NZ581355A - Potentiation of cancer chemotherapy by 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1h-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine - Google Patents
Potentiation of cancer chemotherapy by 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1h-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepineInfo
- Publication number
- NZ581355A NZ581355A NZ581355A NZ58135508A NZ581355A NZ 581355 A NZ581355 A NZ 581355A NZ 581355 A NZ581355 A NZ 581355A NZ 58135508 A NZ58135508 A NZ 58135508A NZ 581355 A NZ581355 A NZ 581355A
- Authority
- NZ
- New Zealand
- Prior art keywords
- chemotherapeutic agent
- fluoro
- imidazo
- dihydro
- compound
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title description 26
- 201000011510 cancer Diseases 0.000 title description 20
- 238000002512 chemotherapy Methods 0.000 title description 8
- XUGQPECVQQKZTM-UHFFFAOYSA-N 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1h-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine Chemical compound C1=2N3CCN=C(C=4C(NC(=O)C=4C=4N5C=CC=CC5=NC=4)=O)C1=CC(F)=CC=2CC3C(=O)N1CCCCC1 XUGQPECVQQKZTM-UHFFFAOYSA-N 0.000 title 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 80
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 70
- 229940127089 cytotoxic agent Drugs 0.000 claims abstract description 66
- 229960005079 pemetrexed Drugs 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- 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 claims abstract description 43
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims abstract description 43
- 229960004316 cisplatin Drugs 0.000 claims abstract description 43
- 239000012453 solvate Substances 0.000 claims abstract description 43
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 40
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229960004562 carboplatin Drugs 0.000 claims abstract description 38
- 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 claims abstract description 27
- 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 claims abstract description 21
- 229960004679 doxorubicin Drugs 0.000 claims abstract description 19
- 229960005420 etoposide Drugs 0.000 claims abstract description 19
- 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 claims abstract description 19
- 229960005277 gemcitabine Drugs 0.000 claims abstract description 19
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 18
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims abstract description 17
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 17
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims abstract description 16
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 16
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 16
- 229960002949 fluorouracil Drugs 0.000 claims abstract description 15
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 14
- 206010017758 gastric cancer Diseases 0.000 claims abstract description 13
- 208000005718 Stomach Neoplasms Diseases 0.000 claims abstract description 11
- 201000011549 stomach cancer Diseases 0.000 claims abstract description 11
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims abstract 8
- 150000001875 compounds Chemical class 0.000 claims description 129
- 239000003814 drug Substances 0.000 claims description 48
- 229940049706 benzodiazepine Drugs 0.000 claims description 33
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims 1
- HRJWTAWVFDCTGO-UHFFFAOYSA-N LY-2090314 Chemical compound C1CN(C=23)C=C(C=4C(NC(=O)C=4C=4N5C=CC=CC5=NC=4)=O)C3=CC(F)=CC=2CN1C(=O)N1CCCCC1 HRJWTAWVFDCTGO-UHFFFAOYSA-N 0.000 abstract description 2
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- 229940079593 drug Drugs 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 21
- 230000000694 effects Effects 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 101150041968 CDC13 gene Proteins 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 102000001267 GSK3 Human genes 0.000 description 9
- 108060006662 GSK3 Proteins 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 208000012766 Growth delay Diseases 0.000 description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- 230000004614 tumor growth Effects 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 6
- 229960004853 betadex Drugs 0.000 description 6
- 229940044683 chemotherapy drug Drugs 0.000 description 6
- 238000011260 co-administration Methods 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 102000047934 Caspase-3/7 Human genes 0.000 description 5
- 108700037887 Caspase-3/7 Proteins 0.000 description 5
- 102000011727 Caspases Human genes 0.000 description 5
- 108010076667 Caspases Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000001802 infusion Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 239000003039 volatile agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 208000010749 gastric carcinoma Diseases 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 3
- 229960001756 oxaliplatin Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 102000003390 tumor necrosis factor Human genes 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- JNGRENQDBKMCCR-UHFFFAOYSA-N 2-(3-amino-6-iminoxanthen-9-yl)benzoic acid;hydrochloride Chemical compound [Cl-].C=12C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C2C=1C1=CC=CC=C1C(O)=O JNGRENQDBKMCCR-UHFFFAOYSA-N 0.000 description 2
- NHDADOXWSLXLIH-UHFFFAOYSA-N 2-(dibutoxymethyl)-4-fluoro-1-nitrobenzene Chemical compound CCCCOC(OCCCC)C1=CC(F)=CC=C1[N+]([O-])=O NHDADOXWSLXLIH-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 2
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000012131 assay buffer Substances 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- -1 sodium triacetoxyborohydride Chemical compound 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XYXYXSKSTZAEJW-VIFPVBQESA-N (2s)-2-(phenylmethoxycarbonylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 XYXYXSKSTZAEJW-VIFPVBQESA-N 0.000 description 1
- AOUOVFRSCMDPFA-QSDJMHMYSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-amino-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](N)CC(O)=O AOUOVFRSCMDPFA-QSDJMHMYSA-N 0.000 description 1
- YPZARNMVEFFLNZ-UHFFFAOYSA-N 1,10-diazatricyclo[6.4.1.04,13]trideca-2,4(13),5,7,9,11-hexaene Chemical compound C1=CN=CC2=CC=CC3=C2N1C=C3 YPZARNMVEFFLNZ-UHFFFAOYSA-N 0.000 description 1
- GCZYHQNARYIYKS-UHFFFAOYSA-N 1,10-diazatricyclo[6.4.1.04,13]trideca-4(13),5,7-trien-10-yl(piperidin-1-yl)methanone Chemical compound N1(CCCCC1)C(=O)N1CCN2C3=C(C1)C=CC=C3CC2 GCZYHQNARYIYKS-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 description 1
- BHNQPLPANNDEGL-UHFFFAOYSA-N 2-(4-octylphenoxy)ethanol Chemical compound CCCCCCCCC1=CC=C(OCCO)C=C1 BHNQPLPANNDEGL-UHFFFAOYSA-N 0.000 description 1
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 1
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 description 1
- KKAFVHUJZPVWND-UHFFFAOYSA-N 5-fluoro-2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1C=O KKAFVHUJZPVWND-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004695 Polyether sulfone Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- DSXXEELGXBCYNQ-UHFFFAOYSA-N Ro 31-8220 Chemical compound C12=CC=CC=C2N(C)C=C1C1=C(C=2C3=CC=CC=C3N(CCCSC(N)=N)C=2)C(=O)NC1=O DSXXEELGXBCYNQ-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229940064305 adrucil Drugs 0.000 description 1
- 229940110282 alimta Drugs 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 238000005842 biochemical reaction Methods 0.000 description 1
- 201000001531 bladder carcinoma Diseases 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 231100000085 chronic toxic effect Toxicity 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000011498 curative surgery Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RPWXYCRIAGBAGY-UHFFFAOYSA-N ethyl 2-pyridin-3-ylacetate Chemical compound CCOC(=O)CC1=CC=CN=C1 RPWXYCRIAGBAGY-UHFFFAOYSA-N 0.000 description 1
- SIRJFJKWVNTUKV-UHFFFAOYSA-N ethyl 4,4-dimethoxybut-2-enoate Chemical compound CCOC(=O)C=CC(OC)OC SIRJFJKWVNTUKV-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- HBDSHCUSXQATPO-BGBJRWHRSA-N indirubin-3'-monoxime Chemical compound O=C/1NC2=CC=CC=C2C\1=C\1/C(=N/O)/C2=CC=CC=C2N/1 HBDSHCUSXQATPO-BGBJRWHRSA-N 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 208000006178 malignant mesothelioma Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229940063179 platinol Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920006393 polyether sulfone Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival 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
- FMNXFKVTZJWOAD-UHFFFAOYSA-N tert-butyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC(C)(C)C)=CC2=C1 FMNXFKVTZJWOAD-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940035307 toposar Drugs 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Steroid Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94751207P | 2007-07-02 | 2007-07-02 | |
| PCT/US2008/067614 WO2009006043A2 (en) | 2007-07-02 | 2008-06-20 | Potentiation of cancer chemotherapy by 7-(2,5-dihydro-4-imidazo [1,2-a]pyrine-3-yl-2,5-dioxo-ih-pyrrol-3-yl)-9-fluoro-1,2,3,4 tetrahydro-2-(1-piperidinyl-carbonyd-pyrrolo[3,2,1-jk][1,4]benzodiazepine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ581355A true NZ581355A (en) | 2012-04-27 |
Family
ID=39737054
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ581355A NZ581355A (en) | 2007-07-02 | 2008-06-20 | Potentiation of cancer chemotherapy by 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1h-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US8318713B2 (enExample) |
| EP (1) | EP2173348B1 (enExample) |
| JP (2) | JP5551589B2 (enExample) |
| KR (1) | KR101230085B1 (enExample) |
| CN (2) | CN102772416A (enExample) |
| AR (1) | AR067112A1 (enExample) |
| AU (1) | AU2008270732B2 (enExample) |
| BR (1) | BRPI0813789A2 (enExample) |
| CA (1) | CA2691587C (enExample) |
| CL (2) | CL2008001848A1 (enExample) |
| EA (2) | EA023697B1 (enExample) |
| ES (1) | ES2561202T3 (enExample) |
| IL (2) | IL202237A (enExample) |
| MA (1) | MA31677B1 (enExample) |
| MX (1) | MX2009013449A (enExample) |
| MY (1) | MY154472A (enExample) |
| NZ (1) | NZ581355A (enExample) |
| PE (1) | PE20090838A1 (enExample) |
| TW (1) | TWI428132B (enExample) |
| UA (1) | UA97400C2 (enExample) |
| WO (1) | WO2009006043A2 (enExample) |
| ZA (1) | ZA200908725B (enExample) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI428132B (zh) * | 2007-07-02 | 2014-03-01 | Lilly Co Eli | 癌症化療效果之強化 |
| JP5699129B2 (ja) * | 2009-04-14 | 2015-04-08 | イーライ リリー アンド カンパニー | 造血器新生物および白血病の治療のためのベンゾジアゼピン誘導体 |
| WO2013044219A1 (en) * | 2011-09-22 | 2013-03-28 | Bind Biosciences | Methods of treating cancers with therapeutic nanoparticles |
| WO2014050779A1 (ja) * | 2012-09-25 | 2014-04-03 | 第一三共株式会社 | Ｇｓｋ３阻害剤と抗ｄｒ５抗体の組み合わせ |
| US20180110780A1 (en) * | 2015-04-30 | 2018-04-26 | Taiho Pharmaceutical Co., Ltd. | Agent for alleviating side effect of antitumor drug |
| US10201540B2 (en) | 2016-03-02 | 2019-02-12 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: I |
| US10016507B2 (en) * | 2016-03-02 | 2018-07-10 | Frequency Therapeutics, Inc. | Solubilized compositions for controlled proliferation of stem cells / generating inner ear hair cells using GSK3 inhibitors: III |
| US10213511B2 (en) * | 2016-03-02 | 2019-02-26 | Frequency Therapeutics, Inc. | Thermoreversible compositions for administration of therapeutic agents |
| AU2017386417B2 (en) * | 2016-12-30 | 2022-07-14 | Frequency Therapeutics, Inc. | 1H-pyrrole-2,5-dione compounds and methods of using them to induce self-renewal of stem/progenitor supporting cells |
| WO2020163812A1 (en) | 2019-02-08 | 2020-08-13 | Frequency Therapeutics, Inc. | Valproic acid compounds and wnt agonists for treating ear disorders |
| CA3222225A1 (en) * | 2021-06-03 | 2022-12-08 | University Of Cincinnati | Bzd-1 as a chemosensitizer of cancer |
| CN113956157B (zh) * | 2021-11-18 | 2024-05-03 | 西安都创医药科技有限公司 | 一种合成2-甲酰基-1-环丙烷甲酸乙酯的方法 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8904161D0 (en) * | 1989-02-23 | 1989-04-05 | Hoffmann La Roche | Substituted pyrroles |
| US5376645A (en) * | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
| KR0166088B1 (ko) * | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
| EP1788086A1 (en) * | 1997-03-17 | 2007-05-23 | Human Genome Sciences, Inc. | Death Domain Containing Receptor 5 |
| US7034013B2 (en) * | 2001-03-20 | 2006-04-25 | Cydex, Inc. | Formulations containing propofol and a sulfoalkyl ether cyclodextrin |
| ES2276048T3 (es) * | 2002-03-05 | 2007-06-16 | Eli Lilly And Company | Derivados de purina como inhibidores de cinasa. |
| WO2004026867A2 (en) * | 2002-09-19 | 2004-04-01 | Schering Corporation | Imidazopyridines as cyclin dependent kinase inhibitors |
| CA2569091A1 (en) | 2004-07-09 | 2006-01-19 | Agency For Science, Technology And Research | Modulation of gsk-3.beta. and method of treating proliferative disorders |
| GB0418328D0 (en) * | 2004-08-17 | 2004-09-22 | Imp College Innovations Ltd | Cancer methods and medicaments |
| JP2008541701A (ja) * | 2005-05-04 | 2008-11-27 | ユニヴァーシティ オブ サウス フロリダ | がんの対象における処置応答の予測 |
| TWI428132B (zh) * | 2007-07-02 | 2014-03-01 | Lilly Co Eli | 癌症化療效果之強化 |
-
2008
- 2008-06-18 TW TW097122720A patent/TWI428132B/zh not_active IP Right Cessation
- 2008-06-19 PE PE2008001054A patent/PE20090838A1/es not_active Application Discontinuation
- 2008-06-20 UA UAA200913938A patent/UA97400C2/uk unknown
- 2008-06-20 BR BRPI0813789-7A2A patent/BRPI0813789A2/pt not_active IP Right Cessation
- 2008-06-20 NZ NZ581355A patent/NZ581355A/en not_active IP Right Cessation
- 2008-06-20 CL CL2008001848A patent/CL2008001848A1/es unknown
- 2008-06-20 EA EA201201155A patent/EA023697B1/ru not_active IP Right Cessation
- 2008-06-20 EA EA201070085A patent/EA018447B1/ru not_active IP Right Cessation
- 2008-06-20 CN CN2012101150238A patent/CN102772416A/zh active Pending
- 2008-06-20 CA CA2691587A patent/CA2691587C/en not_active Expired - Fee Related
- 2008-06-20 JP JP2010514996A patent/JP5551589B2/ja not_active Expired - Fee Related
- 2008-06-20 US US12/664,664 patent/US8318713B2/en not_active Expired - Fee Related
- 2008-06-20 CN CN2008800231969A patent/CN101743005B/zh not_active Expired - Fee Related
- 2008-06-20 MY MYPI20095640A patent/MY154472A/en unknown
- 2008-06-20 MX MX2009013449A patent/MX2009013449A/es active IP Right Grant
- 2008-06-20 WO PCT/US2008/067614 patent/WO2009006043A2/en not_active Ceased
- 2008-06-20 EP EP08771559.5A patent/EP2173348B1/en active Active
- 2008-06-20 AU AU2008270732A patent/AU2008270732B2/en not_active Ceased
- 2008-06-20 KR KR1020097027543A patent/KR101230085B1/ko not_active Expired - Fee Related
- 2008-06-20 ES ES08771559.5T patent/ES2561202T3/es active Active
- 2008-06-20 AR ARP080102668A patent/AR067112A1/es unknown
-
2009
- 2009-11-19 IL IL202237A patent/IL202237A/en not_active IP Right Cessation
- 2009-12-08 ZA ZA2009/08725A patent/ZA200908725B/en unknown
-
2010
- 2010-01-27 MA MA32562A patent/MA31677B1/fr unknown
-
2011
- 2011-12-02 CL CL2011003046A patent/CL2011003046A1/es unknown
-
2012
- 2012-03-01 IL IL218443A patent/IL218443A0/en unknown
- 2012-10-18 US US13/654,884 patent/US8648063B2/en not_active Expired - Fee Related
-
2014
- 2014-01-17 JP JP2014006560A patent/JP2014114297A/ja active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2008270732B2 (en) | Potentiation of cancer chemotherapy by 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinylcarbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine | |
| US11975002B2 (en) | Preparation and composition for treatment of malignant tumors | |
| KR20160132130A (ko) | 폐의 비소세포 암종 및 난소암을 치료하기 위한 디안하이드로갈락티톨 및 이의 유사체 또는 유도체 | |
| CN102753176B (zh) | 含有cdc7抑制剂和抗癌药的治疗组合物 | |
| KR20190130621A (ko) | Chk1 저해제와 wee1 저해제의 조합물 | |
| JP2010532364A5 (enExample) | ||
| JP2007520522A (ja) | （ａ）ＤＮＡトポイソメラーゼ阻害剤および（ｂ）ＩＡＰ阻害剤の組み合わせ剤 | |
| US20050267140A1 (en) | Method for treating abnormal cell growth | |
| CN1330308C (zh) | 含有4－吡啶基甲基酞嗪的联合产品及其应用 | |
| HK1141236B (en) | Potentiation of cancer chemotherapy | |
| US20160257696A1 (en) | Thieno- and pyrrolopyrimidine analogues as anticancer agents and methods of use thereof | |
| CN102105147B (zh) | 包含aurora激酶抑制剂和抗肿瘤药的治疗组合 | |
| RU2777595C2 (ru) | Препарат и композиция для лечения злокачественных опухолей |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RENW | Renewal (renewal fees accepted) | ||
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 20 JUN 2016 BY THOMSON REUTERS Effective date: 20150514 |
|
| RENW | Renewal (renewal fees accepted) |
Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 20 JUN 2017 BY THOMSON REUTERS Effective date: 20160512 |
|
| LAPS | Patent lapsed |