KR101533166B1 - Ｃｈｋ１ 억제에 유용한 화합물 - Google Patents
Ｃｈｋ１ 억제에 유용한 화합물 Download PDFInfo
- Publication number
- KR101533166B1 KR101533166B1 KR1020137011808A KR20137011808A KR101533166B1 KR 101533166 B1 KR101533166 B1 KR 101533166B1 KR 1020137011808 A KR1020137011808 A KR 1020137011808A KR 20137011808 A KR20137011808 A KR 20137011808A KR 101533166 B1 KR101533166 B1 KR 101533166B1
- Authority
- KR
- South Korea
- Prior art keywords
- cancer
- compound
- pyridin
- methyl
- methoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims description 92
- 101150050673 CHK1 gene Proteins 0.000 title 1
- 230000002401 inhibitory effect Effects 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 201000011510 cancer Diseases 0.000 claims abstract description 16
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 36
- 229960005277 gemcitabine Drugs 0.000 claims description 34
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 26
- 229960004679 doxorubicin Drugs 0.000 claims description 13
- 229940127089 cytotoxic agent Drugs 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 230000005865 ionizing radiation Effects 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 4
- 206010027406 Mesothelioma Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 4
- 229960004316 cisplatin Drugs 0.000 claims description 4
- 229960005420 etoposide Drugs 0.000 claims description 4
- 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 4
- 229960002949 fluorouracil Drugs 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 229960000485 methotrexate Drugs 0.000 claims description 4
- LAEFIEWPUJMANC-CYBMUJFWSA-N n-[5-(2-methoxy-6-methylpyridin-3-yl)-1h-pyrazol-3-yl]-6-[(3r)-piperidin-3-yl]oxypyrazin-2-amine Chemical compound COC1=NC(C)=CC=C1C1=NNC(NC=2N=C(O[C@H]3CNCCC3)C=NC=2)=C1 LAEFIEWPUJMANC-CYBMUJFWSA-N 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- 229960005079 pemetrexed Drugs 0.000 claims description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- 101150113535 chek1 gene Proteins 0.000 abstract description 40
- -1 aminopyrazole compound Chemical class 0.000 abstract description 24
- 210000004027 cell Anatomy 0.000 description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- 239000003112 inhibitor Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 238000003556 assay Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 20
- 238000000034 method Methods 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000006180 TBST buffer Substances 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 15
- 239000012528 membrane Substances 0.000 description 14
- 101150006084 CHKB gene Proteins 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- 239000000758 substrate Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000010790 dilution Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 11
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000007758 minimum essential medium Substances 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 101100220616 Caenorhabditis elegans chk-2 gene Proteins 0.000 description 8
- 230000005778 DNA damage Effects 0.000 description 8
- 231100000277 DNA damage Toxicity 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 102000053602 DNA Human genes 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000006166 lysate Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229920001213 Polysorbate 20 Polymers 0.000 description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 5
- 230000035578 autophosphorylation Effects 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 230000012746 DNA damage checkpoint Effects 0.000 description 4
- 239000004743 Polypropylene Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 238000005341 cation exchange Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 210000004080 milk Anatomy 0.000 description 4
- 235000013336 milk Nutrition 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 229920001155 polypropylene Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000013207 serial dilution Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 108010019244 Checkpoint Kinase 1 Proteins 0.000 description 3
- 102000006459 Checkpoint Kinase 1 Human genes 0.000 description 3
- 102100033636 Histone H3.2 Human genes 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- 229930182816 L-glutamine Natural products 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000013415 human tumor xenograft model Methods 0.000 description 3
- 238000003384 imaging method Methods 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 230000011278 mitosis Effects 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000012723 sample buffer Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- OYTOCPQDCCQMPI-UHFFFAOYSA-N 3-(2-methoxy-6-methylpyridin-3-yl)-3-oxopropanenitrile Chemical compound COC1=NC(C)=CC=C1C(=O)CC#N OYTOCPQDCCQMPI-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101150012716 CDK1 gene Proteins 0.000 description 2
- 229910016523 CuKa Inorganic materials 0.000 description 2
- 240000006497 Dianthus caryophyllus Species 0.000 description 2
- 235000009355 Dianthus caryophyllus Nutrition 0.000 description 2
- 241000283074 Equus asinus Species 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 108020002230 Pancreatic Ribonuclease Proteins 0.000 description 2
- 102000005891 Pancreatic ribonuclease Human genes 0.000 description 2
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 2
- 230000018199 S phase Effects 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000010256 biochemical assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 230000025084 cell cycle arrest Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- 239000011536 extraction buffer Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000834 fixative Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- ZPRQXQNPWCCUOQ-UHFFFAOYSA-N methyl 2-methoxy-6-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(C)N=C1OC ZPRQXQNPWCCUOQ-UHFFFAOYSA-N 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 229940080469 phosphocellulose Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004289 pyrazol-3-yl group Chemical group [H]N1N=C(*)C([H])=C1[H] 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- RDZTWEVXRGYCFV-UHFFFAOYSA-M sodium 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonate Chemical compound [Na+].OCCN1CCN(CCS([O-])(=O)=O)CC1 RDZTWEVXRGYCFV-UHFFFAOYSA-M 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- PYMMGFFHCGSMQV-SNVBAGLBSA-N tert-butyl (3r)-3-(6-chloropyrazin-2-yl)oxypiperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC[C@H]1OC1=CN=CC(Cl)=N1 PYMMGFFHCGSMQV-SNVBAGLBSA-N 0.000 description 2
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000013414 tumor xenograft model Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 1
- ODWNBAWYDSWOAF-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-yloxybenzene Chemical compound CC(C)(C)CC(C)(C)OC1=CC=CC=C1 ODWNBAWYDSWOAF-UHFFFAOYSA-N 0.000 description 1
- LSEAAPGIZCDEEH-UHFFFAOYSA-N 2,6-dichloropyrazine Chemical compound ClC1=CN=CC(Cl)=N1 LSEAAPGIZCDEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- BBPCMBUCSQOXBW-UHFFFAOYSA-N 5-(2-methoxy-6-methylpyridin-3-yl)-1h-pyrazol-3-amine Chemical compound COC1=NC(C)=CC=C1C1=NNC(N)=C1 BBPCMBUCSQOXBW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108010019243 Checkpoint Kinase 2 Proteins 0.000 description 1
- 102000006457 Checkpoint Kinase 2 Human genes 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000002427 Cyclin B Human genes 0.000 description 1
- 108010068150 Cyclin B Proteins 0.000 description 1
- 102000003909 Cyclin E Human genes 0.000 description 1
- 108090000257 Cyclin E Proteins 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 239000012623 DNA damaging agent Substances 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 239000012594 Earle’s Balanced Salt Solution Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 1
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 241000764238 Isis Species 0.000 description 1
- 239000012741 Laemmli sample buffer Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 1
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 102000019355 Synuclein Human genes 0.000 description 1
- 108050006783 Synuclein Proteins 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- LWGMWOFJXKGSRD-BTQNPOSSSA-N acetic acid;n-[5-(2-methoxy-6-methylpyridin-3-yl)-1h-pyrazol-3-yl]-6-[(3r)-piperidin-3-yl]oxypyrazin-2-amine Chemical compound CC(O)=O.COC1=NC(C)=CC=C1C1=NNC(NC=2N=C(O[C@H]3CNCCC3)C=NC=2)=C1 LWGMWOFJXKGSRD-BTQNPOSSSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 101150073031 cdk2 gene Proteins 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000012820 cell cycle checkpoint Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000024321 chromosome segregation Effects 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- GSYVOYKMDBXYIX-BTQNPOSSSA-N methanesulfonic acid;n-[5-(2-methoxy-6-methylpyridin-3-yl)-1h-pyrazol-3-yl]-6-[(3r)-piperidin-3-yl]oxypyrazin-2-amine Chemical compound CS(O)(=O)=O.COC1=NC(C)=CC=C1C1=CC(NC=2N=C(O[C@H]3CNCCC3)C=NC=2)=NN1 GSYVOYKMDBXYIX-BTQNPOSSSA-N 0.000 description 1
- SHKDOGHJQHIIRD-UHFFFAOYSA-N methyl 2-chloro-6-methylpyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(C)N=C1Cl SHKDOGHJQHIIRD-UHFFFAOYSA-N 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
- SUXYIEOTUUFSDE-BTQNPOSSSA-N n-[5-(2-methoxy-6-methylpyridin-3-yl)-1h-pyrazol-3-yl]-6-[(3r)-piperidin-3-yl]oxypyrazin-2-amine;hydrate Chemical compound O.COC1=NC(C)=CC=C1C1=NNC(NC=2N=C(O[C@H]3CNCCC3)C=NC=2)=C1 SUXYIEOTUUFSDE-BTQNPOSSSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005312 nonlinear dynamic Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- UIJXHKXIOCDSEB-MRVPVSSYSA-N tert-butyl (3r)-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](O)C1 UIJXHKXIOCDSEB-MRVPVSSYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/08—Acetic acid
- C07C53/10—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
- C07C55/07—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41113710P | 2010-11-08 | 2010-11-08 | |
| US61/411,137 | 2010-11-08 | ||
| PCT/US2011/058692 WO2012064548A1 (en) | 2010-11-08 | 2011-11-01 | Compounds useful for inhibiting chk1 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20130099146A KR20130099146A (ko) | 2013-09-05 |
| KR101533166B1 true KR101533166B1 (ko) | 2015-07-01 |
Family
ID=45044707
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020137011808A Active KR101533166B1 (ko) | 2010-11-08 | 2011-11-01 | Ｃｈｋ１ 억제에 유용한 화합물 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US9067920B2 (https=) |
| EP (1) | EP2638033B1 (https=) |
| JP (1) | JP5792316B2 (https=) |
| KR (1) | KR101533166B1 (https=) |
| CN (1) | CN103180311B (https=) |
| AR (1) | AR083575A1 (https=) |
| AU (1) | AU2011326230B2 (https=) |
| BR (1) | BR112013010009B1 (https=) |
| CA (1) | CA2816944C (https=) |
| DK (1) | DK2638033T3 (https=) |
| EA (1) | EA022096B1 (https=) |
| ES (1) | ES2541414T3 (https=) |
| HR (1) | HRP20150530T1 (https=) |
| JO (1) | JO3145B1 (https=) |
| ME (1) | ME02119B (https=) |
| MX (1) | MX2013005181A (https=) |
| PL (1) | PL2638033T3 (https=) |
| PT (1) | PT2638033E (https=) |
| RS (1) | RS54012B1 (https=) |
| SI (1) | SI2638033T1 (https=) |
| TW (1) | TWI501956B (https=) |
| WO (1) | WO2012064548A1 (https=) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201402277D0 (en) | 2014-02-10 | 2014-03-26 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| HRP20220351T1 (hr) | 2016-02-04 | 2022-05-13 | Pharmaengine, Inc. | 3,5-disupstituirani pirazoli korisni kao inhibitori kinaze 1 kontrolne točke (chk1), i njihove pripreme i primjene |
| EP3461480A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer |
| CN112457306A (zh) | 2019-09-06 | 2021-03-09 | 上海瑛派药业有限公司 | 3,5-二取代吡唑化合物作为激酶抑制剂及其应用 |
| AU2021389190A1 (en) | 2020-11-30 | 2023-06-29 | Sumitomo Pharma Co., Ltd. | 5-heteroaryl-1h-pyrazol-3-amine derivative |
| US11564920B2 (en) | 2020-11-30 | 2023-01-31 | Sumitomo Pharma Co., Ltd. | 5-heteroaryl-1H-pyrazol-3-amine derivative |
| US11932648B2 (en) | 2021-06-28 | 2024-03-19 | Blueprint Medicines Corporation | CDK2 inhibitors |
| US20250129049A1 (en) * | 2021-12-24 | 2025-04-24 | Sumitomo Pharma Co., Ltd. | 1h-pyrazole-3-amine derivative having bicyclic backbone |
| US20250352541A1 (en) * | 2022-05-27 | 2025-11-20 | Sumitomo Pharma Co., Ltd. | Therapeutic for cancer refractory to immune checkpoint inhibitor |
| TW202442234A (zh) * | 2023-04-14 | 2024-11-01 | 美商纜圖藥品公司 | Ｃｄｋ２抑制劑 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005009435A1 (en) * | 2003-07-25 | 2005-02-03 | Pfizer Inc. | Aminopyrazole compounds and use as chk1 inhibitors |
| WO2008117050A1 (en) * | 2007-03-27 | 2008-10-02 | Astrazeneca Ab | Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0418351A (pt) * | 2004-01-05 | 2007-05-08 | Astrazeneca Ab | composto ou um sal farmaceuticamente aceitável do mesmo, métodos de limitar a proliferação celular em um humano ou animal, de tratamento de um humano ou animal sofrendo de cáncer, de tratamento de profilaxia de cáncer, de tratamento de um humano ou animal sofrendo de uma doença neoplásica, de tratamento de um humano ou animal sofrendo de uma doença prolifetativa de tratamento de cáncer, para o tratamento de infecções associadas com cáncer, para o tratamento profilático de infecções associadas com cáncer, composição farmacêutica, uso de um composto ou um sal farmaceuticamente aceitável do mesmo, método de inibir a chk1 quinase, e, processo para a preparação de um composto ou um sal farmaceuticamente aceitável do mesmo |
| EA011671B1 (ru) | 2004-06-04 | 2009-04-28 | Арена Фармасьютикалз, Инк. | Замещенные производные арила и гетероарила в качестве модуляторов метаболизма и для профилактики и лечения связанных с ним расстройств |
| CN101218229A (zh) * | 2005-05-05 | 2008-07-09 | 阿斯利康(瑞典)有限公司 | 吡唑基-氨基取代的嘧啶及其在癌症治疗中的应用 |
| AU2006258101A1 (en) * | 2005-06-09 | 2006-12-21 | Merck Sharp & Dohme Corp. | Inhibitors of checkpoint kinases |
| PA8850801A1 (es) * | 2008-12-17 | 2010-07-27 | Lilly Co Eli | Compuestos útiles para inhibir chk1 |
-
2011
- 2011-10-27 JO JOP/2011/0323A patent/JO3145B1/ar active
- 2011-10-27 AR ARP110103973A patent/AR083575A1/es active IP Right Grant
- 2011-10-28 TW TW100139492A patent/TWI501956B/zh active
- 2011-11-01 EA EA201390499A patent/EA022096B1/ru not_active IP Right Cessation
- 2011-11-01 WO PCT/US2011/058692 patent/WO2012064548A1/en not_active Ceased
- 2011-11-01 AU AU2011326230A patent/AU2011326230B2/en active Active
- 2011-11-01 SI SI201130467T patent/SI2638033T1/sl unknown
- 2011-11-01 US US13/877,923 patent/US9067920B2/en active Active
- 2011-11-01 KR KR1020137011808A patent/KR101533166B1/ko active Active
- 2011-11-01 JP JP2013537756A patent/JP5792316B2/ja active Active
- 2011-11-01 CA CA2816944A patent/CA2816944C/en active Active
- 2011-11-01 EP EP11788263.9A patent/EP2638033B1/en active Active
- 2011-11-01 DK DK11788263T patent/DK2638033T3/en active
- 2011-11-01 RS RS20150352A patent/RS54012B1/sr unknown
- 2011-11-01 BR BR112013010009-5A patent/BR112013010009B1/pt active IP Right Grant
- 2011-11-01 ME MEP-2015-69A patent/ME02119B/me unknown
- 2011-11-01 HR HRP20150530TT patent/HRP20150530T1/hr unknown
- 2011-11-01 MX MX2013005181A patent/MX2013005181A/es active IP Right Grant
- 2011-11-01 CN CN201180053779.8A patent/CN103180311B/zh active Active
- 2011-11-01 PT PT117882639T patent/PT2638033E/pt unknown
- 2011-11-01 PL PL11788263T patent/PL2638033T3/pl unknown
- 2011-11-01 ES ES11788263.9T patent/ES2541414T3/es active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005009435A1 (en) * | 2003-07-25 | 2005-02-03 | Pfizer Inc. | Aminopyrazole compounds and use as chk1 inhibitors |
| WO2008117050A1 (en) * | 2007-03-27 | 2008-10-02 | Astrazeneca Ab | Pyrazolyl-amino-substituted pyrazines and their use for the treatment of cancer |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2011326230A1 (en) | 2013-05-09 |
| EP2638033A1 (en) | 2013-09-18 |
| JP5792316B2 (ja) | 2015-10-07 |
| EA201390499A1 (ru) | 2013-08-30 |
| CA2816944C (en) | 2015-12-22 |
| BR112013010009B1 (pt) | 2021-10-19 |
| CN103180311A (zh) | 2013-06-26 |
| DK2638033T3 (en) | 2015-04-27 |
| BR112013010009A2 (pt) | 2020-09-29 |
| PT2638033E (pt) | 2015-06-01 |
| JO3145B1 (ar) | 2017-09-20 |
| EP2638033B1 (en) | 2015-04-08 |
| CA2816944A1 (en) | 2012-05-18 |
| TWI501956B (zh) | 2015-10-01 |
| AR083575A1 (es) | 2013-03-06 |
| CN103180311B (zh) | 2014-08-20 |
| JP2013541586A (ja) | 2013-11-14 |
| ME02119B (me) | 2015-10-20 |
| US20130190262A1 (en) | 2013-07-25 |
| HRP20150530T1 (hr) | 2015-06-19 |
| US9067920B2 (en) | 2015-06-30 |
| WO2012064548A1 (en) | 2012-05-18 |
| EA022096B1 (ru) | 2015-10-30 |
| RS54012B1 (sr) | 2015-10-30 |
| PL2638033T3 (pl) | 2015-09-30 |
| ES2541414T3 (es) | 2015-07-20 |
| KR20130099146A (ko) | 2013-09-05 |
| SI2638033T1 (sl) | 2015-05-29 |
| AU2011326230B2 (en) | 2015-02-19 |
| TW201305138A (zh) | 2013-02-01 |
| MX2013005181A (es) | 2013-10-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101533166B1 (ko) | Ｃｈｋ１ 억제에 유용한 화합물 | |
| CN113614083B (zh) | 咪唑酮基喹啉化合物及其治疗用途 | |
| AU2009333433B2 (en) | Compounds useful for inhibiting Chk1 | |
| JP6169185B2 (ja) | キナーゼ阻害剤としての新規ベンゾイミダゾール誘導体 | |
| EP3596084A1 (en) | 9,10,11,12-tetrahydro-8h-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one compounds and uses thereof | |
| US20110144126A1 (en) | Compounds useful for inhibiting chk1 | |
| JP2019218361A (ja) | 神経芽細胞腫及び／または軟部組織肉腫の処置における使用のためのｃｈｋ１／２阻害剤 | |
| Faber | Development of Allosteric Inhibitors Against Cyclin-Dependent Kinase 2 (CDK2) | |
| WO2025160079A1 (en) | Indazolo-amino-pyrimidinone compounds | |
| HK1160110B (en) | Compounds useful for inhibiting chk1 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| PA0105 | International application |
Patent event date: 20130507 Patent event code: PA01051R01D Comment text: International Patent Application |
|
| PA0201 | Request for examination |
Patent event code: PA02012R01D Patent event date: 20130507 Comment text: Request for Examination of Application |
|
| PG1501 | Laying open of application | ||
| E902 | Notification of reason for refusal | ||
| PE0902 | Notice of grounds for rejection |
Comment text: Notification of reason for refusal Patent event date: 20141103 Patent event code: PE09021S01D |
|
| E701 | Decision to grant or registration of patent right | ||
| PE0701 | Decision of registration |
Patent event code: PE07011S01D Comment text: Decision to Grant Registration Patent event date: 20150416 |
|
| GRNT | Written decision to grant | ||
| PR0701 | Registration of establishment |
Comment text: Registration of Establishment Patent event date: 20150625 Patent event code: PR07011E01D |
|
| PR1002 | Payment of registration fee |
Payment date: 20150625 End annual number: 3 Start annual number: 1 |
|
| PG1601 | Publication of registration | ||
| FPAY | Annual fee payment |
Payment date: 20180329 Year of fee payment: 4 |
|
| PR1001 | Payment of annual fee |
Payment date: 20180329 Start annual number: 4 End annual number: 4 |
|
| FPAY | Annual fee payment |
Payment date: 20190327 Year of fee payment: 5 |
|
| PR1001 | Payment of annual fee |
Payment date: 20190327 Start annual number: 5 End annual number: 5 |
|
| PR1001 | Payment of annual fee |
Payment date: 20200324 Start annual number: 6 End annual number: 6 |
|
| PR1001 | Payment of annual fee |
Payment date: 20210525 Start annual number: 7 End annual number: 7 |
|
| PR1001 | Payment of annual fee |
Payment date: 20240527 Start annual number: 10 End annual number: 10 |