CN111362967A - 苯并氧杂二氮杂十四碳烯衍生物及其用途 - Google Patents
苯并氧杂二氮杂十四碳烯衍生物及其用途 Download PDFInfo
- Publication number
- CN111362967A CN111362967A CN202010347120.4A CN202010347120A CN111362967A CN 111362967 A CN111362967 A CN 111362967A CN 202010347120 A CN202010347120 A CN 202010347120A CN 111362967 A CN111362967 A CN 111362967A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- methyl
- acceptable salt
- derivative
- cycloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003814 drug Substances 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 58
- 150000003839 salts Chemical class 0.000 claims description 47
- 238000002360 preparation method Methods 0.000 claims description 31
- -1 nitro, hydroxy Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- 229940001447 lactate Drugs 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003094 microcapsule Substances 0.000 claims description 2
- 239000004005 microsphere Substances 0.000 claims description 2
- 239000002105 nanoparticle Substances 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 abstract description 49
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 abstract description 47
- 208000002154 non-small cell lung carcinoma Diseases 0.000 abstract description 18
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 abstract description 18
- 102000004190 Enzymes Human genes 0.000 abstract description 14
- 108090000790 Enzymes Proteins 0.000 abstract description 14
- 230000002503 metabolic effect Effects 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 12
- 206010025323 Lymphomas Diseases 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000001394 metastastic effect Effects 0.000 abstract description 6
- 206010061289 metastatic neoplasm Diseases 0.000 abstract description 6
- 230000003285 pharmacodynamic effect Effects 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 208000012902 Nervous system disease Diseases 0.000 abstract description 2
- 208000025966 Neurological disease Diseases 0.000 abstract description 2
- 208000026278 immune system disease Diseases 0.000 abstract description 2
- 208000030159 metabolic disease Diseases 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- 238000006243 chemical reaction Methods 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 29
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 230000015572 biosynthetic process Effects 0.000 description 19
- 238000003786 synthesis reaction Methods 0.000 description 19
- 239000007787 solid Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000010189 synthetic method Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- IIXWYSCJSQVBQM-LLVKDONJSA-N lorlatinib Chemical compound N=1N(C)C(C#N)=C2C=1CN(C)C(=O)C1=CC=C(F)C=C1[C@@H](C)OC1=CC2=CN=C1N IIXWYSCJSQVBQM-LLVKDONJSA-N 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 201000009030 Carcinoma Diseases 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 229960005061 crizotinib Drugs 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
- 239000003085 diluting agent Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 101000686031 Homo sapiens Proto-oncogene tyrosine-protein kinase ROS Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 102100023347 Proto-oncogene tyrosine-protein kinase ROS Human genes 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 230000000118 anti-neoplastic effect Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- IIXWYSCJSQVBQM-UHFFFAOYSA-N 1454846-35-5 Chemical compound N=1N(C)C(C#N)=C2C=1CN(C)C(=O)C1=CC=C(F)C=C1C(C)OC1=CC2=CN=C1N IIXWYSCJSQVBQM-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 229960001602 ceritinib Drugs 0.000 description 3
- VERWOWGGCGHDQE-UHFFFAOYSA-N ceritinib Chemical compound CC=1C=C(NC=2N=C(NC=3C(=CC=CC=3)S(=O)(=O)C(C)C)C(Cl)=CN=2)C(OC(C)C)=CC=1C1CCNCC1 VERWOWGGCGHDQE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical compound CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 239000008297 liquid dosage form Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000003956 methylamines Chemical group 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 230000005945 translocation Effects 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- YGUFOZWTNSRDDX-UHFFFAOYSA-N 4-bromo-2,5-dimethylpyrazole-3-carbonitrile Chemical compound CC1=NN(C)C(C#N)=C1Br YGUFOZWTNSRDDX-UHFFFAOYSA-N 0.000 description 2
- PXBZPNUOEYENNK-UHFFFAOYSA-N 4-bromo-2,5-dimethylpyrazole-3-carboxamide Chemical compound CC1=NN(C)C(C(N)=O)=C1Br PXBZPNUOEYENNK-UHFFFAOYSA-N 0.000 description 2
- PEELXGPDHUXMEG-UHFFFAOYSA-N 4-bromo-2-methyl-5-(methylaminomethyl)pyrazole-3-carbonitrile Chemical compound CNCC1=NN(C)C(C#N)=C1Br PEELXGPDHUXMEG-UHFFFAOYSA-N 0.000 description 2
- BFINZMOZSWXNEF-UHFFFAOYSA-N 4-bromo-5-(bromomethyl)-2-methylpyrazole-3-carbonitrile Chemical compound CN1N=C(CBr)C(Br)=C1C#N BFINZMOZSWXNEF-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 101100091501 Mus musculus Ros1 gene Proteins 0.000 description 2
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001413 amino acids Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000009585 enzyme analysis Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- KYQGPXFQWUSRMY-UHFFFAOYSA-N methyl 2,5-dimethylpyrazole-3-carboxylate Chemical compound COC(=O)C1=CC(C)=NN1C KYQGPXFQWUSRMY-UHFFFAOYSA-N 0.000 description 2
- NEXBDDSPNVIGGI-MRVPVSSYSA-N methyl 2-[(1r)-1-(2-amino-5-bromopyridin-3-yl)oxyethyl]-4-fluorobenzoate Chemical compound COC(=O)C1=CC=C(F)C=C1[C@@H](C)OC1=CC(Br)=CN=C1N NEXBDDSPNVIGGI-MRVPVSSYSA-N 0.000 description 2
- NWCFXOKZBLZXJD-UHFFFAOYSA-N methyl 4-bromo-2,5-dimethylpyrazole-3-carboxylate Chemical compound COC(=O)C1=C(Br)C(C)=NN1C NWCFXOKZBLZXJD-UHFFFAOYSA-N 0.000 description 2
- GFEZEVUIYRGWNU-UHFFFAOYSA-N methyl 5-methyl-1h-pyrazole-3-carboxylate Chemical compound COC(=O)C=1C=C(C)NN=1 GFEZEVUIYRGWNU-UHFFFAOYSA-N 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 230000003228 microsomal effect Effects 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XXLRKGVZBYVBNQ-UHFFFAOYSA-N tert-butyl n-[(4-bromo-5-cyano-1-methylpyrazol-3-yl)methyl]-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CC1=NN(C)C(C#N)=C1Br XXLRKGVZBYVBNQ-UHFFFAOYSA-N 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229940070710 valerate Drugs 0.000 description 2
- GQGBQRLYBYFVAW-YFKPBYRVSA-N (1s)-1-(5-fluoro-2-iodophenyl)ethanol Chemical compound C[C@H](O)C1=CC(F)=CC=C1I GQGBQRLYBYFVAW-YFKPBYRVSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- NRLSRIONJVBZDT-UHFFFAOYSA-N 1-(5-fluoro-2-iodophenyl)ethanone Chemical compound CC(=O)C1=CC(F)=CC=C1I NRLSRIONJVBZDT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- BUUQMSAXHAZUAW-LLVKDONJSA-N 2-[(1R)-1-[5-amino-2-[5-cyano-1-methyl-3-(methylaminomethyl)pyrazol-4-yl]pyridin-3-yl]oxyethyl]-4-fluorobenzoic acid Chemical compound C[C@H](C1=C(C=CC(=C1)F)C(=O)O)OC2=C(N=CC(=C2)N)C3=C(N(N=C3CNC)C)C#N BUUQMSAXHAZUAW-LLVKDONJSA-N 0.000 description 1
- BMTSZVZQNMNPCT-UHFFFAOYSA-N 2-aminopyridin-3-ol Chemical compound NC1=NC=CC=C1O BMTSZVZQNMNPCT-UHFFFAOYSA-N 0.000 description 1
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 241000208140 Acer Species 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000008096 B7-H1 Antigen Human genes 0.000 description 1
- 108010074708 B7-H1 Antigen Proteins 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006143 Brain stem glioma Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 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 1
- 102100027100 Echinoderm microtubule-associated protein-like 4 Human genes 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101001057929 Homo sapiens Echinoderm microtubule-associated protein-like 4 Proteins 0.000 description 1
- 101000956807 Homo sapiens Leukocyte tyrosine kinase receptor Proteins 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 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 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102100038420 Leukocyte tyrosine kinase receptor Human genes 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- IXJRESGAHNRMAV-UHFFFAOYSA-N NC1=NC=CC=C1OCCC1(C=CC(F)=CC1)C(O)=O Chemical compound NC1=NC=CC=C1OCCC1(C=CC(F)=CC1)C(O)=O IXJRESGAHNRMAV-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 108010089430 Phosphoproteins Proteins 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
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 201000003761 Vaginal carcinoma Diseases 0.000 description 1
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 201000005179 adrenal carcinoma Diseases 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 108010035879 albumin-bilirubin complex Proteins 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229950004272 brigatinib Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 208000022033 carcinoma of urethra Diseases 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000005081 chemiluminescent agent Substances 0.000 description 1
- FWAXWNOGOQKLTC-UHFFFAOYSA-N chloromethyl diethyl phosphate Chemical compound CCOP(=O)(OCC)OCCl FWAXWNOGOQKLTC-UHFFFAOYSA-N 0.000 description 1
- SXWMOVVCNBEFQW-UHFFFAOYSA-N chloromethyl dimethyl phosphate Chemical compound COP(=O)(OC)OCCl SXWMOVVCNBEFQW-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 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
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012866 crystallographic experiment Methods 0.000 description 1
- 208000030381 cutaneous melanoma Diseases 0.000 description 1
- RZZFOJKGQIYSBE-UHFFFAOYSA-N cyclopropyl carbamate Chemical compound NC(=O)OC1CC1 RZZFOJKGQIYSBE-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- UMPRJGKLMUDRHL-UHFFFAOYSA-N ethyl 4-fluorobenzoate Chemical compound CCOC(=O)C1=CC=C(F)C=C1 UMPRJGKLMUDRHL-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 201000001343 fallopian tube carcinoma Diseases 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000008394 flocculating agent Substances 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- FYYHWMGAXLPEAU-OUBTZVSYSA-N magnesium-25 atom Chemical compound [25Mg] FYYHWMGAXLPEAU-OUBTZVSYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical class CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000010279 papillary renal cell carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 208000017954 parathyroid gland carcinoma Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 208000030940 penile carcinoma Diseases 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 208000021310 pituitary gland adenoma Diseases 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 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 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 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 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 208000013013 vulvar carcinoma Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了苯并氧杂二氮杂十四碳烯衍生物及其用途,属于医药领域。本发明提供的具有通式(I)所示结构的一类苯并氧杂二氮杂十四碳烯衍生物具有优异的间变性淋巴瘤酶(ALK)抑制活性和优异的药效学性能,能够显著延长药物大代谢半衰期;可安全、有效的用于治疗间变性淋巴瘤激酶阳性(ALK+)转移性(晚期)非小细胞肺癌(NSCLC)等,从而为治疗癌症、代谢与免疫疾病、心血管病以及神经性疾病等提供新的手段。
Description
技术领域
本发明涉及苯并氧杂二氮杂十四碳烯衍生物及其用途,属于医药领域。
背景技术
众所周知,肺癌是对人类威胁最大的恶性肿瘤之一,在男性中发病率和死亡率排第一位,女性发病率和死亡率排第二位。肺癌中,最常见的属非小细胞肺癌(NSCLC),约占肺癌的85%;其中间变性淋巴瘤酶(ALK)阳性发病率占非小细胞肺癌(NSCLC)的3%~5%。
ALK是受体酪氨酸激酶超家族的一个成员并且氨基酸序列水平和例如Ros-1、白细胞酪氨酸激酶、胰岛素受体和cMet(肝生长因子受体)的成员最密切相关,如同此基因家族的所有成员,其具有细胞外配体结合区、跨透膜序列和细胞内激酶催化区/信号区。间变性淋巴瘤酶(ALK)的信号配体特性还没有被阐明,且不同的机制己在文献中被提出(StoicaG.E.et a l.,].Bio l.Chem.,2001,276,16772-16779;Stoica G.E.et al.,].Biol.Chem.,2002,277,35990-35999;Mewng K.et a l.,PNAS,2000,97,2603-2608;Perez-Pinera P.et a l.,].Biol.Chem.,2007,282,28683-28690),通过磷脂酶C、PI3激酶和STAT3(在其他信号蛋白中)刺激间变性淋巴瘤酶(ALK)导致细胞内信号级联。间变性淋巴瘤酶(ALK)主要在发育中的神经***中被大量表达,尽管其表达在大脑、脊髓和眼睛的某些区域中被保留,然而其在成年动物体内的相对含量有减少的倾向。间变性淋巴瘤酶(ALK)在肿瘤学中有一个重要的作用,引起该酶活化并使全长酶表达增加的全长ALK酶点突变皆己被证明导致神经母细胞瘤。此外,由于基因易位缘故ALK和其他蛋白质的融合也己被证明导致与癌症相关的活化的激酶区。在淋巴瘤中看到许多引起基因融合的此类ALK易位,最普遍是在间变性大细胞淋巴瘤中看到的核磷蛋白NPM-ALK融合。ALK和EML4融合产生嵌合蛋白(EML4-ALK),其被认为对3至5%的非小细胞肺腺癌(NSCLC)有相关性。
2011年,ALK/ROS1/c-MET抑制剂克唑替尼被批准用于治疗通过FDA批准的测试检测到的ALK阳性的局部晚期或转移性NSCLC患者。克唑替尼还显示出治疗具有ROS1易位的NSCLC的效力,正如针对其它酪氨酸激酶抑制剂在临床上观察到的那样,已经赋予对ALK抑制剂的抗性的ALK和ROS1中的突变。
因此,ALK和ROS1是癌症治疗干预的有吸引力的分子靶标。仍然需要鉴定具有针对野生型和突变形式的ALK和ROS1的新型活性谱的化合物。
目前针对ALK突变的靶向药物有一代ALK靶向药克唑替尼(Crizotinib),二代ALK靶向药包括色瑞替尼(Ceritinib)、艾乐替尼(Alectinib)、布加替尼(brigatinib)以及刚上市的三代ALK靶向药物劳拉替尼(Lorlatinib)。
劳拉替尼(Lorlatinib,PF-06463922)是由辉瑞开发的一款新型抗耐药的新型ALK抑制剂,用于治疗间变性淋巴瘤激酶阳性(ALK+)转移性(晚期)非小细胞肺癌(NSCLC)的研究性治疗。,而且,由于其血脑屏障通透性高,对发生中枢神经***转移的非小细胞肺癌认可发挥较好的效力。
然而该药物的代谢稳定性并不好,半衰期较短,药物的用量较大,容易产生耐药性问题及毒副作用问题。
发明内容
为了解决上述问题,本发明人研制了一类新型苯并氧杂二氮杂十四碳烯衍生物用作ALK抑制剂,该类化合物具有毒副作用更低,血脑屏障通过率有效增加,半衰期更长,安全性更好。预期此类抑制剂将会有好的疗效,有望克服耐药性问题及毒副作用问题,具有良好的开发前景。本发明新型苯并氧杂二氮杂十四碳烯衍生物及盐类能够有效抑制间变性淋巴瘤酶(ALK)并可用于治疗或改善异常细胞增殖性病症。
本发明提供一种作为间变性淋巴瘤酶(ALK)抑制剂的新型苯并氧杂二氮杂十四碳烯衍生物,该结构化合物药效学性能更好、代谢稳定性更高。
本发明提供一种具有通式(I)所示结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐:
其中,当R1为氢时,R2、R3分别独立的选自C3-C6环烷基、氘代甲基;其中,环烷基可任选地被下述相同或不相同的取代基单取代至五取代,所述取代基选自卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基;
当R1选自C1-C4烷基、C3-C6环烷基、-CH2OR4、-COOR5、-COR6或-CH2OP(O)OR7OR8时,R2、R3分别独立的选自C1-C4烷基、氘代甲基或C3-C6环烷基;其中所述烷基、环烷基可任选地被相同或不相同的取代基单取代至五取代,所述的取代基选自卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基;其中,R4,R5,R6分别独立选自氢、C1-C4烷基或C3-C6环烷基;R7,R8分别独立的选自氢、C1-C4烷基或C3-C6环烷基;其中,所述烷基、环烷基可任选地被下述相同或不相同的取代基单取代至五取代,所述的取代基选自:卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基。
本发明提供的一种具有通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,当R1为氢时,R2、R3分别中至少有一个为氘代甲基,另一个选自C1-C4烷基、C3-C6环烷基、氘代甲基。其中,C3-C6环烷基优选环丙基;C1-C4烷基优选甲基。
本发明提供的一种具有通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,R4优选氢、C1-C4烷基。进一步优选甲基和氢。
本发明提供的一种具有通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,R5优选自氢、甲基、乙基或异丙基;
本发明提供的一种具有通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,R6优选氢。
本发明提供的一种具有通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,R7,R8分别独立的优选氢、甲基、乙基、异丙基、叔丁基;进一步优选乙基、叔丁基。
本发明提供的一种具有通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐选自:
本发明通式(I)结构的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,其中所述的药学上可接受的盐为无机盐或有机盐,无机盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机盐选自乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、以磺酸盐、苯磺酸盐、水杨酸盐。
本发明再一个目的是提供药物组合物,它含有上述本发明通式(I)化合物或其药学上可接受的盐、以及药学上可接受的载体、药用辅料。
所述药物载体包含:微囊、微球、纳米粒、脂质体。
所述药用辅料包括:包含溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂以及释放阻滞剂。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体制剂,包括,但不限于胶囊剂、片剂、丸剂、散剂、颗粒剂等。
本发明化合物或其药学上可接受的盐的单次用量可以为0.01-1000mg,例如0.05-800mg、0.1-500mg、0.01-300mg、0.01-200mg、0.05-150mg、0.05-50mg等。
另一方面,本发明提供了上述通式(I)的化合物或其药学可接受的盐在制备用作ALK抑制剂的药物中的用途。
另一方面,本发明提供了上述通式(I)的化合物或其药学可接受的盐在制备用于治疗癌症的药物中的用途。
本发明所提及的癌症,可选自非小细胞肺癌(NSCLC)、鳞状细胞癌、激素难治疗性***癌、乳突状肾细胞癌、大肠直肠腺癌、神经母细胞瘤、间变性大细胞淋巴瘤(ALCL)、胃癌和转移性脑癌等。
本发明的有益效果:
本发明提供的具有通式(I)所示结构的一类苯并氧杂二氮杂十四碳烯衍生物具有较为便捷的合成方法以及良好的间变性淋巴瘤酶(ALK)抑制活性和优异的药效学性能,能够显著延长药物大代谢半衰期。
本发明新型苯并氧杂二氮杂十四碳烯衍生物,具有抑制ALK的生物学功能,用于间变性淋巴瘤激酶阳性(ALK+)转移性(晚期)非小细胞肺癌(NSCLC)的治疗,为寻找治疗癌症、代谢与免疫疾病、心血管病以及神经性疾病等提供新手段。
具体实施方式
下面将结合实施例对本发明的技术方案进行详细的描述。
在本发明中“C1-C4烷基”是指分别为1至4个碳原子的饱和的直链或支链的单价烃基。实例包括,但不限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丙基、2-丁基和2-甲基-2-丙基。
在本发明中“C3-C6环烷基”是指分别为3至6个碳原子的环烷基。
在本发明中“给药”或“给予”个体化合物是指向需要治疗的个体提供本发明的化合物。
<化合物或其药学上可接受的盐>
本发明提供了一类作为间变性淋巴瘤酶(ALK)抑制剂的新型苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,其结构式如通式(I)所示:
本发明还提供通式(I)所述的化合物的制备方法,所述方法通过以下反应式进行:
反应方案1:
其中R4选自氢、C1-C4烷基或C3-C6环烷基,当R4为氢时可通过式(II)化合物与甲醛在四丁基氟化铵条件下获得,当R4为C1-C4烷基、C3-C6环烷基可通过与R4OCH2Br在碱性条件下获得;
或者,反应方案2:
其中R5选自氢、C1-C4烷基或C3-C6环烷基,可通过式(II)化合物与R5OCOCl在碱性条件下获得;
或者,反应方案3:
其中R6选自氢、C1-C4烷基或C3-C6环烷基,当R6为氢时可通过式(II)化合物与甲酸反应获得,当R6为C1-C4烷基或C3-C6环烷基,可通过式(II)化合物与R6COCl在碱性条件下获得;
或者,反应方案4:
其中R7,R8独立选自氢、C1-C4烷基或C3-C6环烷基;
合适的碱包括叔胺碱例如二异丙基乙胺(DIEA)和三乙胺、无机碱等。
<药物组合物>
本发明还提供药物组合物,包含上述本发明通式(I)化合物或其药学上可接受的盐、以及药学上可接受的载体、赋形剂或稀释剂。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体制剂,包括,但不限于胶囊剂、片剂、丸剂、散剂、颗粒剂等。在这些固体剂型中,本发明通式(I)化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合,例如与柠檬酸钠或磷酸二钙。或与下属成分混合:(1)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等;(2)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、***胶等;(3)保湿剂,例如,甘油等;(4)崩解剂、例如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些符合硅酸盐和碳酸钠等;(5)缓溶剂,例如石蜡等;(6)吸收加速剂,例如季铵化合物等;(7)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯等;(8)吸附剂,例如,高岭土等;(9)润滑剂,例如,滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫酸钠等,或其混合物。胶囊剂、片剂、丸剂中也可包含缓冲剂。
所述固体剂型例如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料如肠溶衣和其他本领域公知的材料晶型包衣或微囊化。他们可包含不透明剂,并且,这种组合物中活性成分的释放可以延迟的方式在消化道的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性成分也可与上述赋形剂中的一种或者多种形成微胶囊形式。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型,包括,但不限于药学上可接受的乳液、溶液、悬浮液、糖浆、酊剂等。除了作为活性成分的通式(I)化合物或其药学上可接受的盐外,液体剂型可包含本领域中常规采用的惰性稀释剂,例如水和其他溶剂,增溶剂和乳化剂、例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油类,特别是棉籽油、花生油、玉米油、橄榄油、蓖麻油、芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外,本发明液体剂型也可包括常规助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括,例如,乙氧基化十八烷醇、聚氧乙烯山梨醇、和脱水山梨醇、微晶纤维素、琼脂等或这些物质的混合物。
本发明化合物和其药学上可接受的盐可以配置为用于胃肠外注射的剂型,包括,但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,以及用于重新溶解成无菌的可注射溶液和分散液的无菌粉末。适宜的载体、稀释剂、溶剂、赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐可以配置为用于局部给药的剂型,包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明通式(I)化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂,和必要时可能需要的推进剂一起混合。
本发明的药物组合物包括通式(I)化合物或其药学上可接受的盐作为活性成分,以及药学上可接受载体、赋形剂、稀释剂。在制备药物组合物时,通常是将本发明通式(I)化合物或其药学上可接受的盐与药学上可接受载体、赋形剂或稀释剂混合。其中通式(I)化合物或其药学上可接受的盐的含量可以为0.01-1000mg,例如0.05-800mg、0.1-500mg、0.01-300mg、0.01-200mg、0.05-150mg、0.05-50mg等。
<用途>
本发明还提供通式(I)化合物或其药学上可接受的盐在制备用于治疗哺乳动物的癌症的用途。
通式(I)化合物或其药学上可接受的盐,通过抑制间变性淋巴瘤酶(ALK)活性,用于治疗哺乳动物包括人的转移性(晚期)非小细胞肺癌(NSCLC)疾病的方法,所述方法包括向所述哺乳动物包括人施用治疗有效量的上述式I的化合物或其药学上可接受的盐。
“治疗有效量”为个体中有效产生生物或医学应答(例如降低或抑制酶活蛋白活性,或者改善症状、减轻病况、减缓或延迟疾病进展或者预防疾病)的本发明的化合物的量。
本发明所提及的癌症,包括肺癌、骨癌、膜腺癌、皮肤癌、头或颈癌、皮肤黑色素癌或眼球内黑色素癌、子宫癌、卵巢癌、直肠癌、胆门部癌、胃癌、结肠癌、乳癌、输卵管癌、子宫内膜癌、子***、***癌、阴门癌、霍奇金氏病、食道癌、小肠癌、内分泌***癌、甲状腺癌、副甲状腺癌、肾上腺癌、软组织肉癌、尿道癌、***癌、***癌、慢性或急性白血病、淋巴细胞性淋巴癌、膀肮癌、肾癌或输尿管癌、肾细胞癌、肾孟癌、中枢神经***(CNS)癌、原发性中枢神经***淋巴癌、脊髓轴癌、脑干神经胶质瘤、脑垂腺腺瘤等。
本发明的化合物或其药学上可接受的盐可给药于哺乳动物包括人,可以口服、直肠、胃肠外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂、滴剂)或瘤内给药。
本发明所述的化合物或其药学上可接受的盐可以单独给药,或者与其他药学上可接受的治疗剂联合给药,与其他抗肿瘤药物组合。此联合治疗可通过同时、顺序或分开使用治疗的各个组分来实现。所述治疗剂包括但不限于:作用于DNA化学结构的抗肿瘤药物,如顺铂,影响核苷酸合成的抗肿瘤药物如甲氨蝶呤、5-氟尿嘧啶等,影响核酸转录的抗肿瘤药物如阿霉素、表阿霉素、阿克拉霉素等,作用于微管蛋白合成的抗肿瘤药物如紫杉醇、长春瑞滨等,芳香化酶抑制剂如氨鲁米特、来曲唑、瑞宁德等,细胞信号通路抑制剂如ALK抑制剂克唑替尼、色瑞替尼、艾乐替尼、劳拉替尼等。抗肿瘤单抗,免疫抑制剂PD-1、PD-L1等,待组合的各成分可同时或顺序的给予,以单一制剂形式或者以不同制剂的形式给予。所述组合不仅包括本发明化合物的一种或其他活性剂的组合,而且也包括本发明化合物的两种或更多的其他活性剂的组合。
下面结合具体实施例,进一步阐述本发明。应理解为这些实施例仅用于举例说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件。
具体实施方式中涉及如下中间体物质,可参见下述路线过程合成得到:
中间体9:叔丁基((4-溴-5-氰基-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基甲酸酯的制备
路线如下所示:
具体过程:
步骤a:2,4-二羰基戊酸甲酯(中间体1)的制备:
将冰盐浴下乙二酸二甲酯(23.6g,0.2mol)和丙酮(29.2g,0.2mol)慢慢滴加至25%甲醇钠的甲醇(200mL,0.2mol)中,0℃下搅拌8小时,反应液倾入200mL水中,乙酸乙酯萃取,水相用浓盐酸调pH为2-3,经乙酸乙酯萃取,有机相水洗,饱和食盐水洗,干燥后浓缩得产物26g,产率:90%。
步骤b:3-甲基-1H-吡唑-5-羧酸甲酯(中间体2)的制备:
将2,4-二羰基戊酸甲酯(中间体1)(12g,0.076mol)溶于100mL二氯甲烷中,冰盐浴下慢慢滴加水合肼(85%,5.3g,0.091mol),0℃下搅拌3小时,反应液倾入200mL水中,二氯甲烷萃取,有机相经水洗,干燥,浓缩得产物8.8g,产率:83%。
步骤c:1,3-二甲基-1H-吡唑-5-羧酸甲酯(中间体3)的制备:
将3-甲基-1H-吡唑-5-羧酸甲酯(中间体2)(5g,0.036mol)溶于50mL四氢呋喃中,加入碘甲烷(6.1g,0.043mol),50℃反应3小时,反应液倾入100mL水中,乙酸乙酯萃取,有机相经水洗,干燥,浓缩得产物4.5g,产率:82%。
步骤d:4-溴-1,3-二甲基-1H-吡唑-5-羧酸甲酯(中间体4)的制备:
将1,3-二甲基-1H-吡唑-5-羧酸甲酯(中间体3)(1g,6.49mmol)溶于5mL DMF中,分批加入NBS(1.73g,9.73mmol),加完后室温搅拌4小时。将反应液滴加至50mL冰水中,白色固体析出,过滤,滤饼水洗,烘干得产物1.1g,产率:73%。
步骤e:4-溴-1,3-二甲基-1H-吡唑-5-羧酰胺(中间体5)的制备
将4-溴-1,3-二甲基-1H-吡唑-5-羧酸甲酯(中间体4)(1g,0.0043mol)加至10mL氨水中,室温搅拌过夜,固体析出,抽滤,烘干得产物0.65g,产率:69.5%。
步骤f:4-溴-1,3-二甲基-1H-吡唑-5-腈(中间体6)的制备
将4-溴-1,3-二甲基-1H-吡唑-5-羧酰胺(中间体5)(400mg,1.83mmol)混悬于5mL乙腈中,加入三氯氧磷(844mg,3.0eq),升温至80℃反应3小时,反应液冷却至室温后,慢慢倒至冰水中,固体析出,过滤,水洗,烘干得产物200mg,产率54.5%。
步骤g:4-溴-3-(溴甲基)-1-甲基-1H-吡唑-5-腈(中间体7)的制备
将4-溴-1,3-二甲基-1H-吡唑-5-腈(中间体6)(500mg,2.5mmol),NBS(489mg,2.75mmol),AIBN(82mg,0.5mmol)溶于10mL四氯化碳中,氮气保护并回流过夜。反应液冷却至室温后,过滤,滤液旋干得产物600mg,产率86%。
步骤h:4-溴-1-甲基-3-((甲基氨基)甲基)-1H-吡唑-5-腈(中间体8)的制备
将4-溴-3-(溴甲基)-1-甲基-1H-吡唑-5-腈(中间体7)(1g,3.6mmol)溶于10mL甲胺醇溶液中,室温搅拌过夜,旋蒸至干,加入稀盐酸调pH=2-3,乙酸乙酯洗涤除杂质,水相用1M NaOH水溶液调pH=9-10,乙酸乙酯萃取,合并有机相,经水洗,干燥,浓缩得产物600mg,产率:73%。
步骤i:叔丁基((4-溴-5-氰基-1-甲基-1H-吡唑-3-基)甲基)(甲基)氨基甲酸酯(中间体9)的制备
将4-溴-1-甲基-3-((甲基氨基)甲基)-1H-吡唑-5-腈(中间体8)(500mg,2.18mmol)溶于10mL四氢呋喃中,加入三乙胺(330mg,3.27mmol)和二碳酸二叔丁酯(713mg,3.27mmol),室温搅拌3小时,反应液经乙酸乙酯稀释,柠檬酸水溶液洗涤,水洗,干燥,浓缩得产物680mg,产率:95%。1H NMR(400MHz,CDCl3)δ4.46(br s,2H),4.01(s,3H),2.83(brs,3H),1.47(s,9H).
中间体14:(R)-2-(1-((2-氨基-5-溴吡啶-3-基)氧基)乙基)-4-氟苯甲酸甲酯的制备
路线如下所示:
步骤j:(S)-1-(5-氟-2-碘苯基)乙-1-醇(中间体10)的制备
将(-)-DIPCI(5.7g,17.8mmol)的四氢呋喃(50mL)溶液冷却至-20至-30℃,然后逐滴加入1-(5-氟-2-碘苯基)乙酮(3.13g,11.9mmol)的四氢呋喃(50mL)溶液,加热反应液到室温。2小时后,冷却至-30℃,加入另一部分(-)-DIPCl(3.8g,11.9mmol),保温反应30分钟,然后升至室温,1小时后,浓缩至干,用甲基叔丁基醚(100mL)溶解残留物。冰浴下,二乙醇胺(3.1g,29.6mmol)的乙醇/四氢呋喃(7.5mL/15mL)溶液慢慢滴加入反应液中,加热回流2小时,然后冷却到室温,过滤,浓缩滤液。使残留物在7:3的庚烷/乙酸乙酯(100mL)中析出固体,过滤。重复此步骤直到该液体浓缩后不会再观察到固体为止。柱层析提纯,得油状物。将所得无色油状用庚烷进行重结晶化进一步提纯,得到白色结晶1.8g,产率:57%。
步骤k:(S)-1-(5-氟-2-碘苯基)甲磺酸乙酯(中间体11)的制备
将中间体10(2.2g,8.3mmol)的甲基叔丁基醚(35mL)溶液冷却至0℃,依次逐滴加入三乙胺(2.3mL,16.6mmol)与甲磺酰氯(0.96mL,12.4mmol),然后加热反应到室温并搅拌3小时。过滤,用乙酸乙酯洗涤固体。浓缩滤液,得到浅黄色油状物3.5g,产率:80%
步骤l:(R)-3-(1-(5-(5-氟-2-碘苯基)乙氧基)吡啶-2-胺(中间体12)的制备
将碳酸铯(6.5g,20.1mmol)加至2-氨基-3-羟基吡啶(1.33g,12.1mmol)的甲基四氢呋喃(60mL)与丙酮(30mL)混合溶剂中,室温搅拌30分钟,然后加热至40℃,逐滴加入中间体11(3.44g,80mmol)的甲基四氢呋喃(30mL)溶液。80℃反应24小时。过滤反应液,浓缩滤液,柱层析纯化得到白色固体1.4g,产率:38%
步骤m:(R)-2-(1-(((2-氨基吡啶-3-基)氧基)乙基)-4-氟苯甲酸甲酯(中间体13)的制备
将中间体12(2g,5.7mmol)溶于20mL甲醇中,依次加入三乙胺(1.54mL,11.3mmol)与Pd(dppf)C12(0.41g,0.57mmol)。在压力为100psi的一氧化碳氛围中,100℃反应16小时。过滤反应混合物,浓缩滤液,柱层析纯化得到棕色油状物1.3g,产率:79%。
步骤n:(R)-2-(1-((2-氨基-5-溴吡啶-3-基)氧基)乙基)-4-氟苯甲酸甲酯(中间体14)的制备
将中间体13(1.3g,4.5mmol)溶于20mL乙腈中,0℃下慢慢加入NBS(0.79g,4.5mmol)的乙腈(20mL溶液),加完后搅拌混合物2小时。浓缩至干,用乙酸乙酯溶解残留物,用2M氢氧化钠水溶液与10%硫代硫酸纳水溶液洗涤。干燥,浓缩,柱层析得到1.2g,产率:73%。
lHNMR(400MHz,DMSO-d6)δ:7.97-7.93(m,1H),7.61-7.51(m,1H),7.54(s,1H),7.29-7.24(m,1H),6.89(s,1H),6.25-6.08(m,3H),3.91(s,3H),1.59(d,J=8.0Hz,3H).
中间体18:(10R)-7-氨基-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈的制备
路线如下所示:
步骤o:甲基(R)-2-(1-((5-氨基-2-(3-((((叔丁氧基羰基)(甲基)氨基)甲基]--5-氰基-1-甲基-1H-吡唑-4-)吡啶-3-基)氧基)乙基-4-氟苯甲酸酯(中间体15)的制备
将中间体14(0.9g,2.4mmo l)、中间体9(1.0g,3.0mmo l)、联硼酸频哪醇酯(0.9g,3.6mmo l)、氟化铯(1.9g,12.6mmo l)溶于9:1甲醇/水(12mL)的溶液中,加热至60℃,氮气保护下加入Pd(dppf)Cl2(175mg,0.24mmol)的甲苯(1.5mL)溶液,回流搅拌3小时。加入另一部分的Pd(dppf)Cl2(87mg,0.12mmol)的甲苯(1.5mL)溶液,60℃搅拌过夜。冷却到室温后,加入乙酸乙酯,过滤,滤液依次用水与盐水洗涤,干燥,浓缩。柱层析纯化得到黄色油状物570mg,产率:43%。
步骤p:(R)-2-(1-((5-氨基-2-(3-((((叔丁氧羰基)(甲基)氨基)甲基]-5-氰基-1-甲基-1H-吡唑-4-基)吡啶-3-基)氧基)乙基)-4-氟苯甲酸(中间体16)的制备
将中间体15(2.7g,5mmol)溶于甲醇(20mL)中,加入氢氧化钠(1.0g,25mmol)的水(2mL)溶液,在40℃搅拌混合物3小时。用水稀释反应液,浓缩除去甲醇,水相用乙酸乙酯洗涤。水相经稀盐酸中和,乙酸乙酯萃取,干燥,浓缩得到浅黄色固体2g,产率:76%。
步骤q:(R)-2-(1-((5-氨基-2-(5-氰基-1-甲基-3-((甲基氨基)甲基)-1H-吡唑-4-基)吡啶-3-基)氧基)乙基)-4-氟苯甲酸(中间体17)的制备
将中间体16(960mg,1.82mmol)溶于4M氯化氢-二氧六环溶液(15mL)中,室温搅拌反应2.5小时。浓缩得到灰白色固体700mg,产率:83.1%。
步骤r:(10R)-7-氨基-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(中间体18)的制备
将中间体17(100mg,0.217mmol)溶于DMF(10mL)中,加入DIPEA(42mg,0.325mmol),降温至0℃,慢慢加入HATU(123.5mg,0.325mmol),0℃反应2小时。反应液加入水中,乙酸乙酯萃取,有机相经水洗,干燥,浓缩,柱层析得40mg,产率:45%。
lHNMR(400MHz,DMSO-d6)δ:7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.19(s,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),2.99(s,3H),1.68(d,J=8.0Hz,3H).
中间体25:叔丁基((4-溴-5-氰基-1-氘代甲基-1H-吡唑-3-基)甲基)(环丙基)氨基甲酸酯的制备
路线如下所示:
合成方法参考中间体9的合成,其中碘甲烷替换为氘代碘甲烷,甲胺替换为环丙基胺,ESI-MS m/z:358.2/360.2[M+H]+。
中间体27:叔丁基((4-溴-5-氰基-1-氘代甲基-1H-吡唑-3-基)甲基)(氘代甲基)氨基甲酸酯的制备
路线如下所示:
合成方法参考中间体25的合成,其中环丙基胺替换为氘代甲胺,ESI-MS m/z:335.2/337.2[M+H]+。
中间体34:叔丁基((4-溴-5-氰基-1-环丙基-1H-吡唑-3-基)甲基)(氘代甲基)氨基甲酸酯的制备
路线如下所示:
合成方法参考中间体9的合成,其中碘甲烷替换为溴代环丙烷,甲胺替换为氘代甲胺,ESI-MS m/z:358.2/360.2[M+H]+。
中间体36:叔丁基((4-溴-5-氰基-1-环丙基-1H-吡唑-3-基)甲基)(甲基)氨基甲酸酯的制备
合成方法参考中间体25的合成,其中环丙基胺替换为甲胺,ESI-MS m/z:332.2/334.2[M+H]+。
中间体38:叔丁基((4-溴-5-氰基-1-甲基-1H-吡唑-3-基)甲基)(氘代甲基)氨基甲酸酯的制备:
路线如下所示:
合成方法参考中间体9的合成,其中甲胺替换为氘代甲胺,ESI-MS m/z:332.2/334.2[M+H]+。
中间体40:叔丁基((4-溴-5-氰基-1-甲基-1H-吡唑-3-基)甲基)(环丙基)氨基甲酸酯的制备
路线如下所示:
合成方法参考中间体9的合成,其中甲胺替换为环丙胺,ESI-MS m/z:355.2/357.2[M+H]+。
实施例1:(10R)-7-羟甲基氨基-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物1)
将中间体18(100mg,0.245mmol)混悬于水(1mL),二氯甲烷(1mL),甲醇(1mL)中,加入甲醛水溶液(37%,0.4mL)和四丁基氟化铵(1M,0.08mL)。室温过夜,反应液经二氯甲烷萃取,有机相经饱和氯化钠洗,无水硫酸钠干燥,柱纯化得固体80mg,产率74.7%。
ESI-MS m/z:437.2[M+H]+。
lHNMR(400MHz,DMSO-d6)δ:9.29(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.39(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),2.99(s,3H),1.68(d,J=8.0Hz,3H).
实施例2:(10R)-7-氨基甲酸乙酯-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物2)
将中间体18(100mg,0.245mmol)溶于THF中,加入DIPEA(38mg,0.294mmol),0℃下慢慢加入氯甲酸乙酯(26.5mg,0.245mmol),然后室温搅拌过夜,反应液经水洗,乙酸乙酯萃取,有机相经干燥旋干,柱纯化得35mg,产率:29.7%。
ESI-MS m/z:479.2[M+H]+。
lHNMR(400MHz,DMSO-d6)δ:9.51(s,1H),7.98(s,1H),7.83-7.80(m,1H),7.49-7.47(m,1H),7.21-7.16(m,2H),5.66(q,J=8.0Hz,1H),4.48(d,J=16.0Hz,1H),4.25(d,J=12.0Hz,1H),4.18(q,J=8.0Hz,2H),4.08(s,3H),3.00(s,3H),1.68(d,J=8.0Hz,3H),1.28(t,J=8.0Hz,3H).
实施例3:(10R)-7-氨甲醛基-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物3)
冰浴条件下,将中间体18(100mg,0.245mmol)慢慢加至甲酸(113mg,2.45mmol)中,慢慢加入乙酸酐(37mg,0.367mmol),加完后室温搅拌过夜。反应液经乙酸乙酯稀释,水洗,干燥,浓缩,柱层析得固体42mg,产率:39.2%。
ESI-MS m/z:435.2[M+H]+。
lHNMR(400MHz,DMSO-d6)δ:10.42(d,J=12.0Hz,1H),9.23(s,1H),7.89(s,1H),7.81(d,J=8.0Hz,1H),7.50-7.46(m,1H),7.21-7.17(m,2H),5.73(q,J=8.0Hz,1H),4.48(d,J=16.0Hz,1H),4.23(d,J=12.0Hz,1H),4.08(s,3H),3.01(s,3H),1.72(d,J=8.0Hz,3H).
实施例4:(10R)-7-氨基-12-氟-2-氘代甲基-10-甲基-16-环丙基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物4)
合成方法参考中间体18的合成,其中中间体9代替为中间体25。
ESI-MS m/z:436.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.19(s,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),2.30-2.22(m,1H),1.68(d,J=8.0Hz,3H),0.83-0.56(m,4H).
实施例5:(10R)-7-氨基-12-氟-2,16-二氘代甲基-10-甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物5)
合成方法参考中间体18的合成,其中中间体9代替为中间体27。
ESI-MS m/z:413.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.19(s,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),1.68(d,J=8.0Hz,3H).
实施例6:(10R)-7-氨基-12-氟-2-环丙基-10-甲基-16-氘代甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物6)
合成方法参考中间体18的合成,其中中间体9代替为中间体34。
ESI-MS m/z:436.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.19(s,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),2.32-2.25(m,1H),1.68(d,J=8.0Hz,3H),0.81-0.58(m,4H).
实施例7:(10R)-7-羟甲基氨基-12-氟-2,10-二甲基-16-氘代甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物7)
合成方法参考实施例1的合成,其中中间体9代替为中间体38。
ESI-MS m/z:440.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.29(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.39(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),1.68(d,J=8.0Hz,3H).
实施例8:(10R)-7-羟甲基氨基-12-氟-2,16-二氘代甲基-10-甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物8)
合成方法参考实施例1的合成,其中中间体9代替为中间体27。
ESI-MS m/z:443.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.29(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.39(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),1.68(d,J=8.0Hz,3H).
实施例9:(10R)-7-羟甲基氨基-12-氟-2-氘代甲基-10,16-二甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物9)
合成方法参考实施例1的合成,其中中间体9代替为中间体36。
ESI-MS m/z:440.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.29(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.39(d,J=4.0Hz,2H),5.65(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),2.99(s,3H),1.68(d,J=8.0Hz,3H).
实施例10:(10R)-7-氨基甲基磷酸二叔丁酯-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物10)
将中间体18(100mg,0.246mmol)溶于1mL DMF中,冰浴下加入NaH(10mg,0.246mmol),加完后0℃下反应0.5h,然后将二叔丁基氯甲基磷酸酯(67mg,0.246mmol)的DMF(0.5mL)加至反应液中,室温反应2h,反应液倒至水中,DCM萃取,有机相经水洗,饱和氯化钠洗,无水硫酸钠干燥,柱纯化得固体20mg,产率:13%。
ESI-MS m/z:629.4[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.36(d,J=4.0Hz,2H),5.63(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),2.99(s,3H),1.68(d,J=8.0Hz,3H),1.32(s,18H)
实施例11:(10R)-7-氨基磷酸二氢甲酯-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物11)
将化合物13(100mg,0.159mmol)溶于1mL稀盐酸(1M)和1mL四氢呋喃中,室温搅拌1小时,二氯甲烷萃取,干燥后旋干得固体25mg,产率:30.5%。
ESI-MS m/z:517.1[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.34(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),2.99(s,3H),1.68(d,J=8.0Hz,3H).
实施例12:(10R)-7-氨基磷酸二乙酯-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物12)
合成方法参照实施例10,其中二叔丁基氯甲基磷酸酯代替为二乙基氯甲基磷酸酯。
ESI-MS m/z:573.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.36(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),4.03(q,J=8.0Hz,4H),2.99(s,3H),1.68(d,J=8.0Hz,3H),1.41(t,J=8.0Hz,6H).
实施例13:(10R)-7-氨基酸二甲酯-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物13)
合成方法参照实施例10,其中二叔丁基氯甲基磷酸酯代替为二甲基氯甲基磷酸酯。
ESI-MS m/z:545.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.36(d,J=4.0Hz,2H),5.63(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),3.78(s,6H),2.99(s,3H),1.68(d,J=8.0Hz,3H).
实施例14:(10R)-7-甲氧基甲氨基-12-氟-2,10,16-三甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物14)
将中间体18(100mg,0.246mmol)溶于1mL DMF中,冰浴下加入NaH(10mg,0.246mmol),加完后0℃下反应0.5h,然后加入溴甲基甲基醚(30.7mg,0.246mmol),室温反应2h,反应液倒至水中,DCM萃取,有机相经水洗,饱和氯化钠洗,无水硫酸钠干燥,柱纯化得固体32mg,产率:28.9%。
ESI-MS m/z:451.2[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.29(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.39(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),3.32(s,3H),2.99(s,3H),1.68(d,J=8.0Hz,3H).
实施例15:(10R)-7-氨基甲基磷酸二叔丁酯-12-氟-2,10-二甲基-16-氘代甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物15)
合成方法参照实施例10,其中中间体9代替为中间体38。
ESI-MS m/z:632.3[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.36(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),1.68(d,J=8.0Hz,3H),1.32(s,18H).
实施例16:(10R)-7-氨基甲基磷酸二叔丁酯-12-氟-2-氘代甲基-10,16-二甲基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物16)
合成方法参照实施例10,其中中间体9代替为中间体36。
ESI-MS m/z:632.3[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.36(d,J=4.0Hz,2H),5.62(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),2.99(s,3H),1.68(d,J=8.0Hz,3H),1.32(s,18H).
实施例17:(10R)-7-氨基甲基磷酸二叔丁酯-12-氟-2,10-二甲基-16-环丙基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物17)
合成方法参照实施例10,其中中间体9代替为中间体40。
ESI-MS m/z:655.3[M+H]+
lHNMR(400MHz,DMSO-d6)δ:9.28(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.36(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.04(s,3H),2.30-2.22(m,1H),1.68(d,J=8.0Hz,3H),1.32(s,18H),0.83-0.56(m,4H).
实施例18:(10R)-7-羟甲基氨基-12-氟-2,10-二甲基-16-环丙基-5-氧代-10,15,16,17-四氢-2H-8,4-(次甲基桥)-吡唑并[4,3-h][2,5,11]苯并氧杂二氮杂十四熳环-3-甲腈(化合物18)
合成方法参考实施例1的合成,其中中间体9代替为中间体40。
ESI-MS m/z:463.3[M+H]+。
lHNMR(400MHz,DMSO-d6)δ:9.29(s,1H),7.61-7.58(m,2H),7.48-7.45(m,1H),7.20-7.16(m,1H),6.81(s,1H),6.39(d,J=4.0Hz,2H),5.61(q,J=8.0Hz,1H),4.44(d,J=16.0Hz,1H),4.20(d,J=12.0Hz,1H),4.03(s,3H),2.30-2.22(m,1H),1.67(d,J=8.0Hz,3H),0.83-0.56(m,4H).
实施例19探究新型苯并氧杂二氮杂十四碳烯衍生物的ALK抑制作用
野生型ALK与L1196M突变体ALK酶分析
用微射流迁移率变动分析测量野生型ALK与L1196M突变体ALK酶抑制作用。在96孔盘中以50μL体积进行反应,其含有预活化的人重组野生型(1.3nM)或L1196M(0.5nM)ALK激酶结构域(第1093至1411位氨基酸)、1.5μM磷受体肤、5'FAM-KKSRGDYMTMQIG-CONH2(CPCScientific,Sunnyva1e,CA)、试验化合物(11-剂量三倍连续稀释,最终2%二甲亚枫)或纯二甲亚砜、1mM DTT、0.002%Tween-20与5mM氯化镁/25mM Hepes(pH 7.1),预温育20分钟,加入ATP(60μM终浓度,~km等级)来起始。以室温温育反应物1小时,加入0.1M EDTA(pH8)来终止,以LabChip EZ Reader II(Ca1iperLife Sciences,Hopkinton,MA)电泳分离荧光标记的肽底物与磷酸化产物,测定反应程度(在无抑制剂下~5%至20%转化率)。动力学与结晶学研究证实该抑制剂是ATP竞争性的。用非线性回归法(GraphPad Prism,GraphPadSoftware,San Diego,CA)使转化率拟合竞争性抑制用的方程式来计算出Ki值,以及通过实验测得野生型ATP Km 58μM和L1196M激酶的ATP Km值=55μM。自己制备ATP酶(杆状病毒表达),在室温、2mM ATP、10mM氯化镁与4mM DTT/20mM Hepes(pH 7.5)存在下、利用16μM未活化的酶的自体磷酸化预活化~1小时,通过Q-TOF质谱法证实ALK激酶结构域完全磷酸化(每个蛋白质分子~4个磷酸化物)。
EML4-ALK用的细胞Phospho-ALK(Tyr1604)ELISA分析:
细胞株:
NIH-3T3EML4-ALK wt v1与NIH-3T3EML4-ALK v1 Ll196M细胞是人类稳定细胞株。将该细胞保存于37℃与5%二氧化碳培养箱内T-75烧瓶中的DMEM(Invitrogen,Car1sbad,CA)培养基中,该培养基添加1%L-谷氨酰胺、1%青霉素与链霉素、1μg/mL嘌呤霉素与10%新生牛血清(NCS)。
分析:
用PBS洗涤细胞,使细胞悬浮于DMEM培养基中,该培养基添加0.5%NCS和1%青霉素与链霉素,以20,000个细胞/孔/100μL的密度接种于96孔盘中,在37℃与5%二氧化碳培养箱内温育。在温育20小时后将100μL含有指定PF-合物浓体或对照组(二甲亚砜)的检验培养基DMEM加入盘中,以培养箱温育1小时。除去培养基,将含有磷酸酯酶抑制剂与苯甲磺酰氟(PMSF)的裂解液加入孔中,以4℃震荡30分钟得到蛋白质裂解液。随后用PathScanphospho-ALK(Tyr1604)化学发光三明治型ELISA试剂盒(Cell Signal Technology Inc.,cat#7020)评估ALK的磷酸化,请参见下列:
将phospho-ALK(Tyr1604)兔抗体涂覆于96孔微型盘上。取50μL细胞裂解液加到涂覆抗体的盘中,以室温温育2小时。用0.1%Tween20/PBS大量洗涤除去未结合的物质,加入ALK小鼠mAb以检测被捕获的phospho-ALK(Tyr1604)与phospho-ALK融合蛋白。然后用抗小鼠IgG(HRP酶结合抗体)辨识结合检验抗体。最后加入化学发光剂,温育10分钟使信号发展。用Envision板读数仪以发光模式读取该检验定盘。用四参数分析法通过浓度反应曲线拟合计算出IC50值。
ALK酶分析和WT EML4-ALK与L1196M EML4-ALK用的细胞Phospho-ALK(Tyr1604)ELISA分析得到的Ki与IC50数据表示在表1。
表1不同化合物的细胞抑制性能结果
通过野生型ALK与L1196M突变体ALK酶活性数据分析,其中化合物4、5、6在激酶水平和细胞水平上均体现了优于劳拉替尼的效果,化合物1、2、3、7、8、9、18在激酶水平和细胞水平上与劳拉替尼表现相当;化合物10、11、12、13、15、16、17作为磷酸酯前药虽然在激酶水平上稍弱于劳拉替尼,但是,其中的化合物10、11、12、13、14均为化合物1的前体、化合物15是化合物7的前体、化合物16是化合物9的前体,化合物17是化合物18的前体,它们在细胞水平的效果是与劳拉替尼相当的。
实施例20探究新型苯并氧杂二氮杂十四碳烯衍生物的代谢稳定性
使用人体肝脏微粒体进行化合物稳定性的评价。将实施例化合物的肝微粒体酶稳定性与Lorlatinib(PF-06463922)进行比较。
测定***:本发明化合物的代谢稳定性利用由男女混合的肝脏微粒体用1mMNADPH进行试验。样品使用质谱仪进行分析。将HRMS用于确定峰面积响应比率(对应于试验化合物或对照物的峰面积除以分析内标的峰面积)而不运行标准曲线。为了检测到所有的可能代谢物,在适当的m/z范围内进行HRMS扫描。
测定条件:该测定用一次孵育(N=1)v进行。将试验化合物在37℃下在含有0.5毫克/毫升肝脏微粒体蛋白的缓冲液中孵育。通过加入辅因子引发反应,并于0、2、4、8、16、24、36、48小时取样,平行孵育阳性对照物(5μM***)并于0、2、4、8、16、24、36、48小时取样。
测定质量控制:平行进行对照化合物***以证实(肝脏)微粒体的酶活性。最终时间点后,利用荧光测定法来确认NADPH添加到反应混合物中。对照物的T1/2满足可接受的内标。
分析方法:
液相色谱柱:Thermo BDS Hypersil C18 30X2.0mm,3μm,具有保护柱M.P.,缓冲液:25mM甲酸接缓冲液,pH 3.5;
水相(A):90%水,10%缓冲液;
有机相(B):90%乙腈,10%缓冲液;
流速:300微升/分钟
自动进样器:注射体积10微升
梯度程序参见表2。
表2梯度程序
通过使用人体肝微粒体,如本发明中所述实施例4、5、6表现出大于36小时的代谢半衰期,10、12、15、16、17表现出24-36小时的代谢半衰期,显著大于Lorlatinib(PF-06463922)20小时的代谢半衰期,实施例1、2、3、7、8、9、11、13、14、18表现出于Lorlatinib(PF-06463922)相似代谢半衰期。结果显示,相对较长的代谢半衰期使得它们具有降低医疗剂量和扩大给药时间间隔的潜能。
由实施例1-17的化合物的酶活性、IC50值及代谢半衰期数据可知,对于通式(I)类的化合物而言,连接基团和取代基团对于化合物的药效学性能和代谢稳定性有着重要的影响。尽管本发明通过之前的特定实施例说明,但不应将其解释为受此限制;而是本发明涵盖之前公开的一般方面。可在不背离本发明的精神和范围下进行多种修饰并具有多种实施方案。
Claims (10)
1.一种苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,结构如通式(I)所示,
其中,当R1为氢时,R2、R3分别独立的选自C3-C6环烷基、氘代甲基;其中,环烷基可任选地被下述相同或不相同的取代基单取代至五取代,所述取代基选自卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基;
当R1选自C1-C4烷基、C3-C6环烷基、-CH2OR4、-COOR5、-COR6或-CH2OP(O)OR7OR8时,R2、R3分别独立的选自C1-C4烷基、氘代甲基或C3-C6环烷基;其中所述烷基、环烷基可任选地被相同或不相同的取代基单取代至五取代,所述的取代基选自卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基;其中,R4,R5,R6分别独立选自氢、C1-C4烷基或C3-C6环烷基;R7,R8分别独立的选自氢、C1-C4烷基或C3-C6环烷基;其中,所述烷基、环烷基可任选地被下述相同或不相同的取代基单取代至五取代,所述的取代基选自:卤素、三氟甲基、氰基、硝基、羟基或C1-C4烷基。
3.根据权利要求1所述的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,其特征在于,R4选自甲基和氢。
4.根据权利要求1所述的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,其特征在于,R5选自氢、甲基、乙基、异丙基。
5.根据权利要求1所述的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,R7,R8分别独立的选自氢、甲基、乙基、异丙基、叔丁基。
7.根据权利要求1-6任一所述的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,其特征在于,所述的药学上可接受的盐选自无机盐或有机盐;其中,无机盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐、酸式磷酸盐;所述有机盐选自乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、以磺酸盐、苯磺酸盐、水杨酸盐。
8.一种药物组合物,包括权利要求1-7任一所述的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐,以及药物可接受载体和药用辅料。
9.根据权利要求8所述的药物组合物,其特征在于,药物可接受载体包括:微囊、微球、纳米粒、脂质体。
10.权利要求1-7任一所述的苯并氧杂二氮杂十四碳烯衍生物或其药学上可接受的盐在制备用于治疗癌症的药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010347120.4A CN111362967B (zh) | 2020-04-28 | 2020-04-28 | 苯并氧杂二氮杂十四碳烯衍生物及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010347120.4A CN111362967B (zh) | 2020-04-28 | 2020-04-28 | 苯并氧杂二氮杂十四碳烯衍生物及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111362967A true CN111362967A (zh) | 2020-07-03 |
CN111362967B CN111362967B (zh) | 2021-09-07 |
Family
ID=71203781
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010347120.4A Active CN111362967B (zh) | 2020-04-28 | 2020-04-28 | 苯并氧杂二氮杂十四碳烯衍生物及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111362967B (zh) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112209879A (zh) * | 2020-10-19 | 2021-01-12 | 河北省药品医疗器械检验研究院 | 一种西地那非杂质及其制备方法和应用 |
CN112724077A (zh) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | 一种劳拉替尼中间体的合成方法 |
CN115246843A (zh) * | 2021-04-26 | 2022-10-28 | 苏州东南药业股份有限公司 | 一类十四元稠环衍生物及其应用 |
US11542278B1 (en) | 2020-05-05 | 2023-01-03 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
US11667649B2 (en) | 2020-05-05 | 2023-06-06 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
WO2023245847A1 (zh) * | 2022-06-22 | 2023-12-28 | 中山大学 | 一种硼酸类小分子化合物在制备增强免疫检查点抑制剂疗效及治疗白血病药物中的应用 |
WO2024036097A1 (en) | 2022-08-12 | 2024-02-15 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether compounds and isotopologues thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL311444A (en) | 2021-10-01 | 2024-05-01 | Nuvalent Inc | Solid forms, pharmaceutical preparations and preparation of macrocyclic heteroaromatic ether compounds |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107207528A (zh) * | 2014-08-20 | 2017-09-26 | 苏州韬略生物科技有限公司 | 作为激酶抑制剂的经取代大环及其使用方法 |
WO2018137679A1 (en) * | 2017-01-25 | 2018-08-02 | Teligene Ltd | Process for the Preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile |
WO2019073347A1 (en) * | 2017-10-10 | 2019-04-18 | Pfizer Inc. | CRYSTALLINE BASE FREE HYDRATE SHAPE OF LORLATINIB |
CN108699081B (zh) * | 2016-03-03 | 2019-10-18 | 深圳市塔吉瑞生物医药有限公司 | 一种大环化合物及包含该化合物的组合物 |
-
2020
- 2020-04-28 CN CN202010347120.4A patent/CN111362967B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107207528A (zh) * | 2014-08-20 | 2017-09-26 | 苏州韬略生物科技有限公司 | 作为激酶抑制剂的经取代大环及其使用方法 |
CN108699081B (zh) * | 2016-03-03 | 2019-10-18 | 深圳市塔吉瑞生物医药有限公司 | 一种大环化合物及包含该化合物的组合物 |
WO2018137679A1 (en) * | 2017-01-25 | 2018-08-02 | Teligene Ltd | Process for the Preparation of (10R) -7- (2-aminoacetyl) amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (metheno) pyrazolo [4, 3-h] [2, 5, 11] -benzoxadiazacyclotetradecine-3-carbonitrile |
WO2019073347A1 (en) * | 2017-10-10 | 2019-04-18 | Pfizer Inc. | CRYSTALLINE BASE FREE HYDRATE SHAPE OF LORLATINIB |
Non-Patent Citations (1)
Title |
---|
SHENGQUAN DUAN ET AL.: "Developing an Asymmetric Transfer Hydrogenation Process for (S)-5-Fluoro-3-methylisobenzofuran-1(3H)-one, a Key Intermediate to Lorlatinib", 《ORG. PROCESS RES. DEV》 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11542278B1 (en) | 2020-05-05 | 2023-01-03 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
US11667649B2 (en) | 2020-05-05 | 2023-06-06 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether chemotherapeutic agents |
CN112209879A (zh) * | 2020-10-19 | 2021-01-12 | 河北省药品医疗器械检验研究院 | 一种西地那非杂质及其制备方法和应用 |
CN112724077A (zh) * | 2020-12-29 | 2021-04-30 | 武汉利昌医药科技有限公司 | 一种劳拉替尼中间体的合成方法 |
CN112724077B (zh) * | 2020-12-29 | 2023-07-11 | 武汉利昌医药科技有限公司 | 一种劳拉替尼中间体的合成方法 |
CN115246843A (zh) * | 2021-04-26 | 2022-10-28 | 苏州东南药业股份有限公司 | 一类十四元稠环衍生物及其应用 |
WO2023245847A1 (zh) * | 2022-06-22 | 2023-12-28 | 中山大学 | 一种硼酸类小分子化合物在制备增强免疫检查点抑制剂疗效及治疗白血病药物中的应用 |
WO2024036097A1 (en) | 2022-08-12 | 2024-02-15 | Nuvalent, Inc. | Heteroaromatic macrocyclic ether compounds and isotopologues thereof |
Also Published As
Publication number | Publication date |
---|---|
CN111362967B (zh) | 2021-09-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN111362967B (zh) | 苯并氧杂二氮杂十四碳烯衍生物及其用途 | |
TW202200562A (zh) | 喹喔啉二酮衍生物作為kras g12c突變蛋白的不可逆抑制劑 | |
CN105153122B (zh) | [(吲哚-3-基)嘧啶-2-基]氨基苯基丙-2-烯酰胺衍生物及盐、制备方法、应用 | |
CN110407856B (zh) | 一种大环化合物及包含该化合物的组合物 | |
CN112608318B (zh) | 一种作为蛋白质激酶抑制剂的化合物及其用途 | |
JP2022538917A (ja) | Bet阻害剤としてのヘテロ環式化合物 | |
JP7077323B2 (ja) | キナゾリン化合物並びにその調製方法、使用及び医薬組成物 | |
CN115043842A (zh) | 胺基取代双环类抑制剂及其制备方法和应用 | |
US20220289716A1 (en) | Crystalline forms of a cd73 inhibitor | |
CN110520416B (zh) | 多取代吡啶酮类衍生物、其制备方法及其医药用途 | |
WO2020038433A1 (zh) | 一种egfr激酶抑制剂及其制备方法和应用 | |
WO2022083657A1 (zh) | 取代苯并或吡啶并嘧啶胺类抑制剂及其制备方法和应用 | |
CN114437077A (zh) | 用作激酶抑制剂的化合物及其应用 | |
CN115368378A (zh) | 取代的大环化合物及包含该化合物的组合物及其用途 | |
CN114885607B (zh) | 喹啉基膦氧化合物及其组合物和用途 | |
CN110938104A (zh) | 环状二核苷酸类似物、其药物组合物及应用 | |
CN113045569B (zh) | 用作ret激酶抑制剂的化合物及其应用 | |
CN114437116A (zh) | 杂环化合物及其制备方法、药物组合物和应用 | |
CN112300173B (zh) | 一类含氮多环类化合物、制备方法和用途 | |
KR20230002706A (ko) | 결정질 ret 억제제 | |
CN110066272B (zh) | 取代的苯并[d]咪唑类化合物及其药物组合物 | |
CN112142747A (zh) | 一种吡唑酮并嘧啶类化合物、其制备方法及应用 | |
JP2023036957A (ja) | ジアリールピラゾール化合物、該化合物を含む組成物およびその使用 | |
JP2024516194A (ja) | Pd1/pd-l1阻害剤としての化合物及びその方法 | |
WO2021057867A1 (zh) | 一类基于有机胂的cdk抑制剂及其制备方法和用途 |
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 | ||
GR01 | Patent grant | ||
GR01 | Patent grant |