TW200400941A - Sulfonyl-derivatives as novel inhibitors of histone deacetylase - Google Patents
Sulfonyl-derivatives as novel inhibitors of histone deacetylase Download PDFInfo
- Publication number
- TW200400941A TW200400941A TW092105283A TW92105283A TW200400941A TW 200400941 A TW200400941 A TW 200400941A TW 092105283 A TW092105283 A TW 092105283A TW 92105283 A TW92105283 A TW 92105283A TW 200400941 A TW200400941 A TW 200400941A
- Authority
- TW
- Taiwan
- Prior art keywords
- alkyl
- group
- amine
- amino
- base
- Prior art date
Links
- 102000003964 Histone deacetylase Human genes 0.000 title claims abstract description 29
- 108090000353 Histone deacetylase Proteins 0.000 title claims abstract description 29
- 239000003112 inhibitor Substances 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 251
- 238000002360 preparation method Methods 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 651
- 125000003545 alkoxy group Chemical group 0.000 claims description 176
- -1 methylimidazolyl Chemical group 0.000 claims description 143
- 125000003277 amino group Chemical group 0.000 claims description 136
- 150000001412 amines Chemical group 0.000 claims description 134
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 129
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 96
- 238000000034 method Methods 0.000 claims description 76
- 229910052739 hydrogen Inorganic materials 0.000 claims description 75
- 239000001257 hydrogen Substances 0.000 claims description 71
- 229910001868 water Inorganic materials 0.000 claims description 68
- 125000003118 aryl group Chemical group 0.000 claims description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 230000002079 cooperative effect Effects 0.000 claims description 50
- 229910052757 nitrogen Inorganic materials 0.000 claims description 42
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 41
- 239000002253 acid Substances 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 32
- 239000000460 chlorine Chemical group 0.000 claims description 31
- 125000001544 thienyl group Chemical group 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 150000003254 radicals Chemical class 0.000 claims description 26
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 23
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 20
- 125000004104 aryloxy group Chemical group 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 15
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 14
- 125000002541 furyl group Chemical group 0.000 claims description 13
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 150000003973 alkyl amines Chemical class 0.000 claims description 11
- 125000002619 bicyclic group Chemical group 0.000 claims description 11
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 11
- 125000002971 oxazolyl group Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 230000036961 partial effect Effects 0.000 claims description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- YRBKSJIXFZPPGF-UHFFFAOYSA-N hexazine Chemical compound N1=NN=NN=N1 YRBKSJIXFZPPGF-UHFFFAOYSA-N 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 239000004575 stone Substances 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
- 241000907681 Morpho Species 0.000 claims description 6
- 150000001204 N-oxides Chemical class 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 229960005181 morphine Drugs 0.000 claims description 4
- 230000002062 proliferating effect Effects 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 claims description 2
- ZENKESXKWBIZCV-UHFFFAOYSA-N 2,2,4,4-tetrafluoro-1,3-benzodioxin-6-amine Chemical group O1C(F)(F)OC(F)(F)C2=CC(N)=CC=C21 ZENKESXKWBIZCV-UHFFFAOYSA-N 0.000 claims description 2
- 241000270666 Testudines Species 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims description 2
- 229960001915 hexamidine Drugs 0.000 claims description 2
- OQLKNTOKMBVBKV-UHFFFAOYSA-N hexamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCCOC1=CC=C(C(N)=N)C=C1 OQLKNTOKMBVBKV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 10
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 claims 5
- 241000700159 Rattus Species 0.000 claims 4
- 241000283074 Equus asinus Species 0.000 claims 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 2
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 claims 2
- 239000011593 sulfur Substances 0.000 claims 2
- MZOJPUKCQRFOAB-UHFFFAOYSA-N 1,2,3,4,5-pentamethyl-6-(1-phenylprop-1-en-2-yl)benzene Chemical compound CC(C1=C(C(=C(C(=C1C)C)C)C)C)=CC1=CC=CC=C1 MZOJPUKCQRFOAB-UHFFFAOYSA-N 0.000 claims 1
- MLRVZFYXUZQSRU-UHFFFAOYSA-N 1-chlorohexane Chemical compound CCCCCCCl MLRVZFYXUZQSRU-UHFFFAOYSA-N 0.000 claims 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- CVQIVQWRZCBIBC-UHFFFAOYSA-N 2-hexylpiperidine Chemical compound CCCCCCC1CCCCN1 CVQIVQWRZCBIBC-UHFFFAOYSA-N 0.000 claims 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 claims 1
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims 1
- 229910014033 C-OH Inorganic materials 0.000 claims 1
- SGWAEKXTHJALKK-UHFFFAOYSA-N CCCCCC[N] Chemical compound CCCCCC[N] SGWAEKXTHJALKK-UHFFFAOYSA-N 0.000 claims 1
- 229910014570 C—OH Inorganic materials 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 239000007983 Tris buffer Substances 0.000 claims 1
- 239000013543 active substance Substances 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 125000006177 alkyl benzyl group Chemical group 0.000 claims 1
- 125000006319 alkynyl amino group Chemical group 0.000 claims 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 238000010586 diagram Methods 0.000 claims 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 claims 1
- 125000005493 quinolyl group Chemical group 0.000 claims 1
- 125000004149 thio group Chemical group *S* 0.000 claims 1
- 229910052719 titanium Inorganic materials 0.000 claims 1
- 239000010936 titanium Substances 0.000 claims 1
- PYHOFAHZHOBVGV-UHFFFAOYSA-N triazane Chemical compound NNN PYHOFAHZHOBVGV-UHFFFAOYSA-N 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- JLYXXMFPNIAWKQ-UHFFFAOYSA-N γ Benzene hexachloride Chemical compound ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 219
- 230000002401 inhibitory effect Effects 0.000 abstract description 13
- 230000002255 enzymatic effect Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 390
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 374
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 252
- 239000002904 solvent Substances 0.000 description 164
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 125
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 88
- 239000002244 precipitate Substances 0.000 description 74
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 73
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 71
- 239000012044 organic layer Substances 0.000 description 69
- 239000002585 base Substances 0.000 description 67
- 238000002844 melting Methods 0.000 description 66
- 230000008018 melting Effects 0.000 description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 60
- 239000003480 eluent Substances 0.000 description 49
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- 210000001519 tissue Anatomy 0.000 description 44
- 239000005457 ice water Substances 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 41
- 210000004027 cell Anatomy 0.000 description 41
- 238000010898 silica gel chromatography Methods 0.000 description 38
- 238000003756 stirring Methods 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 239000000047 product Substances 0.000 description 30
- 108090000623 proteins and genes Proteins 0.000 description 30
- 238000004458 analytical method Methods 0.000 description 28
- 102000004190 Enzymes Human genes 0.000 description 27
- 108090000790 Enzymes Proteins 0.000 description 27
- 230000000694 effects Effects 0.000 description 27
- 238000012360 testing method Methods 0.000 description 26
- 102000004169 proteins and genes Human genes 0.000 description 24
- 125000005843 halogen group Chemical group 0.000 description 23
- 206010028980 Neoplasm Diseases 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 19
- 235000011114 ammonium hydroxide Nutrition 0.000 description 19
- 239000011347 resin Substances 0.000 description 17
- 229920005989 resin Polymers 0.000 description 17
- 239000000523 sample Substances 0.000 description 17
- 239000000872 buffer Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000010790 dilution Methods 0.000 description 14
- 239000012895 dilution Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 230000002503 metabolic effect Effects 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 11
- 230000004060 metabolic process Effects 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 9
- 201000011510 cancer Diseases 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 230000035699 permeability Effects 0.000 description 9
- 238000007639 printing Methods 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 159000000000 sodium salts Chemical class 0.000 description 9
- 239000000758 substrate Substances 0.000 description 9
- 101150053185 P450 gene Proteins 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000000499 gel Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 210000001589 microsome Anatomy 0.000 description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 230000010261 cell growth Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 108010037444 diisopropylglutathione ester Proteins 0.000 description 6
- 102000015694 estrogen receptors Human genes 0.000 description 6
- 108010038795 estrogen receptors Proteins 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 230000007721 medicinal effect Effects 0.000 description 6
- OPECTNGATDYLSS-UHFFFAOYSA-N naphthalene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC(S(=O)(=O)Cl)=CC=C21 OPECTNGATDYLSS-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000022131 cell cycle Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 238000006911 enzymatic reaction Methods 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 108091007914 CDKs Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 101000944380 Homo sapiens Cyclin-dependent kinase inhibitor 1 Proteins 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 241000863480 Vinca Species 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000823 artificial membrane Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 229940011871 estrogen Drugs 0.000 description 4
- 239000000262 estrogen Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 4
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 235000000346 sugar Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 239000011534 wash buffer Substances 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- 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 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 3
- PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 description 3
- 125000004326 2H-pyran-2-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])(*)O1 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- HAZHUELNIGDYQH-UHFFFAOYSA-N 7-methoxy-4-(trifluoromethyl)chromen-2-one Chemical compound FC(F)(F)C1=CC(=O)OC2=CC(OC)=CC=C21 HAZHUELNIGDYQH-UHFFFAOYSA-N 0.000 description 3
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 3
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 description 3
- ZYUZLEUJKZZXNN-UHFFFAOYSA-N C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 Chemical group C1=CC(CC(N)C(O)=O)=CC=C1OS(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 ZYUZLEUJKZZXNN-UHFFFAOYSA-N 0.000 description 3
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 3
- 108010077544 Chromatin Proteins 0.000 description 3
- 108050006400 Cyclin Proteins 0.000 description 3
- 102100033270 Cyclin-dependent kinase inhibitor 1 Human genes 0.000 description 3
- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 3
- 229940045799 anthracyclines and related substance Drugs 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000013068 control sample Substances 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000003381 deacetylation reaction Methods 0.000 description 3
- 230000036267 drug metabolism Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- SHVJIPVRIOSGCA-UHFFFAOYSA-N ethyl 2-methylsulfonylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(S(C)(=O)=O)N=C1 SHVJIPVRIOSGCA-UHFFFAOYSA-N 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 235000012054 meals Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 239000008177 pharmaceutical agent Substances 0.000 description 3
- 239000007981 phosphate-citrate buffer Substances 0.000 description 3
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 3
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 238000010532 solid phase synthesis reaction Methods 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- 229960000575 trastuzumab Drugs 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JKSIXVZIFHKAPJ-UHFFFAOYSA-N 2h-benzotriazole;hydrate Chemical compound O.C1=CC=C2NN=NC2=C1 JKSIXVZIFHKAPJ-UHFFFAOYSA-N 0.000 description 2
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 2
- 102100031126 6-phosphogluconolactonase Human genes 0.000 description 2
- 108010029731 6-phosphogluconolactonase Proteins 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 description 2
- 102100039205 Cytochrome P450 3A4 Human genes 0.000 description 2
- 108010052832 Cytochromes Proteins 0.000 description 2
- 102000018832 Cytochromes Human genes 0.000 description 2
- 229940122964 Deacetylase inhibitor Drugs 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 229940102550 Estrogen receptor antagonist Drugs 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108010018962 Glucosephosphate Dehydrogenase Proteins 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 102100036691 Proliferating cell nuclear antigen Human genes 0.000 description 2
- 201000004681 Psoriasis Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- 241001116500 Taxus Species 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 229910052770 Uranium Inorganic materials 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 229940045696 antineoplastic drug podophyllotoxin derivative Drugs 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000012062 aqueous buffer Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 229950011260 betanaphthol Drugs 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000001354 calcination Methods 0.000 description 2
- 229940127093 camptothecin Drugs 0.000 description 2
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 230000011712 cell development Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- JEVCWSUVFOYBFI-UHFFFAOYSA-N cyanyl Chemical group N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 230000009849 deactivation Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000012470 diluted sample Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 229960004679 doxorubicin Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 235000013601 eggs Nutrition 0.000 description 2
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- 230000006203 ethylation Effects 0.000 description 2
- 238000006200 ethylation reaction Methods 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical group I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 2
- 229960005280 isotretinoin Drugs 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 206010025135 lupus erythematosus Diseases 0.000 description 2
- 235000012680 lutein Nutrition 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000011733 molybdenum Substances 0.000 description 2
- 229910052750 molybdenum Inorganic materials 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000001139 pH measurement Methods 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 102000013415 peroxidase activity proteins Human genes 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229960001237 podophyllotoxin Drugs 0.000 description 2
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 2
- 239000003600 podophyllotoxin derivative Substances 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 229960004622 raloxifene Drugs 0.000 description 2
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 2
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000012898 sample dilution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 125000005630 sialyl group Chemical group 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 2
- 229960001278 teniposide Drugs 0.000 description 2
- 150000003573 thiols Chemical class 0.000 description 2
- 229960000303 topotecan Drugs 0.000 description 2
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 230000037426 transcriptional repression Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- VRPSOXSTRRDMAA-BWLLBFHSSA-N (4R,4aR,7S,7aR,12bS)-3,8a-dimethyl-1,2,4,4a,7,7a,9,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol Chemical compound O[C@H]([C@@H]1OC2(C)C(O)C=C3)C=C[C@H]4[C@]5([H])N(C)CC[C@@]41C2=C3C5 VRPSOXSTRRDMAA-BWLLBFHSSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- BWDQBBCUWLSASG-MDZDMXLPSA-N (e)-n-hydroxy-3-[4-[[2-hydroxyethyl-[2-(1h-indol-3-yl)ethyl]amino]methyl]phenyl]prop-2-enamide Chemical compound C=1NC2=CC=CC=C2C=1CCN(CCO)CC1=CC=C(\C=C\C(=O)NO)C=C1 BWDQBBCUWLSASG-MDZDMXLPSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- MIZLGWKEZAPEFJ-UHFFFAOYSA-N 1,1,2-trifluoroethene Chemical compound FC=C(F)F MIZLGWKEZAPEFJ-UHFFFAOYSA-N 0.000 description 1
- ZOWSTJBTHYZCNM-UHFFFAOYSA-N 1,2,2,3,3,4-hexamethyl-4H-pyridine Chemical compound CC1C(C(N(C=C1)C)(C)C)(C)C ZOWSTJBTHYZCNM-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 1
- OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 1
- ZRERYCAEIILUFT-UHFFFAOYSA-N 1-(9h-fluoren-2-ylsulfonyl)piperidine Chemical compound C=1C=C(C2=CC=CC=C2C2)C2=CC=1S(=O)(=O)N1CCCCC1 ZRERYCAEIILUFT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FNQIGYRDLYROLW-UHFFFAOYSA-N 1-hydroxy-2h-1,2,3-benzotriazine Chemical compound C1=CC=C2N(O)NN=CC2=C1 FNQIGYRDLYROLW-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 1
- LLZIVCIANZGPFN-UHFFFAOYSA-N 2,2-dimethylpropane-1,3-diamine;hydrochloride Chemical compound Cl.NCC(C)(C)CN LLZIVCIANZGPFN-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- NBWRJAOOMGASJP-UHFFFAOYSA-N 2-(3,5-diphenyl-1h-tetrazol-1-ium-2-yl)-4,5-dimethyl-1,3-thiazole;bromide Chemical compound [Br-].S1C(C)=C(C)N=C1N1N(C=2C=CC=CC=2)N=C(C=2C=CC=CC=2)[NH2+]1 NBWRJAOOMGASJP-UHFFFAOYSA-N 0.000 description 1
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NKBWMBRPILTCRD-UHFFFAOYSA-N 2-Methylheptanoic acid Chemical compound CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- HPMZBILYSWLILX-UMDUKNJSSA-N 3'''-O-acetyldigitoxin Chemical compound C1[C@H](OC(C)=O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O HPMZBILYSWLILX-UMDUKNJSSA-N 0.000 description 1
- KKSGOOJPXBUJIA-UHFFFAOYSA-N 3-[2-(diethylamino)ethyl]-7-hydroxy-4-methylchromen-2-one Chemical compound C1=C(O)C=C2OC(=O)C(CCN(CC)CC)=C(C)C2=C1 KKSGOOJPXBUJIA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JBZIYBRHFPZFGH-UHFFFAOYSA-N 3-hexylpyridazine Chemical compound CCCCCCC1=CC=CN=N1 JBZIYBRHFPZFGH-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- VIIIJFZJKFXOGG-UHFFFAOYSA-N 3-methylchromen-2-one Chemical compound C1=CC=C2OC(=O)C(C)=CC2=C1 VIIIJFZJKFXOGG-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- DANLZOIRUUHIIX-UHFFFAOYSA-N 4-[1-[2-chloro-6-(trifluoromethyl)benzoyl]indazol-3-yl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C(C1=CC=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C(F)(F)F DANLZOIRUUHIIX-UHFFFAOYSA-N 0.000 description 1
- YRNWIFYIFSBPAU-UHFFFAOYSA-N 4-[4-(dimethylamino)phenyl]-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1C1=CC=C(N(C)C)C=C1 YRNWIFYIFSBPAU-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-M 4-phenylbutyrate Chemical compound [O-]C(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-M 0.000 description 1
- IMRLLSROFHJYDK-UHFFFAOYSA-N 4-phenylmethoxy-3-(trifluoromethyl)chromen-2-one Chemical compound C12=CC=CC=C2OC(=O)C(C(F)(F)F)=C1OCC1=CC=CC=C1 IMRLLSROFHJYDK-UHFFFAOYSA-N 0.000 description 1
- FITXCUFMGMHHRK-UHFFFAOYSA-N 4-piperidin-1-ylsulfonylmorpholine Chemical compound C1COCCN1S(=O)(=O)N1CCCCC1 FITXCUFMGMHHRK-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- JTDYUFSDZATMKU-UHFFFAOYSA-N 6-(1,3-dioxo-2-benzo[de]isoquinolinyl)-N-hydroxyhexanamide Chemical compound C1=CC(C(N(CCCCCC(=O)NO)C2=O)=O)=C3C2=CC=CC3=C1 JTDYUFSDZATMKU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- BUCORZSTKDOEKQ-UHFFFAOYSA-N 7-chloro-4-hydroxy-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-imine Chemical compound C=12C=C(Cl)C=CC2=NC(=NC)CN(O)C=1C1=CC=CC=C1 BUCORZSTKDOEKQ-UHFFFAOYSA-N 0.000 description 1
- CCKWMCUOHJAVOL-UHFFFAOYSA-N 7-hydroxy-4-(trifluoromethyl)chromen-2-one Chemical compound FC(F)(F)C1=CC(=O)OC2=CC(O)=CC=C21 CCKWMCUOHJAVOL-UHFFFAOYSA-N 0.000 description 1
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 108010000239 Aequorin Proteins 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- ZOKJMAXRNRNEOS-UHFFFAOYSA-N C(CCCCCCCCCCCCCCCCC)(=O)OCCCCCCCCCCCCCCCCCC.[Mg] Chemical compound C(CCCCCCCCCCCCCCCCC)(=O)OCCCCCCCCCCCCCCCCCC.[Mg] ZOKJMAXRNRNEOS-UHFFFAOYSA-N 0.000 description 1
- VVFPAXPIVFHCNF-XTHKVDEBSA-N C1(=CC=CC=2C3=CC=CC=C3CC12)N[C@H]1C(O)O[C@@H]([C@H]([C@@H]1O)O)CO Chemical compound C1(=CC=CC=2C3=CC=CC=C3CC12)N[C@H]1C(O)O[C@@H]([C@H]([C@@H]1O)O)CO VVFPAXPIVFHCNF-XTHKVDEBSA-N 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- GGYHQPICLQIQAM-UHFFFAOYSA-N CC1=C(C=CC=C1)OOB(OO)O Chemical compound CC1=C(C=CC=C1)OOB(OO)O GGYHQPICLQIQAM-UHFFFAOYSA-N 0.000 description 1
- 101150027159 CIP1 gene Proteins 0.000 description 1
- MHBCYTWTYGSYRN-UHFFFAOYSA-N COC(=O)C1=CC=CC=C1C1=CC=CC(CBr)=C1 Chemical compound COC(=O)C1=CC=CC=C1C1=CC=CC(CBr)=C1 MHBCYTWTYGSYRN-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- 101710150820 Cellular tumor antigen p53 Proteins 0.000 description 1
- 101000577520 Chlamydomonas reinhardtii Photosystem I reaction center subunit III, chloroplastic Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 102100031048 Coiled-coil domain-containing protein 6 Human genes 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- 108010000543 Cytochrome P-450 CYP2C9 Proteins 0.000 description 1
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 1
- 108010015742 Cytochrome P-450 Enzyme System Proteins 0.000 description 1
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 102100029358 Cytochrome P450 2C9 Human genes 0.000 description 1
- 102100021704 Cytochrome P450 2D6 Human genes 0.000 description 1
- 102100037579 D-3-phosphoglycerate dehydrogenase Human genes 0.000 description 1
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 229940126190 DNA methyltransferase inhibitor Drugs 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical group CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 1
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 108010002156 Depsipeptides Proteins 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010016935 Follicular thyroid cancer Diseases 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- QMXOFBXZEKTJIK-UHFFFAOYSA-N Glycinol Natural products C1=C(O)C=C2OCC3(O)C4=CC=C(O)C=C4OC3C2=C1 QMXOFBXZEKTJIK-UHFFFAOYSA-N 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 241000545744 Hirudinea Species 0.000 description 1
- 102100021454 Histone deacetylase 4 Human genes 0.000 description 1
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 description 1
- 101000603420 Homo sapiens Nuclear pore complex-interacting protein family member A1 Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 108010020056 Hydrogenase Proteins 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000004195 Isomerases Human genes 0.000 description 1
- 108090000769 Isomerases Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- 206010023347 Keratoacanthoma Diseases 0.000 description 1
- FKUISVKPMQSWTN-UHFFFAOYSA-N Kesselringine Natural products C1CC(C2=C34)N(C)CCC2=CC(O)=C4OC2(OC)C(O)CCC31C2 FKUISVKPMQSWTN-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 108010026217 Malate Dehydrogenase Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000570861 Mandragora autumnalis Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101710169105 Minor spike protein Proteins 0.000 description 1
- 101710081079 Minor spike protein H Proteins 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 102100030626 Myosin-binding protein H Human genes 0.000 description 1
- 101710139548 Myosin-binding protein H Proteins 0.000 description 1
- PTJGLFIIZFVFJV-UHFFFAOYSA-N N'-hydroxy-N-(3-pyridinyl)octanediamide Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CN=C1 PTJGLFIIZFVFJV-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- IMFKHOOELGOICS-UHFFFAOYSA-N N1N=NC2=C1C=CC=C2.C2=CC=CC=1C3=CC=CC=C3CC21 Chemical compound N1N=NC2=C1C=CC=C2.C2=CC=CC=1C3=CC=CC=C3CC21 IMFKHOOELGOICS-UHFFFAOYSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000060390 Nothapodytes nimmoniana Species 0.000 description 1
- 102100038845 Nuclear pore complex-interacting protein family member A1 Human genes 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 101710203930 RNA polymerase-associated transcription-specificity factor RAP94 Proteins 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108050002653 Retinoblastoma protein Proteins 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010067269 Uterine fibrosis Diseases 0.000 description 1
- 206010046788 Uterine haemorrhage Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- NTJQFQZGODVLLG-UHFFFAOYSA-N [Li+].[O-2].[Ar].[Li+] Chemical compound [Li+].[O-2].[Ar].[Li+] NTJQFQZGODVLLG-UHFFFAOYSA-N 0.000 description 1
- QHMLGYJOGFXZOP-UHFFFAOYSA-N [Ni]N Chemical group [Ni]N QHMLGYJOGFXZOP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- XLUXHEZIGIDTCC-UHFFFAOYSA-N acetonitrile;ethyl acetate Chemical compound CC#N.CCOC(C)=O XLUXHEZIGIDTCC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 102000005421 acetyltransferase Human genes 0.000 description 1
- 108020002494 acetyltransferase Proteins 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000005122 aminoalkylamino group Chemical group 0.000 description 1
- 229960002684 aminocaproic acid Drugs 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- NXQOQNROJJFYCJ-FZFXZXLVSA-N androst-16-ene Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C=CC4)[C@@H]4[C@@H]3CCC21 NXQOQNROJJFYCJ-FZFXZXLVSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 125000005235 azinium group Chemical group 0.000 description 1
- 125000003943 azolyl group Chemical group 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 206010004398 benign neoplasm of skin Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000012888 bovine serum Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000009172 bursting Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- DCSUBABJRXZOMT-IRLDBZIGSA-N cisapride Chemical compound C([C@@H]([C@@H](CC1)NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)OC)N1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-IRLDBZIGSA-N 0.000 description 1
- 229960005132 cisapride Drugs 0.000 description 1
- DCSUBABJRXZOMT-UHFFFAOYSA-N cisapride Natural products C1CC(NC(=O)C=2C(=CC(N)=C(Cl)C=2)OC)C(OC)CN1CCCOC1=CC=C(F)C=C1 DCSUBABJRXZOMT-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000007398 colorimetric assay Methods 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229920002770 condensed tannin Polymers 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- WPJRFCZKZXBUNI-HCWXCVPCSA-N daunosamine Chemical compound C[C@H](O)[C@@H](O)[C@@H](N)CC=O WPJRFCZKZXBUNI-HCWXCVPCSA-N 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000006204 deethylation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940075894 denatured ethanol Drugs 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000012850 discrimination method Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003968 dna methyltransferase inhibitor Substances 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000008472 epithelial growth Effects 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- AXYVXVXZUCFQGF-UHFFFAOYSA-N ethyl 4-chloro-2-methylsulfonylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(S(C)(=O)=O)N=C1Cl AXYVXVXZUCFQGF-UHFFFAOYSA-N 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- SZIKRGHFZTYTIT-UHFFFAOYSA-N ethyl piperidine-2-carboxylate Chemical compound CCOC(=O)C1CCCCN1 SZIKRGHFZTYTIT-UHFFFAOYSA-N 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000005189 flocculation Methods 0.000 description 1
- 230000016615 flocculation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 239000004312 hexamethylene tetramine Substances 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical group C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 102000049765 human CDKN1A Human genes 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 125000005597 hydrazone group Chemical group 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000000968 medical method and process Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- GZQBGAMLHSVJRT-UHFFFAOYSA-N n-(9h-fluoren-1-yl)-9h-fluoren-1-amine Chemical compound C1C2=CC=CC=C2C2=C1C(NC=1C=CC=C3C4=CC=CC=C4CC=13)=CC=C2 GZQBGAMLHSVJRT-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- IDTXSDSJJGNDGL-UHFFFAOYSA-N n-[2-(hydroxyamino)ethyl]hydroxylamine Chemical compound ONCCNO IDTXSDSJJGNDGL-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- GASFVSRUEBGMDI-UHFFFAOYSA-N n-aminohydroxylamine Chemical compound NNO GASFVSRUEBGMDI-UHFFFAOYSA-N 0.000 description 1
- YSNXOQGDHGUKCZ-UHFFFAOYSA-N n-benzylhydroxylamine;hydron;chloride Chemical compound Cl.ONCC1=CC=CC=C1 YSNXOQGDHGUKCZ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000006715 negative regulation of smooth muscle cell proliferation Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 208000018360 neuromuscular disease Diseases 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- QJPQVXSHYBGQGM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000015927 pasta Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003961 penetration enhancing agent Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 238000005424 photoluminescence Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 235000018192 pine bark supplement Nutrition 0.000 description 1
- LDKPZNCITZLOFV-UHFFFAOYSA-N piperidine;1,2,3,4-tetrahydropyridine Chemical compound C1CCNCC1.C1CNC=CC1 LDKPZNCITZLOFV-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 208000030428 polyarticular arthritis Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000021738 protein deacetylation Effects 0.000 description 1
- 229940106796 pycnogenol Drugs 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 229910052704 radon Inorganic materials 0.000 description 1
- SYUHGPGVQRZVTB-UHFFFAOYSA-N radon atom Chemical compound [Rn] SYUHGPGVQRZVTB-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- PITRLQVCKQARGI-UHFFFAOYSA-N sulfane Chemical compound S.S.S PITRLQVCKQARGI-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-M valproate Chemical compound CCCC(C([O-])=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-M 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 230000002034 xenobiotic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Biochemistry (AREA)
- Analytical Chemistry (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Dermatology (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- General Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
Description
200400941
發明說明 本發明係有關—種具 制酵素活性之化人* * Ί蛋去乙_(腿〇抑 化。物。並有關其製法、 及其於活體内及活體外抑制HDAr少物、 之用途n作為用途及其作為醫藥 醫藥之用途。,”'、生性病症(如:癌症與乾癬)之 所有真核生物細胞巾’染色質中 織蛋白結合形成捗鲈A 土 U、.且UNA興組 H2A H9R ^ 。各核體分別由各組織蛋白質 H2A、H2B ' H3 盘 V[a ^ 10 15 經濟部智慧財產局員工消費合作、社印製 20 /、 之兩套複本形成之蛋白質八聚體 =。DNA賴此蛋自f核心,雜織蛋白之驗性胺基 之帶負電㈣酸根交互作用。此等組織蛋白核 袁㊉見之轉譯後修飾作用為已保留之高驗性Ν_末端離 ^酉夂殘基之ε_胺基之可逆性乙醯化仙H織蛋白乙 酿基轉化酶(群)與本文中稱為"HDAC"之組織蛋白去乙醯 酶(群)之間競爭形成之動力平衡建立組織蛋白 乙醯化作用 之穩足狀癌。組織蛋白乙醯化作用與去乙醯化作用長久 以來即與轉錄控制相關。近來所選殖出編碼不同組織蛋 白乙醒基轉化酶及組織蛋白去乙醯酶之基因提供為組織 蛋白乙醯化作用與轉錄控制之間關係之可能解釋。組織 蛋白之可逆性乙醯化作用可造成染色質再造及作為基因 轉錄之控制機轉。通常,'組織蛋白之過度乙酿化作用會 促使基因表現,而組織蛋白去乙醯化作用則與轉錄壓抑 有相關性。已知.组織蛋白乙醯基轉化酶具有作為轉錄共 活化劑之作用,而組織蛋白去乙醯酶則屬於轉錄壓抑途 徑。 兆:本紙張尺度適財國國家標準(CNS)A4規格⑵0 x 297公 200400941 A7 B7 五、發明說明(2) 組織蛋白乙酿化與去乙酿化之間之動力平衡係正常 細胞生長所必需。抑制組織蛋白去乙酿酶則可造成細胞 循環停止、細胞分化'細胞凋亡及使轉形之表型逆轉。 因此’ HDAC抑制劑在治療細胞增生疾病或病症上具有 5 極大醫療潛力(Marks 等人,Nature Reviews:Cancer 1:194- 202,2001) 有關組織蛋白去乙醯酶(HDAC)之抑制劑研究顯示, 此等酵素的確在細胞增生及分化上扮演重要角色。抑制 劑三克定A(Trichostatin A)(TSA)造成G1與G2期之細胞 10循環停止,使不同細胞株之已轉形表型反轉,並誘發弗 瑞德(Friend)白血病細胞及其他細胞分化。已有文獻指 出,TSA(與辛二醯基替苯胺異羥肟酸SAHA)在小白鼠體 内,可制抑細胞生長,誘發末端分化,及防止腫瘤形成 (Finnin 等人,Nature,401:188-193,1999)。 15 亦有文獻指出,三克定A適用於治療纖維變性,例 如:肝纖維變性與肝硬化(Greets等人,1998年3月11曰 公告之歐洲專利申請案EP 0 827 742)。 經濟部智慧財產局員工消費合作社印製 2001年5月31日公告之專利申請案w〇 01/38322 特別揭示通式Cy-U-Ar-Yi-CCOKMH-Z之其他組織蛋白去 20乙醯酶抑制劑,並提供治療細胞增生疾病與病症之組合 物與方法。 » ·· 2001年9 '月27日公告之專利申請案w〇 01/70675 揭示如式Cy-S(0)2-NH-Y3-W之組織蛋白去乙醯酶抑制 劑,並進一步提供治療細胞增生疾病與病症之組合物與 -4- d!X,:本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 Α7 Β7 五、發明說明(3) 方法。 所要解決之問題為提供具有高酵素活性之組織蛋白 去乙醯酶抑制劑,亦需具備有利性質,如:細胞活性及 提高之生體可用率,最好提高口服之生體可用率,且副 5 作用很小或沒有。 本發明新穎化合物可解決上述問題。本化合物之結 構式不同於先前技藝。 本發明化合物展現優越之活體外組織蛋白去乙醯酶 抑制酵素活性。本化合物在細胞活性上具有有利性質, 10 且針對抑制G1與G2兩個檢查點之細胞循環發展具有專 一性質(p21誘發能力)。本發明化合物具有良好代謝安定 性及高度生體可用率,更特定言之,其展現口服生體可 用性。此外,本發明化合物對P450酵素之親和性低,可 降低藥物-藥物不良交互作用之危險,因此亦可提供較廣 15 之安全範圍。 本發明係有關式(I)化合物
R2 經濟部智慧財產局員工消費合作社印製 其N-氧化物型'、其醫藥上可接受之加成鹽及立體化學異 構型,其中 η為0、1、2或3,且當η為0時,則為一直接鍵結; 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(4) t為0、1、2、3或4,且當t為0時,則為一直接鍵結; 各Q為氮或一C<; 各X為氮或一C< ; 各Y為氮或一C< ; 5 各Z為氮或一CH< ; R1 為-C(0)NR7R8、-N(H)C(0)R9、-C(0)CN6 烷二基 SR9、-NR1()C(0)N(0H)R9、-NR^CCCOCk 烷二基 SR9、-NR1QC(0)C=N(OH)R9 或另一個 Zn-螯合基, 其中R7與R8分別獨立選自:氫、羥基、Cw烷基、羥 10 基Ci_6烧基、胺基Ci_6烧基或胺芳基; R9分別獨立選自:氫、Ct_6烷基、Q.6烷羰基、芳基Cm 烷基、Cm烷基吡啩基、吡啶酮、吡咯啶酮或甲基 咪σ坐基; R1Q分別獨立選自:氫或Cw烷基; 15 R2為氫、鹵基、羥基、胺基、硝基、Q.6烷基、C!_6烷氧 基、三氟甲基、二(<^_6烷基)胺基、羥胺基或萘磺醯基 0比σ井基; 經濟部智慧財產局員工消費合作社印製 -L-為一直接鍵結或選自下列之二價基團:Cu烷二基、 胺基、羰基或胺羰基; 20 各R3分別獨立代表氫原子,且其中一個氫原子可被芳基 置換; * · R4為氫、輕基V胺基、輕基Cl-6烧基、Cl _6烧基、Cl.6烧 氧基、芳基Cw烷基、胺羰基、羥羰基、胺基Cw烷 基、胺羰基Cm烷基、羥羰基Cm烷基、羥胺羰基、CN6 -6- -本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明 1-6 烷氧羰基、Cm烷胺基Q-6烷基或二(Cm烷基)胺基C 烧基; 為選自下列之基團: (R5),
R5)s iR6)s
本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(6 )
200400941 A7 B7 五、發明說明(7 ) 、4 I N (a-45) 0 /R6)
NH Ν Ν (a-46)
ο μ\ 11/ c N
Ο Ν (a-47) 、Ν
(a-48)
(a-49)
J:R)s Ν ,ΝΗ (a-51) 其中各s分別為0、1、2、3、4或5; 10 15 經濟部智慧財產局員工消費合作社印製 20 各R5與R6分別獨立選自氮;鹵基;經基;胺基;頌基; 三鹵Ci-6燒基;三Ci_6烧氧基;Ci_6烧基;經芳基與 C3_1Q環烷基取代之Ci_6烷基;(:1_6烷氧基;Cm烷氧基 Cw烷氧基;Cw烷羰基;C!_6烷氧羰基;Cm烷磺醯 基;氰基Ci_6烧基;經基Ci_6烧基;經基Ci_6烧氧 基;經基Ci_6烧胺基;胺基Cm烧氧基;二(Ci_6院基) 胺截基;二(經基Ci-6烧基)胺基;(芳基)(Ci_6烧基)胺 基;二(〇1_6烧基)胺基匚1_6烧氧基;二((^1.6烧基)胺基 Ci_6跪胺基;二(Ci_6燒基)胺基Ci_6烧胺基Ck院基; 芳基磺基;芳基磺醯基胺基;芳氧基;芳氧基C!_6 烧基;芳基C2-6稀二基;二(Ci-6烧基)胺基;二(Ci—6烧 基)胺基Ci.6烧基,二(Ci_6烧基)胺基(Cu烧基)胺基; t · · 二(C1.6烧基)胺基(Ci_6烧基)胺基Ci_6院基,二(Ci_6院 基)胺基Ci.6龍基(Ci-6競•基)胺基;二(Ci_6院基)胺基C!_6 烧基(C!_6院基)胺基Ck競》基; 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(ο 胺基續酿基胺基(Cl-6烧基)胺基; 胺基磺醯基胺基(C!_6烧基)胺基c16燒基; 二(Cw烷基)胺基磺醯基胺基(Cm烷基)胺基; 二(Ci-6烧基)胺基續醯基胺基(Cu烧基)胺基Cl·6烧 5 基;氰基;硫苯基; 經下列基團取代之硫笨基:二(Cl.6烷基)胺基Cw烷基 (Ci_6炫基)胺基Cl·6院基、二(Ch6烧基)胺基Ci-6炫基、 (^1-6烧基六氮井基Ck燒基、經基C〗_6炫*基六風"^比^井 基Cm烷基、羥基Cw烷氧基Cl.6烷基六氫吡畊基Cm 10 烧基、>一(Ci_6烧基)胺基續酿基六氮b比σ井基Cl.6炫*基、 Cl-6烷氧基六、氩吡啶基、Cu烷氧基六氫吡啶基Cl.6烷 基、嗎福咐基Ci_6烧基、經基Cu烧基(C!-6炫基)胺基 Cl·6烧基、或一(¾基Ci-6烧基)胺基Ci_6烧基’ 呋喃基;經羥基CN6烧基取代之呋喃基;苯並呋喃 15 基;咪唑基;畤唑基;經芳基與Cm烷基取代之畤唑 經濟部智慧財產局員工消費合作社印製 基;Cm烷基三唑基;四唑基;吡咯啶基;吡咯基;六 氫吼啶基Cw烷氧基;嗎福啉基;Cl-6烷基嗎福唯基; 嗎福啉基Cw烷氧基;嗎福咁基cN6烧基;嗎福咁基 Cl_6院胺基,嗎福咐基C!·6烧胺基Ci-6烧基;六氫咐^井 20 基;C!-6烷基六氫吡啡基;Cl_6烷基六氫吡畊基Ci 6烷 氧基’六氫°比啡基C!_6烧基;萘續酸基六氫吡畊基; 奈石頁醯基六氫吨唆基;萘續醯基;Cm烧基六氫吼„井基 C!-6烷基;C!-6烷基六氫吡畊基Cl.6烷胺基;Ci_6烷基 六氫吡畊基Cm烷胺基Cm烷基;Cl_6烷基六氫吡畊基 -10- 本紙張尺度適用中國國家標準(CNS)A4規格—(210 x 297公爱) 200400941 Α7 Β7 五、發明說明(9) 石黃酿基;胺基續酸基六氮°比ϋ井基C1.6烧氧基;胺基石黃 酸基六氮1σ井基,胺基續酸基六氮吼ϋ井基C 1 烧基, 二(Ci-6燒基)胺基續驢基六氮吼17井基;二(Ci_6烧基)胺 基項酿基六氫σ比π井基Ci-6烧基;輕基Ci-6烧基六氫叫匕 5 σ井基;經基Ck院基六氫峨17井基Ck院基;Ci_6貌氧基 六氮3比淀基,Ci-6院氧基六氮吼。定基C!_6烧基,六氮u比 淀基胺基Cu院胺基;六氫吼淀基胺基Ci_6院胺基Ck 烧基, (Ci_6烧基六氫峨咬基)(备基Ci_6院基)腔基C!_6烧胺 10 基; (C!_6院基六氫吼淀基)(經基Cu貌基)胺基Ci_6烧胺基 Ci_6烷基; 羥基Ci_6烷氧基Cm烷基六氫吡畊基; 輕基Ci_6院氧基Ci„6競'基六氮咕ϋ井基Ci_6烧基; 15 (¾基Ci_6院基)(Ci-6院基)胺基;(¾基Ci_<5虎基)(Ci_6 烧基)胺基Ci_6烧基; 經基Ci_6院胺基Ci-6烧基;二(經基Ci_6貌基)胺基Ci_6 烧基; 經濟部智慧財產局員工消費合作社印製 11比洛σ定基C U烧基,σ比略σ定基C1 _6院氧基:吼σ坐基; 20 硫吡唑基;經選自cN6烷基或三A cN6烷基中兩個取 代基取代之吡唑基; J- ·· 吡啶基;經烷氧基、芳氧基或芳基取代之吡啶 基;嘧啶基;四氫嘧啶基六氫吡畊基;四氫嘧啶基六 氫11比併基C K烧基;啥啡基;丨σ朵基;苯基;經分別 -11- : ¾本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 Α7 Β7 五、發明說明(10) 獨立選自下列1、2或3個取代基取代之苯基:i基、 胺基、頌基、Ci-6院基、C!.6烧氧基、經基Ci.4炫基、 三氟曱基、三氟甲氧基、羥基CU4烷氧基、Cm烷基磺 醯基、Cm烷氧基Cw烷氧基、Cw烷氧羰基、胺基 5 Cw烷氧基、二(Cm烷基)胺基Cm烷氧基、二(Cm烷 基)胺基、二(Cm烷基)胺羰基、二(Cm烷基)胺基Cm 烧基、二((1!1.4烧基)胺基€11_4烧胺基(^1-4烧基、二(匚1-4 烧基)胺基(Ci_4烧基)胺基、二(Ci.4烧基)胺基(Cm燒基) 胺基Ci.4烧基、二(Ci-4烧基)胺基Ci_4烧基(Ci.4烧基)胺 10 基、二(Cw烷基)胺基Cm烷基(CN4烷基)胺基Cm烷 基、胺基續酿基胺基(Ci_4烧基)胺基、胺基續酿基胺基 (Ci-4烧基)胺基Ci-4烧基、二(Cl-4烧基)胺基續酿基胺 基(Ci.4烧基)胺基、二(Ci-4烧基)胺基續酸基胺基(Cl-4 烷基)胺基Cw烷基、氰基、六氫吡啶基Cm烷氧基、 I5 β比嘻咬基Cl-4烧氧基、胺基續酿基六氮吼π井基、胺基 經濟部智慧財產局員工消費合作社印製 磺醯基六氫吡畊基CN4烷基、二(Cm烷基)胺基磺醯基 六氫吡畊基、二(Cm烷基)胺基磺醯基六氫吡畊基C!_4 烷基、羥基CN4烷基六氫吡畊基、羥基Cm烷基六氫 吼畊基Cm烷基、Cm烷氧基六氫吡啶基、Cm烷氧基 20 六氫吡啶基Cm烷基、.羥基Cw烷氧基Cm烷基六氫 11比畊基、羥基Cm烷氧基Cm烷基六氫吡畊基Cw烷 I. ·· 基、(羥基Cw烷基XQ.4烷基)胺基、(羥基CM烷 基XCm烷基)胺基CN4烷基、二(羥基C!_4烷基)胺基、 二(羥基CN4烷基)胺基Q.4烷基、呋喃基、經-CH=CH- -12- 1本紙張尺度適用中國國家標準(CNS)A4規格(21〇χ297公釐) 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(η) CH=CH-取代之呋喃基、吡咯啶基CM烷基、吡咯啶基 Cp4院乳基、嗎福σ林基、嗎福^1林基Ci_4燒氧基、嗎福咐 基Ci_4跪基、嗎福啡基Ci_4燒胺基、嗎福咐基Ci_4龍胺 基Cm競*基、六氫°比σ井基、Ci_4院基六氳3比σ井基、Cp4 5 烧基六氮啦0井基Ci_4競*氧基、六氮咕13井基Ci„4燒基、Cm 烷基六氳吡畊基Cm烷基、(:1_4烷基六氫吡呼基<^_4烷 胺基、Cl-4貌基六氮吼11井基Cl _4院胺基Cl _6烧基、四氮 嗤唆基六氫吡σ井基、四氫喊淀基六氫吡畊基院 基、六鼠0比淀基胺基Ci „4烧胺基、六氮σ比咬基胺基C!-4 1〇 院胺基Ci_4烧基、(Ci-4院基六氫°比淀基)(經基C!_4烧基) 胺基Ci_4能胺基、(Ci_4燒基六氫哎味基)(經基Ci_4院基) 胺基C!_4烧胺基Cm烧基、σ比淀基Cp4烧氧基、經基 Ci_4烧胺基、髮基Ci_4烧胺基Ci_4烧基、二(Ci_4烧基) 胺基C!_4烷胺基、胺基噻二唑基、胺基磺醯基六氫吡 15 啡基Cw烷氧基、或硫苯基Cm烷胺基; /—(CH2)n \ —N Z — 中心之 \_/部份基團亦可與亞甲基、伸乙基或 伸丙基橋連基形成橋連(亦即形成雙環狀部份基團); 各R5與R6可置於氮上替代氫; 20 上述芳基為苯基,或經一個或多個分別獨立選自:鹵 基、Ci_6烧基、Ci_6烧氧基、三氟曱基、氰基或經幾基 之取代基取代之苯基。 ”組織蛋白去乙醯酶抑制劑”係指可與組織蛋白去乙醯 酶交互作用且可抑制其活性,更特定言之抑制其酵素活 -13- 本纸張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
200400941 A7 B7 五、發明說明(12 經濟部智慧財產局員工消費合作社印製 性之化合物。抑制組織蛋白去乙醯酶酵素活性意指降低 組織蛋白去乙醯酶脫除組織蛋白之乙醯基之能力。較佳 者,此等抑制作用為專一性,亦即組織蛋白去乙醯酶抑 制劑降低組織蛋白去乙醯酶脫除組織蛋白之乙醢基之能 5力時所需濃度低於該抑制劑為了產生一些其他不相關生 物效應時所需濃度。 如上文與下文中定義所使用之鹵基通指氟、氯、漠 與破,Ci·4烧基指含有1至4個碳原子之直鍵與分支鍵飽 和烴基,如’例如:甲基、乙基、丙基、丁基、1_甲基乙 10基、2-甲基丙基’等等;Ci·6烧基包括Ci_4烧基及含有5 至6個碳原子之較高碳數同系物,如,例如:戊基、2_甲 基-丁基、己基、2-甲基戊基,等等;Cl.6烷二基指含有i 至6個碳原子之二價直鏈與分支鏈飽和烴基,如,例 如:亞甲基、1,2-乙二基、1,3-丙二基、1,4-丁二基、1,5-戊二基' 1,6-己二基,及其分支之異構物,如:2-曱基戊 二基、3-甲基戊二基、2,2-二甲基丁二基、2,3-二甲基丁 一基’等等;三鹵C!_6烧基指含有三個相同或相異鹵基 取代基之CN6烷基,例如:三氟曱基;C2_6烯二基指含有 一個雙鍵及2至6個碳原子之二價直鏈與分支鏈烴基, 如,例如:乙烯二基、2-丙烯二基、3-丁烯二基、2-戊烯 二基、3-戊烯二基、3-曱基-2-丁烯二基,等等;芳基指 * “ 一. 苯基’及經一個或多個選自:_基、C,_6烷基、Cm烷氧 基、三氟甲基、氰基或羥羰基中之取代基取代之苯基; 胺芳基指經胺基取代之芳基;及C3-1Q環烷基包括含有3 15 20 -14- s/i本紙張尺度適用中國國家標準(CNS)A4規格(21〇χ297公釐) 裝 計 線 200400941 A7
發明說明 至10個兔原子之環狀烴基,如:環丙基、環丁基、環戊 基、環戊烯基、環己基、環己烯基、環庚基、環辛基、 等等。 ”另一個Zn-螯合劑”指可與Zn_離子交互作用之基 團’其可出現在酵素結合位置。 10 15 經濟部智慧財產局員工消費合作社印製 20 醫藥上可接受之加成鹽包括醫藥上可接受之酸加成 鹽及醫藥上可接受之驗加成鹽。如上述之醫藥上可接受 之酸加成鹽包括式(I)化合物可形成之具醫療活性之無毒 性酸加成鹽型。具有鹼性性質之式⑴化合物之鹼型經過 適當酸處理後,可轉化成其醫藥上可接受之酸加成鹽。 適當之酸包括例如:無機酸類,如:氩函酸,例如:鹽 酸或氫溴酸;硫酸;硝酸;磷酸,等等酸類;或有機酸 類如’例如:乙酸、三氟乙酸、丙酸、羥乙酸、乳酸、 丙酮酸、草酸、丙二酸、琥珀酸(亦即丁二酸)、馬來酸、 富馬酸、蘋果酸、酒石酸、檸檬酸' 甲磺酸、乙磺酸、 苯磺酸、對曱笨磺酸、環己胺磺酸、水楊酸、對胺基_水 揚酸、雙羥萘酸,等等酸類。 具有酸性性質之式(I)化合物可經過適當有機或無機 鹼處理後’轉化成其醫藥上可接受之鹼加成鹽。適當之 鹼鹽型包括例如:銨鹽、.鹼金屬與鹼土金屬鹽,例如: 鋰、鈉'鉀、鎂、鈣鹽等等,與有機鹼形成之鹽例如: * ' 雙羥基乙二胺、:N-曱基-D-葡糖胺、哈胺青黴素之鹽類, 及與胺基酸如,例如:精胺酸、離胺酸,等等形成之鹽 類。 -15- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明Ο4) 10 15 經濟部智慧財產局員工消費合作社印製 20 ”酸或鹼加成鹽,,一詞亦包括式⑴化合物可形成之水合 物及溶劑加成型。此等型式之實例為例如:水合物與醇 化物,等等。 本文所採用"式(I)化合物之立體化學異構型”指由式(I: •化合物之相同原子組成相同鍵結順序但具有無法交換之 不同立體結構之所有可能化合物。除非另有說明,否則 化合物之化學式包括該化合物可能出現之所有可能立體 化學異構塑之混合物。該混合物可包含該化合物基本分 子結構之所有非對映異構物與/或對映異構物。呈純型或 其混合物之式(I)化合物之所有立體化學異構型均涵括在 本發明範圍内。 式(I)化合物之N-氧化物型包括彼等式(I)中一個或數 個氮原子被氧化成所謂之N-氧化物之化合物,特定言 之,彼等式中一個或多個六氫吡啶基、六氫吡啡基或嗒 畊基之氮為N-氧化之N-氧化物。 、有些式⑴化合物亦可呈其互變異構型。此等型式雖 d未出現在上式中,但亦包括在本發明範圍内。 本文中若使用”式⑴化合物”一詞日寺,亦包括#藥上可 接戈之加成鹽及所有立體異構型。 ^文所採用”組織蛋白去乙_,,與,,hdac”意指可自 酵幸族itN:末端__紅ε •胺基上麟乙《之 蛋除非本文中另有說明,否則|·組織 包括何物種之任何組織蛋白之蛋白質, 、H2A、H2B、H3、H4 與 H5。人類 HDac 本紙張尺度適用中國g ^^NS)A4
200400941 A7 B7 五、發明說明(15) 質或基因產物包括(但不限於):HDAC-1、HDAC-2、 HDAC-3、HDAC-4、HDAC-5、HDAC-6、HDAC-7、 HDAC-8、HDAC-9與HDAC-10。組織蛋白去乙醯酶亦可 衍生自原蟲或真菌來源。 5 第一類值得注意之化合物包括彼等式(I)中符合下列 一項或多項限制之化合物: a) n為1或2 ; b) t 為 0、1 或 2 ; c) 各Z為氮, 10 d)R1()為氫; 6)112為氫、硝基、(31-6烧氧基、三氟曱基、二(〇1.6燒基) 胺基、羥胺基或萘磺醢基吡畊基; f)-L-為一直接鍵結或選自下列之二價基團:C!_6烷二基、 羰基或胺羰基; 15 g)各R3代表氫原子; h)R4為氫、羥基Cw烷基、胺羰基、羥胺羰基或二(Cw 烧基)胺基Cl_6烧基; 經濟部智慧財產局員工消費合作社印製 為選自@-1)、(狂-7)、(3-9)、(3-10)、(&-12)、(3-14)、(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-30)、(a-20 34)、(a-49)或(a-50)之基團; j) 各s分別為0、1、2或5 ; k) 各R5與R6分別獨立選自:氳;鹵基;硝基;三鹵CN6 炫基,三鹵Ci.6院氧基;Ci_6烧基;炫*氧基;Ci.6烧 磺醯基;(芳基XC^烷基)胺基;芳基磺醯基;芳氧基; -17- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(16) 芳基c2_6烯二基;二(Cw烷基)胺基;硫苯基;經下列 基團取代之硫苯基.二(Ci_6炫基)胺基院基(Ci-6燒 基)胺基Ci_6院基、二(Ck院基)胺基Ci.6烧基、Ci_6院 基六氫吼。井基Ci_6院基、經基Ci_6院基六氫σ比17井基Ci_6 5 烧基、經基C!_6院氧基Cu院基六氫吼17井基Ci_6烧基、 二(Ci_6烧基)胺基續縫基六氫咐*°井基C〗_6烧基、C!_6院氧 基六氫啦17定基Ci_6院基、嗎福嘴基Ci_6燒基、經基Ci-6 烧基(Ci_6烧基)胺基Ck烧基、或二(經基Ck烧基)胺基 Cu院基; 經濟部智慧財產局員工消費合作社印製 10 呋喃基;啐唑基;吡咯基;吡唑基;吡啶基;經Ci_6烷 氧基取代之吡啶基;喳啉基;吲哚基;苯基;經分別獨 立選自下列1、2或3個取代基取代之苯基:鹵基、胺 基、Ci_6烧基、C!_6燒氧基、經基C!_4跪基、三氟甲 基、三氟甲氧基、二(Cw烷基)胺基Cm烷氧基、二(C!_4 15 院基)胺基、二(Ci_4燒基)胺基Ci_4燒基、二(Cl-4院基)胺 基Ci_4院基(C1-4烧基)胺基、二(Ci_4院基)胺基C!-4院基 (Ci-4烧基)胺基C!_4烧基、輕基Ci_4貌基六氮井基Ci_4 燒基、經基Ci-4貌氧基Ci _4院基六氯吼σ井基Cl-4燒基、 二(¾基Ci_4院基)胺基Ci_4院基、σ比咯淀基Ci_4烧基、 20 峨略12定基C!_4烧氧基、嗎福咐基Ci胃4烧氧基、嗎福17林基 C 1 _4烧基、C 1 -4焼*基六氮。比3井基C 1 _4院基’或 3- · /-—(CU2)n 中心之部份基團亦可與亞曱基橋連基形 成橋連(亦即形成雙環狀部份基團)。 -18- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Μ Β7 五、發明說明(17) 第二類值得注意之化合物包括彼等式⑴中符合下列 一項或多項限制之化合物: a) n為1或2 ; b) t為0或2 ; 5 c)各Z為氣; (i)R1 為-C(0)NH(0H); e) R2為氫; f) -L-為一直接鍵結; g) 各R3代表氫原子; 10 h) R4 為氫; i) —為選自(a-1)、(a-9)、(a-19)、(a-20)、(a-21)、 (a-22)、(a-23)、(a-49)或(a-50)之基團; j) 各s分別為0、1、2或5 ; k) 各R5與R6分別獨立選自:氫;鹵基;三鹵Ci_6烷基; 15 三鹵Ci_6说氧基;C〗_6烧基;C〖_6烧氧基;芳基C2-6稀 經濟部智慧財產局員工消費合作社印制衣 二基;二(Ci_6烷基)胺基;硫苯基;經下列基圑取代之 硫苯基.二(Ci_6院基)胺基Ci_6烧基(Ci_6烧基)按基Ci-6 烧基、二(C!_6院基)胺基Ck烧基、Ck烧基六氮吼σ井基 Ci_6烧基、备基C!_6院基六氫吼。井基C!_6烧基、經基Ci_6 20 烷氧基烷基六氫吡畊基CK6烷基、烷氧基六氫 吡啶基Cw烷基、嗎福啉基Cw烷基、羥基Q_6烷基 (Ci_6院基)胺基貌基、或二(¾基Ci_6院基)胺基Ci_6 烧基; 呋喃基;啐唑基;吡唑基;吡啶基;經Cw烷氧基取 -19- Θ77本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(1〇 代之吡啶基;喳啉基;吲哚基;苯基;經分別獨立選 自下列1、2或3個取代基取代之苯基:鹵基、胺基、 Ci_6炫基、Ci-6烧氧基、备基Ci_4院基、三氟甲基、三 氟曱氧基、二(Ci-4烧基)胺基Ci.4烧氧基、二(Ci_4烧基) 5 胺基、二(CN4烷基)胺基C 1-4烧基、二(Ci_4院基)胺基 Cl-4 焼基(C!_4烧基)胺基C 1-4烧基、經基Ci_4院基六氫 咐。井基Ci_4烧基、备基C!_4燒氧基Ci_4規基六氮峨11井基 Ci-4烧基、二(¾基烧基)胺基C1-4烧基、咐》略淀基 C!-4烧基、啦略11 定基Ci_4燒氧基、嗎福0林基Ci_4烧氧 10 基、嗎福咐基Cl-4院基、Ci_4院基六氮吼σ井基Ci_4貌 基,或 /—(CH2)n 中心之—_/z—部份基團亦可與亞曱基橋連基形成 橋連(亦即形成雙環狀部份基團)。 15 第三類值得注意之化合物包括彼等式(I)中符合下列 一項或多項限制之化合物: a) n 為 1 ; b) t 為 0 ; 經濟部智慧財產局員工消費合作社印製 c) 各Z為氮; 20 (i)R1 為-C(0)NH(0H); e) R2為氫; * -· f) -L-為一直接鍵:結; g) 各R3代表氫原子; h) R4為氫; -20- ί,本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐) 200400941 A7 _ B7 五、發明說明(19) i) 〜為選自(a-Ι)或(a-20)之基團; j) 各s分別為〇或1 ; k) 各R5與R6分別獨立選自:氫;硫苯基;經下列基團取 代之硫苯基:二(Cu烷基)胺基C!-6烷基、或Cu烷基 5 六氫吡畊基Ck烷基;呋喃基;苯基;經分別獨立選自 下列之1個取代基取代之苯基:二(Cw烷基)胺基Ci-4 烧氧基、二(C1.4烧基)胺基、二(Cl-4烧基)胺基C1-4烧 基、二(Cm烷基)胺基Cm烷基(Cw烷基)胺基CM烧 基、吼17各咬基Cm烧基、批嘻咬基Ci.4烧氧基或Cl-4炫 10 基六氫吡啡基Cm烷基。 第四類值得注意之化合物包括彼等式⑴申r1為_ C(0)NH(OH)且-L-為一直接鍵結之化合物。 第五類值得注意之化合物包括彼等式(I)中以為- C(0)NH(0H),R2為氫且-L-為一直接鍵結之化合物。 15 第六類值得注意之化合物包括彼等式⑴中符合下列 一項或多項限制之化合物: a)t 為 0 ; 經濟部智慧財產局員K消費合作社印製 tOR1 為-C(0)NR7R8、-CCCOCm 烷二基 SR9、-NR1QC(0)N(0H)R9、-NR^CCCOC^ 烷二基 SR9、-20 NR1QC(0)C=N(0H)R9 或另一個 Zn-螯合基, 其中R7與R8分別獨立選自:氫、羥基、羥基Cw烷基 或胺基Cu6炫;基; c)R2為氫、鹵基 '羥基、胺基、硝基、q.6烷基、Ci-6炫 氧基、三氟甲基或二(CN6烷基)胺基; -21- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐) 200400941 Μ Β7 五、發明說明(20 ) d) -L-為一直接鍵結或選自下列之二價基團:Ci-6烷二基、 胺基或羰基; e) R4為氫、經基、胺基、經基Ci-6烧基、Ci-6烧基、C!-6 烷氧基、芳基Cw烷基、胺羰基、胺基Cw烷基、Cw 5 烧基胺基Ci_6炫*基或二(Cl-6烧基)胺基Ci.6烧基; 為選自下列 2*®:(a-l)、(a-3)、(a-4)、(a-5)、(a-6)、(a-7)、(a-8)、(a-9)、(a-10)、(a-11)、(a-12)、 (a-13)、(a-14)、(a-15)、(a-16)、(a-17)、(a-18)、(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-24)、(a-25)、 10 (a-26)、(a-28)、(a-29)、(a-30)'(a-31)、(a-32)、(a- 33)、(a-34)、(a-35)、(a-36)、(a-37)、(a-38)、(a-39)、 (a-40)、(a-41)、(a-42)、(a-44)、(a-45)、(a-46)、(a-47)、(a-48)或(a-51); g)各s分別為0、1、2、3或4; 經濟部智慧財產局員工消費合作社印製 15 h)R5為氫;鹵基;羥基;胺基;硝基;三鹵C!-6烷基; 三鹵C!_6烷氧基;C丨-6烷基;Ci.6烷氧基;C丨_6烷羰基; Ck6烷氧羰基;Cm烷磺醯基;羥基Cw烷基;芳氧 基;二(Cw烷基)胺基;氰基;硫苯基;呋喃基;經羥 基Cu烷基取代之呋喃基;苯並呋喃基;咪唑基;畤唑 20 基;經芳基與烷基取代之唑基;Cm烷基三唑 基;四唑基;吡咯啶基;吡咯基;嗎福咁基;Cu烷基 * ·· 嗎福啉基;六'氫吡啡基;Cu烧基六氫吡畊基;羥基 Ci-6烧基六鼠吼B井基;Ci-6烧氧基六氮n比咬基;13比。坐 基;經選自C〗·6烧基或三鹵Ci·6烧基中一或兩個取代基 -22- 9㈣本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(21) 取代之吡唑基;吡啶基;經Cl6烷氧基、芳氧基或芳基 取代之吼咬基;嘴唆基;喳咐基;吲哚基;笨基;或經 分別獨立選自:鹵基、Cw烷基、烷氧基或三氟甲 基中之1或2個取代基取代之苯基; 5 i)R6為氫;鹵基;羥基;胺基;硝基;三鹵Cu烷基;三 鹵C!_6烧氧基;C!-6烧基;Cw烷氧基;Q.6烷羰基;Cm 烷氧羰基;Ck烷磺醯基;羥基Cy烷基;芳氧基;二 (Ci·6烧基)胺基;氰基;吡啶基;苯基;或經分別獨立 選自:鹵基、Cm烷基、Cw烷氧基或三氟甲基中之1 10 或2個取代基取代之苯基; /—(CH2)n j)中心之 一 N /Z—部份基團亦可與伸乙基橋連基 形成橋連(亦即形成雙環狀部份基團)。 第七類值得注意之化合物包括彼等式(I)中符合下列 15 一項或多項限制之化合物: a) R7與R8分別獨立選自:氫、羥基、羥基Cl.6烷基、胺 基Ck燒基或胺芳基; 經濟部智慧財產局員工消費合作社印製 b) R2為氫、鹵基、羥基、胺基、硝基、Cl_6烷基、Cl.6烷 氧基、三氟甲基、羥胺基或萘磺醯基吡4基; 20 c)R4為氫、羥基、胺基、羥基Cl_6烷基、Cl.6烷氧基、芳 基Ci·6烷基、胺羰基、羥羰基、胺基Cy烷基、胺羰基 t ·
Cl·6燒基、羥羰基CN6烷基、羥胺羰基、Cb6烷氧基羰 基、CN6烷胺基Q-6烷基或二(Cm烷基)胺基烷基; d) —為選自下列之基團:(a-1)、(a-2)、(a-3)、(a- -23- gS i本纸張尺度適时_家標準(c 4規格G χ Μ?公爱) 200400941 A7 B7 五、發明說明(22 ) 4)、(a-5)、(a-6)、(a-7)、(a-8)、(a-9)、(a-10)、(a-11)、 (a-12)、(a-13)、(a-14)、(a-15)、(a-16)、(a-17)、(a-18)、(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-24)、 (a-25)、(a-26)、(a-27)、(a-28)、(a-29)、(a-30)、(a-5 31)、(a-32)、(a-33)、(a-34)、(a-35)、(a-36)、(a-37)、 (a-38)、(a-39)、(a-40)、(a-41)、(a-42)、(a-43)或(a-44); 經濟部智慧財產局員工消費合作社印製 e)各R5與R6分別獨立選自氫;鹵基;羥基;胺基;硝 基;三i (:丨_6烷基;三鹵Cw烷氧基;C丨-6烷基;C丨-6 10 烷氧基;Ci_6烷氧基Cw烷氧基;CN6烷羰基;Cw烷 磺醯基;氰基C!.6烷基;羥基Ck烷基;羥基Ci.6烷 氧基;羥基CN6烷胺基;胺基Cu烷氧基;二(Cu烷 基)fe氣基,一'(經基Ci.6烧基)胺基;二(C!_6烧基)胺基 Q-6烷氧基;二(Cu6烷基)胺基Cm烷胺基;芳基磺醯 15 基;芳基磺醯基胺基;芳氧基;芳基C2_6烯二基;二 (Ck烷基)胺基;氰基;硫苯基;經下列基團取代之硫 苯基:二(Cm烷基)胺基Cw烷基(Cw烷基)胺基Cw烷 基、二(CK6烷基)胺基CN6烷基、Cm烷基六氫吡畊基 Cl·6烧基或·一(¾基Ci_6烧基)胺基Ci_6烧基;咬鳴基; 20 咪唑基;Cm烷基三唑基;四唑基;六氫吡啶基c!_6烷 氧基;嗎福咁基;Cw烷基嗎福咁基;嗎福咁基cK6烷 ί ·· 氧基;嗎福啉基Cw烷基;Cb6烷基六氫吡畊基Cm烷 氧基;烷基六氫吡畊基Ci_6烷基;Ci.6烷基六氫吡 畊基磺醯基;胺基磺醯基六氫吡畊基Cl_6烷氧基;胺 -24- 9¾本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(23) 經濟部智慧財產局員工消費合作社印製 基磺醯基六氫批σ井基;胺基磺醯基六氫吡畊基Cu烷 基;二(Cu炫基)胺基項酿基六虱吼11 井基,二(Cl-6烧基) 胺基磺醯基六氫吡畊基Ci_6烷基;羥基Cw烷基六氫 吡畊基;羥基Cw烷基六氫吡4基C!.6烷基;C!_6烷氧 5 基六氫吡啶基;Cw烷氧基六氫吡啶基CV6烷基;羥基 Cm烷氧基Cm烷基六氫吡讲基;經基CU6烷氧基C〗-6 烷基六氫吡4基Cw烷基;(羥基Cw烷基xq.6烷基) 胺基;(羥基cN6烷基xcm烷基)胺基c〗.6烷基;吡咯 啶基C!.6烷氧基;吡唑基;硫吡。坐基;經選自Cw烷 ίο 基或三i Cw烷基中兩個取代基取代之吡唑基;吡啶 基;經Cm烷氧基或芳基取代之吡啶基;嘧啶基;喳 啉基;苯基;經分別獨立選自下列1、2或3個取代基 取代之苯基:A基、胺基、Ci.6烧基、Ci_6烧氧基、輕 基Cm烷基、三氟曱基、三氟甲氧基、羥基Cm烷氧 15 基、Ci-4烧氧基Ci.4烧氧基、胺基Ci-4烧氧基、二(Cl-4 烷基)胺基Cm烷氧基、二(Cm烷基)胺基、六氫吡啶基 Cw烷氧基、吡咯啶基C!_4烷氧基、胺基磺醯基六氫吡 畊基、胺基磺醯基六氫吡畊基(^_4烷基、二(Cm烷基) 胺基磺醯基六氫吡畊基 '二(CN4烷基)胺基磺醯基六氫 20 α比σ井基Cm烧基、經基‘C^-4烧基六氫吼11井基、經基Ci-4 炫基六氫D比°井基Cm烧基、Cm烧氧基六氫吼咬基、 *· ··
Cw烷氧基六氫吡啶基Cm烷基、羥基CN4烷氧基Cm 烷基六氫吡啩基、羥基C〗-4烷氧基Q.4烷基六氫吡〇井 基Cm烷基、(羥基Cm烷基)(c,_4烷基)胺基、(羥基 -25- 本紙張尺度適用中國國家標準(CNS)A4規袼(210 X 297公釐) 200400941 A7 B7 五 發明說明 24 經濟部智慧財產局員工消費合作社印製 C!-4烧基XCm烧基)胺基C!·4烧基、Π比d各唆基q.4燒氧 基、嗎福咁基Cm烷氧基、嗎福啉基C,-4烷基、Cw燒 基六虱π比σ井基Cu烧氧基、Cm烧基六氩吼σ井基烧 基、羥基Cm烷胺基、二(經基Cw烷基)胺基、二(Ci_4 燒基)胺基Cm烧胺基、胺基嗔二嗤基、胺基項酿基六 氫吡畊基Cm烷氧基、或硫苯基CV4烷胺基。 有一類較佳化合物係由彼等式(I)中如下說明之化合 物組成: R7與R8分別獨立選自:氫、羥基、羥基Cl_6烷基、胺基 Ci-6烧基或胺芳基; R2為氫、鹵基、羥基、胺基、硝基、c!-6烷基、cK6烷氧 基、三氟甲基、羥胺基或萘磺醯基吡畊基; R4為氫、羥基、胺基、羥基Cm烷基、Cw烷氧基、芳基 C!-6烷基、胺羰基、羥羰基、胺基Cm烷基、胺羰基 Cw烷基、羥羰基Cw烷基、羥胺羰基、c!.6烷氧基羰 基' Ci-6烧胺基C!_6烧基或二(Ci_6烧基)胺基Ci.6烧 基; —為選自下列之基團:(a-1)、(a-2)、(a-3)、(a-4)、 (a-5) 、 (a-6) 、 (a-7) 、 (a-8) 、 (a-9) 、 (a-10) 、 (a-11) 、 (a-20 12)、(a-13)、(a-14)、(a-15)、(a-16)、(a-17)、(a-18)、(a- 19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-24)、(a-25)、(a-26)、(a-27)、(d-.28)、(a-29)、(a-30)、(a-31)、(a-32)、(a-33)、(a-34)、(a-35)、(a-36)、(a-37)、(a-38)、(a-39)、(a-40)、(a-41)、(a-42)、(a-43)或(a-44);及 5 10 15 -26- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 計 線 200400941 A7 B7 五、發明說明(25 ) 經濟部智慧財產局員工消費合作社印製 各R5與R6分別獨立選自氫;鹵基;經基;胺基;瑞基; 三鹵C〗_6烧基;二齒Ci_6院氧基;Cu院基;Ci_6烧氧 基;c,_6烷氧基CN6烷氧基;Cw烷羰基;Cw烷磺醯 基;亂基Ci_6院基,每基Ci_6貌基;輕基Ci_6烧氧 5 基;經基Ci_6烧胺基;胺基Ci_6院氧基;二(Ci_6院基) 胺戴基;二(輕基C!-6燒基)胺基;二(Ck烧基)胺基C!-6 烷氧基;二(Cw烷基)胺基烷胺基;芳基磺醯基; 芳基石黃醯基胺基;芳氧基;芳基C2-6烯二基;二(Ci-6 烷基)胺基;氰基;硫苯基;經下列基團取代之硫苯 10 基:二(Ci_6烧基)胺基Ci-6燒基(Ci_6競*基)胺基Ci_6競* 基、二(Cl-6烧基)胺基院基、Ci_6烧基六氣吼11井基 Ci_6烧基或二(經基Cu競*基)胺基Ck烧基;吱喘基; 咪唑基;Cu烷基三唑基;四唑基;吡咯啶基;六氫 。比淀基Ck烧氧基,嗎福咐基,Cu烧基嗎福咐基, 15 嗎福咐基Ci_6跪氧基;嗎福σ林基Ci-6烧基;Ci_6院基六 氮σ比σ井基C!_6院氧基;Ci_6院基六氮。比。井基Ci-6炫基; C 烧基六氮吼σ井基續酿基,胺基項酿基六氮吼ϋ井基 C 1 -6烧氧基,胺基項龜基六氣吼σ井基;胺基確龜基六 氮π比u井基Cu烧基,二(Ci_6烧基)胺基續龜基六氮0比。井 20 基;二(Ci_6烧基)胺基橫酿基六氫吼σ井基Cu烧基;經 基c!_6烷基六氫吡畊基;羥基Cw烷基六氫吡畊基Ci_6 院基;Ci_6烧氧基六氫σ比11 定基;Ci„6競*氧基六氫°比淀基 Ci-6燒基;备基Ci_6烧氧基Ci_6院基六氫井基;經基 Ci_6烧氧基Ci-6院基六氫井基Ci_6烧基;(輕基Ci-6 -27- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Λ7 B7 五、發明說明(26 5
ο 1A
5 1A 經濟部智慧財產局員工消費合作社印製 20 烧基XL减)絲;(織Cl.6妓XCi 6絲)胺基 Q-6烷基;吡咯啶基Cw烷氧基;吡唑基;硫吡唑 基’經選自。烧基或二_ (3“;^基巾兩個取代基取 代之㈣基;㈣基;經h絲基或祕取代之批 咬基,01咬基,4咐基,笨基;經分別獨立選自下列 1、2或3個取代基取代之苯基:錄、胺基、Ci_a 基、Cm烧氧基、經基Cl-4烧基、三氣甲基、三說甲 氧基、經* h絲基、Cl.4^& c"絲基、胺基 Cw烷氧基、二(Cw烷基)胺基Cm烷氧基、二(Ci 4烷 基)胺基 '六氫吡啶基CM烷氧基、吡咯啶基CN4烷氧 基、胺基磺醯基六氫批畊基、胺基磺醯基六氫咐啡基 C!·4烷基、二(cM烷基)胺基磺醯基六氫吡畊基、二(Cm烷 基)胺基磺醯基六氫吡畊基cM烷基、羥基Ci 4烷基六 氫吡啡基、羥基Cm烷基六氫吡畊基烷基、烷 氧基六氫吡啶基、Cm烧氧基六氫吡啶基Ci 4烧基、 羥基Cm烷氧基C!·4烷基六氫吡畊基、羥基Ci 4烷氧 基c〗_4烧基六氫吡畊基Cl 4烷基 '⑽基Ci 4烷基4 烷基)胺基、(羥基Cl_4烷基)(Cm烷基)胺基Ci 4烷基、 吡咯啶基Cm烷氧基、嗎福咁基Ci_4烷氧基、嗎福啉 基Cm炫基、Cw烷基六氫吡畊基Cl_4烷氧基、CN4烷 基六氮吡畊基Cw烷基、羥基Cl 4烷胺基、二(羥基 * · Cm貌基)胺基、二(Cm烷基)胺基Cw烷胺基、胺基噻 二唑基、胺基磺醯基六氫吡畊基CN4烷氧基、或硫苯 基Cw烷胺基。 -28- 9㈣本纸張尺度適用争國國家標準(CNS)A4规格(210 X 297公釐)
200400941 A7 B7
另一類較佳化合物係由彼等式(I)中如下說明之化合 物組成: 其中t為〇 ;
Rl 為-C(0)NR7R8 、烷二基 SR9 、_ 5 NRlGC(0)N(0H)R9、-NRWCCCOCw 烷二基 SR9、- NR1QC(0)C=N(0H)R9或另一個Zn-螯合基,其中R7與 R8分別獨立選自:氫、羥基、羥基Q_6烷基或胺基Cw 烷基; R2為氫、鹵基、羥基、胺基、硝基' Cw烷基、Cy烷氧 10 基、三氟甲基或二(Cm烷基)胺基; -L-為一直接鍵結或選自下列之二價基團:c!_6烷二基、 胺基或羰基; R4為氫、羥基、胺基、羥基Cm烷基、C!.6烷基、Cm烷 氧基、芳基<^_6烷基、胺羰基、胺基Cm烷基、Cm烷 15 基胺基Cw烷基或二(Q.6烷基)胺基Cw烷基; 經濟部智慧財產局員工消費合作社印製 -〇 為選自下列之基團:(a-1)、(a-3)、(a-4)、(a-5)、 (a-6)、(a-7)、(a-8)、(a-9)、(a-10)、(a-ll)、(a-12)、(a-13)、(a-14)、(a-15)、(a-16)、(a-17)、(a-18)'(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-24)、(a-25)、(a-26)、(a-20 28)、(a-29)、(a-30)、(a-31)、(a-32)、(a-33)、(a-34)、(a- 35)、(a-36)、(a-37)、(a-38)、(a-39)、(a-40)、(a-41)、(a-42)、(a-44)、(a-45)、(a-46)、(a-47)、(a-48)或(a-51); 各s分別為0、1、2、3或4 ; R5為氫;鹵基;羥基;胺基;硝基;三鹵C〗-6烷基;三 -29- 本紙張尺度適用中國國家標準(CNS)A4規格(2〗〇 x 297公釐) 200400941 ΑΊ Β7 五、發明說明(28 ) 鹵Ci-6烧氧基;Ci-6烧基;Ci-6烧氧基;Ci-6烧幾基; Ci_6烧氧幾基;Ci_6烧石黃酿基;經基Cj_6烧基;芳氧 -.f 基;二(Ci-6炫•基)胺基;氰基;硫苯基;咬喃基;經經 基Cw烷基取代之呋喃基;笨並呋喃基;咪唑基;呤 5 唑基;經芳基與<^_6烷基取代之畤唑基;Cp6烷基三唑 基,四15圭基,吼格咬基,etb略基,嗎福β林基;C1 -6烧基 嗎福嘴基;六氫批σ井基;Cι_6淀基六氫峨π井基;經基 CK6烷基六氳吡畊基;(^_6烷氧基六氫吡啶基;吡唑 基;經選自C!_6烷基或三函Ci.6烷基中1或2個取代 10 基取代之吡唑基;吡啶基;經烷氧基、芳氧基或 芳基取代之吡啶基;嘧啶基;喳啉基;吲哚基;苯 基,或經分別獨立選自.画基、C!_6烧基、C! 烧氧基 或三氟甲基中之1或2個取代基取代之苯基; 經濟部智慧財產局員工消費合作社印製 且R6為氮;鹵基;輕基;胺基;石肖基;三鹵Cl-6烧基; 15 三1¾ Ci-6烧氧基;Ci-6烧基;Ci.6烧氧基;Ci_6烧幾 基;Ci_6烧氧戴基;Ci-6烧續醯基;經基Ci.6烧基;芳 氧基;二(C!_6烷基)胺基;氰基;吡啶基、苯基;或經 分別獨立選自:齒基、Ci_6烧基、Ci _6烧氧基或三氟曱 基中之1或2個取代基取代之苯基;或 20 /-(CH2)n —>J '7 — 中心之 \_/ 部份基團亦可與伸乙基橋連基形成 橋連(亦即形成雙環狀部份基團)。 另一類較佳化合物係由彼等式(I)中如下說明之化合 物組成: -30- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製 五 '發明說明(29 10 15 20 其中η為1或2;t為〇、1或2;各Z為氮;R10為氫; R2為氫、硝基、Cm烷氧基、三氟曱基、二(Cm烷基)胺 基、經胺基或萘場醯基吼η井基;-L-為一直接鍵結或選自 下列之二價基團:CV6烷二基、羰基或胺羰基;各R3代 表氳原子;R4為氳、羥基CN6烷基、胺羰基、羥胺羰基 或二(CV6烷基)胺基Cy烷基;為選自(&-1)、(&-7)、(8-9)、(&-10)、(压-12)、(3- 14)、(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-30)、(a-34)、(a-49)或(a-50)之基團;各s分別獨立為〇、i、2或 5 ;且各R5與R6分別獨立選自氫;鹵基;硝基;三鹵Cl_6 烷基;三鹵Cm烷氧基;Cw烷基;C〖_6烷氧基;C丨_6烷 磺醯基;(芳基XCm烷基)胺基;芳基磺醯基;芳氧基; 芳基C2-6烯二基;二(c!_6烷基)胺基;硫苯基;經下列基 團取代之硫苯基:二(Cm烷基)胺基Cm烷基(Cm烷基)胺 基Cm烷基、二(Cu烷基)胺基(^_6烷基、CN6烷基六氫 吼畊基C〗_6烷基、羥基Cm烷基六氫吡畊基Cm烷基、 羥基Ci_6烷氧基Cw烷基六氫吡畊基Cm烷基、二(Cw 烧基)胺基磺醯基六氫吡畊基Cm烷基、(^.6烷氧基六氫 11比啶基CV6烷基、嗎福啉基Cw烷基、羥基Cm烷基(Cw 烧基)胺基Cm烷基、或二(羥基CN6烷基)胺基Cm烷 基;呋喃基;畤唑基;吡咯基;吡唑基;吡啶基;經Cm 烧氧基取代之吡啶基;4唯基;吲哚基;苯基;經分別 獨立選自下列1、2或3個取代基取代之苯基:鹵基、胺 基、Cw烷基、Cw烷氧基、羥基Cw烷基、三氟甲基、 -31- t朗本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱) 裝 計 線 200400941 Α7 ____ B7 丨" 丨丨丨丨丨 五、發明說明(30 ) ' ~~~-- 三氟甲氧基、二(c】-4烧基)胺基Ci4烧氧基、二(c“烧基) «、二(Cl-4炫基)胺基C“道基 '二(c]道基)胺基Cm 絲(Cm烧基)胺基、二1燒基)胺基CM燒基&炫基) 胺基Cm絲、基禮基六,氫料基k烧基、經 5基C]-4烧氧基Cm炫基六氫。比喷基Ci 4燒基、二遴基cm 燒基)胺基C〗_4烧基、吡°各唆基Γ 、ΚΆ , 疋岙1丨-4烷基、吡咯啶基Cl_4 烧氧基、嗎福咐基h垸氧基、嗎福嘴基Cm餘、Cm 烷基六氫吡讲基Cm烷基;或 /(CH2)n 1〇中’^之 \——/部份基團亦可與亞甲基橋連基形 成橋連(亦即形成雙環狀部份基團p 另一類更佳化合物係由彼等式⑴中如下說明之化合 物組成: 其中η為1或2’t為〇或2;各z為氮;汉1為_ 15 C(〇)NH(OH) ; R2為氫;-L-為一直接鍵結;各r3代表氫 原子;R4為氫; 句為選 |(a-l)、(a-9)、(a-i9)、(a_2〇)、(a-21)、(a_ 經濟部智慧財產局員Κ消費合作'社印製 22)、(a-23)、(a-49)或(a-50)之基圏;各s分別獨立為〇、 1、2或5 ;且各R5與R6分別獨立選自氫;鹵基;三鹵cU6 20烷基;三i Cm烷氧基;Cm烷基;Cl_6烷氧基;芳基 C2-6烯二基;二(Cm烷基)胺基;硫苯基;經下列基團取 代之硫苯基:二(Cw烷基)胺基Cw烷基(C】_6烷基)胺基 C!-6燒基、二(C!-6烧基)胺基C〗.6燒基、Ci-6烧*基六氫π比°井 基規基、經基Ci-6烧基六氫吼°井基Ci-6烧基、經基 -32-
中國國家標準(CNS)A4規格(210 x297公釐)
經濟部智慧財產局員工消費合作社印製 200400941 五、發明說明
Cl_6烷氧基Cl-6’元土六氫咄。井基C丨_6烷基、Ci_6烷氧基六 氫吼咬基Cl'6絲、嗎則基Cw絲、轉Ci 6燒基 (Cu烧纂)胺基,:6燒基、或二(經基Cw烧基)胺基Ci_6 烷基;峡喊基’ °亏唾基;吼唾基;錢基;經k貌氧 5基取代之毗啶基,喳唯基;吲哚基;笨基;經分別獨立 選自下列1、2或3個取代基取代之苯基:齒基、胺基、 Ci_6烧基、C1 6…氧基輕基C!_4垸基、三氟甲基、三氟 甲氧基、>(C1-4烧基)胺& Cw烧氧基' :(C1·4烧基)胺 基、二((:1,基)胺基C]·4院基、二(〇1禮基)胺基c㈤基 ίο (Ci·4烧基)胺基η院基故基cM炫基六氫吼ρ井基q 4 烷基、羥棊Cl-4烷氧基C!-4烷基六氫吡畊基Ci.4烷基、 二(經基Cl-4炫基)胺基烧基' t各咬基Cl_4烧基、吼 咯啶基Cm炼氧基、嗎福啉基Cm烷氧基、嗎福咁基ci 4 烷基、Cm烷基六氫吡畊基c,·4烷基;或 4 15 厂($2上 中心之一--/ 部份基團亦可與亞曱基橋連基形成 橋連(亦即衫成雙環狀部份基團)。 另〆類更佳化合物係由彼等式(I)中如下說明之化合 物組成: 20其中η為1;1為0;各Z為氮;R1;R2 為氫;-L-為一直接鍵結;各R3代表氫原子;r4為氫; 為選自(a-Ι)或(a-20)之基團;各s分別獨立為〇 或1 ;且各R與R6分別獨立選自氫;硫苯基;經下列基 團取代之硫苯基:二(C!_6烷基)胺基cN6烷基或(:!_6烷基 -33- QQ1 本紙張尺度適用1f7國國家標準(CNS)A4規格(210 X 297公髮)
200400941 A7 B7 五、發明說明(32 ) 六氫吡畊基C〗_6烷基;呋喃基;苯基;經一個分別獨立 選自下列之取代基取代之苯基:二(Cm烷基)胺基Cw烷 r 氧基、二(C1-4烧基)胺基、二(C1-4烧基)胺基Ci_4競•基、二 (Cw烷基)胺基C!_4烷基(Cw烷基)胺基C!_4烷基、吡咯啶 5 基 Ci-4 烧基、吡咯啶基c 1-4 烧氧基或 Ci_4 烷基六氫。比畊 基C 1.4烧基。 最佳化合物為 Νο·6、No.100、No.104、No.128、 Νο·144、Νο·124、Νο·154、No.125、Νο·157、No.156、 Νο.159 ' Νο.163、Νο.164、Νο·168、Νο.169、Νο.127、 10 Νο.171、Νο·170、Νο·172 與 Νο.173 化合物。 經濟部智慧財產局員工消費合作杜印製
-34- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 ΑΊ B7 五、發明說明(33) 經濟部智慧財產局員工消費合作社印製
-35- :::本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五 '發明說明(34
最佳化合物為No.6化合物 N、
HO^ Ο 10 化合物6 式(I)化合物及其醫藥上可接受之鹽與Ν-氧化物及立 體化學異構型可依一般方式製備。其一般合成途徑包括 例如: la)式(I)中R1為-C(0)NH(0H)之異羥肟酸(稱為式(I-a)化 15 合物)之製法可由式(II)中間物與適當酸,如,例如: 三氟乙酸反應。該反應係於適當溶劑中進行,如,例 如:曱醇。 經濟部智慧財產局員工消費合作社印製 20 〇 R4 R2 (Π)
(CH2)n f /—S— (C(R3)2)r-(A) O
CF.COOH HO、
O II
N H
.Q=X ΐ R4 -(CH2)n || Z-S— (C(R3)2)H^) (I-a) 'i -36- yy4 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(35) 1 b)式(II)中間物之製法可由式(III)中間物與式(IV)中間物 於適當試劑之存在下反應,如:Ν’-(乙基碳化亞胺醯 ·. * 基)-Ν,Ν-二甲基-1,3-丙二胺單鹽酸鹽(EDC)與1-羥基-1Η-苯並三°圭(ΗΟΒΤ)。該反應可於合適溶劑中進行, 5 如·· DCM與THF之混合物。
(II) lc)式(III)中間物之製法可由式(V)中間物與適當鹼(如: 15 NaOH),於合適溶劑之存在下反應,如:乙醇。
經濟部智慧財產局員工消費合作社印製
R2 (III) -37- 99S本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 Β7
2)式(I)中R為-C(0)NH(0H)之異羥肟酸(稱為式㈣化合 物)之製法亦可由式(VI)中間物與氫於觸媒(如,例如: Pd/C(10°/。))之存在下進行催化性氫化反應。該反應係於 適當溶劑中進行,如,例如:二曱基甲醯胺(dmf)或 THF。或者,此等化合物之製法亦可由式(VI)中間物與 環己一烯,於觸媒(如,例如:Pd/C(10%))之存在下進 行。該反應係於適當溶劑中進行,如,例如:丙醇。 10 α 0 ,〇-n々q=x Η -γ R4 r2 (VI)
-(CH2)n Y yZ~~S~(C(R3)2)t—<a)—-O HO-
O N /K-L-N R4
-(CH2)n V J7"—S~~(C(R3)2)t-(A) O 計 15 3)式⑴中R為如下式基團之化合物 ch3 Λ ΗNV、 〇 (I-a) 線 經濟部智慧財產局員工消費合作社印製 20 CH3^N.w、 〇 〇
〇
〇 ο 或 (稱為式(I-b)化合物)之製法可由式(νπ)中間物與式(VIII) 中間物,其中R’為 ch3Λ CH3t、k U ΙΌ k 或
HN
·38· 0Q(_,本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(37 ) ,於N’-(乙基後化亞胺醯基)-N,N-二甲基_i,3_丙二胺單鹽 酸鹽(EDC)與羥基苯並三唑(HOBT)之存在下反應。該反 應可於合適溶劑中進行,如,例如:二氣甲烧(DCM)與 THF之混合物。 10 15 R2 R4 0 (VH)
0 II
R1——C-OH -(cn2)n I! , ^ (Vm) Z—s—(C(R3)2)t—(a)-
s—(C(R3)2)t—(a) (I-b) 裝 計 經濟部智慧財產局員Η消費合作祛印製 20 式(1)化合物亦可使用固相合成技術製備。通常,固 相合成法涉及由中間物於合成法中與聚合物擔體反應。 此由聚合物承載之中間物可再進行許多合成步驟。每一 步驟之後’過濾樹脂,以多種不同溶劑洗滌數次,以排 除雜質。每一步驟之樹脂可以分開與下一個步驟中之不 同中間物反應,以合成大量化合物。製程中最後一個步 驟之後’以試劑處理樹脂或加工裂解樹脂上之樣本。固 相化學中所使用技術之更詳細說明示於例如:"The Combinatorial Index"(B.Bunin, Academic Press)及 Novabiochem's 1999 Catalogue & Peptide Synthesis Handbook(瑞士 Novabiochem AG),其内容已以引用之方 -39- 本軼張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 線 200400941 A7 五、發明說明(38 B7 10 15 20 消 式併入本文中。 式(I)化合物及—此士 B 立體二二, 之消旋化合物可經由知之解析法分離。式(1) 應之#對映異構性鹽;;適之對掌性酸反應而轉化成相 如:選擇性或分段心“映異構性鹽塑再經例 物。另—種分離式‘=分離,使用驗釋出對映異構 用對掌性固相進行液之對映異構型之方法涉及使 應時,該純立體化㈣:析。若該反料立體專一性反 應純立體化學異構型::=亦可射自適當起始物之相 好以立體專-性!^人右〶要專-性立體異構物時,最 純對映異構麵㈣。5 _化合物。料方法最好使用 構型、其醫藥上可接受之酸加成鹽及立體里 醫藥性質。 *白去乙_(HDAC)效果之有價值之 =胞其==機㈣(亦5二接觸4 化成癌症細胞生長停止、末端分化及/ ==樓输狀树獅種作法來本發明亦提供-種抑繼瘤生長之方法,其係對有 個 線 -40- 本紙張尺度適用中國國家標準(CNS)M規格(2版297公楚) 200400941 A7 B7 五、發明說明(39 ) 此需要之個體例如:哺乳動物(更特定言之人類)投與有效 量之本發明化合物。特定言之,本發明提供一種抑制腫 ..? 瘤生長之方法,其係投與有效量之本發明化合物。可受 抑制之腫瘤實例為(但不限於):肺癌(例如:腺癌瘤,包 5 括非小細胞肺癌)、胰癌(例如:胰癌瘤,如,例如:外分 泌胰癌瘤)、結腸癌(例如:結腸直腸癌瘤,如,例如:結 腸腺癌瘤與結腸腺瘤)、攝護腺癌包括前進式疾病、類淋 巴球之造血性腫瘤(例如:急性淋巴球性白血病、B-細 胞淋巴瘤、伯基特淋巴瘤(Burkitt's lymphoma))、骨藤性 10 白血病(例如:急性骨髓性白血病(AML))、甲狀腺濾泡 癌、脊髓發育不良症候群(MDS)、間質性腫瘤(例如:纖 維肉瘤與橫紋肌肉瘤)、黑色素瘤、惡性畸胎瘤、神經母 細胞瘤、神經膠質瘤、良性皮膚腫瘤(例如:角化棘皮 瘤)、乳癌瘤(例如:前進式乳癌)、腎癌瘤、卵巢癌瘤、 15 膀胱癌瘤、與上皮癌瘤。 根據本發明化合物可用於其他醫療目的,例如: a) 在治療癌症之腫瘤放射法之前、期間或之後投與根據本 發明化合物,使腫瘤對放射療法產生敏化作用; 經濟部智慧財產局員工消費合作社印製 b) 治療關節病變與骨病變病症,如:類風濕關節炎、骨關 20 節炎、幼年型關節炎、痛風、多關節炎、乾癬性關節 炎、僵直性脊柱炎與全身性紅斑狼瘡; c) 抑制平滑肌細胞增生,包括血管增生性病變、動脈粥樣 硬化及術後再狹窄; d) 治療炎症與皮膚病,如:潰瘍性結腸炎、克隆氏症、過 -41- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 B7 一11 — 五、發明說明(4〇 敏性鼻炎、移植物對抗宿主疾病、結膜炎、 ARDS、貝希特氏症(触咖disease)、移植排斥、專麻 療、過敏性皮膚炎、局部性脫髮、硬皮症、療病、濕 疹、皮肌炎、痤瘡、糖展病、全身性紅斑狼瘡、川崎氏 5症、多發性硬化、肺氣腫、囊性纖維變性與慢性支氣管 炎; e) 治療子宮内膜異位症、子宮纖_、功輯礙性子宮出 血及子宮内膜增生; f) /口療眼睛血&形成,包括影響_膜與脈賴▲營之血 10 管病變; g) 治療心功能障礙; 治療HIV感染; h) 抑制免疫壓抑性病症,如 i) 治療腎功能障礙; j) 壓抑内分泌病變; 15 k)抑制生糖作用異常之功能障礙; l) 治療神經病變’例如:巴金森氏症或造成認知異常之神 、-病變例如.阿兹海默氏症或與聚楚醯胺病變有關之 神經元疾病; 經濟部智慧財產局員工消費合作社印制衣 m) 抑制神經肌肉病變,例如:肌萎縮性側索硬化; 2〇 n)治療脊柱肌肉萎縮; 〇)治療其他可因加強基因表現^療之其他病變; Ρ)加強基因療法。 因此’本發明揭示以式(1)化合物作為錢之用途及 以式⑴化合物製造醫隸錢上述—種舒種病症 -42- 200400941 A7 B7 五、發明說明(41) 途。 式(I)化合物、其醫藥上可接受之酸加成鹽及立體異 構型基於其可用於生物檢體中,檢測或判別HDAC,而 具有有價值之診斷性質,其包括檢測或測定有標記之化 5 合物與HDAC之間所形成之錯合物。 該檢測或判別法可使用標記如:放射性同位素、酵 素、螢光物質、發光物質,等等之標記試劑之化合物。 放射性同位素實例包括1251、1311、3H與14C。酵素之檢測 法通常與適當受質共輛後,再催化可檢測之反應。其實 10 例包括例如:/3 -半乳糖菩酶、/9 -葡糖菩酶、驗性填酸 酶、過氧化酶與蘋果酸脫氫酶,以辣根過氧化酶較佳。 發光物質包括例如:魯米諾(luminol)及魯米諾衍生物、螢 光素、多管水母素(aequorin)與螢光素酶。 生物樣本之定義為體組織或體液。體液實例為腦脊 15 體液、▲液、血漿、血清、尿液、痰、唾液,等等。 就其實用之醫藥性質而言,本化合物可製成不同 投藥用之醫藥形式。 為了製備本發明之醫藥組合物,使用有效量之鹼 或酸加成鹽型特定化合物作為活性成分,與醫藥上可 20 接受之載劑均勻混合,該載劑可呈多種不同形式,端 賴所需投藥製劑型式而定。此等醫藥組合物最好呈適 合例如:經口、直腸、經皮膚投藥或非經腸式注射用 之單位劑型。例如:製備口服劑型組合物時,任何常 用之醫藥介質均可使用,如,例如:水、甘醇、油 -43- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐)
經濟部智慧財產局員工消費合作社印製 5 10 15 20 五、發明說明
類、醇類,耸;榮 懸浮:J 7用於製備口服用液體製劑,如: 糖類、高嶺土、潤滑劑t或固麵如:殿粉、 用?:政劑、丸劑、膠囊 了 由於錠劑與膠囊方便 服單位劑型,此時告'、目此代表取有利之口 組合物中之載劑通;:括:=醫藥載劑。非經腸式 但亦可包含並仙士八 滴水,至少佔絕大部份, 可製備注射液,/中載Hi助於溶解之成份。例如: 萄糖溶液或生理食鹽====液、葡 ♦等等。適合經皮膚投藥之組合物中,載劑 耑要包含渗透加強劑及人 w ^ 刎及7或合適濕化劑,可視需要鱼任 何性質之少量合適添 、 引起顯著之不w 不可對皮膚 起初之不良效應。此等添加物可 及/或可能有助於製備所♦細人此 又衆主皮膚 、线所物。此等组合物可依多 種方法技樂三例如·呈穿皮式貝占布、滴劑、或油膏。 上述面藥組合物特別有利於調配形 劑量Γ之單位劑型。本說明書與申請專二:; 用之早位劑型指物理性分離之單位劑量,各單位 經計算可產生所需醫療效果之預定量活性成分,^ 需之醫藥載劑組合。此等單位劑型實例為錠劑(包括有 畫線或有包衣之錠劑)、膠囊、丸劑、散劍包、扁囊 片、注射用溶液或懸浮液、茶匙劑、湯匙劑,等等,、 -44- 裝 計 線 本紙張尺度適用中國國家標準(CNS)A4規格 (210x297 公釐) 200400941 A7 B7 五、發明說明(43 ) 及其多重劑量組合。 熟諳相關技藝之人士很容易即可由下文出示之試 ..< 驗結果決定有效量。通常,醫療有效量為每公斤體重 0.005毫克至100毫克,特定言之每公斤體重0.005毫 5 克至1〇毫克。可以在一天内將所需劑量分成2、3、4 或更多個小劑量,在適當間隔時間下投藥。該小劑量 可調配C單位劑型,例如:每單位劑型包含0.5至500 毫克,特定言之10至500毫克活性成分。 本發明另一方面,提出一種含HDAC-抑制劑與另 1〇 一種抗癌劑之組合,尤其用為醫藥,更明確言之,用 於治療癌症或相關疾病。 治療上述病症時,本發明化合物宜用於與一種或 多種其他醫藥劑組合,更特定言之,與其他抗癌劑組 合。抗癌劑之實例為: 15 -鈾配位化合物,例如:順氯敍顧(cisplatin)、卡始 (carboplatin)或草酸翻(oxalyplatin) -紫杉烧化合物,例如:帕尼特西(paclitaxel)或哚希特西 (docetaxel); -拓樸異構酶I抑制劑,如:喜樹鹼化合物,例如:抑特 20 康(irinotecan)或托普特康(topotecan); -拓樸異構酶II抑制劑’如.抗腫瘤鬼臼毒素衍生物 ^ 如:抑托泊苷(etoposide)或登尼泊苷(teniposide); -抗腫瘤長春花植物鹼’例如:長春花鹼、長1此 &耷新鹼或哀 春瑞賓(vinorelbine) ; -45- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
經濟部智慧財產局員Η消費合作社印製 200400941 A7 __ B7 五、發明說明(44 ) -抗腫瘤核苷衍生物,例如:5-氟尿嘧啶、真希嗒本 (gemcitabine)或卡希。荅本(capecitabine); -烷化劑,如:氮芥或亞硝基脲,例如:環磷醯胺、苯丁 酸氮芬、卡莫司^(carmustin)或洛莫司丁(lomustin); 5 _抗腫瘤蒽環素衍生物,例如:道諾紅菌素 (da皿orubicin)、道索紅菌素(doxorubicin)、依道紅菌素 (idarubicin)或米托恩 S(mit〇Xantrone); -HER2抗體’例如:。荅兹美布(trastuzumab); -雌激素受體擷抗劑或選擇性雌激素受體調控劑,例如: 10 令莫希务(tamoxifen)、妥洛米芬(toremifene)、特洛希尺 (droloxifene)、法洛得斯(fasl〇dex)或拉洛希芬 (raloxifene); _芳構酶抑制劑’如:抑美斯坦(exemestane)、安斯特唉 (anastrozole)、樂特β坐(letrazole)與弗洛。坐(vorozole); 15 _分化劑,如:類視黃素、維生素D與視黃酸代謝阻斷气 (RAMBA) ’ 例如:異維曱酸(accutane); -DNA曱基轉化酶抑制劑’例如:阿扎跑芬 (azacytidine); -激酶抑制劑’例如:黃咕哚(f|av0perid〇i)、抑麻特本 2〇 (imatinib)甲石黃酸鹽或吉菲特本(gef|tinib); -法呢基轉化酶抑制劑;或 -其他HDAC抑制劑。
”鉑配位化合物”一詞在本文中指可抑制任何腫瘤細胙 生長之鉑配位化合物,其可提供離子形式之鉑。 L -46- ' …丨丨 .... - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐)
計
經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 200400941 A7
10 15 經濟部智慧財產局員工消費合作社印製 20 "紫杉烷化合物"一詞指具有紫杉烷環系且與某些紫杉 類(Taxus)樹木之萃出物相關或其所衍生之化合物。 ”拓樸異構酶抑糊,,—詞係射於真核生物細胞中改 變DNA拓樸結構之酵素。其對細胞重要功能及細胞增生 具有重要性。真核生物細胞中有兩類拓樸異構酶,亦即工 型與II型。拓樸異構酶j為一種分子量約1〇〇,〇〇〇之單體 酵素。該酵素會結合DNA,引進一個暫時性單股裂口, 打開雙螺旋(或使之解開),然後先使裂口封合後,再自 DNA股上解離。拓樸異構酶π之作用機制類似,其涉及 引進DNA股裂口或形成游離基。 "喜樹鹼化合物"係指與喜樹鹼母化合物有關或其所衍 生之化合物,其係衍生自中國樹種Campt〇thedn acuminata及印度樹種Nothapodytes foetida之不可溶於水 之植物驗。 "鬼臼毒素化合物”一詞指與自剝度比爾謨(mandrake) 植物萃出之鬼臼毒素母化合物有關或其所衍生之化合 物。 ’’抗腫瘤長春花植物鹼”一詞指與自長春花(Vinca r〇sea) 植物之萃出物有關或其所衍生之化合物。 "烷化劑”一詞包括一類共同特色為在生理條件下有能 力七供烧基給具有生物活性之大分子如:DNA之化學 劑。大多數之較重要製劑如:氮芬及亞硝基脲中之活性 烷化部份基團係於活體内複雜之降解反應(其中有些為酵 素反應)之後產生。烷化劑之最重要醫藥作用為特別在 -47- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐
200400941 A7 B7 五、發明說明(46 10 15 經濟部智慧財產局員工消費合作社印制衣 20 DNA合成與細胞分裂過程中干擾與細胞增生有關之基本 機制。烧化劑在快速增生組織中干擾DNA功能與整合性 之能力可作為其醫療用途及其多種毒性之基礎。 π抗腫瘤蒽環素衍生物"一詞包括得自波赛鏈黴菌 (Strep, peuticus var. caesius)之抗生素及其衍生物,其特徵 在於具有個四彡衣素壤結構’利用糖甘鍵連接一種罕見 糖.道諾糖胺(daunosamine) 〇 已知原發性乳癌瘤中人類上皮生長因子受體2蛋白 質(HER2)之擴增作用與某些患者之臨床預後結果不佳有 相關性。今茲美布(trastuzumab)為一種高度純化之重組 DNA-衍生之擬人化單株1§〇1_凡抗體,其與Her2受體 之細胞外功能部位具有高度專一結合性。 許多乳癌有雌激素受體,且此等腫瘤之生長可受到 雌激素刺激。”雌激素受體擷抗劑"及"選擇性雌激素受體 調控劑"係指與雌激素受體(ER)結合之雌二醇之競爭性抑 制劑。選擇性雌激素受體調控劑與ER結合時,會绣發受 體之二度空間形狀改變,抑制其與DNA上雌激素反鹿元 素(ERE)之結合。 ”心 ,停經後婦女之循環雌激素主要來源為腎上腺與卵巢 雄激素(雄烯二醇與睪固酮)經由周邊組織中芳構酶酵素轉 化成雌激素(雌__二醇)。經由抑制 活 Γ消耗雖激素之作法可有效且選擇性治療停S竿此 與激素相關之乳癌患者。 ’'一 '抗雖激素劑"—詞不僅包括雌激素受 體梅抗劑與選擇 -48- 2〇〇4〇〇941 A7
、發明說明 性雌激素受體調控劑,而且包括如上述芳構酶抑制劑。 ”分化劑"-詞包括可依不同方式抑制細胞增生及誘發 分化之化合物。已知維生素D與類視黃素在調節多種正 常及惡性細胞型態之生長與分化上扮演重要角色。視黃 酸代謝作用阻斷劑(RAMBA’s)藉由抑制細胞色素p45〇_= 媒介之視黃酸分解代謝作用而提高内因性視黃酸含量。 10 15 經濟部智慧財產局員工消費合作社印製 20 DNA之甲基化反應變化為人體贅生瘤最常見之異常 現象。特定基因之發動子中過度甲基化通常與所涉及之 基因失去活性有關。"DNA甲基轉化酶抑制劑,,一詞指透 過DNA曱基轉化酶之醫藥抑制作用發揮作用及使腫瘤抑 制基因表現再度活化之化合物。 "激酶抑制劑”一詞包括涉及細胞循環發展及計畫性細 胞死亡(細胞凋亡)之激酶之強力抑制劑。 ”法呢基轉化酶抑制劑"一詞指其設計用於防止Ras及 其他細胞内蛋白質之法呢基化反應之化合物。已知其可 影響惡性細胞增生與存活。 ”其他HDAC抑制劑"一詞包括(但不限於): -短鏈脂肪酸,例如:丁酸酯、4-苯基丁酸酯或2-丙基戊 酸; -異羥肟酸,例如:辛二醢基替笨胺異羥肟酸(SAHA)、雙 芳基異羥肟酸酯A-161906、雙環芳基-N-羥基羧醯胺、 焦醯胺(pyroxamide)、CG-1521 ' PDX-101、磺醯胺異羥 两酸、LAQ-824、三克定 A(trichostatin A)(TSA)、歐色 弗丁 (oxamfiatin)、史克。荅(scriptaid)、間幾基肉桂酸雙異 -49- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 Β7 五、發明說明(48 餐月亏酸或查布辛素(trap〇xin)_異經射酸類似物; -環狀四狀’例如:查布辛素、阿狄辛(apidicin)或狄希淑 (depsipeptide); -苯醯胺’例如:MS-275或CI-994,或 5 -狄普特辛(depudecin)。 治療癌症之根據本發明化合物可配合放射療法,你 上述投與患者。放射療法指離子線照射,特定言之指场 瑪射線,尤指由直線加速器發射者或由現在常用之放制 〇 ^種發射者。使用放射核種照射腫瘤之方法可外用或内 本發明亦有關抗癌劑與根據本發明HDAC 根據本發明之組合。 Μ之 本發明亦有關以根據本發明之组合於例如 瘤細胞生長之醫療法上之用途。 Ρ制壊 15 树明亦有_根據本料之衫於 生長上之用途。 艰層細跑 本發明亦有關-種於人體中抑制腫瘤细 法,其包括對該個體投與有效 長之方 經濟部智慧財產局員工消費合作社印製 20 本發明亦提供—種抑制異;=本發明之級合。 之方法,其係投與有效量 細胞)生長 其他醫_與舰c抑H㈣之組合。 單-組合物)或按任何次序投藥问時(例如.分開或呈 物將在同一時期投举, 其用量與1!1乍?中:兩種化合 利或增效之效用。咸了解 式應足以確保達成有 合中各成分之較佳投藥 -50- 200400941 A7 B7 五、發明說明(49 法/、投藥順序及個別劑量與療程將依所投與特定之其他 醫藥劑及HDAC抑制劑、其投藥途徑、所治療之特定腫 瘤及所治療之特定宿主而定。最佳投藥方法及順序及劑 里與療程很谷易由熟諳相關技藝之人士使用常用方法, 5 依據本文中所示之資料即可決定。 鉑配位化合物之合宜投藥劑量為每平方米體表面積 使用1至500毫克(mg/m2),例如:5〇至400 mg/m2,特 定言之,每個療程之順氣銨鉑(cisplatin)劑量為約75 mg/m2 ,卡鉑(carboplatin)劑量為約 300 mg/m2。 10 紫杉烧化合物之合宜投藥劑量為每平方米體表面積 使用5〇至400毫克(mg/m2),例如:75至250mg/m2,特 定言之’每個療程之帕尼特西(paclitaxel)劑量為約175至 250 mg/m2 ’及哚希特西(docetaxel)之劑量為約75至150 mg/m2 ° 15 喜樹鹼化合物之合宜投藥劑量為每平方米體表面積 使用0.1至400宅克(mg/m2) ’例如:1至300 mg/m2,特 定言之’每個療程之抑特康(irinotecan)劑量為約100至 350mg/m2,托普特康(t〇p〇tecan)劑量為約 1 至 2mg/m2。 抗腫瘤鬼臼毒素衍生物之合宜投藥劑量為每平方米 20 體表面積使用30至300毫克(mg/m2),例如:50至 250mg/m2 ’特定言之,每個療程之抑托泊苷(et0p0Side)劑 量為約35至100mg/m2,登尼泊苷(teniposide)劑量為約 50 至 250 mg/m2 〇 抗腫瘤長春花植物鹼之合宜投藥劑量為每平方米體 -51- (i本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) % 言. 經濟部智慧財產局員工消費合作、社印製 200400941 A7 B7 五、發明說明(5〇 10 15 經濟部智慧財產局員工消費合作、社印製 20 表面積使用2至30毫克(mg/m2),特定言之,每個 。 長春花鹼劑量為約3至12mg/m2 ’長春新臉齊丨量為約 2mg/m2 ’長春瑞賓(vinorelbine)劑量為約1〇至3〇mg/ 2至 抗腫瘤核苷衍生物之合宜投藥劑量為每平方米 ° 面積使用2〇〇至25〇〇毫克(mg/m2),例如:7 • /〇〇 至 1500mg/m2,特定言之,每個療程之5-FU劑量為2〇〇 500mg/m2,真希°荅本(gemcitabine)劑量為約8〇〇至 1200mg/m2 ’ 卡希 °荅本(capecitabine)劑量為約 1〇〇〇 至 2500mg/m2 〇 烧化劑,如:氮芥或亞硝基脲之合宜投藥劑量為每 平方米體表面積使用100至500毫克(mg/m2),例如:120 至200mg/m2,特定言之,每個療程之環磷醯胺劑量為約 100至500mg/m2,苯丁酸氮芥劑量為約〇.1至 0.2mg/m2 ’卡莫司汀(carmustin)劑量為約 15〇至 200mg/m2,洛莫司汀(lomustin)劑量為約100至 150mg/m2 ° 抗腫瘤蒽環素衍生物之合宜投藥劑量為每平^ 表面積使用10至75毫克(mg/m2),例如· 1 A紅·菌素 60mg/m2,特定言之,每個療程之道漆. (daunorubicin)劑量為約 40 至 75mg/m,道’ (doxorubicin)劑量為約 25 至 45mg/m2,依匕、 (idarubicin)劑量為約 10 至 15mg/m2。 錄 塔茲美布(trastuzumab)之合宜投藥劑量爲娘’ ’^,ι , 务個#私— 表面積使用1至5毫克(mg/m2),特定言之,亦 體表 -52- ΰ 11 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 200400941 A7 B7 五、發明說明 51 10 量為2至4mg/rn2。 抗雌激素劑之合宜投藥劑量為每天使用,1至100 毫克,依所使用之特定藥劑及所治療病症而定。嗒莫希 芬(tam〇xifen)之合宜口服劑量為—天服用兩次5至50毫 克,較佳為10至20毫克,持續治療一段足夠時間,以 達成及維持百療效果。妥洛米芬(加代爪丨免狀)之合宜口服 劑量為一天服用一次約6〇毫克,持續治療一段足夠時 間,以達成及維持醫療效果。安斯特唾(anastr〇z〇le)之合 宜口服劑量為—天服用一次約1毫克。特洛希芬 (droloxifene)之合宜口服劑量為一天服用一次約2〇_丨⑻毫 克。拉洛希芬(ral〇xifene)之合宜口服劑量為一天服用一次 約60耄克。抑美斯坦(exemestane)之合宜口服劑量為一 天服用一次約25毫克。 此等劑量可以每個療程投藥例如: 15次,可以每7、14、21或28天重覆一次 次、兩次或j 經濟部智慧財產局員工消費合作社印製 20 就其有用之醫藥性質而言,根據本發明之組合中 成分(亦即其他醫_與HDAC抑_)可調配成各賴 同投藥用醫藥型式。各成分可於分開之醫藥組合物中 開調配’或於單-醫藥組合物中同時含有兩種成分。因此本發明亦有關包含其他醫藥劑與HDAC抑♦ 及一種或多種醫藥用載劑之醫藥組合物。本發明亦有關呈醫藥組合物型式之_本發明之 合,其包含抗癌劑與根據本發明HDAC抑制劑及— 多種醫藥用載劑。
200400941 A7 B7 五、發明說明(52 ) 本發明亦有關以根據本發明之組合於製造抑制腫瘤 細胞生長之醫藥組合物上之用途。 本發明亦有關一種產品,其包含根據本發明HDAC 抑制劑作為第一種活性成分,及包含抗癌劑作為第二種 5 活性成分,形成組合製劑,供同時、分開或順序用於治 療癌症患者。 實驗部份 下列實例係供說明用。 Μ 下文中,”AMMC”指3-[2-(N,N-二乙基-N-曱胺基)乙 10 基]-7-甲氧基-4-曱基香豆素,”BFC_'指苯甲氧基-三氟甲基 香豆素"BINAP”指2,2’-雙(二苯基膦基)-1,Γ-聯萘,”Bocn 指第三丁氧羰基,"BuLi”指正丁基鋰,"BTEAC”指苯甲 基三乙基銨化氯,”BSA”指牛血清白蛋白,"DCM”指二氯 曱烷,"DIC”指二異丙基碳化二亞胺,”DIEA"指二異丙基 15 乙胺,”DIPE”指二異丙基醚,"DMAP”指二甲胺基吡啶, 經濟部智慧財產局員工消費合作社印制衣 ”DMF”指二曱基甲醯胺,”DMSCT指二甲亞礙,nEDCn指 Ν’-(乙基碳化亞胺醯基)-N,N-二曱基-1,3-丙二胺單鹽酸 鹽,”EDTA”指乙二胺四乙酸,”EtOAC”指乙酸乙酯, "Fmoc”指芴基曱氧羰基,”Hepes”指4-(2-羥乙基)-1-六氫 20 吡4-乙磺酸,”HOAC”指乙酸,nMeOH”指甲醇,"ΜΤΤΠ 指3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑鑌溴化 物,”NMP”指N-甲基吡咯啶酮,” PBSH指磷酸鹽緩衝生理 食鹽水,”PyBOP"指苯並三唑-1-基-氧-參-吡咯啶基-鱗六 氟磷酸鹽,"PyBrOP"指溴-參-吡咯啶基-鱗六氟磷酸鹽, -54- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 1 TEA”指三乙胺,"TFA”指三氟乙酸,”TISn指三異丙基矽 烷,’’THF”指四氫呋喃,”THp”指四氫'吼喃基,及 TMSOTf指二甲石夕烧基三氟甲磺酸g旨。Extrelut™為德國 Darmstadt市Merck KgaA藥廠之產品,係一種含矽藻土 5之短管柱。FlashtubeTM為Trikonex之產品,係一種填充 8.0克含螢光指示劑之矽石之聚乙稀管。 A.中間物之f法 實例A1 10 a)取含4-(六氫-111-1,4-二吖呼_ι_基)_苯甲酸乙醋鹽酸鹽(1:2) (0.01 mol)與 2-萘磺醯氯(〇.011 m〇l)之 DCM p,a.(150 ml) 混合物於室溫下攪拌。添加NaHC〇3(飽和水溶液,5〇 ml),反應混合物於室溫下攪拌4小時。分層。有機層 脫水,過濾及蒸發溶劑》殘質與2-丙醇研磨,過濾及 15 乾燥,產生4‘5§(全收量Μ-[六氳-4-(2-萘磺醯基)-1Η-1,4-二P丫呼-1-基]_苯甲酸乙g旨(中間物1)。 經濟部智慧財產局員工消費合作社印製 b) 取含中間物 i(〇.〇〇9i mol)之 35〇/〇 hc1(1〇 ml)與 1,4_二0号 烷(30 ml)之混合物攪拌及回流24小時,然後冷卻,過 濾所得沉澱,以二哼烷洗滌,乾燥。取一部份(〇9g)殘 20 質(3·9§,96%)自含有少量DMF之乙醇中再結晶,過濾 及乾燥,產生0.43g 4_[六氫_4_(2_萘磺醯基)_田_丨,4_二吖 呼-1-基]-苯甲酸(中間物2)。 c) 取含中間物2(0.0067 m〇l)、〇_(苯基甲基)_羥基胺鹽酸鹽 (2 當量,0.0134 mol)、4-甲基嗎福啡(4 當量,0.027 mol) -55- 200400941 A7 B7 五、發明說明(μ 與DMAP(0.5 g)之DCM p.a.(200 ml)混合物於室溫下攪 拌。添加DIC(2當量,〇·〇ΐ34 mol),反應,混合物於室 溫下攪拌2小時。蒸發溶劑。殘質與乙醇研磨,過濾及 乾燥。殘質經玻璃濾器上之矽膠純化(溶離液: 5 DCM/MeOH 99/1)。收集所需溶離份,蒸發溶劑。殘質 與DCM(30 ml)研磨,過濾及乾燥,產生l.9g(55%)4-[六氫_4-(2-萘石黃酿基二p丫呼-1-基)-N-(苯基甲氧 基)-苯醢胺(中間物3)。 10 實例A2 a) 取含4-(4-羧苯基)小六氫吡畊羧酸丨_(1,1_二曱基乙基)酿 (0.032 mol)、〇-(苯基甲基羥基胺鹽酸鹽(0·064 m〇l)、 DMAP (0.03 m〇l)之 DCM p.a.(250mi)與 TEA(14ml)混合 物於室溫下攪拌。添加DIC (0.064 mol)。反應混合物於 15 室溫下攪拌8小時,然後以水、HCi (0.5N)與水洗 務。分離之有機層脫水(MgS04),過濾及蒸發溶劑。殘 質經石夕膠管柱層析法純化(溶離液:DCM/Me〇H 98/2)。 收集所需溶離份,蒸發溶劑,產生13 7g 4_[4_[[(苯基甲 經濟部智慧財產局員工消費合作社印製 氧基)胺基]羰基]苯基]-1-六氫吡畊叛酸1,1-二曱基乙酯 20 (中間物4)。 b) 取含中間物 4(0.0137 mol)之 TFA(57ml)與 DCM(300ml) 混合物於室溫下攪拌2小時。蒸發溶劑。殘質溶於水 /DCM中,以NH4〇H鹼化。分離之水層經NaCl飽 和,以DCM萃取。合併之有機層脫水(MgS〇4),過濾 -56- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7
10 15 經濟部智慧財產局員工消費合作社印製 20 及蒸發溶劑。殘質懸浮於mpE巾。沉殿物過渡及乾 燥,產生1.6g (37·6%)Ν_(苯基甲氧基)_4_(1_六氫吡畊 基)-苯醯胺(中間物5)。 ^ C)取含中間物取011 mol)之 DCM(150ml)與 TEA(1.75ml) 混合物於室溫下授拌。取2_萘石黃醯氣(〇〇i3 m〇i)溶於 DCM (10ml)中,滴加至反應混合物中。反應混合物於 至溫下授拌3G分鐘’織以水⑽。分離之有機層脫 水(MgS〇4) ’過濾及蒸發溶劑。殘質懸浮於dipe中。 過濾沉殺物及乾燥,產生3如4_[4_(2_茶石黃酿基)冬六氮 峨》井基]-N-(笨基甲氧基)_苯醯胺(中間物6)。 實例A3 取含1-(2-萘磺醢基)_4_(4_硝基笨基)_六氫吡畊(7 5 mmol)之 THF (150ml)混合物於 50°C 下,使用 pd/C 10% (lg)為觸媒,於η塞吩溶液(〇 5mi)之存在下氫化。吸收氏(3 當里)後’濾'出觸媒’蒸發濾液。殘質自2_丙酵中結晶。 濾出所形成之沉殿,以2-丙醇洗務及乾燥(55°c,真空), 產生2.39g(87%)l-(4-胺基笨基)-4-(2-萘確醯基)_六氫π比σ井 (中間物7)。 實例A4 a)於室溫下分批添加NaH 60% (0.0217 mol)至N2氣流 下’含1-(2-萘項醯基)-六氫》比畊(O.oii m〇i)之THF(50ml) 溶液中。混合物於室溫下攪拌1小時,然後冷卻至〇 -57- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) Μ 200400941 A7 B7 五、發明說明(56 ) C。快速添加含2-(曱磺醯基)_5_嘧啶羧酸乙酯(〇.〇14 mol)之THF(30ml)溶液。混合物於室溫下授^丰2小時, 倒至水中’以EtOAC萃取。分離有機層,脫水 (MgS〇4) ’過;慮及蒸發溶劑。殘質溶於乙鍵中。滅出沉 5 澱及乾燥’產生3.92§ (84%) 2-[4-(2-萘磺醯基)小六氫吡 畊基]-5-嘧啶羧酸乙酯(中間物,溶點>26(rc。 b) 取含中間物8(0.0011 mol)與氫氧化鉀(4.7 mm〇l)之乙醇 (5ml)混合物授拌及回流24小時,然後冷卻,倒至冰水 中’以HC1 6N酸化。混合物部份蒸發,冷卻。渡出沉 10 殿,以水洗蘇,乾燥,產生〇.47g (1〇〇%)2-[4-(2-萘石黃醯 基)-1-六氫吡畊基]-5-嘧啶羧酸(中間物9),熔點> 260 。0。 c) 於室溫下添加 ΤΕΑ(0.0011 mol)、EDC(0.0011 mol)、1_ 羥基苯並三唑(l.lmmol)與0-(四氫·2Η-吡喃-2-基)-經基 15 胺(0.0011 mol)至N2氣流下,含中間物9(8 mol)之 DCM/THF (5〇/50)(20ml)溶液中。混合物攪拌24小時, 經濟部智慧財產局員工消費合作社印製 然後倒至冰水中,以EtOAC卒取。分離有機層,脫水 (MgS〇4),過濾及蒸發溶劑。殘質(〇.56g)經矽膠管柱層 析法純化(溶離液:DCM 100至DCM/MeOH 90/10; 20 5μηι)。收集純溶離份’蒸發溶劑。殘質(〇.4i7g)經石夕膠 管柱層析法純化(溶離液:DCM/MeOH/NH4〇H 92/8/U 15-40μηι)。收集純溶離份,蒸發溶劑,產生Q.293g (69%) 2-[4_(2_奈續酿基)-1-六氫。比B井基][(四氫_2幵-〇比 喃-2-基)氧]-5-嘧啶羧醢胺(中間物1〇),熔點198<^。 -58- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、、發明說明(57 ) 實例A5 a)中間物11之製法
中間物11 10 取含1-(2-萘基磺醯基)-六氫吡畊(1當量;37 mmol)、3- (溴甲基)-苯曱酸甲酯(0.00037mol)與嗎福咁基甲基聚苯 乙烯 2% DVB (0.2 g, Novabiochem 01-64-0171,200-400 篩目,承載量 3.2-3.8mmol/g )之 DMP,p.a.(5 ml)混合物 於l〇〇°C下攪拌一夜(20小時)。反應混合物過濾。樹脂經 15 DMF洗滌。於80°C及溫和之N2氣流下蒸發溶劑。殘質 經管柱層析法純化(溶離液:CH2Cl2/EtOAC 1/1)。收集產物 溶離份,產生〇.〇44g中間物11。 b)中間物12之製法
經濟部智慧財產局員工消費合作社印製
-59- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 —.- - B7 五、發明說明(58)
取含中間物 11(1 mm〇l)之 THF p.a.(3 ml)與 Na〇H 1N(lml)混合物於60°C下攪拌一夜。添加HC1 添加DCM (1〇叫’反應混合物經奴杜也严町(供應商: MERCK藥廠藥廠)過濾。濾液(有機層)蒸發,產生〇〇36g 5 中間物12。 c)中間物13製法
中間物13 經濟部智慧財產局員工消費合作社印製 取中間物 12(0.088 mmol)溶於 THF/DCM 50/50(6 ml) 中。依序添加EDC(1.1當量)、TEA(1.2當量)、1-羥基-15 ίΗ_苯並三唑(1.1當量)、及〇-(四氫_2H-吡喃-2-基)-羥基 胺(1.3當量)。反應混合物於室溫下攪拌一夜。添加水(2 ml) ’反應混合物攪拌15分鐘。添加DCM(10 ml),混合 物經Extrelm™ NT (供應商:MERCK藥廠)脫水。分離有 機層’於50°C及N2氣流下蒸發溶劑。殘質經FlashtubeTM 20 2008 (供應商Trikonex藥薇)(溶離液:Et〇A〇急驟管柱 層析法純化。收集產物溶離份(分段),然後以 DCM/MeOH(90/10)溶離。收集產物溶離份,於刈艺及凡 氣流下蒸發溶劑,產生0.025g中間物π。 -60- 本纸張尺度適用中國國家標準(CNS)A4規格(2ΐ〇χ297公釐) 200400941 A7 B7
五、發明說明 實例A6 a)中間物14之劁法
中間物15 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 中間物14 取含4-[[[4-(苯基甲基)-1-六氫吼畊基]幾基]胺基]_苯甲 酸乙醋(9.6 mmol)之乙醇(100 ml)混合物於室溫下使用 10 Pd/C 10% (1 g)為觸媒氫化。吸收h2(1當量)後,經矽藻 土濾、出觸媒,蒸發濾、液,產生3 g中間物14。 b)中間物15之製法 15 取含中間物 l4(9.6mmol)與 ΤΕΑ(0·01;2 mol)之 20 DCM(100 ml)混合物於室溫下攪拌。於室溫下分批添加2_ 蒸磺醢氣(9.6 mmol)。反應混合物於室溫下攪拌3〇分 鐘’然後以水洗滌,脫水(MgS〇4),過濾及蒸發溶劑。殘 質自DIPE/CE^CN中結晶,過渡及乾躁,產生 3.02g(67.4°/〇)中間物 15,熔點 182°C。 -61- 200400941
五、發明說明(6〇 C)中間物16之製法
5 〇 中間物16 取含中間物 15(2 mmol)之 NaOH 1Ν(30 ml)、THF(8〇 ml)與MeOH (20ml)混合物於室溫下擾拌2〇小時。混合物 經HC1 1N(30 ml)中和。混合物加水(100mi)稀釋,然後以 10 DCM萃取3次。分離有機層,脫水(MgS〇4),過濾及蒸 發溶劑’產生0.9g(95.7%)中間物16,熔點242。(:。 d)中間物17之Μ法
經濟部智慧財產局員工消費合作杈印製 中間物17 取含中間物16(0.23mmol)、0-(四氫-2Η-吡喃-2-基)_ 20 羥基胺(〇.25 mmol)、1-羥基-苯並三唑(0.00025 mol)與 ΤΕΑ(0·00030 mol)之 DCM,p.a.(10 ml)混合物於室溫下授 拌。添加EDC(0.00025 mol) ’反應混合物於室溫下授掉 一個週末。反應混合物經水洗滌,脫水(MgS〇4),過減及 蒸發溶劑,產生中間物17。 -62- ---— 本紙?& 紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐)
200400941 A7 B7 五、發明說明(61 ) 實例A7 a)中間物18之製法
中間物18
取含1-(2-萘磺醯基)-4-(4-硝基苯基)-六氫吼畊 10 (7.5mmol)之 THF(150ml)混合物於 50°C 下,使用 Pd/C 10% (lg)為觸媒,於噻吩溶液(0.5ml)之存在下氫化。吸收 H2(3當量)後,過濾觸媒,蒸發濾液。殘質自2-丙醇中結 晶。濾出所形成之沉澱,以2-丙醇洗滌,及乾燥(55°C,真 空),產生2.39g(87°/〇)中間物18。 15 b)中間物19之製法
經濟部智慧財產局員工消費合作社印製 20 中間物19 於室溫下添加〇_(四氮_21^-。比喃-2-基)-經基胺(8.5]11111〇1) 至含α-氧代-苯丙酸(7.8 mmol)之吡啶(12ml)與乙醇(23ml) 混合物中。混合物於室溫下攪拌1小時。蒸發溶劑至 乾。殘質(2.6g)經梦膠管柱層析法純化(溶離液: -63- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(62 DCM/MeOH/NH4OH 85/15/1 70/30/3; 15-40μπι)。收集純溶 離份,蒸發溶劑,產生1.7g(83%)中間物19。 c)中間物20之絮法
經濟部智慧財產局員工消費合作社印製 中間物20 10 於室溫與A氣流下,添加EDC(1.3 mol)至含中間物 18(l.lmmol)、中間物19(1.3 mmol)與1-羥基苯並三唑水 合物(I.3 mmol)之DCM/THF(8ml)混合物中。混合物於室 溫下攪拌一夜。添加10%K2C〇3。混合物經DCM萃取。 分離有機層,脫水(MgS〇4) ’過濾,蒸發溶劑至乾,殘質 15 (0.9幻經矽膠管柱層析法純化(溶離液:環己烷/Et〇Ac 65/35; 15-35μπι)。收集純溶離份,蒸發溶劑”篆質⑴ 52%)自CHsCN中結晶。濾出沉澱及乾燥,產生〇3以45%) 中間物20,熔點213。(:。 ° 20 實例A8 a)土間物21之贺法
中間物21 -64-
200400941 A7 B7 五、發明說明(63 ) 取含1-(2-萘磺醯基)-六氫吡畊(7.2mmol)、1-(4-氟苯 基)-乙酮(11 mmol)與Na2C03(llmmol)之二甲基乙醯胺 (5ml)混合物於140°C下攪拌24小時,添加1-(4-氟苯基)-乙酮(4 mmol)。混合物於140°C下攪拌48小時,然後冷 5 卻,倒至冰水中,以EtOAC萃取。有機層以水洗滌, 脫水(MgS04),過濾及蒸發溶劑。殘質(3.5g)經矽膠管柱 層析法純化(溶離液:環己烷/EtOAC 65/35; 15-35μιη)。收 集純溶離份,蒸發溶劑。殘質(0.95g,34%)自乙腈中結 晶。濾出沉澱,及乾燥,產生0.8g中間物21,熔點218 10 °C。 b)中間物22之製法
中間物22 經濟部智慧財產局員工消費合作社印製 於室溫下,添加含中間物21(2.2mmol)之三氯曱烷 (15ml)溶液至含 CuBr2(3.7 mmol)之 EtOAC(25ml)混合物 20 中。混合物於50°C下攪拌' 12小時,然後冷卻至室溫,倒 至水中,以EtOAC萃取。分離有機層,脫水(MgS04), * · 過濾,及蒸發溶劑,產生lg(96%)中間物22。 實例A9 -65- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐) 200400941 A7 B7 五、發明說明(64 ) a)中間物23之製法
中間物23 取含1-(2-萘石黃醯基)-六氫崎井(3.6 mmol)、4-氟-2-(三 氟甲基)-苯曱酸乙酯(7.2 mmol)與Na2C03(7.2 mmol)之二 10 甲基乙醯胺(l〇ml)混合物於140°C下攪拌20小時,然後 冷卻至室溫,倒至冰水中,以EtOAC萃取。有機層經水 洗滌,脫水(MgS04),過濾及蒸發溶劑。殘質(2.93g)經矽 膠管柱層析法純化(溶離液:環己烷/EtOAC 75/35; 15-40μιη)。收集純溶離份,蒸發溶劑。殘質(1.8g)自乙醚中 15 結晶。濾出沉澱及乾燥,產生1.265g中間物23(71%), 熔點122°C。 b)中間物24之製法
Ο 經濟部智慧財產局員工消費合作社印製 中間物24 取含中間物23(3.4 mmol)與KOH(0.017 mol)之乙醇 (15ml)混合物攪拌及回流24小時,倒至冰水中,以HC1 _66~ 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(65 ) 3N萃取。濾出沉澱,以水/乙醚洗滌及乾燥,產生 1.255g(80%)中間物 24,熔點 194°C。 c)中間物25之製法
於 12°C 下,依序添加 TEA(1.4mmol)、EDC(1.4 10 mmol)、1-經基苯並三吐水合物(1.4 mmol)與0-(四氫-2H_ 吡喃-2-基)-羥基胺(1.4 mmol)至N2氣流下,含(中間物24) (lmmol)之DCM/THF 50/50 (20ml)溶液中。混合物於室溫 下攪拌24小時,倒至冰水中,以DCM萃取。分離有機 層,脫水(MgS04),過濾及蒸發溶劑。殘質自DCM/乙醚 15 中結晶。濾出沉澱,及乾燥,產生0.48g(79%)中間物 25,熔點 192°C。 實例A10 經濟部智慧財產局員工消費合作社印製 a)中間物26之1法 20
中間物26 於室溫下分批添加NaH 60% (15 mmol)至含1-(2-寨石黃 -67- 本故張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 ——m—LJ ^ ^__ r> / 五、發明說明(66) 醯基)-六氫吡畊(7.5 mmo〇之τΗρ(35πιιμι合物中。混合 物於室溫與Ν2氣流下攪拌1小時30分鐘。滴加含4-氯-2-(甲磺醯基)-5-嘧啶羧酸乙酯(9 8 mm〇1)之THF(35ml)溶 液。混合物於室溫下攪拌3小時3〇分鐘,倒至冰水中, 5以EtOAC萃取。分離有機層,脫水(MgS04),過濾及蒸 發溶劑。殘質(4.6g)經矽膠管柱層析法純化(溶離液·♦環己 烷/EtOAC 80/20 至 20/80; 15-40μπι)。收集三個溶離份, 蒸發溶劑。其中一個溶離份即用於進行下一個反應,產 生 0.48g(14%)中間物 26 ,熔點 i23°c。 10 b)中間物27之匍法
n 中間物27 取含中間物26(0.8 mmol)與κ〇Η(4·2 mmol)之乙醇 (10ml)混合物擾拌及回流24小時,然後冷卻至室溫,倒 至冰水中,以HC1 6N酸化。濾出沉澱,以水/乙醚洗 經濟部智慧財產局員工消費合作社印製 滌’及乾燥’產生0.33g(93〇/o)中間物27,熔點244°C。 20 c)中間物28之贺法
中間物28 -68- Θ27本紙張尺度適用中國國家標準(CNS)A4規格(210x297 ^57 200400941 A7 B7 五、發明說明(67 ) 於室溫下依序添加TEA(0.8 mmol)、1-羥基苯並三唑 水合物(0.8 mmol)、EDC(0.8 mmol)及 0-(四氫-2H-吼喃-2-基)-羥基胺(0.8 mmol)至N2氣流下,含(中間物27) (0.6 mmol)之DCM/THF(l〇ml)溶液中。混合物於室溫下授拌 5 24小時,倒至冰水中,以DCM萃取。分離有機層,脫 水(MgS〇4) ’過濾及蒸發溶劑。殘質(〇.47g)經矽膠管柱層 析法純化(溶離液:DCM/MeOH/NH4OH ΡΒα/Ο.ΙΗ-^μιη) 。 收集纯溶離份 ,蒸發溶劑 ,產生 〇.i8g (53%) 中 間物28,熔點80°C。 10 實例All a)中間物29之t法
中間物29 經濟部智慧財產扃員工湞費合作社印製 取1-(苯基曱基)-六氩吼η井(〇.i25mol)溶於乙腈(200ml) 中。添加K2C〇3(0_34 mol)。滴加含2-(曱磺醯基)-5-嘧啶 20 羧酸乙酯(0.161 mol)之乙腈(200ml)溶液。混合物於室溫 下攪拌2小時,然後以DCM (1000ml)稀釋,以水洗蘇。 分離有機層,脫水(MgS04),過濾及蒸發溶劑。殘質經矽 膠管柱層析法純化(DCM/MeOH 98/2)。收集純溶離份, 蒸發溶劑。殘質於50°C下真空乾燥,產生33.6g(82.5%) -69- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(68 ) 中間物29。 b、中間物30之1法
中間物30 10 取含中間物29(0.〇3m〇l)之乙醇(250 ml)混合物於50 。〇下使用Pd/C 10% (2 g)為觸媒進行氫化。吸收H2(1當 量)後,經矽藻土過濾觸媒,濾液於旋轉蒸發器上蒸發。 殘質經碎膠管柱層析法純化(溶離液:DCM/(MeOH/NH3) 9〇/10)。收集產物溶離份,蒸發溶劑,產生6 8 g (>96〇/〇) 中間物30。 c)中間物31之絮法
15 中間物31 經濟部智慧財產局員工消費合作社印製 20 添加TEA(0.038 mol)至含中間物3〇(〇〇29腦如 dcm(15〇 ml)溶液中。添加2_萘磺醯氯(ο·咖丨),反力 現合物於室溫下㈣mx水洗祕合物。分离 ^層,以水洗務,脫水(MgS〇4),過濾、及蒸發溶劑。, 貝自CH3CN中結晶,過淚及真空乾燥,產生74g(>祕 中間物31,熔點>260。(:。 -70- 以·:ΐ本紙張尺度5^酬家標準(CNS)A4規格(210x297 &j^ 200400941 A7 B7 五 、發明說明(69) 匈土間物32之劁法
HO N .Λ 0、| 中間物32 取含中間物 31(0.017 mol)之 THF(25〇 _、NaC)H η 10 (25〇 ml)與MeOH(5〇 ml)之混合物於室溫下攪拌5小時。 添加HC1 IN (250 ml),混合物於室溫下攪拌幻分鐘。 濾出 >儿澱,乾燥(真空,60°c,一夜),產生6 〇g(89〇/。)中 間物32,熔點>26(TC。 物33之贺法 、0,'
15 中間物33 經濟部智慧財產局員工消費合作社印製 20 取中間物 32(0.015 mol)於 DCM/THF 50/50(650 ml): 授拌。添加 EDC(0.018mol)。添加 TEA(0.020mol)。依/ 添加1-羥基-1H-苯並三唾(0.018麵1)及0-(四氫-2H-吼脅 2-基)-羥基胺(p:〇18 m〇i)。反應混合物於室溫下攪拌6 Λ 時’然後以水洗.蘇2次,添加DCM。分離有機層,脫^ CMgS〇4) ’過濾及蒸發溶劑。殘質懸浮於煮沸之CH3C] 中,然後於室溫下攪拌一夜。濾出所得沉澱,以ch3c] -71- 本紙張尺度公爱Γ 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明( 70 洗滌,乾燥(真空;5〇°C),產生6.1g(82%)中間物33,溶 點 198°C。 實例A12 a)中間物34之製法
、〇 10 中間物34 於室溫下添加NaH(6.5mmol)至Ν2氣流下,含4-(1-六 氫吡畊基磺醯基)-嗎福啉(3.2mmol)之THF(15ml)溶液中。 混合物攪拌1小時,然後冷卻至0°C。添加含2-(甲磺醢 基)-5-嘴咬叛酸乙醋(4.2mmol)之THF(9ml)溶液。混合物 15 攪拌2小時,倒至冰水中。濾出沉澱,及乾燥。殘質 (0.665g)溶於乙醚中。濾出沉澱,及乾燥。濾液蒸發,與 沉澱合併,產生0.408g中間物34。 b)中間物35之製法 20
HO
/Ν、^Ν、 \\ 中間物35 取含中間物 34(lmmol)與 LiOH H20(3.1mmol)之 -72-
β 31本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(π ) THF(6ml)與水(6ml)混合物攪拌及回流24小時,然後冷 卻。蒸發溶劑。混合物經HC1 3N酸化。添加EtOAC。混 合物經寅式鹽過濾。有機層經EtOAC萃取。分離有機 層’脫水(MgS〇4),過渡及蒸發溶劑,產生〇j39g中間 5 物 35。 c)中間物36之制法
中間物36 經濟部智慧財產局員工消費合作社印製 於l〇°C下添加1-羥基苯並三唑水合物(0.5mmol)與 EDC (0.5 mmol)至N2氣流下,含中間物35(0.3 mmol)與 TEA(0.5 mmol)之THF/DCM (6ml)溶液中。混合物攪拌1 15 小時。添加0-(四氫-2H-11比喃-2-基)-經基胺(0.5mmol)。混 合物於室溫下攪拌一夜。添加冰與水。混合物經DCM 萃取。分離有機層,脫水(MgS04),過濾,蒸發溶劑。殘 質(〇.259g)經矽膠管柱層析法純化(溶離 液:CH2Cl2/iPrOH/NH4OH 98/2/0·2;10μηι)。收集純溶離 20 份,蒸發溶劑,產生〇.〇24g中間物36。 實例A13 a)中間物37之槊法 -73- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱)
-*·-} <: I 200400941 A7 ____ B7 五、發明說明(72 )
中間物37 5 取中間物30(114 mmol)於800 ml DCM中攪拌,添加 TEA (180 mm〇i),分批添加4-碘-笨磺醯氯(149 mmol)。 反應混合物於室溫下攪拌一夜。添加DCM(lOOOml)與水 (300 ml)。萃取有機層,分層及脫水(MgS04),過濾及蒸 發溶劑。(粗)產物懸浮於煮沸之乙腈中,使之回到室溫, 10 過濾。產物於50°C下真空乾燥,產生51.4g(89.5%)中間 物37。 b)中間物38之劁法
中間物38 經濟部智慧財產局員工消費合作社印製 添加含中間物37(0.1 mmol)與碳酸铯(0.15 mmol)之 DMF(2 ml)溶液至含(3-甲氧苯基)二羥硼酸(0.149mmol)之 20 DMF(lml)溶液中。反應混合物於N2蒙氣下振盪2分 鐘。添加乙酸鈀(II)(0.02mmol)及1,3-雙(二苯膦基)丙烷 (0.02mmol)〇反應混合物於80°C下振盡4小時,然後使 之回到室溫。於80 °C下真空蒸發溶劑。殘質溶於 DCM(20ml)與 MeOH(2ml)中,然後以 3 ml 10%Na2CO3 之 -74- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(73 ) 水溶液洗務。反應混合物經ExtreiutTMNT(供應商: MERCK藥廠)脫水,於5(TC與N2氣流下濃縮。產物經矽 膠管柱層析法純化。收集純溶離份,蒸發溶劑,於5 〇。〇 與N2氣流下乾燥,產生中間物38。 5 c)中間物39之贺法
1〇 中間物39 取中間物 38(0.0352 mmol)溶於 THF(4ml)與 MeOH(lml)中。添加NaOH(1.5mmol)。混合物於室溫下擾 拌一夜。添加含HCl(1.5ml)與10至20 ml THF之混合 物。反應混合物經Extrelut™ NT(供應商:MERCK藥廠) 15 脫水。蒸發溶劑(60°C,N2氣流)。添加甲苯。於70°C下真 空蒸發溶劑。再添加甲苯。於8(TC下真空蒸發溶劑,產 生 16mg (1〇〇〇/0)中間物 39。 d)中間物40夕法
中間物40 經濟部智慧財產局員工消費合作社印製 添加含1-經基苯並三吐(O.lmmol)、EDC(O.lmmol)與 -75- 本纸張尺度適用中國國家標準(CNS)A4規格(21〇χ297公釐) 200400941 A7 B7
五、發明說明(74 TEA(0.12mmol)之 DCM (3ml)與 THF(4ml)溶液至(中間物 39)(0.lmmol)中。反應混合物於室溫下攪拌5分鐘,添加 〇-(四氫-2H-a!i^-2-基)-輕基胺(O.lmmol)。反應混合物於 室溫下擾拌一夜。添加水(3 ml)與DCM (10 ml)。反應混 5 合物脫水。反應混合物於60°(:與N2蒙氣下濃縮。殘質溶 於DCM(5ml)中,與150 mg異氰酸甲酯聚苯乙烯2% DVB 200-400 篩目,承載量 1.4-1.8 mmol/g(供應商: NovabioChem 01-64-0169)溫和振靈4小時,以清除過量 0-(四氫-2H-W比喃-2-基)-經基胺。混合物過濾,樹脂經 10 DCM(2ml)洗蘇2次。混合物於40°C與N2氣流下濃縮, 然後經矽膠管柱層析法純化(溶離液 50 % EtOAC/DCM)。收集純溶離份’蒸發溶劑,產生中間物 40 ° 15 實例A14 中間物41之贺法
經濟部智慧財產局員工湞費合作社印製 20 中間物41 取含3,6-二氣-嗒畊(〇.〇〇34mol)與ι_(2·萘磺醯基)-六 -76- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 Β7 五、發明說明(75 ) 氳吡畊(0.0034 mol)之DMF(2ml)混合物於11〇。〇下攪拌4 小時,然後冷卻至室溫,倒至Et0AC/H20中。過濾混合 物。萃取濾液。有機層經水洗滌,脫水(MgS04),過遽 及蒸發溶劑。殘質(〇.85g)經矽膠管柱層析法純化(2〇_ 5 450111)(溶離液:3哀己烧/£1;〇八〇9〇/1〇)。收集純溶離份, 蒸發溶劑(0.56g,42%)。溶離份自乙醚中結晶。濾出沉殿 及乾燥’產生〇.178g (14%)中間物41,熔點213°C。 實例A15 10 a)中間物42之製法 Y〇Y^bo I 0 (SS) !5 中間物42 於〇 °C下’滴加含2-萘磺醯氯(0.0066 mol)之 0(31(151111)溶液至含2,5-重氮雙環[2.2.1]庚烷-2-羧酸1,1- 經濟部智慧財產局員Κ消費合作祆印製 二甲基乙酯,(13,48)(0.0051 111〇1)與丁£入(0.0098 111〇1)之 DCM(15ml)混合物中。混合物室溫下攪拌12小時,倒至 20冰水中,以DCM萃取。'有機層以1〇%碳酸鉀洗滌,脫 水(MgS〇4) ’ $濾及蒸發溶劑。殘質自乙醚中結晶。濾出 沉澱及乾燥,產生2.05g(850/。)中間物42 (S,S),熔點129 V。 b)中間物43之Μ法 -77- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱) 200400941 ΑΊ Β7 五、發明說明(76)
(s,s) 中間物43 5 取含中間物 42(S,S)(0.0049 mol)之 HC1 6N(20ml)與 THF(5ml)混合物於80°C下攪拌12小時,然後冷卻至室 溫,倒至冰水中’以NH:4〇H鹼化,以DCM萃取。分離 有機層’脫水(MgS04),過濾,蒸發溶劑。殘質(i.4g)自 乙中結晶。濾、出沉殿及乾燥,產生〇.5g(36%)中間物 10 43(S,S),熔點 159°C。 c)中間物44之製法
中間物44 緩濟部智慧財產局員Η消費合作社印製 於0°C下添加氫化鈉60% (0.0051 mol)至Ν2氣流下, 含中間物43(S,S)(0.0034 mol)之THF(20ml)混合物中。混 合物授拌1小時。滴加含2-(曱續醢基)-5-嘧唆缓酸乙酿 20 (0.0045 mol)之THF(lOml)溶液。混合物於室溫下攪拌2 小時,倒至冰水中。添加EtOAC。混合物過濾,以乙鍵 洗滌’乾燥’產生〇.4g中間物44(S,S),熔點212。(:。萃 取濾液。有機層以水洗滌,脫水(MgS〇4),過濾及蒸發溶 劑。殘質(1.7g)經矽膠管柱層析法純化(15-35μπι)(溶離液: -78-
200400941 A7 B7 五、發明說明(77 ) 環己烷/EtOAC60/40)。收集純溶離份,蒸發溶劑,產生 lg(66%)中間物 44(S,S)。 d)中間物45之鈉鹽之製法
HO
(S,s) 中間物45之鈉鹽 取含中間物44(S,S)(0.0021 m〇i)與氫氧化鈉(0.0042 10 mol)之EtOH(40ml)混合物攪拌及回流12小時,然後冷 卻。濾出沉澱’以乙醚洗滌及乾燥,產生〇.56g(620/。)中 間物 45.Na(S,S)。 e)中間物46之製法 15
6ΝΐΌ0 (s,s) 中間物46 經濟部智慧財產局員工消費合作社印製 於室溫下添加EDC(0.0017 mol)與DCM(20ml)至含中 2〇 間物45 (0.0013 mol)、〇-(四氫_2H-吡喃-2-基)-羥基胺 (0.0017m〇l)與 經基苯並三唑(0.0017 mol)之 THF(20ml) 混合物中。混奋物於室溫下攪拌12小時,倒至水中,以 DCM萃取。分離有機層,脫水(MgS04),過濾,蒸發溶 劑。殘質(0_8g)經矽膠管柱層析法純化(ΐ5-40μιη)(溶離液: -79- …本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ^ -30 200400941 A7 B7 五、發明說明(7〇 DCM/MeOH 90.5/0.5)。收集純溶離份,蒸發溶劑。殘質 (0.43g,66%)自乙醚/DIPE中結晶。濾出沉澱及乾燥,產 生 0.36g 中間物 46 (S,S),熔點 176°C。 5 實例A16 a)中間物47法 10
15 中間物47 取含中間物26(0.001 mol)、N-甲基-甲胺鹽酸鹽 (0.0015 mol)與碳酸鉀(0.003 mol)之乙腈(10ml)混合物於 8〇°C下攪拌24小時,然後冷卻,倒至冰水中,以DCM 萃取。分離有機層,脫水(MgS04),過濾,蒸發溶劑。殘 質(〇.45g)自DIPE中結晶。濾出沉澱及乾燥,產生 0.254g(53%)中間物 47,熔點 117°C。 b)中間物48 $ f法 經濟部智慧財產局員工消費合作社印製 20
HO
ΟΚΟ 中間物48 取含中間物47(0.0008 mol)與氫氧化鈉(0.0019 m〇l)之 EtOH (10ml)混合物攪拌及回流24小時,然後冷卻至室 -80- ^本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(79 溫’倒至冰水中’以HC1 3N酸化’以Et〇AC萃取。分 離有機層’脫水(MgS〇4) ’過渡’蒸發溶劑,產生 0.25g(670/。)中間物48。此產物直接用於下^個反應。 c)中間物49之製法
〇iNC〇 10 15 經濟部智慧財產局—工消費合作钍印製 20 中間物49 於室溫下添加1-羥基笨並三唑(〇 00〇7 mol)與 EDC(0.0007 mol)至含中間物 48(0.0005 mol)與 TEA(0.0007mol)之THF/DCM (6ml)溶液中。混合物授拌 30分鐘。添加0-(四氫-2H-吡喃-2-基)-羥基胺(0.0007 mol)。混合物於至溫下擾掉24小時,倒至冰水中。混合 物經EtOAC萃取。分離有機層,脫水(MgS〇4),過濾, 蒸發溶劑。殘質(0.48g)經矽膠管柱層析法純化(1〇μηα)(溶 離液:DCM/MeOH 98/2)。收集純溶離份,蒸發溶劑。殘 質(0.127g)自乙醚中結晶。濾出沉澱及乾燥,產生 0.12g(40%)中間物 49,溶點 life。 f 例 A17 a)^間物50之盤法 -81- Q'4(:i 氏張尺度適用中國國家標準(CNS)A4規格(21〇: ‘297公釐)
200400941 A7 B7
五、發明說明(SO Ύ
10 中間物50 於至溫下添加氫化納(0.0181mol)至N2氣流下含1-(2 萘磺醯基)-六氫吡畊(0.009 mol)之THF(15ml)溶液中 合物攪拌1小時,然後冷卻至〇°C。添加含5_氣_吡畊羧酸甲酯(0.0136 m〇l)之THF (5ml)溶液。混合物於9〇。(:下 攪拌一夜’然後冷卻’倒至冰水中。濾出沉澱,以水洗 務’然後以乙醚洗蘇,乾燥,產生3.3g (89%)中間物 50,熔點 216°C。 b)中間物SI之事』法 ho 15 HO、
NJ
經濟部智慧財產局員工消費合作社印製 20 中間物51取含中間物50(0.0079 mol)與氫氧化鉀(〇.〇39mmol)之 Me〇H (50ml)混合物攪拌及回流一夜,然後冷卻,倒至冰 水中,以HC13N酸化。濾出沉澱,以水洗滌,乾燥,產生 2.88g (92%)中間物 51,熔點 273°C。 間物52之贺法 -82- 一 ί
$ / y Z
200400941 A7 __B7 五、發明說明(si)
ο 中間物52 5 於室溫下添加EDC(0.0092 mol)與1-羥基苯並三唑 (0.0092 mol)至N2氣流下,含中間物51(0.007mol)與 TEA(0.0092 mol)之 THF/DCM (96ml)溶液中。混合物攪拌 1小時。添加〇·(四氫-2H-0比喃-2-基)-經基胺(0.0092 mol)。混合物於室溫下授拌2天,倒至冰水中,以DCM 10 萃取。分離有機層,脫水(MgS04),過濾’蒸發溶劑。殘 質(4.2g)經矽膠管柱層析法純化(15·40μπι)(溶離液: DCM/MeOH/NH4〇H 98/2/0.1)。收集兩份溶離份,蒸發溶 劑’產生2g F1與l.2g F2。取F1自乙醚中結晶。濾出沉 澱及乾燥,產生1.84g中間物52,熔點201。(:。取F2自 15乙醚/DCM/MeOH中結晶。濾出沉澱及乾燥,產生i.2g (24%)中間物52。共產生2.576g(77%)中間物52。 實例A18 經濟部智慧財產局員工消費合作社印製 a)中間物53之製法
中間物53 -83- 〇本紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公髮) 200400941 A7 B7 82 五、發明說明 於室溫下添加氫化鈉6〇%(〇 〇〇52 mol)至N2氣流 下’含1-(2-蓁磺醯基)-六氫吡畊(〇 〇〇26 之THF(lOml) 溶液中。混合物於室溫下攪拌丨小時,然後冷卻至〇〇c。 快速添加含4-氣-2-(曱項醯基)_ 5_嘧啶羧酸乙酯(〇 〇〇〇8 5 mol)i THF(5ml)溶液。混合物於〇。(:下授拌3小時,倒 至冰水中’以EtOAC萃取。分離有機層,脫水 (MgS〇4) ’過濾,蒸發溶劑。殘質(0.86g)經矽膠管柱層析 法純化(10μιη)(溶離液:環己烷/Et〇AC 80/2〇)。收集純溶 離份’蒸發溶劑。殘質(0.29g)溶於乙醚中。濾出沉澱, 10及乾燥,產生〇-264g(43%)中間物53,熔點124°C。 b)中間物54之掣法
中間物54 經濟部智慧財產局員Η消費合作社印製 取含中間物53 (0.0003 mol)與氫氧化鉀(0.0012 mol) 20之Et〇H (8ml)混合物攪拌及回流24小時,然後冷卻。蒸 發溶劑。殘質溶於冰水中,以HC1 3N酸化,以EtOAC 萃取。分離有掩層,脫水(MgS04),過濾,蒸發溶劑,產 生(0.14g)中間物54。此溶離份直接進行下一個反應。 分中間物55之贺法 -84- CU产紙張尺度適用中國國家標準(CNS)A4規袼(210 X 297公釐) :>_·· ; _· 200400941 A7 B7 五、發明說明(83 15 緩濟部智慧財產局員工消費合作、社印製
K〇NtCO
‘:丫N 中間物55 於室溫下添加1-羥基苯並三唑(0.0002 mol)與 10 EDC(0.0002 mol)至 N2 氣流下,含中間物 54(0.0002 mol) and TEA (0.0002 mol)之 THF/DCM(6ml)溶液中。混合物 於室溫下攪拌1小時。添加0-(四氫-2H-吡喃-2-基)-羥基 胺(0.0002 mol)。混合物於室溫下攪拌一夜,倒至冰水 中,以DCM萃取。分離有機層,脫水(MgS04),過濾, 蒸發溶劑。殘質(0.16g)經碎膠管柱層析法純化(i〇gm)(溶 離液:DCM 100然後DCM/MeOH 99/1)。收集純溶離 份,蒸發溶劑,產生0.023g中間物55。 實例A19 20 a)中間物56之f法
中間物56 I __ 軼張尺度適用中國國家標準(CNS)A4規格(21〇χ297公髮) 200400941 A7 B7 五、發明說明(84 ) 於〇°C下滴加含2-萘磺醯氯(〇·〇〇22 m〇i)之DCM(5ml) 溶液至含3-(胺基镍基)-1-六氫井缓酸1,1—二曱基乙酉旨 (0.0022 mol)與 TEA(0.0044 mol)之 DCM(5ml)混合物中。 混合物室溫下搜拌20小時,倒至冰水中,以DCM萃 取。分離有機層,脫水(MgS〇4),過濾及蒸發溶劑。殘質 (〇.9g)自DCM/甲醇/乙醚中結晶。濾出沉澱,及乾燥,產 生0.7g(76%)中間物56,熔點200°C。 b)中間物57之製法
10
5 TX 經濟部智慧財產局員X消費合作'社印製 20 中間物57 添加三氟乙酸(2ml)至含中間物56(0.0015mol)之DCM (20ml)溶液中,於室溫下攪拌7小時。混合物倒至冰水 中’以NHUOH鹼化,以DCM萃取。分離有機層,脫水 (MgSCU) ’過濾,蒸發溶劑,產生〇.44g(9〇〇/0)中間物 57,熔點 148°C。 c)中間物58之费法
中間物58 -86-
J 妇4[本轶張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 _ Β7 五、發明說明(85 ) 於l〇°C下添加2-(曱磺醯基)-5-喷啶羧酸乙酯(0.0164 mol)之乙腈(30ml)溶液至含中間物57(〇 〇164腦1)與碳酸 鉀(0.019 mol)之乙腈(3〇mi)溶液中。混合物於室溫下攪拌 4小時’倒至冰水中’以EtOAC萃取。分離有機層,脫 5 水(MgS〇4) ’過濾’蒸發溶劑。殘質(8 4g)經矽膠管柱層
析法純化(15-40μηι)(溶離液:DCM/MeOH/Na^OH 97/3/0.1)。收集兩份溶離份,蒸發溶劑,產生149g F1與 2.41 g F2。取F1自乙醚中結晶。濾出沉澱及乾燥,產生
1.42g(19%)中間物58,熔點171。(:。取F2自乙醚/MeOH 10 中結晶。濾出沉殿及乾燥’產生1.405g (18%)中間物 58。共產生2.8g(37%)中間物58。 d)中間物59之贺法
經濟部智慧財產局員工消費合作社印製 取含中間物58(0.0059 mol)與氫氧化鋰單水合物 (0.0095 mol)之THF(50ml)與水(5〇ml)混合物於室溫下攪拌 20 5小時’倒至冰水中,以HC1 3N酸化。濾出沉殿,過 濾’以水洗滌,於真空下使用乙醚乾燥,產生1.96g(760/Q;) 中間物59,熔點277°C。此溶離份直接用於下一個反 應。 e)中間物60之製法 -87- ;:::本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐) 200400941 A7 B7 五、發明說明(86 )
於10°C下添加EDC(0.0058 mol)與1-羥基苯並三唑 (0.0058 mol)至N2氣流下,含中間物59(0.0044 mol)與 TEA(0.0058 mol)之 THF/DCM(40ml)溶液中。混合物攪拌 1小時。添加0-(四氫-2H-吡喃-2-基)-羥基胺(0.0058 10 mol)。混合物由10°C擾拌至室溫一夜,倒至冰水中,以 DCM萃取。分離有機層,脫水(MgS〇4),過遽,蒸發溶 劑。殘質(2,95g)經矽膠管柱層析法純化(15-40μηι)(溶離液: DCM/MeOH/NH4OH 97/3/0.1)。收集純溶離份,蒸發溶 劑。殘質(1.6g)自乙醚中結晶。濾出沉澱及乾燥,產生 15 1.355g(57%)中間物 60,熔點 160°C。 實例A20 a)中間物61之製法
經濟部智慧財產局員工消費合作社印製 20 中間物61 取含中間物26 (0.0043 mol)與氩氧化鋰單水合物 -88- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(87 ) (0.013mol)之THF(60ml)與水(60ml)混合物於室溫下攪拌 24小時,倒至冰水中,以HC1 3N酸化,以EtOAC萃 取。分離有機層,脫水(MgS〇4),過濾,蒸發溶劑。殘質 (2.37g)自乙醚中結晶。濾出沉澱乾燥,產生1.76g (94%) 5 中間物61。 b)中間物62之製法
中間物62 於室溫下添加EDC(0.0007 mol)與1-羥基苯並三唑 (0.0007 mol)至含中間物 61(0.0005 mol)與 TEA(0.0007 mol) 15 之THF/DCM(6ml)溶液中。混合物授拌30分鐘,添加 〇-(四氫-2H-吡喃-2-基)-羥基胺(0.0007 mol)。混合物於 室溫下攪拌24小時,再添加〇-(四氫-2H-吡喃-2-基)-羥 基胺(0.0007 mol)。混合物授拌一夜,倒至冰水中,以 DCM萃取。分離有機層,脫水(MgS〇4),過濾,蒸發溶 20劑。殘質(0.47g)經矽膠管柱層析法純化(l〇pm)(溶離液: DCM 100然後DCM/MeOH 99/1)。收集純溶離份,蒸發 溶劑。殘質(0.2$g,82%)自乙醚中結晶。濾出沉澱,及乾 燥,產生0.215g (70%)中間物62,熔點122T:。 -89- f國國家標準(CNS)A4規格(210x:297公餐)
200400941 A7 B7 五、發明說明(88 ) 實例A21 a)中間物63之製法
V
〇 中間物63 取含中間物 41(0.0013 mol)、Pd(OAC)2(0.0006 mol)、 1,3-丙烧二基雙[二苯基]膦(0.0006 mol)與乙酸卸鹽(0.0026 10 mol)之MeOH (35ml)混合物於5巴CO壓力及i〇〇°c下攪 拌5小時’倒至冰水中。添加DCM。混合物經寅式鹽過 濾。分離有機層’脫水(MgS04),過濾,蒸發溶劑。殘質 (2.06g)經石夕勝管柱層析法純化(ΐ5-40μιη)(;溶離 液:DCM/MeOH/NH4〇H 97/3/0.1)。收集純溶離份,蒸發溶 15 劑,產生0.40g (74%)中間物63。 b)中間物64之贺法 經濟部智慧財產局員X消費合作枉印製 20
中間物64 取含中間物63(0.0014 mol)與氫氧化鉀(0.0059 mol)之 -90- 彳詞$;本紙張尺度適用中國國家標準(CNS)A4規格(210χ297公釐) 200400941 A7 B7 五、發明說明(89 )
MeOH(15ml)混合物於6〇°C下攪拌5小時,然後冷卻至室 溫,倒至冰水中,以HC1 3N酸化。遽出沉澱’以水/乙 醚洗滌,乾燥,產生0·47β (80%)中間物64,熔點238 °C。此產物直接用於下一個反應。 5 c)中間物65之製法
10 中間物65 於室溫下添加含EDC(0.0015 mol)與1-羥基苯並三唑 (0.0015 mol)之溶液至A氣流下,含中間物64(0.0012 mol)與 TEA(0.0015mol)之 THF/DCM (50/50)(16ml)中。混 合物攪拌30分鐘。添加〇-(四氫-;2H-吡喃-2-基)-羥基胺 15 (0.0015 mol)。混合物於室溫下攪拌24小時,倒至冰水 經濟部智慧財產局員工消費合作社印製 中,以DCM萃取。分離有機層,脫水(MgS04),過渡, 蒸發溶劑。殘質(lg)經矽膠管柱層析法純化(15-40μπι)(溶 離液:DCM/MeOH/NH4OH 98/2/0.1)。收集純溶離份,蒸發 溶劑。殘質(〇.36g)自乙醚中結晶。濾出沉殿及乾燥,產 2〇 生 0_275g (46%)中間物 65,熔點 211°C。 * ·· ΨΜ Α22 αΦ間物66之製法 -91- ❹^本袜張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(90 )
5 中間物66 於〇 °C下,滴加含2-萘磺醯氯(0.028 mol)之 DCM(40ml)溶液至N2氣流下,含4_(三苯基甲基)_2_六氫 吡畊羧酸乙酯(0.025 mol)與 TEA(0.038 mol)之 DCM(70 ml) 混合物中。混合物於室溫下授拌12小時,倒至冰水中, 10以DCM萃取。有機層以水洗滌,脫水(MgS〇4),過濾, 蒸發溶劑。殘質(15g)自乙腈中結晶。濾出沉澱,及乾 燥’產生6g中間物66 ’熔點145。(:。母液層蒸發,自 CHsCN/乙醚中結晶。濾出沉澱,及乾燥。產生:2.2g中間 物66。母液層蒸發,產生:4.5g中間物66。 15 b)中間物67之贺法
經濟部智慧財產局員工消費合作社印製 20 於〇°C下,分批添加中間物66(0.0102mol)至N2氣流 下,含 LiAlH4(0.0203 mol)之 THF (60ml)懸浮液中,然後 添加THF(200ml)。混合物於0°C攪拌至室溫2小時。依 序添加EtOAC與水。混合物經寅式鹽過濾。以MeOH 洗務寅式鹽。分離有機層’脫水(MgS04),過渡及蒸發溶 25 劑,產生5.3g(95%)中間物67。取部份此溶離份(〇,i5g)自 -92- Q51本紙張尺度適用中國國家標準(CNS)A4規格(210x297公;i ) 200400941 A7 _ 一 _ B7 五、發明說明(91) 乙醚/DIPE中結晶。濾出沉澱及乾燥,產生〇.049g中間 物67,熔點277°C。 c)中間物68之贺法
中間物68 取含中間物67(0.0091^01)之HC1 3N(3ml)與2-丙酮 (100ml)混合物於室溫下授掉3小時。蒸發溶劑3加水。 10混合物經乙醚萃取2次。分離有機層,脫水(MgS04),過 濾,蒸發溶劑’產生1.4g(50%)中間物68。取部份此溶 離份(0.2g)自DIPE中結晶。濾出沉澱及乾燥,產生 0.08g中間物68,熔點i3〇°c。 d)中間物69之塑法 15
敏濟部智慧財產局員工消費合作、社印制衣 中間物69 20 取含中間物68(0.0036mol)、2-(甲磺醯基)-5-嘧啶羧 酸乙酯(0.0047 mol)與碳酸鉀(〇.〇〇72mol)之乙腈(80ml)混 合物於室溫下掩拌一夜,倒至水中,以EtOAC萃取。分 離有機層,脫水(MgS04),過濾,蒸發溶劑。殘質(1.5g) 經矽膠管柱層析法純化(15-40μπι)(溶離液: 25 DCM/MeOH/NH4OH 97/3/0.1)。收集溶離份,蒸發溶劑。 -93- QSJ本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(92 ) 產生〇.91g中間物69。取部份此溶離份(0.59g)自 CH3CN/DIPE中結晶。濾出沉澱及乾燥,產生0.3g中間 物69,熔點151°C。 e)中間物70鈉鹽之製法
中間物70鈉鹽 10 取含中間物69(0.0011 mol)與氫氧化鈉(0.0022 mol)之
EtOH (30ml)混合物於80°C下攪拌12小時,然後冷卻至 室溫。濾出沉澱,以EtOH洗滌,然後以乙醚洗滌,乾 燥,產生〇.36g(72%)中間物70 .Na鹽,熔點>260°C。 f)中間物71之製法
經濟部智慧財產局員工消費合作社印製 2〇 於室溫下依序添加' 1-經基苯並三唾(0.001 mol)與 EDC(0.001 mol)至含中間物 70(0.0007 mol)與 0-(四氫-2H-吡喃-2-基)-羥基胺(o.ooi mol)之 DCM(20ml)與 THF(20ml)混合物中。混合物於室溫下攪拌12小時,倒 至水中,以DCM萃取。分離有機層,脫水(MgS〇4),過 25濾’蒸發溶劑。殘質(0.4g)自CH3CN/乙醚中結晶。濾出 -94- 本紙張尺度適用中國國家標準(CNS)A4規袼(210 X 297公髮) 200400941 A7 B7 五、發明說明(93 ) 沉澱及乾燥,產生0J7g(41%)中間物71,熔點194°C 實例A23 a)中間物72之製法
中間物72 10 取含2-六氫吡畊羧酸乙酯(0·0108 mol)、2-(甲磺醯 基)-5-嘧啶羧酸乙酯(0.012 mol)與碳酸鉀(0.0215mol)之乙 腈(20ml)混合物於80°C下攪拌24小時,然後冷卻至室 溫,倒至冰水中,以DCM萃取。分離有機層,脫水 (MgS04),過濾,蒸發溶劑,產生2.65g中間物72。此產 15 物直接用於下一個反應。 b)中間物73之製法
經濟部智慧財產局員工消費合作社印製 20 中間物73 於10 °C下,添加含2-萘磺醯氯(0.0095 mol)之 -95- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(94) DCM(30ml)溶液至含中間物 72(〇 〇〇86 mol)與 TEA(0.0172 mol)之DCM(30ml)溶液中。混合物於室溫下攪拌6小 時,倒至冰水中,以DCM萃取。分離有機層,脫水 (MgSOO,過濾’蒸發溶劑。殘質(6 04g)經矽膠管柱層析 5法純化(溶離液:環己烷/EtOAC 80/20 ; 15-40μηι),收集 純溶離份,蒸發溶劑。殘質(〇.69g,16%)自乙醚/DCM中結 晶。濾出沉澱及乾燥,產生〇.45g(10%)中間物73,溶點 148°C。 c)中間物74之製法 10
中間物74 15 取含中間物73(0.0011mol)與氫氧化鋰單水合物 經濟部智慧財產局員工消費合作社印製 (0.0〇44mol)之THF(5ml)與水(5ml)混合物於室溫下授拌27 小時’倒至冰水中,以HC1 3N酸化,以EtOAC萃取。 分離有機層’脫水(MgS〇4),過濾,蒸發溶劑。殘質 (〇.62g)自乙醚中結晶。濾出沉澱,乾燥,產生〇 26g 20 (54%)中間物 74,熔點 247。(:。 d)中間物75之製法
-96- 25 中間物75 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(95 ) 於室溫下依序添加EDC(0·0027 mm〇l)與1-羥基苯並 三唑(0.0027 mol)至N2氣流下,含中間物74(0.001 mol) 之 TEA(0.0027 mol)與 THF/DCM(16ml)溶液中。混合物於 室溫下攪拌48小時,倒至冰水中,以DCM萃取。分離 5 有機層,脫水(MgS〇4) ’過濾,蒸發溶劑。殘質(2.22g) 經矽膠管柱層析法純化(15-40μιη)(溶離液: DCM/MeOH/NH4OH 97/3/0.1)。收集純溶離份,蒸發溶 劑,產生〇.242g中間物75。 10 實例A24 a)中間物76之贺法
經濟部智慧財產局員工消費合作社印製 15 中間物76 於l〇°C下,添加含2-(甲磺醯基)-5-嘧啶羧酸乙酯 (0.0048 mol)之乙腈(20ml)溶液至N2氣流下,含N,N-二甲 基-2-六氫〇比°井甲胺(0.01 mol)與石炭酸钟(〇.〇2 mol)之乙騎 (20ml)溶液中。混合物於室溫下攪拌4小時,倒至冰水 20中,以DCM萃取。分離'有機層,脫水(MgS04),過濾, 蒸發溶劑。殘質(2.25g)經矽膠管柱層析法純化(15- > · 40μιη)(溶離液:DCM/MeOH/NH4OH 96/4/0.5)。收集純溶 離份’蒸發溶劑,產生1.34g (91%)中間物76。 b)中間物77之镅法 -97- ^本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(96 )
0 5 中間物77 於10°C下滴加含2-萘磺醯氯(0.0027 mol)之DCM(5ml) 溶液至N2氣流下’含中間物 76(0.0018 mol)與 TEA(0.0〇37mol)之DCM(lOml)溶液中。混合物於室溫下 攪拌5小時’倒至冰水中,以DCM萃取。分離有機 10層’脫水(MgS〇4),過濾,蒸發溶劑。殘質(i.22g)經石夕膠 管柱層析法純化(15-40μηι)(溶離液:DCM/MeOH/NH4OH 98/2/0.1)。收集純溶離份,蒸發溶劑。殘質(i.ig)自乙醚中 結晶。濾出沉澱及乾燥,產生〇.74g(84%)中間物77,炼 點 138〇C。 15 c)中間物78之鈉鹽之製法
20 中間物78之鈉鹽 取含中間物77(0.0014 mol)與氫氧化鈉(0 〇〇57 m〇l)之 EtOH(20ml)混合物授拌及回流6小時,然後冷卻至室 溫。濾出沉澱,以乙醚洗蘇’及乾燥,產生〇.56g (84%) 中間物78 .Na鹽。此產物直接用於下一個反應。 -98- 一本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) ~ ' ~
200400941 ΑΊ B7
97 d)中間物79之费法
中間物79 於室溫下添加EDC(0.0015 mol)與1-經基苯並三唾 (0.0015 mol)至N2氣流下,含中間物78(0.0012 mol)之 THF(5ml)與DCM(5ml)溶液中。混合物攪拌45分鐘。添 10 加〇-(四氫-2H-吡喃-2-基)-羥基胺(0.0015 mol)。混合物於 室溫下授拌一夜’倒至冰水中,以DCM萃取。分離有 機層’脫水(MgS04),過濾,蒸發溶劑。殘質(〇.62g)經矽 勝管柱層析法純化(15-40μιη)(溶離液:DCM/MeOH/NH4OH 94/6/0.1)。收集純溶離份’蒸發溶劑,產生〇.55g (77〇/〇) 15中間物79,熔點i〇〇°c。 免例A25 a)_中間物80之f冰
經濟部智慧財產局員工消費合作社印製 中間物80
取含中間物 30(0.066 mol)之 TEA(O.lmol)與 DCM -99- |;^§本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 B7 五、發明說明(98) ~ "" '"""" (500 ml)之混合物於室溫下攪拌,然後於室溫下滴加含4-破-苯磺酸氯(〇.〇79mol)之DCM (50 ml)溶液,反應混合物 於至溫下授拌2小時。混合物經水洗滌,脫水(MgS〇4)及 蒸發溶劑。殘質懸浮於CH3CN中,濾出所得沉澱,然後 5 以CH3CN洗滌,乾燥,產生27g (81.4 %)中間物80 ’熔 點 257°C。 b)中間物8〗夕^氺
中間物81 經濟部智慧財產局員工消費合作社印製 取含中間物80(0.0995 mol)懸浮於DMF(250 ml)中, 混合物於N2蒙氣下攪拌5分鐘。依序添加碳酸铯(0.0184 15 mol)及(2-曱醯基噻吩基)-二羥硼酸(0.0149 mol),反應 混合物於Ns蒙氣下攪拌5分鐘。最後,添加二氣雙三 苯基膦)-鈀(0.00199 mol),反應混合物於N2蒙氣與80-100 C下授拌及回流3.5小時。使混合物回升室溫,蒸發 溶劑(真空)。殘質懸浮於乙腈中,濾出所得沉澱,然後 20經矽膠管柱層析法純化(溶離液:DCM/MeOH由100/0至 98/2)。收集產物溶離份,蒸發溶劑,過濾殘質後,乾燥 (真空),產生4.250g(87.8%)中間物81。 c)土显_物82之贺法 -100- #纸張尺度適用中國國家標準(CNS)A4規格(210χ297公釐) 200400941 A7 B7 五、發明說明(99 )
取含N-曱基-曱胺(0.011 m〇1)與中間物81(〇 〇〇21 m〇i) 之EtOH (100ml)混合物於5(TC下使用pd/c 10°/。(lg)為觸 媒,於噻吩溶液(1 ml)之存在下進行氫化一夜。吸收 當量)後,反應混合物經矽藻土過濾,蒸發溶劑。殘質經 10矽膠管柱層析法純化(梯度溶離液:DCM/MeOH由100/0 至97/3)。收集產物溶離份,蒸發溶劑,產生〇.54g (51 〇/0) 中間物82。 d)中間物83之製法 15
經濟部智慧財產局員工消費合作社印製 20 中間物83 取含中間物82(0.001 m〇l)與氫氧化鈉(〇 〇1〇 m〇1)之 THF(10 ml)混合物於室溫下攪拌4天,然後添加HC1 1N(10 ml),反應混合物攪拌10分鐘。濾出所得沉澱, 於50°C下真空乾燥5小時’產生〇.47g (92 %)中間物 -101- 本紙張尺度適用中國國家標準(CNS)A4規格(210 χ 297公釐) 200400941 A7 B7 五、發明說明(100) 83 〇 e)中間物84之製法
中間物84 取中間物 83(0.0009639 mol)於 DCM(20 m])與 THF(20 ml)中攪拌,然後依序添加Ν’-(乙基碳化亞胺醯基>Ν,Ν_ 10 二甲基-1,3-丙二胺單鹽酸鹽(0.001253 mol)、1-羥基_1Η_ 苯並三唾(0.001253 mol)與0-(四氫-2Η-Π比喃-2-基)-羥基胺 (0.001253 mol) ’反應混合物於室溫下攪拌2天。加水, 分離有機層’脫水(MgS〇4),蒸發溶劑β殘質經梦膠管柱 層析法純化(梯度溶離液:DCM/MeOH由100/0至97/3)。 15 收集產物溶離份,蒸發溶劑’產生〇.5g(88.41%)中間物 84 ° 實例A26 經濟部智慧財產局員工消費合作社印製 a)中間物85之贺法
-102- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(1〇1) 取含中間物80(0.015 mol)之DMF(700 ml)混合物於 N2蒙氣下攪拌15分鐘,然後添加碳酸鉋(0.023 m〇l),混 合物於N2蒙氣下攪拌5分鐘。依序添加2_(4,4,5,5_四甲 基-1,3,2-二氧硼戊環_2_基)_苯酚(0.023 mol)與二氯雙(三苯 5基膦)-把(0.00〇3〇 mol),反應混合物於80°C與N2蒙氣下 攪拌4小時。混合物經矽藻土過濾,此矽藻土經DCM 與DMF洗滌。分離有機層,濃縮。添加DCM,混合物 經10%碳酸鈉溶液洗滌,然後分離有機層,脫水 (MgS〇4) ’過濾及蒸發溶劑。殘質經矽膠管柱層析法純化 10 (溶離液:DCM/MeOH 97/3)。收集產物溶離份,蒸發溶 劑’產生5.6g (79 %)中間物85。 b)中間物86之镅法
經濟部智慧財產局員工消費合作社印製 20 中間物86 此製程之第一部份進行1〇次:取含1-(2-氣乙基)-吼洛 唆鹽酸鹽(0.0006 m〇l)與中間物 85(0.0002 mol)之 THF(4ml) 混合物與氫氧化鈉(2ml)於150°C之微波爐中反應2小 時。然後合併10次反應混合物,加水稀釋,以HC1(1N) -103- .,香紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、lx明说明(102 ) 酸化至pH: 4.5-5.5。濾出所得沉澱,及乾燥(真空),產 生2g中間物86。 c)t_H^ 87之製法
中間物87 10 取中間物 86(0.00372 mol)於 DCM(50 ml)與 THF(50 ml)中授拌。依序添加TEA(0.03594 mol)、Ν’-(乙基碳化 亞胺醯基)-Ν,Ν-二甲基-U-丙二胺單鹽酸鹽(0.00372 m〇0、1-經基-1Η-苯並三。圭mol)及最後添加0-(四氫-2Η-Ϊ1比。南-2-基)-經基胺(0.004836 mol)。反應混合物 15 於室溫下攪拌1天,然後使混合物溶於DCM中,以水洗 滌。分離有機層,脫水(MgS〇4),過濾及蒸發溶劑。殘質 經矽膠管柱層析法純化(Biotage, 40M,梯度溶離液: DCM/(MeOH/NH3)由100/0至93/7)。合併產物溶離份, 經濟部智慧財產局員工消費合作社印製 蒸發溶劑,產生〇.770g中間物87。 20 . 實例A27 a)中間物88夕,法 -104- .…本纸張尺度適用中國國家標準(CNS)A4規格(21〇 x 297公釐) 200400941 A7 B7 五、發明說明(1〇3
5 中間物88 取中間物80(0.020 m〇i)於EtOH(500 ml)中攪拌,然 後於N2蒙氣及室溫下攪拌20分鐘。依序添加(2-甲醯基 苯基)-二羥硼酸(〇.〇3〇 mol)、碳酸铯(0.030 mol)及最後添 加二氣雙(三苯基膦)-鈀(0.00040 mol)。反應混合物於N2-10蒙氣下攪拌及回流6小時,然後蒸發溶劑。殘質溶於 DCM中’以水洗滌。分離有機層,脫水(MgS04),過 濾,蒸發溶劑。殘質經矽膠管柱層析法純化(梯度溶離液: DCM/MeOH由100/0至98/2)。收集產物溶離份,蒸發 溶劑,產生5.1g(53%)中間物88。 15 b)中間物89之製法
經濟部智慧財產局員工消費合作社印製 20 中間物89 取含中間物88(0.00208 mol)與N-甲基-曱胺(0.0222 mol)之MeOH (100ml)混合物於室溫下,使用pd/C 10%(0_5g)為觸媒’於噻吩溶液(1 ml)之存在下氫化1天。 -105- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 ___B7 五、發明說明(1〇4) 吸收H2(l當量)後’反應混合物經矽藻土過壚,滤液蒸 發。殘質經石夕膠管柱層析法純化(梯度溶離液:DCM/MeOH 由100/0至90/10)。收集產物溶離份,蒸發溶劑。殘質自 乙腈中結晶,濾、出所得沉殿,經洗蘇及乾燥(真空),產生 5 0.710名(66.9%)中間物89。 c)中間物90之贺法
10 中間物90 取含中間物89(0.00139 mol)與氫氧化鈉1Ν(0.〇1〇 mol)之THF (1〇 ml)與MeOH (2 ml)混合物於室溫下授拌 一夜,然後添加HC1 1N(10 ml),反應混合物於室溫下授 15 拌15分鐘。濾出所得沉澱,及乾燥(真空,6〇。〇,產生 0.610g(9〇.9%)中間物 90。 d)中間物91之f法 經濟部智慧財產局員工消費合作社印製 ο 2
中間物91 取中間物 90(0.001267 mol)於 DCM (50 ml)與 •106- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 0 五、發明說明(l〇5 ) THF(50ml)中攪拌。依序添加 TEA(0.007189 mol)、Ν’-(乙 基碳化亞胺醯基)-Ν,Ν-二甲基-I,3-丙二胺單鹽酸鹽 (0.001647 mol)、1-經基_ιΗ-苯並三嗤(0.001647 mol)及最 後添加〇-(四氫-2H-吡喃-2-基)-羥基胺(0.001647 m〇I)。反 5 應混合物於室溫下擾拌1夭,然後使混合物溶於DCM 中,以水洗務。分離有機廣,脫水(MgS〇4) ’過濾及蒸發 溶劑。殘質自乙腈中結晶,濾出所得沉澱,及乾燥(真 空,50°C),產生 0.560g(76.13%)中間物 91。 10 實例A28 a)中間物92之絮法
15 中間物92 經濟部智慧財產局員X-消費合作枉印製 於-70°(:下,滴加沾111^1.61^之己烧溶液(〇.〇〇69 111〇1) 至N2氣流下,含[2_(3_漠苯基)乙氧基](1,丨_二甲基乙基)二 甲基-矽烧(0.0063 mol)之THF(2〇ml)溶液中。混合物攪 20拌1小時。滴加參-異丙氧硼烷(0.0069 mol)。混合物於-7〇°C下攪拌30分鐘,然後回升至_2〇。(:。加水。混合物 經DCM萃取。分離有機層,脫水(MgS04),過濾,蒸發 溶劑至乾’產生1.8g(l〇〇%)中間物92。 b)中間物93之f法 -107- U -Φν SJL Π7 rA- ' " _________............................................................................- ν氏張尺度適用中國國家ii^NS)A4規格(210x57Ii7 200400941 A7
中間物93 添加含中間物92(0.0063 m〇l)2DMF(6〇mi)溶液至含 :間物 80 (0.0045 mol)與石農酸鉋(〇 〇〇63,之 DMF(2〇ml) 混合物中。混合物攪拌15分鐘。添加肆_(三苯基膦)_鈀 10 (0.0004mol)。混合物於8〇t下攪拌18小時,然後冷卻至 室溫。添加HC1 3N。混合物於室溫下攪拌3小時,然後 Ί貝式鹽過it。以水洗滌寅式鹽數次。渡液溶於DCM中 數次。有機層經水洗蘇,稅水⑽叫,過渡及蒸發溶劑 至乾。殘質(2.4g)經矽膠管柱層析法純κ(15_4〇μιη)(溶離 15液:DCM/MeOH 99/1)。收集純溶離份’蒸發溶劑,產生 1.76g(78%)中間物 93。 c)中間物94之贺法 9
經濟部智慧財產局員工消費合作社印製 中間物94 於5 C下滴加甲項醯氯(0.0133 mol)至n2氣流下,含 -108- G67本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(1〇7) 中間物 93(0.0044 mol)與 ΤΕΑ(0.0177 mol)之 DCM(30ml) 混合物中。混合物攪拌1小時,然後回升室溫。加冰 水。混合物經DCM萃取。分離有機層,脫水(MgS04), 過濾及蒸發溶劑至乾,產生3.43g(> 100%)中間物94。此 5 產物未再純化即使用。 d)中間物95之劁法
經濟部智慧財產局員工消費合作杜印製 中間物95 取含中間物94(0.0014 mol)、吡咯啶酮(0.0147 mol)與 碳酸鉀(0.0222 mol)之乙腈(20ml)混合物攪拌及回流18小 時。加水。混合物經DCM/MeOH萃取。分離有機層, 15 脫水(MgS04),過濾及蒸發溶劑至乾。殘質(ig)經矽膠管 柱層析法純化(70-200μιη)(溶離液:DCM/MeOH/NH4〇H 95/5/0.1)。收集純溶離份,蒸發溶劑,產生〇.4g (49%) 中間物95,熔點190°C。 e)中間物96之鈉鹽之製法 20
-109- 本紙張尺度適用+國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(10〇 取含中間物95(0.0007mol)與氫氧化鈉(0.0014 m〇l)之 EtOH (10ml)混合物授拌及回流3小時,然後冷卻至室 溫。濾出沉澱,以EtOH洗滌’然後以乙醚洗滌,於50 °C下真空乾燥,產生〇.35g (88%)中間物96 .Na鹽。 5 f)中間物97之製法
10 15 中間物97 添加EDC(0.0008 mol)至N2氣流下,含中間物96 (0.0006 mol)、0-(四氫-2H-吡喃-2-基)-羥基胺(0.0008 mol) 與1-羥基苯並三唑(0.0008 mol)之DCM/THF(10ml)混合物 中。混合物於室溫下授掉18小時。加水。混合物以 DCM萃取。分離有機層,脫水(MgS04),過濾,蒸發溶 劑至乾。殘質(〇.7g)經矽膠管柱層析法純化(5μιη)(溶離液: DCM/MeOH/NH4OH 92/8/0.1)。收集純溶離份,蒸發溶 劑’產生0.31g(77%)中間物97。 經濟部智慧財產局員Η消費合作社印製 20 實例A29 a)±_間物98之贺法 25
中間物98 110- .I.…珠張尺度適用中國國家標準(CNS)A4規格(21〇 x 297公楚 200400941 A7 B7 五、發明說明(1〇9) 取含中間物30(0.00021 mol)、[1,1'_聯苯]-4-磺醯氯 (土0.00032 mol,1.5當量)與嗎福啉基甲基-PS-清除劑(供應 商:NovabioChem 目錄 No 01-64-0171) (0.150 g)之 DCM(5 ml)混合物於室溫下攪拌20小時,然後添加參-(2-5 胺基乙基)胺-PS清除劑(供應商:NovabioChem目錄No 01-64-0170) (0.150 g),混合物再攪拌4小時,產生中間 物98。 b)中間物99之製法
^ 中間物99 取含中間物98(0.00021 mol)之氫氧化鈉 1Ν(1·5 15 ml)、MeOH(l ml)與 THF(4 ml)混合物於 60°C 下攪拌 2 小 時,然後於室溫下攪拌20小時。反應混合物經1.5 ml HC1 IN中和。收集所需產物,乾燥,產生中間物99。 c)中間物100之製法 經濟部智慧財產局員工消費合作社印製 Ο
-111- ,本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7
取含中間物99(0.00021 mol)、1-經基-1H-苯並三。坐 (O.OOOHmol)、Ν'-(乙基碳化亞胺醯基)_N,N_二曱基],3_丙 二胺單鹽酸鹽(0.00015 m〇i)與〇_(四氫_2私吡喃_2_基)_羥 基胺(0.00015 mol)之 TEA(0.025 ml)與 DCM/THF(10 ml) 5混合物於室溫下攪拌一夜,然後加水(2 ml),反應混合物 經ExtrehitTMNT (供應商:MERCK藥廠)過濾。添加異氰 酸酯-PS-樹脂(供應商:Argonaut目錄No 800260) (0.100g),混合物於室溫下攪拌4小時,然後濾出樹脂, 濾液蒸發。殘質經Flashtube™ 2008 (供應商Trikonex)管 10 柱層析法純化(溶離液:DCM/EtOAC 1/1)。收集產物溶離 份,蒸發溶劑,產生中間物100。 實例A30 a)中間物101之鈉鹽贺法 15
經濟部智慧財產局員工消費合作社印製 中間物101之鈉鹽 20 取含中間物93(〇.〇〇lmol)與氫氧化鈉(0.004 m〇][)之
EtOH(20ml)混合物攪拌及回流4小時,然後冷卻至室 溫。添加乙醚。濾、出沉殿,及乾燥,產生〇.476g (97%)中 間物lOl.Na鹽。 b)中間物之製法 -112- ;本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(⑴)
5 中間物102 於室溫下添加EDC(0.0014 mol)與1-羥基苯並三唑 (0.0014 mol)至含中間物 1〇1(〇.〇〇〇9 mol)之 THF(5ml)與 DCM(5ml)溶液中。混合物於室溫下攪拌30分鐘,添加 〇-(四氫-2H-吡喃-2-基)-羥基胺(0.0014 mol)。混合物於室 10溫下攪拌2天,倒至冰水中,以DCM萃取。分離有機 層’脫水(MgSCXO ’過濾,蒸發溶劑。殘質(0.62g)經矽膠 管柱層析法純化(5μιη)(溶離液:DCM/MeOH/NH4OH 97/3/0.3)。收集純溶離份,蒸發溶劑。殘質(〇38g, 69%) 自乙醚中結晶,濾出沉澱及乾燥,產生〇.3g(54〇/o)中間物 15 102,熔點 214°C。 B.最終化合物之製法 實例B1 經濟部智慧財產局員工消費合作钍印製 N-Fmoc-輕基胺2-氯三苯甲基樹脂(N〇vabiochem,01-20 64-0165)經50%六氫吡啶之DMF溶液處理而脫除保護 基(室溫,24小時y。樹脂經DCM與DMF洗滌2,於 DMF中膨脹。一次添加全量2當量酸3,PyBr0P4及4當 量D1EA。混合物振盪24小時,瀝乾液體,樹脂經DCM 與DMF洗蘇數次。樹脂於含2當量胺之DMF中膨脹, -113- 紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公釐) 200400941 A7 B7 五、發明說明(m) 於室溫下振盪24小時。瀝乾液體’樹脂經DCM與DMF 洗蘇。一次添加全量芳基確隨氣(2當量)至已於含4當量 TEA之DMF中膨脹之樹脂中。反應攪拌一夜,瀝乾,樹 脂經DCM與DMF洗滌。以含5% TFA之DCM溶液裂 5 解終產物’以HPLC及MS分析,於已預先稱重之試管 中蒸發。 1其中一項實例使用化合物16甘胺醇2-氯三苯甲基-樹脂 (Novabiochem, 01-64-0087)。另兩項實例使用2_氯三笨 甲基氯-樹脂(Novabiochem,01-64-0114)與 1,2-伸苯二胺 10 化合物Π或伸苯二胺化合物18。另一項實例使用化合 物19羧基甲硫醇4-曱氧基三苯甲基樹脂(Novabiochem, 01-64-0238)。 2有些例子亦以MeOH用於化合物16、17、18與19之不 同洗務過程中。 15 3以樹脂之承載量為基準計。 4有些例子改用PyBOP (化合物16、17、18與19)替代 PyBrOP。 為了說明本發明,本文中包括下列反應圖: 經濟部智慧財產局員Η消費合作社印製
-114- S? 3本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(in
TFA ~DCM*"
S02Ar S02Ar
10 實例B2 4匕合物1之製法 HO、
經濟部智慧財產局員工消費合作社印製 20 15 化合物1 取含中間物3(0.0027 mol)之DMF(100 ml)混合物於 室溫下使用Pd/C 10% (0.5 g)為觸媒氫化48小時。吸收 H2(l當量)後,濾出觸媒,濾液蒸發。殘質與DCM研 磨,過濾,然後自HOAc'中再結晶,過濾,以HOAc與 乙醇洗滌,然後乾燥,產生0.75 g(65%)化合物1。 實例B3 化合物2之製法 -115- :本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7
五、發明說明(1H
化合物2 10 取含中間物 6(0.0022 mol)之 THF(lOOml)使用 Pd/C 10%(lg)為觸媒氳化5小時。吸收H2(l當量)後,經矽藻 土過濾觸媒,蒸發溶劑。殘質懸浮於DCM中。濾出沉 澱,以少量DCM洗滌,乾燥(真空),產生〇.9g (100%) 化合物2。 實例B4 化合物3之贺法 15 rxx
經濟部智慧財產扃員工消費合作社印製 20 25 化合物3 於N2氣流下,依序添加TEA(0.0008 mol)與乙醯氯 (0.0008 mol)至含中間物 7 (0.0008 mol)之 DCM(5ml)混合 物中。混合物保持在室溫下30分鐘,倒至 10%K2CCVH2〇中’以DCM萃取。分離有機層,脫水 (MgS〇4) ’過濾’蒸發溶劑至乾。殘質(〇.41g)經矽膠管柱 層析法純化(溶離液:DCM/MeOH 98/2;10μηι)。收集純溶 離伤’蒸發溶劑。殘質(〇.22g,66%)自DCM/CH3CN中結 曰曰;處出沉澱’以乙醚洗滌,乾燥’產生〇.i8g(54%)化 116- I纸張尺度適用中國(210x29f:幻 200400941 A7 B7 五、發明說明(115) 合物3,熔點200°C。 實例B5 4匕合物4之製法
化合物4 10 於室溫下添加1,1-羰基二咪唑(0.0003 mol)至N2氣流 下,含中間物7 (0.0002 mol)之DCM (lml)混合物中。混 合物保持室溫下1小時。添加羥基胺(0.0003 mol)。混合 物攪拌一夜。添加1〇°/〇K2C03。混合物經DCM萃取。濾 出沉澱,以乙醚洗滌及乾燥,產生0.034g (29%)化合物 15 4,熔點 210°C。 實例B6 化合物5之製法 經濟部智慧財產局員工消費合作社印製
化合物5 -117- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(116) 取含中間物7(0.0013 mol)、1-曱基-1H-咪唑-4-羧酸 (0.002mol)、EDC (0.002 mol)與 1-羥基苯並三峻(0.002 mol)之DCM/THF(10ml)混合物於室溫下搜拌18小時,倒 至10%K2CO3中,以DCM萃取。分離有機層,脫水 5 (MgS04) ’過濾,蒸發溶劑至乾。殘質(i.3g)經矽膠管柱 層析法純化(溶離液:DCM/MeOH 98/2; 15-40μπι)。收集純 溶離份,蒸發溶劑。殘質(〇.25g,39°/。)溶於CH3CN中。濾 出沉澱,及乾燥,產生0.15g (23%)化合物5,熔點252 實例B7 化合物6之製法
經濟部智慧財產局員工消費合作社印製 於〇°C下添加TFA(4ml)至含中間物1〇(〇.〇〇〇5 mol)之 MeOH (20ml)溶液中。混合物於室溫下攪拌48小時。蒸 發溶劑至乾。殘質溶於乙醚中。濾出沉澱,及乾燥,產 2〇 生 〇_195g (83%)化合物 6,熔點 265。(:。 另一種製備化合物6之方法:
添加 CF3COOH (25 ml)至含中間物 33(0.012 mol)之 DCM p.a.(250ml)與MeOHp.a.(250 ml)混合物中。反應混合物於 室溫下攪拌24小時。濾出沉澱,懸浮液於熱CH3CN -118- 1本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐) 200400941 A7 B7 117 五、發明說明 中,然後攪拌冷卻至室溫,然後過濾,以CH3CN洗滌, 乾燥(真空,50°C),產生3.43g化合物6。取相應之濾液濃 縮。固體殘質懸浮於熱CH3CN中,攪拌,使之冷卻至室 溫,過濾及乾燥(真空,50°C),產生1.22 g化合物6。共產 生4.65g(94%)化合物6。 實例B8 化合物7之製法
,ΟΗ 10 化合物7
15 取含中間物 13(0.000049 mol)之 5% CF3COOH 經濟部智慧財產局員工消費合作社印製 /MeOH(5 ml)混合物於室溫下振盪40小時。於室溫及N2 氣流下蒸發溶劑。添加DCM,然後再蒸發溶劑。添加二 哼烷,然後再於室溫及N2氣流下蒸發溶劑。添加 DCM,於30°(:及N2氣流下蒸發溶劑。殘質於40°C下真 20 空乾燥一個週末,產生0.024g化合物7。 實例B9 化合物8之製法 -119- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(118)
化合物8 5 取含中間物 17(0.00018111〇1)之5%€?3(:0011/^^0执6 ml)混合物於室溫下攪拌一個週末。混合物於溫和之氮氣 流下風乾。殘質懸浮於EtOAC中,然後過濾及真空乾 燥,產生〇.〇222g化合物8。 10 f 例 B10 化合物9之製法
經濟部智慧財產局員工消費合作、社印製 化合物9 於室溫下添加甲磺酸(1.5ml)至含中間物20(0.0018 mol)之MeOH (15ml)混合物中。混合物保持18小時。加 冰。混合物經10%K2CO3鹼化,以DCM萃取。有機層 20 經水洗滌,脫水(MgS〇4),過濾、及蒸發溶劑至乾。殘質 (l.lg)自DCM/MeOH中結晶。濾出沉澱,乾燥,產生 0.68g(76%)化合物9(E組態),熔點226°C。 膏例B11 -120- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公t ) 200400941 A7 B7 五、發明說明(II9 化合物10之製法
又 化合物10 於0 °C下添加乙硫代酸(0.0023 mol)至含中間物 22(0.0021mol)與 TEA(0.0032 mol)之 2-丙酮(l〇mi)混合物 中。使混合物回升室溫,然後攪拌2小時。加水。混合 10 物經DCM萃取。有機層經水洗滌2次,脫水(MgS〇4), 過濾,蒸發溶劑。殘質(〇.85g)經矽膠管柱層析法純化(溶 離液:環己烷/EtOAC 70/30;10μηι)。收集溶離份,蒸發溶 劑。殘質自乙醚中結晶。濾出沉澱,及乾燥,產生 0.088g(10%)化合物 10,熔點 179°C。 15 實例B12 化合物11之製法
經濟部智慧財產局員工消費合作社印製 化合物11 添加 CF3COOH(0.7ml)至含中 fa]物 25(〇.〇〇〇7mc)i)之
MeOH(7ml)與DCM(7ml)溶液中。混合物於室溫下授掉— -121- GSQ本羝張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公釐) 200400941 A7 B7 五、發明說明(120) 夜。濾出沉澱,以乙醚洗滌及乾燥。殘質(0.23g,68%)再 乾燥一次,產生〇.194g(57%)化合物11,熔點196°C。 實例B13 5 化合物12之槊法
Ο 1〇 化合物12 添加 CF3C00H(2.6ml)至含中間物 28(0.0005mol)之 MeOH(12ml)與DCM(lOml)溶液中。混合物於24°C下攪拌 一夜。蒸發溶劑至乾。殘質自DCM/乙醚中結晶。濾出沉 澱及乾燥,產生〇.124g(49%)化合物12,熔點197。(:。 15 實例B14 化合物13之,沐
經濟部智慧財產局員工消費合作社印製 化合物13 於室溫下添加EDC (0.0026 mol)與1-羥基苯並三唑 水 δ 物(0.0023 mol)至含中間物 32(0.0017 mol)與 -122-㈣丨本紙張尺度適用中國國家標準(CNs)m規格⑵〇χ297公爱) 200400941 A7 B7 五、發明說明(121) TEA(0.0021 mol)之DMF(14ml)溶液中。混合物攪拌1小 時。添加1,2-苯二胺(0.0021 mol)。混合物於室溫下授拌 一夜,然後於60°C下3小時,倒至冰水中,以EtOAC 萃取。分離有機層,脫水(MgS04),過濾,蒸發溶劑。殘 5 質(0.9g)經矽膠管柱層析法純化(溶離 液:DCM/MeOH/NH4OH 97/3/0.1; 15-40μιη)。收集純溶離 份,蒸發溶劑。殘質(〇.45g)自乙醚中結晶。濾出沉殿, 乾燥,產生〇.414g(48%)化合物13,熔點238°C。 10 實例B15 化合物14之製法
15 〇 化合物14 經濟部智慧財產局員工消費合作社印製 於0 °C下,添加CF3COOH(0.2ml)至含中間物 36(0.0005mol)之 MeOH(lml)與 DCM(lml)混合物中。混合 物於室溫下攪拌24小時。蒸發溶劑至乾,產生 20 0.0174g(89%)化合物 14。 實例B16 化合物15之製法 -123- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(l22)
化合物15 取中間物 40(〇.〇903mmol)溶於 DCM(2ml)與 MeOH(3ml)中。添加三氟乙酸(25〇μυ。混合物於室溫下 擾拌2天。於室溫及Ν2氣流下蒸發溶劑。添加兩次二咩 烷。產物於40°C及Ν2氣流下吹乾’產生化合物15。 Α11ΒΠ ik金物113之製法
經濟部智慧財產局員工消費合作社印制取 化合物113 添加 Pd(PPh3)4(0.0002 mol)與碳酸鉀(0.0056 mol)至含 中間物 41 (0.0028 mol)之 EtOH(22ml)與 DMF(22ml)混合 20 物中。混合物於80°C與5巴CO壓力下攪拌48小時, 然後溶於Et0Ac/H20中,經寅式鹽過濾。有機層以水洗 # ’脫水(MgS04),過濾及蒸發溶劑。殘質經矽膠管柱層 析法純化(15-40μηι)(溶離液:DCM/MeOH/NH4OH 98/2/〇.1)。收集純溶離份,蒸發溶劑,產生〇.27g(23%) -124- :本氏張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐: 200400941 A7 B7 五、發明說明(123) 化合物Π3,熔點200°C。 實例B18 化合物114之絮法
化合物114 10 於 〇°C 下添加 TFA (0.5ml)至含中間物 46(S,S)(0.0006 mol)之MeOH (10ml)混合物中。使混合物回升室溫,然後 攪拌12小時。再添加TFA。混合物於室溫下攪拌72小 時。濾出沉澱,以MeOH洗滌,然後以乙醚洗滌,及乾 燥。殘質(〇.276g)於60°C下乾燥4小時,產生〇,258g,然 15 後於75°C下乾燥8小時,然後溶於DCM中,於室溫下 攪拌。濾出沉澱,以乙醚洗滌,乾燥,產生〇158g (56%) 化合物114(S,S)。 經濟部智慧財產局員工消費合作社印製 實例B19 20 化合物115之制法
0 C2HF3〇2 化合物115 -125- 氣張尺度適用中國國家標準(CNS)A4規格(210x297公;t) 200400941 ΑΊ Β7 五、發明說明(124) 取含中間物 49(0.〇〇〇lmol)之 TFA(2ml)、MeOH(4ml) 與DCM(3ml)之混合物於室溫下攪拌19天。蒸發溶劑。 殘質自乙醚中結晶。濾出沉澱,產生0.0852g (85%)化合 物 115,熔點 135°C。 5 實例B20 化合物116之製法 Ον1ΌΟ no 10 化合物116 15 於0°C下添加TFA(lOml)至含中間物52(0.0051 mol) 之MeOH(50ml)與DCM(50ml)溶液中。混合物於室溫下攪 拌48小時。濾出沉澱,以乙醚洗滌及乾燥,產生2.07g (97%)化合物116,熔點249°C。 實例B21 #合物117之禦法 經濟部智慧財產局員工消費合作社印製 20 25 HO,
,C2HF302(1:2) 化合物117 -126- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 085 — 200400941 A7 B7 五、發明說明( 125 ) 取含中間物 55(0.00003 mol)之 TFA(0.5ml)、
MeOH(3ml)與DCM(2ml)之混合物於室溫下授拌5天。蒸 發溶劑至乾,產生0.017g (62%)化合物m 2 C2HF3〇2, 熔點80°C。 5 實例B22 化合物118之製法
經濟部智慧財產局員工消費合作社印製 化合物118 取含中間物 60(0.0022 mol)之 TFA(3ml) ' MeOH(lOml) 與DCM(lOml)混合物於室溫下攪拌24小時。添加乙醚。 15 濾出沉澱及乾燥,產生lg(97°/。)化合物ι18,溶點21〇 t:。 實例B23 化合物119之製法
Ο 化合物119 -127-本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公复) 200400941 A7 B7 五、發明說明(丨26) 取含中間物 62(0.0024 mol)之 TFA(5ml)、MeOH(22ml) 與DCM(lOml)之混合物於室溫下攪拌8天,然後過濾。 沉澱棄置不要,濾液蒸發。殘質(1.4g)自 DCM/MeOH/CH3CN/乙醚中結晶。濾出沉澱及乾燥,產生 5 0.388g(36%)化合物 119,熔點 225°C(純度:90%)。 實例B24 化合物120之製法
化合物120 取含中間物 65(0.0004 mol)之 TFA(2ml)、MeOH(20ml) 15 與DCM(lOml)之混合物於室溫下攪拌72小時。蒸發溶 劑。添加乙醚。濾出沉澱及乾燥,產生0.19g(94%)化合 物 120,熔點>260°C。 經濟部智慧財產局員工消費合作社印製 實例B25 20 化合物121之盤法
化合物121 -128- ;本紙張尺度適用中國國家標準(CNS)A4規格(210 X297公釐) 200400941 A7 B7 五 、發明說明(l27 取含中間物 71(0.0003 mol)之 TFA(lml)與 MeOH(lOml) 混合物於室溫下攪拌4天。濾出沉澱,以MeOH洗滌, 然後以乙醚洗滌及乾燥,產生〇.〇96g (72%) 化合物 i2l,熔點 220°C。 幻歹丨J B26 化合勒122之乾法 10
15 取含中間物 75(0.0003 mol)之 TFA(2ml)與 MeOH(5ml) 混合物於室溫下攪拌72小時。濾出沉澱,以乙醚洗滌及 乾燥’產生0.112g(63%)化合物122,熔點166。(:。 實例B2Z 之邀法 經濟部智慧財產局員工消費合作、社印製 20
化合物123 取含中間物 79(0.0009 mol)之 TFA(0.5ml)與 25 Me〇H(5ml)混合物於室溫下攪拌48小時,然後蒸發溶劑 -129- 尺度 準(cns)A4 規? (210x297 公釐) 200400941 A7 B7 五、發明說明(m) 至乾。殘質溶於MeOH/乙醚中。濾出沉澱及乾燥,產生 0.42g(82o/〇)化合物 123.C2HF302,熔點 114°C。 實例B28 化合物124之製法
10 化合物124 15 取中間物 84(0.000852 mol)於 TFA(5% MeOH/DCM 溶液)(40ml)中攪拌3天,然後濾出所得沉澱及乾燥(真 空,50°C),產生 〇_316g (60%)化合物 124.C2HF302,熔點 192〇C。 實例B29 化合物125之製法 經濟部智慧財產局員工消費合作社印製 20 25
0 .0.2 H20 .C2HF3〇2 化合物125 -130- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 __B7 五、發明說明(129) 於室溫下’取中間物87(0.00121 mol)於TFA(5% MeOH溶液)(60ml)中攪拌6天(4天後即添加〇.25ml TFA)’於室溫下蒸發溶劑(真空)。殘質自EtOAC中,於 回流下結晶,濾出所得沉澱及乾燥(真空),產生 5 0.356g(44.2%)化合物 125·0·2 氏0.(:册3〇2,熔點 i46 9 V。 實例B30 化合物126之製法
化合物126 於室溫下,取中間物91(0 00096 〇1〇1)於TF 5% DCM/MeOH溶液)中攪拌4天,於室溫下部伶i4〇m1, 劑(真空)。於濃縮液中產生沉澱,濾出沉爽,然:、發洛 20 (真空,50。〇),產生 〇.455g(78 %)化合物 126.C2Hj;、逡乾燥 點 190.7°C。 2 3〇2,線 經濟部智慧財產局員工消費合作社印製 實例B31 j_匕合物127之槊法 -131- 本紙張尺度翻巾s S家鮮(CNS)A4規袼(21G χ 297公爱) 200400941 A7 B7 五、發明說明(130)
化合物127 添加TFA(0.5ml)至含中間物97(0.0004 mol)之 MeOH(lOml)混合物中。混合物於室溫下授拌a小時。 濾出沉澱,及乾燥,產生0.22g (66%)化合物127。1 16 C2HF302,熔點 243°C。 實例B32 化合物128之製法 Ο
經濟部智慧財產局員工消費合作社印製 化合物128
取含中間物 100(0.00021 mol)之 TFA(5ml,5 % MeG>H 溶液)與DCM(lml)混合物於室溫下攪拌48小時,然後蒸 發溶劑,產生化合物128。 實例B33 -132- 一本纸張尺度適用中國國家標準(CMS)A4規格(210 X 297公釐) --—---- 200400941 A7 B7 五、發明說明(m) 化合物129之贺法 η
經濟部智慧財產局員工消費合作社印製 化合物129 取含中間物 102(0.0005 mol)之 TFA( 1.2ml) ' MeOH(lOml)與DCM (2ml)混合物於室溫下攪拌3天。添 加乙醚。濾出沉澱及乾燥,產生〇.232g (94%)化合物 10 129,熔點:>260°C。 表F-1列出根據上述一種實例製備之化合物。表中= 用下列縮寫:Co.No.代表化合物編號,Εχ·[Βη0]指與 實例中所述之相同方法,c2hf3o2代表三氟乙酸鳞。名〆 化合物已說明其熔點特性(mp),其他化合物以質譜黎 15 [MH+](ms)說明其特性。
-133- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公愛) 200400941 A7 B7 五、發明說明(I32) 經濟部智慧財產局員工消費合作社印製
-134- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(m) 經濟部智慧財產局員工消費合作社印製 ο 〇rNjaV- C2HF3〇2 (1:1), Co. No. 18; Ex. [Bl] C2HF3〇2 (1:1), Co. No. 19; Ex. [Bl] H0、_ •crN>o ho、nh -〇/N、0 、~ .C2HF302 (1:1), Co. No. 20; Ex. [Bl]; ms. 447 .C2HF3O2 Co. No. 21; Ex. [Bl]; ms. 457 αΛ3^ HO 〇 h%h 0 .C2HF302 (1:1), Co. No. 22; Ex. [Bl]; ms. 447 .C2HF3〇2 (1:1), Co. No. 23; Ex. [Bl]; ms. 452 H〇、 ^ f V。--〇〜 cl_^=yi_Nn P y-fS ^ b- Ci HN-"\ HO 〇 .C2HF302 (1:1), Co. No. 24; Ex. [Bl]; ms. 452 .C2HF3〇2 (1:1), Co. No. 25; Ex. [Bl]; ms. . 477 ho、nh 〇Λΐ>〇-^· -crN>〇 /°Oi~0~0"N;〇- .C2HF302 (1:1), Co. No. 26; Ex. [Bl]; ms. 533 .C2HF3〇2 (1:1), Co. No. 27; Ex. [Bl]; ms.437 ho、nh - 〇Xf>o-to 〇^N^o /rF F F ho'nh 0威 -crN、〇 .C2HF302 (1:1), Co. No. 28; Ex. [Bl]; ms. 475 .C2HF3〇2 (1:1), Co. No. 29; Ex. [Bl]; ms. 482 -135- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(I34 ) 經濟部智慧財產局員工消費合作社印製 ho、nh 输 / ,。 〇-< .C2HF3〇2 (1:1), Co. No. 30; Ex. [Bl]; ms. 500 .C2HF3〇2 (1:1), Co. No. 31; Ex. [Bl]; ms. 425 ho、nh h0、nh αΝ>〇 .C2HF3O2 (1^1), Co. No. 32; Ex. [Bl]; ms. 457 .C2HF3〇2 (1:1), Co. No. 33; Ex. [Bl]; ms. 441 '°Λ h7\ .C2HF3O2 (1:1), Co. No. 34; Ex. [Bl]; ms. 457 .C2HF3〇2 (1:1), Co. No. 35; Ex. [Bl]; ms. 452 C, hH H〇、NH crN、o .C2HF3O2 (1:1X Co. No. 36; Ex. [Bl]; ms. 483 .C2HF3〇2 (1:1), Co. No. 37; Ex. [Bl]; ms. 451 r>4-N^N-_/-yN? /N^-〇^>v HN—i HO 〇 .C2HF3〇2 (1:1), Co. No. 38; Ex. [Bl]; ms. 475 .C2HF3〇2 (1:1), Co. No. 39; Ex. [Bl]; ms. 500 °n-〇- i_〇iKD'^NC. .C2HF302 (l:i), Co. No. 40; Ex. [Bi]; ms. 452 .C2HF3〇2 (1:1), Co. No. 41; Ex. [Bl]; ms. 533 ™136™ 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 經濟部智慧財產局員工消費合作社印製 五、 發明說明(I35) H〇"NH F- 。^〇被 0^0 ho、nh °^V-o-i〇- -〇'N〜。 .C2HF3〇2 (1:1). Co. No. 42; Ex. [ΒΪ]; ms. 475 .C2HF3〇2 (1:1), Co. No. 43; Ex. [Bl]; ms. 421 ho、nh .〇'〜。 c,X>7-〇^C HO 0 .C2HF3〇2 (1:1), Co. No. 44; Ex. [Bl]; ms. 458 .C2HF3〇2 (1:1), Co. No. 45; Ex. [Bl]; ms. 481 ς>κ> 令 c 。丨 HN-< HO’ 〇 .C2HF3O2 Co. No. 46; Ex. [Bl]; ms. 441 .C2HF3〇2 (1:1), Co. No. 47; Ex. [Bl]; ms. 457 ho、Nh 〇Λ^〇-0α ό"Ν^ο .C2HF3O2 (1:1), Co. No. 48; Ex. [Bl]; ms. 421 .C2HF3O2 (1:1), Co. No. 49; Ex. [Bl]; ms. 441 \-fS w )=/ V 〆〇 HN 一 HO’飞 CI—/~V-S-^~、N c’ HO 〇 .C2HF3〇2 (1:1), Co. No. 50; Ex. [Bl]; ms. 451 .C2HF3O2 (1:1), Co. No. 51; Ex. [Bl]; ms. 477 H%H a -crN>〇 F HN—/ F H〇’ 〇 .C2HF302 (l:i), Co. No. 52; Ex. [Bl]; ms. 475 .C2HF302 (1:1), Co. No. 53; Ex. [Bl]; ms. 475 -137- 格 規 4 )A s) N (c 標 家 國 國 中 用 適 度 尺 張 紙 本 釐 公 97 200400941 A7 五、發明說明(m) 經濟部智慧財產局員工消費合作社印製
II \__/ \==/ 、。- ΗΝ-Λ HO’ 〇 h0、nh 〇Λ^-〇-Κχ〇, Ό"Ν^〇 .C2HF3〇2 (1:1), Co. No. 54; Ex. [Bl]; ms. 458 .C2HF3〇2 (1:1), Co- No. 55; Ex. [Bl]; ms. 481 ho、nh -crN、〇 ho'nh -Λ .C2HF302 (1:1), Co. No. 56; Ex. [Bl]; ms. 425 .C2HF3〇2 (1:1), Co. No. 57; Ex. [Bl]; ms. 437 ho、nh •〇"N^o pl-O^v Cl HN -¾ HO7 〇 .C2HF302 (1:1), Co. No. 58; Ex. [Bl]; ms. 407 .C2HF3〇2 (1:1), Co. No. 59; Ex. [Bl]; ms. 441 o^%NWN-\_>1_oh \ r~\ γ^\Ρ ^%nv_/nA>1_〇h Co. No. 60; Ex. [Bl] Co. No. 61; Ex. [Bl];mp. 228°C Co. No. 62; Ex. [Bl] Co. No. 63; Ex. [Bl]; mp. 230°C 0%nCn-〇1--〇h n=4 XO^^I-oh \ Co. No. 64; Ex. [Bl] Co. No. 65; Ex. [Bl]; mp. 252°C %_N^N /=w° ς—/ 〇、-/ \™/ HN-OH /~\ /=\ p Co. No. 66; Ex. [ΒΠ; mp.231°C Co. No. 67; Ex. [Bl]; mp. 226°C -138- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(I37 ) 經濟部智慧財產局員工消費合作社印製 s y%NwN~v/l-〇H Co. No. 68; Ex. [Bl] Co. No. 69; Ex. [Bl] sXO^^N-OH c> Co. No. 70; Ex. [Bl]; mp. 228°C Co. No. 71; Ex. [Bl] <^WSnwnA_/^1_〇h k〇-〇i_〇H 0 Co. No. 72; Ex. [ΒΠ Co. No. 73; Ex. [Bl] Co. No.7 4; Ex. [Bl]; mp. 234°C F F a’ Co. No. 75; Ex. ΓΒΠ Co. No. 76; Ex. [Bl]; mp.224°C Co. No. 77; Ex. [Bl] 说H Bf _____Co. No. 78; Ex. [Bl]; mp. 221°C Co. No. 79; Ex. [Bl]; mp. 219°C ^ ' Cl R\ /~\ /=\ p Co. No. 8〇; Ex. [Bl] Co. No. 81; Ex. [Bl] rjV (TXXC^ 4 〇Ar〇、 Co. No. 82; Ex. [Bl]; mp. 222°C Co. No. 83; Ex. ΓΒΙΙ; mp. 214°C -139- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200400941 A7 B7 五、發明說明(l38) 經濟部智慧財產局員工消費合作社印制衣 。乂 〇 以0^€0 0 丫]L H N ιΓΝΥ^1 〇以〇、?切 I Co. No. 84; Ex. fB61; mp. 232°C Co. No. 85; Ex. ΓΒ61; mp. 250°C A% 〇以〇抑 o ^rSr'^ri ° 0 ^OoXT) l Co. No. 86; Ex. [B6]; mp. 264°C Co. No. 87; Ex. [B6]; mp. >260°C roVXQsp〇 O o Co. No. 88; Ex. [B8] Co. No. 89; Ex. [B9] O N-^Y^N'〇、H 〇备 s6 ryJ H H Co. No. 90; Ex. [B15] Co. No. 91; Ex. [B15] ~/ N-q y_/ r/ h S-( '7 N=/ 广0、 H H F Co. No. 92; Ex. [B15] Co. No. 93; Ex. [B15] r~\ FF F OH W ^ 广' Xci Η H N Co. No. 94; Ex. [B15] Co. No. 95; Ex. [B15] J-OOi, / \ Η H K H H ~o p Co. No· 96; Ex. [B15] Co. No. 97; Ex JB15] -140- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(I39) 經濟部智慧財產局員工消費合作社印製 Γ ?,〇 h,H ' Co. No. 98; Ex. [B16] Co. No. 99; Ex. [B161 ?^〇 rVasOL 〇yCT h〇,nh ίν〇Ί h〇,nh Co. No. 100; Ex. [B16] Co. No. 101; Ex. [B16] t。 :H 7-p tp 〇y〇T° Co. No. 102; Ex. [B16] Co. No. 103; Ex. [B16] %p rVasO. 〇^ΤΝσΊα0υ ho’h Co. No. 104; Ex. [B16] Co. No. 105; Ex. fB 16] 〇yCt° ho’nh 5^〇 XO^ HO, 一 Co. No. 106; Ex. [B16] Co. No. 107; Ex. fB 161 ?/) 〇Y〇rari0 h,H h〇-NH Co. No. 108; Ex. [B16] Co. No. 109; Ex. [B16] • Zp X^O H, F F V/~V^-A HO—NH ~’ \~~λ Co. No. 110; Ex. [B16T Co. No. Ill; Ex. [B16] -141- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7
7 B 五、發明說明(MO) 經濟部智慧財產局員工消費合作社印製 HO-NH ~1 \~\ 0^X1° ^°T) H, 《 Co. No. 112; Ex. [B16] Co. No. 130; Ex, [B16] %P ho-nh ~ \ % Co. No. 131; Ex. [B16] Co. No. 132; Ex. [B16] O Η〇-Νγ^Ν 0 1 Co. No. 133; Ex. [B16] Co. No. 134; Ex. [B16] O Η〇^τσ^ Ο 1 .C2HF3O2; Co. No. 135; Ex. [B16] Co. No. 136; Ex. [B16] ηΛχϊ°Ά 〇 s Co. No. 137; Ex. [B16] .1.6 C2HFi〇2; Co. No. 138; Ex. [B16] H〇 HO’ H0 ^nh2 Co. No. 139; Ex. [B16] .1.5 C2F3O2; Co. No. 140; Ex. [B16] O h .νβ W ho^Y^n 0 Co. No. 113; Ex. [B17]; mp. 200°C (S,S); Co. No. 114; Ex. [B18]; mp. 225°C -142- .裝— 計, 4 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(14i) rVi?TO Ο ho^Y^n 0 Co. No. 141; Ex. [B18]; mp. 240°C .C2HF3O2; Co. No. 115; Ex. [B19]; mp. 135°C rV0"fTO O rVato 〇 Co. No. 116; Ex. [B20]; mp. 249°C Co. No. 142; Ex. [B20]; mp. 183°C h"X〇w N丫 N 0 o+o rV0NlOO h〇』Y^n 0 .2 C2HF3O2; Co. No. 117; Ex. [B21]; mp. 80°C Co. No. 118; Ex. [B22]; mp. 210°C h〇-yv〇1XX) ho^Y^n 0 h 々cAdo HO^Y^ 0 Co. No. 119; Ex. [B23]; mp. 225°C Co. No. 120; Ex. [B24]; mp. >260°C ^OH Ho-yCT 0 ' 0 HO、,人 、人 〇ii0H Co. No. 121; Ex. [B25]; mp. 220°C Co. No. 122; Ex. [B26]; mp. 166°C J rVOW h〇』Y^n 0 〇 .C2HF3O2; Co. No. 123; Ex. [B27]; mp. 114°C .0.82 C2HF302;Co. No. 143; Ex. [B27]; mp. 153°C -143- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200400941 A7 B7 經濟部智慧財產局員工消費合作社印製
-144- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(⑷ 經濟部智慧財產局員工消費合作社印製
-145- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(H〇 經濟部智慧財產局員工消費合作社印製
0 η,〇、νΛ^ν ΗΎΐ ΓΊΓΡ 〇1 .C2HF3O2; Co. No. 161; Ex. [B30]; mp. >260°C .C2HF3O2; Co. No. 162; Ex. [B30]; mp. 164°C H、<rNY^N 〇 …0¾½ , H、(TNY^N ο 1 .0.6 H20 .C2HF3O2; Co. No. 163; Ex. [B30] .0.7 H2O.I.5.C2HF3O2; Co. No. 164; Ex. [B30]; mp. 139°C g H「々nJ 广n〜cx^〇.h Η-σΝγ^Ν 〇 0 h fUYU^ r^N"^aH Η'σΝ^Λ^Ν 0 .C2HF3O2; Co. No. 165; Ex. [B30]; mp. 197°C .C2HF3O2; Co. No. 166; Ex. [B30]; mp. 183°C v f丫0 H、0,NY^N KJ 。 O 0 .C2HF3O2; Co. No. 167; Ex. [B30] .C2HF3O2; Co. No. 168; Ex. [B30] Η、〇;γΛ^Ν \β 0 HQvCT〇inQxr, 〇 .1.1 C2HF3O2; Co. No. 169; Ex. [B30]; mp. 184°C .0.94 C2HF3〇2; Co. No. 170; Ex. [B30]; mp. 130°C ΗΛΧτ〇1χν〇 o -. Η,/Τ〇Νΐχ^〇 .1.03 C2HF3O2; Co. No. 171; Ex. [B30]; mp. 205°C .1.16 C2HF3O2; Co. No. 127; Ex. [B31]; mp. 243°C -146- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(I45) 經濟部智慧財產局員工消費合作社印製 〇 〇 .1.18 C2HF3O2; Co. No. 172; Ex. [B31]; mp. 254°C .1.17 C2HF302; Co. No. 173; Ex. [B31]; mp. 224°C O 0 N,^V^kNX〇'-H 〇 P人』A .C2HF3O2; Co. No. 174; Ex. [B31]; mp. 164°C Co. No. 128; Ex. [B32] 0 Ν^Η /° 〇 rxA' i Co. No. 175; Ex. [B321 Co. No. 176; Ex. [B32] 0 ^nAn^ " 0 1 1 1 、 Cl n-^V^'n"°''h O I I ί F Co. No. 177; Ex. [B32] Co. No. 178; Ex. [B32] -147- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200400941 A7 B7 五、發明說明(l46) 經濟部智慧財產局員工消費合作社印製 ν-^Υ^'ν"〇'Ή 。广 Ν乂 d i ί 广 xtV、h 〇 〇 N X F Co. No. 179; Ex. [B32] Co. No. 180; Ex. [B32] 十0人 夕 Co. No. 181; Ex. [B32] Co. No. 182; Ex. [B32] n-^Y^n-°-h 。广人h 〇 r;〇V Cl Co. No. 183; Ex. [B32] Co. No. 184; Ex. [B32] ___ 0 ^ iYr% 1 -: 0 〇ν〇ΛΧ,ί σΝ、 Co. No. 185; Ex. [B32] Co. No. 186; Ex. [B32] -148- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 " _’丨丨丨丨丨丨 1 五、發明說明(I47)
5 C.藥理眚例 组織蛋白去乙醯酶抑制作用之活體外分析法(參見實 例C · 1)係測定式(I)化合物所得之抑制HDAC酵素活性。 式(I)化合物之細胞活性係於A278〇腫瘤細胞上,採 1〇用測試細胞毒性或存活性之比色測定法測定(Mosmamm Tim,J0urnal 〇f Immunol〇gical Meth〇ds 65:55 63,198从參 見實例C.2)。 少 於水性介質中之動力溶解性係測定該化合物於稀釋 時保持水溶液狀悲之能力(參見實例C 3)。 15 DMSO母液係使用單一水性緩衝溶劑,於連續3個 步驟中稀釋。每一次稀釋後之濁度均使用濁度計測定。 藥物之通透性表現其由-種介質移動至或通過另― 種介質之能力。明確言之’其移動通過腸膜進人血/ 經濟部智慧財產局員工消費合作社印製 或自血流進人目標中之能力。通透性(參見實例C取測 20定法可測定濾器固定化之人工膜磷脂雙層形成量。濾器 固定化之人工膜分析法中,由96孔微滴定板與96孔過 渡板形成,,夾心,,,因此每個组成之孔中即分隔成兩個隔 間,底層為供體溶液,上層為受體溶液,中間以塗覆 2%(重量/體積)二油醯基磷脂酿基_膽驗之十二碳烧溶液之 -149-
Igg本纸張尺度適用巾關家標準(CNS)A4規格(210x297公愛) 200400941 A7 _ B7 五、發明說明(148) U5微米微過濾片(0.45微米孔徑)分隔,當該系統接觸到 水性緩衝液時,濾片通道内會形成多層膜之雙層物。測 定通過此人工膜之化合物通透性’以公分/秒表示。其目 的為檢視藥物在兩種不同pH : 4.0與7_4下通過平行人工 5 瞑之通透性。採用UV-分光光度計,於250至5〇〇nm之 間之最適當波長下檢測化合物。 藥物之代謝作用指該脂溶性異種生物化合物或生物 内生化合物經酵素轉化成極性、水溶性且可排泄之代謝 物(群)。藥物代謝作用之主要器官為肝臟。代謝產物之活 10性通常低於母化合物或無活性。然而,有些代謝物可能 加強活性或毒性效果。因此,藥物代謝作用可包括”去毒 化與毒化”過程。其中決定生物體是否有能力處理藥物 與化學物之主要酵素系統代表為細胞色素p45〇單氧化 酶,其係依賴NADPH之酵素。化合物之代謝安定性可於 15活體外,使用亞細胞人類組織測定(參見實例C.4)。本文 中化合物之代謝安定性係由此等化合物與微粒體培養^ 5 分鐘後之藥物代謝%表示。以LC-MS分析法為化合物定 量。 經濟部智慧財產局員工消費合作社印製 腫瘤抑制子p53可因應DNA損傷,轉錄性活化許多 20種基因,包括WAF1/CIP1基因。WAF1基因之2lkDa產 物出現在正常細胞中包括環素、依賴環素之激酶(Cdks) 及增生細胞核抗原(PCNA)之複合體中,但不出現在轉形 細胞中,且似乎為CDK活性之通用抑制劑。p21 waf 1結 合並抑制CDKs之一種後果為防止依賴CDK之磷酸化反 -150- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱) 200400941 A7 B7 五、發明說明(149 ) 應及隨後為Rb蛋白質之去活化作用,後者係細胞循環發 展所必要者。因此,使用HDAC抑制劑因與細胞接觸而 誘發產生之P21WAF1即可成為細胞循環發展過程中,在 G1與G2檢查點之抑制作用之強力且專一性之指標。 5 化合物誘發P21WAF1之能力係採用p21WAFl酵素 經濟部智慧財產局員工消費合作社印製 連結免疫吸附性分析法測定(致癌基因之WAF1 ELISA)。 p21WAFl分析法為一種同時使用小白鼠單株抗體與兔子 多株抗體之"夾心"酵素免疫分析法。對人類WAF1蛋白質 具專一性之兔子多株抗體已固定在試驗套組所提供之塑 10 膠孔表面上。樣本中所要分析之任何p21WAF均會與捕 捉抗體結合。生物素基化檢測劑單株抗體亦可辨識人類 p21WAFl蛋白質,而且會與捕捉抗體所保留之任何 P21WAF1結合。檢測劑抗體則再與辣根過氧化酶_共軛之 抗生物素結合。辣根過氧化酶催化發色性受質四甲基聯 15苯胺之有色溶液轉呈藍色溶液(或當添加中止反應劑後, 則轉呈黃色),其深度與分析板上p21WAFl蛋白質之結 合量成比例。採用分光光度計定量有色反應產物。使用 已知濃度之P21WAF1(冷凍乾燥物)所構成之標準曲線進 行定量(參見實例C.6)。 20 專一性HDAC抑制劑不應限制其它例如大量存在之 CYP P450蛋白質之酵素。CYP P450(大腸桿菌所表現)蛋 白質3A4、2D6.及2C9可將其專—性受f轉化成榮光分 子。CYP 3A4例可使7_苯甲氧基_三氣甲基香豆素 (BFC)轉化唪7-羥基-三氟曱基香豆素。CYp 2D6蛋白質 -151- ^本紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公餐) 經濟部智慧財產局員工消費合作社印製 200400941 Α7 Β7 五、發明說明(丨5〇 轉化H2-(N,N-二乙基曱胺基)乙基]冬甲氧基冰甲基 香豆素(AMMC)形成3_[2_(N,N_二乙基_胺基)乙基]_7_羥 基-4-甲基香豆素鹽酸鹽,CYP 2C9蛋白質轉化7-甲氧基_ 4-三氟甲基香豆素(MFC)形成7-羥基-4-三氟甲基香豆素。 5抑制此等酵素反應之化合物即會降低螢光訊號(參見實例 C.7)。 實例C· 1 :組線.蛋..电';^^酿酶之抑制作用之活體外分;):斤沐 * ' I. 取60ug/ml HeLa核萃出物供應商:Bi〇in〇l)與2 χ ίο i〇-8m放射性標記之肽受質培養,測定HDAC活性所使 用之受質為合成肽’亦即組織蛋白H4之胺基酸14-21。 該受質之NH2末端部份經6_胺基己酸間隔基進行生物素 基化’其COOH-末端部份則被醯胺基保護,並於離胺酸 16上專一性[3H]乙醯化。添加受質:生物素_(6_胺基己 15 酸)Gly-Ala-([H ]-乙醯基 _LyS_Arg-His-Arg-Lys-Val-NH2)至 含 25mM Hepes、1M 嚴糖、〇.img/mi BSA 與 0.01%Triton X-100之ρΗ7·4緩衝液中。30分鐘後,添加HC1與乙酸 中止去乙醯化反應(終濃度分別為〇.035nlM與3.8mM)。 反應停止後’以乙酸乙酯萃取游離之3h_乙酸酯。混合與 20離心後’於β _計數器上計算上層有機相之放射活性。每 次實驗均平行進行對照組(含HeLa核萃物與DMSO,但 不含化合物)、空白培養组(含DMSO,但不含HeLa核萃 物或化合物)及樣本試驗組(含溶於DMSO中之化合物與 HeLa核萃物)。第一例中,化合物之試驗濃度為ι〇·5μ。 -152- U 本紙張尺度適用中國國家標準(CNS)A4規格(21〇χ297公髮)
200400941 A7 B7 五、發明說明(1M) 當化合物於1〇-5Μ下展現活性時,則在ι〇·5μ與i〇-i2M 之間濃度測試化合物,製成濃度-效應曲線。每次試驗之 對照組與樣本組之數值均扣除空白組數值。對照組樣本 代表100%受質去乙醯化。各樣本之放射活性以相對於對 5照組平均值之百分比表示。若適當時,採用概率分析法 計算已分級之數據,計算1(:5()值(使代謝物量下降至對照 組之50%時所需藥物濃度)。此時,以pIC5〇 (IC5〇值之負 對數值)表示試驗化合物之效應。所有試驗化合物在l〇-5m之試驗濃度下均展現酵素活性,有144種化合物之 10 pic5()25(參見表 F-2)。 复例C.2 :於A2780細胞上測定抗增生活性 所有試驗化合物均溶於DMSO中,再於培養基中稀 釋。細胞增生分析法中之最終DMSO濃度不可超過 15 0.1%(v/v)。對照組含有A278〇細胞及不含化合物之 經濟部智慧財產局員工消費合作社印製 DMSO ’而空白組則含有DMSO,但不含細胞。取MTT 溶於PBS中,5mg/ml。製備甘胺酸緩衝液,其包含o.im 甘胺酸與O.lMNaa,經lNNaOH緩衝至pH10.5(所有試 劑均來自Merck藥逼)。 20 取人類AW80卵巢癌瘤細胞(係美國賓州Fox Chase 癌症中心T.C.Hamilton博士之熱心捐贈)於補充2mM L-麵 醯胺、50ug/mr健大黴素與1〇%胎牛血清之RPMI 1640培 養基中培養。細胞照例呈單層培養物保持在37°C之潮濕 5% C02大氣中。每週使用胰蛋白酶/EDTA溶液傳代細胞 -153- 本每_張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 B7 A7
一次,分割比例為1 : 40。所有培養基與補充物均得自 Life Technologies。採用Gen-Probe黴漿菌組織培養套組 (供應商:BioMerieux)測得細胞中不含黴漿菌污染物。 將細胞接種在NUNCTM96孔培養板中(供應商: 5 Technologies) ’使之附著在塑膠板上一夜。用於塗覆之贫 度為每孔1500個細胞,總體積為2〇〇μ1培養基。細胞附 著在培養板上後,換下培養基,添加藥物與/溶劑至最終 體積200μ1。培養4天後,以200μ1新鮮培養基置換纟立養 基,採用以ΜΤΤ為主之分析法分析細胞密度與活力。每 10孔中添加25μ1 ΜΤΤ溶液,細胞再於37°C下培養2 j 經濟部智慧財產局員工消費合作社印製 時。小心吸出培養基,依序添加25μ1甘胺酸緩衝液及 ΙΟΟμΙ DMSO,使藍色ΜΤΤ-曱腊產物溶解。微試驗板於 微試驗板振盪器上振盪10分鐘,使用EmaX96孔分光光 度計(供應商:Sopachem)測定540nm之吸光度。實驗 15中,各實驗條件之結果均為3個重覆孔之平均值。初a 篩選用之化合物係於單一固定濃度1〇-6M下測試。活= 化合物則重覆試驗,以建立完整之濃度_效應曲線。每次 實驗之對照組(不含藥物)及空白培養組(不含細胞或藥物A) 均平行進行。所有對照組與樣本組數值均扣除空白組數 20值。每個樣本之細胞生長平均值(以吸光度為單位)均以相 對於對照組細胞生長平均值之百分比表示。若適當時, 採用概率分析法計算已分級之數據,計算Km值(使細胞 生長下降至對照組之50%時所需藥物濃D.j., Analyses ’ 第 2 版,第 1〇 章,Graded Resp〇nse, -154- )^彳本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(153)
Cambridge University Press,Cambridge,1962)。本文中 以pIC5〇 (IC5〇值之負對數值)表示試驗化合物之效果。大 多數試驗化合物在1〇_6Μ之試驗濃度下展現細胞活性且 有129種化合物之pic5(^5(參見表F-2)。 5 實例C.3 :於水性介質中之動力溶解性 經濟部智慧財產局員工消費合作社印製 第一個稀釋步驟中,取ΙΟμΙ活性化合物之濃縮母液 溶於DMSO中(5mM),加至ΙΟΟμΙ磷酸鹽檸檬酸鹽缓衝 液ρΗ7.4中,混合。第二個稀釋步驟中,取一部份(20μ1) 10 第一個稀釋步驟溶液再加至ΙΟΟμΙ磷酸鹽檸檬酸鹽缓衝液 ρΗ7.4中,混合。最後,第三個稀釋步驟中,取一部份 (20μ1)第二個稀釋步驟溶液再加至ΙΟΟμΙ磷酸鹽檸檬酸鹽 缓衝液ρΗ7.4中稀釋,混合。所有稀釋液均於96孔板中 進行。最後一次稀釋後,立即使用濁度計測定連續3個 15 稀釋步驟之濁度。每種化合物之稀釋液均進行三重覆, 以排除偶然誤差。依據濁度測定值,分成3級。高溶解 度之化合物得到3分,此等化合物之第一次稀釋呈澄清 狀。中度溶解度之化合物得到2分。此等化合物之第一 次稀釋液不澄清,但第二次稀釋液即澄清。低溶解度之 20 化合物得到1分。此等化合物之第一次與第二次稀釋液 均不澄清。測定112種化合物之溶解度。其中有42種化 合物得到3分,32種化合物得到2分,及38種化合物得 到1分(參見表F-2)。 -155- 本紙張尺度適用t國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 ______ B7 五、發明說明(154) 行人工膜通透性分析法 於含2ml水性緩衝液系統pH 4或pH 7.4(PSR4系統 溶液濃縮物(ΡΙ0Ν))之深孔或預混合板中稀釋母液樣本 (10μ1含於1〇〇%DMS〇中之5πιμ母液)。添加樣本至參
5考板中之前’先添加150μ1緩衝液至孔中’測定空白UV 值。之後,棄置緩衝液,此板子用為參考板。所有測定 法均於耐UV之板子上進行(供應商:coaster或 Greiner)。 測定參考板之空白值後,添加15〇μ1稀釋之樣本至 10參考板中,添加200μ1稀釋樣本至供體板1中。使用4 μΐ人工膜形成溶液(1,2_二油醯基_順式_甘油_3_膽驗鱗酸 含於含0.1% 2,6-二-第三丁基-4-曱基苯酚之十二碳烷中) 塗覆受體過濾、板1(供應商:Millipore,ΜΑΙΡ Ν45型), 置於供體板1上方,形成’夾心’。添加緩衝液(2〇〇y)至上 15方之受體孔中。此”夾心”加蓋,保存在室溫與黑暗中18 小時。 經濟部智慧財產局員工消費合作社印製 添加150μ1緩衝液至孔中後,測定υν值’測定受體 板2之空白值。受體板2測定空白值後,棄置緩衝液, 自受體過濾板1中取出150μ1受體溶液移至受體板2中。 20然後自夾心中取出受體過濾板1。測定供體板2之空白值 (如上述)後,自供體板1中取出150μ1供體溶液移至供體 板2中。掃描供體板2、受體板2及參考板之孔中υν光 譜(Spectra MAX 190)。所有光譜均經PSR4p精算軟體 (Command Software)計算通透性。所有化合物均進行三重 -156- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(155) 覆。每次實驗均使用醯胺咪σ井(carbamazepine)、灰黃黴素 (griseofulvin)、無環鳥苷(acycloguanosine)、胺醯心安 (atenolol)、腹安酸(furosemide)與氣噻畊(chlorothiazide)作 為標準物。化合物分成三類:低通透性(平均值<0.5 χΐ〇_ 5 6cm/s ;得分 1) ’ 中通透性(1 xl〇'6cm/s>·^均值20.5 xlCT 6cm/s ;得分2)或高通透性㈣.5 X l(T6cm/s ;得分3)。所 試驗之22種化合物中’有14種化合物在所測試之兩種 pH值中之一得到至少3分。有3種化合物在其中一種 pH測定值下得到至少2分,及有5種化合物在其中一種 10 pH測定值下只得到1分。 眚例C.5 :代謝安定性 經濟部智慧財產局員工消費合作社印製 依據 Gorrod 等人(Xenobiotica 5 : 453-462,1975)製備 亞細胞組織製劑,其係使組織經過機械性均質化後離心 15 分離。肝組織於冰冷0.1M Tris-HCl(pH 7.4)缓衝液中潤 洗,以洗除過量血液。隨後吸乾組織,稱重,使用手術 用剪刀粗略剪斷。組織碎片於3倍體積冰冷之0.1M磷酸 鹽缓衝液(pH 7.4)中,使用裝有鐵弗龍搗杵之P〇tter-S(義 大利Braun公司)或Sorvall Omni-Mix均質器均質化7 xl〇 20 秒,均質化期間,容器保持在冰中/上。 組織均質液於4 °C下,使用Sorvall離心機或 Beckmann超離心機,於9000 xg下離心20分鐘。所得上 澄液保存在-80°C下,稱為"S9"。 此S9部份再使用Beckmann超離心機,於100,000 -157- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公爱) 200400941 A7 發明說明 156 經濟部智慧財產局員工消費合作社印製 xg下離心60分鐘(4。〇。小心吸出所得上澄液,此部份 稱為”皰液"。離心塊再懸浮於0.1M磷酸鹽緩衝液中(pH 7·4),每0.5克組織原始重之終體積為lml,稱為"微粒體 "〇 所有亞細胞組織部份分開後,立即於液態氮中冷 康’保存在_8(TC下,直到使用時為止。 試驗樣本之培養混合物含有PBS(O.IM)、化合物 (5咖)、微粒體(lmg/ml)與NADPHi生系統(〇.8mM葡萄 糖-6-磷酸、〇.8mM氯化鎂及0.8單位葡萄糖_6-磷酸去氫 酶)。對照組樣本含有相同材料,但微粒體改為經受熱去 活性(95。(3下10分鐘)之微粒體。對照組樣本中化合物之 回收率總是100%。 作匕合物於37 C下預培養5分鐘。添加〇.8mM 之零時間點(t=0)開始反應,樣本培養15分鐘 (t=15)。添加2倍體積DMSO停止反應。樣本隨後於 900xg下離心1〇分鐘’分析前保存在室温下之上澄液不 可超過24小時。所有培養均進行二重覆。採用LC-MS 分析法分析上澄液。於Xterra MS C18(50 x4.6 mm,5um,美 國Waters公司)上溶離樣本。採用Alliance 2790(供應 商:美國Waters公司)HPLC系統。溶離液為缓衝液A(含 於H20/乙腈(95/5)中之25mM乙酸銨(pH5.2)),溶劑B為 乙腈,且溶劑C為甲醇,流速為2.4ml/分鐘。所使用之 梯度為在5分鐘内’以線性梯度,使有機相濃度由0%逐 漸提高至50°/〇B與50%C,於1分鐘内至1〇〇%Β,然後保 10 15 20 -158- 本紙張尺度適用中國國家標準(cns)a4規格(2ΐ〇χ297公釐) 計 200400941 A7 B7 五、發明說明(丨57) 持有機相固定濃度1.5分鐘。注射樣本總體積為25μ1。 採用附有ESI光源之Quattro(供應商:英國曼徹斯特 市Microsome公司)三重四極質譜儀作為檢測器。光源與 去溶劑化溫度分別設定在120與35CTC,使用氮氣作為氣 5 霧劑及脫水氣體。以正掃瞄模式取得數據(單離子反應), 錐管電壓設定在10V,滯留時間為1秒。 代謝安定性以化合物於活性微粒體(E(act))之存在下 I5分鐘培養後之代謝%表示(代謝。/〇=100%-((E(act)於 t=15時之總離子電流(TIC)/ E(act)於t=〇時之TIC) X 10 100)。代謝百分比小於20%之化合物則定義為具高度代 經濟部智慧財產局員工消費合作社印制^ 謝安定性。代謝百分比在20與70%之間之化合物則定義 為具中度安定性’而代謝百分比南於70%之化合物則定 義為具低度代謝安定性。當進行代謝安定性試驗時,總 是包含3種參考化合物。使用菲帕米(VerapamU)作為低度 I5 代謝安定性之化合物(代謝%=73%)。使用希普萊德 (Cisapride)作為中度代謝安定性之化合物(代謝%^^%)。 使用丙醇作為中度至高度代謝安定性之化合物(代謝 %=25°/〇)。使用此等參考化合物確認代謝安定性分析法之 有效性。 20 試驗5種化合物’ 3種化合物之代謝百分比小於 20%,2種之代謝百分比在20至70之間。 實例C.6 : D21諉發能力 採用下列方法’於人類A2780卵巢癌瘤細胞上測定 -159- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 _ Β7 五、發明說明(158) P21蛋白質表現程度。將A2780細胞(20000個細胞/180μ1) 接種在96孔微分析板中’補充2mM L-筵醯胺、5〇Kg/ml 健大黴素與10%胎牛血清之RjpMI 164〇培養基中。溶解 細胞前24小時,化合物之最終添加濃度為1〇-5、10-6、 5 10與10 8M。所有試驗化合物均溶在dms〇中,再於培 養基中稀釋。添加化合物24小時後,排出細胞之上澄 液。以200μ1冰冷PBS洗蘇細胞。吸清凹孔,添加30μ1 溶胞緩衝液(5〇mM Tris.HCl(pH7.6),150mM HC1, 1%Ν— P40與10%甘油)。分析板於_7〇。〇下培養一 10 夜。 自金屬箔包裝中取出適量微滴定孔,置入空的凹孔 維持器中。製備洗滌緩衝液(20 χ分析板洗滌濃縮液: l〇〇ml PBS與界面活性劑之20倍濃縮液,含有2%氯乙醯 胺)之操作溶液(1 X)。冷凍乾燥之p21WAF標準物與蒸餾 15水重新組合,再經樣本稀釋液(由套組中供應)稀釋。 經濟部智慧財產局員工消費合作社印製 樣本經樣本稀釋液稀釋1 : 4。吸取樣本(1〇〇μ1)與 p21WAFl標準物(ΐ〇〇μΐ)加至適當凹孔中,於室溫下培養 2小時。以1 χ洗滌缓衝液洗滌凹孔3次後,吸取1〇〇μ1 檢測劑抗體試劑(生物素基化單株p21WAF1抗體溶液)加 20至各孔中。凹孔於室溫下培養1小時後,以1 χ洗滌緩 衝液洗蘇3次’稀釋400x共梃物(過氧化酶抗生物素共 軛物:4〇〇倍濃縮液)’取ΙΟΟμΙ 1 x溶液加至孔中。凹孔 於室溫下培養30分鐘後,以1 x洗滌緩衝液洗滌3次, 以蒸餾水洗滌1次。添加受質溶液(發色性受質)(1〇〇μ1)至 -160- m本紙張尺度適用中國國家標準(CNS)A4規格(210x297公楚) 200400941 A7 五、發明說明(I59 10 15 缓濟部智慧財產局員工消費合作钍印製 20 本紙張尺度適用中 孔中於”、、暗中至溫下培養3Q分鐘。依前述添加受質溶 液之相同順序添加停止反應溶液至 度計讀板機,於彻595nm雙重W㈣光 度。母次實驗均平行進行對(*含藥物)與空白培養組 (不含細胞或藥物)。所有賴組與樣本組數值均扣除空白 組數值。各樣本之p21WAF1誘魏值(單位為吸光度)以 相對於對照組中P21 WAF1數值百分比表示。誘發百分比 高於13G%時,定義為㈣誘發。本分析法巾,試驗% 種化合物,其中28種展現顯著之誘發作用。 實例C.7 : P450 #制能力 所有試驗化合物均溶於DMs〇(5mM)中,再於乙腈中 稀釋至5 X 104M。進一步使用分析緩衝液(〇1M NaK^ 酸鹽缓衝液ρΗ7·4)稀釋,最終溶劑濃度不可超過2%。 CYP3A4蛋白質之分析法包括每孔中含15师〇; P450/mg蛋白質(含於0 01M NaK磷酸鹽緩衝液 + 1.15%KC1中)' NADPH發生系統(含3 3mM葡萄糖_6_墙 酸、0.4U/ml葡萄糖-6-鱗酸去氫酶、1 NADP與 3.3mMMgCl26H2〇之分析緩衝液)及化合物,總分析體積 為1〇〇微升。於37t下預培養5分鐘後,添加15〇μΜ 含螢光探針受質BFC之分析緩衝液開始酵素反應。於室 溫下培養30分鐘後,添加2倍體積乙腈中止反應。於激 發波長405nm及發射波長535nm下測定螢光。其中包含 嗣基康哇(KetoconazoleXIC5。值=3 x 1〇-8m)作為此實驗之 -i Ο 丄· 國國家標準(CNS)A4規格(210x297公复)
200400941 A7 B7 五、發明說明(16〇) 參考化合物。 CYP2D6蛋白質之分析法包括每孔中含6pmol P450/mg蛋白質(含於0.01M NaK磷酸鹽缓衝液 + 1.15%KC1中)、NADPH發生系統(含〇,41mM葡萄糖-6- 5填酸、0.4U/ml葡萄糖-6-磷酸去氫酶、〇.〇〇82mM NADP 與〇.41mM MgCl2 6H2〇之分析緩衝液)及化合物,總分析 體積為100微升。於37°C下預培養5分鐘後,添加3μΜ 含螢光探針受質AMMC之分析缓衝液開始酵素反應。於 室溫下培養45分鐘後’添加2倍體積乙腈中止反應。於 10 激發波長405nm及發射波長460nm下測定螢光。其中包 含奎尼定(quinidineXIQo值<5 X 10·8Μ)作為此實驗之參考 化合物。 CYP2C9蛋白質之分析法包括每孔中含i5pmol P450/mg蛋白質(含於o.oiM NaK磷酸鹽缓衝液 15 +1-15%KC1中)、NADPH發生系統(含3.3mM葡萄糖-6-磷 經濟部智慧財產局員工消費合作社印製 酸、〇.4U/ml葡萄糖-6-磷酸去氫酶、i.3mM NADP與 3.3mMMgCl26H20之分析緩衝液)及化合物,總分析體積 為100微升。於37°C下預培養5分鐘後,添加200μΜ 含螢光探針受質MFC之分析緩衝液開始酵素反應。於室 20溫下培養30分鐘後’添加2倍體積乙腈中止反應。於激 發波長405nm及發射波長535nm下測定螢光。其中包含 速吩唑(sulfaph0nazole)(IC50值=6.8 X 1(Γ7Μ)作為此實驗之 參考化合物。 初次篩選時,化合物固定在1 X 1〇-6Μ之單一試驗濃 -162- 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 Α7 五、發明說明(161 度。試驗活性化合物時,則重覆容,、 只艰C ’以建立完替之、,曲 度-效應曲線。每次實驗均平行進杆考 /辰 *白声春租「不A睹去m (不含藥物)與 :白培養.咐3酵钱_)。所有化合 覆。所有對照組與樣核數值均扣除空白組數^ ^ 10 15 經濟部智慧財產局員工消費合作、社印製 20 本之剛活性平均值(以相對螢光單位表示)以相對於對 照组中P450活性平均值之百分比表示。抑制作分 以刚〇/。減去樣本中P450活性平均值表示。若適,匕 計算IQ。值(使P450活性下降至對照組之寫時二需藥 物濃度)。本分析法分析4種化合物。其中只有—種化二 物可使用CYP3A4蛋白質測得IC5〇值為7·9χι〇_6Μ。。 實例c·8 : Α 2780小白鼠異種移棺物禮< 在免疫缺乏性小白鼠皮下注射A 2780卵巢癌瘤細胞 (107個細胞/200μ1/隻)。隨後在第4天至第32天之間每天 一次經口投與10、20與40mpk化合物。此化合物係溶 於0.9o/〇NaCl、20〇/〇泠-環糊精中。第32天時,收集腫 瘤,分別測量每隻小白鼠之各腫瘤重量。每次實驗包括 10隻小白鼠。 每天一次經口投舆10、20與4〇mpk Νο·6化合物之 兩次獨立之Α2780異種移植物實驗顯示,所有試驗劑量 均展現強烈之抗腫瘤效果,最高抑制作用在20mplc時出 現一次,在4〇nipk時出現一次。 -163- } 2本紙張尺度適用尹國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A7 B7 五、發明說明(l62) 表F-2 :表F-2出示依據實例C.l、C.2與C.3試驗之化合 物之結果 經濟部智慧財產局員工消費合作社印製 化合物編號 酵素活性 細胞活性 溶解度分數 1 6.482 <5 2 7.147 5.713 1 3 <5 <5 1 4 <5 <5 2 5 <5 <5 6 8.186 7.336 2 7 <5 8 7.587 5.642 3 9 <5 5.411 10 6.7 <5 1 11 <5 5.995 12 <5 5.086 13 <5 6.355 1 14 6.621 5.237 3 15 7.332 6.971 2 16 <5 <5 17 <5 6.117 1 18 <5 5.389 1 19 <5 <5 1 20 >5 21 6.38 22 <5 23 >5 24 >5 26 >5 28 5.265 29 >5 30 >5 32 ,5.835 33 \·>5 37 5.624 42 >5 43 >5 44 >5 -164- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明( 經濟部智慧財產局員工消費合作社印製 化合物編號 酵素活性 細胞活性 溶解度分數 49 >5 52 >5 55 >5 56 <5 57 >5 58 >5 60 6.247 5.344 3 61 6.255 5.555 2 62 5.409 6.416 1 63 6.215 5.731 1 64 5.753 5.05 3 65 5.775 <5 3 66 6.197 5.877 1 67 5.177 6.068 1 68 6.908 5.911 1 69 5.978 <5 3 70 5.914 5.391 3 71 6.449 5.608 3 72 6.346 6.026 1 73 6.212 5.402 1 74 5.841 5.584 2 75 <5 5.163 76 6.227 5.867 1 ΊΊ 5.937 5.149 78 6.306 5.904 2 79 6.238 5.368 1 80 5.961 5.909 1 81 6.873 5.887 1 82 5.821 5.968 3 83 6.157 5.886 1 84 <5 <5 85 <5 <5 86 * ' <5 <5 87 <5 <5 BB 6.481 5.547 3 89 6.423 5.217 90 7.467 5.953 3 91 7.688 6.106 3 -165- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(!64) 經濟部智慧財產局員工消費合作社印製 化合物編號 酵素活性 細胞活性 溶解度分數 92 7.876 6.141 93 7.464 6.342 3 94 7.497 6.661 2 95 7.363 5.957 3 96 7.49 6.475 3 97 7.938 6.903 98 7.054 6.448 2 99 7.316 6.617 3 100 8.171 7.237 2 101 6.671 6.994 102 7.162 6.452 2 103 7.586 6.826 2 104 8.152 7.233 105 6.494 6.098 1 106 7.797 6.589 2 107 7.663 6.841 2 108 8.117 6.679 1 109 7.176 6.588 2 110 7.713 6.352 2 111 7.561 6.357 1 112 7.54 6.482 3 113 <5 <5 114 7.428 6.125 3 115 <5 5.695 116 7.159 6.065 1 117 <5 5.759 118 6.741 5.276 3 119 5.215 <5 120 6.491 5.994 1 121 6.833 5.557 3 122 7.06 <5 123 6.787 5.589 3 124 8.358 7.32 3 125 8.659 7.031 2 126 8.456 6.989 1 127 8.482 7.162 3 128 8.078 7.09 2 129 7.107 6.687 3 -166- 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200400941 A7 B7 五、發明說明(I65) 經濟部智慧財產局員工消費合作社印制衣 化合物編號 酵素活性 細胞活性 溶解度分數 130 6.159 6.124 2 131 6.058 6.263 2 132 7.162 6.336 133 7.869 5.899 2 134 7.662 6.501 2 135 7.631 6.542 3 136 7.288 6.29 1 137 7.169 5.951 2 138 7.545 6.604 2 139 7.612 7.258 140 7.739 7.001 141 7.125 6.004 142 8.01 6.543 3 143 7.002 5.879 3 144 8.428 7.089 3 145 8.06 6.555 1 146 8.565 6.926 147 6.765 6.159 1 148 7.94 6.755 1 149 8.175 6.843 2 150 8.011 6.784 2 151 8.152 6.864 3 152 8.156 6.785 3 153 8.7 6.561 154 8.869 7.194 1 155 7.939 7.06 156 8.568 7.523 157 8.228 7.017 3 158 7.784 6.351 2 159 8.61 7.018 3 160 8.272 6.556 2 162 8.215 6.933 3 162 ^ 7.83 7.039 1 163 8.553 7.37 164 8.308 7.316 2 165 7.947 7.255 1 166 7.969 7.212 1 167 7.579 6.968 3 -167- 丨ί;本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(⑽) 化合物編號 酵素活性 細胞活性 溶解度分數 168 8.766 7.195 3 169 8.338 7.14 3 170 8.227 7.185 3 171 8.45 7.327 3 172 8.566 7.191 3 173 8.423 7.152 3 174 8.212 7.095 3 175 7.691 7.162 1 176 6.513 6.082 2 177 6.428 6.511 1 178 7.99 7.122 1 179 7.146 6.925 2 180 <5 <5 181 7.098 6.925 3 182 7.634 7.06 1 183 7.631 5.634 2 184 7.22 7.202 1 185 6.417 6.795 1 186 6.539 6.253 2 D.組合物實例:膜衣錠 錠劑核心製法 經濟部智慧財產局員工消費合作社印製 取含100g式(I)化合物、570g乳糖與200g澱粉之混 5 合物混合均勻後,與含5g十二烷基硫酸鈉及10g聚乙烯 吡咯啶酮之約200ml水溶液濕化。濕粉末混合物經過 篩、乾燥及再過篩一次。然後添加100g微晶纖維素與 15g氫化植物油。全部混合均勻,壓成錠劑,產生10,000 片錠劑,各含l〇mg式(I)化合物。 10 包衣 添加含5g乙基纖維素之150ml二氯甲烷溶液至含 10g甲基纖維素之75ml變性乙醇溶液中。然後添加75ml -168- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A7 B7 五、發明說明(l67 ) 二氣曱烷與2.5 ml 1,2,3-丙三.醇。取10g聚乙二醇熔化及 溶解於75 ml二氣曱烷中。後項溶液加至前項溶液中,然 後添加2.5g十八碳烧酸鎂、5g聚乙稀β比咯咬酮與30 ml 濃縮色素懸浮液,全部均質化。於包覆設備中,以所得 5 混合物包覆旋劑核心。 經濟部智慧財產局員工消費合作社印製 -169- 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐)
Claims (1)
- 200400941 A8 B8 C8 D8 、申請專利範圍 1. 一種式(I)化合物 R45 R2 其N-氧化物型、其醫藥上可接受之加成鹽及立體化 學異構型,其中 η為0、1、2或3,且當η為0時,則為一直接鍵 10 結; t為0、1、2、3或4,且當t為0時,則為一直接鍵 結, 各Q為氣或一; 各X為氮或一c< ; 15 各Y為氮或一C<; 各Z為氮或一CH< ; 經濟部智慧財產局員工消費合作社印製 R1 為-C(0)NR7R8、-N(H)C(0)R9、-CCC^Cw 烷二基 SR9、-NR1QC(0)N(0H)R9、烷二基 SR9、-NR1GC(0)C=N(OH)R9 或另一個 Zn-螯合基, 20 其中R7與R8分別獨立選自:氫、羥基、Cp6烧 基、經基烧基、胺基Ci_6烧基或胺芳基; R9分別獨立選自:氫、Cw烷基、Cw烷羰基、芳 基C!.6炫基、Ck统基吼°井基、吼咬®5]、σ比σ各咬 酮或甲基咪唑基; -170 - 本纸張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 92080B 200400941申請專利範圍 10 15 2R分別獨立選自:氫或Cw烷基; R為氫、齒基、羥基、胺基、硝基 烷氧基、三氟浐其、股 基、Cl·6 芏〜1 胺基、_基或 奈石買8&基吡畊基; -L-為一直接鍵結或選自下列之二價基 一 甘 -j, ^ 1-6 — 基、胺基、羰基或胺羰基; 各R3分職立代表氫原子,且其中—個氫原子可被 芳基置換; R4為氫、羥基、胺基、羥基Cm烷基、Cu6烷基、Cl_6 烷氧基、芳基Cw烷基、胺羰基、羥羰基 '胺基 Ci_6烧基、胺幾基c!_6烧基、經幾基Cu烧基、經 胺羰基、CN6烷氧羰基、Cm烷胺基q.6烷基或二 (Ci.6烧基)胺基Ci_6烧基; 為選自下列之基團:(a-l)(a-2) j:R5)s(a-3)(a-4) 經濟部智慧財產局員工消費合作社印製 20 iR6)s(a-5)(a-ό) -171 b)s N ,0 (a-7) H(a-8) 本紙張尺度賴中關家群(cms)A4規格(21()x297 Ai) 200400941 Αδ Β8 C8 D8 申請專利範圍(a-10) (R6)s ,〇、n /(a-12) (a-H) ®6)s 〈r6)s o- -N (a-I3) -N (a-14)-s (a-16) :R6)s〇 iR6)s xh3/ '、八/ H^C N /N - W (a-17) N / NH (a-18)-本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 1 200400941 A8 B8 C8 D8 六、申請專利範圍v、本紙張尺度適用中國國家標準(CNS)A4規格(210 x297公釐) 200400941 A8 B8 C8 D8 六、申請專利範圍 其中各S分別為0、1、2、3、4或5; 各R5與R6分別獨立選自風,画基,每基,胺基;石肖 基;三鹵Ci_6院基;三鹵C!_6燒氧基;Ci_6烧基; 經芳基與C3_H)環烷基取代之CN6烷基;CU6烷氧 5 基;Ci_6院氧基Ci-6烧氧基;Ci_6烧幾基;Ci.6院 氧幾基;Ci-6院績酿基;氰基C!_6烧基;經基Ci_6 烧基;輕基Ci-6燒氧基;經基Cu烧胺基;胺基 Ci_6烧氧基;二(Ci_6烧基)胺戴基;二(¾基Ci.6烧 基)胺基;(芳基)(Cu燒基)胺基,二(Ci-6院基)胺 1〇 基Ci_6烧氧基;二(Ci-6烧基)胺基Ci-6院胺基;二 (Ck院基)胺基Ci-6燒胺基Ci_6院基;芳基石黃酿 基;芳基績釀基胺基;芳氧基;芳氧基Cp6燒 基;芳基C2-6稀二基;二(Ck烧基)胺基;二(Ci-6 烧基)胺基Ci胃6院基;二(Ci_6燒基)胺基(Ci_6院基) 15 胺基;二(Ci_6烧基)胺基(Ci-6烧基)胺基Ci_6院基; 二(Cu烧基)胺基C!_6院基(Ci_6烧基)胺基;二(Ci-6 烧基)胺基C!_6燒基(Ck烧基)胺基C1-6烧基; 胺基確酸基胺基(Ci-6烧基)胺基; 經濟部智慧財產局員工消費合作社印製 胺基績酿基胺基(Ci_6炫基)胺基Ci_6院基; 20 二(Ci_6烧基)胺基墙驢基胺基(C!_6烧基)胺基; 二(Cu烧基)胺基續酿基胺基(Cu烧基)胺基Ck院 基;氰基;硫苯基; 經下列基團取代之硫苯基:二(Cm烷基)胺基C!_6烷 基((^_6烷基)胺基C!_6烷基、二(Cm烷基)胺基C!_6烷 -174 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 A8 B8 C8 D8 六、申請專利範圍 基、Ci-6烧基六氮吼17井基Cu院基、經基Ci_6規基六 鼠σ比π井基C!_6院基、每基Ci-6院氧基Cu院基六氮3比 σ井基Ci-6烧基、二(Ci-6貌基)胺基續酿基六氳。比。井基 Cw烷基、C!_6烷氧基六氫吡啶基、Ci_6烷氧基六氫 5 吡啶基Cw烷基、嗎福咁基CN6烷基、羥基CN6烷基 (Ci_6貌基)胺基Ci-6院基、或二(經基Cu烧基)胺基 Ci-6燒基; 咬喃基:經經基C1 _6烧基取代之咬喃基;苯並吱_ 基;咪唑基;畤唑基;經芳基與C!_6烷基取代之畤唑 10 基;Cw烷基三唑基;四唑基;吡咯啶基;吡咯基; 六氫σ比淀基Ci-6競·氧基;嗎福4基;Ci_6院基嗎福喷 基;嗎福σ林基Cu院氧基;嗎福咐基Ci_6燒基;嗎福 咐基Ci-6烧胺基;嗎福嘴基Ck院胺基Ci_6烧基;六 氫吡畊基;C!_6烷基六氫吡畊基;Ci_6烷基六氫吡畊 15 基烷氧基;六氫吡畊基Cm烷基;萘磺醯基六氫 經濟部智慧財產局員工消費合作社印製 吡畊基;萘磺醯基六氫吡啶基;萘磺醯基;<^_6烷基 六氫峨11井基Ci_6院基;Ci_6院基六氫吼11井基C!_6院胺 基,Ci_6統基六氮吼。井基Ci_6院胺基Ci_6燒基;Ci_6 院基六氮吼啡基墙驢基;胺基項酿基六氮。比讲基C!_6 20 烷氧基;胺基磺醯基六氫峨畊基;胺基磺醯基六氫咕 σ井基Ci_6烧基,二(Ci_6烧基)胺基項醯基六氮。比13井 基;二(Cu院基)胺基續驢基六氫吼σ井基Ci_6烧基; 經基Ci_6院基六氫吼σ井基;羥基Ci_6院基六氫吼11 井基 Cw烷基;Cw烷氧基六氫吡啶基;Cm烷氧基六氫 -175 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X297公釐) 200400941 A8 B8 C8 D8 六、申請專利範圍 σ!λσ定基Ci-6烧基;六氮。比淀基胺基Ci_6烧胺基;六氫 。比淀基胺基C!_6院胺基Cu烧基; (Ci_6烧基六鼠°比淀基)(¾基Ci_6院基)胺基C!_6烧胺 基; 5 (Ci-6烧基六氫σ比淀基)(¾基Ck烧基)胺基Ci_6烧胺基 Cu烧基, 舞基Ci_6烧氧基Ci_6烧基六氳11比17井基; 罗至基Ci_6跪氧基Ci_6烧基六氫。比°井基Ck貌基; (經基Ci_6院基)(Ci_6烧基)胺基;(經基C!_6院基)(Ci_6 10 院基)胺基Ci_6院基; 經基Ci_6烧胺基Ci.6燒基;二(經基Ci_6烧基)胺基Ci_6 烧基; 吡咯啶基C!_6烷基;吡咯啶基Cw烷氧基;吡唑基; 硫1^比。坐基;經選自Ck烧基或三鹵Cu烧基中兩個取 15 代基取代之吡唑基; 經濟部智慧財產局員工消費合作社印制衣 吡啶基;經Ci_6烷氧基、芳氧基或芳基取代之吡啶 基;嘧啶基;四氫嘧啶基六氫吡σ井基;四氫嘧啶基六 鼠吼σ井基C 1_6烧基,0奎啡基,σ朵基;苯基,經分別 獨立選自下列1、2或3個取代基取代之苯基:鹵 20 基、胺基、頌基、Cl-6‘烧基、Ci_6烧氧基、經基Ci-4 烧基、三氟曱基、三氟曱氧基、經基Ci-4烧氧基、 Ci-4院基續釀基、Ci-4院氧基Ci-4院氧基、Ci_4烧氧 罗炭基、胺基Ci_4烧氧基、二(Ci-4院基)胺基Ci_4競》氧 基、二(Ci_4烧基)胺基、二(Ci_4院基)胺幾基、二(C^4 -176 - 、本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 AS Βδ C8 D8 六、申請專利範圍 烷基)胺基C!_4烷基、二(Cm烷基)胺基CK4烷胺基 Cm烷基、二(Cm烷基)胺基(CM烷基)胺基、二((:μ4 烧基)胺基(Ci-4烧基)胺基Ci_4烧基、 (Cl-4貌基)胺 基CN4烷基(Cm烷基)胺基、二(Cm烷基)胺基Cw烷 5 基(Ci_4烧基)胺基Ci-4烧基、胺基續酿基胺基(Ci_4烧 基)胺基、胺基磺醢基胺基(Cm烷基)胺基(^_4烷基、 二(Ci.4院基)胺基確酿基胺基(Ci.4烧基)胺基、二(Cu 烧基)胺基續疏基胺基(Ci.4烧基)胺基Ci.6烧基、氰 基、六氫吡啶基Cm烧氧基、吡咯唆基CN4烧氧基、 1〇 胺基磺醯基六氫吡畊基、胺基磺醯基六氫吡畊基CN4 烷基、二(CM烷基)胺基磺醯基六氫吡畊基、二(Cm 烷基)胺基磺醯基六氫吡畊基cM烷基、羥基cM烷 基六氫吡畊基、羥基CK4烧基六氫吡畊基Ci_4烧基、 Cn4烷氧基六氩吡啶基、Cm烷氧基六氫吡啶基cu4 15 烷基、羥基C!-4烷氧基Cm烷基六氫吡畊基、羥基 經濟部智慧財產局員工消費合作、社印製 Cm烷氧基Cm烷基六氫吡畊基C!.4烷基、(羥基Cm 烷基XCm烷基)胺基、(羥基q.4烷基xq.4烷基)胺基 Ci-4烧基、-—(經基Ci.4烧基)胺基、二(輕基Ci.4烧基) 胺基Cw烷基、呋喃基、經_CH=CH-CH=CH-取代之 20 呋喃基、吡咯啶基Cl4烷基、吡咯啶基CN4烷氧基、 嗎福咁基、嗎福咁基CN4烷氧基、嗎福咁基CM烷 基、嗎福啉基Cm烷胺基、嗎福啉基Cm烷胺基Cm 烧基、六氫吡哨基、Cm烷基六氫吡畊基' Ci-4烷基 六氫吡畊基Cm烷氧基、六氳吡α井基Cm烷基、Cm -177 -ί. 3#轶張尺度適用中國國家標準(CNS)A4規格(210 X 297公笼) 200400941 A8 B8 C8 D8 7、申請專利範圍 院基六氯咐。井基Ci_4烧基、Ci_4貌基六氮咐I 17井基Ci-4 烧胺基、Ci_4院基六鼠吼17井基Ci_4烧胺基Ci_6烧基、 四氫痛淀基六氫。比。井基、四氫嘯淀基六氫咐。井基Cw 烧基、六氮峨咬基胺基Ci _4炫胺基、六氮σ比淀基胺基 5 Ci_4院胺基Ci-4院基、(Ci_4競*基六氫11比淀基)(經基Ci-4 烧基)胺基Ci_4燒胺基、(Cw烧基六氫。比淀基)(經基 Ci_4烧基)胺基Ci_4燒胺基Ci_4烧基、^比。定基Ci_4燒氧 基、輕基Ci_4烧胺基、輕基Ci_4燒胺基Ci_4烧基、二 (Ci_4烧基)胺基C!_4烧胺基、胺基嗟二σ坐基、胺基石黃 10 釀基六氮0比3井基Ci_4烧氧基、或硫苯基Ci-4貌胺基; /—(CH2)n 中心之—_/Z—部份基團亦可與亞甲基、伸乙 基或伸丙基橋連基形成橋連(亦即形成雙環狀部份基 團); 15 各R5與R6可置於氮上替代氫; 上述芳基為苯基,或經一個或多個分別獨立選自:鹵 基、Ci.6烧基、Ci.6烧氧基、三氟甲基、氰基或經幾 基之取代基取代之苯基。 經濟部智慧財產局員工消費合作社印製 2.根據申請專利範圍第1項之化合物,其中 20 R7與R8分別獨立選自’:氫、羥基、羥基Cm烷基、胺 基Ci.6烧基或胺芳基; R2為氫、鹵基、經基、胺基、頌基、Ci.6烧基、Cl.6烧 氧基、三氟甲基、羥胺基或萘磺醯基吡畊基; R4為氫、羥基、胺基、羥基Ci.6烷基、Ci.6烷氧基、 -178 - :本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A8 B8 C8 D8 六、申請專利範圍 芳基Ci_6炫基、胺幾基、經獄基、胺基Ci-6院基、 胺羰基Cm烷基、羥羰基CN6烷基、羥胺羰基、Cu 烧氧基幾基、C!_6烧胺基C1.6烧基或二(C!_6烧基)胺 基Ci-6烧基; 5 —{^)為選自下列之基團:(a·1)、(a-2)、(a_3)、 (a-4) 、 (a-5) 、 (a-6) 、 (a-7) 、 (a-8) 、 (a-9) 、 (a-10) 、 (a_ ll)、(a-12)、(a-13)、(a-14)、(a-15)'(a-16)、(a-17) ' (a-18) ' (a-19) > (a-20) ' (a-21) ' (a-22) ' (a-23)、(a-24)、(a-25)、(a-26)、(a-27)、(a-28)、(a-10 29)、(a-30)、(a-31)、(a-32)、(a-33)、(a-34)、(a- 35)、(a-36)、(a-37)、(a-38)、(a-39)、(a-40)、(a-41)、(a-42)、(a-43)或(a-44); 各R5與R6分別獨立選自氩;鹵基;羥基;胺基;硝 基;三鹵CN6烷基;三鹵C!_6烷氧基;Cm烷基; 15 Cu烷氧基;Cm烷氧基Cm烷氧基;Cu烷羰基; 經濟部智慧財產局員工消費合作社印製 Cm烷磺醯基;氰基Cm烷基;羥基Cm烷基;羥 基Cw烷氧基;羥基CV6烷胺基;胺基CN6烷氧 基;二(Cw烷基)胺羰基;二(羥基Cw烷基)胺基; 二(Cy烷基)胺基Q-6烷氧基;二(C,.6烷基)胺基Cm 20 烷胺基;芳基磺醯基;芳基磺醯基胺基;芳氧基; 方基C2-6稀·一基,·一(Ci_6烧基)胺基,亂基;硫苯 基;經下列基團取代之硫苯基:二((^.6烷基)胺基 (^1-6烧基(^.6院基)胺基〇1_6烧基、二((31.6烧基)胺基 Cj-6烷基、Cw烷基六氫吡a井基Ci_6烷基或二(羥基 -179 - .本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A8 B8 C8 D8 ?、申請專利範圍 Ci-6院基)胺基Ci_6燒基;吱σ南基;11 米11 坐基;Ci_6烧 基二σ坐基,四坐基,六氮σ比唆基Ci _6烧氧基,嗎福 啡基;Cw烷基嗎福咁基;嗎福咁基Cw烷氧基; 嗎福咐基Cu燒基,Cu燒基六氮。比°井基Ci_6烧氧 5 基;Ci-6院基六鼠°比σ井基Ci_6烧基;Ci_6燒基六氮。比 σ井基續釀基,胺基續酸基六氮σ比叫基Ci _6烧氧基; 胺基續酿基六鼠啦。井基,胺基續驢基六氮吼σ井基Ci_6 烧基;二(Ci_6烧基)胺基項聽基六氮°比啡基;二(C!_6 院基)胺基續酸基六氮吼σ井基Ck龍基;經基C!_6烧 10 基六氫吡畊基;羥基Cw烷基六氫吡畊基Cw烷 基;Ci_6烷氧基六氫吡啶基;Cm烷氧基六氫吡啶基 Ci_6烷基;羥基Cm烷氧基CV6烷基六氫吡畊基; 羥基Cg烷氧基C!_6烷基六氫吡畊基Cw烷基; (¾基Ci-6烧基)(Ci-6烧基)胺基;(經基Ci_6烧基)(Ci_6 15 烧基)胺基Ci_6院基; 吡咯啶基CN6烷氧基;吡唑基;硫吡唑基;經選自C!_6 烷基或三鹵Ci_6烷基中兩個取代基取代之吡唑基; 經濟部智慧財產局員工消費合作社印製 吡啶基;經CN6烷氧基或芳基取代之吡啶基;嘧啶 基;喳咁基;苯基;經分別獨立選自下列1、2或3個 20 取代基取代之苯基:函基、胺基、Cw烷基、Cm烷氧 基、經基Ci_4烧基、三氟甲基、三氟甲氧基、經基Ci_4 烧氧基、Ci_4院氧基Ci_4燒氧基、胺基C!_4烧氧基、 二(Ci_4院基)胺基Ci_4烧氧基、二(Ci_4烧基)胺基、六 氫°比咬基Ci_4院氧基、σ比洛咬基Ci_4烧氧基、胺基石黃 -180 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A8 B8 C8 D8 六、申請專利範圍 酿基六氮。比σ井基、胺基續酸基六氮u比π井基C 1 _4院基、 二(Ci.4院基)胺基續酿基六風0比σ井基、二(Ci_4院基)胺 基石黃龜基六氮°比0井基Ci_4烧基、輕基Ci_4院基六氫0比 σ井基、每基C!_4烧基六氮ΰ比σ井基Ci_4院基、Ci_4烧氧 5 基六氫吼淀基、C!-4燒氧基六氫吼σ定基Ci.4院基、經 基Ci.4院氧基Cl-4烧基六氫咐17井基、經基Ci_4烧氧基 Ci_4烧基六氮啦11 井基C〖_4烧基、(¾基Ci_4院基)(Ci_4貌 基)胺基、(¾基Ci_4烧基)(Ci_4烧基)胺基Ci_4烧基、1:7比 略淀基Ci_4院氧基、嗎福咐基Ci_4院氧基、嗎福咐基 1〇 Ci_4烧基、Ci_4烧基六氫σΛσ井基Ci_4院氧基、Ci_4燒基 六氫吼σ井基Ci_4院基、經基Ci_4烧胺基、二(經基Ci_4 烧基)胺基、二(Cm烧基)胺基Ci_4烧胺基、胺基σ塞二 σ坐基、胺基項釀基六氫吼σ井基Ci_4院氧基、或硫苯基 Ci_4烧胺基。 15 3.根據申請專利範圍第1項之化合物,其中 t為0 ; 經濟部智慧財產局員工消費合作社印製 R1 為-C(0)NR7R8、-C(0)Ci_6 烷二基 SR9、-NR1GC(0)N(0H)R9、-NRWCCCOCm 烷二基 SR9、-NR1GC(0)C=N(0H)R9 或另一個 Zn-螯合基, 20 其中R7與R8分別獨立選自:氫、羥基、羥基Cw烷 基或胺基Ci_6烧基; R2為氮、鹵基、备基、胺基、石肖基、Ci_6烧基、匚1_6院 氧基、三It曱基或二(Ci_6燒基)胺基; -L-為一直接鍵結或選自下列之二價基圑:Cw烷二 -181 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A8 B8 C8 /、、申晴專利範圍 基、胺基或獄基; R4為氫、羥基、胺基、羥基Cl_6烷基、<^_6烷基、Cw 烷氧基 '芳基Cm烷基、胺羰基、胺基Ck烷基、 匸1-6烧基胺基(^1_6烧基或二((^1.6烧基)胺基(^1-6烧 5 基; -Ο 為選自下列之基團:(a-1)、(a-3)、(a-4)、 (a-5)、(a-6) ' (a-7) ' (a-8)、(a-9)、(a-10)、(a-11)、 (a-12) ' (a-13) ' (a-14) ' (a-15) ' (a-16) ' (a-17) ' (a-18)、(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-10 24)、(a-25)、(a-26)、(a-28)、(a-29)、(a-30)、(a- 31)、(a-32)、(a-33)、(a-34)、(a-35)、(a-36)、(a-37)、(a-38)、(a-39)、(a-40)、(a-41)、(a-42)、(a-44)、(a-45)、(a-46)、(a-47)、(a-48)或(a-51); 各s分別為0、1、2、3或4 ; 經濟部智慧財產局員工消費合作社印製 15 R5為氫;鹵基;羥基;胺基;硝基;三鹵Cm烷基; 三_ C!-6烧氧基;Ci-6烧基;C丨-6烧氧基;Ci_6烧幾· 基;C!.6烷氧羰基;Cm烷磺醯基;羥基Cu烷基; 芳氧基;二(C!-6烷基)胺基;氰基;硫苯基;呋喃 基;經羥基C!-6烷基取代之呋喃基;苯並呋喃基; 20 咪唑基;啐唑基;經芳基與Cm烷基取代之哼唑 基;C!-6烷基三唑基:四唑基;吡咯啶基;吡咯 基;嗎福咻基;Ck烷基嗎福咁基;六氫吡畊基; Q.6烷基六氫吡畊基;羥基Cw烷基六氫吼畊基; Cu院氧基六氫吼咬基;°比唆基;經選自Ci-6烧基或 -182 - 彳^本紙張尺度適用中國國家標準(CNS)A4規格(210x297公爱) 經濟部智慧財產局員工消費合作社印製 200400941 A8 BS C8 D8 τ、申請專利範圍 三鹵Ci_6烷基中一或兩個取代基取代之吡唑基;吼 啶基;經cN6烷氧基、芳氧基或芳基取代之吡咬 基;嘧啶基;喳啉基;吲哚基;苯基;或經分別獨 立選自:1¾基、Ci_6烧基、Ci-6烧氧基或二氟甲基中 5 之1或2個取代基取代之苯基; R6為氮;ώ基;每基;胺基;石肖基;三鹵C1 _6烧基; 三鹵Ci_6烧氧基;Ci_6烧基;Ci_6炫·氧基;Ci.6烧幾 基,Ci-6烧氧辕基,Ci.6烧續酸基;輕基Ci.6烧基; 芳氧基;二(Cu烷基)胺基;氰基;吡啶基;苯基; 10 或經分別獨立選自:鹵基、Cm烷基、Cm烷氧基或 三氟甲基中之1或2個取代基取代之苯基; /—(CH2)n 中心之—\_产-部份基團亦可與伸乙基橋連基 形成橋連(亦即形成雙環狀部份基團)。 15 4.根據申請專利範圍第1項之化合物,其中η為1或2 ; t為0、1或2;各Ζ為氮;R1Q為氫;R2為氫、硝基、 Ci-6烧氧基、三氟甲基、二(Ci_6烧基)胺基、經胺基或 萘磺醯基吡啡基;-L-為一直接鍵結或選自下列之二價 基團:Cw烷二基、羰基或胺羰基;各R3代表氫原 20 子;R4為氳、經基Ci烧基、胺幾基、經胺幾基或二 (Ci-6娱*基)胺基Ci_6烧基; 為選自(3-1)、(3_ 7)、(a-9)、(a-10)、(a-12)、(a-14)、(a-19)、(a-20)、(a-21)、(a-22)、(a-23)、(a-30)、(a-34)、(a_49)或(a-50)之 基團;各s分別為0、1、2或5 ;各R5與R6分別獨立 -183 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐)200400941 A8 B8 C8 D8 六、申請專利範圍 選自:氮;虐基,石肖基;三鹵Cl _6烧基;三鹵Cl 烧 氧基;Cw烷基;烷氧基;CN6烷磺醯基;(芳 基)(C!_6烧基)胺基;芳基績酿基;芳氧基;芳基C2-6稀 二基;二(Cu烷基)胺基;硫苯基;經下列基團取代之 5 硫苯基:二(Ci_6燒基)胺基院基(Ci_6烧基)胺基Ci-6 院基、二(C!_6烧基)胺基C1-6跪基、Ci_6貌基六氩13比。井 基C1 _6烧基、說基C1 烧基六氮^比σ井基C1 _6烧基、經 基Ci_6烧氧基Cu燒基六氩井基Ci_6貌基、二(C!-6 烧基)胺基續酿基六氫吼u井基C!_6院基、C!„6烧氧基六 10 氫吡啶基c!_6烷基、嗎福咁基cv6烷基、羥基C!_6烷 基(C^6院基)胺基Ci_6烧基、或二(經基Ci.6燒基)胺基 Ck烧基; 經濟部智慧財產局員工消費合作社印製 吱喃基;坐基:吡咯基;坐基;咕淀基;經Ck 烷氧基取代之吡啶基;喳啉基;吲哚基;苯基;經分 15 別獨立選自下列1、2或3個取代基取代之苯基:鹵 基、胺基、Ci_6燒基、Ci_6烧氧基、經基Ci_4烧基、三 氟曱基、三氟甲氧基、二(C!_4炫基)胺基Ci_4烧氧基、 二(Cw烷基)胺基、二(Cm烷基)胺基Cw烷基、二(C!_4 燒基)胺基Ci_4娱•基(Ci_4烧基)胺基、二(Ci_4院基)胺基 20 C!-4烧基(Ci-4烧基)胺基Ci-4院基、备基Ci_4燒基六氮 吡畊基Ci_4烷基、羥基Cw烷氧基Cw烷基六氫吡畊 基Ci_4烧基、二(¾基Ci_4烧基)胺基Ci_4燒基、峨p各咬 基Ci_4烧基、吼σ各淀基Ci_4院氧基、嗎福咐基Ci_4院 氧基、嗎福嘴基Ci_4院基、Ci_4競•基六氯咕11井基Ci_4烧 -184 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200400941 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 τ、申請專利範圍 基,或 /—(CH2)n \ 中心之—_/Z—部份基團亦可與亞甲基橋連基形 成橋連(亦即形成雙環狀部份基團)。 5 5.根據申請專利範圍第1與4項之化合物,其中η為1 或2;t為0、1或2;各Ζ為氮;R1()為氫;R2為氫、 石肖基、Ci_6烧氧基、三氟*甲基、二(Ci_6烧基)胺基、經 胺基或萘磺醯基吡畊基;-L-為一直接鍵結或選自下列 之二價基團:Cw烷二基、羰基或胺羰基;各R3代表 10 氫原子;R4為氫、羥基Cw烷基、胺羰基、羥胺羰基 或二(Cy烷基)胺基Cm烷基;一為選自(a-Ι)、 (a-7)、(a-9)、(a-10)、(a-12)、(a-14)、(a-19)、(a-20)、 (a-21)、(a-22)、(a-23)、(a-30)、(a-34)、(a-49)或(a-50) 之基團;各s分別為0、1、2或5 ;各R5與R6分別獨 15 立選自:氫;鹵基;硝基;三鹵Ck烷基;三鹵CN6 院氧基,競*基,院氧基,Ci_6烧石黃酿基;(芳 基)(Ci_6烧基)胺基;芳基續龜基;芳氧基;芳基C2-6稀 二基;二(CN6烷基)胺基;硫苯基;經下列基圑取代之 硫苯基:二(Ci_6烧基)胺基Ci-6烧基(C!„6烧基)胺基Ci_6 20 烷基、二(Cw烷基)胺基Cw烷基、Cw烷基六氫吡畊 基Ci_6貌基、輕基Ci_6烧基六氫啦σ井基Ci_6烧基、輕基 匚1_6院氧基〇1_6跪基六氫11比喷基^11.6烧基、二((111_6烧基) 胺基項酸基六氫3比°井基Ci_6烧基、Ci-6競*氧基六氫σ比淀 基Ck烧基、嗎福咐基Cu烧基、經基Cu烧基(Ci-6 -185 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐)200400941 A8 B8 C8 D8 申請專利範圍 烷基)胺基C"烷基、或二(輕基烷基)胺基烧 基; 15 經濟邹智慧財產局員工消費合作枉印製 20 呋啥基’ %唑基;吨咯基;咄唑基丨吼淀基丨經Gw烧 氧基取代之吼咬基;啥嘴基;吲喘基;苯基;經分別 獨立選自下列i、2或3個取代基取代之苯基:齒基、 胺基、<^_6烧基、Cm燒氧基、經基Ci_4烧基、三氟甲 基、二氟甲氧基、二(CM烷基)胺基(^4烷氧基、二(Ci 4 烧基)胺基、二((^.4院基)胺基Cl 4烷基、二(Ci 4烷基) 胺基h烧基(Cl·4炫基)胺基、二((:14燒基)胺基Ci 4炫 基(Q·4烷基)胺基Cm烷基、羥基Ci_4烷基六氫吡畊基 Cw烷基、羥基Cl_4烷氧基Ci 4烷基六氫吡畊基C14烷 基、二(羥基CM烷基)胺基Ci 4烷基、吡咯啶基烷 基、吡咯啶基Cm烷氧基、嗎福啉基c14烷氧基、嗎福 唯基Cm烷基、Cm烷基六氫吡畊基Ci 4烷基,或 /~CCH2)n 叶,、 -_ 心( \_/部份基團亦可與亞甲基橋連基 开》成橋連(亦即形成雙環狀部份基團)。 6.根據申請專利範圍第1、4與5項之化合物,其中〇為 為 〇;各 Z 為氮;R1 為 _C(〇)NH(〇H) ; R2 為氫;_ L-為一直接鍵結;各R3代表氫原子;R4為氫;一^) 為選自(a-Ι)或(a-20)之基團;各s分別為〇或1 ;各R5 與R6分別獨立選自:氫;硫苯基;經下列基團取代之 瓜本基.一(Ci_6烧基)胺基C^_6烧基、或d丨·6炫基六氫 吡11 井基Cw烷基;呋喃基;苯基;經分別獨立選自下 -186 K為張尺度適用中國國家標準(CNS)A4規格(210χ297公楚) 200400941 8 8 8 8 A BCD 7、申請專利範圍 列之1個取代基取代之苯基:二(Ci-4炫基)胺基Ci-4焼 氧基、二(Ci-4炫基)胺基、二(Ci-4烧基)胺基Ci_4烧基、 二(Ci-4烧基)胺基Ci-4烧基(Ci_4烧基)胺基Ci-4院基、α比 洛°定基Ci_4炫•基、π比洛°定基Ci.4炫氧基或Ci.4烧基六 5 氫B比σ井基Ci_4烧基。 7.根據申請專利範圍第1、4、5與6項之化合物,其係 選自下列之化合物:Νο·6、No.100、No.104、 No.128、No_144、Νο·124、Νο·154、No.125、Νο·157、 No.156、Νο·159、No.163、No.164、Νο·168、No.169、 10 No.127、No.171、No.170、No.172 與 No.173 化合物。 經濟部智慧財產局員工消費合作社印製-187 - 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印製 六、 申請專利範圍 5 H %々〇 oyCr0 H 0 .0.6 H2O.C2HF3O2; Co. No. 154 0.2 H2〇 .C2HF3O2; Co. No. 125 v° ^rjri〇 ΗΌ-Νγ^Ν HO, 〔N〕 I V 10 .0.5 H20 .1.2 C2HF3O2; Co. No. 157 .0.3 H20.1.2 C2HF3O2C0. No. 156 / /OH 〇Ao Η、〇,γ^Ν 〇 /N、 0.3 H20 .1.5 QHF3O2; Co. No. 159 .0.6 H2O.C2HF3〇2; Co. No. 163 15 H ^ rNrN^ °^Sn i 0 1 、ν〇Τ〇Ν 0 .0.7 H7O.I.5 C2HF3O2; Co. No. 164 .C2HF3O2; Co. No. 168 20 HvNY^N ^ O -ν°γ〇1χ\〇 .1.1 C2HF3〇2;Co. No. 169 .U6C2HF3O2; Co. No. 127 -188 - 7本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 200400941 經濟部智慧財產局員工消費合作社印製10 8 15 20 189 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 物’其中該化合物為化合物N〇 6 -種醫藥組合物,其包含醫藥上可接受之載劑及作為 活性成分之醫療有效量之根據申請專利範圍第丨至8 項之化合物。 10·一種製備根據申請專利範圍第9項之醫藥組合物之方 法,其中均勻混合醫藥上可接受之載劑及根據申請專 利範圍第1至8項之化合物。 11.根據申睛專利範圍苐1至8項中任一項之化合物,其 200400941 A8 B8 C8 D8 六、申請專利範圍 係用為醫藥。 12. —種以根據申請專利範圍第1至8項中任一項之化合 物於製造醫藥,供治療增生疾病上之用途。 13. —種製備根據申請專利範圍第1項之化合物之方法, 5 其特徵在於: a)由式(II)中間物與適當酸,如,例如:三氟乙酸反 應,產生式(I-a)異羥肟酸,式中R1為-C(0)NH(OH); « d 10 Ο 从人.Q=x' Η -Ι-Υ R2 (Π) R4 -(ςΗ2)η ίί -1— (C(R3)2)r_QAj O CF3COOH O HO、 N H R4 -(CH2)n f (C(R3)2)t-(a) 計 15 (i-a) 線•ΐ 經濟部智慧財產局員工消費合作社印製 20 b)由式(VI)中間物與氫於觸媒(如,例如:Pd/C(10%)) 之存在下進行催化性氫化反應,產生式(I-a)異羥肟 酸,式中 R1 為-C(0)NH(0H); 0 /0、« ψ R2 R4 O H2 /-™f(CH2)n II -N —S— (C(R3)2)f乂么) (VD 190 I 本紙張尺度適用中國國家標準(CNS)A4規格(210x297公釐) 200400941 申請專利範圍 A8 Βδ C8 D8 R4 〇 HO、 -(CH2)n II (I-a) C)由式(VII)中間物與式(VIII)中間物,其中R,為 CH〇 Μ Η 〇〜Ν' CH3、/N、0 Η Ν_ 、Ν 或 ΗΝΟ 10 ’於Ν’-(乙基碳化亞胺醯基)-Ν,Ν-二甲基_ι,3_丙二胺 單鹽酸鹽(EDC)與羥基苯並三唑(ΗΟΒΤ)之存在下反 應’產生式(I-b)化合物,式中R1為 αΛ η Ί r、 cf yv 〇 〇 Η〇15 R4 Ο Η-,Ν.R2 /ζ—S— (C(R3)2)r-0- ΟR4 ^Η2)„ cccr3)2)~^ 經濟部智慧財產局員工消費合作社印製 20 (Vil) R·—C—OH (VHI) (I-b) 14. 一種於生物檢體中檢測或判別HDAc之方法, 檢測或測定如申請專利範圍第丨項所定義之〃包括 合物與HDAC之間所形成之錯合物。 有標記化 15. —種含抗癌劑與根據申請專利範圍第丨至 25 項之HDAC抑制劑之組合。 項中任一 -191 - 私纸張尺度適用中國國家標準(CNS)A4規格(21〇 x297公爱 200400941 e (一) 、本案指定代表圖為:第_圖(無) (二) 、本代表圖之元件代表符號簡單說明: M.本案右有化學式日t ’清揭不最能顯不發明特徵的. 化學式:第2-1頁
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36379902P | 2002-03-13 | 2002-03-13 | |
US42098902P | 2002-10-24 | 2002-10-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW200400941A true TW200400941A (en) | 2004-01-16 |
Family
ID=27807998
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW092105283A TW200400941A (en) | 2002-03-13 | 2003-03-12 | Sulfonyl-derivatives as novel inhibitors of histone deacetylase |
Country Status (23)
Country | Link |
---|---|
US (6) | US7205304B2 (zh) |
EP (1) | EP1485365B1 (zh) |
JP (1) | JP4725946B2 (zh) |
KR (1) | KR20040090978A (zh) |
CN (2) | CN101450934B (zh) |
AR (1) | AR039568A1 (zh) |
AT (1) | ATE395343T1 (zh) |
AU (1) | AU2003218738B2 (zh) |
BR (1) | BR0307575A (zh) |
CA (1) | CA2476586C (zh) |
DE (1) | DE60320957D1 (zh) |
DK (1) | DK1485365T3 (zh) |
EA (1) | EA006707B1 (zh) |
ES (1) | ES2306859T3 (zh) |
HR (1) | HRP20040802A2 (zh) |
IL (2) | IL164002A0 (zh) |
MX (1) | MXPA04007775A (zh) |
NO (1) | NO20044314L (zh) |
NZ (1) | NZ534830A (zh) |
OA (1) | OA12792A (zh) |
PL (1) | PL220783B1 (zh) |
TW (1) | TW200400941A (zh) |
WO (1) | WO2003076422A1 (zh) |
Families Citing this family (187)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6897220B2 (en) | 2001-09-14 | 2005-05-24 | Methylgene, Inc. | Inhibitors of histone deacetylase |
EP1429765A2 (en) | 2001-09-14 | 2004-06-23 | Methylgene, Inc. | Inhibitors of histone deacetylase |
US7868204B2 (en) | 2001-09-14 | 2011-01-11 | Methylgene Inc. | Inhibitors of histone deacetylase |
US7390813B1 (en) | 2001-12-21 | 2008-06-24 | Xenon Pharmaceuticals Inc. | Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents |
DE60320957D1 (en) * | 2002-03-13 | 2008-06-26 | Janssen Pharmaceutica Nv | Sulfonylderivate als histone-deacetylase-inhibitoren |
WO2003076438A1 (en) | 2002-03-13 | 2003-09-18 | Janssen Pharmaceutica N.V. | Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase |
ATE396971T1 (de) | 2002-03-13 | 2008-06-15 | Janssen Pharmaceutica Nv | Sulfonylaminoderivate als neue inhibitoren von histondeacetylase |
PL205531B1 (pl) | 2002-03-13 | 2010-04-30 | Janssen Pharmaceutica Nv | Pochodna karbonyloaminowa, jej zastosowanie i sposób wytwarzania oraz kompozycja farmaceutyczna |
WO2003075929A1 (en) | 2002-03-13 | 2003-09-18 | Janssen Pharmaceutica N.V. | Inhibitors of histone deacetylase |
TWI319387B (en) | 2002-04-05 | 2010-01-11 | Astrazeneca Ab | Benzamide derivatives |
US8603949B2 (en) * | 2003-06-17 | 2013-12-10 | California Institute Of Technology | Libraries of optimized cytochrome P450 enzymes and the optimized P450 enzymes |
ES2375134T3 (es) * | 2003-07-30 | 2012-02-27 | Xenon Pharmaceuticals Inc. | Derivados de piperazina y su uso como agentes terapéuticos. |
BRPI0412343A (pt) | 2003-07-30 | 2006-09-05 | Xenon Pharmaceuticals Inc | derivados de piridazina e seu uso como agentes terapêuticos |
US7759348B2 (en) | 2003-07-30 | 2010-07-20 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives and their use as therapeutic agents |
CN101693697A (zh) | 2003-07-30 | 2010-04-14 | 泽农医药公司 | 哌嗪衍生物和它们作为治疗剂的用途 |
CA2539117A1 (en) | 2003-09-24 | 2005-04-07 | Methylgene Inc. | Inhibitors of histone deacetylase |
AR048427A1 (es) * | 2004-03-11 | 2006-04-26 | Altana Pharma Ag | Derivados de sulfonilpirroles con actividad inhibitoria de la histona deacetilasa, composiciones farmaceuticas que los contienen y el uso de las mismas para el tratamiento de enfermedades relacionadas. |
US7253204B2 (en) | 2004-03-26 | 2007-08-07 | Methylgene Inc. | Inhibitors of histone deacetylase |
WO2005120515A2 (en) * | 2004-06-10 | 2005-12-22 | Kalypsys, Inc. | Novel sulfonamides as inhibitors of histone deacetylase for the treatment of disease |
ATE537830T1 (de) * | 2004-07-06 | 2012-01-15 | Xenon Pharmaceuticals Inc | Nicotinamid derivate und ihre verwendung als therapeutika |
UA86066C2 (ru) | 2004-07-28 | 2009-03-25 | Янссен Фармацевтика Н.В. | Производные замещенного пропенилпиперазина как ингибиторы гистондеацетилазы |
EA010652B1 (ru) * | 2004-07-28 | 2008-10-30 | Янссен Фармацевтика Н.В. | Замещенные индолильные алкиламинопроизводные в качестве новых ингибиторов гистондеацетилазы |
TW200626138A (en) | 2004-09-20 | 2006-08-01 | Xenon Pharmaceuticals Inc | Heterocyclic derivatives and their use as therapeutic agents |
WO2006034440A2 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
WO2006034341A2 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase |
MX2007003318A (es) | 2004-09-20 | 2007-05-18 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como agentes terapeuticos. |
JP5094398B2 (ja) | 2004-09-20 | 2012-12-12 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | 複素環式誘導体およびステアロイル−CoAデサチュラーゼのメディエータとしてのそれらの使用 |
CA2580857A1 (en) | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
WO2006034441A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
GB0421908D0 (en) * | 2004-10-01 | 2004-11-03 | Angeletti P Ist Richerche Bio | New uses |
GB0426313D0 (en) * | 2004-12-01 | 2005-01-05 | Merck Sharp & Dohme | Therapeutic agents |
EP1819669A2 (en) * | 2004-12-09 | 2007-08-22 | Kalypsys, Inc. | Novel inhibitors of histone deacetylase for the treatment of disease |
CA2596015A1 (en) | 2005-02-14 | 2006-08-24 | Sampath K. Anandan | Fused heterocyclic compounds useful as inhibitors of histone deacetylase |
WO2006105127A2 (en) * | 2005-03-31 | 2006-10-05 | Takeda San Diego, Inc. | Hydroxysteroid dehydrogenase inhibitors |
EP1874755A4 (en) | 2005-04-20 | 2010-04-28 | Merck Sharp & Dohme | BENZOTHIOPHENE-hydroxamic acid derivatives |
JP2008536924A (ja) | 2005-04-20 | 2008-09-11 | メルク エンド カムパニー インコーポレーテッド | ベンゾチオフェンヒドロキサミン酸のカーバメート、ウレア、アミドおよびスルホンアミド置換誘導体 |
EP1874295A4 (en) | 2005-04-20 | 2009-08-12 | Merck & Co Inc | benzothiophene |
GB0509223D0 (en) | 2005-05-05 | 2005-06-15 | Chroma Therapeutics Ltd | Enzyme inhibitors |
GB0509225D0 (en) | 2005-05-05 | 2005-06-15 | Chroma Therapeutics Ltd | Inhibitors of enzymatic activity |
DK1885710T3 (en) | 2005-05-18 | 2015-11-23 | Janssen Pharmaceutica Nv | SUBSTITUTED AMINOPROPENYLPIPERIDINE OR MORPHOLINE DERIVATIVES AS UNKNOWN INHIBITORS OF HISTONDEACETYLASE |
GB0510204D0 (en) * | 2005-05-19 | 2005-06-22 | Chroma Therapeutics Ltd | Enzyme inhibitors |
AU2006343359A1 (en) | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
US8158825B2 (en) | 2005-06-24 | 2012-04-17 | Merck Sharp & Dohme Corp. | Modified malonate derivatives |
WO2007008143A1 (en) * | 2005-07-08 | 2007-01-18 | Astrazeneca Ab | Heterocyclic sulfonamide derivatives as inhibitors of factor xa |
BRPI0613429A2 (pt) | 2005-07-14 | 2009-02-10 | Takeda San Diego Inc | inibidores de histona desacetilase |
EP2258358A3 (en) | 2005-08-26 | 2011-09-07 | Braincells, Inc. | Neurogenesis with acetylcholinesterase inhibitor |
EP2275095A3 (en) | 2005-08-26 | 2011-08-17 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
RU2405770C2 (ru) * | 2005-09-27 | 2010-12-10 | Сионоги Энд Ко., Лтд. | Производное сульфонамида, обладающее антагонистической активностью в отношении рецептора pgd2 |
CN101273013B (zh) * | 2005-09-27 | 2013-06-12 | 盐野义制药株式会社 | 具有pgd2受体拮抗活性的磺酰胺衍生物 |
JP2009512711A (ja) | 2005-10-21 | 2009-03-26 | ブレインセルス,インコーポレイティド | Pde阻害による神経新生の調節 |
EP1943232B1 (en) * | 2005-10-27 | 2011-05-18 | Janssen Pharmaceutica NV | Squaric acid derivatives as inhibitors of histone deacetylase |
CA2625210A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
WO2007055942A2 (en) * | 2005-11-03 | 2007-05-18 | Merck & Co., Inc. | Substituted nicotinamide compounds |
AR057579A1 (es) | 2005-11-23 | 2007-12-05 | Merck & Co Inc | Compuestos espirociclicos como inhibidores de histona de acetilasa (hdac) |
AU2006326540A1 (en) | 2005-12-14 | 2007-06-21 | Amgen Inc. | Diaza heterocyclic sulfonamide derivatives and their uses |
SI1981874T1 (sl) | 2006-01-19 | 2009-10-31 | Janssen Pharmaceutica Nv | Aminofenilni derivati kot novi inhibitorji histon deacetilaze |
JP5137848B2 (ja) * | 2006-01-19 | 2013-02-06 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ヒストンデアセチラーゼのインヒビターとしてのピリジン及びピリミジン誘導体 |
CN101374828B (zh) | 2006-01-19 | 2012-09-19 | 詹森药业有限公司 | 作为组蛋白脱乙酰酶抑制剂的杂环烷基衍生物 |
WO2007082874A1 (en) | 2006-01-19 | 2007-07-26 | Janssen Pharmaceutica N.V. | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase |
JP5261192B2 (ja) | 2006-01-19 | 2013-08-14 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ヒストンデアセチラーゼのインヒビターとしてのピリジン及びピリミジン誘導体 |
DK1981875T3 (da) | 2006-01-19 | 2014-07-14 | Janssen Pharmaceutica Nv | Substituerede indolylalkylaminoderivater som inhibitorer af histondeacetylase |
PA8713501A1 (es) | 2006-02-07 | 2009-09-17 | Wyeth Corp | INHIBIDORES DE 11-BETA HIDROXIESTEROIDE DEHIDROGENASA - 11ßHSD1 |
JP2009528354A (ja) | 2006-02-28 | 2009-08-06 | メルク エンド カムパニー インコーポレーテッド | ヒストン脱アセチル化酵素のインヒビター |
US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
ES2452820T3 (es) | 2006-04-07 | 2014-04-02 | Methylgene, Inc. | Derivados de benzamida como inhibidores de histona desacetilasa |
US8119685B2 (en) | 2006-04-26 | 2012-02-21 | Merck Sharp & Dohme Corp. | Disubstituted aniline compounds |
JP2009536667A (ja) | 2006-05-09 | 2009-10-15 | ブレインセルス,インコーポレイティド | 5ht受容体介在性の神経新生 |
AU2007249399A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
EP2023924B1 (en) | 2006-05-18 | 2016-08-03 | Merck Sharp & Dohme Corp. | Aryl-fused spirocyclic compounds |
AU2007275743A1 (en) | 2006-07-20 | 2008-01-24 | Merck Sharp & Dohme Corp. | Phosphorus derivatives as histone deacetylase inhibitors |
AU2007281911B2 (en) | 2006-08-04 | 2014-02-06 | Beth Israel Deaconess Medical Center | Inhibitors of pyruvate kinase and methods of treating disease |
WO2008027837A2 (en) * | 2006-08-28 | 2008-03-06 | The Regents Of The University Of California | Small molecule potentiator of hormonal therapy for breast cancer |
KR20090064418A (ko) | 2006-09-08 | 2009-06-18 | 브레인셀즈 인코퍼레이션 | 4-아실아미노피리딘 유도체 포함 조합물 |
BRPI0716838A2 (pt) * | 2006-09-15 | 2013-10-01 | Janssen Pharmaceutica Nv | combinaÇÕes de inibidores de histona deacetilase especÍfica de classe i com inibidores de proteosome |
US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
GB0619753D0 (en) | 2006-10-06 | 2006-11-15 | Chroma Therapeutics Ltd | Enzyme inhibitors |
BRPI0622100A2 (pt) | 2006-10-30 | 2011-12-27 | Chroma Therapeutics Ltd | hidroxamatos como inibidores de desacetilase de histona |
KR20090083477A (ko) * | 2006-11-20 | 2009-08-03 | 그렌마크 파머수티칼스 에스. 아. | 스테아로일-CoA 불포화효소 저해제인 아세틸렌 유도체 |
ES2449482T3 (es) * | 2007-01-09 | 2014-03-19 | Amgen Inc. | Derivados de bis-aril-amida útiles para el tratamiento de cáncer |
US8030344B2 (en) | 2007-03-13 | 2011-10-04 | Methylgene Inc. | Inhibitors of histone deacetylase |
CN103265501B (zh) * | 2007-03-27 | 2015-06-03 | 盐野义制药株式会社 | N-苯基-n’-苯磺酰基哌嗪衍生物的制造方法 |
JP5603770B2 (ja) * | 2007-05-31 | 2014-10-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr2受容体拮抗薬およびその使用 |
BRPI0813331A2 (pt) * | 2007-06-08 | 2014-12-23 | Janssen Pharmaceutica Nv | Derivados de piperidina/piperazina |
AU2008258549B2 (en) | 2007-06-08 | 2013-11-14 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
JO2972B1 (en) | 2007-06-08 | 2016-03-15 | جانسين فارماسوتيكا ان. في | Piperidine / piperazine derivatives |
CA2687918C (en) | 2007-06-08 | 2016-11-08 | Janssen Pharmaceutica N.V. | Piperidine/piperazine derivatives |
US8461189B2 (en) | 2007-06-27 | 2013-06-11 | Merck Sharp & Dohme Corp. | Pyridyl derivatives as histone deacetylase inhibitors |
US8389553B2 (en) | 2007-06-27 | 2013-03-05 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
KR20100095430A (ko) * | 2007-11-02 | 2010-08-30 | 메틸진 인크. | 히스톤 탈아세틸화효소의 저해물질 |
US20110044952A1 (en) * | 2007-11-27 | 2011-02-24 | Ottawa Health Research Institute | Amplification of cancer-specific oncolytic viral infection by histone deacetylase inhibitors |
CA2708281A1 (en) | 2007-12-11 | 2009-08-27 | Viamet Pharmaceuticals, Inc. | Metalloenzyme inhibitors using metal binding moieties in combination with targeting moieties |
DK2274301T3 (da) | 2008-03-27 | 2013-01-02 | Janssen Pharmaceutica Nv | Azabicyclohexylsubstituerede indolylalkylaminoderivater som hidtil ukendte inhibitorer af histondeacetylase |
WO2009137462A2 (en) * | 2008-05-05 | 2009-11-12 | Envivo Pharmaceuticals, Inc. | Methods for treating cognitive disorders using inhibitors of histone deacetylase |
WO2009147170A2 (en) | 2008-06-05 | 2009-12-10 | Janssen Pharmaceutica Nv | Drug combinations comprising a dgat inhibitor and a ppar-agonist |
WO2010001366A1 (en) * | 2008-07-04 | 2010-01-07 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Piperazines derivatives as proteasome modulators |
WO2010007027A1 (en) | 2008-07-14 | 2010-01-21 | Novartis Ag | Selective hydroxamic acid based mmp-12 and mmp-13 inhibitors |
GB0813142D0 (en) | 2008-07-17 | 2008-08-27 | Glaxo Group Ltd | Novel compounds |
GB0813144D0 (en) | 2008-07-17 | 2008-08-27 | Glaxo Group Ltd | Novel compounds |
WO2010011700A2 (en) | 2008-07-23 | 2010-01-28 | The Brigham And Women's Hospital, Inc. | Treatment of cancers characterized by chromosomal rearrangement of the nut gene |
EP2330894B8 (en) | 2008-09-03 | 2017-04-19 | BioMarin Pharmaceutical Inc. | Compositions including 6-aminohexanoic acid derivatives as hdac inhibitors |
JP5702293B2 (ja) | 2008-11-10 | 2015-04-15 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | Atrキナーゼの阻害剤として有用な化合物 |
LT3354650T (lt) | 2008-12-19 | 2022-06-27 | Vertex Pharmaceuticals Incorporated | Junginiai, naudingi kaip atr kinazės inhibitoriai |
JP2012512834A (ja) | 2008-12-19 | 2012-06-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 炎症、喘息及びcopdの処置のためのccr2受容体アンタゴニストとしての環状ピリミジン−4−カルボキサミド |
DK2385832T3 (en) | 2009-01-08 | 2015-09-21 | Curis Inc | Phosphoinositid-3-kinase-inhibitorer med en zink-bindingsdel |
WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
GB0903480D0 (en) | 2009-02-27 | 2009-04-08 | Chroma Therapeutics Ltd | Enzyme Inhibitors |
CN102448951B (zh) | 2009-04-06 | 2017-05-10 | 安吉奥斯医药品有限公司 | 丙酮酸激酶m2调节剂、治疗组合物和相关使用方法 |
PL2448582T3 (pl) | 2009-06-29 | 2017-09-29 | Agios Pharmaceuticals, Inc. | Pochodne chinolino-8-sulfonamidowe mające działanie przeciwnowotworowe |
EP2448581B1 (en) * | 2009-06-29 | 2016-12-07 | Agios Pharmaceuticals, Inc. | Therapeutic compositions and related methods of use |
CN102933579B (zh) | 2009-12-17 | 2015-07-15 | 贝林格尔.英格海姆国际有限公司 | 新的ccr2受体拮抗剂及其用途 |
JP5725475B2 (ja) * | 2010-01-21 | 2015-05-27 | 公立大学法人名古屋市立大学 | ヒドロキサム酸誘導体及びそれを用いたhdac8阻害剤 |
US8217079B2 (en) | 2010-03-26 | 2012-07-10 | Italfarmaco Spa | Method for treating Philadelphia-negative myeloproliferative syndromes |
EP2569287B1 (en) | 2010-05-12 | 2014-07-09 | Vertex Pharmaceuticals Inc. | Compounds useful as inhibitors of atr kinase |
RU2012153675A (ru) | 2010-05-12 | 2014-06-20 | Вертекс Фармасьютикалз Инкорпорейтед | Соединения, пригодные в качестве ингибиторов atr киназы |
US8962631B2 (en) | 2010-05-12 | 2015-02-24 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
US9062008B2 (en) | 2010-05-12 | 2015-06-23 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
WO2011141474A1 (en) | 2010-05-12 | 2011-11-17 | Boehringer Ingelheim International Gmbh | Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
WO2011143422A1 (en) | 2010-05-12 | 2011-11-17 | Vertex Pharmaceuticals Incorporated | 2 -aminopyridine derivatives useful as inhibitors of atr kinase |
EP2568984A1 (en) | 2010-05-12 | 2013-03-20 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
WO2011141477A1 (en) | 2010-05-12 | 2011-11-17 | Boehringer Ingelheim International Gmbh | New ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
EP2571870B1 (en) | 2010-05-17 | 2015-01-21 | Boehringer Ingelheim International GmbH | Ccr2 antagonists and uses thereof |
JP5636094B2 (ja) | 2010-05-25 | 2014-12-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr2受容体アンタゴニスト |
WO2011151251A1 (en) | 2010-06-01 | 2011-12-08 | Boehringer Ingelheim International Gmbh | New ccr2 antagonists |
NZ605627A (en) | 2010-06-23 | 2015-06-26 | Vertex Pharma | Pyrrolo-pyrazine derivatives useful as inhibitors of atr kinase |
JP5248585B2 (ja) * | 2010-12-15 | 2013-07-31 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | 治療薬としてのニコチンアミド誘導体およびそれらの使用 |
JP5837091B2 (ja) | 2010-12-17 | 2015-12-24 | アジオス ファーマシューティカルズ, インコーポレイテッド | ピルビン酸キナーゼm2(pkm2)調節剤としての新規n−(4−(アゼチジン−1−カルボニル)フェニル)−(ヘテロ−)アリールスルホンアミド誘導体 |
US9328077B2 (en) | 2010-12-21 | 2016-05-03 | Agios Pharmaceuticals, Inc | Bicyclic PKM2 activators |
TWI549947B (zh) | 2010-12-29 | 2016-09-21 | 阿吉歐斯製藥公司 | 治療化合物及組成物 |
US9249087B2 (en) | 2011-02-01 | 2016-02-02 | The Board Of Trustees Of The University Of Illinois | HDAC inhibitors and therapeutic methods using the same |
AU2012223509B2 (en) | 2011-02-28 | 2016-11-10 | Biomarin Pharmaceutical Inc. | Histone deacetylase inhibitors |
US8957066B2 (en) | 2011-02-28 | 2015-02-17 | Biomarin Pharmaceutical Inc. | Histone deacetylase inhibitors |
US10059723B2 (en) | 2011-02-28 | 2018-08-28 | Biomarin Pharmaceutical Inc. | Histone deacetylase inhibitors |
SG10201602569RA (en) | 2011-04-01 | 2016-05-30 | Curis Inc | Phosphoinositide 3-kinase inhibitor with a zinc binding moiety |
EP2694498B1 (en) | 2011-04-05 | 2016-03-30 | Vertex Pharmaceuticals Incorporated | Aminopyrazine compounds useful as inhibitors of tra kinase |
CN103764147B (zh) | 2011-05-03 | 2018-05-22 | 安吉奥斯医药品有限公司 | 用于治疗的丙酮酸激酶活化剂 |
WO2012151440A1 (en) | 2011-05-03 | 2012-11-08 | Agios Pharmaceuticals, Inc. | Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia |
CN102260225B (zh) * | 2011-06-02 | 2013-08-21 | 蒋杰 | 用于抑制肿瘤转移和肿瘤血管生长的苯基哌嗪类衍生物 |
WO2012178124A1 (en) | 2011-06-22 | 2012-12-27 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
WO2012178123A1 (en) | 2011-06-22 | 2012-12-27 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
JP2014517079A (ja) | 2011-06-22 | 2014-07-17 | バーテックス ファーマシューティカルズ インコーポレイテッド | Atrキナーゼ阻害剤として有用な化合物 |
JP5786258B2 (ja) | 2011-07-15 | 2015-09-30 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規かつ選択的なccr2拮抗薬 |
JP6162126B2 (ja) | 2011-09-30 | 2017-08-23 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | Atr阻害剤による膵臓癌及び非小細胞肺癌の治療 |
ES2751741T3 (es) | 2011-09-30 | 2020-04-01 | Vertex Pharma | Procedimiento para fabricar compuestos útiles como inhibidores de la quinasa ATR |
EP2751088B1 (en) | 2011-09-30 | 2016-04-13 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
US8853217B2 (en) | 2011-09-30 | 2014-10-07 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
WO2013049722A1 (en) | 2011-09-30 | 2013-04-04 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
WO2013071093A1 (en) | 2011-11-09 | 2013-05-16 | Vertex Pharmaceuticals Incorporated | Pyrazine compounds useful as inhibitors of atr kinase |
US8846917B2 (en) | 2011-11-09 | 2014-09-30 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
EP2776429A1 (en) | 2011-11-09 | 2014-09-17 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
US8841337B2 (en) | 2011-11-09 | 2014-09-23 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
EP2776419B1 (en) | 2011-11-09 | 2016-05-11 | Vertex Pharmaceuticals Incorporated | Pyrazine compounds useful as inhibitors of atr kinase |
WO2013142817A2 (en) | 2012-03-23 | 2013-09-26 | Dennis Brown | Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo |
SI2833973T1 (en) | 2012-04-05 | 2018-04-30 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase and their combination therapy |
WO2014000178A1 (en) * | 2012-06-27 | 2014-01-03 | Merck Sharp & Dohme Corp. | Sulfonamide derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
EP2904406B1 (en) | 2012-10-04 | 2018-03-21 | Vertex Pharmaceuticals Incorporated | Method for measuring atr inhibition mediated increases in dna damage |
US8912198B2 (en) | 2012-10-16 | 2014-12-16 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
CA2892608C (en) | 2012-12-07 | 2021-10-19 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
EP2970135B1 (en) | 2013-03-14 | 2018-07-18 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
US9765035B2 (en) | 2013-03-14 | 2017-09-19 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
US9120757B2 (en) | 2013-03-14 | 2015-09-01 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
EP2970133B1 (en) | 2013-03-14 | 2018-10-24 | Epizyme, Inc. | Pyrazole derivatives as prmt1 inhibitors and uses thereof |
WO2014178954A1 (en) | 2013-03-14 | 2014-11-06 | Epizyme, Inc. | Pyrazole derivatives as arginine methyltransferase inhibitors and uses thereof |
AU2014236146B2 (en) | 2013-03-14 | 2018-05-17 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
US9365527B2 (en) * | 2013-03-14 | 2016-06-14 | Epizyme, Inc. | Arginine methyltransferase inhibitors and uses thereof |
US9663519B2 (en) | 2013-03-15 | 2017-05-30 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of ATR kinase |
WO2014139144A1 (en) | 2013-03-15 | 2014-09-18 | Agios Pharmaceuticals, Inc. | Therapeutic compounds and compositions |
ES2680224T3 (es) | 2013-03-15 | 2018-09-05 | Biomarin Pharmaceutical Inc. | Inhibidores de HDAC |
US10188756B2 (en) * | 2013-10-18 | 2019-01-29 | The General Hospital Corporation | Imaging histone deacetylases with a radiotracer using positron emission tomography |
SG10201804791UA (en) | 2013-12-06 | 2018-07-30 | Vertex Pharma | 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof |
AU2015218402B2 (en) | 2014-02-14 | 2019-07-11 | Takeda Pharmaceutical Company Limited | Pyrazines modulators of GPR6 |
JP6392888B2 (ja) * | 2014-03-12 | 2018-09-19 | チョン クン ダン ファーマシューティカル コーポレーション | ヒストン脱アセチル化酵素6阻害剤としての新規化合物およびこれを含む薬剤学的組成物 |
PT3152212T (pt) | 2014-06-05 | 2020-03-13 | Vertex Pharma | Derivados radiomarcados de um composto de 2-amino-6-fluoro-n-[5-fluoro-piridin-3-il]-pirazolo[1,5-a]pirimidin-3-carboxamida útil como inibidor de atr quinase, preparação do dito composto e diferentes formas sólidas do mesmo |
KR20170016498A (ko) | 2014-06-17 | 2017-02-13 | 버텍스 파마슈티칼스 인코포레이티드 | Chk1 및 atr 저해제의 병용물을 사용하는 암의 치료 방법 |
EP3292113B1 (en) | 2014-12-12 | 2020-07-08 | Regenacy Pharmaceuticals, LLC | Piperidine derivatives as hdac1/2 inhibitors |
CA2975605C (en) | 2015-02-02 | 2023-12-12 | Forma Therapeutics, Inc. | 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as hdac inhibitors |
MA44392B1 (fr) | 2015-06-11 | 2023-10-31 | Agios Pharmaceuticals Inc | Procédés d'utilisation d'activateurs de la pyruvate kinase |
ES2811098T3 (es) | 2015-07-02 | 2021-03-10 | Centrexion Therapeutics Corp | Citrato de (4-((3r,4r)-3-metoxitetrahidro-pirano-4-ilamino)piperidin-1-il)(5-metil-6-(((2r, 6s)-6-(p-tolil)tetrahidro-2hpirano-2-il) metilamino)pirimidin-4il) metanona |
JP7187308B2 (ja) | 2015-09-30 | 2022-12-12 | バーテックス ファーマシューティカルズ インコーポレイテッド | Dna損傷剤とatr阻害剤との組み合わせを使用する、がんを処置するための方法 |
ITUB20155193A1 (it) | 2015-11-03 | 2017-05-03 | Italfarmaco Spa | Sospensioni orali di Givinostat fisicamente e chimicamente stabili |
EP3472131B1 (en) * | 2016-06-17 | 2020-02-19 | Forma Therapeutics, Inc. | 2-spiro-5- and 6-hydroxamic acid indanes as hdac inhibitors |
WO2018054960A1 (en) | 2016-09-21 | 2018-03-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting and treating resistance to chemotherapy in npm-alk(+) alcl |
KR102236356B1 (ko) | 2017-11-24 | 2021-04-05 | 주식회사 종근당 | 루푸스의 예방 또는 치료를 위한 조성물 |
US11234986B2 (en) | 2018-09-11 | 2022-02-01 | Curis, Inc. | Combination therapy with a phosphoinositide 3-kinase inhibitor with a zinc binding moiety |
CA3112796A1 (en) * | 2018-10-12 | 2020-04-16 | Chong Kun Dang Pharmaceutical Corp. | Pharmaceutical composition comprising histone deacetylase inhibitor and methotrexate |
CA3119313A1 (en) * | 2018-11-23 | 2020-05-28 | Chong Kun Dang Pharmaceutical Corp. | Pharmaceutical composition comprising histone deacetylase 6 inhibitors |
CN110156729B (zh) * | 2019-05-14 | 2022-12-06 | 浙江大学 | 一种苯基哌嗪类ube2f小分子抑制剂及其合成方法 |
CN116120261B (zh) * | 2022-11-30 | 2024-01-23 | 浙大宁波理工学院 | 一种3-[(4-磺胺哌嗪-1-基)甲基]苯甲酸类化合物的制备方法 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0827742A1 (en) | 1996-09-04 | 1998-03-11 | Vrije Universiteit Brussel | Use of histone deacetylase inhibitors for treating fribosis or cirrhosis |
AUPO721997A0 (en) | 1997-06-06 | 1997-07-03 | Queensland Institute Of Medical Research, The | Anticancer compounds |
DE19743435A1 (de) | 1997-10-01 | 1999-04-08 | Merck Patent Gmbh | Benzamidinderivate |
DE60009777T2 (de) * | 1999-04-01 | 2004-08-19 | Pfizer Products Inc., Groton | Verbindung für Behandlung und Vorsorge bei Diabetes |
CA2391952C (en) * | 1999-11-23 | 2012-01-31 | Methylgene Inc. | Inhibitors of histone deacetylase |
DE10000739A1 (de) | 2000-01-11 | 2001-07-12 | Merck Patent Gmbh | Piperidin- und Piperazinderivate |
AU2001248701A1 (en) | 2000-03-24 | 2001-10-03 | Methylgene, Inc. | Inhibitors of histone deacetylase |
GB0127929D0 (en) * | 2001-11-21 | 2002-01-16 | Celltech R&D Ltd | Chemical compounds |
DE60320957D1 (en) * | 2002-03-13 | 2008-06-26 | Janssen Pharmaceutica Nv | Sulfonylderivate als histone-deacetylase-inhibitoren |
ATE396971T1 (de) * | 2002-03-13 | 2008-06-15 | Janssen Pharmaceutica Nv | Sulfonylaminoderivate als neue inhibitoren von histondeacetylase |
WO2003075929A1 (en) * | 2002-03-13 | 2003-09-18 | Janssen Pharmaceutica N.V. | Inhibitors of histone deacetylase |
-
2003
- 2003-03-11 DE DE60320957T patent/DE60320957D1/de not_active Expired - Lifetime
- 2003-03-11 AU AU2003218738A patent/AU2003218738B2/en not_active Expired
- 2003-03-11 MX MXPA04007775A patent/MXPA04007775A/es active IP Right Grant
- 2003-03-11 WO PCT/EP2003/002516 patent/WO2003076422A1/en active IP Right Grant
- 2003-03-11 EA EA200401202A patent/EA006707B1/ru unknown
- 2003-03-11 CA CA2476586A patent/CA2476586C/en not_active Expired - Lifetime
- 2003-03-11 CN CN2008101704232A patent/CN101450934B/zh not_active Expired - Lifetime
- 2003-03-11 JP JP2003574641A patent/JP4725946B2/ja not_active Expired - Lifetime
- 2003-03-11 OA OA1200400246A patent/OA12792A/en unknown
- 2003-03-11 CN CNB038059525A patent/CN100445276C/zh not_active Expired - Lifetime
- 2003-03-11 NZ NZ534830A patent/NZ534830A/en unknown
- 2003-03-11 AT AT03711982T patent/ATE395343T1/de not_active IP Right Cessation
- 2003-03-11 DK DK03711982T patent/DK1485365T3/da active
- 2003-03-11 PL PL370990A patent/PL220783B1/pl unknown
- 2003-03-11 EP EP03711982A patent/EP1485365B1/en not_active Expired - Lifetime
- 2003-03-11 ES ES03711982T patent/ES2306859T3/es not_active Expired - Lifetime
- 2003-03-11 US US10/507,708 patent/US7205304B2/en not_active Expired - Lifetime
- 2003-03-11 KR KR10-2004-7011013A patent/KR20040090978A/ko not_active Application Discontinuation
- 2003-03-11 BR BR0307575-3A patent/BR0307575A/pt not_active IP Right Cessation
- 2003-03-11 IL IL16400203A patent/IL164002A0/xx unknown
- 2003-03-12 AR ARP030100856A patent/AR039568A1/es not_active Application Discontinuation
- 2003-03-12 TW TW092105283A patent/TW200400941A/zh unknown
-
2004
- 2004-09-03 HR HR20040802A patent/HRP20040802A2/hr not_active Application Discontinuation
- 2004-09-09 IL IL164002A patent/IL164002A/en active IP Right Grant
- 2004-10-12 NO NO20044314A patent/NO20044314L/no not_active Application Discontinuation
-
2007
- 2007-01-30 US US11/668,906 patent/US7709487B2/en not_active Expired - Lifetime
- 2007-10-29 US US11/926,759 patent/US7704998B2/en not_active Expired - Lifetime
-
2010
- 2010-04-13 US US12/759,256 patent/US8097611B2/en not_active Expired - Fee Related
-
2011
- 2011-12-14 US US13/325,330 patent/US8557825B2/en not_active Expired - Lifetime
-
2013
- 2013-10-14 US US14/053,119 patent/US8865720B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TW200400941A (en) | Sulfonyl-derivatives as novel inhibitors of histone deacetylase | |
JP4648628B2 (ja) | ヒストンデアセチラーゼの新規な阻害剤としてのカルボニルアミノ誘導体 | |
JP4644428B2 (ja) | ヒストンデアセチラーゼの新規な阻害剤 | |
JP4674045B2 (ja) | ヒストンデアセチラーゼの新規な阻害剤としてのピペラジニル−、ピペリジニル−およびモルホリニル−誘導体 | |
JP4725945B2 (ja) | ヒストンデアセチラーゼの新規な阻害剤としてのスルホニルアミノ誘導体 |