JP2019512492A5 - - Google Patents

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Publication number

JP2019512492A5

JP2019512492A5 JP2018548056A JP2018548056A JP2019512492A5 JP 2019512492 A5 JP2019512492 A5 JP 2019512492A5 JP 2018548056 A JP2018548056 A JP 2018548056A JP 2018548056 A JP2018548056 A JP 2018548056A JP 2019512492 A5 JP2019512492 A5 JP 2019512492A5

Authority

JP

Japan

Prior art keywords

formula

optionally substituted

alkyl

compound

drug linker

Prior art date

2017-03-24

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

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• 229940079593 drug Drugs 0.000 claims description 152
• 239000003814 drug Substances 0.000 claims description 152
• 150000001875 compounds Chemical class 0.000 claims description 118
• 125000005647 linker group Chemical group 0.000 claims description 99
• 150000003839 salts Chemical class 0.000 claims description 93
• 238000000034 method Methods 0.000 claims description 87
• 125000000217 alkyl group Chemical group 0.000 claims description 83
• 229910052739 hydrogen Inorganic materials 0.000 claims description 80
• 229910052799 carbon Inorganic materials 0.000 claims description 54
• 125000003118 aryl group Chemical group 0.000 claims description 43
• -1 linker compound Chemical class 0.000 claims description 39
• 125000000732 arylene group Chemical group 0.000 claims description 38
• 125000005549 heteroarylene group Chemical group 0.000 claims description 38
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
• 150000002148 esters Chemical group 0.000 claims description 31
• 239000000203 mixture Substances 0.000 claims description 31
• 108010044540 auristatin Proteins 0.000 claims description 30
• 125000000623 heterocyclic group Chemical group 0.000 claims description 30
• 125000006239 protecting group Chemical group 0.000 claims description 27
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
• 125000002947 alkylene group Chemical group 0.000 claims description 21
• 125000006244 carboxylic acid protecting group Chemical group 0.000 claims description 19
• 125000004474 heteroalkylene group Chemical group 0.000 claims description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
• 239000002904 solvent Substances 0.000 claims description 15
• 239000012351 deprotecting agent Substances 0.000 claims description 14
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 9
• 239000012190 activator Substances 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
• 239000007818 Grignard reagent Substances 0.000 claims description 8
• GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 claims description 8
• 150000004795 grignard reagents Chemical class 0.000 claims description 8
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 6
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 6
• 239000007822 coupling agent Substances 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 150000004820 halides Chemical class 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
• PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 4
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
• GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 4
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
• MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 claims description 4
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
• 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 4
• UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
• YHNUDLCUIKMNSN-UHFFFAOYSA-N bis(1,2,4-triazol-1-yl)methanone Chemical compound C1=NC=NN1C(=O)N1C=NC=N1 YHNUDLCUIKMNSN-UHFFFAOYSA-N 0.000 claims description 3
• IUBUFBCVRWLOCA-UHFFFAOYSA-N 2,3,6,7-tetramethylnaphthalene-1,4-dicarboxamide Chemical compound CC1=C(C)C(C(N)=O)=C2C=C(C)C(C)=CC2=C1C(N)=O IUBUFBCVRWLOCA-UHFFFAOYSA-N 0.000 claims description 2
• ABFPKTQEQNICFT-UHFFFAOYSA-M 2-chloro-1-methylpyridin-1-ium;iodide Chemical compound [I-].C[N+]1=CC=CC=C1Cl ABFPKTQEQNICFT-UHFFFAOYSA-M 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 2
• PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 2
• 239000007821 HATU Substances 0.000 claims description 2
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
• NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 2
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
• 125000002837 carbocyclic group Chemical group 0.000 claims description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 239000003153 chemical reaction reagent Substances 0.000 claims description 2
• 125000004185 ester group Chemical group 0.000 claims description 2
• CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 2
• VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical group [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
• 239000002243 precursor Substances 0.000 claims description 2
• YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
• UVRNDTOXBNEQBA-UHFFFAOYSA-N trichloromethyl carbonochloridate Chemical compound ClC(=O)OC(Cl)(Cl)Cl.ClC(=O)OC(Cl)(Cl)Cl UVRNDTOXBNEQBA-UHFFFAOYSA-N 0.000 claims description 2
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims 2
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 2
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
• QGHDLJAZIIFENW-UHFFFAOYSA-N 4-[1,1,1,3,3,3-hexafluoro-2-(4-hydroxy-3-prop-2-enylphenyl)propan-2-yl]-2-prop-2-enylphenol Chemical group C1=C(CC=C)C(O)=CC=C1C(C(F)(F)F)(C(F)(F)F)C1=CC=C(O)C(CC=C)=C1 QGHDLJAZIIFENW-UHFFFAOYSA-N 0.000 claims 1
• NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims 1
• 229910019142 PO4 Inorganic materials 0.000 claims 1
• 230000003213 activating effect Effects 0.000 claims 1
• WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 claims 1
• 239000003795 chemical substances by application Substances 0.000 claims 1
• 229910052749 magnesium Inorganic materials 0.000 claims 1
• 239000011777 magnesium Substances 0.000 claims 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
• 239000010452 phosphate Substances 0.000 claims 1
• 0 *C(O[C@@]([C@@]1OC(*)=O)[C@]2OC(*)=*=C(CCNC([C@](CCCCN*)N*)=O)Nc(cc(CO)cc3)c3O[C@]2O[C@@]1C(O*)=O)=O Chemical compound *C(O[C@@]([C@@]1OC(*)=O)[C@]2OC(*)=*=C(CCNC([C@](CCCCN*)N*)=O)Nc(cc(CO)cc3)c3O[C@]2O[C@@]1C(O*)=O)=O 0.000 description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
• 125000001072 heteroaryl group Chemical group 0.000 description 11
• 239000001257 hydrogen Substances 0.000 description 11
• 239000000611 antibody drug conjugate Substances 0.000 description 8
• 229940049595 antibody-drug conjugate Drugs 0.000 description 8
• 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 8
• 206010028980 Neoplasm Diseases 0.000 description 3
• 102000003886 Glycoproteins Human genes 0.000 description 2
• 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
• 102000018697 Membrane Proteins Human genes 0.000 description 2
• 108010052285 Membrane Proteins Proteins 0.000 description 2
• 101100170604 Mus musculus Dmap1 gene Proteins 0.000 description 2
• 239000000427 antigen Substances 0.000 description 2
• 102000036639 antigens Human genes 0.000 description 2
• 108091007433 antigens Proteins 0.000 description 2
• 125000004432 carbon atom Chemical group C* 0.000 description 2
• 229910052717 sulfur Inorganic materials 0.000 description 2
• 125000004434 sulfur atom Chemical group 0.000 description 2
• BSKOLJVTLRLTHE-GVHYBUMESA-N CCC1[C@H](C)CCC1 Chemical compound CCC1[C@H](C)CCC1 BSKOLJVTLRLTHE-GVHYBUMESA-N 0.000 description 1
• BPXIAOQZTQCRJT-WCQYABFASA-N C[C@H]([C@H](c1ccccc1)OC)C(C)=C Chemical compound C[C@H]([C@H](c1ccccc1)OC)C(C)=C BPXIAOQZTQCRJT-WCQYABFASA-N 0.000 description 1
• 206010066476 Haematological malignancy Diseases 0.000 description 1
• 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
• 206010025323 Lymphomas Diseases 0.000 description 1
• 230000002159 abnormal effect Effects 0.000 description 1
• 210000003719 b-lymphocyte Anatomy 0.000 description 1
• 201000011510 cancer Diseases 0.000 description 1
• 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
• 210000004027 cell Anatomy 0.000 description 1
• 238000010511 deprotection reaction Methods 0.000 description 1
• 208000032839 leukemia Diseases 0.000 description 1
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
• 230000036210 malignancy Effects 0.000 description 1
• 125000001302 tertiary amino group Chemical group 0.000 description 1
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1