NZ521851A - Nitroaniline-based unsymmetrical mustard alkylating agents for gene dependent enzyme prodrug therapy - Google Patents
Nitroaniline-based unsymmetrical mustard alkylating agents for gene dependent enzyme prodrug therapyInfo
- Publication number
- NZ521851A NZ521851A NZ521851A NZ52185102A NZ521851A NZ 521851 A NZ521851 A NZ 521851A NZ 521851 A NZ521851 A NZ 521851A NZ 52185102 A NZ52185102 A NZ 52185102A NZ 521851 A NZ521851 A NZ 521851A
- Authority
- NZ
- New Zealand
- Prior art keywords
- amino
- dinitroanilino
- bromoethyl
- carbonyl
- ethyl methanesulfonate
- Prior art date
Links
- 235000003351 Brassica cretica Nutrition 0.000 title claims abstract description 36
- 235000003343 Brassica rupestris Nutrition 0.000 title claims abstract description 36
- 235000010460 mustard Nutrition 0.000 title claims abstract description 36
- 229940002612 prodrug Drugs 0.000 title claims abstract description 26
- 239000000651 prodrug Substances 0.000 title claims abstract description 26
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 102000004190 Enzymes Human genes 0.000 title claims abstract description 10
- 108090000790 Enzymes Proteins 0.000 title claims abstract description 10
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 10
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 10
- 230000001419 dependent effect Effects 0.000 title claims abstract description 8
- 241000219198 Brassica Species 0.000 title claims description 25
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 title claims description 21
- 239000002168 alkylating agent Substances 0.000 title description 3
- 229940100198 alkylating agent Drugs 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 38
- 102000004459 Nitroreductase Human genes 0.000 claims abstract description 19
- 108020001162 nitroreductase Proteins 0.000 claims abstract description 19
- 241000219193 Brassicaceae Species 0.000 claims abstract description 11
- 238000010317 ablation therapy Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 231100000599 cytotoxic agent Toxicity 0.000 claims abstract description 7
- 230000007954 hypoxia Effects 0.000 claims abstract description 7
- 239000002619 cytotoxin Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 60
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 58
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- -1 2-[5-(Aminocarbonyl)(2-bromoethyl)-2,4-dinitroanilino]ethyl Chemical group 0.000 claims description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000003512 tertiary amines Chemical class 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000001204 N-oxides Chemical class 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 9
- 239000002798 polar solvent Substances 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 6
- 150000008045 alkali metal halides Chemical class 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000872 buffer Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- ZSQFUUPUDPDTDW-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(2,3-dihydroxypropylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(=O)NCC(O)CO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O ZSQFUUPUDPDTDW-UHFFFAOYSA-N 0.000 claims description 3
- AZICEEZSDKZDHX-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(2-hydroxyethylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(=O)NCCO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O AZICEEZSDKZDHX-UHFFFAOYSA-N 0.000 claims description 3
- KQNJLOZYSLLLQE-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-(2-hydroxypropylcarbamoyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CC(O)CNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCOS(C)(=O)=O KQNJLOZYSLLLQE-UHFFFAOYSA-N 0.000 claims description 3
- BDBWGNXWWSWBBX-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-2-carbamoyl-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O BDBWGNXWWSWBBX-UHFFFAOYSA-N 0.000 claims description 3
- LZWPIIDISNWNNG-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-5-(2-hydroxyethylcarbamoyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=CC(C(=O)NCCO)=C([N+]([O-])=O)C=C1[N+]([O-])=O LZWPIIDISNWNNG-UHFFFAOYSA-N 0.000 claims description 3
- AILFTHBWIYPGNH-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-5-(3-hydroxypropylcarbamoyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=CC(C(=O)NCCCO)=C([N+]([O-])=O)C=C1[N+]([O-])=O AILFTHBWIYPGNH-UHFFFAOYSA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000000565 sulfonamide group Chemical group 0.000 claims description 3
- TVGZVOAGMXONFJ-UHFFFAOYSA-N 2-[2-(2-hydroxyethylcarbamoyl)-n-(2-iodoethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCI)C1=C(C(=O)NCCO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O TVGZVOAGMXONFJ-UHFFFAOYSA-N 0.000 claims description 2
- ZVRVEGANQYXFIP-UHFFFAOYSA-N 2-[3-carbamoyl-n-(2-chloroethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCCl)C1=CC=C([N+]([O-])=O)C(C(N)=O)=C1[N+]([O-])=O ZVRVEGANQYXFIP-UHFFFAOYSA-N 0.000 claims description 2
- RPEHTIARZISZKN-UHFFFAOYSA-N 2-[5-carbamoyl-n-(2-iodoethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCI)C1=CC(C(N)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O RPEHTIARZISZKN-UHFFFAOYSA-N 0.000 claims description 2
- TYEGHUHXJVQCDJ-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-3-(3-morpholin-4-ylpropylcarbamoyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=CC=C([N+]([O-])=O)C(C(=O)NCCCN2CCOCC2)=C1[N+]([O-])=O TYEGHUHXJVQCDJ-UHFFFAOYSA-N 0.000 claims description 2
- NXNNTLKMCKZDSJ-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-3-(4-hydroxybutylcarbamoyl)-2,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C([N+]([O-])=O)C=CC(C(=O)NCCCCO)=C1[N+]([O-])=O NXNNTLKMCKZDSJ-UHFFFAOYSA-N 0.000 claims description 2
- FHEDOICSCKZDAP-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-3-carbamoyl-2,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C([N+]([O-])=O)C=CC(C(N)=O)=C1[N+]([O-])=O FHEDOICSCKZDAP-UHFFFAOYSA-N 0.000 claims description 2
- LHJUHUSJGFZIGY-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-5-carbamoyl-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=CC(C(N)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O LHJUHUSJGFZIGY-UHFFFAOYSA-N 0.000 claims description 2
- LOHNWIILSUAXFV-UHFFFAOYSA-N 2-[n-(2-chloroethyl)-3-(3-hydroxypropylcarbamoyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCCl)C1=CC=C([N+]([O-])=O)C(C(=O)NCCCO)=C1[N+]([O-])=O LOHNWIILSUAXFV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
- ZSOMHSLKERBJSE-UHFFFAOYSA-N bromo methanesulfonate Chemical compound CS(=O)(=O)OBr ZSOMHSLKERBJSE-UHFFFAOYSA-N 0.000 claims description 2
- VIPZXRPGSXHETD-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-3-(2,3-dihydroxypropylcarbamoyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=CC=C([N+]([O-])=O)C(C(=O)NCC(O)CO)=C1[N+]([O-])=O VIPZXRPGSXHETD-UHFFFAOYSA-N 0.000 claims 2
- RZLVXJOFACPFHU-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-5-(2,3-dihydroxypropylcarbamoyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=CC(C(=O)NCC(O)CO)=C([N+]([O-])=O)C=C1[N+]([O-])=O RZLVXJOFACPFHU-UHFFFAOYSA-N 0.000 claims 2
- NQCRZMHCVYQOJN-UHFFFAOYSA-N 2-[n-(2-bromoethyl)-3-(2-hydroxyethylcarbamoyl)-2,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCBr)C1=C([N+]([O-])=O)C=CC(C(=O)NCCO)=C1[N+]([O-])=O NQCRZMHCVYQOJN-UHFFFAOYSA-N 0.000 claims 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 1
- YIBANNNXXGVGBK-UHFFFAOYSA-N 5-[2-bromoethyl(2-chloroethyl)amino]-2,4-dinitrobenzamide Chemical compound NC(=O)C1=CC(N(CCCl)CCBr)=C([N+]([O-])=O)C=C1[N+]([O-])=O YIBANNNXXGVGBK-UHFFFAOYSA-N 0.000 claims 1
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 claims 1
- 238000012986 modification Methods 0.000 claims 1
- 230000004048 modification Effects 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 description 127
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 58
- 238000005481 NMR spectroscopy Methods 0.000 description 47
- 238000010828 elution Methods 0.000 description 43
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
- 239000000741 silica gel Substances 0.000 description 35
- 229910002027 silica gel Inorganic materials 0.000 description 35
- 239000003208 petroleum Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 22
- 239000006260 foam Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 210000004881 tumor cell Anatomy 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
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- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 4
- 101150091037 nfsB gene Proteins 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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- YQANFKDQYSESFK-UHFFFAOYSA-N 2-[3-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC=C([N+]([O-])=O)C(C(=O)NCC(O)CO)=C1[N+]([O-])=O YQANFKDQYSESFK-UHFFFAOYSA-N 0.000 description 3
- SDNHGKBEWGELIX-UHFFFAOYSA-N 2-[3-carbamoyl-n-(2-methylsulfonyloxyethyl)-2,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C([N+]([O-])=O)C=CC(C(N)=O)=C1[N+]([O-])=O SDNHGKBEWGELIX-UHFFFAOYSA-N 0.000 description 3
- URZIYPKNXKUFAJ-UHFFFAOYSA-N 2-[5-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(=O)NCC(O)CO)=C([N+]([O-])=O)C=C1[N+]([O-])=O URZIYPKNXKUFAJ-UHFFFAOYSA-N 0.000 description 3
- MHOHFBMVOJCKIE-UHFFFAOYSA-N 2-[5-carbamoyl-n-(2-chloroethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCCl)C1=CC(C(N)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O MHOHFBMVOJCKIE-UHFFFAOYSA-N 0.000 description 3
- MVWHPUZNLDBOLH-UHFFFAOYSA-N 5-[bis(2-methylsulfonyloxyethyl)amino]-2,4-dinitrobenzoic acid Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(O)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O MVWHPUZNLDBOLH-UHFFFAOYSA-N 0.000 description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- NLCOFJNMNIDBCV-UHFFFAOYSA-N 2-[2-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C(C(=O)NCC(O)CO)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NLCOFJNMNIDBCV-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ521851A NZ521851A (en) | 2002-10-08 | 2002-10-08 | Nitroaniline-based unsymmetrical mustard alkylating agents for gene dependent enzyme prodrug therapy |
| CA2501388A CA2501388C (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
| PCT/NZ2003/000225 WO2004033415A1 (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
| US10/529,772 US7776924B2 (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
| AU2003278628A AU2003278628B2 (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
| JP2004542927A JP4582519B2 (ja) | 2002-10-08 | 2003-10-08 | ニトロアニリン系のアルキル化剤およびそれらのプロドラッグとしての使用 |
| CNB2003801028127A CN100546976C (zh) | 2002-10-08 | 2003-10-08 | 基于硝基苯胺的烷化剂和它们作为前体药物的用途 |
| EP03770163A EP1558568A4 (en) | 2002-10-08 | 2003-10-08 | ALKYLATION AGENTS BASED ON NITROANILINE AND THEIR USE AS PROMEDICAMENTS |
| JP2010136139A JP2010265272A (ja) | 2002-10-08 | 2010-06-15 | ニトロアニリン系のアルキル化剤およびそれらのプロドラッグとしての使用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ521851A NZ521851A (en) | 2002-10-08 | 2002-10-08 | Nitroaniline-based unsymmetrical mustard alkylating agents for gene dependent enzyme prodrug therapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ521851A true NZ521851A (en) | 2005-02-25 |
Family
ID=32089872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ521851A NZ521851A (en) | 2002-10-08 | 2002-10-08 | Nitroaniline-based unsymmetrical mustard alkylating agents for gene dependent enzyme prodrug therapy |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US7776924B2 (https=) |
| EP (1) | EP1558568A4 (https=) |
| JP (2) | JP4582519B2 (https=) |
| CN (1) | CN100546976C (https=) |
| AU (1) | AU2003278628B2 (https=) |
| CA (1) | CA2501388C (https=) |
| NZ (1) | NZ521851A (https=) |
| WO (1) | WO2004033415A1 (https=) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2004285831B2 (en) * | 2003-10-31 | 2011-09-15 | Auckland Uniservices Limited | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents |
| JP4761899B2 (ja) * | 2005-09-12 | 2011-08-31 | Ｈｏｙａ株式会社 | 電子内視鏡システム |
| NZ549659A (en) * | 2006-09-04 | 2008-12-24 | Auckland Uniservices Ltd | Processes of preparing asymmetric dinitrobenzamide mustard compounds, intermediate compounds useful therein and products obtained therefrom |
| EP2350664B1 (en) | 2008-10-21 | 2021-05-19 | ImmunoGenesis, Inc. | Treatment of cancer using the hypoxia activated prodrug th-302 in combination with docetaxel or pemetrexed |
| CN101723932B (zh) * | 2008-10-31 | 2013-11-20 | 北京以岭生物工程技术有限公司 | 硝基吡啶乙烯亚胺化合物、其药物组合物及其制备方法和用途 |
| ES2877629T3 (es) | 2010-07-12 | 2021-11-17 | Immunogenesis Inc | Administración de profármacos activados por hipoxia y agentes antiangiogénicos para el tratamiento del cáncer |
| EP2793882A4 (en) | 2011-12-22 | 2015-04-29 | Threshold Pharmaceuticals Inc | ADMINISTRATION OF HYPOXIA-ACTIVATED PRODRUGS IN COMBINATION WITH CHK1 INHIBITORS FOR THE TREATMENT OF CANCER |
| EP2888227B1 (en) * | 2012-08-23 | 2020-07-29 | Convert Pharmaceuticals SA | Novel prodrugs and methods of use thereof |
| US10202408B2 (en) | 2012-08-23 | 2019-02-12 | Health Innovation Ventures B.V. | Prodrugs and methods of use thereof |
| WO2014062856A1 (en) | 2012-10-16 | 2014-04-24 | Halozyme, Inc. | Hypoxia and hyaluronan and markers thereof for diagnosis and monitoring of diseases and conditions and related methods |
| JP2016528217A (ja) | 2013-07-26 | 2016-09-15 | スレッショルド ファーマシューティカルズ，インコーポレイテッド | 低酸素活性化プロドラッグおよびタキサンの組合せを用いた膵臓癌の治療 |
| BR112017007765B1 (pt) | 2014-10-14 | 2023-10-03 | Halozyme, Inc | Composições de adenosina deaminase-2 (ada2), variantes do mesmo e métodos de usar o mesmo |
| JP7327900B2 (ja) | 2015-06-24 | 2023-08-16 | スレッシュホールド ファーマシューティカルズ， インコーポレイテッド | アジリジン含有ｄｎａアルキル化剤 |
| CN106995815B (zh) * | 2016-01-22 | 2020-09-01 | 南京农业大学 | 硝基还原酶基因pnr及其编码的蛋白和应用 |
| CN106905184B (zh) * | 2017-03-05 | 2019-03-29 | 北京化工大学 | 含有苯甲酰胺基团的氮芥类化合物及其制备方法和用途 |
| EP3774743B1 (en) * | 2018-03-29 | 2023-11-22 | Achilles Medical Limited | Prodrug compounds activated by akr1c3 and their use for treating hyperproliferative disorders |
| CN112961082B (zh) * | 2021-02-22 | 2022-09-06 | 沈阳药科大学 | 一种血管阻断剂与双载药仿生脂质体联用的给药系统 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8705477D0 (en) | 1987-03-09 | 1987-04-15 | Carlton Med Prod | Drug delivery systems |
| NZ240785A (en) * | 1991-11-28 | 1995-08-28 | Cancer Res Campaign Tech | Substituted nitro aniline derivatives and medicaments |
-
2002
- 2002-10-08 NZ NZ521851A patent/NZ521851A/en not_active IP Right Cessation
-
2003
- 2003-10-08 US US10/529,772 patent/US7776924B2/en not_active Expired - Fee Related
- 2003-10-08 AU AU2003278628A patent/AU2003278628B2/en not_active Ceased
- 2003-10-08 CA CA2501388A patent/CA2501388C/en not_active Expired - Fee Related
- 2003-10-08 WO PCT/NZ2003/000225 patent/WO2004033415A1/en not_active Ceased
- 2003-10-08 JP JP2004542927A patent/JP4582519B2/ja not_active Expired - Fee Related
- 2003-10-08 EP EP03770163A patent/EP1558568A4/en not_active Withdrawn
- 2003-10-08 CN CNB2003801028127A patent/CN100546976C/zh not_active Expired - Fee Related
-
2010
- 2010-06-15 JP JP2010136139A patent/JP2010265272A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| CN1711236A (zh) | 2005-12-21 |
| WO2004033415A1 (en) | 2004-04-22 |
| CA2501388C (en) | 2011-01-04 |
| US20050256191A1 (en) | 2005-11-17 |
| JP2010265272A (ja) | 2010-11-25 |
| AU2003278628A1 (en) | 2004-05-04 |
| EP1558568A1 (en) | 2005-08-03 |
| JP4582519B2 (ja) | 2010-11-17 |
| CN100546976C (zh) | 2009-10-07 |
| CA2501388A1 (en) | 2004-04-22 |
| JP2006502214A (ja) | 2006-01-19 |
| US7776924B2 (en) | 2010-08-17 |
| AU2003278628B2 (en) | 2010-09-23 |
| EP1558568A4 (en) | 2006-10-18 |
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| RENW | Renewal (renewal fees accepted) | ||
| RENW | Renewal (renewal fees accepted) | ||
| LAPS | Patent lapsed |