CA2501938A1 - Compounds, compositions, and methods - Google Patents
Compounds, compositions, and methods Download PDFInfo
- Publication number
- CA2501938A1 CA2501938A1 CA002501938A CA2501938A CA2501938A1 CA 2501938 A1 CA2501938 A1 CA 2501938A1 CA 002501938 A CA002501938 A CA 002501938A CA 2501938 A CA2501938 A CA 2501938A CA 2501938 A1 CA2501938 A1 CA 2501938A1
- Authority
- CA
- Canada
- Prior art keywords
- optionally substituted
- alkyl
- hydrogen
- phenyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims description 300
- 238000000034 method Methods 0.000 title claims description 55
- 239000000203 mixture Substances 0.000 title description 59
- 230000000694 effects Effects 0.000 claims abstract description 44
- 230000001413 cellular effect Effects 0.000 claims abstract description 14
- 230000002062 proliferating effect Effects 0.000 claims abstract description 12
- -1 cyano, nitro, methylenedioxy Chemical group 0.000 claims description 386
- 229910052739 hydrogen Inorganic materials 0.000 claims description 112
- 239000001257 hydrogen Substances 0.000 claims description 111
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
- 125000001072 heteroaryl group Chemical group 0.000 claims description 80
- 125000003107 substituted aryl group Chemical group 0.000 claims description 77
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 62
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 59
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 43
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 41
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000005059 halophenyl group Chemical group 0.000 claims description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000006178 methyl benzyl group Chemical group 0.000 claims description 23
- 125000004803 chlorobenzyl group Chemical group 0.000 claims description 21
- 125000002946 cyanobenzyl group Chemical group 0.000 claims description 21
- 125000006289 hydroxybenzyl group Chemical group 0.000 claims description 21
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical group 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 14
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 14
- 102000010638 Kinesin Human genes 0.000 claims description 13
- 108010063296 Kinesin Proteins 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 125000001624 naphthyl group Chemical group 0.000 claims description 11
- 125000003944 tolyl group Chemical group 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 5
- 125000004799 bromophenyl group Chemical group 0.000 claims description 5
- 125000004802 cyanophenyl group Chemical group 0.000 claims description 5
- 125000006286 dichlorobenzyl group Chemical group 0.000 claims description 5
- 230000004054 inflammatory process Effects 0.000 claims description 5
- 125000006223 tetrahydrofuranylmethyl group Chemical group 0.000 claims description 5
- 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
- 208000006029 Cardiomegaly Diseases 0.000 claims description 4
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 4
- 206010020718 hyperplasia Diseases 0.000 claims description 4
- 208000026278 immune system disease Diseases 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000037803 restenosis Diseases 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 3
- 238000002372 labelling Methods 0.000 claims description 2
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 208000037765 diseases and disorders Diseases 0.000 abstract description 2
- MDTUWBLTRPRXBX-UHFFFAOYSA-N 1,2,4-triazol-3-one Chemical class O=C1N=CN=N1 MDTUWBLTRPRXBX-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- 238000006243 chemical reaction Methods 0.000 description 83
- 239000000243 solution Substances 0.000 description 72
- 210000004027 cell Anatomy 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000003795 chemical substances by application Substances 0.000 description 46
- 230000000394 mitotic effect Effects 0.000 description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- 230000027455 binding Effects 0.000 description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 34
- 150000002431 hydrogen Chemical class 0.000 description 33
- 239000002585 base Substances 0.000 description 29
- 238000002360 preparation method Methods 0.000 description 26
- 102000029749 Microtubule Human genes 0.000 description 24
- 108091022875 Microtubule Proteins 0.000 description 24
- 239000002253 acid Substances 0.000 description 24
- 210000004688 microtubule Anatomy 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 150000001412 amines Chemical class 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 23
- 239000000010 aprotic solvent Substances 0.000 description 22
- 238000003556 assay Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- 235000018102 proteins Nutrition 0.000 description 17
- 102000004169 proteins and genes Human genes 0.000 description 17
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 230000004663 cell proliferation Effects 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 12
- 230000011278 mitosis Effects 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 229910001868 water Inorganic materials 0.000 description 11
- 108091006112 ATPases Proteins 0.000 description 10
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 10
- 150000001299 aldehydes Chemical class 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 229940000406 drug candidate Drugs 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 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 8
- 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 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 230000020347 spindle assembly Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 101001008953 Homo sapiens Kinesin-like protein KIF11 Proteins 0.000 description 7
- 206010025323 Lymphomas Diseases 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 208000009956 adenocarcinoma Diseases 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000008121 dextrose Substances 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000012216 screening Methods 0.000 description 7
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 7
- 201000009030 Carcinoma Diseases 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 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
- 238000002835 absorbance Methods 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 230000003833 cell viability Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 102000055595 human KIF11 Human genes 0.000 description 6
- 238000001990 intravenous administration Methods 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000002538 fungal effect Effects 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 229910052740 iodine Chemical group 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000005415 substituted alkoxy group Chemical group 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 4
- XSGMGAINOILNJR-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methyl-3-tritylsulfanylbutanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)NC(C(O)=O)C(C)(C)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XSGMGAINOILNJR-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
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- 150000001408 amides Chemical class 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
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- 239000003054 catalyst Substances 0.000 description 4
- 230000025084 cell cycle arrest Effects 0.000 description 4
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- 239000000460 chlorine Chemical group 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- DHZYXWMZLAKTQV-UHFFFAOYSA-N diazepin-3-one Chemical class O=C1C=CC=CN=N1 DHZYXWMZLAKTQV-UHFFFAOYSA-N 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 230000036244 malformation Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Hospice & Palliative Care (AREA)
- Transplantation (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41788902P | 2002-10-11 | 2002-10-11 | |
| US60/417,889 | 2002-10-11 | ||
| PCT/US2003/031413 WO2004032840A2 (en) | 2002-10-11 | 2003-10-02 | Compounds, compositions, and methods |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2501938A1 true CA2501938A1 (en) | 2004-04-22 |
Family
ID=32094113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002501938A Abandoned CA2501938A1 (en) | 2002-10-11 | 2003-10-02 | Compounds, compositions, and methods |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US7476743B2 (https=) |
| EP (1) | EP1558588A4 (https=) |
| JP (1) | JP2006502219A (https=) |
| KR (1) | KR20050075356A (https=) |
| CN (1) | CN1726198A (https=) |
| AR (1) | AR044193A1 (https=) |
| AU (1) | AU2003282665A1 (https=) |
| BR (1) | BR0315247A (https=) |
| CA (1) | CA2501938A1 (https=) |
| IL (1) | IL167936A0 (https=) |
| IS (1) | IS7798A (https=) |
| MX (1) | MXPA05003830A (https=) |
| NO (1) | NO20052267L (https=) |
| NZ (1) | NZ539643A (https=) |
| PL (1) | PL375889A1 (https=) |
| RU (1) | RU2005114491A (https=) |
| TW (1) | TW200418818A (https=) |
| WO (1) | WO2004032840A2 (https=) |
| ZA (1) | ZA200503733B (https=) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101170925B1 (ko) * | 2004-06-18 | 2012-08-07 | 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 | 암 치료용 키네신 방추 단백질 (ｋｓｐ) 억제제로서의ｎ-(1-(1-벤질-4-페닐-1ｈ-이미다졸-2-일)-2,2-디메틸프로필)벤자미드 유도체 및 관련 화합물 |
| CN101027309B (zh) | 2004-08-18 | 2010-10-27 | 阿斯利康(瑞典)有限公司 | 所选择的稠合嘧啶酮的对映体和在治疗和预防癌症中的用途 |
| DE102006023337A1 (de) * | 2006-05-18 | 2007-11-22 | Merck Patent Gmbh | Triazolderivate II |
| JP5343363B2 (ja) * | 2008-01-31 | 2013-11-13 | アイシン精機株式会社 | シートクッション調整装置 |
| CN101643451B (zh) * | 2008-08-07 | 2013-03-06 | 浙江海正药业股份有限公司 | 过氧化物酶增殖物激活受体亚型δ类激动剂化合物及其制备方法 |
| JP2013523867A (ja) | 2010-04-15 | 2013-06-17 | ノバルティス アーゲー | Ｋｓｐ阻害剤としてのトリアゾール化合物 |
| WO2012095691A1 (en) * | 2011-01-15 | 2012-07-19 | Jubilant Life Sciences Ltd. | An improved process for producing aminopyridines |
| WO2013134562A1 (en) | 2012-03-09 | 2013-09-12 | Inception 2, Inc. | Triazolone compounds and uses thereof |
| AU2013363398B2 (en) | 2012-12-20 | 2017-06-01 | Tempest Therapeutics, Inc. | Triazolone compounds and uses thereof |
| US9776976B2 (en) | 2013-09-06 | 2017-10-03 | Inception 2, Inc. | Triazolone compounds and uses thereof |
| RU2751512C2 (ru) | 2015-06-22 | 2021-07-14 | Байер Фарма Акциенгезельшафт | Конъюгаты антитела и лекарственного средства (adc) и конъюгаты антитела и пролекарства (apdc), содержащие ферментативно расщепляемые группы |
| TW201722958A (zh) * | 2015-09-15 | 2017-07-01 | 葛蘭素史克智慧財產（第二）有限公司 | 化學化合物 |
| JP7066714B2 (ja) | 2016-12-21 | 2022-05-13 | バイエル・ファルマ・アクティエンゲゼルシャフト | 酵素的に切断可能な基を有する抗体薬物コンジュゲート（ａｄｃ） |
| US20250215039A1 (en) * | 2022-03-30 | 2025-07-03 | Primefour Therapeutics, Inc. | Nucleosides for treating cancer |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793532A (fr) * | 1971-12-29 | 1973-06-29 | Upjohn Co | Nouvelles 1,2,4-triazol-3-ones et leur preparation |
| US3748339A (en) * | 1972-05-05 | 1973-07-24 | Upjohn Co | 2-(3-(1-(dimethylamino)alkyl)-1,5-dihydro-5-oxo - 1 - substituted-4h-1,2,4-triazol-4-yl)benzophenone and process |
| IT1068010B (it) * | 1976-11-17 | 1985-03-21 | Montedison Spa | Nuovi esteri fosforici derivati dall' 1-2-4 triazolo ad azione insetticida,nematocida e acaricida e loro preparazione |
| NL7712430A (nl) * | 1976-11-17 | 1978-05-19 | Montedison Spa | Nieuwe fosforzuuresters, afgeleid van 1.2.4- -triazool, met een insecticide, nematocide en acaricide werking en werkwijze ter bereiding daarvan. |
| US4487773A (en) * | 1981-03-16 | 1984-12-11 | Mead Johnson & Company | 1,2,4-Triazol-3-one antidepressants |
| US5250558A (en) * | 1992-01-28 | 1993-10-05 | Merck & Co., Inc. | Substituted triazolinones, triazolinethiones, and triazolinimines as neurotensin antagonists used to treat psychosis |
| GB9211193D0 (en) * | 1992-05-27 | 1992-07-08 | Merck Sharp & Dohme | Therapeutic agents |
| IL106142A (en) * | 1992-06-29 | 1997-03-18 | Merck & Co Inc | Morpholine and thiomorpholine tachykinin receptor antagonists, their preparation and pharmaceutical compositions containing them |
| AU722883B2 (en) * | 1995-10-18 | 2000-08-10 | Merck & Co., Inc. | Cyclopentyl tachykinin receptor antagonists |
| JP2002234874A (ja) * | 2000-09-26 | 2002-08-23 | Tanabe Seiyaku Co Ltd | ５−フェニルベンジルアミン誘導体、その製法及びその合成中間体 |
| WO2002034699A2 (en) * | 2000-10-26 | 2002-05-02 | Merck & Co., Inc. | Mammalian metabolites of a tachykinin receptor antagonist |
| MXPA04012642A (es) * | 2002-06-14 | 2005-03-23 | Merck & Co Inc | Inhibidores de la cinesina mitotica. |
-
2003
- 2003-10-02 PL PL03375889A patent/PL375889A1/xx unknown
- 2003-10-02 MX MXPA05003830A patent/MXPA05003830A/es unknown
- 2003-10-02 KR KR1020057006260A patent/KR20050075356A/ko not_active Withdrawn
- 2003-10-02 RU RU2005114491/04A patent/RU2005114491A/ru not_active Application Discontinuation
- 2003-10-02 CN CNA200380105737XA patent/CN1726198A/zh active Pending
- 2003-10-02 US US10/529,634 patent/US7476743B2/en not_active Expired - Fee Related
- 2003-10-02 EP EP03774548A patent/EP1558588A4/en not_active Withdrawn
- 2003-10-02 WO PCT/US2003/031413 patent/WO2004032840A2/en not_active Ceased
- 2003-10-02 BR BR0315247-2A patent/BR0315247A/pt not_active IP Right Cessation
- 2003-10-02 CA CA002501938A patent/CA2501938A1/en not_active Abandoned
- 2003-10-02 JP JP2004543136A patent/JP2006502219A/ja active Pending
- 2003-10-02 NZ NZ539643A patent/NZ539643A/en unknown
- 2003-10-02 AU AU2003282665A patent/AU2003282665A1/en not_active Abandoned
- 2003-10-09 AR ARP030103684A patent/AR044193A1/es unknown
- 2003-10-09 TW TW092128029A patent/TW200418818A/zh unknown
-
2005
- 2005-04-10 IL IL167936A patent/IL167936A0/en unknown
- 2005-04-11 IS IS7798A patent/IS7798A/is unknown
- 2005-05-10 NO NO20052267A patent/NO20052267L/no not_active Application Discontinuation
- 2005-05-10 ZA ZA200503733A patent/ZA200503733B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA05003830A (es) | 2005-06-23 |
| PL375889A1 (en) | 2005-12-12 |
| NO20052267L (no) | 2005-05-31 |
| AR044193A1 (es) | 2005-09-07 |
| AU2003282665A1 (en) | 2004-05-04 |
| EP1558588A4 (en) | 2006-11-02 |
| EP1558588A2 (en) | 2005-08-03 |
| TW200418818A (en) | 2004-10-01 |
| CN1726198A (zh) | 2006-01-25 |
| RU2005114491A (ru) | 2006-02-10 |
| ZA200503733B (en) | 2006-02-22 |
| NZ539643A (en) | 2006-11-30 |
| US20060189671A1 (en) | 2006-08-24 |
| IL167936A0 (en) | 2009-02-11 |
| WO2004032840A2 (en) | 2004-04-22 |
| US7476743B2 (en) | 2009-01-13 |
| BR0315247A (pt) | 2005-08-30 |
| JP2006502219A (ja) | 2006-01-19 |
| WO2004032840A3 (en) | 2004-10-14 |
| IS7798A (is) | 2005-04-11 |
| KR20050075356A (ko) | 2005-07-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |