CN1319967C - 2-酰基氨基噻唑衍生物或其盐 - Google Patents
2-酰基氨基噻唑衍生物或其盐 Download PDFInfo
- Publication number
- CN1319967C CN1319967C CNB038044579A CN03804457A CN1319967C CN 1319967 C CN1319967 C CN 1319967C CN B038044579 A CNB038044579 A CN B038044579A CN 03804457 A CN03804457 A CN 03804457A CN 1319967 C CN1319967 C CN 1319967C
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- CN
- China
- Prior art keywords
- group
- thiazol
- alkyl
- substituted
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 150000003839 salts Chemical class 0.000 title claims abstract description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 188
- 206010043554 thrombocytopenia Diseases 0.000 claims abstract description 16
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 119
- -1 Cyano group Chemical group 0.000 claims description 96
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 87
- 125000005843 halogen group Chemical group 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 29
- 239000011570 nicotinamide Substances 0.000 claims description 29
- 229960003966 nicotinamide Drugs 0.000 claims description 29
- 235000005152 nicotinamide Nutrition 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 25
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000003107 substituted aryl group Chemical group 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 208000005485 Thrombocytosis Diseases 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000001118 alkylidene group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 7
- 239000000470 constituent Substances 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- VZQHOSMWLZNNRL-UHFFFAOYSA-N ClC=1C=C(SC1)C=1N=C(SC1N1CCN(CC1)C1CCCCC1)N1CC2=CC=CC=C2C=C1 Chemical compound ClC=1C=C(SC1)C=1N=C(SC1N1CCN(CC1)C1CCCCC1)N1CC2=CC=CC=C2C=C1 VZQHOSMWLZNNRL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- YRRYISXSYXKBED-UHFFFAOYSA-N n-[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]-3-fluoro-4-hydroxybenzamide Chemical compound C1=C(F)C(O)=CC=C1C(=O)NC1=NC(C=2SC=C(Cl)C=2)=C(N2CCN(CC2)C2CCCCC2)S1 YRRYISXSYXKBED-UHFFFAOYSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 27
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 2
- 125000002837 carbocyclic group Chemical group 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 239000003446 ligand Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 29
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 230000002062 proliferating effect Effects 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 145
- 239000000460 chlorine Substances 0.000 description 125
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 106
- 239000002585 base Substances 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 73
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 70
- 229910052739 hydrogen Inorganic materials 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 239000007864 aqueous solution Substances 0.000 description 61
- 238000003756 stirring Methods 0.000 description 56
- 235000002639 sodium chloride Nutrition 0.000 description 53
- 239000002904 solvent Substances 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 238000010898 silica gel chromatography Methods 0.000 description 46
- 238000007670 refining Methods 0.000 description 42
- 238000005406 washing Methods 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 41
- 238000000034 method Methods 0.000 description 40
- 238000002386 leaching Methods 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 229920006395 saturated elastomer Polymers 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- 238000000605 extraction Methods 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 27
- 230000006837 decompression Effects 0.000 description 27
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 27
- 229910052938 sodium sulfate Inorganic materials 0.000 description 27
- 235000011152 sodium sulphate Nutrition 0.000 description 27
- 239000002244 precipitate Substances 0.000 description 26
- 238000001035 drying Methods 0.000 description 25
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- 238000010025 steaming Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- 239000007787 solid Substances 0.000 description 20
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 15
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- 230000004663 cell proliferation Effects 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 235000015320 potassium carbonate Nutrition 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- SNIABFMMCKVXSY-UHFFFAOYSA-N benzoylazanium;chloride Chemical compound Cl.NC(=O)C1=CC=CC=C1 SNIABFMMCKVXSY-UHFFFAOYSA-N 0.000 description 9
- 210000001772 blood platelet Anatomy 0.000 description 9
- 229910052801 chlorine Inorganic materials 0.000 description 9
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- UDHZYEWSTDYKCZ-UHFFFAOYSA-N pyridine-4-carboxamide;hydrochloride Chemical compound Cl.NC(=O)C1=CC=NC=C1 UDHZYEWSTDYKCZ-UHFFFAOYSA-N 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 102100034195 Thrombopoietin Human genes 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 241001425800 Pipa Species 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 150000003851 azoles Chemical class 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- 210000001501 megacaryocyte Anatomy 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- OBLVPWTUALCMGD-UHFFFAOYSA-N pyridin-1-ium-3-carboxamide;chloride Chemical compound Cl.NC(=O)C1=CC=CN=C1 OBLVPWTUALCMGD-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 150000003557 thiazoles Chemical class 0.000 description 5
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 230000008030 elimination Effects 0.000 description 4
- 238000003379 elimination reaction Methods 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 208000024908 graft versus host disease Diseases 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 229910000039 hydrogen halide Inorganic materials 0.000 description 4
- 239000012433 hydrogen halide Substances 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
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- 125000003710 aryl alkyl group Chemical group 0.000 description 3
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- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 3
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000005847 immunogenicity Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
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- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 3
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
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- VXGYRCVTBHVXMZ-UHFFFAOYSA-N quinoline-6-carboxylic acid Chemical compound N1=CC=CC2=CC(C(=O)O)=CC=C21 VXGYRCVTBHVXMZ-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
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- 239000012266 salt solution Substances 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- XSXTUTSLQCTYJB-UHFFFAOYSA-N tert-butyl 2-chloro-4-fluorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(F)C=C1Cl XSXTUTSLQCTYJB-UHFFFAOYSA-N 0.000 description 1
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- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- 230000003582 thrombocytopenic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
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- JKVRTUCVPZTEQZ-UHFFFAOYSA-N tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 1
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- 230000009385 viral infection Effects 0.000 description 1
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Classifications
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- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
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- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
基于良好的人c-mp1-Ba/F3细胞增殖作用及巨核细胞集落形成促进作用而具有血小板增多活性的2-酰基氨基噻唑衍生物或其制药学上允许的盐。对血小板减少症的治疗有用的化合物或其制药学上允许的盐。
Description
技术领域
本发明涉及医药品,特别涉及作为血小板减少症治疗剂有用的新的2-酰基氨基噻唑衍生物或其盐及以该化合物为有效成分的医药品。
背景技术
血小板是对生理止血及病态血栓的形成起主要作用的无核血细胞,在生物体内,血细胞由作为前体细胞的巨核细胞不断产生。血小板的产生与其它血细胞一样来自于多能干细胞,多能干细胞转变为巨核细胞系的前体细胞,再由此转变为原始巨核细胞、幼稚巨核细胞、巨核细胞。该巨核细胞的成熟过程中,未成熟的巨核细胞仅进行不伴随细胞分裂的DNA合成,形成多倍体。其后,细胞质开始成熟,形成血小板分离膜,细胞质断裂,血小板被释放出来。
另一方面,再生障碍性贫血、骨髓发育不良综合征或恶性肿瘤的化学疗法、放射疗法等中的各种造血障碍导致的血小板减少会引发出血倾向等严重的症状,所以正在尝试进行以治疗这些疾病为目的的使血小板增多的各种技术的开发。现在,血小板减少症治疗的有力手段是输血小板,但并不能供给足够量的血小板,由于输入的血小板的寿命很短等原因,很难充分改善血小板减少症。此外,输血小板存在病毒感染、同种抗体的产生和移植物抗宿主病(Graft Versus Host Disease;GVHD)等问题。因此,希望开发出缓解由各种症状或疗法所引起的造血机能的抑制状态,促进血小板数目的恢复的药物制剂。
其中,有报道与巨核细胞系细胞的分化有关的主要因子,作为c-Mpl配体的血小板生成素(以下称为TPO)已被克隆,可刺激巨核细胞系细胞的分化和增殖,刺激血小板的产生(Kaushansky K.等,Nature,369,568-571,1994:非专利文献1)。TPO作为血小板增多剂已被进行临床试验,确认其对人的有用性和耐受性。但是,作为TPO的一种的PEG-rHuMGDF(TPO的N末端开始第163号的氨基酸被聚乙二醇修饰的物质)的临床试验中,确认了中和抗体(Li J.等,Blood,98,3241-3248,2001:非专利文献2,以及Basser R.L.等,Blodd,99,2599-2602,2002:非专利文献3),所以担心TPO有免疫原性。此外,由于TPO为蛋白质,所以会在消化管内被分解,作为口服制剂并不实用。基于同样的理由,低分子肽作为口服制剂也不实用。这种情况下,以血小板减少症的治疗为目的进行着免疫原性少、可口服的非肽性c-Mpl配体的开发。
上述化合物已知的有日本专利特开平11-152276号(专利文献1)记载的苯并二氮杂衍生物、国际公开WO 99/11262号(专利文献2)记载的酰基腙衍生物、国际公开WO 00/35446号(专利文献3)记载的重氮萘衍生物、国际公开WO98/09967号(专利文献4)记载的吡咯并咔唑衍生物、日本专利特开平10-212289号(专利文献5)记载的吡咯并菲啶衍生物、日本专利特开2000-44562号(专利文献6)记载的吡咯并苯二甲酰亚胺衍生物。
此外,国际公开WO 01/07423号(专利文献7)记载了以下的通式(VII)表示的化合物具有血小板增多作用。
式中符号含义参照该公报。
该公报中记载了X1为可被取代的噻唑,Y1为-NHCO-的化合物。但是本发明化合物中的Ar1或Ar2未被该公报中的具有相当于噻唑基的A1的取代基取代。而且,该公报中的实施例及其它地方对噻唑5位上氮原子直接取代的化合物无具体记载。
此外,国际公开WO 01/53267号(专利文献8)记载了以下通式(VIII)表示的化合物具有血小板增多作用。
X1-Y1-Z1-W1 (VIII)
式中符号含义参照该公报。
该公报中,有关于X1为可被取代的噻唑,Y1为-NHCO-的化合物的记载。但是本发明化合物中的Ar1或Ar2未被该公报中的具有W1的取代基取代。而且,该公报中的实施例及其它地方对噻唑5位上氮原子直接取代的化合物无具体记载。
除了上述专利文献7和上述专利文献8之外,本发明的2-酰基氨基噻唑化合物在专利3199451号(专利文献9)中作为缩胆囊素及胃泌素受体拮抗剂,或在Chemical and Pharmaceutical Bulletin,25,9,2292-2299,1977(非专利文献4)中作为具有抗炎症特性的化合物被揭示,但均未触及本发明的血小板增多作用。
上述情况下,希望以血小板减少症的治疗为目的,进行免疫原性少、可口服的非肽性c-Mpl配体的开发。
[专利文献1]日本专利特开平11-152276号公报
[专利文献2]国际公开第99/11262号小册子
[专利文献3]国际公开第00/35446号小册子
[专利文献4]国际公开第98/09967号小册子
[专利文献5]日本专利特开平10-212289号公报
[专利文献6]日本专利特开2000-44562号公报
[专利文献7]国际公开第01/07423号小册子
[专利文献8]国际公开第01/53267号小册子
[专利文献9]专利第3199451号公报
[非专利文献1]Nature,1994年,第369号,p.568-571
[非专利文献2]Blood,2001年,第98卷,p.3241-3248
[非专利文献3]Blood,2002年,第99卷,p.2599-2602
[非专利文献4]Chemical and Pharmaceutical Bulletin,1977年,第25卷,第9号,p.2292-2299
发明的揭示
本发明者对具有血小板增多作用的化合物进行认真研究后发现了新颖的2-酰基氨基噻唑衍生物具有良好的血小板增多作用,从而完成了本发明。
即,本发明提供了以下(1)~(17)。
(1)以式(I)表示的2-酰基氨基噻唑衍生物或其制药学上允许的盐为有效成分的血小板增多剂,
式中符号具有以下含义:
Ar1:可分别被取代的芳基、单环芳香族杂环或二环系稠合杂环(R1为可被选自低级烷基、-CO-低级烷基、-COO-低级烷基、-OH、-O-低级烷基、-OCO-低级烷基及卤原子的1个以上的基团分别取代的芳基或吡啶基,且R2为下式(II)表示的基团时,可被选自低级烷基、-CO-低级烷基、-COO-低级烷基、-OH、-O-低级烷基、-OCO-低级烷基及卤原子的1个以上的基团分别取代的苯基或吡啶基除外),
R1:可分别被取代的芳基或单环芳香族杂环,
R2:式(II)、式(III)或式(IV)表示的基团,
式中符号具有以下含义:
n:1~3的整数,
m:1~3的整数,
这里,n或m为2以上的整数时,CR20R21及CR22R23可分别表示不同的基团,
X:O、S、N-R26、C(-R27)-R28表示的基团,
E、G、J、L:分别独立地为N或C-R29表示的基团(其中至少一个表示C-R29),
R20、R21、R22、R23、R26、R27、R28、R29:可相同或不同,表示-H,-OH,-O-低级烷基,可被取代的低级烷基,可被取代的环烷基,可被取代的芳基,可被取代的芳基烷基,可被取代的芳香族杂环,可被取代的芳香族杂环烷基,可被取代的非芳香族杂环,可被取代的低级链烯基,可被取代的低级1,1-亚烷基,-COOH,-COO-低级烷基,-COO-低级链烯基,-COO-低级亚烷基-芳基、-COO-低级亚烷基-芳香族杂环,可分别被选自低级烷基及环烷基的1个以上的基团取代的氨基甲酰基或氨基,该低级烷基及环烷基可分别被卤原子、-OH、-O-低级烷基或-O-芳基取代,-NHCO-低级烷基或氧代基,
R24、R25:可相同或不同,表示-H、可被取代的低级烷基,可被取代的环烷基或可被取代的非芳香族杂环。
式(I)表示的化合物中的Ar1较好为可分别被取代的苯基或单环芳香族杂环,其中更好的是可分别被取代的苯基或吡啶基,其中特别好的是2位及6位无取代,3位可被-F、-Cl或-Br取代,5位可被-F、-Cl或-Br取代,4位可被取代的苯基,或2位及4位无取代,5位可被-F、-Cl或-Br取代,6位可被取代的吡啶-3-基,其中最好的是可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在4位取代的苯基,或可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在6位取代的吡啶-3-基,
其中,RY表示可被选自-OH、-O-低级烷基、可被1个或2个低级烷基取代的氨基、-CO2H、-CO2-低级烷基、可被1个或2个低级烷基取代的氨基甲酰基、氰基、芳基、芳香族杂环、非芳香族杂环及卤原子的1个以上的基团取代的低级烷基(下同),
式(I)表示的化合物中的R1较好为可分别被取代的苯基或噻吩基,更好为可分别被选自卤原子及三氟甲基的1个以上的基团取代的苯基或噻吩基,特别好的是可被1~3个卤原子分别取代的苯基或噻吩基(有2个或3个卤原子取代时,可以是相同或不同的卤原子),
式(I)表示的化合物中的R2较好为式(II)表示的基团,更好是式(II)表示的基团中n为2、m为2、X为N-R26或C(-R27)-R28表示的基团,特别好的是4-(哌啶-1-基)哌啶-1-基、4-丙基哌啶-1-基、4-环己基哌嗪-1-基或4-丙基哌嗪-1-基。
(2)进一步限定(1)记载的医药组合物,R1为分别被1~3个卤原子取代的苯基或噻吩基(卤原子为2个或3个时,可以是相同或不同的卤原子),R2为(1)记载的式(II)表示的基团,n为2,m为2,X为N-R26或C(-R27)-R28表示的基团,Ar1为可分别被取代的苯基或吡啶基。
(3)进一步限定(1)或(2)记载的医药组合物,该组合物为血小板减少症治疗剂。
(4)进一步限定(1)或(2)记载的医药组合物,该组合物为c-Mpl配体。
(5)式(V)表示的2-酰基氨基噻唑衍生物或其制药学上允许的盐,
式中符号具有以下的含义:
Ar2:(1)记载的Ar1表示的基团,但吲哚-2-基除外,
R3:(1)记载的R1表示的基团,
R4:(1)记载的R2表示的基团,但式(IV)表示的基团除外,
式(V)表示的化合物中的Ar2较好的是可分别被取代的苯基或单环芳香族杂环,其中更好的是可分别被取代的苯基或吡啶基,其中特别好的是2位及6位无取代,3位被-H、-F、-Cl或-Br取代,5位被-F、-Cl或-Br取代,4位被取代的苯基,或2位及4位无取代,5位被-F、-Cl或-Br取代,6位被取代的吡啶-3-基,其中最好的是可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在4位取代的苯基,或可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在6位取代的吡啶-3-基,
式(V)表示的化合物中的R3较好为可分别被取代的苯基或噻吩基,其中更好的是可分别被选自卤原子及三氟甲基的1个以上的基团取代的苯基或噻吩基,其中特别好的是分别被1~3个卤原子取代的苯基或噻吩基(卤原子为2个或3个时,可以是相同或不同的卤原子),
式(V)表示的化合物中的R4较好为式(II)表示的基团,更好为式(II)表示的基团中的n为2、m为2、X为N-R26或C(-R27)-R28表示的基团,特别好的是4-(哌啶-1-基)哌啶-1-基、4-丙基哌啶-1-基、4-环己基哌嗪-1-基或4-丙基哌嗪-1-基。
(6)进一步限定(5)记载的化合物,Ar2为可分别被取代的苯基或单环芳香族杂环。
(7)进一步限定(6)记载的化合物,R3为可分别被取代的苯基或噻吩基,R4为(1)记载的式(II)表示的基团,Ar2为可分别被取代的苯基或吡啶基。
(8)进一步限定(7)记载的化合物,n为2,m为2,X为N-R26或C(-R27)-R28表示的基团。
(9)进一步限定(8)记载的化合物,R3为分别被1~3个卤原子取代的苯基或噻吩基(卤原子为2个或3个时,可以是相同或不同的卤原子)。
(10)进一步限定(9)记载的化合物,R4为4-(哌啶-1-基)哌啶-1-基、4-丙基哌啶-1-基、4-环己基哌嗪-1-基或4-丙基哌嗪-1-基。
(11)进一步限定(10)记载的化合物,Ar2为2位及6位无取代,3位被-H、-F、-Cl或-Br取代,5位被-F、-Cl或-Br取代,4位被取代的苯基,或2位及4位无取代,5位被-F、-Cl或-Br取代,6位被取代的吡啶-3-基。
(12)进一步限定(11)记载的化合物,Ar2为可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在4位取代的苯基,或可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在6位取代的吡啶-3-基。
(13)(5)~(12)中的任一项记载的化合物中,选自化合物组X及化合物组Y的化合物或其制药学上允许的盐,较好的是选自化合物组X的化合物或其制药学上允许的盐,
这里,“化合物组X”为
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-3-氟-4-羟基苯甲酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
N-[4-(4-氯噻吩-2-基)-5-(4-丙基-1-哌啶基)噻唑-2-基]-2-甲氧基异烟酰胺、
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]异喹啉-6-酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(3-羟基丙氧基)烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[(3-羟基丙基)氨基]烟酰胺、
1-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
1-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(4-氰基-1-哌啶基)-3,5-二氟苯甲酰胺、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-羧酸、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-6-氟苯基)哌啶-4-羧酸、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(4-羟基甲基-1-哌啶基)烟酰胺、
1-(3-氯-5-{[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
1-(3-氯-5-{[5-(4-环己基哌嗪-1-基)-4-(3-三氟甲基苯基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(2-甲氧基乙基)氨基甲酰]-1-哌啶基}烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(3-甲氧基丙基)氨基甲酰]-1-哌啶基}烟酰胺、以及
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[4-(吗啉代羰基)-1-哌啶基}烟酰胺组成的化合物组,
“化合物组Y”为
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-2-甲氧基异烟酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-甲氧基乙氧基)苯甲酰胺、
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]喹啉-6-酰胺、
3-氯-N-[4-(5-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-5-氟-4-(2-羟基乙氧基)苯甲酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(3-羟基丙氧基)苯甲酰胺、
3,5-二氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
3-溴-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-2-氧代-2,3-二氢苯并唑-6-酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-羟基苯甲酰胺、
(±)-5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(3-羟基吡咯烷-1-基)烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(4-羟基-1-哌啶基)烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]-6-(2-羟基乙基)氨基]烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]-6-(4-羟基-1-哌啶基)烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(3-氧代哌嗪-1-基)烟酰胺、
6-(4-氨基甲酰-1-哌啶基)-5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]烟酰胺、
(±)-5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[(2,3-二羟基丙基)氨基]烟酰胺、
(±)-5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[(四氢-3-呋喃基)甲氧基]烟酰胺、
6-(4-氨基甲酰-1-哌啶基)-5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]烟酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(4-羟基-1-哌啶基)苯甲酰胺、
1-(2-溴-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-羧酸、
1-(2-溴-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-酰胺、
1-(4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2,6-二氟苯基)哌啶-4-羧酸、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(4-氰基-1-哌啶基)苯甲酰胺、
1-(4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2,6-二氟苯基)哌啶-4-酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]-4-(4-羟基-1-哌啶基)苯甲酰胺、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-酰胺、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-羧酸、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(4-氰基-1-哌啶基)-5-氟苯甲酰胺、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-6-氟苯基)哌啶-4-酰胺、
1-(3-氯-5-{[4-(3-氯苯基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(5-氧代-1,4-二氮杂庚环-1-基)烟酰胺、
[1-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-基]乙酸、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(二甲基氨基)羰基]-1-哌啶基}烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(甲基氨基)羰基]-1-哌啶基}烟酰胺、
[4-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌嗪-1-基]乙酸、
6-[4-(乙酰基氨基)-1-哌啶基]-5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]烟酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-5-氟-4-[4-(甲氧基乙酰基)哌嗪-1-基]苯甲酰胺、
[4-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-6-氟苯基)哌嗪-1-基]乙酸、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-5-氟-4-(4-氨磺酰哌嗪-1-基)苯甲酰胺、
4-[4-(氨基甲酰甲基)哌嗪-1-基]-3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-5-氟苯甲酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[4-(丙基氨基甲酰)-1-哌啶基]烟酰胺、以及
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(2-乙氧基乙基)氨基甲酰]-1-哌啶基}烟酰胺组成的化合物组。
(14)医药组合物,其有效成分为(5)~(13)中的任一项记载的化合物。
(15)进一步限定(14)记载的医药组合物,为血小板增多剂。
(16)进一步限定(14)记载的医药组合物,为血小板减少症治疗剂。
(17)进一步限定(14)记载的医药组合物,为c-Mpl配体。
本发明化合物的化学结构上的特征在于是2位被酰基氨基取代、5位直接由氮原子取代的2-酰基氨基噻唑衍生物。本发明化合物的药理学上的特征是显现出人c-mpl-Ba/F3细胞增殖活性,人CD34+细胞向巨核细胞分化的促进活性,以及小鼠口服试验中的良好的口服活性,其结果是,具有血小板增多作用。
对式(I)或式(V)表示的化合物进行以下的进一步的说明。
本说明书中,对“低级”一词如无特别说明,表示碳原子数1~6的直链或支链碳链。
“低级烷基”表示C1-6烷基,具体可例举甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、己基,较好为作为C1-3烷基的甲基、乙基、丙基、异丙基。
“低级链烯基”表示C2-6链烯基,具体可例举乙烯基、丙烯基、丁烯基、戊烯基、己烯基,较好为作为C2-3链烯基的乙烯基、1-丙烯基、2-丙烯基、3-丙烯基。
“低级1,1-亚烷基”表示C1-6的1,1-亚烷基,具体可例举亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基,较好为作为C1-3亚烷基的亚甲基、亚乙基、1-亚丙基、2-亚丙基。
“低级亚烷基”表示C1-6烷基的2价基团,较好的是作为C1-4亚烷基的亚甲基、亚乙基、亚丙基、甲基亚乙基、亚丁基、二甲基亚甲基、二甲基亚乙基。
“环烷基”表示C3-8的碳环,它们可部分具有不饱和键。因此,具体可例举环丙基、环丁基、环戊基、环己基、环辛基、环丁烯基、环己烯基、环辛二烯基。
“芳基”表示C6-14的单环至3环的芳香环,较好为苯基、萘基,更好为苯基。
“芳基烷基”表示上述“低级烷基”被上述“芳基”取代后的基团,具体可例举苄基、1-苯乙基、2-苯乙基、萘基甲基、1-萘基乙基、2-萘基乙基。
“单环芳香族杂环”表示可含有氮、氧、硫的5~6元环芳香族杂环或它们的部分被氢化的环的1价基团,具体可例举噻吩基、呋喃基、吡咯基、噻唑基、唑基、咪唑基、异噻唑基、异唑基、吡唑基、噻二唑基、二唑基、三唑基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基。
“二环系稠合杂环”表示与芳基或单环芳香族杂环稠合的可含有氮、氧、硫的芳香族杂环或它们的部分氢化的环的1价基团,具体可例举吲哚基、异吲哚基、中氮茚基、咪唑基、喹啉基、异喹啉基、喹嗪基、2,3-二氮杂萘基、1,5-二氮杂萘基、喹喔啉基、喹唑啉基、噌啉基、苯并咪唑基、咪唑并吡啶基、苯并呋喃基、苯并唑基、1,2-苯并异唑基、苯并噻吩基、苯并噻唑基、唑并吡啶基、噻唑并吡啶基、二氢吲哚基、异二氢吲哚基、1,2-二氢喹啉基、1,2,3,4-四氢喹啉基、3,4-二氢-2H-1,4-苯并嗪基、1,4-二氢-2H-3,1-苯并嗪基、苯并二氢吡喃基、异苯并二氢吡喃基、苯并氧杂戊环基、苯并二氧戊环基、苯并二烷基等。
“芳香族杂环”表示上述“单环芳香族杂环”及“二环系稠合杂环”的组合。
“芳香族杂环烷基”表示上述“低级烷基”被上述“芳香族杂环”取代后的基团,具体可例举噻吩基甲基、呋喃基甲基、吡啶基甲基、噻唑基甲基、唑基甲基、咪唑基甲基、噻吩基乙基、呋喃基乙基、吡啶基乙基等。
“非芳香族杂环”表示可与芳基或单环芳香族杂环稠合的具有1个以上选自氮、氧、硫的相同或不同的杂原子的可稠合的非芳香族杂环的1价基团,具体可例举氮杂环丁烷基、吡咯烷基、咪唑啉基、咪唑烷基、吡唑烷基、吡唑啉基、哌啶基、氮杂基、哌嗪基、高哌嗪基、吗啉基、硫代吗啉基、二氢吲哚基、异二氢吲哚基等。
“卤原子”包括氟、氯、溴及碘原子。
“配体”是指与酶、受体、蛋白质等结合的低分子物质,包括激动剂和拮抗剂,较好为激动剂。
本说明书中的“可被取代”一词所允许的取代基作为不同基团的取代基可以是所有常用的取代基,各基团可具有1个以上的取代基。
R1中的“可分别被取代的芳基或单环芳香族杂环”,R20、R21、R22、R23、R26、R27、R28、R29中的“可被取代的环烷基”、“可被取代的芳基”、“可被取代的芳基烷基”、“可被取代的芳香族杂环”、“可被取代的芳香族杂环烷基”、“可被取代的非芳香族杂环”,以及R24、R25中的“可被取代的环烷基”、“可被取代的非芳香族杂环”中的所允许的取代基,可例举以下的(a)~(h)所示的取代基。其中,“RZ”表示可被选自-OH、-O-低级烷基、可被1个或2个低级烷基取代的氨基、可被1个或2个低级烷基取代的氨基甲酰基、芳基、芳香族杂环及卤原子的1个以上的基团取代的低级烷基(下同)。
(a)卤原子,(b)-OH、-O-RZ、-O-芳基、-OCO-RZ、氧代基(=O),(c)-SH、-S-RZ、-S-芳基、-SO-RZ、-SO-芳基、-SO2-RZ、-SO2-芳基、可被1个或2个RZ取代的氨磺酰基,(d)可被1个或2个RZ取代的氨基、-NHCO-RZ、-NHCO-芳基、-NHCO2-RZ、-NHCONH2、-NHSO2-RZ、-NHSO2-芳基、-NHSO2NH2、硝基,(e)-CHO、-CO-RZ、-CO2H、-CO2-RZ、可被1个或2个RZ取代的氨基甲酰基、氰基,(f)可被选自-OH、-O-低级烷基、可被1个或2个低级烷基取代的氨基、卤原子及RZ的1个以上的基团分别取代的芳基或环烷基,(g)可被选自-OH、-O-低级烷基、可被1个或2个低级烷基取代的氨基、卤原子及RZ的1个以上的基团分别取代的芳香族杂环或非芳香族杂环,(h)可被选自上述(a)~(g)所示的取代基的1个以上的基团取代的低级烷基。
R20、R21、R22、R23、R26、R28、R29、R29中的“可被取代的低级烷基”、“可被取代的低级链烯基”、“可被取代的低级1,1-亚烷基”,以及R24、R25中的“可被取代的低级烷基”所允许的取代基可例举上述(a)~(g)所示的基团。
Ar1中的“可分别被取代的芳基、单环芳香族杂环或二环系稠合杂环”中所允许的取代基可例举氧代基(氧代基仅在二环系稠合杂环中被允许),以及通式(VI)表示的基团,
-A-B-C-D-E (VI)
式中符号含义如下所述:
-A-:单键或可被取代的环胺二基(aminediyl)(仅限于氮原子取代),-B-:单键、-O-、-NH-、-N(-RZ)-、-NHCO-、-CO-、-CONH-或-CON(-RZ)-,-C-:单键或可分别被选自卤原子及-OH的1个以上的基团取代的低级亚烷基或低级亚烯基,-D-:单键、-NHCO-、-NHSO2-、-CO-或-SO2-,-E:-H、卤原子、-OH、-O-RZ、-O-CO-RZ、可被1个或2个RZ取代的氨基、-RZ、氰基、可分别被取代的芳基、环烷基、芳香族杂环或非芳香族杂环,但是,作为通式(VI)表示的基团,-CH2-(非芳香族杂环)、-CH=(非芳香族杂环)除外(该非芳香族杂环的碳原子都仅限于被次甲基取代);Ar1为可分别被取代的芳基或单环芳香族杂环时,-A-及-B-为单键,-C-为单键或可分别被选自卤原子及-OH的1个以上的基团取代的亚乙基或亚乙烯基,-D-为-CO-的基团,-A-及-B-为单键,-C-为单键或可分别被选自卤原子及-OH的1个以上的基团取代的亚乙基或亚乙烯基,-D-为-SO2-,-E为可被1个或2个RZ取代的氨基的基团,-A-及-B-为单键,-C-为单键或可分别被选自卤原子及-OH的1个以上的基团取代的亚乙基或亚乙烯基,-D-为单键,-E为可分别被取代的芳基、未部分氢化的单环芳香族杂环或与未部分氢化的单环芳香族杂环稠合的环的1价基团的基团,以及-A-为单键,-B-为-CO-的基团,-A-、-B-、-C-及-D-为单键,-E为可分别被取代的芳基、未部分氢化的单环芳香族杂环或与未部分氢化的单环芳香族杂环稠合的环的1价基团的基团除外。
-A-中的“环胺二基(仅限于氮原子取代)”表示包含稠合环及螺环,具有至少1个氮原子,还可具有1个以上选自氮、氧、硫的相同或不同的杂原子的3~8元环(稠合环或螺环为5~15元环)的芳香族或非芳香族环状胺的2价基团,表示所具有的至少1个氮原子直接在Ar1上取代的基团,具体可例举氮杂、吡咯烷、哌啶、哌嗪、N-甲基哌嗪、氮杂庚环、二氮杂庚环、N-甲基二氮杂庚环、吗啉、硫代吗啉、异二氢吲哚、1,4-二氧杂-8-氮杂螺[4,5]癸烷、1-氧杂-8-氮杂螺[4,5]癸烷、1-氧杂-8-氮杂螺[4,5]十一烷等的2价基团。
-A-中的“可被取代的环胺二基”及-E中的“可分别被取代的芳基、环烷基、芳香族杂环或非芳香族杂环”所允许的取代基可例举上述(a)~(h)所示的基团及可被上述(a)~(g)所示的基团取代的低级1,1-亚烷基。
通式(I)或(V)所示的本发明的化合物有因取代基的种类不同而含有手性碳原子的情况,可存在基于此的光学异构体。本发明包含所有这些光学异构体的混合物和分离体。此外,本发明化合物有时还存在互变异构体,本发明包含这些异构体的分离体或混合物。作为该互变异构体可例举2-羟基吡啶和2-吡啶酮间的互变异构体。此外,本发明还包含标记物,即,本发明化合物的1个以上的原子被放射性同位素或非放射性同位素取代的化合物。
本发明的化合物可形成盐,所述盐只要是制药学上允许的盐即可,也包括在本发明的范围内。具体包括与盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、对甲苯磺酸、天冬氨酸或谷氨酸等有机酸形成的酸加成盐,与包含钠、钾、钙、镁等金属的无机碱,甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等有机碱形成的盐和铵盐等,本发明还包含本发明化合物及其制药学上允许的盐的各种水合物、溶剂合物及具有多晶形的物质。本发明化合物还包含所有在生物体内被代谢而转变为具有前述通式(I)或(V)的化合物或其盐的所谓前体药物。形成本发明的前体药物的基团可例举Prog.Med.5:2157-2161(1985)记载的基团,或广川书店1990年刊《医药品的开发》第7卷分子设计163-198页记载的基团。
制备方法
本发明化合物及其制药学上允许的盐可利用基于其基本骨架或取代基的种类的特征,采用各种公知的合成方法制得。以下对其代表性的制法进行例示。根据官能团的种类,在原料至中间体的阶段将该官能团转变为适当的保护基,即容易转化为该官能团的基团在制备技术上是有效的。然后,根据需要除去保护基,就能够获得所希望的化合物。该官能团可例举羟基、羧基、氨基等。这些保护基可例举Greene及Wuts著《Protective Groups in OrganicSynthesis(third edition)》中记载的保护基,可根据反应条件适当采用之。
(制法1)
(式中,R1、R2、Ar1如前所述,下同。)
本制法是按照常规方法使化合物(1e)或其反应性衍生物与化合物(1d)或其盐酰胺化,再根据需要除去保护基,制得本发明化合物(I)或(V)的方法。
化合物(1e)的反应性衍生物可例举甲酯、乙酯、叔丁酯等常用酯,酰氯、酰溴这样的酰卤,酰基叠氮,与N-羟基苯并三唑、对硝基苯酚或N-羟基琥珀酰亚胺等的活性酯,对称型酸酐,与烷基碳酸酯、对甲苯磺酸等的混合酸酐等。
此外,使化合物(1e)以游离酸反应时,或不分离出活性酯和酰卤而进行反应时,最好采用二环己基碳化二亚胺、羰基二咪唑、二苯基磷酰叠氮、二乙基磷酰基氰化物或1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(WSC·HCl)等缩合剂,在吡啶溶剂中使用氯氧化磷使反应进行。
反应因所用的反应性衍生物和缩合剂的不同而不同,通常在二氯甲烷、二氯乙烷、氯仿等卤代烃类,苯、甲苯、二甲苯等芳香族烃类,醚、四氢呋喃(THF)等醚类,乙酸乙酯等酯类,乙腈、N,N-二甲基甲酰胺(DMF)或二甲亚砜(DMSO)等对反应无活性的有机溶剂中,在冷却下、冷却至室温下或室温至加热条件下进行反应。
反应时,采用过量的化合物(1e),或在N-甲基吗啉、三甲胺、三乙胺、N,N-二甲基苯胺、吡啶、4-(N,N-二甲基氨基)吡啶、甲基吡啶、二甲基吡啶等碱存在下进行反应,有利于反应的顺利进行。此外,也可采用吡啶盐酸盐、吡啶对甲苯磺酸盐、N,N-二甲基苯胺盐酸盐等弱碱和强酸形成的盐。吡啶也可作为溶剂使用。
特别好的是在乙腈、DMF等溶剂中,采用吡啶、N,N-二甲基苯胺等碱或采用吡啶作为溶剂使反应进行。
反应中所用的原料化合物(1d)可通过使化合物(1a)的5位卤化合成化合物(1b),然后使化合物(1c)作用而制得(根据需要在任意阶段除去保护基)。化合物(1b)可不分离而直接用于其后的反应。
卤化过程中所用的卤化剂只要是芳香环上氢的卤原子取代反应中常用的卤化剂即可,可采用氯、溴等卤素单体,二烷二溴化物,苯基三甲基铵三溴化物,吡啶氢溴化物过溴化物、吡咯烷酮氢三溴化物等吡啶,α-吡咯烷酮、季铵、二烷等过溴化物等,也可采用N-溴琥珀酰亚胺或N-氯琥珀酰亚胺等酰亚胺系卤化剂,氯化氢、溴化氢等氢卤酸,溴化铜、氯化铜等卤化铜等金属试剂。
作为卤化剂使用卤素单体或过溴化物时,可在卤代烃类,醚类,甲醇(MeOH)、乙醇(EtOH)、2-丙醇、乙二醇等醇类,芳香族烃类,乙酸,乙酸乙酯(EtOAc)等酯类等对反应无活性的有机溶剂中使其作用于化合物(1a)。此时,根据需要可在少量卤化氢等催化剂存在下进行,最好在-30℃至所用溶剂的回流温度的反应温度下进行反应。
卤化剂使用卤化氢的情况下,可在其酸性溶液或氢氧化钠水溶液等碱性溶液中使卤化氢作用于化合物(1a),此时的反应温度为-30℃至所用溶剂的回流温度。使用金属试剂的反应通常将化合物(1a)溶于卤代烃类、醚类、醇类、芳香族烃类、乙酸、酯类等对反应无活性的有机溶剂或水或它们的混合溶剂中,使试剂发挥作用,根据需要可在少量卤化氢等催化剂存在下,在室温乃至加热下实施反应。
在DMF、N-甲基-2-吡咯烷酮、DMSO等非质子性极性溶剂,卤代烃类,醚类,芳香族烃类等对反应无活性的有机溶剂或水或它们的混合溶剂中,使化合物(1c)作用于以上制得的化合物(1b),合成化合物(1d)。此时的反应温度为室温乃至所用溶剂的回流温度。
反应时,使用过量的化合物(1c),或在N-甲基吗啉、三乙胺、二乙基异丙基胺、N,N-二甲基苯胺、吡啶、4-(N,N-二甲基氨基)吡啶、甲基吡啶、二甲基吡啶等碱存在下将有利于反应的进行。
(制法2)
本制法是利用常规方法使制法1所示方法合成的化合物(1b)和化合物(1e)或其反应性衍生物酰胺化,合成化合物(2a),然后,使化合物(1c)作用,根据需要除去保护基,制得本发明化合物(I)或(V)的方法。
任一步骤都可采用制法1所示的方法。
式(I)或式(V)所示的这些化合物可由以上获得的化合物,通过任意组合公知的烷基化、酰化、置换反应、氧化、还原、水解等本领域普通技术人员通常可采用的工艺制得。
以上制得的本发明化合物可游离或按照常规方法进行成盐处理,其盐被分离精制。分离精制可采用萃取、浓缩、蒸馏、结晶化、过滤、重结晶、各种色谱法等常规的化学操作进行。
各种异构体可按照常规方法利用异构体间的物理化学性质的差异进行分离。例如,外消旋混合物,例如可形成与酒石酸等一般的光学活性酸的非对映异构体盐,通过光学拆分的方法等常用的外消旋体拆分法获得光学纯的异构体。此外,非对映异构体混合物例如可通过分别结晶化或各种色谱法等进行分离。光学活性化合物也可采用适当的光学活性原料制得。
产业上利用的可能性
本发明化合物及其盐具有良好的血小板增多作用。因此,本发明化合物对再生障碍性贫血,骨髓发育不良综合征中的血小板减少症,恶性肿瘤的化学疗法,放射疗法中的血小板减少症,特发性血小板减少性紫癜病,肝病中的血小板减少症,HIV中的血小板减少症等各种血小板减少症的治疗及/或预防有用。此外,在采用化学疗法和放射疗法可能导致血小板减少的情况下,可在实施这些疗法之前预先服用本发明化合物。
本发明化合物的药理作用通过以下的试验确认。
(i)人c-mpl-Ba/F3细胞增殖试验
在96孔的微型板中,于37℃在添加了各浓度的被验化合物、并含有10%胎牛血清的RPMI1640培养基(100μl/孔)中对2×105个/ml的人c-mpl-Ba/F3细胞进行培养。培养开始24小时后以10μl/孔添加WST-1/1-甲氧基PMS(细胞计数盒,同仁)。添加后立刻及2小时后,用微型板读数计(Model 3350:Bio-Rad)测定A450/A650的吸光度,将2小时的吸光度的增加作为各被验化合物的增殖活性,其结果示于表1。
表中的词的含义如下所示。
pot:促进细胞增殖为实施例9的化合物(实施例9的化合物及rhTPO中的rhTPO)的最大细胞增殖活性值的30%时的被验化合物浓度。
Efficacy:实施例9的化合物(实施例9的化合物及rhTPO中的rhTPO)的最大细胞增殖活性值作为100%时的被验化合物的最大细胞增殖活性值。
(表1)本发明化合物的人c-mpl-Ba/F3细胞增殖作用
被验化合物 | pot.[nM] | Efficacy[%] |
实施例9 | 10 | 87 |
实施例16 | 2.4 | 93 |
实施例66 | 14 | 99 |
实施例103 | 18 | 97 |
实施例214 | 15 | 106 |
实施例250 | 6.7 | 87 |
实施例272 | 3.3 | 96 |
实施例276 | 8.7 | 100 |
实施例280 | 4.9 | 107 |
实施例328 | 9.0 | 88 |
比较化合物1 | 4.4 | 101 |
比较化合物2 | 2.1 | 96 |
比较化合物3 | 6.9 | 96 |
rhTPO | 0.012 | 100 |
表中,比较化合物1是上述专利文献7记载的化合物编号A-1的化合物,比较化合物2为上述专利文献8记载的化合物编号A-14的化合物,比较化合物3为上述专利文献8记载的化合物编号J-14的化合物。比较化合物1~3的结构如下所示。
从上述结果可确认本发明化合物具有通过c-Mpl引起的Ba/F3细胞增殖作用。
(ii)巨核细胞集落形成促进作用测定试验
于37℃,用MegaCultTM-C(StemCell Technologies公司),在被验物质存在下,通过2 well chamber slide对人CD34+细胞进行10~14天的培养。按照所附说明书进行脱水和固定后,对抗糖蛋白IIb/IIIa抗体进行染色。将3个以上被染色的巨核细胞的集团作为1个集落,用显微镜测定每1个孔中的集落数。通过剂量曲线算出各被验化合物的EC30值。
其结果是,实施例9的化合物的EC30值为12nM,实施例66的化合物的EC30值为47nM,实施例250的化合物的EC30值为26nM。
从以上结果可确认,本发明化合物具有良好的巨核细胞集落形成促进作用。
(iii)小鼠口服试验
以100mg/kg或10mg/kg给雄性ICR小鼠口服被验化合物溶解或悬浮于0.5%甲基纤维素水溶液而形成的化合物混合液。口服2小时后,以1/10容积的3.8%柠檬酸钠为抗凝剂从腹部下大静脉采血,以12000rpm进行3分钟的离心分离,于56℃对所得血浆进行30分钟的保温,将保温后的血浆加入(1)记载的人c-mpl-Ba/F3细胞增殖试验系统中,使最终浓度达到10%血浆,测定细胞增殖活性。求出各被验化合物的最大细胞增殖活性作为100%时的各血浆的细胞增殖活性(%)。其结果示于表2。
(表2)口服被验化合物后的血浆的人
c-mpl-Ba/F3细胞增殖活性
被验化合物 | 给药量[mg/kg p.o.] | 细胞增殖活性[%] |
实施例16 | 10 | >80% |
实施例66 | 10 | 61% |
实施例214 | 10 | >80% |
实施例250 | 10 | >80% |
实施例272 | 10 | >80% |
实施例276 | 10 | >80% |
实施例280 | 10 | >80% |
实施例328 | 10 | >80% |
比较化合物1 | 100 | <10% |
比较化合物2 | 100 | <10% |
比较化合物3 | 100 | <10% |
从以上结果可确认,本发明化合物对小鼠具有口服活性。特别令人意外的是,比较化合物以100mg/kg的量也未显现出口服活性,但本发明化合物以10mg/kg的量就具有良好的口服活性,这可以认为是在噻唑5位导入直接结合的氮原子而实现的。比较化合物2及比较化合物3的给药量(10mg/kg p.o.)与实施例化合物相同时,其细胞增殖活性<10%。
移植人的造血干细胞后,给确认产生了人血小板的小鼠服用本发明化合物,可确认其血小板增多活性。
本发明的医药品可通过常用的方法,由通式(I)或(V)表示的本发明化合物的1种或2种以上和常用于制剂化的药剂用单体、赋形剂及其它添加剂调制。给药可采用片剂、丸剂、胶囊剂、颗粒剂、散剂、溶液剂等方式口服,或静注、肌注等注射剂或栓剂、经鼻、经粘膜、经皮等非口服方式中的任一种。
本发明的口服的固体组合物采用片剂、散剂、颗粒剂等。这种固体组合物中混合了1种或2种以上的活性物质和至少1种惰性稀释剂,例如,乳糖、甘露糖醇、葡萄糖、羟丙纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、偏硅酸铝酸镁等。组合物中利用常规方法可含有惰性稀释剂以外的添加剂,例如,硬酯酸镁等润滑剂,纤维素乙醇酸钙等崩解剂,乳糖等稳定剂,谷氨酸或天冬氨酸等助溶剂等。片剂或丸剂可根据需要用蔗糖、明胶、羟丙纤维素、羟丙甲基纤维素邻苯二甲酸酯等糖衣或胃溶性或肠溶性薄膜包覆。
口服液体组合物含有药物制剂中允许的乳浊剂、溶液剂、悬浮剂、糖浆剂、酏剂等,包含常用的惰性稀释剂,例如精制水和乙醇。该组合物除了惰性稀释剂以外还含有湿润剂、悬浮剂等助剂,甜味剂,矫味剂,芳香剂和防腐剂。
非口服的注射剂含有无菌的水性或非水性溶液剂、悬浮剂、乳浊剂。水性溶液剂、悬浮剂例如含有注射用蒸馏水及生理食盐水。非水性溶液剂、悬浮剂例如有丙二醇、聚乙二醇、橄榄油等植物油、乙醇等醇类、吐温80等。该组合物还可含有防腐剂,湿润剂,乳化剂,分散剂,例如乳糖等稳定剂,例如谷氨酸或天冬氨酸等助溶剂等助剂。它们例如可通过除菌滤器过滤、配合杀菌剂或照射而灭菌。此外,也可制造无菌的固体组合物,在使用前以无菌水或无菌的注射用溶剂溶解后使用。
通常口服的情况下,1天的给药量按照体重约0.0001~50mg/kg,较好约为0.001~10mg/kg,更好为0.01~1mg/kg,可1次或分2~4次给药。静脉给药时,1天的给药量按照体重约为0.0001~1mg/kg,较好约为0.0001~0.1mg/kg,1天1次或分多次给药。给药量可根据症状、年龄、性别等作适当决定。
实施发明的最佳方式
以下,通过实施例对本发明进行具体说明,但本发明并不仅限于这些实施例。实施例中所用的原料化合物中也包含新物质,作为参考例对从公知物获得这种原料化合物的制备方法进行说明。
参考例1
冰冷下,在4.18g的4-氯-2-乙酰基噻吩和30ml乙醚的溶液中加入1.5ml的溴,室温下搅拌2小时。在反应液中加水,分液,所得有机层用饱和食盐水(盐水)洗涤,再用无水硫酸钠干燥。减压蒸除溶剂获得溴化物。室温下,在溴化物的EtOH 30ml溶液中加入2.1g的硫脲,于80℃搅拌一晚。过滤析出的固体,减压蒸干所得溶液,加入氯仿后,有机层用碳酸钾水溶液(aq)、盐水洗涤后,用硫酸钠干燥。减压蒸除溶剂后,所得残渣用己烷∶EtOAc=1∶1的溶液洗涤,获得2.57g的2-氨基-4-(4-氯噻吩-2-基)噻唑。
与上述参考例1的方法同样,分别使用对应的原料,制备表3所示的参考例2~8。
表中符号的含义如下所述(下同)。
Rf:参考例编号,Data:物理学数据(MS:FAB-MS(M+H)+,MN:FAB-MS(M-H)-,MM:FAB-MS(M)+,NMR:以(CH3)4Si为内标,如无特别记载,以DMSO-d6为测定溶剂的1H-NMR中的峰的δ(ppm)),structure:化学结构,R1、R2、Ar:通式中的取代基(Me:甲基,Et:乙基,nPr:正丙基,nBu:正丁基,tBu:叔丁基,cHex:环己基,cHep:环庚基,allyl:烯丙基,Ph:苯基,Bn:苄基,cyano:氰基,Ac:乙酰基,Boc:叔丁氧基羰基,Fur:呋喃基,The:噻吩基,azet:氮杂环丁烷-1-基,pyrr:吡咯烷-1-基,pipe;哌啶-1-基,pipa:哌嗪-1-基,mor:吗啉-4-基,tmor:硫代吗啉-4-基,imid:咪唑-1-基,TBS:叔丁基二甲基甲硅烷基。取代基前的数字表示取代位置,例如,5-Cl-3-The表示5-氯噻吩-3-基,4-cHex-pipa表示4-环己基哌嗪-1-基)。
表3
Rf | R1 | Data |
1 | 4-Cl-2-The | MS;217. |
2 | 5-Cl-3-The | MS;217. |
3 | 5-F-2-The | MS;201. |
4 | 3-F-2-The | MS;201. |
5 | 5-Me-2-The | MS;197. |
6 | 4-Me-2-The | MS;197. |
7 | 4-F-5-Cl-2-The | MS;235. |
8 | 4-F-2-The | MS;201. |
参考例9
在6.0g的2-氨基-4-(4-氟苯基)噻唑和100ml的THF的溶液中滴入1.60ml的溴,于室温搅拌90分钟。蒸干反应液后,加入100ml的DMF、10.4g的1-环己基哌嗪、17.2ml的三乙胺,于90℃搅拌31小时。减压蒸干反应液,加入饱和NaHCO3水溶液后,用氯仿萃取,再用盐水洗涤有机层,然后用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(洗脱液:氯仿-MeOH=100∶1~100∶3)精制,获得11.26g的2-氨基-5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑。
与上述参考例9的方法同样,分别使用对应的原料制备表4所示的参考例10~40。
参考例41
冰冷却下,在参考例1的化合物0.5g和5ml的DMF的溶液中加入0.45g的N-溴琥珀酰亚胺,相同温度下搅拌50分钟。依次在反应液中加入0.6g的环己基哌嗪和0.6ml的三乙胺,于70℃搅拌3天。减压蒸干反应液,加入氯仿后,用碳酸钾水溶液和盐水洗涤有机层,然后用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=1∶1)精制,获得300mg的2-氨基-4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑。
与上述参考例41的方法同样,分别使用对应的原料制备表4所示的参考例42~71。
表4
Rf | R1 | R2 | Data |
9 | 4-F-Ph | 4-cHex-pipa | MS;361. |
10 | 4-F-Ph | 4-nPr-pipe | MS;320. |
(表4续)
(表4续)
Rf | R1 | R2 | Data |
49 | 4-Cl-2-The | 4-mor-pipe | MS;385. |
50 | 4-Cl-2-The | (1-nBu-吡咯烷-3-基)(Me)N- | MS;371. |
51 | 4-Cl-2-The | (奎宁环-3-基)(Me)N- | MS;355. |
52 | 4-F-5-Cl-2-The | 4-cHex-pipa | MS;401. |
53 | 4-Cl-2-The | 4-nPr-pipa | MS;343. |
54 | 4-Cl-2-The | mor | MS;302. |
55 | 4-F-2-The | 4-cHex-pipa | MS;367. |
56 | 4-Cl-2-The | (mor-(CH2)3)(Me)N- | MS;373. |
57 | 4-Cl-2-The | (mor-(CH2)2)(cHex)N- | MS;427. |
58 | 4-Cl-2-The | 4-tmor-pipe | MS;401. |
59 | 4-Cl-2-The | tmor | MS;318. |
60 | 4-Cl-2-The | 3-oxo-pipa | MS;315. |
61 | 4-Cl-2-The | 4-(cHex)(Me)N-pipe | MS;411. |
62 | 4,5-diCl-2-The | 4-cHex-pipa | MS;417. |
63 | 4-Cl-2-The | 4-pipe-pipe | MS;383. |
64 | 4-Cl-2-The | 4-(F3C-CH2)(Me)N-pipe | MS;411. |
65 | 4-Cl-2-The | (3R*,5S*)-3,5-diMe-4-nPr-pipa | MS;371. |
66 | 4-Cl-2-The | 4-cHep-pipa | MS;397. |
67 | 4-Cl-2-The | 4-(nPr)(Me)N-pipe | MS;371. |
68 | 4-Cl-2-The | 4-(F3C-(CH2)2)(Me)N-pipe | MS;425. |
69 | 4-Cl-2-The | 3-EtO2C-pipe | MS;372. |
70 | 4-Cl-2-The | 2-EtO2C-pipe | MS;372. |
71 | 4-Cl-2-The | 4-(3-F-pyrr)-pipe | MS;387. |
参考例72
在参考例69的化合物830mg的THF 10ml、EtOH 2ml的溶液中加入1M的NaOH水溶液6ml,室温搅拌一晚。蒸除溶剂后加水,用乙醚萃取。在残留的水层中加入6.5ml的1M的HCl水溶液,滤取生成的沉淀,减压下干燥,获得726mg的1-[2-氨基-4-(4-氯噻吩-2-基)噻唑-5-基]哌啶-3-羧酸。
与上述参考例72的方法同样,使用对应的原料制备表5所示的参考例73。
表5
Rf | R1 | R2 | Data |
72 | 4-Cl-2-The | 3-HO2C-pipe | MS;344. |
73 | 4-Cl-2-The | 2-HO2C-pipe | MS;344. |
参考例74
在参考例72的化合物683mg的DMF 20ml溶液中加入1-羟基苯并三唑(HOBt)359mg、WSC·HCl 506mg、二甲胺盐酸盐432mg、三乙胺1.11ml,室温搅拌一晚。减压下蒸除溶剂后加入饱和NaHCO3水溶液,滤取生成的沉淀物。在氯仿中溶解该沉淀物,加入饱和NaHCO3水溶液,用氯仿萃取。用MgSO4干燥后蒸除溶剂,所得残渣用以氯仿∶MeOH(100∶1~50∶1)为洗脱溶剂的硅胶柱色谱法精制,获得628mg的1-[2-氨基-4-(4-氯噻吩-2-基)噻唑-5-基]-N,N-二甲基哌啶-3-酰胺。
与上述参考例74的方法同样,使用对应的原料制备表6所示的参考例75。
表6
Rf | R1 | R2 | Data |
74 | 4-Cl-2-The | 3-Me2NOC-pipe | MS;371. |
75 | 4-Cl-2-The | 2-Me2NOC-pipe | MS;371. |
参考例76
在143mg的LAH的THF 10ml悬浮液中加入参考例74的化合物608mg的THF10ml溶液,加热回流一晚,冷却至室温,加入0.14ml的水、0.14ml的2M的NaOH水溶液和0.42ml的水。滤去生成的沉淀,减压下蒸除溶剂,所得残渣用以氯仿∶MeOH(20∶1)为洗脱溶剂的硅胶柱色谱法精制,获得156mg的2-氨基-4-(4-氯噻吩-2-基)-5-{3-[(二甲基氨基)甲基]哌啶-1-基}噻唑。
与上述参考例76的方法同样,使用对应的原料制备表7所示的参考例77。
表7
Rf | R1 | R2 | Data |
76 | 4-Cl-2-The | 3-(Me2N-CH2)-pipe | MS;357. |
77 | 4-Cl-2-The | 2-(Me2N-CH2)-pipe | MS;357. |
参考例78
在3-氯-4-羟基苯甲酸甲酯2.50g的DMF 25ml溶液中加入2.78g的碳酸钾和4.31ml的2-(叔丁基二甲基甲硅烷氧基)乙基溴化物,于50℃加热搅拌15小时。蒸馏反应液,加入EtOAc,有机层用水和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=10∶1~5∶1)精制,获得4.88g的4-[2-(叔丁基二甲基甲硅烷氧基)乙氧基]-3-氯苯甲酸甲酯。
与上述参考例78的方法同样,分别使用对应的原料制备表8所示的参考例79~89。
参考例90
在1.5g的3-氯-4-羟基苯甲酸甲酯和THF 20ml的溶液中加入1.8ml的1-叔丁氧基-2-丙醇、3.16g的三苯基膦和1.9ml的偶氮二羧酸二乙酯,室温下搅拌1小时。减压蒸干反应液后,所得残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=100∶1~5∶1)精制,获得2.3g的4-(1-叔丁氧基-2-丙氧基)-3-氯苯甲酸甲酯。
与上述参考例90的方法同样,分别使用对应的原料制备表8所示的参考例91~93。
参考例94
使4.0g的6-喹啉羧酸悬浮于30ml的MeOH,冰冷却下加入2.0ml的浓硫酸,于70℃搅拌22小时。减压下浓缩反应液加水,用碳酸钾中和,过滤析出的固体,干燥后获得4.28g的6-喹啉羧酸甲酯。使0.5g所得的酯溶于5ml的甲酰胺,室温下依次加入0.15ml的浓硫酸、0.05g的硫酸铁七水合物和0.4ml的31%的过氧化氢水溶液,于80℃搅拌50分钟。在反应液中加水,用碳酸钾调整为碱性。加入10%的MeOH-氯仿,经硅藻土过滤不溶物。将所得滤液分液,所得有机层用无水硫酸钠干燥,再用EtOH对浓缩后所得的残留物进行洗涤,获得0.15g的6-甲氧基羰基-2-喹啉酰胺。
参考例95
在1.96g的5-甲基吡唑-3-羧酸乙酯和40ml的DMF溶液中加入2.64g的碳酸钾和3.53ml的3-(叔丁基二甲基甲硅烷氧基)丙基溴化物,于50℃加热搅拌18小时。蒸干反应液,加入EtOAc,有机层用水和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=15∶1~5∶1)精制,获得1.39g的1-[3-(叔丁基二甲基甲硅烷氧基)丙氧基]-5-甲基吡唑-3-羧酸乙酯。
参考例96
在0.50g的3-氯-4-甲酰基苯甲酸甲酯和10ml二氯甲烷的溶液中加入0.5ml乙酸、0.3ml的2-甲氧基乙胺和0.85g的三乙酰氧基氢硼化物,室温搅拌1天。在反应液中加水,用碳酸钾中和后,加入EtOAc,有机层用水和盐水洗涤后,用硫酸钠干燥。蒸除溶剂,获得苯甲胺体。
在苯甲胺体的THF 10ml溶液中加入焦碳酸二叔丁酯0.70g,室温搅拌一晚。蒸干反应液后,残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=10∶1~8∶1)精制,获得0.87g的N-(2-氯-4-甲氧基羰基苯甲基)-N-(2-甲氧基乙基)氨基甲酸叔丁酯。
与上述参考例96的方法同样,使用对应的原料制备表8所示的参考例97。
参考例98
冰冷却下,在3,4,5-三氟苯甲酸1.52g和15ml二氯甲烷的溶液中加入0.92ml的草酰氯,相同温度下搅拌30分钟后,室温下再搅拌80分钟。加入数滴DMF后,室温下搅拌1小时。减压下蒸除溶剂,冰冷却下,在所得残渣中加入20ml的吡啶、3.40ml的2-叔丁氧基乙醇和1勺DMAP,室温搅拌一晚。减压蒸干反应液后,加入饱和NaHCO3水溶液,用EtOAc萃取,用水和盐水洗涤后,用MgSO4干燥。减压下蒸除溶剂,获得2.10g粗制的3,4,5-三氟苯甲酸2-叔丁氧基乙酯。冰冷却下,在1.03g的叔丁醇钾的THF 15ml溶液中加入1.50ml的2-叔丁氧基乙醇,直接搅拌40分钟。将反应液冷却至-78℃,加入2.10g粗制的3,4,5-三氟苯甲酸2-叔丁氧基乙酯的THF 5ml溶液,冰冷却下搅拌1小时,于室温再搅拌30分钟。加入饱和的氯化铵水溶液,用EtOAc萃取,再用水和盐水洗涤,然后用MgSO4干燥。减压下蒸除溶剂,所得残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=100∶1~20∶1)精制,获得2.24g的4-(2-叔丁氧基乙氧基)-3,5-二氟苯甲酸2-叔丁氧基乙酯。
参考例99
在1.15g的3-氯-4-氟苯甲酸叔丁酯和DMSO 20ml的溶液中加入碳酸钾1.3g和1.4g的六氢异烟酸乙酯,于80℃加热搅拌2天。在反应液中加入EtOAc,用水和盐水洗涤有机层后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(洗脱液:己烷∶EtOAc=20∶1~10∶1)精制,获得1.42g的N-(4-叔丁氧基羰基-2-氯苯基)六氢异烟酸乙酯。
与上述参考例99的方法同样,分别使用对应的原料制备表8所示的参考例100~108。
参考例109
在0.70g的3-氯-4-(4-羟基-1-哌啶基)苯甲酸甲酯和15ml二氯甲烷的溶液中加入1.5ml的2,6-二甲基吡啶和2.7g的叔丁基二甲基甲硅烷基三氟甲磺酸酯,于室温搅拌2周。在反应液中加入EtOAc,有机层用水和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(洗脱液:己烷∶EtOAc=50∶1)精制,获得0.93g的4-(4-叔丁基二甲基甲硅烷氧基-1-哌啶基)-3-氯苯甲酸甲酯。
参考例110
于-78℃,在1.50g的1-(4-乙氧基羰基-2-氟苯基)哌啶-4-酰胺和THF 20ml的溶液中加入2.0ml的三乙胺和0.9ml的三氟乙酸酐,室温搅拌6小时。蒸干反应液,加入EtOAc,有机层用水和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=5∶1~4∶1)精制,获得1.43g的4-(4-氰基-1-哌啶基)-3-氟苯甲酸乙酯。
参考例111
在0.50g的N-(4-叔丁氧基羰基-2-氟苯基)六氢异烟酸乙酯和DMF 5ml的溶液中加入0.21g的N-氯琥珀酰亚胺,室温下搅拌1天。蒸干反应液后,残渣用硅胶柱色谱法(洗脱液:己烷-EtOAc=5∶1~1∶1)精制,获得0.51g的N-(叔丁氧基羰基-2-氯-6-氟苯基)六氢异烟酸乙酯。
与上述参考例111的方法同样,分别使用对应的原料制备表8所示的参考例112~113。
(表8)
(表8续)
(表8续)
(表8续)
参考例114
在参考例78的化合物2.16g和MeOH 20ml-THF 15ml的溶液中加入7.5ml的1M的NaOH水溶液,室温搅拌3天。蒸干反应液,加入5%硫酸氢钾水溶液,使其呈酸性后,用氯仿-2-丙醇(3∶1)萃取。有机层用盐水洗涤后,用硫酸钠干燥,蒸除溶剂,获得1.17g的4-[2-(叔丁基二甲基甲硅烷氧基)乙氧基]-3-氯苯甲酸。
与上述参考例114的方法同样,分别使用对应的原料制备表9所示的参考例115~138。
参考例139
在1.56g的3,4,5-三氟苯甲酰氯中加入6.32ml的2-甲氧基乙醇和6.53g的碳酸铯,于100℃搅拌20小时。在反应液中加入50ml的THF,过滤,蒸干滤液,获得4.36g的无色固体。将该固体溶于15ml的THF,加入3.16ml的2-甲氧基乙醇和1.35g的叔丁醇钾,室温下搅拌4天。在反应液中加入5%硫酸氢钾水溶液后,用EtOAc萃取,有机层用盐水洗涤后,用硫酸钠干燥,蒸除溶剂,获得1.76g的3,5-二氟-4-(2-甲氧基乙氧基)苯甲酸。
参考例140
使0.3g的参考例94的化合物悬浮于THF-MeOH混合溶剂10ml(1∶1)中,室温下加入1.5ml的1M的NaOH水溶液,相同温度下搅拌3天。减压下浓缩反应液,加水后,用1.5ml的1M的HCl水溶液中和,过滤所得固体,干燥后获得0.29g的2-氨基甲酰喹啉-6-羧酸。
参考例141
在410mg的参考例130的化合物和10ml吡啶的溶液中加入0.24ml的乙酸酐,室温搅拌15小时。蒸干反应液,加入EtOAc,有机层用1M的HCl水溶液、水和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(洗脱液:氯仿-MeOH=100∶1~50∶1)精制,获得351mg的4-[2-(乙酰氧基)乙氧基]-3-甲基苯甲酸。
与上述参考例141的方法同样,使用对应的原料制备表9所示的参考例142。
参考例143
在2.00g的2-氯异烟酸中加入15ml的乙二醇和4.28g的叔丁醇钾,于150℃搅拌6天。将反应液倾入5%硫酸氢钾水溶液后,用EtOAc萃取,有机层用盐水洗涤后,用MgSO4干燥,蒸除溶剂,获得0.54g的2-(2-羟基乙氧基)异烟酸。
参考例144
在4.74g的1-{4-[(烯丙氧基)羰基]苯基}哌啶-4-羧酸乙酯的THF 15ml溶液中加入2.10ml的吗啉和390mg的四(三苯基膦)钯,于60℃搅拌1.5小时。减压下蒸除溶剂后,加入EtOAc,用饱和NaHCO3水溶液洗涤3次。在收集的饱和NaHCO3水溶液中加入浓HCl,滤取生成的沉淀,减压下干燥,获得2.73g的4-[4-(乙氧基羰基)哌啶-1-基]苯甲酸。
与上述参考例144的方法同样,使用对应的原料制备表9所示的参考例145。
参考例146
使1.42g参考例99的化合物溶于5ml的二氯甲烷,冰冷却下加入5ml的三氟乙酸,室温下搅拌1天。减压下浓缩反应液,加水后用NaOH水溶液中和,过滤所得固体,干燥后获得1.16g的3-氯-4-(4-乙氧基羰基-1-哌啶基)苯甲酸。
与上述参考例146的方法同样,使用对应的原料制备表9所示的参考例147。
参考例148
在1.12g的参考例144的化合物的DMF 20ml溶液中加入775mg的N-溴琥珀酰亚胺,室温下搅拌70分钟后,在50℃搅拌2小时。减压下蒸除溶剂后加水,滤取生成的沉淀。加入饱和NaHCO3水溶液、EtOAc和HCl后用氯仿萃取,再用MgSO4干燥。减压下蒸除溶剂,所得残渣用硅胶柱色谱法(洗脱液:氯仿-甲醇=100∶1~30∶1)精制,获得1.29g的3-溴-4-[4-(乙氧基羰基)哌啶-1-基]苯甲酸。
(表9)
(表9续)
(表9续)
(表9续)
(表9续)
参考例149
在2.00g的参考例9的化合物、1.14g的4-甲酰基苯甲酸和DMF 30ml的溶液中加入N-羟基苯并三唑(HOBt)992mg和1.39g的WSC-HCl,室温下搅拌一晚。减压蒸干反应液后,加入饱和NaHCO3水溶液,用氯仿萃取,有机层用MgSO4干燥后,蒸除溶剂,所得残渣用以氯仿∶MeOH(100∶1~30∶1)为洗脱溶剂的硅胶柱色谱法及以己烷∶EtOAc(5∶1~1∶1)为洗脱溶剂的硅胶柱色谱法精制,获得1.32g的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-甲酰基苯甲酰胺。
与上述参考例149的方法同样,使用对应的原料制备表10所示的参考例150。
(表10)
(表10续)
实施例1
冰冷却下,在300mg的参考例9的化合物和5ml吡啶的溶液中加入280mg的4-氰基苯甲酰氯,升温至室温后搅拌3天,然后于50℃搅拌1天。减压蒸干反应液后加入氯仿,有机层用饱和NaHCO3水溶液和盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用EtOAc重结晶,获得230mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-氰基苯甲酰胺。在该化合物80mg的EtOAc 5ml溶液中,加入0.4M HCl-EtOAc溶液0.4ml,搅拌一晚后过滤,得57mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-氰基苯甲酰胺盐酸盐。
实施例2
在500mg的参考例24的化合物和10ml DMF的溶液中加入300mg的2-甲氧基异烟酸、376mg的WSC-HCl和265mg的HOBt,室温下搅拌4天。蒸干反应液后加入EtOAc,用饱和NaHCO3水溶液和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(己烷-EtOAc=8∶1~2∶1)精制,将精制品溶于10ml的EtOAc中,加入0.46ml的0.4M的HCl-EtOAc溶液搅拌一会儿后,滤取析出物,获得72mg的N-[4-(5-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例3
在342mg的参考例28的化合物和DMF 10ml的溶液中加入306mg的2-甲氧基异烟酸、383mg的WSC-HCl、270mg的HOBt和244mg的4-(二甲基氨基)吡啶,于50℃搅拌3天。蒸干反应液,加入EtOAc,用饱和NaHCO3水溶液和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(己烷-EtOAc=8∶1)精制,将精制品溶于30ml的EtOAc中,加入0.1M的HCl-EtOAc溶液4.1ml,搅拌一会儿后,滤取析出物,获得120mg的N-[4-(5-氯噻吩-2-基)-5-(4-丙基哌啶-1-基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例4
在1.72g的参考例78的化合物和MeOH 17ml-THF 10ml的混合溶剂的溶液中加入1M的NaOH水溶液6ml,室温下搅拌3天。在反应液中加入1M的HCl水溶液5.5ml后,减压蒸除溶剂,获得4-[2-(叔丁基二甲基甲硅烷氧基)乙氧基]-3-氯苯甲酸的粗品。在其中加入参考例78的化合物720mg、DMF 20ml、WSC·HCl 959mg、HOBt 676mg和4-(二甲基氨基)吡啶611mg,于50℃搅拌22小时,90℃搅拌20小时。蒸干反应液,加入饱和NaHCO3水溶液后,用EtOAc萃取,有机层用饱和NaHCO3水溶液和盐水洗涤后,用硫酸钠干燥。蒸除溶剂后,残渣用以氯仿-MeOH(100∶1~10∶1)为洗脱溶剂的硅胶柱色谱法及以己烷∶EtOAc(2∶1~1∶1)为洗脱溶剂的硅胶柱色谱法精制,获得38mg的3-氯-4-{2-[3-氯-4-(2-羟基乙氧基)苯甲酰氧基]乙氧基}-N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]苯甲酰胺。在此物质中加入0.5ml的MeOH、1ml的THF和225μl的1M的NaOH水溶液,于室温搅拌5天。在反应液中加入EtOAc后,用饱和NaHCO3水溶液和盐水洗涤,再用硫酸钠干燥。蒸除溶剂后,残渣用硅胶柱色谱法(氯仿-MeOH=100∶0~100∶2)精制,将此精制品溶于5ml的EtOAc中,加入1.0ml的0.1M HCl-EtOAc溶液,搅拌一会儿后,滤取析出物,获得18mg的3-氯-N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺盐酸盐。
实施例5
在参考例41的化合物1.0g和30ml的吡啶的溶液中加入602mg的5,6-二氯烟酸,于-25℃加入0.27ml的磷酰氯,升温至室温后搅拌4小时。减压蒸干反应液,加入水和碳酸钾后,用氯仿萃取,有机层用盐水洗涤后,用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(己烷-EtOAc=200∶1~100∶1)精制,获得1.21g的5,6-二氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]烟酰胺。
实施例6
在实施例246的化合物100mg的EtOH 5ml的溶液中加入0.2ml的4M的HCl-EtOAc溶液,搅拌27小时。在反应液中加入氯仿后,有机层用饱和NaHCO3水溶液和盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(氯仿-MeOH=100∶1~5∶1)精制,将精制品溶于15ml的MeOH中,再加入10ml的4M的HCl-EtOAc溶液,搅拌一会儿后,减压蒸除溶剂,用乙醚洗涤后,获得28mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-羟基烟酰胺盐酸盐。
实施例7
在实施例233的化合物183mg中加入5ml的三氟乙酸,搅拌40小时后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=100∶1~20∶1)精制,获得50mg的3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(1-羟基-2-丙氧基)苯甲酰胺三氟乙酸盐。
实施例8
使0.34g的实施例218的化合物悬浮于5ml的MeOH,冰冷却下加入1ml的浓HCl,于50℃搅拌一晚。在反应液中再加入0.5ml的浓HCl,于50℃搅拌5小时,于60℃搅拌一晚。反应液自然冷却至室温后,过滤干燥析出的固体,获得0.33g的N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-3-氟-4-羟基苯甲酰胺盐酸盐。
实施例9
使187mg的实施例230的化合物溶于10ml的MeOH,加入3.5ml的浓HCl,搅拌18小时后,过滤析出物,用乙醚洗涤后,获得90mg的3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺盐酸盐。
实施例10
于0℃,在5.23g的实施例101的化合物的THF 100ml的溶液中加入17.0g的氢化三丁基锡,冷却至-78℃,加入670mg的四(三苯基膦)钯,慢慢升温至室温后搅拌1.5小时。在反应液中加入1.6ml的乙酸,室温搅拌15分钟后,减压下蒸除溶剂,在所得残渣中加入己烷,滤取析出物,减压下干燥,获得4.30g的N-[4-(4-氯噻吩-2-基)-5-(哌嗪-1-基)噻唑-2-基]-2-甲氧基异烟酰胺乙酸盐。
实施例11
使0.15g的实施例136的化合物溶于5.0ml的THF,于-78℃合计加入1.3ml的丁基锂(1.55M),相同温度下搅拌4个半小时,确认原料消失。加入0.5ml乙酸停止反应,升温至室温。在反应液中加水,用碳酸钾使其呈碱性,用氯仿萃取。有机层用无水硫酸钠干燥后,减压下浓缩溶剂,所得残渣用硅胶柱色谱法精制,获得0.12g的N-[5-(4-环己基哌嗪-1-基)-4-(噻吩-2-基)噻唑-2-基]-2-甲氧基异烟酰胺。使所得化合物溶于2ml的EtOAc中,冰冷却下加入0.25ml的1M的HCl-EtOAc溶液,室温搅拌一晚。过滤干燥析出的固体,获得98mg的N-[5-(4-环己基哌嗪-1-基)-4-(噻吩-2-基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例12
室温下,在48mg的40%氢化钠和1ml的乙二醇的溶液中加入100mg实施例5的化合物,升温至50℃后搅拌4天。在反应液中加入氯仿后,有机层用饱和NaHCO3水溶液和盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(氯仿-MeOH=200∶1~20∶1)精制,将精制品溶于5ml的EtOAc中,加入0.8ml的0.1M的HCl-EtOAc溶液,搅拌一会儿后,减压蒸除溶剂,用乙醚洗涤,获得34mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(2-羟基乙氧基)烟酰胺盐酸盐。
实施例13
室温下,在750mg实施例5的化合物和10m的THF的溶液中加入2.1ml的六氢异烟酸乙酯,升温至50℃后搅拌5小时。在反应液中加入氯仿后,有机层用饱和NaHCO3水溶液和盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(氯仿-MeOH=200∶1~100∶1)精制,获得881mg的1-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸乙酯。
实施例14
在9ml的1,2-二氯乙烷-3ml乙酸中溶解231mg的实施例10的化合物和80μl的苯甲醛,于0℃加入210mg的乙酸硼氢化钠,于0℃搅拌30分钟,室温搅拌30分钟。在反应液中加入饱和NaHCO3水溶液和1M的NaOH水溶液,呈碱性后,用氯仿萃取。有机层用MgSO4干燥后,减压蒸除溶剂,在所得残渣中加入5ml的乙酸、合计160μl的苯甲醛和合计404mg的乙酸硼氢化钠,于50℃搅拌4小时。减压蒸除溶剂,在所得残渣中加入饱和NaHCO3水溶液,滤取不溶物。加入氯仿溶解,再加入饱和NaHCO3水溶液,用氯仿萃取。有机层用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(己烷-EtOAc=4∶1)精制,将精制品溶于EtOAc后,加入0.5M的HCl-EtOAc溶液,滤取析出物,获得64mg的N-[5-(4-苄基哌嗪-1-基)-4-(4-氯噻吩-2-基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例15
冰冷却下,在0.35g的实施例243的化合物和5ml的EtOAc溶液中加入4M的HCl-EtOAc,室温搅拌1天。过滤析出的固体,获得345mg的4-氨基甲基-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]苯甲酰胺盐酸盐。
实施例16
室温下,在30mg的实施例13的化合物和1ml的MeOH的溶液中加入0.12ml的1M的NaOH水溶液,搅拌24小时。减压蒸干反应液后,将所得残渣溶于5ml的EtOAc,再加入0.2ml的1M的HCl水溶液,搅拌一会儿后,减压蒸除溶剂,用乙醚洗涤,获得20mg的1-(3-氯-5{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}吡啶-2-基)哌啶-4-羧酸盐酸盐。
实施例17
在180mg的实施例143的化合物和5ml DMF的悬浮液中加入1,1’-羰基二咪唑100mg,室温搅拌4小时后,加入1ml的28%氨水,室温搅拌1小时半。在反应液中加水,用氯仿萃取。有机层用MgSO4干燥后,减压蒸除溶剂,所得残渣用乙醇洗涤。将其悬浮于EtOH后,加入0.35ml的1M的HCl-EtOAc溶液,搅拌一晚后滤取析出物,获得151mg的N-[4-(4-氟苯基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-氨基甲酰甲基苯甲酰胺盐酸盐。
实施例18
在138mg的实施例147的化合物中加水3ml和浓HCl 3ml,于80℃搅拌17小时。反应液冷却至室温后,滤取沉淀,用水洗涤,在其中加入1M的NaOH水溶液、MeOH和乙醚,滤去不溶物,所得滤液用乙醚萃取后,在水层加入浓HCl,滤取析出物,减压下干燥,获得101mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-[(3,4-二氧代-2-羟基环丁-1-烯-1-基)氨基]苯甲酰胺盐酸盐。
实施例19
在430mg的实施例198的化合物中加入水15ml和浓HCl 15ml,于80℃搅拌3.5小时。将反应液冷却至0℃后,加水50ml,滤取沉淀物,减压下干燥,获得101mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-2,3-二羟基喹喔啉-6-酰胺盐酸盐。
实施例20
0℃下,在100mg参考例149的化合物和5ml MeOH的溶液中加入24mg硼氢化钠,室温下搅拌1小时,加入2ml的DMF,搅拌1小时,然后加入36mg的硼氢化钠再搅拌1小时。将反应液注入1M的HCl水溶液后,用饱和NaHCO3水溶液使溶液呈碱性,用氯仿萃取,有机层用MgSO4干燥。减压蒸除溶解后,所得残渣用硅胶柱色谱法(氯仿-MeOH=100∶1~20∶1)精制,将精制品溶于EtOAc后,加入0.5M的HCl-EtOAc溶液,滤取析出物,获得73mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-羟基甲基苯甲酰胺盐酸盐。
实施例21
在279mg的实施例141的化合物和10ml甲苯的悬浮液中加入1.81g叠氮化三丁基锡,加热回流14小时。然后,加入乙醚、1M的NaOH水溶液、EtOAc和浓HCl,滤取生成的沉淀,减压下干燥后,加入1M的NaOH水溶液和MeOH溶解,用乙醚洗涤。0℃冷却下在水层中加入浓HCl,滤取析出物,获得138mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-(1H-四唑-5-基甲基)苯甲酰胺。
实施例22
使0.15g的实施例149的化合物溶于10ml的THF,冰冷却下依次加入三乙胺0.1ml和氯甲酸甲酯40mg的THF 2ml溶液,室温搅拌一晚。浓缩反应液,加水后用EtOAc萃取。所得有机层用盐水洗涤后,用无水硫酸钠干燥。减压下浓缩溶剂,所得残留物用EtOAc重结晶,获得0.12g的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-(甲氧基羰基氨基甲基)苯甲酰胺。使所得化合物悬浮于5ml的EtOAc,冰冷却下加入0.6ml的0.4M的HCl-EtOAc溶液,搅拌一晚。过滤干燥析出的固体,获得115mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-(甲氧基羰基氨基甲基)苯甲酰胺盐酸盐。
实施例23
使0.15g的实施例149的化合物悬浮于5ml的THF,冰冷却下依次加入0.2ml的三乙胺、35mg的甲磺酰氯的THF 2ml溶液,室温下搅拌3小时。浓缩反应液后加水,用EtOAc萃取。所得有机层用盐水洗涤后,用无水硫酸钠干燥。减压下浓缩溶剂,所得残留物用EtOAc-己烷混合溶剂重结晶,获得0.12g的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-(甲磺酰基氨基甲基)苯甲酰胺。使所得化合物悬浮于5ml的EtOAc中,冰冷却下加入1M的HCl-EtOAc溶液0.2ml,搅拌一晚。过滤干燥析出的固体,获得111mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-(甲磺酰基氨基甲基)苯甲酰胺盐酸盐。
实施例24
0℃下,在57mg的实施例168的化合物和2ml吡啶的溶液中加入18μl的氯化氧代乙酸甲酯,从0℃至室温搅拌2小时。减压下蒸除溶剂后,加入饱和NaHCO3水溶液,用氯仿萃取,有机层用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(洗脱液:氯仿-MeOH=100∶1)精制。在精制品中加入二异丙醚,滤取析出物。获得19mg的N-(4-{[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]氨基甲酰}苯基)草氨酸甲酯。
实施例25
在71mg实施例168的化合物和5ml的DMF的悬浮液中加入71mg的3-甲氧基丙酸、120mg的HOBt、180mg的WSC·HCl,从室温至50℃总计搅拌29天。减压下蒸除溶剂后,加入饱和NaHCO3水溶液,用氯仿萃取,有机层用MgSO4干燥后,蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=100∶1~50∶1)精制。再加入MeOH和1M的HCl水溶液,用ODS柱色谱法(0.001M HCl水溶液-MeOH=2∶1~1∶1)精制后,加入饱和NaHCO3水溶液,用氯仿萃取。有机层用MgSO4干燥后,蒸除溶剂,加入二异丙醚,滤取生成的析出物,获得20mg的N-[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-4-[(3-甲氧基丙酰基)氨基]苯甲酰胺。
实施例26
在1.00g的实施例83的化合物的15ml乙酸的溶液中加入氢氧化钯-碳(20重量%)合计886mg,在氢气氛中总计搅拌2天。用硅藻土过滤反应液后,蒸除乙酸,在所得残渣中加入饱和NaHCO3水溶液,滤取析出物,减压下干燥,获得505mg的N-[4-(4-氟苯基)-5-(哌嗪-1-基)噻唑-2-基]-2-甲氧基异烟酰胺。
实施例27
0℃下,在202mg的实施例26的化合物、207mg的碳酸钾和15ml的DMF的悬浮液中加入46μl的烯丙基溴,慢慢升温,室温下搅拌一晚。减压下蒸除溶剂后加水,用氯仿萃取,有机层用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=300∶0~100∶1)精制。将该精制品溶于EtOAc,加入0.5M的HCl-EtOAc,滤取析出物,获得165mg的N-[5-(4-烯丙基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例28
冰冷却下,在178mg的实施例56的化合物的氯仿4ml的溶液中加入90mg的m-氯过苯甲酸(mCPBA),室温搅拌一晚。在其中加入MeOH、饱和NaHCO3水溶液和氯仿,滤去不溶物后,用氯仿萃取。用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=300∶1~100∶1)精制。将精制品悬浮于EtOAc,加入0.5M的HCl-EtOAc溶液,滤取析出物,获得39mg的N-[4-(4-氯-2-噻吩基)-5-(1-氧化硫代吗啉基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例29
在185mg的实施例75的化合物的4ml乙酸的溶液中加入100μl的过氧化氢水溶液(30%),室温下搅拌一晚。加入饱和NaHCO3水溶液、1M的NaOH水溶液和1M的HCl水溶液,滤取生成的沉淀。在其中加入氯仿和MeOH使沉淀溶解后,加入饱和NaHCO3水溶液,用氯仿萃取。用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=300∶1~100∶1)精制。使精制品悬浮于EtOAc,加入0.5M的HCl-EtOAc,滤取析出物,获得47mg的N-{4-(4-氯噻吩-2-基)-5-[4-(1-氧化硫代吗啉基)-1-哌啶基]噻唑-2-基}-2-甲氧基异烟酰胺盐酸盐。
实施例30
在268mg的参考例41的化合物和8ml的吡啶的溶液中加入241mg的参考例127的化合物,-25℃下加入72μl的磷酰氯,升温至室温后搅拌1.5小时。减压蒸干反应液,加水和碳酸钾后,用氯仿萃取,有机层用盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(氯仿-MeOH=200∶1~100∶1)精制,将精制品溶于EtOAc后,加入0.1M的HCl-EtOAc溶液,滤取析出物,获得137mg的3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2,3-二羟基丙氧基)苯甲酰胺盐酸盐。
实施例31
在132mg的实施例244的化合物和5ml的MeOH的溶液中加入61mg的碳酸钾,室温下搅拌1.5小时。减压蒸干反应液,加水后,用氯仿萃取。有机层用盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(氯仿-MeOH=200∶1~50∶1)精制,将精制品溶于EtOAc后,加入0.1M的HCl-EtAOc溶液,滤取析出物,获得77mg的N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)-3-甲基苯甲酰胺盐酸盐。
实施例32
在255mg的实施例56的化合物的10ml氯仿的溶液中加入303mg的mCPBA,室温搅拌3天。加入MeOH、饱和NaHCO3水溶液和氯仿,滤去不溶物后,用氯仿萃取。用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=300∶1)精制。将精制品悬浮于EtOAc后,加入0.5M的HCl-EtOAc溶液,滤取析出物,获得130mg的N-[4-(4-氯-2-噻吩基)-5-(1,1-二氧化硫代吗啉基)噻唑-2-基]-2-甲氧基异烟酰胺盐酸盐。
实施例33
室温下,在0.35g的实施例210的化合物和15ml DMF的溶液中加入0.2ml的三乙胺、32mg的二苯基膦基二茂铁和13mg的乙酸钯,在一氧化碳气氛中于70℃搅拌1天。减压下蒸除溶剂后加水,用氯仿萃取,有机层用MgSO4干燥后,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=100∶0~98∶2)精制。将精制品溶于5ml的MeOH中,加入0.1ml的4M的HCl-EtOAc溶液,滤取析出物,获得102mg的N-[4-(4-氯-2-噻吩基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-2-甲氧基羰基喹啉-6-酰胺盐酸盐。
实施例34
室温下,在0.27g的实施例213的化合物和10ml三氟乙酸的溶液中加入0.36g的五甲基苯,室温下搅拌6天。减压下蒸除溶剂后加水,用碳酸钾中和。用氯仿萃取后,有机层用MgSO4干燥,减压蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=100∶0~97∶3)精制。将精制品溶于5ml的EtOAc,加入0.47ml的1M的HCl-EtOAc溶液后,滤取析出物,获得148mg的N-[4-(4-氯-2-噻吩基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-7-羟基喹啉-3-酰胺盐酸盐。
实施例35
室温下在0.30g的实施例217的化合物和5ml的MeOH的溶液中加入2.0ml的浓HCl,于70℃搅拌3天。自然冷却至室温后,滤取析出物,获得122mg的4-氨基-3-氯-N-[4-(4-氯-2-噻吩基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]苯甲酰胺盐酸盐。
实施例36
在350mg实施例5的化合物中加入5ml的DMF、0.5ml的哌啶-4-基乙酸乙酯和1.0ml的三乙胺,于80℃搅拌8.5小时。蒸干反应液,加水40ml,用氯仿萃取,有机层用盐水洗涤后,用硫酸钠干燥,蒸除溶剂。在其中加入10ml的EtOH进行溶解,室温下加入1M的NaOH水溶液0.5ml,室温搅拌2天后,加入0.5ml的1M的NaOH水溶液,室温搅拌5小时。室温下,在反应液中加入3ml的1M的HCl水溶液,搅拌一会儿后,过滤干燥析出的固体,获得58mg的[1-(3-氯-5-{[4-(4-氯-2-噻吩基)-5-(4-环己基哌啶-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)-4-哌啶基]乙酸盐酸盐。
实施例37
在272mg的实施例356的化合物中加入10ml的THF、10ml的1,4-二烷、50.5mg的氰酸钾和0.5ml的1M的HCl,于40℃搅拌5小时,于80℃搅拌13小时后,室温下加2ml的1M的HCl,于80℃搅拌10分钟。减压蒸除溶剂,所得残渣中加入40ml的饱和NaHCO3水溶液,用氯仿萃取,有机层用盐水洗涤后,用硫酸钠干燥,蒸除溶剂,所得残渣用硅胶柱色谱法(氯仿-MeOH=5∶1~1∶1)精制。将精制品溶于60ml的MeOH、80ml的氯仿和10ml的1,4-二烷中,加入4ml的4M的HCl-EtOAc搅拌一会儿后,减压蒸除溶剂,用乙醚洗涤,获得102mg的4-(3-氯-5-{[4-(4-氯-2-噻吩基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌嗪-1-酰胺盐酸盐。
实施例38
在1.20g的实施例331的化合物和40ml THF的溶液中加入1.29ml的三乙胺,冰冷却下加入0.57ml的三氟乙酸酐,升温至室温后搅拌3天。减压蒸除溶剂,加入饱和NaHCO3水溶液后,用氯仿-MeOH(7∶3)萃取,有机层用盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(己烷-EtOAc=6∶1~1∶1,己烷-THF=1∶1~0∶1)精制,将精制品用氯仿洗涤,获得882mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(4-氰基哌啶-1-基)烟酰胺。
使其中的120mg悬浮于THF-MeOH,加入0.1M的HCl-EtOAc溶液,减压蒸除溶剂后,加入EtOH-乙醚,滤取析出物,获得106mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(环己基哌嗪-1-基)噻唑-2-基]-6-(4-氰基哌啶-1-基)烟酰胺盐酸盐。
实施例39
在300mg的实施例16的化合物的6mlTHF的溶液中加入56μl的N-甲基吗啉,在-15℃加入60μl的氯甲酸异丁酯,搅拌2小时。在其中加入于219mg的甲磺酰胺219mg和4ml THF的溶液中加入74mg的氢化钠并在室温下搅拌2小时而形成的悬浮液,室温下搅拌2小时,50℃搅拌20小时。使反应液冷却至室温,滤取析出的固体,用THF洗涤后,用硅胶柱色谱法(氯仿-MeOH=100∶0~5∶1)精制。使精制品悬浮于EtOH,加入0.4M的HCl-EtOAc溶液,滤取析出物,获得119mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[4-(N-甲磺酰基氨基甲酰)哌啶-1-基]烟酰胺盐酸盐。
实施例40
在300mg实施例16的化合物和6ml的THF的溶液中加入56μl的N-甲基吗啉,在-15℃加入60μl的氯甲酸异丁酯,搅拌1.5小时。在其中加入96mg甲磺酰胺-4ml THF溶液和348μl的1,8-二氮杂二环[5.4.0]-7-十一烯,室温下搅拌19小时,50℃搅拌2天。在反应液中加入饱和NaHCO3水溶液后,用EtOAc萃取,有机层用盐水洗涤,再用硫酸钠干燥。减压蒸除溶剂后,所得残渣用硅胶柱色谱法(己烷-THF=2∶1~0∶1)精制,再用硅胶柱色谱法(氯仿-MeOH=100∶0~100∶3)精制。使精制品溶于氯仿-EtOH中,再加入0.1M的HCl-EtOAc溶液,减压蒸除溶剂,加入EtOH-乙醚,滤取析出物,获得30mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(4-(3-[2-(甲磺酰基亚氨基)氮杂-1-基]丙基氨基羰基)哌啶-1-基)烟酰胺盐酸盐。
实施例41
在实施例16的化合物的THF溶液(0.0856mM)1.8ml中加入70mg的肌氨酸乙酯盐酸盐、342mg的PS-DCC(1.35mmol/g)、0.2ml的HOBt的THF溶液(0.77mM)和60μl的三乙胺,室温搅拌一晚。在反应液中加入2ml的THF、370mg的PS-异氰酸酯(1.25mmol/g)和205mg的PS-trisamine(3.75mmol/g),室温搅拌1小时。过滤反应混合物,所得残渣用硅胶柱色谱法(氯仿-MeOH=99∶1~97∶3)精制。使精制品溶于EtOAc 2ml,室温下加入1ml的4M的HCl-EtOAc,搅拌15分钟,滤取析出的固体。将该固体溶于2ml的EtOH中,室温下加入0.2ml的1M的NaOH水溶液,于50℃搅拌160分钟后,室温下加入0.6ml的1M的HCl水溶液,搅拌一晚。然后,滤取析出的固体,获得49mg的[{[1-(3-氯-5-{[4-(4-氯-2-噻吩基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)-4-哌嗪基]羰基}(甲基)氨基]乙酸盐酸盐。
实施例42
在实施例16的化合物的THF溶液(0.0856mM)1.8ml中加入39mg的吗啉、342mg的PS-DCC(1.35mmol/g)和0.2ml的HOBt的THF溶液(0.77mM),室温搅拌一晚。在反应液中加入2ml的THF、370mg的PS-异氰酸酯(1.25mmol/g)和205mg的PS-trisamine(3.75mmol/g),室温搅拌1小时。过滤反应混合物,所得残渣用硅胶柱色谱法(氯仿-MeOH=99∶1~97∶3)精制,将精制品溶于2ml的EtOAc中,室温下加入1ml的4M的HCl-EtOAc,搅拌15分钟,滤取析出的固体,获得84mg的5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[4-(吗啉代羰基)-1-哌啶基]烟酰胺盐酸盐。
以下的表11~21所示为实施例化合物的结构和物理性质。表中符号的含义如下所述(下同)。
Ex:实施例编号(Ex栏中仅记载实施例编号时,表示该化合物为盐酸盐,实施例编号后有斜线(/)及其它符号时,/AcOH表示乙酸盐,/TFA表示三氟乙酸盐,/free表示游离体),Syn:制备方法(数字表示该编号与实施例编号相同的实施例同样合成),RA、RB、RC、RD、RE、RF、RG、RH、RI:通式中的取代基(nPen:正戊基,cPen:环戊基,vinyl:乙烯基,naph:萘基,Ms:甲磺酰基,oxo:氧代,Py:吡啶基,pra:吡唑-3-基,ttrz:四唑-5-基,bimid:苯并咪唑-1-基,oxido:氧化,di及tri:二及三(表示有2个或3个该取代基取代))。
(表11)
(表11续)
(表12)
Ex | RA | RB | RC | MS | Syn |
43 | 3,5-diMeO-Ph | 4-F-Ph | -N(Me)((CH2)2OMe) | 446. | 2 |
44 | 3,5-diMeO-Ph | 4-F-Ph | -N(Me)((CH2)2NMe2) | 459. | 2 |
45 | 3,5-diMeO-Ph | 4-F-Ph | -N(Me)((CH2)3NMe2) | 473. | 2 |
46 | 3,5-diMeO-Ph | 4-F-Ph | -N(Me)((CH2)2N(Me)(cHex)) | 527. | 2 |
47 | 3,5-diMeO-Ph | 4-F-Ph | -N(Me)((CH2)2-pipe) | 499. | 2 |
48 | 2-MeO-4-py | 4-Cl-2-The | -N(Me)((CH2)3-mor) | 508. | 5 |
49 | 2-MeO-4-py | 4-Cl-2-The | -N(Me)(1-nBu-吡咯烷-3-基) | 506. | 5 |
50 | 2-MeO-4-py | 4-Cl-2-The | -N(Me)(1-nBu-哌啶-4-基) | 520. | 5 |
51 | 2-MeO-4-py | 4-Cl-2-The | -N(Me)(奎宁环-3-基) | 490. | 5 |
52 | 2-MeO-4-py | 4-Cl-2-The | -N(cHex)((CH2)2-mor) | 562. | 5 |
(表13)
Ex | RA | RB | RC | MS | Syn |
53 | 2-MeO-4-py | 4-F-Ph | imid | 396. | 2 |
54 | 2-MeO-4-py | 4-F-Ph | 4-Ph-imid | 472. | 2 |
55 | 2-MeO-4-py | 4-F-Ph | 3-pipe-azet | 468. | 2 |
56 | 2-MeO-4-py | 4-Cl-2-The | tmor | 453. | 5 |
57 | 2-MeO-4-py | 4-Cl-2-The | 3-(4-nPr-pipe)-azet | 532. | 5 |
58 | 喹啉-6-基 | 4-Cl-2-The | mor | 457. | 5 |
(表14)
(表15)
Ex | RA | RB | RE | MS | Syn |
81/free | 2-MeO-4-py | 4-F-Ph | 4-((HO2C)-CH2) | 472. | 16 |
82/free | 2-MeO-4-py | 4-F-Ph | 4-((EtO2C)-CH2) | 500. | 27 |
83 | 2-MeO-4-py | 4-F-Ph | 4-BnO2C | 547. | 2 |
84 | 2-MeO-4-py | 4-F-Ph | 4-(cyano-CH2) | MM;452- | 27 |
85 | 2-MeO-4-py | 4-F-Ph | 4-((Me2N)-(CH2)2) | 485. | 27 |
86 | 2-MeO-4-py | 4-F-Ph | (trans)-2,5-diMe-4-nBu | 498. | 3 |
87 | 2-MeO-4-py | 4-Cl-2-The | 3-oxo | 450. | 5 |
88 | 2-MeO-4-py | 4-Cl-2-The | 4-nPr | 478. | 5 |
89 | 2-MeO-4-py | 4-Cl-2-The | 4-nBu | 492. | 14 |
90 | 2-MeO-4-py | 4-Cl-2-The | (3R*,5S*)-3,5-diMe-4-nPr | 506. | 5 |
91/free | 2-MeO-4-py | 4-Cl-2-The | 4-((HO2C)-CH2) | 494. | 16 |
92 | 2-MeO-4-py | 4-Cl-2-The | 4-((EtO2C)-CH2) | 522. | 14 |
93 | 2-MeO-4-py | 4-Cl-2-The | 4-((Me2NOC)-CH2) | 521. | 25 |
94 | 2-MeO-4-py | 4-Cl-2-The | 4-((pipe-OC)-CH2) | 561. | 25 |
95 | 2-MeO-4-py | 4-Cl-2-The | 4-((2-py)-CH2) | 527. | 14 |
96 | 2-MeO-4-py | 4-Cl-2-The | 4-((2-The)-CH2) | 532. | 14 |
97 | 2-MeO-4-py | 4-Cl-2-The | 4-((2-oxo-pyrr)-(CH2)2) | 547. | 27 |
98 | 2-MeO-4-py | 4-Cl-2-The | 4-cPen | 504. | 14 |
99 | 2-MeO-4-py | 4-Cl-2-The | 4-(4-Et-cHex) | 546. | 14 |
100 | 2-MeO-4-py | 4-Cl-2-The | 4-cHept | 532. | 5 |
101 | 2-MeO-4-py | 4-Cl-2-The | 4-(allyl-O2C) | 519. | 5 |
102 | 2-MeO-4-py | 4-Cl-2-The | 4-(四氢-2H-吡喃-4-基) | 520. | 14 |
103 | 3-Cl-4-HO(CH2)2O-Ph | 4-Cl-2-The | 4-nPr | 541. | 9 |
104/free | 5,6-diCl-3-py | 4-Cl-2-The | 4-nPr | 516. | 5 |
105 | 5-Cl-6-HO(CH2)2HN-3-py | 4-Cl-2-The | 4-nPr | 541. | 13 |
(表16)
Ex | RA | RB | MS | Syn |
106 | 2-MeO-4-py | 3-F3C-Ph | 546. | 5 |
107 | 2-MeO-4-py | 4-F3C-Ph | 546. | 2 |
108 | 2-MeO-4-py | 4-HO2C-Ph | 522. | 16 |
109 | 2-MeO-4-py | 4-H2NOC-Ph | 521. | 17 |
110 | 2-MeO-4-py | 3-cyano-Ph | 503. | 5 |
111 | 2-MeO-4-py | 4-cyano-Ph | 503. | 2 |
112 | 2-MeO-4-py | 4-Me2N-Ph | 521. | 2 |
113 | 2-MeO-4-py | 4-O2N-Ph | 523. | 2 |
114/free | 5,6-diCl-3-py | 3-Cl-Ph | 550. | 5 |
115/free | 5,6-diCl-3-py | 3-F3C-Ph | 584. | 5 |
116 | 2-MeO-4-py | 5-Me-2-Fur | 482. | 2 |
117 | 2-MeO-4-py | 3-F-2-The | 502. | 5 |
118 | 2-MeO-4-py | 4-F-2-The | 502. | 5 |
119 | 2-MeO-4-py | 5-F-2-The | 502. | 5 |
120 | 2-MeO-4-py | 3-Cl-2-The | 518. | 5 |
121 | 3-F-4-HO-Ph | 5-Cl-2-The | 521. | 8 |
122/free | 3-F-4-MeOCH2O-Ph | 5-Cl-2-The | 5 | |
123 | 3-F-4-MeO(CH2)2O-ph | 5-Cl-2-The | 579. | 3 |
124 | 3,5-diF-4-MeO(CH2)2O-Ph | 5-Cl-2-The | 597. | 3 |
125 | 3-Cl-4-HO(CH2)2O-Ph | 5-Cl-2-The | 581. | 9 |
126 | 3-Cl-4-MeO(CH2)2O-Ph | 5-Cl-2-The | 595. | 3 |
127/free | 3-Cl-4-TBSO(CH2)2O-Ph | 5-Cl-2-The | 695. | 5 |
128 | 2-Cl-6-Me-4-py | 5-Cl-2-The | 536. | 3 |
129 | 2-Cl-6-MeO-4-py | 5-Cl-2-The | 552. | 3 |
130 | 5-MeO-3-py | 5-Cl-2-The | 518. | 3 |
131 | 2-MeO-6-Me-4-py | 5-Cl-2-The | 532. | 3 |
132/free | 2,6-diMeO-嘧啶-4-基 | 5-Cl-2-The | 549. | 3 |
133 | 喹啉-6-基 | 5-Cl-2-The | 538. | 3 |
134 | 2-MeO-4-py | 5-Cl-3-The | 518. | 5 |
135 | 2-MeO-4-py | 4-Br-2-The | 562,564. | 5 |
136 | 2-MeO-4-py | 5-Br-2-The | 562,564. | 2 |
137 | 2-MeO-4-py | 4-F-5-Cl-2-The | 536. | 5 |
138 | 2-MeO-4-py | 4,5-diCl-2-The | 552. | 5 |
139 | 2-MeO-4-py | 4-Me-2-The | 498. | 5 |
140 | 2-MeO-4-py | 5-Me-2-The | 498. | 2 |
(表17)
(表17续)
Ex | RA | MS | Syn |
171 | 4-((HO2C)-CH2HN)-Ph | 538. | 16 |
172/free | 4-((EtO2C)-CH2HN)-Ph | 566. | 14 |
173/free | 4-(MeOCH2-(OCHN)-Ph | 552. | 24 |
174 | 4-((HO2C)-(OCHN)-Ph | 552. | 16 |
175 | 4-mor-Ph | 550. | 5 |
176 | 4-pipa-Ph | 549. | 15 |
177 | 4-(4-Me-pipa)-Ph | 563. | 14 |
178 | 4-(4-Ac-pipa)-Ph | 591. | 5 |
179/free | 4-(4-Boc-pipa)-Ph | 649. | 5 |
180/free | 4-HO3S-Ph | 545. | 2 |
181 | 2-naph | 515. | 1 |
182 | 6-HO-2-naph | 531. | 2 |
183/free | 5,6-diCl-3-py | 534. | 5 |
184 | 1,3-苯并二氧戊环-5-基 | 509. | 1 |
185 | 3-oxo-3,4-dihydro-2H-1,4-苯并嗪-7-基 | 536. | 5 |
186/free | 1H-indol-5-yl | MM;503. | 2 |
187 | 2-Me-isoindolin-5-yl | 520. | 2 |
188 | 5-bimid | 505. | 2 |
189 | 喹啉-2-基 | 516. | 2 |
190 | 喹啉-3-基 | 516. | 2 |
191 | 喹啉-4-基 | 516. | 5 |
192 | 喹啉-6-基 | 516. | 2 |
193 | 喹啉-7-基 | 516. | 5 |
194 | 2-HO-喹啉-6-基 | 532. | 2 |
195 | 2-MeO-喹啉-6-基 | 546. | 5 |
196 | 异喹啉-3-基 | 516. | 2 |
197 | 异喹啉-7-基 | 516. | 5 |
198/free | 2,3-diBnO-喹喔啉-6-基 | 729. | 5 |
199 | 咪唑并[1,2-a]吡啶-6-基 | 505. | 2 |
(表18)
Ex | RA | MS | Syn |
200 | 5-Me-1-HO(CH2)3-pra | 549. | 9 |
201/free | 5-Me-1-TBSO(CH2)3-pra | 663. | 5 |
(表18续)
Ex | RA | MS | Syn |
202 | 3-oxo-3,4-dihydro-2H-1,4-苯并嗪-7-基 | 558. | 5 |
203 | 2-oxo-2,3-dihydro苯并唑-5-基 | 544. | 5 |
204 | 2-oxo-2,3-dihydro苯并唑-6-基 | 544. | 5 |
205 | 2-oxo-3-HO(CH2)2-2,3-dihydro苯并唑-6-基 | 588. | 9 |
206/free | 2-oxo-3-TBSO(CH2)2-2,3-dihydro苯并唑-6-基 | 702. | 5 |
207 | 喹啉-3-基 | 538. | 5 |
208 | 喹啉-6-基 | 538. | 5 |
209 | 喹啉-7-基 | 538. | 5 |
210/free | 2-Br-喹啉-6-基 | 615,617. | 5 |
211 | 2-HO2C-喹啉-6-基 | MN;580. | 16 |
212 | 2-H2NOC-喹啉-6-基 | 581. | 5 |
213/free | 7-BnO-喹啉-3-基 | 644. | 5 |
214 | 异喹啉-6-基 | 538. | 5 |
215 | 异喹啉-7-基 | 538. | 5 |
216 | 咪唑并[1,2-a]吡啶-7-基 | 527. | 5 |
217 | 3-Cl-4-((1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-Ph) | 662. | 5 |
218/free | 3-F-4-MeOCH2O-Ph | 565. | 5 |
219 | 3,5-diF-4-HO(CH2)2O-Ph | 583. | 7 |
220 | 3,5-diF-4-tBuO(CH2)2O-Ph | 639. | 5 |
221 | 3,4,5-triF-Ph | 541. | 5 |
222 | 3-Cl-5-F-4-HO(CH2)2O-Ph | 599. | 9 |
223/free | 3-Cl-5-F-4-TBSO(CH2)2O-Ph | 713. | 5 |
224 | 3-Cl-4-MeO(CH2)2HNCH2-Ph | 608. | 15 |
225/free | 3-Cl-4-MeO(CH2)2N(Boc)CH2-Ph | 708. | 5 |
226 | 3-Cl-4-HO-Ph | 537. | 8 |
227/free | 3-Cl-4-MeOCH2O-Ph | 581. | 5 |
228 | 3-Cl-4-((tetrahydro-2-fur)-CH2O)-Ph | 621. | 5 |
229 | 3-Cl-4-MeO(CH2)2O-Ph | 595. | 5 |
230/free | 3-Cl-4-TBSO(CH2)2O-Ph | 695. | 5 |
231 | 3-Cl-4-H2N(CH2)2O-Ph | 580. | 15 |
232/free | 3-Cl-4-BocHN(CH2)2O-Ph | 680. | 5 |
233 | 3-Cl-4-tBuOCH2CH(Me)O-Ph | 651. | 5 |
234 | 3-Cl-4-HO(CH2)3O-Ph | 595. | 9 |
235/free | 3-Cl-4-TBSO(CH2)3O-Ph | 709. | 5 |
236 | 3-Cl-4-(tetrahydro-3-fur-O)-Ph | 607. | 5 |
237 | 3,5-diCl-4-HO-Ph | 571 | 5 |
238 | 3,5-diCl-4-HO(CH2)2O-Ph | 615. | 9 |
239/free | 3,5-diCl-4-TBSO(CH2)2O-Ph | 729. | 5 |
240 | 3-Br-4-HO(CH2)2O-Ph | 625,627. | 9 |
241/free | 3-Br-4-TBSO(CH2)2O-Ph | 739,741. | 5 |
242 | 4-((Me2N)-CH2)-Ph | 544. | 14 |
243/free | 4-BocHNCH2-Ph | 616. | 5 |
(表18续)
Ex | RA | MS | Syn |
244 | 3-Me-4-AcO(CH2)2O-Ph | 603. | 5 |
245 | 2-MeO-4-py | 518. | 5 |
246 | 5-Cl-6-MeO-3-py | 552. | 5 |
247 | 2-EtO-4-py | 532. | 5 |
248 | 5-Cl-6-(HO(CH2)2)(Me)N-3-py | 595. | 13 |
249 | 5-Cl-6-HO(CH2)2HN-3-py | 581. | 13 |
250 | 5-Cl-6-HO(CH2)3O-3-py | 596. | 12 |
251 | 2-AcO(CH2)2O-4-py | 590. | 5 |
252 | 2-HO(CH2)2O-4-py | 548. | 31 |
253 | 5-Cl-6-HO(CH2)3HN-3-py | 595. | 13 |
254 | 5-Cl-6-MeO(CH2)3HN-3-py | 609. | 13 |
255 | 5-Cl-6-(1-Me-pyrrolidin-2-yl-(CH2)2O)-3-py | 649. | 12 |
256 | 5-Cl-6-(HO(CH2)2)2N-3-py | 625. | 13 |
257 | 5-Cl-6-HOCH(Me)CH2HN-3-py | 595. | 13 |
258 | 5-Cl-6-((4-(4-F-Bn)-吗啉-2-基)CH2HN)-3-py | 744. | 13 |
259 | 5-Cl-6-((MeO2C)-CH2HN)-3-py | 609. | 13 |
260 | 5-Cl-6-H2N(CH2)3HN-3-py | 594. | 13 |
261 | 5-Cl-6-(4-HO-cHex)HN-3-py | 635. | 13 |
262 | 5-Cl-6-H2NCH2CH(OH)CH2HN-3-py | 610. | 13 |
263 | 5-Cl-6-(2-HO-cHex)HN-3-py | 635. | 13 |
264 | 5-Cl-6-HOCH2CH(OH)CH2HN-3-py | 611. | 13 |
265 | 5-Cl-6-((HO2C)-CH2HN)-3-py | 595. | 16 |
266 | 5-Cl-6-(3-Me-oxetan-3-yl-CH2O)-3-py | 622. | 12 |
267 | 5-Cl-6-(tetrahydro-3-Fur-CH2O)-3-py | 622. | 12 |
268 | 5-Cl-6-MeO(CH2)2HN-3-py | 595. | 13 |
(表19)
Ex | X | RF | RB | RC | MS | Syn |
269 | CH | 4-cyano-pipe | 4-Cl-2-The | 4-nPr-pipa | 589. | 5 |
270 | CH | 4-HO2C-pipe | 4-Cl-2-The | 4-nPr-pipa | 608. | 16 |
271 | CH | 4-EtO2C-pipe | 4-Cl-2-The | 4-nPr-pipa | 636. | 5 |
272 | CH | 4-H2NOC-pipe | 4-Cl-2-The | 4-nPr-pipa | 607. | 7 |
273/free | CH | 4-(PhC(Me)2-(HNOC))-pipe | 4-Cl-2-The | 4-nPr-pipa | 725. | 25 |
274 | CH | 4-HO-pipe | 4-Cl-2-The | 4-nPr-pipa | 580. | 9 |
275/free | CH | 4-TBSO-pipe | 4-Cl-2-The | 4-nPr-pipa | 694. | 5 |
276 | N | 4-HO2C-pipe | 4-F-Ph | 4-cHex-pipa | 627. | 16 |
277/free | N | 4-EtO2C-pipe | 4-F-Ph | 4-cHex-pipa | 655. | 13 |
(表19续)
Ex | X | RF | RB | RC | MS | Syn |
278 | N | 4-HO2C-pipe | 3-Cl-Ph | 4-cHex-pipa | 643 | 16 |
279 | N | 4-EtO2C-pipe | 3-Cl-Ph | 4-cHex-pipa | 671. | 13 |
280 | N | 4-HO2C-pipe | 3-F3C-Ph | 4-cHex-pipa | 677. | 16 |
281 | N | 4-EtO2C-pipe | 3-F3C-Ph | 4-cHex-pipa | 705. | 13 |
282 | N | 4-HO2C-pipe | 4-Cl-2-The | 4-nPr-pipa | 609. | 16 |
283/free | N | 4-EtO2C-pipe | 4-Cl-2-The | 4-nPr-pipa | 637. | 13 |
284 | N | 4-H2NOC-pipe | 4-Cl-2-The | 4-nPr-pipa | 608. | 13 |
285 | N | 4-HO-pipe | 4-Cl-2-The | 4-nPr-pipa | 581. | 13 |
286 | N | 4-HO2C-pipe | 4-Cl-2-The | 4-(3-F-pyrr)-pipe | 653. | 16 |
287/free | N | 4-EtO2C-pipe | 4-Cl-2-The | 4-(3-F-pyrr)-pipe | 681. | 13 |
288 | N | 4-H2NOC-pipe | 4-Cl-2-The | 4-pipe-pipe | 648. | 13 |
(表20)
Ex | RG | RH | Y | MS | Syn |
289 | Cl | H | CH-cyano | 629. | 5 |
290 | Cl | H | CH-CO2H | 648. | 16 |
291 | Cl | H | CH-CO2Et | 676. | 5 |
292 | Cl | H | CH-CONH2 | 647. | 17 |
293 | Cl | H | CH-OH | 620. | 9 |
294/free | Cl | H | CH-OTBS | 734. | 5 |
295 | Br | H | CH-CO2H | 694. | 16 |
296/free | Br | H | CH-CO2Et | 722. | 5 |
297 | Br | H | CH-CONH2 | 693. | 25 |
298 | F | F | CH-cyano | 631. | 5 |
299 | F | F | CH-CO2H | 650. | 16 |
300/free | F | F | CH-CO2Et | 678. | 5 |
301 | F | F | CH-CONH2 | 649. | 25 |
302 | F | Cl | CH-cyano | 647. | 5 |
303 | F | Cl | CH-CO2H | 666. | 16 |
304 | F | Cl | CH-CO2Et | 694. | 5 |
305 | F | Cl | CH-CONH2 | 664. | 7 |
306/free | F | Cl | CH-CONH-C(Me)2Ph | 783. | 25 |
307/free | F | Cl | NH | 623. | 15 |
308 | F | Cl | N-(2-HO-Bn) | 729. | 14 |
(表20续)
Ex | RG | RH | Y | MS | Syn |
309 | F | Cl | N-CH2-CO2H | 681. | 16 |
310/free | F | Cl | N-CH2-CO2Et | 709. | 14 |
311 | F | Cl | N-CH2-CONH2 | 680. | 25 |
312/free | F | Cl | N-Boc | 723. | 5 |
313 | F | Cl | N-CO-CH2OMe | 695. | 24 |
314 | F | Cl | N-CO-CO2H | 695. | 16 |
315/free | F | Cl | N-CO-CO2Et | 723. | 24 |
316 | F | Cl | N-SO2NH2 | 702. | 15 |
317/free | F | Cl | N-SO2NHBoc | 802. | 23 |
(表21)
(表21续)
Ex | R1 | MS | Syn |
338 | 4-(MeO(CH2)2-(HNOC))-pipe | 706. | 42 |
339 | 4-(EtO(CH2)2-(HNOC))-pipe | 720. | 42 |
340 | 4-(MeO(CH2)3-(HNOC))-pipe | 720. | 42 |
341 | 4-(Me2N(CH2)3-(HNOC))-pipe | 733. | 42 |
342 | 4-(Me2N(CH2)4-(HNOC))-pipe | 747. | 42 |
343 | 4-(Me2N(CH2)6-(HNOC))-pipe | 775. | 42 |
344 | 4-Me2NOC-pipe | 676. | 25 |
345 | 4-((Me)(nPr)N-OC)-pipe | 704. | 42 |
346 | 4-(MeO(CH2)2-((Me)NOC))-pipe | 720. | 42 |
347 | 4-(pipe-OC)-pipe | 716. | 42 |
348 | 4-(tmor-OC)-pipe | 734. | 42 |
349 | 3-HO-pipe | 621. | 13 |
350 | 4-HO-pipe | 621. | 13 |
351 | 4-H2N-pipe | 620. | 15 |
352 | 4-BnHN-pipe | 710. | 13 |
353 | 4-AcHN-pipe | 662. | 24 |
354/free | 4-BocHN-pipe | 720. | 13 |
355 | 4-MsHN-pipe | 698. | 23 |
356 | pipa | 606. | 13 |
357 | 3-HOCH2-4-Me-pipa | 650. | 13 |
358 | 4-((HO2C)-CH2)-pipa | 664 | 16 |
359/free | 4-((EtO2C)-CH2)-pipa | 692 | 13 |
360 | 4-HO(CH2)2-pipa | 650. | 13 |
361 | 4-MeO(CH2)2-pipa | 664. | 13 |
362 | 3-oxo-pipa | 620. | 13 |
363 | 3,5-dioxo-pipa | 634. | 13 |
364 | 4-Ac-pipa | 648. | 13 |
365/free | 4-EtO2C-pipa | 678. | 13 |
366 | 4-((4-Me-pipa)-OC)-pipe | 731. | 25 |
367 | 4-Ms-pipa | 684. | 23 |
368 | mor | 607. | 13 |
369 | tmor | 623. | 13 |
370 | 1,4-diazepan-1-yl | 620. | 13 |
371 | 4-Ac-1,4-diazepan-1-yl | 662. | 13 |
372 | 5-oxo-1,4-diazepan-1-yl | 634. | 13 |
373 | 5-HO2C-isoindolin-2-yl | 683. | 16 |
374 | 5-MeO2C-isoindolin-2-y1 | 697. | 13 |
以下的表22所示为一些实施例化合物的NMR数据。
(表22)
Ex | NMR |
8 | 1.05-1.20(1H,m),1.21-1.36(2H,m),1.38-1.55(2H,m),1.58-1.68(1H,m),1.82-1.91(2H,m),2.14-2.25(2H,m),3.20-3.40(7H,m),3.55-3.65(2H,m),7.11(1H,dd,J=8.3,8.8Hz),7.49(1H,s),7.56(1H,s),7.83(1H,dd,J=1.4,8.3Hz),8.21(1H,dd,J=1.4,12.6Hz),10.95(1H,brs),12.50(1H,brs). |
9 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.43-1.56(2H,m),1.59-1.68(1H,m),1.80-1.92(2H,m),2.17-2.27(2H,m),3.20-3.44(7H,m),3.54-3.63(2H,m),3.78(2H,t,J=4.9Hz),4.21(2H,t,J=4.9Hz),7.33(1H,d,J=8.8Hz),7.50(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.08(1H,dd,J=2.0,8.8Hz),8.24(1H,d,J=2.0Hz),10.89(1H,brs),12.61(1H,brs). |
16 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.40-1.55(2H,m),1.58-1.70(3H,m),1.78-2.00(4H,m),2.15-2.25(2H,m),2.50-2.58(1H,m),2.98-3.09(2H,m),3.23-3.40(7H,m),3.54-3.66(2H,m),3.93-4.02(2H,m),7.48(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.40(1H,d,J=1.9Hz),8.83(1H,d,J=1.9Hz),10.98(1H,brs),12.28(1H,brs),12.68(1H,s). |
36 | 1.08-1.20(1H,m),1.21-1.38(4H,m),1.38-1.55(2H,m),1.60-1.68(1H,m),1.74-2.00(4H,m),2.16-2.22(5H,m),2.87(2H,t,J=12.2Hz),3.20-3.34(9H,m),4.04(2H,d,J=13.2Hz),7.50(1H,s),7.57(1H,s),8.39(1H,d,J=2.0Hz),8.83(1H,d,J=2.0Hz),10.34(1H,brs),12.09(1H,brs),12.66(1H,brs). |
42 | 1.14-1.20(1H,m),1.21-1.32(2H,m),1.38-1.53(2H,m),1.60-1.77(5H,m),1.81-1.92(2H,m),2.14-2.25(2H,m),2.88-3.08(3H,m),3.30-3.37(2H,m),3.42-3.50(2H,m),3.52-3.64(4H,m),3.76-3.88(9H,m),4.05-4.12(2H,m),7.49(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),8.40(1H,d,J=1.9Hz),8.83(1H,d,J=1.9Hz),10.77(1H,brs),12.67(1H,brs). |
66 | 0.90(3H,t,J=6.8Hz),1.22-1.49(7H,m),1.75-1.85(2H,m),2.63-2.71(2H,m),3.06-3.16(2H,m),3.92(3H,s),7.42(1H,d,J=2.0Hz),7.43(1H,s),7.51(1H,d,J=2.0Hz),7.54(1H,d,J=5.4Hz),8.36(1H,d,J=5.4Hz),12.80(1H,brs). |
103 | 0.95(3H,t,J=7.3Hz),1.71-1.82(2H,m),3.11-3.36(8H,m),3.60(2H,d,J=10.3Hz),3.78(2H,t,J=5.2Hz),4.21(2H,t,J=4.9Hz),7.33(1H,d,J=8.8Hz),7.50(1H,d,J=1.9Hz),7.58(1H,d,J=2.0Hz),8.08(1H,dd,J=2.0Hz,J=8.8Hz),8.24(1H,d,J=2.0Hz),10.73(1H,brs),12.62(1H,s). |
105 | 0.90(3H,t,J=7.3Hz),1.72-1.82(2H,m),3.11-3.33(8H,m),3.55-3.61(6H,m),7.22(1H,brs),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.28(1H,d,J=1.9Hz),8.74(1H,d,J=2.0Hz),10.88(1H,brs),12.48(1H,s). |
125 | 1.07-1.20(1H,m),1.22-1.36(2H,m),1.42-1.55(2H,m),1.60-1.68(1H,m),1.81-1.91(2H,m),2.16-2.26(2H,m),3.20-3.29(7H,m),3.56-3.65(2H.m),3.78(2H,t,J=4.9Hz),4.21(2H,t,J=4.9Hz),7.12(1H,d,J=3.9Hz),7.33(1H,d,J=8.8Hz),7.47(1H,d,J=3.9Hz),8.08(1H,dd,J=8.8,2.0Hz),8.23(1H,d,J=2.0Hz),10.93(1H,brs),12.63(1H,brs). |
204 | 1.07-1.20(1H,m),1.22-1.36(2H,m),1.41-1.55(2H,m),1.59-1.68(1H,m),1.82-1.92(2H,m),2.14-2.24(2H,m),3.27-3.35(7H,m),3.55-3.65(2H,m),7.24(1H,d,J=8.3Hz),7.50(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),7.97(1H,dd,J=1.5,8.3Hz),8.06(1H,s),10.74(1H,brs),12.13(1H,s),12.63(1H,brs). |
208 | 1.03-1.20(1H,m),1.21-1.36(2H,m),1.38-1.55(2H,m),1.60-1.68(1H,m),1.82-1.91(2H,m),2.18-2.25(2H,m),3.22-3.40(7H,m),3.55-3.65(2H,m),7.52(1H,s),7.58(1H,s),7.76(1H,dd,J=4.2,8.3Hz),8.21(1H,d,J=8.8Hz),8.40(1H,dd,J=1.5,8.8Hz),8.67(1H,d,J=8.3Hz),8.89(1H,d,J=1.5Hz),9.11(1H,d,J=4.2Hz),11.05(1H,brs),12.96(1H,brs). |
(表22续)
Ex | NMR |
214 | 1.03-1.20(1H,m),1.21-1.36(2H,m),1.40-1.55(2H,m),1.60-1.68(1H,m),1.82-1.91(2H,m),2.18-2.28(2H,m),3.20-3.43(7H,m),3.52-3.65(2H,m),7.52(1H,s),7.59(1H,s),8.33-8.40(2H,m),8.50(1H,d,J=8.8Hz),8.73(1H,d,J=5.8Hz),8.90(1H,s),9.78(1H,s),11.20(1H,brs),13.12(1H,brs). |
222 | 1.07-1.20(1H,m),1.21-1.36(2H,m),1.41-1.54(2H,m),1.58-1.68(1H,m),1.80-1.92(2H,m),2.14-2.25(2H,m),3.25-3.37(7H,m),3.56-3.64(2H,m),3.73(2H,t,J=4.9Hz),4.24(2H,t,J=4.9Hz),7.50(1H,d,J=1.0Hz),7.58(1H,d,J=1.0Hz),8.01(1H,dd,J=2.0,11.7Hz),8.11(1H,brs),10.77(1H,brs),12.77(1H,brs). |
226 | 1.06-1.20(1H,m),1.21-1.36(2H,m),1.42-1.56(2H,m),1.59-1.68(1H,m),1.81-1.91(2H,m),2.16-2.26(2H,m),3.20-3.45(7H,m),3.54-3.63(2H,m),7.17(1H,d,J=8.8Hz),7.49(1H,d,J=1.4Hz),7.56(1H,d,J=1.4Hz),7.94(1H,dd,J=2.4,8.8Hz),8.19(1H,d,J=2.4Hz),11.26(1H,brs),12.51(1H,brs). |
229 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.44-1.56(2H,m),1.58-1.68(1H,m),1.80-1.92(2H,m),2.15-2.26(2H,m),3.17-3.47(7H,m),3.35(3H,s),3.56-3.63(2H,m),3.73(2H,t,J=3.9Hz),4.31(2H,t,J=3.9Hz),7.33(1H,d,J=8.8Hz),7.49(1H,d,J=0.9Hz),7.56(1H,d,J=0.9Hz),8.08(1H,dd,J=1.9,8.8Hz),8.24(1H,d,J=1.9Hz),11.31(1H,brs),12.61(1H,brs). |
234 | 1.08-1.20(1H,m),1.22-1.36(2H,m),1.41-1.55(2H,m),1.58-1.68(1H,m),1.82-1.90(2H,m),1.92(2H,t,J=6.3Hz),2.19-2.22(2H,m),3.21-3.37(7H,m),3.55-3.63(4H,m),4.25(2H,t,J=6.3Hz),7.32(1H,d,J=8.8Hz),7.50(1H,s),7.57(1H,s),8.09(1H,dd,J=2.0,8.8Hz),8.24(1H,d,J=2.0Hz),10.83(1H,brs),12.62(1H,brs). |
238 | 1.07-1.20(1H,m),1.22-1.36(2H,m),1.44-1.56(2H,m),1.60-1.68(1H,m),1.83-1.91(2H,m),2.17-2.26(2H,m),3.20-3.42(7H,m),3.56-3.63(2H,m),3.78(2H,t,J=4.9Hz),4.13(2H,t,J=4.9Hz),7.49(1H,s),7.57(1H,s),8.21(2H,s),11.18(1H,brs),12.79(1H,brs). |
240 | 1.07-1.20(1H,m),1.22-1.36(2H,m),1.42-1.56(2H,m),1.60-1.67(1H,m),1.81-1.90(2H,m),2.18-2.25(2H,m),3.17-3.43(7H,m),3.55-3.65(2H,m),3.78(2H,t,J=4.9Hz),4.20(2H,t,J=4.9Hz),7.29(1H,d,J=8.8Hz),7.49(1H,d,J=1.5Hz),7.56(1H,d,J=1.5Hz),8.12(1H,dd,J=2.4,8.8Hz),8.39(1H,d,J=2.4Hz),11.19(1H,brs),12.61(1H,brs). |
245 | 1.08-1.20(1H,m),1.21-1.34(2H,m),1.40-1.53(2H,m),1.60-1.68(1H,m),1.82-1.89(2H,m),2.14-2.24(2H,m),3.22-3.45(7H,m),3.55-3.65(2H,m),3.95(3H,s),7.44(1H,s),7.50(1H,s),7.54(1H,d,J=4.9Hz),7.56(1H,s),8.37(1H,d,J=4.9Hz),10.61(1H,brs),12.95(1H,brs). |
250 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.41-1.54(2H,m),1.60-1.68(1H,m),1.82-1.95(2H,m),1.92(2H,t,J=6.4Hz),2.15-2.24(2H,m),3.22-3.36(7H,m),3.55-3.63(2H,m),3.58(2H,t,J=6.4Hz),4.51(2H,t,J=6.4Hz),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.53(1H,d,J=2.0Hz),8.82(1H,d,J=2.0Hz),10.83(1H,brs),12.78(1H,s). |
253 | 1.05-1.20(1H,m),1.22-1.36(2H,m),1.42-1.54(2H,m),1.60-1.68(1H,m),1.70-1.77(2H,m),1.82-1.92(2H,m),2.15-2.25(2H,m),3.20-3.40(7H,m),3.45-3.65(4H,m),3.49(2H,t,J=6.3Hz),7.39(1H,brs),7.48(1H,d,J=1.5Hz),7.56(1H,d,J=1.5Hz),8.27(1H,d,J=2.0Hz),8.74(1H,d,J=2.0Hz),10.98(1H,brs),12.45(1H,s). |
264 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.40-1.54(2H,m),1.59-1.68(1H,m),1.80-1.91(2H,m),2.13-2.24(2H,m),3.24-3.33(9H,m),3.55-3.45(2H,m),3.54-3.65(2H,m),3.68-3.75(1H,m),7.01-7.07(1H,m),7.49(1H,d,J=1.5Hz),7.56(1H,d,J=1.5Hz),8.29(1H,d,J=1.9Hz),8.74(1H,d,J=1.9Hz),10.68(1H,brs),12.48(1H,s). |
(表22续)
Ex | NMR |
267 | 1.07-1.20(1H,m),1.22-1.36(2H,m),1.39-1.54(2H,m),1.60-1.75(2H,m),1.82-1.92(2H,m),1.98-2.08(1H,m),2.13-2.24(2H,m),2.68-2.78(1H,m),3.22-3.37(4H,m),3.41-3.51(4H,m),3.54-3.71(3H,m),3.76-3.82(2H,m),4.32-4.45(2H,m),7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),8.55(1H,d,J=2.0Hz),8.82(1H,d,J=2.0Hz),10.60(1H,brs),12.80(1H,s). |
270 | 0.93(3H,t,J=7.3Hz),1.42-1.81(4H,m),1.90-2.00(2H,m),2.40-2.48(1H,m),2.72-2.86(2H,m),2.80-3.70(12H,m),7.24(1H,d,J=8.8Hz),7.48(1H,brs),7.55(1H,brs),8.03(1H,dd,J=1.9,8.8Hz),8.18(1H,d,J=1.9Hz),10.68(1H,brs),12.25(1H,brs),12.58(1H,s). |
272 | 0.95(3H,t,J=7.8Hz),1.68-1.88(6H,m),2.23-2.34(1H,m),2.70-2.79(2H,m),3.10-3.19(2H,m),3.20-3.35(5H,m),3.40-3.53(3H,m),3.56-3.64(2H,m),6.80(1H,brs),7.24(1H,d,J=8.3Hz),7.33(1H,brs)7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),8.03(1H,dd,J=2.0,8.3Hz),8.18(1H,d,J=2.0Hz),10.86(1H,brs),12.61(1H,s). |
274 | 0.94(3H,t,J=7.3Hz),1.51-1.63(2H,m),1.71-1.82(2H,m),1.83-1.92(2H,m),2.81-2.90(2H,m),3.10-3.17(2H,m),3.17-3.37(8H,m),3.55-3.63(2H,m),3.63-3.72(1H,m),7.24(1H,d,J=8.3Hz),7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),8.03(1H,dd,J=1.9,8.3Hz),8.18(1H,d,J=1.9Hz),10.92(1H,brs),12.61(1H,s). |
276 | 1.05-1.20(1H,m),1.22-1.37(2H,m),1.40-1.52(2H,m),1.60-1.75(3H,m),1.80-1.97(4H,m),2.15-2.24(2H,m),2.50-2.52(1H,m),3.04(2H,t,J=10.8Hz),3.17-3.38(7H,m),3.47-3.60(2H,m),3.98(2H,d,J=13.2Hz),7.27(2H,t,J=8.8Hz),8.15(2H,dd,J=5.8,8.8Hz),8.40(1H,d,J=2.0Hz),8.84(1H,d,J=2.0Hz),10.85(1H,brs),12.28(1H,brs),12.59(1H,brs). |
278 | 1.08-1.20(1H,m),1.22-1.36(2H.m),1.38-1.52(2H,m),1.58-1.75(3H,m),1.81-1.99(4H,m),2.11-2.22(2H,m),2.50-2.52(1H,m),2.98-3.08(2H,m),3.19-3.35(7H,m),3.48-3.64(2H,m),3.92-4.22(2H,m),7.34-7.41(1H,m),7.49(1H,d,J=7.8Hz),8.09-8.11(1H,m),8.12-8.17(1H,m),8.41(1H,d,J=2.0Hz),8.84(1H,d,J=2.0Hz),10.55(1H,brs),12.28(1H,brs),12.59(1H,brs). |
280 | 1.08-1.20(1H,m),1.21-1.38(2H,m),1,39-1.51(2H,m),1.60-1.73(3H,m),1.80-2.00(4H,m),2.10-2.22(2H,m),2.50-2.52(1H,m),2.99-3.10(2H,m),3.22-3.40(7H,m),3.52-3.62(2H,m),3.94-4.03(2H,m),7.67-7.74(2H,m),8.40(2H,d,J=2.0Hz),8.48-8.50(1H,m),8.85(1H,d,J=2.0Hz),10.49(1H,brs),12.28(1H,brs),12.63(1H,brs). |
282 | 0.90(3H,t,J=7.3Hz),1.51(2H,brs),1.64-1.73(2H,m),1.91-1.99(2H,m),2.33-3.38(13H,m),3.97(2H,d,J=13.2Hz),7.45(1H,d,J=1.5Hz),7.53(1H,d,J=1.0Hz),8.40(1H,d,J=1.9Hz),8.83(1H,d,J=2.0Hz),12.00-12.50(1H,br),12.58(1H,brs). |
284 | 0.95(3H,t,J=7.3Hz),1.63-1.83(6H,m),2.33-2.41(1H,m),2.95(2H,t,J=11.5Hz),3.13-3.42(8H,m),3.60(2H,d,J=10.8Hz),4.07(2H,d,J=13.2Hz),6.80(1H,s)7.32(1H,s),7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),8.40(1H,d,J=1.9Hz),8.84(1H,d,J=1.9Hz),10.65(1H,brs),12.68(1H,s). |
285 | 0.95(3H,t,J=7.3Hz),1.47-1.55(2H,m),1.72-1.91(4H,m),3.12-3.34(10H,m),3.59-3.86(5H,m),7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),8.39(1H,d,J=1.9Hz),8.82(1H,d,J=1.9Hz),10.80(1H,brs),12.66(1H,s). |
289 | 1.10-1.20(1H,m),1.22-1.36(2H,m)1.40-1.55(2H,m),1.59-1.68(1H,m),1.81-1.94(4H,m),2.00-2.09(2H,m),2.15-2.24(2H,m),2.98-3.07(2H,m),3.07-3.16(1H,m),3.18-3.35(4H,m),3.55-3.74(7H,m),7.28(1H,d,J=8.3Hz),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.04(1H,dd,J=1.9,8.3Hz),8.18(1H,d,J=1.9Hz),10.82(1H,brs),12.63(1H,s). |
(表22续)
Ex | NMR |
290 | 1.06-1.20(1H,m),1.22-1.50(4H,m),1.56-2.30(9H,m),2.39-2.48(1H,m),2.75-2.86(2H,m),2.80-3.80(11H,m),7.23(1H,d,J=8.3Hz),7.48(1H,brs),7.56(1H,brs),8.03(1H,dd,J=1.9,8.3Hz),8.18(1H,d,J=1.9Hz),10.50(1H,brs),12.28(1H,brs),12.68(1H,s). |
292 | 1.08-1.20(1H,m),1.21-1.35(2H,m),1.38-1.55(2H,m),1.58-1.90(7H,m),2.10-2.25(2H,m),2.22-2.36(1H,m),2.68-2.79(2H,m),3.20-3.37(7H,m),3.42-3.49(2H,m),3.50-3.70(2H,m),6.82(1H,brs),7.25(1H,d,J=8.8Hz),7.33(1H,brs),7.49(1H,brs),7.56(1H,brs),8.03(1H,dd,J=1.9,8.8Hz),8.18(1H,d,J=1.9Hz),10.62(1H,brs),12.61(1H,s). |
293 | 1.08-1.20(1H,m),1.20-1.36(2H,m)1.36-1.53(2H,m),1.53-1.68(3H,m),1.80-1.93(4H,m),2.15-2.25(2H,m),2.80-2.91(2H,m),3.20-3.40(9H,m),3.55-3.63(2H,m),3.63-3.71(1H,m),7.24(1H,d,J=8.3Hz),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.02(1H,dd,J=1.9,8.3Hz),8.18(1H,d,J=1.9Hz),10.98(1H,brs),12.60(1H,s). |
295 | 1.11-1.20(1H,m),1.22-1.36(2H,m),1.38-1.50(2H,m),1.64(1H,d,J=12.2Hz),1.69-1.80(2H,m),1.87(2H,d,J=12.2Hz),1.91-2.00(2H,m),2.17(2H,d,J=10.3Hz),2.42-3.42(12H,m),3.62(2H,d,J=9.7Hz),7.24(1H,d,J=8.3Hz),7.50(1H,d,J=1.9Hz),7.58(1H,d,J=1.4Hz),8.08(1H,dd,J=1.9,8.3Hz),8.36(1H,d,J=1.9Hz),9.99(1H,brs),12.27(1H,brs),12.65(1H,s). |
297 | 1.06-1.19(1H,m),1.29(2H,q,J=13.2Hz),1.48(2H,q,J=11.2Hz),1.64(1H,d,J=12.7Hz),1.71-1.91(6H,m),2.19-2.33(3H,m),2.67-2.83(2H,m),3.22-3.46(9H,m),3.60(2H,d,J=7.4Hz),6.81(1H,s),7.25(1H,d,J=8.3Hz),7.34(1H,s),7.50(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.08(1H,dd,J=2.2,8.6Hz),8.36(1H,d,J=1.9Hz),10.86(1H,brs),12.64(1H,s). |
298 | 1.14-1.19(1H,m),1.29(2H,q,J=11.7Hz),1.48(2H,q,J=11.2Hz),1.64(1H,d,J=12.7Hz),1.78-1.91(4H,m),1.96-2.01(2H,m),2.20(2H,d,J=10.2Hz),3.09-3.35(12H,m),3.60(2H,d,J=8.8Hz),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),7.80-7.86(2H,m),10.96(1H,brs),12.68(1H,s). |
299 | 1.07-1.18(1H,m),1.29(2H,q,J=12.8Hz),1.47(2H,q,J=11.2Hz),1.59-1.72(3H,m),1.82-1.94(4H,m),2.19(2H,d,J=10.2Hz),2.42-2.46(1H,m),3.13(2H,d,J=11.3Hz),3.26-3.41(9H,m),3.60(2H,brs),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),7.77-7.86(2H,m),10.72(1H,brs),12.27(1H,brs),12.65(1H,s). |
301 | 1.07-1.19(1H,m),1.29(2H,q,J=12.9Hz),1.47(2H,q,J=11.0Hz),1.57-1.72(3H,m),1.72-1.81(2H,m),1.86(2H,d,J=13.1Hz),2.18-2.33(3H,m),3.09(2H,t,J=11.7Hz),3.22-3.44(9H,m),3.59(2H,brs),6.81(1H,s),7.31(1H,s),7.50(1H,d,J=1.5Hz),7.57(1H,d,J=1.4Hz),7.77-7.86(2H,m),10.70(1H,brs),12.66(1H,s). |
302 | 1.08-1.20(1H,m),1.21-1.36(2H,m),1.40-1.55(2H,m),1.59-1.68(1H,m),1.78-1.91(4H,m),1.95-2.05(2H,m),2.14-2.25(2H,m),3.09-3.21(3H,m),3.21-3.45(9H,m),3.55-3.65(2H,m),7.50(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),7.93(1H,dd,J=2.0,12.7Hz),8.07(1H,brs),10.81(1H,brs),12.73(1H,s). |
303 | 1.08-1.20(1H,m),1.22-1.37(2H,m),1.42-1.55(2H,m),1.59-1.76(3H,m),1.81-1.95(4H,m),2.16-2.25(2H,m),2.40-2.48(1H,m),3.08-3.17(2H,m),3.24-3.36(7H,m),3.46-3.65(4H,m),7.49(1H,d,J=1.4Hz),7.57(1H,d,J=1.4Hz),7.89(1H,dd,J=2.0,13.2Hz),8.06(1H,d,J=2.0Hz),10.90(1H,brs),12.25(1H,brs),12.72(1H,s). |
305 | 1.08-1.20(1H,m),1.20-1.35(2H,m),1.38-1.52(2H,m),1.58-1.90(7H,m),2.10-2.24(2H,m),2.25-2.36(1H,m),3.03-3.14(2H,m),3.15-3.35(9H,m),3.50-3.70(2H,m),6.80(1H,brs),7.30(1H,brs),7.48(1H,brs),7.56(1H,brs),7.90(1H,dd,J=2.0,13.8Hz),8.06(1H,brs),10.80(1H,brs),12.69(1H,s). |
(表22续)
Ex | NMR |
309 | 1.07-1.20(1H,m),1.21-1.35(2H,m),1.38-1.53(2H,m),1.58-1.67(1H,m),1.80-1.92(2H,m),2.08-2.24(2H,m),2.75-2.88(4H,m),3.16-3.92(15H,m),7.49(1H,d,J=1.4Hz),7.53(1H,d,J=1.4Hz),7.92(1H,dd,J=2.0,13.2Hz),8.06(1H,s),12.7(1H,s). |
311 | 1.08-1.18(1H,m),1.22-1.35(2H,m),1.42-1.56(2H,m),1.58-1.68(1H,m),1.82-1.92(2H,m),2.18-2.26(2H,m),3.24-3.50(9H,m),3.51-3.68(8H,m),4.04(2H,s),7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),7.72(1H,s),7.95(1H,dd,J=1.9,12.7Hz),8.05(1H,s),8.10(1H,s),8.32(1H,s),10.33(1H,brs),11.10(1H,brs),12.8(1H,s). |
313 | 1.05-1.08(1H,m),1.24-1.35(2H,m)1.43-1.52(2H,m),1.60-1.69(1H,m),1.82-1.92(2H,m),2.12-2.22(2H,m),3.13-3.24(4H,m),3.31(3H,s),3.26-3.35(3H,m),3.46-3.64(10H,m),4.14(2H,s),7.50(1H,d,J=1.4Hz),7.58(1H,d,J=1.4Hz),7.94(1H,dd,J=2.2,12.9Hz),8.09(1H,s),1011(1H,brs),12,76(1H,brs). |
316 | 1.01-1.20(1H,m),1.21-1.37(2H,m),1.41-1.57(2H,m),1.58-1.67(1H,m),1.75-1.92(2H,m),2.14-2.28(2H,m),3.03-3.15(4H,m),3.21-3.44(11H,m),3.55-3.64(2H,m),6.88(2H,m),7.49(1H,d,J=1.4Hz),7.57(1H,d,J=1.4Hz),7.95(1H,dd,J=2.0,12.7Hz),8.08(1H,brs),11.2(1H,brs),12.7(1H,brs). |
322 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.40-1.54(2H,m),1.58-1.68(1H,m),1.81-2.00(4H,m),2.14-2.24(2H,m),3.20-3.38(7H,m),3.54-3.64(3H,m),3.73-3.81(1H,m),3.82-3.91(2H,m),4.33-4.39(1H,m),7.49(1H,d,J=1.5Hz),7.56(1H,d,J=1.5Hz),8.29(1H,d,J=2.0Hz),8.74(1H,d,J=2.0Hz),10.70(1H,brs),12.51(1H,s). |
328 | 1.05-1.20(1H,m),1.22-1.36(4H,m),1.41-1.55(2H,m),1.58-1.70(2H,m),1.73-1.81(2H,m),1.82-1.91(2H,m),2.17-2.26(2H,m),2.90(2H,t,J=11.2Hz),3.23-3.36(9H,m),3.60(2H,d,J=9.8Hz),4.08(2H,d,J=12.7Hz),7.49(1H,d,J=1.4Hz),7.56(1H,d,J=1.4Hz),8.38(1H,d,J=2.0Hz),8.82(1H,d,J=2.0Hz),11.03(1H,brs),12.65(1H,brs). |
331 | 1.05-1.20(1H,m),1.22-1.36(2H,m),1.41-1.54(2H,m),1.58-1.74(3H,m),1.77-1.92(4H,m),2.16-2.24(2H,m),2.34-2.42(1H,m),2.95(2H,t,J=12.2Hz),3.25-3.36(7H,m),3.52-3.64(2H,m),4.07(2H,d,J=12.2Hz),6.80(1H,s),7.32(1H,s),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.40(1H,d,J=2.4Hz),8.83(1H,d,J=2.4Hz),10.73(1H,brs),12.67(1H,s). |
332 | 1.08-1.19(1H,m),1.29(2H,q,J=13.0Hz),1.47(2H,q,J=11.2Hz),1.60-1.82(5H,m),1.87(2H,d,J=13.2Hz),2.19(2H,d,J=10.7Hz),2.32-2.41(1H,m),2.58(3H,d,J=4.4Hz),2.94(2H,t,J=11.5Hz),3.24-3.66(9H,m),4.08(2H,d,J=12.7Hz),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),7.79(1H,q,J=4.6Hz),8.40(1H,d,J=1.9Hz),8.83(1H,d,J=1.9Hz),10.68(1H,brs),12.67(1H,s). |
333 | 0.84(3H,t,J=7.3Hz),1.08-1.21(1H,m),1.22-1.34(2H,m),1.35-1.54(4H,m),1.59-1.82(5H,m),1.83-1.92(2H,m),2.14-2.23(2H,m),2.34-2.43(1H,m),2.90-2.99(2H,m),3.01(2H,q,J=6.9Hz),3.20-3.60(7H,m),3.55-3.65(2H,m),4.04-4.12(2H,m),7.50(1H,d,J=1.5Hz),7.58(1H,d,J=1.5Hz),7.83(1H,t,J=5.8Hz),8.40(1H,d,J=2.4Hz),8.83(1H,d,J=2.4Hz),10.53(1H,brs),12.68(1H,brs). |
338 | 1.13-1.20(1H,m),1.21-1.35(2H,m),1.42-1.55(2H,m),1.58-1.74(7H,m),2.16-2.23(2H,m),2.38-2.46(1H,m)2.88-3.00(2H,m),3.18-3.36(7H,m),3.25(3H,s),3.48-3.68(6H,m),4.08-4.13(2H,m),7.49(1H,d,J=1.4Hz),7.56(1H,d,J=1,4Hz),7.94(1H,t,J=5.8Hz),8.39(1H,d.J=2.0Hz),8.83(1H,d,J=2.0Hz),10.81(1H,brs),12.66(1H,brs). |
(表22续)
Ex | NMR |
339 | 1.11(3H,t,J=6.9Hz),1.07-1.21(1H,m),1.23-1.36(2H,m),1.42-1.52(2H,m),1.60-1.91(7H,m),2.14-2.27(2H,m)2.35-2.48(1H,m),2.87-3.00(2H,m),3.20(2H,q,J=5.8Hz),3.20-3.42(9H,m),3.43(2H,q,J=6.9Hz),3.54-3.66(2H,m),4.00-4.14(2H,m),7.49(1H,d,J=1.4Hz),7.58(1H,d,J=1.4Hz),7.92(1H,t,J=5.8Hz),8.40(1H,d,J=1.9Hz),8.82(1H,d,J=1.9Hz),11.00(1H,brs),12.67(1H,brs). |
340 | 1.04-1.20(1H,m),1.23-1.36(2H,m),1.46-1.56(2H,m),1.57-1.92(7H,m),1.63(2H,t,J=6.9Hz),2.16-2.28(2H,m)2.32-2.42(1H,m),2.85-2.98(2H,m),3.06-3.13(2H,m),3.22(3H,s),3.21-3.45(9H,m),3.54-3.67(2H,m),4.02-4.20(2H,m),7.49(1H,d,J=1.5Hz),7.56(1H,d,J=1.5Hz),7.88(1H,t,J=5.5Hz),8.39(1H,d,J=2.0Hz),8.82(1H,d,J=2.0Hz),11.27(1H,brs),12.65(1H,brs). |
344 | 1.07-1.19(1H,m),1.29(2H,q,J=12.1Hz),1.48(2H,q,J=11.2Hz),1.60-1.78(5H,m),1.86(2H,d,J=12.7Hz),2.20(2H,d,J=10.2Hz),2.83(3H,s),2.89-3.06(3H,m),3.07(3H,s),3.22-3.38(7H,m),3.60(2H,d,J=7.8Hz),4.09(2H,d,J=13.2Hz),7.49(1H,d,J=1.4Hz),7.57(1H,d,J=1.4Hz),8.39(1H,d,J=2.5Hz),8.83(1H,d,J=2.4Hz),10.88(1H,brs),12.66(1H,s). |
350 | 1.07-1.20(1H,m),1.22-1.36(2H,m),1.41-1.56(4H,m),1.60-1.67(1H,m),1.80-1.92(4H,m),2.15-2.24(2H,m),3.13-3.37(9H,m),3.55-3.63(2H,m),3.68-3.76(1H,m),3.79-3.87(2H,m),7.49(1H,d,J=1.4Hz),7.57(1H,d,J=1.4Hz),8.38(1H,d,J=2.4Hz),8.82(1H,d,J=2.4Hz),10.92(1H,brs),12.66(1H,s). |
353 | 1.06-1.20(1H,m),1.22-1.37(2H,m),1.42-1.57(4H,m),1.59-1.68(1H,m),1.81(3H,s),1.82-1.90(4H,m),2.16-2.26(2H,m),3.07(2H,t,J=11.2Hz),3.21-3.41(7H,m),3.54-3.64(2H,m),3.82-4.08(3H,m),7.49(1H,d,J=1.4Hz),7.57(1H,d,J=1.4Hz),7.90(1H,d,J=7.8Hz),8.40(1H,d,J=1.9Hz),8.84(1H,d,J=1.9Hz),11.06(1H,brs),12.67(1H,s). |
358 | 1.05-1.20(1H,m),1.21-1.36(2H,m),1.42-1.55(2H,m),1.57-1.67(1H,m),1.81-1.92(2H,m),2.18-2.24(2H,m),2.94-3.03(4H,m),3.18-3.80(15H,m),7.49(1H,d,J=1.4Hz),7.57(1H,d,J=1.4Hz),8.42(1H,d,J=2.2Hz),8.88(1H,d,J=2.2Hz),11.16(1H,brs),12.71(1H,brs). |
362 | 1.06-1.20(1H,m),1.22-1.36(2H,m),1.40-1.54(2H,m),1.58-1.69(1H,m),1.81-1.92(2H,m),2.13-2.24(2H,m),3.23-3.38(9H,m),3.57-3.63(2H,m),3.77(2H,t,J=5.4Hz),4.05(2H,brs),7.49(1H,d,J=1.5Hz),7.57(1H,d,J=1.5Hz),8.05(1H,brs),8.45(1H,d,J=1.9Hz),8.86(1H,d,J=1.9Hz),10.62(1H,brs),12.73(1H,s). |
372 | 1.07-1.21(1H,m),1.20-1.37(2H,m),1.37-1.52(2H,m),1.60-1.77(1H,m),1.83-1.92(2H,m),2.10-2.23(2H,m),2.53-2.54(2H,m),3.15-3.37(9H,m),3.57-3.68(6H,m),7.50(1H,s),7.57(1H,s),7.63-7.70(1H,m),8.43(1H,s)8.82(1H,s),10.26(1H,brs),12.68(1H,brs). |
以下的表23~33所示为其它本发明化合物的结构。它们可通过上述制备方法、实施例记载的方法或本领域普通技术人员了解的方法或这些方法的变化例容易地制得。
表中,No表示化合物编号,RJ、RK、RL、RM、RN、RO、RP、RQ、RR、RS、RT、RAA、RBB、RCC、RDD、REE、RFF、RGG表示通式中的取代基。因此,例如表23中的“(No:RJ)=(A0001:HO-CH2-O)”是指“化合物编号A0001的化合物作为通式中的取代基RJ具有羟基甲氧基”。
(表23)
(No:RJ)=(A0001:HO-CH2-O),(A0002:MeO-CH2-O),(A0003:EtO2C-CH2-O),(A0004:HO2C-CH2-O),(A0005:H2NOC-CH2-O),(A0006:cyano-CH2-O),(A0007:MeHNOC-CH2-O),(A0008:Me2NOC-CH2-O),(A0009:F3C-CH2-O),(A0010:HO-(CH2)2-O),(A0011:MeO-(CH2)2-O),(A0012:EtO2C-(CH2)2-O),(A0013:HO2C-(CH2)2-O),(A0014:H2NOC-(CH2)2-O),(A0015:cyano-(CH2)2-O),(A0016:MeHNOC-(CH2)2-O),(A0017:Me2NOC-(CH2)2-O),(A0018:F3C-(CH2)2-O),(A0019:HO-(CH2)3-O),(A0020:MeO-(CH2)3-O),(A0021:EtO2C-(CH2)3-O),(A0022:HO2C-(CH2)3-O),(A0023:H2NOC-(CH2)3-O),(A0024:cyano-(CH2)3-O),(A0025:MeHNOC-(CH2)3-O),(A0026:Me2NOC-(CH2)3-O),(A0027:F3C-(CH2)3-O),(A0028:1-HO-cHex-O),(A0029:1-MeO-cHex-O),(A0030:1-EtO2C-cHex-O),(A0031:1-HO2C-cHex-O),(A0032:1-H2NOC-cHex-O),(A0033:1-cyano-cHex-O),(A0034:1-MeHNOC-cHex-O),(A0035:1-Me2NOC-cHex-O),(A0036:1-F3C-cHex-O),(A0037:2-HO-cHex-O),(A0038:2-MeO-cHex-O),(A0039:2-EtO2C-cHex-O),(A0040:2-HO2C-cHex-O),(A0041:2-H2NOC-cHex-O),(A0042:2-cyano-cHex-O),(A0043:2-MeHNOC-cHex-O),(A0044:2-Me2NOC-cHex-O),(A0045:2-F3C-cHex-O),(A0046:3-HO-cHex-O),(A0047:3-MeO-cHex-O),(A0048:3-EtO2C-cHex-O),(A0049:3-HO2C-cHex-O),(A0050:3-H2NOC-cHex-O),(A0051:3-cyano-cHex-O),(A0052:3-MeHNOC-cHex-O),(A0053:3-Me2NOC-cHex-O),(A0054:3-F3C-cHex-O),(A0055:4-HO-cHex-O),(A0056:4-MeO-cHex-O),(A0057:4-EtO2C-cHex-O),(A0058:4-HO2C-cHex-O),(A0059:4-H2NOC-cHex-O),(A0060:4-cyano-cHex-O),(A0061:4-MeHNOC-cHex-O),(A0062:4-Me2NOC-cHex-O),(A0063:4-F3C-cHex-O),(A0064:3-HO-cPen-O),(A0065:3-MeO-cPen-O),(A0066:3-EtO2C-cPen-O),(A0067:3-HO2C-cPen-O),(A0068:3-H2NOC-cPen-O),(A0069:3-cyano-cPen-O),(A0070:3-MeHNOC-cPen-O),(A0071:3-Me2NOC-cPen-O),(A0072:3-F3C-cPen-O),(A0073:3-HO-cBu-O),(A0074:3-MeO-cBu-O),(A0075:3-EtO2C-cBu-O),(A0076:3-HO2C-cBu-O),(A0077:3-H2NOC-cBu-O),(A0078:3-cyano-cBu-O),(A0079:3-MeHNOC-cBu-O),(A0080:3-Me2NOC-cBu-O),(A0081:3-F3C-cBu-O),(A0082:2-HO-cPr-O),(A0083:2-MeO-cPr-O),(A0084:2-EtO2C-cPr-O),(A0085:2-HO2C-cPr-O),(A0086:2-H2NOC-cPr-O),(A0087:2-cyano-cPr-O),(A0088:2-MeHNOC-cPr-O),(A0089:2-Me2NOC-cPr-O),(A0090:2-F3C-cPr-O),(A0091:HO-CH2-HN),(A0092:MeO-CH2-HN),(A0093:EtO2C-CH2-HN),(A0094:HO2C-CH2-HN), |
(表23续)
(A0095:H2NOC-CH2-HN),(A0096:cyano-CH2-HN),(A0097:MeHNOC-CH2-HN),(A0098:Me2NOC-CH2-HN),(A0099:F3C-CH2-HN),(A0100:HO-(CH2)2-HN),(A0101:MeO-(CH2)2-HN),(A0102:EtO2C-(CH2)2-HN),(A0103:HO2C-(CH2)2-HN),(A0104:H2NOC-(CH2)2-HN),(A0105:cyano-(CH2)2-HN),(A0106:MeHNOC-(CH2)2-HN),(A0107:Me2NOC-(CH2)2-HN),(A0108:F3C-(CH2)2-HN),(A0109:HO-(CH2)3-HN),(A0110:MeO-(CH2)3-HN),(A0111:EtO2C-(CH2)3-HN),(A0112:HO2C-(CH2)3-HN),(A0113:H2NOC-(CH2)3-HN),(A0114:cyano-(CH2)3-HN),(A0115:MeHNOC-(CH2)3-HN),(A0116:Me2NOC-(CH2)3-HN),(A0117:F3C-(CH2)3-HN),(A0118:1-HO-cHex-HN),(A0119:1-MeO-cHex-HN),(A0120:1-EtO2C-cHex-HN),(A0121:1-HO2C-cHex-HN),(A0122:1-H2NOC-cHex-HN),(A0123:1-cyano-cHex-HN),(A0124:1-MeHNOC-cHex-HN),(A0125:1-Me2NOC-cHex-HN),(A0126:1-F3C-cHex-HN),(A0127:2-HO-cHex-HN),(A0128:2-MeO-cHex-HN),(A0129:2-EtO2C-cHex-HN),(A0130:2-HO2C-cHex-HN),(A0131:2-H2NOC-cHex-HN),(A0132:2-cyano-cHex-HN),(A0133:2-MeHNOC-cHex-HN),(A0134:2-Me2NOC-cHex-HN),(A0135:2-F3C-cHex-HN),(A0136:3-HO-cHex-HN),(A0137:3-MeO-cHex-HN),(A0138:3-EtO2C-cHex-HN),(A0139:3-HO2C-cHex-HN),(A0140:3-H2NOC-cHex-HN),(A0141:3-cyano-cHex-HN),(A0142:3-MeHNOC-cHex-HN),(A0143:3-Me2NOC-cHex-HN),(A0144:3-F3C-cHex-HN),(A0145:4-HO-cHex-HN),(A0146:4-MeO-cHex-HN),(A0147:4-EtO2C-cHex-HN),(A0148:4-HO2C-cHex-HN),(A0149:4-H2NOC-cHex-HN),(A0150:4-cyano-cHex-HN),(A0151:4-MeHNOC-cHex-HN),(A0152:4-Me2NOC-cHex-HN),(A0153:4-F3C-cHex-HN),(A0154:3-HO-cPen-HN),(A0155:3-MeO-cPen-HN),(A0156:3-EtO2C-cPen-HN),(A0157:3-HO2C-cPen-HN),(A0158:3-H2NOC-cPen-HN),(A0159:3-cyano-cPen-HN),(A0160:3-MeHNOC-cPen-HN),(A0161:3-Me2NOC-cPen-HN),(A0162:3-F3C-cPen-HN),(A0163:3-HO-cBu-HN),(A0164:3-MeO-cBu-HN),(A0165:3-EtO2C-cBu-HN),(A0166:3-HO2C-cBu-HN),(A0167:3-H2NOC-cBu-HN),(A0168:3-cyano-cBu-HN),(A0169:3-MeHNOC-cBu-HN),(A0170:3-Me2NOC-cBu-HN),(A0171:3-F3C-cBu-HN),(A0172:2-HO-cPr-HN),(A0173:2-MeO-cPr-HN),(A0174:2-EtO2C-cPr-HN),(A0175:2-HO2C-cPr-HN),(A0176:2-H2NOC-cPr-HN),(A0177:2-cyano-cPr-HN),(A0178:2-MeHNOC-cPr-HN),(A0179:2-Me2NOC-cPr-HN),(A0180:2-F3C-cPr-HN),(A0181:HO-CH2-MeN),(A0182:MeO-CH2-MeN),(A0183:EtO2C-CH2-MeN),(A0184:HO2C-CH2-MeN),(A0185:H2NOC-CH2-MeN),(A0186:cyano-CH2-MeN),(A0187:MeHNOC-CH2-MeN),(A0188:Me2NOC-CH2-MeN),(A0189:F3C-CH2-MeN),(A0190:HO-(CH2)2-MeN),(A0191:MeO-(CH2)2-MeN),(A0192:EtO2C-(CH2)2-MeN),(A0193:HO2C-(CH2)2-MeN),(A0194:H2NOC-(CH2)2-MeN),(A0195:cyano-(CH2)2-MeN),(A0196:MeHNOC-(CH2)2-MeN),(A0197:Me2NOC-(CH2)2-MeN),(A0198:F3C-(CH2)2-MeN),(A0199:HO-(CH2)3-MeN),(A0200:MeO-(CH2)3-MeN),(A0201:EtO2C-(CH2)3-MeN),(A0202:HO2C-(CH2)3-MeN),(A0203:H2NOC-(CH2)3-MeN),(A0204:cyano-(CH2)3-MeN),(A0205:MeHNOC-(CH2)3-MeN),(A0206:Me2NOC-(CH2)3-MeN), |
(表23续)
(A0207:F3C-(CH2)3-MeN),(A0208:1-HO-cHex-MeN),(A0209:1-MeO-cHex-MeN),(A0210:1-EtO2C-cHex-MeN),(A0211:1-HO2C-cHex-MeN),(A0212:1-H2NOC-cHex-MeN),(A0213:1-cyano-cHex-MeN),(A0214:1-MeHNOC-cHex-MeN),(A0215:1-Me2NOC-cHex-MeN),(A0216:1-F3C-cHex-MeN),(A0217:2-HO-cHex-MeN),(A0218:2-MeO-cHex-MeN),(A0219:2-EtO2C-cHex-MeN),(A0220:2-HO2C-cHex-MeN),(A0221:2-H2NOC-cHex-MeN),(A0222:2-cyano-cHex-MeN),(A0223:2-MeHNOC-cHex-MeN),(A0224:2-Me2NOC-cHex-MeN),(A0225:2-F3C-cHex-MeN),(A0226:3-HO-cHex-MeN),(A0227:3-MeO-cHex-MeN),(A0228:3-EtO2C-cHex-MeN),(A0229:3-HO2C-cHex-MeN),(A0230:3-H2NOC-cHex-MeN),(A0231:3-cyano-cHex-MeN),(A0232:3-MeHNOC-cHex-MeN),(A0233:3-Me2NOC-cHex-MeN),(A0234:3-F3C-cHex-MeN),(A0235:4-HO-cHex-MeN),(A0236:4-MeO-cHex-MeN),(A0237:4-EtO2C-cHex-MeN),(A0238:4-HO2C-cHex-MeN),(A0239:4-H2NOC-cHex-MeN),(A0240:4-cyano-cHex-MeN),(A0241:4-MeHNOC-cHex-MeN),(A0242:4-Me2NOC-cHex-MeN),(A0243:4-F3C-cHex-MeN),(A0244:3-HO-cPen-MeN),(A0245:3-MeO-cPen-MeN),(A0246:3-EtO2C-cPen-MeN),(A0247:3-HO2C-cPen-MeN),(A0248:3-H2NOC-cPen-MeN),(A0249:3-cyano-cPen-MeN),(A0250:3-MeHNOC-cPen-MeN),(A0251:3-Me2NOC-cPen-MeN),(A0252:3-F3C-cPen-MeN),(A0253:3-HO-cBu-MeN),(A0254:3-MeO-cBu-MeN),(A0255:3-EtO2C-cBu-MeN),(A0256:3-HO2C-cBu-MeN),(A0257:3-H2NOC-cBu-MeN),(A0258:3-cyano-cBu-MeN),(A0259:3-MeHNOC-cBu-MeN),(A0260:3-Me2NOC-cBu-MeN),(A0261:3-F3C-cBu-MeN),(A0262:2-HO-cPr-MeN),(A0263:2-MeO-cPr-MeN),(A0264:2-EtO2C-cPr-MeN),(A0265:2-HO2C-cPr-MeN),(A0266:2-H2NOC-cPr-MeN),(A0267:2-cyano-cPr-MeN),(A0268:2-MeHNOC-cPr-MeN),(A0269:2-Me2NOC-cPr-MeN),(A0270:2-F3C-cPr-MeN),(A0271:(oxetan-3-yl)-O),(A0272:(tetrahydrofuran-3-yl)-O),(A0273:(tetrahydro-2H-pyran-3-yl)-O),(A0274:(tetrahydro-2H-pyran-4-yl)-O),(A0275:(oxetan-2-yl)-CH2-O),(A0276:(oxetan-3-yl)-CH2-O),(A0277:(tetrahydrofuran-2-yl)-CH2-O),(A0278:(tetrahydrofuran-3-yl)-CH2-O),(A0279:(tetrahydro-2H-pyran-2-yl)-CH2-O),(A0280:(tetrahydro-2H-pyran-3-yl)-CH2-O),(A0281:(tetrahydro-2H-pyran-4-yl)-CH2-O),(A0282:(morpholin-2-yl)-CH2-O),(A0283:(morpholin-3-yl)-CH2-O),(A0284:mor-CH2-O),(A0285:(1,4-dioxan-2-yl)-CH2-O),(A0286:(oxetan-2-yl)-(CH2)2-O),(A0287:(oxetan-3-yl)-HN),(A0288:(tetrahydrofuran-3-yl)-HN),(A0289:(tetrahydro-2H-pyran-3-yl)-HN),(A0290:(tetrahydro-2H-pyran-4-yl)-HN),(A0291:(oxetan-2-yl)-CH2-HN),(A0292:(oxetan-3-yl)-CH2-HN),(A0293:(tetrahydrofuran-2-yl)-CH2-HN),(A0294:(tetrahydrofuran-3-yl)-CH2-HN),(A0295:(tetrahydro-2H-pyran-2-yl)-CH2-HN),(A0296:(tetrahyd ro-2H-pyran-3-yl)-CH2-HN),(A0297:(tetrahyd ro-2H-pyran-4-yl)-CH2-HN),(A0298:(morpholin-2-yl)-CH2-HN),(A0299:(morpholin-3-yl)-CH2-HN),(A0300:mor-CH2-HN),(A0301:(1,4-dioxan-2-yl)-CH2-HN),(A0302:(oxetan-3-yl)-MeN),(A0303:(tetrahydrofuran-3-yl)-MeN),(A0304:(tetrahydro-2H-pyran-3-yl)-MeN), |
(表23续)
(A0305:(tetrahydro-2H-pyran-4-yl)-MeN),(A0306:(oxetan-2-yl)-CH2-MeN),(A0307:(oxetan-3-yl)-CH2-MeN),(A0308:(tetrahydrofuran-2-yl)-CH2-MeN),(A0309:(tetrahydrofuran-3-yl)-CH2-MeN),(A0310:(tetrahydro-2H-pyran-2-yl)-CH2-MeN),(A0311:(tetrahydro-2H-pyran-3-yl)-CH2-MeN),(A0312:(tetrahydro-2H-pyran-4-yl)-CH2-MeN),(A0313:(morpholin-2-yl)-CH2-MeN),(A0314:(morpholin-3-yl)-CH2-MeN),(A0315:mor-CH2-MeN),(A0316:(1,4-dioxan-2-yl)-CH2-MeN),(A0317:HO2C-CH2CH(OH)-O),(A0318:H2NOC-CH2CH(OH)-O),(A0319:cyano-CH2CH(OH)-O),(A0320:HO2C-CH2CH(OMe)-O),(A0321:H2NOC-CH2CH(OMe)-O),(A0322:cyano-CH2CH(OMe)-O),(A0323:HO-CH2CH(OH)CH2-O),(A0324:MeO-CH2CH(OH)CH2-O),(A0325:HO2C-CH2CH(OH)CH2-O),(A0326:H2NOC-CH2CH(OH)CH2-O),(A0327:cyano-CH2CH(OH)CH2-O),(A0328:HO-CH2CH(OMe)CH2-O),(A0329:MeO-CH2CH(OMe)CH2-O),(A0330:HO2C-CH2CH(OMe)CH2-O),(A0331:H2NOC-CH2CH(OMe)CH2-O),(A0332:cyano-CH2CH(OMe)CH2-O),(A0333:HO2C-CH2CH(OH)-HN),(A0334:H2NOC-CH2CH(OH)-HN),(A0335:cyano-CH2CH(OH)-HN),(A0336:HO2C-CH2CH(OMe)-HN),(A0337:H2NOC-CH2CH(OMe)-HN),(A0338:cyano-CH2CH(OMe)-HN),(A0339:HO-CH2CH(OH)CH2-HN),(A0340:MeO-CH2CH(OH)CH2-HN),(A0341:HO2C-CH2CH(OH)CH2-HN),(A0342:H2NOC-CH2CH(OH)CH2-HN),(A0343:cyano-CH2CH(OH)CH2-HN),(A0344:HO-CH2CH(OMe)CH2-HN),(A0345:MeO-CH2CH(OMe)CH2-HN),(A0346:HO2C-CH2CH(OMe)CH2-HN),(A0347:H2NOC-CH2CH(OMe)CH2-HN),(A0348:cyano-CH2CH(OMe)CH2-HN),(A0349:HO2C-CH2CH(OH)-MeN),(A0350:H2NOC-CH2CH(OH)-MeN),(A0351:cyano-CH2CH(OH)-MeN),(A0352:HO2C-CH2CH(OMe)-MeN),(A0353:H2NOC-CH2CH(OMe)-MeN),(A0354:cyano-CH2CH(OMe)-MeN),(A0355:HO-CH2CH(OH)CH2-MeN),(A0356:MeO-CH2CH(OH)CH2-MeN),(A0357:HO2C-CH2CH(OH)CH2-MeN),(A0358:H2NOC-CH2CH(OH)CH2-MeN),(A0359:cyano-CH2CH(OH)CH2-MeN),(A0360:HO-CH2CH(OMe)CH2-MeN),(A0361:MeO-CH2CH(OMe)CH2-MeN),(A0362:HO2C-CH2CH(OMe)CH2-MeN),(A0363:H2NOC-CH2CH(OMe)CH2-MeN),(A0364:cyano-CH2CH(OMe)CH2-MeN),(A0365:HO-(CH2)2-(HO(CH2)2)N),(A0366:MeO-(CH2)2-(HO(CH2)2)N),(A0367:HO2C-(CH2)2-(HO(CH2)2)N),(A0368:H2NOC-(CH2)2-(HO(CH2)2)N),(A0369:cyano-(CH2)2-(HO(CH2)2)N),(A0370:HO-(CH2)3-(HO(CH2)2)N),(A0371:MeO-(CH2)3-(HO(CH2)2)N),(A0372:HO2C-(CH2)3-(HO(CH2)2)N),(A0373:H2NOC-(CH2)3-(HO(CH2)2)N),(A0374:cyano-(CH2)3-(HO(CH2)2)N),(A0375:HO-(CH2)2-(MeO(CH2)2)N),(A0376:MeO-(CH2)2-(MeO(CH2)2)N),(A0377:HO2C-(CH2)2-(MeO(CH2)2)N),(A0378:H2NOC-(CH2)2-(MeO(CH2)2)N),(A0379:cyano-(CH2)2-(MeO(CH2)2)N),(A0380:HO-(CH2)3-(MeO(CH2)2)N),(A0381:MeO-(CH2)3-(MeO(CH2)2)N),(A0382:HO2C-(CH2)3-(MeO(CH2)2)N),(A0383:H2NOC-(CH2)3-(MeO(CH2)2)N),(A0384:cyano-(CH2)3-(MeO(CH2)2)N). |
(表24)
(No:RK)=(A0385:3-HO-pyrr),(A0386:3-MeO-pyrr),(A0387:3-HO2C-pyrr),(A0388:3-H2NOC-pyrr),(A0389:3-cyano-pyrr),(A0390:3-MeHNOC-pyrr),(A0391:3-Me2NOC-pyrr),(A0392:3-F3C-pyrr),(A0393:3-F-pyrr),(A0394:3-oxo-pyrr),(A0395:3-H2NO2S-pyrr),(A0396:3-HO3S-pyrr),(A0397:3-ttrz-pyrr),(A0398:3-HOCH2-pyrr),(A0399:3-MeOCH2-pyrr),(A0400:3-HO2CCH2-pyrr),(A0401:3-H2NOCCH2-pyrr),(A0402:3-(cyano-CH2)-pyrr),(A0403:3-HO2CCH2O-pyrr),(A0404:3-H2NOCCH2O-pyrr),(A0405:3-HO-pipe),(A0406:3-MeO-pipe),(A0407:3-HO2C-pipe),(A0408:3-H2NOC-pipe),(A0409:3-cyano-pipe),(A0410:3-MeHNOC-pipe),(A0411:3-Me2NOC-pipe),(A0412:3-F3C-pipe),(A0413:3-F-pipe),(A0414:3-oxo-pipe),(A0415:3-H2NO2S-pipe),(A0416:3-HO3S-pipe),(A0417:3-ttrz-pipe),(A0418:3-HOCH2-pipe),(A0419:3-MeOCH2-pipe),(A0420:3-HO2CCH2-pipe),(A0421:3-H2NOCCH2-pipe),(A0422:3-(cyano-CH2)-pipe),(A0423:3-HO2CCH2O-pipe),(A0424:3-H2NOCCH2O-pipe),(A0425:4-HO-pipe),(A0426:4-MeO-pipe),(A0427:4-HO2C-pipe),(A0428:4-H2NOC-pipe),(A0429:4-cyano-pipe),(A0430:4-MeHNOC-pipe),(A0431:4-Me2NOC-pipe),(A0432:4-F3C-pipe),(A0433:4-F-pipe),(A0434:4-oxo-pipe),(A0435:4-H2NO2S-pipe),(A0436:4-HO3S-pipe),(A0437:4-ttrz-pipe),(A0438:4-HOCH2-pipe),(A0439:4-MeOCH2-pipe),(A0440:4-HO2CCH2-pipe),(A0441:4-H2NOCCH2-pipe),(A0442:4-(cyano-CH2)-pipe),(A0443:4-HO2CCH2O-pipe),(A0444:4-H2NOCCH2O-pipe). |
(表25)
(NO:RL)=(A0445:HO-CH2-O),(A0446:MeO-CH2-O),(A0447:EtO2C-CH2-O),(A0448:HO2C-CH2-O),(A0449:H2NOC-CH2-O),(A0450:cyano-CH2-O),(A0451:HO-(CH2)2-O), |
(表25续)
(A0452:MeO-(CH2)2-O),(A0453:EtO2C-(CH2)2-O),(A0454:HO2C-(CH2)2-O),(A0455:H2NOC-(CH2)2-O),(A0456:cyano-(CH2)2-O),(A0457:HO-(CH2)3-O),(A0458:MeO-(CH2)3-O),(A0459:EtO2C-(CH2)3-O),(A0460:HO2C-(CH2)3-O),(A0461:H2NOC-(CH2)3-O),(A0462:cyano-(CH2)3-O),(A0463:HO-CH2-HN),(A0464:MeO-CH2-HN),(A0465:EtO2C-CH2-HN),(A0466:HO2C-CH2-HN),(A0467:H2NOC-CH2-HN),(A0468:cyano-CH2-HN),(A0469:HO-(CH2)2-HN),(A0470:MeO-(CH2)2-HN),(A0471:EtO2C-(CH2)2-HN),(A0472:HO2C-(CH2)2-HN),(A0473:H2NOC-(CH2)2-HN),(A0474:cyano-(CH2)2-HN),(A0475:HO-(CH2)3-HN),(A0476:MeO-(CH2)3-HN),(A0477:EtO2C-(CH2)3-HN),(A0478:HO2C-(CH2)3-HN),(A0479:H2NOC-(CH2)3-HN),(A0480:cyano-(CH2)3-HN),(A0481:HO-CH2-MeN),(A0482:MeO-CH2-MeN),(A0483:EtO2C-CH2-MeN),(A0484:HO2C-CH2-MeN),(A0485:H2NOC-CH2-MeN),(A0486:cyano-CH2-MeN),(A0487:HO-(CH2)2-MeN),(A0488:MeO-(CH2)2-MeN),(A0489:EtO2C-(CH2)2-MeN),(A0490:HO2C-(CH2)2-MeN),(A0491:H2NOC-(CH2)2-MeN),(A0492:cyano-(CH2)2-MeN),(A0493:HO-(CH2)3-MeN),(A0494:MeO-(CH2)3-MeN),(A0495:EtO2C-(CH2)3-MeN),(A0496:HO2C-(CH2)3-MeN),(A0497:H2NOC-(CH2)3-MeN),(A0498:cyano-(CH2)3-MeN). |
(表26)
(No:RM)=(A0499:2-HO2C-azet),(A0500:2-H2NOC-azet),(A0501:2-cyano-azet),(A0502:2-MeHNOC-azet),(A0503:2-Me2NOC-azet),(A0504:2-(MeO(CH2)2-(HNOC))-azet),(A0505:2-(MeO(CH2)3-(HNOC))-azet),(A0506:2-(mor-OC)-azet),(A0507:2-F3C-azet),(A0508:2-oxo-azet),(A0509:2-H2NO2S-azet),(A0510:2-HO3S-azet),(A0511:2-ttrz-azet),(A0512:2-HOCH2-azet),(A0513:2-MeOCH2-azet),(A0514:2-HO2CCH2-azet),(A0515:2-H2NOCCH2-azet),(A0516:2-(cyano-CH2)-azet),(A0517:2-HO(CH2)2-azet),(A0518:2-MeO(CH2)2-azet),(A0519:2-HO2C(CH2)2-azet),(A0520:2-H2NOC(CH2)2-azet),(A0521:2-(cyano-(CH2)2)-azet),(A0522:3-HO-azet),(A0523:3-MeO-azet),(A0524:3-HO2C-azet),(A0525:3-H2NOC-azet),(A0526:3-cyano-azet),(A0527:3-MeHNOC-azet),(A0528:3-Me2NOC-azet),(A0529:3-(MeO(CH2)2-(HNOC))-azet),(A0530:3-(MeO(CH2)3-(HNOC))-azet),(A0531:3-(mor-OC)-azet),(A0532:3-F3C-azet),(A0533:3-F-azet),(A0534:3-oxo-azet),(A0535:3-H2NO2S-azet),(A0536:3-HO3S-azet),(A0537:3-ttrz-azet),(A0538:3-HOCH2-azet),(A0539:3-MeOCH2-azet),(A0540:3-HO2CCH2-azet), |
(表26续)
(A0541:3-H2NOCCH2-azet),(A0542:3-(cyano-CH2)-azet),(A0543:3-HO(CH2)2-azet),(A0544:3-MeO(CH2)2-azet),(A0545:3-HO2C(CH2)2-azet),(A0546:3-H2NOC(CH2)2-azet),(A0547:3-(cyano-(CH2)2)-azet),(A0548:3-HO2CCH2O-azet),(A0549:3-H2NOCCH2O-azet),(A0550:2-HO2C-pyrr),(A0551:2-H2NOC-pyrr),(A0552:2-cyano-pyrr),(A0553:2-MeHNOC-pyrr),(A0554:2-Me2NOC-pyrr),(A0555:2-(MeO(CH2)2-(HNOC))-pyrr),(A0556:2-(MeO(CH2)3-(HNOC))-pyrr),(A0557:2-(mor-OC)-pyrr),(A0558:2-F3C-pyrr),(A0559:2-oxo-pyrr),(A0560:2-H2NO2S-pyrr),(A0561:2-HO3S-pyrr),(A0562:2-ttrz-pyrr),(A0563:2-HOCH2-pyrr),(A0564:2-MeOCH2-pyrr),(A0565:2-HO2CCH2-pyrr),(A0566:2-H2NOCCH2-pyrr),(A0567:2-(cyano-CH2)-pyrr),(A0568:3-HO-pyrr),(A0569:3-MeO-pyrr),(A0570:3-HO2C-pyrr),(A0571:3-H2NOC-pyrr),(A0572:3-cyano-pyrr),(A0573:3-MeHNOC-pyrr),(A0574:3-Me2NOC-pyrr),(A0575:3-(MeO(CH2)2-(HNOC))-pyrr),(A0576:3-(MeO(CH2)3-(HNOC))-pyrr),(A0577:3-(mor-OC)-pyrr),(A0578:3-F3C-pyrr),(A0579:3-F-pyrr),(A0580:3-oxo-pyrr),(A0581:3-H2NO2S-pyrr),(A0582:3-HO3S-pyrr),(A0583:3-ttrz-pyrr),(A0584:3-HOCH2-pyrr),(A0585:3-MeOCH2-pyrr),(A0586:3-HO2CCH2-pyrr),(A0587:3-H2NOCCH2-pyrr),(A0588:3-(cyano-CH2)-pyrr),(A0589:3-HO2CCH2O-pyrr),(A0590:3-H2NOCCH2O-pyrr),(A0591:2-HO2C-pipe),(A0592:2-H2NOC-pipe),(A0593:2-cyano-pipe),(A0594:2-MeHNOC-pipe),(A0595:2-Me2NOC-pipe),(A0596:2-(MeO(CH2)2-(HNOC))-pipe),(A0597:2-(MeO(CH2)3-(HNOC))-pipe),(A0598:2-(mor-OC)-pipe),(A0599:2-F3C-pipe),(A0600:2-oxo-pipe),(A0601:2-H2NO2S-pipe),(A0602:2-HO3S-pipe),(A0603:2-ttrz-pipe),(A0604:2-HOCH2-pipe),(A0605:2-MeOCH2-pipe),(A0606:2-HO2CCH2-pipe),(A0607:2-H2NOCCH2-pipe),(A0608:2-(cyano-CH2)-pipe),(A0609:2-HO(CH2)2-pipe),(A0610:3-HO-pipe),(A0611:3-MeO-pipe),(A0612:3-HO2C-pipe),(A0613:3-H2NOC-pipe),(A0614:3-cyano-pipe),(A0615:3-MeHNOC-pipe),(A0616:3-Me2NOC-pipe),(A0617:3-(MeO(CH2)2-(HNOC))-pipe),(A0618:3-(MeO(CH2)3-(HNOC))-pipe),(A0619:3-(mor-OC)-pipe),(A0620:3-F3C-pipe),(A0621:3-F-pipe),(A0622:3-oxo-pipe),(A0623:3-H2NO2S-pipe),(A0624:3-HO3S-pipe),(A0625:3-ttrz-pipe),(A0626:3-HOCH2-pipe),(A0627:3-MeOCH2-pipe),(A0628:3-HO2CCH2-pipe),(A0629:3-H2NOCCH2-pipe),(A0630:3-(cyano-CH2)-pipe),(A0631:3-HO2CCH2O-pipe),(A0632:3-H2NOCCH2O-pipe),(A0633:4-HO-pipe),(A0634:4-MeO-pipe),(A0635:4-HO2C-pipe),(A0636:4-H2NOC-pipe),(A0637:4-cyano-pipe),(A0638:4-MeHNOC-pipe),(A0639:4-Me2NOC-pipe),(A0640:4-(MeO(CH2)2-(HNOC))-pipe),(A0641:4-(MeO(CH2)3-(HNOC))-pipe),(A0642:4-(mor-OC)-pipe),(A0643:4-F3C-pipe),(A0644:4-F-pipe),(A0645:4-oxo-pipe),(A0646:4-H2NO2S-pipe),(A0647:4-HO3S-pipe),(A0648:4-ttrz-pipe),(A0649:4-HOCH2-pipe),(A0650:4-MeOCH2-pipe),(A0651:4-HO2CCH2-pipe),(A0652:4-H2NOCCH2-pipe),(A0653:4-(cyano-CH2)-pipe),(A0654:4-HO2CCH2O-pipe),(A0655:4-H2NOCCH2O-pipe),(A0656:2-HO2C-pipa),(A0657:2-H2NOC-pipa),(A0658:2-cyano-pipa),(A0659:2-MeHNOC-pipa),(A0660:2-Me2NOC-pipa), |
(表26续)
(A0661:2-(MeO(CH2)2-(HNOC))-pipa),(A0662:2-(MeO(CH2)3-(HNOC))-pipa),(A0663:2-(mor-OC)-pipa),(A0664:2-F3C-pipa),(A0665:2-oxo-pipa),(A0666:2-H2NO2S-pipa),(A0667:2-HO3S-pipa),(A0668:2-ttrz-pipa),(A0669:2-HOCH2-pipa),(A0670:2-MeOCH2-pipa),(A0671:2-HO2CCH2-pipa),(A0672:2-H2NOCCH2-pipa),(A0673:2-(cyano-CH2)-pipa),(A0674:3-HO2C-pipa),(A0675:3-H2NOC-pipa),(A0676:3-cyano-pipa),(A0677:3-MeHNOC-pipa),(A0678:3-Me2NOC-pipa),(A0679:3-(MeO(CH2)2-(HNOC))-pipa),(A0680:3-(MeO(CH2)3-(HNOC))-pipa),(A0681:3-(mor-OC)-pipa),(A0682:3-F3C-pipa),(A0683:3-oxo-pipa),(A0684:3-H2NO2S-pipa),(A0685:3-HO3S-pipa),(A0686:3-ttrz-pipa),(A0687:3-HOCH2-pipa),(A0688:3-MeOCH2-pipa),(A0689:3-HO2CCH2-pipa),(A0690:3-H2NOCCH2-pipa),(A0691:3-(cyano-CH2)-pipa),(A0692:4-H2NOC-pipa),(A0693:4-MeHNOC-pipa),(A0694:4-Me2NOC-pipa),(A0695:4-(MeO(CH2)2-(HNOC))-pipa),(A0696:4-(MeO(CH2)3-(HNOC))-pipa),(A0697:4-(mor-OC)-pipa),(A0698:4-F3C-pipa),(A0699:4-H2NO2S-pipa),(A0700:4-EtO2C-pipa),(A0701:4-HO2CCH2-pipa),(A0702:4-H2NOCCH2-pipa),(A0703:4-(cyano-CH2)-pipa),(A0704:2-HO2C-mor),(A0705:2-H2NOC-mor),(A0706:2-cyano-mor),(A0707:2-MeHNOC-mor),(A0708:2-Me2NOC-mor),(A0709:2-(MeO(CH2)2-(HNOC))-mor),(A0710:2-(MeO(CH2)3-(HNOC))-mor),(A0711:2-(mor-OC)-mor),(A0712:2-F3C-mor),(A0713:2-oxo-mor),(A0714:2-H2NO2S-mor),(A0715:2-HO3S-mor),(A0716:2-ttrz-mor),(A0717:2-HOCH2-mor),(A0718:2-MeOCH2-mor),(A0719:2-HO2CCH2-mor),(A0720:2-H2NOCCH2-mor),(A0721:2-(cyano-CH2)-mor),(A0722:3-HO2C-mor),(A0723:3-H2NOC-mor),(A0724:3-cyano-mor),(A0725:3-MeHNOC-mor),(A0726:3-Me2NOC-mor),(A0727:3-(MeO(CH2)2-(HNOC))-mor),(A0728:3-(MeO(CH2)3-(HNOC))-mor),(A0729:3-(mor-OC)-mor),(A0730:3-F3C-mor),(A0731:3-oxo-mor),(A0732:3-H2NO2S-mor),(A0733:3-HO3S-mor),(A0734:3-ttrz-mor),(A0735:3-HOCH2-mor),(A0736:3-MeOCH2-mor),(A0737:3-HO2CCH2-mor),(A0738:3-H2NOCCH2-mor),(A0739:3-(cyano-CH2)-mor),(A0740:2-HO2C-tmor),(A0741:2-H2NOC-tmor),(A0742:2-cyano-tmor),(A0743:2-MeHNOC-tmor),(A0744:2-Me2NOC-tmor),(A0745:2-(MeO(CH2)2-(HNOC))-tmor),(A0746:2-(MeO(CH2)3-(HNOC))-tmor),(A0747:2-(mor-OC)-tmor),(A0748:2-F3C-tmor),(A0749:2-oxo-tmor),(A0750:2-H2NO2S-tmor),(A0751:2-HO3S-tmor),(A0752:2-ttrz-tmor),(A0753:2-HOCH2-tmor),(A0754:2-MeOCH2-tmor),(A0755:2-HO2CCH2-tmor),(A0756:2-H2NOCCH2-tmor),(A0757:2-(cyano-CH2)-tmor),(A0758:3-HO2C-tmor),(A0759:3-H2NOC-tmor),(A0760:3-cyano-tmor),(A0761:3-MeHNOC-tmor),(A0762:3-Me2NOC-tmor),(A0763:3-(MeO(CH2)2-(HNOC))-tmor),(A0764:3-(MeO(CH2)3-(HNOC))-tmor),(A0765:3-(mor-OC)-tmor),(A0766:3-F3C-tmor),(A0767:3-oxo-tmor),(A0768:3-H2NO2S-tmor),(A0769:3-HO3S-tmor),(A0770:3-ttrz-tmor),(A0771:3-HOCH2-tmor),(A0772:3-MeOCH2-tmor),(A0773:3-HO2CCH2-tmor),(A0774:3-H2NOCCH2-tmor),(A0775:3-(cyano-CH2)-tmor),(A0776:1-oxido-tmor),(A0777:1,1-dioxido-tmor),(A0778:4-HO-cHex), |
(表26续)
(A0779:4-MeO-cHex),(A0780:4-HO2C-cHex),(A0781:4-H2NOC-cHex),(A0782:4-cyano-cHex),(A0783:4-MeHNOC-cHex),(A0784:4-Me2NOC-cHex),(A0785:4-(MeO(CH2)2-(HNOC))-cHex),(A0786:4-(MeO(CH2)3-(HNOC))-cHex),(A0787:4-(mor-OC)-cHex),(A0788:4-F3C-cHex),(A0789:4-F-cHex),(A0790:4-oxo-cHex),(A0791:4-H2NO2S-cHex),(A0792:4-HO3S-cHex),(A0793:4-ttrz-cHex),(A0794:4-HOCH2-cHex),(A0795:4-MeOCH2-cHex),(A0796:4-HO2CCH2-cHex),(A0797:4-H2NOCCH2-cHex),(A0798:4-(cyano-CH2)-cHex),(A0799:4-HO2CCH2O-cHex),(A0800:4-H2NOCCH2O-cHex),(A0801:1-H2NOC-piperidin-4-yl),(A0802:1-MeHNOC-piperidin-4-yl),(A0803:1-Me2NOC-piperidin-4-yl),(A0804:1-(MeO(CH2)2-(HNOC))-piperidin-4-yl),(A0805:1-(MeO(CH2)3-(HNOC))-piperidin-4-yl),(A0806:1-(mor-OC)-piperidin-4-yl),(A0807:1-F3C-piperidin-4-yl),(A0808:1-H2NO2S-piperidin-4-yl),(A0809:1-EtO2C-piperi din-4-yl),(A0810:1-HO2CCH2-pipe ridin-4-yl),(A0811:1-H2NOCCH2-piperidin-4-yl),(A0812:1-(cyano-CH2)-piperidin-4-yl),(A0813:2-HO2C-4-HO-pipe),(A0814:2-H2NOC-4-HO-pipe),(A0815:2-cyano-4-HO-pipe),(A0816:2-HOCH2-4-HO-pipe),(A0817:3-HO-4-HO-pipe),(A0818:3-MeO-4-HO-pipe),(A0819:3-HO2C-4-HO-pipe),(A0820:3-H2NOC-4-HO-pipe),(A0821:3-cyano-4-HO-pipe),(A0822:3-HOCH2-4-HO-pipe),(A0823:4-HO-4-HO-pipe),(A0824:4-MeO-4-HO-pipe),(A0825:4-HO2C-4-HO-pipe),(A0826:4-H2NOC-4-HO-pipe),(A0827:4-cyano-4-HO-pipe),(A0828:2-HO2C-4-MeO-pipe),(A0829:2-H2NOC-4-MeO-pipe),(A0830:2-cyano-4-MeO-pipe),(A0831:2-HOCH2-4-MeO-pipe),(A0832:3-HO-4-MeO-pipe),(A0833:3-MeO-4-MeO-pipe),(A0834:3-HO2C-4-MeO-pipe),(A0835:3-H2NOC-4-MeO-pipe),(A0836:3-cyano-4-MeO-pipe),(A0837:3-HOCH2-4-MeO-pipe),(A0838:4-HO-4-MeO-pipe),(A0839:4-MeO-4-MeO-pipe),(A0840:4-HO2C-4-MeO-pipe),(A0841:4-H2NOC-4-MeO-pipe),(A0842:4-cyano-4-MeO-pipe),(A0843:2-HO2C-4-HO2C-pipe),(A0844:2-H2NOC-4-HO2C-pipe),(A0845:2-cyano-4-HO2C-pipe),(A0846:2-HOCH2-4-HO2C-pipe),(A0847:3-HO-4-HO2C-pipe),(A0848:3-MeO-4-HO2C-pipe),(A0849:3-HO2C-4-HO2C-pipe),(A0850:3-H2NOC-4-HO2C-pipe),(A0851:3-cyano-4-HO2C-pipe),(A0852:3-HOCH2-4-HO2C-pipe),(A0853:4-HO-4-HO2C-pipe),(A0854:4-MeO-4-HO2C-pipe),(A0855:4-HO2C-4-HO2C-pipe),(A0856:4-H2NOC-4-HO2C-pipe),(A0857:4-cyano-4-HO2C-pipe),(A0858:2-HO2C-4-H2NOC-pipe),(A0859:2-H2NOC-4-H2NOC-pipe),(A0860:2-cyano-4-H2NOC-pipe),(A0861:2-HOCH2-4-H2NOC-pipe),(A0862:3-HO-4-H2NOC-pipe),(A0863:3-MeO-4-H2NOC-pipe),(A0864:3-HO2C-4-H2NOC-pipe),(A0865:3-H2NOC-4-H2NOC-pipe),(A0866:3-cyano-4-H2NOC-pipe),(A0867:3-HOCH2-4-H2NOC-pipe),(A0868:4-HO-4-H2NOC-pipe),(A0869:4-MeO-4-H2NOC-pipe),(A0870:4-HO2C-4-H2NOC-pipe),(A0871:4-H2NOC-4-H2NOC-pipe),(A0872:4-cyano-4-H2NOC-pipe),(A0873:2-HO2C-4-cyano-pipe),(A0874:2-H2NOC-4-cyano-pipe),(A0875:2-cyano-4-cyano-pipe),(A0876:2-HOCH2-4-cyano-pipe),(A0877:3-HO-4-cyano-pipe),(A0878:3-MeO-4-cyano-pipe), |
(表26续)
(A0879:3-HO2C-4-cyano-pipe),(A0880:3-H2NOC-4-cyano-pipe),(A0881:3-cyano-4-cyano-pipe),(A0882:3-HOCH2-4-cyano-pipe),(A0883:4-HO-4-cyano-pipe),(A0884:4-MeO-4-cyano-pipe),(A0885:4-HO2C-4-cyano-pipe),(A0886:4-H2NOC-4-cyano-pipe),(A0887:4-cyano-4-cyano-pipe),(A0888:2-HO2C-4-(HOCH2)-pipe),(A0889:2-H2NOC-4-(HOCH2)-pipe),(A0890:2-cyano-4-(HOCH2)-pipe),(A0891:2-HOCH2-4-(HOCH2)-pipe),(A0892:3-HO-4-(HOCH2)-pipe),(A0893:3-MeO-4-(HOCH2)-pipe),(A0894:3-HO2C-4-(HOCH2)-pipe),(A0895:3-H2NOC-4-(HOCH2)-pipe),(A0896:3-cyano-4-(HOCH2)-pipe),(A0897:3-HOCH2-4-(HOCH2)-pipe),(A0898:4-HO-4-(HOCH2)-pipe),(A0899:4-MeO-4-(HOCH2)-pipe),(A0900:4-HO2C-4-(HOCH2)-pipe),(A0901:4-H2NOC-4-(HOCH2)-pipe),(A0902:4-cyano-4-(HOCH2)-pipe),(A0903:2-HO2C-4-HO-pyrr),(A0904:2-H2NOC-4-HO-pyrr),(A0905:2-cyano-4-HO-pyrr),(A0906:2-HOCH2-4-HO-pyrr),(A0907:3-HO-4-HO-pyrr),(A0908:3-MeO-4-HO-pyrr),(A0909:3-HO2C-4-HO-pyrr),(A091O:3-H2NOC-4-HO-pyrr),(A0911:3-cyano-4-HO-pyrr),(A0912:3-HOCH2-4-HO-pyrr),(A0913:2-HO2C-4-MeO-pyrr),(A0914:2-H2NOC-4-MeO-pyrr),(A0915:2-cyano-4-MeO-pyrr),(A0916:2-HOCH2-4-MeO-pyrr),(A0917:3-HO-4-MeO-pyrr),(A0918:3-MeO-4-MeO-pyrr),(A0919:3-HO2C-4-MeO-pyrr),(A0920:3-H2NOC-4-MeO-pyrr),(A0921:3-cyano-4-MeO-pyrr),(A0922:3-HOCH2-4-MeO-pyrr),(A0923:2-HO2C-4-HO2C-pyrr),(A0924:2-H2NOC-4-HO2C-pyrr),(A0925:2-cyano-4-HO2C-pyrr),(A0926:2-HOCH2-4-HO2C-pyrr),(A0927:3-HO-4-HO2C-pyrr),(A0928:3-MeO-4-HO2C-pyrr),(A0929:3-HO2C-4-HO2C-pyrr),(A0930:3-H2NOC-4-HO2C-pyrr),(A0931:3-cyano-4-HO2C-pyrr),(A0932:3-HOCH2-4-HO2C-pyrr),(A0933:2-HO2C-4-H2NOC-pyrr),(A0934:2-H2NOC-4-H2NOC-pyrr),(A0935:2-cyano-4-H2NOC-pyrr),(A0936:2-HOCH2-4-H2NOC-pyrr),(A0937:3-HO-4-H2NOC-pyrr),(A0938:3-MeO-4-H2NOC-pyrr),(A0939:3-HO2C-4-H2NOC-pyrr),(A0940:3-H2NOC-4-H2NOC-pyrr),(A0941:3-cyano-4-H2NOC-pyrr),(A0942:3-HOCH2-4-H2NOC-pyrr),(A0943:2-HO2C-4-cyano-pyrr),(A0944:2-H2NOC-4-cyano-pyrr),(A0945:2-cyano-4-cyano-pyrr),(A0946:2-HOCH2-4-cyano-pyrr),(A0947:3-HO-4-cyano-pyrr),(A0948:3-MeO-4-cyano-pyrr),(A0949:3-HO2C-4-cyano-pyrr),(A0950:3-H2NOC-4-cyano-pyrr),(A0951:3-cyano-4-cyano-pyrr),(A0952:3-HOCH2-4-cyano-pyrr),(A0953:2-HO2C-4-(HOCH2)-pyrr),(A0954:2-H2NOC-4-(HOCH2)-pyrr),(A0955:2-cyano-4-(HOCH2)-pyrr),(A0956:2-HOCH2-4-(HOCH2)-pyrr),(A0957:3-HO-4-(HOCH2)-pyrr),(A0958:3-MeO-4-(HOCH2)-pyrr),(A0959:3-HO2C-4-(HOCH2)-pyrr),(A0960:3-H2NOC-4-(HOCH2)-pyrr),(A0961:3-cyano-4-(HOCH2)-pyrr),(A0962:3-HOCH2-4-(HOCH2)-pyrr),(A0963:2-HO2C-3-HO-pyrr),(A0964:2-H2NOC-3-HO-pyrr),(A0965:2-cyano-3-HO-pyrr),(A0966:2-HOCH2-3-HO-pyrr),(A0967:3-HO-3-HO-pyrr),(A0968:3-MeO-3-HO-pyrr),(A0969:3-HO2C-3-HO-pyrr),(A0970:3-H2NOC-3-HO-pyrr),(A0971:3-cyano-3-HO-pyrr),(A0972:2-HO2C-3-MeO-pyrr),(A0973:2-H2NOC-3-MeO-pyrr),(A0974:2-cyano-3-MeO-pyrr),(A0975:2-HOCH2-3-MeO-pyrr), |
(表26续)
(A0976:3-HO-3-MeO-pyrr),(A0977:3-MeO-3-MeO-pyrr),(A0978:3-HO2C-3-MeO-pyrr),(A0979:3-H2NOC-3-MeO-pyrr),(A0980:3-cyano-3-MeO-pyrr),(A0981:2-HO2C-3-HO2C-pyrr),(A0982:2-H2NOC-3-HO2C-pyrr),(A0983:2-cyano-3-HO2C-pyrr),(A0984:2-HOCH2-3-HO2C-pyrr),(A0985:3-HO-3-HO2C-pyrr),(A0986:3-MeO-3-HO2C-pyrr),(A0987:3-HO2C-3-HO2C-pyrr),(A0988:3-H2NOC-3-HO2C-pyrr),(A0989:3-cyano-3-HO2C-pyrr),(A0990:2-HO2C-3-H2NOC-pyrr),(A0991:2-H2NOC-3-H2NOC-pyrr),(A0992:2-cyano-3-H2NOC-pyrr),(A0993:2-HOCH2-3-H2NOC-pyrr),(A0994:3-HO-3-H2NOC-pyrr),(A0995:3-MeO-3-H2NOC-pyrr),(A0996:3-HO2C-3-H2NOC-pyrr),(A0997:3-H2NOC-3-H2NOC-pyrr),(A0998:3-cyano-3-H2NOC-pyrr),(A0999:2-HO2C-3-cyano-pyrr),(A1000:2-H2NOC-3-cyano-pyrr),(A1001:2-cyaro-3-cyano-pyrr),(A1002:2-HOCH2-3-cyano-pyrr),(A1003:3-HO-3-cyano-pyrr),(A1004:3-MeO-3-cyano-pyrr),(A1005:3-HO2C-3-cyano-pyrr),(A1006:3-H2NOC-3-cyano-pyrr),(A1007:3-cyano-3-cyano-pyrr),(A1008:2-HO2C-3-(HOCH2)-pyrr),(A1009:2-H2NOC-3-(HOCH2)-pyrr),(A1010:2-cyano-3-(HOCH2)-pyrr),(A1011:2-HOCH2-3-(HOCH2)-pyrr),(A1012:3-HO-3-(HOCH2)-pyrr),(A1013:3-MeO-3-(HOCH2)-pyrr),(A1014:3-HO2C-3-(HOCH2)-pyrr),(A1015:3-H2NOC-3-(HOCH2)-pyrr),(A1016:3-cyano-3-(HOCH2)-pyrr),(A1017:8-azaspiro[4,5]dec-8-yl),(A1018:1-oxa-8-azaspiro[4,5]dec-8-yl),(A1019:2’-oxo-(piperidine-4-spiro-3’-pyrrolidine)-1-yl),(A1020:1’-methyl-2’-oxo-(piperidine-4-spiro-3’-pyrrolidine)-1-yl),(A1021:1-phenyl-4-oxo-1,3,8-t riazaspiro[4.5]dec-8-yl),(A1022:(piperidine-4-spiro-5’-hydantoin)-1-yl),(A1023:(1,3-dihydroisobenzofuran-1-spiro-4’-pipe ridin)-1’-yl),(A1024:3-oxo-(1,3-dihydroisobenzofuran-1-spiro-4’-pipe ridin)-1’-yl). |
(表27)
(No:RN,RO,RP)=(A1025:H,HO,H),(A1026:H,HO-(CH2)2-O,H),(A1027:H,HO-(CH2)3-O,H),(A1028:H,4-HO-pipe,H),(A1029:H,3-HO-pyrr,H),(A1030:H,4-HO2C-pipe,H),(A1031:H,4-(cyano)-pipe,H),(A1032:H,4-Ac-pipa,H),(A1033:H,3-oxo-pipa,H),(A1034:F,HO,H),(A1035:F,HO-(CH2)2-O,H),(A1036:F,HO-(CH2)3-O,H),(A1037:F,4-HO-pipe,H),(A1038:F,3-HO-pyrr,H),(A1039:F,4-HO2C-pipe,H),(A1040:F,4-(cyano)-pipe,H),(A1041:F,4-Ac-pipa,H),(A1042:F,3-oxo-pipa,H),(A1043:F,HO,F),(A1044:F,HO-(CH2)2-O,F),(A1045:F,HO-(CH2)3-O,F),(A1046:F,4-HO-pipe,F),(A1047:F,3-HO-pyrr,F), |
(表27续)
(A1048:F,4-HO2C-pipe,F),(A1049:F,4-(cyano)-pipe,F),(A1050:F,4-Ac-pipa,F),(A1051:F,3-oxo-pipa,F),(A1052:F,HO,Cl),(A1053:F,HO-(CH2)2-O,Cl),(A1054:F,HO-(CH2)3-O,Cl),(A1055:F,4-HO-pipe,Cl),(A1056:F,3-HO-pyrr,Cl),(A1057:F,4-HO2C-pipe,Cl),(A1058:F,4-(cyano)-pipe,Cl),(A1059:F,4-Ac-pipa,Cl),(A1060:F,3-oxo-pipa,Cl),(A1061:F,HO,Br),(A1062:F,HO-(CH2)2-O,Br),(A1063:F,HO-(CH2)3-O,Br),(A1064:F,4-HO-pipe,Br),(A1065:F,3-HO-pyrr,Br),(A1066:F,4-HO2C-pipe,Br),(A1067:F,4-(cyano)-pipe,Br),(A1068:F,4-Ac-pipa,Br),(A1069:F,3-oxo-pipa,Br),(A1070:F,HO,Me),(A1071:F,HO-(CH2)2-O,Me),(A1072:F,HO-(CH2)3-O,Me),(A1073:F,4-HO-pipe,Me),(A1074:F,3-HO-pyrr,Me),(A1075:F,4-HO2C-pipe,Me),(A1076:F,4-(cyano)-pipe,Me),(A1077:F,4-Ac-pipa,Me),(A1078:F,3-oxo-pipa,Me),(A1079:F,HO,HO),(A1080:F,HO-(CH2)2-O,HO),(A1081:F,HO-(CH2)3-O,HO),(A1082:F,4-HO-pipe,HO),(A1083:F,3-HO-pyrr,HO),(A1084:F,4-HO2C-pipe,HO),(A1085:F,4-(cyano)-pipe,HO),(A1086:F,4-Ac-pipa,HO),(A1087:F,3-oxo-pipa,HO),(A1088:F,HO,MeO),(A1089:F,HO-(CH2)2-O,MeO),(A1090:F,HO-(CH2)3-O,MeO),(A1091:F,4-HO-pipe,MeO),(A1092:F,3-HO-pyrr,MeO),(A1093:F,4-HO2C-pipe,MeO),(A1094:F,4-(cyano)-pipe,MeO),(A1095:F,4-Ac-pipa,MeO),(A1096:F,3-oxo-pipa,MeO),(A1097:Cl,HO,Cl),(A1098:Cl,HO-(CH2)2-O,Cl),(A1099:Cl,HO-(CH2)3-O,Cl),(A1100:Cl,4-HO-pipe,Cl),(A1101:Cl,3-HO-pyrr,Cl),(A1102:Cl,4-HO2C-pipe,Cl),(A1103:Cl,4-(cyano)-pipe,Cl),(A1104:Cl,4-Ac-pipa,Cl),(A1105:Cl,3-oxo-pipa,Cl),(A1106:Cl,HO,Br),(A1107:Cl,HO-(CH2)2-O,Br),(A1108:Cl,HO-(CH2)3-O,Br),(A1109:Cl,4-HO-pipe,Br),(A1110:Cl,3-HO-pyrr,Br),(A1111:Cl,4-HO2C-pipe,Br),(A1112:Cl,4-(cyano)-pipe,Br),(A1113:Cl,4-Ac-pipa,Br),(A1114:Cl,3-oxo-pipa,Br),(A1115:Cl,HO,Me),(A1116:Cl,HO-(CH2)2-O,Me),(A1117:Cl,HO-(CH2)3-O,Me),(A1118:Cl,4-HO-pipe,Me),(A1119:Cl,3-HO-py rr,Me),(A1120:Cl,4-HO2C-pipe,Me),(A1121:Cl,4-(cyano)-pipe,Me),(A1122:Cl,4-Ac-pipa,Me),(A1123:Cl,3-oxo-pipa,Me),(A1124:Cl,HO,HO),(A1125:Cl,HO-(CH2)2-O,HO),(A1126:Cl,HO-(CH2)3-O,HO),(A1127:Cl,4-HO-pipe,HO),(A1128:Cl,3-HO-pyrr,HO),(A1129:Cl,4-HO2C-pipe,HO),(A1130:Cl,4-(cyano)-pipe,HO),(A1131:Cl,4-Ac-pipa,HO),(A1132:Cl,3-oxo-pipa,HO),(A1133:Cl,HO,MeO),(A1134:Cl,HO-(CH2)2-O,MeO),(A1135:Cl,HO-(CH2)3-O,MeO),(A1136:Cl,4-HO-pipe,MeO),(A1137:Cl,3-HO-pyrr,MeO),(A1138:Cl,4-HO2C-pipe,MeO),(A1139:Cl,4-(cyano)-pipe,MeO),(A1140:Cl,4-Ac-pipa,MeO),(A1141:Cl,3-oxo-pipa,MeO),(A1142:Br,HO,H),(A1143:Br,HO-(CH2)2-O,H),(A1144:Br,HO-(CH2)3-O,H),(A1145:Br,4-HO-pipe,H),(A1146:Br,3-HO-pyrr,H),(A1147:Br,4-HO2C-pipe,H),(A1148:Br,4-(cyano)-pipe,H),(A1149:Br,4-Ac-pipa,H),(A1150:Br,3-oxo-pipa,H),(A1151:Me,HO,H),(A1152:Me,HO-(CH2)2-O,H),(A1153:Me,HO-(CH2)3-O,H),(A1154:Me,4-HO-pipe,H),(A1155:Me,3-HO-pyrr,H),(A1156:Me,4-HO2C-pipe,H),(A1157:Me,4-(cyano)-pipe,H),(A1158:Me,4-Ac-pipa,H),(A1159:Me,3-oxo-pipa,H),(A1160:HO,HO,H),(A1161:HO,HO-(CH2)2-O,H),(A1162:HO,HO-(CH2)3-O,H),(A1163:HO,4-HO-pipe,H),(A1164:HO,3-HO-pyrr,H), |
(表27续)
(A1165:HO,4-HO2C-pipe,H),(A1166:HO,4-(cyano)-pipe,H),(A1167:HO,4-Ac-pipa,H),(A1168:HO,3-oxo-pipa,H),(A1169:MeO,HO,H),(A1170:MeO,HO-(CH2)2-O,H),(A1171:MeO,HO-(CH2)3-O,H),(A1172:MeO,4-HO-pipe,H),(A1173:MeO,3-HO-py rr,H),(A1174:MeO,4-HO2C-pipe,H),(A1175:MeO,4-(cyano)-pipe,H),(A1176:MeO,4-Ac-pipa,H),(A1177:MeO,3-oxo-pipa,H),(A1178:H,H,HO),(A1179:H,H,HO-(CH2)2-O),(A1180:H,H,HO-(CH2)3-O),(A1181:H,H,4-HO-pipe),(A1182:H,H,3-HO-pyrr),(A1183:H,H,4-HO2C-pipe),(A1184:H,H,4-(cyano)-pipe),(A1185:H,H,4-Ac-pipa),(A1186:H,H,3-oxo-pipa),(A1187:F,H,HO),(A1188:F,H,HO-(CH2)2-O),(A1189:F,H,HO-(CH2)3-O),(A1190:F,H,4-HO-pipe),(A1191:F,H,3-HO-pyrr),(A1192:F,H,4-HO2C-pipe),(A1193:F,H,4-(cyano)-pipe),(A1194:F,H,4-Ac-pipa),(A1195:F,H,3-oxo-pipa),(A1196:Cl,H,HO),(A1197:Cl,H,HO-(CH2)2-O),(A1198:Cl,H,HO-(CH2)3-O),(A1199:Cl,H,4-HO-pipe),(A1200:Cl,H,3-HO-pyrr),(A1201:Cl,H,4-HO2C-pipe),(A1202:Cl,H,4-(cyano)-pipe),(A1203:Cl,H,4-Ac-pipa),(A1204:Cl,H,3-oxo-pipa),(A1205:Br,H,HO),(A1206:Br,H,HO-(CH2)2-O),(A1207:Br,H,HO-(CH2)3-O),(A1208:Br,H,4-HO-pipe),(A1209:Br,H,3-HO-pyrr),(A1210:Br,H,4-HO2C-pipe),(A1211:Br,H,4-(cyano)-pipe),(A1212:Br,H,4-Ac-pipa),(A1213:Br,H,3-oxo-pipa),(A1214:Me,H,HO),(A1215:Me,H,HO-(CH2)2-O),(A1216:Me,H,HO-(CH2)3-O),(A1217:Me,H,4-HO-pipe),(A1218:Me,H,3-HO-pyrr),(A1219:Me,H,4-HO2C-pipe),(A1220:Me,H,4-(cyano)-pipe),(A1221:Me,H,4-Ac-pipa),(A1222:Me,H,3-oxo-pipa),(A1223:HO,H,HO),(A1224:HO,H,HO-(CH2)2-O),(A1225:HO,H,HO-(CH2)3-O),(A1226:HO,H,4-HO-pipe),(A1227:HO,H,3-HO-pyrr),(A1228:HO,H,4-HO2C-pipe),(A1229:HO,H,4-(cyano)-pipe),(A1230:HO,H,4-Ac-pipa),(A1231:HO,H,3-oxo-pipa),(A1232:MeO,H,HO),(A1233:MeO,H,HO-(CH2)2-O),(A1234:MeO,H,HO-(CH2)3-O),(A1235:MeO,H,4-HO-pipe),(A1236:MeO,H,3-HO-pyrr),(A1237:MeO,H,4-HO2C-pipe),(A1238:MeO,H,4-(cyano)-pipe),(A1239:MeO,H,4-Ac-pipa),(A1240:MeO,H,3-oxo-pipa). |
(表28)
(No:RQ,RR)=(A1241:H,HO),(A1242:H,HO-(CH2)2-O),(A1243:H,HO-(CH2)3-O),(A1244:H,4-HO-pipe),(A1245:H,3-HO-pyrr),(A1246:H,4-HO2C-pipe),(A1247:H,4-(cyano)-pipe),(A1248:H,4-Ac-pipa),(A1249:H,3-oxo-pipa),(A1250:F,HO),(A1251:F,HO-(CH2)2-O),(A1252:F,HO-(CH2)3-O),(A1253:F,4-HO-pipe),(A1254:F,3-HO-pyrr),(A1255:F,4-HO2C-pipe),(A1256:F,4-(cyano)-pipe),(A1257:F,4-Ac-pipa),(A1258:F,3-oxo-pipa),(A1259:Br,HO),(A1260:Br,HO-(CH2)2-O),(A1261:Br,HO-(CH2)3-O),(A1262:Br,4-HO-pipe),(A1263:Br,3-HO-pyrr),(A1264:Br,4-HO2C-pipe),(A1265:Br,4-(cyano)-pipe),(A1266:Br,4-Ac-pipa),(A1267:Br,3-oxo-pipa),(A1268:Me,HO),(A1269:Me,HO-(CH2)2-O),(A1270:Me,HO-(CH2)3-O),(A1271:Me,4-HO-pipe),(A1272:Me,3-HO-pyrr),(A1273:Me,4-HO2C-pipe),(A1274:Me,4-(cyano)-pipe),(A1275:Me,4-Ac-pipa),(A1276:Me,3-oxo-pipa),(A1277:HO,HO),(A1278:HO,HO-(CH2)2-O),(A1279:HO,HO-(CH2)3-O),(A1280:HO,4-HO-pipe),(A1281:HO,3-HO-pyrr),(A1282:HO,4-HO2C-pipe),(A1283:HO,4-(cyano)-pipe),(A1284:HO,4-Ac-pipa),(A1285:HO,3-oxo-pipa),(A1286:MeO,HO),(A1287:MeO,HO-(CH2)2-O),(A1288:MeO,HO-(CH2)3-O),(A1289:MeO,4-HO-pipe),(A1290:MeO,3-HO-pyrr),(A1291:MeO,4-HO2C-pipe),(A1292:MeO,4-(cyano)-pipe),(A1293:MeO,4-Ac-pipa),(A1294:MeO,3-oxo-pipa),(A1295:HO,H),(A1296:HO-(CH2)2-O,H),(A1297:HO-(CH2)3-O,H),(A1298:4-HO-pipe,H),(A1299:3-HO-pyrr,H),(A1300:4-HO2C-pipe,H),(A1301:4-(cyano)-pipe,H),(A1302:4-Ac-pipa,H),(A1303:3-oxo-pipa,H). |
(表29)
(No:RS,RT)=(A1304:H,H),(A1305:H,HO-(CH2)2-O),(A1306:H,HO-(CH2)3-O),(A1307:H,4-HO-pipe),(A1308:H,3-HO-pyrr),(A1309:H,4-HO2C-pipe),(A1310:H,4-(cyano)-pipe),(A1311:H,4-Ac-pipa),(A1312:H,3-oxo-pipa),(A1313:Cl,HO-(CH2)2-O),(A1314:Cl,HO-(CH2)3-O),(A1315:Cl,4-HO-pipe),(A1316:Cl,3-HO-pyrr),(A1317:Cl,4-HO2C-pipe),(A1318:Cl,4-(cyano)-pipe),(A1319:Cl,4-Ac-pipa),(A1320:Cl,3-oxo-pipa),(A1321:Me,HO-(CH2)2-O),(A1322:Me,HO-(CH2)3-O),(A1323:Me,4-HO-pipe),(A1324:Me,3-HO-pyrr),(A1325:Me,4-HO2C-pipe),(A1326:Me,4-(cyano)-pipe),(A1327:Me,4-Ac-pipa),(A1328:Me,3-oxo-pipa),(A1329:MeO,HO-(CH2)2-O),(A1330:MeO,HO-(CH2)3-O),(A1331:MeO,4-HO-pipe),(A1332:MeO,3-HO-pyrr),(A1333:MeO,4-HO2C-pipe),(A1334:MeO,4-(cyano)-pipe),(A1335:MeO,4-Ac-pipa),(A1336:MeO,3-oxo-pipa). |
(表30)
(No:RAA,RBB)=(A1337:H,HO),(A1338:H,HO-(CH2)2-O),(A1339:H,HO-(CH2)3-O),(A1340:H,4-HO-pipe),(A1341:H,3-HO-pyrr),(A1342:H,4-HO2C-pipe),(A1343:H,4-(cyano)-pipe),(A1344:H,4-Ac-pipa),(A1345:H,3-oxo-pipa),(A1346:F,HO),(A1347:F,HO-(CH2)2-O),(A1348:F,HO-(CH2)3-O),(A1349:F,4-HO-pipe),(A1350:F,3-HO-pyrr),(A1351:F,4-HO2C-pipe),(A1352:F,4-(cyano)-pipe),(A1353:F,4-Ac-pipa),(A1354:F,3-oxo-pipa),(A1355:Cl,HO),(A1356:Cl,HO-(CH2)2-O),(A1357:Cl,HO-(CH2)3-O),(A1358:Cl,4-HO-pipe),(A1359:Cl,3-HO-pyrr),(A1360:Cl,4-HO2C-pipe),(A1361:Cl,4-(cyano)-pipe),(A1362:Cl,4-Ac-pipa),(A1363:Cl,3-oxo-pipa),(A1364:Br,HO),(A1365:Br,HO-(CH2)2-O),(A1366:Br,HO-(CH2)3-O),(A1367:Br,4-HO-pipe),(A1368:Br,3-HO-pyrr),(A1369:Br,4-HO2C-pipe),(A1370:Br,4-(cyano)-pipe),(A1371:Br,4-Ac-pipa),(A1372:Br,3-oxo-pipa), |
(表30续)
(A1373:Me,HO),(A1374:Me,HO-(CH2)2-O),(A1375:Me,HO-(CH2)3-O),(A1376:Me,4-HO-pipe),(A1377:Me,3-HO-pyrr),(A1378:Me,4-HO2C-pipe),(A1379:Me,4-(cyano)-pipe),(A1380:Me,4-Ac-pipa),(A1381:Me,3-oxo-pipa),(A1382:HO,HO),(A1383:HO,HO-(CH2)2-O),(A1384:HO,HO-(CH2)3-O),(A1385:HO,4-HO-pipe),(A1386:HO,3-HO-pyrr),(A1387:HO,4-HO2C-pipe),(A1388:HO,4-(cyano)-pipe),(A1389:HO,4-Ac-pipa),(A1390:HO,3-oxo-pipa),(A1391:MeO,HO),(A1392:MeO,HO-(CH2)2-O),(A1393:MeO,HO-(CH2)3-O),(A1394:MeO,4-HO-pipe),(A1395:MeO,3-HO-pyrr),(A1396:MeO,4-HO2C-pipe),(A1397:MeO,4-(cyano)-pipe),(A1398:MeO,4-Ac-pipa),(A1399:MeO,3-oxo-pipa). |
(表31)
(No:RCC,RDD)=(A1400:H2N,HO),(A1401:H2N,HO-(CH2)2-O),(A1402:H2N,HO-(CH2)3-O),(A1403:H2N,4-HO-pipe),(A1404:H2N,3-HO-pyrr),(A1405:H2N,4-HO2C-pipe),(A1406:H2N,4-(cyano)-pipe),(A1407:H2N,4-Ac-pipa),(A1408:H2N,3-oxo-pipa),(A1409:MeHN,HO),(A1410:MeHN,HO-(CH2)2-O),(A1411:MeHN,HO-(CH2)3-O),(A1412:MeHN,4-HO-pipe),(A1413:MeHN,3-HO-pyrr),(A1414:MeHN,4-HO2C-pipe),(A1415:MeHN,4-(cyano)-pipe),(A1416:MeHN,4-Ac-pipa),(A1417:MeHN,3-oxo-pipa),(A1418:HO,HO),(A1419:HO,HO-(CH2)2-O),(A1420:HO,HO-(CH2)3-O),(A1421:HO,4-HO-pipe),(A1422:HO,3-HO-pyrr),(A1423:HO,4-HO2C-pipe),(A1424:HO,4-(cyano)-pipe),(A1425:HO,4-Ac-pipa),(A1426:HO,3-oxo-pipa),(A1427:MeO,HO),(A1428:MeO,HO-(CH2)2-O),(A1429:MeO,HO-(CH2)3-O),(A1430:MeO,4-HO-pipe),(A1431:MeO,3-HO-pyrr),(A1432:MeO,4-HO2C-pipe),(A1433:MeO,4-(cyano)-pipe),(A1434:MeO,4-Ac-pipa),(A1435:MeO,3-oxo-pipa),(A1436:Cl,HO),(A1437:Cl,HO-(CH2)2-O),(A1438:Cl,HO-(CH2)3-O),(A1439:Cl,4-HO-pipe),(A1440:Cl,3-HO-pyrr),(A1441:Cl,4-HO2C-pipe),(A1442:Cl,4-(cyano)-pipe),(A1443:Cl,4-Ac-pipa),(A1444:Cl,3-oxo-pipa). |
(表32)
(No:REE,RFF)=(A1445:H,HO-(CH2)2),(A1446:H,HO-(CH2)3),(A1447:F,HO-(CH2)2),(A1448:F,HO-(CH2)3),(A1449:Cl,HO-(CH2)2),(A1450:Cl,HO-(CH2)3),(A1451:Me,HO-(CH2)2),(A1452:Me,HO-(CH2)3),(A1453:HO,HO-(CH2)2),(A1454:HO,HO-(CH2)3),(A1455:MeO,HO-(CH2)2),(A1456:MeO,HO-(CH2)3). |
(表33)
(No:RGG)=(A1457:5-F-2-The),(A1458:5-Cl-2-The),(A1459:5-Br-2-The),(A1460:5-Me-2-The),(A1461:5-F3C-2-The),(A1462:4-F-2-The),(A1463:4-Cl-2-The),(A1464:4-Br-2-The),(A1465:4-Me-2-The),(A1466:4-F3C-2-The),(A1467:4-F-5-Cl-2-The),(A1468:4,5-diCl-2-The),(A1469:4-Br-5-Cl-2-The),(A1470:4-Me-5-Cl-2-The),(A1471:4-F3C-5-Cl-2-The),(A1472:4-F-Ph),(A1473:4-Cl-Ph),(A1474:4-Br-Ph),(A1475:4-Me-Ph),(A1476:4-F3C-Ph),(A1477:3-F-Ph),(A1478:3-Cl-Ph),(A1479:3-Br-Ph),(A1480:3-Me-Ph),(A1481:3-F3C-Ph),(A1482:2-F-Ph),(A1483:2-Cl-Ph),(A1484:2-Br-Ph),(A1485:2-Me-Ph),(A1486:2-F3C-Ph),(A1487:3,4-diF-Ph),(A1488:3-Cl-4-F-Ph),(A1489:3-Br-4-F-Ph),(A1490:3-Me-4-F-Ph),(A1491:3-F3C-4-F-Ph),(A1492:5-Me-2-Py),(A1493:6-Me-3-Py),(A1494:4-Py),(A1495:2-pyrimidinyl),(A1496:2-Me-4-pyrimidinyl),(A1497:2-Me-5-pyrimidinyl),(A1498:4-pyridazinyl),(A1499:6-Me-3-pyridazinyl),(A1500:5-Me-2-pyrazinyl),(A1501:4-Me-2-Fur),(A1502:1-Me-3-pyrrolyl),(A1503:4-Me-2-thiazolyl),(A1504:4-Cl-2-thiazolyl),(A1505:4-F3C-2-thiazolyl),(A1506:5-Me-2-thiazolyl),(A1507:2-Me-5-thiazolyl),(A1508:5-Me-2-oxazolyl),(A1509:2-Me-5-oxazolyl),(A1510:4-Me-2-imidazolyl),(A1511:2-Me-4-imidazolyl),(A1512:1-Me-4-imidazolyl),(A1513:5-Me-3-isothiazolyl),(A1514:3-Me-5-isothiazolyl),(A1515:5-Me-3-isoxazolyl), |
(表33续)
(A1516:3-Me-5-isoxazolyl),(A1517:5-Me-3-pyrazolyl),(A1518:1-Me-4-pyrazolyl),(A1519:1-Me-3-pyrazolyl),(A1520:5-Me-1,3,4-thiadiazol-2-yl),(A1521:5-Me-1,3,4-oxadiazol-2-yl),(A1522:5-Me-1,2,4-triazol-3-yl),(A1523:1-Me-1,2,4-triazol-3-yl),(A1524:5-Me-1,2,4-thiadiazol-3-yl),(A1525:3-Me-1,2,4-thiadiazol-5-yl),(A1526:5-Me-1,2,4-oxadiazol-3-yl),(A1527:3-Me-1,2,4-oxadiazol-5-yl),(A1528:1-Me-1,2,3-triazol-4-yl). |
Claims (16)
1.血小板增多剂,其特征在于,以式(I)表示的2-酰基氨基噻唑衍生物或其制药学上允许的盐为有效成分,
式中符号具有以下含义:
Ar1:可分别被取代的芳基、单环芳香族杂环或二环系稠合杂环,
所述芳基表示C6-14的单环至3环的芳香环,
所述单环芳香族杂环表示可含有氮、氧、硫的5~6元环芳香族杂环或它们的部分被氢化的环的1价基团,
所述二环系稠合杂环表示与所述芳基或单环芳香族杂环稠合的可含有氮、氧、硫的芳香族杂环或它们的部分氢化的环的1价基团,
所述“可分别被取代的芳基、单环芳香族杂环或二环系稠合杂环”上的取代基表示i)氧代基,其仅在二环系稠合杂环中被允许),以及
ii)通式(VI)表示的基团,
-A-B-C-D-E (VI)
式中,
-A-:a)单键,或b)可被取代的环胺二基,但仅限于氮原子取代,
-B-:单键、-O-、-NH-、-N(-RZ)-、-NHCO-、-CO-、-CONH-或-CON(-RZ)-,
-C-:单键,或可分别被选自卤原子及-OH的1个以上的基团取代的C1-C6亚烷基或C2-C6亚烯基,
-D-:单键、-NHCO-、-NHSO2-、-CO-或-SO2-,
-E:-H;卤原子;-OH;-O-RZ;-O-CO-RZ;可被1个或2个RZ取代的氨基;-RZ;氰基;可分别被取代的苯基、萘基、C3-C8环烷基、上述单环芳香族杂环或二环系稠合杂环、或非芳香族杂环,
但是,作为通式(VI)表示的基团,-CH2-(非芳香族杂环)、-CH=(非芳香族杂环)除外,且该非芳香族杂环的碳原子被次甲基取代;
Ar1为可分别被取代的芳基或单环芳香族杂环时,下列基团被排除在式(VI)的范围之外:
其中的-A-及-B-为单键,-C-为单键或可分别被选自卤原子及-OH的1个以上的基团取代的亚乙基或亚乙烯基,-D-为-CO-的基团,
其中的-A-及-B-为单键,-C-为单键或可分别被选自卤原子及-OH的1个以上的基团取代的亚乙基或亚乙烯基,-D-为-SO2-,-E为可被1个或2个RZ取代的氨基的基团,
其中的-A-及-B-为单键,-C-为单键或可分别被选自卤原子及-OH的1个以上的基团取代的亚乙基或亚乙烯基,-D-为单键,-E为可分别被取代的芳基、未部分氢化的单环芳香族杂环或与未部分氢化的单环芳香族杂环稠合的环的1价基团的基团,
其中的-A-为单键,-B-为-CO-的基团,
其中的-A-、-B-、-C-及-D-为单键,-E为可分别被取代的芳基、未部分氢化的单环芳香族杂环或与未部分氢化的单环芳香族杂环稠合的环的1价基团的基团;
所述-A-中的“环胺二基,仅限于氮原子取代”中的“环胺二基”表示3~8元环芳香族或非芳香族环状胺的2价基团,当为稠合环或螺环时,其为5~15元环,所述环胺二基具有至少1个氮原子,还可具有1个以上选自氮、氧、硫的相同或不同的杂原子;
所述-A-中的“可被取代的环胺二基”及-E中的“可分别被取代的芳基、环烷基、芳香族杂环或非芳香族杂环”中的取代基表示下述(a)~(h)所示的基团及可被(a)~(g)所示的基团取代的1,1-C1-C6亚烷基:
(a)卤原子,
(b)-OH、-O-RZ、-O-苯基或-O-萘基、-OCO-RZ、=O,
(c)-SH、-S-RZ、-S-苯基或-S-萘基、-SO-RZ、-SO-苯基或-SO-萘基、-SO2-RZ、-SO2-苯基或-SO2-萘基、可被1个或2个RZ取代的氨磺酰基,
(d)可被1个或2个RZ取代的氨基、-NHCO-RZ、-NHCO-苯基或-NHCO-萘基、-NHCO2-RZ、-NHCONH2、-NHSO2-RZ、-NHSO2-苯基或-NHSO2-萘基、-NHSO2NH2、硝基,
(e)-CHO、-CO-RZ、-CO2H、-CO2-RZ、可被1个或2个RZ取代的氨基甲酰基、氰基,
(f)可被选自-OH、-O-C1-C6烷基、可被1个或2个C1-C6烷基取代的氨基、卤原子及RZ的1个以上的基团分别取代的苯基或萘基或C3-C8环烷基,
(g)可被选自-OH、-O-C1-C6烷基、可被1个或2个C1-C6烷基取代的氨基、卤原子及RZ的1个以上的基团分别取代的上述单环芳香族杂环或二环系稠合杂环或非芳香族杂环,
(h)可被选自上述(a)~(g)所示的取代基的1个以上的基团取代的C1-C6烷基,
所述RZ表示可被选自-OH、-O-C1-C6烷基、可被1个或2个C1-C6烷基取代的氨基、可被1个或2个C1-C6烷基取代的氨基甲酰基、苯基或萘基、上述单环芳香族杂环或二环系稠合杂环及卤原子的1个以上的基团取代的C1-C6烷基;
但R1为可被选自C1-C6烷基、-CO-C1-C6烷基、-COO-C1-C6烷基、-OH、-O-C1-C6烷基、-OCO-C1-C6烷基及卤原子的1个以上的基团分别取代的上述C6-14的单环至3环的芳香环或吡啶基,且R2为下式(II)表示的基团时,可被选自C1-C6烷基、-CO-C1-C6烷基、-COO-C1-C6烷基、-OH、-O-C1-C6烷基、-OCO-C1-C6烷基及卤原子的1个以上的基团分别取代的苯基或吡啶基除外,
R1:可分别被取代的芳基或单环芳香族杂环,所述“可分别被取代的芳基或单环芳香族杂环”的定义与前述Ar1中的相同,
R2:式(II)、式(III)或式(IV)表示的基团,
式中符号具有以下含义:
n:1~3的整数,
m:1~3的整数,
这里,n或m为2以上的整数时,CR20R21及CR22R23可分别表示不同的基团,
X:O、S、N-R26、C(-R27)-R28表示的基团,
E、G、J、L:分别独立地为N或C-R29表示的基团,其中至少-个表示C-R29,
R20、R21、R22、R23、R26、R27、R28、R29:可相同或不同,表示-H,-OH,-O-C1-C6烷基,可被取代的C1-C6烷基,可被取代的环烷基,可被取代的芳基,可被取代的芳基C1-C6烷基,可被取代的芳香族杂环,可被取代的芳香族杂环烷基,可被取代的非芳香族杂环,可被取代的C2-C6链烯基,可被取代的1,1-C1-C6亚烷基,-COOH,-COO-C1-C6烷基,-COO-C2-C6链烯基,-COO-C1-C6亚烷基-芳基、-COO-C1-C6亚烷基-芳香族杂环,可分别被选自C1-C6烷基及环烷基的1个以上的基团取代的氨基甲酰基或氨基,该C1-C6烷基及环烷基可分别被卤原子、-OH、-O-C1-C6烷基或-O-芳基取代,-NHCO-C1-C6烷基或氧代基,
R24、R25:可相同或不同,表示-H、可被取代的C1-C6烷基,可被取代的环烷基或可被取代的非芳香族杂环,
R20~R29中,所述环烷基表示表示C3-C8的碳环,它们可部分具有不饱和键;所述芳基、芳香族杂环、非芳香族杂环的定义与前述Ar1中的相同。
2.如权利要求1所述的医药组合物,其特征还在于,R1为可被1~3个卤原子取代的苯基或噻吩基,有2个或3个卤原子取代时,可以是相同或不同的卤原子,R2为权利要求1所述的式(II)表示的基团,n为2,m为2,X为N-R26或C(-R27)-R28表示的基团,Ar1为可分别被取代的苯基或吡啶基。
3.如权利要求1或2所述的医药组合物,其特征还在于,为血小板减少症治疗剂。
4.如权利要求1或2所述的医药组合物,其特征还在于,为c-Mpl配体。
6.如权利要求5所述的化合物,其特征还在于,Ar2为可分别被取代的苯基或单环芳香族杂环。
7.如权利要求6所述的化合物,其特征还在于,R3为可分别被取代的苯基或噻吩基,R4为权利要求1所述的式(II)表示的基团,Ar2为可分别被取代的苯基或吡啶基。
8.如权利要求7所述的化合物,其特征还在于,n为2,m为2,X为N-R26或C(-R27)-R28表示的基团。
9.如权利要求8所述的化合物,其特征还在于,R3为被1~3个卤原子取代的苯基或噻吩基,卤原子为2个或3个时,可以是相同或不同的卤原子。
10.如权利要求9所述的化合物,其特征还在于,R4为4-(哌啶-1-基)哌啶-1-基、4-丙基哌啶-1-基、4-环己基哌嗪-1-基或4-丙基哌嗪-1-基。
11.如权利要求10所述的化合物,其特征还在于,Ar2为2位及6位无取代,3位被-H、-F、-Cl或-Br取代,5位被-F、-Cl或-Br取代,4位被取代的苯基;或2位及4位无取代,5位被-F、-Cl或-Br取代,6位被取代的吡啶-3-基。
12.如权利要求11所述的化合物,其特征还在于,Ar2为可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在4位取代的苯基,或可被选自-O-RY、-NH-RY、可被取代的哌啶-1-基及可被取代的哌嗪-1-基的基团在6位取代的吡啶-3-基,其中,RY表示可被选自-OH、-O-低级烷基、可被1个或2个低级烷基取代的氨基、-CO2H、-CO2-低级烷基、可被1个或2个低级烷基取代的氨基甲酰基、氰基、芳基、芳香族杂环、非芳香族杂环及卤原子的1个以上的基团取代的低级烷基。
13.如权利要求5~12中任一项所述的化合物,为
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-3-氟-4-羟基苯甲酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
N-[4-(4-氯噻吩-2-基)-5-(4-丙基-1-哌啶基)噻唑-2-基]-2-甲氧基异烟酰胺、
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]异喹啉-6-酰胺、
3-氯-N-[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]-4-(2-羟基乙氧基)苯甲酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(3-羟基丙氧基)烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[(3-羟基丙基)氨基]烟酰胺、
1-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
1-(3-氯-5-{[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-4-(4-氰基-1-哌啶基)-3,5-二氟苯甲酰胺、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-羧酸、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]氨基甲酰}-6-氟苯基)哌啶-4-羧酸、
1-(2-氯-4-{[4-(4-氯噻吩-2-基)-5-(4-丙基哌嗪-1-基)噻唑-2-基]氨基甲酰}苯基)哌啶-4-酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-(4-羟基甲基-1-哌啶基)烟酰胺、
1-(3-氯-5-{[5-(4-环己基哌嗪-1-基)-4-(4-氟苯基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
1-(3-氯-5-{[5-(4-环己基哌嗪-1-基)-4-(3-三氟甲基苯基)噻唑-2-基]氨基甲酰}-2-吡啶基)哌啶-4-羧酸、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(2-甲氧基乙基)氨基甲酰]-1-哌啶基}烟酰胺、
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-{4-[(3-甲氧基丙基)氨基甲酰]-1-哌啶基}烟酰胺、或
5-氯-N-[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)噻唑-2-基]-6-[4-(吗啉代羰基)-1-哌啶基}烟酰胺或其制药学上允许的盐。
14.一种血小板增多用组合物,其特征在于,以权利要求5-13中任一项所述的化合物为有效成分。
15.一种血小板减少症治疗用组合物,其特征在于,以权利要求5-13中任一项所述的化合物为有效成分。
16.一种c-Mpl配体组合物,其特征在于,以权利要求5-13中任一项所述的化合物为有效成分。
Applications Claiming Priority (5)
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JP10447/2002 | 2002-01-18 | ||
JP2002010447 | 2002-01-18 | ||
JP10413/2002 | 2002-01-18 | ||
JP2002010413 | 2002-01-18 | ||
PCT/JP2003/000270 WO2003062233A1 (fr) | 2002-01-18 | 2003-01-15 | Derive de 2-acylaminothiazole et son sel |
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CN1639157A CN1639157A (zh) | 2005-07-13 |
CN1319967C true CN1319967C (zh) | 2007-06-06 |
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US (4) | US7638536B2 (zh) |
EP (2) | EP2314586B1 (zh) |
JP (2) | JP4120586B2 (zh) |
KR (1) | KR101010905B1 (zh) |
CN (1) | CN1319967C (zh) |
BE (1) | BE2019C547I2 (zh) |
CA (1) | CA2472711C (zh) |
CY (2) | CY1114169T1 (zh) |
DK (1) | DK1466912T3 (zh) |
ES (2) | ES2610611T3 (zh) |
FR (1) | FR19C1072I2 (zh) |
HU (1) | HUS1900052I1 (zh) |
LU (1) | LUC00137I2 (zh) |
NL (1) | NL301020I2 (zh) |
PT (1) | PT1466912E (zh) |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749226A (zh) * | 2017-03-15 | 2017-05-31 | 广东赛拓医药科技有限公司 | 一种avatrombopag马来酸盐晶型C的制备方法 |
Families Citing this family (58)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI284639B (en) * | 2000-01-24 | 2007-08-01 | Shionogi & Co | A compound having thrombopoietin receptor agonistic effect |
ES2610611T3 (es) | 2002-01-18 | 2017-04-28 | Astellas Pharma Inc. | Derivado de 2-acilaminotiazol o sal del mismo |
PL213783B1 (pl) * | 2002-03-13 | 2013-05-31 | Janssen Pharmaceutica Nv | Podstawiona pochodna piperydyny lub piperazyny, jej zastosowanie i sposób wytwarzania oraz kompozycja farmaceutyczna |
WO2004029049A1 (ja) * | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | 2-アシルアミノチアゾール誘導体の新規な塩 |
MXPA06000441A (es) * | 2003-07-17 | 2006-04-05 | Astellas Pharma Inc | Derivado de 2-acilaminotiazole o sal del mismo. |
CN103130739B (zh) * | 2003-08-12 | 2015-09-16 | 盐野义制药株式会社 | 具有血小板生成素受体激动作用的化合物 |
PT1700856E (pt) * | 2003-12-26 | 2016-02-19 | Kyowa Hakko Kirin Co Ltd | Derivado de tiazole |
WO2005118551A2 (en) * | 2004-05-28 | 2005-12-15 | Ligand Pharmaceuticals Inc. | Thrombopoietin activity modulating compounds and methods |
AU2004321997A1 (en) * | 2004-07-06 | 2006-02-09 | Xenon Pharmaceuticals Inc. | Nicotinamide derivatives and their use as therapeutic agents |
AR051095A1 (es) * | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso comoinhibidores de la estearoil-coa desaturasa |
AU2005299720B2 (en) * | 2004-10-25 | 2010-02-04 | Ligand Pharmaceuticals Incorporated | Thrombopoietin activity modulating compounds and methods |
CA2588979C (en) | 2004-12-08 | 2013-01-22 | Nissan Chemical Industries, Ltd. | 3-ethylidenehydrazino substituted heterocyclic compounds as thrombopoietin receptor activators |
WO2006064957A1 (ja) * | 2004-12-14 | 2006-06-22 | Nissan Chemical Industries, Ltd. | アミド化合物及びトロンボポエチンレセプター活性化剤 |
JP4665769B2 (ja) * | 2005-01-12 | 2011-04-06 | アステラス製薬株式会社 | アシルアミノチアゾール誘導体の製造法 |
JP4774995B2 (ja) * | 2005-01-12 | 2011-09-21 | アステラス製薬株式会社 | アシルアミノチアゾール誘導体を有効成分とする医薬組成物 |
JPWO2006137527A1 (ja) | 2005-06-23 | 2009-01-22 | 協和発酵キリン株式会社 | チアゾール誘導体 |
WO2007036769A1 (en) * | 2005-07-05 | 2007-04-05 | Pfizer Products Inc. | Aminothiazole derivatives as agonists of the thrombopoietin receptor |
WO2007004038A1 (en) * | 2005-07-05 | 2007-01-11 | Pfizer Products Inc. | Aminothiazole derivatives as agonists of the thrombopoietin receptor |
AU2006267148A1 (en) * | 2005-07-13 | 2007-01-18 | Astrazeneca Ab | New pyridine analogues |
TWI368617B (en) * | 2005-07-15 | 2012-07-21 | Nissan Chemical Ind Ltd | Thiophene compounds and thrombopoietin receptor activators |
WO2007011056A1 (en) * | 2005-07-20 | 2007-01-25 | Nissan Chemical Industries, Ltd. | Pyrazole compounds and thrombopoietin receptor activators |
EP1947101A4 (en) | 2005-11-07 | 2009-09-16 | Nissan Chemical Ind Ltd | HYDRAZIDE COMPOUND AND THROMBOPOIETIN RECEPTOR ACTIVATOR |
CA2628848A1 (en) * | 2005-11-08 | 2007-05-18 | Astellas Pharma Inc. | Compositions and methods for treating thrombocytopenia |
WO2007142308A1 (ja) | 2006-06-07 | 2007-12-13 | Nissan Chemical Industries, Ltd. | 含窒素ヘテロ環化合物及びトロンボポエチンレセプター活性化剤 |
JP2010500361A (ja) * | 2006-08-08 | 2010-01-07 | アカークス,インコーポレーテッド | ヒトの血小板レベルを増加させるための組成物および方法 |
JP5164510B2 (ja) * | 2006-10-06 | 2013-03-21 | 日本曹達株式会社 | 含窒素複素環化合物および有害生物防除剤 |
UY30915A1 (es) | 2007-02-16 | 2008-09-02 | Smithkline Beecham Corp | Método de tratamiento de canceres |
US20110129550A1 (en) * | 2007-02-16 | 2011-06-02 | Connie Erickson-Miller | Cancer treatment method |
US20110160130A1 (en) * | 2007-02-16 | 2011-06-30 | Connie Erickson-Miller | Cancer treatment method |
CN101809008B (zh) | 2007-07-31 | 2013-09-18 | 盐野义制药株式会社 | 含有具血小板生成素受体激动作用的光学活性化合物的药物组合物及其中间体 |
ES2331220B1 (es) * | 2007-10-02 | 2010-09-23 | Palobiofarma, S.L. | Nuevos compuestos como antagonistas de los receptores a1 de adenosina. |
EP2211855A4 (en) * | 2007-10-09 | 2011-12-07 | Univ Pennsylvania | THROMBOPOIETIN RECEPTOR AGONIST (TPORA) DESTROYING THE CELLS OF ACUTE HUMAN MYELOID LEUKEMIA |
ES2581386T3 (es) * | 2008-02-25 | 2016-09-05 | Merck Patent Gmbh | Activadores de la glucoquinasa |
US8476249B2 (en) | 2009-05-07 | 2013-07-02 | Glaxosmithkline Llc | Method of treating thrombocytopenia |
US8680150B2 (en) * | 2009-05-28 | 2014-03-25 | Ligand Pharmaceuticals, Inc. | Small molecule hematopoietic growth factor mimetic compounds that activate hematopoietic growth factor receptors |
WO2011019990A1 (en) * | 2009-08-14 | 2011-02-17 | Eisai, Inc. | Use of e5501 for stimulating platelet production |
GB201111704D0 (en) | 2011-07-07 | 2011-08-24 | Takeda Pharmaceutical | Novel compounds |
GB201111705D0 (en) | 2011-07-07 | 2011-08-24 | Takeda Pharmaceutical | Compounds and their use |
JP2014144916A (ja) | 2011-08-03 | 2014-08-14 | Astellas Pharma Inc | 2−アシルアミノチアゾール化合物の結晶 |
JO3115B1 (ar) | 2011-08-22 | 2017-09-20 | Takeda Pharmaceuticals Co | مركبات بيريدازينون واستخدامها كمثبطات daao |
AP2014007637A0 (en) | 2011-11-15 | 2014-05-31 | Takeda Pharmaceutical | Dihydroxy aromatic heterocyclic compound |
US9499533B2 (en) | 2012-03-27 | 2016-11-22 | Shionogi & Co., Ltd. | Aromatic 5-membered heterocyclic derivative having TRPV4-Inhibiting activity |
GB201222711D0 (en) | 2012-12-17 | 2013-01-30 | Takeda Pharmaceutical | Novel compounds |
TWI647227B (zh) * | 2013-02-28 | 2019-01-11 | 日商安斯泰來製藥股份有限公司 | 2-醯胺噻唑衍生物或其鹽 |
EP2970125B1 (en) * | 2013-03-14 | 2018-07-18 | Dart Neuroscience (Cayman) Ltd. | Substituted naphthyridine and quinoline compounds as mao inhibitors |
CN105518005B (zh) | 2013-07-02 | 2018-07-20 | 百时美施贵宝公司 | 作为rock抑制剂的三环吡啶-甲酰胺衍生物 |
CN105492444B (zh) | 2013-07-02 | 2018-09-07 | 百时美施贵宝公司 | 作为rock抑制剂的三环吡啶-甲酰胺衍生物 |
US9951060B2 (en) | 2014-06-06 | 2018-04-24 | Astellas Pharma Inc. | 2-acylaminothiazole derivative or salt thereof |
EP3196200B1 (en) * | 2014-08-26 | 2019-05-08 | Astellas Pharma Inc. | 2-aminothiazole derivatives or salt thereof as muscarinic m3 ligands for the treatment of bladder diseases |
SG11201703407UA (en) | 2014-10-31 | 2017-05-30 | Nissan Chemical Ind Ltd | Ligand-binding fiber and cell culture substrate using said fiber |
JP2019529342A (ja) * | 2016-09-08 | 2019-10-17 | 四川科倫博泰生物医薬股▲フン▼有限公司Sichuan Kelun−Biotech Biopharmaceutical Co., Ltd. | 新型2−アミドチアゾール誘導体、及びその製造方法と用途 |
CN107383000A (zh) * | 2017-08-07 | 2017-11-24 | 瑞阳制药有限公司 | 血小板增多剂的制备方法 |
WO2020044364A1 (en) | 2018-08-27 | 2020-03-05 | Mylan Laboratories Limited | Polymorphic forms of avatrombopag maleate |
RU2709496C1 (ru) * | 2019-08-01 | 2019-12-18 | Марат Феликсович Фазылов | Способ получения аватромбопага |
CN110586047B (zh) * | 2019-10-08 | 2022-03-11 | 辽宁工业大学 | 一种用于吸附铅离子的改性双醛淀粉制备方法 |
CN111620863A (zh) * | 2020-06-23 | 2020-09-04 | 苏州明锐医药科技有限公司 | 阿曲波帕的制备方法 |
CN115057854A (zh) * | 2022-04-19 | 2022-09-16 | 河北常山生化药业股份有限公司 | 马来酸阿伐曲泊帕中间体的制备方法 |
CN115477645A (zh) * | 2022-09-28 | 2022-12-16 | 湖南先施制药有限公司 | 马来酸阿伐曲泊帕系列杂质及其制备方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5314889A (en) * | 1991-06-05 | 1994-05-24 | Elf Sanofi | Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaceutical compositions containing them |
WO2002062775A1 (fr) * | 2001-02-02 | 2002-08-15 | Yamanouchi Pharmaceutical Co., Ltd. | Dérivé de 2-acylaminothiazole ou son sel |
Family Cites Families (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5330998A (en) | 1988-03-08 | 1994-07-19 | Pfizer Inc. | Thiazolidinedione derivatives as hypoglycemic agents |
TW205041B (zh) | 1989-08-07 | 1993-05-01 | Fujisawa Pharmaceutical Co | |
US5256675A (en) | 1989-08-07 | 1993-10-26 | Fujisawa Pharmaceutical Co., Ltd. | Thiazole derivatives, processes for production thereof and pharmaceutical compositions comprising the same |
JPH078863B2 (ja) | 1989-09-21 | 1995-02-01 | 久光製薬株式会社 | 新規なジフェニルチアゾール誘導体 |
IE68593B1 (en) | 1989-12-06 | 1996-06-26 | Sanofi Sa | Heterocyclic substituted acylaminothiazoles their preparation and pharmaceutical compositions containing them |
JPH03199451A (ja) | 1989-12-26 | 1991-08-30 | Asahi Chem Ind Co Ltd | エアージェットルーム用筬 |
US5250732A (en) * | 1991-07-18 | 1993-10-05 | Genentech, Inc. | Ketamine analogues for treatment of thrombocytopenia |
GB9126677D0 (en) * | 1991-12-16 | 1992-02-12 | Johnson Matthey Plc | Improvements in chemical compounds |
JP3173876B2 (ja) | 1992-06-26 | 2001-06-04 | 日本パイオニクス株式会社 | 有害ガスの検知システム |
AU7545894A (en) | 1993-09-02 | 1995-03-22 | Yamanouchi Pharmaceutical Co., Ltd. | Carbamate derivative and medicine containing the same |
WO1995021820A1 (fr) | 1994-02-10 | 1995-08-17 | Yamanouchi Pharmaceutical Co., Ltd. | Nouveau derive du carbamate et composition correspondante |
AU4889496A (en) * | 1995-03-09 | 1996-10-02 | Kyowa Hakko Kogyo Co. Ltd. | Pyrrolocarbazole derivatives |
US5750540A (en) * | 1995-04-28 | 1998-05-12 | Banyu Pharmaceutical Co., Ltd. | 1,4-di-substituted piperidine derivatives |
ZA964814B (en) * | 1995-06-07 | 1998-02-09 | Glaxo Group Ltd | Peptides and compounds that bind to a receptor. |
US5963666A (en) * | 1995-08-18 | 1999-10-05 | International Business Machines Corporation | Confusion matrix mediated word prediction |
AU702751B2 (en) * | 1995-10-17 | 1999-03-04 | Daiichi Suntory Pharma Co., Ltd | Therapeutics for thrombocytopenia |
US5981551A (en) | 1996-05-22 | 1999-11-09 | Smithkline Beecham Corporation | 2,5-diimino-3a,6a-diaryl-1,2,3,3a,4,5,6,6a-octahydroimidazo[4,5-d]imidazoles which are effective as G-CSF mimetics |
AU4136197A (en) | 1996-09-09 | 1998-03-26 | Kyowa Hakko Kogyo Co. Ltd. | Pyrrolocarbazole derivatives |
US5932546A (en) * | 1996-10-04 | 1999-08-03 | Glaxo Wellcome Inc. | Peptides and compounds that bind to the thrombopoietin receptor |
US6187797B1 (en) * | 1996-12-23 | 2001-02-13 | Dupont Pharmaceuticals Company | Phenyl-isoxazoles as factor XA Inhibitors |
JPH10212289A (ja) | 1997-01-31 | 1998-08-11 | Kyowa Hakko Kogyo Co Ltd | ピロロフェナンスリジン誘導体 |
AU9265698A (en) | 1997-09-02 | 1999-03-22 | Boehringer Mannheim Gmbh | Mpl-receptor ligands, process for their preparation, medicaments containing themand their use for the treatment and prevention of thrombocytopaenia and anaemia |
JPH11152276A (ja) | 1997-11-20 | 1999-06-08 | Hokuriku Seiyaku Co Ltd | ベンゾジアゼピン誘導体 |
JP2000044562A (ja) | 1998-07-31 | 2000-02-15 | Kyowa Hakko Kogyo Co Ltd | ピロロフタルイミド誘導体 |
CA2337755C (en) | 1998-09-18 | 2008-07-29 | Vertex Pharmaceuticals Incorporated | Inhibitors of p38 |
DE69929464T2 (de) * | 1998-11-17 | 2006-09-07 | Smithkline Beecham Corp. | Zyklische polyamine zur behandlung der thrombozytopenie |
GC0000177A (en) | 1998-12-17 | 2006-03-29 | Smithkline Beecham | Thrombopoietin mimetics |
EP1207155A4 (en) | 1999-07-26 | 2005-01-12 | Shionogi & Co | DRUG COMPOSITIONS HAVING AGONIST THROMBOPOIETINE ACTIVITY |
TWI284639B (en) | 2000-01-24 | 2007-08-01 | Shionogi & Co | A compound having thrombopoietin receptor agonistic effect |
GB0028383D0 (en) * | 2000-11-21 | 2001-01-03 | Novartis Ag | Organic compounds |
US8263657B2 (en) | 2000-12-18 | 2012-09-11 | Institute Of Medicinal Molecular Design, Inc. | Inhibitors against the production and release of inflammatory cytokines |
WO2002053160A1 (en) | 2000-12-29 | 2002-07-11 | Alteon, Inc. | Method for treating glaucoma ivb |
CA2437248A1 (en) | 2001-02-02 | 2002-08-15 | Takeda Chemical Industries, Ltd. | Jnk inhibitor |
ES2610611T3 (es) | 2002-01-18 | 2017-04-28 | Astellas Pharma Inc. | Derivado de 2-acilaminotiazol o sal del mismo |
DK1482931T3 (da) | 2002-03-05 | 2011-12-19 | Transtech Pharma Inc | Mono- og bicycliske azolderivater der inhiberer interaktionen af ligander med RAGE |
WO2003084544A2 (en) | 2002-04-04 | 2003-10-16 | Cv Therapeutics, Inc. | Compounds dor increasing abca-1 expression useful for treating coronary artery disease and atherosclerosis |
AU2003242124A1 (en) | 2002-06-11 | 2003-12-22 | Institute Of Medicinal Molecular Design, Inc. | Medicament for treatment of neurodegenerative diseases |
CA2744893A1 (en) * | 2002-06-27 | 2004-01-08 | Novo Nordisk A/S | Aryl carbonyl derivatives as glucokinase activators |
WO2004029049A1 (ja) | 2002-09-30 | 2004-04-08 | Yamanouchi Pharmaceutical Co., Ltd. | 2-アシルアミノチアゾール誘導体の新規な塩 |
JP2006518738A (ja) | 2003-02-12 | 2006-08-17 | トランス テック ファーマ,インコーポレイテッド | 治療薬としての置換アゾール誘導体 |
WO2004087698A2 (en) * | 2003-03-25 | 2004-10-14 | Vertex Pharmaceuticals Incorporated | Thiazoles useful as inhibitors of protein kinases |
MXPA06000441A (es) | 2003-07-17 | 2006-04-05 | Astellas Pharma Inc | Derivado de 2-acilaminotiazole o sal del mismo. |
CN103130739B (zh) * | 2003-08-12 | 2015-09-16 | 盐野义制药株式会社 | 具有血小板生成素受体激动作用的化合物 |
CA2628848A1 (en) | 2005-11-08 | 2007-05-18 | Astellas Pharma Inc. | Compositions and methods for treating thrombocytopenia |
JP2010500361A (ja) | 2006-08-08 | 2010-01-07 | アカークス,インコーポレーテッド | ヒトの血小板レベルを増加させるための組成物および方法 |
-
2003
- 2003-01-15 ES ES11154632.1T patent/ES2610611T3/es not_active Expired - Lifetime
- 2003-01-15 EP EP11154632.1A patent/EP2314586B1/en not_active Expired - Lifetime
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- 2003-01-15 DK DK03700571.7T patent/DK1466912T3/da active
- 2003-01-15 ES ES03700571T patent/ES2416304T3/es not_active Expired - Lifetime
- 2003-01-15 US US10/500,964 patent/US7638536B2/en active Active
- 2003-01-15 KR KR1020047010846A patent/KR101010905B1/ko active IP Right Grant
- 2003-01-15 SI SI200332274T patent/SI1466912T1/sl unknown
- 2003-01-15 JP JP2003562111A patent/JP4120586B2/ja not_active Expired - Lifetime
- 2003-01-15 CN CNB038044579A patent/CN1319967C/zh not_active Expired - Lifetime
- 2003-01-15 WO PCT/JP2003/000270 patent/WO2003062233A1/ja active Application Filing
- 2003-01-15 CA CA2472711A patent/CA2472711C/en not_active Expired - Lifetime
-
2008
- 2008-02-04 JP JP2008023950A patent/JP4844574B2/ja not_active Expired - Lifetime
-
2009
- 2009-11-10 US US12/615,968 patent/US8338429B2/en not_active Expired - Lifetime
- 2009-11-10 US US12/615,979 patent/US20100222329A1/en not_active Abandoned
-
2012
- 2012-11-15 US US13/677,520 patent/US8765764B2/en not_active Expired - Lifetime
-
2013
- 2013-07-24 CY CY20131100629T patent/CY1114169T1/el unknown
-
2019
- 2019-11-06 BE BE2019C547C patent/BE2019C547I2/fr unknown
- 2019-11-12 LU LU00137C patent/LUC00137I2/fr unknown
- 2019-12-06 FR FR19C1072C patent/FR19C1072I2/fr active Active
- 2019-12-11 HU HUS1900052C patent/HUS1900052I1/hu unknown
- 2019-12-11 NL NL301020C patent/NL301020I2/nl unknown
- 2019-12-17 CY CY2019045C patent/CY2019045I2/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5314889A (en) * | 1991-06-05 | 1994-05-24 | Elf Sanofi | Heterocyclic substituted 2-acylamino-5-thiazoles, their preparation and pharmaceutical compositions containing them |
WO2002062775A1 (fr) * | 2001-02-02 | 2002-08-15 | Yamanouchi Pharmaceutical Co., Ltd. | Dérivé de 2-acylaminothiazole ou son sel |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106749226A (zh) * | 2017-03-15 | 2017-05-31 | 广东赛拓医药科技有限公司 | 一种avatrombopag马来酸盐晶型C的制备方法 |
CN106749226B (zh) * | 2017-03-15 | 2019-12-20 | 广东赛拓医药科技有限公司 | 一种avatrombopag马来酸盐晶型C的制备方法 |
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