JP2009542610A5 - - Google Patents
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- JP2009542610A5 JP2009542610A5 JP2009517411A JP2009517411A JP2009542610A5 JP 2009542610 A5 JP2009542610 A5 JP 2009542610A5 JP 2009517411 A JP2009517411 A JP 2009517411A JP 2009517411 A JP2009517411 A JP 2009517411A JP 2009542610 A5 JP2009542610 A5 JP 2009542610A5
- Authority
- JP
- Japan
- Prior art keywords
- acid
- compound
- kinase
- aurora
- cancer
- 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.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims description 226
- -1 cyano, nitro, carboxy, amino Chemical group 0.000 claims description 109
- 238000011282 treatment Methods 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 201000010099 disease Diseases 0.000 claims description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 42
- 230000002265 prevention Effects 0.000 claims description 40
- 206010028980 Neoplasm Diseases 0.000 claims description 35
- 201000011510 cancer Diseases 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 31
- 239000003112 inhibitor Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 230000003827 upregulation Effects 0.000 claims description 30
- 102000003989 Aurora kinases Human genes 0.000 claims description 28
- 108090000433 Aurora kinases Proteins 0.000 claims description 28
- 208000024891 symptom Diseases 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 26
- LOLPPWBBNUVNQZ-UHFFFAOYSA-N chembl495727 Chemical compound C=1NN=C(C=2NC3=CC=C(CN4CCOCC4)C=C3N=2)C=1NC(=O)NC1CC1 LOLPPWBBNUVNQZ-UHFFFAOYSA-N 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 241000124008 Mammalia Species 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 24
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 claims description 21
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 claims description 21
- 238000002405 diagnostic procedure Methods 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 21
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
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- 108090000461 Aurora Kinase A Proteins 0.000 claims description 18
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- 102000003903 Cyclin-dependent kinases Human genes 0.000 claims description 17
- 108090000266 Cyclin-dependent kinases Proteins 0.000 claims description 17
- 229910005965 SO 2 Inorganic materials 0.000 claims description 17
- 230000002159 abnormal effect Effects 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 230000004663 cell proliferation Effects 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 12
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 12
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 12
- 108091007914 CDKs Proteins 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 11
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
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- 230000009467 reduction Effects 0.000 claims description 11
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 10
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 10
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- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 claims description 10
- 229960002989 glutamic acid Drugs 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical group FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 claims description 10
- 230000001404 mediated effect Effects 0.000 claims description 10
- 150000003058 platinum compounds Chemical class 0.000 claims description 10
- 230000008685 targeting Effects 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 9
- 108091000080 Phosphotransferase Proteins 0.000 claims description 9
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 9
- 229940100198 alkylating agent Drugs 0.000 claims description 9
- 239000002168 alkylating agent Substances 0.000 claims description 9
- 230000002280 anti-androgenic effect Effects 0.000 claims description 9
- 239000000051 antiandrogen Substances 0.000 claims description 9
- 238000002648 combination therapy Methods 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 102000020233 phosphotransferase Human genes 0.000 claims description 9
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims description 9
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 8
- KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 claims description 8
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 8
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 8
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- LSPHULWDVZXLIL-QUBYGPBYSA-N camphoric acid Chemical compound CC1(C)[C@H](C(O)=O)CC[C@]1(C)C(O)=O LSPHULWDVZXLIL-QUBYGPBYSA-N 0.000 claims description 8
- 229940127093 camptothecin Drugs 0.000 claims description 8
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 8
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 8
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 8
- 229940121372 histone deacetylase inhibitor Drugs 0.000 claims description 8
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 8
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 8
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 8
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 8
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N thiocyanic acid Chemical group SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 8
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 7
- 229940123237 Taxane Drugs 0.000 claims description 7
- 239000005441 aurora Substances 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims description 6
- 102000004127 Cytokines Human genes 0.000 claims description 6
- 108090000695 Cytokines Proteins 0.000 claims description 6
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 6
- 235000021355 Stearic acid Nutrition 0.000 claims description 6
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- SSJXIUAHEKJCMH-UHFFFAOYSA-N cyclohexane-1,2-diamine Chemical compound NC1CCCCC1N SSJXIUAHEKJCMH-UHFFFAOYSA-N 0.000 claims description 6
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- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
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- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 claims description 4
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
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- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 4
- 210000004027 cell Anatomy 0.000 claims description 4
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| EP3226915B1 (en) | 2014-12-03 | 2019-02-20 | Janssen Pharmaceutica NV | Radiolabelled mglur2 pet ligands |
| RU2711382C2 (ru) | 2014-12-03 | 2020-01-16 | Янссен Фармацевтика Нв | 6,7-ДИГИДРОПИРАЗОЛО[1,5-a]ПИРАЗИН-4(5H)-ОНОВЫЕ СОЕДИНЕНИЯ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ОТРИЦАТЕЛЬНЫХ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ MGLUR2 |
| CN105801563B (zh) * | 2015-01-15 | 2020-01-14 | 广东东阳光药业有限公司 | 吡唑类衍生物及其用途 |
| JP6929285B2 (ja) | 2015-12-18 | 2021-09-01 | ヤンセン ファーマシューティカ エヌ．ベー． | 放射性標識ｍＧｌｕＲ２／３ＰＥＴリガンド |
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2007
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- 2007-06-29 WO PCT/GB2007/002447 patent/WO2008001115A2/en not_active Ceased
- 2007-06-29 EP EP07733424A patent/EP2049119A2/en not_active Withdrawn
- 2007-06-29 US US12/306,479 patent/US8435970B2/en not_active Expired - Fee Related
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