CN1239485C - 作为IL-1β和TNF-α抑制剂的二苯酮类 - Google Patents
作为IL-1β和TNF-α抑制剂的二苯酮类 Download PDFInfo
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- CN1239485C CN1239485C CNB018098657A CN01809865A CN1239485C CN 1239485 C CN1239485 C CN 1239485C CN B018098657 A CNB018098657 A CN B018098657A CN 01809865 A CN01809865 A CN 01809865A CN 1239485 C CN1239485 C CN 1239485C
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- Prior art keywords
- compound
- chloro
- amino
- methyl
- benzophenone
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- 239000012965 benzophenone Substances 0.000 title claims description 45
- 108060008682 Tumor Necrosis Factor Proteins 0.000 title abstract description 15
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 title abstract description 15
- 102000003777 Interleukin-1 beta Human genes 0.000 title abstract description 14
- 108090000193 Interleukin-1 beta Proteins 0.000 title abstract description 14
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 title abstract description 12
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000008366 benzophenones Chemical class 0.000 title description 4
- -1 Heteroaryl aminobenzophenones Chemical class 0.000 claims abstract description 74
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 410
- 150000002576 ketones Chemical class 0.000 claims description 214
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 76
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 59
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 51
- 239000000460 chlorine Substances 0.000 claims description 49
- 239000000203 mixture Substances 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 36
- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 26
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
- 229910052794 bromium Inorganic materials 0.000 claims description 24
- 229910052731 fluorine Inorganic materials 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 22
- 239000011737 fluorine Substances 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- KSDAWMBESDCQQS-UHFFFAOYSA-N [2-chloro-4-[(4-methylpyridin-3-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=NC=C1NC(C=C1Cl)=CC=C1C(=O)C1=CC=CC=C1C KSDAWMBESDCQQS-UHFFFAOYSA-N 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 12
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- POFVJRKJJBFPII-UHFFFAOYSA-N N-cyclopentyl-5-[2-[[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]amino]-5-fluoropyrimidin-4-yl]-4-methyl-1,3-thiazol-2-amine Chemical compound C1(CCCC1)NC=1SC(=C(N=1)C)C1=NC(=NC=C1F)NC1=NC=C(C=C1)CN1CCN(CC1)CC POFVJRKJJBFPII-UHFFFAOYSA-N 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 9
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- LVUPUWCGGIZBFR-UHFFFAOYSA-N [2-chloro-4-(isoquinolin-4-ylamino)phenyl]-(2,5-dimethylphenyl)methanone Chemical compound CC1=CC=C(C)C(C(=O)C=2C(=CC(NC=3C4=CC=CC=C4C=NC=3)=CC=2)Cl)=C1 LVUPUWCGGIZBFR-UHFFFAOYSA-N 0.000 claims description 8
- ZQFOABLMISQBCQ-UHFFFAOYSA-N [2-chloro-4-(pyridin-3-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CN=C1 ZQFOABLMISQBCQ-UHFFFAOYSA-N 0.000 claims description 8
- CQRYWWHLFQEVPD-UHFFFAOYSA-N [2-chloro-4-[(4-methylpyridin-3-yl)amino]phenyl]-(2,5-dimethylphenyl)methanone Chemical compound CC1=CC=C(C)C(C(=O)C=2C(=CC(NC=3C(=CC=NC=3)C)=CC=2)Cl)=C1 CQRYWWHLFQEVPD-UHFFFAOYSA-N 0.000 claims description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 8
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 210000002966 serum Anatomy 0.000 claims description 8
- VACUVWWOBCUSEW-UHFFFAOYSA-N [2-chloro-4-(quinolin-3-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CN=C(C=CC=C2)C2=C1 VACUVWWOBCUSEW-UHFFFAOYSA-N 0.000 claims description 7
- BXKZNZIEJZTIJJ-UHFFFAOYSA-N [2-chloro-4-(quinolin-8-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CC2=CC=CN=C12 BXKZNZIEJZTIJJ-UHFFFAOYSA-N 0.000 claims description 7
- AFBFXOVOFOJAIW-UHFFFAOYSA-N [2-chloro-4-[(5-nitropyridin-2-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=C([N+]([O-])=O)C=N1 AFBFXOVOFOJAIW-UHFFFAOYSA-N 0.000 claims description 7
- KQELNYAVHIVGQA-UHFFFAOYSA-N [2-chloro-4-[(6-methylpyridin-3-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound C1=NC(C)=CC=C1NC(C=C1Cl)=CC=C1C(=O)C1=CC=CC=C1C KQELNYAVHIVGQA-UHFFFAOYSA-N 0.000 claims description 7
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 7
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 7
- 230000002757 inflammatory effect Effects 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 6
- LZHTYJYUXKYSLO-UHFFFAOYSA-N [2-chloro-4-(pyridin-2-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CC=N1 LZHTYJYUXKYSLO-UHFFFAOYSA-N 0.000 claims description 6
- RLFVADQMRPQAQD-UHFFFAOYSA-N [2-chloro-4-(pyrimidin-2-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=NC=CC=N1 RLFVADQMRPQAQD-UHFFFAOYSA-N 0.000 claims description 6
- DWRBZDMLPXEONJ-UHFFFAOYSA-N [2-chloro-4-(pyrimidin-5-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CN=CN=C1 DWRBZDMLPXEONJ-UHFFFAOYSA-N 0.000 claims description 6
- JGSLPDRRHPXCGY-UHFFFAOYSA-N [2-chloro-4-[(2-methyl-1,3-benzothiazol-5-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound C=1C=C2SC(C)=NC2=CC=1NC(C=C1Cl)=CC=C1C(=O)C1=CC=CC=C1C JGSLPDRRHPXCGY-UHFFFAOYSA-N 0.000 claims description 6
- SVLVYYQWIZBBIM-UHFFFAOYSA-N [2-chloro-4-[(3-nitropyridin-2-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=NC=CC=C1[N+]([O-])=O SVLVYYQWIZBBIM-UHFFFAOYSA-N 0.000 claims description 6
- NKMLLANVXWLEEU-UHFFFAOYSA-N [2-chloro-4-[[2-methyl-5-(trifluoromethyl)pyridin-3-yl]amino]phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC(C(F)(F)F)=CN=C1C NKMLLANVXWLEEU-UHFFFAOYSA-N 0.000 claims description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 235000019166 vitamin D Nutrition 0.000 claims description 6
- 239000011710 vitamin D Substances 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- IRBAWVGZNJIROV-SFHVURJKSA-N 9-(2-cyclopropylethynyl)-2-[[(2s)-1,4-dioxan-2-yl]methoxy]-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one Chemical compound C1=C2C3=CC=C(C#CC4CC4)C=C3CCN2C(=O)N=C1OC[C@@H]1COCCO1 IRBAWVGZNJIROV-SFHVURJKSA-N 0.000 claims description 5
- HHMRJOQAKKWCCK-UHFFFAOYSA-N [2-chloro-4-(quinolin-4-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=NC2=CC=CC=C12 HHMRJOQAKKWCCK-UHFFFAOYSA-N 0.000 claims description 5
- ZANFJEPVUKIYSZ-UHFFFAOYSA-N [2-chloro-4-[(2-methylquinolin-6-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound C1=CC2=NC(C)=CC=C2C=C1NC(C=C1Cl)=CC=C1C(=O)C1=CC=CC=C1C ZANFJEPVUKIYSZ-UHFFFAOYSA-N 0.000 claims description 5
- JYEVUDXCQHLXNG-UHFFFAOYSA-N tert-butyl pyridine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CN=C1 JYEVUDXCQHLXNG-UHFFFAOYSA-N 0.000 claims description 5
- OIIOPWHTJZYKIL-PMACEKPBSA-N (5S)-5-[[[5-[2-chloro-3-[2-chloro-3-[6-methoxy-5-[[[(2S)-5-oxopyrrolidin-2-yl]methylamino]methyl]pyrazin-2-yl]phenyl]phenyl]-3-methoxypyrazin-2-yl]methylamino]methyl]pyrrolidin-2-one Chemical compound C1(=C(N=C(C2=C(C(C3=CC=CC(=C3Cl)C3=NC(OC)=C(N=C3)CNC[C@H]3NC(=O)CC3)=CC=C2)Cl)C=N1)OC)CNC[C@H]1NC(=O)CC1 OIIOPWHTJZYKIL-PMACEKPBSA-N 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- PAYROHWFGZADBR-UHFFFAOYSA-N 2-[[4-amino-5-(5-iodo-4-methoxy-2-propan-2-ylphenoxy)pyrimidin-2-yl]amino]propane-1,3-diol Chemical compound C1=C(I)C(OC)=CC(C(C)C)=C1OC1=CN=C(NC(CO)CO)N=C1N PAYROHWFGZADBR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- IJRKLHTZAIFUTB-UHFFFAOYSA-N 5-nitro-2-(2-phenylethylamino)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1NCCC1=CC=CC=C1 IJRKLHTZAIFUTB-UHFFFAOYSA-N 0.000 claims description 4
- LIMFPAAAIVQRRD-BCGVJQADSA-N N-[2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl]-8-[(2R,3S)-2-methyl-3-(methylsulfonylmethyl)azetidin-1-yl]-5-propan-2-ylisoquinolin-3-amine Chemical compound F[C@H]1CN(CC[C@H]1OC)C1=NC=CC(=N1)NC=1N=CC2=C(C=CC(=C2C=1)C(C)C)N1[C@@H]([C@H](C1)CS(=O)(=O)C)C LIMFPAAAIVQRRD-BCGVJQADSA-N 0.000 claims description 4
- DWKVSRCZKNQQCO-UHFFFAOYSA-N [2-chloro-4-[(5-nitro-1,3-thiazol-2-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=NC=C([N+]([O-])=O)S1 DWKVSRCZKNQQCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 claims description 3
- SQVNITZYWXMWOG-UHFFFAOYSA-N 2-cyclohexyl-1-(2-methylquinolin-4-yl)-3-(1,3-thiazol-2-yl)guanidine Chemical compound C=12C=CC=CC2=NC(C)=CC=1NC(=NC1CCCCC1)NC1=NC=CS1 SQVNITZYWXMWOG-UHFFFAOYSA-N 0.000 claims description 3
- WFOVEDJTASPCIR-UHFFFAOYSA-N 3-[(4-methyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)methylamino]-n-[[2-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound N=1N=C(C=2C=CN=CC=2)N(C)C=1CNC(C=1)=CC=CC=1C(=O)NCC1=CC=CC=C1C(F)(F)F WFOVEDJTASPCIR-UHFFFAOYSA-N 0.000 claims description 3
- GSDQYSSLIKJJOG-UHFFFAOYSA-N 4-chloro-2-(3-chloroanilino)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1NC1=CC=CC(Cl)=C1 GSDQYSSLIKJJOG-UHFFFAOYSA-N 0.000 claims description 3
- PFWLFWPASULGAN-UHFFFAOYSA-N 7-methylxanthine Chemical compound N1C(=O)NC(=O)C2=C1N=CN2C PFWLFWPASULGAN-UHFFFAOYSA-N 0.000 claims description 3
- IYHHRZBKXXKDDY-UHFFFAOYSA-N BI-605906 Chemical compound N=1C=2SC(C(N)=O)=C(N)C=2C(C(F)(F)CC)=CC=1N1CCC(S(C)(=O)=O)CC1 IYHHRZBKXXKDDY-UHFFFAOYSA-N 0.000 claims description 3
- BGGALFIXXQOTPY-NRFANRHFSA-N C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC Chemical compound C1(=C(C2=C(C=C1)N(C(C#N)=C2)C[C@@H](N1CCN(CC1)S(=O)(=O)C)C)C)CN1CCC(CC1)NC1=NC(=NC2=C1C=C(S2)CC(F)(F)F)NC BGGALFIXXQOTPY-NRFANRHFSA-N 0.000 claims description 3
- UHNRLQRZRNKOKU-UHFFFAOYSA-N CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O Chemical compound CCN(CC1=NC2=C(N1)C1=CC=C(C=C1N=C2N)C1=NNC=C1)C(C)=O UHNRLQRZRNKOKU-UHFFFAOYSA-N 0.000 claims description 3
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 claims description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 3
- 206010039361 Sacroiliitis Diseases 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Chemical group 0.000 claims description 3
- 229930003316 Vitamin D Natural products 0.000 claims description 3
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 3
- OWFCMOYZCAENKW-UHFFFAOYSA-N [2-chloro-4-(pyridin-4-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=NC=C1 OWFCMOYZCAENKW-UHFFFAOYSA-N 0.000 claims description 3
- IAORNBCJIKPTKE-UHFFFAOYSA-N [2-chloro-4-(quinolin-2-ylamino)phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=C(C=CC=C2)C2=N1 IAORNBCJIKPTKE-UHFFFAOYSA-N 0.000 claims description 3
- QGIIDNQMDGJLHQ-UHFFFAOYSA-N [2-fluoro-4-[(4-methylpyridin-3-yl)amino]phenyl]-(2-methylphenyl)methanone Chemical compound CC1=CC=NC=C1NC(C=C1F)=CC=C1C(=O)C1=CC=CC=C1C QGIIDNQMDGJLHQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000005557 antagonist Substances 0.000 claims description 3
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 3
- 230000001387 anti-histamine Effects 0.000 claims description 3
- 239000003529 anticholesteremic agent Substances 0.000 claims description 3
- 229940127226 anticholesterol agent Drugs 0.000 claims description 3
- 239000000739 antihistaminic agent Substances 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 claims description 3
- 229960004369 flufenamic acid Drugs 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 229960000905 indomethacin Drugs 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 229960002009 naproxen Drugs 0.000 claims description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 3
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Classifications
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
通式(I)的杂芳基氨基二苯酮类抑制白细胞介素-1β和TNF-α且由此可以用于炎性疾病和疾患的治疗。
Description
发明领域
本发明涉及包括杂芳基氨基二苯酮衍生物在内的表现出抗炎作用的一类新化合物,涉及含有这些化合物的药物组合物并涉及它们在治疗和预防炎性疾病中的用途。
发明背景
先前已经描述了一系列氨基二苯酮类(例如4-(2-氨基-4-硝基苯基氨基)二苯酮)(Hussein,F.A.等,《伊拉克科学杂志》(Iraqi J.Sci.),22,54-66(1981))。然而,在该公开文献中,没有记载这类化合物的任何潜在治疗用途。WO 98/32730中公开了白细胞介素1β(IL1-1β)和肿瘤坏死因子α(TNF-α)体外分泌的氨基二苯酮抑制剂并表明了这些化合物在治疗炎性疾病中的潜在用途,在所述的炎性疾病中,促炎细胞因子的产生与发病机制有关,例如哮喘、类风湿性关节炎、银屑病、接触性皮炎和特应性皮炎。此外,在12-O-十四酰佛波醇-13-乙酸酯(TPA)诱发的鼠慢性皮肤炎症模型中测试了WO98/32730中公开的化合物的体内抗炎特性(De Young,L.M.等,《活性剂作用》(Agents Actions)26,335-341(1989);Carlson,R.P.等,《活性剂作用》(Agents Actions)17,197-204(1985);Alford,J.G.等,《活性剂作用》(Agents Actions)37,(1992);Stanley,P.L.等,《皮肤药理学》(Skin Pharmacol.)4,262-271(1991))。在这种慢性皮肤炎症模型中,所述的化合物与参比化合物氢化可的松相比具有相同的功效。
本发明的目的是进一步提供在结构上不同于WO 98/32730中公开的那些化合物的具药理活性的二苯酮衍生物。
发明概述
已经令人惊奇地发现新型二苯酮衍生物是白细胞介素1β(IL-1β)和肿瘤坏死因子α(TNF-α)体外分泌的有效抑制剂,从而使得它们能够用于治疗和/或预防炎性疾病和其它疾病,其中细胞因子或更具体地说是白细胞介素1β(IL-1β)和肿瘤坏死因子α(TNF-α)的分泌和调节与发病机制有关。对细胞因子的抑制作用或减量调节可能是由于对MAP激酶、更具体地说是p38MAP激酶的抑制作用所导致的,其中所述的p38MAP激酶是一种应激活化蛋白,它是导致促炎细胞因子产生的信号转导途径中的重要成分。
因此,本发明涉及具有通式I的化合物或其可药用盐、水合物、溶剂合物或酯类以及R5取代基的氮原子被氧化的N-氧化物:
其中R1选自卤素、卤代烷基、羟基、羟烷基、羟基烷氧基、巯基、氰基、羧基、硝基、烷基、链烯基、炔基、环烷基、环烯基、杂环烷基、芳基、杂芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氧基、烷氧基羰基氧基、烷基磺酰氧基、烷氧基磺酰基、烷基羰基氨基、氨基羰氨基烷基(aminocarboaminoalkyl)、氨基磺酰基、烷基磺酰基氨基、烷酰基、烷基羰基、-NR9R10或-CONR9R10,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
R2代表一个或多个相同或不同的取代基,它们选自氢、卤素、卤代烷基、羟基、羟烷基、羟基烷氧基、巯基、氰基、羧基、硝基、烷基、链烯基、炔基、环烷基、环烯基、杂环烷基、芳基、杂芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氧基、烷氧基羰基氧基、烷基磺酰氧基、烷氧基磺酰基、烷基羰基氨基、氨基羰氨基烷基、氨基磺酰基、烷基磺酰基氨基、烷酰基、烷基羰基、-NR9R10或-CONR9R10,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
R3代表一个或多个相同或不同的取代基,它们选自氢、卤素、卤代烷基、羟基、羟烷基、巯基、氰基、硝基、烷基、链烯基、炔基、环烷基、芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氨基、烷基羰基氧基、烷氧基羰基氧基、烷基羰基、-NR9R10或-CONR9R10,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
R4代表氢、烷基、链烯基、炔基、环烷基、环烯基、羧基或芳基;
R5代表含有1-4个杂原子的杂芳香单环或双环系统,除了三嗪,所述的环系可以任选被氢、卤素、卤代烷基、羟基、羟基烷基、羟基烷氧基、巯基、氰基、羧基、硝基、烷基、链烯基、炔基、环烷基、环烯基、杂环烷基、芳基、杂芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氧基、烷氧基羰基氧基、烷基磺酰氧基、烷氧基磺酰基、烷基羰基氨基、氨基羰氨基烷基、氨基磺酰基、烷基磺酰基氨基、烷酰基、烷基羰基、-NR9R10或-CONR9R10取代,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
X代表氧、硫、N-OH或NR11,其中R11是氢或烷基。
发明详述
定义
在本文的上下文中,术语″烷基″用以指通过从任意碳原子上除去一个氢而来源于直链或支链烷烃的单价基团。烷基链一般含有1-10个碳原子,特别是1-6个碳原子。该术语包括亚类:正烷基、仲烷基和叔烷基,诸如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基和异己基。
术语″卤代烷基″用以指被一个或多个诸如氯、氟、溴或碘这样的卤素取代的如上所定义的烷基。
术语″羟烷基″用以指被一个或多个羟基取代的如上所定义的烷基。
术语″烷氧基″用以指式OR’的基团,其中R’是如上所定义的烷基,例如甲氧基、乙氧基、丙氧基、丁氧基等。
术语″羟基烷氧基″用以指被一个或多个羟基取代的如上所定义的烷氧基。
术语″链烯基″用以指一般含有2-10个碳原子、特别是2-6个碳原子的一-、二-、三-、四-或五不饱和的烷基,例如乙烯基、丙烯基、丁烯基、戊烯基或己烯基。术语″炔基″用以指含有1-5个C-C三键的烷基,该烷烃链一般含有2-10个碳原子、特别是2-6个碳原子,诸如乙炔基、丙炔基、丁炔基、戊炔基或己炔基。
术语″烷氧羰基″用以指式-COOR’的基团,其中R’是如上所定义的烷基,例如甲氧羰基、乙氧羰基、正丙氧羰基、异丙氧羰基等。
术语″环烷基″用以指一般含有3-10个碳原子、特别是3-8个碳原子的饱和环烷基,例如环丙基、环丁基、环戊基或环己基。术语″环烯基″用以指一-、二-、三-或四不饱和的环烷基,例如环丙烯基、环丁烯基、环戊烯基或环己烯基。术语″杂环烷基″用以指含有一个或多个选自O、N或S的杂原子的如上所定义的环烷基。
术语″芳基″用以包括碳环芳香环、特别是5-或6-元环、任选稠合的双环的基团,例如苯基或萘基。术语″杂芳基″用以包括杂环芳香环、特别是含有1-4个选自O、S和N的杂原子的5-或6-元环或含有1-4个杂原子的任选稠合的双环的基团,例如吡啶基、喹啉基、异喹啉基、吲哚基、四唑基、噻唑基、咪唑基、吡唑基、噁唑基、异噁唑基、噻吩基、吡嗪基、异噻唑基、苯并咪唑基和苯并呋喃基。
术语″烷基羰基氧基″指的是式R’-COO-的基团,其中R’是如上所述的烷基。术语″烷氧基羰基氧基″指的是式R’O-COO-的基团,其中R’是如上所定义的烷基。术语″烷基磺酰氧基″指的是式R’-(SO2)-O-的基团,其中R’是如上所定义的烷基。术语″烷氧基磺酰基″指的是式R’O-(SO2)-的基团,其中R’是如上所定义的烷基。
术语″芳烷基″用以指含有如上所定义的烷基侧链的芳环,例如苄基。术语″烷芳基″用以指含有芳族侧链的如上所定义的烷基。
术语″卤素″用以指氟、氯、溴或碘。
术语″烷硫基″用以指式-SR的基团,其中R是如上所定义的烷基,且包括甲硫基、乙硫基、正丙硫基和2-丙硫基。
术语″烷氨基″用以指式-NHR或-NR2的基团,其中R是含有1-6个碳原子的如上所定义的烷基,且包括例如甲氨基、二甲氨基、二(正丙基)氨基和正丁基(乙基)氨基。
术语″氨基甲酰基″用以指基团-OCONH2、-OCONHR和OCONRR’,其中R和R’代表如上所定义的烷基。
术语″可药用盐″用以指碱金属盐或碱土金属盐,例如钠、钾、镁或钙的盐以及银盐和与合适的无机酸或有机酸形成的盐,所述的无机酸或有机酸诸如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、乙酸、乳酸、马来酸、苯二甲酸、柠檬酸、丙酸、苯甲酸、戊二酸、葡糖酸、甲磺酸、水杨酸、琥珀酸、酒石酸、甲苯磺酸、氨基磺酸或富马酸。
术语″可药用酯类″用以指:易于水解的酯类,诸如烷酰基氧基烷基酯类、芳烷酰氧基烷基酯类、芳酰氧基烷基酯类,例如乙酰氧基甲酯、新戊酰氧基甲酯、苯甲酰氧基甲酯和相应的1’-乙氧基衍生物;或烷氧羰基氧基烷基酯类,例如甲氧羰基氧基甲基酯类和乙氧羰基氧基甲酯类和相应的1’-乙氧基衍生物;或内酯基酯类,例如2-苯并[c]呋喃酮基酯类或二烷氨基烷基酯类,例如二甲氨基乙酯类。易于水解的酯类包括式I化合物的在体内可水解的酯类。这类酯可以通过本领域技术人员所公知的常规方法来制备,如GB专利1490852中公开的方法,将该文献引入本文作为参考。
″p38MAP激酶″是一种以几种同种型形式(p38α、p38β、p38β2、p38γ和p38δ)存在的应激活化蛋白。p38MAP激酶被不同的刺激激活,所述的刺激包括加热、化学品、渗透压、pH和氧化性应激反应、生长因子撤退、高或低葡萄糖和紫外线照射。p38也受到介导对外伤、感染和炎症的初期生理反应的活性剂刺激,诸如LPS和促炎细胞因子IL-1β、TNF-α、FasL、CD40L和TGF-β。与其它MAP激酶相似,p38在邻近ATP和底物结合位点的活化环(Thr-Xaa-Tyr)中的苏氨酸和酪氨酸上被包括MKK3、MEK6和MKK6在内的激酶磷酸化。p38依次使丝氨酸-苏氨酸蛋白激酶MAPKAP激酶-2、MAPKAP激酶-3、MAPKAP激酶-5、MNK-1和MSK-1磷酸化和活化。已经确定p38的活化直接通过使涉及细胞因子表达的转录因子磷酸化和活化或间接例如通过使在被激活时激活转录因子CREB的MSK-1磷酸化而调节许多细胞类型中细胞因子的生物合成。还显示某些吡啶基咪唑类例如SB203580抑制IL-1β和TNF-α从LPS-处理的人单核细胞中产生,这些化合物是p38激酶的抑制剂。由此推断p38为开发抗炎化合物提供了可能非常有意义的靶物(参见JC Lee等,《免疫药理学》(Immunopharmacology)47,2000,第185-201页和其中回顾的参考文献;PR Young,“信号传输网络和细胞周期控制中的“p38 MAP激酶的特异性抑制剂”(″SpecificInhibitors of p38 MAP kinase”in Signaling Networks and CellCycle Control″):《癌症和其它疾病的分子学基础》(The MolecularBasis of Cancer and Other Diseases),JS Gutkind(编辑),HumanaPress,Inc.,Totowa,NJ及其中综述的参考文献)。
本发明的优选实施方案
在式I的化合物中:
R1优选代表选自卤素、羟基、巯基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷氨基、(C1-C6)烷氧羰基、氰基、-CONH2、苯基和硝基的取代基;特别是氟、氯、溴、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)链烯基、(C1-C3)烷氧基、(C1-C3)烷氧羰基、氰基或-CONH2;
R2代表一个或多个相同或不同的取代基,它们选自氢、卤素、羟基、巯基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷氨基、(C1-C6)烷氧羰基、氰基、-CONH2、苯基和硝基;特别是氢、氟、氯、溴、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)链烯基、(C1-C3)烷氧基、(C1-C3)烷氧羰基、氰基或-CONH2;
R3代表一个或多个相同或不同的取代基,它们选自氢、卤素、羟基、巯基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷氨基、(C1-C6)烷氧羰基、氰基、-CONH2、苯基和硝基;特别是氢、氟、氯、溴、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)链烯基和(C1-C3)烷氧基;
R4代表氢、(C1-C6)烷基、(C2-C6)链烯基或(C3-C6)环烷基或环烯基;特别是氢、(C1-C4)烷基或(C2-C4)链烯基;
X代表氧或NH;
在R5代表的单环-或双环杂芳环系统中,杂原子可以选自N、S或O。各环优选含有5个或6个环原子。合适的杂芳环系的实例选自吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基、喹唑啉基、哒嗪基、2,3-二氨杂萘基、嘌呤基、喹喔啉基、异嘌呤基、苯并呋喃基、异苯并呋喃基、苯并咪唑基、苯并噁唑基、苯并噻吩基、别苯并噻吩基、苯并噻唑基、苯并异噻唑基、苯并三唑基、中氮茚基、异吲哚基、吲哚基、吲唑基、三唑基、噁唑基、噻二唑基、噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基或异噁唑基。
R5优选选自含有1个或2个氮原子的杂芳环系,例如下列结构的环:
R5环系可以任选被氧化成相应的N-氧化物,如以下所例举的异喹啉环系:
R6和R7代表一个或多个相同或不同的取代基,它们选自氢、卤素、羟基、巯基、三氟甲基、氰基、羧基、氨基甲酰基、氨基、硝基、(C1-C10)烷基、(C2-C10)链烯基、(C3-C8)环烷基或环烯基、(C1-C10)烷氧基、(C1-C10)烷硫基、(C1-C10)烷氧羰基和苯基;R6和R7特别代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷氧羰基、氰基、羧基和-CONH2;并且
R8代表氢、(C1-C6)烷基、(C2-C6)链烯基或(C3-C6)环烷基或环烯基。
在式I的化合物中更优选:
R1代表选自氟、氯、溴、羟基、甲基和甲氧基的取代基;
R2代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、三氟甲基、甲基、乙基和甲氧基;
R3代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、甲基和甲氧基;
R4代表氢、甲基或乙基;
R5是选自取代的或未取代的3-吡啶基、2-吡啶基、3-喹啉基、4-异喹啉基、4-吲哚基、5-吲哚基、6-吲哚基和7-吲哚基和相应的N-氧化物;
R6和R7代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、甲基、甲氧基、氰基和羧基;
R8代表氢、(C1-C4)烷基、(C2-C6)链烯基、如烯丙基;且更优选R8代表氢、甲基、乙基、烯丙基、丙基或叔丁基;和/或
X代表氧。
R1、R2、R3、R6和R7的苯基可以任选被例如羟基、氨基、硝基、氰基或卤素、优选氟或氯取代。
本发明的特定化合物是:
2-氯-2’-甲基-4-(4-吡啶基氨基)二苯酮(化合物101);
2-氯-2’-甲基-4-(2-吡啶基氨基)二苯酮(化合物102);
2-氯-2’-甲基-4-(5-硝基-2-吡啶基氨基)二苯酮(化合物103);
4-(6-氨基-5-硝基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物104);
6-氯-2-(3-氯-4-(2-甲基苯甲酰基)苯基氨基)异烟酸(化合物105);
4-(6-腈-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物106);
2-氯-2’-甲基-4-(3-吡啶基氨基)二苯酮(化合物107);
2-氯-4-(5,6-二氨基-2-吡啶基氨基)-2’-甲基二苯酮(化合物108);
2-氯-2’-甲基-4-(3-硝基-2-吡啶基氨基)二苯酮(化合物109);
4-(3-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物110);
4-(5-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物111);
2-氯-4-(4-异喹啉基氨基)-2-甲基二苯酮(化合物114);
5-(3-氯-4-(2-甲基苯甲酰基)苯基氨基)烟酸叔丁酯(化合物115);
2-氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物116);
2-氯-2’-甲基-4-(6-甲基-3-吡啶基氨基)二苯酮(化合物117);
4-(5-溴-3-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物118);
4-(5-腈-3-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物119);
4-(3-溴-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物120);
2-氯-2’-甲基-4-(8-喹啉基氨基)二苯酮(化合物121);
2-氯-4-(6-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物122);
4-(4-溴-1-异喹啉基氨基)-2-氯-2’-甲基二苯酮(化合物123);
2-氯-2’-甲基-4-(2-甲基-5-三氟甲基-3-吡啶基氨基)二苯酮(化合物124);
2-氯-2’-甲基-4-(3-喹啉基氨基)二苯酮(化合物125);
2-氯-4-(4-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物126);
2-氯-4-(2-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物127);
2-氯-2’-甲基-4-(2-甲基-6-喹啉基氨基)二苯酮(化合物129);
2-氯-4-(7-氯-4-喹啉基氨基)-2’-甲基二苯酮(化合物130);
2-氯-2’-甲基-4-(2-喹啉基氨基)二苯酮(化合物131);
2-氯-2’-甲基-4-(4-喹啉基氨基)二苯酮(化合物132);
2-氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物133);
2-氯-2’-甲基-4-(1-甲基-5-吲哚基氨基)二苯酮(化合物134);
2-氯-2’,5’-二甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物135);
2-氯-2’,5’-二甲基-4-(4-异喹啉基氨基)二苯酮(化合物136);
2-氯-4-(4-异喹啉基氨基)-2’,4’,5’-三甲基二苯酮(化合物137);
2,3’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物138);
2-氟-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物139);
2,4’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物140);
2-氯-4’-氟-4-(4-异喹啉基氨基)-2’-甲基二苯酮(化合物141);
4’-正丁基-2-氯-4-(4-异喹啉基氨基)-2’-甲基二苯酮(化合物142);
2-氯-4-(5-异喹啉基氨基)-2’-甲基二苯酮(化合物143);
2-氯-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮(化合物144);
2-氟-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮(化合物145);
2,4’-二氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物146);
2-氯-4-(1-甲基-7-吲哚基氨基)-2’,4’,5’-三甲基二苯酮(化合物147);
2-氯-2’,5’-二甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物148);
2-氯-4-(3-乙氧基-4-异喹啉基氨基)-2’-甲基二苯酮(化合物149);
2-氯-4-(1-乙氧基-4-异喹啉基氨基)-2’-甲基二苯酮(化合物150);
4-(2-苯并噁唑基氨基)-2-氯-2’-甲基二苯酮(化合物151);
4-(1-甲基-2-苯并咪唑基氨基)-2-氯-2’-甲基二苯酮(化合物152);
4-(2-苯并噻唑基氨基)-2-氯-2’-甲基二苯酮(化合物153);
2-氯-2’-甲基-4-(2-嘧啶基氨基)二苯酮(化合物154);
2-氯-2’-甲基-4-(7-甲基-嘌呤-6-基氨基)二苯酮(化合物155);
2-氯-2’-甲基-4-(2-甲基-5-苯并噻唑基氨基)二苯酮(化合物156);
2-氯-2’-甲基-4-(吡嗪-2-基氨基)二苯酮(化合物157);
2-氯-2’-甲基-4-(5-嘧啶基氨基)二苯酮(化合物158);
2-氯-2’-甲基-4-(5-硝基-2-噻唑基氨基)二苯酮(化合物159);
2-氯-2’-甲基-4-((4-甲基-3-硝基-(1,2,4-三唑-5-基氨基))二苯酮(化合物160);
及其杂环R5取代基中的氮原子被特别氧化的N-氧化物。
更优选的化合物是:
2-氯-2’-甲基-4-(3-吡啶基氨基)二苯酮(化合物107);
4-(3-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物110);
2-氯-4-(4-异喹啉基氨基)-2-甲基二苯酮(化合物114);
2-氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物116);
2-氯-2’-甲基-4-(6-甲基-3-吡啶基氨基)二苯酮(化合物117);
4-(5-溴-3-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物118);
2-氯-2’-甲基-4-(8-喹啉基氨基)二苯酮(化合物121);
2-氯-4-(6-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物122);
2-氯-2’-甲基-4-(3-喹啉基氨基)二苯酮(化合物125);
2-氯-4-(4-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物126);
2-氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物133);
2-氯-2’-甲基-4-(1-甲基-5-吲哚基氨基)二苯酮(化合物134);
2-氯-2’,5’-二甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物135);
2-氯-2’,5’-二甲基-4-(4-异喹啉基氨基)二苯酮(化合物136);
2-氯-4-(4-异喹啉基氨基)-2’,4’,5’-三甲基二苯酮(化合物137);
2-氟-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物139);
2,4’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物140);
2-氯-4’-氟-4-(4-异喹啉基氨基)-2’-甲基二苯酮(化合物141);
2-氯-4-(5-异喹啉基氨基)-2’-甲基二苯酮(化合物143);
2-氯-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮(化合物144);
2-氟-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮(化合物145);
2-氯-4-((3-乙氧基)-4-异喹啉基氨基)-2’-甲基二苯酮(化合物149);
2-氯-4-((1-乙氧基)-4-异喹啉基氨基)-2’-甲基二苯酮(化合物150);
和N-氧化物:
2-氯-2’-甲基-4((2-吡啶基-N-氧化物)氨基)二苯酮(化合物112);
2-氯-2’-甲基-4-((3-吡啶基-N-氧化物)氨基)二苯酮(化合物113);
2-氯-4-((4-异喹啉基-N-氧化物)氨基)-2’-甲基二苯酮(化合物128)。
一般还优选式Ia的化合物和式Ib的化合物,在式Ia中,X=S且其中R1、R2、R3、R4、R5、R6、R7和R8如上所述;且在式Ib中,X=N-OH且其中R1、R2、R3、R4、R5、R6、R7和R8如上所述。
式Ia的特定化合物是:
2-氯-2’-甲基-4-(4-吡啶基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(2-吡啶基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(5-硝基-2-吡啶基氨基)硫代二苯酮;
4-(6-氨基-5-硝基-2-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
6-氯-2-(3-氯-4-(2-甲硫基苯甲酰基)苯基氨基)异烟酸;
4-(6-腈-2-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(3-吡啶基氨基)硫代二苯酮;
2-氯-4-(5,6-二氨基-2-吡啶基氨基)-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(3-硝基-2-吡啶基氨基)硫代二苯酮;
4-(3-氨基-2-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
4-(5-氨基-2-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
2-氯-4-(4-异喹啉基氨基)-2’-甲基(硫代二苯酮);
5-(3-氯-4-(2-甲硫基苯甲酰基)苯基氨基)烟酸叔丁酯;
2-氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(6-甲基-3-吡啶基氨基)硫代二苯酮;
4-(5-溴-3-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
4-(5-腈-3-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
4-(3-溴-2-吡啶基氨基)-2-氯-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(8-喹啉基氨基)硫代二苯酮;
2-氯-4-(6-乙氧基-3-吡啶基氨基)-2’-甲基(硫代二苯酮);
4-(4-溴-1-异喹啉基氨基)-2-氯-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(2-甲基-5-三氟甲基-3-吡啶基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(3-喹啉基氨基)硫代二苯酮;
2-氯-4-(4-乙氧基-3-吡啶基氨基)-2’-甲基(硫代二苯酮);
2-氯-4-(2-乙氧基-3-吡啶基氨基)-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(2-甲基-6-喹啉基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(2-喹啉基氨基)硫代二苯酮;
2-氯-4-(7-氯-4-喹啉基氨基)-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(4-喹啉基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)硫代二苯酮;和
2-氯-2’-甲基-4-(1-甲基-5-吲哚基氨基)硫代二苯酮;
2-氯-2’,5’-二甲基-4-(4-甲基-3-吡啶基氨基)硫代二苯酮;
2-氯-2’,5’-二甲基-4-(4-异喹啉基氨基)硫代二苯酮;
2-氯-4-(4-异喹啉基氨基)-2’,4’,5’-三甲基(硫代二苯酮);
2,3’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)硫代二苯酮;
2-氟-2’-甲基-4-(4-甲基-3-吡啶基氨基)硫代二苯酮;
2,4’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)硫代二苯酮;
2-氯-4’-氟-4-(4-异喹啉基氨基)-2’-甲基(硫代二苯酮);
4’-正丁基-2-氯-4-(4-异喹啉基氨基)-2’-甲基(硫代二苯酮);
2-氯-4-(5-异喹啉基氨基)-2’-甲基(硫代二苯酮);
2-氯-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基(硫代二苯酮);
2-氟-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基(硫代二苯酮);
2,4’-二氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)硫代二苯酮;
2-氯-4-(1-甲基-7-吲哚基氨基)-2’,4’,5’-三甲基(硫代二苯酮);
2-氯-2’,5’-二甲基-4-(1-甲基-7-吲哚基氨基)硫代二苯酮;
2-氯-4-(3-乙氧基-4-异喹啉基氨基)-2’-甲基(硫代二苯酮);
2-氯-4-(1-乙氧基-4-异喹啉基氨基)-2’-甲基(硫代二苯酮);
4-(2-苯并噁唑基氨基)-2-氯-2’-甲基(硫代二苯酮);
4-(1-甲基-2-苯并咪唑基氨基)-2-氯-2’-甲基(硫代二苯酮);
4-(2-苯并噻唑基氨基)-2-氯-2’-甲基(硫代二苯酮);
2-氯-2’-甲基-4-(2-嘧啶基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(2-甲基-嘌呤-6-基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(2-甲基-5-苯并噻唑基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(吡嗪-2-基氨基)硫代二苯酮;
2-氯-2’-甲基-4-(5-嘧啶基氨基)硫代二苯酮;
及其与可药用酸形成的盐、水合物和溶剂合物。
式Ib的特定化合物是:
2-氯-2’-甲基-4-(4-吡啶基氨基)二苯酮肟;
2-氯-2’-甲基-4-(2-吡啶基氨基)二苯酮肟;
2-氯-2’-甲基-4-(5-硝基-2-吡啶基氨基)二苯酮肟;
4-(6-氨基-5-硝基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
6-氯-2-((3-氯-4-((羟基亚氨基)(2-甲基苯基)甲基))苯基氨基)异烟酸;
4-(6-腈-2-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(3-吡啶基氨基)二苯酮肟;
2-氯-4-(5,6-二氨基-2-吡啶基氨基)-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(3-硝基-2-吡啶基氨基)二苯酮肟;
4-(3-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
4-(5-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
2-氯-4-(4-异喹啉基氨基)-2’-甲基二苯酮肟;
5-((3-氯-4-((羟基亚氨基)(2-甲基苯基)甲基))苯基氨基)烟酸叔丁酯;
2-氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮肟;
2-氯-2’-甲基-4-(6-甲基-3-吡啶基氨基)二苯酮肟;
4-(5-溴-3-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
4-(5-腈-3-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
4-(3-溴-2-吡啶基氨基)-2-氯-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(8-喹啉基氨基)二苯酮肟;
2-氯-4-(6-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮肟;
4-(4-溴-1-异喹啉基氨基)-2-氯-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(2-甲基-5-三氟甲基-3-吡啶基氨基)二苯酮肟;
2-氯-2’-甲基-4-(3-喹啉基氨基)二苯酮肟;
2-氯-4-(4-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮肟;
2-氯-4-(2-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(2-甲基-6-喹啉基氨基)二苯酮肟;
2-氯-2’-甲基-4-(2-喹啉基氨基)二苯酮肟;
2-氯-4-(7-氯-4-喹啉基氨基)-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(4-喹啉基氨基)二苯酮肟;
2-氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮肟;和
2-氯-2’-甲基-4-(1-甲基-5-吲哚基氨基)二苯酮肟;
2-氯-2’,5’-二甲基-4-(4-甲基-3-吡啶基氨基)二苯酮肟;
2-氯-2’,5’-二甲基-4-(4-异喹啉基氨基)二苯酮肟;
2-氯-4-(4-异喹啉基氨基)-2’,4’,5’-三甲基二苯酮肟;
2,3’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮肟;
2-氟-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮肟;
2,4’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮肟;
2-氯-4’-氟-4-(4-异喹啉基氨基)-2’-甲基二苯酮肟;
4’-正丁基-2-氯-4-(4-异喹啉基氨基)-2’-甲基二苯酮肟;
2-氯-4-(5-异喹啉基氨基)-2’-甲基二苯酮肟;
2-氯-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮肟;
2-氟-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮肟;
2,4’-二氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮肟;
2-氯-4-(1-甲基-7-吲哚基氨基)-2’,4’,5’-三甲基二苯酮肟;
2-氯-2’,5’-二甲基-4-(1-甲基-7-吲哚基氨基)二苯酮肟;
2-氯-4-(3-乙氧基-4-异喹啉基氨基)-2’-甲基二苯酮肟;
2-氯-4-(1-乙氧基-4-异喹啉基氨基)-2’-甲基二苯酮肟;
4-(2-苯并噁唑基氨基)-2-氯-2’-甲基二苯酮肟;
4-(1-甲基-2-苯并咪唑基氨基)-2-氯-2’-甲基二苯酮肟;
4-(2-苯并噻唑基氨基)-2-氯-2’-甲基二苯酮肟;
2-氯-2’-甲基-4-(2-嘧啶基氨基)二苯酮肟;
2-氯-2’-甲基-4-(7-甲基-嘌呤-6-基氨基)二苯酮肟;
2-氯-2’-甲基-4-(2-甲基-5-苯并噻唑基氨基)二苯酮肟;
2-氯-2’-甲基-4-(吡嗪-2-基氨基)二苯酮肟;
2-氯-2’-甲基-4-(5-嘧啶基氨基)二苯酮肟;
及其与可药用酸形成的盐、水合物和溶剂合物。
一般优选通式Ic的化合物及其与可药用酸形成的盐、水合物和溶剂合物:
其中R1、R2、R4、R5、R6、R7、R8和X如上所述且R3代表(C1-C3)烷基、氟、氯、溴、甲氧基和羟基。
在通式Ic中,R1优选代表甲基或卤素,更优选F或Cl;R2代表一个或多个取代基,优选氢、卤素、(C1-C3)烷基、甲氧基或乙氧基;且R3代表甲基、甲氧基或氯。
药理学方法
为了研究本发明化合物在体外的作用,使用下列步骤测定对IL-1β和TNF-α分泌的抑制作用:
在培养基中测定从脂多糖(LPS)刺激的外周血单核的细胞中产生的细胞因子。通过Lymphoprep(Nycomed,Norway)分级分离从人外周血中分离单核的细胞并将其悬浮于含有胎牛血清(FCS,2%)的RPMI1640(生长培养基)中,浓度为5×105个细胞/ml。以1mL等份将细胞在24孔组织培养板中培养。将测试化合物溶于二甲亚砜(DMSO,10mM)并用所述培养基稀释。将化合物加入到细胞中30分钟,然后加入LPS(终浓度为1mg/mL)。将板温育18小时并通过酶联免疫吸附测定法测定培养基中IL-1β和TNF-α的浓度。计算所述化合物的半数抑制浓度(IC50)。结果如表1中所示。
本发明的化合物还在抑制PMN(多形核白细胞)超氧化物分泌能力方面表现出相似的活性,也表明它们是潜在有效的抗炎药物。使用下列步骤测试所述的化合物:
通过对污染红细胞进行葡聚糖沉降、Lymphoprep分级分离和低渗裂解而从人血中分离人多形核(PMN)粒细胞。
将超氧阴离子的产生测定为可被超氧化物歧化酶抑制的高铁细胞色素C的还原(Madhu,S.B.等,《炎症》(Inflammation),16,241,(1992))。将细胞悬浮于Hanks’平衡盐溶液中并在37℃下与测试化合物一起温育10分钟。通过添加TNF-α(终浓度为3ng/mL)使细胞致敏10分钟,然后添加高铁细胞色素C(终浓度为750μg/mL)、牛血清白蛋白(BSA,终浓度为1mg/mL)和甲酰甲硫氨酰-亮氨酰-苯丙氨酸(fMLP,终浓度为10-7M)3分钟。将细胞在冰上冷却并旋转沉降。用分光光度计测定不含细胞的上清液中的光密度。计算化合物的半数抑制浓度(IC50)。结果与测试化合物的log P一起如表1中所示。
表1.本发明化合物在体外对细胞因子和PMN-超氧本发明化合物
化物产生的抑制作用。半数抑制浓度(IC50,的Log P
nM)
化合物序号 IL-1β TNF-α PMN-超氧化物
化合物114 31 5.0 15 4.2
化合物128 15.8 3.1 12.6 4.4
参比化合物 13 7.1 5.0 4.9
参比化合物:(4-(2-氨基苯基氨基)-2-氯-2’-甲基二苯酮WO98/32730中公开的化合物156。
这些结果表明本发明的化合物能够抑制IL-1β、TNF-α和PMN-超氧化物的产生,且显示了与参比化合物类似的药理活性,由此使得它们能够用于治疗炎性疾病。本发明的化合物较低的log P值反映出了较低的亲脂性,这一结果表明化合物与参比化合物相比具有改善的生物利用度。
p38αMAP激酶测定
细胞培养
COS-1细胞(来源于含有在SV40启动子控制下的野生型T抗原的非洲绿猴肾成纤维细胞样细胞)获自ATCC(ATCC号CRL-1650)并使之在37℃和5%CO2下生长在生长培养基中(不含酚红的DMEM、10%FCS、2mML-谷氨酰胺、100U青霉素和100μg链霉素/ml)。使细胞通过胰蛋白酶消化(0.25%胰蛋白酶、1mM EDTA的PBS溶液)每周传代两次并按1:10分裂。隔天或每隔2天换一次培养基。定期用支原体PCR引物组(Stratagene)测试细胞系并发现不含支原体。组织培养基、FCS、L-谷氨酰胺以及青霉素和链霉素来自Bribco BRL,Gaithersburg,MD,USA。
COS-1细胞的瞬时表达
在第1天将COS-1细胞接种在143cm2的培养皿内的生长培养基中、密度为2×104个细胞/cm2。在第2天将细胞用5μg(总计)表达FLAG-p38α和FLAG-MKK6(EE)的实验质粒DNA一起共转染。使用DOTAPTM(Boehringer Mannheim,Mannheim,Germany)将质粒导入在不含血清的培养基中的COS-1细胞中。使用QIAGEN不含内毒素的Maxiprep-500试剂盒(Hilden,Germany)制备质粒DNA并纯化。简单地说,在37℃下CO2培养箱中将DNA和DOTAPTM混合恰好15分钟。此后将转染混合物转入15-mL falcon-管并向该转染混合物中加入转染培养基(含有L-谷氨酰胺和青霉素/链霉素、但不含血清的DMEM),随后将其加入细胞单层。在与DOTAPTM和质粒一起温育4小时后,向细胞中加入含有双倍量血清的培养基,从而使血清终浓度达到10%。然后在激酶反应前将细胞培养24小时。
免疫沉淀
温育24小时后,通过将培养皿置于冰浴上终止该反应。吸出培养基并用冰冷PBS(137mM NaCl、1.5mM KH2PO4、2.7mM KCl、8.1mMNa2HPO4·2H2O)将细胞单层洗涤1次且此后加入1.5mL裂解缓冲液(50mM HEPES,pH7.5、150mM NaCl、10mM EDTA、10mM Na4P2O7、100mMNaF、2mM Na3VO4、1% Triton-X-100、Pefabloc 500μM、亮抑蛋白酶肽10μg/μl、抑酶肽10μg/μl)溶解10分钟。用胶乳刮刷刮取细胞单层并转入微量离心管。通过在4℃下以10,000×g离心10分钟使溶解的细胞澄清。将上清液转到50μl HNT-缓冲液(30mM HEPES,pH7.5、30mM NaCl、0.1%Triton X-100)中的预洗涤的蛋白质G琼脂糖珠并在室温下与2μg/样本的单克隆抗-FLAGTM M2抗体(针对FLAG-表位NH2-Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys-COOH产生)一起温育1小时。抗-FLAG M2单克隆抗体获自Sigma(目录号F-3165)。将约60μg澄清细胞裂解物的蛋白质加入预吸附在蛋白质G琼脂糖珠上的抗-FLAG抗体中,并在4℃下血样混合器中温育90分钟。在免疫沉淀期后,在裂解缓冲液中将琼脂糖珠洗涤2次并在激酶反应缓冲液(25mMHEPES,pH7.5、10mM乙酸镁、50μM ATP)中洗涤2次。
化合物与纯化的p38α激酶的温育
将预洗涤的免疫沉淀的吸附在蛋白质G琼脂糖珠上的抗FLAG-p38在1x激酶缓冲液(25mM HEPES pH7.5、10mM乙酸镁、50μM ATP)中洗涤2次并吸出上清液。将化合物用1x激酶缓冲液稀释至适宜浓度。在30℃下100μl体积中将该化合物加入到洗涤的免疫沉淀的和活化的吸附在蛋白质G琼脂糖珠上的FLAG-p38中30分钟。每10分钟轻拍微量离心管以确保所述珠和所述化合物处于溶液中。30分钟温育后,使所述珠旋转沉降并吸出上清液。
p38αMAP激酶反应
通过添加1μg GST-ATF-2底物(Santa Cruz,LaJolla,CA,USA,目录号sc-4114)与在1x激酶缓冲液中的2μCiγ-32P-ATP/样本来启动激酶反应。在30℃下使该反应进行30分钟并通过向激酶反应体系中添加40μl的2x SDS-样本缓冲液来终止该反应。使样本沸腾、旋转沉降并在15% SDS-PAGE上分离。使干的SDS-PAGE凝胶暴露于Phospho-Imager屏幕并通过应用ImageQuaNT软件用STORM860Phospho-Imager(Molecular Dynamics,Sunnyvale,CA,USA)对放射性PHAS-1条带进行定量。
在本试验中化合物114表现出的抑制作用如下表2中所示:
表2
化合物序号 抑制p38αMAP激酶的IC50值,平均浓度(nM)
化合物114 12.8
参比化合物SB203580 1056.6
参比化合物SB203580是用于p38αMAP激酶抑制的广泛使用的参比化合物。该化合物商购自Calbiochem(Calbiochem-NovabiochemLaJolla,CA,USA)。
这些结果表明:本发明的化合物与参比化合物相比是具有改善的药理活性的有效的p38αMAP激酶抑制剂,由此使得它们能够用于治疗炎性疾病。
为了在体内研究本发明化合物,可以使用12-O-十四酰佛波醇-13-乙酸酯(TPA)诱发的鼠慢性皮肤炎症模型(De Young,
L.M.等,《活性剂作用》(Agents Actions)26,335-341(1989);Carlson,R.P.等,《活性剂作用》(Agents Actions)17,197-204(1985);Alford,J.G.等,《活性剂作用》(Agents Actions)37,(1992);Stanley,P.L等,《皮肤药理学》(SkinPharmacol.)4,262-271(1991)),参见WO 98/32730中描述的方法,将该文献引入本文作为参考。这些结果表明本发明的化合物与已知的参比化合物例如具有公知副作用的氢化可的松相比具有相同的功效,而本发明的化合物可充分耐受且无毒性。本类化合物中的某些成员表现出吸收量极低,由此使得它们可特别用于治疗各种皮肤病。一般来说,它们可以通过例如口服、静脉内、鼻内、局部或经皮途径施用。
式I化合物的制备方法
可以通过有机合成技术领域普通技术人员所公知的许多方式来制备本发明的化合物。可以使用下述方法和合成有机化学领域中公知的方法或其如本领域技术人员所理解的变化形式来合成本发明的化合物。优选的方法包括但不限于下述的那些方法。
可以使用该部分中所述的反应和技术来制备式I、Ia和Ib的新型化合物。反应在适于所用试剂和物质的溶剂中进行且该反应适合于完成转化。此外,在下述合成反应中,可以理解的是将包括溶剂选择、反应气氛、反应温度、实验持续时间和操作步骤在内的所有提出的反应条件选作应由本领域技术人员易于认可的该反应的标准条件。有机合成领域的普通技术人员应理解离析物分子中各部分上存在的官能团必须与所提出的试剂和反应相容。并非所有属于指定类型的式I的化合物都可以与某些所述方法中所需的反应条件相容。这类对与反应条件相容的取代基的限制对本领域技术人员而言是显而易见的且可以使用可选择的其它方法。
在本说明书中使用下列缩写:BINAP=外消旋的或非外消旋的2,2’-双(二苯膦基)-1,1’-联萘;CDCl3=氘氯仿;DMF=N,N-二甲基甲酰胺;DMSO-d6=六氘二甲亚砜;DMSO=二甲亚砜;EtOAc=乙酸乙酯;Et2O=乙醚;Pd2(dba)3=三(二亚苄基丙酮)二钯(O);mCPBA=间氯过苯甲酸;MeOH=甲醇;NaOt-Bu=叔丁醇钠;KOt-Bu=叔丁醇钾;THF=四氢呋喃;TLC=薄层层析法。
反应流程1
L:F、Cl、Br、I或OSO2CF3
Y:C1、Br、I、OSO2R’
FGI:官能团互变
可以通过一种方法来制备本发明的化合物,该方法包括下列步骤:如反应流程1中所示使式III的胺与式II的溴化物、碘化物、氟化物、氯化物或三氟甲磺酸盐偶联,其中R1、R2、R3、R4、R5和X如通式I中所定义,但除外下列情况:在该偶联反应中可能起反应的任意取代基或官能基在进行偶联反应前本身可以被保护且随后被除去。
使用有机合成领域普通技术人员所公知的用于形成二苯胺类的任意方法来进行偶联反应。
优选的方法是钯催化的氨基化方法,该方法包括下列步骤:在有碱、合适的Pd源和合适的膦配体存在的情况下在惰性溶剂中使胺与杂芳基卤化物(或杂芳基三氟甲磺酸盐)偶联。(参考文献:Wolfe,J.P.;Wagaw,S.;Buchwald,S.L.;《美国化学协会杂志》(J.Am.Chem.Soc.),(1996),118,7215-16;Wagaw,S.;Buchwald,S.L.;《有机化学杂志》(J.Org.Chem.),(1996),61,7240-41;Wolfe,J.P.;Buchwald,S.L.;《四面体通讯》(Tetrahedron Lett.),(1997),38,6359-62;Hong.Y.等,《四面体通讯》(TetrahedronLett.),(1997),38,5607-10)。
对在本方法中所用的钯化合物没有特别限定,且作为特定的实例是乙酸钯(II)、氯化钯(II)、溴化钯(II)、二氯双(三苯膦)钯(II)、四(三苯膦)钯(O)、三(二亚苄基丙酮)二钯(O)。优选的配体包括但不限于外消旋的或非外消旋的2,2’-双(二苯膦基)-1,1’-联萘(下文称作BINAP)、三-o-甲苯基膦、三叔丁基膦、1,1’-双(二苯膦基)-二茂铁、双[(2-二苯膦基)苯基]醚(DPEphos)、2-二环己基苯膦基-2’-二甲氨基联苯、2-(二叔丁基膦基)联苯和9,9-二甲基-4,6-双(二苯膦基)呫吨(Xantphos)。在本方法中所用的钯和配体的量一般占所用芳香卤化物(或三氟甲磺酸盐)用量的0.1-10%(摩尔)。
特别是已经证实NaOt-Bu和碳酸铯(Cs2CO3)是本方法中最佳的碱,但也可以使用其它的碱。
该反应一般在升温(80-120℃)条件下和如1,4-二噁烷、甲苯、苯和四氢呋喃这样的惰性溶剂中以及如氩气和氮气这样的惰性气体环境中进行。
该偶联反应还可以在有碱存在的情况下在极性非质子溶剂中或不使用溶剂通过用胺亲核取代杂芳基卤化物来进行。优选的碱是KOt-Bu或NaH,但也可以使用其它碱。优选的溶剂是二甲亚砜,但也可以使用诸如DMF这样的其它溶剂。该反应在升温(120℃-150℃)下进行12-24小时。
可以通过一种方法来制备其中R4不是氢的本发明化合物,该方法包括下列步骤:如反应流程1中所示使式I(R4=H)的胺与烷基化剂偶联,其中R1、R2、R3、R5和X如通式I中所定义,但除外下列情况:在该偶联反应中可能起反应的任意取代基或官能基在进行偶联反应前本身可以被保护且随后被除去。
通式R-Y的烷化剂一般包括但不限于碘化物(Y=I)、溴化物(Y=Br)、氯化物(Y=Cl)和磺酸酯(Y=OSO2R’,其中R’代表甲基、三氟甲基或4-甲基苯基)。
在特定的情况中,可以通过简单的官能基互变(FGI)来制备本发明的化合物,即一种有机合成领域普通技术人员所公知的标准方法,其中在一个或多个合成步骤中将具有通式I的化合物上的官能基转化成不同的官能基,从而产生具有通式I的新化合物。这类方法的实例有、但不限于在碱性条件下将酯水解产生酸;通过用例如三溴化硼(BBr3)处理而使甲基醚去保护而得到苯酚;对烯烃催化氢化而得到饱和烃和将硝基还原得到胺。
可以通过这类FGI法、通过使用有机合成领域普通技术人员所公知的许多硫代羰基化试剂之一而由酮(具有通式I,C=O)来制备X=S的通式I的本发明化合物。这类硫代羰基化试剂的实例包括但不限于五硫化二磷(P4S10)或Lawesson’s试剂(2,4-双(4-甲氧基苯基)-1,3,2,4-dithiaphosphetane-2,4-二硫化物)等。
相应地,可以在类似于例如吡啶或甲醇这样的适宜溶剂中通过用羟胺处理或用其保护的衍生物处理、随后去保护而由酮(具有通式I,C=O)来制备X=N-OH的通式I的本发明化合物。
反应流程2
可以通过几种有机合成领域普通技术人员所公知的方法来制备具有通式III的本发明化合物。一种可用的程序如反应流程2中所示。关键步骤包括使通式VI的溴化物(或碘化物)与通式V的酰基氯偶联而得到具有通式IV的二苯酮。然后可以通过用标准还原剂处理而将该化合物IV还原成相应的具有通式III的胺。这类还原剂的实例包括但不限于氯化亚锡二水合物、氢、甲酸铵或水合肼和催化量的钯/碳。通过将所述的溴化物(VI)转化成活性有机金属中间体、例如通过用丁基锂处理而得到锂衍生物或通过用镁处理而得到镁衍生物来完成该偶联反应。然后通过金属转移成例如锌(通过用ZnCl2、ZnBr2或Znl2处理)来调节这种中间体的反应性。接着在催化量的钯(O)复合物的影响下使这种有机锌化合物与通式V的酰基氯偶联。这类催化剂的实例包括但不特别限于四(三苯膦)钯(O)、四(三苯胂)钯(O)、二氯双(三苯膦)钯(II)或苄基氯双(三苯膦)钯(II)。
正如反应流程2中所示,可以通过FGI法将具有通式IV(X=O)的化合物转化成具有如上所述的通式IV(X=S或X=N-OH)的化合物。这只是为了举例说明合成中的灵活性且一般来说所述的反应顺序仅是合成本发明化合物的许多可能的策略之一。也就是说,在某些情况中,更有利的是改变上述反应顺序。并不将所述的反应顺序看作是对于制备具有通式I的本发明化合物的限制,且对反应顺序的改变对有机合成领域的普通技术人员而言显然是可选择的。
药物组合物
本发明在另一个方面中涉及包含式I、Ia、Ib或Ic的化合物作为活性成分和可药用赋形剂或载体的药物组合物。术语″可药用″用以指在该组合物中包括的赋形剂或载体与其它成分相容且对施用组合物的患者而言是无毒性或是无害的。
本发明的药物组合物可以是诸如片剂、丸剂、胶囊、粉剂、颗粒、酏剂、糖浆剂、乳剂、安瓿、栓剂或非肠道用溶液或混悬液这样的单位剂型用于口服、非肠道、眼部、经皮、关节内、局部、肺部、鼻部、口含或直肠给药或适于抗炎化合物制剂和符合认可的实践操作的任意其它形式,诸如那些公开在Remington的《制药学科学与实践》(TheScience and Practice of Pharmacy.)第19版,Mack PublishingCompany,1995中。术语″单位剂量″用以指一个单元,即能够施用于患者的且易于操作和包装的单一剂量,保持作为包含所述的活性成分或其与固体或液体药物赋形剂或载体的混合物的物理和化学稳定的单位剂量。在本发明的组合物中,活性成分的含量约为该组合物重量的0.1-100%。
就以片剂或胶囊形式口服而言,可以将式I的化合物适当与诸如乙醇、甘油、水等这样口服无毒性的可药用载体混合。此外,如果合适,可以向该混合物中加入合适的粘合剂、润滑剂、崩解剂、调味剂和着色剂。合适的粘合剂包括例如乳糖、葡萄糖、淀粉、明胶、阿拉伯胶、黄蓍胶、藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。润滑剂包括例如油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括例如淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
就制备诸如片剂这样的固体组合物而言,将式I的活性化合物与一种或多种诸如上述的赋形剂和其它诸如水这样的药物稀释剂混合来制备含有式I化合物的均匀混合物的固体预制组合物(preformulation composition)。将术语″均匀的″理解为将通式I的化合物均匀分散在整个组合物中,使得可以易于将该组合物再分成等效的诸如片剂或胶囊这样的单位剂型。然后将预制组合物再分成含有约0.05至约1000mg、特别是约0.1至约500mg本发明活性化合物的单位剂型。
用于口服或非肠道施用本发明化合物的液体制剂包括例如水溶液、糖浆剂、含水混悬液或油混悬液和含有诸如棉籽油、芝麻油、椰子油或花生油这样的可食用油的乳剂。含水混悬液用的合适分散剂或混悬剂包括诸如黄蓍胶、藻酸盐、阿拉伯胶、葡聚糖、羧甲基纤维素钠、明胶、甲基纤维素或聚乙烯吡咯烷酮这样的合成或天然树胶。
就例如肌内、腹膜内、皮下或静脉内注射或输注这样的非肠道给药而言,所述的药物组合物优选包含溶于或溶解于适宜的可药用溶剂的式I的化合物。就非肠道给药而言,本发明的组合物可以包括无菌含水溶剂或非水溶剂、特别是水、等渗盐水、等渗葡萄糖溶液、缓冲溶液或通常用于治疗活性物质、特别是抗增殖药的非肠道给药的其它溶剂。可以通过例如截留细菌的滤器过滤、向该组合物添加灭菌剂、照射该组合物或加热该组合物来令组合物灭菌。或者,可以将本发明的化合物制成无菌的固体制剂,例如在应用前立即溶于无菌溶剂的冻干粉。
非肠道给药用的组合物可以另外包括诸如稳定剂、缓冲剂或防腐剂这样的常用添加剂,例如诸如甲基羟基苯甲酸酯等这样的抗氧化剂。
直肠给药用组合物可以是混有活性成分和诸如可可脂这样的载体的栓剂的形式或灌肠剂的形式。
适于关节内给药的组合物可以是活性成分的无菌含水制剂形式,其可以为微晶形式、例如含水的微晶混悬液形式。还可以将脂质体制剂或可生物降解的聚合物系统用于活性成分的关节内或眼部给药。
适于局部给药包括眼部治疗在内的组合物包括:液体或半液体制剂,诸如搽剂、洗剂、凝胶、涂敷剂(applicants)、水包油或油包水型乳剂,诸如霜剂、软膏剂或糊剂;或溶液或混悬液,诸如滴剂。就局部给药而言,活性成分优选占组合物重量的1%-20%,不过,活性成分可以占到达50%w/w。
适于对鼻部或口腔给药或用于吸入的组合物包括粉末、诸如气雾剂和喷雾剂这样的自推进喷雾制剂。适于鼻部或口腔给药的组合物可以包括0.1%-20%w/w、例如约2%w/w的活性组分。
所述的组合物可以另外包括一种或多种通常用于治疗各种炎性疾病和疾患的活性成分。这类其它活性成分的实例可以选自糖皮质激素、维生素D和维生素D类似物、抗组胺药、血小板活化因子(PAF)拮抗剂、抗胆碱能药、甲基黄嘌呤、β-肾上腺素能药、COX-2抑制剂、水杨酸盐类、吲哚美辛、氟芬那酸、萘普生、替美加定、金盐、青霉胺、降血清胆固醇药、类维生素A、锌盐和柳氮磺胺吡啶。
本发明在另一个方面中涉及式I的化合物在制备用于治疗或预防炎性疾病或疾患的药物中的用途。本发明的另一个方面中涉及一种炎性疾病或疾患的治疗方法,该方法包括对需要治疗的患者施用有效量的式I的化合物。
本发明化合物的合适剂量特别取决于选择用于治疗的特定化合物、给药途径、患者年龄和一般健康情况、所治疗疾病的严重程度和有经验临床医师众所周知的其它因素。可以按照例如每天或每周间隔这样的不同给药方案经口腔或经肠道外给予所述的化合物。一般来说,单剂量可以在0.01-400mg/kg体重、诸如0.1-100mg/kg体重的范围。可以将所述化合物作为大丸给药(即一次给予全部日剂量)或每天分剂量给予2次或多次。
预计用本发明化合物治疗的炎性疾病或疾患是可以由MAP激酶诸如如上所述p38MAP激酶介导对细胞因子表达和分泌的调节的炎性疾病。认为由p38MAP激酶介导的炎性疾病或疾患的实例选自下列疾病组成的组:哮喘;过敏反应;关节炎,包括类风湿性关节炎、骨关节炎和脊椎关节炎;痛风;动脉粥样硬化;炎性肠病;局限性回肠炎;增殖性和炎性皮肤病,诸如银屑病、特应性皮炎和寻常痤疮;眼色素层炎;脓毒病;败血症性休克;与AIDS相关的疾病;和骨质疏松。
所述治疗可以另外包括给予一种或多种其它抗炎活性成分诸如糖皮质激素、维生素D或维生素D类似物、抗组胺药、血小板活化因子(PAF)拮抗剂、抗胆碱能药、甲基黄嘌呤、β-肾上腺素能药、COX-2抑制剂、水杨酸盐类、吲哚美辛、氟芬那酸、萘普生、替美加定、金盐、青霉胺、降血清胆固醇药、类维生素A、锌盐和柳氮磺胺吡啶。
本发明进一步通过下列通用步骤、制备和实施例来描述,但这些通用步骤、制备和实施例不以任何方式来限定所要求保护的本发明范围。
实施例
通用步骤、制备和实施例
式I化合物的特定实例列在表3中。所有的熔点均未作校正。除非另有说明,使用以内标四甲基硅烷(δ0.00)或氯仿(1H NMR δ7.25,13CNMR δ76.81)为基准的氘代氯仿和六氘代二甲亚砜溶液,就1H和13C核磁共振(NMR)光谱(对1H为300MHz)而言,引用化学位移值(δ)(按ppm计)。将最终定义为双峰(d)、三重峰(t)或四重峰(q)的多峰(m)值指定在近似中间的点上,否则另外例举。还将信号定义为单峰(s)或宽峰(b)。所用的有机溶剂是无水的。术语″层析法″指的是使用急骤技术的柱层析法且在硅胶上进行。
表3通式I的化合物
表3中的编号方式指的是下列通式中的编号方式,R6和R7如通式I所定义:
通用步骤1
通式II的化合物与通式III的化合物偶联得到通式I的化合物或其被护衍生物。
在螺丝帽容器中,将具有通式III的胺(1.0eq.)溶于1,4-二噁烷或甲苯,并加入具有通式II的卤化物(1.0-1.1eq.)。将该容器用氩气吹洗并加入碱(Cs2CO3或NaOt-Bu,1.4eq.)、Pd2(dba)3(0.02eq.)和BINAP(0.04eq.),将该容器再次用氩气吹洗并密封。首先将所得混悬液在室温下剧烈振摇5分钟,然后在100℃-110℃下剧烈振摇4-20小时或直到在TLC上观察到卤化物II消失为止。使该反应混合物冷却至室温。将该反应混合物倾入EtOAc和水的混合物。分离有机相并用EtOAc将水相提取3次。将合并的有机相用水和饱和NaCl水溶液洗涤、干燥(MgSO4)、过滤并在真空中浓缩。将残余物通过层析法和/或结晶法纯化而得到具有通式I的偶联产物或其被护衍生物。
通用步骤2
通式II的化合物与通式III的化合物偶联得到通式I的化合物或其被护衍生物。
将具有通式(III)的胺(1eq.)溶于DMSO(0.1-0.2M)并加入通式(II)的杂芳基氯化物或杂芳基氟化物(1eq.)。如果将化合物I I制成盐酸盐,那么将2eq.或3eq.的叔丁醇钾溶于DMSO(0.2-0.4M)并逐滴向上述反应混合物中加入该溶液。在120-150℃氩气环境中将该反应混合物搅拌12-24小时。将该反应混合物倾入水并用EtOAc提取3次。将合并的有机相用水和饱和NaCl水溶液洗涤、干燥(MgSO4)、过滤并在真空中浓缩,且将粗产物通过急骤层析法纯化而得到具有通式I的偶联产物或其被护衍生物。
通用步骤(3)
通式VI的化合物与通式V的化合物偶联得到通式IV的化合物或其护衍生物。
将具有通式VI的溴化物(80mmol)溶于干THF(65mL)并在氩气环境中通过搅拌冷却至-78℃。然后逐滴加入正丁基锂(80mmol,1.6M己烷溶液),保持内部温度低于-65℃并再将所得混合物搅拌15分钟。逐滴加入ZnCl2的THF溶液(100mmol,1.0M)并将该反应混合物温至室温。2小时后将该反应混合物冷却至0℃并加入四(三苯膦)钯(0)(4.0mmol),随后逐滴添加具有通式V的酰基氯(84mmol)的THF溶液。将该反应混合物温至20℃并搅拌约16小时。过滤所得黄色溶液并将滤液倾入EtOAc/水的1∶1混合物、振摇并分离。将水相再用两部分的EtOAc提取。将有机相合并、干燥(MgSO4)、过滤并在真空中浓缩而得到粗产物。通过急骤层析法和/或结晶法进一步纯化而得到标题化合物IV或其被护衍生物。
通用步骤(4)
用氯化亚锡二水合物将通式IV的化合物还原成通式III的化合物或其被护衍生物。
在氩气环境中将具有通式IV的化合物(5mmol)与氯化亚锡二水合物(5.64g,25mmol)在无水乙醇(50mL)中的混合物加热至70℃。1小时后,或在TLC上观察到原料消失为止,将该溶液冷却至室温且然后倾入冰/水。通过添加饱和氢氧化钠(50mL)使pH呈碱性,此后用乙酸乙酯(3×100mL)提取。将有机相干燥(MgSO4)、过滤并蒸发以得到粗产物。通过结晶法或急骤层析法进一步纯化粗产物而得到标题化合物或其被护衍生物。
通用步骤(5)
用mCPBA将通式I的化合物氧化得到相应的N-氧化物
将通式I的化合物(1eq.)溶于CH2Cl2并加入mCPBA(1.2eq.)且将该反应混合物在室温下搅拌1-3小时。加入Na2S2O5(1.5eq.)并将该混悬液搅拌并过滤。向滤液中加入K2CO3(3eq.)并搅拌0.5-1小时。加入MgSO4、过滤该混悬液并在真空中浓缩滤液。通过急骤层析法和/或通过结晶法进行纯化。
制备1:
2-氯-4-硝基-2’-甲基二苯酮,(化合物1)
通用步骤:3
原料化合物VI:2-溴甲苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:使用EtOAc/戊烷1∶9作为洗脱剂的层析法
13C NMR(CDCl3):δ195.1,148.9,145.5,140.6,135.0,133.1,132.7,132.4,131.9,130.0,125.9,125.4,121.9,21.5
制备2:
4-氨基-2-氯-2’-甲基二苯酮,(化合物2)
通用步骤:4
原料化合物IV:2-氯-4-硝基-2’-甲基二苯酮(化合物1)
纯化:使用EtOAc/戊烷1∶9、随后是EtOAc/戊烷1∶4作为洗脱剂的层析法
13C NMR(CDCl3):δ196.7,150.5,139.5,137.6,135.1,133.9,131.2,130.7,129.5,127.5,125.3,116.0,112.2,20.3
制备3:
2-氯-4’-甲氧基-2’-甲基-4-硝基二苯酮(化合物3)
通用步骤:3
原料化合物VI:2-溴-5-甲氧基甲苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:从MeOH/环己烷10∶1中结晶
13C NMR(CDCl3):δ193.3,163.3,148.6,146.3,144.3,135.5,132.4,129.6,127.5,125.3,121.9,118.1,110.9,55.5,22.4
制备4:
4-氨基-2-氯-4’-甲氧基-2’-甲基二苯酮(化合物4)
通用步骤:4
原料化合物IV:2-氯-4’-甲氧基-2’-甲基-4-硝基二苯酮(化合物3)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ195.7,161.7,149.6,141.6,134.2,133.3,132.8,131.4,129.1,117.0,115.8,112.4,110.3,55.3,21.3
制备5:
2,4’-二氯-2’-甲基-4-硝基二苯酮(化合物5)
通用步骤:3
原料化合物VI:2-溴-5-氯甲苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:使用EtOAc/戊烷1∶15、随后是EtOAc/戊烷1∶10作为洗脱剂的层析法
13C NMR(CDCl3):δ194.1,149.0,145.0,142.6,139.4,133.5,133.1,132.7,132.5,130.1,126.1,125.5,122.0,21.4
制备6:
4-氨基-2,4’-二氯-2’-甲基二苯酮(化合物6)
通用步骤:4
原料化合物IV:2,4’-二氯-2’-甲基-4-硝基二苯酮(化合物5)
13C NMR(CDCl3):δ195.4,150.5,139.8,137.9,136.5,135.1,133.7,131.2,130.9,127.5,125.6,115.9,112.3,20.2
制备7:
2-氯-4’-氟-2’-甲基-4-硝基二苯酮(化合物7)
通用步骤:3
原料化合物VI:2-溴-5-氟甲苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:使用Et0Ac/戊烷1∶20作为洗脱剂的层析法
13C NMR(CDCl3):δ193.7,165.1,148.9,145.3,144.6,134.7,132.6,131.4,129.9,125.5,122.0,119.5,113.0,21.8
制备8:
4-氨基-2-氯-4’-氟-2’-甲基二苯酮(化合物8)
通用步骤:4
原料化合物IV:2-氯-4’-氟-2’-甲基-4-硝基二苯酮(化合物7)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ195.4,163.9,150.3,141.5,135.5,134.9,133.5,132.2,128.0,118.1,115.9,112.4,112.3,20.6
制备9.
2-氟-4-硝基-2’-甲基二苯酮(化合物9)
通用步骤:3
原料化合物VI:2-溴甲苯
原料化合物V:2-氟-4-硝基-苯甲酰氯
纯化:从MeOH/环己烷6∶1混合物中结晶
13C NMR(CDCl3):δ193.1,159.9,150.3,139.3,136.4,133.8,132.6,132.1,131.7,130.8,125.8,119.4,112.4,21.0
制备10.
4-氨基-2-氟-2’-甲基二苯酮(化合物10)
通用步骤:4
原料化合物IV:2-氟-4-硝基-2’-甲基二苯酮(化合物9)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ194.3,163.8,153.0,140.7,136.1,134.0,130.8,129.9,127.9,125.3,116.8,110.1,101.3,19.8
制备11:
2-氯-2’,5’-二甲基-4-硝基二苯酮(化合物11)
通用步骤:3
原料化合物VI:2-溴-1,4-二甲苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ195.3,148.9,145.6,137.4,135.5,135.0,133.9,132.8,132.3,132.2,130.0,125.5,121.9,21.1,20.8
制备12:
4-氨基-2-氯-2’,5’-二甲基二苯酮(化合物12)
通用步骤:4
原料化合物IV:2-氯-2’,5’-二甲基-4-硝基二苯酮(化合物11)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ196.8,150.2,139.3,135.1,134.9,134.5,133.8,131.4,131.1,130.0,128.0,116.0,112.2,20.8,19.9
制备13:
2,3’-二氯-2’-甲基-4-硝基二苯酮(化合物13)
通用步骤:3
原料化合物VI:2-溴-3-氯甲苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:从MeOH/环己烷9∶1混合物中结晶
13C NMR(CDCl3):δ194.6,149.2,144.5,138.2,137.3,137.0,133.5,133.2,130.7,129.0,126.5,125.7,122.0,17.3
制备14:
4-氨基-2,3’-二氯-2’-甲基二苯酮(化合物14)
通用步骤:4
原料化合物IV:2,3’-二氯-2’-甲基-4-硝基二苯酮(化合物13)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ195.3,150.9,142.4,135.8,135.8,134.8,134.6,131.0,126.8,126.7,126.4,116.2,112.2,17.1
制备15:
2-氟-4’-甲氧基-2’-甲基-4-硝基二苯酮(化合物15)
通用步骤:3
原料化合物VI:2-溴-5-甲氧基甲苯
原料化合物V:2-氟-4-硝基-苯甲酰氯
纯化:从MeOH/环己烷/CH2Cl2混合物中重结晶
13C NMR(CDCl3):δ191.3,163.1,159.3,143.6,135.0,134.8,131.2,128.5,119.4,117.8,112.2,110.8,55.5,22.1
制备16:
4-氨基-2-氟-4’-甲氧基-2’-甲基二苯酮(化合物16)
通用步骤:4
原料化合物IV:2-氟-4’-甲氧基-2’-甲基-4-硝基二苯酮(化合物15)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ193.4,163.1,161.2,152.2,140.1,133.7,132.6,131.7,117.8,116.6,110.3,110.1,101.3,55.3,20.7
制备17:
2-氯-4-硝基-2’,4’,5’-三甲基二苯酮(化合物17
通用步骤:3
原料化合物VI:5-溴-1,2,4-三甲基苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:从EtOAc中重结晶
EO 01720-000(CDCL3)
13C NMR(CDCl3):δ194.8,148.7,146.1,143.0,138.3,134.1,134.0,133.4,132.6,132.5,129.8,125.4,121.9,21.2,19.9,19.2
制备18:
4-氨基-2-氯-2’,4’,5’-三甲基二苯酮(化合物18)
通用步骤:4
原料化合物IV:2-氯-4-硝基-2’,4’,5’-三甲基二苯酮(化合物17)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ196.6,149.9,140.0,136.6,135.5,134.7,133.4,132.7,131.4,128.5,115.9,112.2,20.0,19.7,19.1
制备19:
4’-正丁基-2-氯-2’-甲基-4-硝基二苯酮(化合物19)
通用步骤:3
原料化合物VI:4-正丁基-2-甲基碘苯
原料化合物V:2-氯-4-硝基-苯甲酰氯
纯化:层析法,洗脱剂EtOAc∶石油醚1∶15
13C NMR(CDCl3):δ194.6,149.2,148.7,146.0,141.1,132.7,132.7,132.6,132.3,129.8,125.9,125.3,121.8,35.7,33.1,22.4,21.8,13.9
制备20.
4-氨基-4’-正丁基-2-氯-2’-甲基二苯酮(化合物20)
通用步骤:4
原料化合物IV:4’-正丁基-2-氯-2’-甲基-4-硝基二苯酮(化合物19)
纯化:通过硅胶短柱过滤
13C NMR(CDCl3):δ196.5,150.0,146.3,138.3,136.5,134.7,133.4,131.5,130.4,128.4,125.3,115.9,112.2,35.6,33.3,22.4,20.6,13.9
实施例1:2-氯-2’-甲基-4-(4-吡啶基氨基)二苯酮(化合物101),
通用步骤:2
原料化合物II:4-氯-吡啶盐酸盐(0.30g,2.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:DMSO(15mL)
碱:叔丁醇钾(0.67g,6.0mmol)的DMSO(10mL)溶液
反应时间:22小时
反应温度:150℃
纯化:使用EtOAc∶MeOH 15∶1的层析法
产物:化合物101,0.20g油状物
1H NMR(CDCl3):δ8.39(d,1H),7.43(d,1H),7.40-7.20(m,5H),7.08(dd,1H),6.97(d,3H),2.50(s,3H)
实施例2:2-氯-2’-甲基-4-(2-吡啶基氨基)二苯酮(化合物102),
通用步骤:2
原料化合物II:2-氯-吡啶(0.19mL,2.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:DMSO(15mL)
碱:叔丁醇钾(0.45g,4.0mmol)的DMSO(10mL)溶液
反应时间:22小时
反应温度:150℃
纯化:使用EtOAc∶石油醚1∶5的层析法
产物:化合物102,0.21g油状物
1H NMR(CDCl3):88.28(d,1H),7.65(d,1H),7.58(t,1H),7.41(d,1H),7.40-7.25(m,4H),7.19(t,1H),6.95(s,1H),6.86(m,2H),2.47(s,3H)
实施例3:2-氯-2’-甲基-4-(5-硝基-2-吡啶基氨基)二苯酮(化合物103)
通用步骤:2
原料化合物II:2-氯-5-硝基-吡啶(0.32g,2.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:DMSO(10mL)
碱:叔丁醇钾(0.45g,4.0mmol)的DMSO(20mL)溶液
反应时间:18小时
反应温度:150℃
纯化:使用EtOAc∶石油醚2∶7-1∶3的层析法
产物:化合物103,0.09g结晶化合物
13C NMR(丙酮d-6):δ196.7,159.4,146.2,144.2,139.2,139.0,138.8,133.8,133.6,133.5,132.4,132.4,132.3,131.0,126.5,121.0,118.3,112.1,20.8
实施例4:4-(6-氨基-5-硝基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物104),
通用步骤:2
原料化合物II:2-氨基-6-氯-3-硝基-吡啶(0.69g,4.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.98g,4.0mmol)
溶剂:DMSO(15mL)
碱:叔丁醇钾(0.90g,8.0mmol)的DMSO(25mL)溶液
反应时间:48小时
反应温度:150℃
纯化:使用CH2Cl2∶EtOAc 50∶1-30∶1的层析法
产物:化合物104,0.58g结晶化合物
13C NMR(DMSO):δ195.9,157.7,154.7,143.5,138.0,137.4,135.7,131.9,131.8,131.5,131.4,129.9,125.8,119.9,119.5,117.5,103.2,20.2
实施例5:6-氯-2-(3-氯-4-(2-甲基苯甲酰基)苯基氨基)异烟酸(化合物105),
通用步骤:2
原料化合物II:2,6-二氯-4-氰基-吡啶(0.70g,4.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.98g,4.0mmol)
溶剂:DMSO(15mL)
碱:叔丁醇钾(0.90g,8.0mmol)的DMSO(25mL)溶液
反应时间:48小时
反应温度:150℃
纯化:使用EtOAc∶MeOH 5∶1的层析法
产物:化合物105,0.52g油状物,在反应或操作过程中氰基取代基已经水解。
13C NMR(DMSO):δ195.7,166.6,154.8,150.5,147.2,145.0,138.4,137.0,132.3,132.1,131.2,131.1,129.5,129.4,125.7,118.0,115.6,114.8,111.3,20.0
实施例6:4-(6-腈-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物106),
通用步骤:2
原料化合物II:2-氯-3-氰基-吡啶(0.28g,2.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:DMSO(10mL)
碱:叔丁醇钾(0.45g,4.0mmol)的DMSO(20mL)溶液
反应时间:18小时
反应温度:150℃
纯化:使用EtOAc∶石油醚1∶1-1∶0的层析法
产物:化合物106,0.07g结晶化合物
13C NMR(CDCl3):δ195.9,155.5,144.3,142.9,142.1,140.3,140.0,136.0,133.2,132.6,132.1,131.8,131.1,128.8,125.7,125.3,115.7,105.7,102.4,21.3
实施例7:2-氯-2’-甲基-4-(3-吡啶基氨基)二苯酮(化合物107),
通用步骤:1
原料化合物II:3-氯-吡啶(1.18mL,12.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(2.95g,12.0mmol)
溶剂:甲苯(60mL)
碱:叔丁醇钠
反应时间:45小时
反应时间:45小时
反应温度:110℃
纯化:使用CH2Cl2∶丙酮4∶1的层析法
产物:化合物107,2.05g结晶化合物
13C NMR(CDCl3):δ196.5,146.8,144.4,142.7,138.7,138.1,137.3,134.9,133.3,131.4,131.1,130.4,129.9,127.1,125.4,124.0,117.0,113.4,20.5
实施例8:2-氯-4-(5,6-二氨基-2-吡啶基氨基)-2’-甲基二苯酮(化合物108),
将化合物104(0.38g,1.0mmol)溶于EtOH (10mL)和DMF(10mL)。加入SnCl2*H2O(1.12g,5.0mmol)并在90℃下将该溶液搅拌20小时。将该反应混合物倾入冰水(100mL),加入2N NaOH(50mL)并用EtOAc(50mL)和Et2O(2×50mL)提取水相。将合并的有机相用饱和NaCl水溶液(50mL)洗涤、干燥(Na2SO4)、过滤并在真空中浓缩。通过急骤层析法(EtOAc∶石油醚2∶1-1∶0)纯化残余物。
产物:化合物108,0.05g油状物
13C NMR(CDCl3):δ196.7,148.9,146.2,145.6,139.2,137.9,134.6,133.1,131.2,130.8,129.7,129.2,126.7,125.4,122.5,117.4,114.0,102.1,20.4
实施例9:2-氯-2’-甲基-4-(3-硝基-2-吡啶基氨基)二苯酮(化合物109),
将2-氯-3-硝基-吡啶(0.32g,2.0mmol)和4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)充分混合。在100℃下将该反应混合物温热0.5小时且然后在160℃下温热0.5小时。将该反应混合物冷却至室温并溶于饱和NaHCO3水溶液(10mL)和EtOAc(30mL)。分离出各相,并用饱和NaHCO3水溶液(10mL)洗涤有机相、干燥(MgSO4)、过滤并在真空中浓缩。通过使用EtOAc∶石油醚1∶7的急骤层析法进行纯化。
产物:化合物109,0.26g从Et2O中重结晶得到的结晶化合物
13C NMR(CDCl3):δ196.6,154.8,149.2,141.4,138.9,137.9,135.6,134.2,133.4,131.6,131.6,131.5,130.6,129.4,125.5,122.5,119.0,115.3,20.9
实施例10:4-(3-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物110),
将化合物109(0.15g,0.4mmol)悬浮于EtOH(10mL)中并加入SnCl2*H2O(0.46g,2.0mmol)。在70℃下将该反应混合物搅拌1小时,此后将其倾入冰水(50mL)。加入2N NaOH (50mL)并用EtOAc(3×20mL)提取水相。将合并的有机相干燥(MgSO4)、过滤并在真空中浓缩。通过使用EtOAc∶石油醚2∶3的急骤层析法进行纯化。
产物:化合物110,0.12g油状物。
13C NMR(CDCl3):δ196.9,145.3,143.9,139.2,138.9,138.1,134.2,132.7,131.7,131.3,131.0,130.3,130.0,125.4,124.6,118.8,118.5,114.9,20.5
实施例11:4-(5-氨基-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物111),
将化合物103(0.07g,0.19mmol)悬浮于EtOH(5mL)并加入SnCl2*H2O(0.21g,1.0mmol)。在70℃下将该反应混合物搅拌3小时并如对化合物110所述操作处理该反应混合物。通过使用EtOAc∶石油醚3∶2的急骤层析法进行纯化。
产物:化合物111,0.038g油状物
13C NMR(CDCl3):δ196.7,146.3,146.0,139.1,137.9,137.6,135.1,134.6,133.1,131.3,130.9,129.8,129.6,125.5,125.4,117.3,113.9,112.7,20.5
实施例12:2-氯-2’-甲基-4((2-吡啶基-N-氧化物)氨基)二苯酮(化合物112)
通用步骤:5
原料化合物I:化合物102(0.16g,0.5mmol)
反应时间:1小时
通过使用Et0Ac∶MeOH 8∶1的层析法进行纯化
产物:化合物112,0.098g可以从MeOH中重结晶的结晶化合物
13C NMR(DMSO):δ195.8,146.0,142.8,137.7,137.5,132.2,132.0,131.8,131.6,131.4,130.0,127.0,125.8,121.0,117.7,116.1,109.8,20.2
实施例13:2-氯-2’-甲基-4((3-吡啶基-N-氧化物)氨基)二苯酮(化合物113)
通用步骤:5
原料化合物I:化合物107(0.18g,0.54mmol)
反应时间:2小时
通过使用EtOAc∶MeOH 7∶1的层析法进行纯化
产物:化合物113,0.12g结晶化合物
13C NMR(CD3OD):δ198.5,146.6,143.7,139.7,139.4,135.4,134.0,133.2,133.0,132.7,132.6,131.2,130.4,128.1,126.8,120.0,119.6,116.5,20.8
实施例14:2-氯-4-(4-异喹啉基氨基)-2’-甲基二苯酮(化合物114),
通用步骤:1
原料化合物II:4-溴-异喹啉(0.42g,2.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49,2.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮10∶1的层析法
产物:化合物114,0.64g非晶形化合物。
13C NMR(CDCl3):δ196.6,150.1,149.3,139.0,138.6,137.9,135.1,133.5,132.1,131.3,131.1,130.9,130.8,129.7,129.3,129.3,128.2,127.9,125.4,121.6,116.3,112.6,20.5
实施例15:5-(3-氯-4-(2-甲基苯甲酰基)苯基氨基)烟酸叔丁酯(化合物115,)
将5-溴烟酸(4.7g,23mmol)加入到7mL冷凝的异丁烯的CH2Cl2(15mL)溶液中,且此后加入浓H2SO4(0.75mL)。在室温下将该反应混合物在带有螺丝帽的容器中搅拌24小时,此后将该体系倾入饱和NaHCO3水溶液(100mL)。将水相用EtOAc(100mL)提取,将有机相用NaHCO3洗涤、干燥(MgSO4)、过滤并浓缩。通过使用洗脱剂EtOAc∶石油醚1∶10的层析法来纯化粗产物。
产物:5-溴烟酸叔丁酯,结晶化合物。
13C NMR(CDCl3):δ163.06,154.02,148.85,139.38,129.10,120.48,82.82,28.12
通用步骤:1
原料化合物II:5-溴烟酸叔丁酯,(0.12g,0.45mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.13g,0.53mmol)
溶剂:甲苯(3mL)
碱:叔丁醇钠
反应时间:12小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶2的层析法
产物:化合物115,0.035g油状物
13C NMR(CDCl3):δ196.7,164.1,146.1,145.1,144.8,138.5,138.2,137.4,134.8,133.2,131.5,131.3,131.0,130.1,128.4,126.9,125.5,117.7,113.7,82.5,28.1,20.6
实施例16:2-氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物116),
通用步骤:1
原料化合物II:3-溴-4-甲基吡啶(0.172g,1.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:110℃
纯化:使用EtOAc∶石油醚1∶3-1∶1的层析法
产物:化合物116,0.08g油状物
13C NMR(CDCl3):δ196.5,148.5,146.5,146.1,142.1,139.0,138.0,135.4,135.1,133.5,131.3,131.0,129.8,129.3,125.9,125.4,116.0,112.3,20.5,17.5
实施例17:2-氯-2’-甲基-4-(6-甲基-3-吡啶基氨基)二苯酮(化合物117),
通用步骤:1
原料化合物II:5-溴-2-甲基吡啶(0.172g,1.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:110℃
纯化:使用EtOAc∶石油醚1∶4-1∶2的层析法
产物:化合物117,0.15g油状物
1H NMR(CDCl3):δ8.37(d,1H),7.45(dd,1H),7.4-7.15(m,6H),6.93(d,1H),6.78(dd,1H),6.29(s,1H),2.54(s,3H),2.44(s,3H)
实施例18:4-(5-溴-3-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物118),
通用步骤:1
原料化合物II:3,5-二溴-吡啶(0.237g,1.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:5小时
反应温度:110℃
纯化:使用丙酮∶CH2Cl2 1∶10的层析法
产物:化合物118,0.05g油状物
13C NMR(CDCl3):δ196.6,145.4,144.7,139.9,138.6,138.4,138.3,134.8,133.0,131.6,131.6,131.4,130.2,128.3,125.5,120.8,118.1,114.3,20.7
实施例19:4-(5-腈-3-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物119),
通用步骤:1
原料化合物II:5-溴烟酰腈(0.22g,1.2mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:甲苯(5mL)
碱:Cs2CO3
反应时间:18小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶2的层析法
产物:化合物119,0.11g油状物
13C NMR(DMSO):δ195.6,145.8,144.5,144.5,138.4,138.1,137.1,133.0,131.3,131.3,129.8,129.5,126.6,125.8,117.3,116.9,114.2,109.3,20.1
实施例20:4-(3-溴-2-吡啶基氨基)-2-氯-2’-甲基二苯酮(化合物120),
通用步骤:1
原料化合物II:3-溴-2-氯-吡啶(0.23g,1.2mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:反相HPLC,(0.1%TFA的H2O溶液)∶(0.1%TFA的90%CH3CN+10%H2O溶液)1∶1-0∶1
产物:化合物120
13C NMR(CDCl3):δ196.7,150.8,146.5,143.3,140.6,138.5,133.8,132.1,131.5,131.3,130.3,125.4,119.9,117.2,116.4,107.0,20.7
实施例21:2-氯-2’-甲基-4-(8-喹啉基氨基)二苯酮(化合物121),
通用步骤:1
原料化合物II:8-溴-喹啉(0.16mL,1.25mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.28g,1.14mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用Et2O∶石油醚1∶3的急骤层析法
产物:化合物121,0.28g从Et2O中重结晶的结晶化合物
13C NMR(CDCl3):δ196.5,147.9,145.9,139.0,138.9,138.1,137.7,136.4,134.7,133.1,131.4,131.0,130.6,129.9,128.8,127.0,125.4,121.9,119.1,118.7,115.3,110.7,20.6
实施例22:2-氯-4-(6-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物122),
通用步骤:1
原料化合物II:5-溴-2-乙氧基-吡啶(0.24g,1.2mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:反相HPLC
产物:化合物122
1H NMR(CDCl3):δ8.09(d,1H),7.54(dd,1H),7.40-7.20(m,5H),6.80(m,2H),6.66(dd,1H),4.35(q,2H),2.43(s,3H),1.42(t,3H)
实施例23:4-(4-溴-1-异喹啉基氨基)-2-氯-2’-甲基二苯酮(化合物123),
通用步骤:1
原料化合物II:4-溴-1-氯异喹啉(0.14g,0.5mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.13g,0.56mmol)
溶剂:1,4-二噁烷(3mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:反相HPLC
产物:化合物123
1H NMR(CDCl3):δ8.24(s,1H),8.18(d,1H),8.00(d,1H),7.85(t,1H),7.77(d,1H),7.65(t,1H),7.45-7.35(m,4H),7.28(d,1H),7.20(t,1H),2.52(s,3H)
实施例24:2-氯-2’-甲基-4-(2-甲基-5-三氟甲基-3-吡啶基氨基)二苯酮(化合物124),
通用步骤:1,不使用Pd2(dba)3和BINAP
原料化合物II:3-氯-2-甲基-5-(三氟甲基)吡啶(0.20,1.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
催化剂:Pd(P(环己基)3)2Cl2(30mg,0.04mmol)
反应时间:18小时
反应温度:110℃
纯化:反相HPLC
产物:化合物124
13C NMR(CDCl3):δ196.4,152.6,144.5,138.8,137.9,137.5,137.2,134.8,133.0,132.9,131.7,130.4,125.6,123.8,119.4,115.4,20.8,19.5
实施例25:2-氯-2’-甲基-4-(3-喹啉基氨基)二苯酮(化合物125),
通用步骤:1
原料化合物II:3-溴-喹啉(0.23g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
通过使用EtOAc∶石油醚2∶3的急骤层析法进行纯化
产物:化合物125,0.23g非晶形化合物。
13C NMR(CDCl3):8196.5,146.6,146.1,144.9,138.7,138.2,135.0,134.2,133.3,131.4,131.2,130.7,130.0,129.2,128.4,128.0,127.5,126.9,125.5,122.4,117.2,113.6,20.6
实施例26:2-氯-4-(4-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物126),
通用步骤:1
原料化合物II:3-溴-4-乙氧基吡啶(0.22g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:7小时
反应温度:100℃
通过使用EtOAc∶石油醚1∶3-1∶0的急骤层析法、随后使用反相HPLC进行纯化。
产物:化合物126,油状物。
13C NMR(CDCl3):δ196.3,158.5,142.6,138.9,137.5,136.5,134.3,134.1,132.5,131.9,131.8,131.6,130.7,126.8,125.7,120.8,116.8,107.7,66.9,20.9,14.2
实施例27:2-氯-4-(2-乙氧基-3-吡啶基氨基)-2’-甲基二苯酮(化合物127),
通用步骤:1
原料化合物II:3-溴-2-乙氧基吡啶(0.22g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:3小时
反应温度:100℃
通过使用EtOAc∶石油醚1∶5的急骤层析法进行纯化
产物:化合物127,0.20g油状物。
13C NMR(CDCl3):8196.4,154.1,145.9,138.8,138.7,138.2,134.8,133.1,131.4,131.1,130.5,129.9,125.4,125.2,122.8,117.8,116.6,114.3,62.2,20.5,14.7
实施例28:2-氯-4((4-异喹啉基-N-氧化物)氨基)-2’-甲基二苯酮(化合物128)
通用步骤:5
原料化合物I:化合物114(0.37g,1.0mmol)
反应时间:2小时
通过使用EtOAc∶MeOH 8∶1的层析法进行纯化
产物:化合物128,0.22g结晶化合物
13C NMR(DMSO):δ195.5,147.5,138.3,137.0,136.0,132.9,131.2,131.2,130.9,129.9,129.7,129.5,127.9,125.7,125.3,123.4,122.1,117.7,114.6,20.0
实施例29:2-氯-2’-甲基-4-(2-甲基-6-喹啉基氨基)二苯酮(化合物129),
通用步骤:1
原料化合物II:6-溴喹哪啶(0.24g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
通过使用Et0Ac∶石油醚1∶1的急骤层析法进行纯化
产物:化合物129,0.27g油状物。
13C NMR(CDCl3):δ196.6,157.7,147.3,144.9,139.0,138.0,137.9,135.2,135.0,133.4,131.3,131.0,130.2,129.9,129.8,127.3,125.4,124.6,122.7,117.1,115.2,113.5,25.1,20.5
实施例30:2-氯-4-(7-氯-4-喹啉基氨基)-2’-甲基二苯酮(化合物130),
将4,7-二氯喹啉(0.20g,1.0mmol)溶于i-PrOH(10mL)并加入4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.27g,1.1mmol)。将该反应混合物在回流状态下搅拌2小时,此后将该体系倾入饱和NaHCO3水溶液(30mL)。将水相用EtOAc(3×30mL)提取,将合并的有机相用盐水洗涤、干燥(MgSO4)、过滤并在真空中浓缩。通过使用EtOAc∶石油醚1∶3-1∶1的急骤层析法进行纯化。
产物:化合物130,0.28g结晶化合物。
13C NMR(DMSO):δ195.67,152.08,149.58,145.60,145.01,137.84,137.39,134.19,132.34,132.26,131.50,131.39,129.82,127.78,125.76,125.65,124.51,120.52,119.25,117.52,105.38,20.13
实施例31:2-氯-2’-甲基-4-(2-喹啉基氨基)二苯酮(化合物131),
将2-氯喹啉(0.16g,1.0mmol)溶于i-PrOH(10mL)并加入4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.27g,1.1mmol)。将该反应混合物在回流状态下搅拌18小时并如对合成化合物130所述操作该反应混合物。
通过使用EtOAc∶石油醚1∶4的急骤层析法进行纯化。
产物:化合物131,0.24g油状物
13C NMR(CDCl3):δ196.9,152.6,147.1,144.1,138.6,138.4,138.1,134.0,132.4,131.6,131.4,131.2,130.2,130.1,127.4,127.3,125.5,124.5,124.1,119.8,116.1,112.9,20.7
实施例32:2-氯-2’-甲基-4-(4-喹啉基氨基)二苯酮(化合物132),
将4-氯喹啉(0.16g,1.0mmol)溶于I-PrOH(10mL)并加入4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.27g,1.1mmol)。将该反应混合物在回流状态下搅拌18小时,此后将该体系倾入饱和NaHCO3水溶液(30mL)。将水相用EtOAc(3×30mL)提取,将合并的有机相用盐水洗涤、干燥(MgSO4)、过滤并在真空中浓缩。通过使用EtOAc∶石油醚1∶3-1∶1的急骤层析法进行纯化。
产物:化合物132,0.16g非晶形化合物。
13C NMR(CDCl3):δ196.58,150.79,149.37,145.25,144.37,138.74,137.98,134.30,133.22,132.51,131.67,131.61,130.45,130.28,129.84,126.10,125.54,121.10,120.75,120.07,117.54,105.43,20.80
实施例33:2-氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物133),
将7-溴吲哚(0.37g,1.9mmol)溶于干DMF。加入K2CO3(0.52g,3.8mmo1)和甲基碘(0.13mL,2.08mmol)。将该反应体系在室温下搅拌5天,此后加入H2O(20mL),将水相用Et2O(3×20mL)提取并将合并的有机相用盐水洗涤、干燥(MgSO4)、过滤并在真空中浓缩。通过层析法纯化粗产物,使用的洗脱剂为EtOAc∶石油醚1∶20,从而得到7-溴-1-甲基吲哚,为一种结晶化合物。
13C NMR(CDCl3):δ133.07,131.75,126.54,120.46,120.34,103.89,101.18,36.84
如下制备化合物133:
通用步骤:1
原料化合物II:7-溴-1-甲基吲哚(0.23g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的层析法
产物:化合物133,0.23g非晶形化合物。
13C NMR(CDCl3):δ196.55,151.82,139.37,137.71,135.36,133.85,132.97,131.62,131.19,131.05,130.68,129.50,127.92,125.30,123.76,121.83,120.53,120.19,115.06,111.34,101.50,35.49,20.35
实施例34:2-氯-2’-甲基-4-(1-甲基-5-吲哚基氨基)二苯酮(化合物134),
如对由7-溴吲哚制备7-溴-1-甲基吲哚所述而由5-溴吲哚制备5-溴-1-甲基吲哚。通过使用EtOAc∶石油醚1∶10的层析法进行纯化。
13C NMR(CDCl3):δ135.37,130.12,129.94,124.30,123.27,112.66,110.63,100.53,32.96
如下制备化合物134:
通用步骤:1
原料化合物II:5-溴-1-甲基吲哚(0.23g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的层析法
产物:化合物134,0.12g结晶化合物。
13C NMR(CDCl3):δ7.45(d,1H),7.36-7.18(m,6H),7.08(d,1H),7.06(dd,1H),6.82(d,1H),6.66(dd,1H),6.45(dd,1H),6.01(s,1H),3.80(s.3H),2.41(s,3H)
实施例35:2-氯-2’,5’-二甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物135)
通用步骤:1
原料化合物II:3-溴-4-甲基吡啶(0.092g,0.5mmol)
原料化合物III:4-氨基-2-氯-2’,5’-二甲基二苯酮(0.134g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物135,0.078g油状物。
13C NMR(CDCl3):δ196.7,148.4,146.5,146.0,142.1,138.9,135.5,135.1,134.9,134.8,133.5,131.7,131.2,130.1,129.4,125.9,116.0,112.3,20.8,19.9,17.5
实施例36:2-氯-2’,5’-二甲基-4-(4-异喹啉基氨基)二苯酮(化合物136)
通用步骤:1
原料化合物II:4-溴异喹啉(0.103g,0.49mmol)
原料化合物III:4-氨基-2-氯-2’,5’-二甲基二苯酮(0.131g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:4小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶1的急骤层析法
产物:化合物136,0.18g结晶化合物。
13C NMR(CDCl3):δ196.8,150.1,149.2,139.0,138.6,135.1,134.9,134.8,133.5,132.1,131.7,131.2,131.1,130.8,130.1,129.4,129.3,128.2,127.9,121.6,116.4,112.6,20.8,20.0
实施例37 2-氯-4-(4-异喹啉基氨基)-2’,4’,5’-三甲基二苯酮(化合物137)
通用步骤:1
原料化合物II:4-溴异喹啉(0.103g,0.49mmol)
原料化合物III:4-氨基-2-氯-2’,4’,5’-三甲基二苯酮(0.148g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物137,0.16g结晶化合物。
13C NMR(CDCl3):δ196.6,149.9,148.9,140.3,138.3,136.2,135.8,134.6,133.5,133.0,132.8,132.0,131.5,131.3,130.7,130.0,129.3,128.1,127.8,121.6,116.4,112.7,20.1,19.7,19.1
实施例38:2,3’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物138)
通用步骤:1
原料化合物II:3-溴-4-甲基吡啶(O.095g,0.5mmol)
原料化合物III:4-氨基-2,3’-二氯-2’-甲基二苯酮(0.144g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物138,0.09g油状物。
13C NMR(CDCl3):δ195.3,149.2,146.8,146.4,142.5,142.0,135.9,135.8,135.1,134.9,134.3,131.2,127.9,126.9,126.4,126.0,116.0,112.1,17.5,17.1
实施例39:2-氟-2-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物139)
通用步骤:1
原料化合物II:3-溴-4-甲基吡啶(0.092g,0.5mmol)
原料化合物III:4-氨基-2-氟-2’-甲基二苯酮(0.120g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶1的急骤层析法
产物:化合物139,0.02g油状物。
13C NMR(CDCl3):δ194.3,163.7,151.3,146.8,146.6,142.8,140.3,136.3,135.2,134.0,130.9,130.2,128.1,126.0,125.3,117.9,109.9,101.1,19.9,17.4
实施例40:2,4’-二氯-2’-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物140)
通用步骤:1
原料化合物II:3-溴-4-甲基吡啶(0.086g,0.5mmol)
原料化合物III:4-氨基-2,4’-二氯-2’-甲基二苯酮(0.132g,0.47mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物140,0.12g油状物。
13C NMR(CDCl3):δ195.4,148.7,146.7,146.2,142.2,140.1,137.4,136.8,135.3,135.2,133.4,131.3,131.1,128.9,125.9,125.6,115.8,112.4,20.4,17.5
实施例41:2-氯-4’-氟-4-(4-异喹啉基氨基)-2’-甲基二苯酮(化合物141)
通用步骤:1
原料化合物II:4-溴异喹啉(0.104g,0.5mmol)
原料化合物III:4-氨基-2-氯-4’-氟-2’-甲基二苯酮(0.140g,0.53mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物141,0.13g结晶化合物。
13C NMR(CDCl3):δ195.4,164.0,150.3,149.3,141.8,138.7,135.0,134.9,133.1,132.4,132.4,131.0,130.8,129.4,129.3,128.2,127.9,121.6,118.2,116.2,112.7,112.3,20.8
实施例42:4’-正丁基-2-氯-4-(4-异喹啉基氨基)-2’-甲基二苯酮(化合物142)
通用步骤:1
原料化合物II:4-溴异喹啉(0.104g,0.5mmol)
原料化合物III:4-氨基-2’-正丁基-2-氯-2’-甲基二苯酮(0.150g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物142,0.17g油状物。
13C NMR(CDCl3):δ196.4,150.0,148.8,146.7,138.6,138.5,136.0,134.7,133.0,132.1,131.7,131.2,130.8,130.7,130.1,129.3,128.2,127.9,125.4,121.6,116.3,112.7,35.6,33.3,22.4,20.8,13.9
实施例43:2-氯-4-(5-异喹啉基氨基)-2’-甲基二苯酮(化合物143)
通用步骤:1
原料化合物II:5-溴异喹啉(0.104g,0.5mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.122g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物143,0.16g油状物。
13C NMR(CDCl3):δ196.6,153.0,148.7,143.4,138.9,138.0,135.5,135.0,133.5,131.6,131.3,131.0,129.8,129.5,127.4,125.4,124.8,123.8,116.6,115.1,113.0,20.5
实施例44:2-氯-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮(化合物144)
通用步骤:1
原料化合物II:4-溴异喹啉(0.104g,0.5mmol)
原料化合物III:4-氨基-2-氯-4’-甲氧基-2’-甲基二苯酮(0.136g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用CH2Cl2∶丙酮9∶1的急骤层析法
产物:化合物144,0.19g结晶化合物。
13C NMR(CDCl3):δ195.5,161.9,149.9,148.5,142.0,138.3,134.2,133.7,132.4,132.0,131.4,130.9,130.7,129.3,128.2,127.8,121.6,117.1,116.3,112.9,110.4,55.3,21.5
实施例45:2-氟-4-(4-异喹啉基氨基)-4’-甲氧基-2’-甲基二苯酮(化合物145)
通用步骤:1
原料化合物II:4-溴异喹啉(0.103g,0.5mmol)
原料化合物III:4-氨基-2-氟-4’-甲氧基-2’-甲基二苯酮(0.130g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶1的急骤层析法,随后从EtOAc中重结晶。
产物:化合物145,0.07g结晶化合物。
1H NMR(DMSO-D6):δ9.18(s,1H),9.13(s,1H),8.54(s,1H),8.20(d,1H),8.03(d,1H),7.83(t,1H),7.75(t,1H),7.42(t,1H),7.30(d,1H),6.87(d,1H),6.81(dd,1H),6.77(dd,1H),6.58(dd,1H),3.80(s,3H),2.34(s,3H)
实施例46:2,4’-二氯-2’-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物146)
通用步骤:1
原料化合物II:如实施例33中所述制备7-溴-1-甲基吲哚(0.115g,0.55mmol)
原料化合物III:4-氨基-2,4’-二氯-2’-甲基二苯酮(0.140g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的急骤层析法
产物:化合物146,0.08g结晶化合物。
13C NMR(CDCl3):δ195.5,152.1,139.8,137.8,136.5,135.4,133.8,132.9,131.6,131.2,131.1,130.8,127.5,125.5,123.6,121.8,120.6,120.2,115.0,111.4,101.5,35.5,20.2
实施例47:2-氯-4-(1-甲基-7-吲哚基氨基)-2’,4’,5’-三甲基二苯酮(化合物147)
通用步骤:1
原料化合物II:如实施例33中所述制备的7-溴-1-甲基吲哚(0.115g,0.55mmol)。
原料化合物III:4-氨基-2-氯-2’,4’,5’-三甲基二苯酮(0.137g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的急骤层析法
产物:化合物147,0.097g结晶化合物。
13C NMR(CDCl3):δ196.6,151.5,140.0,136.6,135.5,135.0,133.5,133.4,133.0,132.7,131.6,131.3,131.0,128.6,124.0,121.8,120.4,120.2,115.0,111.3,101.5,35.5,20.0,19.7,19.1
实施例48:2-氯-2’,5’-二甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物148)
通用步骤:1
原料化合物II:如实施例33中所述制备的7-溴-1-甲基吲哚(0.115g,0.55mmol)。
原料化合物III:4-氨基-2-氯-2’,5’-二甲基二苯酮(0.148g,0.5mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的急骤层析法
产物:化合物148,0.30g结晶化合物。
1H NMR(CDCl3):δ7.56(d,1H),7.28(d,1H),7.17-7.02(m,4H),6.98(d,1H),6.95(d,1H),6.61(d,1H),6.50(d,1H),6.42(dd,1H),5.93(s,Br,1H),3.81(s,3H),2.32(s,3H),2.27(s,3H)
实施例49:2-氯-4-(3-乙氧基-4-异喹啉基氨基)-2’-甲基二苯酮(化合物149)
通用步骤:1
原料化合物II:4-溴-3-乙氧基异喹啉(0.097g,0.39mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.095g,0.39mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的急骤层析法
产物:化合物149,0.11g结晶化合物。
13C NMR(CDCl3):δ196.6,155.1,149.9,147.4,139.3,137.8,134.8,133.3,131.2,130.7,130.5,129.6,128.7,128.1,125.6,125.3,124.5,121.9,116.2,113.9,112.4,62.7,20.4,15.0
实施例50:2-氯-4-(1-乙氧基-4-异喹啉基氨基)-2’-甲基二苯酮(化合物150)
通用步骤:1
原料化合物II:4-溴-1-乙氧基异喹啉(0.097g,0.39mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.095g,0.39mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3的急骤层析法
产物:化合物150,0.11g结晶化合物。
13C NMR(CDCl3):δ196.5,159.7,151.2,139.4,138.5,137.7,135.5,135.3,133.8,131.2,131.0,130.7,129.5,128.0,127.1,125.3,125.0,124.6,121.8,120.3,115.1,111.4,62.4,20.4,14.6
实施例51 4-(2-苯并噁唑基氨基)-2-氯-2’-甲基二苯酮(化合物151)
通用步骤:1
原料化合物II:2-氯苯并噁唑(0.35mL,3.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:16小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶4的急骤层析法
产物:化合物151,0.17g结晶化合物。
13C NMR(CDCl3):δ196.9,157.3,147.8,141.4,141.3,138.7,138.0,134.0,133.1,132.2,131.6,130.6,125.5,124.7,124.5,122.6,119.3,117.4,115.7,109.5,20.8
实施例52 4-(1-甲基-2-苯并咪唑基氨基)-2-氯-2’-甲基二苯酮(化合物152)
通用步骤:1
原料化合物II:2-氯-1-甲基苯并咪唑(0.33g,2.0mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:24小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶2的急骤层析法
产物:化合物152,0.27g结晶化合物
13C NMR(CDCl3):δ196.0,147.0,140.4,139.0,137.1,135.4,133.9,132.0,131.8,130.9,129.8,125.6,125.4,124.6,121.1,117.6,113.7,110.1,31.3,20.9
实施例53 4-(2-苯并噻唑基氨基)-2-氯-2’-甲基二苯酮(化合物153)
通用步骤:1
原料化合物II:2-氯苯并噻唑(0.26mL,2.0mmol)
原料化合物III:4-氨基-2-氨-2’-甲基二苯酮(化合物2)(0.49g,2.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:20小时
反应温度:100℃
纯化:使用丙酮∶CH2Cl2 1∶100的急骤层析法
产物:化合物153,0.24g结晶化合物
13C NMR(CDCl3):δ196.9,161.5,151.1,143.1,138.7,138.0,134.1,133.1,132.3,131.6,130.5,130.3,126.5,125.5,123.4,121.0,120.3,119.6,116.0,20.8
实施例54 2-氯-2’-甲基-4-(2-嘧啶基氨基)二苯酮(化合物154)
通用步骤:1
原料化合物II:2-溴嘧啶(0.18g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用丙酮∶CH2Cl2 2∶100的急骤层析法
产物:化合物154,0.14g结晶化合物
13C NMR(CDCl3):δ196.8,159.4,158.1,143.0,138.4,133.9,132.1,132.0,131.5,131.3,130.3,125.4,119.8,116.2,113.8,20.7
实施例55 2-氯-2’-甲基-4-(7-甲基-嘌呤-6-基氨基)二苯酮(化合物155)
通用步骤:1
原料化合物II:6-溴-7-甲基嘌呤(0.18g,0.84mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.19g,0.77mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3→1∶0的急骤层析法,随后从Et2O中重结晶。
产物:化合物155,0.06g结晶化合物
13C NMR(CDCl3):δ196.7,152.7,151.4,150.4,142.3,141.8,138.7,138.2,133.7,133.1,131.9,131.6,131.4,130.5,125.5,120.7,120.6,117.1,30.0,20.8
实施例56 2-氯-2’-甲基-4-(2-甲基-5-苯并噻唑基氨基)二苯酮(化合物156)
通用步骤:1
原料化合物II:5-溴-2-甲基苯并噻唑(0.25g,1.1mol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:18小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶3→1∶2的急骤层析法
产物:化合物156,0.21g油状物。
13C NMR(CDCl3):δ196.5,168.7,154.6,147.8,139.1,138.8,138.0,135.1,133.4,131.3,130.9,130.8,129.8,129.5,125.4,122.2,119.3,116.5,114.3,113.0,20.5,20.2
实施例57 2-氯-2’-甲基-4-(吡嗪-2-基氨基)二苯酮(化合物157)
通用步骤:1
原料化合物II:2-碘吡嗪(0.23g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(6mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶1的急骤层析法,随后在RP HPLC上纯化
产物:化合物157,油状物
13C NMR(CDCl3):δ196.8,151.0,143.2,141.6,138.6,138.3,136.3,134.5,134.0,132.4,132.2,131.6,131.4,130.4,125.5,119.7,116.1,20.7
实施例58 2-氯-2’-甲基-4-(5-嘧啶基氨基)二苯酮(化合物158)通用步骤:1
原料化合物II:5-溴嘧啶(0.18g,1.1mmol)
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.25g,1.0mmol)
溶剂:1,4-二噁烷(5mL)
碱:叔丁醇钠
反应时间:6小时
反应温度:100℃
纯化:使用EtOAc∶石油醚1∶1→1∶0的急骤层析法,随后在RPHPLC上纯化
产物:化合物158,油状物
13C NMR(CDCl3):δ196.3,153.3,148.0,145.0,138.6,138.2,134.9,133.0,132.2,131.6,131.5,130.2,125.5,117.7,114.2,20.7物159)
将4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.246g,1.0mmol)、2-溴-5-硝基噻唑(0.209g,1.0mmol)和N,N-二异丙基乙胺(0.18mL,1.0mmol)在4mL带螺丝帽的容器中混合并在60℃下保持18小时。使该反应混合物分配在EtOAc与水之间并用H2O(3×10mL)和盐水(10mL)洗涤有机相、干燥(MgSO4)并在真空中蒸发。通过使用EtOAc∶CH2Cl2 1∶50作为洗脱剂的急骤层析法纯化粗化合物。
产物:化合物159,0.12g结晶化合物。
13C NMR(DMSO-D-6):δ195.8,166.5,145.2,142.1,138.6,137.8,137.4,133.1,131.9,131.8,131.6,130.3,125.9,119.3,117.0,54.9,20.3
实施例60 2-氯-2’-甲基-4-((4-甲基-3-硝基-(1,2,4-三唑-5-基氨基))二苯酮(化合物160)
5-溴-4-甲基-3-硝基-1,2,4-三唑的制备:
将5-溴-3-硝基-1,2,4-三唑(0.78g,4.0mmol)溶于DMF(20mL)。加入K2CO3(1.11g,8.0mmol)和CH3I(0.28mL,4.4mmol)并在室温下将该混合物搅拌18小时。加入H2O并用Et2O将水相提取3次。将合并的有机用盐水洗涤、干燥(MgSO4)并蒸发,且通过使用EtOAc∶石油醚1∶1作为洗脱剂的急骤层析法纯化粗产物。
产物:2-溴-1-甲基-5-硝基-1,2,4-三唑,0.44g
13C NMR(CDCl3):δ131.3,80.6,38.0
化合物160的制备:
通用步骤:1
原料化合物II:5-溴-4-甲基-3-硝基-1,2,4-三唑(0.22g,1.1mmol
原料化合物III:4-氨基-2-氯-2’-甲基二苯酮(化合物2)(0.24g,1.0mmol)
溶剂:甲苯(5mL)
碱:Cs2CO3
碱:Cs2CO3
反应时间:18小时
反应温度:100℃
18小时后,加入额外部分的BINAP(24mg)和Pd2(dba)3(17mg),并在100℃下将该反应混合物再振摇24小时。
如通用步骤1中所述操作。
纯化:使用EtOAc∶石油醚1∶1的急骤层析法,随后在反相HPLC上纯化
产物:化合物160,油状物
13C NMR(DMSO-D-6):δ195.8,158.3,151.0,142.8,137.8,137.4,131.9,131.6,131.4,131.4,129.9,125.8,117.9,115.6,35.6,20.1
实施例61
含有化合物116的片剂
化合物116(活性物质) 50mg
乳糖 125mg
淀粉 12mg
甲基纤维素 2mg
羧甲基纤维素钠 10mg
硬脂酸镁 1mg
将活性物质、乳糖和淀粉在合适的混合器中混合至均匀状态并用15cps甲基纤维素的5%水溶液润湿。将混合步骤持续至形成颗粒为止。如果必要,使温颗粒通过合适的筛并在例如流化床或干燥箱这样合适的干燥器中干燥至水分小于1%。使干颗粒通过1mm筛并与羧甲基纤维素钠混合至均匀状态。加入硬脂酸镁并将混合步骤持续短暂时间。使用合适的制片机将所述颗粒制成具有200mg重量的片剂。
实施例62:含有化合物116的注射剂
化合物116(活性物质) 1%
氯化钠 适量
注射用水 至100%
将活性物质溶于乙醇(10%),然后加入用氯化钠使其等渗的注射用水而制成100%。将该混合物灌入安瓿并灭菌。
实施例63含有化合物116的霜剂
将化合物116(10g)溶于肉豆蔻酸辛基十二醇酯(250g)而形成A部分。将羟苯甲酸甲酯(1g)和对羟苯甲酸丙酯(0.2g)溶于苯氧基乙醇(6g)并与0.025M磷酸盐缓冲液pH=7.5(632,8g)混合成B部分。在70℃-80℃下将十六醇十八醇混合物(50g)和ARLACEL 165(50g)在容器中熔化。加入A部分并加热至60-70℃。同样将水相加热至60-70℃并将其在高速搅拌条件下缓慢加入到熔化的油相中。将匀化的成分冷却至室温。
Claims (38)
1.下列通式I的化合物及其与可药用酸形成的盐、水合物和溶剂合物,以及任选地其杂环R5取代基的氮原子被氧化的N-氧化物:
其中
R1选自卤素、卤代烷基、羟基、羟烷基、羟基烷氧基、巯基、氰基、羧基、硝基、烷基、链烯基、炔基、环烷基、环烯基、杂环烷基、芳基、杂芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氧基、烷氧基羰基氧基、烷基磺酰氧基、烷氧基磺酰基、烷基羰基氨基、氨基羰氨基烷基、氨基磺酰基、烷基磺酰基氨基、烷酰基、烷基羰基、-NR9R10或-CONR9R10,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
R2代表一个或多个相同或不同的取代基,它们选自氢、卤素、卤代烷基、羟基、羟烷基、羟基烷氧基、巯基、氰基、羧基、硝基、烷基、链烯基、炔基、环烷基、环烯基、杂环烷基、芳基、杂芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氧基、烷氧基羰基氧基、烷基磺酰氧基、烷氧基磺酰基、烷基羰基氨基、氨基羰氨基烷基、氨基磺酰基、烷基磺酰基氨基、烷酰基、烷基羰基、-NR9R10或-CONR9R10,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
R3代表一个在C=X邻位的取代基,它们选自卤素、卤代烷基、羟基、羟烷基、巯基、氰基、硝基、烷基、链烯基、炔基、环烷基、芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氨基、烷基羰基氧基、烷氧基羰基氧基、烷基羰基、-NR9R10或-CONR9R10,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
R4代表氢、烷基、链烯基、炔基、环烷基、环烯基、羧基或芳基;
R5代表含有1-4个杂原子的杂芳香单环或双环系统,除了三嗪,所述的环系可以任选被氢、卤素、卤代烷基、羟基、羟烷基、羟基烷氧基、巯基、氰基、羧基、硝基、烷基、链烯基、炔基、环烷基、环烯基、杂环烷基、芳基、杂芳基、芳烷基、烷芳基、烷氧基、芳烷氧基、烷硫基、烷氧羰基、烷基羰基氧基、烷氧基羰基氧基、烷基磺酰氧基、烷氧基磺酰基、烷基羰基氨基、氨基羰氨基烷基、氨基磺酰基、烷基磺酰基氨基、烷酰基、烷基羰基、-NR9R10或-CONR9R10取代,其中R9和R10相同或不同且各自代表氢、烷基或芳基;
X代表氧、硫、N-OH或NR11,其中R11是氢或烷基。
2.权利要求1的化合物,其中R1选自卤素、羟基、巯基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷氨基、(C1-C6)烷氧羰基、氰基、-CONH2、苯基和硝基。
3.权利要求1的化合物,其中R1选自氟、氯、溴、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)链烯基、(C1-C3)烷氧基、(C1-C3)烷氧羰基、氰基和-CONH2。
4.权利要求1的化合物,其中R2代表一个或多个相同或不同的取代基,它们选自氢、卤素、羟基、巯基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷氨基、(C1-C6)烷氧羰基、氰基、-CONH2、苯基和硝基。
5.权利要求1的化合物,其中R2代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)链烯基、(C1-C3)烷氧基、(C1-C3)烷氧羰基、氰基和-CONH2。
6.权利要求1的化合物,其中R3代表一个取代基,它们选自卤素、羟基、巯基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷硫基、(C1-C6)烷氨基、(C1-C6)烷氧羰基、氰基、-CONH2、苯基和硝基。
7.权利要求1的化合物,其中R3代表一个取代基,其选自氟、氯、溴、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)链烯基和(C1-C3)烷氧基。
8.权利要求1的化合物,其中R4代表氢、(C1-C6)烷基、(C2-C6)链烯基或(C3-C6)环烷基或-环烯基。
9.权利要求1的化合物,其中R4代表氢、(C1-C4)烷基或(C2-C4)链烯基。
10.权利要求1的化合物,其中R5代表含1个或2个稠合的5个或6个环原子的环并含有1个或2个氮原子的杂芳环系,该杂芳环系任选被权利要求1中所定义的取代基取代。
12.权利要求1的化合物,其中X代表氧、硫或NH。
13.权利要求11的化合物,其中R6和R7代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、三氟甲基、氨基、(C1-C6)烷基、(C2-C6)链烯基、(C1-C6)烷氧基、(C1-C6)烷氧羰基、氰基、羧基和-CONH2。
14.权利要求11的化合物,其中R8代表氢、(C1-C4)烷基、(C2-C6)链烯基。
15.权利要求11的化合物,其中R8代表氢、(C1-C4)烷基或烯丙基。
16.权利要求11的化合物,其中R8代表氢、甲基、乙基、烯丙基、丙基、苄基或叔丁基。
17.权利要求1-16中任意一项的化合物,其中R1代表选自氟、氯、溴、羟基、甲基和甲氧基的取代基。
18.权利要求1-16中任意一项的化合物,其中R2代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、三氟甲基、甲基、乙基和甲氧基。
19.权利要求1-16中任意一项的化合物,其中R3代表一个取代基,它们选自氢、氟、氯、溴、羟基、甲基和甲氧基。
20.权利要求1-16中任意一项的化合物,其中R4代表氢、甲基或乙基。
21.权利要求1-16中任意一项的化合物,其中R5选自取代的或未取代的3-吡啶基、2-吡啶基、3-喹啉基、4-异喹啉基、4-吲哚基、5-吲哚基、6-吲哚基或7-吲哚基和相应的N-氧化物。
22.权利要求11的化合物,其中R6和R7代表一个或多个相同或不同的取代基,它们选自氢、氟、氯、溴、羟基、甲基、甲氧基、氰基和羧基。
23.权利要求1-16中任意一项的化合物,其中X代表氧。
24.权利要求11的化合物,其特征在于R1、R2、R3、R6和R7中的至少一个代表苯基。
25.权利要求1-16中任意一项的化合物,其中所述卤素选自氟、氯和溴。
27.权利要求1的通式Ic的化合物,其中R1代表F或Cl,R2代表氢、(C1-C3)烷基、甲氧基或乙氧基,且R3代表甲基、甲氧基或氯。
28.权利要求1的化合物,其中R3代表卤原子。
29.权利要求28的化合物,其中R3代表氯。
30.式I的化合物,选自下列化合物组成的组:
2-氯-2′-甲基-4-(4-吡啶基氨基)二苯酮(化合物101);
2-氯-2′-甲基-4-(2-吡啶基氨基)二苯酮(化合物102);
2-氯-2′-甲基-4-(5-硝基-2-吡啶基氨基)二苯酮(化合物103);
4-(6-氨基-5-硝基-2-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物104);
6-氯-2-(3-氯-4-(2-甲基苯甲酰基)苯基氨基)异烟酸(化合物105);
4-(6-腈-2-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物106);
2-氯-2′-甲基-4-(3-吡啶基氨基)二苯酮(化合物107);
2-氯-4-(5,6-二氨基-2-吡啶基氨基)-2′-甲基二苯酮(化合物108);
2-氯-2′-甲基-4-(3-硝基-2-吡啶基氨基)二苯酮(化合物109);
4-(3-氨基-2-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物110);
4-(5-氨基-2-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物111);
2-氯-4-(4-异喹啉基氨基)-2-甲基二苯酮(化合物114);
5-(3-氯-4-(2-甲基苯甲酰基)苯基氨基)烟酸叔丁酯(化合物115);
2-氯-2′-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物116);
2-氯-2′-甲基-4-(6-甲基-3-吡啶基氨基)二苯酮(化合物117);
4-(5-溴-3-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物118);
4-(5-腈-3-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物119);
4-(3-溴-2-吡啶基氨基)-2-氯-2′-甲基二苯酮(化合物120);
2-氯-2′-甲基-4-(8-喹啉基氨基)二苯酮(化合物121);
2-氯-4-(6-乙氧基-3-吡啶基氨基)-2′-甲基二苯酮(化合物122);
4-(4-溴-1-异喹啉基氨基)-2-氯-2′-甲基二苯酮(化合物123);
2-氯-2′-甲基-4-(2-甲基-5-三氟甲基-3-吡啶基氨基)二苯酮(化合物124);
2-氯-2′-甲基-4-(3-喹啉基氨基)二苯酮(化合物125);
2-氯-4-(4-乙氧基-3-吡啶基氨基)-2′-甲基二苯酮(化合物126);
2-氯-4-(2-乙氧基-3-吡啶基氨基)-2′-甲基二苯酮(化合物127);
2-氯-2′-甲基-4-(2-甲基-6-喹啉基氨基)二苯酮(化合物129);
2-氯-4-(7-氯-4-喹啉基氨基)-2′-甲基二苯酮(化合物130);
2-氯-2′-甲基-4-(2-喹啉基氨基)二苯酮(化合物131);
2-氯-2′-甲基-4-(4-喹啉基氨基)二苯酮(化合物132);
2-氯-2′-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物133);
2-氯-2′-甲基-4-(1-甲基-5-吲哚基氨基)二苯酮(化合物134);
2-氯-2′,5′-二甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物135);
2-氯-2′,5′-二甲基-4-(4-异喹啉基氨基)二苯酮(化合物136);
2-氯-4-(4-异喹啉基氨基)-2′,4′,5′-三甲基二苯酮(化合物137);
2,3′-二氯-2′-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物138);
2-氟-2′-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物139);
2,4′-二氯-2′-甲基-4-(4-甲基-3-吡啶基氨基)二苯酮(化合物140);
2-氯-4′-氟-4-(4-异喹啉基氨基)-2′-甲基二苯酮(化合物141);
4′-正丁基-2-氯-4-(4-异喹啉基氨基)-2′-甲基二苯酮(化合物142);
2-氯-4-(5-异喹啉基氨基)-2′-甲基二苯酮(化合物143);
2-氯-4-(4-异喹啉基氨基)-4′-甲氧基-2′-甲基二苯酮(化合物144);
2-氟-4-(4-异喹啉基氨基)-4′-甲氧基-2′-甲基二苯酮(化合物145);
2,4′-二氯-2′-甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物146);
2-氯-4-(1-甲基-7-吲哚基氨基)-2′,4′,5′-三甲基二苯酮(化合物147);
2-氯-2′,5′-二甲基-4-(1-甲基-7-吲哚基氨基)二苯酮(化合物148);
2-氯-4-(3-乙氧基-4-异喹啉基氨基)-2′-甲基二苯酮(化合物149);
2-氯-4-(1-乙氧基-4-异喹啉基氨基)-2′-甲基二苯酮(化合物150);
4-(2-苯并噁唑基氨基)-2-氯-2′-甲基二苯酮(化合物151);
4-(1-甲基-2-苯并咪唑基氨基)-2-氯-2′-甲基二苯酮(化合物152);
4-(2-苯并噻唑基氨基)-2-氯-2′-甲基二苯酮(化合物153);
2-氯-2′-甲基-4-(2-嘧啶基氨基)二苯酮(化合物154);
2-氯-2′-甲基-4-(7-甲基-嘌呤-6-基氨基)二苯酮(化合物155);
2-氯-2′-甲基-4-(2-甲基-5-苯并噻唑基氨基)二苯酮(化合物156);
2-氯-2′-甲基-4-(吡嗪-2-基氨基)二苯酮(化合物157);
2-氯-2′-甲基-4-(5-嘧啶基氨基)二苯酮(化合物158);
2-氯-2′-甲基-4-(5-硝基-2-噻唑基氨基)二苯酮(化合物159);
2-氯-2′-甲基-4-((4-甲基-3-硝基-(1,2,4-三唑-5-基氨基))二苯酮(化合物160);
及其杂环R5取代基中的氮原子被特别氧化的N-氧化物,包括下列N-氧化物:
2-氯-2′-甲基-4((2-吡啶基-N-氧化物)氨基)二苯酮(化合物112);
2-氯-2′-甲基-4-((3-吡啶基-N-氧化物)氨基)二苯酮(化合物113);
2-氯-4-((4-异喹啉基-N-氧化物)氨基)-2′-甲基二苯酮(化合物128);
及其与可药用酸形成的盐、水合物和溶剂合物。
32.含有权利要求1-31中任意一项的化合物作为活性成分和可药用赋形剂或载体的药物组合物。
33.权利要求32的组合物,进一步包括第二种活性组分,该活性组分可任选选自糖皮质激素、维生素D或维生素D类似物、抗组胺药、血小板活化因子(PAF)拮抗剂、抗胆碱能药、甲基黄嘌呤、β-肾上腺素能药、水杨酸盐类、吲哚美辛、氟芬那酸、萘普生、替美加定、金盐、青霉胺、降血清胆固醇药、类维生素A、锌盐和柳氮磺胺吡啶。
34.权利要求32或33的组合物,它取含有0.05-1000mg所述活性组分的单位剂型。
35.权利要求1-31中任意一项的化合物在制备用于治疗或预防炎性疾病或疾患的药物中的用途。
36.权利要求35所述的用途,其中所述的疾病或疾患是:哮喘;过敏反应;关节炎;痛风;动脉粥样硬化;炎性肠病;局限性回肠炎;增殖性和炎性皮肤病。
37.权利要求36所述的用途,其中所述关节炎选自类风湿性关节炎、骨关节炎和脊椎关节炎。
38.权利要求35所述的用途,其中所述疾病或疾患是银屑病、特应性皮炎和寻常痤疮;眼色素层炎;脓毒病;败血症性休克;与AIDS相关的疾病和骨质疏松。
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HUP0301932A3 (en) | 2007-09-28 |
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US6432962B2 (en) | 2002-08-13 |
CA2408727A1 (en) | 2001-11-29 |
WO2001090074A3 (en) | 2002-05-02 |
BR0111034A (pt) | 2003-06-17 |
HK1055949A1 (en) | 2004-01-30 |
RU2270194C2 (ru) | 2006-02-20 |
AU2001260081B2 (en) | 2005-07-28 |
HUP0301932A2 (hu) | 2003-09-29 |
PL359862A1 (en) | 2004-09-06 |
CN1430607A (zh) | 2003-07-16 |
EP1289958A2 (en) | 2003-03-12 |
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