CA2335115C - Fused azepinone cyclin dependent kinase inhibitors - Google Patents
Fused azepinone cyclin dependent kinase inhibitors Download PDFInfo
- Publication number
- CA2335115C CA2335115C CA002335115A CA2335115A CA2335115C CA 2335115 C CA2335115 C CA 2335115C CA 002335115 A CA002335115 A CA 002335115A CA 2335115 A CA2335115 A CA 2335115A CA 2335115 C CA2335115 C CA 2335115C
- Authority
- CA
- Canada
- Prior art keywords
- dihydro
- benzazepin
- indolo
- bromo
- hydrogen
- 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.)
- Expired - Fee Related
Links
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title abstract description 11
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 title abstract description 6
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical compound O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 148
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 76
- 239000001257 hydrogen Substances 0.000 claims abstract description 74
- 239000000203 mixture Substances 0.000 claims abstract description 67
- -1 aliphatic alcohols Chemical class 0.000 claims abstract description 66
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000002367 halogens Chemical class 0.000 claims abstract description 36
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 35
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 23
- 125000002252 acyl group Chemical group 0.000 claims abstract description 21
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 19
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 18
- 239000001301 oxygen Substances 0.000 claims abstract description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 16
- 125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000011593 sulfur Substances 0.000 claims abstract description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 12
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 11
- 230000035755 proliferation Effects 0.000 claims abstract description 10
- 125000005907 alkyl ester group Chemical group 0.000 claims abstract description 8
- 150000002576 ketones Chemical class 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 7
- 239000004593 Epoxy Substances 0.000 claims abstract description 6
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract description 6
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 44
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 27
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 9
- MILILGJHFMDHIJ-UHFFFAOYSA-N 9-(trifluoromethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(C(F)(F)F)=CC=C1N2 MILILGJHFMDHIJ-UHFFFAOYSA-N 0.000 claims description 8
- DUZUWJBAONJCTE-UHFFFAOYSA-N 9-bromo-2,3-dimethoxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2C=C(OC)C(OC)=CC=2NC(=O)CC2=C1NC1=CC=C(Br)C=C21 DUZUWJBAONJCTE-UHFFFAOYSA-N 0.000 claims description 7
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- RVTOIQOTZUKDTE-UHFFFAOYSA-N 2,3-dimethoxy-9-(trifluoromethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2C=C(OC)C(OC)=CC=2NC(=O)CC2=C1NC1=CC=C(C(F)(F)F)C=C21 RVTOIQOTZUKDTE-UHFFFAOYSA-N 0.000 claims description 6
- LBVIZFWUIQSZHP-UHFFFAOYSA-N 6-oxo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepine-9-carbonitrile Chemical compound C12=CC=CC=C2NC(=O)CC2=C1NC1=CC=C(C#N)C=C21 LBVIZFWUIQSZHP-UHFFFAOYSA-N 0.000 claims description 6
- XLKHCIUFNPNLIE-UHFFFAOYSA-N dnc004090 Chemical compound C12=CC(Br)=CC=C2NC2=C1CC(=O)NC1=C2SC=C1 XLKHCIUFNPNLIE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- GWFCNMFOAORLDH-UHFFFAOYSA-N 9-bromo-12-(2-hydroxyethyl)-5,7-dihydroindolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2CCO GWFCNMFOAORLDH-UHFFFAOYSA-N 0.000 claims description 5
- JKVBIBIZBZBAKL-UHFFFAOYSA-N 9-bromo-2-iodo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=C(I)C=C2C2=C1C1=CC(Br)=CC=C1N2 JKVBIBIZBZBAKL-UHFFFAOYSA-N 0.000 claims description 5
- XOAKRYSSJJAKLL-UHFFFAOYSA-N 9-methoxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(OC)=CC=C1N2 XOAKRYSSJJAKLL-UHFFFAOYSA-N 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- YAKJZHVHEIOVIR-UHFFFAOYSA-N 2,3-dimethoxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2C=C(OC)C(OC)=CC=2NC(=O)CC2=C1NC1=CC=CC=C21 YAKJZHVHEIOVIR-UHFFFAOYSA-N 0.000 claims description 4
- CZOVMHCLKVCOEM-UHFFFAOYSA-N 2-bromo-9-(trifluoromethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=C(Br)C=C2C2=C1C1=CC(C(F)(F)F)=CC=C1N2 CZOVMHCLKVCOEM-UHFFFAOYSA-N 0.000 claims description 4
- CYWSKAGHMPTBMS-UHFFFAOYSA-N 9-bromo-12-methyl-5,7-dihydroindolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2C CYWSKAGHMPTBMS-UHFFFAOYSA-N 0.000 claims description 4
- FDMHWATUIRUWOF-UHFFFAOYSA-N 9-methyl-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(C)=CC=C1N2 FDMHWATUIRUWOF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000006193 alkinyl group Chemical group 0.000 claims description 4
- OLUKILHGKRVDCT-UHFFFAOYSA-N alsterpaullone Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC([N+](=O)[O-])=CC=C1N2 OLUKILHGKRVDCT-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000000872 buffer Substances 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 235000019634 flavors Nutrition 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- YKGKBQYSHBGZQB-UHFFFAOYSA-N 11-bromo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C(C=CC=C1Br)=C1N2 YKGKBQYSHBGZQB-UHFFFAOYSA-N 0.000 claims description 3
- LOOYKDRIOSVHMM-UHFFFAOYSA-N 11-ethyl-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C(C=CC=C1CC)=C1N2 LOOYKDRIOSVHMM-UHFFFAOYSA-N 0.000 claims description 3
- XWKMAJPZELTMLH-UHFFFAOYSA-N 11-methyl-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C(C=CC=C1C)=C1N2 XWKMAJPZELTMLH-UHFFFAOYSA-N 0.000 claims description 3
- TUMYZJPVQGGVEN-UHFFFAOYSA-N 2,3-dimethoxy-6-oxo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepine-9-carbonitrile Chemical compound C1=2C=C(OC)C(OC)=CC=2NC(=O)CC2=C1NC1=CC=C(C#N)C=C21 TUMYZJPVQGGVEN-UHFFFAOYSA-N 0.000 claims description 3
- KYRQRRGDKAIFMA-UHFFFAOYSA-N 2,3-dimethoxy-9-nitro-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2C=C(OC)C(OC)=CC=2NC(=O)CC2=C1NC1=CC=C([N+]([O-])=O)C=C21 KYRQRRGDKAIFMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
- OQBFFVLVOYLSHP-UHFFFAOYSA-N 3-[6-oxo-9-(trifluoromethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-2-yl]prop-2-enoic acid Chemical compound C12=CC(C=CC(=O)O)=CC=C2NC(=O)CC2=C1NC1=CC=C(C(F)(F)F)C=C21 OQBFFVLVOYLSHP-UHFFFAOYSA-N 0.000 claims description 3
- UQYAOCPYYWTPID-UHFFFAOYSA-N 6-oxo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepine-2-carbonitrile Chemical compound C12=CC(C#N)=CC=C2NC(=O)CC2=C1NC1=CC=CC=C21 UQYAOCPYYWTPID-UHFFFAOYSA-N 0.000 claims description 3
- CSJPCQXZZVBCHG-UHFFFAOYSA-N 9-bromo-2,3-dihydroxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2C=C(O)C(O)=CC=2NC(=O)CC2=C1NC1=CC=C(Br)C=C21 CSJPCQXZZVBCHG-UHFFFAOYSA-N 0.000 claims description 3
- MHKWLZUWJABEIX-UHFFFAOYSA-N 9-bromo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepine-6-thione Chemical compound C1C(=S)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2 MHKWLZUWJABEIX-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- IGVYXSVOVAENJU-UHFFFAOYSA-N chembl118406 Chemical compound C12=CC(C)=CC=C2NC2=C1CC(=O)NC1=C2SC=C1 IGVYXSVOVAENJU-UHFFFAOYSA-N 0.000 claims description 3
- IUCQPIROBHBEID-UHFFFAOYSA-N chembl334031 Chemical compound C12=CC(Cl)=CC=C2NC2=C1CC(=O)NC1=C2SC=C1 IUCQPIROBHBEID-UHFFFAOYSA-N 0.000 claims description 3
- 238000007907 direct compression Methods 0.000 claims description 3
- 230000003463 hyperproliferative effect Effects 0.000 claims description 3
- 238000007912 intraperitoneal administration Methods 0.000 claims description 3
- 238000001990 intravenous administration Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000007920 subcutaneous administration Methods 0.000 claims description 3
- FZSXLUDKOYPBMM-UHFFFAOYSA-N 2,3-dihydroxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2C=C(O)C(O)=CC=2NC(=O)CC2=C1NC1=CC=CC=C21 FZSXLUDKOYPBMM-UHFFFAOYSA-N 0.000 claims description 2
- IEEQWYMIVLKPFP-UHFFFAOYSA-N 2-bromo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C12=CC(Br)=CC=C2NC(=O)CC2=C1NC1=CC=CC=C21 IEEQWYMIVLKPFP-UHFFFAOYSA-N 0.000 claims description 2
- IAJGQMXAKJOLBA-UHFFFAOYSA-N 2-bromo-9-nitro-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=C(Br)C=C2C2=C1C1=CC([N+](=O)[O-])=CC=C1N2 IAJGQMXAKJOLBA-UHFFFAOYSA-N 0.000 claims description 2
- MVWNPTRDUDXOPY-UHFFFAOYSA-N 3-[6-oxo-9-(trifluoromethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-2-yl]prop-2-enenitrile Chemical compound C1C(=O)NC2=CC=C(C=CC#N)C=C2C2=C1C1=CC(C(F)(F)F)=CC=C1N2 MVWNPTRDUDXOPY-UHFFFAOYSA-N 0.000 claims description 2
- SHBOZSJPVRMXBA-UHFFFAOYSA-N 3-[6-oxo-9-(trifluoromethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-2-yl]propanenitrile Chemical compound C1C(=O)NC2=CC=C(CCC#N)C=C2C2=C1C1=CC(C(F)(F)F)=CC=C1N2 SHBOZSJPVRMXBA-UHFFFAOYSA-N 0.000 claims description 2
- ATOAEKSFKWKAIO-UHFFFAOYSA-N 4-methoxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2NC3=CC=CC=C3C=2CC(=O)NC2=C1C=CC=C2OC ATOAEKSFKWKAIO-UHFFFAOYSA-N 0.000 claims description 2
- SYGNSFGBDJEBOK-UHFFFAOYSA-N 8,10-dichloro-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=C(Cl)C=C(Cl)C=C1N2 SYGNSFGBDJEBOK-UHFFFAOYSA-N 0.000 claims description 2
- HEAJGTIEQPBAMJ-UHFFFAOYSA-N 9-bromo-12-ethyl-5,7-dihydroindolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2CC HEAJGTIEQPBAMJ-UHFFFAOYSA-N 0.000 claims description 2
- GJZCFRVBDYYNIV-UHFFFAOYSA-N 9-bromo-12-prop-2-enyl-5,7-dihydroindolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2CC=C GJZCFRVBDYYNIV-UHFFFAOYSA-N 0.000 claims description 2
- VPNVMVMFLHEGBV-UHFFFAOYSA-N 9-bromo-4-hydroxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2NC3=CC=C(Br)C=C3C=2CC(=O)NC2=C1C=CC=C2O VPNVMVMFLHEGBV-UHFFFAOYSA-N 0.000 claims description 2
- OPGZTFCRUXGMRT-UHFFFAOYSA-N 9-fluoro-12-prop-2-enyl-5,7-dihydroindolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(F)=CC=C1N2CC=C OPGZTFCRUXGMRT-UHFFFAOYSA-N 0.000 claims description 2
- NNDLCXNIMGREEF-UHFFFAOYSA-N 9-fluoro-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(F)=CC=C1N2 NNDLCXNIMGREEF-UHFFFAOYSA-N 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 2
- IMVYUVOHSQUHJD-UHFFFAOYSA-N chembl331783 Chemical compound C12=CC=CC=C2NC(=O)CC2=C1NC1=NC=CC=C21 IMVYUVOHSQUHJD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- XHZYYJIRPPAMPY-UHFFFAOYSA-N tert-butyl 9-bromo-6-oxo-5,7-dihydroindolo[3,2-d][1]benzazepine-12-carboxylate Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2C(=O)OC(C)(C)C XHZYYJIRPPAMPY-UHFFFAOYSA-N 0.000 claims description 2
- NJWBEJMJZBWMOO-UHFFFAOYSA-N tritert-butyl 9-bromo-6-oxo-7h-indolo[3,2-d][1]benzazepine-5,7,12-tricarboxylate Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C(=O)C(C(=O)OC(C)(C)C)C2=C1N(C(=O)OC(C)(C)C)C1=CC=C(Br)C=C21 NJWBEJMJZBWMOO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- KIZLESRPUNYYNU-UHFFFAOYSA-N 2,9-dibromo-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C12=CC(Br)=CC=C2NC(=O)CC2=C1NC1=CC=C(Br)C=C21 KIZLESRPUNYYNU-UHFFFAOYSA-N 0.000 claims 3
- IWTCPWHGHSZDRD-UHFFFAOYSA-N 13-(trifluoromethyl)-3-thia-7,17-diazatetracyclo[8.7.0.02,6.011,16]heptadeca-1(10),2(6),4,11(16),12,14-hexaen-8-one Chemical compound C12=CC(C(F)(F)F)=CC=C2NC2=C1CC(=O)NC1=C2SC=C1 IWTCPWHGHSZDRD-UHFFFAOYSA-N 0.000 claims 1
- HLNLXECKTICCDT-UHFFFAOYSA-N 4-hydroxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1=2NC3=CC=CC=C3C=2CC(=O)NC2=C1C=CC=C2O HLNLXECKTICCDT-UHFFFAOYSA-N 0.000 claims 1
- YBTFSTRMFPNVDQ-UHFFFAOYSA-N 9-bromo-10-hydroxy-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C(N2)=C1C1=C2C=C(O)C(Br)=C1 YBTFSTRMFPNVDQ-UHFFFAOYSA-N 0.000 claims 1
- JGELUIOSDAYQLO-UHFFFAOYSA-N 9-bromo-11-(hydroxymethyl)-7,12-dihydro-5h-indolo[3,2-d][1]benzazepin-6-one Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C(C=C(Br)C=C1CO)=C1N2 JGELUIOSDAYQLO-UHFFFAOYSA-N 0.000 claims 1
- XNVMFDGFXSZPDU-UHFFFAOYSA-N cyano nitroformate Chemical group [O-][N+](=O)C(=O)OC#N XNVMFDGFXSZPDU-UHFFFAOYSA-N 0.000 claims 1
- KZGUEWREZGMORL-UHFFFAOYSA-N ditert-butyl 9-bromo-6-oxo-7,12-dihydroindolo[3,2-d][1]benzazepine-5,7-dicarboxylate Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C(=O)C(C(=O)OC(C)(C)C)C2=C1NC1=CC=C(Br)C=C21 KZGUEWREZGMORL-UHFFFAOYSA-N 0.000 claims 1
- MRTWJQDNVKEBIF-UHFFFAOYSA-N ditert-butyl 9-bromo-6-oxo-7h-indolo[3,2-d][1]benzazepine-5,12-dicarboxylate Chemical compound C1C(=O)N(C(=O)OC(C)(C)C)C2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2C(=O)OC(C)(C)C MRTWJQDNVKEBIF-UHFFFAOYSA-N 0.000 claims 1
- 238000007918 intramuscular administration Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- FTHAZLWBEMCLBS-UHFFFAOYSA-N methyl 2-(9-bromo-6-oxo-5,7-dihydroindolo[3,2-d][1]benzazepin-12-yl)acetate Chemical compound C1C(=O)NC2=CC=CC=C2C2=C1C1=CC(Br)=CC=C1N2CC(=O)OC FTHAZLWBEMCLBS-UHFFFAOYSA-N 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 46
- 210000004027 cell Anatomy 0.000 abstract description 34
- 238000000034 method Methods 0.000 abstract description 33
- 238000003556 assay Methods 0.000 abstract description 15
- 125000005233 alkylalcohol group Chemical group 0.000 abstract description 9
- 210000005170 neoplastic cell Anatomy 0.000 abstract description 3
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 112
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 78
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 44
- 230000015572 biosynthetic process Effects 0.000 description 43
- 238000000338 in vitro Methods 0.000 description 35
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Classifications
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- 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
-
- 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
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8961998P | 1998-06-16 | 1998-06-16 | |
| US60/089,619 | 1998-06-16 | ||
| PCT/US1999/013579 WO1999065910A1 (en) | 1998-06-16 | 1999-06-16 | Fused azepinone cyclin dependent kinase inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2335115A1 CA2335115A1 (en) | 1999-12-23 |
| CA2335115C true CA2335115C (en) | 2009-01-27 |
Family
ID=22218651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002335115A Expired - Fee Related CA2335115C (en) | 1998-06-16 | 1999-06-16 | Fused azepinone cyclin dependent kinase inhibitors |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6610684B2 (https=) |
| EP (1) | EP1086105B1 (https=) |
| JP (1) | JP4555476B2 (https=) |
| AT (1) | ATE318818T1 (https=) |
| AU (1) | AU778735B2 (https=) |
| CA (1) | CA2335115C (https=) |
| DE (1) | DE69930120T2 (https=) |
| WO (1) | WO1999065910A1 (https=) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2804959B1 (fr) * | 2000-02-15 | 2006-04-28 | Centre Nat Rech Scient | Utilisation de derives de paullones pour la fabrication de medicaments |
| JP4527404B2 (ja) | 2002-04-04 | 2010-08-18 | エンゾン，インコーポレーテッド | インドールのポリマー性アシル誘導体 |
| DE10260618B4 (de) * | 2002-12-23 | 2005-06-09 | Faustus Forschungs Cie. Translational Cancer Research Gmbh | Tumorhemmende annellierte Azepinonderivate |
| PL1748691T3 (pl) * | 2004-05-12 | 2011-04-29 | Bayer Cropscience Ag | Sposób regulacji wzrostu roślin |
| WO2006089874A1 (en) * | 2005-02-22 | 2006-08-31 | Gpc Biotech Ag | Benzo[2,3]azepino[4,5-b]indol-6-ones |
| EP1757607A1 (en) | 2005-08-24 | 2007-02-28 | Molisa GmbH | N5-substituted benzo¬2,3|azepino¬4,5-b|indol-6-ones for treating tropical diseases |
| FR2899107B1 (fr) * | 2006-03-30 | 2008-06-13 | Neurokin Entpr Unipersonnelle | Utilisation de la (s)-roscovitine pour la fabrication d'un medicament |
| WO2009010298A2 (en) * | 2007-07-18 | 2009-01-22 | Technische Universität Carolo-Wilhelmina Zu Braunschweig | Paullone derivatives and its use |
| US8716308B2 (en) | 2008-01-11 | 2014-05-06 | Albany Molecular Research, Inc. | (1-azinone)-substituted pyridoindoles |
| JP2012504646A (ja) * | 2008-10-01 | 2012-02-23 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | 選択的サイクリン依存性キナーゼ４／６阻害剤を用いた化学療法化合物に対する造血系の防護 |
| CN102231983A (zh) * | 2008-10-01 | 2011-11-02 | 北卡罗来纳大学查珀尔希尔分校 | 使用选择性细胞周期蛋白依赖性激酶4/6抑制剂对抗电离辐射的造血防护 |
| EP2414358A1 (en) * | 2009-03-31 | 2012-02-08 | ArQule, Inc. | Substituted tetrahydropyrazolo-pyrido-azepin compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3642779A (en) * | 1969-10-22 | 1972-02-15 | Robins Co Inc A H | Indolo(1 2-d)(1 4)benzodiazepin-6-ones |
| US5866702A (en) * | 1996-08-02 | 1999-02-02 | Cv Therapeutics, Incorporation | Purine inhibitors of cyclin dependent kinase 2 |
| ATE239020T1 (de) * | 1996-10-09 | 2003-05-15 | Schering Corp | Tricyclische verbindungen als ras-fpt inhibitoren |
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- 1999-06-16 AT AT99928715T patent/ATE318818T1/de not_active IP Right Cessation
- 1999-06-16 JP JP2000554735A patent/JP4555476B2/ja not_active Expired - Fee Related
- 1999-06-16 AU AU45714/99A patent/AU778735B2/en not_active Ceased
- 1999-06-16 CA CA002335115A patent/CA2335115C/en not_active Expired - Fee Related
- 1999-06-16 DE DE69930120T patent/DE69930120T2/de not_active Expired - Lifetime
- 1999-06-16 EP EP99928715A patent/EP1086105B1/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| EP1086105A1 (en) | 2001-03-28 |
| CA2335115A1 (en) | 1999-12-23 |
| DE69930120D1 (de) | 2006-04-27 |
| US20020042412A1 (en) | 2002-04-11 |
| AU4571499A (en) | 2000-01-05 |
| EP1086105B1 (en) | 2006-03-01 |
| ATE318818T1 (de) | 2006-03-15 |
| US6610684B2 (en) | 2003-08-26 |
| JP4555476B2 (ja) | 2010-09-29 |
| WO1999065910A9 (en) | 2000-03-16 |
| JP2002518395A (ja) | 2002-06-25 |
| DE69930120T2 (de) | 2006-11-02 |
| WO1999065910A1 (en) | 1999-12-23 |
| AU778735B2 (en) | 2004-12-16 |
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