BRPI0612542A2 - derivados de indol com atividade antitumoral - Google Patents
derivados de indol com atividade antitumoral Download PDFInfo
- Publication number
- BRPI0612542A2 BRPI0612542A2 BRPI0612542-5A BRPI0612542A BRPI0612542A2 BR PI0612542 A2 BRPI0612542 A2 BR PI0612542A2 BR PI0612542 A BRPI0612542 A BR PI0612542A BR PI0612542 A2 BRPI0612542 A2 BR PI0612542A2
- Authority
- BR
- Brazil
- Prior art keywords
- indol
- bis
- formula
- compound
- tumor
- Prior art date
Links
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 11
- 150000002475 indoles Chemical class 0.000 title claims abstract description 7
- 229940054051 antipsychotic indole derivative Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 230000003034 chemosensitisation Effects 0.000 claims abstract description 8
- -1 7,7-bis- (4-fluoro-1H-indol-3-yl) -heptanoic acid hydroxyamide 7, 7-bis- (5-methyl-1H-indol-3-yl) -heptanoic acid hydroxyamide 7,7-bis- (7-ethyl-1H-indol-3-yl) -heptanoic acid hydroxyamide Chemical compound 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000002246 antineoplastic agent Substances 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- XOABRVOPAZJQCU-UHFFFAOYSA-N 7,7-bis(1h-indol-3-yl)heptanoic acid Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCCCC(=O)O)=CNC2=C1 XOABRVOPAZJQCU-UHFFFAOYSA-N 0.000 claims description 12
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 206010059866 Drug resistance Diseases 0.000 claims description 8
- 230000007170 pathology Effects 0.000 claims description 8
- 125000002947 alkylene group Chemical group 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 229940041181 antineoplastic drug Drugs 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229930002330 retinoic acid Natural products 0.000 claims description 6
- SHGAZHPCJJPHSC-YCNIQYBTSA-N retinoic acid group Chemical group C\C(=C/C(=O)O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- GGGOHLKTYWKLQS-UHFFFAOYSA-N 7,7-bis(7-methoxy-1h-indol-3-yl)heptanoic acid Chemical compound C1=CC=C2C(C(CCCCCC(O)=O)C=3C=4C=CC=C(C=4NC=3)OC)=CNC2=C1OC GGGOHLKTYWKLQS-UHFFFAOYSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000003147 glycosyl group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 229940088710 antibiotic agent Drugs 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- JAKKVYLKVYJELP-UHFFFAOYSA-N n-hydroxy-6,6-bis(1h-indol-3-yl)hexanamide Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCCC(=O)NO)=CNC2=C1 JAKKVYLKVYJELP-UHFFFAOYSA-N 0.000 claims description 4
- AMCCNRABUUCWIM-UHFFFAOYSA-N n-hydroxy-6-(1h-indol-3-yl)hexanamide Chemical compound C1=CC=C2C(CCCCCC(=O)NO)=CNC2=C1 AMCCNRABUUCWIM-UHFFFAOYSA-N 0.000 claims description 4
- QNHLDXNWBDOXOP-UHFFFAOYSA-N n-hydroxy-8,8-bis(1h-indol-3-yl)octanamide Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCCCCC(=O)NO)=CNC2=C1 QNHLDXNWBDOXOP-UHFFFAOYSA-N 0.000 claims description 4
- 125000006681 (C2-C10) alkylene group Chemical group 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 3
- 208000018084 Bone neoplasm Diseases 0.000 claims description 3
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- 208000017604 Hodgkin disease Diseases 0.000 claims description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 3
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 claims description 3
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004419 alkynylene group Chemical group 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 208000002458 carcinoid tumor Diseases 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- DJVHYWLVIXMHKA-UHFFFAOYSA-N n-hydroxy-4,4-bis(1h-indol-3-yl)butanamide Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCC(=O)NO)=CNC2=C1 DJVHYWLVIXMHKA-UHFFFAOYSA-N 0.000 claims description 3
- UNKOKDUSFRTJQV-UHFFFAOYSA-N n-hydroxy-5,5-bis(1h-indol-3-yl)pentanamide Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCC(=O)NO)=CNC2=C1 UNKOKDUSFRTJQV-UHFFFAOYSA-N 0.000 claims description 3
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims description 3
- 201000011519 neuroendocrine tumor Diseases 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 206010000871 Acute monocytic leukaemia Diseases 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 229940123237 Taxane Drugs 0.000 claims description 2
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 2
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 claims description 2
- 229940088598 enzyme Drugs 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 238000009830 intercalation Methods 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229930014626 natural product Natural products 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 claims description 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 claims 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 150000003973 alkyl amines Chemical class 0.000 claims 1
- 230000000447 dimerizing effect Effects 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 208000025113 myeloid leukemia Diseases 0.000 claims 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical class C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
- 239000000243 solution Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 210000004881 tumor cell Anatomy 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- HQERNOHMGPEZSO-UHFFFAOYSA-N 5,5-bis(1h-indol-3-yl)pentanoic acid Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCC(=O)O)=CNC2=C1 HQERNOHMGPEZSO-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000004007 reversed phase HPLC Methods 0.000 description 8
- UQJFQBCSRSWTMT-UHFFFAOYSA-N 6,6-bis(1h-indol-3-yl)hexanoic acid Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCCC(=O)O)=CNC2=C1 UQJFQBCSRSWTMT-UHFFFAOYSA-N 0.000 description 7
- XSVCYDUEICANRJ-UHFFFAOYSA-K dysprosium(3+);trifluoromethanesulfonate Chemical compound [Dy+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F XSVCYDUEICANRJ-UHFFFAOYSA-K 0.000 description 7
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- SQOMZPCAODNNSO-UHFFFAOYSA-N ethyl 7-oxoheptanoate Chemical compound CCOC(=O)CCCCCC=O SQOMZPCAODNNSO-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229910001868 water Inorganic materials 0.000 description 6
- 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 5
- XCDIJFXDWBEHSC-UHFFFAOYSA-N 8,8-bis(1h-indol-3-yl)octanoic acid Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCCCCC(=O)O)=CNC2=C1 XCDIJFXDWBEHSC-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZXKINMCYCKHYFR-UHFFFAOYSA-N aminooxidanide Chemical compound [O-]N ZXKINMCYCKHYFR-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 4
- CWDRXWUNLQMMEO-UHFFFAOYSA-N 7,7-bis(4-fluoro-1h-indol-3-yl)heptanoic acid Chemical compound C1=CC(F)=C2C(C(C=3C4=C(F)C=CC=C4NC=3)CCCCCC(=O)O)=CNC2=C1 CWDRXWUNLQMMEO-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- XVEQQXYYEHWLBU-UHFFFAOYSA-N n-hydroxy-7,7-bis[5-(morpholin-4-ylmethyl)-3h-indol-3-yl]heptanamide Chemical compound C1=NC2=CC=C(CN3CCOCC3)C=C2C1C(CCCCCC(=O)NO)C(C1=C2)C=NC1=CC=C2CN1CCOCC1 XVEQQXYYEHWLBU-UHFFFAOYSA-N 0.000 description 4
- YRBZDDSKSDEOKC-UHFFFAOYSA-N n-hydroxy-7-(1h-indol-2-yl)-7-(1h-indol-3-yl)heptanamide Chemical compound C1=CC=C2C(C(C=3NC4=CC=CC=C4C=3)CCCCCC(=O)NO)=CNC2=C1 YRBZDDSKSDEOKC-UHFFFAOYSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- FMDYOUUUJFZVRQ-UHFFFAOYSA-N 7,7-bis(5-methyl-1h-indol-3-yl)heptanoic acid Chemical compound C1=C(C)C=C2C(C(CCCCCC(O)=O)C3=CNC4=CC=C(C=C43)C)=CNC2=C1 FMDYOUUUJFZVRQ-UHFFFAOYSA-N 0.000 description 3
- OUOXATPGCGZWAK-UHFFFAOYSA-N 7,7-bis(7-ethyl-1h-indol-3-yl)-n-hydroxyheptanamide Chemical compound C1=CC=C2C(C(CCCCCC(=O)NO)C=3C=4C=CC=C(C=4NC=3)CC)=CNC2=C1CC OUOXATPGCGZWAK-UHFFFAOYSA-N 0.000 description 3
- RVWRRVDMVRVBGM-UHFFFAOYSA-N 7,7-bis(7-ethyl-1h-indol-3-yl)heptanoic acid Chemical compound C1=CC=C2C(C(CCCCCC(O)=O)C=3C=4C=CC=C(C=4NC=3)CC)=CNC2=C1CC RVWRRVDMVRVBGM-UHFFFAOYSA-N 0.000 description 3
- OVWXFEQTQFBFLR-UHFFFAOYSA-N 7,7-bis[5-(morpholin-4-ylmethyl)-3h-indol-3-yl]heptanoic acid Chemical compound C1=NC2=CC=C(CN3CCOCC3)C=C2C1C(CCCCCC(=O)O)C(C1=C2)C=NC1=CC=C2CN1CCOCC1 OVWXFEQTQFBFLR-UHFFFAOYSA-N 0.000 description 3
- 102000003964 Histone deacetylase Human genes 0.000 description 3
- 108090000353 Histone deacetylase Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000002001 anti-metastasis Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- ZWBFOQJCRGCPED-UHFFFAOYSA-N n-hydroxy-7,7-bis(1h-indol-3-yl)heptanamide Chemical compound C1=CC=C2C(C(C=3C4=CC=CC=C4NC=3)CCCCCC(=O)NO)=CNC2=C1 ZWBFOQJCRGCPED-UHFFFAOYSA-N 0.000 description 3
- OGZQMWDPHWVYAK-UHFFFAOYSA-N n-hydroxy-7,7-bis(5-methyl-1h-indol-3-yl)heptanamide Chemical compound C1=C(C)C=C2C(C(CCCCCC(=O)NO)C3=CNC4=CC=C(C=C43)C)=CNC2=C1 OGZQMWDPHWVYAK-UHFFFAOYSA-N 0.000 description 3
- FSLXJUDEBBIVKO-UHFFFAOYSA-N n-hydroxy-7,7-bis(7-methoxy-1h-indol-3-yl)heptanamide Chemical compound C1=CC=C2C(C(CCCCCC(=O)NO)C=3C=4C=CC=C(C=4NC=3)OC)=CNC2=C1OC FSLXJUDEBBIVKO-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ZALBCDKLQFUZNN-UHFFFAOYSA-N 7,7-bis(4-fluoro-1h-indol-3-yl)-n-hydroxyheptanamide Chemical compound C1=CC(F)=C2C(C(C=3C4=C(F)C=CC=C4NC=3)CCCCCC(=O)NO)=CNC2=C1 ZALBCDKLQFUZNN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05012562.4 | 2005-06-10 | ||
| EP05012562 | 2005-06-10 | ||
| PCT/EP2006/062798 WO2006131484A1 (en) | 2005-06-10 | 2006-05-31 | Indole derivatives having antitumor activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0612542A2 true BRPI0612542A2 (pt) | 2010-11-23 |
Family
ID=35062959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0612542-5A BRPI0612542A2 (pt) | 2005-06-10 | 2006-05-31 | derivados de indol com atividade antitumoral |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US8053460B2 (enExample) |
| EP (1) | EP1891007A1 (enExample) |
| JP (1) | JP2008542428A (enExample) |
| KR (1) | KR20080029967A (enExample) |
| CN (1) | CN101193861A (enExample) |
| AR (1) | AR053891A1 (enExample) |
| AU (1) | AU2006256771A1 (enExample) |
| BR (1) | BRPI0612542A2 (enExample) |
| CA (1) | CA2607337A1 (enExample) |
| EA (1) | EA013542B1 (enExample) |
| MX (1) | MX2007015274A (enExample) |
| TW (1) | TW200716545A (enExample) |
| WO (1) | WO2006131484A1 (enExample) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2650810T3 (es) * | 2009-01-28 | 2018-01-22 | Karus Therapeutics Limited | Isósteros de Scriptaid y su uso en terapia |
| TWI429628B (zh) * | 2010-03-29 | 2014-03-11 | Univ Taipei Medical | 吲哚基或吲哚啉基羥肟酸化合物 |
| MX364295B (es) * | 2012-11-07 | 2019-04-22 | Karus Therapeutics Ltd | Inhibidores de histona desacetilasa novedosos y su uso en terapia. |
| LT2994465T (lt) | 2013-05-10 | 2018-10-10 | Karus Therapeutics Limited | Nauji histono deacetilazės inhibitoriai |
| GB201419264D0 (en) | 2014-10-29 | 2014-12-10 | Karus Therapeutics Ltd | Compounds |
| GB201419228D0 (en) | 2014-10-29 | 2014-12-10 | Karus Therapeutics Ltd | Compounds |
| RU2633266C2 (ru) * | 2015-07-02 | 2017-10-11 | Рауф Ашрафович Ашрафов | Способ моделирования карциноидного синдрома |
| CN105367479A (zh) * | 2015-11-16 | 2016-03-02 | 青岛大学 | 一种组蛋白去乙酰酶抑制剂2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1氢-吲哚-3-基-n-(2-(羟氨基)-2-酮乙基)乙酰胺及其制备方法和应用 |
| CN109928909A (zh) * | 2019-04-02 | 2019-06-25 | 南华大学 | 具有抗抑郁活性化合物及其制备方法 |
| CN120136763B (zh) * | 2025-03-13 | 2025-10-10 | 遵义医科大学 | 一种c-3苄基化吲哚类化合物、制备方法及其应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0887348A1 (en) * | 1997-06-25 | 1998-12-30 | Boehringer Mannheim Italia S.p.A. | Bis-Indole derivatives having antimetastatic activity, a process for their preparation and pharmaceutical compositions containing them |
| IT1317925B1 (it) * | 2000-11-03 | 2003-07-15 | Sigma Tau Ind Farmaceuti | Bis-eterocicli ad attivita' antitumorale e chemosensibilizzante. |
| WO2003032982A1 (en) | 2001-10-19 | 2003-04-24 | Transtech Pharma, Inc. | Bis-heteroaryl alkanes as therapeutic agents |
| JP4790594B2 (ja) * | 2003-02-25 | 2011-10-12 | トポターゲット ユーケー リミテッド | Ｈｄａｃインヒビターとしての、二環式ヘテロアリール基を含むヒドロキサム酸化合物 |
-
2006
- 2006-05-24 TW TW095118475A patent/TW200716545A/zh unknown
- 2006-05-31 JP JP2008515199A patent/JP2008542428A/ja not_active Withdrawn
- 2006-05-31 KR KR1020077029390A patent/KR20080029967A/ko not_active Ceased
- 2006-05-31 MX MX2007015274A patent/MX2007015274A/es not_active Application Discontinuation
- 2006-05-31 WO PCT/EP2006/062798 patent/WO2006131484A1/en not_active Ceased
- 2006-05-31 EA EA200702672A patent/EA013542B1/ru not_active IP Right Cessation
- 2006-05-31 AU AU2006256771A patent/AU2006256771A1/en not_active Abandoned
- 2006-05-31 EP EP06777259A patent/EP1891007A1/en not_active Withdrawn
- 2006-05-31 CA CA002607337A patent/CA2607337A1/en not_active Abandoned
- 2006-05-31 BR BRPI0612542-5A patent/BRPI0612542A2/pt not_active IP Right Cessation
- 2006-05-31 CN CNA2006800205522A patent/CN101193861A/zh active Pending
- 2006-05-31 US US11/917,065 patent/US8053460B2/en not_active Expired - Fee Related
- 2006-06-08 AR ARP060102385A patent/AR053891A1/es not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| TW200716545A (en) | 2007-05-01 |
| CN101193861A (zh) | 2008-06-04 |
| EA200702672A1 (ru) | 2008-04-28 |
| EA013542B1 (ru) | 2010-06-30 |
| AR053891A1 (es) | 2007-05-23 |
| EP1891007A1 (en) | 2008-02-27 |
| US8053460B2 (en) | 2011-11-08 |
| WO2006131484A1 (en) | 2006-12-14 |
| CA2607337A1 (en) | 2006-12-14 |
| JP2008542428A (ja) | 2008-11-27 |
| KR20080029967A (ko) | 2008-04-03 |
| MX2007015274A (es) | 2008-02-22 |
| US20080207729A1 (en) | 2008-08-28 |
| AU2006256771A1 (en) | 2006-12-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B08F | Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette] |
Free format text: REFERENTE 7A. ANUIDADE(S). |
|
| B08K | Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette] |
Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2213 DE 04/06/2013. |