JP2014506925A - 置換型キノリン化合物及び使用方法 - Google Patents
置換型キノリン化合物及び使用方法 Download PDFInfo
- Publication number
- JP2014506925A JP2014506925A JP2013556713A JP2013556713A JP2014506925A JP 2014506925 A JP2014506925 A JP 2014506925A JP 2013556713 A JP2013556713 A JP 2013556713A JP 2013556713 A JP2013556713 A JP 2013556713A JP 2014506925 A JP2014506925 A JP 2014506925A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- cancer
- mmol
- phenyl
- acid
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 59
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 230
- -1 quinoline compound Chemical class 0.000 claims abstract description 164
- 239000000203 mixture Substances 0.000 claims abstract description 127
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 230000000694 effects Effects 0.000 claims abstract description 29
- 230000001105 regulatory effect Effects 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 46
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 29
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 108091008605 VEGF receptors Proteins 0.000 claims description 20
- 229940124597 therapeutic agent Drugs 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000002246 antineoplastic agent Substances 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 15
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 15
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 15
- 239000003981 vehicle Substances 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 239000002207 metabolite Substances 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 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 10
- 102000001253 Protein Kinase Human genes 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 108060006633 protein kinase Proteins 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 230000002062 proliferating effect Effects 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 239000002147 L01XE04 - Sunitinib Substances 0.000 claims description 7
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 7
- 239000003798 L01XE11 - Pazopanib Substances 0.000 claims description 7
- 230000001028 anti-proliverative effect Effects 0.000 claims description 7
- 239000012472 biological sample Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229940127089 cytotoxic agent Drugs 0.000 claims description 7
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 7
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 229960005395 cetuximab Drugs 0.000 claims description 6
- 229960004397 cyclophosphamide Drugs 0.000 claims description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims description 5
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 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 5
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 229960004641 rituximab Drugs 0.000 claims description 5
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 claims description 5
- 229960001796 sunitinib Drugs 0.000 claims description 5
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 claims description 4
- 229960000455 brentuximab vedotin Drugs 0.000 claims description 4
- 229960002448 dasatinib Drugs 0.000 claims description 4
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 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
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 4
- 229960005277 gemcitabine Drugs 0.000 claims description 4
- 229960005386 ipilimumab Drugs 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 229960001346 nilotinib Drugs 0.000 claims description 4
- 229960000639 pazopanib Drugs 0.000 claims description 4
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 4
- 229960000235 temsirolimus Drugs 0.000 claims description 4
- 229960005267 tositumomab Drugs 0.000 claims description 4
- 229960004528 vincristine Drugs 0.000 claims description 4
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound 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 4
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products 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 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 229940009456 adriamycin Drugs 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 229960003957 dexamethasone Drugs 0.000 claims description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 3
- 229960005167 everolimus Drugs 0.000 claims description 3
- 201000006585 gastric adenocarcinoma Diseases 0.000 claims description 3
- 229960000578 gemtuzumab Drugs 0.000 claims description 3
- 208000005017 glioblastoma Diseases 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229960004891 lapatinib Drugs 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 229960002450 ofatumumab Drugs 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 229960001972 panitumumab Drugs 0.000 claims description 3
- 229960003876 ranibizumab Drugs 0.000 claims description 3
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 2
- 239000002145 L01XE14 - Bosutinib Substances 0.000 claims description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 229960001686 afatinib Drugs 0.000 claims description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 claims description 2
- 229960003005 axitinib Drugs 0.000 claims description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims description 2
- 229960003736 bosutinib Drugs 0.000 claims description 2
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 claims description 2
- 201000007455 central nervous system cancer Diseases 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 229960002411 imatinib Drugs 0.000 claims description 2
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 claims description 2
- 229960003784 lenvatinib Drugs 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000037819 metastatic cancer Diseases 0.000 claims description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 claims description 2
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 claims description 2
- 229960000215 ruxolitinib Drugs 0.000 claims description 2
- 229960004964 temozolomide Drugs 0.000 claims description 2
- 201000002510 thyroid cancer Diseases 0.000 claims description 2
- 150000001204 N-oxides Chemical class 0.000 claims 2
- 229960001350 tofacitinib Drugs 0.000 claims 2
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 claims 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 claims 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 claims 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 claims 1
- 208000014767 Myeloproliferative disease Diseases 0.000 claims 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 claims 1
- 239000004012 Tofacitinib Substances 0.000 claims 1
- 238000011374 additional therapy Methods 0.000 claims 1
- 229960000397 bevacizumab Drugs 0.000 claims 1
- 229960001433 erlotinib Drugs 0.000 claims 1
- 229960002584 gefitinib Drugs 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 229960002014 ixabepilone Drugs 0.000 claims 1
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 claims 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims 1
- 229950003968 motesanib Drugs 0.000 claims 1
- RAHBGWKEPAQNFF-UHFFFAOYSA-N motesanib Chemical compound C=1C=C2C(C)(C)CNC2=CC=1NC(=O)C1=CC=CN=C1NCC1=CC=NC=C1 RAHBGWKEPAQNFF-UHFFFAOYSA-N 0.000 claims 1
- 229950008835 neratinib Drugs 0.000 claims 1
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 claims 1
- 229960000572 olaparib Drugs 0.000 claims 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 claims 1
- 229960001131 ponatinib Drugs 0.000 claims 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 claims 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims 1
- 229960004836 regorafenib Drugs 0.000 claims 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 claims 1
- 229950006764 rigosertib Drugs 0.000 claims 1
- OWBFCJROIKNMGD-BQYQJAHWSA-N rigosertib Chemical compound COC1=CC(OC)=CC(OC)=C1\C=C\S(=O)(=O)CC1=CC=C(OC)C(NCC(O)=O)=C1 OWBFCJROIKNMGD-BQYQJAHWSA-N 0.000 claims 1
- 229950009919 saracatinib Drugs 0.000 claims 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 claims 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims 1
- 229960002930 sirolimus Drugs 0.000 claims 1
- 229960003787 sorafenib Drugs 0.000 claims 1
- 229960004066 trametinib Drugs 0.000 claims 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 23
- 241000124008 Mammalia Species 0.000 abstract description 7
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 abstract description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 abstract description 6
- 238000009472 formulation Methods 0.000 abstract description 6
- 230000003463 hyperproliferative effect Effects 0.000 abstract description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 abstract description 3
- 230000005012 migration Effects 0.000 abstract description 3
- 238000013508 migration Methods 0.000 abstract description 3
- 230000006907 apoptotic process Effects 0.000 abstract description 2
- 230000001413 cellular effect Effects 0.000 abstract description 2
- 230000004069 differentiation Effects 0.000 abstract description 2
- 230000035755 proliferation Effects 0.000 abstract description 2
- 230000009545 invasion Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 83
- 206010028980 Neoplasm Diseases 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 70
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 210000004027 cell Anatomy 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 53
- 150000002500 ions Chemical class 0.000 description 43
- 235000002639 sodium chloride Nutrition 0.000 description 41
- 101100262697 Mus musculus Axl gene Proteins 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 201000011510 cancer Diseases 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 26
- 239000000725 suspension Substances 0.000 description 25
- 230000011664 signaling Effects 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000001914 filtration Methods 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- 239000003112 inhibitor Substances 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 239000002552 dosage form Substances 0.000 description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 18
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 17
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 230000005764 inhibitory process Effects 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 108091000080 Phosphotransferase Proteins 0.000 description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 102000020233 phosphotransferase Human genes 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 230000033115 angiogenesis Effects 0.000 description 13
- 238000003556 assay Methods 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000012010 growth Effects 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 238000003566 phosphorylation assay Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
- 239000004698 Polyethylene Substances 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- 238000000576 coating method Methods 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- 229920001223 polyethylene glycol Polymers 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 230000004614 tumor growth Effects 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 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 description 8
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 230000001225 therapeutic effect Effects 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 7
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000011717 athymic nude mouse Methods 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 6
- 229910052698 phosphorus Inorganic materials 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 6
- 238000001959 radiotherapy Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 230000019491 signal transduction Effects 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 6
- 239000001993 wax Substances 0.000 description 6
- GELKGHVAFRCJNA-UHFFFAOYSA-N 2,2-Dimethyloxirane Chemical compound CC1(C)CO1 GELKGHVAFRCJNA-UHFFFAOYSA-N 0.000 description 5
- 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 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 108010089836 Proto-Oncogene Proteins c-met Proteins 0.000 description 5
- 108091005729 TAM receptors Proteins 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 229940022353 herceptin Drugs 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229940043355 kinase inhibitor Drugs 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000007909 solid dosage form Substances 0.000 description 5
- 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 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 229960000575 trastuzumab Drugs 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 5
- 229960000237 vorinostat Drugs 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- FIGVRJRUEDTTQF-UHFFFAOYSA-N 4-(4-nitrophenoxy)quinolin-7-ol Chemical compound C=1C=NC2=CC(O)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1 FIGVRJRUEDTTQF-UHFFFAOYSA-N 0.000 description 4
- 108010024976 Asparaginase Proteins 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 208000032612 Glial tumor Diseases 0.000 description 4
- 206010018338 Glioma Diseases 0.000 description 4
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 4
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 238000012338 Therapeutic targeting Methods 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 4
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 229940044683 chemotherapy drug Drugs 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 238000007876 drug discovery Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 229940082789 erbitux Drugs 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- VQYYQSZNRVQLIS-UHFFFAOYSA-N n-[3-fluoro-4-[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C4=CC=C(OCC(C)(C)O)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 VQYYQSZNRVQLIS-UHFFFAOYSA-N 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 229910017604 nitric acid Inorganic materials 0.000 description 4
- 239000000346 nonvolatile oil Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000012552 review Methods 0.000 description 4
- 238000003118 sandwich ELISA Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000009518 sodium iodide Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 230000000638 stimulation Effects 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 229960001603 tamoxifen Drugs 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 239000003656 tris buffered saline Substances 0.000 description 4
- 102000003390 tumor necrosis factor Human genes 0.000 description 4
- 230000002792 vascular Effects 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- DHFYEFAILLBNHD-UHFFFAOYSA-N 1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxylic acid Chemical compound CN1C(C)=C(C(O)=O)C(=O)N1C1=CC=CC=C1 DHFYEFAILLBNHD-UHFFFAOYSA-N 0.000 description 3
- HRGDNTOCJTWYES-UHFFFAOYSA-N 4-(2-fluoro-4-nitrophenoxy)-7-phenylmethoxyquinoline Chemical compound FC1=CC([N+](=O)[O-])=CC=C1OC1=CC=NC2=CC(OCC=3C=CC=CC=3)=CC=C12 HRGDNTOCJTWYES-UHFFFAOYSA-N 0.000 description 3
- APLCYJSNIKGCES-UHFFFAOYSA-N 4-(4-nitrophenoxy)-7-phenylmethoxyquinoline Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1=CC=NC2=CC(OCC=3C=CC=CC=3)=CC=C12 APLCYJSNIKGCES-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 102000015790 Asparaginase Human genes 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 208000005623 Carcinogenesis Diseases 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 101150022345 GAS6 gene Proteins 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 108091008603 HGF receptors Proteins 0.000 description 3
- 206010021143 Hypoxia Diseases 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- 102000010638 Kinesin Human genes 0.000 description 3
- 108010063296 Kinesin Proteins 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 3
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- 239000007993 MOPS buffer Substances 0.000 description 3
- 102000047918 Myelin Basic Human genes 0.000 description 3
- 101710107068 Myelin basic protein Proteins 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- 206010029113 Neovascularisation Diseases 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 3
- 102000001332 SRC Human genes 0.000 description 3
- 108060006706 SRC Proteins 0.000 description 3
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 150000001334 alicyclic compounds Chemical class 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 229960003272 asparaginase Drugs 0.000 description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 3
- 230000035578 autophosphorylation Effects 0.000 description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000008827 biological function Effects 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 235000019437 butane-1,3-diol Nutrition 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 230000036952 cancer formation Effects 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 231100000504 carcinogenesis Toxicity 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 230000006690 co-activation Effects 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 229960005061 crizotinib Drugs 0.000 description 3
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000945 filler Substances 0.000 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 description 3
- 229960002074 flutamide Drugs 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 201000011066 hemangioma Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- 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 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229940045773 jakafi Drugs 0.000 description 3
- 238000000021 kinase assay Methods 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 3
- 239000011654 magnesium acetate Substances 0.000 description 3
- 235000011285 magnesium acetate Nutrition 0.000 description 3
- 229940069446 magnesium acetate Drugs 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 230000036210 malignancy Effects 0.000 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 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 229940127084 other anti-cancer agent Drugs 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229960004063 propylene glycol Drugs 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229940069905 tasigna Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 229960000303 topotecan Drugs 0.000 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 description 3
- 229940094060 tykerb Drugs 0.000 description 3
- 238000000825 ultraviolet detection Methods 0.000 description 3
- 229960000241 vandetanib Drugs 0.000 description 3
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 3
- 229960003862 vemurafenib Drugs 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- HOFQVRTUGATRFI-XQKSVPLYSA-N vinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 HOFQVRTUGATRFI-XQKSVPLYSA-N 0.000 description 3
- FKBHRUQOROFRGD-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2[C]3C=CC=CC3=NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC FKBHRUQOROFRGD-IELIFDKJSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- 229940069559 votrient Drugs 0.000 description 3
- 229940034727 zelboraf Drugs 0.000 description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- BWDQBBCUWLSASG-MDZDMXLPSA-N (e)-n-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1h-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide Chemical compound C=1NC2=CC=CC=C2C=1CCN(CCO)CC1=CC=C(\C=C\C(=O)NO)C=C1 BWDQBBCUWLSASG-MDZDMXLPSA-N 0.000 description 2
- HRUAWSQBQLYDKH-UHFFFAOYSA-N 1-(3-methoxy-4-phenylmethoxyphenyl)ethanone Chemical compound COC1=CC(C(C)=O)=CC=C1OCC1=CC=CC=C1 HRUAWSQBQLYDKH-UHFFFAOYSA-N 0.000 description 2
- JZUMPNUYDJBTNO-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 JZUMPNUYDJBTNO-UHFFFAOYSA-N 0.000 description 2
- FPYJSJDOHRDAMT-KQWNVCNZSA-N 1h-indole-5-sulfonamide, n-(3-chlorophenyl)-3-[[3,5-dimethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1h-pyrrol-2-yl]methylene]-2,3-dihydro-n-methyl-2-oxo-, (3z)- Chemical compound C=1C=C2NC(=O)\C(=C/C3=C(C(C(=O)N4CCN(C)CC4)=C(C)N3)C)C2=CC=1S(=O)(=O)N(C)C1=CC=CC(Cl)=C1 FPYJSJDOHRDAMT-KQWNVCNZSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- UJTSTSTWTHOXMG-UHFFFAOYSA-N 2-[4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl]oxy-2-methylpropan-1-ol Chemical compound C=1C=NC2=CC(OC(C)(CO)C)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1F UJTSTSTWTHOXMG-UHFFFAOYSA-N 0.000 description 2
- TVLVBWNTBKQVCF-UHFFFAOYSA-N 2-[4-(4-amino-2-fluorophenoxy)quinolin-7-yl]oxy-2-methylpropan-1-ol Chemical compound C=1C=NC2=CC(OC(C)(CO)C)=CC=C2C=1OC1=CC=C(N)C=C1F TVLVBWNTBKQVCF-UHFFFAOYSA-N 0.000 description 2
- 125000004398 2-methyl-2-butyl group Chemical group CC(C)(CC)* 0.000 description 2
- 125000004922 2-methyl-3-pentyl group Chemical group CC(C)C(CC)* 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 2
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 2
- 125000004919 3-methyl-2-pentyl group Chemical group CC(C(C)*)CC 0.000 description 2
- 125000004921 3-methyl-3-pentyl group Chemical group CC(CC)(CC)* 0.000 description 2
- ORSCRIJOVRKFEO-UHFFFAOYSA-N 4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol Chemical compound C=1C=NC2=CC(O)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1F ORSCRIJOVRKFEO-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- RRZVGDGTWNQAPW-UHFFFAOYSA-N 4-[5-(1-methylpyrazol-4-yl)-3-[2-(1-methylpyrazol-4-yl)ethyl]imidazol-4-yl]benzonitrile Chemical compound C1=NN(C)C=C1CCN1C(C=2C=CC(=CC=2)C#N)=C(C2=CN(C)N=C2)N=C1 RRZVGDGTWNQAPW-UHFFFAOYSA-N 0.000 description 2
- TXHLONYFVBSHDY-UHFFFAOYSA-N 4-chloro-7-phenylmethoxyquinoline Chemical compound C=1C=C2C(Cl)=CC=NC2=CC=1OCC1=CC=CC=C1 TXHLONYFVBSHDY-UHFFFAOYSA-N 0.000 description 2
- 125000004920 4-methyl-2-pentyl group Chemical group CC(CC(C)*)C 0.000 description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- OXRDTRDGXMHOOV-UHFFFAOYSA-N 6-methoxy-7-phenylmethoxy-1h-quinolin-4-one Chemical compound COC1=CC2=C(O)C=CN=C2C=C1OCC1=CC=CC=C1 OXRDTRDGXMHOOV-UHFFFAOYSA-N 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 0 CC(C(C1=C2)N=CC=C1Oc(cc1)c(C)cc1NC(C(C1O)=C(C)N(C)N1c1ccccc1)=*)C(OCC(C)(C)O)=C2OC Chemical compound CC(C(C1=C2)N=CC=C1Oc(cc1)c(C)cc1NC(C(C1O)=C(C)N(C)N1c1ccccc1)=*)C(OCC(C)(C)O)=C2OC 0.000 description 2
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 2
- 102100025832 Centromere-associated protein E Human genes 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 description 2
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 2
- 101000878540 Homo sapiens Protein-tyrosine kinase 2-beta Proteins 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
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- WWOUJJVFERJKDD-UHFFFAOYSA-N N-[4-(7-hydroxy-6-methoxyquinolin-4-yl)oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(O)C(OC)=CC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 WWOUJJVFERJKDD-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 229940096437 Protein S Drugs 0.000 description 2
- 102000029301 Protein S Human genes 0.000 description 2
- 108010066124 Protein S Proteins 0.000 description 2
- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 2
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- GOOHAUXETOMSMM-VKHMYHEASA-N S-propylene oxide Chemical compound C[C@H]1CO1 GOOHAUXETOMSMM-VKHMYHEASA-N 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 2
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 108091005605 Vitamin K-dependent proteins Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000002111 antiemetic agent Substances 0.000 description 2
- 229940125683 antiemetic agent Drugs 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229940120638 avastin Drugs 0.000 description 2
- 229960003270 belimumab Drugs 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 238000002725 brachytherapy Methods 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
- PUQLFUHLKNBKQQ-UHFFFAOYSA-L calcium;trifluoromethanesulfonate Chemical compound [Ca+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PUQLFUHLKNBKQQ-UHFFFAOYSA-L 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000033077 cellular process Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 108010031379 centromere protein E Proteins 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- ARQRPTNYUOLOGH-UHFFFAOYSA-N chcl3 chloroform Chemical compound ClC(Cl)Cl.ClC(Cl)Cl ARQRPTNYUOLOGH-UHFFFAOYSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 231100000599 cytotoxic agent Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- 238000004090 dissolution Methods 0.000 description 2
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 2
- 229940043264 dodecyl sulfate Drugs 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 238000010894 electron beam technology Methods 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 238000009261 endocrine therapy Methods 0.000 description 2
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 230000029578 entry into host Effects 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- OLAMWIPURJGSKE-UHFFFAOYSA-N et2o diethylether Chemical compound CCOCC.CCOCC OLAMWIPURJGSKE-UHFFFAOYSA-N 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940080856 gleevec Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000367 immunologic factor Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000007972 injectable composition Substances 0.000 description 2
- 229940102223 injectable solution Drugs 0.000 description 2
- 229940102213 injectable suspension Drugs 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229910001410 inorganic ion Inorganic materials 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 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 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 2
- 229960001786 megestrol Drugs 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 2
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 2
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 2
- FHGKCNHKMUMCLI-UHFFFAOYSA-N n-[3-fluoro-4-[7-(1-hydroxy-2-methylpropan-2-yl)oxyquinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C4=CC=C(OC(C)(C)CO)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 FHGKCNHKMUMCLI-UHFFFAOYSA-N 0.000 description 2
- NNVFVZWTQYUWJO-GOSISDBHSA-N n-[3-fluoro-4-[7-[(2r)-2-hydroxypropoxy]quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C=1C=NC2=CC(OC[C@H](O)C)=CC=C2C=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 NNVFVZWTQYUWJO-GOSISDBHSA-N 0.000 description 2
- WGMLTJQUQNBOBH-UHFFFAOYSA-N n-[4-[7-(2-hydroxy-2-methylpropoxy)-6-methoxyquinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(OCC(C)(C)O)C(OC)=CC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 WGMLTJQUQNBOBH-UHFFFAOYSA-N 0.000 description 2
- JNVFMMAYSXTMTJ-UHFFFAOYSA-N n-[4-[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound CN1C(C)=C(C(=O)NC=2C=CC(OC=3C4=CC=C(OCC(C)(C)O)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 JNVFMMAYSXTMTJ-UHFFFAOYSA-N 0.000 description 2
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 2
- 231100000344 non-irritating Toxicity 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 229960005184 panobinostat Drugs 0.000 description 2
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 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 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 150000003014 phosphoric acid esters Chemical class 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 150000003057 platinum Chemical class 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000649 purine antagonist Substances 0.000 description 2
- 125000002755 pyrazolinyl group Chemical group 0.000 description 2
- 239000003790 pyrimidine antagonist Substances 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 150000003248 quinolines Chemical class 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229960002218 sodium chlorite Drugs 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 229940034785 sutent Drugs 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229940063683 taxotere Drugs 0.000 description 2
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 2
- APBDREXAUGXCCV-UHFFFAOYSA-L tetraethylazanium;carbonate Chemical compound [O-]C([O-])=O.CC[N+](CC)(CC)CC.CC[N+](CC)(CC)CC APBDREXAUGXCCV-UHFFFAOYSA-L 0.000 description 2
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 2
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 2
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 2
- 238000000015 thermotherapy Methods 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 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 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 1
- WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IDEGEPZMQCDSNE-GFCCVEGCSA-N (2r)-1-[4-(4-nitrophenoxy)quinolin-7-yl]oxypropan-2-ol Chemical compound C=1C=NC2=CC(OC[C@H](O)C)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1 IDEGEPZMQCDSNE-GFCCVEGCSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ZZKNRXZVGOYGJT-VKHMYHEASA-N (2s)-2-[(2-phosphonoacetyl)amino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC(=O)CP(O)(O)=O ZZKNRXZVGOYGJT-VKHMYHEASA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- MWTUOSWPJOUADP-XDJHFCHBSA-N (5z)-5-(4-hydroxy-6-oxo-3-propan-2-ylcyclohexa-2,4-dien-1-ylidene)-4-(1-methylindol-5-yl)-1,2,4-triazolidin-3-one Chemical compound O=C1C=C(O)C(C(C)C)=C\C1=C\1N(C=2C=C3C=CN(C)C3=CC=2)C(=O)NN/1 MWTUOSWPJOUADP-XDJHFCHBSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- ODOYPGHNQKAPBX-UHFFFAOYSA-N 1-(2-amino-5-methoxy-4-phenylmethoxyphenyl)ethanone Chemical compound COC1=CC(C(C)=O)=C(N)C=C1OCC1=CC=CC=C1 ODOYPGHNQKAPBX-UHFFFAOYSA-N 0.000 description 1
- TYWOWCDENNDOES-UHFFFAOYSA-N 1-(5-methoxy-2-nitro-4-phenylmethoxyphenyl)ethanone Chemical compound COC1=CC(C(C)=O)=C([N+]([O-])=O)C=C1OCC1=CC=CC=C1 TYWOWCDENNDOES-UHFFFAOYSA-N 0.000 description 1
- ISCMIHAYGCEAEX-UHFFFAOYSA-N 1-[4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl]oxy-2-methylpropan-2-ol Chemical compound C=1C=NC2=CC(OCC(C)(O)C)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1F ISCMIHAYGCEAEX-UHFFFAOYSA-N 0.000 description 1
- ZOOIQKNZIHKMAM-UHFFFAOYSA-N 1-[4-(4-amino-2-fluorophenoxy)quinolin-7-yl]oxy-2-methylpropan-2-ol Chemical compound C=1C=NC2=CC(OCC(C)(O)C)=CC=C2C=1OC1=CC=C(N)C=C1F ZOOIQKNZIHKMAM-UHFFFAOYSA-N 0.000 description 1
- YKROPNAUCVJZAP-UHFFFAOYSA-N 1-[4-(4-aminophenoxy)quinolin-7-yl]oxy-2-methylpropan-2-ol Chemical compound C=1C=NC2=CC(OCC(C)(O)C)=CC=C2C=1OC1=CC=C(N)C=C1 YKROPNAUCVJZAP-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 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
- 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 1
- PBOXNDVZQKTIAV-UHFFFAOYSA-N 2-[4-(4-nitrophenoxy)quinolin-7-yl]oxyethanol Chemical compound C=1C=NC2=CC(OCCO)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1 PBOXNDVZQKTIAV-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- PHNKNHMLYLJSRP-UHFFFAOYSA-N 2-methyl-1-[4-(4-nitrophenoxy)quinolin-7-yl]oxypropan-2-ol Chemical compound C=1C=NC2=CC(OCC(C)(O)C)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1 PHNKNHMLYLJSRP-UHFFFAOYSA-N 0.000 description 1
- 125000004918 2-methyl-2-pentyl group Chemical group CC(C)(CCC)* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- LGEXGKUJMFHVSY-UHFFFAOYSA-N 2-n,4-n,6-n-trimethyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(NC)=NC(NC)=N1 LGEXGKUJMFHVSY-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- ONBHOTJYTLCXHB-UHFFFAOYSA-N 2-phenyl-1,5-dihydropyrazole-4-carboxylic acid Chemical compound C1(=CC=CC=C1)N1NCC(=C1)C(=O)O ONBHOTJYTLCXHB-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001698 2H-pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001137 3-hydroxypropoxy group Chemical group [H]OC([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004364 3-pyrrolinyl group Chemical group [H]C1=C([H])C([H])([H])N(*)C1([H])[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- IMBBXSASDSZJSX-UHFFFAOYSA-N 4-Carboxypyrazole Chemical compound OC(=O)C=1C=NNC=1 IMBBXSASDSZJSX-UHFFFAOYSA-N 0.000 description 1
- ZRHDKBOBHHFLBW-UHFFFAOYSA-N 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one 2-hydroxypropanoic acid Chemical compound CC(O)C(O)=O.C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 ZRHDKBOBHHFLBW-UHFFFAOYSA-N 0.000 description 1
- SYKLZPMKNBDEOF-UHFFFAOYSA-N 4-chloro-6-methoxy-7-phenylmethoxyquinoline Chemical compound COC1=CC2=C(Cl)C=CN=C2C=C1OCC1=CC=CC=C1 SYKLZPMKNBDEOF-UHFFFAOYSA-N 0.000 description 1
- MDOJTZQKHMAPBK-UHFFFAOYSA-N 4-iodo-3-nitrobenzamide Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- ORPHLVJBJOCHBR-UHFFFAOYSA-N 403-19-0 Chemical compound OC1=CC=C([N+]([O-])=O)C=C1F ORPHLVJBJOCHBR-UHFFFAOYSA-N 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- HFEKDTCAMMOLQP-RRKCRQDMSA-N 5-fluorodeoxyuridine monophosphate Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C(F)=C1 HFEKDTCAMMOLQP-RRKCRQDMSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- JRWCBEOAFGHNNU-UHFFFAOYSA-N 6-[difluoro-[6-(1-methyl-4-pyrazolyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]methyl]quinoline Chemical compound C1=NN(C)C=C1C1=NN2C(C(F)(F)C=3C=C4C=CC=NC4=CC=3)=NN=C2C=C1 JRWCBEOAFGHNNU-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- KWQRHYWEGFFXKV-UHFFFAOYSA-N 7-phenylmethoxy-1h-quinolin-4-one Chemical compound C=1C=C2C(O)=CC=NC2=CC=1OCC1=CC=CC=C1 KWQRHYWEGFFXKV-UHFFFAOYSA-N 0.000 description 1
- 102100036409 Activated CDC42 kinase 1 Human genes 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102100039339 Atrial natriuretic peptide receptor 1 Human genes 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- YFBYIDBFOMUONS-UHFFFAOYSA-N CC(COc1cc2nccc(Oc(cc3)ccc3NC(C(C3=O)=C(C)N(C)N3C3=CC=CC=C=C3)=O)c2cc1OC)O Chemical compound CC(COc1cc2nccc(Oc(cc3)ccc3NC(C(C3=O)=C(C)N(C)N3C3=CC=CC=C=C3)=O)c2cc1OC)O YFBYIDBFOMUONS-UHFFFAOYSA-N 0.000 description 1
- YHDXQKCKFNCRLF-UHFFFAOYSA-N COc(c(OCCO)cc1ncc2)cc1c2Oc(cc1)ccc1N Chemical compound COc(c(OCCO)cc1ncc2)cc1c2Oc(cc1)ccc1N YHDXQKCKFNCRLF-UHFFFAOYSA-N 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100023263 Cyclin-dependent kinase 10 Human genes 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 1
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products 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 description 1
- 102100036725 Epithelial discoidin domain-containing receptor 1 Human genes 0.000 description 1
- 101710131668 Epithelial discoidin domain-containing receptor 1 Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000402754 Erythranthe moschata Species 0.000 description 1
- 101100306202 Escherichia coli (strain K12) rpoB gene Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000975394 Evechinus chloroticus Species 0.000 description 1
- 102100026130 Extracellular tyrosine-protein kinase PKDCC Human genes 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 101150017750 FGFRL1 gene Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
- 102100026149 Fibroblast growth factor receptor-like 1 Human genes 0.000 description 1
- 102000002090 Fibronectin type III Human genes 0.000 description 1
- 108050009401 Fibronectin type III Proteins 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102100031487 Growth arrest-specific protein 6 Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 1
- 102100032742 Histone-lysine N-methyltransferase SETD2 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
- 101000928956 Homo sapiens Activated CDC42 kinase 1 Proteins 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101000961044 Homo sapiens Atrial natriuretic peptide receptor 1 Proteins 0.000 description 1
- 101000908138 Homo sapiens Cyclin-dependent kinase 10 Proteins 0.000 description 1
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
- 101000923005 Homo sapiens Growth arrest-specific protein 6 Proteins 0.000 description 1
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 1
- 101000889893 Homo sapiens Inactive serine/threonine-protein kinase TEX14 Proteins 0.000 description 1
- 101001103039 Homo sapiens Inactive tyrosine-protein kinase transmembrane receptor ROR1 Proteins 0.000 description 1
- 101000977771 Homo sapiens Interleukin-1 receptor-associated kinase 4 Proteins 0.000 description 1
- 101001137642 Homo sapiens Kinase suppressor of Ras 1 Proteins 0.000 description 1
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 101001106413 Homo sapiens Macrophage-stimulating protein receptor Proteins 0.000 description 1
- 101001059535 Homo sapiens Megakaryocyte-associated tyrosine-protein kinase Proteins 0.000 description 1
- 101000663003 Homo sapiens Non-receptor tyrosine-protein kinase TNK1 Proteins 0.000 description 1
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101001038337 Homo sapiens Serine/threonine-protein kinase LMTK1 Proteins 0.000 description 1
- 101001038335 Homo sapiens Serine/threonine-protein kinase LMTK2 Proteins 0.000 description 1
- 101001038341 Homo sapiens Serine/threonine-protein kinase LMTK3 Proteins 0.000 description 1
- 101000582914 Homo sapiens Serine/threonine-protein kinase PLK4 Proteins 0.000 description 1
- 101000662993 Homo sapiens Serine/threonine-protein kinase TNNI3K Proteins 0.000 description 1
- 101000989953 Homo sapiens Serine/threonine-protein kinase haspin Proteins 0.000 description 1
- 101000922131 Homo sapiens Tyrosine-protein kinase CSK Proteins 0.000 description 1
- 101000727826 Homo sapiens Tyrosine-protein kinase RYK Proteins 0.000 description 1
- 101000661459 Homo sapiens Tyrosine-protein kinase STYK1 Proteins 0.000 description 1
- 101000604583 Homo sapiens Tyrosine-protein kinase SYK Proteins 0.000 description 1
- 101000587313 Homo sapiens Tyrosine-protein kinase Srms Proteins 0.000 description 1
- 101000606067 Homo sapiens Tyrosine-protein kinase TXK Proteins 0.000 description 1
- 101000889732 Homo sapiens Tyrosine-protein kinase Tec Proteins 0.000 description 1
- 101001103033 Homo sapiens Tyrosine-protein kinase transmembrane receptor ROR2 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound 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 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products 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 description 1
- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 102100040173 Inactive serine/threonine-protein kinase TEX14 Human genes 0.000 description 1
- 102100039615 Inactive tyrosine-protein kinase transmembrane receptor ROR1 Human genes 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100039137 Insulin receptor-related protein Human genes 0.000 description 1
- 102100020944 Integrin-linked protein kinase Human genes 0.000 description 1
- 102100023533 Interleukin-1 receptor-associated kinase 4 Human genes 0.000 description 1
- 206010073678 Juvenile angiofibroma Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 102100021001 Kinase suppressor of Ras 1 Human genes 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 101150028321 Lck gene Proteins 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 101150058160 Lyn gene Proteins 0.000 description 1
- 108010066373 MLK-like mitogen-activated protein triple kinase Proteins 0.000 description 1
- 101150078127 MUSK gene Proteins 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 102100021435 Macrophage-stimulating protein receptor Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102100028905 Megakaryocyte-associated tyrosine-protein kinase Human genes 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 102100033116 Mitogen-activated protein kinase kinase kinase 20 Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100306001 Mus musculus Mst1r gene Proteins 0.000 description 1
- 101100091501 Mus musculus Ros1 gene Proteins 0.000 description 1
- 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102100038168 Muscle, skeletal receptor tyrosine-protein kinase Human genes 0.000 description 1
- 201000003793 Myelodysplastic syndrome 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
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- NWLWBJPWCDXRGF-UHFFFAOYSA-N N-[3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yl)oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(O)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 NWLWBJPWCDXRGF-UHFFFAOYSA-N 0.000 description 1
- DFZCVKQCJCIQLS-UHFFFAOYSA-N N-[3-fluoro-4-(7-hydroxyquinolin-4-yl)oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C4=CC=C(O)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 DFZCVKQCJCIQLS-UHFFFAOYSA-N 0.000 description 1
- VNBRGSXVFBYQNN-UHFFFAOYSA-N N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide Chemical compound O=C1C(C(=O)NC=2C=C(F)C(OC=3C(=C(N)N=CC=3)Cl)=CC=2)=C(OCC)C=CN1C1=CC=C(F)C=C1 VNBRGSXVFBYQNN-UHFFFAOYSA-N 0.000 description 1
- CXQHYVUVSFXTMY-UHFFFAOYSA-N N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 CXQHYVUVSFXTMY-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 102100037669 Non-receptor tyrosine-protein kinase TNK1 Human genes 0.000 description 1
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
- 102100022673 Nuclear receptor subfamily 4 group A member 3 Human genes 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 208000004072 Oncogene Addiction Diseases 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 101150001863 PKDCC gene Proteins 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 208000007135 Retinal Neovascularization Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 101100091511 Rhizobium radiobacter ros gene Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 102100040293 Serine/threonine-protein kinase LMTK1 Human genes 0.000 description 1
- 102100040292 Serine/threonine-protein kinase LMTK2 Human genes 0.000 description 1
- 102100040291 Serine/threonine-protein kinase LMTK3 Human genes 0.000 description 1
- 102100030267 Serine/threonine-protein kinase PLK4 Human genes 0.000 description 1
- 102100037670 Serine/threonine-protein kinase TNNI3K Human genes 0.000 description 1
- 102100029332 Serine/threonine-protein kinase haspin Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101001045447 Synechocystis sp. (strain PCC 6803 / Kazusa) Sensor histidine kinase Hik2 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
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 101150098329 Tyro3 gene Proteins 0.000 description 1
- 102100031167 Tyrosine-protein kinase CSK Human genes 0.000 description 1
- 102100024537 Tyrosine-protein kinase Fer Human genes 0.000 description 1
- 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 1
- 102100022356 Tyrosine-protein kinase Mer Human genes 0.000 description 1
- 102100029759 Tyrosine-protein kinase RYK Human genes 0.000 description 1
- 102100037781 Tyrosine-protein kinase STYK1 Human genes 0.000 description 1
- 102100038183 Tyrosine-protein kinase SYK Human genes 0.000 description 1
- 102100029654 Tyrosine-protein kinase Srms Human genes 0.000 description 1
- 102100039079 Tyrosine-protein kinase TXK Human genes 0.000 description 1
- 102100039616 Tyrosine-protein kinase transmembrane receptor ROR2 Human genes 0.000 description 1
- 208000025865 Ulcer Diseases 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
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 208000034698 Vitreous haemorrhage Diseases 0.000 description 1
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-UHFFFAOYSA-N 0.000 description 1
- 229940088990 ammonium stearate Drugs 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 229940124691 antibody therapeutics Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- DFYRUELUNQRZTB-UHFFFAOYSA-N apocynin Chemical compound COC1=CC(C(C)=O)=CC=C1O DFYRUELUNQRZTB-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 108010023337 axl receptor tyrosine kinase Proteins 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- JPNZKPRONVOMLL-UHFFFAOYSA-N azane;octadecanoic acid Chemical compound [NH4+].CCCCCCCCCCCCCCCCCC([O-])=O JPNZKPRONVOMLL-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 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
- FVOPECXQGXCUDP-UHFFFAOYSA-N benzenesulfonic acid;n-[3-fluoro-4-[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound OS(=O)(=O)C1=CC=CC=C1.CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C4=CC=C(OCC(C)(C)O)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 FVOPECXQGXCUDP-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 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 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 108010018804 c-Mer Tyrosine Kinase Proteins 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001717 carbocyclic compounds Chemical class 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 150000001723 carbon free-radicals Chemical class 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000017455 cell-cell adhesion Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 208000023819 chronic asthma Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 125000000392 cycloalkenyl 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
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 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
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 1
- 229950002205 dacomitinib Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 150000001987 diarylethers Chemical class 0.000 description 1
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 125000005057 dihydrothienyl group Chemical group S1C(CC=C1)* 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 125000005411 dithiolanyl group Chemical group S1SC(CC1)* 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229930013356 epothilone Natural products 0.000 description 1
- 150000003883 epothilone derivatives Chemical class 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 208000011404 female reproductive system disease Diseases 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229950008692 foretinib Drugs 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 229950004161 ganetespib Drugs 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- JEGUKCSWCFPDGT-UHFFFAOYSA-N h2o hydrate Chemical compound O.O JEGUKCSWCFPDGT-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- PSXRWZBTVAZNSF-UHFFFAOYSA-N hydron;quinoline;chloride Chemical compound Cl.N1=CC=CC2=CC=CC=C21 PSXRWZBTVAZNSF-UHFFFAOYSA-N 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229950002133 iniparib Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 108010054372 insulin receptor-related receptor Proteins 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 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
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 208000012496 juvenile nasopharyngeal angiofibroma Diseases 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229950002216 linifanib Drugs 0.000 description 1
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 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
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- GXHFUVWIGNLZSC-UHFFFAOYSA-N meldrum's acid Chemical compound CC1(C)OC(=O)CC(=O)O1 GXHFUVWIGNLZSC-UHFFFAOYSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960004635 mesna Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- YSMOBHDFGSQPQO-UHFFFAOYSA-N methyl 2-[4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl]oxy-2-methylpropanoate Chemical compound C=1C=NC2=CC(OC(C)(C)C(=O)OC)=CC=C2C=1OC1=CC=C([N+]([O-])=O)C=C1F YSMOBHDFGSQPQO-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- HNDZJFGTHKMGAS-UHFFFAOYSA-N n-[3-fluoro-4-[7-(2-hydroxy-2-methylpropoxy)-6-methoxyquinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(OCC(C)(C)O)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 HNDZJFGTHKMGAS-UHFFFAOYSA-N 0.000 description 1
- NAUYISNCVNUUDK-UHFFFAOYSA-N n-[3-fluoro-4-[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C4=CC=C(OCC(C)(C)O)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 NAUYISNCVNUUDK-UHFFFAOYSA-N 0.000 description 1
- ZNMVISMEGWJRLS-UHFFFAOYSA-N n-[3-fluoro-4-[7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide;hydrochloride Chemical compound Cl.CN1C(C)=C(C(=O)NC=2C=C(F)C(OC=3C4=CC=C(OCC(C)(C)O)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 ZNMVISMEGWJRLS-UHFFFAOYSA-N 0.000 description 1
- NNVFVZWTQYUWJO-SFHVURJKSA-N n-[3-fluoro-4-[7-[(2s)-2-hydroxypropoxy]quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C=1C=NC2=CC(OC[C@@H](O)C)=CC=C2C=1OC(C(=C1)F)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 NNVFVZWTQYUWJO-SFHVURJKSA-N 0.000 description 1
- CVMVMBQNLKTHPW-UHFFFAOYSA-N n-[4-[7-(2-hydroxyethoxy)-6-methoxyquinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(OCCO)C(OC)=CC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 CVMVMBQNLKTHPW-UHFFFAOYSA-N 0.000 description 1
- GCXYBMOPOKCRKR-UHFFFAOYSA-N n-[4-[7-(2-hydroxyethoxy)quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound CN1C(C)=C(C(=O)NC=2C=CC(OC=3C4=CC=C(OCCO)C=C4N=CC=3)=CC=2)C(=O)N1C1=CC=CC=C1 GCXYBMOPOKCRKR-UHFFFAOYSA-N 0.000 description 1
- UZRODWUDRUOPFC-LJQANCHMSA-N n-[4-[7-[(2r)-2-hydroxypropoxy]-6-methoxyquinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(OC[C@@H](C)O)C(OC)=CC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 UZRODWUDRUOPFC-LJQANCHMSA-N 0.000 description 1
- XERFIRFMKJGFDC-LJQANCHMSA-N n-[4-[7-[(2r)-2-hydroxypropoxy]quinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C=1C=NC2=CC(OC[C@H](O)C)=CC=C2C=1OC(C=C1)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 XERFIRFMKJGFDC-LJQANCHMSA-N 0.000 description 1
- UZRODWUDRUOPFC-IBGZPJMESA-N n-[4-[7-[(2s)-2-hydroxypropoxy]-6-methoxyquinolin-4-yl]oxyphenyl]-1,5-dimethyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C1=CN=C2C=C(OC[C@H](C)O)C(OC)=CC2=C1OC(C=C1)=CC=C1NC(=O)C(C1=O)=C(C)N(C)N1C1=CC=CC=C1 UZRODWUDRUOPFC-IBGZPJMESA-N 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004999 nitroaryl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- VLCMRTMCMQJSKM-UHFFFAOYSA-N phenyl-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone Chemical class C=1C=CC=CC=1C(=O)C1=CN=C2C(C(F)(F)F)=CC=CC2=C1C1=CC=CC=C1 VLCMRTMCMQJSKM-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 230000010118 platelet activation Effects 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 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
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 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 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 108700015048 receptor decoy activity proteins Proteins 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 208000032253 retinal ischemia Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 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 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124788 therapeutic inhibitor Drugs 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000013414 tumor xenograft model Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 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 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Images
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
- C07D401/02—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 two hetero rings
- C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- 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
- 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
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- 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)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
【選択図】図1
Description
本出願は、2011年2月28日に出願された、その内容全体が参照により本明細書に組み込まれる米国仮出願第61/447,104号の利益を主張する。
本発明は、哺乳類における癌などの過剰増殖性疾患の治療に有用である、新規の置換型キノリン化合物及びその塩に関する。特に本発明は、タンパク質チロシンキナーゼ活性を阻害し、その結果、細胞間及び/又は細胞内シグナル伝達の阻害をもたらす化合物に関する。本発明はまた、哺乳類、特にヒトにおける過剰増殖性疾患の治療においてこうした化合物を使用する方法、及びこうした化合物を含有する医薬組成物にも関する。
プロテインキナーゼは、非常に様々な細胞プロセスの調節における中心的役割を担う大きなファミリーのタンパク質に相当する。プロテインキナーゼは、一連のシグナル経路の調節を通して、細胞代謝、細胞周期進行、細胞増殖及び細胞死、分化、及び生存を制御する。ヒトカイノームには500種を超えるキナーゼが存在し、これらのうちの150種超は、炎症性疾患、循環器疾患、代謝性疾患、神経変性疾患、及び癌、を含めた様々なヒト疾患の発症及び/又は進行に関与することが提示又は提案されている。
上記は、本発明のある態様の概要を述べたに過ぎず、限定の意図は全くない。これらの態様及び他の態様及び実施態様を、以下に、より十分に説明する。
(定義及び一般的用語法)
ここより、本発明のある実施態様に関して詳細に言及することとし、その例を、付随する構造及び式において例示する。本発明は、特許請求の範囲によって定義される通りの本発明の範囲内に含まれ得るすべての代替物、改変物、及び等価物を包含するものとする。当業者は、本発明の実施の際に使用することができる、本明細書に記述した方法及び材料と同様又は等価な多くの方法及び材料を理解するであろう。本発明は、本明細書に記述する方法及び材料に、決して限定されない。限定はされないが、用語の定義、用語の用法、記載された技術などを含めて、組み込まれた文献、特許、及び類似の資料の1以上が、本出願と異なる又は矛盾する場合、本出願が支配する。
本発明は、受容体チロシンキナーゼ、特にVEGFR、c-Met、及びAxl受容体によって調節される疾患、状態、及び障害の治療に潜在的に有用である、キノリン化合物、塩、及びその医薬製剤を提供する。より具体的には、本発明は、式Iの化合物:
一態様によれば、本発明は、式Iの化合物、表1に列挙した化合物、及び医薬として許容し得る担体、アジュバント、又はビヒクルを含む医薬組成物を特徴とする。本発明の組成物中の化合物の量は、生体試料において又は患者においてプロテインキナーゼを検出可能な程度に阻害するのに有効であるような量である。
本発明は、式Iの化合物又は表1に列挙した化合物と、医薬として許容し得る担体、アジュバント、又はビヒクルとを含む医薬組成物を特徴とする。本発明の組成物中の化合物の量は、VEGFR、Axl、及びc-Met阻害活性などのプロテインキナーゼを検出可能な程度に阻害するのに有効であるような量である。本発明の化合物は、抗腫瘍剤としての治療法において、或いはVEGFR、Axl、及びc-Metシグナル伝達の悪影響を最小限にするために、有用である。
本発明を例示するために、以下の実施例が挙げられる。しかし、これらの実施例は、本発明を限定せず、かつ本発明を実施する方法を示唆することを意図するに過ぎないことを理解されたい。
本明細書全体を通して、次の略語を使用する:
HOAc 酢酸
MeCN、CH3CN アセトニトリル
NH3 アンモニア
NH4Cl 塩化アンモニウム
HBTA ヘキサフルオロリン酸O-ベンゾトリアゾール-1-イル-N,N,N',N'-テトラメチルウロニウム
HATU ヘキサフルオロリン酸O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウム
PyBop ヘキサフルオロリン酸ベンゾトリアゾール-1-イル-オキシ-トリピロリジノ-ホスホニウム
Pd2(dba)3 ビス(ジベンジリデンアセトン)パラジウム
BINAP 2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル
TEAC ビス(テトラ-エチルアンモニウム)カーボネート
BBr3 三臭化ホウ素
BSA ウシ血清アルブミン
BOC、Boc ブチルオキシカルボニル
Ca(SO3CF3)2 トリフルオロメチルスルホン酸カルシウム
Cs2CO3 炭酸セシウム
CHCl3 クロロホルム
CDCl3 重水素化クロロホルム
Cu 銅
CuI ヨウ化銅(I)
Et2O ジエチルエーテル
DBU 1,8-ジアザビシクロ[5,A0]ウンデカ-7-エン
DIBAL 水素化ジイソブチルアルミニウム
DIAD アゾジカルボン酸ジイソプロピル
DIEA又はDIPEA ジイソプロピルエチルアミン
DEAD アゾジカルボン酸ジメチル
DMF ジメチルホルムアミド
DMAP 4-ジメチルアミノピリジン
DMSO ジメチルスルホキシド
EDC、EDCI 塩酸1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド
dppa アジ化ジフェニルホスホリル
EtOAc、EA 酢酸エチル
FBS ウシ胎児血清
g グラム
h 時間
HBr 臭化水素酸
HCl 塩酸
HOBt 1-ヒドロキシベンゾトリアゾール水和物
H2 水素
H2O2 過酸化水素
Fe 鉄
LiHMDS リチウムビス(トリメチルシリル)-アミド
LDA リチウムジイソプロピルアミド
MCPBA メタ-クロロ過安息香酸
MgSO4 硫酸マグネシウム
MeOH、CH3OH メタノール
MeI ヨウ化メチル
2-MeTHF 2-メチルテトラヒドロフラン
CH2Cl2、DCM 塩化メチレン
NMP N-メチルピロリジノン
mL、ml ミリリットル
N2 窒素
Pd/C 炭素担持パラジウム
Pd(OAc)2 酢酸パラジウム
Pd(OH)2 水酸化パラジウム
Pd(PPh3)4 テトラキストリフェニルホスフィンパラジウム
Pd(dppf)Cl2 塩化1,1-ビス(ジフェニルホスフィノ)フェロセンパラジウム
PE 石油エーテル(60〜90℃)
PBS リン酸緩衝塩類溶液
POCl3 オキシ塩化リン
K2CO3 炭酸カリウム
KOH 水酸化カリウム
RT rt r.t. 室温
Rt 保持時間
NaHCO3 炭酸水素ナトリウム
NaBH4 水素化ホウ素ナトリウム
NaBHsCN シアノ水素化ホウ素ナトリウム
NaOtBu ナトリウムtert-ブトキシド
NaOH 水酸化ナトリウム
NaClO2 亜塩素酸ナトリウム
NaCl 塩化ナトリウム
NaH2PO4 リン酸ナトリウム(sodium biphosphate)
NaH 水素化ナトリウム
NaI ヨウ化ナトリウム
Na2SO4 硫酸ナトリウム
TBTU テトラフルオロホウ酸O-ベンゾトリアゾール-1-イル-N,N,N',N'-テトラメチルウロニウム
THF テトラヒドロフラン
Et3N、TEA トリエチルアミン
TFA トリフルオロ酢酸
P(t-bu)3 トリ(tert-ブチル)ホスフィン
H2O 水
N-(3-フルオロ-4-((7-(2-ヒドロキシ-2-メチルプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
3-(ベンジルオキシ)ベンゼンアミン(970g、4.9mol、Wuhan Xinghuayuan Tech社)と2,2-ジメチル-1,3-ジオキサン-4,6-ジオン(842.3g、5.8mol)の、無水EtOH(970mL)溶液に、トリエトキシメタン(865.7g、5.8mol)を添加した。この懸濁液を、1時間加熱還流した。次いで、反応混合物を室温まで冷却し、さらに2時間撹拌を続けた。この懸濁液を濾過し、固体を無水EtOH(970mL)に入れて2時間撹拌し、濾過によって収集した。固体を45℃で真空乾燥させ、淡黄色固体として表題化合物を得た(1.7kg、96.5%)。
MS (ESI, neg. ion) m/z: 352.3 [M-1];
5-((3-(ベンジルオキシ)フェニルアミノ)メチレン)-2,2-ジメチル-1,3-ジオキサン-4,6-ジオン(300g、849.8mol)の1,2-ジクロロベンゼン(3L、Aladdin社)溶液を、5時間加熱還流した。反応混合物を室温まで冷却し、それに続いてさらに、氷浴中で2時間冷却した。濾過を介して固体を収集し、MeOH(300mL)と共に室温で2時間撹拌した。濾過を介して固体を収集し、45℃で真空乾燥させ、青白い固体として表題化合物をもたらした(103g、48.5%)。
MS (ESI, pos. ion) m/z: 252.2 [M+1];
7-(ベンジルオキシ)キノリン-4-オール(72g、287mmol)をトルエン(134mL)に入れた懸濁液に、三塩化ホスホリル(44g、287mmol、Tianjin FuChen Chem社)を添加した。この懸濁液を、120℃まで1時間加熱した。次いで、反応混合物を70℃に冷却し、EtOAc(600mL)で希釈した。得られた混合物を、氷浴を使用して15℃まで冷却しながら、30分間撹拌した。この混合物を、溶液の温度を20℃未満に維持しながら、3M NaOH水溶液を用いてpH7〜8に中和した。水層を分離し、EtOAc(200mL)で抽出した。合わせた有機層を、ブライン(200mL)で洗浄し、無水Na2SO4で乾燥させ、真空中で濃縮し、淡黄色固体として表題化合物を得た(70.8g、91.6%)。
MS (ESI, pos. ion) m/z: 270.1 [M+1];
7-(ベンジルオキシ)-4-クロロキノリン(45g、0.17mol)と2-フルオロ-4-ニトロフェノール(28.9g、0.18mol)の、トルエン(42mL)懸濁液に、DIPEA(25.9g、0.2mol)を添加した。この懸濁液を、115℃まで12時間加熱し、次いで、真空中で濃縮した。残渣をEtOH(45mL)で希釈し、60℃で30分間撹拌し、次いで、氷浴中で0℃まで冷却した。濾過を介して固体を収集し、45℃で24時間真空乾燥させ、薄灰色の固体として表題化合物をもたらした(59.1g、91%)。
MS (ESI, pos. ion) m/z: 391.1 [M+1];
7-(ベンジルオキシ)-4-(2-フルオロ-4-ニトロフェノキシ)キノリン(100g、256.4mmol)をジオキサン(425mL)及び濃塩酸(425mL、5.1mol)に入れた懸濁液を、100℃で24時間撹拌した。次いで、反応混合物を室温まで冷却し、濾過を介して固体を収集した。次いで、固体を無水EtOH(100mL)に懸濁し、2時間撹拌した。固体を収集し、60℃で12時間真空乾燥させ、青白い固体として表題化合物を得た(73.3g、85%)。
MS (ESI, pos. ion) m/z: 301 [M+1];
4-(2-フルオロ-4-ニトロフェノキシ)キノリン-7-オール(60g、0.2mol)のTHF/H2O(1L、THF/H2O=1:1、v/v)溶液に、NaOH(24g、0.6mol)を室温で、それに続いてイソブチレンオキシド(144g、2mol)を添加した。この反応物を45℃で10時間撹拌し、次いでEtOAc(1L)で希釈した。得られた溶液を1M NaOH水溶液(500mL×4)で洗浄した。有機層を分離し、Na2SO4で乾燥させ、真空中で濃縮した。残渣を500mLの石油エーテルで洗浄し、濾過を介して収集し、淡黄色固体として表題化合物を得た(31.6g、42.5%)。
MS (ESI, pos. ion) m/z: 373.1 [M+1];
1-((4-(2-フルオロ-4-ニトロフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン-2-オール(10.04g、27mmol)とHCOOK(15.87g、189mmol)を、THF/H2O(54mL、THF/H2O=4:1)に入れた混合物に、触媒量のPd/C(5%、含水率53%〜55%、w/w)を添加した。この反応物を45℃で5時間撹拌し、次いで、THF/H2O(40mL、v/v=1:1)で希釈した。得られた混合物を濾過し、濾液を真空中で濃縮した。残渣をEtOH/H2O(30mL×3、v/v=5:1)で洗浄し、45℃で24時間真空乾燥させ、薄灰色の固体として表題化合物を得た(8.1g、87%)。
MS (ESI, pos. ion) m/z: 343.1 [M+1];
1-((4-(4-アミノ-2-フルオロフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン-2-オール(5g、14.6mmol)と、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(3.46g、14.9mmol)と、HOAT(0.39g、2.9mmol)とを、ジクロロメタン(30mL)に入れた溶液に、EDCI(3.35g、17.5mmol)を添加した。この混合物を、41℃で6時間撹拌し、室温まで冷却し、酢酸エチル(30mL)で希釈した。得られた懸濁液を濾過し、固体を95%エタノール(50mL×2)で洗浄した。濾過を介して固体を収集し、45℃で6時間真空乾燥させ、白色固体として表題化合物を得た(6.35g、78%)。
MS (ESI, pos. ion) m/z: 557.2 [M+1]; LC-MS Rt: 2.905 min;
(R)-N-(3-フルオロ-4-((7-(2-ヒドロキシプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
7-(ベンジルオキシ)-4-(2-フルオロ-4-ニトロフェノキシ)キノリン(16.38g、42mmol)とHCOONH4(26.46g、420mmol)とを、EtOH/H2O(84mL、v/v=4:1)の混合溶液に入れた混合物に、触媒量のPd/C(0.50g、含量5%、含水率53%〜55%、w/w)を添加した。この反応物を30℃で24時間撹拌し、LC-MSによってモニタリングした。7-(ベンジルオキシ)-4-(2-フルオロ-4-ニトロフェノキシ)キノリンの完全な消費後、固体が溶解するまで、反応混合物に6M HCl(80mL)を添加した。得られた溶液を濾過した。濾液にNaHCO3飽和水溶液(210mL)を添加して最終pHを6.0〜6.5に調整し、それに続いて、水(20mL)とCH2Cl2(50mL)との混合物を添加した。得られた混合物を、室温で4時間撹拌した。濾過によって固体を収集し、MeOH/DCM(50mL、v/v=1/1)の混合物で洗浄し、45℃で真空乾燥させ、淡黄色固体として表題化合物を得た(11.0g、92%)。
MS (ESI, pos. ion) m/z: 271.2 [M+1]; LC-MS Rt: 2.421 min;
4-(4-アミノ-2-フルオロフェノキシ)キノリン-7-オール(10g、37.0mmol)と、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(10g、44.4mmol)と、HOAT(0.5g、3.7mmol)とを、DMF(50mL)及びトルエン(30mL)に入れた溶液に、EDCI(8.5g、44.4mmol)を添加した。この反応物を終夜、45℃で撹拌し、次いで水(100mL)で希釈し、室温で2時間撹拌し続けた。濾過を介して固体を収集し、95% EtOH(50mL)とDCM(25mL)との混合物で洗浄し、次いで、3M塩酸(10.5mL)で処理した。得られた固体を収集し、95% EtOHとH2O(90mL、EtOH/H2O=5:1、v/v)との混合物中で再結晶させ、白色固体として表題化合物を得た(11.7g、60.8%)。
MS (ESI, pos. ion) m/z: 485.2 [M+1];
N-(3-フルオロ-4-((7-ヒドロキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド(100mg、0.21mmol)とCs2CO3(337mg、1.03mmol)とを、10mL DMFに入れた混合物に、(R)-2-メチルオキシラン(5mL、71.60mmol)を添加した。この反応物を40℃に温め、2日間撹拌した。この混合物を真空中で濃縮し、残渣をシリカゲルカラムクロマトグラフィー(1:15(v/v) MeOH/DCM)によって精製し、白色固体として表題化合物を得た(60mg、54%)。
MS (ESI, pos. ion) m/z: 543.2 [M+1]; LC-MS Rt: 2.983 min;
(S)-N-(3-フルオロ-4-((7-(2-ヒドロキシプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
MS (ESI, pos. ion) m/z: 543.2 [M+1]; LC-MS Rt: 2.935 min;
N-(3-フルオロ-4-((7-(2-ヒドロキシ-2-メチルプロポキシ)-6-メトキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
MS (ESI, pos. ion) m/z: 587.2 [M+1]; LC-MS Rt: 2.911 min;
N-(3-フルオロ-4-((7-(2-ヒドロキシ-2-メチルプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド塩酸塩
マレイン酸N-(3-フルオロ-4-((7-(2-ヒドロキシ-2-メチルプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
p-トルエンスルホン酸N-(3-フルオロ-4-((7-(2-ヒドロキシ-2-メチルプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
ベンゼンスルホン酸N-(3-フルオロ-4-((7-(2-ヒドロキシ-2-メチルプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
N-(4-((7-(2-ヒドロキシ-2-メチルプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
7-(ベンジルオキシ)-4-クロロキノリン(10g、37.1mmol)と4-ニトロフェノール(6.2g、44.5mmol)とをトルエン(10mL)に入れた懸濁液に、DIPEA(6.2g、48.2mmol)を添加した。この反応混合物を、115℃で12時間還流させ、次いで室温まで冷却した。この混合物にDCM(50mL)を添加し、得られた溶液を、1M NaOH(各30mL)で、水相が無色になるまで数回洗浄した。有機相を真空中で濃縮し、褐色の固体をもたらした(13.2g、95.7%)。この固体を95% EtOH(30mL)中で室温で12時間撹拌し、濾過し、灰褐色固体として表題化合物を得た(12.1g、91.7%)。
MS (ESI, pos. ion) m/z: 373.1 [M+1];
7-(ベンジルオキシ)-4-(4-ニトロフェノキシ)キノリン(10.85g、29.14mmol)と1,4-ジオキサン(38mL)との混合物に、濃塩酸(38mL)を添加した。この反応物を油浴中で100℃で9時間撹拌し、TLC及びLC-MSによってモニタリングした。7-(ベンジルオキシ)-4-(4-ニトロフェノキシ)キノリンの完全な消費後、混合物を室温まで冷却した。固体を収集し、95% EtOH(30mL)中で2時間撹拌した。濾過によって表題化合物をベージュ色の固体として収集した(8.25g、88.7%)。
MS (ESI, pos. ion) m/z: 283.1 [M+1];
4-(4-ニトロフェノキシ)キノリン-7-オール(14.45g、45.33mmol)を含有するフラスコに、水酸化ナトリウム(3.63g、90.66mmol)を水/95% EtOH(90mL/10mL)に入れた溶液、それに続いてイソブチレンオキシド(12.12mL、136mmol、予め0℃に冷却)を添加した。45℃で10分間撹拌した後、さらなるイソブチレンオキシド(12.12mL、136mmol、予め0℃に冷却)を添加した。この反応物をさらに12時間撹拌し続けた。この混合物を室温まで冷却し、4時間撹拌し続け、次いで、0℃に冷却し、さらに10分間撹拌した。得られた固体を濾過し、次いでDCM(130mL)に溶解した。この溶液を濾過し、真空中で濃縮した。残渣を石油エーテル(30mL)で洗浄し、45℃で終夜、真空乾燥させ、黄色固体として表題化合物をもたらした(6.86g、42.7%)。
2-メチル-1-((4-(4-ニトロフェノキシ)キノリン-7-イル)オキシ)プロパン-2-オール(2.8g、7.9mmol)とHCOOK(4.6g、55.3mmol)とを水(4mL)及びTHF(12mL)に入れた溶液に、10% Pd/C(0.24g)を添加した。この反応混合物を、45℃で21時間撹拌し、次いで室温まで冷却した。この混合物をセライトパッドを通して濾過した。有機相を分離し、ブライン(20mL)で洗浄した。水相をEtOAc(15mL)で抽出した。合わせた有機相を真空中で濃縮し、残渣を50℃で終夜、真空乾燥させ、黄色固体として表題化合物を得た(2.5g、97.7%)。
MS (ESI, pos. ion) m/z: 325.2 [M+1];
1-((4-(4-アミノフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン-2-オール(3.75g、11.6mmol)のDCM(31mL)溶液に、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(2.7g、11.8mmol)、HOAT(0.32g、2.32mmol)、EDCI(2.7g、13.9mmol)を添加した。この反応混合物を、3時間還流させ、次いで、45℃に冷却し、4時間撹拌し続けた。追加のEDCI(0.4当量、0.90g、4.64mmol)を添加し、反応物を終夜、45℃で撹拌した。この混合物を室温まで冷却し、EtOAc(30mL)と水(30mL)との混合物で希釈した。室温で2時間撹拌した後、混合物を濾過した。固体を95% EtOH(15mL)中で-5℃で5時間撹拌した。濾過を介して固体を収集し、終夜、50℃で真空乾燥させ、灰白色固体として表題化合物を得た(3.04g、48.87%)。
MS (ESI, pos. ion) m/z: 539.2 [M+1];
N-(4-((7-(2-ヒドロキシエトキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
4-(4-ニトロフェノキシ)キノリン-7-オール(2.82g、10mmol)のDMF(20mL)溶液に、KOHペレット(1.12g、20mmol)及び2-ブロモエタノール(1.87g、15mmol)を室温で添加した。次いで、この反応物を、45℃まで温め、12時間撹拌した。次いで、この混合物を、真空中で濃縮し、残渣をシリカゲル上でのカラムクロマトグラフィー(EtOAc/PE=1:1)によって精製し、淡黄色固体(417mg、12.8%)として表題化合物を得た。
MS (ESI, pos. ion) m/z: 327.1 [M+1].
2-((4-(4-ニトロフェノキシ)キノリン-7-イル)オキシ)エタノール(0.32g、1mmol)と、HCOOK(0.59g、7mmol)とを、水(1mL)及びTHF(3mL)に入れた懸濁液に、10% Pd/C(0.03 g)を添加した。この反応物を45℃で4時間撹拌した。この混合物をEtOAc(5mL)で希釈し、セライトパッドを通して濾過した。濾液を真空中で濃縮し、95%エタノール(1mL)と水(5mL)との混合物で洗浄した。濾過によって固体を収集し、終夜、50℃で真空乾燥させ、淡黄色固体として表題化合物を得た(140mg、47.3%)。
MS (ESI, pos. ion) m/z: 297.2 [M+1].
2-((4-(4-アミノフェノキシ)キノリン-7-イル)オキシ)エタノール(0.14g、0.5mmol)と、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(0.11g、0.51mmol)とを、DCM(1.5mL)に入れた溶液に、HOAT(0.014g、0.1mmol)及びEDCI(0.11g、0.6mmol)を添加した。この反応物を3時間還流させた。冷却した混合物を水(30mL)で希釈し、濾過した。固体を収集し、EtOAc(3mL)と水(3mL)との混合物中で終夜撹拌した。濾過によって固体を収集し、50℃で9時間真空乾燥させ、灰白色固体として表題化合物をもたらした(180mg、74.7%)。
MS (ESI, pos. ion) m/z: 511.3 [M+1].
(R)-N-(4-((7-(2-ヒドロキシプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
4-(4-ニトロフェノキシ)キノリン-7-オール(10g、35.5mmol)をTHF(35mL)/NaOH(水溶液)(37.8g、7.4%)に入れた懸濁液に、(R)-2-メチルオキシラン(10.3g、177.3mmol)を添加した。この反応物を、30℃で18時間撹拌し、次いで、真空中で濃縮した。この混合物を、EtOAc(50mL)で希釈した。有機相を分離し、真空中で濃縮した。残渣をシリカゲル上でのカラムクロマトグラフィー(EtOAc/PE=1:1)によって精製し、黄色固体として表題化合物を提供した(3.6g、29.9%)。
MS (ESI、正イオン) m/z: 341.10 [M+1];
ステップ2)(R)-1-((4-(4-アミノフェノキシ)キノリン-7-イル)オキシ)プロパン-2-オール
(R)-1-((4-(4-ニトロフェノキシ)キノリン-7-イル)オキシ)プロパン-2-オール(3.6g、10.6mmol)とHCOOK(6.2g、74.1mmol)とを、THF/H2O(33mL/11mL)に入れた懸濁液に、触媒量の10% Pd/C(33mg)を添加した。73℃で5時間撹拌した後、反応混合物を室温まで冷却した。この混合物を、セライトパッドを通して濾過し、濾過ケークをDCM(50mL)で洗浄した。有機相を分離し、Na2SO4で乾燥させ、真空中で濃縮した。残渣をシリカゲル上でのカラムクロマトグラフィー(EtOAc/PE=1:1)によって精製し、黄色固体として表題化合物を得た(2.5g、76.2%)。
MS (ESI, pos. ion) m/z: 311.2 [M+1];
(R)-1-((4-(4-アミノフェノキシ)キノリン-7-イル)オキシ)プロパン-2-オール(2.5g、11.9mmol)と、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(2.0g、8.6mmol)と、HOAT(0.2g、1.6mmol)とを、DCM(35mL)に入れた溶液に、EDCI(1.9g、9.7mmol)を添加した。この反応混合物を、43℃で12時間撹拌し、次いで、室温まで冷却し、DCMとH2O(50mL/50mL)との混合物で希釈した。有機相を分離し、Na2SO4で乾燥させ、真空中で濃縮した。残渣をシリカゲル上でのカラムクロマトグラフィー(EtOAc)によって精製し、黄色固体として表題化合物をもたらした(0.6g、14.3%)。
MS (ESI, pos. ion) m/z: 525.20 [M+1];
(S)-N-(4-((7-(2-ヒドロキシプロポキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
MS (ESI, pos. ion) m/z: 525.20 [M+1];
N-(3-フルオロ-4-((7-(2-ヒドロキシエトキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
LC-MS (ESI, pos, ion) m/z: 529 [M+1], Rt = 3.062 min;
N-(3-フルオロ-4-((7-((1-ヒドロキシ-2-メチルプロパン-2-イル)オキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
4-(2-フルオロ-4-ニトロフェノキシ)キノリン-7-オール(5g、16.7mmol)とNaOH(6.7g、166.7mmol)とを、アセトン(67mL)に入れた混合物に、室温でクロロホルム(21.9g、183.3mmol)を液滴として添加した。混合物が褐色に変化した後、この反応物を1時間加熱還流させた。次いで、この反応混合物に、水(10mL)を添加し、得られた溶液を、1N HCl溶液でpH3〜4に調整した。得られた混合物を真空中で濃縮し、次いで、EtOAc(30mL)で抽出した。有機相を分離し、真空中で濃縮し、95% EtOH(10mL)で処理した。得られた固体を濾過によって収集し、終夜真空乾燥させて、褐色の固体として表題化合物をもたらした(2.34g、36.4%)。
LC-MS (ESI, pos, ion) m/z: 387 [M+1];
2-((4-(2-フルオロ-4-ニトロフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン酸(3g、7.75mmol)と、EDCI(1.8g、9.3mmol)と、HOAT(0.2g、1.6mmol)とを、CH2Cl2(60mL)に入れた溶液に、CH3OH(5mL)を添加した。この反応混合物を、室温で1時間撹拌し、次いで、20mLのCH2Cl2で希釈した。有機相を分離し、水(20mL)で洗浄し、真空中で濃縮した。シリカゲル上でのカラムクロマトグラフィー(PE/EtOAc=2:1)によって、未精製生成物を精製し、黄色油として表題化合物をもたらした(3g、96.5%)。
2-((4-(2-フルオロ-4-ニトロフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン酸メチル(3g、7.5mmol)のTHF(25mL)溶液に、LiAlH4(0.34g、9mmol)を0℃で何度かに分けて添加した。この反応物を、0℃で4時間撹拌し、次いで、H2O(30mL)で反応停止させた。有機溶媒を真空中で除去し、残渣をDCM(100mL)で希釈した。有機相を分離し、Na2SO4で乾燥させ、真空中で濃縮した。黄色固体として表題化合物を得た(0.95g、34.1%)。
MS (ESI, pos, ion) m/z: 373 [M+1];
2-((4-(2-フルオロ-4-ニトロフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン-1-オール(5.8g、15.6mmol)のTHF(23mL)溶液に、HCOOK(9.16g、10.9mmol)の水(7.8mL)溶液、それに続いて触媒量のPd/C(5%、含水率53%〜55%)を添加した。この混合物を45℃に加熱し、12時間撹拌し、次いで、セライトパッドを通して濾過した。有機相を分離し、Na2SO4で乾燥させ、真空中で濃縮して、黄色のフォーム(foam)固体をもたらした。シリカゲルクロマトグラフィー(EtOAc/DCM=1/1)によって表題化合物を精製し、淡黄色固体を得た(4.0g、75%)。
MS (ESI、正イオン) m/z: 343.1 [M+1];
HPLC:保持時間:7.467分、純度:254nmで99.17%及び210nmで99.09%;
2-((4-(4-アミノ-2-フルオロフェノキシ)キノリン-7-イル)オキシ)-2-メチルプロパン-1-オール(2.84g、8.3mmol)のDCM(30mL)溶液に、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(1.97g、8.4mmol)、EDCI(1.92g、10.0mmol)、及びHOAT(0.23g、1.7mmol)を添加した。この反応混合物を撹拌し、還流で4時間撹拌し、次いで、真空中で濃縮した。残渣を95% EtOH(50mL)/水(30mL)中で撹拌し、次いで濾過し、淡黄色固体として表題化合物を得た(3.52g、76.2%)。
MS (ESI, pos. ion) m/z: 557.2 [M+1];
N-(4-((7-(2-ヒドロキシ-2-メチルプロポキシ)-6-メトキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
4-ヒドロキシ-3-メトキシアセトフェノン(40g、240mmol)と、臭化ベンジル(34.1mL、260mmol)と、炭酸カリウム(50.0g、360mmol)とを、DMF(800mL)に入れた混合物を、40℃で5時間撹拌した。この反応物を、室温まで冷却し、氷と水(2000mL)との混合物に注いだ。濾過によって固体を収集し、水で洗浄し、真空乾燥させて、白色固体として表題化合物を得た(60.66g、98%)。
MS (ESI, pos. ion) m/z: 257.2 [M+1].
1-(4-ベンジルオキシ-3-メトキシフェニル)エタノン(51.3g、200mmol)の0℃のDCM(750mL)溶液に、硝酸(68%、21mL、300mmol)を20分かけて液滴として、それに続いて、硫酸(98%、16.3mL、300mmol)を40分かけて添加した。追加の硝酸(14.3mL、200mmol)を、さらに20分間、液滴として添加した。次いで、反応混合物をpHが7〜8になるまで水で洗浄し、Na2SO4で乾燥させ、真空中で濃縮した。残渣をエタノール(850mL)から再結晶させて、淡黄色固体(40g、68%)として表題化合物を得た。
MS (ESI, pos. ion) m/z: 302.1 [M+1];
1-(4-ベンジルオキシ-5-メトキシ-2-ニトロフェニル)エタノン(36.00g、120mmol)と、鉄粉(26.80g、480mmol)と、HCOONH4(31.53g、500mmol)とを、トルエン/水(500mL/500mL)の混合物に入れた懸濁液を、終夜、103℃で撹拌した。この混合物を室温まで冷却し、EtOAc(500mL)で希釈し、室温で3時間撹拌し、セライトパッドを通して濾過した。濾液を真空中で濃縮し、黄色固体として表題化合物を得た(32.1g、99%)。
MS (ESI, pos. ion) m/z: 272.2 [M+1];
1-(2-アミノ-4-(ベンジルオキシ)-5-メトキシフェニル)エタノン(29.00g、108mmol)のDME(700mL)溶液に、ナトリウムメトキシド(46.70g、864mmol)を、何度かに分けて添加した。この反応物を室温で30分間撹拌し、次いで、ギ酸エチルを添加し(64mL、648mmol)、8時間撹拌し続けた。この混合物をH2O(500mL)で希釈し、1N HClで中和した。得られた固体を濾過を介して収集し、水で洗浄し、終夜真空乾燥させて、黄色固体として表題化合物をもたらした(15.9g、53%)。
MS (ESI, pos. ion) m/z: 282.2 [M+1];
7-(ベンジルオキシ)-6-メトキシキノリン-4-オール(24.60g、87.45mmol)のトルエン(75mL)溶液に、オキシ塩化リン(90mL)をゆっくりと添加した。この反応物を2時間加熱還流し、次いで、室温まで冷却し、EtOAc(200mL)で希釈した。得られた溶液を、氷と3N NaOHとの混合物に、何度かに分けて注いだ。この混合物のpHを、3N NaOHで7〜8に調整した。有機相を分離し、水(200mL)、続いてブライン(100mL)で洗浄し、真空中で濃縮した。白色固体として表題化合物を得た(22.1g、84.5%)。
MS (ESI, pos. ion) m/z: 300.01 [M+1];
7-(ベンジルオキシ)-4-クロロ-6-メトキシキノリン(20.00g、70.92mmol)とp-ニトロフェノール(13.83g、100mmol)とを、キシレン(40mL)及びN-エチルジイソプロピルアミン(90mL)に入れた懸濁液を、12時間還流させた。この混合物を室温に冷却し、EtOH(200mL)で希釈した。濾過によって固体を収集し、終夜、60℃で真空乾燥させて、淡黄色固体として表題化合物を得た(22.6g、84.3%)。
MS (ESI, pos. ion) m/z: 403.1[M+1];
7-(ベンジルオキシ)-6-メトキシ-4-(4-ニトロフェノキシ)キノリン(43.00g、120mmol)と、10% Pd/C(4.30g)と、HCOOK(89.93g、600mmol)とを、MeOH/H2O(345mL/200mL)に入れた懸濁液を、終夜還流させた。この混合物を室温まで冷却し、EtOAc(300mL)で希釈し、セライトパッドを通して濾過した。濾液を真空中で濃縮し、残渣を水で洗浄し、終夜、60℃で真空乾燥させ、黄色固体として表題化合物を得た(28.8g、95.5%)。
MS (ESI, pos. ion) m/z: 283.1 [M+1];
4-(4-アミノフェノキシ)-6-メトキシキノリン-7-オール(3.61g、12.8mmol)と、1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(2.85g、12.27mmol)とを、DMF(50mL)に入れた溶液に、EDCI(2.81g、14.66mmol)とHOAT(0.33g、2.4mmol)を添加した。この反応物を60℃で10時間撹拌し、室温まで冷却し、H2O(200mL)で希釈した。濾過によって固体を収集し、終夜、60℃で真空乾燥させて、白色固体として表題化合物を得た(5.7g、89.9%)。
MS (ESI, pos. ion) m/z: 497.2 [M+1].
N-(4-((7-ヒドロキシ-6-メトキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド(4.93g、9.93mmol)と、イソブチレンオキシド(8.8mL、100mmol)とを、DMF/H2O(21mL/4mL)に入れた溶液に、K2CO3(2.74g、2mmol)を添加した。この反応混合物を、60℃で12時間撹拌し、次いで、室温まで冷却し、NaH2PO4水溶液(飽和溶液、10mL)で処理し、この混合物のpHを7〜8に調整した。濾過によって固体を収集し、EtOAc/EtOH(80mL/15mL)で洗浄した。淡黄色固体として表題化合物を得た(1.93g、34.3%)。
MS (ESI, pos. ion) m/z: 569.2 [M+1].
(S)-N-(4-((7-(2-ヒドロキシプロポキシ)-6-メトキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
MS (ESI, pos. ion) m/z: 555.2 [M+1].
(R)-N-(4-((7-(2-ヒドロキシプロポキシ)-6-メトキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
MS (ESI, pos. ion) m/z: 555.2 [M+1].
N-(4-((7-(2-ヒドロキシエトキシ)-6-メトキシキノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
MS (ESI, pos. ion) m/z: 541.2 [M+1].
c-Met、VEGFR、及びAxl関連活性などの受容体チロシンキナーゼの阻害剤としての、また、異種移植動物モデルにおける抗腫瘍剤としての、本発明の化合物の有効性を、次の通りに評価することができる。これらのアッセイ結果は、本発明のある種の化合物が、細胞におけるc-Met、VEGF-R2、及びAxlリン酸化を強力に阻害することを実証し、また、ある種の異種移植モデルにおける強力な用量依存性の抗腫瘍活性を実証する。
固定化されたミエリン塩基性タンパク質(MBP)へのγ-33P ATPの取り込みの測定によって、キナーゼアッセイを実施することができる。高結合型白色384ウェルプレート(Greiner社)を、60μl/ウェルの20μg/ml MBP(Tris-緩衝塩類溶液(TBS;50mM Tris pH8.0、138mM NaCl、2.7mM KCl)中)の4℃での24時間のインキュベーションによって、MBP(Sigma社 #M-1891)でコーティングする。プレートを100μl TBSで3回洗浄する。キナーゼ緩衝液(5mM Hepes pH7.6、15mM NaCl、0.01%ウシガンマグロブリン(Sigma社 #I-5506)、10mM MgCl2、1mM DTT、0.02% TritonX-100)中で、総体積34μlで、キナーゼ反応を実施する。DMSO中で化合物希釈を実施し、アッセイウェルに加えて、1%の最終DMSO濃度とする。各データポイントを、2つ組で測定し、個々の化合物測定のために、少なくとも2回の2つ組アッセイを実施する。酵素を添加し、例えば10nM又は20nMの最終濃度とする。非標識ATPとγ-33P ATPとの混合物を添加し、反応を開始する(通常、ウェルあたり2×106cpmのγ-33P ATP(3000Ci/mmol)と、10μM非標識ATP)。撹拌しながら室温で1時間、反応を実施する。プレートをTBSで7回洗浄し、続いて、50μl/ウェルのシンチレーション液(Wallac)を添加する。Wallac Triluxカウンターを使用してプレートを読み取る。これは、こうしたアッセイの1つの形式に過ぎず;当業者に公知である通り、種々の他の形式が可能である。
Met(h)を、8mM MOPS pH7.0、0.2mM EDTA、250μM KKKSPGEYVNIEFG、10mM酢酸マグネシウム、及び[γ-33P-ATP](比活性およそ500cpm/pmol、必要とされる濃度)と共にインキュベートする。MgATP混合物の添加によって反応を開始する。室温での40分間のインキュベート後、3%リン酸溶液の添加によって反応を停止する。次いで、この反応物の10μLをP30フィルターマットにスポットし、75mMリン酸中で5分間(3回)、メタノール中で1回洗浄した後、乾燥及びシンチレーション測定を行う。
KDR(h)を、8mM MOPS pH7.0、0.2mM EDTA、0.33mg/mLミエリン塩基性タンパク質、10mM酢酸マグネシウム、及び[γ-33P-ATP](比活性およそ500cpm/pmol、必要とされる濃度)と共にインキュベートする。MgATP混合物の添加によって反応を開始する。室温での40分間のインキュベート後、3%リン酸溶液の添加によって反応を停止する。次いで、この反応物の10μLをP30フィルターマットにスポットし、75mMリン酸中で5分間(3回)、メタノール中で1回洗浄した後、乾燥及びシンチレーション測定を行う。
Axl(h)を、8mM MOPS pH7.0、0.2mM EDTA、250μM KKSRGDYMTMQIG、10mM酢酸マグネシウム、及び[γ-33P-ATP](比活性およそ500cpm/pmol、必要とされる濃度)と共にインキュベートする。MgATP混合物の添加によって反応を開始する。室温での40分間のインキュベート後、3%リン酸溶液の添加によって反応を停止する。次いで、この反応物の10μLをP30フィルターマットにスポットし、75mMリン酸中で5分間(3回)、メタノール中で1回洗浄した後、乾燥及びシンチレーション測定を行う。
一般に、細胞は、完全な標的結合を可能にするために、試験化合物と共に予めインキュベートする。自己リン酸化レベルは、サンドイッチ-ELISA技術によって決定した。IC50値は、片対数ステップにおける8化合物濃度(各濃度は2つ組)を試験することによって決定した。細胞リン酸化アッセイのステップは、図1に例示する。本明細書に記述する細胞リン酸化アッセイは、ProQinase社のBreisacher Strabe 117 D-79106(Freiburg、Germany)で実施した。
ヒト胃腺癌細胞株MKN45は、c-Metを過剰発現することが公知である。c-Met過剰発現は、キナーゼの恒常的なリガンド非依存性の自己リン酸化をもたらす。SU11274を添加することによって、リン酸化METレベルが大きく低下するので、化合物の潜在的阻害能力を決定するための動的挙動が得られた。続いて、リン酸化METシグナルを、サンドイッチ-ELISA技術によって数量化する。このアッセイは、METキナーゼ活性の公知の阻害剤に基づいて実証される。
不死化されたヒト臍帯静脈内皮細胞(HUE)は、ヒトVEGF-R2を過剰発現することが公知である。この細胞をその生理学的リガンドVEGF-Aで刺激することは、頑強な受容体自己リン酸化をもたらす。完全な標的結合を可能にするために、細胞刺激の前に、化合物を予めインキュベートする。刺激条件を最適化してリン酸化VEGF-R2シグナルの用量関連の阻害を決定し、続いて、サンドイッチ-ELISA技術によって数量化する。このアッセイは、VEGF-R2キナーゼ活性の公知の阻害剤に基づいて実証される。
細胞のAXLリン酸化アッセイを、マウス胎児線維芽細胞(MEF)バックグラウンドについて行った。細胞を、完全長のAXLタンパク質を発現するように形質移入した。クローン選別の後、高レベルの自己リン酸化されたAXLを伴う形質移入された細胞株が得られた。スタウロスポリンを添加することによって、リン酸化AXL レベルが大きく低下するので、化合物の潜在的抑制能力を判定するための動的挙動が得られた。リン酸化AXLレベルは、サンドイッチ-ELISA技術によって数量化した。
本明細書に開示した化合物の有効性を、腫瘍形成の標準のマウスモデルにおいて評価した。ヒト腫瘍細胞(U87MG膠芽腫細胞、MKN45胃腺癌細胞、Caki-1腎癌細胞、HUH 7肝癌細胞、NCI-H441肺腺癌上皮細胞、MDA-MB-231乳腺癌細胞、SMMC-7721肝種細胞(すべてATCCより))を、培養に使用し、収集し、生後6〜7週の雌の胸腺欠損ヌードマウス(BALB/cA nu/nu、Shanghai SLAC Laboratory Animal社)の脾腹に皮下注射した(ビヒクル群についてはn=10、各投薬群についてはn=8)。腫瘍が100〜250mm3の体積に到達したら、動物をビヒクル対照(例えば、2% HPMC+1% Tween-80の水溶液)と化合物群とに無作為に分けた。その後、腫瘍細胞誘発の0日から15日後のいずれかの時点で、強制経口投与による化合物の投与(例えば、3〜50mpk/投与、2% HPMC+1% Tween-80の水溶液に溶解)を開始し、一般に、実験期間中、1日1回続けた。本明細書に記述する腫瘍異種移植動物モデルを使用する研究は、Shanghai Institute of Materia Medica,Chinese Academy of Sciences(555 Zu Chong Zhi Road、Zhang Jiang Hi-Tech Park、Pudong、Shanghai、201203、China)で実施した。
腫瘍成長の進行を、腫瘍体積によって評価し、時間の関数として記録する。皮下腫瘍の長軸(L)及び短軸(W)を、測径器(caliper)で1週間に2回測定し、腫瘍体積(TV)を(L×W2)/2)として算出した。TGIを、ビヒクル治療マウスと薬物治療マウスとの腫瘍体積中央値の差から算出し、以下の相関によって、ビヒクル治療対照群の中央値に対する割合として表した:
本明細書全体を通して、次の略語を使用する:
HOAc 酢酸
MeCN、CH3CN アセトニトリル
NH3 アンモニア
NH4Cl 塩化アンモニウム
HBTA ヘキサフルオロリン酸O-ベンゾトリアゾール-1-イル-N,N,N',N'-テトラメチルウロニウム
HATU ヘキサフルオロリン酸O-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウム
PyBop ヘキサフルオロリン酸ベンゾトリアゾール-1-イル-オキシ-トリピロリジノ-ホスホニウム
Pd2(dba)3 ビス(ジベンジリデンアセトン)パラジウム
BINAP 2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル
TEAC ビス(テトラ-エチルアンモニウム)カーボネート
BBr3 三臭化ホウ素
BSA ウシ血清アルブミン
BOC、Boc ブチルオキシカルボニル
Ca(SO3CF3)2 トリフルオロメチルスルホン酸カルシウム
Cs2CO3 炭酸セシウム
CHCl3 クロロホルム
CDCl3 重水素化クロロホルム
Cu 銅
CuI ヨウ化銅(I)
Et2O ジエチルエーテル
DBU 1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
DIBAL 水素化ジイソブチルアルミニウム
DIAD アゾジカルボン酸ジイソプロピル
DIEA又はDIPEA ジイソプロピルエチルアミン
DEAD アゾジカルボン酸ジメチル
DMF ジメチルホルムアミド
DMAP 4-ジメチルアミノピリジン
DMSO ジメチルスルホキシド
EDC、EDCI 塩酸1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド
dppa アジ化ジフェニルホスホリル
EtOAc、EA 酢酸エチル
FBS ウシ胎児血清
g グラム
h 時間
HBr 臭化水素酸
HCl 塩酸
HOBt 1-ヒドロキシベンゾトリアゾール水和物
H2 水素
H2O2 過酸化水素
Fe 鉄
LiHMDS リチウムビス(トリメチルシリル)-アミド
LDA リチウムジイソプロピルアミド
MCPBA メタ-クロロ過安息香酸
MgSO4 硫酸マグネシウム
MeOH、CH3OH メタノール
MeI ヨウ化メチル
2-MeTHF 2-メチルテトラヒドロフラン
CH2Cl2、DCM 塩化メチレン
NMP N-メチルピロリジノン
mL、ml ミリリットル
N2 窒素
Pd/C 炭素担持パラジウム
Pd(OAc)2 酢酸パラジウム
Pd(OH)2 水酸化パラジウム
Pd(PPh3)4 テトラキストリフェニルホスフィンパラジウム
Pd(dppf)Cl2 塩化1,1-ビス(ジフェニルホスフィノ)フェロセンパラジウム
PE 石油エーテル(60〜90℃)
PBS リン酸緩衝塩類溶液
POCl3 オキシ塩化リン
K2CO3 炭酸カリウム
KOH 水酸化カリウム
RT rt r.t. 室温
Rt 保持時間
NaHCO3 炭酸水素ナトリウム
NaBH4 水素化ホウ素ナトリウム
NaBHsCN シアノ水素化ホウ素ナトリウム
NaOtBu ナトリウムtert-ブトキシド
NaOH 水酸化ナトリウム
NaClO2 亜塩素酸ナトリウム
NaCl 塩化ナトリウム
NaH2PO4 リン酸ナトリウム(sodium biphosphate)
NaH 水素化ナトリウム
NaI ヨウ化ナトリウム
Na2SO4 硫酸ナトリウム
TBTU テトラフルオロホウ酸O-ベンゾトリアゾール-1-イル-N,N,N',N'-テトラメチルウロニウム
THF テトラヒドロフラン
Et3N、TEA トリエチルアミン
TFA トリフルオロ酢酸
P(t-bu)3 トリ(tert-ブチル)ホスフィン
H2O 水
N-(3-フルオロ-4-((7-(2-ヒドロキシエトキシ)キノリン-4-イル)オキシ)フェニル)-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミド
LC-MS (ESI, pos, ion) m/z: 529 [M+1], Rt = 3.062 min;
Claims (13)
- R1が、ヒドロキシC2〜6アルコキシであり; R3がH又はFであり; R2がH又はメトキシであり;R4が、H、F、Cl、Br、I、CN、C1〜3ハロアルキル、C2〜5ヘテロシクリル、C2〜5ヘテロシクリルC1〜3アルキル、C3〜6シクロアルキル、又はC3〜6シクロアルキルC1〜3アルキルである、請求項1記載の化合物。
- R1が、ヒドロキシC2〜6アルコキシであり;R2がH又はメトキシであり;R3がH又はFであり;R4がH又はFであり;かつXがCHである、請求項1記載の化合物。
- R1が、ヒドロキシC2〜6アルコキシであり;R2がHであり;R3がH又はFであり;R4がHであり;かつXがCHである、請求項1記載の化合物。
- 請求項1から5のいずれか1項記載の化合物と、医薬として許容し得る担体、賦形剤、希釈剤、アジュバント、ビヒクル、又はこれらの組み合わせとを含む医薬組成物。
- 化学療法薬、抗増殖薬、アテローム性動脈硬化症を治療するための薬剤、肺線維症を治療するための薬剤、及びこれらの組み合わせから選択される治療薬をさらに含む、請求項6記載の医薬組成物。
- 追加の治療薬が、アドリアマイシン、ラパマイシン、テムシロリムス、エベロリムス、イクサベピロン、ゲムシタビン、シクロホスファミド、デキサメタゾン、エトポシド、フルオロウラシル、アファチニブ、アリセルチブ、アムバチニブ、アキシチニブ、ボスチニブ、ブリバニブ、カボザンチニブ、セジラニブ、クレノラニブ、クリゾチニブ、ダブラフェニブ、ダコミチニブ、ダサチニブ、ダヌセルチブ、ドビチニブ、エルロチニブ、フォレチニブ、ガネテスピブ、ゲフィチニブ、イブルチニブ、イマチニブ、イニパリブ、ラパチニブ、レンバチニブ、リニファニブ、リンシチニブ、マシチニブ、モメロチニブ、モテサニブ、ネラチニブ、ニラパリブ、ニロチニブ、オプロゾミブ、オラパリブ、パゾパニブ、ピクチリシブ、ポナチニブ、キザルチニブ、レゴラフェニブ、リゴセルチブ、ルカパリブ、ルクソリチニブ、サラカチニブ、サリデジブ、ソラフェニブ、スニチニブ、タソシチニブ、テラチニブ、タイバンチニブ、チボザニブ、トファシチニブ、トラメチニブ、バンデタニブ、ベリパリブ、ベムラフェニブ、ビスモデジブ、ボラセルチブ、インターフェロン、カルボプラチン、トポテカン、タキソール、ビンブラスチン、ビンクリスチン、テモゾロミド、トシツモマブ、トラベデクチン、ベリムマブ、ベバシズマブ、ブレンツキシマブ、セツキシマブ、ゲムツズマブ、イピリムマブ、オファツムマブ、パニツムマブ、ラニビズマブ、リツキシマブ、トシツモマブ、トラスツズマブ、又はこれらの組み合わせである、請求項7記載の医薬組成物。
- 患者における増殖性障害を予防する、管理する、治療する、又は重症度を軽減するのに使用するための、請求項1から5のいずれか1項記載の化合物、又は請求項6から8のいずれか1項記載の医薬組成物。
- 前記増殖性障害が、転移性癌、大腸癌、胃腺癌、膀胱癌、乳癌、腎癌、肝癌、肺癌、甲状腺癌、頭頸部癌、前立腺癌、膵臓癌、中枢神経系の癌、膠芽腫、骨髄増殖性障害、アテローム性動脈硬化症、又は肺線維症である、請求項9記載の使用のための化合物又は医薬組成物。
- 生体試料中のプロテインキナーゼ活性を阻害又は調節する方法であって、請求項1から5のいずれか1項記載の化合物、又は請求項6から8のいずれか1項記載の医薬組成物と生体試料を接触させることを含む前記方法。
- 前記プロテインキナーゼが、受容体チロシンキナーゼである、請求項11記載の方法。
- 前記受容体チロシンキナーゼが、VEGFR、c-Met、及びAxlである、請求項12記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161447104P | 2011-02-28 | 2011-02-28 | |
US61/447,104 | 2011-02-28 | ||
PCT/US2012/025834 WO2012118632A1 (en) | 2011-02-28 | 2012-02-21 | Substituted quinoline compounds and methods of use |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2014506925A true JP2014506925A (ja) | 2014-03-20 |
JP5707518B2 JP5707518B2 (ja) | 2015-04-30 |
Family
ID=46719110
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013556713A Active JP5707518B2 (ja) | 2011-02-28 | 2012-02-21 | 置換型キノリン化合物及び使用方法 |
Country Status (15)
Country | Link |
---|---|
US (2) | US9133162B2 (ja) |
EP (1) | EP2680886B1 (ja) |
JP (1) | JP5707518B2 (ja) |
KR (1) | KR101546693B1 (ja) |
AU (1) | AU2012223639B2 (ja) |
BR (1) | BR112013014708B1 (ja) |
CA (1) | CA2820709C (ja) |
ES (1) | ES2590778T3 (ja) |
HK (1) | HK1187259A1 (ja) |
MX (1) | MX352844B (ja) |
MY (1) | MY181439A (ja) |
RU (1) | RU2568258C2 (ja) |
SG (1) | SG190735A1 (ja) |
WO (1) | WO2012118632A1 (ja) |
ZA (1) | ZA201303793B (ja) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017530142A (ja) * | 2014-10-01 | 2017-10-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 急性骨髄性白血病及び骨髄異形成症候群の併用療法iii |
JP2018513150A (ja) * | 2015-04-07 | 2018-05-24 | グアンドン・チョンシェン・ファーマスーティカル・カンパニー・リミテッド | チロシンキナーゼ阻害剤およびそれを含む医薬組成物 |
JP2018533608A (ja) * | 2015-11-14 | 2018-11-15 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | 置換キノリン化合物の結晶形およびその医薬組成物 |
JP2018538260A (ja) * | 2015-11-14 | 2018-12-27 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | 置換キノリン化合物の結晶形およびその医薬組成物 |
JP2019534323A (ja) * | 2016-10-09 | 2019-11-28 | ナンジン ナーティンフェイ ファーマテック カンパニー リミテッドNanjing Natinefy Pharmatech Co., Ltd. | ナフチリジン化合物、薬物組成物およびそれらの応用 |
JP2021504367A (ja) * | 2017-11-24 | 2021-02-15 | 南京明徳新薬研発有限公司Medshine Discovery Inc. | c−MET/AXL阻害剤としてのウラシル系化合物 |
JP2021525270A (ja) * | 2018-05-30 | 2021-09-24 | キュリエント カンパニー, リミテッド | Axl/mer rtkおよびcsf1rの阻害剤としてのキノリン誘導体 |
Families Citing this family (63)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2322175T3 (es) * | 2004-09-17 | 2009-06-17 | EISAI R&D MANAGEMENT CO., LTD. | Composicion medicinal con estabilidad mejorada y gelificacion reducida. |
JP4989476B2 (ja) | 2005-08-02 | 2012-08-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 血管新生阻害物質の効果を検定する方法 |
US20090053236A1 (en) | 2005-11-07 | 2009-02-26 | Eisai R & D Management Co., Ltd. | USE OF COMBINATION OF ANTI-ANGIOGENIC SUBSTANCE AND c-kit KINASE INHIBITOR |
WO2007136103A1 (ja) * | 2006-05-18 | 2007-11-29 | Eisai R & D Management Co., Ltd. | 甲状腺癌に対する抗腫瘍剤 |
KR101445892B1 (ko) * | 2007-01-29 | 2014-09-29 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 미분화형 위암 치료용 조성물 |
US8952035B2 (en) * | 2007-11-09 | 2015-02-10 | Eisai R&D Management Co., Ltd. | Combination of anti-angiogenic substance and anti-tumor platinum complex |
EP3311818A3 (en) | 2008-07-16 | 2018-07-18 | Pharmacyclics, LLC | Inhibitors of bruton's tyrosine kinase for the treatment of solid tumors |
MX2020004501A (es) | 2010-06-03 | 2021-11-09 | Pharmacyclics Llc | El uso de inhibidores de la tirosina quinasa de bruton (btk). |
BR112012032462A2 (pt) | 2010-06-25 | 2016-11-08 | Eisai R&D Man Co Ltd | agente antitumoral empregando compostos que, em combinação, têm efeito inibidor de quinase. |
CA2829131C (en) | 2011-03-04 | 2018-11-20 | Glaxosmithkline Intellectual Property (No.2) Limited | Amino-quinolines as kinase inhibitors |
US8962650B2 (en) * | 2011-04-18 | 2015-02-24 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
EP3444363B1 (en) | 2011-06-03 | 2020-11-25 | Eisai R&D Management Co., Ltd. | Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds |
CA2841080A1 (en) | 2011-07-13 | 2013-01-17 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
TWI547494B (zh) | 2011-08-18 | 2016-09-01 | 葛蘭素史克智慧財產發展有限公司 | 作為激酶抑制劑之胺基喹唑啉類 |
AU2012332424A1 (en) | 2011-11-02 | 2014-06-05 | Synta Pharmaceuticals Corp. | Combination therapy of Hsp90 inhibitors with platinum-containing agents |
WO2013074594A1 (en) * | 2011-11-14 | 2013-05-23 | Synta Pharmaceuticals Corp. | Combination therapy of hsp90 inhibitors with braf inhibitors |
CN102643268B (zh) * | 2011-12-30 | 2014-05-21 | 沈阳药科大学 | 喹啉类及噌啉类化合物及其应用 |
WO2013180949A1 (en) * | 2012-05-27 | 2013-12-05 | Ning Xi | Substituted quinoline compounds and methods of use |
KR20180088926A (ko) | 2012-07-24 | 2018-08-07 | 파마싸이클릭스 엘엘씨 | 브루톤 티로신 키나제(btk)의 억제제에 대한 내성과 관련된 돌연변이 |
US8969388B1 (en) | 2012-07-28 | 2015-03-03 | Sunshine Lake Pharma Co., Ltd. | Substituted pyrazolone compounds and methods of use |
US8975282B2 (en) | 2012-07-28 | 2015-03-10 | Sunshine Lake Pharma Co., Ltd. | Substituted pyrazolone compounds and methods of use |
TW201425307A (zh) | 2012-09-13 | 2014-07-01 | Glaxosmithkline Llc | 作為激酶抑制劑之胺基-喹啉類 |
TWI592417B (zh) | 2012-09-13 | 2017-07-21 | 葛蘭素史克智慧財產發展有限公司 | 胺基喹唑啉激酶抑制劑之前藥 |
JP6407504B2 (ja) | 2012-09-21 | 2018-10-17 | アログ・ファーマシューティカルズ・インコーポレイテッドArog Pharmaceuticals,Inc. | 恒常的に活性であるリン酸化型flt3キナーゼの阻害方法 |
CN103724349A (zh) * | 2012-10-11 | 2014-04-16 | 韩冰 | 一类治疗脑性瘫痪的化合物及其用途 |
WO2014066606A2 (en) * | 2012-10-25 | 2014-05-01 | Glaxosmithkline Llc | Combination |
IL266415B2 (en) * | 2012-11-30 | 2024-03-01 | Glaxosmithkline Llc | Innovative pharmaceutical composition |
MX2015004979A (es) | 2012-12-21 | 2015-07-17 | Eisai R&D Man Co Ltd | Forma amorfa de derivado de quinolina y metodo para su produccion. |
CA2902132C (en) | 2013-02-21 | 2020-09-22 | Glaxosmithkline Intellectual Property Development Limited | Quinazolines as kinase inhibitors |
UA122822C2 (uk) * | 2013-04-08 | 2021-01-06 | Байєр Фарма Акцієнгезелльшафт | ЗАСТОСУВАННЯ ЗАМІЩЕНИХ 2,3-ДИГІДРОІМІДАЗО[1,2-c]ХІНАЗОЛІНІВ ДЛЯ ЛІКУВАННЯ ЛІМФОМ |
ES2687968T3 (es) | 2013-05-14 | 2018-10-30 | Eisai R&D Management Co., Ltd. | Biomarcadores para pronosticar y evaluar la reactividad de sujetos con cáncer de endometrio a compuestos con lenvatinib |
JP6429292B2 (ja) | 2013-08-12 | 2018-11-28 | ファーマサイクリックス エルエルシー | Her2増幅性癌の処置のための方法 |
CN103788067A (zh) * | 2014-01-14 | 2014-05-14 | 北京万全德众医药生物技术有限公司 | 一种3-[3-乙氧基-4-(n-邻苯二甲先亚胺基)]苯氨基-n-[3-氯-4-(2-吡啶基甲氧基)]苯基-2-氰基-2-丙烯酰胺的制备方法 |
WO2015142867A1 (en) * | 2014-03-18 | 2015-09-24 | Stc.Unm | Synergistic enhancement of 5-fluorouracil cytotoxicity by deoxyuridine analogs in cancer cells |
US9885086B2 (en) | 2014-03-20 | 2018-02-06 | Pharmacyclics Llc | Phospholipase C gamma 2 and resistance associated mutations |
US9718841B2 (en) | 2014-04-22 | 2017-08-01 | Calitor Sciences, Llc | Bicyclic pyrazolone compounds and methods of use |
CN104119317B (zh) * | 2014-07-25 | 2016-08-17 | 沈阳药科大学 | 含1,2,3-三氮唑的喹啉类化合物及其制备方法和应用 |
BR112017002827B1 (pt) | 2014-08-28 | 2023-04-18 | Eisai R&D Management Co., Ltd | Derivado de quinolina altamente puro e método para produção do mesmo |
MX2017010474A (es) | 2015-02-25 | 2017-11-28 | Eisai R&D Man Co Ltd | Metodo para suprimir el amargor de un derivado de quinoleina. |
KR20240064733A (ko) | 2015-03-04 | 2024-05-13 | 머크 샤프 앤드 돔 코포레이션 | 암을 치료하기 위한 pd-1 길항제 및 vegfr/fgfr/ret 티로신 키나제 억제제의 조합 |
SG11201707638UA (en) | 2015-04-14 | 2017-10-30 | Qurient Co Ltd | Quinoline derivatives as tam rtk inhibitors |
WO2016183071A1 (en) | 2015-05-11 | 2016-11-17 | Incyte Corporation | Hetero-tricyclic compounds and their use for the treatment of cancer |
SG11201710198YA (en) | 2015-06-16 | 2018-01-30 | Eisai R&D Man Co Ltd | Anticancer agent |
WO2017027717A1 (en) | 2015-08-12 | 2017-02-16 | Incyte Corporation | Bicyclic fused pyrimidine compounds as tam inhibitors |
WO2017035366A1 (en) | 2015-08-26 | 2017-03-02 | Incyte Corporation | Pyrrolopyrimidine derivatives as tam inhibitors |
CN106632253B (zh) * | 2015-11-02 | 2019-03-22 | 广东东阳光药业有限公司 | 一种取代的喹啉化合物的晶型及其药物组合物和用途 |
CN106632254B (zh) * | 2015-11-02 | 2019-03-01 | 广东东阳光药业有限公司 | 一种取代的喹啉化合物的晶型及其药物组合物和用途 |
CN105330646B (zh) * | 2015-12-04 | 2019-05-24 | 上海勋和医药科技有限公司 | 一种抗肿瘤药马来酸来那替尼的制备方法 |
SG11201808582RA (en) | 2016-03-28 | 2018-10-30 | Incyte Corp | Pyrrolotriazine compounds as tam inhibitors |
KR101796684B1 (ko) | 2016-05-19 | 2017-11-10 | 건국대학교 산학협력단 | 케라틴 8 인산화 억제제를 포함하는 황반변성 예방 또는 치료용 약학 조성물 및 황반변성 치료제의 스크리닝 방법 |
WO2017218365A1 (en) * | 2016-06-16 | 2017-12-21 | Sunshine Lake Pharma Co., Ltd. | Crystalline form of a substituted quinoline compound and pharmaceutical compositions thereof |
CN107641099A (zh) * | 2016-07-20 | 2018-01-30 | 广东东阳光药业有限公司 | 取代的4‑羟基喹啉类化合物的制备方法 |
US9957233B1 (en) | 2016-08-05 | 2018-05-01 | Calitor Sciences, Llc | Process for preparing substituted quinolin-4-ol compounds |
WO2018049329A1 (en) * | 2016-09-12 | 2018-03-15 | Zhuhai Beihai Biotech Co., Ltd. | Formulations of cabozantinib |
RU2644155C1 (ru) * | 2016-12-12 | 2018-02-08 | Закрытое акционерное общество "Р-Фарм" (ЗАО "Р-Фарм") | 2-(3-(4-(7H-пирроло[2,3-d]пиримидин-4-ил)-1H-пиразол-1-ил)-1-(этилсульфонил)азетидин-3-ил)ацетонитрила геминафтилдисульфонат в качестве ингибитора Янус киназ |
AU2018209164B2 (en) | 2017-01-17 | 2021-11-04 | Heparegenix Gmbh | Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death |
JP7108018B2 (ja) * | 2017-04-17 | 2022-07-27 | イエール ユニバーシティ | 急性肺傷害を処置または予防する化合物、組成物および方法 |
PT3687996T (pt) | 2017-09-27 | 2022-01-21 | Incyte Corp | Sais de derivados de pirrolotriazina úteis como inibidores de tam |
CA3101983A1 (en) * | 2018-06-01 | 2019-12-05 | Rigel Pharmaceuticals, Inc. | Quinoline derivatives useful as tyrosine kinase inhibitors |
US11241438B2 (en) | 2018-06-29 | 2022-02-08 | Incyte Corporation | Formulations of an AXL/MER inhibitor |
CN110845406B (zh) * | 2019-12-04 | 2021-07-20 | 广州安岩仁医药科技有限公司 | 喹啉类化合物的制备方法 |
CN111440177B (zh) * | 2020-05-25 | 2022-06-14 | 辽宁大学 | 一种取代吡唑并[1,5-a]嘧啶类化合物及其制备方法和应用 |
CN113912628B (zh) * | 2020-07-10 | 2023-05-02 | 北京范恩柯尔生物科技有限公司 | 三嗪类化合物及其组合物和用途 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008539275A (ja) * | 2005-04-27 | 2008-11-13 | アムジエン・インコーポレーテツド | タンパク質キナーゼ阻害薬としての置換アミド誘導体 |
WO2009140549A1 (en) * | 2008-05-14 | 2009-11-19 | Amgen Inc. | Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer |
WO2010039248A1 (en) * | 2008-10-01 | 2010-04-08 | Ludwig Institute For Cancer Research | Methods for the treatment of cancer |
US20100093727A1 (en) * | 2008-10-14 | 2010-04-15 | Ning Xi | Compounds and methods of use |
US20100239576A1 (en) * | 2009-03-21 | 2010-09-23 | Ning Xi | Amino ester derivatives, sailts thereof and methods of use |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5886026A (en) | 1993-07-19 | 1999-03-23 | Angiotech Pharmaceuticals Inc. | Anti-angiogenic compositions and methods of use |
JPH09506253A (ja) | 1993-11-30 | 1997-06-24 | マクギル・ユニヴァーシティ | Dnaメチルトランスフェラーゼの阻害 |
US5578716A (en) | 1993-12-01 | 1996-11-26 | Mcgill University | DNA methyltransferase antisense oligonucleotides |
US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
US6268137B1 (en) | 1996-05-22 | 2001-07-31 | Methylgene, Inc. | Specific inhibitors of DNA methyl transferase |
US6020318A (en) | 1997-05-30 | 2000-02-01 | Methylgene, Inc. | DNA methyltransferase genomic sequences and antisense oligonucleotides |
AU8125098A (en) | 1997-05-30 | 1998-12-30 | Mcgill University | Dna methyltransferase genomic sequences and antisense oligonucleotides |
US6066625A (en) | 1998-02-03 | 2000-05-23 | Methylgene, Inc. | Optimized antisense oligonucleotides complementary to DNA methyltransferase sequences |
US6953783B1 (en) | 1998-10-19 | 2005-10-11 | Methylgene, Inc. | Modulation of gene expression by combination therapy |
CA2366408A1 (en) | 1999-05-03 | 2000-11-30 | Methylgene, Inc. | Inhibition of histone deacetylase |
EP1233958B1 (en) | 1999-11-23 | 2011-06-29 | MethylGene Inc. | Inhibitors of histone deacetylase |
EP1280764B1 (en) | 2000-03-24 | 2010-11-24 | Methylgene, Inc. | Inhibitors of histone deacetylase |
EP1438404A2 (en) | 2000-03-24 | 2004-07-21 | Methylgene, Inc. | Inhibition of specific histone deacetylase isoforms |
US7868204B2 (en) | 2001-09-14 | 2011-01-11 | Methylgene Inc. | Inhibitors of histone deacetylase |
BR0212510A (pt) | 2001-09-14 | 2004-08-24 | Methylgene Inc | Inibidor de histona desacetilase, composto e composição |
US6897220B2 (en) | 2001-09-14 | 2005-05-24 | Methylgene, Inc. | Inhibitors of histone deacetylase |
CN100448844C (zh) | 2002-10-17 | 2009-01-07 | 梅特希尔基因公司 | 组蛋白脱乙酰酶抑制剂 |
WO2005030704A1 (en) | 2003-09-24 | 2005-04-07 | Methylgene, Inc. | Inhibitors of histone deacetylase |
WO2005092899A1 (en) | 2004-03-26 | 2005-10-06 | Methylgene Inc. | Inhibitors of histone deacetylase |
MX2007001216A (es) | 2004-07-30 | 2007-03-23 | Methylgene Inc | Inhibidores de la senalizacion del receptor del factor de crecimiento endotelial vascular y del receptor del factor de crecimiento del hepatocito. |
KR101378716B1 (ko) | 2005-05-20 | 2014-04-10 | 메틸진 인코포레이티드 | Vegf 수용체 및 hgf 수용체 신호전달의 억제제 |
WO2007033196A1 (en) | 2005-09-14 | 2007-03-22 | Bristol-Myers Squibb Company | Met kinase inhibitors |
US7880004B2 (en) | 2005-09-15 | 2011-02-01 | Bristol-Myers Squibb Company | Met kinase inhibitors |
RU2008139599A (ru) | 2006-03-07 | 2010-04-20 | Эррэй Биофарма Инк. (Us) | Гетеробициклические производные пиразола и способы их применения |
JP2009537632A (ja) | 2006-05-19 | 2009-10-29 | バイエル・ヘルスケア・アクチェンゲゼルシャフト | 過剰増殖性障害および血管新生障害の処置に有用なピリドンカルボキサミド誘導体 |
WO2008035209A2 (en) | 2006-05-30 | 2008-03-27 | Methylgene Inc. | Inhibitors of protein tyrosine kinase activity |
CA2655128A1 (en) | 2006-06-08 | 2007-12-21 | Array Biopharma Inc. | Quinoline compounds and methods of use |
ES2449482T3 (es) | 2007-01-09 | 2014-03-19 | Amgen Inc. | Derivados de bis-aril-amida útiles para el tratamiento de cáncer |
EP2170395A1 (en) | 2007-07-02 | 2010-04-07 | Wyeth LLC | Modulators of axl for use in treating bone disorders |
JPWO2009096435A1 (ja) | 2008-01-29 | 2011-05-26 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
WO2009108670A1 (en) | 2008-02-28 | 2009-09-03 | Merck Serono S.A. | Protein kinase inhibitors and use thereof |
US8445509B2 (en) | 2008-05-08 | 2013-05-21 | Takeda Pharmaceutical Company Limited | Fused heterocyclic derivatives and use thereof |
TWI365185B (en) | 2008-07-24 | 2012-06-01 | Lilly Co Eli | Amidophenoxyindazoles useful as inhibitors of c-met |
KR100961410B1 (ko) | 2008-10-14 | 2010-06-09 | (주)네오팜 | 단백질 키나제 억제제로서 헤테로사이클릭 화합물 |
ES2433230T3 (es) | 2009-08-06 | 2013-12-10 | Merck Patent Gmbh | Compuestos bicíclicos novedosos de urea |
CN102086211B (zh) | 2009-12-08 | 2013-09-11 | 广东东阳光药业有限公司 | 作为蛋白激酶抑制剂的芳杂环化合物 |
CN102212062B (zh) | 2010-04-02 | 2015-04-29 | 广东东阳光药业有限公司 | 氨基酯类衍生物及其盐和使用方法 |
KR101538707B1 (ko) | 2010-07-14 | 2015-07-22 | 베타 파머수티컬 컴퍼니 리미티드 | c-MET 티로신 키나제 억제제로서 유용한 신규 융합된 헤테로사이클릭 유도체 |
WO2012008564A1 (ja) | 2010-07-16 | 2012-01-19 | 協和発酵キリン株式会社 | 含窒素芳香族複素環誘導体 |
AU2011295441B2 (en) | 2010-08-27 | 2015-04-09 | Merck Patent Gmbh | Furopyridine derivatives |
EP2423208A1 (en) | 2010-08-28 | 2012-02-29 | Lead Discovery Center GmbH | Pharmaceutically active compounds as Axl inhibitors |
WO2012044577A1 (en) | 2010-09-27 | 2012-04-05 | Exelixis, Inc. | Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases |
CN103420986A (zh) | 2012-05-18 | 2013-12-04 | 广东东阳光药业有限公司 | 取代的喹啉化合物及其使用方法和用途 |
WO2013180949A1 (en) | 2012-05-27 | 2013-12-05 | Ning Xi | Substituted quinoline compounds and methods of use |
-
2012
- 2012-02-21 EP EP12752321.5A patent/EP2680886B1/en active Active
- 2012-02-21 JP JP2013556713A patent/JP5707518B2/ja active Active
- 2012-02-21 BR BR112013014708-3A patent/BR112013014708B1/pt not_active IP Right Cessation
- 2012-02-21 SG SG2013041892A patent/SG190735A1/en unknown
- 2012-02-21 CA CA2820709A patent/CA2820709C/en active Active
- 2012-02-21 AU AU2012223639A patent/AU2012223639B2/en active Active
- 2012-02-21 MX MX2013007278A patent/MX352844B/es active IP Right Grant
- 2012-02-21 KR KR1020137015842A patent/KR101546693B1/ko active IP Right Grant
- 2012-02-21 WO PCT/US2012/025834 patent/WO2012118632A1/en active Application Filing
- 2012-02-21 US US13/400,586 patent/US9133162B2/en active Active
- 2012-02-21 ES ES12752321.5T patent/ES2590778T3/es active Active
- 2012-02-21 RU RU2013135662/04A patent/RU2568258C2/ru active
- 2012-02-21 MY MYPI2013002065A patent/MY181439A/en unknown
-
2013
- 2013-05-24 ZA ZA2013/03793A patent/ZA201303793B/en unknown
-
2014
- 2014-01-09 HK HK14100267.0A patent/HK1187259A1/zh unknown
-
2015
- 2015-08-12 US US14/824,096 patent/US9598400B2/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008539275A (ja) * | 2005-04-27 | 2008-11-13 | アムジエン・インコーポレーテツド | タンパク質キナーゼ阻害薬としての置換アミド誘導体 |
WO2009140549A1 (en) * | 2008-05-14 | 2009-11-19 | Amgen Inc. | Combinations vegf(r) inhibitors and hepatocyte growth factor (c-met) inhibitors for the treatment of cancer |
WO2010039248A1 (en) * | 2008-10-01 | 2010-04-08 | Ludwig Institute For Cancer Research | Methods for the treatment of cancer |
US20100093727A1 (en) * | 2008-10-14 | 2010-04-15 | Ning Xi | Compounds and methods of use |
US20100239576A1 (en) * | 2009-03-21 | 2010-09-23 | Ning Xi | Amino ester derivatives, sailts thereof and methods of use |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017530142A (ja) * | 2014-10-01 | 2017-10-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 急性骨髄性白血病及び骨髄異形成症候群の併用療法iii |
JP2018513150A (ja) * | 2015-04-07 | 2018-05-24 | グアンドン・チョンシェン・ファーマスーティカル・カンパニー・リミテッド | チロシンキナーゼ阻害剤およびそれを含む医薬組成物 |
JP2018533608A (ja) * | 2015-11-14 | 2018-11-15 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | 置換キノリン化合物の結晶形およびその医薬組成物 |
JP2018538260A (ja) * | 2015-11-14 | 2018-12-27 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | 置換キノリン化合物の結晶形およびその医薬組成物 |
JP2019534323A (ja) * | 2016-10-09 | 2019-11-28 | ナンジン ナーティンフェイ ファーマテック カンパニー リミテッドNanjing Natinefy Pharmatech Co., Ltd. | ナフチリジン化合物、薬物組成物およびそれらの応用 |
JP2021054871A (ja) * | 2016-10-09 | 2021-04-08 | シージャーヂュアン ナンバー4 ファーマシューティカル カンパニー リミテッドShijiazhuang No.4 Pharmaceutical Co., Ltd. | ナフチリジン化合物、薬物組成物およびそれらの応用 |
JP7085032B2 (ja) | 2016-10-09 | 2022-06-15 | シージャーヂュアン ナンバー4 ファーマシューティカル カンパニー リミテッド | ナフチリジン化合物、薬物組成物およびそれらの応用 |
JP2021504367A (ja) * | 2017-11-24 | 2021-02-15 | 南京明徳新薬研発有限公司Medshine Discovery Inc. | c−MET/AXL阻害剤としてのウラシル系化合物 |
JP7377798B2 (ja) | 2017-11-24 | 2023-11-10 | 南京明徳新薬研発有限公司 | c-MET/AXL阻害剤としてのウラシル系化合物 |
JP2021525270A (ja) * | 2018-05-30 | 2021-09-24 | キュリエント カンパニー, リミテッド | Axl/mer rtkおよびcsf1rの阻害剤としてのキノリン誘導体 |
JP7390313B2 (ja) | 2018-05-30 | 2023-12-01 | キュリエント カンパニー, リミテッド | Axl/mer rtkおよびcsf1rの阻害剤としてのキノリン誘導体 |
Also Published As
Publication number | Publication date |
---|---|
RU2568258C2 (ru) | 2015-11-20 |
RU2013135662A (ru) | 2015-04-10 |
CA2820709A1 (en) | 2012-09-07 |
KR101546693B1 (ko) | 2015-08-24 |
EP2680886A4 (en) | 2014-08-27 |
US20120219522A1 (en) | 2012-08-30 |
MX352844B (es) | 2017-12-11 |
JP5707518B2 (ja) | 2015-04-30 |
CA2820709C (en) | 2016-02-16 |
SG190735A1 (en) | 2013-07-31 |
MY181439A (en) | 2020-12-22 |
HK1187259A1 (zh) | 2014-04-04 |
WO2012118632A1 (en) | 2012-09-07 |
AU2012223639B2 (en) | 2015-03-19 |
BR112013014708A2 (pt) | 2016-10-04 |
ZA201303793B (en) | 2014-07-30 |
US20150342945A1 (en) | 2015-12-03 |
BR112013014708B1 (pt) | 2021-10-19 |
US9133162B2 (en) | 2015-09-15 |
US9598400B2 (en) | 2017-03-21 |
ES2590778T3 (es) | 2016-11-23 |
EP2680886B1 (en) | 2016-08-10 |
KR20130095806A (ko) | 2013-08-28 |
MX2013007278A (es) | 2013-09-13 |
EP2680886A1 (en) | 2014-01-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5707518B2 (ja) | 置換型キノリン化合物及び使用方法 | |
JP6342393B2 (ja) | 置換型ピラゾロン化合物及び使用方法 | |
EP2532657B1 (en) | Compounds and methods of use | |
JP5583751B2 (ja) | アミノエステル誘導体、その塩、及び使用方法 | |
AU2012223639A1 (en) | Substituted quinoline compounds and methods of use | |
US9326975B2 (en) | Substituted pyrazolone compounds and methods of use | |
WO2013180949A1 (en) | Substituted quinoline compounds and methods of use | |
WO2014022128A1 (en) | Pi3 kinase modulators and methods of use | |
WO2013177092A1 (en) | Substituted alkynyl pyridine compounds and methods of use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130927 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20130927 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140930 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141225 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20141225 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150210 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150302 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5707518 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313117 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
S533 | Written request for registration of change of name |
Free format text: JAPANESE INTERMEDIATE CODE: R313533 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |