HRP20040422A2 - C-5 modified indazolylpyrrolotriazines - Google Patents

Info

Publication number

HRP20040422A2

HRP20040422A2 HR20040422A HRP20040422A HRP20040422A2 HR P20040422 A2 HRP20040422 A2 HR P20040422A2 HR 20040422 A HR20040422 A HR 20040422A HR P20040422 A HRP20040422 A HR P20040422A HR P20040422 A2 HRP20040422 A2 HR P20040422A2

Authority

HR

Croatia

Prior art keywords

pyrrolo

indazol

triazin

fluorobenzyl

ylmethyl

Prior art date

2001-11-14

Links

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• -1 C-5 modified indazolylpyrrolotriazines Chemical class 0.000 title claims description 51
• 150000001875 compounds Chemical class 0.000 claims description 124
• 239000000203 mixture Substances 0.000 claims description 41
• 238000011282 treatment Methods 0.000 claims description 36
• 102000001301 EGF receptor Human genes 0.000 claims description 24
• 238000000034 method Methods 0.000 claims description 24
• 206010028980 Neoplasm Diseases 0.000 claims description 23
• 125000000217 alkyl group Chemical group 0.000 claims description 22
• 125000003118 aryl group Chemical group 0.000 claims description 22
• 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 21
• 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 21
• 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 claims description 18
• 101100118549 Homo sapiens EGFR gene Proteins 0.000 claims description 18
• 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 claims description 18
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• 230000000694 effects Effects 0.000 claims description 15
• 229920006395 saturated elastomer Polymers 0.000 claims description 15
• 201000010099 disease Diseases 0.000 claims description 14
• 125000000623 heterocyclic group Chemical group 0.000 claims description 13
• 125000003107 substituted aryl group Chemical group 0.000 claims description 13
• 229940002612 prodrug Drugs 0.000 claims description 12
• 239000000651 prodrug Substances 0.000 claims description 12
• 102000005962 receptors Human genes 0.000 claims description 12
• 108020003175 receptors Proteins 0.000 claims description 12
• 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 claims description 11
• 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 claims description 11
• 108091000080 Phosphotransferase Proteins 0.000 claims description 10
• 239000002246 antineoplastic agent Substances 0.000 claims description 10
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
• 125000002837 carbocyclic group Chemical group 0.000 claims description 10
• 102000020233 phosphotransferase Human genes 0.000 claims description 10
• 230000000259 anti-tumor effect Effects 0.000 claims description 9
• 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 8
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• 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 claims description 7
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• 125000002619 bicyclic group Chemical group 0.000 claims description 6
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• 231100000599 cytotoxic agent Toxicity 0.000 claims description 6
• 239000001257 hydrogen Substances 0.000 claims description 6
• 229910052739 hydrogen Inorganic materials 0.000 claims description 6
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
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• COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
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• 108010092160 Dactinomycin Proteins 0.000 claims description 3
• WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 claims description 3
• GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
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• JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 claims description 3
• 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 3
• 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 3
• 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 3
• 150000001412 amines Chemical class 0.000 claims description 3
• XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims description 3
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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 3
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• JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
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• UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 claims description 3
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• CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 claims description 3
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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 3
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• CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 claims description 3
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• BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 claims description 3
• XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 claims description 3
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• RHDDYMLSGOAXFS-UHFFFAOYSA-N 2-[4-[[4-[[1-[(3-fluorophenyl)methyl]indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]-1,4-diazepan-1-yl]ethanol Chemical compound C1CN(CCO)CCCN1CC1=C2C(NC=3C=C4C=NN(CC=5C=C(F)C=CC=5)C4=CC=3)=NC=NN2C=C1 RHDDYMLSGOAXFS-UHFFFAOYSA-N 0.000 claims description 2
• YVHIBMWTWVBAAS-UHFFFAOYSA-N 2-[[1-[[4-[[1-[(3-fluorophenyl)methyl]indazol-5-yl]amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-4-yl]amino]ethanol Chemical compound C1CC(NCCO)CCN1CC1=C2C(NC=3C=C4C=NN(CC=5C=C(F)C=CC=5)C4=CC=3)=NC=NN2C=C1 YVHIBMWTWVBAAS-UHFFFAOYSA-N 0.000 claims description 2
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