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
- 239000002904 solvent Substances 0.000 description 5
- 239000003039 volatile agent Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- 241001112696 Clostridia Species 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YQANFKDQYSESFK-UHFFFAOYSA-N 2-[3-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC=C([N+]([O-])=O)C(C(=O)NCC(O)CO)=C1[N+]([O-])=O YQANFKDQYSESFK-UHFFFAOYSA-N 0.000 description 3
- SDNHGKBEWGELIX-UHFFFAOYSA-N 2-[3-carbamoyl-n-(2-methylsulfonyloxyethyl)-2,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C([N+]([O-])=O)C=CC(C(N)=O)=C1[N+]([O-])=O SDNHGKBEWGELIX-UHFFFAOYSA-N 0.000 description 3
- URZIYPKNXKUFAJ-UHFFFAOYSA-N 2-[5-(2,3-dihydroxypropylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(=O)NCC(O)CO)=C([N+]([O-])=O)C=C1[N+]([O-])=O URZIYPKNXKUFAJ-UHFFFAOYSA-N 0.000 description 3
- 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 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
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 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
- GABZTCDFXGIBLI-UHFFFAOYSA-N 2-[2-carbamoyl-n-(2-methylsulfonyloxyethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O GABZTCDFXGIBLI-UHFFFAOYSA-N 0.000 description 2
- NEHFIJDJOAYEIT-UHFFFAOYSA-N 2-[5-(2-hydroxyethylcarbamoyl)-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(=O)NCCO)=C([N+]([O-])=O)C=C1[N+]([O-])=O NEHFIJDJOAYEIT-UHFFFAOYSA-N 0.000 description 2
- XEIJNVSHRWQDQH-UHFFFAOYSA-N 2-[5-carbamoyl-n-(2-methylsulfonyloxyethyl)-2,4-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC(C(N)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O XEIJNVSHRWQDQH-UHFFFAOYSA-N 0.000 description 2
- YNVFNFQIWUXEGO-UHFFFAOYSA-N 2-[bis(2-bromoethyl)amino]-n-(3-morpholin-4-ylpropyl)-3,5-dinitrobenzamide Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC(C(=O)NCCCN2CCOCC2)=C1N(CCBr)CCBr YNVFNFQIWUXEGO-UHFFFAOYSA-N 0.000 description 2
- ADTKEYLCJYYHHH-UHFFFAOYSA-N 2-chloro-3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl ADTKEYLCJYYHHH-UHFFFAOYSA-N 0.000 description 2
- QFGXKJGQMYAPIM-UHFFFAOYSA-N 2-chloro-3,5-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(Cl)=O)=C(Cl)C([N+]([O-])=O)=C1 QFGXKJGQMYAPIM-UHFFFAOYSA-N 0.000 description 2
- BTBFCBQZFMQBNT-UHFFFAOYSA-N 3,4-difluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1F BTBFCBQZFMQBNT-UHFFFAOYSA-N 0.000 description 2
- SXQNWQIEDASNKY-UHFFFAOYSA-N 3-[bis(2-bromoethyl)amino]-2,6-dinitrobenzamide Chemical compound NC(=O)C1=C([N+]([O-])=O)C=CC(N(CCBr)CCBr)=C1[N+]([O-])=O SXQNWQIEDASNKY-UHFFFAOYSA-N 0.000 description 2
- QTFJFCYPSYADLT-UHFFFAOYSA-N 3-[bis(2-methylsulfonyloxyethyl)amino]-2,6-dinitrobenzoic acid Chemical compound CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C1=CC=C([N+]([O-])=O)C(C(O)=O)=C1[N+]([O-])=O QTFJFCYPSYADLT-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101100037762 Caenorhabditis elegans rnh-2 gene Proteins 0.000 description 2
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 2
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- VJKBIUDSLICPPV-UHFFFAOYSA-N OC(CC=1C(=C(C(=O)N)C=CC1[N+](=O)[O-])[N+](=O)[O-])CO Chemical compound OC(CC=1C(=C(C(=O)N)C=CC1[N+](=O)[O-])[N+](=O)[O-])CO VJKBIUDSLICPPV-UHFFFAOYSA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000000981 bystander Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HMPHJJBZKIZRHG-UHFFFAOYSA-N chloromethanesulfonic acid Chemical compound OS(=O)(=O)CCl HMPHJJBZKIZRHG-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
- ALKUXDWPJSKEQI-UHFFFAOYSA-N methyl 3-[bis(2-methylsulfonyloxyethyl)amino]-2,6-dinitrobenzoate Chemical compound COC(=O)C1=C([N+]([O-])=O)C=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=C1[N+]([O-])=O ALKUXDWPJSKEQI-UHFFFAOYSA-N 0.000 description 2
- VWTTWTKBUUZRBB-UHFFFAOYSA-N methyl 5-[bis(2-methylsulfonyloxyethyl)amino]-2,4-dinitrobenzoate Chemical compound COC(=O)C1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=C([N+]([O-])=O)C=C1[N+]([O-])=O VWTTWTKBUUZRBB-UHFFFAOYSA-N 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 2
- 239000013603 viral vector Substances 0.000 description 2
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- 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 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- BLCMUMHBRDDXAM-UHFFFAOYSA-N 2-[2-carbamoyl-n-(2-chloroethyl)-4,6-dinitroanilino]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN(CCCl)C1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O BLCMUMHBRDDXAM-UHFFFAOYSA-N 0.000 description 1
- YJQPJJHWRFQIIW-UHFFFAOYSA-N 2-[3-(3-hydroxypropylcarbamoyl)-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)NCCCO)=C1[N+]([O-])=O YJQPJJHWRFQIIW-UHFFFAOYSA-N 0.000 description 1
- UUWNDZURQIAAJE-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]-3,5-dinitrobenzamide Chemical compound NC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCO)CCO UUWNDZURQIAAJE-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- KLGQWSOYKYFBTR-UHFFFAOYSA-N 2-nitrobenzamide Chemical compound NC(=O)C1=CC=CC=C1[N+]([O-])=O KLGQWSOYKYFBTR-UHFFFAOYSA-N 0.000 description 1
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 description 1
- ZXVONLUNISGICL-UHFFFAOYSA-N 4,6-dinitro-o-cresol Chemical group CC1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1O ZXVONLUNISGICL-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- DJMSRFQEEDIQLX-UHFFFAOYSA-N 5-chloro-2,4-dinitroaniline Chemical compound NC1=CC(Cl)=C([N+]([O-])=O)C=C1[N+]([O-])=O DJMSRFQEEDIQLX-UHFFFAOYSA-N 0.000 description 1
- VVQOEJCXWMGEJG-UHFFFAOYSA-N 5-chloro-2,4-dinitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=C([N+]([O-])=O)C=C1[N+]([O-])=O VVQOEJCXWMGEJG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010057573 Flavoproteins Proteins 0.000 description 1
- 102000003983 Flavoproteins Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108700028146 Genetic Enhancer Elements Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 108010045510 NADPH-Ferrihemoprotein Reductase Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 229910006074 SO2NH2 Inorganic materials 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- BQDQXEQTGWFVRA-UHFFFAOYSA-N aziridine;2,3-dinitrobenzamide Chemical class C1CN1.NC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O BQDQXEQTGWFVRA-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000006360 carbonyl amino methylene group Chemical group [H]N(C([*:1])=O)C([H])([H])[*:2] 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical class OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- RDFJFVXMRYVOAC-UHFFFAOYSA-N methiodal Chemical compound OS(=O)(=O)CI RDFJFVXMRYVOAC-UHFFFAOYSA-N 0.000 description 1
- YQUWPPGZHGDYPU-UHFFFAOYSA-N methyl 3-[(2-chloro-3,5-dinitrobenzoyl)amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1Cl YQUWPPGZHGDYPU-UHFFFAOYSA-N 0.000 description 1
- QBPHLAQJBIIFAZ-UHFFFAOYSA-N methyl 3-[[2-[2-bromoethyl(2-methylsulfonyloxyethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCOS(C)(=O)=O QBPHLAQJBIIFAZ-UHFFFAOYSA-N 0.000 description 1
- CCRHRAFGFFFSNM-UHFFFAOYSA-N methyl 3-[[2-[bis(2-bromoethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCBr)CCBr CCRHRAFGFFFSNM-UHFFFAOYSA-N 0.000 description 1
- PZVXPUGUODFQJC-UHFFFAOYSA-N methyl 3-[[2-[bis(2-chloroethyl)amino]-3,5-dinitrobenzoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1N(CCCl)CCCl PZVXPUGUODFQJC-UHFFFAOYSA-N 0.000 description 1
- MVXWPONEUMUAOU-UHFFFAOYSA-N methyl 3-[bis(2-hydroxyethyl)amino]-2,6-dinitrobenzoate Chemical compound COC(=O)C1=C([N+]([O-])=O)C=CC(N(CCO)CCO)=C1[N+]([O-])=O MVXWPONEUMUAOU-UHFFFAOYSA-N 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
- C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (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 |
| 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 |
| EP03770163A EP1558568A4 (en) | 2002-10-08 | 2003-10-08 | ALKYLATION AGENTS BASED ON NITROANILINE AND THEIR USE AS PROMEDICAMENTS |
| 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 |
| AU2003278628A AU2003278628B2 (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 |
| PCT/NZ2003/000225 WO2004033415A1 (en) | 2002-10-08 | 2003-10-08 | Nitroaniline-based alkylating agents and their use as prodrugs |
| 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 (enExample) |
| EP (1) | EP1558568A4 (enExample) |
| JP (2) | JP4582519B2 (enExample) |
| CN (1) | CN100546976C (enExample) |
| AU (1) | AU2003278628B2 (enExample) |
| CA (1) | CA2501388C (enExample) |
| NZ (1) | NZ521851A (enExample) |
| WO (1) | WO2004033415A1 (enExample) |
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 |
| WO2010048330A1 (en) | 2008-10-21 | 2010-04-29 | Threshold Pharmaceuticals, Inc. | Treatment of cancer using hypoxia activated prodrugs |
| 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 |
| 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 |
| US20160158253A1 (en) | 2013-07-26 | 2016-06-09 | Threshold Pharmaceuticals, Inc. | Treatment of pancreatic cancer with a combination of a hypoxia-activated prodrug and a taxane |
| AU2015332533B2 (en) | 2014-10-14 | 2018-08-30 | Halozyme, Inc. | Compositions of adenosine deaminase-2 (ADA2), variants thereof and methods of using same |
| US20180169064A1 (en) | 2015-06-24 | 2018-06-21 | Threshold Pharmaceuticals, Inc. | Aziridine containing dna alkylating agents |
| 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 |
| WO2019190331A1 (en) * | 2018-03-29 | 2019-10-03 | 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 CN CNB2003801028127A patent/CN100546976C/zh not_active Expired - Fee Related
- 2003-10-08 EP EP03770163A patent/EP1558568A4/en not_active Withdrawn
- 2003-10-08 WO PCT/NZ2003/000225 patent/WO2004033415A1/en not_active Ceased
- 2003-10-08 CA CA2501388A patent/CA2501388C/en not_active Expired - Fee Related
- 2003-10-08 AU AU2003278628A patent/AU2003278628B2/en not_active Ceased
- 2003-10-08 JP JP2004542927A patent/JP4582519B2/ja not_active Expired - Fee Related
- 2003-10-08 US US10/529,772 patent/US7776924B2/en not_active Expired - Fee Related
-
2010
- 2010-06-15 JP JP2010136139A patent/JP2010265272A/ja not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| JP2010265272A (ja) | 2010-11-25 |
| CN100546976C (zh) | 2009-10-07 |
| AU2003278628A1 (en) | 2004-05-04 |
| CA2501388C (en) | 2011-01-04 |
| JP4582519B2 (ja) | 2010-11-17 |
| US20050256191A1 (en) | 2005-11-17 |
| US7776924B2 (en) | 2010-08-17 |
| JP2006502214A (ja) | 2006-01-19 |
| CN1711236A (zh) | 2005-12-21 |
| EP1558568A4 (en) | 2006-10-18 |
| EP1558568A1 (en) | 2005-08-03 |
| CA2501388A1 (en) | 2004-04-22 |
| AU2003278628B2 (en) | 2010-09-23 |
| WO2004033415A1 (en) | 2004-04-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2010265272A (ja) | 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 | |
| JP2006502214A6 (ja) | 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 | |
| AU2004285831B2 (en) | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic agents | |
| EA005210B1 (ru) | Сульфонамиды гидроксидифенилмочевины в качестве антагонистов рецептора ил-8 | |
| OA11746A (en) | Benzoheterocycles and their use as MEK inhibitors. | |
| CA2404439A1 (en) | Diphenyl ether compounds useful in therapy | |
| US6448293B1 (en) | Diphenyl ether compounds useful in therapy | |
| DE60316683T2 (de) | Phenylcyclohexylpropanolaminderivate, deren herstellung und therapeutsche anwendung | |
| US20100121091A1 (en) | Processes of preparing asymmetric dinitrobenzamide mustard compounds, intermediate compounds useful therein and products obtained therefrom | |
| US7776866B2 (en) | Deuterium-enriched risperidone | |
| HU210683B (en) | Process for producing n-benzyl-n1-(phenyl-alkyl)-thiourea derivatives and pharmaceutical compositions containing the same | |
| JPS62234083A (ja) | 鎮吐薬または精神病治療薬として有用なカルボキサミド類 | |
| FR2481280A1 (fr) | Procede de preparation de derives de 2-guanidinothiazole, nouveaux produits ainsi obtenus et leur utilisation comme agents contre les ulceres d'estomac | |
| ZA200504064B (en) | Substituted tetralins and indanes and their use | |
| US3927093A (en) | 2-(O-aminophenylthio)benzyl alcohols | |
| US7915309B2 (en) | Deuterium-enriched oseltamivir | |
| NZ529249A (en) | Novel nitrophenyl mustard and nitrophenylaziridine alcohols and their corresponding phosphates and their use as targeted cytotoxic | |
| US4256888A (en) | Preparation of 2-chloropyrimidines | |
| JPH02221254A (ja) | ビス―（４―フルオロ―２―クロルフェニル）ジスルフィド誘導体 | |
| JPH051023A (ja) | アルカンスルホンアニリド誘導体の製法 | |
| Babii et al. | Conversion of N-(1-Arylsulfonyl-2, 2-dichloroethenyl) carboxamides into Derivatives of 4, 5-Dimercaptooxazole | |
| Sui et al. | A convenient Synthesis of 3, 5-bis (trifluoromethyl) salicylic Acid | |
| US20090082469A1 (en) | Deuterium-enriched terbinafine | |
| JPH075563B2 (ja) | ジスルフイド誘導体およびその製造方法 | |
| JPS61122274A (ja) | 複素多環式化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PSEA | Patent sealed | ||
| S883 | Correction of error according to section 88(3) (mistake in register caused on part of patentee or applicant) |
Free format text: THE NAME OF THE INVENTORS (72) HAS BEEN CORRECTED |
|
| RENW | Renewal (renewal fees accepted) | ||
| RENW | Renewal (renewal fees accepted) | ||
| LAPS | Patent lapsed |