JP2004538247A

JP2004538247A - セミカルバジド及びサイクリン依存キナーゼ阻害剤

セミカルバジド及びサイクリン依存キナーゼ阻害剤 Download PDF

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Publication number: JP2004538247A
Authority: JP; Japan
Prior art keywords: substituted; compound; phenyl; indeno; methyl
Prior art date: 2000-12-08
Legal status : Abandoned

Application number

JP2002547920A

Other languages

English (en)

Japanese (ja)

Other versions

JP2004538247A5 (https=

Inventor

デイヴィットジェイカリーニ

Current Assignee

Bristol Myers Squibb Pharma Co

Original Assignee

Bristol Myers Squibb Pharma Co

Priority date

2000-12-08

Filing date

2001-12-07

Publication date

2004-12-24

2001-12-07 Application filed by Bristol Myers Squibb Pharma Co filed Critical Bristol Myers Squibb Pharma Co

2004-12-24 Publication of JP2004538247A publication Critical patent/JP2004538247A/ja

2006-01-05 Publication of JP2004538247A5 publication Critical patent/JP2004538247A5/ja

Status Abandoned legal-status Critical Current

Links

229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title description 12
239000002875 cyclin dependent kinase inhibitor Substances 0.000 title description 7
DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 title description 6
150000001875 compounds Chemical class 0.000 claims abstract description 210
238000000034 method Methods 0.000 claims abstract description 111
150000003839 salts Chemical class 0.000 claims abstract description 93
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 39
206010028980 Neoplasm Diseases 0.000 claims abstract description 34
201000010099 disease Diseases 0.000 claims abstract description 28
201000011510 cancer Diseases 0.000 claims abstract description 27
GHFDYLOGYDGRHI-UHFFFAOYSA-N 1h-indeno[1,2-c]pyrazol-4-one Chemical class C12=CC=CC=C2C(=O)C2=C1NN=C2 GHFDYLOGYDGRHI-UHFFFAOYSA-N 0.000 claims abstract description 24
230000002062 proliferating effect Effects 0.000 claims abstract description 16
239000003112 inhibitor Substances 0.000 claims abstract description 15
239000003795 chemical substances by application Substances 0.000 claims abstract description 10
230000001028 anti-proliverative effect Effects 0.000 claims abstract description 3
-1 imidazo [2,1-b] thiazolyl Chemical group 0.000 claims description 122
125000000623 heterocyclic group Chemical group 0.000 claims description 63
239000000203 mixture Substances 0.000 claims description 54
238000003786 synthesis reaction Methods 0.000 claims description 53
230000015572 biosynthetic process Effects 0.000 claims description 52
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
229940002612 prodrug Drugs 0.000 claims description 45
239000000651 prodrug Substances 0.000 claims description 45
230000000694 effects Effects 0.000 claims description 44
229910052757 nitrogen Inorganic materials 0.000 claims description 44
229910052717 sulfur Inorganic materials 0.000 claims description 37
108091007914 CDKs Proteins 0.000 claims description 30
125000000217 alkyl group Chemical group 0.000 claims description 27
230000002401 inhibitory effect Effects 0.000 claims description 27
125000005842 heteroatom Chemical group 0.000 claims description 24
229910052760 oxygen Inorganic materials 0.000 claims description 24
125000001072 heteroaryl group Chemical group 0.000 claims description 23
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 22
125000004429 atom Chemical group 0.000 claims description 22
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 17
125000005843 halogen group Chemical group 0.000 claims description 17
229910052799 carbon Inorganic materials 0.000 claims description 16
125000004432 carbon atom Chemical group C* 0.000 claims description 16
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 15
125000004434 sulfur atom Chemical group 0.000 claims description 15
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
210000004027 cell Anatomy 0.000 claims description 14
229910052739 hydrogen Inorganic materials 0.000 claims description 13
NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 12
125000003118 aryl group Chemical group 0.000 claims description 12
125000000753 cycloalkyl group Chemical group 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 12
125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
125000003373 pyrazinyl group Chemical group 0.000 claims description 11
OYODOQNYJLSLJE-UHFFFAOYSA-N pyrazol-4-one Chemical compound O=C1C=NN=C1 OYODOQNYJLSLJE-UHFFFAOYSA-N 0.000 claims description 11
125000001544 thienyl group Chemical group 0.000 claims description 11
125000000392 cycloalkenyl group Chemical group 0.000 claims description 10
208000035475 disorder Diseases 0.000 claims description 10
229940079593 drug Drugs 0.000 claims description 10
FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 9
UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims description 9
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125000003226 pyrazolyl group Chemical group 0.000 claims description 8
125000002098 pyridazinyl group Chemical group 0.000 claims description 8
125000004076 pyridyl group Chemical group 0.000 claims description 8
230000009385 viral infection Effects 0.000 claims description 8
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
125000001786 isothiazolyl group Chemical group 0.000 claims description 7
125000004430 oxygen atom Chemical group O* 0.000 claims description 7
125000000168 pyrrolyl group Chemical group 0.000 claims description 7
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 6
ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 6
XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 claims description 6
RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims description 6
238000002648 combination therapy Methods 0.000 claims description 6
229960003668 docetaxel Drugs 0.000 claims description 6
229930013356 epothilone Natural products 0.000 claims description 6
VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 6
229960005420 etoposide Drugs 0.000 claims description 6
229960000390 fludarabine Drugs 0.000 claims description 6
GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 6
229960002949 fluorouracil Drugs 0.000 claims description 6
MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 claims description 6
229960002074 flutamide Drugs 0.000 claims description 6
229950008991 lobaplatin Drugs 0.000 claims description 6
GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 6
208000015122 neurodegenerative disease Diseases 0.000 claims description 6
125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
229960001603 tamoxifen Drugs 0.000 claims description 6
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UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 6
229960000303 topotecan Drugs 0.000 claims description 6
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BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 claims description 5
108010069236 Goserelin Proteins 0.000 claims description 5
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VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 5
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
229960004562 carboplatin Drugs 0.000 claims description 5
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 5
229960004316 cisplatin Drugs 0.000 claims description 5
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 5
HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 claims description 5
125000002541 furyl group Chemical group 0.000 claims description 5
229960002913 goserelin Drugs 0.000 claims description 5
125000001041 indolyl group Chemical group 0.000 claims description 5
229950010897 iproplatin Drugs 0.000 claims description 5
RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 claims description 5
125000002757 morpholinyl group Chemical group 0.000 claims description 5
125000004193 piperazinyl group Chemical group 0.000 claims description 5
125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 4
VBXZSFNZVNDOPB-UHFFFAOYSA-N 1,4,5,6-tetrahydropyrimidine Chemical compound C1CNC=NC1 VBXZSFNZVNDOPB-UHFFFAOYSA-N 0.000 claims description 4
YFMGMLYLTWKYMF-UHFFFAOYSA-N 1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-4-oxo-2h-indeno[1,2-c]pyrazol-5-yl]-3-[methyl(oxan-4-yl)amino]urea Chemical compound C1COCCC1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C=1SC(C)=NC=1C YFMGMLYLTWKYMF-UHFFFAOYSA-N 0.000 claims description 4
UMLHPJQKVJJUFG-UHFFFAOYSA-N 1-[3-[4-(4-ethylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]-3-[methyl(oxan-4-yl)amino]urea Chemical compound C1CN(CC)CCN1C1=CC=C(C2=C3C(=O)C4=C(NC(=O)NN(C)C5CCOCC5)C=CC=C4C3=NN2)C=C1 UMLHPJQKVJJUFG-UHFFFAOYSA-N 0.000 claims description 4
ZOOWQWMJUNKICE-UHFFFAOYSA-N 1-[3-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]-3-[methyl(1,3-thiazol-2-yl)amino]urea Chemical compound N=1C=CSC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCN(C)CC1 ZOOWQWMJUNKICE-UHFFFAOYSA-N 0.000 claims description 4
APIGPHDSZSFWTR-UHFFFAOYSA-N 1-[3-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]-3-[methyl(pyrazin-2-yl)amino]urea Chemical compound C=1N=CC=NC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCN(C)CC1 APIGPHDSZSFWTR-UHFFFAOYSA-N 0.000 claims description 4
MZCTYFCSJNIYTA-UHFFFAOYSA-N 1-[3-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]-3-[methyl(pyridin-3-yl)amino]urea Chemical compound C=1C=CN=CC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCN(C)CC1 MZCTYFCSJNIYTA-UHFFFAOYSA-N 0.000 claims description 4
IHCIBEUAPFOGMQ-UHFFFAOYSA-N 1-[cyclohexyl(methyl)amino]-3-[3-[4-(4-ethylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C1CN(CC)CCN1C1=CC=C(C2=C3C(=O)C4=C(NC(=O)NN(C)C5CCCCC5)C=CC=C4C3=NN2)C=C1 IHCIBEUAPFOGMQ-UHFFFAOYSA-N 0.000 claims description 4
PWHOSMWTLZIJBV-UHFFFAOYSA-N 1-[cyclohexyl(methyl)amino]-3-[3-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C1CCCCC1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCN(C)CC1 PWHOSMWTLZIJBV-UHFFFAOYSA-N 0.000 claims description 4
ZWEZGNFTHWWSGI-UHFFFAOYSA-N 1-[cyclohexyl(methyl)amino]-3-[4-oxo-3-[4-(4-propan-2-ylpiperazin-1-yl)phenyl]-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C1CN(C(C)C)CCN1C1=CC=C(C2=C3C(=O)C4=C(NC(=O)NN(C)C5CCCCC5)C=CC=C4C3=NN2)C=C1 ZWEZGNFTHWWSGI-UHFFFAOYSA-N 0.000 claims description 4
UVCWRUZNUNUVTR-UHFFFAOYSA-N 1-[methyl(1,3-thiazol-2-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound N=1C=CSC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 UVCWRUZNUNUVTR-UHFFFAOYSA-N 0.000 claims description 4
PDVQFIUVCVLMHG-UHFFFAOYSA-N 1-[methyl(oxan-4-yl)amino]-3-[3-[4-(4-methylpiperazin-1-yl)phenyl]-4-oxo-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C1COCCC1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCN(C)CC1 PDVQFIUVCVLMHG-UHFFFAOYSA-N 0.000 claims description 4
IZKOSUJSODTJGO-UHFFFAOYSA-N 1-[methyl(oxan-4-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C1COCCC1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 IZKOSUJSODTJGO-UHFFFAOYSA-N 0.000 claims description 4
JOOCWOAUSDJSQF-UHFFFAOYSA-N 1-[methyl(oxan-4-yl)amino]-3-[4-oxo-3-[4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl]-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C1COCCC1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N(CC1)CCC1N1CCCC1 JOOCWOAUSDJSQF-UHFFFAOYSA-N 0.000 claims description 4
IDCOZGMVPAZOAM-UHFFFAOYSA-N 1-[methyl(pyrazin-2-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C=1N=CC=NC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 IDCOZGMVPAZOAM-UHFFFAOYSA-N 0.000 claims description 4
KAWFIYJMZVLRRF-UHFFFAOYSA-N 1-[methyl(pyridin-2-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C=1C=CC=NC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 KAWFIYJMZVLRRF-UHFFFAOYSA-N 0.000 claims description 4
DJMXFKPCBLSZRS-UHFFFAOYSA-N 1-[methyl(pyridin-3-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C=1C=CN=CC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 DJMXFKPCBLSZRS-UHFFFAOYSA-N 0.000 claims description 4
NRXVIVKRRIZCSQ-UHFFFAOYSA-N 1-[methyl(pyridin-4-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound C=1C=NC=CC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 NRXVIVKRRIZCSQ-UHFFFAOYSA-N 0.000 claims description 4
QXDUGHAHZDXFQK-UHFFFAOYSA-N 1-[methyl(pyrimidin-2-yl)amino]-3-[4-oxo-3-(4-piperazin-1-ylphenyl)-1h-indeno[1,2-c]pyrazol-5-yl]urea Chemical compound N=1C=CC=NC=1N(C)NC(=O)NC(C=1C(=O)C2=3)=CC=CC=1C2=NNC=3C(C=C1)=CC=C1N1CCNCC1 QXDUGHAHZDXFQK-UHFFFAOYSA-N 0.000 claims description 4
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