TWI577667B - Ｎｅｄｄ８－活化酵素之抑制劑 - Google Patents

Info

Publication number

TWI577667B

TWI577667B TW101130884A TW101130884A TWI577667B TW I577667 B TWI577667 B TW I577667B TW 101130884 A TW101130884 A TW 101130884A TW 101130884 A TW101130884 A TW 101130884A TW I577667 B TWI577667 B TW I577667B

Authority

TW

Taiwan

Prior art keywords

chemical entity

methyl

chloro

methoxy

cancer

Prior art date

2011-08-24

Links

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• 239000003112 inhibitor Substances 0.000 title description 18
• 239000012190 activator Substances 0.000 title description 4
• -1 9-fluorenylmethyl Chemical group 0.000 claims description 181
• 239000000203 mixture Substances 0.000 claims description 108
• 150000005829 chemical entities Chemical class 0.000 claims description 88
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 63
• 238000000634 powder X-ray diffraction Methods 0.000 claims description 53
• 206010028980 Neoplasm Diseases 0.000 claims description 40
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
• 230000000694 effects Effects 0.000 claims description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
• 238000000034 method Methods 0.000 claims description 30
• 150000003839 salts Chemical class 0.000 claims description 29
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 28
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
• 150000001412 amines Chemical class 0.000 claims description 26
• 102000004190 Enzymes Human genes 0.000 claims description 24
• 108090000790 Enzymes Proteins 0.000 claims description 24
• 239000002253 acid Substances 0.000 claims description 24
• 229940088598 enzyme Drugs 0.000 claims description 24
• LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 22
• 201000011510 cancer Diseases 0.000 claims description 20
• 238000011282 treatment Methods 0.000 claims description 20
• 201000010099 disease Diseases 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
• 238000002411 thermogravimetry Methods 0.000 claims description 15
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
• 239000012453 solvate Substances 0.000 claims description 14
• 238000000113 differential scanning calorimetry Methods 0.000 claims description 11
• 229910052757 nitrogen Inorganic materials 0.000 claims description 11
• 239000000126 substance Substances 0.000 claims description 10
• 102100031911 NEDD8 Human genes 0.000 claims description 9
• 101150107958 NEDD8 gene Proteins 0.000 claims description 9
• 229940099983 activase Drugs 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 150000002148 esters Chemical class 0.000 claims description 9
• 238000004519 manufacturing process Methods 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 239000000843 powder Substances 0.000 claims description 8
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
• JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 6
• GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
• 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 5
• PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 238000000338 in vitro Methods 0.000 claims description 5
• JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
• 229940011051 isopropyl acetate Drugs 0.000 claims description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 4
• 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 claims description 4
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
• 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
• 239000007983 Tris buffer Substances 0.000 claims description 4
• 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
• 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
• 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 claims description 4
• 208000016261 weight loss Diseases 0.000 claims description 4
• 230000004580 weight loss Effects 0.000 claims description 4
• XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 claims description 3
• 206010006895 Cachexia Diseases 0.000 claims description 3
• 208000002250 Hematologic Neoplasms Diseases 0.000 claims description 3
• 208000017604 Hodgkin disease Diseases 0.000 claims description 3
• 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 3
• 208000034578 Multiple myelomas Diseases 0.000 claims description 3
• 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 3
• 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 3
• 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
• 206010060862 Prostate cancer Diseases 0.000 claims description 3
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
• 230000002378 acidificating effect Effects 0.000 claims description 3
• XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 3
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 claims description 3
• 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 3
• 230000004968 inflammatory condition Effects 0.000 claims description 3
• 235000001968 nicotinic acid Nutrition 0.000 claims description 3
• 229960003512 nicotinic acid Drugs 0.000 claims description 3
• 239000011664 nicotinic acid Substances 0.000 claims description 3
• 229940049953 phenylacetate Drugs 0.000 claims description 3
• SODPIMGUZLOIPE-UHFFFAOYSA-N (4-chlorophenoxy)acetic acid Chemical compound OC(=O)COC1=CC=C(Cl)C=C1 SODPIMGUZLOIPE-UHFFFAOYSA-N 0.000 claims description 2
• PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 claims description 2
• CLCMSGXEVLGRNG-UHFFFAOYSA-N 2,2-diphenylethanimidamide Chemical compound C=1C=CC=CC=1C(C(=N)N)C1=CC=CC=C1 CLCMSGXEVLGRNG-UHFFFAOYSA-N 0.000 claims description 2
• FFFIRKXTFQCCKJ-UHFFFAOYSA-M 2,4,6-trimethylbenzoate Chemical compound CC1=CC(C)=C(C([O-])=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-M 0.000 claims description 2
• 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims description 2
• 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 2
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
• 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
• 125000006494 2-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C([H])=C(C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 2
• GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 claims description 2
• 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 claims description 2
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 claims description 2
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
• 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
• 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
• 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
• 206010005003 Bladder cancer Diseases 0.000 claims description 2
• 206010005949 Bone cancer Diseases 0.000 claims description 2
• 208000018084 Bone neoplasm Diseases 0.000 claims description 2
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 2
• 206010006187 Breast cancer Diseases 0.000 claims description 2
• 208000026310 Breast neoplasm Diseases 0.000 claims description 2
• HHBRQXMWTVLXIQ-UHFFFAOYSA-N CC(=N)N(C(C)(C)C)C(C)(C)C Chemical compound CC(=N)N(C(C)(C)C)C(C)(C)C HHBRQXMWTVLXIQ-UHFFFAOYSA-N 0.000 claims description 2
• 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
• 206010009944 Colon cancer Diseases 0.000 claims description 2
• 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
• 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
• BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 2
• 206010061218 Inflammation Diseases 0.000 claims description 2
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
• 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
• 206010033128 Ovarian cancer Diseases 0.000 claims description 2
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 206010039491 Sarcoma Diseases 0.000 claims description 2
• 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 2
• 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
• 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
• 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
• 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
• 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 claims description 2
• 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 2
• DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims description 2
• 229940022663 acetate Drugs 0.000 claims description 2
• IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 claims description 2
• 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 claims description 2
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
• 239000004305 biphenyl Substances 0.000 claims description 2
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• 201000010881 cervical cancer Diseases 0.000 claims description 2
• 229940089960 chloroacetate Drugs 0.000 claims description 2
• FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims description 2
• 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 2
• LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 claims description 2
• 229940120124 dichloroacetate Drugs 0.000 claims description 2
• 201000004101 esophageal cancer Diseases 0.000 claims description 2
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims description 2
• 206010017758 gastric cancer Diseases 0.000 claims description 2
• 229960001867 guaiacol Drugs 0.000 claims description 2
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• 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
• 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
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• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
• 201000001441 melanoma Diseases 0.000 claims description 2
• RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 claims description 2
• 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 2
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• LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
• 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 claims description 2
• 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
• 201000002528 pancreatic cancer Diseases 0.000 claims description 2
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• HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 claims description 2
• LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims description 2
• WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 2
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
• 229950010765 pivalate Drugs 0.000 claims description 2
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• LHGVFZTZFXWLCP-UHFFFAOYSA-N pyrocatechol monomethyl ether Natural products COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 claims description 2
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• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 2
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• YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
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• 150000001408 amides Chemical class 0.000 claims 2
• 125000006301 indolyl methyl group Chemical group 0.000 claims 2
• ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 claims 1
• QUALCVSUMFOHID-UHFFFAOYSA-N 1,1'-biphenyl;formic acid Chemical compound OC=O.C1=CC=CC=C1C1=CC=CC=C1 QUALCVSUMFOHID-UHFFFAOYSA-N 0.000 claims 1
• 125000006508 2,6-difluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C(F)=C1[H])C([H])([H])* 0.000 claims 1
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