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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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- IOOMXAQUNPWDLL-UHFFFAOYSA-M lissamine rhodamine anion Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S([O-])(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-M 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 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
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 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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- 150000007524 organic acids Chemical class 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
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 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
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
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- 101150114085 soc-2 gene Proteins 0.000 description 1
- 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
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 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)
- Radiation-Therapy Devices (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (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 | ||
| NZ535618 | 2004-09-28 | ||
| NZ53561804 | 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
ID=34555019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004285831A Ceased AU2004285831B2 (en) | 2003-10-31 | 2004-10-29 | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents |
Country Status (10)
| Country | Link |
|---|---|
| US (2) | US7629332B2 (https=) |
| EP (1) | EP1680394A4 (https=) |
| JP (1) | JP4760712B2 (https=) |
| KR (1) | KR101167335B1 (https=) |
| AU (1) | AU2004285831B2 (https=) |
| BR (1) | BRPI0416085A (https=) |
| CA (1) | CA2544335A1 (https=) |
| IL (1) | IL175000A0 (https=) |
| RU (1) | RU2372324C2 (https=) |
| WO (1) | WO2005042471A1 (https=) |
Families Citing this family (25)
| 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 |
| 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 |
| 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 |
| EP2593796A4 (en) | 2010-07-16 | 2016-07-27 | Auckland Uniservices Ltd | BACTERIAL NITROREDUCTASE ENZYMES AND METHOD THEREFOR |
| CN104039328B (zh) * | 2011-11-11 | 2018-10-09 | 米伦纽姆医药公司 | 对蛋白酶体抑制剂的反应的生物标记 |
| 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 |
| EP2793871A4 (en) * | 2011-12-23 | 2015-07-22 | Auckland Uniservices Ltd | 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 |
| EP2888227B1 (en) * | 2012-08-23 | 2020-07-29 | Convert Pharmaceuticals SA | Novel 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 |
| 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 |
| 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 |
|---|---|---|---|---|
| CA2460345A1 (en) * | 2001-09-13 | 2003-03-20 | Synta Pharmaceuticals Corp. | 2-aroylimidazole compounds for treating cancer |
| 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 |
-
2004
- 2004-10-29 AU AU2004285831A patent/AU2004285831B2/en not_active Ceased
- 2004-10-29 US US10/577,078 patent/US7629332B2/en not_active Expired - Fee Related
- 2004-10-29 RU RU2006118785/04A patent/RU2372324C2/ru not_active IP Right Cessation
- 2004-10-29 EP EP04817434A patent/EP1680394A4/en not_active Withdrawn
- 2004-10-29 JP JP2006537921A patent/JP4760712B2/ja not_active Expired - Fee Related
- 2004-10-29 KR KR1020067010566A patent/KR101167335B1/ko not_active Expired - Fee Related
- 2004-10-29 WO PCT/NZ2004/000275 patent/WO2005042471A1/en not_active Ceased
- 2004-10-29 BR BRPI0416085-1A patent/BRPI0416085A/pt not_active IP Right Cessation
- 2004-10-29 CA CA002544335A patent/CA2544335A1/en not_active Abandoned
-
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 |
|---|---|
| EP1680394A1 (en) | 2006-07-19 |
| US20100010094A1 (en) | 2010-01-14 |
| IL175000A0 (en) | 2006-08-20 |
| US20070032455A1 (en) | 2007-02-08 |
| WO2005042471A1 (en) | 2005-05-12 |
| US7629332B2 (en) | 2009-12-08 |
| JP2007509928A (ja) | 2007-04-19 |
| EP1680394A4 (en) | 2006-10-11 |
| KR20070006677A (ko) | 2007-01-11 |
| BRPI0416085A (pt) | 2007-01-02 |
| AU2004285831A1 (en) | 2005-05-12 |
| JP4760712B2 (ja) | 2011-08-31 |
| RU2006118785A (ru) | 2007-12-10 |
| KR101167335B1 (ko) | 2012-07-19 |
| RU2372324C2 (ru) | 2009-11-10 |
| CA2544335A1 (en) | 2005-05-12 |
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