AU2004285831B2 - Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents - Google Patents
Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents Download PDFInfo
- Publication number
- AU2004285831B2 AU2004285831B2 AU2004285831A AU2004285831A AU2004285831B2 AU 2004285831 B2 AU2004285831 B2 AU 2004285831B2 AU 2004285831 A AU2004285831 A AU 2004285831A AU 2004285831 A AU2004285831 A AU 2004285831A AU 2004285831 B2 AU2004285831 B2 AU 2004285831B2
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- Prior art keywords
- amino
- ethyl
- conh
- halogen
- bis
- Prior art date
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- -1 nitrophenyl mustard Chemical compound 0.000 title claims abstract description 48
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 29
- 235000021317 phosphate Nutrition 0.000 title abstract description 24
- 150000003013 phosphoric acid derivatives Chemical class 0.000 title abstract description 15
- 231100000599 cytotoxic agent Toxicity 0.000 title abstract description 13
- 235000003351 Brassica cretica Nutrition 0.000 title abstract description 10
- 235000003343 Brassica rupestris Nutrition 0.000 title abstract description 10
- 235000010460 mustard Nutrition 0.000 title abstract description 10
- 241000219198 Brassica Species 0.000 title abstract description 7
- 229940127089 cytotoxic agent Drugs 0.000 title abstract description 5
- 239000002254 cytotoxic agent Substances 0.000 title abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 72
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 59
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 25
- 150000001204 N-oxides Chemical class 0.000 claims description 24
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 239000010452 phosphate Substances 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 11
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000003381 stabilizer Substances 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 230000000865 phosphorylative effect Effects 0.000 claims description 4
- 238000011394 anticancer treatment Methods 0.000 claims description 3
- LILVPOWBAKZYDQ-UHFFFAOYSA-N 2-[[2-[bis(2-bromopropyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound CC(Br)CN(CC(C)Br)C1=C(C(=O)NCCOP(O)(O)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O LILVPOWBAKZYDQ-UHFFFAOYSA-N 0.000 claims description 2
- ROCGFSWNPWZYNV-UHFFFAOYSA-N 3-[[3-[bis(2-bromoethyl)amino]-2,6-dinitrobenzoyl]amino]propyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCCNC(=O)C1=C([N+]([O-])=O)C=CC(N(CCBr)CCBr)=C1[N+]([O-])=O ROCGFSWNPWZYNV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000006308 propyl amino group Chemical group 0.000 claims description 2
- FYTRJEQYJWXSIF-UHFFFAOYSA-N propyl dihydrogen phosphate Chemical compound [CH2]CCOP(O)(O)=O FYTRJEQYJWXSIF-UHFFFAOYSA-N 0.000 claims 2
- ALNMHZYCWFICCG-UHFFFAOYSA-N 2-[[2-[bis(2-bromoethyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCBr ALNMHZYCWFICCG-UHFFFAOYSA-N 0.000 claims 1
- CCQRILWYQGCXNU-UHFFFAOYSA-N 2-[[2-[bis(2-chloroethyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCCl)CCCl CCQRILWYQGCXNU-UHFFFAOYSA-N 0.000 claims 1
- AJUYDWUWNBPUND-UHFFFAOYSA-N 2-[[2-[bis(2-iodoethyl)amino]-3,5-dinitrobenzoyl]amino]ethyl dihydrogen phosphate Chemical compound OP(O)(=O)OCCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCI)CCI AJUYDWUWNBPUND-UHFFFAOYSA-N 0.000 claims 1
- GZSOKPMDWVRVMG-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2,4-dinitro-6-(2-phosphonooxyethylcarbamoyl)anilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(=O)NCCOP(O)(O)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O GZSOKPMDWVRVMG-UHFFFAOYSA-N 0.000 claims 1
- LGGNXHXSYDUPSG-UHFFFAOYSA-N 2-[n-(2-iodoethyl)-2,4-dinitro-3-(3-phosphonooxypropylcarbamoyl)anilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCI)C1=CC=C([N+]([O-])=O)C(C(=O)NCCCOP(O)(O)=O)=C1[N+]([O-])=O LGGNXHXSYDUPSG-UHFFFAOYSA-N 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 206010021143 Hypoxia Diseases 0.000 abstract description 29
- 229940002612 prodrug Drugs 0.000 abstract description 27
- 239000000651 prodrug Substances 0.000 abstract description 27
- 230000001146 hypoxic effect Effects 0.000 abstract description 20
- 102000004459 Nitroreductase Human genes 0.000 abstract description 16
- 108020001162 nitroreductase Proteins 0.000 abstract description 16
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 abstract description 15
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- 238000002679 ablation Methods 0.000 abstract description 7
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 236
- 235000019439 ethyl acetate Nutrition 0.000 description 118
- 238000005481 NMR spectroscopy Methods 0.000 description 117
- 229910052739 hydrogen Inorganic materials 0.000 description 100
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 84
- PWCKZOYILCIVQN-UHFFFAOYSA-N 5-[bis(2-bromoethyl)amino]-2,4-dinitrobenzoic acid Chemical compound OC(=O)C1=CC(N(CCBr)CCBr)=C([N+]([O-])=O)C=C1[N+]([O-])=O PWCKZOYILCIVQN-UHFFFAOYSA-N 0.000 description 63
- 229910052799 carbon Inorganic materials 0.000 description 62
- JSAULSYCZUEMIA-UHFFFAOYSA-N methyl 5-fluoro-4-methylsulfonyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC(F)=C(S(C)(=O)=O)C=C1[N+]([O-])=O JSAULSYCZUEMIA-UHFFFAOYSA-N 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
- 239000000741 silica gel Substances 0.000 description 46
- 229910002027 silica gel Inorganic materials 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 42
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 40
- 239000003208 petroleum Substances 0.000 description 40
- 239000007787 solid Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 36
- 239000000460 chlorine Substances 0.000 description 31
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- 239000006260 foam Substances 0.000 description 31
- 229910052794 bromium Inorganic materials 0.000 description 30
- 238000011282 treatment Methods 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000010828 elution Methods 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- 230000002829 reductive effect Effects 0.000 description 20
- 102100026450 POU domain, class 3, transcription factor 4 Human genes 0.000 description 18
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- 229910052740 iodine Inorganic materials 0.000 description 18
- 102000004190 Enzymes Human genes 0.000 description 16
- 108090000790 Enzymes Proteins 0.000 description 16
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- 230000026731 phosphorylation Effects 0.000 description 13
- 238000006366 phosphorylation reaction Methods 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
- 231100000682 maximum tolerated dose Toxicity 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 10
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 230000005855 radiation Effects 0.000 description 10
- 150000001298 alcohols Chemical class 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 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 8
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 239000002619 cytotoxin Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- ZJXZSIYSNXKHEA-UHFFFAOYSA-N ethyl dihydrogen phosphate Chemical compound CCOP(O)(O)=O ZJXZSIYSNXKHEA-UHFFFAOYSA-N 0.000 description 7
- 230000007954 hypoxia Effects 0.000 description 7
- XABKGGOCDGDENP-UHFFFAOYSA-N methyl 5-[bis(2-bromoethyl)amino]-4-methylsulfonyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC(N(CCBr)CCBr)=C(S(C)(=O)=O)C=C1[N+]([O-])=O XABKGGOCDGDENP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- KIMCGLHTSSZPNS-UHFFFAOYSA-N 2,3-dinitrobenzamide Chemical compound NC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O KIMCGLHTSSZPNS-UHFFFAOYSA-N 0.000 description 5
- 101710112752 Cytotoxin Proteins 0.000 description 5
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- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 5
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
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- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 description 4
- SLAMLWHELXOEJZ-UHFFFAOYSA-M 2-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-M 0.000 description 4
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- 210000004072 lung Anatomy 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- KUKSUQKELVOKBH-UHFFFAOYSA-N n-[bis[(2-methylpropan-2-yl)oxy]phosphanyl]-n-ethylethanamine Chemical compound CCN(CC)P(OC(C)(C)C)OC(C)(C)C KUKSUQKELVOKBH-UHFFFAOYSA-N 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide 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](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 230000002018 overexpression Effects 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
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- 239000003755 preservative agent Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
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- 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
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07C237/32—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 an acyclic carbon atom of a hydrocarbon radical substituted by oxygen 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
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/14—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom with carbocyclic rings directly attached to the ring nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Radiation-Therapy Devices (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ529249A NZ529249A (en) | 2003-10-31 | 2003-10-31 | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic |
| NZ529249 | 2003-10-31 | ||
| NZ53561804 | 2004-09-28 | ||
| NZ535618 | 2004-09-28 | ||
| PCT/NZ2004/000275 WO2005042471A1 (en) | 2003-10-31 | 2004-10-29 | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2004285831A1 AU2004285831A1 (en) | 2005-05-12 |
| AU2004285831B2 true AU2004285831B2 (en) | 2011-09-15 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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Country Status (10)
| Country | Link |
|---|---|
| US (2) | US7629332B2 (enExample) |
| EP (1) | EP1680394A4 (enExample) |
| JP (1) | JP4760712B2 (enExample) |
| KR (1) | KR101167335B1 (enExample) |
| AU (1) | AU2004285831B2 (enExample) |
| BR (1) | BRPI0416085A (enExample) |
| CA (1) | CA2544335A1 (enExample) |
| IL (1) | IL175000A0 (enExample) |
| RU (1) | RU2372324C2 (enExample) |
| WO (1) | WO2005042471A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4760712B2 (ja) * | 2003-10-31 | 2011-08-31 | オークランド ユニサーヴィスィズ リミテッド | 新規ニトロフェニルマスタードおよびニトロフェニルアジリジンアルコールおよびそれらの対応するリン酸エステルおよびターゲットが決められた細胞毒性剤としてのそれらの使用 |
| 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 |
| WO2008033041A1 (en) * | 2006-09-11 | 2008-03-20 | Auckland Uniservices Limited | Cancer treatment |
| WO2008033039A1 (en) * | 2006-09-11 | 2008-03-20 | Adam Vorn Patterson | Cancer treatment |
| NZ549831A (en) * | 2006-09-11 | 2009-03-31 | Auckland Uniservices Ltd | Combination of docetaxel and a nitrophenyl phosphate derivative for the treatment of cancer |
| ES2884044T3 (es) | 2006-12-26 | 2021-12-10 | Immunogenesis Inc | Profármaco alquilante de fosforamidato para el tratamiento del cáncer |
| US8309554B2 (en) * | 2008-05-15 | 2012-11-13 | Threshold Pharmaceuticals | Hypoxia activated drugs of nitrogen mustard alkylators |
| WO2010044685A1 (en) * | 2008-10-17 | 2010-04-22 | Auckland Uniservices Limited | Nitrophenyl mustard alcohols, their corresponding phosphates and their use as targeted cytotoxic agents |
| JP5765634B2 (ja) | 2008-10-21 | 2015-08-19 | 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 | 低酸素活性化型プロドラッグを用いるがんの処置 |
| 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 |
| RU2597844C2 (ru) | 2010-07-12 | 2016-09-20 | Тресхолд Фармасьютикалз, Инк. | Введение гипоксически активируемых пролекарств и средств, препятствующих ангиогенезу, для лечения рака |
| WO2012008860A2 (en) * | 2010-07-16 | 2012-01-19 | Auckland Uniservices Limited | Bacterial nitroreductase enzymes and methods relating thereto |
| JP6397765B2 (ja) * | 2011-11-11 | 2018-09-26 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | プロテアソーム阻害剤に応答するバイオマーカー |
| WO2013096687A1 (en) | 2011-12-22 | 2013-06-27 | Threshold Pharmaceuticals, Inc. | Administration of hypoxia activated prodrugs in combination with chk1 inhibitors for treating cancer |
| US20150010474A1 (en) * | 2011-12-23 | 2015-01-08 | Auckland Uniservices Limited | Compounds And Methods For Selective Imaging And/Or Ablation |
| US10202408B2 (en) | 2012-08-23 | 2019-02-12 | Health Innovation Ventures B.V. | Prodrugs and methods of use thereof |
| US9505791B2 (en) | 2012-08-23 | 2016-11-29 | 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 |
| WO2015013448A1 (en) | 2013-07-26 | 2015-01-29 | Threshold Pharmaceuticals, Inc. | Treatment of pancreatic cancer with a combination of a hypoxia-acti vated prodrug and a taxane |
| CA2990665A1 (en) | 2015-06-24 | 2016-12-29 | Threshold Pharmaceuticals, Inc. | Aziridine containing dna alkylating agents |
| US10348685B2 (en) * | 2016-04-29 | 2019-07-09 | Nicira, Inc. | Priority allocation for distributed service rules |
| CN108571241B (zh) * | 2017-03-14 | 2021-08-17 | 福特环球技术公司 | 用于推按式闩锁类型车辆抽屉的惯性锁系统 |
| WO2019125184A1 (en) | 2017-12-19 | 2019-06-27 | Auckland Uniservices Limited | Use of biomarker in cancer therapy |
| EP3774743B1 (en) * | 2018-03-29 | 2023-11-22 | Achilles Medical Limited | Prodrug compounds activated by akr1c3 and their use for treating hyperproliferative disorders |
| JP7541512B2 (ja) * | 2018-05-30 | 2024-08-28 | コンバート ファーマシューティカルズ エス．エー． | プロドラッグおよびその医学的使用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993011099A1 (en) * | 1991-11-28 | 1993-06-10 | Cancer Research Campaign Technology Limited | Nitroaniline derivatives and their use as antitumor agents |
| WO2000013683A2 (en) * | 1998-09-07 | 2000-03-16 | Cancer Research Campaign Technology Limited | Novel nitrophenylaziridine compounds and their use as prodrugs |
| AU2003278628A1 (en) * | 2002-10-08 | 2004-05-04 | Auckland Uniservices Limited | Nitroaniline-based alkylating agents and their use as prodrugs |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005504789A (ja) * | 2001-09-13 | 2005-02-17 | シンタ ファーマスーティカルズ コーポレイション | 癌治療のための２−アロイルイミダゾール化合物 |
| JP4760712B2 (ja) * | 2003-10-31 | 2011-08-31 | オークランド ユニサーヴィスィズ リミテッド | 新規ニトロフェニルマスタードおよびニトロフェニルアジリジンアルコールおよびそれらの対応するリン酸エステルおよびターゲットが決められた細胞毒性剤としてのそれらの使用 |
-
2004
- 2004-10-29 JP JP2006537921A patent/JP4760712B2/ja not_active Expired - Fee Related
- 2004-10-29 CA CA002544335A patent/CA2544335A1/en not_active Abandoned
- 2004-10-29 RU RU2006118785/04A patent/RU2372324C2/ru not_active IP Right Cessation
- 2004-10-29 WO PCT/NZ2004/000275 patent/WO2005042471A1/en not_active Ceased
- 2004-10-29 KR KR1020067010566A patent/KR101167335B1/ko not_active Expired - Fee Related
- 2004-10-29 AU AU2004285831A patent/AU2004285831B2/en not_active Ceased
- 2004-10-29 BR BRPI0416085-1A patent/BRPI0416085A/pt not_active IP Right Cessation
- 2004-10-29 US US10/577,078 patent/US7629332B2/en not_active Expired - Fee Related
- 2004-10-29 EP EP04817434A patent/EP1680394A4/en not_active Withdrawn
-
2006
- 2006-04-11 IL IL175000A patent/IL175000A0/en unknown
-
2009
- 2009-08-11 US US12/461,419 patent/US20100010094A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993011099A1 (en) * | 1991-11-28 | 1993-06-10 | Cancer Research Campaign Technology Limited | Nitroaniline derivatives and their use as antitumor agents |
| WO2000013683A2 (en) * | 1998-09-07 | 2000-03-16 | Cancer Research Campaign Technology Limited | Novel nitrophenylaziridine compounds and their use as prodrugs |
| AU2003278628A1 (en) * | 2002-10-08 | 2004-05-04 | Auckland Uniservices Limited | Nitroaniline-based alkylating agents and their use as prodrugs |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2372324C2 (ru) | 2009-11-10 |
| KR20070006677A (ko) | 2007-01-11 |
| US20070032455A1 (en) | 2007-02-08 |
| US20100010094A1 (en) | 2010-01-14 |
| AU2004285831A1 (en) | 2005-05-12 |
| US7629332B2 (en) | 2009-12-08 |
| CA2544335A1 (en) | 2005-05-12 |
| EP1680394A1 (en) | 2006-07-19 |
| JP2007509928A (ja) | 2007-04-19 |
| EP1680394A4 (en) | 2006-10-11 |
| RU2006118785A (ru) | 2007-12-10 |
| BRPI0416085A (pt) | 2007-01-02 |
| IL175000A0 (en) | 2006-08-20 |
| WO2005042471A1 (en) | 2005-05-12 |
| JP4760712B2 (ja) | 2011-08-31 |
| KR101167335B1 (ko) | 2012-07-19 |
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