WO2015076359A1 - Compose inhibiteur du proteasome - Google Patents
Compose inhibiteur du proteasome Download PDFInfo
- Publication number
- WO2015076359A1 WO2015076359A1 PCT/JP2014/080859 JP2014080859W WO2015076359A1 WO 2015076359 A1 WO2015076359 A1 WO 2015076359A1 JP 2014080859 W JP2014080859 W JP 2014080859W WO 2015076359 A1 WO2015076359 A1 WO 2015076359A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- proteasome
- pharmaceutically acceptable
- atom
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 134
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 title claims abstract description 103
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 title claims abstract description 103
- 230000002401 inhibitory effect Effects 0.000 title abstract description 75
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 37
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 229940079156 Proteasome inhibitor Drugs 0.000 claims description 19
- 125000002947 alkylene group Chemical group 0.000 claims description 19
- 239000003207 proteasome inhibitor Substances 0.000 claims description 19
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 125000004434 sulfur atom Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000005382 boronyl group Chemical group 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000000732 arylene group Chemical group 0.000 claims description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 201000011510 cancer Diseases 0.000 abstract description 27
- 238000000034 method Methods 0.000 abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- -1 ester compounds Chemical class 0.000 description 36
- 210000004027 cell Anatomy 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 31
- 230000000694 effects Effects 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000003921 oil Substances 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 12
- 229960001467 bortezomib Drugs 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 230000002159 abnormal effect Effects 0.000 description 8
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 7
- QCMHGCDOZLWPOT-FMNCTDSISA-N COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 Chemical compound COC1=C(CC[C@@H]2CCC3=C(C2)C=CC(=C3)[C@H]2CC[C@](N)(CO)C2)C=CC=C1 QCMHGCDOZLWPOT-FMNCTDSISA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 208000034578 Multiple myelomas Diseases 0.000 description 6
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 230000006907 apoptotic process Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- SOHLZANWVLCPHK-LBPRGKRZSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-4-phenylmethoxybutanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC(=O)OCC1=CC=CC=C1 SOHLZANWVLCPHK-LBPRGKRZSA-N 0.000 description 5
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- TXEBWPPWSVMYOA-UHFFFAOYSA-N 4-[3-[(1-amino-2-chloroethyl)amino]propyl]-1-[[3-(2-chlorophenyl)phenyl]methyl]-5-hydroxyimidazolidin-2-one Chemical compound NC(CCl)NCCCC1NC(=O)N(Cc2cccc(c2)-c2ccccc2Cl)C1O TXEBWPPWSVMYOA-UHFFFAOYSA-N 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 239000012131 assay buffer Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 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 4
- 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 4
- RSINFFVFOTUDEC-UHFFFAOYSA-N 2,5-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC(Cl)=CC=C1Cl RSINFFVFOTUDEC-UHFFFAOYSA-N 0.000 description 4
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 4
- 102100025566 Chymotrypsin-like protease CTRL-1 Human genes 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 101000856199 Homo sapiens Chymotrypsin-like protease CTRL-1 Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 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 4
- 230000005856 abnormality Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 4
- 230000037012 chymotrypsin-like activity Effects 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 229940125797 compound 12 Drugs 0.000 description 4
- 229940125758 compound 15 Drugs 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 239000013256 coordination polymer Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 201000005787 hematologic cancer Diseases 0.000 description 4
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 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 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 3
- 102000005572 Cathepsin A Human genes 0.000 description 3
- 108010059081 Cathepsin A Proteins 0.000 description 3
- 108090000617 Cathepsin G Proteins 0.000 description 3
- 102000004173 Cathepsin G Human genes 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- 125000003180 beta-lactone group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- MOILFCKRQFQVFS-BDNRQGISSA-N (1r,3s,4r,5r)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical group C1[C@@H]2C(C)(C)[C@H]1C[C@H](O)[C@@]2(O)C MOILFCKRQFQVFS-BDNRQGISSA-N 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 2
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- SZCBDIVMCGFVPW-UHFFFAOYSA-N 1-[4-(aminomethyl)-2,6-di(propan-2-yl)phenyl]-3-[1-butyl-4-(3-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]urea;hydrochloride Chemical compound Cl.CC(C)C=1C=C(CN)C=C(C(C)C)C=1NC(=O)NC=1C(=O)N(CCCC)C2=NC=CC=C2C=1C1=CC=CC(OC)=C1 SZCBDIVMCGFVPW-UHFFFAOYSA-N 0.000 description 2
- TZHOKOVQYMRTEI-UHFFFAOYSA-N 4-phenylmethoxybutan-1-amine Chemical compound NCCCCOCC1=CC=CC=C1 TZHOKOVQYMRTEI-UHFFFAOYSA-N 0.000 description 2
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 102100021117 Serine protease HTRA2, mitochondrial Human genes 0.000 description 2
- 101710146118 Serine protease HTRA2, mitochondrial Proteins 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000007771 core particle Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000009422 growth inhibiting effect Effects 0.000 description 2
- 230000009036 growth inhibition Effects 0.000 description 2
- 230000013632 homeostatic process Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000002427 irreversible effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 2
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 2
- 238000003375 selectivity assay Methods 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012289 standard assay Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000001810 trypsinlike Effects 0.000 description 2
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010065553 Bone marrow failure Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- NFDBTAVVTTVUHO-HQGMTDATSA-N C(C)(=O)N[C@@H](CC(=O)OCC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)B1O[C@@]2([C@H](O1)C[C@H]1C([C@@H]2C1)(C)C)C Chemical compound C(C)(=O)N[C@@H](CC(=O)OCC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)B1O[C@@]2([C@H](O1)C[C@H]1C([C@@H]2C1)(C)C)C NFDBTAVVTTVUHO-HQGMTDATSA-N 0.000 description 1
- KMADGJJFXWBOEM-HFAFVFOLSA-N C(C)(=O)N[C@@H](CCC(=O)OCC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)B1O[C@@]2([C@H](O1)C[C@H]1C([C@@H]2C1)(C)C)C Chemical compound C(C)(=O)N[C@@H](CCC(=O)OCC1=CC=CC=C1)C(=O)N[C@@H](CC(C)C)B1O[C@@]2([C@H](O1)C[C@H]1C([C@@H]2C1)(C)C)C KMADGJJFXWBOEM-HFAFVFOLSA-N 0.000 description 1
- 0 CC(C)C[C@@](B1O[C@@](C)([C@@](C2)C(C)(C)[C@@]2C2)[C@@]2O1)NC(C(*(C)C*C(N*(C)CC(C)C(COCc1ccccc1)COCc1ccccc1)=O)NC(C)=O)=O Chemical compound CC(C)C[C@@](B1O[C@@](C)([C@@](C2)C(C)(C)[C@@]2C2)[C@@]2O1)NC(C(*(C)C*C(N*(C)CC(C)C(COCc1ccccc1)COCc1ccccc1)=O)NC(C)=O)=O 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000024777 Prion disease Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- BMGMQYRPZOGZFU-YFKPBYRVSA-N [(1r)-1-amino-3-methylbutyl]boronic acid Chemical compound CC(C)C[C@H](N)B(O)O BMGMQYRPZOGZFU-YFKPBYRVSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001241 acetals Chemical group 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000036953 caspase-like activity Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000006355 external stress Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical group CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
- 108010040003 polyglutamine Proteins 0.000 description 1
- 229920000155 polyglutamine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- UVFAEQZFLBGVRM-MSMWPWNWSA-N succinyl-Leu-Leu-Val-Tyr-7-amino-4-methylcoumarin Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)CCC(O)=O)CC(C)C)C(=O)NC=1C=C2OC(=O)C=C(C)C2=CC=1)C1=CC=C(O)C=C1 UVFAEQZFLBGVRM-MSMWPWNWSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- FRACPXUHUTXLCX-BELIEFIBSA-N tert-butyl N-{1-[(1S)-1-{[(1R,2S)-1-(benzylcarbamoyl)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamoyl}-2-cyclopropylethyl]-2-oxopyridin-3-yl}carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CN(C1=O)[C@@H](CC2CC2)C(=O)N[C@@H](C[C@@H]3CCNC3=O)[C@H](C(=O)NCC4=CC=CC=C4)O FRACPXUHUTXLCX-BELIEFIBSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a novel compound having proteasome inhibitory activity, a proteasome inhibitor containing the compound, a pharmaceutical composition containing the compound as an active ingredient, particularly a pharmaceutical composition for treating a proteasome-related disease such as cancer.
- ubiquitin-proteasome system Proteolysis called ubiquitin-proteasome system is used to break down proteins that are no longer necessary for eukaryotic cells, such as they cannot be folded normally, become inactivated by external stress such as active oxygen, or reach the end of their lives. It is known that a system exists.
- the ubiquitin-proteasome system is a marker that is formed by modifying a protein that is no longer needed with a protein consisting of 76 amino acids called ubiquitin, and the protein is recognized and decomposed by a huge enzyme complex called a proteasome. .
- the ubiquitin-proteasome system not only processes the degradation of unwanted proteins, but also quantitatively regulates cell cycle-related factors, signal transduction factors, transcription factors, etc. It has been clarified that it is also involved in the control of apoptosis, and it has been found that it is a system related to the basis of life activity. And as abnormalities occur in this ubiquitin-proteasome system, it is known that various modulations are caused to cells, and by controlling the function of this ubiquitin-proteasome system, it is thought that abnormalities in ubiquitin-proteasome are involved. The possibility of treating various diseases and malignant cells in which apoptosis is difficult to induce is pointed out, and proteasome inhibitors are attracting attention as therapeutic agents for various diseases.
- Proteasome is a huge enzyme complex that recognizes and degrades all proteins labeled with ubiquitin.
- This complex is called a 19S complex or 11S complex at both ends of a cylindrical structure called a core particle (CP, 20S proteasome) in which four ring structures composed of two ⁇ rings and two ⁇ rings are stacked. It has a shape in which the structure is bound, and proteolysis is performed in the cavity portion in the 20S proteasome.
- molecules constituting the core particle molecules called ⁇ 1, ⁇ 2, and ⁇ 5 are known to have different catalytic activities such as caspase-like, trypsin-like, and chymotrypsin-like, respectively.
- proteasome inhibitors for example, compounds such as bortezomib or ester compounds thereof (for example, Patent Documents 1 to 5), compounds having a peptide-like structure such as belactocin, and the like are known.
- Bortezomib (trade name: Velcade), whose compound name is N-2-pyrazinecarbonyl-L-phenylalanine-L-leucineboronic acid, was first approved in Japan as a treatment for refractory multiple myeloma Proteasome inhibitor. Although the mechanism of action on cancer cells has not been completely elucidated, it has been found that cancer cells stop abnormal cell division and induce apoptosis by accumulation of unwanted proteins in the cells.
- proteasome inhibitors as pharmaceutical preparations.
- they have strong side effects.
- peripheral neuropathy e.g., peripheral neuropathy, gastrointestinal disorders such as vomiting and diarrhea, and myelosuppression are recognized as side effects. This is considered to occur because the proteasome is present in both normal cells and abnormal cells in common, thereby inhibiting the proteasome in normal cells. Therefore, development of a proteasome inhibitor that selectively exerts an effect only in abnormal cells is desired.
- proteasome inhibitors are expected to be effective therapeutic agents not only in currently approved multiple myeloma but also in other solid tumors.
- side effects are a problem when proteasome inhibitors are used in the treatment of diseases. Therefore, development of a novel proteasome inhibitor having an inhibitory action and protease selectivity different from those of conventional proteasome inhibitors is required.
- the object of the present invention is to solve the problems of the prior art, is highly proteasome-selective, and is more irreversible, so there are few side effects even at high doses, which is equivalent to or equivalent to conventional proteasome inhibitory compounds.
- Non-Patent Document 1 a novel proteasome-inhibiting compound, which improves the currently known proteasome-inhibiting compound, belactocin, and has a proteasome-inhibiting activity higher than that of belactocin.
- Non-Patent Document 1 a novel proteasome-inhibiting compound, which improves the currently known proteasome-inhibiting compound, belactocin, and has a proteasome-inhibiting activity higher than that of belactocin.
- such a compound has a large number of asymmetry points in its skeleton, and further improvement is necessary in terms of practicality as a pharmaceutical from the viewpoint of complexity of synthesis, membrane permeability, biological stability, and the like. I faced a new challenge.
- a 1 and A 2 are each independently a 5-membered or 6-membered aromatic ring, and one or more hydrogen atoms present in the aromatic ring are optionally halogen, hydroxyl group, nitro group, amino group , May be substituted with a group selected from a cyano group or a C1-10 alkyl group, S 1 and S 2 are each independently C1-5 alkylene, and among the carbon atoms present in the alkylene, any one of carbon atoms not adjacent to X and A 1 or A 2 is arbitrary.
- R 1 is a C1-5 alkyl group
- R 2 is a C1-10 hydrocarbon group
- one or two or more carbon atoms present in R 1 and R 2 are replaced with oxygen atoms, nitrogen atoms or sulfur atoms, provided that when two or more atoms are replaced, these atoms are Not adjacent to each other
- One or more hydrogen atoms present in R 1 and R 2 may be optionally substituted with a substituent selected from halogen, hydroxyl group, carboxyl group, nitro group, amino group or cyano group
- Y 1 and Y 2 are each independently a hydrogen atom or a boronyl protecting group
- Y 1 and Y 2 may be combined to form a ring structure
- m and n are independently of each other, 1, 2 or 3.
- One or two or more hydrogen atoms of the alkylene group may be optionally substituted with a group selected from halogen, hydroxyl group, nitro group, amino group or cyano group, and Two hydrogen atoms of one carbon atom may be substituted with one oxygen atom to form a carbonyl group, Or formula III
- ring Y ′ is a C4-10 cycloalkenyl group or arylene group, and one or more ring carbon atoms constituting Y ′ are optionally replaced with an oxygen atom, a nitrogen atom or a sulfur atom.
- One or two or more hydrogen atoms of each ring member atom may optionally be a group selected from a halogen, a C1-4 alkyl group, a hydroxyl group, a carboxyl group, a nitro group, an amino group, or a cyano group. May be substituted, or two hydrogen atoms of one carbon atom may be substituted with one oxygen atom to form a carbonyl group. Or a pharmaceutically acceptable salt thereof.
- a proteasome inhibitor comprising an effective amount of the compound of [1] to [8] or a pharmaceutically acceptable salt thereof.
- a pharmaceutical composition for treating a proteasome-related disease comprising at least one compound of [1] to [8] or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition according to [10], wherein the proteasome-related disease is a tumor.
- the novel compound which has the proteasome inhibitory activity which is comparable to the conventional compound which has proteasome inhibitory activity, and exhibits suitable protease selectivity and the stability (biostability) in a biological environment is provided. Therefore, the compound of the present invention can be used as an excellent antitumor agent compared with an antitumor agent containing a conventional proteasome inhibitor compound, such as sufficient antitumor activity and few side effects.
- FIG. 1 is a graph showing the results of a reversibility test of the compound of the present invention (bottom) and bortezomib (top), which is a known proteasome inhibitory compound. It can be seen that when bortezomib is washed, the inhibitory activity is greatly reduced, whereas the inhibitory activity of the compound of the present invention is hardly reduced.
- FIG. 2 is a graph comparing the results of a reversibility test of Compound 4a of the present invention, Compound 11a having a structure similar to the compound of the present invention, and bortezomib, which is a known proteasome inhibitory compound.
- the vertical axis of the graph shows the ratio when the control chymotrypsin-like proteasome activity is taken as 100%. It can be seen that the similar compound 11a and bortezomib greatly recovers chymotrypsin-like proteasome activity when washed, whereas compound 4a of the present invention keeps chymotrypsin-like proteasome activity low.
- the present invention relates to a novel compound having proteasome inhibitory activity.
- the compound of this aspect has the following general formula: It is a compound which has a structure represented by these.
- proteasome inhibitory compound means a compound having an activity of inhibiting the enzymatic reaction of the proteasome.
- the proteasome is an enzyme complex, and is considered to have a plurality of enzyme activities such as chymotrypsin-like activity, trypsin-like activity, and caspase-like activity. If any one of them can be inhibited, the “proteasome of the present invention is used. It corresponds to “inhibitory compound”. Of course, it may be possible to simultaneously inhibit a plurality of enzyme activities.
- the proteasome-inhibiting compound of the present invention is a compound suitable as a pharmaceutical composition as described herein. Thus, when referring simply to a “compound” or “proteasome inhibiting compound”, it is intended to include “pharmaceutically acceptable salts thereof” unless otherwise indicated.
- alkyl or “alkyl group” includes saturated linear or branched alkyl groups, and unsaturated linear or branched alkyl groups such as alkenyl and alkynyl groups.
- alkylene or “alkylene group” means a group in which one hydrogen atom is eliminated from the alkyl.
- cycloalkyl or “cycloalkyl group” includes cyclic saturated alkyl groups and unsaturated cyclic alkyl groups such as alkenyl and alkynyl groups.
- Groups are also encompassed by “cycloalkyl”. Therefore, the number of carbon atoms in the cycloalkyl in which the number of carbon atoms is specified means the number of carbon atoms in the whole group including the number of carbon atoms contained in these substituted alkyl groups.
- aryl or “aryl group” means an aromatic hydrocarbon group, such as a group in which a ring member atom is further substituted with an alkyl group or a cycloalkyl group, such as 2-methylphenyl, A group in which a hydrogen atom of an alkyl group or a cycloalkyl group is substituted with an aryl group is also included in the “aryl group”. Therefore, the number of carbon atoms in the aryl group in which the number of carbon atoms is specified means the number of carbon atoms in the whole group including the number of carbon atoms contained in these substituted alkyl groups.
- the term “hydrocarbon group” is a term encompassing all the “alkyl group”, “cycloalkyl group” and “aryl group”.
- protecting group is a group for inactivating the reaction activity of a functional group to be protected, and can be easily eliminated by an appropriate reaction to yield the original functional group.
- boronyl group protecting group includes an ether protecting group, an acetal protecting group, an acyl protecting group, etc., which are protecting groups for the hydroxy group of the boronyl group.
- Examples of the protecting group for the boronyl group include Although not limited thereto, a pinanediol group, a pinacol group, a methyl group, a phenyl group and the like can be mentioned.
- S 1 and S 2 may be the same or different independently from each other, and mean alkylene having 1 to 5 carbon atoms. Both S 1 and S 2 may be saturated alkylene or unsaturated alkylene, but are preferably saturated alkylene.
- the number of carbon atoms may be any as long as it is 1 to 5 (C1 to 5), preferably 2 or 3, and most preferably 3.
- any one of carbon atoms at both ends that is, a carbon atom adjacent to A 1 or A 2 and a carbon atom other than a carbon atom adjacent to X is ,
- Optionally may be replaced by S or O, preferably O.
- S 1 and S 2 are most preferably —CH 2 —O—CH 2 —.
- a 1 and A 2 are each independently a 5-membered or 6-membered aromatic ring, and one or more hydrogen atoms present in the aromatic ring are optionally halogen, hydroxyl group, It may be substituted with a group selected from a nitro group, an amino group, a cyano group, and a C1-10 alkyl group.
- Such an aromatic ring is preferably phenyl, pyridyl, furanyl, thiophenyl, naphthyl, biphenyl and the like, and most preferably phenyl.
- X represents C or N, preferably C.
- the number of asymmetric points in the skeleton of the compound is small. Accordingly, it is preferable that X is not an asymmetric center, that is, -S 1 -A 1 and -S 2 -A 2 are the same.
- X is not an asymmetric center, that is, -S 1 -A 1 and -S 2 -A 2 are the same.
- m and n may be any integer as long as they do not adversely affect the proteasome inhibitory activity of the whole compound, but if too large, the compound itself becomes too large to bind to the proteasome, and is small. Number is preferred. Thus, in a preferred embodiment, m and n are 1, 2 or 3. m and n are independent of each other, and may be the same number or different numbers.
- R 1 and R 2 independently of each other may be any hydrocarbon group of C1 to 12, and one or more carbon atoms present in the hydrocarbon group are oxygen atoms May be replaced by a nitrogen atom or a sulfur atom, but when two or more atoms are replaced, these atoms are not adjacent to each other.
- one or more hydrogen atoms of the hydrocarbon group may be optionally substituted with a substituent such as halogen, hydroxyl group, carboxyl group, nitro group, amino group, cyano group.
- R 1 may be any hydrocarbon group as long as it does not adversely affect the proteasome inhibitory activity of the whole compound, but is preferably a C1-6 hydrocarbon group, more preferably a C1-5 alkyl group. is there.
- R 1 include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, isopentyl, t-butyl, vinyl, 2-propen-2-yl, and the like.
- R 2 may be any hydrocarbon group as long as it does not adversely affect the proteasome inhibitory activity of the whole compound, and is a C1-7 hydrocarbon group in a preferred embodiment, and C1-5 in a more preferred embodiment. It is an alkyl group. In another preferred embodiment, R 2 is a natural amino acid side chain.
- In represents a proteasome inhibitory active site.
- a known proteasome-inhibiting compound, belactocin A has a portion that binds to a portion called S1 pocket present in the proteasome CP, and in contrast to threonine 1 (Thr1) that is a proteasome active site, It is believed that the ⁇ -lactone ring opens and binds by acylating the threonine residue, thereby inhibiting the enzyme activity.
- the structure in the above general formula I Is presumed to exhibit proteasome inhibitory activity by binding to the S1 pocket present in the CP of the proteasome and binding of In to Thr1, which is the proteasome active site.
- In preferably has a site that easily forms a bond such as a hydrogen bond or an electrophilic attack on the hydroxyl group present in the side chain of threonine.
- proteasome inhibitory active sites present in compounds known as proteasome inhibitory compounds are also preferred as In of the present invention.
- Examples of In include, but are not limited to, a ⁇ -lactone ring, a boronic acid, a boronic acid ester, an epoxide, and the like, and more preferably a structure having high in vivo stability such as a boronic acid and a boronic acid ester. It is.
- In is a boronic acid or boronic ester.
- the proteasome inhibitory compound of the present invention has the following formula I It is a compound represented by these.
- a 1 , A 2 , S 1 , S 2 , X, R 1 , R 2 , m and n are as defined above.
- Y 1 and Y 2 are each independently a hydrogen atom or a protecting group for a boronyl group. Y 1 and Y 2 may be combined to form a ring structure. Examples of Y 1 and Y 2 include, but are not limited to, the above-described protecting groups for the boronyl group.
- Y is a C1-10 alkylene group, and among the carbon atoms present in the alkylene, any one of the carbon atoms not adjacent to O is optionally an oxygen atom, a nitrogen atom or a sulfur atom.
- one or more hydrogen atoms of the alkylene group may be optionally substituted with a group selected from a halogen, a hydroxyl group, a nitro group, an amino group, or a cyano group.
- two hydrogen atoms of one carbon atom may be substituted with one oxygen atom to form a carbonyl group.
- ring Y ′ is a C4-10 cycloalkenyl group or arylene group, and one or more ring carbon atoms constituting Y ′ are optionally an oxygen atom, a nitrogen atom or a sulfur atom.
- —B (OY 1 ) OY 2 is It is. These structures are also known as inhibitory active sites of known proteasome inhibitory compounds.
- the compounds of the present invention have the formula IV Where m and n are as defined above. It is a compound represented by these.
- Any known synthesis method can be used alone or in combination for the synthesis of the compound of the present invention. It will be understood by those skilled in the art that an optimum synthesis method for the compound of the present invention can be appropriately selected and necessary conditions can be appropriately determined. In the following examples, some examples of the synthesis of specific compounds included in the present invention are shown, but it is understood by those skilled in the art that alternative synthetic methods may be used. It is.
- proteasome inhibitor containing the compound of the present invention is a compound having proteasome inhibitory activity as described above. Accordingly, proteasome inhibitors comprising an effective amount of a compound of the invention are also included in the invention.
- the “effective amount” means the amount of an active ingredient necessary for achieving the use of the composition, that is, for the composition to function effectively, and there is an adverse effect exceeding the benefit of the use of the active ingredient. An amount that does not occur is preferred. The amount varies depending on the use of the composition, the method of use, the type of compound used as an active ingredient, and the conditions of the intended use. For example, in vitro tests using cultured cells, model animals such as mice and rats, etc. It can be appropriately determined by a test method well known to those skilled in the art, such as a test in the above.
- the proteasome inhibitor of the present invention contains at least one compound of the present invention as an active ingredient, but further contains other compounds of the present invention and / or known proteasome inhibitory compounds as long as the proteasome inhibitory activity is not adversely affected. It's okay.
- a component for effectively achieving the proteasome inhibitory activity effect of the compound of the present invention such as a pharmaceutically acceptable carrier and other optional components such as excipients may be included. These other components are well known in the art, and those skilled in the art can appropriately select these components according to the purpose and method of use.
- composition containing the compound of the present invention is a novel compound, has the property of inhibiting the activity of the proteasome, and also has in vivo stability. It is suitable as. Accordingly, pharmaceutical compositions comprising an effective amount of a compound of the present invention are also encompassed by the present invention.
- the pharmaceutical composition of the present invention can be suitably used particularly for treating a proteasome-related disease, that is, a disease whose pathological condition is improved by inhibiting the function of the proteasome.
- proteasome-related disease means a disease in which the activity of the proteasome is related to the onset or exacerbation of the disease.
- the ubiquitin-proteasome system is considered to perform protein quality control in vivo, and homeostasis cannot be maintained due to an abnormality in this system, which leads to cell abnormalities.
- proteasome-related diseases include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, polyglutamine disease, prion disease, amyotrophic lateral sclerosis, tumors such as cancer, rheumatism And other immune system diseases.
- Proteasome-inhibiting compounds fail by inhibiting abnormal degradation of normal proteins in cells that cannot maintain homeostasis as a result of excessive degradation of normal proteins due to abnormal ubiquitination of normal proteins and increased proteasome expression Can be eliminated and lead to apoptosis. Therefore, the pharmaceutical composition of the present invention can be suitably used particularly for the treatment of proteasome-related diseases.
- Proteasome-inhibiting compounds are known to have therapeutic effects, particularly in cancer, and are approved as pharmaceuticals. For example, in tumor cells, it is known that various normal proteins such as p53 are abnormally ubiquitinated, and excessive degradation of these normal proteins plays a part in the cause of tumorigenesis. Conceivable. Proteasome-inhibiting compounds can lead tumor cells to apoptosis by inhibiting abnormal degradation of normal cells. Accordingly, in a preferred embodiment, the pharmaceutical composition of the present invention is used to treat cancer.
- tumor includes benign tumors and malignant tumors (cancer, malignant neoplasm).
- cancer includes hematopoietic tumors, including blood cancers, epithelial malignant tumors (cancer, carcinoma) and non-epithelial malignant tumors (sarcoma, sarcoma).
- Examples of cancer treated with the pharmaceutical composition of the present invention include, but are not limited to, blood cancer, colon cancer, skin cancer and the like.
- the pharmaceutical composition of the present invention contains at least one compound of the present invention as an active ingredient.
- other pharmaceutical compounds of the present invention and // Known proteasome inhibitory compounds may be included.
- it may contain other optional components such as a component for effectively achieving the proteasome inhibitory activity effect of the compound of the present invention, such as a pharmaceutically acceptable carrier and a surfactant, and an excipient. .
- a component for effectively achieving the proteasome inhibitory activity effect of the compound of the present invention such as a pharmaceutically acceptable carrier and a surfactant, and an excipient.
- these other components are well known in the art, and those skilled in the art can appropriately select these components according to the purpose and method of use.
- the dosage form of the pharmaceutical composition containing the proteasome-inhibiting compound of the present invention as an active ingredient is not particularly limited, but tablets, solutions, oil emulsions (emulsion formulations), polymer nanoparticles, liposome formulations, Particulate preparations bound to beads having a diameter of several ⁇ m, preparations attached with lipids, microsphere preparations, microcapsule preparations and the like can be mentioned, and those skilled in the art can appropriately select a suitable dosage form.
- Examples of the administration method of the pharmaceutical composition of the present invention include any known administration method such as intradermal administration, subcutaneous administration, intramuscular administration, and intravenous administration.
- the dosage of the proteasome-inhibiting compound of the present invention in the preparation can be appropriately adjusted according to the disease to be treated, the age, body weight, etc. of the patient, but is usually 1 mg to 1000 mg, preferably 10 mg to 100 mg per day. Preferably, it is administered once.
- the present invention is also a method for preventing and / or treating cancer in a subject, comprising an effective amount of one or more proteasome-inhibiting compounds of the present invention. In a method comprising administering to a subject in need thereof.
- the “subject” in the present invention may be any individual organism as long as it can suffer from cancer, but preferably human and non-human mammals (eg, mouse, rat, guinea pig, hamster, etc.) Dentates, primates such as chimpanzees, cloven-hoofed animals such as cows, goats, and sheep, terridae such as horses, rabbits, dogs, and cats), and more preferably human individuals.
- the subject may be healthy or afflicted with some disease, but when cancer prevention and / or treatment is intended, the subject is typically afflicted with cancer.
- the cancer is a cancer in which abnormally increased proteasome expression is observed.
- proteasome inhibitory compound of the present invention used in the prevention / treatment method of the present invention examples include any of those described herein.
- the specific dose of the active ingredient depends on various conditions relating to the subject in need thereof, such as severity of symptoms, general health status of the subject, age, weight, subject sex, diet, timing and frequency of administration, It can be determined in consideration of the drug used in combination, the response to treatment, the dosage form, compliance with the treatment, and the like.
- a specific dose for example, in the case of the proteasome inhibitory compound of the present invention, it is usually preferable to administer 1 mg to 1000 mg, preferably 10 mg to 100 mg once a day.
- any known appropriate administration method such as intradermal administration, subcutaneous administration, intramuscular administration, intravenous administration and the like can be used.
- the prevention / treatment method of the present invention may further include a step of selecting a subject for which administration of the proteasome-inhibiting compound is effective as the subject of prevention / treatment before the administration step.
- This aspect of the present invention may further include the step of determining the presence or absence of abnormally enhanced proteasome expression in the subject tumor cells prior to the selecting step. Presence / absence of abnormally increased proteasome expression in the subject can be determined by any known technique.
- the target compounds 6a to 11a were also synthesized by a similar method.
- the Bn group of compound 13a was removed and then condensed with 16 to give compound 18a.
- the Boc group of 18a was removed and then condensed with the corresponding carboxylic acid or acyl chloride to obtain the target compounds 6a to 9a.
- the Bn group of compound 14a was removed, and then condensed with CH 3 NH 2 or 4- (benzyloxy) butan-1-amine to obtain the target compound 10a or 11a, respectively. Details of each synthesis reaction are shown below.
- the flask was purged with hydrogen and the reaction mixture was stirred under a hydrogen atmosphere for 3 hours.
- the reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give the corresponding carboxylic acid as a white amorphous solid.
- reaction mixture is concentrated in vacuo, the residue is dissolved in AcOEt, washed with 1M HCl, saturated NaHCO 3 and brine, dried over Na 2 SO 4 , and the solvent is removed under reduced pressure to provide compound 18a ( 2.07 g, 4.04 mmol, 68% yield over 3 steps) was obtained as a colorless viscous oil.
- the flask was purged with hydrogen and the reaction mixture was stirred under a hydrogen atmosphere for 2 hours.
- the reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo to give the corresponding carboxylic acid 19a as a white amorphous solid.
- Example 2 Proteasome Inhibition Assay The inhibitory activity of various compounds synthesized in Example 1 and other proteasome inhibitory compounds on the human 20S proteasome is shown in Asai et al., Biochem Pharmacol. 2004 Jan 15; 67 (2): 227-34. The procedure was as described. Briefly, 3 nM human 20S proteasome was prepared by reacting various compounds and DMSO in reaction buffer (50 mM Tris-HCl (pH 7.5), 25 mM KCl, 10 mM NaCl, 1 mM MgCl 2 , 0.018% SDS).
- reaction buffer 50 mM Tris-HCl (pH 7.5), 25 mM KCl, 10 mM NaCl, 1 mM MgCl 2 , 0.018% SDS.
- Suc-LLVY-AMC which is a chymotrypsin-like activity-selective substrate
- 75 ⁇ M Suc-LLVY-AMC which is a chymotrypsin-like activity-selective substrate
- the fluorescence intensity of the degradation product AMC was measured with a microplate reader.
- the activity value when treated with DMSO alone was taken as 100%, and the inhibitory activity of various compounds was determined.
- results are shown in Table 2 and Table 3. As can be seen from the table below, all of the compounds showed a sufficient inhibitory effect on the chymotrypsin-like activity of proteasome CP. Among them, compounds 3a-9a, 11a and 3b-5b are bortezomib which are known proteasome inhibitory compounds. Inhibiting activity equivalent to
- Example 3 Cell growth inhibition assay (1) Colon cancer cell line HCT 116
- HCT 116 strain which is a human colon cancer cell line.
- the experiment was performed according to the product protocol using Cell counting kit-8 (Dojindo Laboratories). Cells were seeded in a 96-well microtiter plate at 3000 cells / well and treated with the test compound for 72 hours. The results are shown in Table 4. As can be seen from Table 4, any compound other than Compound 10a was able to effectively inhibit the growth of HCT 116.
- MM Multiple myeloma cell line MM.
- MM which is a multiple myeloma cell line instead of the colon cancer cell line HCT116.
- 1S and MM Using 1R, the growth inhibitory effect on the cells of the compound of the present invention was verified by the same method as in (1) above.
- MM The 1S cell line is dexamethasone-sensitive human multiple myeloma cells, MM.
- 1R is dexamethasone-resistant human multiple myeloma cells, all of which were obtained from ATCC.
- the compound of the present invention was able to suppress cell proliferation to an extent comparable to that of existing proteasome inhibitors. Moreover, like existing proteasome inhibitors, cell proliferation could be suppressed regardless of the presence or absence of resistance to dexamethasone.
- Example 4 Inhibitory Activity Reversibility Assay
- a reversibility assay was performed using compounds 4a, 11a and bortezomib. 15 nM 20S proteasome was preincubated with each inhibitory compound at 25 ° C. for 12 hours. 37.5 ⁇ M Suc-LLVY-amc was then added as a substrate to initiate the “standard assay” reaction of the 20S proteasome. After incubation at 25 ° C. for 1 hour, fluorescence (excitation light: 390 nm, emission light: 450 nm) of each reaction was measured with a VersaMax Pro microplate reader (Molecular Devices).
- each pre-incubated reaction mixture was subjected to a Microcon Centrifugal Filter (100 kDa molecular weight cut) prior to reaction with substrate to remove inhibitors not bound to the 20S proteasome. Off) and washed 5 times with assay buffer by centrifuging at 11,000 ⁇ g for 3 min. Thereafter, the reaction was carried out by adding a substrate in the same manner as in the “standard assay”.
- Example 5 Protease selectivity assay To verify the proteasome specificity of the inhibitory activity of the compounds of the present invention, a protease selectivity assay was performed using compound 4a and bortezomib. It was performed as described in Arastu-Kapur et al., Clin. Cancer Res .. 2011, 17 (9), 2734-2743.
- cathepsin A the activity of 22 ng / mL cathepsin A (R & D systems) and 40 ⁇ M Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys (Dnp)- After incubation with OH (R & D systems) mixed with assay buffer (50 mM MOPS, pH 5.5) at 25 ° C. for 2 hours, fluorescence (excitation light: 320 nm, emission light: 405 nm) of each reaction was obtained. Measured.
- cathepsin B the activity of cathepsin B (R & D systems) at 40 ng / mL and 10 ⁇ M Z-Leu-Arg-AMC (R & D systems) as a substrate mixed in assay buffer (25 mM MES, pH 5.0) Then, each reaction product was measured for fluorescence (excitation light: 380 nm, emission light: 460 nm).
- cathepsin G the activity of 8.0 ⁇ U / mL cathepsin G (R & D systems) and 200 ⁇ M Suc-Ala-Ala-Pro-Phe-AMC (Bachem) as an assay buffer (50 mM Tris-HCl, pH 7) were used.
- the present invention provides a novel proteasome inhibitory compound.
- a novel proteasome inhibitory compound has irreversible inhibitory activity, high proteasome inhibitory selectivity, and high in vivo stability while having inhibitory activity equivalent to previously known proteasome inhibitory compounds. It can be said that it has many advantages compared to conventional proteasome inhibitory compounds in its use as an active ingredient. Therefore, it is particularly useful as a therapeutic agent for proteasome-related diseases such as cancer.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention vise à fournir un nouveau composé possédant une activité inhibitrice du protéasome, une composition pharmaceutique contenant ledit composé, en particulier une composition pharmaceutique pour le traitement du cancer et d'autres maladies liées au protéasome, un procédé pour le traitement de maladies liées au protéasome mettant en œuvre ledit composé, et analogues. Cet objectif est atteint par la fourniture d'un composé représenté par la formule générale (I).
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015549201A JP6468562B2 (ja) | 2013-11-21 | 2014-11-21 | プロテアソーム阻害性化合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2013241039 | 2013-11-21 | ||
JP2013-241039 | 2013-11-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015076359A1 true WO2015076359A1 (fr) | 2015-05-28 |
Family
ID=53179618
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2014/080859 WO2015076359A1 (fr) | 2013-11-21 | 2014-11-21 | Compose inhibiteur du proteasome |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP6468562B2 (fr) |
WO (1) | WO2015076359A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018536635A (ja) * | 2015-10-15 | 2018-12-13 | コーネル・ユニバーシティーCornell University | プロテアソーム阻害剤およびその用途 |
CN113105486A (zh) * | 2021-02-24 | 2021-07-13 | 南京师范大学 | 一种硼酸酯类化合物及其药学上可接受的盐、其制备方法及其用途 |
US11202817B2 (en) | 2014-08-18 | 2021-12-21 | Cornell University | Dipeptidomimetics as inhibitors of human immunoproteasomes |
US11203613B2 (en) | 2017-10-11 | 2021-12-21 | Cornell University | Peptidomimetic proteasome inhibitors |
USRE49816E1 (en) | 2014-01-10 | 2024-01-30 | Cornell University | Dipeptides as inhibitors of human immunoproteasomes |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10510245A (ja) * | 1994-10-28 | 1998-10-06 | プロスクリプト・インコーポレーテッド | ボロン酸エステルおよびボロン酸化合物、合成および使用 |
JP2004517931A (ja) * | 2001-01-25 | 2004-06-17 | アメリカ合衆国 | ボロン酸化合物製剤 |
WO2013033396A2 (fr) * | 2011-08-30 | 2013-03-07 | Trustees Of Tufts College | Inhibiteurs de protéasome activés par fap utilisés pour traiter les tumeurs solides |
-
2014
- 2014-11-21 JP JP2015549201A patent/JP6468562B2/ja not_active Expired - Fee Related
- 2014-11-21 WO PCT/JP2014/080859 patent/WO2015076359A1/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH10510245A (ja) * | 1994-10-28 | 1998-10-06 | プロスクリプト・インコーポレーテッド | ボロン酸エステルおよびボロン酸化合物、合成および使用 |
JP2004517931A (ja) * | 2001-01-25 | 2004-06-17 | アメリカ合衆国 | ボロン酸化合物製剤 |
WO2013033396A2 (fr) * | 2011-08-30 | 2013-03-07 | Trustees Of Tufts College | Inhibiteurs de protéasome activés par fap utilisés pour traiter les tumeurs solides |
Non-Patent Citations (1)
Title |
---|
KAWAMURA, S. ET AL.: "Structurally novel highly potent proteasome inhibitors created by the structure-based hybridization of nonpeptidic belactosin derivatives and peptide boronates", JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, 2014, pages 2726 - 2735 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE49816E1 (en) | 2014-01-10 | 2024-01-30 | Cornell University | Dipeptides as inhibitors of human immunoproteasomes |
US11202817B2 (en) | 2014-08-18 | 2021-12-21 | Cornell University | Dipeptidomimetics as inhibitors of human immunoproteasomes |
JP2018536635A (ja) * | 2015-10-15 | 2018-12-13 | コーネル・ユニバーシティーCornell University | プロテアソーム阻害剤およびその用途 |
US11066397B2 (en) | 2015-10-15 | 2021-07-20 | Cornell University | Proteasome inhibitors and uses thereof |
US11629141B2 (en) | 2015-10-15 | 2023-04-18 | Cornell University | Proteasome inhibitors and uses thereof |
US11203613B2 (en) | 2017-10-11 | 2021-12-21 | Cornell University | Peptidomimetic proteasome inhibitors |
US11732005B2 (en) | 2017-10-11 | 2023-08-22 | Cornell University | Peptidomimetic proteasome inhibitors |
CN113105486A (zh) * | 2021-02-24 | 2021-07-13 | 南京师范大学 | 一种硼酸酯类化合物及其药学上可接受的盐、其制备方法及其用途 |
CN113105486B (zh) * | 2021-02-24 | 2023-08-15 | 南京师范大学 | 一种硼酸酯类化合物及其药学上可接受的盐、其制备方法及其用途 |
Also Published As
Publication number | Publication date |
---|---|
JP6468562B2 (ja) | 2019-02-13 |
JPWO2015076359A1 (ja) | 2017-03-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Hennessy et al. | Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582) | |
JP6468562B2 (ja) | プロテアソーム阻害性化合物 | |
CN108164474B (zh) | 作为免疫调节剂的1,2,4-二唑衍生物 | |
JP6871310B2 (ja) | ジペプチド及びトリペプチドエポキシケトンプロテアーゼ阻害剤 | |
Ugwu et al. | Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide | |
Alterman et al. | Design and synthesis of new potent C 2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold | |
Onaran et al. | Squaric acid-based peptidic inhibitors of matrix metalloprotease-1 | |
DE60209227T2 (de) | 2-((n-(2-amino-3-(heteroaryl- oder -aryl)propionyl)aminoacyl)amino)-alkylboronsäurederivate | |
CA2777749C (fr) | Peptides therapeutiques comportant un beta-amino acide disubstitue pour traiter les infections microbiennes ou les tumeurs | |
Cohen et al. | Orally bioavailable antagonists of inhibitor of apoptosis proteins based on an azabicyclooctane scaffold | |
Fehrentz et al. | Solid phase synthesis of C-terminal peptide aldehydes | |
US20200253995A1 (en) | Method to treat hypercholesterolemia by modulation of proprotein convertase subtilisin/kexin type 9 (pcsk9) protein activity with small molecule ligands | |
Dai et al. | Total synthesis of syringolin A | |
Lee et al. | Development of a new type of protease inhibitors, efficacious against FIV and HIV variants | |
JP4144811B2 (ja) | ペプチジル−2−アミノ−1−ヒドロキシアルカンスルホン酸システインプロテアーゼインヒビター | |
Ozcan et al. | Oxadiazole-isopropylamides as potent and noncovalent proteasome inhibitors | |
Küçükbay et al. | Synthesis and carbonic anhydrase inhibitory properties of novel 4-(2-aminoethyl) benzenesulfonamide-dipeptide conjugates | |
Zask et al. | Synthesis and Biological Activity of Analogues of the Antimicrotubule Agent N, β, β-Trimethyl-l-phenylalanyl-N-[(1 S, 2 E)-3-carboxy-1-isopropylbut-2-enyl]-N 1, 3-dimethyl-l-valinamide (HTI-286) | |
WO2017151587A1 (fr) | Aldéhydes et cétones aza-peptidiques | |
Baranyai et al. | In vitro biological evaluation of new antimycobacterial salicylanilide-tuftsin conjugates | |
Pacifico et al. | Synthesis and biological activity of peptide α-ketoamide derivatives as proteasome inhibitors | |
CA2943817C (fr) | Compose epoxycetone tripeptidique construit a partir d'un heterocycle et procede pour le preparer et l'utiliser | |
Graf von Roedern et al. | Design and synthesis of malonic acid-based inhibitors of human neutrophil collagenase (MMP8) | |
Schade et al. | Highly selective sub-nanomolar cathepsin S inhibitors by merging fragment binders with nitrile inhibitors | |
JP2003508512A (ja) | 非ペプチド性サイクロフィリン結合化合物とその用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14864020 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2015549201 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14864020 Country of ref document: EP Kind code of ref document: A1 |