CN112584875A - 稳定的、浓缩的放射性核素络合物溶液 - Google Patents
稳定的、浓缩的放射性核素络合物溶液 Download PDFInfo
- Publication number
- CN112584875A CN112584875A CN201880095724.5A CN201880095724A CN112584875A CN 112584875 A CN112584875 A CN 112584875A CN 201880095724 A CN201880095724 A CN 201880095724A CN 112584875 A CN112584875 A CN 112584875A
- Authority
- CN
- China
- Prior art keywords
- solution
- stabilizer
- aqueous pharmaceutical
- concentration
- 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.)
- Pending
Links
- 239000003381 stabilizer Substances 0.000 claims abstract description 153
- 238000006731 degradation reaction Methods 0.000 claims abstract description 28
- 230000015556 catabolic process Effects 0.000 claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims description 114
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 96
- 239000003186 pharmaceutical solution Substances 0.000 claims description 93
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 86
- 238000000034 method Methods 0.000 claims description 60
- 229960005219 gentisic acid Drugs 0.000 claims description 46
- 239000002738 chelating agent Substances 0.000 claims description 44
- 229960005070 ascorbic acid Drugs 0.000 claims description 41
- 235000010323 ascorbic acid Nutrition 0.000 claims description 39
- 239000011668 ascorbic acid Substances 0.000 claims description 39
- 230000009918 complex formation Effects 0.000 claims description 39
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 37
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 33
- 229960003330 pentetic acid Drugs 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- WDLRUFUQRNWCPK-UHFFFAOYSA-N Tetraxetan Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1 WDLRUFUQRNWCPK-UHFFFAOYSA-N 0.000 claims description 24
- 108050001286 Somatostatin Receptor Proteins 0.000 claims description 23
- 102000011096 Somatostatin receptor Human genes 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 23
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 23
- 239000008351 acetate buffer Substances 0.000 claims description 18
- 229940010982 dotatate Drugs 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- OHSVLFRHMCKCQY-NJFSPNSNSA-N lutetium-177 Chemical compound [177Lu] OHSVLFRHMCKCQY-NJFSPNSNSA-N 0.000 claims description 16
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 12
- 239000001632 sodium acetate Substances 0.000 claims description 12
- 235000017281 sodium acetate Nutrition 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 7
- 239000000872 buffer Substances 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 5
- 230000002285 radioactive effect Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000012777 commercial manufacturing Methods 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 24
- 229940127557 pharmaceutical product Drugs 0.000 abstract description 18
- 239000000126 substance Substances 0.000 abstract description 10
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- -1 (2, 4-dichloro-5-methoxyphenyl) amino Chemical group 0.000 description 48
- 239000003814 drug Substances 0.000 description 30
- 102000005962 receptors Human genes 0.000 description 30
- 108020003175 receptors Proteins 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 28
- 239000003112 inhibitor Substances 0.000 description 20
- 206010052399 Neuroendocrine tumour Diseases 0.000 description 19
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 15
- 108010016076 Octreotide Proteins 0.000 description 15
- 238000005755 formation reaction Methods 0.000 description 15
- 229940079593 drug Drugs 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 229960002700 octreotide Drugs 0.000 description 13
- 239000012217 radiopharmaceutical Substances 0.000 description 12
- 229940124597 therapeutic agent Drugs 0.000 description 12
- QVFLVLMYXXNJDT-CSBVGUNJSA-N (2s,3r)-2-[[(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-19-[[(2r)-3-phenyl-2-[[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]pro Chemical compound C([C@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC1=O)C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1)C1=CC=CC=C1 QVFLVLMYXXNJDT-CSBVGUNJSA-N 0.000 description 11
- 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 description 11
- 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 10
- 206010028980 Neoplasm Diseases 0.000 description 10
- 229940121896 radiopharmaceutical Drugs 0.000 description 10
- 230000002799 radiopharmaceutical effect Effects 0.000 description 10
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 9
- QFCXANHHBCGMAS-UHFFFAOYSA-N 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxymethyl]-n-methylpyridine-2-carboxamide Chemical compound C1=NC(C(=O)NC)=CC(COC=2C=3OC=CC=3C(NC=3C=CC(Cl)=CC=3)=NN=2)=C1 QFCXANHHBCGMAS-UHFFFAOYSA-N 0.000 description 9
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- XKFTZKGMDDZMJI-HSZRJFAPSA-N N-[5-[(2R)-2-methoxy-1-oxo-2-phenylethyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-1-piperazinyl)benzamide Chemical compound O=C([C@H](OC)C=1C=CC=CC=1)N(CC=12)CC=1NN=C2NC(=O)C(C=C1)=CC=C1N1CCN(C)CC1 XKFTZKGMDDZMJI-HSZRJFAPSA-N 0.000 description 8
- 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 8
- 238000010668 complexation reaction Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 238000002347 injection Methods 0.000 description 8
- 229960004378 nintedanib Drugs 0.000 description 8
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 8
- 230000002685 pulmonary effect Effects 0.000 description 8
- CVWXJKQAOSCOAB-UHFFFAOYSA-N quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 description 8
- 229960001796 sunitinib Drugs 0.000 description 8
- 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 description 8
- 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 8
- RZHKDBRREKOZEW-AAXZNHDCSA-N 2-[4-[2-[[(2r)-1-[[(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-4-[[(2r,3r)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl] Chemical compound C([C@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)NC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC1)C1=CC=CC=C1 RZHKDBRREKOZEW-AAXZNHDCSA-N 0.000 description 7
- 108700038672 Edotreotide Proteins 0.000 description 7
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 7
- 208000002458 carcinoid tumor Diseases 0.000 description 7
- 238000002648 combination therapy Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229960002411 imatinib Drugs 0.000 description 7
- 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 description 7
- ONDPWWDPQDCQNJ-UHFFFAOYSA-N n-(3,3-dimethyl-1,2-dihydroindol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide;phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(O)=O.C=1C=C2C(C)(C)CNC2=CC=1NC(=O)C1=CC=CN=C1NCC1=CC=NC=C1 ONDPWWDPQDCQNJ-UHFFFAOYSA-N 0.000 description 7
- 238000003608 radiolysis reaction Methods 0.000 description 7
- 229960004836 regorafenib Drugs 0.000 description 7
- HHFBDROWDBDFBR-UHFFFAOYSA-N 4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC1=NC=C(CN=C(C=2C3=CC=C(Cl)C=2)C=2C(=CC=CC=2F)F)C3=N1 HHFBDROWDBDFBR-UHFFFAOYSA-N 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
- 102000000588 Interleukin-2 Human genes 0.000 description 6
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 6
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 6
- 206010041067 Small cell lung cancer Diseases 0.000 description 6
- 229960000473 altretamine Drugs 0.000 description 6
- 229960001292 cabozantinib Drugs 0.000 description 6
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Substances OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940126534 drug product Drugs 0.000 description 6
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 6
- AZUQEHCMDUSRLH-UHFFFAOYSA-N n-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine;dihydrochloride Chemical compound Cl.Cl.C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 AZUQEHCMDUSRLH-UHFFFAOYSA-N 0.000 description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 229960003862 vemurafenib Drugs 0.000 description 6
- 206010007275 Carcinoid tumour Diseases 0.000 description 5
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 5
- 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 description 5
- 102000003815 Interleukin-11 Human genes 0.000 description 5
- 108090000177 Interleukin-11 Proteins 0.000 description 5
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 5
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 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 5
- 239000003978 infusion fluid Substances 0.000 description 5
- 229940074383 interleukin-11 Drugs 0.000 description 5
- 108010021336 lanreotide Proteins 0.000 description 5
- 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 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 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 description 5
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- 239000003352 sequestering agent Substances 0.000 description 5
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 4
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 4
- QULDDKSCVCJTPV-UHFFFAOYSA-N BIIB021 Chemical compound COC1=C(C)C=NC(CN2C3=NC(N)=NC(Cl)=C3N=C2)=C1C QULDDKSCVCJTPV-UHFFFAOYSA-N 0.000 description 4
- 108010092160 Dactinomycin Proteins 0.000 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 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 4
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 4
- 229910052765 Lutetium Inorganic materials 0.000 description 4
- GCIKSSRWRFVXBI-UHFFFAOYSA-N N-[4-[[4-(4-methyl-1-piperazinyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyrimidinyl]thio]phenyl]cyclopropanecarboxamide Chemical compound C1CN(C)CCN1C1=CC(NC2=NNC(C)=C2)=NC(SC=2C=CC(NC(=O)C3CC3)=CC=2)=N1 GCIKSSRWRFVXBI-UHFFFAOYSA-N 0.000 description 4
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229960005061 crizotinib Drugs 0.000 description 4
- 229960000640 dactinomycin Drugs 0.000 description 4
- 229950002966 danusertib Drugs 0.000 description 4
- 229960002448 dasatinib Drugs 0.000 description 4
- 229960005167 everolimus Drugs 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229960002437 lanreotide Drugs 0.000 description 4
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- CPMDPSXJELVGJG-UHFFFAOYSA-N methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate Chemical compound OC=1NC2=CC(=CC=C2C=1C(=NC1=CC=C(C=C1)N(C(CN1CCN(CC1)C)=O)C)C1=CC=CC=C1)C(=O)OC CPMDPSXJELVGJG-UHFFFAOYSA-N 0.000 description 4
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 description 4
- 229950010203 nimotuzumab Drugs 0.000 description 4
- 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 description 4
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 4
- 108010091666 romidepsin Proteins 0.000 description 4
- SUVMJBTUFCVSAD-UHFFFAOYSA-N sulforaphane Chemical compound CS(=O)CCCCN=C=S SUVMJBTUFCVSAD-UHFFFAOYSA-N 0.000 description 4
- 208000011580 syndromic disease Diseases 0.000 description 4
- HVXKQKFEHMGHSL-QKDCVEJESA-N tesevatinib Chemical compound N1=CN=C2C=C(OC[C@@H]3C[C@@H]4CN(C)C[C@@H]4C3)C(OC)=CC2=C1NC1=CC=C(Cl)C(Cl)=C1F HVXKQKFEHMGHSL-QKDCVEJESA-N 0.000 description 4
- 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 4
- 108700029852 vapreotide Proteins 0.000 description 4
- 229960002730 vapreotide Drugs 0.000 description 4
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 4
- 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 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 description 3
- OOVTUOCTLAERQD-OJMBIDBESA-N 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one;hydrochloride Chemical compound Cl.OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O OOVTUOCTLAERQD-OJMBIDBESA-N 0.000 description 3
- ABBADGFSRBWENF-UHFFFAOYSA-N 2-[(3-bromo-5-tert-butyl-4-hydroxyphenyl)methylidene]propanedinitrile Chemical compound CC(C)(C)C1=CC(C=C(C#N)C#N)=CC(Br)=C1O ABBADGFSRBWENF-UHFFFAOYSA-N 0.000 description 3
- HHLZCENAOIROSL-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound OC(=O)CN1CCNCCN(CC(O)=O)CCN(CC(O)=O)CC1 HHLZCENAOIROSL-UHFFFAOYSA-N 0.000 description 3
- JHALWMSZGCVVEM-UHFFFAOYSA-N 2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid Chemical compound OC(=O)CN1CCN(CC(O)=O)CCN(CC(O)=O)CC1 JHALWMSZGCVVEM-UHFFFAOYSA-N 0.000 description 3
- IAYGCINLNONXHY-LBPRGKRZSA-N 3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-3-piperidinyl]-2-thiophenecarboxamide Chemical compound NC(=O)NC=1C=C(C=2C=C(F)C=CC=2)SC=1C(=O)N[C@H]1CCCNC1 IAYGCINLNONXHY-LBPRGKRZSA-N 0.000 description 3
- RCLQNICOARASSR-SECBINFHSA-N 3-[(2r)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione Chemical compound FC=1C(=O)N(C)C=2N=CN(C[C@@H](O)CO)C(=O)C=2C=1NC1=CC=C(I)C=C1F RCLQNICOARASSR-SECBINFHSA-N 0.000 description 3
- WJRRGYBTGDJBFX-UHFFFAOYSA-N 4-(2-methyl-3-propan-2-yl-4-imidazolyl)-N-(4-methylsulfonylphenyl)-2-pyrimidinamine Chemical compound CC(C)N1C(C)=NC=C1C1=CC=NC(NC=2C=CC(=CC=2)S(C)(=O)=O)=N1 WJRRGYBTGDJBFX-UHFFFAOYSA-N 0.000 description 3
- MOVBBVMDHIRCTG-LJQANCHMSA-N 4-[(3s)-1-azabicyclo[2.2.2]oct-3-ylamino]-3-(1h-benzimidazol-2-yl)-6-chloroquinolin-2(1h)-one Chemical compound C([N@](CC1)C2)C[C@@H]1[C@@H]2NC1=C(C=2NC3=CC=CC=C3N=2)C(=O)NC2=CC=C(Cl)C=C21 MOVBBVMDHIRCTG-LJQANCHMSA-N 0.000 description 3
- ZLHFILGSQDJULK-UHFFFAOYSA-N 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC(NC=2N=C3C4=CC=C(Cl)C=C4C(=NCC3=CN=2)C=2C(=CC=CC=2F)OC)=C1 ZLHFILGSQDJULK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- BYWWNRBKPCPJMG-UHFFFAOYSA-N 4-dodecyl-n-(1,3,4-thiadiazol-2-yl)benzenesulfonamide Chemical compound C1=CC(CCCCCCCCCCCC)=CC=C1S(=O)(=O)NC1=NN=CS1 BYWWNRBKPCPJMG-UHFFFAOYSA-N 0.000 description 3
- GPSZYOIFQZPWEJ-UHFFFAOYSA-N 4-methyl-5-[2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]-1,3-thiazol-2-amine Chemical compound N1=C(N)SC(C=2N=C(NC=3C=CC(=CC=3)N3CCOCC3)N=CC=2)=C1C GPSZYOIFQZPWEJ-UHFFFAOYSA-N 0.000 description 3
- GMIZZEXBPRLVIV-SECBINFHSA-N 6-bromo-3-(1-methylpyrazol-4-yl)-5-[(3r)-piperidin-3-yl]pyrazolo[1,5-a]pyrimidin-7-amine Chemical compound C1=NN(C)C=C1C1=C2N=C([C@H]3CNCCC3)C(Br)=C(N)N2N=C1 GMIZZEXBPRLVIV-SECBINFHSA-N 0.000 description 3
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=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 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 3
- QADPYRIHXKWUSV-UHFFFAOYSA-N BGJ-398 Chemical compound C1CN(CC)CCN1C(C=C1)=CC=C1NC1=CC(N(C)C(=O)NC=2C(=C(OC)C=C(OC)C=2Cl)Cl)=NC=N1 QADPYRIHXKWUSV-UHFFFAOYSA-N 0.000 description 3
- LQVXSNNAFNGRAH-QHCPKHFHSA-N BMS-754807 Chemical compound C([C@@]1(C)C(=O)NC=2C=NC(F)=CC=2)CCN1C(=NN1C=CC=C11)N=C1NC(=NN1)C=C1C1CC1 LQVXSNNAFNGRAH-QHCPKHFHSA-N 0.000 description 3
- 229940045513 CTLA4 antagonist Drugs 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
- 102000003951 Erythropoietin Human genes 0.000 description 3
- 108090000394 Erythropoietin Proteins 0.000 description 3
- 108010029961 Filgrastim Proteins 0.000 description 3
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 3
- 102000006992 Interferon-alpha Human genes 0.000 description 3
- 108010047761 Interferon-alpha Proteins 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 3
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- OUSFTKFNBAZUKL-UHFFFAOYSA-N N-(5-{[(5-tert-butyl-1,3-oxazol-2-yl)methyl]sulfanyl}-1,3-thiazol-2-yl)piperidine-4-carboxamide Chemical compound O1C(C(C)(C)C)=CN=C1CSC(S1)=CN=C1NC(=O)C1CCNCC1 OUSFTKFNBAZUKL-UHFFFAOYSA-N 0.000 description 3
- VIUAUNHCRHHYNE-JTQLQIEISA-N N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide Chemical compound OC[C@@H](O)CNC(=O)C1=CC=NC=C1NC1=CC=C(I)C=C1F VIUAUNHCRHHYNE-JTQLQIEISA-N 0.000 description 3
- DMMILYKXNCVKOJ-UHFFFAOYSA-N N-[3-[[5-bromo-4-[2-(1H-imidazol-5-yl)ethylamino]-2-pyrimidinyl]amino]phenyl]-1-pyrrolidinecarboxamide Chemical compound N1=C(NCCC=2N=CNC=2)C(Br)=CN=C1NC(C=1)=CC=CC=1NC(=O)N1CCCC1 DMMILYKXNCVKOJ-UHFFFAOYSA-N 0.000 description 3
- DXCUKNQANPLTEJ-UHFFFAOYSA-N PD173074 Chemical compound CC(C)(C)NC(=O)NC1=NC2=NC(NCCCCN(CC)CC)=NC=C2C=C1C1=CC(OC)=CC(OC)=C1 DXCUKNQANPLTEJ-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 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
- AVDSOVJPJZVBTC-UHFFFAOYSA-N [4-[2-carbamoyl-5-[6,6-dimethyl-4-oxo-3-(trifluoromethyl)-5,7-dihydroindazol-1-yl]anilino]cyclohexyl] 2-aminoacetate Chemical compound O=C1CC(C)(C)CC2=C1C(C(F)(F)F)=NN2C(C=1)=CC=C(C(N)=O)C=1NC1CCC(OC(=O)CN)CC1 AVDSOVJPJZVBTC-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000611 antibody drug conjugate Substances 0.000 description 3
- 229940049595 antibody-drug conjugate Drugs 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229960003982 apatinib Drugs 0.000 description 3
- 229960003005 axitinib Drugs 0.000 description 3
- 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 description 3
- ZWVZORIKUNOTCS-OAQYLSRUSA-N chembl401930 Chemical compound C1([C@H](O)CNC2=C(C(NC=C2)=O)C=2NC=3C=C(C=C(C=3N=2)C)N2CCOCC2)=CC=CC(Cl)=C1 ZWVZORIKUNOTCS-OAQYLSRUSA-N 0.000 description 3
- 229940105423 erythropoietin Drugs 0.000 description 3
- 229960004177 filgrastim Drugs 0.000 description 3
- 229950008692 foretinib Drugs 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229960005386 ipilimumab Drugs 0.000 description 3
- 229950008001 matuzumab Drugs 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- MMNNTJYFHUDSKL-UHFFFAOYSA-N methyl n-[6-[2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxoisoindol-1-yl]-1h-benzimidazol-2-yl]carbamate Chemical compound C=1C=C2NC(NC(=O)OC)=NC2=CC=1C(C1=CC=CC=C1C1=O)(O)N1C1=CC(Cl)=CC=C1C MMNNTJYFHUDSKL-UHFFFAOYSA-N 0.000 description 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- 229950008835 neratinib Drugs 0.000 description 3
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 3
- 108700017947 pasireotide Proteins 0.000 description 3
- VMZMNAABQBOLAK-DBILLSOUSA-N pasireotide Chemical compound C([C@H]1C(=O)N2C[C@@H](C[C@H]2C(=O)N[C@H](C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@H](C(N[C@@H](CC=2C=CC(OCC=3C=CC=CC=3)=CC=2)C(=O)N1)=O)CCCCN)C=1C=CC=CC=1)OC(=O)NCCN)C1=CC=CC=C1 VMZMNAABQBOLAK-DBILLSOUSA-N 0.000 description 3
- 229960005415 pasireotide Drugs 0.000 description 3
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 3
- RYYNGWLOYLRZLK-RBUKOAKNSA-N pf03814735 Chemical compound C1([C@H]2CC[C@@H](C1=CC=1)N2C(=O)CNC(=O)C)=CC=1NC(N=1)=NC=C(C(F)(F)F)C=1NC1CCC1 RYYNGWLOYLRZLK-RBUKOAKNSA-N 0.000 description 3
- 229960001131 ponatinib Drugs 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 229960003452 romidepsin Drugs 0.000 description 3
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 3
- BTIHMVBBUGXLCJ-OAHLLOKOSA-N seliciclib Chemical compound C=12N=CN(C(C)C)C2=NC(N[C@@H](CO)CC)=NC=1NCC1=CC=CC=C1 BTIHMVBBUGXLCJ-OAHLLOKOSA-N 0.000 description 3
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 3
- 229960002930 sirolimus Drugs 0.000 description 3
- 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 description 3
- 238000003860 storage Methods 0.000 description 3
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 229950004186 telatinib Drugs 0.000 description 3
- 229960000940 tivozanib Drugs 0.000 description 3
- 229950007217 tremelimumab Drugs 0.000 description 3
- 229960000241 vandetanib Drugs 0.000 description 3
- 229950000578 vatalanib Drugs 0.000 description 3
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 3
- 229960000237 vorinostat Drugs 0.000 description 3
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 3
- KSOVGRCOLZZTPF-QMKUDKLTSA-N (1s,2s,3r,4r)-3-[[5-fluoro-2-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound N([C@H]1[C@H]([C@@]2([H])C[C@@]1(C=C2)[H])C(N)=O)C(C(=CN=1)F)=NC=1NC(C=C1C)=CC=C1N1CCN(C)CC1 KSOVGRCOLZZTPF-QMKUDKLTSA-N 0.000 description 2
- SVNJBEMPMKWDCO-KCHLEUMXSA-N (2s)-2-[[(2s)-3-carboxy-2-[[2-[[(2s)-5-(diaminomethylideneamino)-2-[[4-oxo-4-[[4-(4-oxo-8-phenylchromen-2-yl)morpholin-4-ium-4-yl]methoxy]butanoyl]amino]pentanoyl]amino]acetyl]amino]propanoyl]amino]-3-hydroxypropanoate Chemical compound C=1C(=O)C2=CC=CC(C=3C=CC=CC=3)=C2OC=1[N+]1(COC(=O)CCC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C([O-])=O)CCOCC1 SVNJBEMPMKWDCO-KCHLEUMXSA-N 0.000 description 2
- CSGQVNMSRKWUSH-IAGOWNOFSA-N (3r,4r)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol Chemical compound COC1=CC=CC(NC=2C3=C(CN4C[C@@H](O)[C@H](N)CC4)C=CN3N=CN=2)=C1 CSGQVNMSRKWUSH-IAGOWNOFSA-N 0.000 description 2
- LLOKIGWPNVSDGJ-AFBVCZJXSA-N (3s,6s,9s,12r)-3,6-dibenzyl-9-[6-[(2s)-oxiran-2-yl]-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone Chemical compound C([C@H]1C(=O)N2CCC[C@@H]2C(=O)N[C@H](C(N[C@@H](CC=2C=CC=CC=2)C(=O)N1)=O)CCCCCC(=O)[C@H]1OC1)C1=CC=CC=C1 LLOKIGWPNVSDGJ-AFBVCZJXSA-N 0.000 description 2
- 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 2
- GLBZSOQDAOLMGC-UHFFFAOYSA-N 1-(2-hydroxy-2-methylpropyl)-n-[5-(7-methoxyquinolin-4-yl)oxypyridin-2-yl]-5-methyl-3-oxo-2-phenylpyrazole-4-carboxamide Chemical compound C=1C=NC2=CC(OC)=CC=C2C=1OC(C=N1)=CC=C1NC(=O)C(C1=O)=C(C)N(CC(C)(C)O)N1C1=CC=CC=C1 GLBZSOQDAOLMGC-UHFFFAOYSA-N 0.000 description 2
- SYYBDNPGDKKJDU-ZDUSSCGKSA-N 1-[5-bromo-4-methyl-2-[[(2S)-2-morpholinyl]methoxy]phenyl]-3-(5-methyl-2-pyrazinyl)urea Chemical compound C1=NC(C)=CN=C1NC(=O)NC1=CC(Br)=C(C)C=C1OC[C@H]1OCCNC1 SYYBDNPGDKKJDU-ZDUSSCGKSA-N 0.000 description 2
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 2
- QFWCYNPOPKQOKV-UHFFFAOYSA-N 2-(2-amino-3-methoxyphenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1N QFWCYNPOPKQOKV-UHFFFAOYSA-N 0.000 description 2
- RWEVIPRMPFNTLO-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-3-pyridinecarboxamide Chemical compound CN1C(=O)C(C)=CC(C(=O)NOCCO)=C1NC1=CC=C(I)C=C1F RWEVIPRMPFNTLO-UHFFFAOYSA-N 0.000 description 2
- PZCJTYVWTGPGOH-OKVMNLLFSA-N 2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(2R,3R)-1,3-dihydroxybutan-2-yl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-13-(1H-indol-3-ylmethyl)-16-(naphthalen-1-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid Chemical compound C[C@@H](O)[C@@H](CO)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)CN2CCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)CC2)C(=O)N[C@@H](Cc2cccc3ccccc23)C(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 PZCJTYVWTGPGOH-OKVMNLLFSA-N 0.000 description 2
- XDLYKKIQACFMJG-UHFFFAOYSA-N 2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(OC)=CC=C1C(C1=O)=CC2=C(C)N=C(N)N=C2N1C1CCC(OCCO)CC1 XDLYKKIQACFMJG-UHFFFAOYSA-N 0.000 description 2
- PYEFPDQFAZNXLI-UHFFFAOYSA-N 3-(dimethylamino)-N-[3-[[(4-hydroxyphenyl)-oxomethyl]amino]-4-methylphenyl]benzamide Chemical compound CN(C)C1=CC=CC(C(=O)NC=2C=C(NC(=O)C=3C=CC(O)=CC=3)C(C)=CC=2)=C1 PYEFPDQFAZNXLI-UHFFFAOYSA-N 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 2
- OVPNQJVDAFNBDN-UHFFFAOYSA-N 4-(2,6-dichlorobenzamido)-N-(piperidin-4-yl)-pyrazole-3-carboxamide Chemical compound ClC1=CC=CC(Cl)=C1C(=O)NC1=CNN=C1C(=O)NC1CCNCC1 OVPNQJVDAFNBDN-UHFFFAOYSA-N 0.000 description 2
- SUVMJBTUFCVSAD-JTQLQIEISA-N 4-Methylsulfinylbutyl isothiocyanate Natural products C[S@](=O)CCCCN=C=S SUVMJBTUFCVSAD-JTQLQIEISA-N 0.000 description 2
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 2
- JVYNJRBSXBYXQB-UHFFFAOYSA-N 4-[3-(4-carboxyphenoxy)propoxy]benzoic acid;decanedioic acid Chemical compound OC(=O)CCCCCCCCC(O)=O.C1=CC(C(=O)O)=CC=C1OCCCOC1=CC=C(C(O)=O)C=C1 JVYNJRBSXBYXQB-UHFFFAOYSA-N 0.000 description 2
- XRYJULCDUUATMC-CYBMUJFWSA-N 4-[4-[[(1r)-1-phenylethyl]amino]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenol Chemical compound N([C@H](C)C=1C=CC=CC=1)C(C=1C=2)=NC=NC=1NC=2C1=CC=C(O)C=C1 XRYJULCDUUATMC-CYBMUJFWSA-N 0.000 description 2
- ZCCPLJOKGAACRT-UHFFFAOYSA-N 4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide Chemical compound CC1=CC=C(C(=O)NC=2C=C(C=CC=2)C(F)(F)F)C=C1NC(C=1C=NN(C)C=1N=1)=NC=1C1=CC=CN=C1 ZCCPLJOKGAACRT-UHFFFAOYSA-N 0.000 description 2
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 2
- LSFLAQVDISHMNB-UHFFFAOYSA-N 5-(3-phenylmethoxyphenyl)-7-[3-(pyrrolidin-1-ylmethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=2C(N)=NC=NC=2N(C2CC(CN3CCCC3)C2)C=C1C(C=1)=CC=CC=1OCC1=CC=CC=C1 LSFLAQVDISHMNB-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
- 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 2
- 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 2
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 2
- AECDBHGVIIRMOI-UHFFFAOYSA-N 7-[3-(azetidin-1-ylmethyl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine Chemical compound C1=2C(N)=NC=NC=2N(C2CC(CN3CCC3)C2)C=C1C(C=1)=CC=CC=1OCC1=CC=CC=C1 AECDBHGVIIRMOI-UHFFFAOYSA-N 0.000 description 2
- YXHLJMWYDTXDHS-IRFLANFNSA-N 7-aminoactinomycin 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)=C(N)C=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 YXHLJMWYDTXDHS-IRFLANFNSA-N 0.000 description 2
- 108700012813 7-aminoactinomycin D Proteins 0.000 description 2
- OONFNUWBHFSNBT-HXUWFJFHSA-N AEE788 Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(N[C@H](C)C=4C=CC=CC=4)=C3C=2)C=C1 OONFNUWBHFSNBT-HXUWFJFHSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000003200 Adenoma Diseases 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N Alanine Chemical compound CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 2
- 102400000739 Corticotropin Human genes 0.000 description 2
- 101800000414 Corticotropin Proteins 0.000 description 2
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 2
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- 108010088745 DOTALAN Proteins 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- 229940123457 Free radical scavenger Drugs 0.000 description 2
- DEZZLWQELQORIU-RELWKKBWSA-N GDC-0879 Chemical compound N=1N(CCO)C=C(C=2C=C3CCC(/C3=CC=2)=N\O)C=1C1=CC=NC=C1 DEZZLWQELQORIU-RELWKKBWSA-N 0.000 description 2
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 2
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102000008070 Interferon-gamma Human genes 0.000 description 2
- 239000002211 L-ascorbic acid Substances 0.000 description 2
- 235000000069 L-ascorbic acid Nutrition 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 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 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- UCEQXRCJXIVODC-PMACEKPBSA-N LSM-1131 Chemical compound C1CCC2=CC=CC3=C2N1C=C3[C@@H]1C(=O)NC(=O)[C@H]1C1=CNC2=CC=CC=C12 UCEQXRCJXIVODC-PMACEKPBSA-N 0.000 description 2
- OTPNDVKVEAIXTI-UHFFFAOYSA-N LSM-1274 Chemical compound C12=C3C4=C5C=CC=C[C]5N3C(O3)CCC3N2C2=CC=C[CH]C2=C1C1=C4C(=O)NC1=O OTPNDVKVEAIXTI-UHFFFAOYSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 2
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 2
- MEKASOQEXYKAKM-UHFFFAOYSA-N N-[[5-[3-(4,6-difluoro-1H-benzimidazol-2-yl)-1H-indazol-5-yl]-4-methylpyridin-3-yl]methyl]ethanamine Chemical compound CCNCC1=CN=CC(C=2C=C3C(C=4NC5=CC(F)=CC(F)=C5N=4)=NNC3=CC=2)=C1C MEKASOQEXYKAKM-UHFFFAOYSA-N 0.000 description 2
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 2
- 102100038815 Nocturnin Human genes 0.000 description 2
- YULUCECVQOCQFQ-UHFFFAOYSA-N OSU-03012 Chemical compound C1=CC(NC(=O)CN)=CC=C1N1C(C=2C=C3C(C4=CC=CC=C4C=C3)=CC=2)=CC(C(F)(F)F)=N1 YULUCECVQOCQFQ-UHFFFAOYSA-N 0.000 description 2
- 239000012270 PD-1 inhibitor Substances 0.000 description 2
- 239000012668 PD-1-inhibitor Substances 0.000 description 2
- 239000012271 PD-L1 inhibitor Substances 0.000 description 2
- OYONTEXKYJZFHA-SSHUPFPWSA-N PHA-665752 Chemical compound CC=1C(C(=O)N2[C@H](CCC2)CN2CCCC2)=C(C)NC=1\C=C(C1=C2)/C(=O)NC1=CC=C2S(=O)(=O)CC1=C(Cl)C=CC=C1Cl OYONTEXKYJZFHA-SSHUPFPWSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 2
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 2
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 2
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 2
- BCZUAADEACICHN-UHFFFAOYSA-N SGX-523 Chemical compound C1=NN(C)C=C1C1=NN2C(SC=3C=C4C=CC=NC4=CC=3)=NN=C2C=C1 BCZUAADEACICHN-UHFFFAOYSA-N 0.000 description 2
- RJFAYQIBOAGBLC-UHFFFAOYSA-N Selenomethionine Natural products C[Se]CCC(N)C(O)=O RJFAYQIBOAGBLC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 2
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- VWQVUPCCIRVNHF-OUBTZVSYSA-N Yttrium-90 Chemical compound [90Y] VWQVUPCCIRVNHF-OUBTZVSYSA-N 0.000 description 2
- OGNYUTNQZVRGMN-UHFFFAOYSA-N ZM447439 Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC(C=C1)=CC=C1NC(=O)C1=CC=CC=C1 OGNYUTNQZVRGMN-UHFFFAOYSA-N 0.000 description 2
- LTEJRLHKIYCEOX-PUODRLBUSA-N [(2r)-1-[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]oxypropan-2-yl] 2-aminopropanoate Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@@H](C)OC(=O)C(C)N)=C1 LTEJRLHKIYCEOX-PUODRLBUSA-N 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- 229960001686 afatinib Drugs 0.000 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 description 2
- 229960002833 aflibercept Drugs 0.000 description 2
- 108010081667 aflibercept Proteins 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 229950009447 alisertib Drugs 0.000 description 2
- KUFRQPKVAWMTJO-LMZWQJSESA-N alvespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCCN(C)C)C(=O)C=C1C2=O KUFRQPKVAWMTJO-LMZWQJSESA-N 0.000 description 2
- 229950010817 alvocidib Drugs 0.000 description 2
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229950002365 bafetinib Drugs 0.000 description 2
- ZGBAJMQHJDFTQJ-DEOSSOPVSA-N bafetinib Chemical compound C1[C@@H](N(C)C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=NC=3)C(C)=CC=2)C=C1C(F)(F)F ZGBAJMQHJDFTQJ-DEOSSOPVSA-N 0.000 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 description 2
- 229950005993 brivanib alaninate Drugs 0.000 description 2
- LTEJRLHKIYCEOX-OCCSQVGLSA-N brivanib alaninate Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@@H](C)OC(=O)[C@H](C)N)=C1 LTEJRLHKIYCEOX-OCCSQVGLSA-N 0.000 description 2
- 229960002412 cediranib Drugs 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- VVIPLSCLYCWUQT-XMMPIXPASA-N chembl1094164 Chemical compound C1([C@H](O)CNC2=C(C(NC=C2)=O)C=2NC=3C=C(C=C(C=3N=2)C)N2CCN(CCC#N)CC2)=CC=CC(Cl)=C1 VVIPLSCLYCWUQT-XMMPIXPASA-N 0.000 description 2
- LOLPPWBBNUVNQZ-UHFFFAOYSA-N chembl495727 Chemical compound C=1NN=C(C=2NC3=CC=C(CN4CCOCC4)C=C3N=2)C=1NC(=O)NC1CC1 LOLPPWBBNUVNQZ-UHFFFAOYSA-N 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960002271 cobimetinib Drugs 0.000 description 2
- BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 2
- 229960000258 corticotropin Drugs 0.000 description 2
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- HHNFORCFJOVQNF-UHFFFAOYSA-N cyl-1 Chemical compound N1C(=O)C(CCCCCC(=O)C2OC2)NC(=O)C2CCCN2C(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(OC)C=C1 HHNFORCFJOVQNF-UHFFFAOYSA-N 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 229960002482 dalotuzumab Drugs 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 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 2
- 229960003603 decitabine Drugs 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- XDXWLKQMMKQXPV-QYQHSDTDSA-N eltrombopag Chemical compound CC1=NN(C=2C=C(C)C(C)=CC=2)C(=O)\C1=N/NC(C=1O)=CC=CC=1C1=CC=CC(C(O)=O)=C1 XDXWLKQMMKQXPV-QYQHSDTDSA-N 0.000 description 2
- INVTYAOGFAGBOE-UHFFFAOYSA-N entinostat Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)OCC1=CC=CN=C1 INVTYAOGFAGBOE-UHFFFAOYSA-N 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 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 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 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 description 2
- 239000004052 folic acid antagonist Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 2
- 229960003130 interferon gamma Drugs 0.000 description 2
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 2
- 229950001845 lestaurtinib Drugs 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- 229960003987 melatonin Drugs 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 2
- JZZFDCXSFTVOJY-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide;hydron;dichloride Chemical compound Cl.Cl.C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 JZZFDCXSFTVOJY-UHFFFAOYSA-N 0.000 description 2
- 230000000955 neuroendocrine Effects 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- 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 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- CFODQUSMSYDHBS-UHFFFAOYSA-N octreotate Chemical compound O=C1NC(CC=2C=CC=CC=2)C(=O)NC(CC=2[C]3C=CC=CC3=NC=2)C(=O)NC(CCCCN)C(=O)NC(C(C)O)C(=O)NC(C(=O)NC(C(O)C)C(O)=O)CSSCC1NC(=O)C(N)CC1=CC=CC=C1 CFODQUSMSYDHBS-UHFFFAOYSA-N 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 229940121655 pd-1 inhibitor Drugs 0.000 description 2
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 2
- 229950006299 pelitinib Drugs 0.000 description 2
- 229960002621 pembrolizumab Drugs 0.000 description 2
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 2
- 229960002340 pentostatin Drugs 0.000 description 2
- 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 2
- 208000028591 pheochromocytoma Diseases 0.000 description 2
- YJGVMLPVUAXIQN-HAEOHBJNSA-N picropodophyllotoxin 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-HAEOHBJNSA-N 0.000 description 2
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 2
- 229950004403 polifeprosan Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 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 description 2
- 239000011535 reaction buffer Substances 0.000 description 2
- 108091006082 receptor inhibitors Proteins 0.000 description 2
- 229960001302 ridaforolimus Drugs 0.000 description 2
- 229950001808 robatumumab Drugs 0.000 description 2
- 229950009919 saracatinib Drugs 0.000 description 2
- 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 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 2
- 229950007213 spartalizumab Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 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 2
- 229950003046 tesevatinib Drugs 0.000 description 2
- 125000004149 thio group Chemical group *S* 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 229950000185 tozasertib Drugs 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine 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=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 2
- 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 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=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 GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- 229950008250 zalutumumab Drugs 0.000 description 2
- QJVOZXGJOGJKPT-IGHBBLSQSA-N (1r,2r,5s,11ar)-2-(prop-2-en-1-yl)-1,2,3,4,5,6,11,11a-octahydro-10h-1,5-methanopyrido[1,2-a][1,5]diazocin-10-one Chemical compound C([C@@H]12)C(=O)C=CN1C[C@@H]1CN[C@H](CC=C)[C@H]2C1 QJVOZXGJOGJKPT-IGHBBLSQSA-N 0.000 description 1
- ZVAFCKLQJCZGAP-WDEREUQCSA-N (2r,3s)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 ZVAFCKLQJCZGAP-WDEREUQCSA-N 0.000 description 1
- IXOXBSCIXZEQEQ-XJCFNFQFSA-N (2r,3s,4r,5r)-2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@H](O)[C@@H]1O IXOXBSCIXZEQEQ-XJCFNFQFSA-N 0.000 description 1
- MHFUWOIXNMZFIW-WNQIDUERSA-N (2s)-2-hydroxypropanoic acid;n-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide Chemical compound C[C@H](O)C(O)=O.C1CN(C)CCN1C1=CC(NC2=NNC(C)=C2)=NC(SC=2C=CC(NC(=O)C3CC3)=CC=2)=N1 MHFUWOIXNMZFIW-WNQIDUERSA-N 0.000 description 1
- JWOGUUIOCYMBPV-GMFLJSBRSA-N (3S,6S,9S,12R)-3-[(2S)-Butan-2-yl]-6-[(1-methoxyindol-3-yl)methyl]-9-(6-oxooctyl)-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone Chemical compound N1C(=O)[C@H](CCCCCC(=O)CC)NC(=O)[C@H]2CCCCN2C(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CC1=CN(OC)C2=CC=CC=C12 JWOGUUIOCYMBPV-GMFLJSBRSA-N 0.000 description 1
- GNYCTMYOHGBSBI-SVZOTFJBSA-N (3s,6r,9s,12r)-6,9-dimethyl-3-[6-[(2s)-oxiran-2-yl]-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone Chemical compound C([C@H]1C(=O)N2CCC[C@@H]2C(=O)N[C@H](C(N[C@H](C)C(=O)N1)=O)C)CCCCC(=O)[C@@H]1CO1 GNYCTMYOHGBSBI-SVZOTFJBSA-N 0.000 description 1
- SGYJGGKDGBXCNY-QXUYBEEESA-N (3s,9s,12r)-3-benzyl-6,6-dimethyl-9-[6-[(2s)-oxiran-2-yl]-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone Chemical compound C([C@H]1C(=O)NC(C(N[C@@H](CC=2C=CC=CC=2)C(=O)N2CCC[C@@H]2C(=O)N1)=O)(C)C)CCCCC(=O)[C@@H]1CO1 SGYJGGKDGBXCNY-QXUYBEEESA-N 0.000 description 1
- MHTSQKQLTZCFPE-QJOMJCCJSA-N (3z)-5-(2,3-dihydroindol-1-ylsulfonyl)-3-[[3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1h-pyrrol-2-yl]methylidene]-1h-indol-2-one Chemical compound C1CN(C)CCN1C(=O)C1=C(C)NC(\C=C/2C3=CC(=CC=C3NC\2=O)S(=O)(=O)N2C3=CC=CC=C3CC2)=C1C MHTSQKQLTZCFPE-QJOMJCCJSA-N 0.000 description 1
- JXOCDHNKTVLZLD-ITYLOYPMSA-N (3z)-n-(3-chlorophenyl)-3-[[3,5-dimethyl-4-(3-morpholin-4-ylpropyl)-1h-pyrrol-2-yl]methylidene]-n-methyl-2-oxo-1h-indole-5-sulfonamide Chemical compound C=1C=C2NC(=O)\C(=C/C3=C(C(CCCN4CCOCC4)=C(C)N3)C)C2=CC=1S(=O)(=O)N(C)C1=CC=CC(Cl)=C1 JXOCDHNKTVLZLD-ITYLOYPMSA-N 0.000 description 1
- LBGAPPKREFCCSH-ADPPPVLCSA-N (4R,7S,10S,13R,16S,19S)-10-(4-aminobutyl)-19-[[(2S)-2-amino-3-(4-chlorophenyl)propanoyl]amino]-N-[(2R)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]-13-[[4-(carbamoylamino)phenyl]methyl]-16-[[4-[[(4S)-2,6-dioxo-1,3-diazinane-4-carbonyl]amino]phenyl]methyl]-7-[(1R)-1-hydroxyethyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide Chemical compound C[C@@H](O)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2ccc(NC(N)=O)cc2)NC(=O)[C@H](Cc2ccc(NC(=O)[C@@H]3CC(=O)NC(=O)N3)cc2)NC(=O)[C@@H](CSSC[C@H](NC1=O)C(=O)N[C@H](Cc1ccc(O)cc1)C(N)=O)NC(=O)[C@@H](N)Cc1ccc(Cl)cc1 LBGAPPKREFCCSH-ADPPPVLCSA-N 0.000 description 1
- FYSDQQZUTAKKQX-CULBQIHKSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-19-[[(2r)-3-phenyl-2-[[(2r,3s,4r,5r)-2,3,5-trihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hy Chemical compound C([C@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)NC[C@]1(O)[C@H]([C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)CO1)O)C1=CC=CC=C1 FYSDQQZUTAKKQX-CULBQIHKSA-N 0.000 description 1
- WANLLPADDCXPGO-WMKJBNATSA-N (6r,9s,12s)-3-[(2s)-butan-2-yl]-6-[(4-methoxyphenyl)methyl]-9-[6-(oxiran-2-yl)-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone Chemical compound C([C@@H]1C(=O)NC(C(N2CCCC[C@H]2C(=O)N[C@@H](CCCCCC(=O)C2OC2)C(=O)N1)=O)[C@@H](C)CC)C1=CC=C(OC)C=C1 WANLLPADDCXPGO-WMKJBNATSA-N 0.000 description 1
- SUVMJBTUFCVSAD-SNVBAGLBSA-N (R)-sulforaphane Chemical compound C[S@@](=O)CCCCN=C=S SUVMJBTUFCVSAD-SNVBAGLBSA-N 0.000 description 1
- QRPSQQUYPMFERG-LFYBBSHMSA-N (e)-5-[3-(benzenesulfonamido)phenyl]-n-hydroxypent-2-en-4-ynamide Chemical compound ONC(=O)\C=C\C#CC1=CC=CC(NS(=O)(=O)C=2C=CC=CC=2)=C1 QRPSQQUYPMFERG-LFYBBSHMSA-N 0.000 description 1
- WPWHSFAFEBZWBB-UHFFFAOYSA-N 1-butyl radical Chemical compound [CH2]CCC WPWHSFAFEBZWBB-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- PUDHBTGHUJUUFI-UHFFFAOYSA-N 10-(4-aminobutyl)-n-(1-amino-3-hydroxy-1-oxobutan-2-yl)-19-[(2-amino-3-naphthalen-2-ylpropanoyl)amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide Chemical compound N1C(=O)C(NC(=O)C(N)CC=2C=C3C=CC=CC3=CC=2)CSSCC(C(=O)NC(C(C)O)C(N)=O)NC(=O)C(C(C)C)NC(=O)C(CCCCN)NC(=O)C(CC=2C3=CC=CC=C3NC=2)NC(=O)C1CC1=CC=C(O)C=C1 PUDHBTGHUJUUFI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- DVEXZJFMOKTQEZ-UHFFFAOYSA-N 2,3-bis[amino-[(2-aminophenyl)thio]methylidene]butanedinitrile Chemical compound C=1C=CC=C(N)C=1SC(N)=C(C#N)C(C#N)=C(N)SC1=CC=CC=C1N DVEXZJFMOKTQEZ-UHFFFAOYSA-N 0.000 description 1
- IFUXOVRDQZEGPB-FMOQSIQZSA-N 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3s,4r)-3-hydroxy-1-methylpiperidin-4-yl]-2,3-dihydrochromen-4-one Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)CC2=O IFUXOVRDQZEGPB-FMOQSIQZSA-N 0.000 description 1
- PIMQWRZWLQKKBJ-SFHVURJKSA-N 2-[(2S)-1-[3-ethyl-7-[(1-oxido-3-pyridin-1-iumyl)methylamino]-5-pyrazolo[1,5-a]pyrimidinyl]-2-piperidinyl]ethanol Chemical compound C=1C(N2[C@@H](CCCC2)CCO)=NC2=C(CC)C=NN2C=1NCC1=CC=C[N+]([O-])=C1 PIMQWRZWLQKKBJ-SFHVURJKSA-N 0.000 description 1
- MXDPZUIOZWKRAA-PRDSJKGBSA-K 2-[4-[2-[[(2r)-1-[[(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-4-[[(1s,2r)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1r)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-y Chemical compound [177Lu+3].C([C@H](C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC1=O)C(=O)N[C@@H]([C@H](O)C)C(O)=O)NC(=O)CN1CCN(CC([O-])=O)CCN(CC([O-])=O)CCN(CC([O-])=O)CC1)C1=CC=CC=C1 MXDPZUIOZWKRAA-PRDSJKGBSA-K 0.000 description 1
- DSCDMAQBPMKHAS-UHFFFAOYSA-N 2-[[10-(4-aminobutyl)-16-benzyl-19-[[2-[[2-[2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetyl]amino]-3-phenylpropanoyl]amino]-7-(1-hydroxyethyl)-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,1 Chemical compound O=C1NC(CC=2C=CC=CC=2)C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCCCN)C(=O)NC(C(C)O)C(=O)NC(C(=O)NC(C(O)C)C(O)=O)CSSCC1NC(=O)C(NC(=O)CN(CCN(CCN(CC(O)=O)CC(O)=O)CC(O)=O)CC(O)=O)CC1=CC=CC=C1 DSCDMAQBPMKHAS-UHFFFAOYSA-N 0.000 description 1
- FZDFGHZZPBUTGP-UHFFFAOYSA-N 2-[[2-[bis(carboxymethyl)amino]-3-(4-isothiocyanatophenyl)propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound OC(=O)CN(CC(O)=O)C(C)CN(CC(O)=O)CC(N(CC(O)=O)CC(O)=O)CC1=CC=C(N=C=S)C=C1 FZDFGHZZPBUTGP-UHFFFAOYSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 1
- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-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
- MFEFTTYGMZOIKO-UHFFFAOYSA-N 5-azacytosine Chemical compound NC1=NC=NC(=O)N1 MFEFTTYGMZOIKO-UHFFFAOYSA-N 0.000 description 1
- DEZJGRPRBZSAKI-KMGSDFBDSA-N 565434-85-7 Chemical compound C([C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CO)C(=O)N[C@H](CC=1C(=C(F)C(F)=C(F)C=1F)F)C(=O)N[C@H](CC1CCCCC1)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H](CCCNC(N)=N)C(=O)N[C@H](CCCNC(N)=N)C(O)=O)C(C=C1)=CC=C1C(=O)C1=CC=CC=C1 DEZJGRPRBZSAKI-KMGSDFBDSA-N 0.000 description 1
- WVMANZPBOBRWCB-UHFFFAOYSA-N 7-butyl-6-(4-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine Chemical compound N1C2=NC=CN=C2C(CCCC)=C1C1=CC=C(OC)C=C1 WVMANZPBOBRWCB-UHFFFAOYSA-N 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-HQCWYSJUSA-N 7-hydroxystaurosporine Chemical compound N([C@H](O)C1=C2C3=CC=CC=C3N3C2=C24)C(=O)C1=C2C1=CC=CC=C1N4[C@H]1C[C@@H](NC)[C@@H](OC)[C@]3(C)O1 PBCZSGKMGDDXIJ-HQCWYSJUSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-UHFFFAOYSA-N 7beta-hydroxystaurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3C(O)NC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 PBCZSGKMGDDXIJ-UHFFFAOYSA-N 0.000 description 1
- KVLFRAWTRWDEDF-IRXDYDNUSA-N AZD-8055 Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3[C@H](COCC3)C)N3[C@H](COCC3)C)C2=N1 KVLFRAWTRWDEDF-IRXDYDNUSA-N 0.000 description 1
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 description 1
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- 108090000461 Aurora Kinase A Proteins 0.000 description 1
- 102100032311 Aurora kinase A Human genes 0.000 description 1
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 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 description 1
- 108010059033 BIM 23027 Proteins 0.000 description 1
- 241000731848 Bachia Species 0.000 description 1
- 239000003840 Bafetinib Substances 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm 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
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- FBMSCRMXSHXGIW-SAHAZLINSA-N C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](C)[C@](C)(N)C(O)=O)=C1 Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](C)[C@](C)(N)C(O)=O)=C1 FBMSCRMXSHXGIW-SAHAZLINSA-N 0.000 description 1
- 102100024217 CAMPATH-1 antigen Human genes 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 108010065524 CD52 Antigen Proteins 0.000 description 1
- 102000008203 CTLA-4 Antigen Human genes 0.000 description 1
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 1
- 101100441844 Caenorhabditis elegans cyl-1 gene Proteins 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 108010089388 Cdc25C phosphatase (211-221) Proteins 0.000 description 1
- SGYJGGKDGBXCNY-UHFFFAOYSA-N Chlamydocin Natural products N1C(=O)C2CCCN2C(=O)C(CC=2C=CC=CC=2)NC(=O)C(C)(C)NC(=O)C1CCCCCC(=O)C1CO1 SGYJGGKDGBXCNY-UHFFFAOYSA-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
- 102000007644 Colony-Stimulating Factors Human genes 0.000 description 1
- 108010071942 Colony-Stimulating Factors Proteins 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 102100021906 Cyclin-O Human genes 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 108010063406 Cyl-2 Proteins 0.000 description 1
- WANLLPADDCXPGO-UHFFFAOYSA-N Cyl-2 Natural products N1C(=O)C(CCCCCC(=O)C2OC2)NC(=O)C2CCCCN2C(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(OC)C=C1 WANLLPADDCXPGO-UHFFFAOYSA-N 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
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- DLVJMFOLJOOWFS-UHFFFAOYSA-N Depudecin Natural products CC(O)C1OC1C=CC1C(C(O)C=C)O1 DLVJMFOLJOOWFS-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- 102100031939 Erythropoietin Human genes 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- RVAQIUULWULRNW-UHFFFAOYSA-N Ganetespib Chemical compound C1=C(O)C(C(C)C)=CC(C=2N(C(O)=NN=2)C=2C=C3C=CN(C)C3=CC=2)=C1O RVAQIUULWULRNW-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010051041 HC toxin Proteins 0.000 description 1
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 1
- 101000897441 Homo sapiens Cyclin-O Proteins 0.000 description 1
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 1
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 1
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 1
- 101000851376 Homo sapiens Tumor necrosis factor receptor superfamily member 8 Proteins 0.000 description 1
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 108010043766 IRX 2 Proteins 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
- 108010050904 Interferons Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102100030694 Interleukin-11 Human genes 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 150000001169 Lutetium Chemical class 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 235000003990 Monochoria hastata Nutrition 0.000 description 1
- 240000000178 Monochoria vaginalis Species 0.000 description 1
- 101100382953 Mus musculus Ccnd1 gene Proteins 0.000 description 1
- 101100261153 Mus musculus Mpl gene Proteins 0.000 description 1
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 1
- PTJGLFIIZFVFJV-UHFFFAOYSA-N N'-hydroxy-N-(3-pyridinyl)octanediamide Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CN=C1 PTJGLFIIZFVFJV-UHFFFAOYSA-N 0.000 description 1
- MHXGEROHKGDZGO-UHFFFAOYSA-N N-[(1-methyl-4-piperidinyl)methyl]-3-[3-(trifluoromethoxy)phenyl]-6-imidazo[1,2-b]pyridazinamine Chemical compound C1CN(C)CCC1CNC1=NN2C(C=3C=C(OC(F)(F)F)C=CC=3)=CN=C2C=C1 MHXGEROHKGDZGO-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- JWOGUUIOCYMBPV-UHFFFAOYSA-N OT-Key 11219 Natural products N1C(=O)C(CCCCCC(=O)CC)NC(=O)C2CCCCN2C(=O)C(C(C)CC)NC(=O)C1CC1=CN(OC)C2=CC=CC=C12 JWOGUUIOCYMBPV-UHFFFAOYSA-N 0.000 description 1
- 208000000160 Olfactory Esthesioneuroblastoma Diseases 0.000 description 1
- YZDJQTHVDDOVHR-UHFFFAOYSA-N PLX-4720 Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(Cl)=CN=C3NC=2)=C1F YZDJQTHVDDOVHR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 description 1
- 206010061332 Paraganglion neoplasm Diseases 0.000 description 1
- 241000244269 Peucedanum Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 208000007913 Pituitary Neoplasms Diseases 0.000 description 1
- 201000005746 Pituitary adenoma Diseases 0.000 description 1
- 206010061538 Pituitary tumour benign Diseases 0.000 description 1
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 102000018471 Proto-Oncogene Proteins B-raf Human genes 0.000 description 1
- 108010091528 Proto-Oncogene Proteins B-raf Proteins 0.000 description 1
- 101710141955 RAF proto-oncogene serine/threonine-protein kinase Proteins 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 108010081391 Ristocetin Proteins 0.000 description 1
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 1
- 102000005157 Somatostatin Human genes 0.000 description 1
- 108010056088 Somatostatin Proteins 0.000 description 1
- 102000001854 Steroid 17-alpha-Hydroxylase Human genes 0.000 description 1
- 108010015330 Steroid 17-alpha-Hydroxylase Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- NCLGDOBQAWBXRA-PGRDOPGGSA-N Telotristat Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1[C@H](C(F)(F)F)OC1=CC(C=2C=CC(C[C@H](N)C(O)=O)=CC=2)=NC(N)=N1 NCLGDOBQAWBXRA-PGRDOPGGSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 102000036693 Thrombopoietin Human genes 0.000 description 1
- 108010041111 Thrombopoietin Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- LLOKIGWPNVSDGJ-UHFFFAOYSA-N Trapoxin B Natural products C1OC1C(=O)CCCCCC(C(NC(CC=1C=CC=CC=1)C(=O)N1)=O)NC(=O)C2CCCN2C(=O)C1CC1=CC=CC=C1 LLOKIGWPNVSDGJ-UHFFFAOYSA-N 0.000 description 1
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 102100036857 Tumor necrosis factor receptor superfamily member 8 Human genes 0.000 description 1
- RTJVUHUGTUDWRK-CSLCKUBZSA-N [(2r,4ar,6r,7r,8s,8ar)-6-[[(5s,5ar,8ar,9r)-9-(3,5-dimethoxy-4-phosphonooxyphenyl)-8-oxo-5a,6,8a,9-tetrahydro-5h-[2]benzofuro[6,5-f][1,3]benzodioxol-5-yl]oxy]-2-methyl-7-[2-(2,3,4,5,6-pentafluorophenoxy)acetyl]oxy-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]d Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](OC(=O)COC=4C(=C(F)C(F)=C(F)C=4F)F)[C@@H]4O[C@H](C)OC[C@H]4O3)OC(=O)COC=3C(=C(F)C(F)=C(F)C=3F)F)[C@@H]3[C@@H]2C(OC3)=O)=C1 RTJVUHUGTUDWRK-CSLCKUBZSA-N 0.000 description 1
- LUJZZYWHBDHDQX-QFIPXVFZSA-N [(3s)-morpholin-3-yl]methyl n-[4-[[1-[(3-fluorophenyl)methyl]indazol-5-yl]amino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamate Chemical compound C=1N2N=CN=C(NC=3C=C4C=NN(CC=5C=C(F)C=CC=5)C4=CC=3)C2=C(C)C=1NC(=O)OC[C@@H]1COCCN1 LUJZZYWHBDHDQX-QFIPXVFZSA-N 0.000 description 1
- OCBFFGCSTGGPSQ-UHFFFAOYSA-N [CH2]CC Chemical compound [CH2]CC OCBFFGCSTGGPSQ-UHFFFAOYSA-N 0.000 description 1
- 229960004103 abiraterone acetate Drugs 0.000 description 1
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000003474 anti-emetic effect Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000001062 anti-nausea Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 108010082820 apicidin Proteins 0.000 description 1
- 229930186608 apicidin Natural products 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 description 1
- 229960001215 bendamustine hydrochloride Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 238000001815 biotherapy Methods 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- MJQUEDHRCUIRLF-MDGOTRLRSA-N bryo 1 Chemical compound COC(=O)/C=C(/[C@@H]([C@@](C(C)(C)/C=C/1)(O)O2)OC(=O)/C=C/C=C/CCC)CC2C[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O2)C[C@H](OC(C)=O)C(C)(C)[C@]2(O)C[C@@H]2C\C(=C\C(=O)OC)C[C@H]\1O2 MJQUEDHRCUIRLF-MDGOTRLRSA-N 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 239000011687 calcium folinate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 229950002352 cenisertib Drugs 0.000 description 1
- 150000004697 chelate complex Chemical class 0.000 description 1
- BGTFCAQCKWKTRL-YDEUACAXSA-N chembl1095986 Chemical compound C1[C@@H](N)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]([C@H]1C(N[C@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(C(=C(O)C=4)C)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@@H](C(=O)N3)[C@H](O)C=3C=CC(O4)=CC=3)C(=O)N1)C(O)=O)=O)C(C=C1)=CC=C1OC1=C(O[C@@H]3[C@H]([C@H](O)[C@@H](O)[C@H](CO[C@@H]5[C@H]([C@@H](O)[C@H](O)[C@@H](C)O5)O)O3)O[C@@H]3[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@@H]3[C@H]([C@H](O)[C@@H](CO)O3)O)C4=CC2=C1 BGTFCAQCKWKTRL-YDEUACAXSA-N 0.000 description 1
- XDLYKKIQACFMJG-WKILWMFISA-N chembl1234354 Chemical compound C1=NC(OC)=CC=C1C(C1=O)=CC2=C(C)N=C(N)N=C2N1[C@@H]1CC[C@@H](OCCO)CC1 XDLYKKIQACFMJG-WKILWMFISA-N 0.000 description 1
- JROFGZPOBKIAEW-HAQNSBGRSA-N chembl3120215 Chemical compound N1C=2C(OC)=CC=CC=2C=C1C(=C1C(N)=NC=NN11)N=C1[C@H]1CC[C@H](C(O)=O)CC1 JROFGZPOBKIAEW-HAQNSBGRSA-N 0.000 description 1
- 108700023145 chlamydocin Proteins 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229940047120 colony stimulating factors Drugs 0.000 description 1
- 239000000562 conjugate Substances 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- JLYVRXJEQTZZBE-UHFFFAOYSA-N ctk1c6083 Chemical compound NP(N)(N)=S JLYVRXJEQTZZBE-UHFFFAOYSA-N 0.000 description 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960002465 dabrafenib Drugs 0.000 description 1
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229950007409 dacetuzumab Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- DLVJMFOLJOOWFS-INMLLLKOSA-N depudecin Chemical compound C[C@@H](O)[C@@H]1O[C@H]1\C=C\[C@H]1[C@H]([C@H](O)C=C)O1 DLVJMFOLJOOWFS-INMLLLKOSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- ZJIPHXXDPROMEF-UHFFFAOYSA-N dihydroxyphosphanyl dihydrogen phosphite Chemical compound OP(O)OP(O)O ZJIPHXXDPROMEF-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- GOJNABIZVJCYFL-UHFFFAOYSA-M dimethylphosphinate Chemical compound CP(C)([O-])=O GOJNABIZVJCYFL-UHFFFAOYSA-M 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 229960004137 elotuzumab Drugs 0.000 description 1
- 229960001069 eltrombopag Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 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
- 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 1
- HCZKYJDFEPMADG-UHFFFAOYSA-N erythro-nordihydroguaiaretic acid Natural products C=1C=C(O)C(O)=CC=1CC(C)C(C)CC1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 229950008085 figitumumab Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229950004896 ganitumab Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 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 description 1
- 229960000578 gemtuzumab Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- GNYCTMYOHGBSBI-UHFFFAOYSA-N helminthsporium carbonum toxin Natural products N1C(=O)C(C)NC(=O)C(C)NC(=O)C2CCCN2C(=O)C1CCCCCC(=O)C1CO1 GNYCTMYOHGBSBI-UHFFFAOYSA-N 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229950011216 ilatreotide Drugs 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 229950004101 inotuzumab ozogamicin Drugs 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- 229950005692 larotaxel Drugs 0.000 description 1
- SEFGUGYLLVNFIJ-QDRLFVHASA-N larotaxel dihydrate Chemical compound O.O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@@]23[C@H]1[C@@]1(CO[C@@H]1C[C@@H]2C3)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 SEFGUGYLLVNFIJ-QDRLFVHASA-N 0.000 description 1
- 229950002216 linifanib Drugs 0.000 description 1
- 229950001762 linsitinib Drugs 0.000 description 1
- PKCDDUHJAFVJJB-VLZXCDOPSA-N linsitinib Chemical compound C1[C@](C)(O)C[C@@H]1C1=NC(C=2C=C3N=C(C=CC3=CC=2)C=2C=CC=CC=2)=C2N1C=CN=C2N PKCDDUHJAFVJJB-VLZXCDOPSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229940100352 lynparza Drugs 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960003951 masoprocol Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229950007699 mogamulizumab Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- ZTFBIUXIQYRUNT-MDWZMJQESA-N mubritinib Chemical compound C1=CC(C(F)(F)F)=CC=C1\C=C\C1=NC(COC=2C=CC(CCCCN3N=NC=C3)=CC=2)=CO1 ZTFBIUXIQYRUNT-MDWZMJQESA-N 0.000 description 1
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 description 1
- 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 1
- RDSACQWTXKSHJT-UHFFFAOYSA-N n-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide Chemical compound C1CC1(CC(O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-UHFFFAOYSA-N 0.000 description 1
- RDSACQWTXKSHJT-NSHDSACASA-N n-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2s)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide Chemical compound C1CC1(C[C@H](O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-NSHDSACASA-N 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 201000011519 neuroendocrine tumor Diseases 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 239000003865 nucleic acid synthesis inhibitor Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 229960001494 octreotide acetate Drugs 0.000 description 1
- FDLYAMZZIXQODN-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FDLYAMZZIXQODN-UHFFFAOYSA-N 0.000 description 1
- 201000008859 olfactory neuroblastoma Diseases 0.000 description 1
- 108010046821 oprelvekin Proteins 0.000 description 1
- 229960001840 oprelvekin Drugs 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229950007318 ozogamicin Drugs 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 description 1
- 208000007312 paraganglioma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- 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 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000011170 pharmaceutical development Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 229950002592 pimasertib Drugs 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- OIRUWDYJGMHDHJ-AFXVCOSJSA-N retaspimycin hydrochloride Chemical compound Cl.N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(O)C1=CC(O)=C2NCC=C OIRUWDYJGMHDHJ-AFXVCOSJSA-N 0.000 description 1
- 229950003687 ribociclib Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 229950004257 ristocetin Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- HNMATTJJEPZZMM-BPKVFSPJSA-N s-[(2r,3s,4s,6s)-6-[[(2r,3s,4s,5r,6r)-5-[(2s,4s,5s)-5-[acetyl(ethyl)amino]-4-methoxyoxan-2-yl]oxy-6-[[(2s,5z,9r,13e)-13-[2-[[4-[(2e)-2-[1-[4-(4-amino-4-oxobutoxy)phenyl]ethylidene]hydrazinyl]-2-methyl-4-oxobutan-2-yl]disulfanyl]ethylidene]-9-hydroxy-12-(m Chemical compound C1[C@H](OC)[C@@H](N(CC)C(C)=O)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@@](C/3=C/CSSC(C)(C)CC(=O)N\N=C(/C)C=3C=CC(OCCCC(N)=O)=CC=3)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HNMATTJJEPZZMM-BPKVFSPJSA-N 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 229940072272 sandostatin Drugs 0.000 description 1
- 229950009848 satoreotide Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 108010052231 seglitide Proteins 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 229940075620 somatostatin analogue Drugs 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- IVDHYUQIDRJSTI-UHFFFAOYSA-N sorafenib tosylate Chemical compound [H+].CC1=CC=C(S([O-])(=O)=O)C=C1.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 IVDHYUQIDRJSTI-UHFFFAOYSA-N 0.000 description 1
- OAVGBZOFDPFGPJ-UHFFFAOYSA-N sotrastaurin Chemical compound C1CN(C)CCN1C1=NC(C=2C(NC(=O)C=2C=2C3=CC=CC=C3NC=2)=O)=C(C=CC=C2)C2=N1 OAVGBZOFDPFGPJ-UHFFFAOYSA-N 0.000 description 1
- XFLBOEMFLGLWFF-HDXRNPEWSA-N spiruchostatin Chemical compound C1SSCC\C=C\[C@H]2OC(=O)C[C@H](O)[C@@H](C(C)C)NC(=O)[C@@H]1NC(=O)[C@@H](C)NC(=O)C2 XFLBOEMFLGLWFF-HDXRNPEWSA-N 0.000 description 1
- 108010021003 spiruchostatin A Proteins 0.000 description 1
- XFLBOEMFLGLWFF-UHFFFAOYSA-N spiruchostatin A Natural products C1SSCCC=CC2OC(=O)CC(O)C(C(C)C)NC(=O)C1NC(=O)C(C)NC(=O)C2 XFLBOEMFLGLWFF-UHFFFAOYSA-N 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 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
- 239000008174 sterile solution Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 229960005559 sulforaphane Drugs 0.000 description 1
- 235000015487 sulforaphane Nutrition 0.000 description 1
- 229960002812 sunitinib malate Drugs 0.000 description 1
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 229950003999 tafluposide Drugs 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 229950002246 telotristat Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 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 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008646 thermal stress Effects 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 230000002992 thymic effect Effects 0.000 description 1
- 208000017120 thymic neuroendocrine tumor Diseases 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- 229950005976 tivantinib Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 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 description 1
- 229960001308 trametinib dimethyl sulfoxide Drugs 0.000 description 1
- OQUFJVRYDFIQBW-UHFFFAOYSA-N trametinib dimethyl sulfoxide Chemical compound CS(C)=O.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 OQUFJVRYDFIQBW-UHFFFAOYSA-N 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- GXVXXETYXSPSOA-UFEOFEBPSA-N trapoxin A Chemical compound C([C@H]1C(=O)N2CCCC[C@@H]2C(=O)N[C@H](C(N[C@@H](CC=2C=CC=CC=2)C(=O)N1)=O)CCCCCC(=O)[C@H]1OC1)C1=CC=CC=C1 GXVXXETYXSPSOA-UFEOFEBPSA-N 0.000 description 1
- 108010060596 trapoxin B Proteins 0.000 description 1
- GXVXXETYXSPSOA-UHFFFAOYSA-N trapoxin a Chemical compound C1OC1C(=O)CCCCCC(C(NC(CC=1C=CC=CC=1)C(=O)N1)=O)NC(=O)C2CCCCN2C(=O)C1CC1=CC=CC=C1 GXVXXETYXSPSOA-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 208000024719 uterine cervix neoplasm Diseases 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.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=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- 229940028393 vincasar Drugs 0.000 description 1
- 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 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/121—Solutions, i.e. homogeneous liquid formulation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
本发明涉及高浓度的以及高化学稳定性的放射性核素络合物溶液,其使所述放射性核素络合物溶液能够用作诊断和/或治疗目的的药物产品。通过至少一种抗放射性分解降解的稳定剂实现所述药物产品的稳定性。发现在制造方法期间在不同阶段引入的两种稳定剂的使用是特别有利的。
Description
技术领域
本发明涉及高浓度的以及高化学和放射化学稳定性的放射性核素络合物溶液,其使所述放射性核素络合物溶液能够用作诊断和/或治疗目的的商业药物产品。
背景技术
靶向药物递送的概念基于与不被靶向的细胞相反在靶细胞中过表达的细胞受体。如果药物与那些过表达的细胞受体具有结合位点,则允许药物在高浓度全身施用后递送至那些靶细胞,同时使其他非目的细胞不受影响。例如,如果肿瘤细胞的特征在于特异性细胞受体的过表达,则对所述受体具有结合亲和力的药物在静脉内输注后将在肿瘤组织中以高浓度积累,同时使正常组织不受影响。
该靶向药物递送概念还已用于放射医学中以选择性地将放射性核素递送至靶细胞用于诊断或治疗目的。
对于该放射医学应用,靶细胞受体结合部分通常与螯合剂连接,所述螯合剂能够与放射性核素的金属离子形成强络合物。然后将该放射性药物递送至靶细胞,并且放射性核素的衰变在靶位点释放高能电子、正电子或α粒子以及γ射线。
这些放射性药物产品的一个技术问题是放射性核素的衰变不断发生,例如,还发生在药物产品的制造期间和储存期间,并且释放的高能量发射引起形成药物产品的一部分的分子的化学键的裂解。这通常被称为放射性分解或放射性分解降解。药物的受体结合部分的放射性分解降解可导致其作为诊断和/或治疗剂的功效降低。
这些放射性药物产品的稳定性差且它们缺乏任何显著的保质期,所以要求这些药物到目前为止在医院的实验室中作为单独患者的剂量单位制造并立即施用必须在该医院内且已经在等待放射治疗的患者。为了在医院实验室中促进此类药物制备,已经开发了“冷”(即非放射性)冷冻干燥试剂盒,其包含与不含放射性核素的螯合剂连接的细胞受体结合部分。然后在施用之前即刻用放射性核素溶液重构那些试剂盒小瓶的冷冻干燥的内容物(Das等人J Radioanal Nucl Chem[放射性核素化学杂志]2014,299,1389-1398;Das等人Current Radiopharmaceuticals[当代放射性药物]2014,7,12-19;Luna-Gutierrez等人JRadioanal Nucl Chem[放射性核素化学杂志]2017,314,2181-2188)。然而,这些试剂盒不是“即用型”,因为它们需要重构步骤和另外的进一步加工步骤(例如,对络合反应施加热量)以及在最终施用药物之前的纯化和灭菌步骤。
为了减少放射性药物产品的放射性分解并因此提高稳定性,已经探索了多种策略,并或多或少取得了成功:该药物产品可以在低温下储存,或者以高稀释度生产,或者可以添加稳定剂。
然而,添加稳定剂可能是有问题的,因为这些化学品可能具有对放射性核素与螯合剂的络合作用的负面影响,或者可能具有有限的溶解度并且从溶液中沉淀出来。已报道乙醇是抗放射性分解的稳定剂(WO 2008/009444)。虽然乙醇可能不会具有对络合作用或溶解度问题的负面影响,但输注溶液中较高量的乙醇可能具有生理学方面的问题,并且可能具有对药物产品的耐受性的负面影响。
以高稀释度生产药物产品的缺点是需要施用至患者大容量的输注溶液。为了患者的便利以及药物耐受性原因,非常希望提供高浓度的放射性药物产品。然而,那些高度浓缩的溶液特别容易发生放射性分解。因此,一方面,通过稀释药物产品避免放射性分解,另一方面,通过提供浓缩药物溶液避免患者在治疗期间的不适,如上两方面之间存在矛盾。在Mathur等人Cancer Biotherapy and Radiopharmaceuticals[癌症生物治疗和放射性药物],2017,32(7),266-273中已经报道了一种高浓度的产品,并声称为即用型。然而,该组合物在耐受性方面可能存在问题,因为其含有大量乙醇。
因此,设计可以以商业规模生产并作为高浓度(导致为患者提供方便的小输注量并且是高生理耐受性的组合物(例如不含有乙醇的组合物))的足够稳定和无菌的溶液形式递送的即用型放射性药物产品仍然是一个挑战。
发明内容
本发明人现在已经找到了一种设计和生产高浓度放射性核素络合物溶液的方法,该溶液即使在环境温度或短期升高的温度下储存也在化学和放射化学上非常稳定,因此它可以以商业规模生产并作为即用型放射性药物产品供应。
本发明提供于如下概述的各个方面:
一种药物水溶液,所述药物水溶液包含
(a)由如下形成的络合物
(ai)放射性核素,和
(aii)与螯合剂连接的细胞受体结合有机部分;以及
(b)至少一种抗放射性分解降解的稳定剂;
其中
所述放射性核素以其提供至少100MBq/mL,优选至少250MBq/mL的体积放射性的浓度存在。
所述一种或多种稳定剂(组分(b))以至少0.2mg/mL,优选至少0.5mg/mL,更优选至少1.0mg/mL,甚至更优选至少2.7mg/mL的总浓度存在。
一种药物水溶液,所述药物水溶液包含
(a)由如下形成的络合物
(ai)放射性核素177镥(Lu-177),以其提供为从250至500MBq/mL的体积放射性的浓度存在,和
(aii)连接生长抑素受体结合有机部分DOTA-TATE(奥索度曲肽(oxodotreotide))或DOTA-TOC(依多曲肽(edotreotide))的螯合剂;
(bi)作为抗放射性分解降解的第一稳定剂的龙胆酸或其盐,以从0.5至1mg/mL的浓度存在;
(bii)作为抗放射性分解降解的第二稳定剂的抗坏血酸或其盐,以从2.0至5.0mg/mL的浓度存在。
一种用于制造如上定义的所述药物水溶液的方法,所述方法包括以下方法步骤:
(1)通过如下形成放射性核素和连接细胞受体结合有机部分的螯合剂的络合物
(1.1)制备包含所述放射性核素的水溶液;
(1.2)制备包含连接螯合剂的细胞受体结合有机部分、第一稳定剂、任选的第二稳定剂的水溶液;以及
(1.3)混合步骤(1.1)和(1.2)中得到的溶液并加热所得混合物;
(2)通过如下稀释通过步骤(1)得到的络合物溶液
(2.1)制备任选地包含第二稳定剂的水性稀释溶液;以及
(2.2.)将通过步骤(1)得到的络合物溶液与通过步骤(2.1)得到的稀释溶液混合。
本发明提供以下优点:
该高浓度允许在短时间内施用高剂量。例如,在177Lu-DOTA-TATE的情况下,可以以20.5至25.0mL的小体积提供7.4GBq的高剂量,这允许IV输注施用在约20至30分钟内完成。
根据本文所述的本发明使用合适的一种或多种稳定剂确保了高稳定性,对于细胞受体结合分子(即使这种分子是敏感的肽分子)在25℃下72小时后关于化学纯度的至少95%、96%、97%、98%、99%或100%的化学稳定性。例如,对于DOTA-TATE,在25℃下72小时后发现100%化学纯度,并且甚至在32℃下48小时后发现100%化学纯度。即使在短期升高的温度条件下(32℃下持续12小时和25℃下持续60小时),关于化学纯度发现了如此高的稳定性。
此外,根据本文所述的本发明使用合适的一种或多种稳定剂确保了高稳定性,关于放射化学纯度放射性核素络合物的至少95%的放射化学稳定性。例如,对于177Lu-DOTA-TATE,在25℃下72小时后发现至少95%的放射化学纯度。即使在短期升高的温度条件下(32℃下持续12小时和25℃下持续60小时),关于放射化学纯度发现了如此高的稳定性。
尽管使用单一稳定剂已经实现了足够的稳定性,但已发现使用两种稳定剂特别适合稳定敏感的放射性药物溶液。具体地,在络合物形成期间存在一种稳定剂和在络合物形成后添加另一种稳定剂是有利的,因为一种稳定剂确保在络合反应期间已经保护细胞受体结合分子免于放射性分解并且另一种稳定剂增强对于保质期保护作用。
此外,通过这种两种稳定剂的顺序施用,确保在络合期间仅存在相对少量的稳定剂(这使该稳定剂与络合反应的潜在干扰最小化)并且在络合之后存在大量稳定剂组合(这增强了稳定剂对随后药物储存时间期间的保护能力)。
这种两种稳定剂的顺序施用还降低了那些稳定剂的总热应力,因为当涉及高温的络合反应发生时,其中一种稳定剂不存在。
此外,特别是使用两种不同的稳定剂是有利的,因为这种组合在与可能由细胞受体结合分子的放射性分解形成的各种不同的基团反应方面比仅仅一种单一的稳定剂在上述方面更有效。
放射性药物溶液的组合物不需要乙醇的存在。该溶液在没有乙醇的情况下足够稳定。关于溶液的生理耐受性,不存在乙醇是有利的。
需要至少3天的保质期以允许放射性药物产品从集中式药物生产场所制造并将其商品化为即用型药物产品。
因此,由于高稳定性(在25℃下72小时),本发明允许以最高质量标准(例如,cGMP)和以工业规模集中化的药物生产,例如以74GBq或148GBq的批量大小,这提供多个剂量单位的药物产品,例如可同时治疗10至20名患者的足够的剂量单位的药物产品。
此外,由于高稳定性,本发明有足够的时间从集中式药物生产场所运送到远的临床中心。
甚至进一步,由于高稳定性,本发明可以作为即用型输注溶液提供,其可以立即施用至患者,而无需临床人员在施用前进行任何准备工作。
本发明特别适用于生长抑素受体结合肽,特别是对于非常敏感的生长抑素类似物奥曲肽(octreotide)和奥曲塔特(octreotate),它们特别易于发生降解反应。此外,本发明特别适用于具有特定放射性特征的放射性核素镥-177。
具体实施方式
下文更详细地描述并例示本发明。
通常,本发明涉及药物水溶液,特别是放射性药物水溶液。该溶液用于静脉内(IV)使用/应用/施用。该溶液是稳定的,浓缩的,且为即用型。
通过使用抗放射性分解降解的稳定剂确定溶液的稳定性。
通常,根据本发明使用的稳定剂可选自龙胆酸(2,5-二羟基苯甲酸)或其盐、抗坏血酸(L-抗坏血酸、维生素C)或其盐(例如抗坏血酸钠)、蛋氨酸、组氨酸、褪黑素、乙醇和Se-蛋氨酸。优选的稳定剂选自龙胆酸或其盐和抗坏血酸或其盐。
乙醇被认为是不太优选的稳定剂,因为如果以较高浓度存在,则存在其相关的耐受性问题。在本发明的溶液中应理想地避免乙醇(换句话说:不含乙醇),至少应限制本发明溶液中乙醇的量,例如预期待注射/输注的最终溶液中少于5%,优选少于2%,更优选少于1%。甚至更优选地,该溶液不含乙醇。
根据本发明,提供以下实施例:
1.一种药物水溶液,所述药物水溶液包含
(a)由如下形成的络合物
(ai)放射性核素,和
(aii)与螯合剂连接的细胞受体结合有机部分;以及
(b)至少一种抗放射性分解降解的稳定剂;
其中
所述放射性核素以其提供至少100MBq/mL,优选至少250MBq/mL的体积放射性的浓度存在。
2.根据实施例1所述的药物水溶液,
其中所述一种或多种稳定剂(组分(b))以至少0.2mg/mL,优选至少0.5mg/mL,更优选至少1.0mg/mL,甚至更优选至少2.7mg/mL的总浓度存在。
3.根据前述实施例中任一项所述的药物水溶液,其中所述放射性核素以其提供从100至1000MBq/mL,优选从250至500MBq/mL的体积放射性的浓度存在。
4.根据前述实施例中任一项所述的药物水溶液,其中所述一种或多种稳定剂以从0.2至20.0mg/mL,优选从0.5至10.0mg/mL,更优选从1.0至5.0mg/mL,甚至更优选从2.7至4.1mg/mL的总浓度存在。
5.根据前述实施例中任一项所述的药物水溶液,
其中组分(b)是仅一种抗放射性分解降解的稳定剂,即仅第一稳定剂。
6.根据前述实施例中任一项所述的药物水溶液,
其中组分(b)是至少两种抗放射性分解降解的稳定剂,即至少第一和第二稳定剂,优选仅两种稳定剂,即仅第一和第二稳定剂。
7.根据实施例5至6中任一项所述的药物水溶液,其中所述第一稳定剂以从0.2至5mg/mL,优选从0.5至5mg/mL,更优选从0.5至2mg/mL,甚至更优选从0.5至1mg/mL,甚至更优选从0.5至0.7mg/mL的浓度存在。
8.根据实施例6或7中任一项所述的药物水溶液,其中所述第二稳定剂以从0.5至10mg/mL,更优选从1.0至8.0mg/mL,甚至更优选从2.0至5.0mg/mL,甚至更优选从2.2至3.4mg/mL的浓度存在。
9.根据前述实施例中任一项所述的药物水溶液,其中所述一种或多种稳定剂选自龙胆酸(2,5-二羟基苯甲酸)或其盐、抗坏血酸(L-抗坏血酸、维生素C)或其盐(例如抗坏血酸钠)、蛋氨酸、组氨酸、褪黑素、乙醇和Se-蛋氨酸,优选地选自龙胆酸或其盐和抗坏血酸或其盐。
10.根据实施例5至9中任一项所述的药物水溶液,其中所述第一稳定剂选自龙胆酸和抗坏血酸,优选地所述第一稳定剂是龙胆酸。
11.根据实施例6至10中任一项所述的药物水溶液,其中所述第二稳定剂选自龙胆酸和抗坏血酸,优选地所述第二稳定剂是抗坏血酸。
12.根据实施例6至8中任一项所述的药物水溶液,其中所述第一稳定剂是龙胆酸或其盐,并且所述第二稳定剂是抗坏血酸或其盐,并且所述第一稳定剂的浓度(以mg/mL计)与所述第二稳定剂的浓度(以mg/mL计)的比值为从1:3至1:7,优选从1:4至1:5。
13.根据前述实施例中任一项所述的药物水溶液,其中所述放射性核素选自177Lu、68Ga、18F、99mTc、211At、82Rb、166Ho、225Ac、111In、123I、131I、89Zr、90Y,优选地选自177Lu和68Ga,更优选为177Lu。
14.根据前述实施例中任一项所述的药物水溶液,其中所述细胞受体结合部分是生长抑素受体结合肽,优选地所述生长抑素受体结合肽选自奥曲肽、奥曲塔特、兰瑞肽(lanreotide)、伐普肽(vapreotide)和帕瑞肽(pasireotide),优选地选自奥曲肽和奥曲塔特。
15.根据前述实施例中任一项所述的药物水溶液,其中所述螯合剂选自DOTA、DTPA、NTA、EDTA、DO3A、NOC和NOTA,优选DOTA。
16.根据前述实施例中任一项所述的药物水溶液,其中所述细胞受体结合部分和所述螯合剂一起形成选自DOTA-OC、DOTA-TOC(依多曲肽)、DOTA-NOC、DOTA-TATE(奥索度曲肽)、DOTA-LAN、和DOTA-VAP的分子,优选地选自DOTA-TOC和DOTA-TATE的分子,更优选地是DOTA-TATE。
17.根据前述实施例中任一项所述的药物水溶液,其中所述放射性核素、所述细胞受体结合部分和所述螯合剂一起形成络合物177Lu-DOTA-TOC(177Lu-依多曲肽)或177Lu-DOTA-TATE(177Lu-奥索度曲肽),优选177Lu-DOTA-TATE。
18.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液进一步包含缓冲液,优选地所述缓冲液是乙酸盐缓冲液,优选地以得到从0.3至0.7mg/mL(优选约0.48mg/mL)乙酸浓度和从0.4至0.9mg/mL(优选约0.66mg/mL)乙酸钠的量。
19.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液进一步包含多价螯合剂,优选地所述多价螯合剂是二乙烯三胺五乙酸(DTPA)或其盐,优选地以得到从0.01至0.10mg/mL(优选约0.05mg/mL)的浓度的量。
20.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液具有在≤25℃下至少24小时(h)、在≤25℃下至少48h、在≤25℃下至少72h、在≤25℃下从24h至120h、在≤25℃下从24h至96h、在≤25℃下从24h至84h、在≤25℃下从24h至72h的保质期,特别地具有在≤25℃下72h的保质期。
21.根据前述实施例中任一项所述的药物水溶液,其中所述溶液以商业规模制造进行生产,特别是以至少20GBq、至少50GBq、至少70GBq的批量大小进行生产。
22a.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液是即用型的。
22b.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液用于商业用途。
23.一种药物水溶液,所述药物水溶液包含
(a)由如下形成的络合物
(ai)放射性核素177镥(Lu-177),以其提供为从250至500MBq/mL的体积放射性的浓度存在,和
(aii)连接生长抑素受体结合有机部分DOTA-TATE(奥索度曲肽)或DOTA-TOC(依多曲肽)的螯合剂;
(bi)作为抗放射性分解降解的第一稳定剂的龙胆酸或其盐,以从0.5至1mg/mL的浓度存在;
(bii)作为抗放射性分解降解的第二稳定剂的抗坏血酸或其盐,以从2.0至5.0mg/mL的浓度存在。
24.根据实施例23所述的药物水溶液,所述药物水溶液进一步包含:
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐。
25.根据实施例23或24所述的药物水溶液,所述药物水溶液进一步包含:
(d)浓度为从0.3至0.7mg/mL的乙酸,和浓度为0.4至0.9mg/mL的乙酸钠。
26.根据前述实施例中任一项所述的药物水溶液,其中所述一种或多种稳定剂在组分(ai)和(aii)的络合物形成期间存在于溶液中。
27.根据实施例5至26中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间仅存在所述第一稳定剂,优选地以在最终溶液中得到从0.5至5mg/mL,更优选从0.5至2mg/mL、甚至更优选从0.5至1mg/mL、甚至更优选从0.5至0.7mg/mL的浓度的量。
28.根据实施例6至27中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间,部分量的所述第二稳定剂已经存在于溶液中,并且在组分(ai)和(aii)的络合物形成后添加另一部分量的所述第二稳定剂。
29.根据实施例6至28中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成后添加所述第二稳定剂。
30.根据实施例6或29所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成后添加所述第二稳定剂,优选地以在最终溶液中得到从0.5至10mg/mL,更优选从1.0至8.0mg/mL、甚至更优选从2.0至5.0mg/mL、甚至更优选从2.2至3.4mg/mL的浓度的量。
31.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液进一步包含多价螯合剂,其在组分(ai)和(aii)的络合物形成后添加,用于除去任何未络合的Lu,优选地所述多价螯合剂是二乙烯三胺五乙酸(DTPA)或其盐,优选地以在最终溶液中得到从0.01至0.10mg/mL(优选约0.05mg/mL)的浓度的量。
32.一种用于制造如前述实施例中任一项所定义的药物水溶液的方法,所述方法包括以下方法步骤:
(1)通过如下形成放射性核素和连接细胞受体结合有机部分的螯合剂的络合物
(1.1)制备包含所述放射性核素的水溶液;
(1.2)制备包含连接螯合剂的细胞受体结合有机部分、第一稳定剂、任选的第二稳定剂的水溶液;以及
(1.3)混合步骤(1.1)和(1.2)中得到的溶液并加热所得混合物;
(2)通过如下稀释通过步骤(1)得到的络合物溶液
(2.1)制备任选地包含第二稳定剂的水性稀释溶液;以及
(2.2.)将通过步骤(1)得到的络合物溶液与通过步骤(2.1)得到的稀释溶液混合。
33.根据实施例32所述的方法,其中在步骤(1.3)期间仅存在所述第一稳定剂,优选地以在最终溶液中得到从0.5至5mg/mL,更优选从0.5至2mg/mL、甚至更优选从0.5至1mg/mL、甚至更优选从0.5至0.7mg/mL的浓度的量。
34.根据实施例32至33中任一项所述的方法,其中在步骤(1.3)期间,部分量的所述第二稳定剂已经存在于溶液中,并且在步骤(1.3)之后在步骤(2.1)中添加另一部分量的所述第二稳定剂。
35.根据实施例32至34中任一项所述的药物水溶液,其中在步骤(1.3)之后在步骤(2.1)中添加所述第二稳定剂。
36.根据实施例32-35中任一项所述的药物水溶液,其中在步骤(1.3)之后在步骤(2.1)中添加所述第二稳定剂,优选地以在最终溶液中得到从0.5至10mg/mL,更优选从1.0至8.0mg/mL、甚至更优选从2.0至5.0mg/mL、甚至更优选从2.2至3.4mg/mL的浓度的量。
37.根据实施例32至36中任一项所述的方法,其中步骤(1.2)的溶液进一步包含缓冲液,优选乙酸盐缓冲液。
38.根据实施例32至37中任一项所述的方法,其中在步骤(1.3)中,将所得混合物加热至从70℃至99℃、优选从90℃至98℃的温度,持续从2至59分钟。
39.根据实施例32至38中任一项所述的方法,其中步骤(2.1)的溶液进一步包含二乙烯三胺五乙酸(DTPA)或其盐。
40.根据实施例32至39中任一项所述的方法,该方法进一步包括以下方法步骤:
(3)将步骤(2)得到的溶液过滤通过0.2μm:
(4)将通过步骤(3)得到的过滤的溶液以递送如下放射性剂量所需要的体积分配到剂量单位容器中:从5.0至10MBq、优选从7.0至8.0MBq、更优选从7.3至7.7MBq、甚至更优选从7.4-7.5MBq、优选地所述体积为从10至50mL、更优选从15至30mL、甚至更优选从20至25mL。
41.根据实施例32至40中任一项所述的方法,其中步骤(1.1)的溶液包含LuCl3和HCl。
42.根据实施例32至41中任一项所述的方法,其中步骤(1.2)的溶液包含177Lu-DOTA-TATE或177Lu-DOTA-TOC、龙胆酸、乙酸和乙酸钠。
43.根据实施例32至42中任一项所述的方法,其中步骤(2.1)的溶液包含DTPA和抗坏血酸。
44.根据实施例32至43中任一项所述的方法,其中步骤(4)中的剂量单位容器是封闭在铅容器内的带塞的小瓶。
45.一种通过权利要求32至44中任一项所定义的方法得到的(或可得到的)药物水溶液。
在以下作为“E实施例”中描述了本发明的进一步的实施例:
E1.一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;以及
(b)至少两种不同的抗放射性分解降解的稳定剂;
其中
所述放射性核素以其提供从250至500MBq/mL的体积放射性的浓度存在;以及
所述稳定剂以0.2至20.0mg/mL的总浓度存在。
“由……形成的络合物”可以可替代地表达为:“……的络合物”。
“两种不同稳定剂”中的“不同”是指此类稳定剂的化学实体的差异。“两种不同的稳定剂”具有两种稳定剂是不同的化学实体的含义,例如,龙胆酸和抗坏血酸是两种不同的稳定剂。
“至少两种”意指两种或更多种,然而,优选仅存在两种稳定剂(不是三种或更多种)。进一步优选的是乙醇不是两种稳定剂之一。
E2.根据实施例E1所述的药物水溶液,
其中所述组分(b)包含稳定剂:
(bi)龙胆酸或其盐;以及
(bii)抗坏血酸或其盐。
E3.根据实施例E2所述的药物水溶液,
其中
(bi)龙胆酸以从0.5至2mg/mL、优选从0.5至1mg/mL的浓度存在;以及
(bii)抗坏血酸以从2.0至5.0mg/mL的浓度存在。
在一个具体实施例中,本发明提供了:
一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),浓度为其提供从250至500MBq/mL的体积放射性,和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;以及
(b)抗放射性分解降解的稳定剂
(bi)浓度为从0.5至1mg/mL的龙胆酸和
(bii)浓度为从2.0至5.0mg/mL的抗坏血酸。
E4.根据实施例E3所述的药物水溶液,所述药物水溶液进一步包含:
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐。
E5.根据实施例E3或E4所述的药物水溶液,所述药物水溶液进一步包含:
(d)乙酸盐缓冲液,其由以下构成:
(di)浓度为从0.3至0.7mg/mL的乙酸;以及
(dii)浓度为0.4至0.9mg/mL的乙酸钠;
优选地,所述乙酸盐缓冲液提供从4.5至6.0、优选从4.7至6.0、更优选从5.0至6.0、甚至更优选从5.0至5.5的pH。
在一个具体实施例中,本发明提供了:
一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),浓度为其提供从250至500MBq/mL的体积放射性,和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;
(b)抗放射性分解降解的稳定剂:(bi)浓度为从0.5至1mg/mL的龙胆酸和(bii)浓度为从2.0至5.0mg/mL的抗坏血酸;
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐;以及
(d)乙酸盐缓冲液,其由以下构成:
(di)浓度为从0.3至0.7mg/mL的乙酸;以及
(dii)浓度为0.4至0.9mg/mL的乙酸钠;
优选地,所述乙酸盐缓冲液提供从5.0至5.5的pH。
本文指出的pH值是最终溶液的pH值。然而,它也是溶液制造过程中的pH值,例如,络合物形成过程中的pH值。
E6.根据实施例E1至E5中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在所述稳定剂中的至少一种,并且在组分(ai)和(aii)的络合物形成后添加所述稳定剂中的至少一种。
E7.根据实施例E1至E5中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间至少存在龙胆酸,并且在组分(ai)和(aii)的络合物形成后至少添加抗坏血酸。
E8.根据实施例E1至E5中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在的唯一的稳定剂是龙胆酸,并且在组分(ai)和(aii)的络合物形成后添加的唯一的稳定剂是抗坏血酸。
在一个具体实施例中,本发明提供了:
一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),浓度为其提供从250至500MBq/mL的体积放射性,和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;以及
(b)抗放射性分解降解的稳定剂
(bi)浓度为从0.5至1mg/mL(在最终溶液中)的龙胆酸和
(bii)浓度为从2.0至5.0mg/mL(在最终溶液中)的抗坏血酸;
其中在组分(ai)和(aii)的络合物形成期间存在龙胆酸,并且在组分(ai)和(aii)的络合物形成后添加抗坏血酸。
在一个具体实施例中,如下定义本发明:
一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),浓度为其提供从250至500MBq/mL的体积放射性,和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;
(b)抗放射性分解降解的稳定剂:(bi)浓度为从0.5至1mg/mL的龙胆酸和(bii)浓度为从2.0至5.0mg/mL的抗坏血酸;
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐;以及
(d)乙酸盐缓冲液,其由以下构成:
(di)浓度为从0.3至0.7mg/mL的乙酸;以及
(dii)浓度为0.4至0.9mg/mL的乙酸钠;
优选地,所述乙酸盐缓冲液提供从5.0至5.5的pH;
其中在组分(ai)和(aii)的络合物形成期间存在龙胆酸,并且在组分(ai)和(aii)的络合物形成后添加抗坏血酸。
E9.根据实施例E6至E8中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在的一种或多种所述稳定剂在络合物配制期间以从15至50mg/mL,优选从20至40mg/mL的总浓度存在。
E10.根据实施例E9所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在的唯一的稳定剂是龙胆酸并且在络合物配制期间以从20至40mg/mL,优选从25至35mg/mL的浓度存在。
在一个具体实施例中,如下定义本发明:
一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),浓度为其提供从250至500MBq/mL的体积放射性,和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;
(b)抗放射性分解降解的稳定剂:(bi)浓度为从0.5至1mg/mL的龙胆酸和(bii)浓度为从2.0至5.0mg/mL的抗坏血酸;
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐;以及
(d)乙酸盐缓冲液,其由以下构成:
(di)浓度为从0.3至0.7mg/mL的乙酸;以及
(dii)浓度为0.4至0.9mg/mL的乙酸钠;
优选地,所述乙酸盐缓冲液提供从5.0至5.5的pH;
其中在组分(ai)和(aii)的络合物形成期间存在龙胆酸,并且在组分(ai)和(aii)的络合物形成后添加抗坏血酸;以及其中在组分(ai)和(aii)的络合物形成期间存在的唯一的稳定剂是龙胆酸并且在络合物配制期间以从20至40mg/mL,优选从25至35mg/mL的浓度存在。
可替代地,实施例E6至E10可以通过以下措辞来定义:
E6.根据实施例E1至E5中任一项所述的药物水溶液,其通过在组分(ai)和(aii)的络合物形成期间存在所述稳定剂中的至少一种,和在组分(ai)和(aii)的络合物形成后添加所述稳定剂中的至少一种而产生。
E7.根据实施例E1至E5中任一项所述的药物水溶液,其通过在组分(ai)和(aii)的络合物形成期间存在至少龙胆酸,和在组分(ai)和(aii)的络合物形成后添加至少抗坏血酸而产生。
E8.根据实施例E1至E5中任一项所述的药物水溶液,其通过在组分(ai)和(aii)的络合物形成期间存在作为唯一的稳定剂的龙胆酸,和在组分(ai)和(aii)的络合物形成后添加作为唯一的稳定剂的抗坏血酸而产生。
E9.根据实施例E6至E8中任一项所述的药物水溶液,其通过在组分(ai)和(aii)的络合物形成期间存在的一种或多种所述稳定剂在络合物形成期间以从15至50mg/mL,优选从20至40mg/mL的总浓度存在而产生。
E10.根据实施例E9所述的药物水溶液,其通过在组分(ai)和(aii)的络合物形成期间存在作为唯一的稳定剂的龙胆酸并且在络合物配制期间以从20至40mg/mL,优选从25至35mg/mL的浓度存在而产生。
在本发明的实施例中,特别是在实施例E9和E10中,该放射性核素可以在络合物形成期间以其提供高达20GBq/mL、优选高达15GBq/mL、或从5至20GBq/mL、优选从10至20GBq/mL、更优选从10至15GBq/mL的体积放射性的浓度存在。
在一个具体实施例中,如下定义本发明:
一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),浓度为其提供从250至500MBq/mL的体积放射性(在最终溶液中),和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;
(b)抗放射性分解降解的稳定剂:(bi)浓度为从0.5至1mg/mL的龙胆酸和(bii)浓度为从2.0至5.0mg/mL的抗坏血酸;
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐;以及
(d)乙酸盐缓冲液,其由以下构成:
(di)浓度为从0.3至0.7mg/mL的乙酸;以及
(dii)浓度为0.4至0.9mg/mL的乙酸钠;
优选地,所述乙酸盐缓冲液提供从5.0至5.5的pH;
其中在组分(ai)和(aii)的络合物形成期间存在龙胆酸,并且在组分(ai)和(aii)的络合物形成后添加抗坏血酸;并且其中在组分(ai)和(aii)的络合物形成期间存在的唯一的稳定剂是龙胆酸并且在络合物配制期间以从20至40mg/mL的浓度存在;
并且其中该放射性核素在络合物形成期间以其提供10至20GBq/mL的体积放射性的浓度存在。
E11.根据前述E实施例中任一项所述的药物水溶液,所述药物水溶液在≤25℃下储存时具有至少72小时的保质期,特别是当在25℃下储存时具有至少72小时的保质期。
“保质期”在本文中具有其在药物产品的上下文中的一般含义。保质期是药物产品可以储存同时其产品特征仍然符合药物开发过程中定义的并经卫生当局同意的产品规格的时间长度。
E12.根据前述E实施例中任一项所述的药物水溶液,其放射化学纯度(通过HPLC测定)在25℃下储存时保持≥95%持续至少72小时。
E13.根据前述E实施例中任一项所述的药物水溶液,其中所述溶液以商业制造规模进行生产,特别是以至少20GBq、至少50GBq、至少70GBq的批量大小进行生产。
E14.根据前述实施例中任一项所述的药物水溶液,所述药物水溶液是即用型的。
E15.一种用于制造如前述E实施例中任一项所定义的药物水溶液的方法,所述方法包括以下方法步骤:
(1)通过如下形成放射性核素177Lu和与螯合剂DOTA连接的生长抑素受体结合肽的络合物
(1.1)制备包含所述放射性核素的水溶液;
(1.2)制备包含与所述螯合剂连接的生长抑素受体结合肽和至少一种抗放射性分解降解的稳定剂的水溶液;以及
(1.3)混合步骤(1.1)和(1.2)中得到的溶液并加热所得混合物;
(2)通过如下稀释通过步骤(1)得到的络合物溶液
(2.1)制备任选地包含至少一种抗放射性分解降解的稳定剂的水性稀释溶液;以及
(2.2.)将通过步骤(1)得到的络合物溶液与通过步骤(2.1)得到的稀释溶液混合以获得最终溶液;
其中如果在(1.2)下制备的溶液仅包含一种稳定剂,则在(2.1)下制备的溶液包含至少一种稳定剂。
E16.根据实施例E15所述的方法,其中步骤(1.2)中制备的溶液包含至少一种稳定剂,且步骤(2.1)中制备的溶液包含至少一种稳定剂。
E17.根据实施例E15所述的方法,其中步骤(1.2)中制备的溶液至少包含稳定剂龙胆酸,且步骤(2.1)中制备的溶液至少包含稳定剂抗坏血酸。
E18.根据实施例E15所述的方法,其中步骤(1.2)中制备的溶液仅包含一种稳定剂,所述稳定剂为龙胆酸;并且步骤(2.1)中制备的溶液仅包含一种稳定剂,所述稳定剂为抗坏血酸。
E19.根据实施例E15至E18中任一项所述的方法,其中步骤(1.2)中制备的溶液包含总浓度为从15至50mg/mL、优选从20至40mg/mL的一种或多种稳定剂。
E20.根据实施例E15至E18中任一项所述的方法,其中步骤(1.2)中制备的溶液仅包含一种稳定剂,所述稳定剂为浓度从20至40mg/mL、优选从25至35mg/mL的龙胆酸。
E21.根据实施例E15至E20中任一项所述的方法,其中步骤(1.2)的溶液进一步包含缓冲液,优选乙酸盐缓冲液。
E22.根据实施例E15至E21中任一项所述的方法,其中在步骤(1.3)中,将所得混合物加热至从70℃至99℃、优选从90℃至98℃的温度,持续从2至59分钟、优选从10至15分钟。
E23.根据实施例E15至E22中任一项所述的方法,其中步骤(2.1)的溶液进一步包含二乙烯三胺五乙酸(DTPA)或其盐。
E24.根据实施例E15至E23中任一项所述的方法,所述方法进一步包括以下方法步骤:
(3)将步骤(2)得到的溶液过滤通过0.2μm:
(4)将通过步骤(3)得到的过滤的溶液以递送如下放射性剂量所需要的体积分配到剂量单位容器中:从5.0至10MBq、优选从7.0至8.0MBq、更优选从7.3至7.7MBq、甚至更优选从7.4-7.5MBq、优选地所述体积为从10至50mL、更优选从15至30mL、甚至更优选从20至25mL。
E25.根据实施例E15至E24中任一项所述的方法,其中步骤(1.1)的溶液包含LuCl3和HCl。
E26.根据实施例E15至E25中任一项所述的方法,其中步骤(1.2)的溶液包含177Lu-DOTA-TATE或177Lu-DOTA-TOC、龙胆酸、乙酸和乙酸钠。
E27.根据实施例E15至E26中任一项所述的方法,其中步骤(2.1)的溶液包含DTPA和抗坏血酸。
E28.根据实施例E24至E27中任一项所述的方法,其中步骤(4)中的剂量单位容器是封闭在铅容器内的带塞的小瓶。
E29.一种通过实施例E15至E28中任一项所定义的方法获得(或:可获得)的药物水溶液。
在如本文所述的所有实施例中,与螯合剂DOTA(组分(aii))连接的生长抑素受体结合肽优选为DOTA-TATE(奥索度曲肽)或DOTA-TOC(依多曲肽),更优选为DOTA-TATE(奥索度曲肽)。
本发明进一步提供如本文所定义的药物水溶液,其用于治疗神经内分泌肿瘤(NET)。
可替代地,本发明提供用于治疗需要该治疗的人类患者的NET的方法,所述方法包括施用有效量的如本文所定义的药物水溶液。
作为又一替代方案,本发明提供了如本文所定义的药物水溶液用于制造/制备用于治疗NET的药剂的用途。
作为又一替代方案,本发明提供了用于治疗NET的药剂,其包含如本文所定义的药物水溶液。
可以通过如本文所定义的药物水溶液单独或根据本发明以组合治疗的神经内分泌肿瘤(NET)选自下组,该组由以下组成:胃肠胰神经内分泌肿瘤、类癌肿瘤、嗜铬细胞瘤、副神经节瘤、甲状腺髓样癌、肺神经内分泌肿瘤、胸腺神经内分泌肿瘤、类癌肿瘤或胰腺神经内分泌肿瘤、垂体腺瘤、肾上腺肿瘤、梅克尔细胞癌(Merkel cell carcinoma)、乳腺癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、头颈部肿瘤、尿路上皮癌(膀胱)、肾细胞癌、肝细胞癌、GIST、神经母细胞瘤、胆管肿瘤、***、尤文肉瘤、骨肉瘤、小细胞肺癌(SCLC)、***癌、黑色素瘤、脑膜瘤、胶质瘤、成神经管细胞瘤、成血管细胞瘤、幕上原始神经外胚层肿瘤和嗅神经母细胞瘤。
可以通过如本文所定义的药物水溶液单独或根据本发明以组合治疗的其他NET肿瘤选自下组,该组由以下组成:功能性类癌肿瘤、胰岛瘤、胃泌素瘤、血管活性肠肽(VIP)瘤、胰高血糖素瘤、血清素瘤(serotoninoma)、组胺瘤(histaminoma)、促肾上腺皮质激素腺瘤(ACTH腺瘤(ACTHoma))、嗜铬细胞瘤、和生长抑素瘤。
本发明进一步提供了由放射性核素177Lu(镥-177)和与如本文定义的螯合剂连接的生长抑素受体结合肽形成的络合物的组合或组合疗法,或如本文所定义的药物水溶液与如下所述的一种或多种治疗剂一起的组合或组合疗法:
在某些情况下,将本发明的药物水溶液与其他治疗剂(如其他抗癌剂、抗过敏剂、抗恶心剂(或止吐剂)、止痛剂、细胞保护剂、及其组合)组合。
考虑用于组合疗法中的一般化学治疗剂包括阿那曲唑比卡鲁胺硫酸博莱霉素白消安白消安注射液卡培他滨N4-戊氧羰基-5-脱氧-5-氟胞苷、卡铂卡莫司汀苯丁酸氮芥顺铂克拉屈滨环磷酰胺(或)、阿糖胞苷、胞嘧啶***糖苷阿糖胞苷脂质体注射液达卡巴嗪更生霉素(放线菌素D、Cosmegan)、盐酸柔红霉素柠檬酸柔红霉素脂质体注射液***、多西他赛盐酸阿霉素依托泊苷磷酸氟达拉滨5-氟尿嘧啶氟他胺替扎他滨(tezacitibine)、吉西他滨(双氟脱氧胞苷)、羟基脲伊达比星异环磷酰胺伊立替康L-天冬酰胺酶亚叶酸钙、美法仑6-巯嘌呤甲氨蝶呤米托蒽醌吉妥单抗(mylotarg)、紫杉醇白蛋白结合型紫杉醇phoenix(Yttrium90/MX-DTPA)、喷司他丁(pentostatin)、聚苯丙生(polifeprosan)20与卡莫司汀的植入物枸橼酸它莫西芬替尼泊苷6-硫代鸟嘌呤、噻替派、替拉扎明注射用盐酸托泊替康长春花碱长春新碱和长春瑞滨
与本发明药物水溶液组合的特别感兴趣的抗癌剂包括:
酪氨酸激酶抑制剂:盐酸埃罗替尼利尼法尼(Linifanib)(N-[4-(3-氨基-1H-吲唑-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲,也称为ABT869,可购自基因泰克公司(Genentech));苹果酸舒尼替尼柏舒替尼(Bosutinib)(4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-甲腈,也称为SKI-606,并且描述于美国专利号6,780,996);达沙替尼(Dasatinib)帕唑帕尼索拉非尼凡德他尼(ZD6474);和伊马替尼或甲磺酸伊马替尼(和)。
血管内皮生长因子(VEGF)受体抑制剂:贝伐赛珠单抗阿昔替尼丙氨酸布立尼布(Brivanib alaninate)(BMS-582664,(S)-((R)-1-(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基氧基)丙-2-基)2-氨基丙酸);索拉非尼帕唑帕尼苹果酸舒尼替尼西地尼布(Cediranib)(AZD2171,CAS 288383-20-1);维加特(Vargatef)(BIBF1120,CAS 928326-83-4);氟列替布(Foretinib)(GSK1363089);替拉替尼(Telatinib)(BAY57-9352,CAS 332012-40-5);阿帕替尼(Apatinib)(YN968D1,CAS811803-05-1);伊马替尼(Imatinib)普纳替尼(Ponatinib)(AP24534,CAS943319-70-8);替沃扎尼(Tivozanib)(AV951,CAS 475108-18-0);瑞格非尼(Regorafenib)(BAY73-4506,CAS 755037-03-7);瓦他拉尼二盐酸盐(Vatalanib dihydrochloride)(PTK787,CAS 212141-51-0);布立尼布(Brivanib)(BMS-540215,CAS 649735-46-6);凡德他尼(Vandetanib)(或AZD6474);莫特塞尼二磷酸盐(Motesanibdiphosphate)(AMG706,CAS 857876-30-3,N-(2,3-二氢-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)氨基]-3-吡啶甲酰胺,在PCT公开号WO 02/066470中有所描述);多韦替尼二乳酸(Dovitinib dilactic acid)(TKI258,CAS 852433-84-2);Linfanib(ABT869,CAS796967-16-3);卡博替尼(Cabozantinib)(XL184,CAS 849217-68-1);来他替尼(Lestaurtinib)(CAS 111358-88-4);N-[5-[[[5-(1,1-二甲基乙基)-2-噁唑基]甲基]硫代]-2-噻唑基]-4-哌啶甲酰胺(BMS38703,CAS 345627-80-7);(3R,4R)-4-氨基-1-((4-((3-甲氧基苯基)氨基)吡咯并[2,1-f][1,2,4]三嗪-5-基)甲基)哌啶-3-醇(BMS690514);N-(3,4-二氯-2-氟苯基)-6-甲氧基-7-[[(3aα,5β,6aα)-八氢-2-甲基环戊二烯并[c]吡咯-5-基]甲氧基]-4-喹唑啉胺(XL647,CAS 781613-23-8);4-甲基-3-[[1-甲基-6-(3-吡啶基)-1H-吡唑并[3,4-d]嘧啶-4-基]氨基]-N-[3-(三氟甲基)苯基]-苯甲酰胺(BHG712,CAS940310-85-0);以及阿柏西普(Aflibercept)索凡替尼(sulfatinib、surufatinib)。
血小板源性生长因子(PDGF)受体抑制剂:伊马替尼(Imatinib)利尼法尼(Linifanib)(N-[4-(3-氨基-1H-吲唑-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲,也称为ABT 869,可购自基因泰克公司(Genentech));苹果酸舒尼替尼奎扎替尼(Quizartinib)(AC220,CAS 950769-58-1);帕唑帕尼阿昔替尼(Axitinib)索拉非尼维加特(Vargatef)(BIBF1120,CAS928326-83-4);替拉替尼(Telatinib)(BAY57-9352,CAS 332012-40-5);瓦他拉尼二盐酸盐(Vatalanib dihydrochloride)(PTK787,CAS 212141-51-0);以及莫特塞尼二磷酸盐(Motesanib diphosphate)(AMG706,CAS 857876-30-3,N-(2,3-二氢-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)氨基]-3-吡啶甲酰胺,在PCT公开号WO 02/066470中有所描述)。
成纤维细胞生长因子受体(FGFR)抑制剂:丙氨酸布立尼布(Brivanib alaninate)(BMS-582664,(S)-((R)-1-(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基氧基)丙-2-基)2-氨基丙酸);维加特(Vargatef)(BIBF1120,CAS928326-83-4);多韦替尼二乳酸(Dovitinib dilactic acid)(TKI258,CAS 852433-84-2);3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲(BGJ398,CAS 872511-34-7);达鲁舍替(Danusertib)(PHA-739358);和N-[2-[[4-(二乙基氨基)丁基]氨基]-6-(3,5-二甲氧基苯基)吡啶并[2,3-d]嘧啶-7-基]-N'-(1,1-二甲基乙基)-脲(PD173074,CAS 219580-11-7)。索凡替尼(sulfatinib、surufatinib)。
极光激酶A抑制剂:达鲁舍替(Danusertib)(PHA-739358);N-[4-[[6-甲氧基-7-[3-(4-吗啉基)丙氧基]-4-喹唑啉基]氨基]苯基]苯甲酰胺(ZM447439,CAS 331771-20-1);4-(2-氨基-4-甲基-5-噻唑基)-N-[4-(4-吗啉基)苯基]-2-嘧啶胺(CYC116,CAS 693228-63-6);陶扎色替(Tozasertib)(VX680或MK-0457,CAS 639089-54-6);阿利舍替(Alisertib)(MLN8237);(N-{2-[6-(4-环丁基氨基-5-三氟甲基-嘧啶-2-基氨基)-(1S,4R)-1,2,3,4-四氢-1,4-表氮杂并(epiazano)-萘-9-基]-2-氧代-乙基}-乙酰胺)(PF-03814735);4-[[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂环庚三烯-2-基]氨基]-苯甲酸(MLN8054,CAS 869363-13-3);塞尼舍替(Cenisertib)(R-763);巴雷舍替(AZD1152);以及N-环丙基-N'-[3-[6-(4-吗啉基甲基)-1H-苯并咪唑-2-基]-1H-吡唑-4-基]-脲(AT9283)。
周期蛋白依赖性激酶(CDK)抑制剂:阿洛新A(Aloisine A);阿沃西地(Alvocidib)(也称为黄酮吡多或HMR-1275,2-(2-氯苯基)-5,7-二羟基-8-[(3S,4R)-3-羟基-1-甲基-4-哌啶基]-4-色满酮并描述于美国专利号5,621,002中);克佐替尼(Crizotinib)(PF-02341066,CAS 877399-52-5);2-(2-氯苯基)-5,7-二羟基-8-[(2R,3S)-2-(羟甲基)-1-甲基-3-吡咯烷基]-4H-1-苯并吡喃-4-酮盐酸盐(P276-00,CAS 920113-03-7);英迪舒兰(E7070);洛斯可维汀(Roscovitine)(CYC202);6-乙酰基-8-环戊基-5-甲基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-8H-吡啶并[2,3-d]嘧啶-7-酮,盐酸盐(PD 0332991);地那西利(Dinaciclib)(SCH 727965);N-[5-[[(5-叔丁基噁唑-2-基)甲基]硫代]噻唑-2-基]哌啶-4-甲酰胺(BMS 387032,CAS 345627-80-7);4-[[9-氯-7-(2,6-二氟苯基)-5H-嘧啶并[5,4-d][2]苯并氮杂环庚三烯-2-基]氨基]-苯甲酸(MLN8054,CAS 869363-13-3);5-[3-(4,6-二氟-1H-苯并咪唑-2-基)-1H-吲唑-5-基]-N-乙基-4-甲基-3-吡啶甲胺(AG-024322,CAS837364-57-5);4-(2,6-二氯苯甲酰基氨基)-1H-吡唑-3-甲酸N-(哌啶-4-基)酰胺(AT7519,CAS 844442-38-2);4-[2-甲基-1-(1-甲基乙基)-1H-咪唑-5-基]-N-[4-(甲基磺酰基)苯基]-2-嘧啶胺(AZD5438,CAS 602306-29-6);帕博西尼(PD-0332991);以及(2R,3R)-3-[[2-[[3-[[S(R)]-S-环丙基磺亚胺基]-苯基]氨基]-5-(三氟甲基)-4-嘧啶基]氧基]-2-丁醇(BAY 10000394),利波西利(ribociclib)。
细胞周期检测点激酶(CHK)抑制剂:7-氢氧十字孢碱(UCN-01);6-溴-3-(1-甲基-1H-吡唑-4-基)-5-(3R)-3-哌啶基-吡唑[1,5-a]嘧啶-7-胺(SCH 900776,CAS 891494-63-6);5-(3-氟苯基)-3-脲基噻吩-2-甲酸N-[(S)-哌啶-3-基]酰胺(AZD7762,CAS 860352-01-8);4-[((3S)-1-氮杂双环[2.2.2]辛-3-基)氨基]-3-(1H-苯并咪唑-2-基)-6-氯喹啉-2(1H)-酮(CHIR 124,CAS 405168-58-3);7-氨基放线菌素D(7-AAD)、Isogranulatimide、debromohymenialdisine;N-[5-溴-4-甲基-2-[(2S)-2-吗啉基甲氧基]-苯基]-N'-(5-甲基-2-吡嗪基)脲(LY2603618,CAS 911222-45-2);萝卜硫素(CAS 4478-93-7,4-甲基亚磺酰基丁基异硫氰酸盐);9,10,11,12-四氢-9,12-环氧-1H-二吲哚[1,2,3-fg:3',2',1'-kl]吡咯并[3,4-i][1,6]苯并二氮芳辛-1,3(2H)-二酮(SB-218078,CAS 135897-06-2);和TAT-S216A(YGRKKRRQRRRLYRSPAMPENL)、和CBP501((d-Bpa)sws(d-Phe-F5)(d-Cha)rrrqrr);以及(αR)-α-氨基-N-[5,6-二氢-2-(1-甲基-1H-吡唑-4-基)-6-氧代-1H-吡咯并[4,3,2-ef][2,3]苯并二氮杂环庚三烯-8-基]-环己烷乙酰胺(PF-0477736)。
3-磷脂酰激醇-依赖性激酶-1(PDK1或PDPK1)抑制剂:7-2-氨基-N-[4-[5-(2-菲基)-3-(三氟甲基)-1H-吡唑-1-基]苯基]-乙酰胺(OSU-03012,CAS 742112-33-0);吡咯烷-1-甲酸(3-{5-溴-4-[2-(1H-咪唑-4-基)-乙基氨基]-嘧啶-2-基氨基}-苯基)-酰胺(BX912,CAS 702674-56-4);以及4-十二烷基-N-1,3,4-噻二唑-2-基-苯磺酰胺(PHT-427,CAS1191951-57-1)。
蛋白激酶C(PKC)激活剂:藓苔抑制素I(bryo-1)和索曲滔林(AEB071)。
B-RAF抑制剂:瑞格非尼(Regorafenib)(BAY73-4506,CAS 755037-03-7);图威扎尼(Tuvizanib)(AV951,CAS 475108-18-0);威罗菲尼(Vemurafenib)(PLX-4032,CAS 918504-65-1);5-[1-(2-羟乙基)-3-(吡啶-4-基)-1H-吡唑-4-基]-2,3-二氢茚-1-酮肟(GDC-0879,CAS 905281-76-7);5-[2-[4-[2-(二甲基氨基)乙氧基]苯基]-5-(4-吡啶基)-1H-咪唑-4-基]-2,3-二氢-1H-茚-1-酮肟(GSK2118436或SB590885);(+/-)-甲基(5-(2-(5-氯-2-甲基苯基)-1-羟基-3-氧代-2,3-二氢-1H-异吲哚-1-基)-1H-苯并咪唑-2-基)氨基甲酸酯(也称为XL-281和BMS908662)和N-(3-(5-氯-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(也称为PLX4720)。
C-RAF抑制剂:索拉非尼3-(二甲基氨基)-N-[3-[(4-羟基苯甲酰基)氨基]-4-甲基苯基]-苯甲酰胺(ZM336372,CAS 208260-29-1);以及3-(1-氰基-1-甲基乙基)-N-[3-[(3,4-二氢-3-甲基-4-氧代-6-喹唑啉基)氨基]-4-甲基苯基]-苯甲酰胺(AZ628,CAS 1007871-84-2)。
RET抑制剂:苹果酸舒尼替尼凡德他尼莫特塞尼二磷酸盐(Motesanib diphosphate)(AMG706,CAS 857876-30-3,N-(2,3-二氢-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)氨基]-3-吡啶甲酰胺,在PCT公开号WO 02/066470中有所描述);索拉非尼(BAY 43-9006);瑞格非尼(Regorafenib)(BAY73-4506,CAS755037-03-7);以及达鲁舍替(Danusertib)(PHA-739358)。
FMS样酪氨酸激酶3(FLT3)抑制剂或CD135:苹果酸舒尼替尼奎扎替尼(Quizartinib)(AC220,CAS 950769-58-1);N-[(1-甲基-4-哌啶基)甲基]-3-[3-(三氟甲氧基)苯基]-咪唑并[1,2-b]哒嗪-6-胺硫酸盐(SGI-1776,CAS 1173928-26-1);以及维加特(Vargatef)(BIBF1120,CAS 928326-83-4)。
c-KIT抑制剂:帕唑帕尼多韦替尼二乳酸(Dovitinib dilacticacid)(TKI258,CAS 852433-84-2);莫特塞尼二磷酸盐(Motesanib diphosphate)(AMG706,CAS 857876-30-3,N-(2,3-二氢-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)氨基]-3-吡啶甲酰胺,在PCT公开号WO 02/066470中有所描述);玛司替尼瑞格非尼(Regorafenib)(BAY73-4506,CAS 755037-03-7);替沃扎尼(AV951,CAS 475108-18-0);瓦他拉尼二盐酸盐(Vatalanib dihydrochloride)(PTK787,CAS 212141-51-0);替拉替尼(Telatinib)(BAY57-9352,CAS 332012-40-5);弗瑞替尼(Foretinib)(GSK1363089,以前称为XL880,CAS 849217-64-7);苹果酸舒尼替尼奎扎替尼(Quizartinib)(AC220,CAS 950769-58-1);阿昔替尼(Axitinib)达沙替尼(BMS-345825);以及索拉非尼
Bcr/Abl激酶抑制剂:伊马替尼(Imatinib)Inilotinib盐酸盐;尼洛替尼(Nilotinib)达沙替尼(BMS-345825);柏舒替尼(Bosutinib)(SKI-606);珀那替尼(Ponatinib)(AP24534);巴非替尼(Bafetinib)(INNO406);达努舍替(Danusertib)(PHA-739358)、AT9283(CAS 1133385-83-7);沙卡替尼(Saracatinib)(AZD0530);以及N-[2-[(1S,4R)-6-[[4-(环丁基氨基)-5-(三氟甲基)-2-嘧啶基]氨基]-1,2,3,4-四氢萘-1,4-亚胺-9-基]-2-氧代乙基]-乙酰胺(PF-03814735,CAS 942487-16-3)。
IGF-1R抑制剂:林思替尼(Linsitnib)(OSI-906);[7-[反式-3-[(氮杂环丁烷-1-基)甲基]环丁基]-5-(3-苄氧基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]胺(AEW541,CAS475488-34-7);[5-(3-苄氧基苯基)-7-[反式-3-[(吡咯烷-1-基)甲基]环丁基]-7H-吡咯并[2,3-d]嘧啶-4-基]胺(ADW742或GSK552602A,CAS 475488-23-4);(2-[[3-溴-5-(1,1-二甲基乙基)-4-羟苯基]亚甲基]-丙二腈(酪氨酸磷酸化抑制剂AG1024,CAS 65678-07-1);4-[[(2S)-2-(3-氯苯基)-2-羟乙基]氨基]-3-[7-甲基-5-(4-吗啉基)-1H-苯并咪唑-2-基]-2(1H)-吡啶酮(BMS536924,CAS 468740-43-4);4-[2-[4-[[(2S)-2-(3-氯苯基)-2-羟乙基]氨基]-1,2-二氢-2-氧代-3-吡啶基]-7-甲基-1H-苯并咪唑-5-基]-1-哌嗪丙腈(BMS554417,CAS 468741-42-6);(2S)-1-[4-[(5-环丙基-1H-吡唑-3-基)氨基]吡咯并[2,1-f][1,2,4]三嗪-2-基]-N-(6-氟-3-吡啶基)-2-甲基-2-吡咯烷甲酰胺(BMS754807,CAS1001350-96-4);苦鬼臼毒素(Picropodophyllotoxin)(AXL1717);以及去甲二氢愈创木酸(Nordihydroguareacetic acid)。
IGF-1R抗体:菲吉妥木单抗(Figitumumab)(CP751871);西舒妥木单抗(Cixutumumab)(IMC-A12);加尼妥单抗(Ganitumab)(AMG-479);洛巴妥木单抗(Robatumumab)(SCH-717454);达洛妥珠单抗(Dalotuzumab)(MK0646);R1507(可购自罗氏公司(Roche));BIIB022(可购自生化基因公司(Biogen));以及MEDI-573(可购自米迪缪尼有限公司(MedImmune))。
MET抑制剂:卡博替尼(Cabozantinib)(XL184,CAS 849217-68-1);弗瑞替尼(Foretinib)(GSK 1363089,以前称为XL880,CAS 849217-64-7);替万替尼(Tivantinib)(ARQ197,CAS 1000873-98-2);1-(2-羟基-2-甲基丙基)-N-(5-(7-甲氧基喹啉-4-基氧基)吡啶-2-基)-5-甲基-3-氧代-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺(AMG 458);科利替尼(Cryzotinib)(PF-02341066);(3Z)-5-(2,3-二氢-1H-吲哚-1-基磺酰基)-3-({3,5-二甲基-4-[(4-甲基哌嗪-1-基)羰基]-1H-吡咯-2-基}亚甲基)-1,3-二氢-2H-吲哚-2-酮(SU11271);(3Z)-N-(3-氯苯基)-3-({3,5-二甲基-4-[(4-甲基哌嗪-1-基)羰基]-1H-吡咯-2-基}亚甲基)-N-甲基-2-氧代吲哚啉-5-磺酰胺(SU11274);(3Z)-N-(3-氯苯基)-3-{[3,5-二甲基-4-(3-吗啉-4-基丙基)-1H-吡咯-2-基]亚甲基}-N-甲基-2-氧代吲哚啉-5-磺酰胺(SU11606);6-[二氟[6-(1-甲基-1H-吡唑-4-基)-1,2,4-***[4,3-b]哒嗪-3-基]甲基]-喹啉(JNJ 38877605,CAS 943540-75-8);2-[4-[1-(喹啉-6-基甲基)-1H-[1,2,3]***[4,5-b]吡嗪-6-基]-1H-吡唑-1-基]乙醇(PF04217903,CAS 956905-27-4);N-((2R)-1,4-二噁烷-2-基甲基)-N-甲基-N'-[3-(1-甲基-1H-吡唑-4-基)-5-氧代-5H-苯并[4,5]环庚[1,2-b]吡啶-7-基]磺酰胺(MK2461,CAS 917879-39-1);6-[[6-(1-甲基-1H-吡唑-4-基)-1,2,4-***[4,3-b]哒嗪-3-基]硫代]-喹啉(SGX523,CAS 1022150-57-7);以及(3Z)-5-[[(2,6-二氯苯基)甲基]磺酰基]-3-[[3,5-二甲基-4-[[(2R)-2-(1-吡咯烷基甲基)-1-吡咯烷基]羰基]-1H-吡咯-2-基]亚甲基]-1,3-二氢-2H-吲哚-2-酮(PHA665752,CAS 477575-56-7)。
表皮生长因子受体(EGFR)抑制剂:盐酸厄洛替尼吉非替尼N-[4-[(3-氯-4-氟苯基)氨基]-7-[[(3”S”)-四氢-3-呋喃基]氧基]-6-喹唑啉基]-4(二甲基氨基)-2-丁酰胺,);凡德他尼拉帕替尼(3R,4R)-4-氨基-1-((4-((3-甲氧基苯基)氨基)吡咯并[2,1-f][1,2,4]三嗪-5-基)甲基)哌啶-3-醇(BMS690514);盐酸卡奈替尼(CI-1033);6-[4-[(4-乙基-1-哌嗪基)甲基]苯基]-N-[(1R)-1-苯基乙基]-7H-吡咯并[2,3-d]嘧啶-4-胺(AEE788,CAS497839-62-0);莫利替尼(Mubritinib)(TAK165);培利替尼(Pelitinib)(EKB569);阿法替尼(Afatinib)(BIBW2992);奈雷替尼(Neratinib)(HKI-272);N-[4-[[1-[(3-氟苯基)甲基]-1H-吲唑-5-基]氨基]-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基]-氨基甲酸、(3S)-3-吗啉基甲酯(BMS599626);N-(3,4-二氯-2-氟苯基)-6-甲氧基-7-[[(3aα,5β,6aα)-八氢-2-甲基环戊[c]吡咯-5-基]甲氧基]-4-氨基喹唑啉(XL647,CAS781613-23-8);以及4-[4-[[(1R)-1-苯基乙基]氨基]-7H-吡咯并[2,3-d]嘧啶-6-基]-苯酚(PKI166,CAS187724-61-4)。
EGFR抗体:西妥昔单抗(Cetuximab)帕尼单抗(Panitumumab)马妥珠单抗(Matuzumab)(EMD-72000);曲妥珠单抗(Trastuzumab)尼妥珠单抗(Nimotuzumab)(hR3);扎鲁妥木单抗(Zalutumumab);TheraCIM h-R3;MDX0447(CAS 339151-96-1);和ch806(mAb-806,CAS 946414-09-1)。
mTOR抑制剂:特罗莫司(Temsirolimus)地磷莫司(ridaforolimus)(正式地称为deferolimus,(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-二羟基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五氧杂-11,36-二氧杂-4-氮杂三环[30.3.1.04,9]三十六碳-16,24,26,28-四烯-12-基]丙基]-2-甲氧基环己基二甲基次膦酸酯,也称为AP23573和MK8669,并且描述于PCT公开号WO 03/064383中);依维莫司(Everolimus)(或RAD001);雷帕霉素(Rapamycin)(AY22989,);塞马莫德(simapimod)(CAS 164301-51-3);(5-{2,4-双[(3S)-3-甲基吗啉-4-基]吡啶并[2,3-d]嘧啶-7-基}-2-甲氧基苯基)甲醇(AZD8055);2-氨基-8-[反式-4-(2-羟基乙氧基)环己基]-6-(6-甲氧基-3-吡啶基)-4-甲基-吡啶并[2,3-d]嘧啶-7(8H)-酮(PF04691502,CAS 1013101-36-4);N2-[1,4-二氧代-4-[[4-(4-氧代-8-苯基-4H-1-苯并吡喃-2-基)吗啉鎓-4-基]甲氧基]丁基]-L-精氨酰甘氨酰-L-α-天冬氨酰L-丝氨酸-,内盐(SF1126,CAS 936487-67-1);和N-[4-[[[3-[(3,5-二甲氧基苯基)氨基]-2-喹喔啉基]氨基]磺酰基]苯基]-3-甲氧基-4-甲基-苯甲酰胺(XL765,也称为SAR245409);乙基(1r,4r)-4-(4-氨基-5-(7-甲氧基-1H-吲哚-2-基)咪唑并[1,5-f][1,2,4]三嗪-7-基)环己烷甲酸(OSI-027)。
丝裂原激活蛋白激酶(MEK)抑制剂:XL-518(也称为GDC-0973,Cas号1029872-29-4,可购自ACC集团);舍美替尼(5-[(4-溴-2-氯苯基)氨基]-4-氟-N-(2-羟乙氧基)-1-甲基-1H-苯并咪唑-6-甲酰胺,也称为AZD6244或ARRY 142886,并描述于PCT公开号WO2003077914);2-[(2-氯-4-碘苯基)氨基]-N-(环丙基甲氧基)-3,4-二氟-苯甲酰胺(也称为CI-1040或PD184352,并描述于PCT公开号WO 2000035436);N-[(2R)-2,3-二羟基丙氧基]-3,4-二氟-2-[(2-氟-4-碘苯基)氨基]-苯甲酰胺(也称为PD 0325901,并描述于PCT公开号WO 2002006213);2,3-双[氨基[(2-氨基苯基)硫代]亚甲基]-丁二腈(也称为U0126,并描述于美国专利号2,779,780);N-[3,4-二氟-2-[(2-氟-4-碘苯基)氨基]-6-甲氧基苯基]-1-[(2R)-2,3-二羟基丙基]-环丙烷磺酰胺(也称为RDEA119或BAY869766,并描述于PCT公开号WO 2007014011);(3S,4R,5Z,8S,9S,11E)-14-(乙基氨基)-8,9,16-三羟基-3,4-二甲基-3,4,9,19-四氢-1H-2-苯并氧杂环四癸炔-1,7(8H)-二酮](也称为E6201,并描述于PCT公开号WO 2003076424);2’-氨基-3’-甲氧基黄酮(也称为PD98059可购自德国比亚芬股份有限公司(Biaffin GmbH&Co.,KG));维拉非尼(Vemurafenib)(PLX-4032,CAS 918504-65-1);(R)-3-(2,3-二羟基丙基)-6-氟-5-(2-氟-4-碘苯基氨基)-8-甲基吡啶并[2,3-d]嘧啶-4,7(3H,8H)-二酮(TAK-733,CAS 1035555-63-5);匹玛舍替(Pimasertib)(AS-703026,CAS1204531-26-9);二甲基亚砜曲美替尼(GSK-1120212,CAS 1204531-25-80);2-(2-氟-4-碘苯基氨基)-N-(2-羟乙氧基)-1,5-二甲基-6-氧代-1,6-二氢吡啶-3-甲酰胺(AZD 8330);以及3,4-二氟-2-[(2-氟-4-碘苯基)氨基]-N-(2-羟乙氧基)-5-[(3-氧代-[1,2]唑烷-2-基)甲基]苯甲酰胺(CH 4987655或Ro 4987655)。
烷化剂:奥沙利铂替莫唑胺(和);更生霉素(也称为放线菌素-D、);美法仑(也称为L-PAM、L-溶肉瘤素和苯丙氨酸氮芥、);六甲蜜胺(也称为六甲基三聚氰胺(HMM)、);卡莫司汀苯达莫司汀白消安(和);卡铂洛莫司汀(也称为CCNU、);顺铂(也称为CDDP、和);苯丁酸氮芥环磷酰胺(和);达卡巴嗪(也称为DTIC、DIC和咪唑甲酰胺、);六甲蜜胺(也称为六甲基三聚氰胺(HMM)、);异环磷酰胺Prednumustine;丙卡巴肼二氯甲基二乙胺(也称为氮芥、盐酸氮芥和盐酸二氯甲基二乙胺、);链脲佐菌素噻替派(也称为硫代磷酰胺、TESPA和TSPA、);环磷酰胺 和盐酸苯达莫司汀
DNA合成抑制剂:卡培他滨盐酸吉西他滨奈拉滨((2R,3S,4R,5R)-2-(2-氨基-6-甲氧基-嘌呤-9-基)-5-(羟甲基)氧杂戊环-3,4-二醇,和);和沙西他滨(1-(2-氰基-2-脱氧-β-D-***呋喃基)-4-(棕榈酰氨基)嘧啶-2(1H)-酮)。
免疫调节剂:阿托珠单抗(可购自);聚乙二醇非格司亭来那度胺(CC-5013,);沙利度胺Actimid(CC4047);和IRX-2(包括白介素1、白介素2、和干扰素γ的人细胞因子的混合物,CAS 951209-71-5,可购自IRXTherapeutics公司)。
G-蛋白偶联生长抑素受体抑制剂:奥曲肽(也称为醋酸奥曲肽,和Sandostatin);醋酸兰瑞肽(CAS 127984-74-1);司格列肽(MK678);醋酸伐普肽和环(D-Trp-Lys-Abu-Phe-MeAla-Tyr)(BIM23027)。
组蛋白脱乙酰酶(HDAC)抑制剂:伏立诺他(Voninostat)洛米迪星(Romidepsin)曲古抑菌素A(Treichostatin A)(TSA);Oxamflatin;沃诺司他(Vorinostat)(伏立诺他);Pyroxamide(香柏酰基(syberoyl)-3-氨基吡啶酰胺异羟肟酸);Trapoxin A(RF-1023A);Trapoxin B(RF-10238);环[(αS,2S)-α-氨基-η-氧代-2-环氧乙烷辛酰基-O-甲基-D-酪氨酰基-L-异亮氨酰基-L-脯氨酰基](Cyl-1);环[(αS,2S)-α-氨基-η-氧代-2-环氧乙烷辛酰基-O-甲基-D-酪氨酰基-L-异亮氨酰基-(2S)-2-哌啶羰基](Cyl-2);环[L-丙氨酰基-D-丙氨酰基-(2S)-η-氧代-L-α-氨基环氧乙烷辛酰基-D-脯氨酰基](HC-毒素);环[(αS,2S)-α-氨基-η-氧代-2-环氧乙烷辛酰基-D-苯基丙氨酰基-L-亮氨酰基-(2S)-2-哌啶羰基](WF-3161);Chlamydocin((S)-环(2-甲基丙氨酰基-L-苯基丙氨酰基-D-脯氨酰基-η-氧代-L-α-氨基环氧乙烷辛酰基);Apicidin(环(8-氧代-L-2-氨基癸酰基-1-甲氧基-L-色氨酰基-L-异亮氨酰基-D-2-哌啶羰基);罗米地辛(Romidepsin)(FR-901228);4-苯基丁酸;Spiruchostatin A;Mylproin(丙戊酸);恩诺司他(entinostat)(MS-275,N-(2-氨基苯基)-4-[N-(吡啶-3-基-甲氧基羰基)-氨基-甲基]-苯甲酰胺);和Depudecin(4,5:8,9-双酐-1,2,6,7,11-五脱氧-D-苏式-D-ido-十一-1,6-二烯醇)。
生物反应调节剂:包括治疗剂,如干扰素、白介素、集落刺激因子、单克隆抗体、疫苗(治疗和预防)、基因治疗和非特异性免疫调节剂。干扰素α干扰素β;干扰素γ;白介素-2(IL-2或阿地白介素,);非格司亭沙格司亭***(依泊亭);白介素-11(奥普瑞白介素);咪喹莫德来那度胺拉妥昔单抗曲妥珠单抗卡介苗(和BCG);左旋咪唑和地尼白介素2(Denileukin diftitox)
紫杉烷抗肿瘤剂:紫杉醇多西他赛卡巴紫杉醇(1-羟基-7β,10β-二甲氧基-9-氧代-5β,20-环氧紫杉-11-烯-2α,4,13α-三基-4-乙酸盐-2-苯并酸盐-13-[(2R,3S)-3-{[(叔丁氧基)羰基]氨基}-2-羟基-3-苯基丙酸盐);和拉洛紫杉醇((2α,3ξ,4α,5β,7α,10β,13α)-4,10-双(乙酰基氧基)-13-({(2R,3S)-3-[(叔丁氧基羰基)氨基]-2-羟基-3-苯基氯丙酰基}氧基)-1-羟基-9-氧代-5,20-环氧-7,19-环紫杉-11-烯-2-基苯甲酸盐)。
热休克蛋白(HSP)抑制剂:坦螺旋霉素(17-烯丙基氨基-17-去甲氧基格尔德霉素,也称为KOS-953和17-AAG,可购自西格玛公司(SIGMA),并描述于美国专利号4,261,989中);瑞司匹霉素(IPI504)、加特司匹(STA-9090);[6-氯-9-(4-甲氧基-3,5-二甲基吡啶-2-基甲基)-9H-嘌呤-2-基]胺(BIIB021或CNF2024,CAS 848695-25-0);反式-4-[[2-(氨基羰基)-5-[4,5,6,7-四氢-6,6-二甲基-4-氧代-3-(三氟甲基)-1H-吲唑-1-基]苯基]氨基]环己基甘氨酸酯(SNX5422或PF04929113,CAS 908115-27-5);和17-二甲基氨基乙基氨基-17-脱甲氧基格尔德霉素(17-DMAG)。
CD22抗体药物缀合物:奥英妥珠单抗(也称为CMC-544和WAY-207294,可购自杭州圣科化工有限公司(Hangzhou Sage Chemical Co.,Ltd.));
CD40抗体:达西珠单抗(Dacetuzumab)(也称为SGN-40或huS2C6,可购自西雅图遗传学公司(Seattle Genetics,Inc));
抗-CS1抗体:埃洛妥珠单抗(HuLuc63,CAS号915296-00-3)
CTLA-4抑制剂抗体:曲美利木单抗(Tremelimumab)(IgG2单克隆抗体,可购自辉瑞公司(Pfizer),以前称为ticilimumab,CP-675,206);和伊匹单抗(CTLA-4抗体,也称为MDX-010,CAS号477202-00-9)。
TPH抑制剂:特曲司他(telotristat)
PARP(聚ADP核糖聚合酶)抑制剂:奥拉帕利(Lynparza)、卢卡帕尼(Rubraca)、尼雷帕利(Zeluja)、他佐帕利、维利帕利。
PD-1抑制剂:斯巴达利珠单抗(Spartalizumab)(PDR001,(诺华公司(Novartis))、纳武单抗(百时美施贵宝公司)、派姆单抗(默克公司(Merck&Co))、匹地利珠单抗(CureTech公司)、MEDI0680(医学免疫公司)、REGN2810(再生元公司(Regeneron))、TSR-042(Tesaro公司)、PF-06801591(辉瑞制药公司(Pfizer))、BGB-A317(百济神州公司(Beigene))、BGB-108(百济神州公司)、INCSHR1210(因赛特公司(Incyte))、或AMP-224(Amplimmune公司)。
PD-L1抑制剂:度伐鲁单抗、阿特利珠单抗、阿维鲁单抗
特别地,本发明提供了由放射性核素177Lu(镥-177)和与如本文定义的螯合剂连接的生长抑素受体结合肽形成的络合物的组合或组合疗法,或如本文所定义的药物水溶液与选自下组的一种或多种治疗剂一起的组合或组合疗法,该组由以下组成:奥曲肽、兰瑞肽、伐普肽、帕瑞肽、沙托瑞肽(satoreotide)、依维莫司、替莫唑胺、特曲司他、苹果酸舒尼替尼、索凡替尼、利波西利、恩诺司他、和帕唑帕尼。在特定实施例中,那些组合用于治疗NET肿瘤,例如,GEP-NET、肺NET、pNET、肺NET、类癌肿瘤综合征、SCLC。在特定实施例中,本发明提供了通过施用治疗有效量的那些组合的组分治疗患有NET肿瘤(例如,GEP-NET、肺NET、pNET、肺NET、类癌肿瘤综合征、SCLC)的患者的方法。
在特定实施例中,本发明提供了由放射性核素177Lu(镥-177)和与如本文定义的螯合剂连接的生长抑素受体结合肽形成的络合物的组合或组合疗法,或如本文所定义的药物水溶液与选自下组的一种或多种肿瘤免疫学治疗剂一起的组合或组合疗法,该组由以下组成:PD-1、PD-L1和CTLA-4抑制剂,特别是选自以下的I-O治疗剂:斯巴达利珠单抗、纳武单抗、派姆单抗、匹地利珠单抗、度伐鲁单抗、阿特利珠单抗、阿维鲁单抗、伊匹单抗、和曲美利木单抗。在特定实施例中,那些组合用于治疗NET肿瘤,例如,GEP-NET、肺NET、pNET、肺NET、类癌肿瘤综合征、SCLC。在特定实施例中,本发明提供了通过施用治疗有效量的那些组合的组分治疗患有NET肿瘤(例如,GEP-NET、肺NET、pNET、肺NET、类癌肿瘤综合征、SCLC)的患者的方法。
定义
在下文中,本文使用的术语以其含义定义。
术语“约”或“大约”在本文中的含义是下列值可以变化±20%、优选±10%、更优选±5%、甚至更优选±2%、甚至更优选±1%。
除非另有定义,否则“%”在本文中具有重量百分比(wt%)的含义,也称为重量与重量的百分比(w/w%)。
“总浓度”:一个或多个个体浓度的总和。
“水溶液”:一种或多种溶解物在水中的溶液。
“通过如下形成的络合物:
(ai)放射性核素,和
(aii)与螯合剂连接的细胞受体结合有机部分”:
放射性核素金属离子与螯合剂的官能团(例如胺或羧酸)形成非共价键。螯合剂具有至少两个此类络合官能团,以能够形成螯合络合物。
在本发明的上下文中的螯合剂可以是
DOTA:1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸,
DTPA:二乙烯三胺五乙酸,
NTA:次氮基三乙酸,
EDTA:乙二胺四乙酸,
DO3A:1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸,
NOTA:1,4,7-三氮杂环壬烷-1,4,7-三乙酸,
屈坦(Trizoxetan),
泰坦(Tetraxetan)
或其混合物,优选DOTA。
“细胞受体结合部分”:化学分子,其分子的至少部分与细胞表面的受体分子结合。本发明特别合适的细胞受体结合部分是生长抑素受体结合肽,优选地,所述生长抑素受体结合肽选自奥曲肽、奥曲塔特、兰瑞肽、伐普肽、帕瑞肽、伊拉曲肽(ilatreotide),喷曲肽(pentetreotide)、迪普瑞肽(depreotide)、沙托瑞肽、维多瑞肽(veldoreotide),优选地选自奥曲肽和奥曲塔特。
“连接”:细胞受体结合有机部分直接与螯合剂连接或经由接头分子连接,优选直接连接。一个或多个连接键是细胞受体结合有机部分(和接头)和螯合剂之间的一个或多个共价键或非共价键,优选地所述一个或多个键是共价键。
“抗放射性分解降解稳定剂”:保护有机分子免受放射性分解降解的稳定剂,例如,当从放射性核素发射的γ射线裂解有机分子的原子与自由基之间形成的键时,那些自由基然后被稳定剂清除,这避免了自由基经历可能导致不希望的、潜在无效的或甚至有毒分子的任何其他化学反应。因此,这些稳定剂也被称为“游离自由基清除剂”或简称“自由基清除剂”。那些稳定剂的其他替代术语是“放射稳定性增强剂”,“放射稳定剂”或简称“猝灭剂”。
“在组分(ai)和(aii)的络合物形成期间存在一种或多种稳定剂”:存在的第一稳定剂和任选的第二稳定剂,即存在单独的第一稳定剂或与第二稳定剂的组合
“在络合物形成期间存在”:在添加这两种溶液并且应用可能升高的温度以促进络合物的形成之前,一种或多种稳定剂存在于放射性核素溶液中或含有螯合剂的溶液中。优选地,所述一种或多种稳定剂在含有螯合剂的溶液中。
“在组分(ai)和(aii)的络合物形成期间仅存在第一稳定剂”:存在第一稳定剂,不存在第二稳定剂。换句话说,仅存在一种稳定剂。
“在组分(ai)和(aii)的络合物形成后添加第二稳定剂”:无论第二稳定剂是否在络合物形成期间已经存在,在络合物形成反应完成后添加第二稳定剂,例如,在可能已加热至升高的温度下的反应溶液再次冷却至环境温度之后。
细胞受体结合部分和螯合剂可以一起形成以下分子:
DOTA-OC:[DOTA0,D-Phe1]奥曲肽,
DOTA-TOC:[DOTA0,D-Phe1,Tyr3]奥曲肽、依多曲肽(INN),
由以下式表示:
DOTA-NOC:[DOTA0,D-Phe1,1-Nal3]奥曲肽,
DOTA-TATE:[DOTA0,D-Phe1,Tyr3]奥曲塔特、DOTA-Tyr3-奥曲塔特、DOTA-d-Phe-Cys-Tyr-d-Trp-Lys-Thr-Cys-Thr(环2,7)、奥索度曲肽(INN),由以下式表示:
DOTA-LAN:[DOTA0,D-β-Nal1]兰瑞肽,
DOTA-VAP:[DOTA0,D-Phe1,Tyr3]伐普肽。
屈坦-沙托瑞肽
泰坦-沙托瑞肽
用于本发明的优选的“与螯合剂连接的细胞受体结合部分”分子是DOTA-TOC、DOTA-TATE和屈坦-沙托瑞肽,更优选地该分子是DOTA-TATE。
对于本发明,根据本发明的由放射性核素和与螯合剂连接的细胞受体结合部分形成的优选络合物(或放射性核素和与螯合剂连接的细胞受体结合部分的优选的络合物)是177Lu-DOTA-TATE,其也称为镥(177Lu)奥索度曲肽(INN),即氢[N-{[4,7,10-三(羧酸-κO-甲基)-1,4,7,10-四氮杂环十二烷-1-基-κ4N1,N4,N7,N10]乙酰基-κO}-D-苯丙氨酰-L-半胱氨酰-酪氨酰-D-色氨酰-L-赖氨酰-L-苏氨酰-L-半胱氨酰-L-苏氨酰环(2→7)-二硫化物(4-)](177Lu)镥盐(lutetate)(1-)
并且由以下式表示:
“从4.5至6.0的pH的缓冲液”:可以是乙酸盐缓冲液、柠檬酸盐缓冲液(例如柠檬酸盐+HCl或柠檬酸+磷酸氢二钠)或磷酸盐缓冲液(例如磷酸二氢钠+磷酸氢二钠),优选地,所述缓冲液是乙酸盐缓冲液,优选地,所述乙酸盐缓冲液由乙酸和乙酸钠构成。
“多价螯合剂(Sequestering agent)”,适用于络合放射性核素金属离子的螯合剂,优选DTPA:二乙烯三胺五乙酸。
“对于商业用途”:药物产品,例如药物水溶液,通过遵守此类卫生机构要求的所有药物产品质量和稳定性要求能够获得(优选已获得)卫生当局(例如US-FDA或EMA)的上市许可,能够以商业规模从或在药物产品生产场所制造(优选已制造),然后进行质量控制测试程序,并且能够向远的位置的终端用户(例如医院或病人)供应(优选已供应)。
“组合”:术语“组合”是指呈一种剂量单位形式的固定组合,或组合施用(其中本发明的化合物与组合配偶体(partner)(例如下文所解释的另一种药物,也称为“治疗剂”或“共药剂(co-agent)”)可以在同一时间独立地施用或在时间间隔内分开地施用,特别是在这些时间间隔允许组合配偶体显示协作(例如协同)效应的情况下)。单个组分可以包装在一个试剂盒中或分开包装。可在施用之前将一种或两种组分(例如粉末或液体)重构或稀释至所希望的剂量。如本文所用的术语“共施用”或“组合施用”等意在涵盖将所选择的组合配偶体施用给有需要的单个受试者(例如患者),并且旨在包括其中药剂不一定通过相同的施用途径施用或同时施用的治疗方案。如本文所用,术语“药物组合”意指由多于一种治疗剂的混合或组合所产生的产品,并且包括治疗剂的固定和非固定组合两者。术语“固定组合”意指治疗剂(例如,本发明的化合物和组合配偶体)以单一实体或剂量的形式同时地施用至患者。术语“非固定组合”意指治疗剂(例如,本发明的化合物和组合配偶体)作为分开的实体同时地、并行地或依序地施用至患者(没有特定的时间限制),其中这种施用在患者体内提供治疗有效水平的两种化合物。后者也适用于鸡尾酒疗法,例如三种或更多种治疗剂的施用。
实例
在下文中,将更详细地并且具体地参考实例来描述本发明,但是这些实例无意限制本发明。
材料:
177LuCl3可以从商业来源获得,例如,荷兰I.D.B.公司(I.D.B.Holland BV)。DOTA0-Tyr3-奥曲塔特可以从商业来源获得,例如,由奥地利piCHEM研究开发有限公司(piCHEMForschungs-und Entwicklungs GmbH)提供。药物产品的所有其他组分是可从各种来源商购的。
实例1:药物产品的组成
药物产品(177Lu-DOTA0-Tyr3-奥曲塔特370MBq/mL输液溶液)设计为无菌即用型输液溶液,含有177Lu-DOTA0-Tyr3-奥曲塔特作为药物物质,在参考日期和时间的体积活性为370MBq/mL(校准时间(tc))。校准时间(tc)对应于生产结束(EOP=t0),其是第一QC小瓶的活性的测量时间。药物产品的保质期定义为校准时间后72小时。药物产品是单一剂量小瓶,含有适量的溶液,允许在注射时递送7.4GBq的放射活性。
制造场所制备了生产结束后在7.4GBq±10%(200mCi)范围内校准的单一剂量。分析证书报告所提供的确切活性和达到此活性的时间。该值声明为“注射时间:{日月年}{时:分}({DD MM YYYY}{hh:mm})UTC”。考虑到可变注射时间和放射性核素的恒定衰减,计算了在注射时间7.4GBq活性所需的填充体积,其范围为20.5和25.0mL。
药物产品组成/mL
EOP:生产结束=t0=第一小瓶的活性测量=校准时间tc
RSE:放射稳定性增强剂
实例2:药物产品的制造
对于74GBq批量大小(2Ci批量大小),将177LuCl3溶液(约74GBq于HCl中)与DOTA-Tyr3-奥曲塔特(约2mg)溶液和含有抗氧化剂(和抗放射性分解降解的稳定剂)(即龙胆酸,约157mg)的反应缓冲溶液和缓冲***(即乙酸盐缓冲***)混合,产生总计约5.5mL溶液,其用于在约90℃至约98℃的温度下不到15分钟内发生的放射性标记。
使用安装在合成模块前面的单次使用的一次性试剂盒进行合成,所述合成模块含有流体路径(管道)、反应器小瓶和密封的试剂小瓶。
将得到的母液用含有螯合剂(即DTPA)、抗氧化剂(即抗坏血酸)氢氧化钠和氯化钠的溶液稀释,然后无菌过滤通过0.2μm,以给出如在实例1中描述的即用型溶液,pH为4.5-6.0,特别是5.2-5.3。最后,将溶液以20.5至25.0mL的体积分配到无菌小瓶中。带塞的小瓶封装在铅容器内,用于保护性屏蔽。
制造方法也可实现大于74GBq的批量大小。在这种情况下,原料(镥、肽和反应缓冲液)的量相乘以保证相同的原料比。
实例3:在各种温度条件下储存后的稳定性研究结果。
下表提供了根据实例2中描述的方法以74GBq批量大小进行生产的批次的稳定性测试数据。
“n.d.”=未确定;“LOD”=检测限
对于以148GBq批量大小进行生产的批次得到了非常类似的良好稳定性结果。
Claims (29)
1.一种药物水溶液,所述药物水溶液包含:
(a)由如下形成的络合物
(ai)放射性核素177Lu(镥-177),和
(aii)与螯合剂DOTA连接的生长抑素受体结合肽;以及
(b)至少两种不同的抗放射性分解降解的稳定剂;
其中
所述放射性核素以其提供从250至500MBq/mL的体积放射性的浓度存在;以及
所述稳定剂以0.2至20.0mg/mL的总浓度存在。
2.根据权利要求1所述的药物水溶液,
其中所述组分(b)包含稳定剂:
(bi)龙胆酸或其盐;以及
(bii)抗坏血酸或其盐。
3.根据权利要求2所述的药物水溶液,
其中
(bi)龙胆酸以从0.5至2mg/mL、优选从0.5至1mg/mL的浓度存在;以及
(bii)抗坏血酸以从2.0至5.0mg/mL的浓度存在。
4.根据权利要求3所述的药物水溶液,所述药物水溶液进一步包含:
(c)浓度为从0.01至0.10mg/mL的二乙烯三胺五乙酸(DTPA)或其盐。
5.根据权利要求3或4所述的药物水溶液,所述药物水溶液进一步包含:
(d)乙酸盐缓冲液,其由以下构成:
(di)浓度为从0.3至0.7mg/mL的乙酸;以及
(dii)浓度为0.4至0.9mg/mL的乙酸钠;
优选地,所述乙酸盐缓冲液提供从4.5至6.0、优选从5.0至5.5的pH。
6.根据权利要求1至5中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在所述稳定剂中的至少一种,并且在组分(ai)和(aii)的络合物形成后添加所述稳定剂中的至少一种。
7.根据权利要求1至5中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间至少存在龙胆酸,并且在组分(ai)和(aii)的络合物形成后至少添加抗坏血酸。
8.根据权利要求1至5中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在的唯一的稳定剂是龙胆酸,并且在组分(ai)和(aii)的络合物形成后添加的唯一的稳定剂是抗坏血酸。
9.根据权利要求6至8中任一项所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在的一种或多种所述稳定剂在络合物配制期间以从15至50mg/mL、优选从20至40mg/mL的总浓度存在。
10.根据权利要求9所述的药物水溶液,其中在组分(ai)和(aii)的络合物形成期间存在的唯一的稳定剂是龙胆酸并且在络合物形成期间以从20至40mg/mL、优选从25至35mg/mL的浓度存在。
11.根据前述权利要求中任一项所述的药物水溶液,所述药物水溶液在≤25℃下储存时具有至少72小时的保质期,特别是当在25℃下储存时具有至少72小时的保质期。
12.根据前述权利要求中任一项所述的药物水溶液,其放射化学纯度(通过HPLC测定)在25℃下储存时保持≥95%持续至少72小时。
13.根据前述权利要求中任一项所述的药物水溶液,其中所述溶液以商业制造规模进行生产,特别是以至少20GBq、至少50GBq、至少70GBq的批量大小进行生产。
14.根据前述权利要求中任一项所述的药物水溶液,所述药物水溶液是即用型的。
15.一种用于制造如前述权利要求中任一项所定义的药物水溶液的方法,所述方法包括以下方法步骤:
(1)通过如下形成放射性核素177Lu和与螯合剂DOTA连接的生长抑素受体结合肽的络合物
(1.1)制备包含所述放射性核素的水溶液;
(1.2)制备包含与所述螯合剂连接的生长抑素受体结合肽和至少一种抗放射性分解降解的稳定剂的水溶液;以及
(1.3)混合步骤(1.1)和(1.2)中得到的溶液并加热所得混合物;
(2)通过如下稀释通过步骤(1)得到的络合物溶液
(2.1)制备任选地包含至少一种抗放射性分解降解的稳定剂的水性稀释溶液;以及
(2.2.)将通过步骤(1)得到的络合物溶液与通过步骤(2.1)得到的稀释溶液混合以获得最终溶液;
其中如果在(1.2)下制备的溶液仅包含一种稳定剂,则在(2.1)下制备的溶液包含至少一种稳定剂。
16.根据权利要求15所述的方法,其中步骤(1.2)中制备的溶液包含至少一种稳定剂,并且步骤(2.1)中制备的溶液包含至少一种稳定剂。
17.根据权利要求15所述的方法,其中步骤(1.2)中制备的溶液至少包含稳定剂龙胆酸,且步骤(2.1)中制备的溶液至少包含稳定剂抗坏血酸。
18.根据权利要求15所述的方法,其中步骤(1.2)中制备的溶液仅包含一种稳定剂,所述稳定剂为龙胆酸;并且步骤(2.1)中制备的溶液仅包含一种稳定剂,所述稳定剂为抗坏血酸。
19.根据权利要求15至18中任一项所述的方法,其中步骤(1.2)中制备的溶液包含总浓度为从15至50mg/mL、优选从20至40mg/mL的一种或多种稳定剂。
20.根据权利要求15至18中任一项所述的方法,其中步骤(1.2)中制备的溶液仅包含一种稳定剂,所述稳定剂为浓度从20至40mg/mL、优选从25至35mg/mL的龙胆酸。
21.根据权利要求15至20中任一项所述的方法,其中步骤(1.2)的溶液进一步包含缓冲液,优选乙酸盐缓冲液。
22.根据权利要求15至21中任一项所述的方法,其中在步骤(1.3)中,将所得混合物加热至从70℃至99℃、优选从90℃至98℃的温度,持续从2至59分钟、优选从10至15分钟。
23.根据权利要求15至22中任一项所述的方法,其中步骤(2.1)的溶液进一步包含二乙烯三胺五乙酸(DTPA)或其盐。
24.根据权利要求15至23中任一项所述的方法,所述方法进一步包括以下方法步骤:
(3)将步骤(2)得到的溶液过滤通过0.2μm:
(4)将通过步骤(3)得到的过滤的溶液以递送如下放射性剂量所需要的体积分配到剂量单位容器中:从5.0至10MBq、优选从7.0至8.0MBq、更优选从7.3至7.7MBq、甚至更优选从7.4-7.5MBq、优选地所述体积为从10至50mL、更优选从15至30mL、甚至更优选从20至25mL。
25.根据权利要求15至24中任一项所述的方法,其中步骤(1.1)的溶液包含LuCl3和HCl。
26.根据权利要求15至25中任一项所述的方法,其中步骤(1.2)的溶液包含177Lu-DOTA-TATE或177Lu-DOTA-TOC、龙胆酸、乙酸和乙酸钠。
27.根据权利要求15至26中任一项所述的方法,其中步骤(2.1)的溶液包含DTPA和抗坏血酸。
28.根据权利要求24至27中任一项所述的方法,其中步骤(4)中的剂量单位容器是封闭在铅容器内的带塞的小瓶。
29.一种通过如权利要求15至28中任一项所定义的方法得到的药物水溶液。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB2018/055575 WO2020021310A1 (en) | 2018-07-25 | 2018-07-25 | Stable, concentrated radionuclide complex solutions |
IBPCT/IB2018/055575 | 2018-07-25 | ||
US16/045,484 US20200030465A1 (en) | 2018-07-25 | 2018-07-25 | Stable, concentrated radionuclide complex solutions |
US16/045,484 | 2018-07-25 | ||
PCT/IB2018/057415 WO2020021322A1 (en) | 2018-07-25 | 2018-09-25 | Stable, concentrated radionuclide complex solutions |
Publications (1)
Publication Number | Publication Date |
---|---|
CN112584875A true CN112584875A (zh) | 2021-03-30 |
Family
ID=63794577
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201880095724.5A Pending CN112584875A (zh) | 2018-07-25 | 2018-09-25 | 稳定的、浓缩的放射性核素络合物溶液 |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP3826686A1 (zh) |
JP (2) | JP7402218B2 (zh) |
KR (2) | KR20240033296A (zh) |
CN (1) | CN112584875A (zh) |
AU (3) | AU2018433575B2 (zh) |
BR (1) | BR112021001148A2 (zh) |
CA (1) | CA3153630A1 (zh) |
CO (1) | CO2021000506A2 (zh) |
DE (1) | DE202018006567U1 (zh) |
IL (1) | IL280314A (zh) |
MX (1) | MX2021000805A (zh) |
SG (1) | SG11202100645XA (zh) |
WO (1) | WO2020021322A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114404618A (zh) * | 2022-03-28 | 2022-04-29 | 北京先通国际医药科技股份有限公司 | 放射性药物水溶液及其用途 |
CN114404619A (zh) * | 2022-03-28 | 2022-04-29 | 北京先通国际医药科技股份有限公司 | 放射性药物水溶液及其制备方法和用途 |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11541134B1 (en) | 2021-08-02 | 2023-01-03 | Rayzebio, Inc. | Stabilized compositions of radionuclides and uses thereof |
WO2023100852A1 (ja) * | 2021-11-30 | 2023-06-08 | 日本メジフィジックス株式会社 | 安定化放射性医薬組成物 |
WO2023148680A1 (en) * | 2022-02-04 | 2023-08-10 | Advanced Accelerator Applications | Methods for large scale synthesis of radionuclide complexes |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6261536B1 (en) * | 1996-02-02 | 2001-07-17 | Rhomed Incorporated | Post labeling stabilization of radiolabeled proteins and peptides |
US20070269375A1 (en) * | 2003-07-24 | 2007-11-22 | Bracco Imaging S.P.A. | Stable Radiopharmaceutical Compositions and Methods for Preparation |
WO2008009444A1 (en) * | 2006-07-19 | 2008-01-24 | Van Dulmen, Adrianus, A. | Use of ethanol for stabilizing a single-vial liquid formulation of a radiolabeled peptide |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2779780A (en) | 1955-03-01 | 1957-01-29 | Du Pont | 1, 4-diamino-2, 3-dicyano-1, 4-bis (substituted mercapto) butadienes and their preparation |
US4261989A (en) | 1979-02-19 | 1981-04-14 | Kaken Chemical Co. Ltd. | Geldanamycin derivatives and antitumor drug |
EP0647450A1 (en) | 1993-09-09 | 1995-04-12 | BEHRINGWERKE Aktiengesellschaft | Improved prodrugs for enzyme mediated activation |
CA2346448A1 (en) | 1998-12-16 | 2000-06-22 | Warner-Lambert Company | Treatment of arthritis with mek inhibitors |
DZ3401A1 (fr) | 2000-07-19 | 2002-01-24 | Warner Lambert Co | Esters oxygenes d'acides 4-iodophenylamino benzhydroxamiques |
US6995162B2 (en) | 2001-01-12 | 2006-02-07 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
IL162734A0 (en) | 2002-02-01 | 2005-11-20 | Ariad Gene Therapeutics Inc | Phosphorus-containing compounds & uses thereof |
JP4575667B2 (ja) | 2002-03-08 | 2010-11-04 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 医薬として有用な大環状化合物 |
SI1482932T1 (sl) | 2002-03-13 | 2010-02-26 | Array Biopharma Inc | N3-alkilirani derivati benzimidazola kot inhibitorji mek |
TWI275390B (en) | 2002-04-30 | 2007-03-11 | Wyeth Corp | Process for the preparation of 7-substituted-3- quinolinecarbonitriles |
ES2481402T3 (es) | 2005-07-21 | 2014-07-30 | Ardea Biosciences, Inc. | Inhibidores de N-(arilamino)sulfonamida de MEK |
EP3534969A4 (en) * | 2016-11-04 | 2020-07-01 | Clarity Pharmaceuticals Ltd | FORMULAS FOR RADIATION THERAPY AND DIAGNOSTIC IMAGING |
-
2018
- 2018-09-25 CN CN201880095724.5A patent/CN112584875A/zh active Pending
- 2018-09-25 JP JP2021504167A patent/JP7402218B2/ja active Active
- 2018-09-25 SG SG11202100645XA patent/SG11202100645XA/en unknown
- 2018-09-25 DE DE202018006567.6U patent/DE202018006567U1/de active Active
- 2018-09-25 WO PCT/IB2018/057415 patent/WO2020021322A1/en active Application Filing
- 2018-09-25 EP EP18783136.7A patent/EP3826686A1/en active Pending
- 2018-09-25 BR BR112021001148-0A patent/BR112021001148A2/pt unknown
- 2018-09-25 CA CA3153630A patent/CA3153630A1/en active Pending
- 2018-09-25 MX MX2021000805A patent/MX2021000805A/es unknown
- 2018-09-25 KR KR1020247006883A patent/KR20240033296A/ko active Application Filing
- 2018-09-25 KR KR1020217005212A patent/KR102643582B1/ko active IP Right Grant
- 2018-09-25 AU AU2018433575A patent/AU2018433575B2/en active Active
-
2021
- 2021-01-20 IL IL280314A patent/IL280314A/en unknown
- 2021-01-20 CO CONC2021/0000506A patent/CO2021000506A2/es unknown
-
2022
- 2022-05-30 AU AU2022203683A patent/AU2022203683B2/en active Active
-
2023
- 2023-05-24 JP JP2023085193A patent/JP2023117417A/ja active Pending
-
2024
- 2024-02-23 AU AU2024201217A patent/AU2024201217A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6261536B1 (en) * | 1996-02-02 | 2001-07-17 | Rhomed Incorporated | Post labeling stabilization of radiolabeled proteins and peptides |
US20070269375A1 (en) * | 2003-07-24 | 2007-11-22 | Bracco Imaging S.P.A. | Stable Radiopharmaceutical Compositions and Methods for Preparation |
WO2008009444A1 (en) * | 2006-07-19 | 2008-01-24 | Van Dulmen, Adrianus, A. | Use of ethanol for stabilizing a single-vial liquid formulation of a radiolabeled peptide |
Non-Patent Citations (2)
Title |
---|
ADVANCED ACCELERATOR APPLICATION USA,INC: "LUTATHERA® (lutetium Lu 177 dotatate)注射液的药品说明书", 《NATIONAL LIBRARY OF MEDICINE》 * |
STEPHAN MAUS,ET AL.: "Aspects on radiolabeling of 177Lu-DOTA-TATE: After C18 purification re-addition of ascorbic acid is required to maintain radiochemical purity", 《INTERNATIONAL JOURNAL OF DIAGNOSTIC IMAGING》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114404618A (zh) * | 2022-03-28 | 2022-04-29 | 北京先通国际医药科技股份有限公司 | 放射性药物水溶液及其用途 |
CN114404619A (zh) * | 2022-03-28 | 2022-04-29 | 北京先通国际医药科技股份有限公司 | 放射性药物水溶液及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
CA3153630A1 (en) | 2020-01-30 |
KR20240033296A (ko) | 2024-03-12 |
KR20210035855A (ko) | 2021-04-01 |
JP2023117417A (ja) | 2023-08-23 |
DE202018006567U1 (de) | 2021-02-22 |
MX2021000805A (es) | 2021-05-12 |
JP7402218B2 (ja) | 2023-12-20 |
WO2020021322A1 (en) | 2020-01-30 |
BR112021001148A2 (pt) | 2021-04-20 |
JP2022501313A (ja) | 2022-01-06 |
EP3826686A1 (en) | 2021-06-02 |
AU2022203683B2 (en) | 2023-12-21 |
IL280314A (en) | 2021-03-25 |
CO2021000506A2 (es) | 2021-04-19 |
SG11202100645XA (en) | 2021-02-25 |
AU2018433575A1 (en) | 2021-02-11 |
KR102643582B1 (ko) | 2024-03-05 |
AU2024201217A1 (en) | 2024-03-14 |
AU2018433575B2 (en) | 2022-07-07 |
AU2022203683A1 (en) | 2022-06-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10596278B2 (en) | Stable, concentrated radionuclide complex solutions | |
JP7358484B2 (ja) | 併用療法 | |
US11904027B2 (en) | Stable, concentrated radionuclide complex solutions | |
AU2022203683B2 (en) | Stable, concentrated radionuclide complex solutions | |
US20160220569A1 (en) | CDK4/6 Inhibitor Dosage Formulations For The Protection Of Hematopoietic Stem And Progenitor Cells During Chemotherapy | |
US20210379213A1 (en) | Stable, concentrated radionuclide complex solutions | |
WO2020021465A1 (en) | Method of treatment of neuroendocrine tumors | |
US20220072166A1 (en) | Method of treatment of neuroendocrine tumors | |
JP2024038132A (ja) | 神経内分泌腫瘍の処置の方法 | |
KR20210141621A (ko) | Pkm2 조정제를 포함하는 조성물 및 그를 사용한 치료 방법 | |
WO2022043556A1 (en) | Stable radiopharmaceutical composition | |
RU2789366C2 (ru) | Стабильные концентрированные растворы комплексов радионуклидов | |
US20230338587A1 (en) | Method of treating psma-expressing cancers | |
US20240075171A1 (en) | Stable, concentrated radionuclide complex solutions | |
US20230321285A1 (en) | Method of treating psma-expressing cancers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |