JP2012518598A

JP2012518598A - ピリミドピリミドインダゾール誘導体

ピリミドピリミドインダゾール誘導体 Download PDF

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Publication number: JP2012518598A
Authority: JP; Japan
Prior art keywords: group; pyrimido; indazol; alkyl group; amino
Prior art date: 2009-02-25
Legal status : Pending

Application number

JP2011535742A

Other languages

English (en)

Japanese (ja)

Other versions

JP2012518598A5 (enExample

Inventor

康裕後藤

健治新山

聡角南

啓治 ▲高▼橋

Original Assignee

Ｍｓｄ株式会社

Priority date

2009-02-25

Filing date

2010-02-18

Publication date

2012-08-16

2010-02-18 Application filed by Ｍｓｄ株式会社 filed Critical Ｍｓｄ株式会社

2010-02-18 Priority to JP2011535742A priority Critical patent/JP2012518598A/ja

2012-08-16 Publication of JP2012518598A publication Critical patent/JP2012518598A/ja

2013-04-04 Publication of JP2012518598A5 publication Critical patent/JP2012518598A5/ja

Status Pending legal-status Critical Current

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150000001875 compounds Chemical class 0.000 claims abstract description 533
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 172
125000000217 alkyl group Chemical group 0.000 claims abstract description 161
125000005843 halogen group Chemical group 0.000 claims abstract description 146
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 144
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 50
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 47
125000003118 aryl group Chemical group 0.000 claims abstract description 46
206010028980 Neoplasm Diseases 0.000 claims abstract description 44
201000011510 cancer Diseases 0.000 claims abstract description 39
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 37
239000002246 antineoplastic agent Substances 0.000 claims abstract description 32
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 28
238000011282 treatment Methods 0.000 claims abstract description 20
239000003814 drug Substances 0.000 claims abstract description 17
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 11
-1 perhydro-1,4-diazepinyl group Chemical group 0.000 claims description 481
238000002360 preparation method Methods 0.000 claims description 290
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 136
QSVSMNAYVRURDO-UHFFFAOYSA-N 6,7-dihydroindazol-5-one Chemical compound O=C1CCC2=NN=CC2=C1 QSVSMNAYVRURDO-UHFFFAOYSA-N 0.000 claims description 120
125000001424 substituent group Chemical group 0.000 claims description 119
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 94
125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 55
230000001093 anti-cancer Effects 0.000 claims description 54
150000003839 salts Chemical class 0.000 claims description 48
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 38
125000000623 heterocyclic group Chemical group 0.000 claims description 36
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 34
239000000203 mixture Substances 0.000 claims description 29
229910052757 nitrogen Inorganic materials 0.000 claims description 28
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 26
150000001204 N-oxides Chemical class 0.000 claims description 25
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 23
VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 22
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 19
150000002148 esters Chemical class 0.000 claims description 19
125000004430 oxygen atom Chemical group O* 0.000 claims description 17
125000004093 cyano group Chemical group *C#N 0.000 claims description 16
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 16
KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 15
229940127093 camptothecin Drugs 0.000 claims description 15
229910052717 sulfur Inorganic materials 0.000 claims description 15
102000014150 Interferons Human genes 0.000 claims description 14
108010050904 Interferons Proteins 0.000 claims description 14
125000001931 aliphatic group Chemical group 0.000 claims description 14
125000004043 oxo group Chemical group O=* 0.000 claims description 14
125000004434 sulfur atom Chemical group 0.000 claims description 14
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
125000003342 alkenyl group Chemical group 0.000 claims description 13
125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
229940127084 other anti-cancer agent Drugs 0.000 claims description 13
229910052697 platinum Inorganic materials 0.000 claims description 13
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 13
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 12
SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 12
125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 12
229940100198 alkylating agent Drugs 0.000 claims description 11
239000002168 alkylating agent Substances 0.000 claims description 11
230000000340 anti-metabolite Effects 0.000 claims description 11
229940100197 antimetabolite Drugs 0.000 claims description 11
239000002256 antimetabolite Substances 0.000 claims description 11
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238000006467 substitution reaction Methods 0.000 claims description 11
229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 11
239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 11
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 10
125000001041 indolyl group Chemical group 0.000 claims description 10
125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 10
125000003226 pyrazolyl group Chemical group 0.000 claims description 10
125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 8
239000003085 diluting agent Substances 0.000 claims description 8
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239000008194 pharmaceutical composition Substances 0.000 claims description 8
UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 7
NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 7
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 7
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 7
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 7
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125000004076 pyridyl group Chemical group 0.000 claims description 7
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230000008512 biological response Effects 0.000 claims description 6
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239000003937 drug carrier Substances 0.000 claims description 6
125000002541 furyl group Chemical group 0.000 claims description 6
XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical group C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 6
229960004768 irinotecan Drugs 0.000 claims description 6
125000004193 piperazinyl group Chemical group 0.000 claims description 6
125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
125000000335 thiazolyl group Chemical group 0.000 claims description 6
150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 6
CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 5
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BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 5
125000002393 azetidinyl group Chemical group 0.000 claims description 5
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DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 5
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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 5
229960005420 etoposide Drugs 0.000 claims description 5
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DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 claims description 5
229960001592 paclitaxel Drugs 0.000 claims description 5
125000003386 piperidinyl group Chemical group 0.000 claims description 5
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RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 5
229960001674 tegafur Drugs 0.000 claims description 5
WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 claims description 5
125000001544 thienyl group Chemical group 0.000 claims description 5
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 5
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WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 claims description 4
AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 claims description 4
STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 4
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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 4
108010069236 Goserelin Proteins 0.000 claims description 4
VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 claims description 4
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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 4
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FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 4
JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 claims description 4
RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims description 4
GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 claims description 4
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GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 claims description 4
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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 4
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SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 4
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KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 claims description 4
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