOYSA-N 0.000 claims description 2
- ZSQFUUPUDPDTDW-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(2,3-dihydroxypropylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(=O)NCC(O)CO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O ZSQFUUPUDPDTDW-UHFFFAOYSA-N 0.000 claims description 2
- AZICEEZSDKZDHX-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(2-hydroxyethylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(=O)NCCO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O AZICEEZSDKZDHX-UHFFFAOYSA-N 0.000 claims description 2
- KQNJLOZYSLLLQE-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(2-hydroxypropylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CC(O)CNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCOS(C)(=O)=O KQNJLOZYSLLLQE-UHFFFAOYSA-N 0.000 claims description 2
- BDBWGNXWWSWBBX-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-carbamoyl-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O BDBWGNXWWSWBBX-UHFFFAOYSA-N 0.000 claims description 2
- ZSOMHSLKERBJSE-UHFFFAOYSA-N bromo methanesulfonate Chemical compound CS(=O)(=O)OBr ZSOMHSLKERBJSE-UHFFFAOYSA-N 0.000 claims description 2
- QBPHLAQJBIIFAZ-UHFFFAOYSA-N methyl 3-[[2-[2-bromoethyl(2-methylsulfonyloxyethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCOS(C)(=O)=O QBPHLAQJBIIFAZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 2
- FRJNWXQKGHANOP-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(3-morpholin-4-ylpropylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C(N(CCBr)CCOS(=O)(=O)C)=C1C(=O)NCCCN1CCOCC1 FRJNWXQKGHANOP-UHFFFAOYSA-N 0.000 claims 1
- ZYKKFLOFVPZMCU-UHFFFAOYSA-N methyl 3-[[2-[2-chloroethyl(2-methylsulfonyloxyethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCCl)CCOS(C)(=O)=O ZYKKFLOFVPZMCU-UHFFFAOYSA-N 0.000 claims 1
- 102000004459 Nitroreductase Human genes 0.000 abstract description 18
- 108020001162 nitroreductase Proteins 0.000 abstract description 18
- 241000219193 Brassicaceae Species 0.000 abstract description 10
- 102000004190 Enzymes Human genes 0.000 abstract description 8
- 108090000790 Enzymes Proteins 0.000 abstract description 8
- 108090000623 proteins and genes Proteins 0.000 abstract description 8
- 238000002560 therapeutic procedure Methods 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 7
- 206010021143 Hypoxia Diseases 0.000 abstract description 6
- 231100000599 cytotoxic agent Toxicity 0.000 abstract description 6
- 230000001419 dependent effect Effects 0.000 abstract description 6
- 230000007954 hypoxia Effects 0.000 abstract description 6
- 239000002619 cytotoxin Substances 0.000 abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 128
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 238000010828 elution Methods 0.000 description 43
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 35
- 229910002027 silica gel Inorganic materials 0.000 description 35
- 239000003208 petroleum Substances 0.000 description 30
- 229910052757 nitrogen Inorganic materials 0.000 description 28
- 239000000243 solution Substances 0.000 description 25
- 238000004587 chromatography analysis Methods 0.000 description 21
- 239000006260 foam Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 12
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 150000003512 tertiary amines Chemical group 0.000 description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- 150000001204 N-oxides Chemical class 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000003039 volatile agent Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 241001112696 Clostridia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
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- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 4
- 101150091037 nfsB gene Proteins 0.000 description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YQANFKDQYSESFK-UHFFFAOYSA-N 2-[3-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC=C([N+]([O-])=O)C(C(=O)NCC(O)CO)=C1[N+]([O-])=O YQANFKDQYSESFK-UHFFFAOYSA-N 0.000 description 3
- SDNHGKBEWGELIX-UHFFFAOYSA-N 2-[3-carbamoyl-n-(2-methylsulfonyloxyethyl)-2,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C([N+]([O-])=O)C=CC(C(N)=O)=C1[N+]([O-])=O SDNHGKBEWGELIX-UHFFFAOYSA-N 0.000 description 3
- URZIYPKNXKUFAJ-UHFFFAOYSA-N 2-[5-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(=O)NCC(O)CO)=C([N+]([O-])=O)C=C1[N+]([O-])=O URZIYPKNXKUFAJ-UHFFFAOYSA-N 0.000 description 3
- NEHFIJDJOAYEIT-UHFFFAOYSA-N 2-[5-(2-hydroxyethylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(=O)NCCO)=C([N+]([O-])=O)C=C1[N+]([O-])=O NEHFIJDJOAYEIT-UHFFFAOYSA-N 0.000 description 3
- MHOHFBMVOJCKIE-UHFFFAOYSA-N 2-[5-carbamoyl-n-(2-chloroethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCCl)C1=CC(C(N)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O MHOHFBMVOJCKIE-UHFFFAOYSA-N 0.000 description 3
- MVWHPUZNLDBOLH-UHFFFAOYSA-N 5-[bis(2-methylsulfonyloxyethyl)amino]-2,4-dinitrobenzoic acid Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(O)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O MVWHPUZNLDBOLH-UHFFFAOYSA-N 0.000 description 3
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 3
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- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
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- 239000000284 extract Substances 0.000 description 3
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- ALKUXDWPJSKEQI-UHFFFAOYSA-N methyl 3-[bis(2-methylsulfonyloxyethyl)amino]-2,6-dinitrobenzoate Chemical compound COC(=O)C1=C([N+]([O-])=O)C=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=C1[N+]([O-])=O ALKUXDWPJSKEQI-UHFFFAOYSA-N 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- NLCOFJNMNIDBCV-UHFFFAOYSA-N 2-[2-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C(C(=O)NCC(O)CO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NLCOFJNMNIDBCV-UHFFFAOYSA-N 0.000 description 2
- GABZTCDFXGIBLI-UHFFFAOYSA-N 2-[2-carbamoyl-n-(2-methylsulfonyloxyethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O GABZTCDFXGIBLI-UHFFFAOYSA-N 0.000 description 2
- SQJSKJUTFZCNGA-UHFFFAOYSA-N 2-[5-(3-hydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(=O)NCCCO)=C([N+]([O-])=O)C=C1[N+]([O-])=O SQJSKJUTFZCNGA-UHFFFAOYSA-N 0.000 description 2
- XEIJNVSHRWQDQH-UHFFFAOYSA-N 2-[5-carbamoyl-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(N)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O XEIJNVSHRWQDQH-UHFFFAOYSA-N 0.000 description 2
- FECHUQLECZVXNC-UHFFFAOYSA-N 2-[[4,6-dinitro-6-[2-(oxan-2-yloxy)propylcarbamoyl]cyclohexa-2,4-dien-1-yl]-(2-methylsulfonyloxyethyl)amino]ethyl methanesulfonate Chemical compound C1CCCOC1OC(C)CNC(=O)C1([N+]([O-])=O)C=C([N+]([O-])=O)C=CC1N(CCOS(C)(=O)=O)CCOS(C)(=O)=O FECHUQLECZVXNC-UHFFFAOYSA-N 0.000 description 2
- OAZVGZCFPYNGEO-UHFFFAOYSA-N 2-chloro-3,5-dinitro-n-[2-(oxan-2-yloxy)ethyl]benzamide Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC(C(=O)NCCOC2OCCCC2)=C1Cl OAZVGZCFPYNGEO-UHFFFAOYSA-N 0.000 description 2
- DMPISPVMDRNMGX-UHFFFAOYSA-N 2-chloro-3,5-dinitro-n-[2-(oxan-2-yloxy)propyl]benzamide Chemical compound C1CCCOC1OC(C)CNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl DMPISPVMDRNMGX-UHFFFAOYSA-N 0.000 description 2
- ADTKEYLCJYYHHH-UHFFFAOYSA-N 2-chloro-3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl ADTKEYLCJYYHHH-UHFFFAOYSA-N 0.000 description 2
- QFGXKJGQMYAPIM-UHFFFAOYSA-N 2-chloro-3,5-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=C(Cl)C([N+]([O-])=O)=C1 QFGXKJGQMYAPIM-UHFFFAOYSA-N 0.000 description 2
- MBOJHBJUPDBPGP-UHFFFAOYSA-N 2-chloro-n-(2-hydroxyethyl)-3,5-dinitrobenzamide Chemical compound OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl MBOJHBJUPDBPGP-UHFFFAOYSA-N 0.000 description 2
- XSRCTKACFHFUMA-UHFFFAOYSA-N 2-chloro-n-(3-morpholin-4-ylpropyl)-3,5-dinitrobenzamide Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC(C(=O)NCCCN2CCOCC2)=C1Cl XSRCTKACFHFUMA-UHFFFAOYSA-N 0.000 description 2
- BTBFCBQZFMQBNT-UHFFFAOYSA-N 3,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1F BTBFCBQZFMQBNT-UHFFFAOYSA-N 0.000 description 2
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- 108010011222 cyclo(Arg-Pro) Proteins 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- RDFJFVXMRYVOAC-UHFFFAOYSA-N methiodal Chemical compound OS(=O)(=O)CI RDFJFVXMRYVOAC-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- YQUWPPGZHGDYPU-UHFFFAOYSA-N methyl 3-[(2-chloro-3,5-dinitrobenzoyl)amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl YQUWPPGZHGDYPU-UHFFFAOYSA-N 0.000 description 1
- CCRHRAFGFFFSNM-UHFFFAOYSA-N methyl 3-[[2-[bis(2-bromoethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCBr CCRHRAFGFFFSNM-UHFFFAOYSA-N 0.000 description 1
- PZVXPUGUODFQJC-UHFFFAOYSA-N methyl 3-[[2-[bis(2-chloroethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCCl)CCCl PZVXPUGUODFQJC-UHFFFAOYSA-N 0.000 description 1
- MVXWPONEUMUAOU-UHFFFAOYSA-N methyl 3-[bis(2-hydroxyethyl)amino]-2,6-dinitrobenzoate Chemical compound COC(=O)C1=C([N+]([O-])=O)C=CC(N(CCO)CCO)=C1[N+]([O-])=O MVXWPONEUMUAOU-UHFFFAOYSA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ521851A NZ521851A (en) | 2002-10-08 | 2002-10-08 | Nitroaniline-based unsymmetrical mustard alkylating agents for gene dependent enzyme prodrug therapy |
| NZNZ521851 | 2002-10-08 | ||
| PCT/NZ2003/000225 WO2004033415A1 (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2501388A1 CA2501388A1 (en) | 2004-04-22 |
| CA2501388C true CA2501388C (en) | 2011-01-04 |
Family
ID=32089872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2501388A Expired - Fee Related CA2501388C (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US7776924B2 (https=) |
| EP (1) | EP1558568A4 (https=) |
| JP (2) | JP4582519B2 (https=) |
| CN (1) | CN100546976C (https=) |
| AU (1) | AU2003278628B2 (https=) |
| CA (1) | CA2501388C (https=) |
| NZ (1) | NZ521851A (https=) |
| WO (1) | WO2004033415A1 (https=) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2004285831B2 (en) * | 2003-10-31 | 2011-09-15 | Auckland Uniservices Limited | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents |
| JP4761899B2 (ja) * | 2005-09-12 | 2011-08-31 | Ｈｏｙａ株式会社 | 電子内視鏡システム |
| NZ549659A (en) * | 2006-09-04 | 2008-12-24 | Auckland Uniservices Ltd | Processes of preparing asymmetric dinitrobenzamide mustard compounds, intermediate compounds useful therein and products obtained therefrom |
| EP2350664B1 (en) | 2008-10-21 | 2021-05-19 | ImmunoGenesis, Inc. | Treatment of cancer using the hypoxia activated prodrug th-302 in combination with docetaxel or pemetrexed |
| CN101723932B (zh) * | 2008-10-31 | 2013-11-20 | 北京以岭生物工程技术有限公司 | 硝基吡啶乙烯亚胺化合物、其药物组合物及其制备方法和用途 |
| ES2877629T3 (es) | 2010-07-12 | 2021-11-17 | Immunogenesis Inc | Administración de profármacos activados por hipoxia y agentes antiangiogénicos para el tratamiento del cáncer |
| EP2793882A4 (en) | 2011-12-22 | 2015-04-29 | Threshold Pharmaceuticals Inc | ADMINISTRATION OF HYPOXIA-ACTIVATED PRODRUGS IN COMBINATION WITH CHK1 INHIBITORS FOR THE TREATMENT OF CANCER |
| EP2888227B1 (en) * | 2012-08-23 | 2020-07-29 | Convert Pharmaceuticals SA | Novel prodrugs and methods of use thereof |
| US10202408B2 (en) | 2012-08-23 | 2019-02-12 | Health Innovation Ventures B.V. | Prodrugs and methods of use thereof |
| WO2014062856A1 (en) | 2012-10-16 | 2014-04-24 | Halozyme, Inc. | Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods |
| JP2016528217A (ja) | 2013-07-26 | 2016-09-15 | スレッショルド ファーマシューティカルズ，インコーポレイテッド | 低酸素活性化プロドラッグおよびタキサンの組合せを用いた膵臓癌の治療 |
| BR112017007765B1 (pt) | 2014-10-14 | 2023-10-03 | Halozyme, Inc | Composições de adenosina deaminase-2 (ada2), variantes do mesmo e métodos de usar o mesmo |
| JP7327900B2 (ja) | 2015-06-24 | 2023-08-16 | スレッシュホールド ファーマシューティカルズ， インコーポレイテッド | アジリジン含有ｄｎａアルキル化剤 |
| CN106995815B (zh) * | 2016-01-22 | 2020-09-01 | 南京农业大学 | 硝基还原酶基因pnr及其编码的蛋白和应用 |
| CN106905184B (zh) * | 2017-03-05 | 2019-03-29 | 北京化工大学 | 含有苯甲酰胺基团的氮芥类化合物及其制备方法和用途 |
| EP3774743B1 (en) * | 2018-03-29 | 2023-11-22 | Achilles Medical Limited | Prodrug compounds activated by akr1c3 and their use for treating hyperproliferative disorders |
| CN112961082B (zh) * | 2021-02-22 | 2022-09-06 | 沈阳药科大学 | 一种血管阻断剂与双载药仿生脂质体联用的给药系统 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8705477D0 (en) | 1987-03-09 | 1987-04-15 | Carlton Med Prod | Drug delivery systems |
| NZ240785A (en) * | 1991-11-28 | 1995-08-28 | Cancer Res Campaign Tech | Substituted nitro aniline derivatives and medicaments |
-
2002
- 2002-10-08 NZ NZ521851A patent/NZ521851A/en not_active IP Right Cessation
-
2003
- 2003-10-08 US US10/529,772 patent/US7776924B2/en not_active Expired - Fee Related
- 2003-10-08 AU AU2003278628A patent/AU2003278628B2/en not_active Ceased
- 2003-10-08 CA CA2501388A patent/CA2501388C/en not_active Expired - Fee Related
- 2003-10-08 WO PCT/NZ2003/000225 patent/WO2004033415A1/en not_active Ceased
- 2003-10-08 JP JP2004542927A patent/JP4582519B2/ja not_active Expired - Fee Related
- 2003-10-08 EP EP03770163A patent/EP1558568A4/en not_active Withdrawn
- 2003-10-08 CN CNB2003801028127A patent/CN100546976C/zh not_active Expired - Fee Related
-
2010
- 2010-06-15 JP JP2010136139A patent/JP2010265272A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CN1711236A (zh) | 2005-12-21 |
| WO2004033415A1 (en) | 2004-04-22 |
| NZ521851A (en) | 2005-02-25 |
| US20050256191A1 (en) | 2005-11-17 |
| JP2010265272A (ja) | 2010-11-25 |
| AU2003278628A1 (en) | 2004-05-04 |
| EP1558568A1 (en) | 2005-08-03 |
| JP4582519B2 (ja) | 2010-11-17 |
| CN100546976C (zh) | 2009-10-07 |
| CA2501388A1 (en) | 2004-04-22 |
| JP2006502214A (ja) | 2006-01-19 |
| US7776924B2 (en) | 2010-08-17 |
| AU2003278628B2 (en) | 2010-09-23 |
| EP1558568A4 (en) | 2006-10-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20141008 |