FI111258B - 1,3-diokso-6-(3-metyyliaminopropyyli)-1,2,3,6-tetrahydro-4-(3-tienyyli)pyrrolo[3,4-c]karbatsoli ja sen suolat sekä näiden käyttö ja farmaseuttinen koostumus - Google Patents
1,3-diokso-6-(3-metyyliaminopropyyli)-1,2,3,6-tetrahydro-4-(3-tienyyli)pyrrolo[3,4-c]karbatsoli ja sen suolat sekä näiden käyttö ja farmaseuttinen koostumus Download PDFInfo
- Publication number
- FI111258B FI111258B FI953710A FI953710A FI111258B FI 111258 B FI111258 B FI 111258B FI 953710 A FI953710 A FI 953710A FI 953710 A FI953710 A FI 953710A FI 111258 B FI111258 B FI 111258B
- Authority
- FI
- Finland
- Prior art keywords
- formula
- compound
- thienyl
- acid
- pharmaceutical composition
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- -1 3-methylaminopropyl-1,2,3,6-tetrahydro-4- (3-thienyl) pyrrolo [3,4-c] carbazole Chemical compound 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 238000002360 preparation method Methods 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
- WTOWBVAIDHKDOZ-UHFFFAOYSA-N 6-[3-(methylamino)propyl]-4-thiophen-3-ylpyrrolo[3,4-c]carbazole-1,3-dione Chemical compound C1=C2N(CCCNC)C3=CC=CC=C3C2=C2C(=O)NC(=O)C2=C1C=1C=CSC=1 WTOWBVAIDHKDOZ-UHFFFAOYSA-N 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 230000003211 malignant effect Effects 0.000 claims description 5
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 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
- 208000023958 prostate neoplasm Diseases 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 abstract description 11
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940127089 cytotoxic agent Drugs 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 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 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000007796 conventional method Methods 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000008203 oral pharmaceutical composition Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- LSSICPJTIPBTDD-UHFFFAOYSA-N 2-ethenyl-1h-indole Chemical compound C1=CC=C2NC(C=C)=CC2=C1 LSSICPJTIPBTDD-UHFFFAOYSA-N 0.000 description 4
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 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 4
- 150000001450 anions Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000004714 phosphonium salts Chemical class 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 3
- 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
- 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 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
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 206010041067 Small cell lung cancer Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 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 3
- 239000002775 capsule Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 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
- 230000003111 delayed effect Effects 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 235000019833 protease Nutrition 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- YIMPWIJIKJBRDM-UHFFFAOYSA-N 1-indol-1-yl-n,n-dimethylmethanamine Chemical compound C1=CC=C2N(CN(C)C)C=CC2=C1 YIMPWIJIKJBRDM-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- JAHIEGNMEFWBGK-UHFFFAOYSA-N 2-(2-thiophen-3-ylethenyl)-1h-indole Chemical compound C=1C2=CC=CC=C2NC=1C=CC=1C=CSC=1 JAHIEGNMEFWBGK-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- PQRKJLGGOYZIOI-UHFFFAOYSA-N 3-(2-ethenylindol-1-yl)propan-1-ol Chemical compound C1=CC=C2N(CCCO)C(C=C)=CC2=C1 PQRKJLGGOYZIOI-UHFFFAOYSA-N 0.000 description 2
- RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 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 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000006179 pH buffering agent Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- QNMMYUBZGLXCCK-UHFFFAOYSA-N pyrrolo[3,2-a]carbazole Chemical class N1=C2C=CC=CC2=C2C1=C1C=CN=C1C=C2 QNMMYUBZGLXCCK-UHFFFAOYSA-N 0.000 description 2
- GAAWKLUURLVNGE-UHFFFAOYSA-N pyrrolo[3,4-c]carbazole Chemical compound C1=CC=C2C3=C4C=NC=C4C=CC3=NC2=C1 GAAWKLUURLVNGE-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- MFEIKQPHQINPRI-UHFFFAOYSA-N 3-Ethylpyridine Chemical compound CCC1=CC=CN=C1 MFEIKQPHQINPRI-UHFFFAOYSA-N 0.000 description 1
- WJCHDQCVJXFKJF-UHFFFAOYSA-N 3-[2-(2-thiophen-3-ylethenyl)indol-1-yl]propan-1-ol Chemical compound C=1C2=CC=CC=C2N(CCCO)C=1C=CC=1C=CSC=1 WJCHDQCVJXFKJF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- WVRUNFYJIHNFKD-WDSKDSINSA-N Arg-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CCCN=C(N)N WVRUNFYJIHNFKD-WDSKDSINSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm 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
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 238000000729 Fisher's exact test Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 210000002469 basement membrane Anatomy 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001982 diacylglycerols Chemical class 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 235000021552 granulated sugar Nutrition 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- SYYHFJNDTYWCPB-UHFFFAOYSA-N n-(1,3-dioxo-4-thiophen-3-ylpyrrolo[3,4-c]carbazol-6-yl)-3,3,3-trifluoro-n-methylpropanamide Chemical compound C1=C2N(N(C(=O)CC(F)(F)F)C)C3=CC=CC=C3C2=C2C(=O)NC(=O)C2=C1C=1C=CSC=1 SYYHFJNDTYWCPB-UHFFFAOYSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108010056599 proteinase C Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- NUQCCJCVGGTDJG-UHFFFAOYSA-N tert-butyl-(3-iodopropoxy)-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](OCCCI)(C(C)(C)C)C1=CC=CC=C1 NUQCCJCVGGTDJG-UHFFFAOYSA-N 0.000 description 1
- SSRGSHIUCVIDRC-UHFFFAOYSA-N tert-butyl-diphenyl-[3-[2-(2-thiophen-3-ylethenyl)indol-1-yl]propoxy]silane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OCCCN(C1=CC=CC=C1C=1)C=1C=CC=1C=CSC=1 SSRGSHIUCVIDRC-UHFFFAOYSA-N 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28604394A | 1994-08-04 | 1994-08-04 | |
| US28604394 | 1994-08-04 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI953710A0 FI953710A0 (fi) | 1995-08-03 |
| FI953710L FI953710L (fi) | 1996-02-05 |
| FI111258B true FI111258B (fi) | 2003-06-30 |
Family
ID=23096813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI953710A FI111258B (fi) | 1994-08-04 | 1995-08-03 | 1,3-diokso-6-(3-metyyliaminopropyyli)-1,2,3,6-tetrahydro-4-(3-tienyyli)pyrrolo[3,4-c]karbatsoli ja sen suolat sekä näiden käyttö ja farmaseuttinen koostumus |
Country Status (29)
| Country | Link |
|---|---|
| US (1) | US5721267A (cs) |
| EP (1) | EP0695755B1 (cs) |
| JP (1) | JP2672290B2 (cs) |
| KR (1) | KR100326790B1 (cs) |
| CN (1) | CN1051551C (cs) |
| AT (1) | ATE172463T1 (cs) |
| AU (1) | AU692563B2 (cs) |
| BR (1) | BR9503536A (cs) |
| CA (1) | CA2155148A1 (cs) |
| CO (1) | CO4410329A1 (cs) |
| CZ (1) | CZ288583B6 (cs) |
| DE (1) | DE69505470T2 (cs) |
| DK (1) | DK0695755T3 (cs) |
| ES (1) | ES2123873T3 (cs) |
| FI (1) | FI111258B (cs) |
| HU (1) | HU225567B1 (cs) |
| IL (1) | IL114785A (cs) |
| MA (1) | MA23639A1 (cs) |
| MY (1) | MY117092A (cs) |
| NO (1) | NO304833B1 (cs) |
| NZ (1) | NZ272687A (cs) |
| PE (1) | PE34996A1 (cs) |
| PL (1) | PL180801B1 (cs) |
| RU (1) | RU2162089C2 (cs) |
| SA (1) | SA95160203B1 (cs) |
| TR (1) | TR199500954A1 (cs) |
| TW (1) | TW403652B (cs) |
| UY (1) | UY24010A1 (cs) |
| ZA (1) | ZA956327B (cs) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1283203B1 (it) * | 1996-03-07 | 1998-04-16 | Ausimont Spa | Composizioni estinguenti la fiamma |
| US6020298A (en) * | 1997-03-05 | 2000-02-01 | Ausimont S.P.A. | Solvent cleaning agents including additives of the formula Rf -CFX-L containing perfluoroalkylenic units |
| DE19744257B4 (de) * | 1997-10-07 | 2004-04-15 | Zentaris Gmbh | Beta-Carboline und deren Verwendung zur Behandlung von malignen und anderen, auf pathologischen Zellproliferationen beruhenden Erkrankungen |
| US7122679B2 (en) | 2000-05-09 | 2006-10-17 | Cephalon, Inc. | Multicyclic compounds and the use thereof |
| JPWO2003051883A1 (ja) * | 2001-12-18 | 2005-04-28 | 協和醗酵工業株式会社 | インドール誘導体 |
| EP1501831A1 (en) * | 2002-04-26 | 2005-02-02 | Warner-Lambert Company Llc | Inhibitors of checkpoint kinases (wee1 and chk1) |
| US7094798B1 (en) | 2002-04-26 | 2006-08-22 | Pfizer Inc | Inhibitors of checkpoint kinases (Wee1 and Chk1) |
| JP2012051804A (ja) * | 2008-12-26 | 2012-03-15 | Kyoto Univ | Ｅｇ５阻害剤 |
| RU2404983C1 (ru) * | 2009-06-08 | 2010-11-27 | Федеральное Государственное Образовательное Учреждение Высшего Профессионального Образования "Южный Федеральный Университет" | СПОСОБ ПОЛУЧЕНИЯ 2-R1-6-R2-5-АРИЛ-ПИРРОЛО[3,4-с]КАРБАЗОЛ-1,3(2Н,6Н)-ДИОНОВ |
| MA33418B1 (fr) * | 2009-06-10 | 2012-07-03 | Chugai Pharmaceutical Co Ltd | Composé tétracyclique |
| SG187614A1 (en) | 2010-08-20 | 2013-03-28 | Chugai Pharmaceutical Co Ltd | Composition containing tetracyclic compound |
| CA2885722C (en) | 2012-09-25 | 2020-06-02 | Chugai Seiyaku Kabushiki Kaisha | Ret inhibitor |
| KR101577098B1 (ko) | 2012-11-20 | 2015-12-14 | 주식회사 두산 | 유기 화합물 및 이를 포함하는 유기 전계 발광 소자 |
| PL3135287T3 (pl) | 2014-04-25 | 2025-03-31 | Chugai Seiyaku Kabushiki Kaisha | Preparat zawierający związek tetracykliczny w dużej dawce |
| KR20160142383A (ko) | 2014-04-25 | 2016-12-12 | 추가이 세이야쿠 가부시키가이샤 | 4환성 화합물의 신규 결정 |
| TWI803187B (zh) | 2014-08-08 | 2023-05-21 | 日商中外製藥股份有限公司 | 包含４環性化合物的非晶質體之固體分散體及製劑 |
| WO2016114375A1 (ja) | 2015-01-16 | 2016-07-21 | 中外製薬株式会社 | 併用医薬 |
| WO2020050241A1 (ja) | 2018-09-04 | 2020-03-12 | 中外製薬株式会社 | ４環性化合物の製造方法 |
| KR102509614B1 (ko) * | 2022-08-09 | 2023-03-13 | 김학수 | 부직포 패널 제조방법 및 제조장치 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8611762D0 (en) * | 1986-05-14 | 1986-06-25 | Wellcome Found | Polycyclic biocidal compounds |
| US4785085A (en) * | 1986-11-21 | 1988-11-15 | Bristol-Myers Company | Rebeccamycin analogs |
| NZ227850A (en) * | 1988-02-10 | 1991-11-26 | Hoffmann La Roche | Indole substituted pyrrole derivatives; preparatory process and medicaments for use against inflammatory immunological, bronchopulmonary or vascular disorders |
| DE3833008A1 (de) * | 1988-09-29 | 1990-04-05 | Goedecke Ag | Pyrrolocarbozol-derivate, verfahren zu deren herstellung und deren verwendung als arzneimittel |
| MC2096A1 (fr) * | 1989-02-23 | 1991-02-15 | Hoffmann La Roche | Pyrroles substitues |
| GB2239013B (en) * | 1989-11-01 | 1993-06-02 | Toyama Chemical Co Ltd | Novel isoindole derivatives and salts thereof,processes for producing the same and antitumor agent comprising the same |
| DE4005969A1 (de) * | 1990-02-26 | 1991-08-29 | Boehringer Mannheim Gmbh | Neue trisubstituierte pyrrole, verfahren zu ihrer herstellung sowie arzneimittel, die diese verbindungen enthalten |
| DE4217964A1 (de) * | 1992-05-30 | 1993-12-02 | Goedecke Ag | Indolocarbazol-Imide und deren Verwendung |
| AU678435B2 (en) * | 1993-05-10 | 1997-05-29 | F. Hoffmann-La Roche Ag | Substituted pyrroles |
| AU679752B2 (en) * | 1993-05-28 | 1997-07-10 | Cephalon, Inc. | Use of indolocarbazole derivatives to treat a pathological condition of the prostate |
-
1995
- 1995-07-21 ES ES95111472T patent/ES2123873T3/es not_active Expired - Lifetime
- 1995-07-21 AT AT95111472T patent/ATE172463T1/de not_active IP Right Cessation
- 1995-07-21 DE DE69505470T patent/DE69505470T2/de not_active Expired - Fee Related
- 1995-07-21 DK DK95111472T patent/DK0695755T3/da active
- 1995-07-21 EP EP95111472A patent/EP0695755B1/en not_active Expired - Lifetime
- 1995-07-25 TW TW084107708A patent/TW403652B/zh not_active IP Right Cessation
- 1995-07-27 AU AU27220/95A patent/AU692563B2/en not_active Ceased
- 1995-07-28 ZA ZA956327A patent/ZA956327B/xx unknown
- 1995-07-31 NZ NZ272687A patent/NZ272687A/en unknown
- 1995-07-31 HU HU9502270A patent/HU225567B1/hu not_active IP Right Cessation
- 1995-07-31 IL IL114785A patent/IL114785A/en not_active IP Right Cessation
- 1995-08-01 CA CA002155148A patent/CA2155148A1/en not_active Abandoned
- 1995-08-01 PE PE1995275075A patent/PE34996A1/es not_active Application Discontinuation
- 1995-08-02 MY MYPI95002255A patent/MY117092A/en unknown
- 1995-08-03 JP JP7197846A patent/JP2672290B2/ja not_active Expired - Fee Related
- 1995-08-03 PL PL95309874A patent/PL180801B1/pl not_active IP Right Cessation
- 1995-08-03 KR KR1019950023928A patent/KR100326790B1/ko not_active Expired - Fee Related
- 1995-08-03 TR TR95/00954A patent/TR199500954A1/xx unknown
- 1995-08-03 CO CO95034716A patent/CO4410329A1/es unknown
- 1995-08-03 FI FI953710A patent/FI111258B/fi not_active IP Right Cessation
- 1995-08-03 UY UY24010A patent/UY24010A1/es not_active IP Right Cessation
- 1995-08-03 CZ CZ19951997A patent/CZ288583B6/cs not_active IP Right Cessation
- 1995-08-03 BR BR9503536A patent/BR9503536A/pt not_active IP Right Cessation
- 1995-08-03 CN CN95108687A patent/CN1051551C/zh not_active Expired - Fee Related
- 1995-08-03 RU RU95113107/04A patent/RU2162089C2/ru not_active IP Right Cessation
- 1995-08-03 NO NO953052A patent/NO304833B1/no unknown
- 1995-08-03 MA MA23980A patent/MA23639A1/fr unknown
- 1995-08-27 SA SA95160203A patent/SA95160203B1/ar unknown
-
1997
- 1997-01-22 US US08/787,594 patent/US5721267A/en not_active Expired - Fee Related
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI111258B (fi) | 1,3-diokso-6-(3-metyyliaminopropyyli)-1,2,3,6-tetrahydro-4-(3-tienyyli)pyrrolo[3,4-c]karbatsoli ja sen suolat sekä näiden käyttö ja farmaseuttinen koostumus | |
| US6794391B2 (en) | Derivatives of pyrimido[6.1-a]isoquinolin-4-one | |
| JP4205430B2 (ja) | 疼痛を治療するための、バニロイド受容体アンタゴニストとして、使用するための縮合ピリジン誘導体 | |
| SK3992001A3 (en) | Tetrahydropyridoethers, pharmaceutical composition containing same and use thereof | |
| SK280822B6 (sk) | Imidazopyridíny, spôsob ich prípravy, farmaceutické prostriedky s ich obsahom a ich použitie | |
| US20030187257A1 (en) | Triazolo[4,3-a]pyrido[2,3-d]pyrimidin-5-one derivatives | |
| US6737424B2 (en) | Alpha-substituted pyridazino quinoline compounds | |
| EP0806418A2 (en) | Novel pyrimidine compound and anti-rotavirus agent | |
| RU2200737C2 (ru) | Пиримидо[4,5-b]индолы и промежуточное соединение (варианты) | |
| EP1424326B1 (en) | Fused-polycyclic compounds | |
| FI85481C (fi) | Foerfarande foer framstaellning av 2,3 -dihydro-1-(8-metyl-1,2,4-triazolo/4,3-b/pyridazin-6-yl)-4(1h) -pyridinon. | |
| JP3045355B2 (ja) | チオキサンテノン類およびその抗腫瘍剤 | |
| CA1262545A (en) | Imidazo-isoquinoline and imidazo-thienopyridine compounds | |
| JPH01279864A (ja) | 新規の１，２―ジヒドロピリド〔３，４―ｂ〕―ピラジン類製造用の中間体 | |
| HK1012341B (en) | Pyrrolocarbazole | |
| US6875865B1 (en) | Selected derivatives of K-252a | |
| CA2103457A1 (en) | 1,2-dihydropyrido(3,4-b)pyrazines as fungicides | |
| JP2001522370A (ja) | ピリド［２，３，４−ｋ，ｌ］アクリジン環系の誘導体：細胞毒性化合物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MA | Patent expired |