NZ537523A - Pyrrolo-triazine compounds that inhibit the tyrosine kinase activity of growth factor receptors - Google Patents

Pyrrolo-triazine compounds that inhibit the tyrosine kinase activity of growth factor receptors

Info

Publication number: NZ537523A
Authority: NZ; New Zealand
Prior art keywords: yloxy; methyl; indol; fluoro; compound
Prior art date: 2002-07-19

Application number

NZ537523A

Other languages

English (en)

Inventor

Rajeev S Bhide

Zhen-Wei Cai

Ligang Qian

Stephanie Barbosa

Louis Lombardo

Jeffrey Robl

Original Assignee

Bristol Myers Squibb Co

Priority date (The priority date 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 date listed.)

2002-07-19

Filing date

2003-07-18

Publication date

2007-08-31

2003-07-18 Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co

2007-08-31 Publication of NZ537523A publication Critical patent/NZ537523A/en

Links

230000000694 effects Effects 0.000 title claims abstract description 18
102000009465 Growth Factor Receptors Human genes 0.000 title claims abstract description 14
108010009202 Growth Factor Receptors Proteins 0.000 title claims abstract description 14
102000004022 Protein-Tyrosine Kinases Human genes 0.000 title claims abstract description 10
108090000412 Protein-Tyrosine Kinases Proteins 0.000 title claims abstract description 10
150000003921 pyrrolotriazines Chemical class 0.000 title abstract description 3
150000001875 compounds Chemical class 0.000 claims abstract description 144
-1 [(1R) Chemical class 0.000 claims abstract description 31
150000003839 salts Chemical class 0.000 claims abstract description 16
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
201000010099 disease Diseases 0.000 claims abstract description 12
239000002246 antineoplastic agent Substances 0.000 claims abstract description 9
230000019491 signal transduction Effects 0.000 claims abstract description 4
206010028980 Neoplasm Diseases 0.000 claims description 28
238000002360 preparation method Methods 0.000 claims description 28
239000003112 inhibitor Substances 0.000 claims description 15
201000011510 cancer Diseases 0.000 claims description 13
150000002148 esters Chemical class 0.000 claims description 13
239000003814 drug Substances 0.000 claims description 12
239000008194 pharmaceutical composition Substances 0.000 claims description 12
239000003102 growth factor Substances 0.000 claims description 10
230000008728 vascular permeability Effects 0.000 claims description 9
230000001093 anti-cancer Effects 0.000 claims description 7
239000002254 cytotoxic agent Substances 0.000 claims description 7
229940127089 cytotoxic agent Drugs 0.000 claims description 7
231100000599 cytotoxic agent Toxicity 0.000 claims description 7
239000003937 drug carrier Substances 0.000 claims description 7
KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical class N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 6
AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical class 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
NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical class 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 6
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 6
RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Chemical class 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
230000001772 anti-angiogenic effect Effects 0.000 claims description 6
230000002062 proliferating effect Effects 0.000 claims description 6
230000001603 reducing effect Effects 0.000 claims description 6
ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical class 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 5
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 5
230000002401 inhibitory effect Effects 0.000 claims description 5
208000023275 Autoimmune disease Diseases 0.000 claims description 4
102000001253 Protein Kinase Human genes 0.000 claims description 4
DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical class N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 4
229960004316 cisplatin Drugs 0.000 claims description 4
108060006633 protein kinase Proteins 0.000 claims description 4
LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 claims description 3
AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical class 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 3
DZEADOQXGYJGID-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-5-methyl-6-(3-methylsulfonylpropoxy)pyrrolo[2,1-f][1,2,4]triazine Chemical compound C1=NN2C=C(OCCCS(C)(=O)=O)C(C)=C2C(OC=2C(F)=C3C=C(NC3=CC=2)C)=N1 DZEADOQXGYJGID-UHFFFAOYSA-N 0.000 claims description 3
SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 claims description 3
STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Chemical class 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 3
102000012936 Angiostatins Human genes 0.000 claims description 3
108010079709 Angiostatins Proteins 0.000 claims description 3
BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 claims description 3
COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical class CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 3
CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical class ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical class 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 3
108010092160 Dactinomycin Chemical class 0.000 claims description 3
WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Chemical class 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
AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 claims description 3
ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 claims description 3
HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Chemical class COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 3
GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical class FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
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 3
101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 claims description 3
XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical class C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims description 3
XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Chemical class C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims description 3
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 class 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
108010000817 Leuprolide Proteins 0.000 claims description 3
229940079156 Proteasome inhibitor Drugs 0.000 claims description 3
102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 claims description 3
FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical class C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 3
102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 claims description 3
108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 claims description 3
RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical class 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
150000003838 adenosines 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
229960001220 amsacrine Drugs 0.000 claims description 3
229960002932 anastrozole Drugs 0.000 claims description 3
YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 claims description 3
229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 claims description 3
FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 claims description 3
VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical class [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
229960000397 bevacizumab Drugs 0.000 claims description 3
229960000997 bicalutamide Drugs 0.000 claims description 3
BGECDVWSWDRFSP-UHFFFAOYSA-N borazine Chemical compound B1NBNBN1 BGECDVWSWDRFSP-UHFFFAOYSA-N 0.000 claims description 3
229960001467 bortezomib Drugs 0.000 claims description 3
229960002092 busulfan Drugs 0.000 claims description 3
229960004562 carboplatin Drugs 0.000 claims description 3
229960005395 cetuximab Drugs 0.000 claims description 3
229960004630 chlorambucil Drugs 0.000 claims description 3
JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical class OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 3
229960004397 cyclophosphamide Drugs 0.000 claims description 3
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
229960000978 cyproterone acetate Drugs 0.000 claims description 3
229960000640 dactinomycin Drugs 0.000 claims description 3
STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical class 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 3
CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Chemical class 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
229960003668 docetaxel Drugs 0.000 claims description 3
229960004679 doxorubicin Drugs 0.000 claims description 3
229950004203 droloxifene Drugs 0.000 claims description 3
XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical class C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 claims description 3
229960001904 epirubicin Drugs 0.000 claims description 3
229930013356 epothilone Chemical class 0.000 claims description 3
150000003883 epothilone derivatives Chemical class 0.000 claims description 3
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 3
229960005420 etoposide Drugs 0.000 claims description 3
229960000255 exemestane Drugs 0.000 claims description 3
DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 3
229960004039 finasteride Drugs 0.000 claims description 3
229960002949 fluorouracil Drugs 0.000 claims description 3
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
229960002074 flutamide Drugs 0.000 claims description 3
229960000908 idarubicin Drugs 0.000 claims description 3
229960001101 ifosfamide Drugs 0.000 claims description 3
HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical class ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 3
239000000367 immunologic factor Substances 0.000 claims description 3
102000006495 integrins Human genes 0.000 claims description 3
108010044426 integrins Proteins 0.000 claims description 3
229940043355 kinase inhibitor Drugs 0.000 claims description 3
229960003881 letrozole Drugs 0.000 claims description 3
HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims description 3
HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 3
229960004961 mechlorethamine Drugs 0.000 claims description 3
229960004296 megestrol acetate Drugs 0.000 claims description 3
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 3
229960001924 melphalan Drugs 0.000 claims description 3
SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical class OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 3
239000003475 metalloproteinase inhibitor Substances 0.000 claims description 3
229960000485 methotrexate Drugs 0.000 claims description 3
CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical class 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
229960004857 mitomycin Drugs 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
229960002653 nilutamide Drugs 0.000 claims description 3
230000037361 pathway Effects 0.000 claims description 3
239000003757 phosphotransferase inhibitor Substances 0.000 claims description 3
229960003171 plicamycin Drugs 0.000 claims description 3
239000003207 proteasome inhibitor Substances 0.000 claims description 3
GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 claims description 3
229960004622 raloxifene Drugs 0.000 claims description 3
229960000460 razoxane Drugs 0.000 claims description 3
BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 claims description 3
229960003522 roquinimex Drugs 0.000 claims description 3
229960001603 tamoxifen Drugs 0.000 claims description 3
NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide 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](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 3
229960001278 teniposide Drugs 0.000 claims description 3
229960001196 thiotepa Drugs 0.000 claims description 3
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 3
229960000303 topotecan Drugs 0.000 claims description 3
229960005026 toremifene Drugs 0.000 claims description 3
XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 claims description 3
229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 3
239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 3
OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical class C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 claims description 3
229960004528 vincristine Drugs 0.000 claims description 3
OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Chemical class C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 claims description 3
AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 claims description 2
229930012538 Paclitaxel Chemical class 0.000 claims description 2
229960001592 paclitaxel Drugs 0.000 claims description 2
RCINICONZNJXQF-MZXODVADSA-N taxol Chemical class 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 2
206010061218 Inflammation Diseases 0.000 claims 1
229940022353 herceptin Drugs 0.000 claims 1
230000004054 inflammatory process Effects 0.000 claims 1
229960004768 irinotecan Drugs 0.000 claims 1
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 1
238000011282 treatment Methods 0.000 abstract description 33
108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 abstract description 18
102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 abstract description 16
BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 abstract description 14
102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 abstract description 13
101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 abstract description 13
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 180
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 170
239000000203 mixture Substances 0.000 description 91
239000007787 solid Substances 0.000 description 76
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
239000000243 solution Substances 0.000 description 60
235000019439 ethyl acetate Nutrition 0.000 description 57
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
239000011541 reaction mixture Substances 0.000 description 42
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 38
LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 36
JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 34
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
239000000741 silica gel Substances 0.000 description 28
229910002027 silica gel Inorganic materials 0.000 description 28
238000000034 method Methods 0.000 description 27
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
238000006243 chemical reaction Methods 0.000 description 20
239000000047 product Substances 0.000 description 20
125000000217 alkyl group Chemical group 0.000 description 19
229910052739 hydrogen Inorganic materials 0.000 description 19
239000012267 brine Substances 0.000 description 18
229910000027 potassium carbonate Inorganic materials 0.000 description 18
238000002953 preparative HPLC Methods 0.000 description 18
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
238000003756 stirring Methods 0.000 description 17
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
239000000706 filtrate Substances 0.000 description 16
125000003118 aryl group Chemical group 0.000 description 15
229910052757 nitrogen Inorganic materials 0.000 description 15
239000012044 organic layer Substances 0.000 description 15
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 14
102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 14
108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 14
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
125000004432 carbon atom Chemical group C* 0.000 description 13
229940125782 compound 2 Drugs 0.000 description 13
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
238000004587 chromatography analysis Methods 0.000 description 12
239000001257 hydrogen Substances 0.000 description 12
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 12
239000002253 acid Substances 0.000 description 11
239000013058 crude material Substances 0.000 description 11
238000004128 high performance liquid chromatography Methods 0.000 description 11
102000005962 receptors Human genes 0.000 description 11
108020003175 receptors Proteins 0.000 description 11
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 10
229910052786 argon Inorganic materials 0.000 description 10
239000000284 extract Substances 0.000 description 10
239000010410 layer Substances 0.000 description 10
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
229940126062 Compound A Drugs 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 9
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
239000002585 base Substances 0.000 description 9
238000003818 flash chromatography Methods 0.000 description 9
235000015320 potassium carbonate Nutrition 0.000 description 9
235000011181 potassium carbonates Nutrition 0.000 description 9
239000002904 solvent Substances 0.000 description 9
125000001424 substituent group Chemical group 0.000 description 9
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
125000003710 aryl alkyl group Chemical group 0.000 description 8
229940125904 compound 1 Drugs 0.000 description 8
229940126214 compound 3 Drugs 0.000 description 8
210000002889 endothelial cell Anatomy 0.000 description 8
OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
229910000041 hydrogen chloride Inorganic materials 0.000 description 8
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
239000003921 oil Substances 0.000 description 8
235000019198 oils Nutrition 0.000 description 8
125000000547 substituted alkyl group Chemical group 0.000 description 8
239000003039 volatile agent Substances 0.000 description 8
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 7
108091000080 Phosphotransferase Proteins 0.000 description 7
201000004681 Psoriasis Diseases 0.000 description 7
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 7
125000005843 halogen group Chemical group 0.000 description 7
125000001072 heteroaryl group Chemical group 0.000 description 7
229910052760 oxygen Inorganic materials 0.000 description 7
102000020233 phosphotransferase Human genes 0.000 description 7
229940002612 prodrug Drugs 0.000 description 7
239000000651 prodrug Substances 0.000 description 7
238000000746 purification Methods 0.000 description 7
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
108090000379 Fibroblast growth factor 2 Proteins 0.000 description 6
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
125000003545 alkoxy group Chemical group 0.000 description 6
150000001412 amines Chemical class 0.000 description 6
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 6
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
229940125898 compound 5 Drugs 0.000 description 6
125000004093 cyano group Chemical group *C#N 0.000 description 6
229910052736 halogen Inorganic materials 0.000 description 6
150000002367 halogens Chemical class 0.000 description 6
125000005842 heteroatom Chemical group 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
210000004072 lung Anatomy 0.000 description 6
239000000463 material Substances 0.000 description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
108091008598 receptor tyrosine kinases Proteins 0.000 description 6
238000010992 reflux Methods 0.000 description 6
229910000104 sodium hydride Inorganic materials 0.000 description 6
125000003107 substituted aryl group Chemical group 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
102000001301 EGF receptor Human genes 0.000 description 5
102100024785 Fibroblast growth factor 2 Human genes 0.000 description 5
101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
239000004146 Propane-1,2-diol Substances 0.000 description 5
102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 5
229960000583 acetic acid Drugs 0.000 description 5
125000005236 alkanoylamino group Chemical group 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
210000004027 cell Anatomy 0.000 description 5
239000003153 chemical reaction reagent Substances 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
125000000623 heterocyclic group Chemical group 0.000 description 5
125000004356 hydroxy functional group Chemical group O* 0.000 description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
239000003960 organic solvent Substances 0.000 description 5
229960004063 propylene glycol Drugs 0.000 description 5
102000027426 receptor tyrosine kinases Human genes 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 5
230000004614 tumor growth Effects 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 4
201000001320 Atherosclerosis Diseases 0.000 description 4
206010012689 Diabetic retinopathy Diseases 0.000 description 4
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
102000004190 Enzymes Human genes 0.000 description 4
108090000790 Enzymes Proteins 0.000 description 4
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
101100118549 Homo sapiens EGFR gene Proteins 0.000 description 4
208000007766 Kaposi sarcoma Diseases 0.000 description 4
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
238000005481 NMR spectroscopy Methods 0.000 description 4
101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 4
230000004913 activation Effects 0.000 description 4
125000004423 acyloxy group Chemical group 0.000 description 4
125000003282 alkyl amino group Chemical group 0.000 description 4
125000004414 alkyl thio group Chemical group 0.000 description 4
230000029936 alkylation Effects 0.000 description 4
238000005804 alkylation reaction Methods 0.000 description 4
230000033115 angiogenesis Effects 0.000 description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
125000001589 carboacyl group Chemical group 0.000 description 4
238000001816 cooling Methods 0.000 description 4
125000004122 cyclic group Chemical group 0.000 description 4
238000000921 elemental analysis Methods 0.000 description 4
229940088598 enzyme Drugs 0.000 description 4
229910052731 fluorine Inorganic materials 0.000 description 4
125000002541 furyl group Chemical group 0.000 description 4
201000011066 hemangioma Diseases 0.000 description 4
150000002430 hydrocarbons Chemical group 0.000 description 4
150000002431 hydrogen Chemical group 0.000 description 4
125000002883 imidazolyl group Chemical group 0.000 description 4
208000017169 kidney disease Diseases 0.000 description 4
NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 4
239000012038 nucleophile Substances 0.000 description 4
239000001301 oxygen Substances 0.000 description 4
239000012071 phase Substances 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
125000004076 pyridyl group Chemical group 0.000 description 4
125000000714 pyrimidinyl group Chemical group 0.000 description 4
230000002829 reductive effect Effects 0.000 description 4
206010039073 rheumatoid arthritis Diseases 0.000 description 4
230000011664 signaling Effects 0.000 description 4
239000007858 starting material Substances 0.000 description 4
229910052717 sulfur Inorganic materials 0.000 description 4
125000000335 thiazolyl group Chemical group 0.000 description 4
125000001544 thienyl group Chemical group 0.000 description 4
150000003573 thiols Chemical class 0.000 description 4
FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 3
MUZWURBFVCHTIC-UHFFFAOYSA-N 1-(triazol-1-yl)propan-2-ol Chemical compound CC(O)CN1C=CN=N1 MUZWURBFVCHTIC-UHFFFAOYSA-N 0.000 description 3
238000005160 1H NMR spectroscopy Methods 0.000 description 3
JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 3
229960000549 4-dimethylaminophenol Drugs 0.000 description 3
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
206010003210 Arteriosclerosis Diseases 0.000 description 3
208000037260 Atherosclerotic Plaque Diseases 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
206010006187 Breast cancer Diseases 0.000 description 3
208000026310 Breast neoplasm Diseases 0.000 description 3
108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
239000007821 HATU Substances 0.000 description 3
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
241000124008 Mammalia Species 0.000 description 3
241001465754 Metazoa Species 0.000 description 3
208000008589 Obesity Diseases 0.000 description 3
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
239000007983 Tris buffer Substances 0.000 description 3
102000016548 Vascular Endothelial Growth Factor Receptor-1 Human genes 0.000 description 3
108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 3
230000001154 acute effect Effects 0.000 description 3
125000003342 alkenyl group Chemical group 0.000 description 3
125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
125000000304 alkynyl group Chemical group 0.000 description 3
235000019270 ammonium chloride Nutrition 0.000 description 3
230000001028 anti-proliverative effect Effects 0.000 description 3
206010003246 arthritis Diseases 0.000 description 3
125000002619 bicyclic group Chemical group 0.000 description 3
230000015572 biosynthetic process Effects 0.000 description 3
229910052796 boron Inorganic materials 0.000 description 3
WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 3
210000000481 breast Anatomy 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
230000004663 cell proliferation Effects 0.000 description 3
239000003638 chemical reducing agent Substances 0.000 description 3
238000002512 chemotherapy Methods 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
238000002425 crystallisation Methods 0.000 description 3
230000008025 crystallization Effects 0.000 description 3
239000012024 dehydrating agents‎ Substances 0.000 description 3
230000018109 developmental process Effects 0.000 description 3
206010012601 diabetes mellitus Diseases 0.000 description 3
125000004663 dialkyl amino group Chemical group 0.000 description 3
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
208000035475 disorder Diseases 0.000 description 3
230000002255 enzymatic effect Effects 0.000 description 3
150000002118 epoxides Chemical class 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
125000001153 fluoro group Chemical group F* 0.000 description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
229910052740 iodine Chemical group 0.000 description 3
239000003446 ligand Substances 0.000 description 3
NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 3
238000004519 manufacturing process Methods 0.000 description 3
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
239000002808 molecular sieve Substances 0.000 description 3
125000002950 monocyclic group Chemical group 0.000 description 3
229910000069 nitrogen hydride Inorganic materials 0.000 description 3
235000020824 obesity Nutrition 0.000 description 3
239000012074 organic phase Substances 0.000 description 3
150000002978 peroxides Chemical class 0.000 description 3
230000008569 process Effects 0.000 description 3
230000035755 proliferation Effects 0.000 description 3
230000002441 reversible effect Effects 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
239000002002 slurry Substances 0.000 description 3
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
235000017557 sodium bicarbonate Nutrition 0.000 description 3
239000012312 sodium hydride Substances 0.000 description 3
241000894007 species Species 0.000 description 3
239000000725 suspension Substances 0.000 description 3
210000001685 thyroid gland Anatomy 0.000 description 3
ARCACZWMYGILNI-UHFFFAOYSA-N 1,2,3-trifluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(F)=C1F ARCACZWMYGILNI-UHFFFAOYSA-N 0.000 description 2
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
MDWJZBVEVLTXDE-UHFFFAOYSA-N 2-methyl-1h-indol-5-ol Chemical compound OC1=CC=C2NC(C)=CC2=C1 MDWJZBVEVLTXDE-UHFFFAOYSA-N 0.000 description 2
RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 2
UNSLITXEASVMQB-UHFFFAOYSA-N 5-methyl-4-phenoxypyrrolo[2,1-f][1,2,4]triazin-6-ol Chemical compound C12=C(C)C(O)=CN2N=CN=C1OC1=CC=CC=C1 UNSLITXEASVMQB-UHFFFAOYSA-N 0.000 description 2
208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
208000032467 Aplastic anaemia Diseases 0.000 description 2
206010051113 Arterial restenosis Diseases 0.000 description 2
229910015900 BF3 Inorganic materials 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
101150021185 FGF gene Proteins 0.000 description 2
102100031706 Fibroblast growth factor 1 Human genes 0.000 description 2
206010018364 Glomerulonephritis Diseases 0.000 description 2
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
239000004471 Glycine Substances 0.000 description 2
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
208000022559 Inflammatory bowel disease Diseases 0.000 description 2
125000000899 L-alpha-glutamyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 2
206010025323 Lymphomas Diseases 0.000 description 2
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 description 2
201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
208000022873 Ocular disease Diseases 0.000 description 2
235000019502 Orange oil Nutrition 0.000 description 2
208000034038 Pathologic Neovascularization Diseases 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
108091005682 Receptor kinases Proteins 0.000 description 2
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 2
208000038016 acute inflammation Diseases 0.000 description 2
230000006022 acute inflammation Effects 0.000 description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
229940100198 alkylating agent Drugs 0.000 description 2
239000002168 alkylating agent Substances 0.000 description 2
150000001413 amino acids Chemical group 0.000 description 2
125000003277 amino group Chemical group 0.000 description 2
229910021529 ammonia Inorganic materials 0.000 description 2
238000004458 analytical method Methods 0.000 description 2
239000004037 angiogenesis inhibitor Substances 0.000 description 2
230000000259 anti-tumor effect Effects 0.000 description 2
230000006907 apoptotic process Effects 0.000 description 2
125000001691 aryl alkyl amino group Chemical group 0.000 description 2
125000001769 aryl amino group Chemical group 0.000 description 2
125000004104 aryloxy group Chemical group 0.000 description 2
238000003556 assay Methods 0.000 description 2
229940120638 avastin Drugs 0.000 description 2
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
PVOGIXDLFNKNES-UHFFFAOYSA-N benzyl n-(1-hydroxy-4-methylsulfonylbutan-2-yl)carbamate Chemical compound CS(=O)(=O)CCC(CO)NC(=O)OCC1=CC=CC=C1 PVOGIXDLFNKNES-UHFFFAOYSA-N 0.000 description 2
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
239000000872 buffer Substances 0.000 description 2
210000000170 cell membrane Anatomy 0.000 description 2
239000000460 chlorine Substances 0.000 description 2
229910052801 chlorine Inorganic materials 0.000 description 2
230000001684 chronic effect Effects 0.000 description 2
210000001072 colon Anatomy 0.000 description 2
JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
239000007822 coupling agent Substances 0.000 description 2
239000012043 crude product Substances 0.000 description 2
239000000824 cytostatic agent Substances 0.000 description 2
230000018044 dehydration Effects 0.000 description 2
238000006297 dehydration reaction Methods 0.000 description 2
230000001419 dependent effect Effects 0.000 description 2
238000010511 deprotection reaction Methods 0.000 description 2
238000013461 design Methods 0.000 description 2
238000011161 development Methods 0.000 description 2
PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 2
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
235000019797 dipotassium phosphate Nutrition 0.000 description 2
238000004090 dissolution Methods 0.000 description 2
239000003480 eluent Substances 0.000 description 2
229940082789 erbitux Drugs 0.000 description 2
XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
125000004494 ethyl ester group Chemical group 0.000 description 2
239000011737 fluorine Substances 0.000 description 2
125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
239000000499 gel Substances 0.000 description 2
230000014509 gene expression Effects 0.000 description 2
230000012010 growth Effects 0.000 description 2
125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 2
201000005787 hematologic cancer Diseases 0.000 description 2
208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
125000000592 heterocycloalkyl group Chemical group 0.000 description 2
150000002429 hydrazines Chemical class 0.000 description 2
125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 2
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
125000001041 indolyl group Chemical group 0.000 description 2
230000003834 intracellular effect Effects 0.000 description 2
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 2
HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
229910052943 magnesium sulfate Inorganic materials 0.000 description 2
206010061289 metastatic neoplasm Diseases 0.000 description 2
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 2
KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 2
208000015122 neurodegenerative disease Diseases 0.000 description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
230000003287 optical effect Effects 0.000 description 2
239000010502 orange oil Substances 0.000 description 2
230000002611 ovarian Effects 0.000 description 2
AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
210000000496 pancreas Anatomy 0.000 description 2
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
230000026731 phosphorylation Effects 0.000 description 2
238000006366 phosphorylation reaction Methods 0.000 description 2
LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
239000000843 powder Substances 0.000 description 2
230000002265 prevention Effects 0.000 description 2
210000002307 prostate Anatomy 0.000 description 2
102000004169 proteins and genes Human genes 0.000 description 2
108090000623 proteins and genes Proteins 0.000 description 2
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
230000005855 radiation Effects 0.000 description 2
230000001850 reproductive effect Effects 0.000 description 2
210000001210 retinal vessel Anatomy 0.000 description 2
238000012552 review Methods 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000000377 silicon dioxide Substances 0.000 description 2
210000003491 skin Anatomy 0.000 description 2
239000011734 sodium Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
239000012279 sodium borohydride Substances 0.000 description 2
229910000033 sodium borohydride Inorganic materials 0.000 description 2
235000011006 sodium potassium tartrate Nutrition 0.000 description 2
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
239000012453 solvate Substances 0.000 description 2
210000002784 stomach Anatomy 0.000 description 2
125000005017 substituted alkenyl group Chemical group 0.000 description 2
125000004426 substituted alkynyl group Chemical group 0.000 description 2
239000000758 substrate Substances 0.000 description 2
HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 2
239000011593 sulfur Substances 0.000 description 2
RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)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-XAZOAEDWSA-N 0.000 description 2
229940063683 taxotere Drugs 0.000 description 2
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 2
230000002792 vascular Effects 0.000 description 2
229940099039 velcade Drugs 0.000 description 2
230000029663 wound healing Effects 0.000 description 2
IDFPQEHZYBXIFO-GFCCVEGCSA-N (R)-(4-fluoro-2-propylphenyl)-(1H-imidazol-2-yl)methanol Chemical compound CCCc1cc(F)ccc1[C@@H](O)c1ncc[nH]1 IDFPQEHZYBXIFO-GFCCVEGCSA-N 0.000 description 1
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
UMPKNHLBWNCWJP-UHFFFAOYSA-N 1-(2h-triazol-4-yl)propan-2-ol Chemical compound CC(O)CC=1C=NNN=1 UMPKNHLBWNCWJP-UHFFFAOYSA-N 0.000 description 1
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
HOOOCPBGSWHGQQ-UHFFFAOYSA-N 1-[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropan-2-yl 2-(phenylmethoxycarbonylamino)propanoate Chemical compound C=1N2N=CN=C(OC=3C(=C4C=C(C)NC4=CC=3)F)C2=C(C)C=1OCC(C)OC(=O)C(C)NC(=O)OCC1=CC=CC=C1 HOOOCPBGSWHGQQ-UHFFFAOYSA-N 0.000 description 1
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 1
JHFAEUICJHBVHB-UHFFFAOYSA-N 1h-indol-2-ol Chemical compound C1=CC=C2NC(O)=CC2=C1 JHFAEUICJHBVHB-UHFFFAOYSA-N 0.000 description 1
LKMJVFRMDSNFRT-UHFFFAOYSA-N 2-(methoxymethyl)oxirane Chemical compound COCC1CO1 LKMJVFRMDSNFRT-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
125000004635 2-oxazepinyl group Chemical group O1N(CC=CC=C1)* 0.000 description 1
125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-pentanol Substances CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
125000004610 3,4-dihydro-4-oxo-quinazolinyl group Chemical group O=C1NC(=NC2=CC=CC=C12)* 0.000 description 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
XPXXXQZNUQAFQY-UHFFFAOYSA-N 3-methylsulfonylpropan-1-ol Chemical compound CS(=O)(=O)CCCO XPXXXQZNUQAFQY-UHFFFAOYSA-N 0.000 description 1
CZUGFKJYCPYHHV-UHFFFAOYSA-N 3-methylthiopropanol Chemical compound CSCCCO CZUGFKJYCPYHHV-UHFFFAOYSA-N 0.000 description 1
PLRXAFVBCHEMGD-UHFFFAOYSA-N 3-piperidin-1-ylpropan-1-ol Chemical compound OCCCN1CCCCC1 PLRXAFVBCHEMGD-UHFFFAOYSA-N 0.000 description 1
CHCGEJVYCWSXML-UHFFFAOYSA-N 3-piperidin-3-ylpropan-1-ol Chemical compound OCCCC1CCCNC1 CHCGEJVYCWSXML-UHFFFAOYSA-N 0.000 description 1
UMWRMOYYUHIPDT-UHFFFAOYSA-N 4-fluoro-2-methyl-1h-indol-5-ol Chemical compound OC1=CC=C2NC(C)=CC2=C1F UMWRMOYYUHIPDT-UHFFFAOYSA-N 0.000 description 1
YKJPLFDIYRGJGR-UHFFFAOYSA-N 4-fluoro-2-methyl-5-phenylmethoxy-1h-indole Chemical compound C=1C=C2NC(C)=CC2=C(F)C=1OCC1=CC=CC=C1 YKJPLFDIYRGJGR-UHFFFAOYSA-N 0.000 description 1
USPFMEKVPDBMCG-UHFFFAOYSA-N 4-methyl-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CC(C)CC(C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-UHFFFAOYSA-N 0.000 description 1
125000005986 4-piperidonyl group Chemical group 0.000 description 1
JHKOYJNBWURULH-UHFFFAOYSA-N 5-methyl-4-[(2-methyl-1h-indol-5-yl)oxy]pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid Chemical compound C1=NN2C=C(C(O)=O)C(C)=C2C(OC=2C=C3C=C(NC3=CC=2)C)=N1 JHKOYJNBWURULH-UHFFFAOYSA-N 0.000 description 1
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
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 description 1
208000030507 AIDS Diseases 0.000 description 1
206010065040 AIDS dementia complex Diseases 0.000 description 1
208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
208000024827 Alzheimer disease Diseases 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
206010003571 Astrocytoma Diseases 0.000 description 1
208000003950 B-cell lymphoma Diseases 0.000 description 1
208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
206010055113 Breast cancer metastatic Diseases 0.000 description 1
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
238000006418 Brown reaction Methods 0.000 description 1
101150041968 CDC13 gene Proteins 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
206010058019 Cancer Pain Diseases 0.000 description 1
KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
201000009030 Carcinoma Diseases 0.000 description 1
229940123587 Cell cycle inhibitor Drugs 0.000 description 1
QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
206010009944 Colon cancer Diseases 0.000 description 1
208000001333 Colorectal Neoplasms Diseases 0.000 description 1
238000006969 Curtius rearrangement reaction Methods 0.000 description 1
201000003883 Cystic fibrosis Diseases 0.000 description 1
201000009273 Endometriosis Diseases 0.000 description 1
206010014824 Endotoxic shock Diseases 0.000 description 1
BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
101150009958 FLT4 gene Proteins 0.000 description 1
102000007317 Farnesyltranstransferase Human genes 0.000 description 1
108010007508 Farnesyltranstransferase Proteins 0.000 description 1
102000003971 Fibroblast Growth Factor 1 Human genes 0.000 description 1
102000003974 Fibroblast growth factor 2 Human genes 0.000 description 1
201000008808 Fibrosarcoma Diseases 0.000 description 1
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
206010017533 Fungal infection Diseases 0.000 description 1
101000993347 Gallus gallus Ciliary neurotrophic factor Proteins 0.000 description 1
208000032612 Glial tumor Diseases 0.000 description 1
206010018338 Glioma Diseases 0.000 description 1
CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
102100021866 Hepatocyte growth factor Human genes 0.000 description 1
208000017604 Hodgkin disease Diseases 0.000 description 1
208000021519 Hodgkin lymphoma Diseases 0.000 description 1
208000010747 Hodgkins lymphoma Diseases 0.000 description 1
101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
239000002841 Lewis acid Substances 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
206010058467 Lung neoplasm malignant Diseases 0.000 description 1
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
239000004472 Lysine Substances 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
229910021380 Manganese Chloride Inorganic materials 0.000 description 1
GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
206010027476 Metastases Diseases 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
208000031888 Mycoses Diseases 0.000 description 1
208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
125000004633 N-oxo-pyridyl group Chemical group 0.000 description 1
206010029260 Neuroblastoma Diseases 0.000 description 1
208000009905 Neurofibromatoses Diseases 0.000 description 1
102100026379 Neurofibromin Human genes 0.000 description 1
208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
208000001132 Osteoporosis Diseases 0.000 description 1
102000016979 Other receptors Human genes 0.000 description 1
206010033128 Ovarian cancer Diseases 0.000 description 1
206010061535 Ovarian neoplasm Diseases 0.000 description 1
229910019142 PO4 Inorganic materials 0.000 description 1
206010061902 Pancreatic neoplasm Diseases 0.000 description 1
208000018737 Parkinson disease Diseases 0.000 description 1
YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
101710098940 Pro-epidermal growth factor Proteins 0.000 description 1
102100024028 Progonadoliberin-1 Human genes 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
239000007868 Raney catalyst Substances 0.000 description 1
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
229910000564 Raney nickel Inorganic materials 0.000 description 1
206010063837 Reperfusion injury Diseases 0.000 description 1
208000007014 Retinitis pigmentosa Diseases 0.000 description 1
206010038923 Retinopathy Diseases 0.000 description 1
206010038933 Retinopathy of prematurity Diseases 0.000 description 1
229910006074 SO2NH2 Inorganic materials 0.000 description 1
101100313649 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) POT1 gene Proteins 0.000 description 1
208000016780 Scleredema Diseases 0.000 description 1
206010055953 Scleroedema Diseases 0.000 description 1
201000010208 Seminoma Diseases 0.000 description 1
206010040070 Septic Shock Diseases 0.000 description 1
241000710960 Sindbis virus Species 0.000 description 1
206010041067 Small cell lung cancer Diseases 0.000 description 1
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
208000005718 Stomach Neoplasms Diseases 0.000 description 1
101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 1
208000006011 Stroke Diseases 0.000 description 1
101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
206010042971 T-cell lymphoma Diseases 0.000 description 1
208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
108091008605 VEGF receptors Proteins 0.000 description 1
102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
229940122803 Vinca alkaloid Drugs 0.000 description 1
208000036142 Viral infection Diseases 0.000 description 1
101100161758 Yarrowia lipolytica (strain CLIB 122 / E 150) POX3 gene Proteins 0.000 description 1
WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
230000001594 aberrant effect Effects 0.000 description 1
230000002159 abnormal effect Effects 0.000 description 1
229960001138 acetylsalicylic acid Drugs 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
239000013543 active substance Substances 0.000 description 1
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
239000000654 additive Substances 0.000 description 1
230000011759 adipose tissue development Effects 0.000 description 1
238000012382 advanced drug delivery Methods 0.000 description 1
239000000556 agonist Substances 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
150000001342 alkaline earth metals Chemical class 0.000 description 1
150000001350 alkyl halides Chemical class 0.000 description 1
230000002152 alkylating effect Effects 0.000 description 1
230000004075 alteration Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
229940024606 amino acid Drugs 0.000 description 1
DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 1
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
208000007502 anemia Diseases 0.000 description 1
230000002491 angiogenic effect Effects 0.000 description 1
238000002399 angioplasty Methods 0.000 description 1
239000005557 antagonist Substances 0.000 description 1
229940045799 anthracyclines and related substance Drugs 0.000 description 1
239000003242 anti bacterial agent Substances 0.000 description 1
230000002280 anti-androgenic effect Effects 0.000 description 1
230000003527 anti-angiogenesis Effects 0.000 description 1
229940046836 anti-estrogen Drugs 0.000 description 1
230000001833 anti-estrogenic effect Effects 0.000 description 1
230000003432 anti-folate effect Effects 0.000 description 1
230000003388 anti-hormonal effect Effects 0.000 description 1
230000001740 anti-invasion Effects 0.000 description 1
230000000340 anti-metabolite Effects 0.000 description 1
230000000692 anti-sense effect Effects 0.000 description 1
239000000051 antiandrogen Substances 0.000 description 1
229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 1
229940088710 antibiotic agent Drugs 0.000 description 1
229940127074 antifolate Drugs 0.000 description 1
229940100197 antimetabolite Drugs 0.000 description 1
239000002256 antimetabolite Substances 0.000 description 1
239000003080 antimitotic agent Substances 0.000 description 1
229940041181 antineoplastic drug Drugs 0.000 description 1
230000005735 apoptotic response Effects 0.000 description 1
125000005140 aralkylsulfonyl group Chemical group 0.000 description 1
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
239000003886 aromatase inhibitor Substances 0.000 description 1
229940046844 aromatase inhibitors Drugs 0.000 description 1
125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
125000005239 aroylamino group Chemical group 0.000 description 1
230000006793 arrhythmia Effects 0.000 description 1
206010003119 arrhythmia Diseases 0.000 description 1
125000004659 aryl alkyl thio group Chemical group 0.000 description 1
125000004391 aryl sulfonyl group Chemical group 0.000 description 1
125000005110 aryl thio group Chemical group 0.000 description 1
235000010323 ascorbic acid Nutrition 0.000 description 1
125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
208000006673 asthma Diseases 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
230000001363 autoimmune Effects 0.000 description 1
230000035578 autophosphorylation Effects 0.000 description 1
125000002785 azepinyl group Chemical group 0.000 description 1
150000001541 aziridines Chemical class 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
229940092714 benzenesulfonic acid Drugs 0.000 description 1
125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
125000004602 benzodiazinyl group Chemical group N1=NC(=CC2=C1C=CC=C2)* 0.000 description 1
125000004601 benzofurazanyl group Chemical group N1=C2C(=NO1)C(=CC=C2)* 0.000 description 1
125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
150000001558 benzoic acid derivatives Chemical class 0.000 description 1
125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
125000004599 benzpyrazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
239000012867 bioactive agent Substances 0.000 description 1
238000004166 bioassay Methods 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
230000005540 biological transmission Effects 0.000 description 1
239000004305 biphenyl Substances 0.000 description 1
235000010290 biphenyl Nutrition 0.000 description 1
125000006267 biphenyl group Chemical group 0.000 description 1
210000001109 blastomere Anatomy 0.000 description 1
150000001642 boronic acid derivatives Chemical class 0.000 description 1
210000004556 brain Anatomy 0.000 description 1
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
229910052794 bromium Inorganic materials 0.000 description 1
150000001649 bromium compounds Chemical class 0.000 description 1
RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
239000007853 buffer solution Substances 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
230000003185 calcium uptake Effects 0.000 description 1
239000002775 capsule Substances 0.000 description 1
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 1
150000001718 carbodiimides Chemical class 0.000 description 1
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
125000004181 carboxyalkyl group Chemical group 0.000 description 1
239000000969 carrier Substances 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
230000020411 cell activation Effects 0.000 description 1
230000022131 cell cycle Effects 0.000 description 1
230000010261 cell growth Effects 0.000 description 1
230000001413 cellular effect Effects 0.000 description 1
230000036755 cellular response Effects 0.000 description 1
210000003169 central nervous system Anatomy 0.000 description 1
208000025434 cerebellar degeneration Diseases 0.000 description 1
210000003679 cervix uteri Anatomy 0.000 description 1
239000003610 charcoal Substances 0.000 description 1
238000010568 chiral column chromatography Methods 0.000 description 1
BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 description 1
125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
150000001860 citric acid derivatives Chemical class 0.000 description 1
201000011024 colonic benign neoplasm Diseases 0.000 description 1
208000029742 colonic neoplasm Diseases 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
229940046044 combinations of antineoplastic agent Drugs 0.000 description 1
229940125758 compound 15 Drugs 0.000 description 1
229940125846 compound 25 Drugs 0.000 description 1
229940124558 contraceptive agent Drugs 0.000 description 1
239000003433 contraceptive agent Substances 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
230000008878 coupling Effects 0.000 description 1
238000010168 coupling process Methods 0.000 description 1
238000005859 coupling reaction Methods 0.000 description 1
125000000753 cycloalkyl group Chemical group 0.000 description 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
230000001086 cytosolic effect Effects 0.000 description 1
125000004586 dihydrobenzopyranyl group Chemical group O1C(CCC2=C1C=CC=C2)* 0.000 description 1
125000004582 dihydrobenzothienyl group Chemical group S1C(CC2=C1C=CC=C2)* 0.000 description 1
125000004597 dihydrobenzothiopyranyl group Chemical group S1C(CCC2=C1C=CC=C2)* 0.000 description 1
WOKPSXJEBSRSAT-UHFFFAOYSA-N dihydrobenzothiopyranyl sulfone group Chemical group S1C(CCC2=C1C=CC=C2)S(=O)(=O)C2SC1=C(CC2)C=CC=C1 WOKPSXJEBSRSAT-UHFFFAOYSA-N 0.000 description 1
125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
125000004609 dihydroquinazolinyl group Chemical group N1(CN=CC2=CC=CC=C12)* 0.000 description 1
229940043279 diisopropylamine Drugs 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
238000006471 dimerization reaction Methods 0.000 description 1
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
125000000532 dioxanyl group Chemical group 0.000 description 1
MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
230000008034 disappearance Effects 0.000 description 1
239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
230000007783 downstream signaling Effects 0.000 description 1
229940079593 drug Drugs 0.000 description 1
238000009510 drug design Methods 0.000 description 1
238000009509 drug development Methods 0.000 description 1
XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 1
230000013020 embryo development Effects 0.000 description 1
229940116977 epidermal growth factor Drugs 0.000 description 1
210000003238 esophagus Anatomy 0.000 description 1
239000000328 estrogen antagonist Substances 0.000 description 1
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
XCUHVGKOOKXZNK-UHFFFAOYSA-N ethyl 5-methyl-4-oxo-1h-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate Chemical compound N1C=NC(=O)C2=C(C)C(C(=O)OCC)=CN21 XCUHVGKOOKXZNK-UHFFFAOYSA-N 0.000 description 1
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
239000012065 filter cake Substances 0.000 description 1
238000001914 filtration Methods 0.000 description 1
150000005699 fluoropyrimidines Chemical class 0.000 description 1
239000006260 foam Substances 0.000 description 1
239000004052 folic acid antagonist Substances 0.000 description 1
230000003325 follicular Effects 0.000 description 1
238000009472 formulation Methods 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
125000004615 furo[2,3-b]pyridinyl group Chemical group O1C(=CC=2C1=NC=CC2)* 0.000 description 1
125000004613 furo[2,3-c]pyridinyl group Chemical group O1C(=CC=2C1=CN=CC2)* 0.000 description 1
125000004614 furo[3,1-b]pyridinyl group Chemical group 0.000 description 1
125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 1
210000000232 gallbladder Anatomy 0.000 description 1
239000007789 gas Substances 0.000 description 1
206010017758 gastric cancer Diseases 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=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 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
239000008187 granular material Substances 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
208000014951 hematologic disease Diseases 0.000 description 1
150000004677 hydrates Chemical class 0.000 description 1
229910000042 hydrogen bromide Inorganic materials 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
230000003463 hyperproliferative effect Effects 0.000 description 1
230000001969 hypertrophic effect Effects 0.000 description 1
125000002632 imidazolidinyl group Chemical group 0.000 description 1
125000002636 imidazolinyl group Chemical group 0.000 description 1
238000002513 implantation Methods 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
238000011534 incubation Methods 0.000 description 1
125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
238000009830 intercalation Methods 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
239000011630 iodine Chemical group 0.000 description 1
208000037906 ischaemic injury Diseases 0.000 description 1
125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
125000001786 isothiazolyl group Chemical group 0.000 description 1
125000003971 isoxazolinyl group Chemical group 0.000 description 1
125000000842 isoxazolyl group Chemical group 0.000 description 1
210000003734 kidney Anatomy 0.000 description 1
238000000021 kinase assay Methods 0.000 description 1
210000000867 larynx Anatomy 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
229960004338 leuprorelin Drugs 0.000 description 1
150000007517 lewis acids Chemical class 0.000 description 1
108020001756 ligand binding domains Proteins 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000007788 liquid Substances 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
208000019423 liver disease Diseases 0.000 description 1
238000011068 loading method Methods 0.000 description 1
201000005202 lung cancer Diseases 0.000 description 1
208000020816 lung neoplasm Diseases 0.000 description 1
208000037841 lung tumor Diseases 0.000 description 1
206010025135 lupus erythematosus Diseases 0.000 description 1
210000004324 lymphatic system Anatomy 0.000 description 1
208000002780 macular degeneration Diseases 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
229910001629 magnesium chloride Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
230000014759 maintenance of location Effects 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
239000011976 maleic acid Substances 0.000 description 1
OFOBLEOULBTSOW-UHFFFAOYSA-M malonate(1-) Chemical class OC(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-M 0.000 description 1
239000011572 manganese Substances 0.000 description 1
239000011565 manganese chloride Substances 0.000 description 1
235000002867 manganese chloride Nutrition 0.000 description 1
OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
229950008959 marimastat Drugs 0.000 description 1
238000010907 mechanical stirring Methods 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
201000001441 melanoma Diseases 0.000 description 1
LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
230000009401 metastasis Effects 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
YGDBSBBHEWHVAJ-LBPRGKRZSA-N methyl (2s)-4-methylsulfanyl-2-(phenylmethoxycarbonylamino)butanoate Chemical compound CSCC[C@@H](C(=O)OC)NC(=O)OCC1=CC=CC=C1 YGDBSBBHEWHVAJ-LBPRGKRZSA-N 0.000 description 1
VRETWQDNVUPEIR-UHFFFAOYSA-N methyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate Chemical compound N1=CN=C(Cl)C2=C(C)C(C(=O)OC)=CN21 VRETWQDNVUPEIR-UHFFFAOYSA-N 0.000 description 1
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
230000005012 migration Effects 0.000 description 1
238000013508 migration Methods 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
150000007522 mineralic acids Chemical class 0.000 description 1
239000011259 mixed solution Substances 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
238000002156 mixing Methods 0.000 description 1
238000003032 molecular docking Methods 0.000 description 1
238000012544 monitoring process Methods 0.000 description 1
125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
201000006417 multiple sclerosis Diseases 0.000 description 1
210000002346 musculoskeletal system Anatomy 0.000 description 1
230000035772 mutation Effects 0.000 description 1
208000010125 myocardial infarction Diseases 0.000 description 1
JOWMUPQBELRFRZ-UHFFFAOYSA-N n-carbamoylformamide Chemical compound NC(=O)NC=O JOWMUPQBELRFRZ-UHFFFAOYSA-N 0.000 description 1
125000001624 naphthyl group Chemical group 0.000 description 1
125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
208000007538 neurilemmoma Diseases 0.000 description 1
201000004931 neurofibromatosis Diseases 0.000 description 1
150000002823 nitrates Chemical class 0.000 description 1
150000002829 nitrogen Chemical class 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
201000008968 osteosarcoma Diseases 0.000 description 1
210000001672 ovary Anatomy 0.000 description 1
230000002018 overexpression Effects 0.000 description 1
125000001715 oxadiazolyl group Chemical group 0.000 description 1
125000000160 oxazolidinyl group Chemical group 0.000 description 1
125000002971 oxazolyl group Chemical group 0.000 description 1
125000003566 oxetanyl group Chemical group 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
125000004043 oxo group Chemical group O=* 0.000 description 1
125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
201000002528 pancreatic cancer Diseases 0.000 description 1
230000001575 pathological effect Effects 0.000 description 1
230000035778 pathophysiological process Effects 0.000 description 1
210000001428 peripheral nervous system Anatomy 0.000 description 1
150000004965 peroxy acids Chemical class 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
150000002989 phenols Chemical class 0.000 description 1
WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
238000000053 physical method Methods 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
125000003386 piperidinyl group Chemical group 0.000 description 1
229960005235 piperonyl butoxide Drugs 0.000 description 1
125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
150000003057 platinum Chemical class 0.000 description 1
208000015768 polyposis Diseases 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
239000000583 progesterone congener Substances 0.000 description 1
229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
201000008171 proliferative glomerulonephritis Diseases 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
208000005069 pulmonary fibrosis Diseases 0.000 description 1
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000002755 pyrazolinyl group Chemical group 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000002098 pyridazinyl group Chemical group 0.000 description 1
125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
125000000719 pyrrolidinyl group Chemical group 0.000 description 1
125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
125000000168 pyrrolyl group Chemical group 0.000 description 1
238000010791 quenching Methods 0.000 description 1
125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
125000004620 quinolinyl-N-oxide group Chemical group 0.000 description 1
125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
238000001959 radiotherapy Methods 0.000 description 1
230000000306 recurrent effect Effects 0.000 description 1
230000009467 reduction Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
208000037803 restenosis Diseases 0.000 description 1
238000004007 reversed phase HPLC Methods 0.000 description 1
201000009410 rhabdomyosarcoma Diseases 0.000 description 1
150000003873 salicylate salts Chemical class 0.000 description 1
239000012047 saturated solution Substances 0.000 description 1
230000036573 scar formation Effects 0.000 description 1
208000007754 scleredema adultorum Diseases 0.000 description 1
238000013207 serial dilution Methods 0.000 description 1
201000009890 sinusitis Diseases 0.000 description 1
208000000587 small cell lung carcinoma Diseases 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
229960001922 sodium perborate Drugs 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
229910052938 sodium sulfate Inorganic materials 0.000 description 1
235000011152 sodium sulphate Nutrition 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 description 1
YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000012265 solid product Substances 0.000 description 1
238000007614 solvation Methods 0.000 description 1
208000002320 spinal muscular atrophy Diseases 0.000 description 1
206010041823 squamous cell carcinoma Diseases 0.000 description 1
230000000638 stimulation Effects 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
201000011549 stomach cancer Diseases 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
150000003890 succinate salts Chemical class 0.000 description 1
150000003463 sulfur Chemical class 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
229940032330 sulfuric acid Drugs 0.000 description 1
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
238000001356 surgical procedure Methods 0.000 description 1
230000009885 systemic effect Effects 0.000 description 1
239000003826 tablet Substances 0.000 description 1
FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
230000008685 targeting Effects 0.000 description 1
150000003892 tartrate salts Chemical class 0.000 description 1
230000002123 temporal effect Effects 0.000 description 1
208000001608 teratocarcinoma Diseases 0.000 description 1
FJYBLMJHXRWDAQ-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxymethyl)morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCO[C@H](CO)C1 FJYBLMJHXRWDAQ-QMMMGPOBSA-N 0.000 description 1
UCVBBUBQPDCXCJ-VIFPVBQESA-N tert-butyl (2s)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1 UCVBBUBQPDCXCJ-VIFPVBQESA-N 0.000 description 1
229960003604 testosterone Drugs 0.000 description 1
125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
150000003536 tetrazoles Chemical class 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
125000001113 thiadiazolyl group Chemical group 0.000 description 1
125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
125000001984 thiazolidinyl group Chemical group 0.000 description 1
125000004589 thienofuryl group Chemical group O1C(=CC2=C1C=CS2)* 0.000 description 1
125000004588 thienopyridyl group Chemical group S1C(=CC2=C1C=CC=N2)* 0.000 description 1
125000004587 thienothienyl group Chemical group S1C(=CC2=C1C=CS2)* 0.000 description 1
125000002053 thietanyl group Chemical group 0.000 description 1
125000001730 thiiranyl group Chemical group 0.000 description 1
125000004568 thiomorpholinyl group Chemical group 0.000 description 1
230000007838 tissue remodeling Effects 0.000 description 1
229940044693 topoisomerase inhibitor Drugs 0.000 description 1
239000003053 toxin Substances 0.000 description 1
231100000765 toxin Toxicity 0.000 description 1
108700012359 toxins Proteins 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
229940055764 triaz Drugs 0.000 description 1
125000004306 triazinyl group Chemical group 0.000 description 1
150000003852 triazoles Chemical class 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
238000001665 trituration Methods 0.000 description 1
230000005747 tumor angiogenesis Effects 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
241000701161 unidentified adenovirus Species 0.000 description 1
210000003932 urinary bladder Anatomy 0.000 description 1
238000003828 vacuum filtration Methods 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
238000007631 vascular surgery Methods 0.000 description 1
210000005166 vasculature Anatomy 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
230000009385 viral infection Effects 0.000 description 1
210000003905 vulva Anatomy 0.000 description 1
238000005406 washing Methods 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1

Classifications

- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Organic Chemistry (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Immunology (AREA)
Neurology (AREA)
Physical Education & Sports Medicine (AREA)
Biomedical Technology (AREA)
Virology (AREA)
Neurosurgery (AREA)
Oncology (AREA)
Epidemiology (AREA)
Diabetes (AREA)
Hematology (AREA)
Cardiology (AREA)
Communicable Diseases (AREA)
Orthopedic Medicine & Surgery (AREA)
Heart & Thoracic Surgery (AREA)
Rheumatology (AREA)
Urology & Nephrology (AREA)
Dermatology (AREA)
Pulmonology (AREA)
Endocrinology (AREA)
Molecular Biology (AREA)
Obesity (AREA)
Biotechnology (AREA)
Emergency Medicine (AREA)
Tropical Medicine & Parasitology (AREA)
Psychology (AREA)

NZ537523A 2002-07-19 2003-07-18 Pyrrolo-triazine compounds that inhibit the tyrosine kinase activity of growth factor receptors NZ537523A (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US39725602P	2002-07-19	2002-07-19
US44721303P	2003-02-13	2003-02-13
PCT/US2003/022826 WO2004009784A2 (en)	2002-07-19	2003-07-18	Novel inhibitors of kinases

Publications (1)

Publication Number	Publication Date
NZ537523A true NZ537523A (en)	2007-08-31

Family

ID=30773005

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NZ537523A NZ537523A (en)	2002-07-19	2003-07-18	Pyrrolo-triazine compounds that inhibit the tyrosine kinase activity of growth factor receptors

Country Status (32)

Country	Link
US (6)	US6969717B2 (2)
EP (3)	EP1534290B1 (2)
JP (2)	JP4381978B2 (2)
KR (1)	KR100901939B1 (2)
CN (3)	CN101880283B (2)
AR (1)	AR040500A1 (2)
AT (2)	ATE505471T1 (2)
AU (2)	AU2003254088B2 (2)
BR (2)	BRPI0312940B1 (2)
CA (2)	CA2492665A1 (2)
CO (1)	CO5680407A2 (2)
CY (1)	CY1112628T1 (2)
DE (1)	DE60336732D1 (2)
DK (1)	DK1534290T3 (2)
ES (1)	ES2377963T3 (2)
GE (2)	GEP20074213B (2)
HR (2)	HRP20050058A2 (2)
IL (3)	IL166129A0 (2)
IS (2)	IS2880B (2)
MX (2)	MXPA05000715A (2)
MY (1)	MY134848A (2)
NO (2)	NO330132B1 (2)
NZ (1)	NZ537523A (2)
PE (1)	PE20040680A1 (2)
PL (2)	PL375352A1 (2)
PT (1)	PT1534290E (2)
RS (2)	RS20050041A (2)
RU (2)	RU2005104818A (2)
SI (1)	SI1534290T1 (2)
TW (1)	TWI329112B (2)
UA (1)	UA82846C2 (2)
WO (2)	WO2004009601A1 (2)

Families Citing this family (223)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA2273083C (en) *	1996-12-03	2012-09-18	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto, analogues and uses thereof
EP0881669B1 (en) *	1997-05-30	2005-12-14	STMicroelectronics S.r.l.	Manufacturing process of a germanium implanted heterojunction bipolar transistor
US20020058286A1 (en) *	1999-02-24	2002-05-16	Danishefsky Samuel J.	Synthesis of epothilones, intermediates thereto and analogues thereof
US6982265B1 (en) *	1999-05-21	2006-01-03	Bristol Myers Squibb Company	Pyrrolotriazine inhibitors of kinases
US6670357B2 (en) *	2000-11-17	2003-12-30	Bristol-Myers Squibb Company	Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors
US6867300B2 (en) *	2000-11-17	2005-03-15	Bristol-Myers Squibb Company	Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors
TW200300350A (en) *	2001-11-14	2003-06-01	Bristol Myers Squibb Co	C-5 modified indazolylpyrrolotriazines
PT1497019E (pt)	2002-04-23	2015-09-10	Bristol Myers Squibb Co	Compostos de pirrolotriazina anilina úteis como inibidores de quinase
TW200306841A (en)	2002-04-23	2003-12-01	Bristol Myers Squibb Co	Aryl ketone pyrrolo-triazine compounds useful as kinase inhibitors
TW200401638A (en) *	2002-06-20	2004-02-01	Bristol Myers Squibb Co	Heterocyclic inhibitors of kinases
TWI329112B (en) *	2002-07-19	2010-08-21	Bristol Myers Squibb Co	Novel inhibitors of kinases
US7649006B2 (en)	2002-08-23	2010-01-19	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto and analogues thereof
EP2186811A1 (en) *	2002-08-23	2010-05-19	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US6921769B2 (en)	2002-08-23	2005-07-26	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto and analogues thereof
TW200420565A (en)	2002-12-13	2004-10-16	Bristol Myers Squibb Co	C-6 modified indazolylpyrrolotriazines
JP2006516653A (ja)	2003-02-05	2006-07-06	ブリストル−マイヤーズ　スクイブ　カンパニー	キナーゼ阻害剤ピロロトリアジンの製造方法
TWI476206B (zh)	2003-07-18	2015-03-11	Amgen Inc	對肝細胞生長因子具專一性之結合劑
US7102001B2 (en)	2003-12-12	2006-09-05	Bristol-Myers Squibb Company	Process for preparing pyrrolotriazine
US20060014741A1 (en) *	2003-12-12	2006-01-19	Dimarco John D	Synthetic process, and crystalline forms of a pyrrolotriazine compound
MY145634A (en) *	2003-12-29	2012-03-15	Bristol Myers Squibb Co	Pyrrolotriazine compounds as kinase inhibitors
US7064203B2 (en)	2003-12-29	2006-06-20	Bristol Myers Squibb Company	Di-substituted pyrrolotriazine compounds
US7459562B2 (en) *	2004-04-23	2008-12-02	Bristol-Myers Squibb Company	Monocyclic heterocycles as kinase inhibitors
TW200538453A (en) *	2004-04-26	2005-12-01	Bristol Myers Squibb Co	Bicyclic heterocycles as kinase inhibitors
US7102002B2 (en) *	2004-06-16	2006-09-05	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
US7498342B2 (en)	2004-06-17	2009-03-03	Plexxikon, Inc.	Compounds modulating c-kit activity
US7173031B2 (en) *	2004-06-28	2007-02-06	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
US7432373B2 (en) *	2004-06-28	2008-10-07	Bristol-Meyers Squibb Company	Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors
CN1993130B (zh) *	2004-06-28	2010-06-23	布里斯托尔-迈尔斯斯奎布公司	用于制备稠合杂环激酶抑制剂的方法和中间体
US7439246B2 (en) *	2004-06-28	2008-10-21	Bristol-Myers Squibb Company	Fused heterocyclic kinase inhibitors
US7253167B2 (en) *	2004-06-30	2007-08-07	Bristol-Myers Squibb Company	Tricyclic-heteroaryl compounds useful as kinase inhibitors
TW200600513A (en)	2004-06-30	2006-01-01	Bristol Myers Squibb Co	A method for preparing pyrrolotriazine compounds
US7102003B2 (en) *	2004-07-01	2006-09-05	Bristol-Myers Squibb Company	Pyrrolotriazine compounds
SE0401790D0 (sv) *	2004-07-07	2004-07-07	Forskarpatent I Syd Ab	Tamoxifen response in pre- and postmenopausal breast cancer patients
US7504521B2 (en) *	2004-08-05	2009-03-17	Bristol-Myers Squibb Co.	Methods for the preparation of pyrrolotriazine compounds
TW200618803A (en)	2004-08-12	2006-06-16	Bristol Myers Squibb Co	Process for preparing pyrrolotriazine aniline compounds useful as kinase inhibitors
US7151176B2 (en)	2004-10-21	2006-12-19	Bristol-Myers Squibb Company	Pyrrolotriazine compounds
JP2008521900A (ja)	2004-11-30	2008-06-26	アムジエン・インコーポレーテツド	キノリン及びキナゾリン類似体並びにがん治療のための医薬としてのその使用
DE102004060659A1 (de)	2004-12-15	2006-07-06	Lanxess Deutschland Gmbh	Neue substituierte 1H-Pyrrolo[2,3-b]pyridine und deren Herstellung
US7534882B2 (en)	2005-04-06	2009-05-19	Bristol-Myers Squibb Company	Method for preparing pyrrolotriazine compounds via in situ amination of pyrroles
US20060257400A1 (en) *	2005-05-13	2006-11-16	Bristol-Myers Squibb Company	Combination therapy
US7846941B2 (en)	2005-05-17	2010-12-07	Plexxikon, Inc.	Compounds modulating c-kit and c-fms activity and uses therefor
WO2006130657A2 (en) *	2005-05-31	2006-12-07	Bristol-Myers Squibb Company	Stereoselective reduction process for the preparation of pyrrolotriazine compounds
US20060288309A1 (en) *	2005-06-16	2006-12-21	Cross Charles W Jr	Displaying available menu choices in a multimodal browser
UA95244C2 (ru)	2005-06-22	2011-07-25	Плексикон, Инк.	Соединения и способ модулирования активности киназ, и показания для их применения
US7402582B2 (en) *	2005-07-01	2008-07-22	Bristol-Myers Squibb Company	Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith
US7442700B2 (en) *	2005-07-01	2008-10-28	Bristol-Myers Squibb Company	Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith
US7405213B2 (en) *	2005-07-01	2008-07-29	Bristol-Myers Squibb Company	Pyrrolotriazine compounds useful as kinase inhibitors and methods of treating kinase-associated conditions therewith
GB0517387D0 (en) *	2005-08-26	2005-10-05	Antisoma Res Ltd	Combinations for the treatment of cancer
ATE543914T1 (de)	2005-09-01	2012-02-15	Bristol Myers Squibb Co	Biomarker und verfahren zur bestimmung der empfindlichkeit gegen vegfr2 modulator.
CN101291934B (zh) *	2005-09-27	2012-06-27	布里斯托尔-迈尔斯·斯奎布公司	[(1R),2S]-2-氨基丙酸2-[4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基氧基]-1-甲基乙基酯的晶型
US7547782B2 (en) *	2005-09-30	2009-06-16	Bristol-Myers Squibb Company	Met kinase inhibitors
US7514435B2 (en) *	2005-11-18	2009-04-07	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
PE20070855A1 (es)	2005-12-02	2007-10-14	Bayer Pharmaceuticals Corp	Derivados de 4-amino-pirrolotriazina sustituida como inhibidores de quinasas
WO2007064931A2 (en)	2005-12-02	2007-06-07	Bayer Healthcare Llc	Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
US20080108664A1 (en)	2005-12-23	2008-05-08	Liu Belle B	Solid-state form of AMG 706 and pharmaceutical compositions thereof
AR059066A1 (es)	2006-01-27	2008-03-12	Amgen Inc	Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf)
JP2009526050A (ja)	2006-02-10	2009-07-16	アムジエン・インコーポレーテツド	Ａｍｇ７０６の水和物形態
US8063208B2 (en)	2006-02-16	2011-11-22	Bristol-Myers Squibb Company	Crystalline forms of (3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol
KR20080107408A (ko)	2006-03-07	2008-12-10	브리스톨-마이어스 스큅 컴퍼니	키나제 억제제로서 유용한 피롤로트리아진 아닐린 전구약물화합물
CA2650059A1 (en) *	2006-04-21	2007-11-01	Bristol-Myers Squibb Company	Process for the preparation of [(1r), 2s]-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1h-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester
WO2008005469A2 (en)	2006-06-30	2008-01-10	Schering Corporation	Igfbp2 biomarker
HRP20140688T1 (hr)	2006-07-07	2014-10-24	Bristol-Myers Squibb Company	Inhibitori piroltriazin kinaze
PE20080403A1 (es)	2006-07-14	2008-04-25	Amgen Inc	Derivados heterociclicos fusionados y metodos de uso
US8217177B2 (en)	2006-07-14	2012-07-10	Amgen Inc.	Fused heterocyclic derivatives and methods of use
US7531539B2 (en) *	2006-08-09	2009-05-12	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
WO2008021859A1 (en) *	2006-08-09	2008-02-21	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
CL2007003158A1 (es) *	2006-11-02	2008-05-16	Astrazeneca Ab	Procedimiento de preparacion de compuestos derivados de quinazolina o sus sales farmaceuticamente aceptables; compuestos intermediarios; procedimiento de preparacion.
WO2008063888A2 (en)	2006-11-22	2008-05-29	Plexxikon, Inc.	Compounds modulating c-fms and/or c-kit activity and uses therefor
AU2007338792B2 (en)	2006-12-20	2012-05-31	Amgen Inc.	Substituted heterocycles and methods of use
JP2010514695A (ja)	2006-12-21	2010-05-06	プレキシコン，インコーポレーテッド	キナーゼ調節のための化合物および方法およびそのための適応症
WO2008079909A1 (en) *	2006-12-21	2008-07-03	Plexxikon, Inc.	Pyrrolo [2,3-b] pyridines as kinase modulators
PE20121126A1 (es)	2006-12-21	2012-08-24	Plexxikon Inc	Compuestos pirrolo [2,3-b] piridinas como moduladores de quinasa
US7851500B2 (en)	2007-01-05	2010-12-14	Bristol-Myers Squibb Company	Aminopyrazole kinase inhibitors
AU2008205252B2 (en)	2007-01-09	2013-02-21	Amgen Inc.	Bis-aryl amide derivatives useful for the treatment of cancer
EP2115130B1 (en)	2007-02-08	2011-08-03	Codexis, Inc.	Ketoreductases and uses thereof
MX2009008531A (es)	2007-02-16	2009-08-26	Amgen Inc	Cetonas de heterociclilo que contienen nitrogeno y su uso como inhibidores de c-met.
WO2008127526A2 (en) *	2007-03-12	2008-10-23	Bristol-Myers Squibb Company	Biomarkers and methods for determining sensitivity to vascular endothelial growth factor receptor-2 modulators
US20100234381A1 (en)	2007-04-13	2010-09-16	Bristol-Myers Squibb Company	Biomarkers and methods for determining sensitivity to vascular endothelial growth factor receptor-2 modulators
EP2134716A1 (en) *	2007-04-18	2009-12-23	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
TW200902019A (en) *	2007-04-26	2009-01-16	Ono Pharmaceutical Co	Dicyclic heterocyclic compound
WO2009012283A1 (en)	2007-07-17	2009-01-22	Plexxikon Inc.	Compounds and methods for kinase modulation, and indications therefor
PL2188313T3 (pl)	2007-08-21	2018-04-30	Amgen, Inc.	Białka wiążące ludzki antygen c-fms
JP2011500086A (ja)	2007-10-22	2011-01-06	シェーリングコーポレイション	完全ヒト抗ｖｅｇｆ抗体および使用方法
US20110086850A1 (en) *	2008-04-11	2011-04-14	Board Of Regents, The University Of Texas System	Radiosensitization of tumors with indazolpyrrolotriazines for radiotherapy
CL2009001152A1 (es) *	2008-05-13	2009-10-16	Array Biopharma Inc	Compuestos derivados de n-(4-(cicloalquilo nitrogenado-1-il)-1h-pirrolo[2,3-b]piridin-3-il)amida, inhibidores de cinasa; proceso de preparacion; composicion farmaceutica; y su uso para el tratamiento de una enfermedad proliferativa.
ES2539620T3 (es)	2008-12-19	2015-07-02	Cephalon, Inc.	Pirrolotriazina como inhibidor de ALK y de JAK2
WO2010099139A2 (en)	2009-02-25	2010-09-02	Osi Pharmaceuticals, Inc.	Combination anti-cancer therapy
WO2010099364A2 (en)	2009-02-27	2010-09-02	Osi Pharmaceuticals, Inc.	Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
WO2010099138A2 (en)	2009-02-27	2010-09-02	Osi Pharmaceuticals, Inc.	Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
WO2010099363A1 (en)	2009-02-27	2010-09-02	Osi Pharmaceuticals, Inc.	Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
MY172424A (en)	2009-04-03	2019-11-25	Hoffmann La Roche	Propane- i-sulfonic acid {3- (4-chloro-phenyl)-1h-pyrrolo [2, 3-b] pyridine-3-carconyl] -2, 4-difluoro-phenyl} -amide compositions and uses thereof
US8329724B2 (en)	2009-08-03	2012-12-11	Hoffmann-La Roche Inc.	Process for the manufacture of pharmaceutically active compounds
US20120301463A1 (en)	2009-09-30	2012-11-29	President And Fellows Of Harvard College	Methods for Modulation of Autophagy Through the Modulation of Autophagy-Enhancing Gene Products
WO2011044019A1 (en) *	2009-10-05	2011-04-14	Bristol-Myers Squibb Company	(R)-1-(4-(4-FLUORO-2-METHYL-1H-INDOL-5-YLOXY)-5-METHYLPYRROLO[2,1-f][1,2,4]TRIAZIN-6-YLOXY)PROPAN-2-OL METABOLITES
CN106220623A (zh)	2009-11-06	2016-12-14	普莱希科公司	用于激酶调节的化合物和方法及其适应症
WO2011075620A1 (en)	2009-12-18	2011-06-23	Novartis Ag	Method for treating haematological cancers
WO2011090738A2 (en) *	2009-12-29	2011-07-28	Dana-Farber Cancer Institute, Inc.	Type ii raf kinase inhibitors
WO2011097331A1 (en) *	2010-02-03	2011-08-11	Bristol-Myers Squibb Company	Crystalline forms of (s)-1-(4-(5-cyclopropyl-1h-pyrazol-3- ylamino)pyrrolo [1,2-f] [1,2,4] triazin-2-yl)-n-(6-fluoropyridin- 3-yl)-2-methylpyrrolidine-2-carboxamide
JP5093527B2 (ja) *	2010-02-10	2012-12-12	日本電気株式会社	複合光導波路、波長可変フィルタ、波長可変レーザ、および光集積回路
WO2011161217A2 (en)	2010-06-23	2011-12-29	Palacký University in Olomouc	Targeting of vegfr2
WO2012006550A2 (en) *	2010-07-09	2012-01-12	Obetech Llc	Methods and compositions for treatment of lipogenic virus related conditions
US8338771B2 (en) *	2010-11-05	2012-12-25	Green Plus Co., Ltd.	Apparatus for tracking and condensing sunlight of sliding type
US9624213B2 (en)	2011-02-07	2017-04-18	Plexxikon Inc.	Compounds and methods for kinase modulation, and indications therefor
AR085279A1 (es)	2011-02-21	2013-09-18	Plexxikon Inc	Formas solidas de {3-[5-(4-cloro-fenil)-1h-pirrolo[2,3-b]piridina-3-carbonil]-2,4-difluor-fenil}-amida del acido propano-1-sulfonico
EP2937349B1 (en)	2011-03-23	2016-12-28	Amgen Inc.	Fused tricyclic dual inhibitors of cdk 4/6 and flt3
WO2012149014A1 (en)	2011-04-25	2012-11-01	OSI Pharmaceuticals, LLC	Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment
US8921533B2 (en)	2011-07-25	2014-12-30	Chromatin Technologies	Glycosylated valproic acid analogs and uses thereof
WO2013025939A2 (en)	2011-08-16	2013-02-21	Indiana University Research And Technology Corporation	Compounds and methods for treating cancer by inhibiting the urokinase receptor
US9382239B2 (en)	2011-11-17	2016-07-05	Dana-Farber Cancer Institute, Inc.	Inhibitors of c-Jun-N-terminal kinase (JNK)
AR090263A1 (es)	2012-03-08	2014-10-29	Hoffmann La Roche	Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma
WO2013152252A1 (en)	2012-04-06	2013-10-10	OSI Pharmaceuticals, LLC	Combination anti-cancer therapy
US9724352B2 (en)	2012-05-31	2017-08-08	Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences	Pyrrolo[2,1-F[1,2,4]triazine compounds, preparation methods and applications thereof
CN103450204B (zh)	2012-05-31	2016-08-17	中国科学院上海药物研究所	吡咯[2，1-f][1，2，4]并三嗪类化合物，其制备方法及用途
US9150570B2 (en)	2012-05-31	2015-10-06	Plexxikon Inc.	Synthesis of heterocyclic compounds
CN102675323B (zh) *	2012-06-01	2014-04-09	南京药石药物研发有限公司	吡咯并[2,1-f][1,2,4]三嗪衍生物及其抗肿瘤用途
EP2890696A1 (en)	2012-08-29	2015-07-08	Amgen, Inc.	Quinazolinone compounds and derivatives thereof
CN103664957A (zh) *	2012-09-25	2014-03-26	杨子娇	一类治疗房角狭窄的化合物及其用途
EP2909194A1 (en)	2012-10-18	2015-08-26	Dana-Farber Cancer Institute, Inc.	Inhibitors of cyclin-dependent kinase 7 (cdk7)
USRE48175E1 (en)	2012-10-19	2020-08-25	Dana-Farber Cancer Institute, Inc.	Hydrophobically tagged small molecules as inducers of protein degradation
WO2014063054A1 (en)	2012-10-19	2014-04-24	Dana-Farber Cancer Institute, Inc.	Bone marrow on x chromosome kinase (bmx) inhibitors and uses thereof
FR3000494B1 (fr) *	2012-12-28	2015-08-21	Oribase Pharma	Nouveaux derives d'azaindoles en tant qu'inhibiteurs de proteines kinases
US9050345B2 (en)	2013-03-11	2015-06-09	Bristol-Myers Squibb Company	Pyrrolotriazines as potassium ion channel inhibitors
MX367772B (es)	2013-04-04	2019-09-05	Janssen Pharmaceutica Nv	Derivados de n-(2,3-dihidro-1h-pirrolo[2,3,b]piridin-5-il)-4-quina zolinamina y n-(2,3-dihidro-1h-indol-5-il)-4-quinazolinamina novedosos como inhibidores de perk.
EP3670496A3 (en) *	2013-10-17	2020-09-30	Shionogi&Co., Ltd.	Acc2 inhibitors
EP3057956B1 (en)	2013-10-18	2021-05-05	Dana-Farber Cancer Institute, Inc.	Polycyclic inhibitors of cyclin-dependent kinase 7 (cdk7)
WO2015058126A1 (en)	2013-10-18	2015-04-23	Syros Pharmaceuticals, Inc.	Heteroaromatic compounds useful for the treatment of prolferative diseases
CN104725381B (zh) *	2013-12-19	2018-04-10	南京圣和药业股份有限公司	生长因子受体抑制剂及其应用
US9862688B2 (en)	2014-04-23	2018-01-09	Dana-Farber Cancer Institute, Inc.	Hydrophobically tagged janus kinase inhibitors and uses thereof
WO2015164614A1 (en)	2014-04-23	2015-10-29	Dana-Farber Cancer Institute, Inc.	Janus kinase inhibitors and uses thereof
US9388239B2 (en)	2014-05-01	2016-07-12	Consejo Nacional De Investigation Cientifica	Anti-human VEGF antibodies with unusually strong binding affinity to human VEGF-A and cross reactivity to human VEGF-B
JP6854762B2 (ja)	2014-12-23	2021-04-07	ダナ−ファーバーキャンサーインスティテュート，インコーポレイテッド	サイクリン依存性キナーゼ７（ｃｄｋ７）の阻害剤
HK1247955A1 (zh)	2015-01-08	2018-10-05	小利兰.斯坦福大学托管委员会	提供骨、骨髓及软骨的诱导的因子和细胞
USRE50776E1 (en)	2015-03-27	2026-02-03	Dana-Farber Cancer Institute, Inc.	Inhibitors of cyclin-dependent kinases
WO2016201370A1 (en)	2015-06-12	2016-12-15	Dana-Farber Cancer Institute, Inc.	Combination therapy of transcription inhibitors and kinase inhibitors
AU2016319125B2 (en)	2015-09-09	2021-04-08	Dana-Farber Cancer Institute, Inc.	Inhibitors of cyclin-dependent kinases
ES2969565T3 (es)	2015-09-30	2024-12-13	Max Planck Ges Zur Foerderung Derwissenschaften E V	Derivados heteroarílicos como inhibidores de la sepiapterina reductasa
EP3424505A4 (en)	2016-03-04	2019-10-16	Taiho Pharmaceutical Co., Ltd.	PREPARATION AND COMPOSITION FOR THE TREATMENT OF MALIGNANT TUMORS
US11883404B2 (en)	2016-03-04	2024-01-30	Taiho Pharmaceuticals Co., Ltd.	Preparation and composition for treatment of malignant tumors
US10577382B2 (en) *	2016-04-28	2020-03-03	Takeda Pharmaceutical Company Limited	Fused heterocyclic compound
AU2017362350B2 (en)	2016-11-18	2021-12-23	Cystic Fibrosis Foundation	Pyrrolopyrimidines as CFTR potentiators
US10131670B2 (en) *	2016-12-16	2018-11-20	Cystic Fibrosis Foundation Therapeutics, Inc.	Bicyclic heteroaryl derivatives as CFTR potentiators
CN110366550A (zh)	2016-12-22	2019-10-22	美国安进公司	作为用于治疗肺癌、胰腺癌或结直肠癌的KRAS G12C抑制剂的苯并异噻唑、异噻唑并[3,4-b]吡啶、喹唑啉、酞嗪、吡啶并[2,3-d]哒嗪和吡啶并[2,3-d]嘧啶衍生物
US11130761B2 (en) *	2016-12-29	2021-09-28	Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.	Substituted pyrrolo[2,1-f][1,2,4]triazines as FGFR inhibitors
AU2018273356B2 (en)	2017-05-22	2021-09-16	Amgen Inc.	KRAS G12C inhibitors and methods of using the same
AU2018329920B2 (en)	2017-09-08	2022-12-01	Amgen Inc.	Inhibitors of KRAS G12C and methods of using the same
JP6918204B2 (ja)	2018-03-19	2021-08-11	大鵬薬品工業株式会社	アルキル硫酸ナトリウムを含む医薬組成物
EP3788053B1 (en)	2018-05-04	2024-07-10	Amgen Inc.	Kras g12c inhibitors and methods of using the same
CA3098574A1 (en)	2018-05-04	2019-11-07	Amgen Inc.	Kras g12c inhibitors and methods of using the same
MA52564A (fr)	2018-05-10	2021-03-17	Amgen Inc	Inhibiteurs de kras g12c pour le traitement du cancer
US11096939B2 (en)	2018-06-01	2021-08-24	Amgen Inc.	KRAS G12C inhibitors and methods of using the same
MX2020012204A (es)	2018-06-11	2021-03-31	Amgen Inc	Inhibidores de kras g12c para tratar el cáncer.
US11285156B2 (en)	2018-06-12	2022-03-29	Amgen Inc.	Substituted piperazines as KRAS G12C inhibitors
EP3810132A4 (en)	2018-06-25	2022-06-22	Dana-Farber Cancer Institute, Inc.	TAIRE FAMILY KINASE INHIBITORS AND RELATED USES
JP7516029B2 (ja)	2018-11-16	2024-07-16	アムジエン・インコーポレーテツド	Ｋｒａｓｇ１２ｃ阻害剤化合物の重要な中間体の改良合成法
JP7377679B2 (ja)	2018-11-19	2023-11-10	アムジエン・インコーポレーテツド	がん治療のためのｋｒａｓｇ１２ｃ阻害剤及び１種以上の薬学的に活性な追加の薬剤を含む併用療法
AU2019384118B2 (en)	2018-11-19	2025-06-12	Amgen Inc.	KRAS G12C inhibitors and methods of using the same
AU2019401495B2 (en)	2018-12-20	2025-06-26	Amgen Inc.	Heteroaryl amides useful as KIF18A inhibitors
MA54543A (fr)	2018-12-20	2022-03-30	Amgen Inc	Inhibiteurs de kif18a
JP7686559B2 (ja)	2018-12-20	2025-06-02	アムジエン・インコーポレーテツド	Ｋｉｆ１８ａ阻害剤
JP2022513967A (ja)	2018-12-20	2022-02-09	アムジエン・インコーポレーテツド	Ｋｉｆ１８ａ阻害剤として有用なヘテロアリールアミド
US20220040324A1 (en)	2018-12-21	2022-02-10	Daiichi Sankyo Company, Limited	Combination of antibody-drug conjugate and kinase inhibitor
US12281126B2 (en)	2018-12-28	2025-04-22	Dana-Farber Cancer Institute, Inc.	Inhibitors of cyclin-dependent kinase 7 and uses thereof
MX2021010323A (es)	2019-03-01	2021-12-10	Revolution Medicines Inc	Compuestos bicíclicos de heterociclilo y usos de este.
MX2021010319A (es)	2019-03-01	2021-12-10	Revolution Medicines Inc	Compuestos biciclicos de heteroarilo y usos de estos.
WO2020231990A1 (en)	2019-05-13	2020-11-19	Relay Therapeutics, Inc.	Fgfr inhibitors and methods of use thereof
EP3738593A1 (en)	2019-05-14	2020-11-18	Amgen, Inc	Dosing of kras inhibitor for treatment of cancers
WO2020236947A1 (en)	2019-05-21	2020-11-26	Amgen Inc.	Solid state forms
EP4007753B1 (en)	2019-08-02	2025-09-24	Amgen Inc.	Kif18a inhibitors
EP4007638A1 (en)	2019-08-02	2022-06-08	Amgen Inc.	Pyridine derivatives as kif18a inhibitors
EP4007756B1 (en)	2019-08-02	2025-12-24	Amgen Inc.	Kif18a inhibitors
EP4007752B1 (en)	2019-08-02	2025-09-24	Amgen Inc.	Kif18a inhibitors
EP4048671B1 (en)	2019-10-24	2026-03-18	Amgen Inc.	Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
IL322454A (en)	2019-11-04	2025-09-01	Revolution Medicines Inc	ras inhibitors
TW202132316A (zh)	2019-11-04	2021-09-01	美商銳新醫藥公司	Ｒａｓ抑制劑
AU2020377925A1 (en)	2019-11-04	2022-05-05	Revolution Medicines, Inc.	Ras inhibitors
CA3156359A1 (en)	2019-11-08	2021-05-14	Adrian Liam Gill	Bicyclic heteroaryl compounds and uses thereof
WO2021094209A1 (en)	2019-11-12	2021-05-20	Bayer Aktiengesellschaft	Substituted pyrrolo triazine carboxamide derivatives as prostaglandin ep3 receptor antagonists
JP7837865B2 (ja)	2019-11-14	2026-03-31	アムジエン・インコーポレーテツド	Ｋｒａｓｇ１２ｃ阻害剤化合物の改良合成法
JP2023501528A (ja)	2019-11-14	2023-01-18	アムジエン・インコーポレーテツド	Ｋｒａｓｇ１２ｃ阻害剤化合物の改善された合成
FI4063364T3 (fi) *	2019-11-18	2024-11-19	Jumbo Drug Bank Co Ltd	Mnk-inhibiittoreina toimivat pyrrolotriatsiiniyhdisteet
EP4065231A1 (en)	2019-11-27	2022-10-05	Revolution Medicines, Inc.	Covalent ras inhibitors and uses thereof
WO2021142026A1 (en)	2020-01-07	2021-07-15	Revolution Medicines, Inc.	Shp2 inhibitor dosing and methods of treating cancer
IL299131A (en)	2020-06-18	2023-02-01	Revolution Medicines Inc	Methods for delaying, preventing and treating acquired resistance to RAS inhibitors
US20250195521A1 (en)	2020-09-03	2025-06-19	Revolution Medicines, Inc.	Use of sos1 inhibitors to treat malignancies with shp2 mutations
CA3194067A1 (en)	2020-09-15	2022-03-24	Revolution Medicines, Inc.	Ras inhibitors
JP7849366B2 (ja)	2020-12-22	2026-04-21	キル・レガー・セラピューティクス・インコーポレーテッド	Ｓｏｓ１阻害剤およびその使用
TW202309052A (zh)	2021-05-05	2023-03-01	美商銳新醫藥公司	Ｒａｓ抑制劑
KR20240017811A (ko)	2021-05-05	2024-02-08	레볼루션 메디슨즈, 인크.	암의 치료를 위한 ras 억제제
JP2024516450A (ja)	2021-05-05	2024-04-15	レボリューションメディシンズインコーポレイテッド	共有結合性ｒａｓ阻害剤及びその使用
AR127308A1 (es)	2021-10-08	2024-01-10	Revolution Medicines Inc	Inhibidores ras
AU2022379973A1 (en)	2021-11-08	2024-06-27	Progentos Therapeutics, Inc.	Platelet-derived growth factor receptor (pdgfr) alpha inhibitors and uses thereof
CN119212994A (zh)	2021-12-17	2024-12-27	建新公司	作为shp2抑制剂的吡唑并吡嗪化合物
EP4227307A1 (en)	2022-02-11	2023-08-16	Genzyme Corporation	Pyrazolopyrazine compounds as shp2 inhibitors
KR20240156373A (ko)	2022-03-07	2024-10-29	암젠 인크	4-메틸-2-프로판-2-일-피리딘-3-카르보니트릴의 제조 방법
JP2025510572A (ja)	2022-03-08	2025-04-15	レボリューションメディシンズインコーポレイテッド	免疫不応性肺癌を治療するための方法
IL315733A (en) *	2022-04-08	2024-11-01	SHY Therapeutics LLC	Compounds that Interact with RAS Superfamily Proteins for the Treatment of Cancer, Inflammatory, Basoplastic, and Fibrotic Diseases
CN119255825A (zh)	2022-05-24	2025-01-03	第一三共株式会社	抗-cdh6抗体-药物缀合物的剂量方案
WO2023240263A1 (en)	2022-06-10	2023-12-14	Revolution Medicines, Inc.	Macrocyclic ras inhibitors
AU2023358792A1 (en)	2022-10-14	2025-04-17	Black Diamond Therapeutics, Inc.	Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
WO2024112656A1 (en) *	2022-11-21	2024-05-30	The Board Of Trustees Of The Leland Stanford Junior University	Use of a tyrosine kinase inhibitor for the treatment of hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension
AU2024241633A1 (en)	2023-03-30	2025-11-06	Revolution Medicines, Inc.	Compositions for inducing ras gtp hydrolysis and uses thereof
CR20250420A (es)	2023-04-07	2025-11-20	Revolution Medicines Inc	Inhibidores macrocíclicos de ras
AR132338A1 (es)	2023-04-07	2025-06-18	Revolution Medicines Inc	Inhibidores de ras
CN121100123A (zh)	2023-04-14	2025-12-09	锐新医药公司	Ras抑制剂的结晶形式
CN121464140A (zh)	2023-04-14	2026-02-03	锐新医药公司	Ras抑制剂的结晶形式、含有其的组合物及其使用方法
TW202508595A (zh)	2023-05-04	2025-03-01	美商銳新醫藥公司	用於ｒａｓ相關疾病或病症之組合療法
CN116813526A (zh) *	2023-05-22	2023-09-29	四川省医学科学院·四川省人民医院	异吲哚啉酮类化合物、其制备方法及其应用
US20250049810A1 (en)	2023-08-07	2025-02-13	Revolution Medicines, Inc.	Methods of treating a ras protein-related disease or disorder
AU2024360599A1 (en) *	2023-10-10	2026-04-09	Shy Therapeutics, Llc	Pyrrolo[2,1-f][1,2,4]triazine compounds acting against cancers, inflammatory diseases, and fibrotic disease via interaction with ras superfamily proteins
AU2024360465A1 (en)	2023-10-12	2026-04-09	Revolution Medicines, Inc.	Macrocyclic ras inhibitors
TW202542151A (zh)	2023-12-22	2025-11-01	美商銳格醫藥有限公司	Ｓｏｓ１抑制劑及其用途
WO2025171296A1 (en)	2024-02-09	2025-08-14	Revolution Medicines, Inc.	Ras inhibitors
TW202547461A (zh)	2024-05-17	2025-12-16	美商銳新醫藥公司	Ｒａｓ抑制劑
WO2025255438A1 (en)	2024-06-07	2025-12-11	Revolution Medicines, Inc.	Methods of treating a ras protein-related disease or disorder
WO2025265060A1 (en)	2024-06-21	2025-12-26	Revolution Medicines, Inc.	Therapeutic compositions and methods for managing treatment-related effects
WO2026006747A1 (en)	2024-06-28	2026-01-02	Revolution Medicines, Inc.	Ras inhibitors
WO2026015825A1 (en)	2024-07-12	2026-01-15	Revolution Medicines, Inc.	Use of ras inhibitor for treating pancreatic cancer
WO2026015801A1 (en)	2024-07-12	2026-01-15	Revolution Medicines, Inc.	Methods of treating a ras related disease or disorder
WO2026015790A1 (en)	2024-07-12	2026-01-15	Revolution Medicines, Inc.	Methods of treating a ras related disease or disorder
WO2026015796A1 (en)	2024-07-12	2026-01-15	Revolution Medicines, Inc.	Methods of treating a ras related disease or disorder
WO2026050446A1 (en)	2024-08-29	2026-03-05	Revolution Medicines, Inc.	Ras inhibitors
WO2026072904A2 (en)	2024-09-26	2026-04-02	Revolution Medicines, Inc.	Compositions and methods for treating lung cancer
CN121159543A (zh) *	2025-09-19	2025-12-19	合肥综合性国家科学中心大健康研究院	吡咯并[2,1-f][1,2,4]三嗪类化合物及其制备方法和应用、中间体、药物组合物和cGAS激动剂

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL107041A (en) *	1992-09-25	2000-02-17	Lilly Co Eli	Process for preparing omega(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo-6-¬2,3-d¾pyrimidin-5-YL)alkarylcarboxylic acids and N-(omega-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo¬2,3-d¾pyrimidin-5-YL)alk-aroyl-4-glutamic acids
US6191131B1 (en) *	1997-07-23	2001-02-20	Dupont Pharmaceuticals Company	Azolo triazines and pyrimidines
JP4649046B2 (ja) *	1999-05-21	2011-03-09	ブリストル−マイヤーズスクイブカンパニー	キナーゼのピロロトリアジン阻害剤
US6982265B1 (en) *	1999-05-21	2006-01-03	Bristol Myers Squibb Company	Pyrrolotriazine inhibitors of kinases
US6787545B1 (en) *	1999-08-23	2004-09-07	Shiongi & Co., Ltd.	Pyrrolotriazine derivatives having spla2-inhibitory activities
GB0017256D0 (en) *	2000-07-13	2000-08-30	Merck Sharp & Dohme	Therapeutic agents
WO2002012227A2 (en) *	2000-08-09	2002-02-14	Astrazeneca Ab	Indole, azaindole and indazole derivatives having vegf inhibiting activity
GEP20063915B (en) *	2000-11-17	2006-09-11	Bristol Myers Squibb Co	PYRROLOTRIAZINE COMPOUNDS USEFUL AS KINASE INHIBITORS AND USE THEREOF FOR TREATING p38 KINASE-ASSOCIATED CONDITIONS
US6867300B2 (en) *	2000-11-17	2005-03-15	Bristol-Myers Squibb Company	Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors
US6670357B2 (en)	2000-11-17	2003-12-30	Bristol-Myers Squibb Company	Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors
TW200300350A (en) *	2001-11-14	2003-06-01	Bristol Myers Squibb Co	C-5 modified indazolylpyrrolotriazines
TW200306841A (en) *	2002-04-23	2003-12-01	Bristol Myers Squibb Co	Aryl ketone pyrrolo-triazine compounds useful as kinase inhibitors
PT1497019E (pt) *	2002-04-23	2015-09-10	Bristol Myers Squibb Co	Compostos de pirrolotriazina anilina úteis como inibidores de quinase
TW200400034A (en) *	2002-05-20	2004-01-01	Bristol Myers Squibb Co	Pyrazolo-pyrimidine aniline compounds useful as kinase inhibitors
TW200407143A (en) *	2002-05-21	2004-05-16	Bristol Myers Squibb Co	Pyrrolotriazinone compounds and their use to treat diseases
TWI329112B (en) *	2002-07-19	2010-08-21	Bristol Myers Squibb Co	Novel inhibitors of kinases
TWI272271B (en) *	2002-07-19	2007-02-01	Bristol Myers Squibb Co	Process for preparing certain pyrrolotriazine compounds
AU2003265349A1 (en)	2002-08-02	2004-02-23	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
TW200420565A (en)	2002-12-13	2004-10-16	Bristol Myers Squibb Co	C-6 modified indazolylpyrrolotriazines
JP2006516653A (ja)	2003-02-05	2006-07-06	ブリストル−マイヤーズ　スクイブ　カンパニー	キナーゼ阻害剤ピロロトリアジンの製造方法

2003
- 2003-07-14 TW TW092119165A patent/TWI329112B/zh not_active IP Right Cessation
- 2003-07-17 MY MYPI20032690A patent/MY134848A/en unknown
- 2003-07-18 AU AU2003254088A patent/AU2003254088B2/en not_active Expired
- 2003-07-18 PL PL03375352A patent/PL375352A1/xx not_active Application Discontinuation
- 2003-07-18 BR BRPI0312940-3A patent/BRPI0312940B1/pt active IP Right Grant
- 2003-07-18 US US10/622,593 patent/US6969717B2/en not_active Expired - Lifetime
- 2003-07-18 AR AR20030102587A patent/AR040500A1/es active IP Right Grant
- 2003-07-18 EP EP03765881A patent/EP1534290B1/en not_active Expired - Lifetime
- 2003-07-18 EP EP10180960A patent/EP2280012A3/en not_active Withdrawn
- 2003-07-18 SI SI200332120T patent/SI1534290T1/sl unknown
- 2003-07-18 MX MXPA05000715A patent/MXPA05000715A/es active IP Right Grant
- 2003-07-18 PL PL375389A patent/PL216663B1/pl unknown
- 2003-07-18 CN CN2010101428920A patent/CN101880283B/zh not_active Expired - Lifetime
- 2003-07-18 RS YUP-2005/0041A patent/RS20050041A/sr unknown
- 2003-07-18 WO PCT/US2003/022554 patent/WO2004009601A1/en not_active Ceased
- 2003-07-18 DK DK03765881.2T patent/DK1534290T3/da active
- 2003-07-18 HR HR20050058A patent/HRP20050058A2/hr not_active Application Discontinuation
- 2003-07-18 GE GEAP8643A patent/GEP20074213B/en unknown
- 2003-07-18 RU RU2005104818/04A patent/RU2005104818A/ru not_active Application Discontinuation
- 2003-07-18 DE DE60336732T patent/DE60336732D1/de not_active Expired - Lifetime
- 2003-07-18 GE GEAP8644A patent/GEP20074124B/en unknown
- 2003-07-18 HR HRP20050059A patent/HRP20050059B8/hr not_active IP Right Cessation
- 2003-07-18 JP JP2004523591A patent/JP4381978B2/ja not_active Expired - Fee Related
- 2003-07-18 AT AT03765754T patent/ATE505471T1/de not_active IP Right Cessation
- 2003-07-18 RS YU20050042A patent/RS52325B/sr unknown
- 2003-07-18 AT AT03765881T patent/ATE537843T1/de active
- 2003-07-18 WO PCT/US2003/022826 patent/WO2004009784A2/en not_active Ceased
- 2003-07-18 EP EP03765754A patent/EP1539763B1/en not_active Expired - Lifetime
- 2003-07-18 RU RU2005104422/04A patent/RU2331642C2/ru active
- 2003-07-18 PT PT03765881T patent/PT1534290E/pt unknown
- 2003-07-18 IL IL16612903A patent/IL166129A0/xx active IP Right Grant
- 2003-07-18 JP JP2004523256A patent/JP4361485B2/ja not_active Expired - Lifetime
- 2003-07-18 UA UAA200501515A patent/UA82846C2/uk unknown
- 2003-07-18 ES ES03765881T patent/ES2377963T3/es not_active Expired - Lifetime
- 2003-07-18 KR KR1020087022726A patent/KR100901939B1/ko not_active Expired - Lifetime
- 2003-07-18 BR BRPI0312801-6A patent/BR0312801A/pt unknown
- 2003-07-18 AU AU2003254017A patent/AU2003254017A1/en not_active Abandoned
- 2003-07-18 CN CN038219158A patent/CN1681508B/zh not_active Expired - Lifetime
- 2003-07-18 CA CA002492665A patent/CA2492665A1/en not_active Abandoned
- 2003-07-18 CN CNB038218208A patent/CN1315833C/zh not_active Expired - Fee Related
- 2003-07-18 US US10/623,171 patent/US6869952B2/en not_active Expired - Lifetime
- 2003-07-18 CA CA002492804A patent/CA2492804C/en not_active Expired - Lifetime
- 2003-07-18 NZ NZ537523A patent/NZ537523A/en not_active IP Right Cessation
- 2003-07-18 MX MXPA05000716A patent/MXPA05000716A/es unknown
- 2003-07-21 PE PE2003000721A patent/PE20040680A1/es not_active Application Discontinuation
2005
- 2005-01-03 IL IL166129A patent/IL166129A/en unknown
- 2005-01-06 NO NO20050072A patent/NO330132B1/no not_active IP Right Cessation
- 2005-01-11 IL IL16623205A patent/IL166232A0/xx unknown
- 2005-01-12 IS IS7647A patent/IS2880B/is unknown
- 2005-01-12 IS IS7646A patent/IS7646A/is unknown
- 2005-01-13 US US11/035,248 patent/US7265113B2/en not_active Expired - Lifetime
- 2005-01-19 CO CO05003967A patent/CO5680407A2/es active IP Right Grant
- 2005-01-25 NO NO20050417A patent/NO20050417L/no not_active Application Discontinuation
- 2005-08-29 US US11/214,267 patent/US20060058304A1/en not_active Abandoned
2007
- 2007-08-02 US US11/832,976 patent/US7521450B2/en not_active Expired - Lifetime
2009
- 2009-03-06 US US12/399,429 patent/US7820814B2/en not_active Expired - Lifetime
2012
- 2012-03-14 CY CY20121100271T patent/CY1112628T1/el unknown

Also Published As

Publication number	Publication date
PL216663B1 (pl)	2014-04-30
BRPI0312940B1 (pt)	2019-07-23
US7820814B2 (en)	2010-10-26
EP1539763A4 (en)	2007-08-01
US20070299075A1 (en)	2007-12-27
AU2003254088B2 (en)	2008-07-17
CN101880283B (zh)	2012-07-18
CO5680407A2 (es)	2006-09-29
ATE505471T1 (de)	2011-04-15
NO20050417L (no)	2005-02-17
US6969717B2 (en)	2005-11-29
US20040072832A1 (en)	2004-04-15
CY1112628T1 (el)	2016-02-10
WO2004009784A3 (en)	2004-04-22
IS7646A (is)	2005-01-12
IS2880B (is)	2014-05-15
RS52325B (sr)	2012-12-31
CA2492804C (en)	2009-06-23
TW200412973A (en)	2004-08-01
CN1681818A (zh)	2005-10-12
CN1315833C (zh)	2007-05-16
BR0312940A (pt)	2005-06-21
JP4361485B2 (ja)	2009-11-11
US7521450B2 (en)	2009-04-21
PL375389A1 (en)	2005-11-28
ES2377963T3 (es)	2012-04-03
AU2003254088A1 (en)	2004-02-09
IL166129A (en)	2015-04-30
EP1534290A2 (en)	2005-06-01
HK1072545A1 (en)	2005-09-02
GEP20074124B (en)	2007-06-11
EP1534290A4 (en)	2006-11-29
HRP20050059B8 (hr)	2016-03-25
BR0312801A (pt)	2007-06-26
ATE537843T1 (de)	2012-01-15
DK1534290T3 (da)	2012-04-10
JP2005538990A (ja)	2005-12-22
IL166232A0 (en)	2006-01-15
NO330132B1 (no)	2011-02-21
AR040500A1 (es)	2005-04-06
CN1681508A (zh)	2005-10-12
WO2004009784A2 (en)	2004-01-29
MXPA05000716A (es)	2005-04-08
CN101880283A (zh)	2010-11-10
RS20050041A (sr)	2007-06-04
DE60336732D1 (de)	2011-05-26
HRP20050059A2 (en)	2005-04-30
HRP20050059B1 (hr)	2015-02-27
US20040063707A1 (en)	2004-04-01
TWI329112B (en)	2010-08-21
EP1539763A1 (en)	2005-06-15
WO2004009601A1 (en)	2004-01-29
EP1534290B1 (en)	2011-12-21
IL166129A0 (en)	2006-01-15
US7265113B2 (en)	2007-09-04
PT1534290E (pt)	2012-03-05
GEP20074213B (en)	2007-10-10
MXPA05000715A (es)	2006-02-22
RU2331642C2 (ru)	2008-08-20
EP2280012A2 (en)	2011-02-02
AU2003254017A1 (en)	2004-02-09
JP4381978B2 (ja)	2009-12-09
IS7647A (is)	2005-01-12
KR100901939B1 (ko)	2009-06-10
MY134848A (en)	2007-12-31
RU2005104818A (ru)	2005-07-20
CN1681508B (zh)	2010-10-06
EP1539763B1 (en)	2011-04-13
EP2280012A3 (en)	2011-05-18
RU2005104422A (ru)	2005-08-10
CA2492804A1 (en)	2004-01-29
KR20080095906A (ko)	2008-10-29
US20060058304A1 (en)	2006-03-16
NO20050072L (no)	2005-02-03
US20050124621A1 (en)	2005-06-09
US20090170853A1 (en)	2009-07-02
PE20040680A1 (es)	2004-10-08
BRPI0312940B8 (2)	2021-05-25
SI1534290T1 (sl)	2012-05-31
JP2005538989A (ja)	2005-12-22
US6869952B2 (en)	2005-03-22
HRP20050058A2 (en)	2005-08-31
CA2492665A1 (en)	2004-01-29
PL375352A1 (en)	2005-11-28
RS20050042A (sr)	2007-06-04
UA82846C2 (en)	2008-05-26

Legal Events

Date	Code	Title	Description
2007-07-27	RENW	Renewal (renewal fees accepted)
2008-01-31	PSEA	Patent sealed
2010-08-27	RENW	Renewal (renewal fees accepted)
2013-06-28	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 3 YEARS UNTIL 18 JUL 2016 BY CPA GLOBAL Effective date: 20130607
2016-06-24	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2017 BY CPA GLOBAL Effective date: 20160603
2017-06-30	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2018 BY CPA GLOBAL Effective date: 20170601
2018-06-29	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2019 BY CPA GLOBAL Effective date: 20180531
2019-06-28	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2020 BY CPA GLOBAL Effective date: 20190606
2020-06-26	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2021 BY CPA GLOBAL Effective date: 20200604
2021-06-25	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2022 BY CPA GLOBAL Effective date: 20210603
2022-07-01	RENW	Renewal (renewal fees accepted)	Free format text: PATENT RENEWED FOR 1 YEAR UNTIL 18 JUL 2023 BY CPA GLOBAL Effective date: 20220607
2023-07-28	EXPY	Patent expired