CA2319836C - Hydroxylation activated prodrugs - Google Patents
Hydroxylation activated prodrugs Download PDFInfo
- Publication number
- CA2319836C CA2319836C CA2319836A CA2319836A CA2319836C CA 2319836 C CA2319836 C CA 2319836C CA 2319836 A CA2319836 A CA 2319836A CA 2319836 A CA2319836 A CA 2319836A CA 2319836 C CA2319836 C CA 2319836C
- Authority
- CA
- Canada
- Prior art keywords
- prodrug
- tumour
- compound
- xii
- treatment
- 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 - Fee Related
Links
- 229940002612 prodrug Drugs 0.000 title claims abstract description 61
- 239000000651 prodrug Substances 0.000 title claims abstract description 61
- 230000033444 hydroxylation Effects 0.000 title abstract description 9
- 238000005805 hydroxylation reaction Methods 0.000 title abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 101000725164 Homo sapiens Cytochrome P450 1B1 Proteins 0.000 claims abstract description 10
- 238000007262 aromatic hydroxylation reaction Methods 0.000 claims abstract description 9
- 230000002255 enzymatic effect Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 43
- 239000002207 metabolite Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 102100027417 Cytochrome P450 1B1 Human genes 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 238000003745 diagnosis Methods 0.000 claims description 6
- 239000003080 antimitotic agent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000001727 in vivo Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229940093499 ethyl acetate Drugs 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 231100000433 cytotoxic Toxicity 0.000 description 8
- 230000001472 cytotoxic effect Effects 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 101100497948 Caenorhabditis elegans cyn-1 gene Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VUGQIIQFXCXZJU-UHFFFAOYSA-N 3,4,5-trimethoxyacetophenone Chemical compound COC1=CC(C(C)=O)=CC(OC)=C1OC VUGQIIQFXCXZJU-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- IHAWCLXPXUOJEO-JXMROGBWSA-N (e)-3-(4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1\C=C\C(=O)C1=CC(OC)=C(OC)C(OC)=C1 IHAWCLXPXUOJEO-JXMROGBWSA-N 0.000 description 4
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 4
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 4
- HSLHSXYQLGGUBE-NTUHNPAUSA-N (z)-3-(3-hydroxy-4-methoxyphenyl)-2-pyridin-3-ylprop-2-enenitrile Chemical compound C1=C(O)C(OC)=CC=C1\C=C(/C#N)C1=CC=CN=C1 HSLHSXYQLGGUBE-NTUHNPAUSA-N 0.000 description 3
- OIPHWUPMXHQWLR-UHFFFAOYSA-N 2-pyridin-3-ylacetonitrile Chemical compound N#CCC1=CC=CN=C1 OIPHWUPMXHQWLR-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000003228 microsomal effect Effects 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FMCAFXHLMUOIGG-IWFBPKFRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-formamido-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxy-2,5-dimethylphenyl)propanoyl]amino]-4-methylsulfanylbutanoic acid Chemical compound O=CN[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCSC)C(O)=O)CC1=CC(C)=C(O)C=C1C FMCAFXHLMUOIGG-IWFBPKFRSA-N 0.000 description 2
- KGUGYOFXEFZJMR-VQHVLOKHSA-N (e)-3-(2,4-dimethoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound COC1=CC(OC)=CC=C1\C=C\C(=O)C1=CC(OC)=C(OC)C(OC)=C1 KGUGYOFXEFZJMR-VQHVLOKHSA-N 0.000 description 2
- AYICHAKPDXZAMD-RMKNXTFCSA-N (e)-3-(4-hydroxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound COC1=C(OC)C(OC)=CC(C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 AYICHAKPDXZAMD-RMKNXTFCSA-N 0.000 description 2
- YBYGMVQGEJEQRC-MDWZMJQESA-N (z)-3-(4-hydroxyphenyl)-2-pyridin-3-ylprop-2-enenitrile Chemical compound C1=CC(O)=CC=C1\C=C(/C#N)C1=CC=CN=C1 YBYGMVQGEJEQRC-MDWZMJQESA-N 0.000 description 2
- VSYPHCNZDCVVMG-NTEUORMPSA-N (z)-3-(4-methoxyphenyl)-2-pyridin-3-ylprop-2-enenitrile Chemical compound C1=CC(OC)=CC=C1\C=C(/C#N)C1=CC=CN=C1 VSYPHCNZDCVVMG-NTEUORMPSA-N 0.000 description 2
- GGFQQRXTLIJXNY-AATRIKPKSA-N 1,2,3-trimethoxy-5-[(e)-2-(4-methoxyphenyl)ethenyl]benzene Chemical compound C1=CC(OC)=CC=C1\C=C\C1=CC(OC)=C(OC)C(OC)=C1 GGFQQRXTLIJXNY-AATRIKPKSA-N 0.000 description 2
- GGFQQRXTLIJXNY-WAYWQWQTSA-N 1,2,3-trimethoxy-5-[(z)-2-(4-methoxyphenyl)ethenyl]benzene Chemical compound C1=CC(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 GGFQQRXTLIJXNY-WAYWQWQTSA-N 0.000 description 2
- LWRSYTXEQUUTKW-UHFFFAOYSA-N 2,4-dimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 2
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 description 2
- -1 3,5-dihydroxyphenyl Chemical group 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000002784 cytotoxicity assay Methods 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- YQXBNCFNXOFWLR-UHFFFAOYSA-M (4-methoxyphenyl)methyl-triphenylphosphanium;chloride Chemical compound [Cl-].C1=CC(OC)=CC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YQXBNCFNXOFWLR-UHFFFAOYSA-M 0.000 description 1
- IKMOZUDCUBMIRL-FNORWQNLSA-N (e)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound C1=C(O)C(OC)=CC=C1\C=C\C(=O)C1=CC(OC)=C(OC)C(OC)=C1 IKMOZUDCUBMIRL-FNORWQNLSA-N 0.000 description 1
- NNTQWEXILXMDGK-JLHYYAGUSA-N (e)-3-(4-methoxyphenyl)-2-methyl-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1\C=C(/C)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 NNTQWEXILXMDGK-JLHYYAGUSA-N 0.000 description 1
- FNFSOYGIQWSIEX-UHFFFAOYSA-N 1-(3,4,5-trimethoxyphenyl)propan-1-one Chemical compound CCC(=O)C1=CC(OC)=C(OC)C(OC)=C1 FNFSOYGIQWSIEX-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- REFSKZBXDZGOCW-ONEGZZNKSA-N 2-methoxy-5-[(e)-2-(4-methoxyphenyl)ethenyl]phenol Chemical compound C1=CC(OC)=CC=C1\C=C\C1=CC=C(OC)C(O)=C1 REFSKZBXDZGOCW-ONEGZZNKSA-N 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- MNALUTYMBUBKNX-UHFFFAOYSA-N 6-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(OC)=CC=C21 MNALUTYMBUBKNX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000008142 Cytochrome P-450 CYP1A1 Human genes 0.000 description 1
- 108010074918 Cytochrome P-450 CYP1A1 Proteins 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000003849 Cytochrome P450 Human genes 0.000 description 1
- 108050002014 Cytochrome P450 1B1 Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 238000010541 McMurry coupling reaction Methods 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 229910010062 TiCl3 Inorganic materials 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000012790 confirmation 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
- 238000002425 crystallisation Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012909 foetal bovine serum Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 231100000065 noncytotoxic Toxicity 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 230000002034 xenobiotic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
-
- 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
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9802522.4 | 1998-02-06 | ||
| GBGB9802522.4A GB9802522D0 (en) | 1998-02-06 | 1998-02-06 | Hydroxylation activated prodrugs |
| US09/115,015 US6214886B1 (en) | 1998-02-06 | 1998-07-14 | Hydroxylation activated prodrugs |
| US09/115,015 | 1998-07-14 | ||
| PCT/GB1999/000155 WO1999040056A1 (en) | 1998-02-06 | 1999-02-02 | Hydroxylation activated prodrugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2319836A1 CA2319836A1 (en) | 1999-08-12 |
| CA2319836C true CA2319836C (en) | 2010-11-23 |
Family
ID=26313066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2319836A Expired - Fee Related CA2319836C (en) | 1998-02-06 | 1999-02-02 | Hydroxylation activated prodrugs |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US6677383B1 (https=) |
| EP (1) | EP1051383B1 (https=) |
| JP (1) | JP4642226B2 (https=) |
| AT (1) | ATE272040T1 (https=) |
| AU (1) | AU2173899A (https=) |
| CA (1) | CA2319836C (https=) |
| DE (1) | DE69918950T2 (https=) |
| ES (1) | ES2226332T3 (https=) |
| WO (1) | WO1999040056A1 (https=) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1051383B1 (en) | 1998-02-06 | 2004-07-28 | De Montfort University | Hydroxylation activated prodrugs |
| GB2334256A (en) | 1998-02-12 | 1999-08-18 | Univ Montfort | Hydroxylation activated prodrugs |
| US7321050B2 (en) | 1999-12-06 | 2008-01-22 | Welichem Biotech Inc. | Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues |
| DE60043120D1 (de) * | 1999-12-06 | 2009-11-19 | Welichem Biotech Inc | Polyhydroxystilbene und -stilbenoxide als antipsoriasismittel und proteinkinasehemmer |
| GB0007401D0 (en) | 2000-03-27 | 2000-05-17 | Cancer Res Campaign Tech | Substituted chalcones as therapeeutic compounds |
| WO2001079158A2 (en) * | 2000-04-13 | 2001-10-25 | Hsc Research And Development Limited Partnership | Compounds for modulating cell proliferation |
| JP4862120B2 (ja) | 2001-02-22 | 2012-01-25 | ユニヴァーシティ オブ ブラッドフォード | 腫瘍治療のためのプロドラッグとしてのベンズ−インドールおよびベンゾ−キノリン誘導体 |
| US7626026B2 (en) | 2001-02-22 | 2009-12-01 | University Of Bradford | Pyrrolo-indole and pyrrolo-quinoline derivatives as prodrugs for tumour treatment |
| US6589997B2 (en) * | 2001-06-29 | 2003-07-08 | North Shore-Long Island Jewish Health System | Small-molecule modulators of hepatocyte growth factor/scatter factor activities |
| GB0123777D0 (en) * | 2001-10-03 | 2001-11-21 | Cancer Res Ventures Ltd | Substituted chalcones as therapeutic agents |
| GB0123780D0 (en) * | 2001-10-03 | 2001-11-21 | Cancer Res Ventures Ltd | Substituted chalcones as therapeutic agents |
| CA2463902A1 (en) * | 2001-10-26 | 2003-05-01 | Oxigene, Inc. | Functionalized stilbene derivatives as improved vascular targeting agents |
| GB0126889D0 (en) * | 2001-11-08 | 2002-01-02 | Paterson Inst For Cancer Res | Compounds and their uses |
| US7585866B2 (en) * | 2002-07-31 | 2009-09-08 | Critical Outcome Technologies, Inc. | Protein tyrosine kinase inhibitors |
| AU2003273675A1 (en) * | 2002-10-09 | 2004-05-04 | Wayne R. Danter | Protein tyrosine kinase inhibitors |
| CA2515174A1 (en) * | 2003-02-04 | 2004-08-19 | Kabushiki Kaisha Yakult Honsha | Breast cancer resistance protein (bcrp) inhibitor |
| WO2005092904A1 (en) * | 2004-03-26 | 2005-10-06 | Hsc Research And Development Limited Partnership | Novel compounds for modulating cell proliferation |
| KR101424997B1 (ko) | 2005-03-30 | 2014-07-31 | 가부시키가이샤 야쿠르트 혼샤 | Ｂｃｒｐ／ａｂｃｇ２ 저해제 |
| JP5571387B2 (ja) | 2007-01-11 | 2014-08-13 | クリティカル・アウトカム・テクノロジーズ・インコーポレイテッド | 癌の治療のための化合物および方法 |
| US7784455B1 (en) * | 2007-09-18 | 2010-08-31 | Chong Carlton Le Loong | Reusable pellet shooting grenade |
| CA2710039C (en) * | 2007-12-26 | 2018-07-03 | Critical Outcome Technologies, Inc. | Semicarbazones, thiosemicarbazones and related compounds and methods for treatment of cancer |
| GB0803071D0 (en) * | 2008-02-20 | 2008-03-26 | Care Technologies Inc | Cancer detection methods and techniques |
| EP2318406B1 (en) * | 2008-07-17 | 2016-01-27 | Critical Outcome Technologies, Inc. | Thiosemicarbazone inhibitor compounds and cancer treatment methods |
| GB0907551D0 (en) | 2009-05-01 | 2009-06-10 | Univ Dundee | Treatment or prophylaxis of proliferative conditions |
| CA2999435A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
| PE20210367A1 (es) | 2018-02-02 | 2021-02-26 | Maverix Oncology Inc | Conjugados de farmacos de molecula pequena de monofosfato de gemcitabina |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6176433A (ja) * | 1984-09-21 | 1986-04-18 | Toyobo Co Ltd | 新規なカルコン誘導体 |
| US5773435A (en) | 1987-08-04 | 1998-06-30 | Bristol-Myers Squibb Company | Prodrugs for β-lactamase and uses thereof |
| AU632992B2 (en) * | 1987-12-24 | 1993-01-21 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Pharmaceutical compositions comprising benzylidene- and cinnamylidene-malononitrile derivatives for the inhibition of proliferative processes in mammalian cells, certain such novel compounds and their preparation |
| US5287386A (en) | 1991-03-27 | 1994-02-15 | Thinking Machines Corporation | Differential driver/receiver circuit |
| US5430062A (en) * | 1992-05-21 | 1995-07-04 | Research Corporation Technologies, Inc. | Stilbene derivatives as anticancer agents |
| DE4236237A1 (de) | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
| DE4309344A1 (de) | 1993-03-23 | 1994-09-29 | Gerhard Prof Dr Eisenbrand | Antineoplastische Mittel mit verstärkter Wirksamkeit |
| US5276058A (en) * | 1993-06-09 | 1994-01-04 | Nippon Hypox Laboratories Incorporated | 3,4-dihydroxychalcone derivatives |
| EP0647450A1 (en) | 1993-09-09 | 1995-04-12 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
| FR2710798B1 (fr) | 1993-09-27 | 1995-11-10 | Alcatel Mobile Comm France | Chaîne d'amplification en mode de courant, amplificateur opérationnel, cellule de gain et élément d'amplification correspondants. |
| JPH08188546A (ja) * | 1995-01-04 | 1996-07-23 | Kyowa Hakko Kogyo Co Ltd | カルコン誘導体 |
| GB9519490D0 (en) | 1995-09-25 | 1995-11-29 | Melvin William T | Use of a cytochrome P450 enzyme in tumour cells as a marker and target |
| US5966032A (en) | 1996-09-27 | 1999-10-12 | Northern Telecom Limited | BiCMOS transceiver (driver and receiver) for gigahertz operation |
| EP1051383B1 (en) | 1998-02-06 | 2004-07-28 | De Montfort University | Hydroxylation activated prodrugs |
| GB9802522D0 (en) | 1998-02-06 | 1998-04-01 | Montford University De | Hydroxylation activated prodrugs |
| 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 |
-
1999
- 1999-02-02 EP EP99901732A patent/EP1051383B1/en not_active Expired - Lifetime
- 1999-02-02 JP JP2000530488A patent/JP4642226B2/ja not_active Expired - Fee Related
- 1999-02-02 AU AU21738/99A patent/AU2173899A/en not_active Abandoned
- 1999-02-02 WO PCT/GB1999/000155 patent/WO1999040056A1/en not_active Ceased
- 1999-02-02 AT AT99901732T patent/ATE272040T1/de active
- 1999-02-02 DE DE69918950T patent/DE69918950T2/de not_active Expired - Lifetime
- 1999-02-02 ES ES99901732T patent/ES2226332T3/es not_active Expired - Lifetime
- 1999-02-02 CA CA2319836A patent/CA2319836C/en not_active Expired - Fee Related
-
2000
- 2000-08-07 US US09/633,699 patent/US6677383B1/en not_active Expired - Lifetime
-
2001
- 2001-01-19 US US09/765,861 patent/US6346550B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US6677383B1 (en) | 2004-01-13 |
| WO1999040056A1 (en) | 1999-08-12 |
| EP1051383B1 (en) | 2004-07-28 |
| US20010021717A1 (en) | 2001-09-13 |
| ES2226332T3 (es) | 2005-03-16 |
| AU2173899A (en) | 1999-08-23 |
| EP1051383A1 (en) | 2000-11-15 |
| US6346550B2 (en) | 2002-02-12 |
| JP4642226B2 (ja) | 2011-03-02 |
| ATE272040T1 (de) | 2004-08-15 |
| DE69918950D1 (de) | 2004-09-02 |
| DE69918950T2 (de) | 2005-07-28 |
| JP2002502836A (ja) | 2002-01-29 |
| CA2319836A1 (en) | 1999-08-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2319836C (en) | Hydroxylation activated prodrugs | |
| Rao et al. | Synthesis and biological evaluation of 3′, 4′, 5′-trimethoxychalcone analogues as inhibitors of nitric oxide production and tumor cell proliferation | |
| Kamal et al. | Synthesis and anticancer activity of chalcone-pyrrolobenzodiazepine conjugates linked via 1, 2, 3-triazole ring side-armed with alkane spacers | |
| CA1038763A (en) | Pharmaceutical compositions comprising biphenyl derivatives | |
| US20100331549A1 (en) | Novel compounds useful for modulating abnormal cell proliferation | |
| Simoni et al. | Novel A-ring and B-ring modified combretastatin A-4 (CA-4) analogues endowed with interesting cytotoxic activity | |
| CA2403900C (en) | Substituted chalcones as therapeutic compounds | |
| US6214886B1 (en) | Hydroxylation activated prodrugs | |
| Pandey et al. | Chemotherapy of leishmaniasis part II: synthesis and bioevaluation of substituted arylketene dithioacetals as antileishmanial agents | |
| RU2277531C9 (ru) | Новые соединения для модулирования клеточной пролиферации | |
| CS214819B2 (en) | Method of preparation of substituted acetophens | |
| Ruparelia et al. | The synthesis of chalcones as anticancer prodrugs and their bioactivation in CYP1 expressing breast cancer cells | |
| Barnes et al. | A 2-step synthesis of Combretastatin A-4 and derivatives as potent tubulin assembly inhibitors | |
| Jung et al. | Efficient synthesis and neuroprotective effect of substituted 1, 3-diphenyl-2-propen-1-ones | |
| EA009048B1 (ru) | Ингибитор белка резистентности рака молочной железы (bcrp) | |
| Demin et al. | Tyrenes: synthesis of new antiproliferative compounds with an extended conjugation | |
| Dallman et al. | The winding road of the uvaretin class of natural products: from total synthesis to bioactive agent discovery | |
| CA2307028C (en) | Medicinal uses of phenylalkanols and derivatives | |
| Adaeva et al. | Synthesis of Polyoxygenated 4, 5-Diarylpyridazines with Antiproliferative and Antitubulin Activity via Inverse Electron-Demand Diels-Alder Reaction of 1, 2, 4, 5-Tetrazine# | |
| Gurzadyan et al. | Multigram, Chromatography-Free Synthesis of the Flavonol Morin | |
| Simon et al. | Novel analogues of resveratrol: metabolism and inhibition of colon cancer cell proliferation | |
| Moon et al. | Synthesis, Anti‐inflammatory, and Arginase Inhibitory Activity of Piceatannol and Its Analogs | |
| Adabella et al. | Microwave-Assisted Synthesis of Bis-(Hydroxybenzylidene)-Cycloalkanones via Acid Catalyzed Claisen-Schmidt Condensation | |
| Danova | Synthesis and biological activities of chalcone derivatives | |
| Perera et al. | Construction and Biological Evaluation of Small Libraries Based on the Intermediates within the Total Synthesis of Uvaretin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20170202 |