US20090075945A1 - Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents - Google Patents
Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents Download PDFInfo
- Publication number
- US20090075945A1 US20090075945A1 US12/080,357 US8035708A US2009075945A1 US 20090075945 A1 US20090075945 A1 US 20090075945A1 US 8035708 A US8035708 A US 8035708A US 2009075945 A1 US2009075945 A1 US 2009075945A1
- Authority
- US
- United States
- Prior art keywords
- cancer
- leukemia
- uterine
- tumor
- hodgkins disease
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010021143 Hypoxia Diseases 0.000 title abstract description 31
- 229940002612 prodrug Drugs 0.000 title abstract description 21
- 239000000651 prodrug Substances 0.000 title abstract description 21
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 16
- 239000010452 phosphate Substances 0.000 title abstract description 15
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 title abstract description 8
- ISNKSXRJJVWFIL-UHFFFAOYSA-N (sulfonylamino)amine Chemical class NN=S(=O)=O ISNKSXRJJVWFIL-UHFFFAOYSA-N 0.000 title abstract description 3
- 230000007954 hypoxia Effects 0.000 title description 12
- 239000002246 antineoplastic agent Substances 0.000 title description 7
- 229940034982 antineoplastic agent Drugs 0.000 title description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 201000011510 cancer Diseases 0.000 claims abstract description 28
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 112
- 208000017604 Hodgkin disease Diseases 0.000 claims description 16
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 16
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 11
- 206010025323 Lymphomas Diseases 0.000 claims description 10
- 208000032839 leukemia Diseases 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 9
- 201000001441 melanoma Diseases 0.000 claims description 9
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 8
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 8
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 8
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 8
- 208000034578 Multiple myelomas Diseases 0.000 claims description 8
- 206010029260 Neuroblastoma Diseases 0.000 claims description 8
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 8
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- 208000008383 Wilms tumor Diseases 0.000 claims description 8
- 230000001154 acute effect Effects 0.000 claims description 8
- 210000004556 brain Anatomy 0.000 claims description 8
- 201000009277 hairy cell leukemia Diseases 0.000 claims description 8
- 201000010536 head and neck cancer Diseases 0.000 claims description 8
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 8
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 8
- 201000002528 pancreatic cancer Diseases 0.000 claims description 8
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 8
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 claims 14
- 206010046766 uterine cancer Diseases 0.000 claims 14
- 206010005003 Bladder cancer Diseases 0.000 claims 7
- 208000003174 Brain Neoplasms Diseases 0.000 claims 7
- 206010006187 Breast cancer Diseases 0.000 claims 7
- 208000026310 Breast neoplasm Diseases 0.000 claims 7
- 206010008342 Cervix carcinoma Diseases 0.000 claims 7
- 208000008839 Kidney Neoplasms Diseases 0.000 claims 7
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 claims 7
- 208000003445 Mouth Neoplasms Diseases 0.000 claims 7
- 206010033128 Ovarian cancer Diseases 0.000 claims 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 7
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 claims 7
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 7
- 206010038389 Renal cancer Diseases 0.000 claims 7
- 208000000453 Skin Neoplasms Diseases 0.000 claims 7
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 7
- 208000024313 Testicular Neoplasms Diseases 0.000 claims 7
- 206010057644 Testis cancer Diseases 0.000 claims 7
- 206010043515 Throat cancer Diseases 0.000 claims 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 7
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 7
- 201000007455 central nervous system cancer Diseases 0.000 claims 7
- 201000010881 cervical cancer Diseases 0.000 claims 7
- 208000029742 colonic neoplasm Diseases 0.000 claims 7
- 206010017758 gastric cancer Diseases 0.000 claims 7
- 201000010982 kidney cancer Diseases 0.000 claims 7
- 206010023841 laryngeal neoplasm Diseases 0.000 claims 7
- 201000007270 liver cancer Diseases 0.000 claims 7
- 208000014018 liver neoplasm Diseases 0.000 claims 7
- 201000005202 lung cancer Diseases 0.000 claims 7
- 208000020816 lung neoplasm Diseases 0.000 claims 7
- 201000008006 pharynx cancer Diseases 0.000 claims 7
- 206010038038 rectal cancer Diseases 0.000 claims 7
- 201000001275 rectum cancer Diseases 0.000 claims 7
- 201000000849 skin cancer Diseases 0.000 claims 7
- 201000011549 stomach cancer Diseases 0.000 claims 7
- 201000003120 testicular cancer Diseases 0.000 claims 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 3
- 125000006825 (C2-C5) haloalkyl group Chemical group 0.000 claims 2
- 238000011282 treatment Methods 0.000 abstract description 26
- 230000001146 hypoxic effect Effects 0.000 abstract description 19
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 abstract description 10
- 229940127084 other anti-cancer agent Drugs 0.000 abstract description 6
- 238000001959 radiotherapy Methods 0.000 abstract description 6
- 239000002207 metabolite Substances 0.000 abstract description 5
- 239000000243 solution Substances 0.000 description 39
- 239000003814 drug Substances 0.000 description 31
- 229940079593 drug Drugs 0.000 description 30
- 239000000203 mixture Substances 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 229910052760 oxygen Inorganic materials 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 20
- 239000001301 oxygen Substances 0.000 description 18
- 239000003795 chemical substances by application Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 16
- 102000004459 Nitroreductase Human genes 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 15
- 108020001162 nitroreductase Proteins 0.000 description 15
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 235000021317 phosphate Nutrition 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- -1 oxygen radicals Chemical class 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 239000000654 additive Substances 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 230000009826 neoplastic cell growth Effects 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 238000006722 reduction reaction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- 238000001994 activation Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 230000001988 toxicity Effects 0.000 description 8
- 231100000419 toxicity Toxicity 0.000 description 8
- 0 *N(C)N(C)C(=O)OC([1*])C1=CC=C([N+](=O)[O-])C(P=O)=C1.OOO Chemical compound *N(C)N(C)C(=O)OC([1*])C1=CC=C([N+](=O)[O-])C(P=O)=C1.OOO 0.000 description 7
- 241001529936 Murinae Species 0.000 description 7
- 230000000996 additive effect Effects 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000001472 cytotoxic effect Effects 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000004679 31P NMR spectroscopy Methods 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 108010045510 NADPH-Ferrihemoprotein Reductase Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 231100000433 cytotoxic Toxicity 0.000 description 6
- 230000002349 favourable effect Effects 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 238000007918 intramuscular administration Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 4
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 102000004316 Oxidoreductases Human genes 0.000 description 4
- 108090000854 Oxidoreductases Proteins 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 201000005296 lung carcinoma Diseases 0.000 description 4
- 231100000682 maximum tolerated dose Toxicity 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 150000002989 phenols Chemical class 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 230000033616 DNA repair Effects 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- TZGDGDZGDVGAKM-UHFFFAOYSA-N [2-chloroethyl(methylsulfonyl)amino]-methylsulfonylcarbamic acid Chemical compound ClCCN(S(=O)(=O)C)N(C(O)=O)S(C)(=O)=O TZGDGDZGDVGAKM-UHFFFAOYSA-N 0.000 description 3
- 230000002152 alkylating effect Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000013467 fragmentation Methods 0.000 description 3
- 238000006062 fragmentation reaction Methods 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- JAMOQJZIXYWHJJ-UHFFFAOYSA-N 1-(4-nitrophenyl)ethyl n-aminocarbamate Chemical compound NNC(=O)OC(C)C1=CC=C([N+]([O-])=O)C=C1 JAMOQJZIXYWHJJ-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- IQUPABOKLQSFBK-UHFFFAOYSA-N 2-nitrophenol Chemical compound OC1=CC=CC=C1[N+]([O-])=O IQUPABOKLQSFBK-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108091007187 Reductases Proteins 0.000 description 2
- 108010041388 Ribonucleotide Reductases Proteins 0.000 description 2
- 102000000505 Ribonucleotide Reductases Human genes 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000004983 alkyl aryl ketones Chemical class 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 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 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 208000035269 cancer or benign tumor Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 239000002619 cytotoxin Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine group Chemical group NO AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 150000002443 hydroxylamines Chemical class 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000006213 oxygenation reaction Methods 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 210000003800 pharynx Anatomy 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 description 1
- LHGMRIVCXMLBNA-UHFFFAOYSA-N 1-(3-hydroxy-4-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C([N+]([O-])=O)C(O)=C1 LHGMRIVCXMLBNA-UHFFFAOYSA-N 0.000 description 1
- DEZODTPLVNXUTD-UHFFFAOYSA-N 1-(4-nitrophenyl)ethyl n-[2-chloroethyl(methylsulfonyl)amino]-n-methylsulfonylcarbamate Chemical compound ClCCN(S(C)(=O)=O)N(S(C)(=O)=O)C(=O)OC(C)C1=CC=C([N+]([O-])=O)C=C1 DEZODTPLVNXUTD-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- GBHCABUWWQUMAJ-UHFFFAOYSA-N 2-hydrazinoethanol Chemical compound NNCCO GBHCABUWWQUMAJ-UHFFFAOYSA-N 0.000 description 1
- AUBBVPIQUDFRQI-UHFFFAOYSA-N 3-hydroxy-4-nitrobenzaldehyde Chemical compound OC1=CC(C=O)=CC=C1[N+]([O-])=O AUBBVPIQUDFRQI-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical class [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- 102000002226 Alkyl and Aryl Transferases Human genes 0.000 description 1
- 108010014722 Alkyl and Aryl Transferases Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- 230000000970 DNA cross-linking effect Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 1
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 1
- 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 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- JUQRWCMITUNYSA-UHFFFAOYSA-N O=S(=O)=NN=S(=O)=O Chemical class O=S(=O)=NN=S(=O)=O JUQRWCMITUNYSA-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- RAFKCLFWELPONH-UHFFFAOYSA-N acetonitrile;dichloromethane Chemical compound CC#N.ClCCl RAFKCLFWELPONH-UHFFFAOYSA-N 0.000 description 1
- 150000008062 acetophenones Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- VCDGSBJCRYTLNU-AZWGFFAPSA-N alpine borane Chemical compound C1CCC2CCCC1B2[C@@H]1C[C@H](C2(C)C)C[C@H]2[C@H]1C VCDGSBJCRYTLNU-AZWGFFAPSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-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
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009643 clonogenic assay Methods 0.000 description 1
- 231100000096 clonogenic assay Toxicity 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 101150042537 dld1 gene Proteins 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 208000013210 hematogenous Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000014304 histidine Nutrition 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- BLNWTAHYTCHDJH-UHFFFAOYSA-O hydroxy(oxo)azanium Chemical compound O[NH+]=O BLNWTAHYTCHDJH-UHFFFAOYSA-O 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 239000006204 intramuscular dosage form Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 210000004976 peripheral blood cell Anatomy 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000005838 radical anions Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Images
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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
-
- 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
- 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
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
Definitions
- the present invention relates to metabolically activated sulfonyl hydrazine prodrugs (SHPs) exhibiting anti-tumor activity in mammals.
- SHPs metabolically activated sulfonyl hydrazine prodrugs
- Eradication of solid tumors requires strategies that address the viable populations of malignant cells within hypoxic regions of such tumors.
- An insufficient and poorly organized vasculature a major characteristic of rapidly growing tumor masses, results in poor oxygenation, high interstitial pressure, and a population of cells that are hypoxic, quiescent or slowly cycling, and distal to the blood supply, thus inadequate vascularization in solid tumors results in low oxygen and being difficult to reach with cytotoxic levels of drugs (Hockel, et al. Cancer Res. 1991, 51: 6098). Radiotherapy is thus ineffective in these areas as the radiation fails to generate sufficient oxygen radicals to result in cytotoxicity (Brizel, et al. Radiother Oncol. 1999, 53: 113).
- hypoxic cell fraction can repopulate the tumor (Stratford, et al. Anticancer Drug Des. 1998, 13: 519).
- hypoxic cells are subjected to an environment that enhances the selection of mutations which cause the progression of the neoplasm towards an increasingly aggressive phenotype.
- hypoxia selects for cells deficient in p53-mediated apoptosis, enhances mutation rates, upregulates genes involved in drug resistance, angiogenesis, and tumor invasiveness (including HIF-1 ⁇ ), and thus is associated with a more metastatic phenotype (Ashur-Fabian, et al. Pro Natl Acd Sci USA. 2004, 101: 12236).
- Prodrugs that act as hypoxia-selective cytotoxins generally must be substrates for one electron reductases such as NADPH:cytochrome (P450) reductase.
- the one-electron reduced prodrug radical in the presence of oxygen, redox cycles back to the parent prodrug, preventing progression of the activation cascade and release of the cytotoxic, DNA damaging species.
- further reduction of the radical anions alters the chemistry of the prodrug to allow release of the cytotoxic species (Yang, et al. Cancer Res. 2003, 63: 1520).
- Nitroaromatic and nitroheterocyclic compounds readily undergo one electron reduction to nitro radical anions (Korbelik, et al.
- KS119 1,2-Bis(methylsulfonyl)-2-(2-chloroethyl)-hydrazine carboxylic acid 1-(4-nitrophenyl)ethyl ester
- SHP series requires enzymatic nitro-reduction to generate the alkylating species 90CE, as demonstrated in FIG. 1 .
- KS119 takes advantage of the hypoxic, reductive environment of solid tumors, thus creating an exploitable difference between cells in normal, well oxygenated tissues and hypoxic neoplastic cells (Shyam, et al. J Med Chem. 1999, 42: 941; and Seow, et al. Proc Natl Acad Sci USA. 2005, 102: 9282).
- KS119 is rather insoluble in aqueous solution, even it has not sufficient solubility ( ⁇ 5 mg/mL) in co-solvent system like polyethylene glycol (PEG) and ethanol in order to meet clinical requirements of this drug. Therefore, our aim was to synthesize analogs of KS119 that (a) were capable of improving its water-solubility and stability in aqueous solution at pH 3 to 8; (b) were capable of forming chloroethylating species; and (c) were capable of maintaining hypoxia-selective activation.
- an object of the present invention is to provide compounds, pharmaceutical compositions and methods for the treatments of neoplasia, including animal and human cancer.
- an object of the present invention is to provide methods of treating neoplasia utilizing compositions that exhibit favorable anti-cancer characteristics in hypoxia conditions and enhanced characteristics of activity, pharmacokinetics, bioavailability and reduced toxicity.
- the present invention is directed to compounds according to structures I or II:
- R is C 1-10 alkyl, or C 1-10 haloalkyl
- R′ or R′′ is C 1-10 alkyl, or C 5-20 aryl or heteroaryl
- R 1 is H; C 1-10 alkyl, C 1-10 alkoxyl
- X is O, NH, or NR
- R(P) is a phosphate-bearing alkyl group, for example, R(P) is Y′OPO(OH) 2 where Y is (CH 2 ) n , O(CH 2 ) n , NH(CH 2 ) n , NR(CH 2 ) n , n is 1-5; Y is aryl or heteroaryl; Ar(N) is a nitro-containing aryl group, for example,
- A is CH, CR, or N
- B is CH ⁇ CH, O, S, NH, or NR
- Ar(NP) is a phosphate-bearing and nitro-containing aryl group, for examples,
- A is CH, CR, or N; and B is CH ⁇ CH, O, S, NH, or NR; and Y is (CH 2 ) n , O(CH 2 ) n , NH(CH 2 ) n , NR(CH 2 ) n , OCOO(CH 2 ) n , NHCOO(CH 2 ) n ; n is 1-5.
- the present invention is also directed to compounds according to formulas I, II, III and IV
- R′ and R′′ are independently C 1-10 alkyl, or C 5-20 aryl or heteroaryl (preferably methyl);
- R 1 is H, C 1-10 alkyl, C 1-10 alkoxyl, C 5-20 aryl or heteroaryl or C 5-20 aroxyl or heteroaroxyl (preferably methyl and ethyl);
- X is O, NH, or NR (preferably O);
- the present invention relates to compounds according to structure IA:
- R C 1-10 alkyl, or C 1-10 haloalkyl
- R 1 H
- X O, NH, or NR
- A CH, CR, or N
- B CH ⁇ CH, O, S, NH, or NR.
- the aforementioned compounds include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts, solvates, polymorphs and metabolites from all stages.
- Preferred agents in the compounds are 4-nitrophenyl series of compound structure IA where A is CH; B is CH ⁇ CH; X is O; R is CH 2 CH 2 Cl; R 1 is CH 3 ; a phosphate group can be free acid or salt (preferably Tris).
- a phosphate group can be free acid or salt (preferably Tris).
- KS119W hydrazine-carboxylic acid 1-(4-nitrophenyl)ethyl ester
- R-configuration structure (VNP40541) of the enantiomers is more preferable.
- Compounds according to the present invention and especially the preferred compositions according to the present invention, as set forth above, are extremely effective compounds for the treatment of neoplasia. They also exhibit at least one or more improvements such as an enhanced anti-neoplasia activity, a reduced toxicity, a higher water-solubility, or a more favorable pharmacokinetic profile compared to KS119.
- These compounds according to the present invention are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy.
- Compounds according to the present invention may be used in pharmaceutical compositions for the treatment of cancer, as well as a number of other conditions and/or disease states. Examples according to the present invention may be as intermediates in the synthesis of other compounds exhibiting biological activity as well as standards for determining the biological activity of the present compounds. In some applications, the present compounds may be used for treating microbial infections, especially including viral, bacterial, and fungal infections. These compounds comprise an effective amount of any one or more of the compounds disclosed hereinabove, optionally in combination with a pharmaceutically acceptable additive, carrier, or excipient.
- a further aspect of the present invention relates to the treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound as described hereinabove, optionally in combination with a pharmaceutically acceptable additive, carrier, or excipient.
- the present invention also relates to methods for treating neoplasia in mammals comprising administering an effective amount of a compound as described hereinabove to a patient suffering from cancer.
- the treatment of solid malignant tumors, leukemia, and lymphomas comprising administering to a patient an anti-tumor effective amount of one or more these agents is a preferred embodiment of the present invention.
- the treatment of various other related disease states may also be effected using the compounds of the present invention. This method may also be used in comparison tests such as assays for determining the activities of related analogs as well as for determining the susceptibility of a patient's cancer to one or more of the compounds according to the present invention.
- FIG. 1 is a representation of a suggested mechanism of activation of KS119.
- FIG. 2 is representations of a sample (KS119W) of the chemical embodiments and their proposed mechanism of activation in hypoxia conditions according to the present invention.
- FIGS. 3 and 4 are representations of chemical schemes for synthesizing compounds according to the present invention.
- FIGS. 5 to 7 are representations of experimental results which are presented in the present application related to the selective activation in hypoxic conditions according to the present invention.
- FIGS. 8 to 9 are representations of experimental results which are presented in the present application related to the efficacy and toxicity of certain preferred embodiments according to the present invention.
- patient is used throughout the specification to describe an animal, including a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided.
- treatment including prophylactic treatment
- patient refers to that specific animal.
- an effective amount is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which may be used to produce a favorable change in the disease or condition treated, Whether that change is a remission, a decrease in growth or size of cancer or a tumor, a favorable physiological result, a reduction in the growth or elaboration of a microbe, or the like, depending upon the disease or condition treated.
- compound refers to any specific chemical compound disclosed herein. Within its use in context, the term generally refers to a single compound, but may also refer to stereoisomers and/or optical isomers (including racemic mixtures), well as specific enantiomers, or enantiomerically enriched mixtures of disclosed compounds, as well as tautomers.
- Neoplasia is used throughout the specification to describe the pathological process that results in the formation and growth of a neoplasm, i.e., an abnormal tissue that grows by cellular proliferation more rapidly than normal tissue and continues to grow after the stimuli that initiated the new growth cease.
- Neoplasia could be a distinct mass of tissue that may be benign (benign tumor) or malignant (carcinoma).
- the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic, and solid tumors.
- cancer and the term “tumor” used in this application is interchangeable with the term “neoplasia”.
- Cancer which may be treated using compositions according to the present invention include, for example, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, skin, brain/CNS, head and neck, throat, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, esophagus, larynx, melanoma, kidney and lymphoma, among others.
- the treatment of tumors comprising administering to a patient an anti-tumor effective amount of one or more these agents is a preferred embodiment of the present invention.
- alkyl is used throughout the specification to describe a hydrocarbon radical containing between one to seven carbon units.
- Alkyl groups for use in the present invention include linear or branched-chain groups, such as preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cylcohexyl, methylcyclopropyl and methylcyclohexyl.
- aryl refers to a substituted or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).
- aromatic refers to an aryl group to which is bonded an alkoxy group, preferably through which another group is bonded (e.g. a sulfonyl group).
- heteroaryl refers to heterocyclic aromatic ring groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazolyl, furyl, pyrrolyl, pyridyl, thienyl and indolyl.
- heteroaryl refers to a heteroaryl group to which is bonded an alkoxy group, preferably through which another group is bonded (e.g. a sulfonyl group).
- salt is used throughout the specification to describe any salt consistent with the use of the compounds according to the present invention.
- salt shall mean a pharmaceutically acceptable salt, consistent with the use of the compounds as pharmaceutical agents.
- the present invention relates to compounds according to the structure (IA):
- R C 1-10 alkyl, or C 1-10 haloalkyl
- R 1 H
- X O, NH, or NR
- A CH, CR, or N
- B CH ⁇ CH, O, S, NH, or NR.
- Compounds according to the present invention include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts, solvates, polymorphs and metabolites from all stages.
- the present compounds represent prodrug forms of intermediates that are believed to exhibit their activity of DNA cross-linking through chloroethylation or methylation mechanisms.
- enzyme-activated prodrugs could be converted into active alkylating species (90CE) via a sequence of enzyme activations and prompt fragmentation.
- De-phosphorylation can be accomplished by alkaline phosphatase (AP) enzyme activation to give intermediate 1; nitro-reduction can be catalyzed by nitro reductase (NR) enzyme to form intermediate 2; and subsequent benzyl group fragmentation generated 90CE, as shown in FIG. 2 .
- the compounds according to the present invention are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototherapy or radiotherapy.
- the compounds according to the present invention are primarily useful for their anti-neoplastic activity, including their activity against solid tumors.
- these compositions may also find use as intermediates in the chemical synthesis of other useful anti-neoplastic agents that are, in turn, useful as therapeutic agents or for other purposes, including use as standards for assays.
- Preferred agents in the compounds are 4-nitrophenyl series where A is CH; B is CH ⁇ CH; X is O; R is CH 2 CH 2 Cl; R 1 is CH 3 ; a phosphate group can be the free acid or a salt.
- the R-configuration structure (VNP40541) of the enantiomers is more preferably than S-configuration structure (VNP40551).
- 1,2-bis(methylsulfonyl)-2-(substituted)hydrazine-carbonates of Compounds I are synthesized respectively by reacting an appropriate ⁇ -alkyl 4-nitroarylmethyl alcohol or N-alkyl-N-(4-nitroarylmethyl)amine (3 or 4, where R 1 is —CH 3 ; R* is a protecting group of the phosphate group, such as diethyl or di-tert-butyl or 2-trimethylsilylethyl (TMSE) group with phosgene (20% toluene solution) or its equivalents, such as triphosgene or trichloromethyl chloroformate (see, Majer, et al.
- TMSE 2-trimethylsilylethyl
- de-protection of diethyl ester can be treated with trimethylsilyl bromide (TMSBr) (Matulic-Adamic, et al. J Org Chem. 1995, 60: 2563), de-protection of di-tert-butyl esters can be treated with trifluoroacetic acid (TFA) (Durgam, et al. J Med Chem. 2005, 48: 4919), and de-protection of di-TMSE esters cab be treated with TFA also (Dolye, et al. U.S. Pat. No.
- the phosphate free acid form 7 or 8 is purified by flash column chromatography (FCC) such as normal phase silica gel or reversed phase silica gel, and the desired SHP compound as drug substance is obtained after lyophilization.
- FCC flash column chromatography
- the ⁇ -alkyl 4-nitroarylmethyl alcohol (3) can be synthesized from the corresponding alkyl aryl ketone (9), employing an enantiomerically selective reduction.
- a reducing catalyst can be selected from commercially available reagents such as 2-Me-CBS-oxazaborolidine/BH 3 (Mathre, et al. J Org Chem. 1993, 58: 2880) or diisopinocampheylchloroborane (Brown, et al. J Am Chem Soc. 1988, 110: 1539) or Alpine-borane (Ramachadran, et al. Tetrahedron: Asymm. 5: 1061).
- Asymmetric hydrogenation of the ketone also can be used (Ohkuma, et al. J Am Chem Soc. 1998, 120: 13529; and Baar, et al. J Am Chem Soc. 2004, 126: 8216).
- the N-alkyl-N-(para-nitroarylmethyl)amine (4) can be prepared from the corresponding alkyl aryl ketone.
- sodium borohydride as a reducing agent, the reductive amination of a respective 12 with methylamine affords the corresponding N-arylmethyl-N-methylamine (4).
- the hydroxyl group on the aryl ring can be reacted with chlorophosphate to give their corresponding di-alkyl-protected phosphonoxy-aryl compound (i.e. 3 or 12) under mild conditions.
- Selective phosphorylation of phenols was achieved with phosphite, carbon tetrachloride, DIPEA and catalytic amounts of 4-dimethylaminopyridine (DMAP) (Silverberg, et al. Tetrahedron Lett. 1996, 37: 771). It is common that the phosphorylation may complete prior to asymmetric reduction or the phosphorylation may follow reductive amination.
- DMAP 4-dimethylaminopyridine
- the synthesis of the appropriate 4-nitroaryl compound (9 or 11) for use in these reaction schemes is well known in the art and uses standard chemical techniques such as nitration and acrylation.
- the crude product After synthesis, the crude product generally is purified by reversed phase column chromatography and lyophylization. Treating KS119W (or VNP40541) with an appropriate alkaline solution or amine can readily provide a respective water-soluble salt such as sodium salt, tris(hydroxymethyl)-aminomethane (TRIS) salt, triethanolamine salt, triethylamine salt, or lutidine salt. Modification of the disclosed chemical synthetic methods may be readily made by those of ordinary skill in the art in order to provide alternative synthetic pathways to the present compounds.
- TMS tris(hydroxymethyl)-aminomethane
- compositions based upon the present novel chemical compounds comprise the above-described compounds in a therapeutically effective amount for the treatment of a condition or disease such as cancer, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient.
- Certain of the compounds, in pharmaceutical dosage form, may be used as prophylactic agents for preventing a disease or condition from manifesting itself.
- the present compounds or their derivatives can be provided in the form of pharmaceutically acceptable salts.
- pharmaceutically acceptable salts refers to appropriate salts of the active compounds according to the present invention which retain the desired biological activity of the parent compound.
- Nonlimiting examples of such salts include the sodium and potassium salts of phosphate, among others such as TRIS salt, triethanolamine salt, triethylamine salt, lutidine salt, or other pharmaceutically acceptable salts known in the art.
- Modifications of the active compound can affect the solubility, pharmacokinetic parameters and rate of metabolism of the active species, thus providing control over the delivery of the active species. Further, the modifications can affect the anticancer activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivatives and testing the anticancer activity according to known methods well within the routineer's skill in the art.
- the compounds of this invention may be incorporated into formulations for all routes of administration including for example, parenteral and oral, including intravenous, intramuscular, intraperitoneal, intrabuccal, transdermal and in suppository form. Paranteral administration and in particular, intravenous or intramuscular administration is preferred.
- compositions based upon these novel chemical compounds comprise the above-described compounds in a therapeutically effective amount for treating cancer and other diseases and conditions which have been described herein, optionally in combination with a pharmaceutically acceptable additive, carrier and/or excipient.
- a therapeutically effective amount of one of more compounds according to the present invention will vary with the infection or condition to be treated, its severity, the treatment regiment to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated.
- the compound according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier In general, it is preferable to administer the pharmaceutical composition parenterally and in particular, in intravenously or intramuscular dosage form, but a number of formulations may be administered via other parenteral routes, such as transdermal, buccal, subcutaneous, suppository or other route, including via an oral route of administration.
- Intravenous and intramuscular formulations are preferably administered in sterile saline.
- one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity.
- the modification of the present compounds to render them more soluble in water or other vehicle may be easily accomplished by minor modifications (such as salt formulation, etc.) which are well within the ordinary skill in the art. It is also well within the routineer's skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect to the patient.
- the routineer will take advantage of favorable pharmacokinetic parameters of the prodrug forms of the present invention, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effects of the compound.
- Administration of the active compound may range from continuous (intravenous drip), including bolus administration, intravenously or intramuscularly even less frequently than once a day to several administrations per day and may include topical, parenteral, intravenous, intramuscular, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration, including, in certain instances, oral administration.
- continuous drip including bolus administration, intravenously or intramuscularly even less frequently than once a day to several administrations per day and may include topical, parenteral, intravenous, intramuscular, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration, including, in certain instances, oral administration.
- a therapeutically effective amount of one or more of the compounds according to the present invention is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose.
- a carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous or intramuscular.
- the carrier may comprise sterile water or aqueous sodium chloride solution or dextrose 5% in water (D5W) in combination with other ingredients that aid dispersion, such as ethanol and other pharmaceutically acceptable solvents, including DMSO, among others.
- D5W dextrose 5% in water
- Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can be included the following components: a sterile diluent such as water for injection, saline solution, D5W solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as TRIS, acetates, citrates, phosphates, histidine or sodium bicarbonate solution; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
- the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers include, for example, physiological saline or phosphate buffered saline (PBS).
- any one or more of the usual pharmaceutical media may be used.
- suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used.
- suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used.
- the tablets or capsules may be enteric coated or sustained release by standard techniques.
- the active compounds may be prepared with a carrier that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery system.
- a carrier that will protect the compound against rapid elimination from the body
- a controlled release formulation including implants and microencapsulated delivery system.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polyactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared by dissolving appropriate lipid(s) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. Other methods of preparation well known by those of ordinary skill may be used in this aspect of the present invention.
- the present compounds may be used to treat animals, and in particular, mammals, including humans, as patients.
- humans, equines, canines, bovines and other animals, and in particular, mammals, suffering from tumors, and in particular, cancer, or other diseases as described herein can be treated by administering to the patient an effective amount of one or more of the compounds according to the present invention or its derivative or a pharmaceutically acceptable salt thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known pharmaceutical agents, depending upon the disease to be treated.
- This treatment can also be administered in conjunction with other conventional cancer therapies, such as radiation treatment or surgery.
- the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
- the present compounds are prodrug forms of reactive intermediates.
- the present compounds may be modified to other prodrug forms to take advantage of a particular route of administration of the active compounds.
- One of ordinary skill in the art will recognize how to readily modify the present compounds to alternative prodrug forms to facilitate delivery of active compounds to a targeted site within the patient.
- the individual of ordinary skill also will take advantage of favorable pharmacokinetic parameters of the prodrug forms, where applicable, in delivering the present compounds to a targeted site within the patient to maximize the intended anti-neoplastic effect of the compound.
- the amount of compound included within the therapeutically active formulations according to the present invention is an effective amount for treating cancer.
- a therapeutically effective amount of the compound according to the present invention in dosage form usually ranges from less than about 0.05 mg/kg to about 500 mg/kg of body weight of the patient to be treated, or considerably more, depending upon the compound used, the tumor type to be treated, the ability of the active compound to localize in the tissue to be treated, the route of administration and the pharmacokinetics of the compound in the patient.
- the compound is preferably administered in amounts ranging from about 0.05 mg/kg to about 250 mg/kg or more at one time.
- This dosage range generally produces effective blood level concentrations of active compound ranging from about 0.01 to about 500 micrograms per ml of blood in the patient to be treated.
- the duration of treatment may be for one or more days or may last for several months or considerably longer (years) depending upon the disease state treated.
- the compound is given to the patient at doses of 0.1 mg/kg to 100 mg/kg, twice per day to once per 14 days, for the duration of 1 week to 52 weeks.
- the concentration of active compound in the patient will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage given to the patient will be also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
- the active compound according to the present invention can be also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as other anticancer agents, and in certain instances depending upon the desired therapy or target, antibiotics, antifungals, antiflammatories, or antiviral compounds, among other agents.
- These compounds according to the present invention are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy.
- Compounds according to the present invention may be administered alone or in combination with other agents, especially including other compounds of the present invention.
- an effective amount of one or more of the compounds according to the present invention is co-administered along with an effective amount of at lease one additional anti-neoplastic/anticancer agent such as antimetabolites, etoposide, doxorubicin, taxol, vincristine, cytoxan (cyclophosphamide) or mitomycin C, among numerous others, including topoisomerase I and topoisomerase II inhibitors, such as adriamycin, topotecan, campothecin and irinotecan, other agent such as gemcitabine and agents based upon campothecin and cis-platin.
- additional anti-neoplastic/anticancer agent such as antimetabolites, etoposide, doxorubicin, taxol, vincristine, cytoxan (cyclophosphamide) or mitomycin
- the present compounds which act by a mechanism to damage DNA, will act synergistically with compounds that act by a mechanism to reduce or prevent DNA repair.
- the present compounds may be advantageously combined with any compound which acts by a mechanism to reduce or prevent DNA repair, especially including inhibitors of enzymes which catalyze DNA repair, such as inhibitors of ribonucleotide reductase (RR) and inhibitors of O 6 -alkylguanine-DNA alkyltransferase (AGT).
- RR ribonucleotide reductase
- AGT O 6 -alkylguanine-DNA alkyltransferase
- co-administer it is meant that the present compounds are administered to a patient such that the present compounds as well as the co-administered compound may be found in the patient's bloodstream at the same time, regardless of when the compounds are actually administered, including simultaneously.
- the co-administration of the present compounds with traditional anticancer agents produces a synergistic (i.e., more than additive) result which is unexpected.
- the compounds according to the present invention are given either simultaneously or sequentially with antibodies (conjugated or unconjugated), viruses, or bacteria.
- the antibodies, viruses, or bacteria could carry enzymes or gene encoding enzymes that activate the compounds described in the present invention.
- the enzymes include but not limit to NR.
- the compounds according to the present invention primarily induce their therapeutic effect in treating malignant tumors by functional as hypoxia-selective chloroethylating agents.
- acetone 200 mL was dropwise charged into the reactor at ⁇ 50° C. After stirred at ⁇ 50° C. for 10 minutes, the reaction mixture was allowed to warm up to ambient temperature and stir for 1.5 hours. Concentrated by rotary evaporation on 45° C. bath, the residue was treated with saturated Na 2 CO 3 aqueous solution (2 L). The mixture was heated at 50° C. for 30 min, and then cooled down to room temperature. Added tert-butylmethylether (TBME, 1 L) and hexanes (1 L), the mixture was stirred at RT for 1 hour and then separated. The aqueous layers were charged concentrated HCl dropwise to adjust pH 6, while maintaining temperature at 25° C. The mixture was extracted with ethyl acetate (3 ⁇ 2 L), and the organic phases were concentrated. Crude product was afforded as brown oil, and was purified by re-crystallization from hexanes.
- TBME tert-butylmethylether
- 1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine-carboxylic acid 1-(3-diethylphosphonoxy-4-nitrophenyl)ethyl ester (73.9 g, 124 mmol) was de-protected and yielded 17 (52.8 g, 80%) as a white powder.
- the solubility of KS119W was determined visually by adding incremental quantities of the drug to 2.0 mL of water in a glass vial. The vials were shaken at room temperature in a Glas Col rotary apparatus until the drug dissolved entirely. Additional fixed quantities of drug were added and the vials shaken until complete dissolution. This process was continued until no more drug dissolved.
- the solubility of KS119W (or VNP40541) was found to be more than 400 mg/mL. Aqueous solutions of VNP40541 (or VNP40541) were light yellow.
- the solubility of the newly synthesized KS119W salts was similarly determined by adding an excess amount of the drug in a glass vial containing 2.0 mL of water. The vials were shaken in a Glas Col rotary apparatus at room temperature for 24 hours. The suspension containing undissolved drug was centrifuged; the supernatant was carefully separated and analyzed by HPLC for drug concentration. Water-solubility (mg/mL) of the KS119W salts from Mg(OH) 2 , NaOH, KOH, BET, and TRIS is detected: 51.2, 67.2, 71.0, 58.7, and 70.5, respectively.
- the stabilities of VNP40541 were investigated.
- the sample (20 mg/mL) was dissolved in 20 mM citric acid and titrated to pH 2.0, pH 3.0, pH 4.0, pH 5.0, pH 6.0, and pH 7.0.
- the drug was also titrated to pH 2.0, pH 5.0, and pH 6.0 in the absence of citrate.
- the samples were stored at 40° C. for 3 hours, 24 hours, and 3 days, and at room temperature for 24 hours, 3 days. Upon completion of each time point, samples were placed in a freezer at ⁇ 15° C. Control samples of each preparation were also stored in the freezer.
- Each sample was analyzed by HPLC repetitively, at various time points, to determine the concentration of the respective drug. As demonstrated in Table 1 below, the results indicate clearly that significant degradation was observed after 24 hours at 40° C. The presence of citrate did not appear to affect degradation significantly.
- EMT6 or CHO (parental or human cytochrome P-450 reductase transfected) cells seeded in glass milk dilution bottles, were gassed for 2 hours through a rubber septum fitted with 13 gauge (inflow) and 18 gauge (outflow) needles with a mixture of 5% CO 2 , oxygen at various concentrations, with the balance of the mixture made up of nitrogen, to establish various hypoxic conditions. Drugs were then injected without disrupting hypoxia. After two hours, cells were collected and plated in a clonogenic assay to determine the surviving fraction, compared to untreated controls.
- KS119W For in vitro analysis, KS119W must be converted to KS119OH (1) in an AP-catalyzed reaction shown above in FIG. 2 , as the phosphorylated parent drug cannot cross cell membranes. KS119OH is then used in all subsequent in vitro studies shown in this section.
- EMT6 murine mammary carcinoma cells were exposed to graded concentrations of KS119 or KS119OH at oxygenation levels reflecting normal air (21% oxygen) or a severely hypoxic atmosphere composed of 0.1% oxygen.
- the results, shown in FIG. 5 demonstrate that both drugs are virtually inactive under oxygenated conditions, with very little cytotoxicity to EMT6 cells at concentrations of drug up to 25 ⁇ M.
- both drugs display potent cytotoxic effects with cell kill approaching 5 orders of magnitude at 10 ⁇ M drug concentration.
- EMT6 cells were exposed to 10 or 25 ⁇ M of KS119 and KS119W-OH at graded concentrations of oxygen ranging from 0.05% to 21% to demonstrate drug activity as a function of oxygen concentration.
- the results, shown in FIG. 6 demonstrated significant drug activity at all oxygen concentrations below 10% oxygen, with considerable activity at oxygen concentrations that have been measured in solid tumors (shaded bar).
- KS119OH (1) like KS119 can be reduced under hypoxic conditions by one-electron reductases like cytochrome P-450 reductase to generate an intermediate of hydroxylamine or aniline (2), which spontaneously liberate the DNA alkylating and cytotoxic species, 90CE.
- cytochrome P-450 reductase an intermediate of hydroxylamine or aniline (2), which spontaneously liberate the DNA alkylating and cytotoxic species, 90CE.
- KS119W racemic and two enantiomers
- CHO cells transfected for and overexpressing this reductase were exposed to the drugs, and the sensitivity of this cell line to these agents was compared to the non-transfected parental line expressing low, basal levels of enzyme.
- the anti-tumor effects of aforementioned prodrugs are evaluated in both solid and liquid tumor models, including the B16-F10 murine melanoma, HTB177 human lung carcinoma models, DLD1 human colon carcinoma, EMT-6 murine mammary gland carcinoma, L1210 murine leukemia, lymphoma, prostate cancer, pancreatic cancer, and head-and-neck cancer.
- the prodrugs are given intravenously, orally, or intraperitoneally at doses from 10 mg/kg to 2000 mg/kg; they are give at different dosing schedules such as 4 times daily, once daily, or once every several days for up to 60 doses. Testing tumor cells were implanted subcutaneously into mice, which were randomized into groups immediately after tumor cell implantation (Day 0).
- mice were injected intraperitoneally (ip) with either a bolus injection of 0.1 mL PBS or drug.
- the treatment was carried out in a designed dosing schedule. Tumor measurement in three dimensions was determined once a week with the formula L ⁇ H ⁇ W/2, where L, H, and W represent length, height, and width, respectively.
- the toxicity of these drugs in mice was mild as determined by body weight loss and animal appearance.
- KS119 was studied in murine tumor model and human xenograft models.
- EMT-6 murine mammary carcinoma cells (3 ⁇ 10 5 cells/mouse) were implanted subcutaneously into Balb/c mice.
- H460 human lung carcinoma cells, HT29 human colon carcinoma cells and SHP77 human lung carcinoma cells were established as solid xenografts in nu/nu CD-1 mice and Scid/Beige mice with 7 ⁇ 10 7 cells/mouse, respectively.
- tumors were allowed to grow to a size of 150 to 200 mm 3 before starting treatment with KS119.
- KS119 was formulated in a solvent containing polyethylene glycol 300 (PEG), ethyl alcohol, citric acid, and ascorbic acid.
- PEG polyethylene glycol 300
- citric acid citric acid
- ascorbic acid ascorbic acid
- FIG. 7 The result of representative studies by daily ip administration of KS119 at doses of 80 and 100 mg/kg was shown in FIG. 7 .
- KS119W was formulated with 0.25M sodium bicarbonate solution. The treatment was started when tumors researched 150 to 200 mm 3 , and lasted up to 2 weeks. KS119 at doses of 80 and 100 mg/kg and KS119W at doses of 97.6 and 121.3 mg/kg were daily administrated into mice via ip injection. As showed with an example of H460 tumor ( FIG. 8 ), KS119 and KS119W both inhibited the growths of tumor in mice. In comparison with KS119 at equal molar doses, KS119W was clearly more effective and produced greater antitumor activity.
- the final tumor volumes in the groups treated with 121.6 mg/kg, ⁇ 7 doses and 97.2 mg/kg ⁇ 10 doses of KS119W were reduced 78% and 60%, respectively, compared with those in the control group; whereas the groups treated with equal molar doses of KS119 at 100 mg/kg and 80 mg/kg reduced only 40% inhibition.
- the toxicity of KS119 and KS119W were dose-dependent. To assess the toxicity of treatment, body weight and peripheral blood cell count were monitored after treatment. There was not significant hematological toxicity or severe weight loss in the mice treated with both drugs at the doses described above.
- VNP40541 and VNP40551 were evaluated in three sample tumor models in mice. Thus, they had exhibited quite similar efficacies and therapeutic windows, however VNP40541 had clearly demonstrated lower toxicity, particularly having less edema observed.
- KS119W with cytoxan was evaluated by using KS119W at dose below the MTD in combination with nontoxic dose of CTX against EMT-6 murine mammary carcinoma and H460 human lung carcinoma in CD-1 nude mice.
- the tumors were allowed to grow to a size of approximately 200 mm 3 .
- H460 tumor model the animals received either with 4 doses 180 mg/kg and 1 dose 240 mg/kg of KS119 or CTX at dose of 100 mg/kg per dose per animal, ip injecting the drugs on 15, 22, 27, 34 and 43 days after the tumor implantation.
- CTX was given two hours after dosing KS119W. As showed on FIG.
- KS119W alone resulted in 78% tumor growth inhibition, whereas CTX produced 54% inhibition only.
- the combination treatment of KS119W and CTX resulted in 90% tumor growth inhibitory.
- the inhibition of combination therapy was statistically significant against all control groups with p values of 0.003, 0.015 and 0.038, respectively.
- Additive toxicity at the doses used for combination was manageable; while the 180 mg/kg qw ⁇ 4 doses of KS119W alone caused a maximum net body weight loss of 4.5%, the same dose in combination with 4 doses of CTX at 100 mg/kg per week caused 8.6% weight loss but no death.
- a similar degree of growth inhibition was also observed with EMT-6 tumor model.
- KS119W Treatment of KS119W at dose of daily 97 mg/kg for 7 doses resulted in 59% tumor inhibition, and CTX at dose of 100 mg/kg, ip once per week for 4 doses generated a negligible effect on the tumor growth of EMT-6 in mice. Marked antitumor effects were observed when animals treated with a combination of KS119 and CTX. KS119W and CTX combination resulted in 91.8% growth inhibition of EMT-6 tumor. These results shows agent KS119W in combined with CTX have additive antitumor efficacy.
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)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Novel phosphate-bearing prodrugs of sulfonyl hydrazines have the formula presented below. Methods of treatment of cancer are claimed. The aforementioned prodrugs include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts or solvates and metabolites from all stages. The aforementioned prodrugs are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy.
where R is C1-C10 alkyl or haloalkyl;
R′ and R″ are each independently C1-C10 alkyl; and
R1 is C1-C10 alkyl,
or a pharmaceutically acceptable salt, solvate, polymorph or metabolite thereof.
R′ and R″ are each independently C1-C10 alkyl; and
R1 is C1-C10 alkyl,
or a pharmaceutically acceptable salt, solvate, polymorph or metabolite thereof.
Description
- This application claims priority from U.S. provisional application No. U.S. 60/611,623, filed Sep. 21, 2004; U.S. provisional application No. U.S. 60/615,419, filed Oct. 1, 2004; and U.S. provisional application No. U.S. 60/616,500, filed Oct. 6, 2004, each of which applications is incorporated by reference herein in its entirety.
- The present invention relates to metabolically activated sulfonyl hydrazine prodrugs (SHPs) exhibiting anti-tumor activity in mammals. Methods of treating neoplasia, especially including cancer are additional aspects of the present invention.
- Eradication of solid tumors requires strategies that address the viable populations of malignant cells within hypoxic regions of such tumors. An insufficient and poorly organized vasculature, a major characteristic of rapidly growing tumor masses, results in poor oxygenation, high interstitial pressure, and a population of cells that are hypoxic, quiescent or slowly cycling, and distal to the blood supply, thus inadequate vascularization in solid tumors results in low oxygen and being difficult to reach with cytotoxic levels of drugs (Hockel, et al. Cancer Res. 1991, 51: 6098). Radiotherapy is thus ineffective in these areas as the radiation fails to generate sufficient oxygen radicals to result in cytotoxicity (Brizel, et al. Radiother Oncol. 1999, 53: 113). Moreover, the activity of cytotoxic drugs is also attenuated. Thus cells from these regions are frequently responsible for the re-establishment of disease. After treatment with oxygen-dependent cytotoxins such as x-irradiation, which generates oxygen radicals that damage cellular DNA, and conventional chemotherapeutics that target the well-oxygenated, rapidly growing portion of the tumor mass, the resistant hypoxic cell fraction can repopulate the tumor (Stratford, et al. Anticancer Drug Des. 1998, 13: 519). Moreover, hypoxic cells are subjected to an environment that enhances the selection of mutations which cause the progression of the neoplasm towards an increasingly aggressive phenotype. For example, hypoxia selects for cells deficient in p53-mediated apoptosis, enhances mutation rates, upregulates genes involved in drug resistance, angiogenesis, and tumor invasiveness (including HIF-1α), and thus is associated with a more metastatic phenotype (Ashur-Fabian, et al. Pro Natl Acd Sci USA. 2004, 101: 12236).
- Prodrugs that act as hypoxia-selective cytotoxins generally must be substrates for one electron reductases such as NADPH:cytochrome (P450) reductase. The one-electron reduced prodrug radical, in the presence of oxygen, redox cycles back to the parent prodrug, preventing progression of the activation cascade and release of the cytotoxic, DNA damaging species. Under hypoxic conditions, further reduction of the radical anions alters the chemistry of the prodrug to allow release of the cytotoxic species (Yang, et al. Cancer Res. 2003, 63: 1520). Nitroaromatic and nitroheterocyclic compounds readily undergo one electron reduction to nitro radical anions (Korbelik, et al. Mutal Res, 1980, 78: 201). These molecules react rapidly with oxygen to regenerate the parental molecule. However in the absence of oxygen they are reduced further to generate hydroxylamine derivatives and then final aniline forms. While the nitro group is highly electron withdrawing, the hydroxylamine group is strongly electron donating. This results in a major change in the chemistry of the aromatic or heterocyclic ring, triggering the activation cascade and the release of parent drug.
- As alkylating agents, a novel series of 1,2-bis(sulfonyl)hydrazine prodrugs (SHPs) with the ability to generate active chloroethylating species had been developed recently (Sartorelli, et al. U.S. Pat. No. 6,040,338, 2000; U.S. Pat. No. 5,637,619, 1997; U.S. Pat. No. 5,256,820, 1993; U.S. Pat. No. 5,214,068, 1993; U.S. Pat. No. 5,101,072, 1992; U.S. Pat. No. 4,849,563, 1989; and U.S. Pat. No. 4,684,747, 1987). The anti-tumor activity has been suggested to result from chloroethylating and subsequent cross-linking of DNA (Shealy, et al., J Med Chem. 1984, 27: 664).
- 1,2-Bis(methylsulfonyl)-2-(2-chloroethyl)-hydrazine carboxylic acid 1-(4-nitrophenyl)ethyl ester (KS119), the current lead compound in the SHP series, requires enzymatic nitro-reduction to generate the alkylating species 90CE, as demonstrated in
FIG. 1 . Thus, KS119 takes advantage of the hypoxic, reductive environment of solid tumors, thus creating an exploitable difference between cells in normal, well oxygenated tissues and hypoxic neoplastic cells (Shyam, et al. J Med Chem. 1999, 42: 941; and Seow, et al. Proc Natl Acad Sci USA. 2005, 102: 9282). - However, KS119 is rather insoluble in aqueous solution, even it has not sufficient solubility (<5 mg/mL) in co-solvent system like polyethylene glycol (PEG) and ethanol in order to meet clinical requirements of this drug. Therefore, our aim was to synthesize analogs of KS119 that (a) were capable of improving its water-solubility and stability in aqueous solution at
pH 3 to 8; (b) were capable of forming chloroethylating species; and (c) were capable of maintaining hypoxia-selective activation. - Turning to the present invention, we believe that water-soluble compounds according to the present invention satisfy the above conditions. An example of such an SHP (KS119W) would be the phosphate-containing analog of KS119 shown in
FIG. 2 for the following reasons: -
- (a) In general, a phosphate-bearing analog, including its salt form should have good water-solubility and stability at neutral pH;
- (b) The bioconversion of compounds according to the present invention proceeds via alkaline phosphatase (AP) cleavage of the oxygen-phosphorous bond to form the phenol intermediate, as shown in
FIG. 2 . - (c) The bioconversion of the 2-nitrophenol intermediate is selectively activated under conditions of hypoxia to generate a hydroxylamine derivative or aniline form.
- (d) The above intermediate of the amino analogs subsequently undergo fragmentation resulting in the formation of chloroethylating species (90CE). Release of 90CE would only occur on reduction of the nitro group under conditions of hypoxia.
- (e) Compounds of the present invention are considered as prodrugs of 90CE that has been identified as an alkylating agent against a broad anticancer spectrum of neoplastic disease states, including, for example, numerous solid tumors.
- In one aspect of the invention, an object of the present invention is to provide compounds, pharmaceutical compositions and methods for the treatments of neoplasia, including animal and human cancer.
- In another aspect of the invention, an object of the present invention is to provide methods of treating neoplasia utilizing compositions that exhibit favorable anti-cancer characteristics in hypoxia conditions and enhanced characteristics of activity, pharmacokinetics, bioavailability and reduced toxicity.
- It is yet another object of the invention to provide compositions and methods for the treatment of cancers which are resistant to treatment with traditional chemotherapeutic agents, and for treatment of cancers by combination with other anticancer agents or with phototheraphy or radiotherapy.
- One or more of these and/or other objects of the invention may be readily gleaned from the description of the invention that follows.
- The present invention is directed to compounds according to structures I or II:
- Where R is C1-10 alkyl, or C1-10 haloalkyl;
R′ or R″ is C1-10 alkyl, or C5-20 aryl or heteroaryl;
R1 is H; C1-10 alkyl, C1-10 alkoxyl; - R(P) is a phosphate-bearing alkyl group, for example, R(P) is Y′OPO(OH)2 where Y is (CH2)n, O(CH2)n, NH(CH2)n, NR(CH2)n, n is 1-5; Y is aryl or heteroaryl;
Ar(N) is a nitro-containing aryl group, for example, - where A is CH, CR, or N; and B is CH═CH, O, S, NH, or NR; and
Ar(NP) is a phosphate-bearing and nitro-containing aryl group, for examples, - where A is CH, CR, or N; and B is CH═CH, O, S, NH, or NR; and
Y is (CH2)n, O(CH2)n, NH(CH2)n, NR(CH2)n, OCOO(CH2)n, NHCOO(CH2)n;
n is 1-5. - The present invention is also directed to compounds according to formulas I, II, III and IV
- Where R═CO1-10 alkyl, or C1-10 haloalkyl (preferably containing no more than 5 halogen groups, preferably 2-chloroethyl);
R′ and R″ are independently C1-10 alkyl, or C5-20 aryl or heteroaryl (preferably methyl);
R1 is H, C1-10 alkyl, C1-10 alkoxyl, C5-20 aryl or heteroaryl or C5-20 aroxyl or heteroaroxyl (preferably methyl and ethyl);
X is O, NH, or NR (preferably O);
Y is (CH2)n, O(CH2)n, NH(CH2)n, NR(CH2)n, OCOO(CH2)n, NHCOO(CH2)n; n=1, 2, 3, 4 or 5 (preferably n=2 and 3); or Y=aryl or heteroaryl (preferably para-phenyl);
A=CH, or N (preferably CH); and
B=CH═CH, O, S, NH, or NR (preferably CH═CH); or pharmaceutically acceptable salts, solvates, polymorphs or metabolites, thereof. - In preferred aspects, the present invention relates to compounds according to structure IA:
- Where R=C1-10 alkyl, or C1-10 haloalkyl; R1=H; C1-10 alkyl, C1-10 alkoxyl; X=O, NH, or NR; A=CH, CR, or N; and B=CH═CH, O, S, NH, or NR.
- The aforementioned compounds include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts, solvates, polymorphs and metabolites from all stages.
- Preferred agents in the compounds are 4-nitrophenyl series of compound structure IA where A is CH; B is CH═CH; X is O; R is CH2CH2Cl; R1 is CH3; a phosphate group can be free acid or salt (preferably Tris). In particularly preferred aspects of the hydrazine-carboxylic acid 1-(4-nitrophenyl)ethyl ester (KS119W), R-configuration structure (VNP40541) of the enantiomers is more preferable.
- Compounds according to the present invention and especially the preferred compositions according to the present invention, as set forth above, are extremely effective compounds for the treatment of neoplasia. They also exhibit at least one or more improvements such as an enhanced anti-neoplasia activity, a reduced toxicity, a higher water-solubility, or a more favorable pharmacokinetic profile compared to KS119.
- These compounds according to the present invention are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy.
- Compounds according to the present invention may be used in pharmaceutical compositions for the treatment of cancer, as well as a number of other conditions and/or disease states. Examples according to the present invention may be as intermediates in the synthesis of other compounds exhibiting biological activity as well as standards for determining the biological activity of the present compounds. In some applications, the present compounds may be used for treating microbial infections, especially including viral, bacterial, and fungal infections. These compounds comprise an effective amount of any one or more of the compounds disclosed hereinabove, optionally in combination with a pharmaceutically acceptable additive, carrier, or excipient.
- A further aspect of the present invention relates to the treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound as described hereinabove, optionally in combination with a pharmaceutically acceptable additive, carrier, or excipient. The present invention also relates to methods for treating neoplasia in mammals comprising administering an effective amount of a compound as described hereinabove to a patient suffering from cancer. The treatment of solid malignant tumors, leukemia, and lymphomas comprising administering to a patient an anti-tumor effective amount of one or more these agents is a preferred embodiment of the present invention. The treatment of various other related disease states may also be effected using the compounds of the present invention. This method may also be used in comparison tests such as assays for determining the activities of related analogs as well as for determining the susceptibility of a patient's cancer to one or more of the compounds according to the present invention.
-
FIG. 1 is a representation of a suggested mechanism of activation of KS119. -
FIG. 2 is representations of a sample (KS119W) of the chemical embodiments and their proposed mechanism of activation in hypoxia conditions according to the present invention. -
FIGS. 3 and 4 are representations of chemical schemes for synthesizing compounds according to the present invention. -
FIGS. 5 to 7 are representations of experimental results which are presented in the present application related to the selective activation in hypoxic conditions according to the present invention. -
FIGS. 8 to 9 are representations of experimental results which are presented in the present application related to the efficacy and toxicity of certain preferred embodiments according to the present invention. - The following terms shall be used throughout the specification to describe the present invention.
- The term “patient” is used throughout the specification to describe an animal, including a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal.
- The term “effective amount” is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which may be used to produce a favorable change in the disease or condition treated, Whether that change is a remission, a decrease in growth or size of cancer or a tumor, a favorable physiological result, a reduction in the growth or elaboration of a microbe, or the like, depending upon the disease or condition treated.
- The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein. Within its use in context, the term generally refers to a single compound, but may also refer to stereoisomers and/or optical isomers (including racemic mixtures), well as specific enantiomers, or enantiomerically enriched mixtures of disclosed compounds, as well as tautomers.
- The term “neoplasia” is used throughout the specification to describe the pathological process that results in the formation and growth of a neoplasm, i.e., an abnormal tissue that grows by cellular proliferation more rapidly than normal tissue and continues to grow after the stimuli that initiated the new growth cease. Neoplasia could be a distinct mass of tissue that may be benign (benign tumor) or malignant (carcinoma). As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic, and solid tumors. The term “cancer” and the term “tumor” used in this application is interchangeable with the term “neoplasia”.
- Cancer which may be treated using compositions according to the present invention include, for example, stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, prostate, testis, bladder, renal, skin, brain/CNS, head and neck, throat, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, esophagus, larynx, melanoma, kidney and lymphoma, among others. The treatment of tumors comprising administering to a patient an anti-tumor effective amount of one or more these agents is a preferred embodiment of the present invention.
- The term “alkyl” is used throughout the specification to describe a hydrocarbon radical containing between one to seven carbon units. Alkyl groups for use in the present invention include linear or branched-chain groups, such as preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, cylcohexyl, methylcyclopropyl and methylcyclohexyl.
- The term “aryl” refers to a substituted or unsubstituted monovalent aromatic radical having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). The term “aroxyl” refers to an aryl group to which is bonded an alkoxy group, preferably through which another group is bonded (e.g. a sulfonyl group).
- The term “heteroaryl” refers to heterocyclic aromatic ring groups having one or more nitrogen, oxygen, or sulfur atoms in the ring, such as imidazolyl, furyl, pyrrolyl, pyridyl, thienyl and indolyl. The term “heteroaroxyl” refers to a heteroaryl group to which is bonded an alkoxy group, preferably through which another group is bonded (e.g. a sulfonyl group).
- The term “salt” is used throughout the specification to describe any salt consistent with the use of the compounds according to the present invention. In the case where the compounds are used in pharmaceutical indications, including the treatment of cancer, the term “salt” shall mean a pharmaceutically acceptable salt, consistent with the use of the compounds as pharmaceutical agents.
- In preferred aspects, the present invention relates to compounds according to the structure (IA):
- Where R=C1-10 alkyl, or C1-10 haloalkyl; R1=H; C1-10 alkyl, C1-10 alkoxyl; X=O, NH, or NR; A=CH, CR, or N; and B=CH═CH, O, S, NH, or NR.
- Compounds according to the present invention include enantiomers, stereoisomers and tautomers thereof, as well as pharmaceutically acceptable salts, solvates, polymorphs and metabolites from all stages.
- The present compounds represent prodrug forms of intermediates that are believed to exhibit their activity of DNA cross-linking through chloroethylation or methylation mechanisms. The rationale for the new prodrug design was that enzyme-activated prodrugs could be converted into active alkylating species (90CE) via a sequence of enzyme activations and prompt fragmentation. De-phosphorylation can be accomplished by alkaline phosphatase (AP) enzyme activation to give intermediate 1; nitro-reduction can be catalyzed by nitro reductase (NR) enzyme to form intermediate 2; and subsequent benzyl group fragmentation generated 90CE, as shown in
FIG. 2 . - The compounds according to the present invention are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototherapy or radiotherapy.
- The compounds according to the present invention are primarily useful for their anti-neoplastic activity, including their activity against solid tumors. In addition, these compositions may also find use as intermediates in the chemical synthesis of other useful anti-neoplastic agents that are, in turn, useful as therapeutic agents or for other purposes, including use as standards for assays.
- Preferred agents in the compounds are 4-nitrophenyl series where A is CH; B is CH═CH; X is O; R is CH2CH2Cl; R1 is CH3; a phosphate group can be the free acid or a salt. In particularly preferred aspects of the hydrazine-carboxylic acid 1-(4-nitrophenyl)ethyl ester (KS119W), the R-configuration structure (VNP40541) of the enantiomers is more preferably than S-configuration structure (VNP40551).
- Compounds according to the present invention are synthesized by the adaptation of techniques that are well known in the art and are derived from 90CE. The synthesis of 90CE was published in two-step approach from 2-hydroxyethyl-hydrazine (See, Shyam, et al. J Med Chem. 1993, 36: 3496, also J Med Chem. 1996, 39: 796). Analogs of compounds specifically described herein may be readily synthesized using the above general techniques and analogous synthetic methods available in the art without engaging in undue experimentation.
- By way of specific example, as demonstrated in
FIG. 3 , 1,2-bis(methylsulfonyl)-2-(substituted)hydrazine-carbonates of Compounds I (5, R=CH2CH2Cl) are synthesized respectively by reacting an appropriate α-alkyl 4-nitroarylmethyl alcohol or N-alkyl-N-(4-nitroarylmethyl)amine (3 or 4, where R1 is —CH3; R* is a protecting group of the phosphate group, such as diethyl or di-tert-butyl or 2-trimethylsilylethyl (TMSE) group with phosgene (20% toluene solution) or its equivalents, such as triphosgene or trichloromethyl chloroformate (see, Majer, et al. J Org Chem. 1994, 59: 1937; and Pridgen, et al. J Org Chem. 1989, 54: 3231), and a further condensation in situ with 90CE. This coupling reaction can be achieved in high yield while using N,N-diisopropylethylamine (DIPEA) as a base and keeping the reaction at 0° C. in dry acetonitrile-dichloromethane solvent overnight. The hydrazine-amides of Compounds I (6, R=CH2CH2Cl) can be synthesized by similar phosgene-coupling pathway (Lin, et al. U.S. Pat. No. 6,855,695, 2005). - Following de-dialkyl-protection of 5 or 6 can readily convert to the corresponding phosphate free acid (7 or 8). For examples, de-protection of diethyl ester can be treated with trimethylsilyl bromide (TMSBr) (Matulic-Adamic, et al. J Org Chem. 1995, 60: 2563), de-protection of di-tert-butyl esters can be treated with trifluoroacetic acid (TFA) (Durgam, et al. J Med Chem. 2005, 48: 4919), and de-protection of di-TMSE esters cab be treated with TFA also (Dolye, et al. U.S. Pat. No. 6,458,816, 2002) or with BF3-Et2O (Jansson, et al. Tetrahedron Lett. 1986, 27: 753). The phosphate
free acid form - As shown in
FIG. 4 , the α-alkyl 4-nitroarylmethyl alcohol (3) can be synthesized from the corresponding alkyl aryl ketone (9), employing an enantiomerically selective reduction. A reducing catalyst can be selected from commercially available reagents such as 2-Me-CBS-oxazaborolidine/BH3 (Mathre, et al. J Org Chem. 1993, 58: 2880) or diisopinocampheylchloroborane (Brown, et al. J Am Chem Soc. 1988, 110: 1539) or Alpine-borane (Ramachadran, et al. Tetrahedron: Asymm. 5: 1061). Asymmetric hydrogenation of the ketone also can be used (Ohkuma, et al. J Am Chem Soc. 1998, 120: 13529; and Baar, et al. J Am Chem Soc. 2004, 126: 8216). - The N-alkyl-N-(para-nitroarylmethyl)amine (4) can be prepared from the corresponding alkyl aryl ketone. For example, using sodium borohydride as a reducing agent, the reductive amination of a respective 12 with methylamine affords the corresponding N-arylmethyl-N-methylamine (4).
- The hydroxyl group on the aryl ring can be reacted with chlorophosphate to give their corresponding di-alkyl-protected phosphonoxy-aryl compound (i.e. 3 or 12) under mild conditions. Selective phosphorylation of phenols was achieved with phosphite, carbon tetrachloride, DIPEA and catalytic amounts of 4-dimethylaminopyridine (DMAP) (Silverberg, et al. Tetrahedron Lett. 1996, 37: 771). It is common that the phosphorylation may complete prior to asymmetric reduction or the phosphorylation may follow reductive amination. The synthesis of the appropriate 4-nitroaryl compound (9 or 11) for use in these reaction schemes is well known in the art and uses standard chemical techniques such as nitration and acrylation.
- After synthesis, the crude product generally is purified by reversed phase column chromatography and lyophylization. Treating KS119W (or VNP40541) with an appropriate alkaline solution or amine can readily provide a respective water-soluble salt such as sodium salt, tris(hydroxymethyl)-aminomethane (TRIS) salt, triethanolamine salt, triethylamine salt, or lutidine salt. Modification of the disclosed chemical synthetic methods may be readily made by those of ordinary skill in the art in order to provide alternative synthetic pathways to the present compounds.
- Pharmaceutical compositions based upon the present novel chemical compounds comprise the above-described compounds in a therapeutically effective amount for the treatment of a condition or disease such as cancer, optionally in combination with a pharmaceutically acceptable additive, carrier or excipient.
- Certain of the compounds, in pharmaceutical dosage form, may be used as prophylactic agents for preventing a disease or condition from manifesting itself.
- The present compounds or their derivatives can be provided in the form of pharmaceutically acceptable salts. As used therein, the term pharmaceutically acceptable salts refers to appropriate salts of the active compounds according to the present invention which retain the desired biological activity of the parent compound. Nonlimiting examples of such salts include the sodium and potassium salts of phosphate, among others such as TRIS salt, triethanolamine salt, triethylamine salt, lutidine salt, or other pharmaceutically acceptable salts known in the art. Modifications of the active compound can affect the solubility, pharmacokinetic parameters and rate of metabolism of the active species, thus providing control over the delivery of the active species. Further, the modifications can affect the anticancer activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivatives and testing the anticancer activity according to known methods well within the routineer's skill in the art.
- The compounds of this invention may be incorporated into formulations for all routes of administration including for example, parenteral and oral, including intravenous, intramuscular, intraperitoneal, intrabuccal, transdermal and in suppository form. Paranteral administration and in particular, intravenous or intramuscular administration is preferred.
- Pharmaceutical compositions based upon these novel chemical compounds comprise the above-described compounds in a therapeutically effective amount for treating cancer and other diseases and conditions which have been described herein, optionally in combination with a pharmaceutically acceptable additive, carrier and/or excipient. One of ordinary skill in the art will recognize that a therapeutically effective amount of one of more compounds according to the present invention will vary with the infection or condition to be treated, its severity, the treatment regiment to be employed, the pharmacokinetics of the agent used, as well as the patient (animal or human) treated.
- In the pharmaceutical aspect according to the present invention, the compound according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier. In general, it is preferable to administer the pharmaceutical composition parenterally and in particular, in intravenously or intramuscular dosage form, but a number of formulations may be administered via other parenteral routes, such as transdermal, buccal, subcutaneous, suppository or other route, including via an oral route of administration. Intravenous and intramuscular formulations are preferably administered in sterile saline. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (such as salt formulation, etc.) which are well within the ordinary skill in the art. It is also well within the routineer's skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect to the patient.
- The routineer will take advantage of favorable pharmacokinetic parameters of the prodrug forms of the present invention, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effects of the compound.
- Administration of the active compound may range from continuous (intravenous drip), including bolus administration, intravenously or intramuscularly even less frequently than once a day to several administrations per day and may include topical, parenteral, intravenous, intramuscular, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal and suppository administration, among other routes of administration, including, in certain instances, oral administration.
- To prepare the pharmaceutical compositions according to the present invention, a therapeutically effective amount of one or more of the compounds according to the present invention is preferably intimately admixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques to produce a dose. A carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous or intramuscular. In preparing pharmaceutical compositions in the appropriate dosage form, any of the usual pharmaceutical media may be used. For parenteral formulations, the carrier may comprise sterile water or aqueous sodium chloride solution or
dextrose 5% in water (D5W) in combination with other ingredients that aid dispersion, such as ethanol and other pharmaceutically acceptable solvents, including DMSO, among others. Of course, where solutions are to be used and maintained as sterile, the compositions and carriers must also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. - Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can be included the following components: a sterile diluent such as water for injection, saline solution, D5W solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as TRIS, acetates, citrates, phosphates, histidine or sodium bicarbonate solution; and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers include, for example, physiological saline or phosphate buffered saline (PBS).
- In preparing pharmaceutical compositions in oral dosage form, any one or more of the usual pharmaceutical media may be used. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives including starches, sugar carriers, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used. If desired, the tablets or capsules may be enteric coated or sustained release by standard techniques.
- In one embodiment, the active compounds may be prepared with a carrier that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery system. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polyactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
- Liposomal suspensions may also be pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared by dissolving appropriate lipid(s) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. Other methods of preparation well known by those of ordinary skill may be used in this aspect of the present invention.
- The present compounds may be used to treat animals, and in particular, mammals, including humans, as patients. Thus, humans, equines, canines, bovines and other animals, and in particular, mammals, suffering from tumors, and in particular, cancer, or other diseases as described herein, can be treated by administering to the patient an effective amount of one or more of the compounds according to the present invention or its derivative or a pharmaceutically acceptable salt thereof optionally in a pharmaceutically acceptable carrier or diluent, either alone, or in combination with other known pharmaceutical agents, depending upon the disease to be treated. This treatment can also be administered in conjunction with other conventional cancer therapies, such as radiation treatment or surgery.
- The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
- The present compounds are prodrug forms of reactive intermediates. In certain pharmaceutical dosage forms, the present compounds may be modified to other prodrug forms to take advantage of a particular route of administration of the active compounds. One of ordinary skill in the art will recognize how to readily modify the present compounds to alternative prodrug forms to facilitate delivery of active compounds to a targeted site within the patient. The individual of ordinary skill also will take advantage of favorable pharmacokinetic parameters of the prodrug forms, where applicable, in delivering the present compounds to a targeted site within the patient to maximize the intended anti-neoplastic effect of the compound.
- The amount of compound included within the therapeutically active formulations according to the present invention is an effective amount for treating cancer. In general, a therapeutically effective amount of the compound according to the present invention in dosage form usually ranges from less than about 0.05 mg/kg to about 500 mg/kg of body weight of the patient to be treated, or considerably more, depending upon the compound used, the tumor type to be treated, the ability of the active compound to localize in the tissue to be treated, the route of administration and the pharmacokinetics of the compound in the patient. In the case of treating cancer, the compound is preferably administered in amounts ranging from about 0.05 mg/kg to about 250 mg/kg or more at one time. This dosage range generally produces effective blood level concentrations of active compound ranging from about 0.01 to about 500 micrograms per ml of blood in the patient to be treated. The duration of treatment may be for one or more days or may last for several months or considerably longer (years) depending upon the disease state treated. In a more preferred embodiment, the compound is given to the patient at doses of 0.1 mg/kg to 100 mg/kg, twice per day to once per 14 days, for the duration of 1 week to 52 weeks.
- The concentration of active compound in the patient will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage given to the patient will be also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular patient, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
- The active compound according to the present invention can be also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as other anticancer agents, and in certain instances depending upon the desired therapy or target, antibiotics, antifungals, antiflammatories, or antiviral compounds, among other agents.
- These compounds according to the present invention are preferentially activated in hypoxic tumors and can be given either alone, or in combination with other anticancer agents or with phototheraphy or radiotherapy.
- Compounds according to the present invention may be administered alone or in combination with other agents, especially including other compounds of the present invention. In these aspects according to the present invention, an effective amount of one or more of the compounds according to the present invention is co-administered along with an effective amount of at lease one additional anti-neoplastic/anticancer agent such as antimetabolites, etoposide, doxorubicin, taxol, vincristine, cytoxan (cyclophosphamide) or mitomycin C, among numerous others, including topoisomerase I and topoisomerase II inhibitors, such as adriamycin, topotecan, campothecin and irinotecan, other agent such as gemcitabine and agents based upon campothecin and cis-platin. In theory, the present compounds, which act by a mechanism to damage DNA, will act synergistically with compounds that act by a mechanism to reduce or prevent DNA repair. Thus, the present compounds may be advantageously combined with any compound which acts by a mechanism to reduce or prevent DNA repair, especially including inhibitors of enzymes which catalyze DNA repair, such as inhibitors of ribonucleotide reductase (RR) and inhibitors of O6-alkylguanine-DNA alkyltransferase (AGT). By “co-administer” it is meant that the present compounds are administered to a patient such that the present compounds as well as the co-administered compound may be found in the patient's bloodstream at the same time, regardless of when the compounds are actually administered, including simultaneously. In many instances, the co-administration of the present compounds with traditional anticancer agents produces a synergistic (i.e., more than additive) result which is unexpected. In another embodiment, the compounds according to the present invention are given either simultaneously or sequentially with antibodies (conjugated or unconjugated), viruses, or bacteria. The antibodies, viruses, or bacteria could carry enzymes or gene encoding enzymes that activate the compounds described in the present invention. The enzymes include but not limit to NR.
- While not being limited by way of theory, it is believed that the compounds according to the present invention primarily induce their therapeutic effect in treating malignant tumors by functional as hypoxia-selective chloroethylating agents.
- Having generally described the invention, reference is now made to the following specific examples that are intended to illustrate preferred and other embodiments and comparisons. The included examples are not to be construed as limiting the scope of this invention as is more broadly set forth above and in the appended claims. Other compounds not specifically presented in the examples section of this application may be readily synthesized following analogous methodologies and/or facile syntheses that are presented and known in the art. One of ordinary skill may readily synthesize all compounds set forth and described without engaging in undue experimentation by simply following the detailed synthetic methodology directly or adapting/modifying such synthetic methodology using techniques well known in the art.
- All reagents were purchased at commercial quality and used without further purification, and solvents were dried and/or distilled prior to use where necessary. All NMR spectra (1H, 13C and 31P) were determined on a Bruker AC300 spectrometer. Chemical shifts are measured in parts per million (ppm) relative to tetramethylsilane. Coupling constants are reported in Hertz (Hz). Flash column chromatography (FCC) was performed with Merck silica gel 60 (230-400 mesh), and reserved phase column chromatography (RPCC) was packed with CAT gel (Water, preparative C-18, 125 Å, 55-105 μm) eluting with milli-Q de-ionized water.
- General Procedure A. To a stirred solution of the appropriately phenolic compound (10.0 mmol) in acetonitrile (15 mL) was added DMAP (1 mmol) and DIPEA (20 mmol) at room temperature. The reaction mixture was cooled to −13° C. A solution of dialkyl chlorophosphate (10 mmol) in acetonitrile (5 mL) was added dropwise to maintain internal temperature at less than −10° C. The reaction mixture was raised to 0° C. and then kept stirring for 2 hours, monitoring reaction completion by TLC. The reaction mixture was concentrated by rotary evaporation, and the oil residue was worked up with dichloromethane and 0.5 M aqueous KHSO4 solution. The organic layer was dried over anhydrous MgSO4, then filtered and concentrated to brown viscous oil. The crude dialkylphosphonoxy-aryl compound could be used without further purification.
- 1-(3-Diethylphosphonoxy-4-notrophenyl)ethyl alcohol (13). Following the general procedure A, R-1-(3-hydroxy-4-nitrophaenyl)ethyl alcohol (18.2 g, 100 mmol) reacted with diethyl chlorophosphate (15.0 mL, 100 mmol), and the desired product 13 (32.0 g, 100%) was obtained.
- 1H NMR (300 MHz, CDCl3) δ 1.36 (t, J=7.1 Hz, 6H), 1.47 (d, J=6.6 Hz, 3H), 3.02 (br s, 1H), 4.25 and 4.27 (q, J=7.1 Hz, 4H), 4.91 (q, J=6.6 Hz, 4H), 7.26-7.31 (m, 1H), 7.55 (s, 1H), 7.90 (dd, J=8.5, 0.8 Hz, 1H).
- 13C NMR (75 MHz, CDCl3) δ 16.1 and 16.2, 25.3, 65.6 and 65.7, 68.8, 119.6, 122.2, 126.0, 140.0, 143.5 and 143.6, 154.4.
- 31P NMR (121 MHz, CDCl3) δ-6.7.
- General Procedure B. A solution of phenolic compound (10 mmol), DIEA (20 mmol) and DMAP (1 mmol) in acetonitrile (20 mL) was placed in −50° C. bath. To the above cold solution was added CCl4 (50 mmol) and dialkyl phosphite (10 mmol). The reaction solution was kept for 2 hours at room temperature. Then solvents were removed by rotary evaporation. The residue oil was worked up with 0.5 M aqueous KHSO4 solution and dichloromethane. After separation, dry over anhydrous MgSO4, evaporation and vacuum dry, the crude dialkylphosphonoxy-aryl compound could be used without further purification.
- 1-(3-Diethylphosphonoxy-4-notrophenyl)ethyl alcohol (13). Following the general procedure B, R-1-(3-hydroxy-4-nitrophaenyl)ethyl alcohol (15.0 g, 82.4 mmol) reacted with diethyl chlorophosphate (10.6 mL, 82.4 mmol), and the desired product 13 (27.1 g, 100%) was obtained.
- General Procedure. To a solution of 4-nitrobenzaldehydes (10 mmol) in anhydrous THF (30 mL) was slowly added Grignard reagent such as methylmagnesium bromide in diethyl ether (25 mmol) at −50° C. over 45 minutes. The temperature of the reaction mixture was maintained below 40° C. during the addition Grignard reagent. The reaction mixture was allowed to warm to room temperature and stirred for 3.5 hours. The reaction mixture was cooled to −10° C., and quenched with 5% hydrochloric acid (25 mL). The reaction mixture was diluted with water (25 mL) and the product was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water to
pH 5, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 25% ethyl acetate in hexanes. After evaporated and dried in vacuum, the α-alkyl 4-notrobenzyl alcohol was obtained. - 1-(3-Hydroxy-4-notrophenyl)ethyl alcohol (14). Following the general procedure, 3-hydroxy-4-nitrobenzaldehyde (90.0 g, 539 mmol) gave the desired product 14 (40.0 g, 41%) as red oil.
- 1H NMR (300 MHz, CDCl3) δ 1.50 (d, J=6.6 Hz, 3H), 2.06 (br s, 1H), 4.93 (q, J=6.3 Hz, 1H), 6.98 (dd, J=8.8, 1.9 Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 10.6 (s, 1H).
- 13C NMR (75 MHz, CDCl3) δ 25.3, 69.5, 116.3, 117.6, 125.5, 155.5, 156.9.
- General Procedure. To a solution of the A solution of chiral (R or S)-2-methyl-CBS-oxazaborolidine (1.0 M solution in toluene, 240 mL) and 1.0 M BH3-THF solution (120 mL) was cooled to −50° C. To the above solution was slowly added a solution of 3′-hydroxy-4′-nitroacetophenone (100 g) in THF/toluene (200 mL/800 mL) and 1.0 M BH3-THF solution (1.0 L) simultaneously over 4 hours, while stirring vigorously. The reaction mixture was kept stirring at −50° C. for 2-3 hours, monitoring reaction completion by HPLC. Then, acetone (200 mL) was dropwise charged into the reactor at −50° C. After stirred at −50° C. for 10 minutes, the reaction mixture was allowed to warm up to ambient temperature and stir for 1.5 hours. Concentrated by rotary evaporation on 45° C. bath, the residue was treated with saturated Na2CO3 aqueous solution (2 L). The mixture was heated at 50° C. for 30 min, and then cooled down to room temperature. Added tert-butylmethylether (TBME, 1 L) and hexanes (1 L), the mixture was stirred at RT for 1 hour and then separated. The aqueous layers were charged concentrated HCl dropwise to adjust
pH 6, while maintaining temperature at 25° C. The mixture was extracted with ethyl acetate (3×2 L), and the organic phases were concentrated. Crude product was afforded as brown oil, and was purified by re-crystallization from hexanes. - R-1-(3-Hydroxy-4-nitrophenyl)ethyl alcohol (15). Following the general procedure, 3-hydroxy-4-nitroacetophenone (100 g, 0.55 mol) gave the desired product 15 (52 g, 51%, 99.3% ee) as yellow solid.
- General Procedure. To a solution of benzaldehyde (10 mmol) in dichloromethane (10 mL) was added 2 N solution of methylamine in THF (20 mmol). The reaction solution was kept at room temperature overnight and the precipitate was filtered. The filtrate was concentrated and dried in vacuum, and the resulting crude oil was dissolved in methanol (50 mL). To the above solution was added NaBH4 (20 mmol) in small portions at 0° C., and the solution was kept stirring continuously for 4 hours. After evaporation, the residue was distributed in water (50 mL) and dichloromethane (50 mL). The aqueous phase was separated and extracted with dichloromethane (50 mL) once. The combined organic phases were dried over anhydrous MgSO4, filtered, concentrated and dried in vacuum. Crude N-benzyl-N-methylamine was pure enough for use without further purification.
- N-(4-Diethylphosphonoxybenzyl)-N-methyl amine (16). Following the general procedure, diethylphosphonoxy-benzaldehyde (29.9 g, 116 mmol) gave 15 (22.3 g, 71%) as yellow oil.
- 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 4.21 (m, 4H), 3.73 (s, 2H), 2.42 (s, 3H) and 1.34 (t, J=6.9 Hz, 6H).
- 13C NMR (75 MHz, CDCl3) δ 149.4 (d), 135.6, 129.3, 119.5 (d), 64.2 (d), 54.5, 35.1 and 15.7 (d).
- 31P NMR (121 MHz, CDCl3) δ-5.5.
- General Procedure A. To a stirred solution of 90CE (10 mmol) in acetonitrile (40 mL) was added phosgene (20% in toluene, 10 mmol) and DIPEA (10 mmol). Kept at 0° C. for 20 minutes, to the solution was added N-(dialkylphosphonoxy-benzyl)-N-methylamine (10 mmol) and DIEA (10 mmol). The final reaction solution was kept at 5° C. overnight. After evaporation, the residue was worked up with water and dichloromethane. The combined organic phases were dried over anhydrous MgSO4, filtered and evaporated. The corresponding protected phosphate was obtained as oil.
- General Procedure B. DIPEA (12 mmol) was added to a 20% solution of phosgene in toluene (30 mmol) at 0° C. A solution of 1-(3-diethylphosphonoxy-4-notrophenyl)ethyl alcohol (10 mmol) in acetonitrile (15 mL) was added slowly. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in acetonitrile (15 mL), DIPEA (15 mmol) and 90CE (10 mmol) was added while cooling below 20° C. The mixture was stirred at room temperature for 2 hours. After evaporated solvents, the residue was worked up with water and dichloromethane. The organic phases were washed with 1% HCl solution (35 mL), dried over anhydrous MgSO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluting with 40-50% ethyl acetate in hexanes), concentrated and dried under high vacuum to give the corresponding protected phosphate was obtained as oil.
- 1,2-Bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine-carboxylic acid 1-(3-diethylphosphonoxy-4-nitrophenyl)ethyl ester (16). Following the general procedure B, 1-(3-diethylphosphonoxy-4-notrophenyl)ethyl alcohol (114.3 g, 358 mmol) yielded 16 (151.2 g, 71%).
- 1H NMR (300 MHz, CDCl3) δ 1.30-1.42 (m, 6H), 1.69 and 1.70 (d, J=6.6 Hz, 3H), 3.16 and 3.21 (s, 3H), 3.46 and 3.47 (s, 3H), 3.65-3.75 (m, 2H), 3.80-3.92 (m, 1H), 4.00-4.10 (m, 1H), 4.20-4.35 (m, 4H), 5.95 and 5.96 (q, J=6.6 Hz, 1H), 7.34 and 7.36 (d, J=8.2 Hz, 1H), 7.60 and 7.65 (s, 1H), 7.96 and 7.97 (d, J=8.5 Hz, 1H).
- 31P NMR (121 MHz, CDCl3) δ-6.7.
- General Procedure. A solution of the respective diethyl-protected phosphate (10 mmol) in dichloromethane (60 mL) was treated with excess TMSBr (100 mmol) at 5° C. overnight. Evaporated and dried in vacuum, the crude phosphate free acid was obtained as a glassy solid. To the crude compound (10 mmol) was added water (about 30 mL). The suspension was stirred for 2 hours at ambient temperature, and then a minimum amount of water was added to complete dissolution. The aqueous solution was purified by RPCC with 10% acetonitrile in de-ionized water. The fractions were monitored by UV or 31P NMR and combined. After lyophylization, the purified phosphate free acid was obtained as a white or off-white powder.
- 1,2-Bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine-carboxylic acid 1-(3-dihydrogenphosphonoxy-4-nitrophenyl)ethyl ester (17). Following the general procedure, 1,2-bis(methylsulfonyl)-2-(2-chloroethyl)hydrazine-carboxylic acid 1-(3-diethylphosphonoxy-4-nitrophenyl)ethyl ester (73.9 g, 124 mmol) was de-protected and yielded 17 (52.8 g, 80%) as a white powder.
- 1H NMR (300 MHz, DMSO-d6) δ 1.58 and 1.59 (d, J=6.1 Hz, 3H), 3.25 and 3.29 (s, 3H), 3.54 and 3.55 (s, 3H), 3.65-3.83 (m, 2H), 3.85-4.00 (m, 2H), 5.97 and 5.99 (q, J=6.1 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.60 and 7.65 (s, 1H), 7.96 and 7.97 (d, J=8.4 Hz, 1H).
- 31P NMR (121 MHz, DMSO-d6) δ-5.6.
- General Procedure. A solution of the KS119W (200 mg) and a base as upon stoichiometry is dissolved in water (2.0 mL) and stirred at 20° C. for 1 hour; the solution is lyophilized for 20 hours; and the resulting solid is then analyzed by NMR and HPLC.
- Monosodium salt of KS119W (18). A 5% NaHCO3 solution (210 mL) was slowly added to a stirred solution of KS119W (66.1 g, 122.4 mmol) in methanol (70 mL) and water (400 mL) until a pH of 4.0 to 4.5 is obtained. The reaction mixture was washed with dichloromethane (2×500 mL) followed by diethyl ether (200 mL) to remove the decomposition impurity. The aqueous portion was concentrated below a temperature of 30° C. The residue was dissolved in acetone (200 mL) and slowly added to a cold (10° C.) diethyl ether (2.0 L) with efficient stirring. The resulting slurry was stirred at 0° C. for 1 hour, filtered, washed with diethyl ether (200 mL) and then hexanes (200 mL) and dried to give a light yellow solid 18 (109.7 g, 86%).
- 1H NMR (300 MHz, D2O) δ 1.37 and 1.38 (d, J=6.6 Hz, 3H), 2.91 and 3.00 (s, 3H), 3.24 and 3.25 (s, 3H), 3.30-3.50 (m, 2H), 3.55-3.75 (m, 2H), 5.69 and 5.70 (q, J=6.6 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.24 and 7.25 (s, 1H), 7.65 (d, J=8.4 Hz, 1H).
- 13C NMR (75 MHz, DMSO-d6) δ 22.5, 41.2, 41.3, 41.8, 41.9, 42.5, 42.6, 52.9, 53.1, 77.1, 77.2, 118.6, 118.8, 120.0, 120.2, 124.9, 141.5, 145.8, 145.9, 147.7, 147.8, 151.4.
- 31P NMR (121 MHz, DMSO-d6) δ-4.09.
- The solubility of KS119W (or VNP40541) was determined visually by adding incremental quantities of the drug to 2.0 mL of water in a glass vial. The vials were shaken at room temperature in a Glas Col rotary apparatus until the drug dissolved entirely. Additional fixed quantities of drug were added and the vials shaken until complete dissolution. This process was continued until no more drug dissolved. The solubility of KS119W (or VNP40541) was found to be more than 400 mg/mL. Aqueous solutions of VNP40541 (or VNP40541) were light yellow.
- The solubility of the newly synthesized KS119W salts was similarly determined by adding an excess amount of the drug in a glass vial containing 2.0 mL of water. The vials were shaken in a Glas Col rotary apparatus at room temperature for 24 hours. The suspension containing undissolved drug was centrifuged; the supernatant was carefully separated and analyzed by HPLC for drug concentration. Water-solubility (mg/mL) of the KS119W salts from Mg(OH)2, NaOH, KOH, BET, and TRIS is detected: 51.2, 67.2, 71.0, 58.7, and 70.5, respectively.
- The stabilities of VNP40541 were investigated. The sample (20 mg/mL) was dissolved in 20 mM citric acid and titrated to pH 2.0, pH 3.0, pH 4.0, pH 5.0, pH 6.0, and pH 7.0. To control for buffer catalysis, the drug was also titrated to pH 2.0, pH 5.0, and pH 6.0 in the absence of citrate. The samples were stored at 40° C. for 3 hours, 24 hours, and 3 days, and at room temperature for 24 hours, 3 days. Upon completion of each time point, samples were placed in a freezer at −15° C. Control samples of each preparation were also stored in the freezer. Each sample was analyzed by HPLC repetitively, at various time points, to determine the concentration of the respective drug. As demonstrated in Table 1 below, the results indicate clearly that significant degradation was observed after 24 hours at 40° C. The presence of citrate did not appear to affect degradation significantly.
-
TABLE 1 Short term stability of VNP40541 as a function of pH and presence of citrate buffer. HPLC assay results are expressed relative to control samples stored at −15° C. 24 hrs Room Temp. 3 hrs 40° C.24 hrs 40° C.Final Final Final pH Citrate pH Assay pH Assay pH Assay 2.0 20 mM 2.00 99.3% 2.00 98.8% 2.02 92.3% 2.0 None 2.04 99.4% 2.04 98.9% 2.06 91.7% 3.0 20 mM 3.07 99.3% 3.07 98.9% 3.06 91.3% 4.0 20 mM 4.08 100.1% 4.07 99.8% 4.09 92.2% 5.0 20 mM 5.03 99.4% 5.04 98.8% 5.06 92.2% 5.0 None 5.12 99.7% 5.14 99.4% 5.10 92.5% 6.0 20 mM 6.17 98.6% 6.16 99.0% 6.10 93.8% 6.0 None 6.09 100.0% 6.10 99.3% 6.01 93.8% 7.0 20 mM 7.07 99.7% 7.06 99.6% 6.96 94.0% - EMT6 or CHO (parental or human cytochrome P-450 reductase transfected) cells, seeded in glass milk dilution bottles, were gassed for 2 hours through a rubber septum fitted with 13 gauge (inflow) and 18 gauge (outflow) needles with a mixture of 5% CO2, oxygen at various concentrations, with the balance of the mixture made up of nitrogen, to establish various hypoxic conditions. Drugs were then injected without disrupting hypoxia. After two hours, cells were collected and plated in a clonogenic assay to determine the surviving fraction, compared to untreated controls.
- For in vitro analysis, KS119W must be converted to KS119OH (1) in an AP-catalyzed reaction shown above in
FIG. 2 , as the phosphorylated parent drug cannot cross cell membranes. KS119OH is then used in all subsequent in vitro studies shown in this section. - EMT6 murine mammary carcinoma cells were exposed to graded concentrations of KS119 or KS119OH at oxygenation levels reflecting normal air (21% oxygen) or a severely hypoxic atmosphere composed of 0.1% oxygen. The results, shown in
FIG. 5 , demonstrate that both drugs are virtually inactive under oxygenated conditions, with very little cytotoxicity to EMT6 cells at concentrations of drug up to 25 μM. At 0.1% oxygen, both drugs display potent cytotoxic effects with cell kill approaching 5 orders of magnitude at 10 μM drug concentration. - Similarly, EMT6 cells were exposed to 10 or 25 μM of KS119 and KS119W-OH at graded concentrations of oxygen ranging from 0.05% to 21% to demonstrate drug activity as a function of oxygen concentration. The results, shown in
FIG. 6 , demonstrated significant drug activity at all oxygen concentrations below 10% oxygen, with considerable activity at oxygen concentrations that have been measured in solid tumors (shaded bar). - Moreover, the R- and S-enantiomers of KS119W (VNP40541 and VNP40551) were converted to the corresponding de-phosphorylated forms for study in the in vitro aerobic/hypoxic cell assay. The results demonstrated that the in vitro cytotoxic activity of R-KS119OH and S-KS119OH to EMT6 cells is very similar to the parental racemic drug with respect to both potency and aerobic/hypoxic differential.
- As illustrated in
FIGS. 1 and 2 , KS119OH (1) like KS119 can be reduced under hypoxic conditions by one-electron reductases like cytochrome P-450 reductase to generate an intermediate of hydroxylamine or aniline (2), which spontaneously liberate the DNA alkylating and cytotoxic species, 90CE. To demonstrate that KS119W (racemic and two enantiomers) could be activated by cytochrome P-450 reductase under hypoxia, CHO cells transfected for and overexpressing this reductase were exposed to the drugs, and the sensitivity of this cell line to these agents was compared to the non-transfected parental line expressing low, basal levels of enzyme. The results, displayed in Table 2, demonstrate that cytochrome P-450 reductase sensitized the CHO cell line to all three agents only under hypoxia approximately equally. Like KS119, cytochrome P-450 reductase can activate KS119OH under hypoxic conditions. -
TABLE 2 Effect of Cytochrome P-450 Reductase Expression on R-, S-, and Racemic KS119OH Cytotoxicity Surviving fraction at 0.1% oxygen Drug (10 μM) VNP40541 VNP40551 KS119W CHO-SCS-II 0.04737 0.1188 0.3336 CHO-450red 0.001368 0.002553 0.009444 Surviving fraction in air Drug (10 μM) VNP40541 VNP40551 KS119W CHO-SCS-II 1.086 1.148 1.185 CHO-450red 0.9277 1.015 0.8791 - The anti-tumor effects of aforementioned prodrugs are evaluated in both solid and liquid tumor models, including the B16-F10 murine melanoma, HTB177 human lung carcinoma models, DLD1 human colon carcinoma, EMT-6 murine mammary gland carcinoma, L1210 murine leukemia, lymphoma, prostate cancer, pancreatic cancer, and head-and-neck cancer. The prodrugs are given intravenously, orally, or intraperitoneally at doses from 10 mg/kg to 2000 mg/kg; they are give at different dosing schedules such as 4 times daily, once daily, or once every several days for up to 60 doses. Testing tumor cells were implanted subcutaneously into mice, which were randomized into groups immediately after tumor cell implantation (Day 0). Mice were injected intraperitoneally (ip) with either a bolus injection of 0.1 mL PBS or drug. The treatment was carried out in a designed dosing schedule. Tumor measurement in three dimensions was determined once a week with the formula L×H×W/2, where L, H, and W represent length, height, and width, respectively. The toxicity of these drugs in mice was mild as determined by body weight loss and animal appearance.
- Efficacy of KS119 was studied in murine tumor model and human xenograft models. EMT-6 murine mammary carcinoma cells (3×105 cells/mouse) were implanted subcutaneously into Balb/c mice. H460 human lung carcinoma cells, HT29 human colon carcinoma cells and SHP77 human lung carcinoma cells were established as solid xenografts in nu/nu CD-1 mice and Scid/Beige mice with 7×107 cells/mouse, respectively. After implantation, tumors were allowed to grow to a size of 150 to 200 mm3 before starting treatment with KS119. KS119 was formulated in a solvent containing polyethylene glycol 300 (PEG), ethyl alcohol, citric acid, and ascorbic acid.
- The result of representative studies by daily ip administration of KS119 at doses of 80 and 100 mg/kg was shown in
FIG. 7 . The data indicated that KS119 produced a marginal but statistically significant antitumor effect against all of tumor models tested. The inhibition of KS119 on the growth of all tumors tested was ranged 30 to 50%. The inhibitions were significantly (p<0.05) when compared with vehicle controls. - Efficacies of KS119W and KS119 were compared with equivalence molar doses in EMT-6 tumor and H460 tumor models. KS119W was formulated with 0.25M sodium bicarbonate solution. The treatment was started when tumors researched 150 to 200 mm3, and lasted up to 2 weeks. KS119 at doses of 80 and 100 mg/kg and KS119W at doses of 97.6 and 121.3 mg/kg were daily administrated into mice via ip injection. As showed with an example of H460 tumor (
FIG. 8 ), KS119 and KS119W both inhibited the growths of tumor in mice. In comparison with KS119 at equal molar doses, KS119W was clearly more effective and produced greater antitumor activity. The final tumor volumes in the groups treated with 121.6 mg/kg, ×7 doses and 97.2 mg/kg×10 doses of KS119W were reduced 78% and 60%, respectively, compared with those in the control group; whereas the groups treated with equal molar doses of KS119 at 100 mg/kg and 80 mg/kg reduced only 40% inhibition. The toxicity of KS119 and KS119W were dose-dependent. To assess the toxicity of treatment, body weight and peripheral blood cell count were monitored after treatment. There was not significant hematological toxicity or severe weight loss in the mice treated with both drugs at the doses described above. - In order to fairly select a better compound from two enantiomers of KS119W for future clinical development, finding maximum tolerated dose (MTD) for VNP40541 (R-form) and VNP40551 (S-form) was conducted and the results were shown as Table 3.
-
TABLE 3 MTD Findings for Comparison between Two Enantiomers Mice Nude CD-1 BALB/c Scid/Beige VNP40541 140 mpk x10 100 mpk x5 110 mpk x8 VNP40551 80 mpk x10 85 mpk x5 85 mpk x8 - As illustrated in Table 4, VNP40541 and VNP40551 were evaluated in three sample tumor models in mice. Thus, they had exhibited quite similar efficacies and therapeutic windows, however VNP40541 had clearly demonstrated lower toxicity, particularly having less edema observed.
-
TABLE 4 Efficacies and Therapeutic Windows between Enantiomers H460/Nude EMTG/BLAB-c SHP77/Scid- Mice Mice Beige Dose Inhibi- Dose Inhibi- Dose Inhibi- (mpk) tion (%) (mpk) tion (%) (mpk) tion (%) VNP40541 80-140 52-80 85-115 58-69 110 83 VNP40551 40-80 53-80 55-85 52-78 85 82 - Combined therapy of KS119W with cytoxan (CTX) was evaluated by using KS119W at dose below the MTD in combination with nontoxic dose of CTX against EMT-6 murine mammary carcinoma and H460 human lung carcinoma in CD-1 nude mice. The tumors were allowed to grow to a size of approximately 200 mm3. In H460 tumor model, the animals received either with 4 doses 180 mg/kg and 1 dose 240 mg/kg of KS119 or CTX at dose of 100 mg/kg per dose per animal, ip injecting the drugs on 15, 22, 27, 34 and 43 days after the tumor implantation. In the combination studies, CTX was given two hours after dosing KS119W. As showed on
FIG. 9 , KS119W alone resulted in 78% tumor growth inhibition, whereas CTX produced 54% inhibition only. The combination treatment of KS119W and CTX resulted in 90% tumor growth inhibitory. The inhibition of combination therapy was statistically significant against all control groups with p values of 0.003, 0.015 and 0.038, respectively. Additive toxicity at the doses used for combination was manageable; while the 180 mg/kg qw×4 doses of KS119W alone caused a maximum net body weight loss of 4.5%, the same dose in combination with 4 doses of CTX at 100 mg/kg per week caused 8.6% weight loss but no death. A similar degree of growth inhibition was also observed with EMT-6 tumor model. Treatment of KS119W at dose of daily 97 mg/kg for 7 doses resulted in 59% tumor inhibition, and CTX at dose of 100 mg/kg, ip once per week for 4 doses generated a negligible effect on the tumor growth of EMT-6 in mice. Marked antitumor effects were observed when animals treated with a combination of KS119 and CTX. KS119W and CTX combination resulted in 91.8% growth inhibition of EMT-6 tumor. These results shows agent KS119W in combined with CTX have additive antitumor efficacy. - It is to be understood by those skilled in the art that the foregoing description and examples are illustrative of practicing the present invention, but are not in no way limiting. Variations of the detail presented herein may be made without departing from the spirit and scope of the present invention as defined by the following claims.
Claims (21)
1-52. (canceled)
53. A method of treating cancer in a patient in need of therapy comprising administering to said patient an effective amount of a compound according to the chemical structure:
where R is C1-C10 alkyl or haloalkyl;
R′ and R″ are each independently C1-C10 alkyl;
R1 is C1-C10 alkyl,
or a pharmaceutically acceptable salt, enantiomer or solvate thereof.
54. The method according to claim 53 wherein R is a CH2CH2Cl group and R′ and R″ are CH3, or a pharmaceutically acceptable salt or enantiomer thereof.
55. The method according to claim 53 wherein R is CH3, CH2CH3 or a C2-C3 haloalkyl or a pharmaceutically acceptable salt or enantiomer thereof.
56. The method according to claim 53 wherein R′ and R″ are C1-C3 alkyl or a pharmaceutically acceptable salt or enantiomer thereof.
57. The method according to claim 53 wherein R is a C2-C5 haloalkyl group and R′ and R″ are C1-C3 alkyl, or a pharmaceutically acceptable salt or enantiomer thereof.
58. The method according to claim 53 wherein R1 is CH3, R is a C2-C5 haloalkyl group and R′ and R″ are C1-C3 alkyl, or a pharmaceutically acceptable salt or enantiomer thereof.
59. The method according to claim 53 wherein R1 is CH3.
60. The method according to claim 54 wherein R1 is CH3.
61. The method according to claim 55 wherein R1 is CH3.
62. The method according to claim 56 wherein R1 is CH3.
63. The method according to claim 57 wherein R1 is CH3.
66. The method according to claim 53 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
67. The method according to claim 54 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
68. The method according to claim 55 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
69. The method according to claim 56 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
70. The method according to claim 57 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
71. The method according to claim 64 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
72. The method according to claim 65 wherein said cancer is stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, uterine cancer, corpus uterine cancer, ovarian cancer, prostate cancer, testicular cancer, bladder cancer, renal cancer, skin cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkins disease, non-Hodgkins disease, multiple myeloma, acute lymphocytic leukemia, acute mylogenous leukemia, Ewings Sarcoma, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx cancer, esophageal, cancer of the larynx, melanoma or lymphoma.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/080,357 US20090075945A1 (en) | 2004-09-21 | 2008-04-02 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61162304P | 2004-09-21 | 2004-09-21 | |
US61541904P | 2004-10-01 | 2004-10-01 | |
US61650004P | 2004-10-06 | 2004-10-06 | |
US11/232,252 US7405317B2 (en) | 2004-09-21 | 2005-09-21 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
US12/080,357 US20090075945A1 (en) | 2004-09-21 | 2008-04-02 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/232,252 Division US7405317B2 (en) | 2004-09-21 | 2005-09-21 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090075945A1 true US20090075945A1 (en) | 2009-03-19 |
Family
ID=36090617
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/232,252 Active US7405317B2 (en) | 2004-09-21 | 2005-09-21 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
US12/080,357 Abandoned US20090075945A1 (en) | 2004-09-21 | 2008-04-02 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/232,252 Active US7405317B2 (en) | 2004-09-21 | 2005-09-21 | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents |
Country Status (6)
Country | Link |
---|---|
US (2) | US7405317B2 (en) |
EP (1) | EP1793823B1 (en) |
JP (1) | JP4814245B2 (en) |
AU (1) | AU2005286833B2 (en) |
CA (1) | CA2575269A1 (en) |
WO (1) | WO2006034266A2 (en) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8951733B2 (en) * | 2009-10-16 | 2015-02-10 | Monsanto Technology Llc | Methods of polynucleotide detection |
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 |
EP2777694A1 (en) | 2013-03-14 | 2014-09-17 | Brij P. Giri | Hypoxia-Targeted Polymeric Micelles for Cancer Therapy and Imaging |
KR102608921B1 (en) * | 2015-05-18 | 2023-12-01 | 스미토모 파마 온콜로지, 인크. | Albocidip prodrug with increased bioavailability |
WO2018094275A1 (en) | 2016-11-18 | 2018-05-24 | Tolero Pharmaceuticals, Inc. | Alvocidib prodrugs and their use as protein kinase inhibitors |
US11497756B2 (en) | 2017-09-12 | 2022-11-15 | Sumitomo Pharma Oncology, Inc. | Treatment regimen for cancers that are insensitive to BCL-2 inhibitors using the MCL-1 inhibitor alvocidib |
US11034710B2 (en) | 2018-12-04 | 2021-06-15 | Sumitomo Dainippon Pharma Oncology, Inc. | CDK9 inhibitors and polymorphs thereof for use as agents for treatment of cancer |
US11793802B2 (en) | 2019-03-20 | 2023-10-24 | Sumitomo Pharma Oncology, Inc. | Treatment of acute myeloid leukemia (AML) with venetoclax failure |
CN110437281B (en) * | 2019-07-18 | 2022-03-15 | 南开大学 | Pyridinium-modified prodrug micromolecules containing different nitro aromatic heterocycles |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4684747A (en) * | 1984-12-20 | 1987-08-04 | Yale University | N,N'-bis(sulfonyl)hydrazines having antineoplastic activity |
US4849563A (en) * | 1986-01-21 | 1989-07-18 | Yale University | Novel 1-alkyl-1-arenesulfonyl-2-alkoxycarbonylsulfenylhydrazines having antineoplastic activity |
US5101072A (en) * | 1989-09-06 | 1992-03-31 | Yale University | Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents |
US5214068A (en) * | 1989-09-06 | 1993-05-25 | Yale University | Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents |
US5256820A (en) * | 1991-11-08 | 1993-10-26 | Yale University | 1-alkyl-2-acyl-1,2-disulfonylhydrazines |
US5637619A (en) * | 1995-07-05 | 1997-06-10 | Yale University | Antitumor 2-aminocarbonyl-1, 2-bis(methylsulfonyl)-1-(substituted)hydrazines |
US5767134A (en) * | 1997-05-15 | 1998-06-16 | Vion Pharmaceuticals, Inc. | Prodrug forms of ribonucleotide reductase inhibitors 3-AP and 3-AMP |
US6040338A (en) * | 1997-11-03 | 2000-03-21 | Yale University | N,n-bis(sulfonyl)hydrazines useful as antineoplastic agents |
US6458816B1 (en) * | 2000-10-13 | 2002-10-01 | Vion Pharmaceuticals, Inc. | Modified prodrug forms of AP/AMP |
US6855695B2 (en) * | 2003-06-13 | 2005-02-15 | Vion Pharmaceuticals, Inc. | Water-soluble SHPs as novel alkylating agents |
-
2005
- 2005-09-21 JP JP2007532610A patent/JP4814245B2/en not_active Expired - Fee Related
- 2005-09-21 CA CA002575269A patent/CA2575269A1/en not_active Abandoned
- 2005-09-21 WO PCT/US2005/033641 patent/WO2006034266A2/en active Application Filing
- 2005-09-21 EP EP05812794A patent/EP1793823B1/en active Active
- 2005-09-21 AU AU2005286833A patent/AU2005286833B2/en not_active Ceased
- 2005-09-21 US US11/232,252 patent/US7405317B2/en active Active
-
2008
- 2008-04-02 US US12/080,357 patent/US20090075945A1/en not_active Abandoned
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4684747A (en) * | 1984-12-20 | 1987-08-04 | Yale University | N,N'-bis(sulfonyl)hydrazines having antineoplastic activity |
US4849563A (en) * | 1986-01-21 | 1989-07-18 | Yale University | Novel 1-alkyl-1-arenesulfonyl-2-alkoxycarbonylsulfenylhydrazines having antineoplastic activity |
US5101072A (en) * | 1989-09-06 | 1992-03-31 | Yale University | Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents |
US5214068A (en) * | 1989-09-06 | 1993-05-25 | Yale University | Sulfonylhydrazines and their use as antineoplastic agents and as antitrypanosomal agents |
US5256820A (en) * | 1991-11-08 | 1993-10-26 | Yale University | 1-alkyl-2-acyl-1,2-disulfonylhydrazines |
US5637619A (en) * | 1995-07-05 | 1997-06-10 | Yale University | Antitumor 2-aminocarbonyl-1, 2-bis(methylsulfonyl)-1-(substituted)hydrazines |
US5767134A (en) * | 1997-05-15 | 1998-06-16 | Vion Pharmaceuticals, Inc. | Prodrug forms of ribonucleotide reductase inhibitors 3-AP and 3-AMP |
US6040338A (en) * | 1997-11-03 | 2000-03-21 | Yale University | N,n-bis(sulfonyl)hydrazines useful as antineoplastic agents |
US6458816B1 (en) * | 2000-10-13 | 2002-10-01 | Vion Pharmaceuticals, Inc. | Modified prodrug forms of AP/AMP |
US6855695B2 (en) * | 2003-06-13 | 2005-02-15 | Vion Pharmaceuticals, Inc. | Water-soluble SHPs as novel alkylating agents |
Also Published As
Publication number | Publication date |
---|---|
AU2005286833A1 (en) | 2006-03-30 |
EP1793823A4 (en) | 2010-10-06 |
JP4814245B2 (en) | 2011-11-16 |
US7405317B2 (en) | 2008-07-29 |
WO2006034266A2 (en) | 2006-03-30 |
US20060089332A1 (en) | 2006-04-27 |
AU2005286833B2 (en) | 2012-02-16 |
WO2006034266A3 (en) | 2007-03-01 |
CA2575269A1 (en) | 2006-03-30 |
JP2008513494A (en) | 2008-05-01 |
EP1793823B1 (en) | 2012-08-08 |
EP1793823A2 (en) | 2007-06-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7405317B2 (en) | Phosphate-bearing prodrugs of sulfonyl hydrazines as hypoxia-selective antineoplastic agents | |
AU2010237633B2 (en) | Novel compounds of reverse-turn mimetics, method for manufacturing the same and use thereof | |
CA2290617C (en) | Prodrug forms of ribonucleotide reductase inhibitors 3-ap and 3-amp | |
JP2017534657A (en) | New cytidine derivatives and their applications | |
JPH08509727A (en) | Phosphoramidate useful as an antitumor agent | |
CA2423220C (en) | Modified prodrug forms of ap/amp | |
AU2002211725A1 (en) | Modified prodrug forms of AP/AMP | |
US20040254103A1 (en) | Water-soluble shps as novel alkylating agents | |
KR101872264B1 (en) | New type of cytidine derivative dimer and application thereof | |
JP7096559B2 (en) | Triptolide derivatives and their manufacturing methods and uses | |
BR112020015747A2 (en) | SMALL MOLECULE DRUG CONJUGATES OF GEMCITABINE DERIVATIVES | |
CN101022798A (en) | Sulfonyl hydrazines as hypoxia-selective antineoplastic agents | |
KR101872645B1 (en) | Novel 4-(aryl)-N-(3-alkoxyfuro[2,3-b]pyrazin-2-yl)-piperazine-1-carboxamide derivatives and anti-proliferative effect thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |