KR100795533B1 - 항종양 활성을 갖는 2-(1h-인돌-3-일)-2-옥소-아세트아미드 - Google Patents
항종양 활성을 갖는 2-(1h-인돌-3-일)-2-옥소-아세트아미드 Download PDFInfo
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- KR100795533B1 KR100795533B1 KR1020027007960A KR20027007960A KR100795533B1 KR 100795533 B1 KR100795533 B1 KR 100795533B1 KR 1020027007960 A KR1020027007960 A KR 1020027007960A KR 20027007960 A KR20027007960 A KR 20027007960A KR 100795533 B1 KR100795533 B1 KR 100795533B1
- Authority
- KR
- South Korea
- Prior art keywords
- oxo
- indol
- chlorobenzyl
- acetamide
- dihydrofuran
- Prior art date
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- 230000000259 anti-tumor effect Effects 0.000 title abstract description 9
- AWMLDBKLOPNOAR-UHFFFAOYSA-N 2-(1h-indol-3-yl)-2-oxoacetamide Chemical class C1=CC=C2C(C(=O)C(=O)N)=CNC2=C1 AWMLDBKLOPNOAR-UHFFFAOYSA-N 0.000 title abstract description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 4
- -1 hydroxy, methoxy, trifluoromethoxy, benzyloxy Chemical group 0.000 claims description 98
- 150000001875 compounds Chemical class 0.000 claims description 56
- 239000000460 chlorine Substances 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052705 radium Inorganic materials 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
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- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 2
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- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- UGPXXDWHGJMUBK-RMKNXTFCSA-N (e)-3-[1-[(4-chlorophenyl)methyl]-3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indol-4-yl]prop-2-enoic acid Chemical compound C1=C(C(=O)C(=O)NC=2COC(=O)C=2)C=2C(/C=C/C(=O)O)=CC=CC=2N1CC1=CC=C(Cl)C=C1 UGPXXDWHGJMUBK-RMKNXTFCSA-N 0.000 claims description 2
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- 229910003827 NRaRb Inorganic materials 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000005239 aroylamino group Chemical group 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 235000013305 food Nutrition 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- BUIZGRJRSLLHPA-FMIVXFBMSA-N tert-butyl (e)-3-[1-[(4-chlorophenyl)methyl]-3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indol-4-yl]prop-2-enoate Chemical compound C1=C(C(=O)C(=O)NC=2COC(=O)C=2)C=2C(/C=C/C(=O)OC(C)(C)C)=CC=CC=2N1CC1=CC=C(Cl)C=C1 BUIZGRJRSLLHPA-FMIVXFBMSA-N 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 125000001624 naphthyl group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 208000037841 lung tumor Diseases 0.000 abstract description 3
- 238000002844 melting Methods 0.000 description 107
- 230000008018 melting Effects 0.000 description 107
- 239000003921 oil Substances 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 21
- 238000000921 elemental analysis Methods 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000000034 method Methods 0.000 description 12
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- 239000007787 solid Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
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- 238000002360 preparation method Methods 0.000 description 9
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- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- IAODRFIZLKITMK-UHFFFAOYSA-N furan-2,3-dione Chemical compound O=C1OC=CC1=O IAODRFIZLKITMK-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
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- 239000011521 glass Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
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- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
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- JZYIOWUOANBNIS-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)methyl]-3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indole-5-carboxylate Chemical compound C1=C(C(=O)C(=O)NC=2COC(=O)C=2)C2=CC(C(=O)OC)=CC=C2N1CC1=CC=C(Cl)C=C1 JZYIOWUOANBNIS-UHFFFAOYSA-N 0.000 description 1
- JAFGKHVICVCDFF-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)methyl]-3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C(C(=O)C(=O)NC=2COC(=O)C=2)=CN1CC1=CC=C(Cl)C=C1 JAFGKHVICVCDFF-UHFFFAOYSA-N 0.000 description 1
- AHALLUHSKVGTBF-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)methyl]-3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indole-7-carboxylate Chemical compound C1=2C(C(=O)OC)=CC=CC=2C(C(=O)C(=O)NC=2COC(=O)C=2)=CN1CC1=CC=C(Cl)C=C1 AHALLUHSKVGTBF-UHFFFAOYSA-N 0.000 description 1
- HVJOSKUNSCTYGQ-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)methyl]indole-5-carboxylate Chemical compound C1=CC2=CC(C(=O)OC)=CC=C2N1CC1=CC=C(Cl)C=C1 HVJOSKUNSCTYGQ-UHFFFAOYSA-N 0.000 description 1
- GKWSVIFKNFPWSP-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)methyl]indole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C=CN1CC1=CC=C(Cl)C=C1 GKWSVIFKNFPWSP-UHFFFAOYSA-N 0.000 description 1
- GEBXBEAKNZPYPU-UHFFFAOYSA-N methyl 1-[(4-chlorophenyl)methyl]indole-7-carboxylate Chemical compound C1=2C(C(=O)OC)=CC=CC=2C=CN1CC1=CC=C(Cl)C=C1 GEBXBEAKNZPYPU-UHFFFAOYSA-N 0.000 description 1
- JUFKVERHVVZNPW-UHFFFAOYSA-N methyl 1-[[4-(trifluoromethoxy)phenyl]methyl]indole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C=CN1CC1=CC=C(OC(F)(F)F)C=C1 JUFKVERHVVZNPW-UHFFFAOYSA-N 0.000 description 1
- AVSZYTUNFQJJIW-UHFFFAOYSA-N methyl 3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]-1-[[4-(trifluoromethoxy)phenyl]methyl]indole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C(C(=O)C(=O)NC=2COC(=O)C=2)=CN1CC1=CC=C(OC(F)(F)F)C=C1 AVSZYTUNFQJJIW-UHFFFAOYSA-N 0.000 description 1
- ABYRQXUKLCPEMG-UHFFFAOYSA-N methyl 4-(indol-1-ylmethyl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C2=CC=CC=C2C=C1 ABYRQXUKLCPEMG-UHFFFAOYSA-N 0.000 description 1
- HTQHYDNSUMSHON-UHFFFAOYSA-N methyl 4-[(6-fluoroindol-1-yl)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C2=CC(F)=CC=C2C=C1 HTQHYDNSUMSHON-UHFFFAOYSA-N 0.000 description 1
- SNGJDDHVOLMNIY-UHFFFAOYSA-N methyl 4-[[3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indol-1-yl]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C2=CC=CC=C2C(C(=O)C(=O)NC=2COC(=O)C=2)=C1 SNGJDDHVOLMNIY-UHFFFAOYSA-N 0.000 description 1
- YSGVYZRTYQVHDZ-UHFFFAOYSA-N methyl 4-[[6-fluoro-3-[2-oxo-2-[(5-oxo-2h-furan-3-yl)amino]acetyl]indol-1-yl]methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CN1C2=CC(F)=CC=C2C(C(=O)C(=O)NC=2COC(=O)C=2)=C1 YSGVYZRTYQVHDZ-UHFFFAOYSA-N 0.000 description 1
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- BTWIGYNTLUEHBD-UHFFFAOYSA-N n-(1-benzylindol-5-yl)acetamide Chemical compound C1=CC2=CC(NC(=O)C)=CC=C2N1CC1=CC=CC=C1 BTWIGYNTLUEHBD-UHFFFAOYSA-N 0.000 description 1
- IJRAXYRWNMKNPB-UHFFFAOYSA-N n-[1-[(4-chlorophenyl)methyl]indol-4-yl]acetamide Chemical compound C1=CC=2C(NC(=O)C)=CC=CC=2N1CC1=CC=C(Cl)C=C1 IJRAXYRWNMKNPB-UHFFFAOYSA-N 0.000 description 1
- CLQLMLNUYQATDQ-UHFFFAOYSA-N n-[1-[(4-chlorophenyl)methyl]indol-5-yl]acetamide Chemical compound C1=CC2=CC(NC(=O)C)=CC=C2N1CC1=CC=C(Cl)C=C1 CLQLMLNUYQATDQ-UHFFFAOYSA-N 0.000 description 1
- VRMPNNCEOZOFMT-UHFFFAOYSA-N n-[1-[(4-chlorophenyl)methyl]indol-5-yl]methanesulfonamide Chemical compound C1=CC2=CC(NS(=O)(=O)C)=CC=C2N1CC1=CC=C(Cl)C=C1 VRMPNNCEOZOFMT-UHFFFAOYSA-N 0.000 description 1
- WVJPEBHBXKYSGO-UHFFFAOYSA-N n-[1-[[4-(trifluoromethyl)phenyl]methyl]indol-5-yl]methanesulfonamide Chemical compound C1=CC2=CC(NS(=O)(=O)C)=CC=C2N1CC1=CC=C(C(F)(F)F)C=C1 WVJPEBHBXKYSGO-UHFFFAOYSA-N 0.000 description 1
- OUWNCRKWZXWKHF-UHFFFAOYSA-N n-[2-[1-[(4-chlorophenyl)methyl]indol-2-yl]phenyl]acetamide Chemical compound CC(=O)NC1=CC=CC=C1C1=CC2=CC=CC=C2N1CC1=CC=C(Cl)C=C1 OUWNCRKWZXWKHF-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
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- 239000007968 orange flavor Substances 0.000 description 1
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- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
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- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- RGWYWCSBXUOLSR-FMIVXFBMSA-N tert-butyl (e)-3-[1-[(4-chlorophenyl)methyl]indol-4-yl]prop-2-enoate Chemical compound C1=CC=2C(/C=C/C(=O)OC(C)(C)C)=CC=CC=2N1CC1=CC=C(Cl)C=C1 RGWYWCSBXUOLSR-FMIVXFBMSA-N 0.000 description 1
- MVIQYYAMCQLZTK-UHFFFAOYSA-N tert-butyl 1-[(4-chlorophenyl)methyl]indole-4-carboxylate Chemical compound C1=CC=2C(C(=O)OC(C)(C)C)=CC=CC=2N1CC1=CC=C(Cl)C=C1 MVIQYYAMCQLZTK-UHFFFAOYSA-N 0.000 description 1
- COMUIDKINGXGMF-UHFFFAOYSA-N tert-butyl 2-[4-(indol-1-ylmethyl)phenyl]acetate Chemical compound C1=CC(CC(=O)OC(C)(C)C)=CC=C1CN1C2=CC=CC=C2C=C1 COMUIDKINGXGMF-UHFFFAOYSA-N 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- UMHFSEWKWORSLP-UHFFFAOYSA-N thiophene 1,1-dioxide Chemical compound O=S1(=O)C=CC=C1 UMHFSEWKWORSLP-UHFFFAOYSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
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- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- 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
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Description
본 발명은 항종양 활성, 구체적으로는 충실성 종양, 보다 상세하게는 결장과 폐의 종양에 대하여 활성을 갖는 2-(1H-인돌-3-일)-2-옥소-아세트아미드에 관한 것이다.
결장-직장 암종은 서구에서는 가장 흔한 종양의 하나로서 전세계적으로 해마다 421.000건이 새로이 발병되고 있으며 폐암과 유방암을 제외하고는 가장 빈번한 사망 원인이 되고 있다.
약 40 - 50%의 환자는 외과적 수술이 가능하며, 나머지 환자들의 경우에는 화학요법적 치료를 병행해야 하며 완치율은 5%를 넘지 않는다.
결장직장암은 현재 사용중인 화학요법에 대하여는 대개 내성을 갖거나 감도가 떨어지며, 이러한 유형의 암에 대하여 어느 정도의 효능을 갖는 유일한 약물은 5-플루오로우라실이다.
5-FU를 기본으로 하는 병행 화학요법이 실패하는 경우에 실시할 수 있는 다른 치료대안이 현재로서는 없다. 따라서, 이러한 유형의 종양 치료에 활성인 신규한 약물이 강력하게 요구된다.
WO 00712917호 (출원인: Roche Diagnostics)에는 항종양 활성, 특히 결장 종양에 대한 활성을 갖는 4-우레이도 및 티오우레이도 2(5H)-푸라논 또는 2(5H)-티오페논 유도체가 개시되어 있다.
WO 98/09946호 (출원인: Asta Medica)에는 인돌-3-글리옥실아미드 유도체가 개시되어 있다. 이 화합물은 아미도 질소가 방향족 및 피리딜 잔기로 치환된 것이며 항천식, 항알러지, 면역억제 및 면역조절 활성을 갖는 것으로 보고된다.
참고문헌 [Proceedings of the American Association for Cancer Research, volume 40, abstract 1893 및 4110, 1999]에는 화합물 N-(4-피리딜)-2-(1-(4-클로로벤질)-1H-인돌-3-일)-글리옥시아미드(D-24,851)가 시험관내 및 생체내 항종양 효과를 갖는다고 개시되어 있다.
N-(5-옥소-2,5-디히드로푸란-3-일) 또는 N-(5-옥소-2,5-디히드로티오펜-3-일)-2-(1H-인돌-3-일)-2-옥소-아세트아미도 유도체가 항종양 활성, 특히 사람의 충실성 종양에 대하여 현저한 활성을 갖는다는 것을 발견하기에 이르렀다.
본 발명의 화합물은 하기 화학식 (I)로 표시되는 화합물, 그의 이성체 및 에난티오머 및 혼합물이다:
식중,
- R1, R2 및 R5는 독립적으로 수소 또는 C1-C6 알킬기이고;
- R3는 수소, C1-C4 알킬, 아랄킬, 임의로는 치환된 페닐이며;
- R4는 수소, 선상 또는 분지쇄상의 C1-C8 알킬, C5-C6 싸이클로알킬; 아랄킬; 헤테로아랄킬이고;
- X는 수소; C1-C6 알킬; C1-C6 할로알킬; C1-C6 히드록시알킬; C1-C6 아미노알킬; C1-C6-알콕시-C1-C6-알킬; C1-C18-아실옥시-C1-C6-알킬; 히드록시; C1-C4 알콕시; C1-C3 할로알콕시; 페녹시; 아랄콕시; C1-C3 아실옥시; 아미노; C1-C3 알킬아미노; C1-C3-아실아미노; C1-C3-알킬설포닐아미노; 아로일아미노; 할로겐; 니트로; 시아노; 트리플루오로메틸; 카르복시; C1-C6 알콕시카르보닐; RaRbN(CH2)nC(=O)-기 (식중, Ra 및 Rb는 독립적으로 수소, C1-C3-알킬이거나, Ra 및 Rb는 그들에 연결되어 있는 질소 원자와 함께 피롤리디노, 피페리디노, 페페라지노 또는 모르폴리노 고리를 형성하며, n은 1 내지 4의 정수이다); RaRcN(CH2)nC(=O)-기 (식중, Ra 및 n은 상기 정의한 바와 같고, Rc는 C1-C4-알콕시카르보닐기이다); R1C(=O)-기 (식중, R1은 상기 정의한 바와 같다); 설포닐; 메르캅토; C1-C4-알킬티오; C1-C4-알킬설피닐; C1-C4-알킬설포닐; 아미노설포닐; C1-C3-알킬아미노설포닐; 기 -P(=O)(OR1)(OR2) (식중, R1 및 R2는 상기 정의한 바와 같다); 기 (E)- 또는 (Z)-C(R1)=C(R2)=C(=O)R6 (식중, R6은 히드록시, C1-C6-알콕시이다); NRaRb 또는 식 RaRbN(CH2)mNR1-로 표시되는 기 (식중, m은 2 내지 4의 정수이고, R1, R2, Ra 및 Rb는 상기 정의한 바와 같다)로부터 독립적으로 선택된 1개 또는 그 이상, 최대 4개의 기이며;
Y는 산소 또는 황 원자이다.
또한, 본 발명은 무독성 산 또는 염기를 화합물 (I)에 존재하는 이온화가능한 기와 반응시켜서 얻을 수 있는 화학식 (I)의 화합물의 염에 관한 것이다.
임의로 치환된 페닐은 바람직하게는 페닐, 4-메틸페닐, 2,4-디메톡시-페닐, 4-메톡시-페닐, 4-니트로-페닐, 3-클로로페닐, 4-히드록시페닐, 3,5-디메톡시-4-히드록시-페닐, 3-시아노-페닐, 2-히드록시페닐, 2-카르복시페닐을 의미한다.
아랄킬은 바람직하게는 하나 이상의 클로로, 플루오로, 트리플루오로메틸, 니트로, 시아노, 메틸설포닐, 3급-부틸기로 임의 치환된 벤질, 페네틸, 나프틸메틸, 비페닐메틸을 의미한다.
헤테로아랄킬은 바람직하게는 피리딜메틸을 의미한다.
R1 및 R2 및 R3 및 R5는 바람직하게는 수소와 메틸이다.
R4는 바람직하게는 수소; 메틸; 벤젠 고리 상에 메틸, t-부틸, 불소, 염소, 브롬, 히드록시, 아세톡시, 메톡시, 트리플루오로메톡시, 벤질옥시, 트리플루오로메틸, 시아노, 니트로, 아미노, 아세틸아미노, 메틸설포닐아미노, 메틸메르캅토, 메틸설피닐, 메틸설포닐, 페닐, 에톡시카르보닐, 카르복시, 카르보닐메틸, (에톡시카르보닐)케닐, (3급-부톡시카르보닐)메틸, (벤질옥시카르보닐)메틸, (디메틸카르바모일)메틸로부터 선택된 하나 이상의 치환기를 갖는 벤질; α-나프틸, β나프틸; 4-피리딜; 4-피리딜-N 옥사이드이다.
X는 바람직하게는 메틸, 에틸, 불소, 염소, 브롬, 히드록시, 아세톡시, 메톡시, 페녹시, 트리플루오로메톡시, 트리플루오로메틸, 시아노, 니트로, 아미노, 아세틸아미노, 메틸설포닐아미노, 메틸메르캅토, 메틸설피닐, 메틸설포닐, 카르복시, 메톡시카르보닐, 3급-부톡시카르보닐, 디에틸카르바모일, (2-아미노에틸)카르바모일, (2-디메틸아미노에틸)카르바모일, (E)- 및 (Z)-2-카르복시에텐-1-일, (E)- 및 (Z)-(2-3급-부톡시카르보닐)에텐-1-일, (E)- 및 (Z)-(에톡시카르보닐)에테닐, 히드록시메틸 및 알릴옥시메틸이다.
Y는 바람직하게는 산소 원자이다.
본 발명의 화합물은 하기 화학식 (Ⅱ)의 화합물을 하기 화학식 (Ⅲ)의 화합물과 반응시켜서 제조할 수 있다:
식중, R1, R2, R3, R4, X 및 Y는 상기 정의한 바와 같다.
이 반응은 에틸 에테르, 이소프로필 에테르, 메틸-3급-부틸 에테르, 테트라히드로푸란, 디옥산, 1,2-디메톡시에탄, 디클로로메탄, 1,2-디클로로에탄, 톨루엔, 디메틸포름아미드, 디메틸아세트아미드, 디메틸설폭사이드와 같은 용매에서, 화학식 (Ⅲ)의 화합물 1 내지 3몰 당량을 이용해서 0℃ 내지 용매의 리플럭스 온도 범위의 온도에서 실시된다. 필요에 따라서는, 알칼리 또는 알칼리 토금속의 탄산염의 존재하에서 이 반응을 실시할 수 있다.
에틸에테르, THF 또는 1,2-디메톡시에탄과 같은 에테르 용매에서, 실온 내지 80℃ 범위의 온도로, 1당량 이상의 탄산칼륨 존재하에서 이 반응을 실시하는 것이 바람직하다.
이어서, 에스테르기의 가수분해, 카르복실산의 에스테르화, 아미드화 등과 같은 반응처럼 종래부터 관능기의 변환에 사용되는 방법에 따라서 상기 생성되는 화학식 (I)의 화합물을 다른 화학식 (I)의 화합물로 전환시킬 수 있다. 예를 들어, 화학식 (Ⅱ)에서, X 및 R4가 화학식 (Ⅱ)의 화합물과 화학식 (Ⅲ)의 화합물의 반응에 관여하는 치환기를 함유하고 있는 경우에는 적당한 보호기를 사용한 다음 종래의 방법에 따라서 이 보호기를 제거할 수 있다.
R5가 C1-C6 알킬기인 화학식 (Ⅰ)의 화합물은 R5가 수소인 화학식 (I)의 화합물을 알칼리 또는 알칼리 토금속의 수소화물 존재하에서 R5-Hal 유도체 (여기서, Hal은 바람직하게는 염소, 브롬 또는 요오드이다)로 알킬화시킴으로써 얻어진다.
화학식 (Ⅱ)의 화합물은 하기 화학식 (Ⅳ)의 화합물을 옥살릴 클로라이드와 반응시킴으로써 얻어진다:
식중, X, R3 및 R4는 상기에서 정의한 바와 같다.
이 반응은 대개는 에틸 에테르, 이소프로필 에테르, 3급-부틸 메틸에테르, 테트라히드로푸란, 디옥산, 디클로로메탄과 같은 용매 중에서 1 내지 2몰 당량의 옥살릴 클로라이드를 이용해서 -10℃ 내지 25℃ 범위의 온도에서 실시되거나, 바람직하게는, 에틸 에테르 또는 테트라히드로푸란에서 약간 과량 (1.2몰 당량)의 옥살릴 클로라이드를 이용해서 0℃ 내지 25℃ 범위의 온도로 실시될 수 있다.
화학식 (Ⅳ)의 화합물은 하기 화학식 (V)의 인돌을 산-결합제의 존재하에서 R4-Hal (Ⅵ) (여기서, Hal은 바람직하게는 염소, 브롬 또는 요오드이다)의 할라이드와 반응시킴으로써 얻어진다:
통상 이 반응은 수산화나트륨, 수소화나트륨, 포타슘 3급-부톡사이드와 같은 알칼리 또는 알칼리 토금속의 수산화물 또는 알콕사이드 또는 수소화물의 존재하에서 에탄올, 이소프로판올, 3급-부탄올, 테트라히드로푸란, 디옥산, 디메틸설폭사이드, 디메틸포름아미드, 디메틸아세트아미드, N-메틸피롤리돈, 아세토니트릴과 같은 프로톤성, 쌍극성 비프로톤성 또는 비극성 용매에서 동등몰량 또는 약간 과량의 할라이드 (Ⅵ)를 이용해서 실시된다. 통상 이 반응은 0℃ 내지 용매의 리플럭스 온도 범위에서 30분 내지 24시간 동안 실시되며, 바람직하게는 화학식 (V)의 화합물과 동등몰량의 수소화나트륨 존재하에 0℃ - 25℃에서 상기 화합물 (V)를 디메틸설폭사이드에서 수소화나트륨과 반응시킨 다음, 화합물 (Ⅵ)을 가하고 50℃ 내지 70℃로 가열함으로써 실시된다. 이 반응은 대개 3시간 안에 종료된다.
화학식 (V) 및 (Ⅵ)의 화합물은 공지되었거나, 공지된 방법으로 제조될 수 있는데, 이들중 다수가 상업적으로 입수가능하다.
식중 Y가 산소인 화학식 (Ⅲ)의 화합물은 공지된 화학식 (Ⅶ)의 화합물을 출발물질로 하는 하기의 반응식에 개시된 반응을 통해 얻어진다. 먼저 화합물 (Ⅶ)을 암모늄 아세테이트와 같은 암모늄 염과 반응시켜서 엔아민 (Ⅷ)으로 전환시킨다. 이어서, 디메틸포름아미드에서 가열하여 엔아민을 Y=O인 화학식 (Ⅲ)의 화합물로 전환시킨다.
이와는 다르게, 공지된 푸란디온 또는 티오펜디온 (Ⅸ)을 암모늄 아세테이트와 같은 암모늄염으로 용융시켜서 Y가 산소 또는 황인 화합물 (Ⅲ)을 제조할 수 있 다.
본 발명에 따른 화합물을 4개의 사람 종양 세포주: HT 29 (결장 암종), PC 3 (전립선 암종), H 460M (폐 암종), MKN-45 (위 암종)에 대하여 약리학적으로 테스트하였다. 세포들을 144시간 동안 테스트 화합물로 인큐베이션한 다음, MTT 에세이 (Mosman, T. "Rapid Colorimetric Assay for Celluar Growth and Suvival: Application to Proliferation and Cytotoxicity Assay"; J. Immunolog. Methods, (1983), 65, 66; Green, L.M., Rapid Colorimetric assay for Cell Viability; Application to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines", J.Immunol.Methods, (1984), 70. 257-268)를 이용해서 세포독성을 측정하였다.
얻어진 데이터는, 본 발명의 화합물이 충실성 종양, 특히 결장 종양과 폐 종양에 대하여 탁월한 활성을 갖는다는 것을 입증하였다.
본 발명의 화합물을 0.01㎎ 내지 1g/㎏ 체중/일의 용량만큼 투여할 수 있다. 바람직한 투여량 처방은 약 1㎎ 내지 약 500㎎ / ㎏ 체중 / 일의 범위일 수 있는데, 체중이 약 70㎏인 환자에게 약 70㎎ 내지 약 3.5g의 활성물질을 24시간 내에 투여하도록 하는 단위 복용량을 이용한다. 보다 우수한 치료 효과를 얻기 위해서는 전술한 투여량 처방을 조절할 수 있다. 예를 들어, 환자의 치료 상태를 고려하여 조절할 수 있다. 본 발명의 활성 화합물은 경구, 정맥내, 근육내 또는 피하내 경로를 통해 투여될 수 있다.
본 발명의 화합물을 종양의 퇴화를 유도하는데 사용되는 다른 약제와 함께 이미 알려진 치료 방법에 따라서 투여하여 이 화합물의 항종양 효과를 상승적으로 증가시킬 수 있다. 본 발명의 화합물과 병행하여 사용할 수 있는 화합물의 예로는 시스플라틴, 카르보플라틴, 독소루비신, 토포테칸, 탁솔, 탁소테레, 빈크리스틴, 5-플루오로우라실이다.
본 발명에 따른 약학적 조성물은 치료학적으로 유효량만큼의 본 발명 화합물 하나 이상을 약학적으로 허용가능한 부형제와의 혼합물로 포함한다.
통상 경구용 조성물은 불활성 희석제나 식용 캐리어를 포함하며, 젤라틴 캡슐에 들어있거나 타블렛 내에 압축될 수 있다. 경구 투여하기에 적당한 다른 형태는 캡슐제, 환제, 엘릭시르, 현탁제 또는 시럽제이다.
정제, 환제, 캡슐 및 이와 유사한 조성물은 (활성 물질 이외에) 다음과 같은 성분들을 포함할 수 있다: 미세결정성 셀룰로스, 검 트라카칸트 또는 젤라틴과 같은 바인더; 스타치 또는 락토스와 같은 부형제; 알긴산, 프리모겔, 콘 스타치 등과 같은 붕해제; 마그네슘 스테아레이트와 같은 윤활제; 콜로이드성 이산화실리콘 같은 글리단트(glidant); 슈크로스 또는 사카린과 같은 감미제나, 페퍼민트, 메틸 살리실레이트 또는 오렌지향과 같은 향미제. 선택된 조성물이 캡슐 형태인 경우에는 지방산 오일과 같은 액상 캐리어를 추가로 포함할 수 있다. 다른 조성물은 슈가 또는 쉘락과 같은 (정제 또는 환제용) 코팅제 같이 물리적 형태를 변형시키는 여러 가지 다른 물질을 포함할 수 있다. 이 조성물의 제조에 사용되는 물질은 약학적으로 순수해야 하며 사용된 용량에서 독성이 없어야 한다.
비경구 투여용 약학적 조성물의 제조에 있어서는, 활성 성분을 용액 또는 현탁액에 도입시킬 수 있는데, 상기 용액 또는 현탁액은 다음과 같은 성분을 더 포함할 수 있다: 주사용 물, 식염수, 오일, 폴리에틸렌 글리콜, 글리세린, 프로필렌 글리콜 또는 다른 합성 용매와 같은 멸균 희석제; 벤질 알콜과 같은 항박테리아제; 아스코르브산 또는 소듐 비설페이트와 같은 항산화제; 에틸렌디아미노테트라아세트산과 같은 킬레이트제; 아세테이트, 시트레이트 또는 포스페이트와 같은 버퍼; 및 염화나트륨 또는 덱스트로스와 같은 용액 농도 조절제. 비경구 제제를 앰풀, 일회용 실린지 또는 글라스 또는 플라스틱 바이알에 넣을 수 있다.
하기의 실시예를 들어 본 발명을 더 상세하게 설명하기로 한다.
제조예 1: 4-아미노-5H-푸란-2-온
무수 에탄올 (190㎖) 중의 에틸 4-클로로아세토아세테이트 (7.02㎖) 및 암모늄 아세테이트 (11.8g)의 용액을 3시간 동안 리플러스시킨다. 실온에서 밤새 그대로 둔후, 이 용액을 감압하에 증류시켜서 건조물로 농축시키고 생성되는 잔류물을 플러쉬 크로마토그래피 (실리카겔, 200g; 용리액 CH2Cl2/MeOH/TEA 15/5/02)로 정제하여 에틸 (Z)-3-아미노-4-클로로-2-부테노에이트 6.53g을 어두운색 오일로서 수득하고 이것을 더 이상 정제하지 않고 그대로 사용한다.
1H-NMR (DMSO-d6, ppm): 1.20(t, 3H); 4.0 (q, 2H); 4.15 (s, 2H); 4.65 (s, 1H); 6.80-7.75 (br.s, 2H).
2중 결합 주변의 Z 배열은 NOE핵자기 공명 테스트에 의해 확인된다.
생성물 (6.30g)을 무수 디메틸포름아미드에 용해시키고 이 용액을 질소 분위기 하에 100℃에서 2.5시간 동안 가열한 다음, 130℃에서 1.5시간 동안 가열한다. 이어서, 디메틸포름아미드를 감암하에 90℃에서 증류 제거하고 생성되는 잔류물을 무수 에탄올 (50㎖)에 용해시킨 다음, 활성목탄(1.5g)으로 처리한다. 목탄을 여과하여 제거한후, 여과물을 건조물로 농축시켜서 잔류물을 얻고, 이것을 플러쉬 크로마토그래피(실리카겔, 190g; 용리액 CH2Cl2/MeOH 9/1)로 정제한다. 생성물을 함유하는 크로마토그래피 분획을 합하고 농축 건조시킨 다음, 잔류물을 에틸아세테이트 (3㎖) 및 이소프로필 에테르 (6㎖)로부터 결정화시켜서 2.54g의 4-아미노-5H-푸란-2-온을 수득한다.
융점: 157 - 159℃
1H-NMR (DMSO-D6, ppm): 4.45 (s,1H); 4.57 (s,2H); 7.20 (br.s, 2H).
제조예 2: 1-(2,4,6-트리메틸벤질)인돌
무수 DMSO(3㎖) 중의 인돌 (1.185g) 용액을 무수 DMSO(10㎖) 중의 수소화나트륨 현탁액(60% 미네랄 오일 현탁액: 0.44g)에 적가한다. 2시간 후, 생성되는 용액을 무수 DMSO(2㎖) 중의 2,4,6-트리메틸벤질 클로라이드 (1.9g) 용액과 함께 60℃에서 6시간 동안 가열하면서 가했다. 이 반응 혼합물을 실온에서 밤새 그대로 둔 후, 물(250㎖)에 쏟아붓고 에틸아세테이트로 추출한 다음 건조시켰다 (Na2SO4). 건 조제를 여과하여 제거하고 용매를 감압하에 증발시켜 제거한 다음, 생성되는 잔류물을 컬럼 크로마토그래피(실리카겔; 용리액 n-헥산/AcOEt 9/1)로 정제하여 2.2g의 1-(2,4,6-트리메틸벤질)인돌을 수득한다.
융점: 79 - 81℃.
제조예 3: 1-(n-옥틸)인돌
무수 DMSO (1㎖) 중의 인돌(1.0g) 용액을 무수 DMSO(20㎖) 중의 수소화나트륨 현탁액 (60% 미네랄 오일 현탁액; 0.37g)에 적가한다. 이 혼합물을 60℃에서 1시간 동안 가열한다. 실온으로 냉각후, 생성되는 용액을 무수 DMSO(2.8㎖) 중의 n-옥틸 브로마이드 용액(2.82㎖)에 적가한다. 실온에서 밤새 둔후, 반응 혼합물을 물(200㎖)에 쏟아붓고 에틸아세테이트(2 x 50㎖)로 추출한다. 합해진 유기상을 NaCl 포화 용액으로 수세하고 건조시키고 증발시켜서 건조물을 얻는다. 생성되는 잔류물을 컬럼 크로마토그래피 (실리카겔; 용리액 n-헥산)로 정제하여 1.86g의 1-(n-옥틸)인돌을 오일로서 수득한다. 이 화합물의 특성을 1H-NMR 스펙트럼을 통해 확인한다.
제조예 4: 1-치환 인돌
제조예 2 및 3에 개시된 방법에 따라서, 적당한 인돌 및 할라이드를 출발물질로 하여 하기 1-치환 인돌을 제조한 다음, 필요에 따라서는 표준 화학 변형법에 따라서 얻어진 1-치환 인돌을 변형시킨다:
1-(4-클로로벤질)-5-클로로인돌, 오일;
1-(4-클로로벤질)-6-클로로인돌, 오일;
1-(4-클로로벤질)-2-메틸인돌, 오일;
1-(4-클로로벤질)-5-니트로인돌, 융점: 135 - 137℃;
1-(4-클로로벤질)-6-플루오로인돌, 오일;
1-[4-(메틸설포닐)벤질]-5-클로로인돌, 융점: 133 - 135℃;
1-(4-클로로벤질)-5-메톡시인돌, 오일;
1-(3-클로로벤질)인돌, 오일;
1-(4-클로로벤질)인돌, 오일;
1-(β-나프틸)인돌, 융점: 106 - 108℃;
1-(4-비페닐메틸)인돌, 융점: 130 - 133℃;
1-(4-메톡시벤질)인돌, 오일;
1-벤질인돌, 오일;
1-(4-클로로벤질)인돌, 오일;
1-메틸인돌, 오일;
5-클로로-1-(4-클로로벤질)-2-메틸인돌;
5-메톡시-1-(4-클로벤질)-2-메틸인돌;
1-(4-클로로벤질)-2,5-디메틸인돌;
4-클로로-1-(4-클로로벤질)인돌;
4-아세톡시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-4-메틸인돌, 오일;
1-(4-클로로벤질)-5-시아노인돌, 융점: 108 - 110℃;
5-브로모-1-(4-클로로벤질)인돌, 오일;
5,6-디메톡시-1-(4-클로로벤질)인돌, 오일;
5-벤질옥시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-5-(메톡시카르보닐)인돌;
5-아세틸아미노-1-(4-클로로벤질)인돌;
5-메탄설포닐아미노-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-5-메틸인돌, 오일;
1-(4-클로로벤질)-6-메틸인돌, 오일;
1-(4-클로로벤질)-7-니트로인돌, 융점: 243 - 245℃;
1-(4-클로로벤질)-7-메틸인돌, 오일;
1-(4-클로로벤질)-4-메톡시인돌, 오일;
1-(4-클로로벤질)-4-(에톡시카르보닐)인돌;
1-(4-클로로벤질)-4-니트로인돌, 오일;
4-아세틸아미노-1-(4-클로로벤질)인돌;
6-시아노-1-(4-클로로벤질)인돌;
5,7-디메톡시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-2-페닐인돌, 오일;
1-(4-클로로벤질)-2-페닐-5-메틸인돌;
1-(4-클로로벤질)2,7-디메틸인돌;
1-(4-클로로벤질)-6-메톡시인돌;
2-(4-클로로페닐)-1-에틸인돌;
1-(4-클로로벤질)-2-(2-피리딜)인돌;
5-벤질옥시-1-(4-클로로벤질)-6-메톡시인돌;
7-벤질옥시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-5,6-메틸렌디옥시인돌, 오일;
1-(4-클로로벤질)-2-(4-클로로페닐)인돌;
4-벤질옥시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-7-메톡시인돌;
1-(4-클로로벤질)-4,5,6-트리메톡시인돌;
1-(4-클로로벤질)-2-에틸인돌;
1-(4-클로로벤질)-6-니트로인돌, 오일;
6-벤질옥시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-4-플루오로인돌, 오일;
1-(4-클로로벤질)-2-(4-플루오로페닐)인돌;
1-(4-클로로벤질)-2-(3-클로로-4-플루오로페닐)인돌;
1-(4-클로로벤질)-2-(3,4-디플루오로페닐)인돌;
1-(4-클로로벤질)-2-메틸-5-니트로인돌;
1-(4-클로로벤질)-2-(2-나프틸)인돌;
2-(2-아세틸아미노페닐)-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-7-에틸인돌;
6-아세톡시-1-(4-클로로벤질)인돌;
1-(4-클로로벤질)-4,7-디메톡시인돌;
1-(4-클로로벤질)-4-메톡시카르보닐인돌, 융점: 62 - 63℃;
4-(4-클로로벤조일아미노)-1-(4-클로로벤질)인돌;
(1-(4-클로로벤질)-6-메톡시카르보닐인돌, 오일;
1-(4-클로로벤질)-7-메톡시카르보닐인돌;
1-(4-클로로벤질)-6-(2-디메틸아미노에틸아미노카르보닐)인돌;
1-(4-클로로벤질)-5-인돌인돌;
1-(n-부틸)인돌;
1-(4-클로로벤질)-4,5,6,7-테트라플루오로인돌;
1-(4-클로로벤질)-6-트리플루오로메틸인돌;
4-클로로-1-(4-클로로벤질)-6-메톡시인돌;
6-클로로-1-(4-클로로벤질)-4-메톡시인돌;
1-(4-클로로벤질)-5-페녹시인돌;
1-(4-클로로벤질)-2-(2-클로로페닐)인돌;
1-(2-브로모벤질)인돌;
1-(3-브로모벤질)인돌;
1-(4-브로모벤질)인돌, 오일;
1-(4-브로모벤질)-6-메틸인돌;
1-(2-메틸벤질)인돌;
1-(3-메틸벤질)인돌;
1-(4-메틸벤질)인돌, 오일;
1-(4-메틸벤질)-6-플루오로인돌;
1-(4-3급-부틸벤질)인돌, 오일;
1-(4-3급-부틸벤질)-6-메톡시인돌;
1-(2,3,4,5,6-펜타플루오로벤질)인돌, 오일;
1-(2-플루오로벤질)인돌, 오일;
1-(2,6-디플루오로벤질)인돌;
1-(3-플루오로벤질)인돌, 오일;
1-(3-플루오로벤질)-5-브로모인돌;
1-(3-트리플루오로메틸벤질)-6-니트로인돌;
1-(4-트리플루오로메틸벤질)인돌, 오일;
1-(4-트리플루오로메틸벤질)-5-메탄설포닐아미노인돌;
1-(2-클로로벤질)인돌, 오일;
1-(2,6-디클로로벤질)인돌;
1-(2-시아노벤질)인돌;
1-(3-시아노벤질)인돌, 오일;
1-(4-시아노벤질)-6-플루오로인돌;
1-(4-메톡시카르보닐벤질)인돌;
1-(4-메톡시카르보닐벤질)-6-플루오로인돌;
1-(2-니트로벤질)인돌;
1-(3-니트로벤질)인돌, 오일;
1-(2-메톡시-5-니트로벤질)인돌;
1-(4-니트로벤질)인돌;
1-(3,4-디플루오로벤질)인돌, 오일;
1-(3,4-디플루오로벤질)-6-메톡시인돌;
1-(2,5-디플루오로벤질)인돌;
1-(3,5-비스(트리플루오로메틸)벤질)인돌;
1-(3,5-디플루오로벤질)인돌, 오일;
1-(2,4-비스(트리플루오로메틸)벤질)인돌;
1-(4-메톡시카르보닐메틸)벤질)인돌, 오일;
1-(2,4-디플루오로벤질)인돌;
1-(3,5-디메틸벤질)인돌;
1-(2-트리플루오로메틸벤질)인돌;
1-(2-클로로-6-플루오로벤질)인돌;
1-(3,4-디클로로벤질)인돌, 오일;
1-(3,4-디클로로벤질)-6-클루오로인돌;
1-(3,4-디클로로벤질)-6-메틸인돌;
1-(2-브로모-5-플루오로벤질)인돌;
1-(2-플루오로-3-메틸벤질)인돌;
1-(2,3-디플루오로벤질)인돌;
1-(3-클로로-2-플루오로벤질)인돌;
1-(3-(메톡시카르보닐)벤질)인돌, 오일;
1-(3,5-디브로모벤질)인돌;
1-(4-플루오로-2-(트리플루오로메틸)벤질)인돌;
1-(2,3,6-트리플루오로벤질)인돌, 오일;
1-(2,4,5-트리플루오로벤질)인돌, 오일;
1-(2,4,6-트리플루오로벤질)인돌, 오일;
1-(2,3,4-트리플루오로벤질)인돌, 오일;
1-(4-트리플루오로메톡시벤질)인돌, 오일;
1-(4-트리플루오로메톡시벤질)-6-카르보메톡시인돌;
1-(3-트리플루오로메톡시벤질)인돌;
1-(2-비페닐메틸)인돌;
1-(4-디플루오로메톡시벤질)인돌;
1-(3,4-디메톡시-6-니트로벤질)인돌;
1-(3-메톡시벤질)인돌;
1-(2-클로로-4-플루오로벤질)인돌;
1-(2,5-디클로로벤질)인돌;
1-(4-플루오로벤질)-4-클로로인돌;
1-(4-플루오로벤질)-5-클로로인돌;
1-(4-플루오로벤질)-6-클로로인돌;
1-(4-플루오로벤질)-2-메틸인돌;
1-(4-플루오로벤질)-5-니트로인돌;
1-(4-플루오로벤질)-6-플루오로인돌;
1-(4-플루오로벤질)-5-클로로인돌;
1-(4-플루오로벤질)-5-메톡시인돌;
1-(4-플루오로벤질)-4-메톡시인돌;
1-(4-플루오로벤질)-5-메틸인돌;
1-(4-플루오로벤질)-6-메틸인돌;
1-(4-플루오로벤질)-7-메틸인돌;
1-(4-플루오로벤질)-5,6-메틸렌디옥시인돌;
1-(3-클로로벤질)-5-시아노인돌;
1-(4-비페닐메틸)-6-카르보메톡시인돌;
1-(4-메톡시벤질)-4-클로로인돌;
5-아세틸아미노-1-벤질인돌;
6-플루오로-1-[(4-메틸설포닐)벤질]인돌;
1-메틸-6-메톡시인돌;
5-클로로-1-(4-메톡시벤질)-2-메틸인돌;
1-(4-피리딜메틸)인돌, 오일;
1-(4-피리딜메틸)-6-클로로인돌;
1-[4-(메틸설포닐)벤질]-1H-인돌, 융점: 133 - 135℃;
6-브로모-1-(4-클로로벤질)-1H-인돌, 오일;
1-[(3,5-디메틸-4-이속사졸릴)메틸]-1H-인돌, 오일;
4-(1H-인돌-1-일메틸)벤조니트릴, 오일;
1-(4-클로로벤질)-6-페녹시-1H-인돌, 오일;
1-(5-클로로-2-플루오로벤질)-1H-인돌, 오일;
1-(1H-인돌-1-일메틸)벤조산, 융점: 155 - 158℃;
4-(1H-인돌-1-일메틸)벤조산 에틸 에스테르, 오일 (4-(1H-인돌-1-일메틸)벤조산을 THF 중에서 1,1'-카르보닐디이미다졸과 반응시킨 다음, 70℃에서 3시간 동안 무수 에탄올로 처리하여 제조함);
1-(4-클로로벤질)-7-플루오로-1H-인돌, 오일;
[4-(1H-인돌-1-일메틸)페닐]아세트산;
[4-(1H-인돌-1-일메틸)페닐]아세트산 에틸 에스테르, 오일 ([4-(1H-인돌-1-일메틸)페닐]아세트산을 THF에서 실온에서 4시간 동안 1,1'-카르보닐디이미다졸과 반응시킨 다음 실온에서 밤새 무수 에탄올로 처리하여 제조함);
[4-(1H-인돌-1-일메틸)페닐]아세트산 3급-부틸 에스테르, 오일 ([4-(1H-인돌-1-일메틸)페닐]아세트산을 톨루엔에서 과량의 N,N-디메틸포름아미드 디-3급-부틸 아세탈과 80℃에서 반응시켜서 제조함);
N-[2-(디메틸아미노)에틸]-2-[4-(1H-인돌-1-일메틸)페닐]아세트아미드, 오일 ([4-(1H-인돌-1-일메틸)페닐]아세트산을 THF에서 실온에서 3시간 동안 1,1'-카르보 닐디이미다졸과 반응시킨 다음, 실온에서 2시간 동안 N,N-디메틸에틸렌디아민과 반응시켜서 제조함);
3-(1H-인돌-1-일메틸)벤조산 메틸 에스테르, 오일;
3-(1H-인돌-1-일메틸)벤조산, 융점: 158 - 160℃ (3-(1H-인돌-1-일메틸)벤조산 메틸에스테르의 에탄올 용액을 1N NaOH로 처리한 다음, 2N HCl로 산성화시켜서 제조함);
N-[2-(디메틸아미노)에틸]-3-(1H-인돌-일메틸)벤즈아미드, 오일 (3-(1H-인돌 -1-일메틸)벤조산을 THF에서 실온에서 2시간 1,1'-카르보닐디이미다졸과 반응시킨 다음, 실온에서 2시간 동안 N,N-디메틸에틸렌디아민으로 처리하여 제조함);
[1-(4-클로로벤질)-1H-인돌-4-일]메탄올, 융점: 66 - 67℃ (1-(4-클로로벤질)-4-(메톡시카르보닐)-1H-인돌을 LiAlH4로 환원시켜 제조함);
1-(4-클로로벤질)-1H-인돌-4-카르브알데하이드, 융점: 66 - 68℃ ([1-(4-클로로벤질)-1H-인돌-4-일]메탄올을 리플럭싱 CH2Cl2에서 과량의 MnO2로 산화시켜 제조함);
1-(4-클로로벤질)-1H-인돌-4-카르복실산, 융점: 190 - 193℃;
7-(벤질옥시)-1-(4-플루오로벤질)-1H-인돌, 오일;
2-(디메틸아미노)에틸 1-(4-클로로벤질)-1H-인돌-4-카르복실레이트, 오일 (1-(4-클로로벤질)-1H-인돌-4-카르복실산을 실온에서 2시간 동안 THF에서 1,1'-카르보닐디이미다졸과 반응시킨 다음, 리플럭스 온도에서 과량의 2-디메틸아미노에탄 올로 처리하여 제조함);
2-[4-(1H-인돌-1-일메틸)페닐]-N,N-디메틸아세트아미드, 오일 ([4-(1H-인돌-1-일메틸)페닐]아세트산을 실온에서 2시간 동안 THF에서 1,1'-카르보닐디이미다졸과 반응시킨 다음, 에탄올 중의 5.2N 디메틸아민 용액으로 처리하여 제조함);
[4-(1H-인돌-1-일메틸)페닐]아세트산 벤질 에스테르, 오일 ([4-(1H-인돌-1-일메틸)페닐]아세트산을 실온에서 2시간 동안 THF에서 1,1'-카르보닐디이미다졸과 반응시킨 다음, 벤질 알콜로 처리하여 제조함);
1-(4-클로로벤질)-1H-인돌-4-카르보니트릴, 융점: 85 - 87℃;
1-(4-메틸-3-니트로벤질)-1H-인돌, 오일;
(2E)-3-[1-(4-클로로벤질)-1H-인돌-4-일]-2-프로펜산 3급-부틸 에스테르, 융점: 91 - 94℃ (1-(4-클로로벤질)-1H-인돌-4-카르브알데하이드를 리플럭싱 CH2Cl2에서 Ph3P=CHCOOtBu로 비티히 반응시켜서 제조함);
1-(4-클로로벤질)-1H-인돌-4-카르복실산 3급-부틸 에스테르, 오일 (1-(4-클로로벤질)-1H-인돌-4-카르복실산을 80℃에서 톨루엔에서 과량의 N,N-디메틸포름아미드 디-3급-부틸 아세탈과 반응시켜서 제조함);
1-[4-(벤질옥시)벤질]-1H-인돌, 융점: 78 - 80℃;
1-[1-(4-클로로벤질)-1H-인돌-4-일]에탄올 (1-(4-클로로벤질)-1H-인돌-4-카르브알데하이드를 0℃에서 THF에서 CH3MgCl과 반응시켜서 제조함);
1-[1-(4-클로로벤질)-1H-인돌-4-일]에타논, 융점: 123 - 125℃ (1-[1-(4-클 로로벤질)-1H-인돌-4-일]에탄올을 리플럭싱 CHCl3에서 과량의 MnO2로 산화시켜서 제조함);
2-[4-[(알릴옥시)메틸]-1(4-클로로벤질)-1H-인돌, 오일 ([1-(4-클로로벤질)-1H-인돌-4-일]메탄올을 NaH의 존재하에 실온에서 3시간 동안 DMF 중에서 알릴 브로마이드로 알킬화시켜서 제조함).
제조예 5: 4-아미노-5H-티오펜-2-온
시판되는 4-히드록시-2(5H)-티오펜 (1.16g)을 130℃로 유지된 융용된 암모늄 아세테이트(3.08g)에 가한다. 30분 후, 용융된 혼합물을 냉각시키고 1,2-디메톡시에탄(50㎖)에 가한다. 30분간 교반후, 고형물을 여과하여 제거해서 버린다. 디메톡시에탄 용액을 건조물로 농축시켜서 고체 잔류물을 얻고, 이것을 실리카겔 컬럼 크로마토그래피로 정제한다. 처음에는 CH2Cl2/MeOH 9/1로, 다음에는 CH2Cl
2/MeOH 8/2로 용리한다. 가장 신속하게 이동하는 생성물 함유 분획을 모으고 건조물로 농축시켜서 4-아미노-5H-티오펜-2-온 (0.43)을 수득한다.
1H-NMR (DMSO-D6, ppm): 3.90(s, 2H); 4.95 (s, 1H); 7.43 (br.s, 2H).
융점: 122 - 126℃.
C4H5NOS에 대한 원소분석:
계산치(%): C = 41.72, H = 4.38, N = 12.16; S = 27.84
실측치(%): C = 41.81, H = 4.45, N = 11.81, Cl = 27.24.
실시예 1
2-(1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세틸 클로라이드
교반하에 0℃로 냉각시킨 무수 에틸에테르(5㎖) 중의 1-(4-클로로벤질)-1H-인돌 (2.0g)의 용액을 무수 에틸에테르(2㎖) 중의 옥살릴 클로라이드(0.85㎖)의 용액에 방울방울 가한다. 그후 반응물을 실온에서 2시간 동안 정치한다. 분리된 고형물을 여과하여 회수하고 무수 에틸에테르로 세척한 다음, 진공하에 40℃에서 건조시켜서 2-(1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세틸 클로라이드 (1.64g)을 수득한다.
융점: 151 - 153℃
1H-NMR (CHCl3-d3, ppm): 5.43(s, 2H); 7.12(d,2H); 7.25-7.45(m, 5H); 8.25(s,1H); 8.43(m, 1H).
실시예 2: N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드
무수 테트라히드로푸란(10㎖) 중의 4-아미노-5H-푸란-2-온 (0.30g)과 2-(1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세틸 클로라이드 (0.45g)의 용액을 2시간 동안 리플럭스한다. 실온에서 냉각후, 반응 혼합물을 물(200㎖)에 쏟아붓고 생성되는 현탁액을 1시간 동안 교반하에 둔다. 고형물을 여과해내고, 1시간 동안 교반하에 메탄올(4.3㎖)에 재현탁시킨 다음, 여과시켜 수거하여 N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드 (0.27g)를 수득한다.
융점: 253 - 255℃
1H-NMR (DMSO-d6, ppm): 5.13(s,2H); 5.65(s,2H); 6.05(s,1H); 7.25-7.50(m,6H); 7.65(m,1H); 8.30(m,1H); 9.05(s,1H); 11.90(s,1H).
원소분석:
C21H15ClN3O4에 대한 계산치(%): C = 63.89, H = 3.83, N = 7.10, Cl =8.98
실측치(%): C = 63.65, H = 4.02, N = 6.89, Cl = 9.13.
실시예 3:
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드
무수 에틸에테르 (5㎖) 중의 1-(4-플루오로벤질)-1H-인돌 (0.50g) 용액을 0℃로 냉각된 무수 에틸에테르(5㎖) 중의 옥살릴 클로라이드 (0.209㎖)의 교반 용액에 방울방울 가한다. 그후, 반응 혼합물을 실온에서 2시간 동안 둔 다음, 증발시켜 건조하고 생성되는 잔류물을 무수 테트라히드로푸란(5㎖)에 재용해시킨 다음 이 용액을 무수 테트라히드로푸란(22㎖) 중의 4-아미노-5H-푸란-2-온(0.45g)의 용액에 방울방울 가한다. 그 후, 혼합물을 3시간 동안 환류시킨다. 실온에서 밤새 둔후, 반응 혼합물을 물(300㎖)에 쏟아붓고 생성되는 현탁액을 1시간 동안 교반한다. 고형물을 여과하여 수거하고 30분간 교반하에 뜨거운 메탄올(20㎖)에 재현탁시킨다. 실온에서 2시간후, 고형물을 여과하여 회수해서 N-(5-옥소-2,5-디히드로푸란-3-일) -2-(1-(4-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드 (0.35g)을 수득한다.
융점: 260 - 262℃
1H-NMR (DMSO-d6, ppm): 5.15(s,2H); 5.65(s,2H); 6.05(s,1H); 7.10- 7.25(m,1H); 7.25-7.50(2m, 4+1H); 7.65(m,1H); 8.30(m,1H); 9.1(s,1H); 11.90(s,1H).
원소분석:
C21H15FN2O4에 대한 계산치(%): C = 66.66, H = 4.00, N = 7.40, F = 5.02
실측치(%): C = 66.43, H = 4.12, N = 7.18, F = 4.96.
실시예 4
실시예 1-3에 개시된 것과 유사한 방법에 따라서, 그리고 출발물질로서 적당한 1-치환 인돌을 사용하여 하기의 화합물을 제조한다:
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-클로로-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 251-253℃ (from AcOEt/Et2O);
1H-NMR (DMSO-d6, ppm): 5.13(s,2H); 5.65(s,2H); 6.05(s,1H); 7.40(m,5H); 7.65(d,1H); 8.23(s,1H); 9.12(s,1H); 11.87(s,1H).
C21H14ClN2O4에 대한 원소분석:
계산치(%): C = 58.76, H = 3.29, N = 6.53, Cl = 16.52
실측치(%): C = 58.11, H = 3.43, N = 6.40, Cl = 15.58.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-클로로-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 255-257℃ (from AcOEt/Et2O);
1H-NMR (DMSO-d6, ppm): 5.13(s,2H); 5.68(s,2H); 6.05(s,1H); 7.35(m,5H); 7.80(s,1H); 8.23(d,1H); 9.10(s,1H); 11.87(s,1H).
C21H14ClN2O4에 대한 원소분석:
계산치(%): C = 58.76, H = 3.29, N = 6.53, Cl = 16.52
실측치(%): C = 58.08, H = 3.39, N = 6.10, Cl = 15.17.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 254-256℃ (from 이소프로필알콜);
1H-NMR (DMSO-d6, ppm): 2.65(s,3H), 5.15(s,2H); 5.65(s,2H); 5.95(s,1H); 7.07(d,2H); 7.23(m,4H); 7.40(d,2H); 7.63(m,1H); 7.93(m,1H); 11.98(s,1H).
C22H17ClN2O4에 대한 원소분석:
계산치(%): C = 64.63, H = 4.19, N = 6.85, Cl = 8.67
실측치(%): C = 64.39, H = 4.23, N = 6.80, Cl = 8.62.
N-(5-옥소-2,5-디히드록시푸란-3-일)-2-(1-(4-클로로벤질)-5-(니트로-1H)-인돌-3-일)-2-옥소-아세트아미드;
융점: 248-250℃ (from MeOH);
C21H14ClN3O6에 대한 원소분석:
계산치(%): C = 57.35, H = 3.21, N = 9.55
실측치(%): C = 56.55, H = 3.16, N = 9.05.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 242-245℃ (from 메탄올)
C21H14CFlN2O4에 대한 원소분석:
계산치(%): C = 61.10, H = 3.42, N = 6.79, Cl = 8.59, F = 4.60
실측치(%): C = 61.09, H = 3.43, N = 6.76, Cl = 8.55, F = 4.60.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메틸설포닐)벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 283-285℃ (from 메탄올과 AcOEt);
C22H18N2O6S에 대한 원소분석:
계산치(%): C = 60.27, H = 4.14, N = 6.39, S = 7.31
실측치(%): C = 59.07, H = 4.21, N = 6.25, S = 6.42.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 238-240℃ (from MeOH와 AcOEt);
1H-NMR (DMSO-d6, ppm): 3.80(s,3H), 5.13(s,2H); 5.65(s,2H); 6.05(s,1H); 6.95(m,1H); 7.30-7.55(m,5H); 7.80(m,1H); 9.00(s,1H); 11.90(s,1H).
C22H17ClN2O5에 대한 원소분석:
계산치(%): C = 62.20, H = 4.03, N = 6.59, Cl = 8.34
실측치(%): C = 62.00, H = 4.01, N = 6.52, Cl = 8.81.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 268-270℃ (from MeOH);
C21H15ClN2O4에 대한 원소분석:
계산치(%): C = 63.89, H = 3.83, N = 7.10, Cl = 8.98
실측치(%): C = 64.83, H = 3.98, N = 6.90, Cl = 8.63.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-나프틸메틸)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 283-285℃ (from AcOEt);
1H-NMR (DMSO-d6, ppm): 5.15(s,2H); 5.80(s,2H); 6.05(s,1H); 7.10-7.25(m,2H); 7.25-7.50(m,2H); 7.65(m,1H); 7.90(m,5H); 8.30(m,1H); 9.10(s,1H); 11.90(s,1H).
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메톡시벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 265-267℃ (from 메탄올);
1H-NMR (DMSO-d6, ppm): 5.15(s,2H); 5.60(s,2H); 6.05(s,1H); 6.90(d,1H); 7.35 (2m,4H); 7.65(m,1H); 8.30(m,1H); 9.05(s,1H); 11.90(s,1H).
C22H18N2O5에 대한 원소분석:
계산치(%): C = 67.69, H = 4.65, N = 7.18
실측치(%): C = 66.78, H = 4.67, N = 6.84.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,4,6-트리메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 288-290℃ (from AcOEt);
1H-NMR (DMSO-d6, ppm): 2.40(s,6H); 2.40(s,6H); 5.05(s,2H); 5.45(s,2H); 5.95(s,1H); 7.00(s,2H); 7.40(m,2H); 7.80(m,1H); 8.25(s,1H); 8.35(m,1H); 11.85(s,1H).
C24H22N2O4에 대한 원소분석:
계산치(%): C = 71.63, H = 5.51, N = 6.96
실측치(%): C = 70.70, H = 5.53, N = 6.69.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-벤질-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 275-277℃ (from 에탄올);
1H-NMR (DMSO-d6, ppm): 5.10(s,2H); 5.85(s,2H); 6.05(s,1H); 7.30(m,7H); 7.60(m,1H); 8.25(m,1H); 9.05(s,1H); 11.90(s,1H).
C21H16N2O4에 대한 원소분석:
계산치(%): C = 69.99, H = 4.48, N = 7.77
실측치(%): C = 69.36, H = 4.59, N = 7.45.
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-비페닐메틸)-1H-인돌-3-일)-2-옥소 아세트아미드;
융점: 245-248℃;
1H-NMR (DMSO-d6, ppm): 5.10(s,2H); 5.85(s,2H); 6.05(s,1H); 7.35(m,7H); 7.70(m,5H); 8.25(m,1H); 9.05(s,1H); 11.87(s,1H).
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(n-옥틸)-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 224-226℃ (from 에탄올);
1H-NMR (DMSO-d6, ppm): 0.80(t,3H); 1.01-1.40(m,10H); 4.40(t,2H); 5.13(s,2H); 6.05(s,1H); 7.35(m,2H); 7.67(m.1H), 8.30(m,1H); 8.85(s,1H); 11.90(s,1H).
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
융점: 262-264℃ (from 메탄올);
1H-NMR (DMSO-d6, ppm): 3.95(s,3H); 5.15(s,2H); 6.03(s,1H); 7.35(m,2H); 7.65(m,1H), 8.30(m,1H); 8.85(s,1H); 11.90(s,1H).
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-클로로-1-(4-클로로벤질)-2-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-메톡시-1-(4-클로로벤질)-2-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2,5-디메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-클로로-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-아세톡시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4-메틸-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 217-219℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5-시아노-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 284-287℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-브로모-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 283-286℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5,6-디메톡시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 275-277℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-벤질옥시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5-(메톡시카르보닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-아세틸아미노-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-메탄설포닐아미노-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5-메틸-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 277-280℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-메틸-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 282-284℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-7-니트로-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 243-245℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-7-메틸-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 268-270℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 210-212℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4-(에톡시카르보닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4-니트로-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 242-244℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-아세틸아미노-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-시아노-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5,7-디메톡시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-페닐-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 280-282℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-페닐-5-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2,7-디메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 283-285℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(2-(4-클로로벤질)-1-에틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-(2-피리딜)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-벤질옥시-1-(4-클로로벤질)-6-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(7-벤질옥시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 277-280℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5,6-메틸렌디옥시-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 296-298℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-(4-클로로페닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-벤질옥시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-7-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4,5,6-트리메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-에틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-니트로-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 192-195℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-벤질옥시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-플루오로-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 182-185℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-플루오로-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 242-245℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-(4-플루오로페닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-(3-클로로-4-플루오로페닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-(3,4-디플루오로페닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-아세틸아미노-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-메틸-5-니트로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-2-(2-나프틸)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(2-(2-아세틸아미노페닐)-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-7-에틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-아세톡시-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4,7-디메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4-메톡시카르보닐-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 212-215℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-(4-클로로벤조일아미노)-1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-메톡시카르보닐-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: >300℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-7-메톡시카르보닐-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-(2-디메틸아미노)-에틸아미노카르보닐)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5-요오도-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(n-부틸)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-4,5,6,7-테트라플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-6-트리플루오로메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(4-클로로-1-(4-클로로벤질)-6-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-클로로-1-(4-클로로벤질)-4-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-클로로벤질)-5-페녹시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-브로모벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-브로모벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-브로모벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 278-280℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-브로모벤질)-6-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 298-300℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메틸벤질)-6-플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-3급-부틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 218-220℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-3급-부틸벤질)-6-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,3,4,5,6-펜타플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 280-282℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,6-디플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 252-256℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-플루오로벤질)-5-브로모-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-트리플루오로메틸벤질)-6-니트로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-트리플루오로메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 279-281℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-트리플루오로메틸벤질)-5-(메탄설포닐아미노)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 267-269℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,6-디클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-시아노벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-시아노벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 229-231℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-시아노벤질)-6-플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메톡시카르보닐벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메톡시카르보닐벤질)-6-플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-니트로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-니트로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 257-260℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-메톡시-5-니트로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-니트로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,4-디플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 275-277℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,4-디플루오로벤질)-6-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,5-디플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,5-비스(트리플루오로메틸)벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,5-디플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 276-278℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,4-비스(트리플루오로메틸)벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메톡시카르보닐메틸)벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,4-디플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,5-디메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-트리플루오로메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-클로로-6-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,4-디클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: >270℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,4-디클로로벤질)-6-플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,4-디클로로벤질)-6-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-브로모-5-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-플루오로-3-메틸벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,3-디플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-클로로-2-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-메톡시카르보닐)벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 248-250℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,5-디브로모벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로-2-(트리플루오로메틸)벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,3,6-트리플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 258-261℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,4,5-트리플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 258-260℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,4,6-트리플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 266-268℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,3,4-트리플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 217-220℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-트리플루오로메톡시벤질)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 250-252℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-트리플루오로메톡시벤질)-6-카르보메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-트리플루오로메톡시벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-비스페닐메틸)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-디플루오로메톡시벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3,4-디메톡시-6-니트로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-메톡시벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2-클로로-4-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(2,5-디클로로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-4-클로로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-5-클로로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-6-클로로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-2-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-5-니트로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-6-플루오로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-[4-플루오로벤질]-5-클로로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-5-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-4-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-5-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-6-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-플루오로벤질)-7-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(3-클로로벤질)-5-시아노-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-비페닐메틸)-6-카르보메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-메톡시벤질)-4-클로로-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-아세틸아미노-1-벤질-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(6-플루오로-1-[(4-메틸설포닐)벤질]-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-메틸-6-메톡시-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5-클로로-1-(4-메톡시벤질)-2-메틸-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(5,6-메틸렌디옥시-1-(4-플루오로벤질)-1H-인돌-3-일)-2-옥소-아세트아미드;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-피리딜메틸)-1H-인돌-3-일)-2-옥소-아세트아미드, 융점: 210-212℃;
N-(5-옥소-2,5-디히드로푸란-3-일)-2-(1-(4-피리딜메틸)-6-클로로-1H-인돌-3-일)-2-옥소-아세트아미드;
2-[1-(4-시아노벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: >260℃;
2-[6-브로모-1-(4-클로로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 268-270℃;
1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H인돌-6-카르복실산, 융점: >300℃ (상응하는 6-메톡시카르보닐 유도체를 1-메틸-2-피롤리돈에서 3몰 당량의 1N NaOH와 실온에서 밤새 반응시킨 다음, 진한 HCl을 이용하여 pH 1로 산성화시킴으로써 수득함);
2-{1-[(3,5-디메틸-4-이속사졸릴)메틸]-1H-인돌-3-일}-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 295-297℃;
2-[1-(3-니트로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 257-260℃;
2-[1-(2,5-디플루오로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 272-275℃;
2-[1-(5-클로로-2-플루오로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 258-287℃;
2-[1-(4-3급-부틸벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 218-220℃;
에틸 4-[(3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-1-일)메틸]벤조에이트, 융점: 158-160℃;
2-[1-(4-클로로벤질)-7-플루오로-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 260-263℃;
에틸 {4-[(3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-1-일)메틸]페닐}아세트아미드, 융점: 228-230℃;
2-(1-{4-[2-(디메틸아미노)-2-옥소에틸]벤질}-1H-인돌-3-일)-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 228-229℃;
벤질 {4-[(3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-1-일)메틸]페닐}아세테이트, 융점: 204-205℃;
2-[1-(4-메틸-3-니트로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 238-240℃;
{4-[3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-인돌-1-일메틸]-페닐}-아세트산 3급-부틸 에스테르, 융점: 195-198℃;
1-(4-클로로벤질)-3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-1H-인돌-4-카르복실산 3급-부틸 에스테르, 융점: 278℃;
2-{1-[4-벤질옥시)벤질]-1H-인돌-3-일}-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 258-260℃;
2-[1-(4-클로로벤질)-4-시아노-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: >250℃;
(2E)-3-(1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-일)-2-프로펜산 3급-부틸 에스테르, 융점: 240-242℃;
2-[4-[(알릴옥시)메틸]-1-(4-클로로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 157-160℃.
실시예 5
2-[1-(4-클로로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-티에닐)아세트아미드
1,2-디메톡시에탄(5㎖) 중에 제조예 5의 4-아미노-5H-티오펜-2-온(103㎎), 탄산칼륨 분말(138㎎) 및 실시예 1의 2-(1-(4-클로로벤질)-1H-인돌-3-일)-2-옥소-아세틸 클로라이드(334㎎)을 현탁시켜 제조한 현탁액을 실온에서 2시간 동안 교반 한다. 2시간후, 반응 혼합물을 물(50㎖)에 쏟아붓고 얻어진 침전물을 여과하여 수거한 다음, 물로 철저하게 세척한다. 여전히 젖어있는 고형물을 메탄올에 현탁시키고 30분간 교반한다. 여과하고 40℃에서 진공하에 건조시켜서 2-[1-(4-클로로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-티에닐)아세트아미드(280㎎)을 수득한다.
융점: 268-270℃
1H-NMR (DMSO-d6, ppm):4.49(s,2H); 5.65(s,2H); 6.75(s,1H); 7.34(m,2H); 7.35(m,2H); 7.43(m,2H); 7.63(m,1H); 8.25(m,1H); 9.07(s,1H); 11.70(s,1H).
C21C15ClN2O3S에 대한 원소분석:
계산치(%): C = 61.39, H = 3.68, N = 6.82, Cl = 8.63, S = 7.80
실측치(%): C = 61.26, H = 3.70, N = 6.75, Cl = 8.56, S = 7.72
유사한 방법으로 하기의 화합물을 제조한다:
2-[1-(4-플루오로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-티에닐)아세트아미드, 융점: 248-250℃;
실시예 6
2-[1-(4-클로로벤질)-1H-인돌-3-일]-N-메틸-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드.
질소 분위기 하에서, 수소화나트륨 (미네랄 오일 중의 60% wt/wt 현탁액 10㎎)을 무수 DMF(2㎖) 중의 2-[1-(4-클로로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드(100㎎)의 용액에 가한다. 20분후, 요오드화메 틸(0.016㎖)을 가한다. 3시간후, 용매를 회전 증발시켜서 제거하고 수득된 잔류물을 물과 에틸아세테이트 사이에 분배한다. 유기층을 황산나트륨 상에서 건조하고 건조물로 농축시킨다. 수득된 잔류물을 비등하는 MeOH/i-PrOH 1/1에 현탁시킨다. 실온으로 냉각후, 불용성 물질을 여과시켜 수거하고 60℃에서 3시간 동안 오븐-건조시켜서 2-[1-(4-클로로벤질)-1H-인돌-3-일]-N-메틸-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드(52㎎)를 수득한다.
융점: 205-208℃
1H-NMR (DMSO-d6, ppm):3.27(s,3H), 5.44(s,2H); 5.56(s,2H); 5.87(s,1H); 7.25-7.47(m,6H); 7.55-7.69(m,1H); 8.09-8.22(m,1H); 8.64(s,1H).
C2H17N2O4에 대한 원소분석:
계산치(%): C = 64.43, H = 4.19, N = 6.85
실측치(%): C = 64.42, H = 4.22, N = 6.82
실시예 7
{4-[(3-{옥소-[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-1-일)메틸]페닐}아세트산.
DMF(10㎖) 중의 벤질 {4-[(3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-1-일)메틸]페닐}아세테이트(300㎎)의 용액을 실온 및 가압하에 10% 목탄상 팔라듐(물 중의 50% wt/wt 현탁액 60㎎)의 존재하에서 수소화시킨다. 3시간 30분후, 촉매를 여과하여 제거하고 여과물을 건조물로 농축시킨다. 수득된 잔류물을 무수 에탄올에 현탁시키고 여과시켜 회수하여 {4-[(3-{옥소-[(5-옥소-2,5- 디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-1-일)메틸]페닐}아세트산(160㎎)을 수득한다.
융점: >270℃
1H-NMR (DMSO-d6, ppm): 3.35(s,2H), 5.13(s,2H); 5.60(s,2H); 6.05(s,1H); 7.20-7.40(m,6H); 7.65(m,1H); 8.30(m,1H); 9.05(s,1H); 11.88(br.s,1H), 12,25(br.s,1H).
C23H18N2O6에 대한 원소분석:
계산치(%): C = 66.02, H = 4.34, N = 6.70
실측치(%): C = 65.99, H = 4.39, N = 6.68
유사한 공정을 이용하여 2-{1-[4-(벤질옥시)벤질]-1H-인돌-3-일}-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드를 접촉 수소화시켜서 하기의 화합물을 제조한다:
2-[1-(4-히드록시벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드, 융점: 303-305℃.
실시예 8
1-(4-클로로벤질)-3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-1H-인돌-4-카르복실산
트리플루오로아세트산(0.2㎖)을 CH2Cl2 중의 1-(4-클로로벤질)-3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-1H-인돌-4-카르복실산 3급-부틸 에스테르 (200㎎)의 용액에 가한다. 실온에서 4시간 동안 교반후, 추가량의 트리플루오로아세트산(0.2㎖)을 가하고, 반응 혼합물을 밤새 교반한다. 회전 증발시킨후, 수득된 잔류물을 교반하에 에틸 아세테이트에 현탁시킨 다음, 고형물을 여과하여 회수해서 1-(4-클로로벤질)-3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-1H-인돌-4-카르복실산(120㎎)을 수득한다.
융점: 279℃
C22H15ClN2O6에 대한 원소분석:
계산치(%): C = 66.21, H = 3.45, N = 6.38, Cl = 8.08
실측치(%): C = 59.51, H = 3.47, N = 6.22, Cl = 7.88
유사한 공정을 이용하여 (2E)-3-(1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-일)-2-프로펜산 3급-부틸 에스테르를 출발물질로 하여 하기 화합물을 제조한다:
(2E)-3-(1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-일)-2-프로펜산, 융점: >250℃.
실시예 9
1-(4-클로로벤질)-N-[2-(디메틸아미노)에틸]-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-카르복사미드
질소 분위기 하에서, 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 히드로클로라이드(44㎎)를 무수 DMF(1㎖) 중의 1-(4-클로로벤질)-3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-1H-인돌-4-카르복실산(50㎎)과 N,N-디메틸에틸렌디아민 (0.014㎖)의 교반 용액에 가한다. 실온에서 4시간 동안 교반후, 반응 혼합물을 회전 증발에 의해 건조물로 농축시키고 잔류물에 물을 흡수시킨다. 고형물질을 여과하여 수집하고 물로 철저하게 세척하여 1-(4-클로로벤질)-N-[2-(디메틸아미노)에틸]-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-카르복사미드(49㎎)를 수득한다.
융점: 225-227℃
C26H25ClN4O5에 대한 원소분석:
계산치(%): C = 61.36, H = 4.95, N = 11.01, Cl = 6.97
실측치(%): C = 61.28, H = 5.02, N = 11.02, Cl = 6.90
유사한 공정을 이용하여 1-(4-클로로벤질)-3-(5-옥소-2,5-디히드로-푸란-3-일아미노옥살릴)-1H-인돌-4-카르복실산을 N-(3급-부톡시카르보닐)에틸렌디아민 또는 디에틸아민과 반응시켜서 하기의 화합물들을 수득한다:
3급-부틸 2-{[(1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]-아세틸}-1H-인돌-4-일)카르보닐]아미노}에틸카르바메이트;
1-(4-클로로벤질)-N,N-디에틸-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-카르복사미드, 융점: 218-219℃.
실시예 10
N-(2-아미노에틸)-1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-카르복사미드
트리플루오로아세트산(0.1㎖)을, 실시예 9의 3급-부틸 2-{[(1-(4-클로로벤 질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-일)카르보닐]아미노}에틸카르바메이트(50㎎)를 CH2Cl2(1㎖)에 용해시켜 제조한 교반 용액에 가한다. 실온에서 3시간 동안 교반후, 이 용매를 회전 증발시켜서 제거하고, 잔류물에 물을 흡수시키고, 1N NaOH를 이용하여 pH를 약 8-9로 조절한다. 침전물을 여과하여 수거하고 철저하게 세척하여 N-(2-아미노에틸)-1-(4-클로로벤질)-3-{옥소 [(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-카르복사미드(25㎎)를 수득한다.
융점: 190-196℃
실시예 11
2-[1-(4-클로로벤질)-4-(히드록시메틸)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드
2-[4-[(알릴옥시)메틸]-1-(4-클로로벤질)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드(239㎎)을 MeOH/H2O = 9/1(10㎖) 및 10% Pd/C(12㎎)에 순차적으로 용해시키고, p-톨루엔설폰산(12㎎)을 가한다. 이 반응물을 약 6시간 동안 리플럭스시킨 다음, DMF와 EtOH로 희석하고, 촉매를 셀라이트 상에 여과하고 용매를 감압하에 제거한다. 조 생성물을 아세톤으로 세척하고 여과한다. 여과물을 농축하고, 수득된 고체를 실리카겔 크로마토그래피 (용리액: CH2Cl2/EtOH = 95/5)로 정제하여 50㎎의 순수한 2-[1-(4-클로로벤질)-4-(히드록시메틸)-1H-인돌-3-일]-2-옥소-N-(5-옥소-2,5-디히드로-3-푸라닐)아세트아미드를 수득 한다. 이 고체를 CH3CN으로부터 결정화하여 융점이 약 238-240℃인 화합물 63㎎을 수득한다.
1H-NMR (DMSO): 11.78(br,1H), 8.89(s,1H), 7.49-7.29(m,7H), 6.02(s,1H), 5.63(s,2H), 5.15(s,2H), 5.10(d,2H, J=6.0Hz), 4.89(t,1H,J=6.0Hz).
실시예 12
본 발명의 화합물의 항종양 효과의 평가방법
하기 4종의 사람 종양 세포주에 대한 본 발명 화학물의 약리학적 효과를 테스트하였다: HT 29 (결장 암종), PC 3 (전립선 암종), H 460M (폐 암종), MKN45 (위 암종). 이 세포들을 144시간 동안 테스트 화합물과 인큐베이트한 다음, MTT 검정법 [Mosman, T. "Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assay"; J.Immunolog.Methods, (1983), 65,66; Green, L.M., Rapid Colorimetric Assay for Cell Viability; Appliction to the Quantitation of Cytotoxic and Growth Inhibitory Lymphokines", J.Immunol.Methods, (1984), 70, 257-268]을 이용하여 세포독성을 동정하였다.
수득된 결과로부터, 본 발명의 화합물은 충실성 종양, 특히 결장 종양 및 폐 종양에 대하여 탁월한 활성을 나타내는 것이 입증되었다.
표: 본 발명의 대표적인 화합물들의 인간 종양 세포주에 대한 세포독성 결과
HT29: 사람의 결장 선암종
PC3: 사람의 전립선 암종
H460M: 사람의 폐 암종
MKN-45: 사람의 위 암종
Claims (9)
- 하기 화학식 I의 화합물 및 그의 약학적으로 허용가능한 염.식중,- R1, R2 및 R5는 독립적으로 수소 또는 C1-C6 알킬기이고;- R3는 수소, C1-C4 알킬, 클로로로 치환된 벤질, 선택적으로 치환된 페닐, 피리딜, 나프틸이고;- R4는 수소, 선형 또는 분지형의 C1-C8 알킬, C5-C6 싸이클로알킬; 벤질; 아랄킬; 나프틸메틸; 피리딜메틸이고, 상기 아랄킬은 벤젠 고리 상에 메틸, t-부틸, 불소, 염소, 브롬, 히드록시, 메톡시, 트리플루오로메톡시, 벤질옥시, 트리플루오로메틸, 시아노, 니트로, 메틸설포닐, 페닐, 에톡시카르보닐, 카르복시메틸, (3급-부톡시카르보닐)메틸, (벤질옥시카르보닐)메틸, (디메틸카르바모일)메틸로 이루어진 군으로부터 선택된 하나 이상의 치환기를 갖는 벤질이고;- X는 수소; C1-C6 알킬; C1-C6 할로알킬; C1-C6 히드록시알킬; C1-C6 아미노알킬; C1-C6-알콕시-C1-C6-알킬; C1-C18-아실옥시-C1-C6-알킬; 히드록시; C1-C4 알콕시; C1-C3 할로알콕시; 페녹시; 벤질옥시; C1-C3 아실옥시; 아미노; C1-C3 알킬아미노; C1-C3-아실아미노; C1-C3-알킬설포닐아미노; 아로일아미노; 할로겐; 니트로; 시아노; 트리플루오로메틸; 카르복시; C1-C6 알콕시카르보닐; 식중, Ra 및 Rb는 독립적으로 수소, C1-C3-알킬이거나, Ra 및 Rb는 그들과 결합하는 질소 원자와 함께 피롤리디노, 피페리디노, 페페라지노 또는 모르폴리노 고리를 형성하며, n은 1 내지 4의 정수인 RaRbN(CH2)nC(=O)-기; 식중, Ra 및 n은 상기 정의한 바와 같고, Rc는 C1-C4-알콕시카르보닐기인 RaRcN(CH2)nC(=O)-기; 식중, R1은 상기 정의한 바와 같은 R1C(=O)-기; 설포닐; 메르캅토; C1-C4-알킬티오; C1-C4-알킬설피닐; C1-C4-알킬설포닐; 아미노설포닐; C1-C3-알킬아미노설포닐; 식중, R1 및 R2는 상기 정의한 바와 같은 기 -P(=O)(OR1)(OR2); 식중, R6은 히드록시, C1-C6-알콕시인 기 (E)- 또는 (Z)-C(R1)=C(R2)=C(=O)R6; 식중, m은 2 내지 4의 정수이고, R1, R2, Ra 및 Rb는 상기 정의한 바와 같은 NRaRb 또는 식 RaRbN(CH2)mNR1-로 표시되는 기로부터 독립적으로 선택된 1개 또는 그 이상, 최대 4개의 기이며;Y는 산소 또는 황 원자이다.
- 제1항에 있어서, Y가 산소 원자인 화합물.
- 제1항에 있어서, Y가 황 원자인 화합물.
- 제1항, 2항 또는 3항에 있어서, R1, R2 및 R3가 수소 또는 메틸인 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, R4가 수소; 메틸; 벤젠 고리상에 메틸, t-부틸, 불소, 염소, 브롬, 히드록시, 메톡시, 트리플루오로메톡시, 벤질옥시, 트리플루오로메틸, 시아노, 니트로, 메틸설포닐, 페닐, 에톡시카르보닐, 카르복시메틸, (3급-부톡시카르보닐)메틸, (벤질옥시카르보닐)메틸, (디메틸카르바모일)메틸로 이루어진 군으로부터 선택된 하나 이상의 치환기를 갖는 벤질인 것을 특징으로 하는 화합물.
- 제1항 내지 제3항 중 어느 한 항에 있어서, X가 메틸, 에틸, 불소, 염소, 브롬, 히드록시, 아세톡시, 메톡시, 페녹시, 트리플루오로메톡시, 트리플루오로메틸, 시아노, 니트로, 아미노, 아세틸아미노, 메틸설포닐아미노, 메틸메르캅토, 메틸설피닐, 메틸설포닐, 카르복시, 메톡시카르보닐, 3급-부톡시카르보닐, 디에틸카르바모일, (2-아미노에틸)카르바모일, (2-디메틸아미노에틸)카르바모일, (E)- 및 (Z)-2-카르복시에텐-1-일, (E)- 및 (Z)-(2-3급-부톡시카르보닐)에텐-1-일, (E)- 및 (Z)-(에톡시카르보닐)에테닐, 히드록시메틸 및 알릴옥시메틸인 것을 특징으로 하는 화합물.
- 제1항 내지 제3항 중 어느 한 항 기재의 화합물을 허용가능한 캐리어와의 혼합물로서 포함하는 결장 암 또는 폐 암을 치료하기 위한 약학적 조성물.
- 삭제
- 제1항 또는 제2항에 있어서, 상기 화합물이 (2E)-3-(1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-일)-2-프로펜산 3급-부틸 에스테르 또는 (2E)-3-(1-(4-클로로벤질)-3-{옥소[(5-옥소-2,5-디히드로-3-푸라닐)아미노]아세틸}-1H-인돌-4-일)-2-프로펜산인 것을 특징으로 하는 화합물.
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IT1999MI002693A IT1315267B1 (it) | 1999-12-23 | 1999-12-23 | Derivati di 2-(1h-indol-3-il)-2-oxo-acetammidi ad attivita'antitumorale |
ITMI99A002693 | 1999-12-23 |
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US (1) | US6753342B2 (ko) |
EP (1) | EP1244652B1 (ko) |
JP (1) | JP2003519140A (ko) |
KR (1) | KR100795533B1 (ko) |
CN (1) | CN1250542C (ko) |
AT (1) | ATE302772T1 (ko) |
AU (1) | AU776332B2 (ko) |
BR (1) | BR0016553A (ko) |
CA (1) | CA2395205A1 (ko) |
CZ (1) | CZ20022170A3 (ko) |
DE (1) | DE60022227T2 (ko) |
EA (1) | EA004925B1 (ko) |
ES (1) | ES2246918T3 (ko) |
HU (1) | HUP0203524A3 (ko) |
IL (2) | IL150329A0 (ko) |
IT (1) | IT1315267B1 (ko) |
MX (1) | MXPA02006217A (ko) |
NO (1) | NO323312B1 (ko) |
NZ (1) | NZ519689A (ko) |
PL (1) | PL356541A1 (ko) |
SK (1) | SK285682B6 (ko) |
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UA59443C2 (uk) | 1998-04-28 | 2003-09-15 | Арцнайміттельверк Дрезден Гмбх | Гідроксііндол, спосіб його одержання, лікарська форма на його основі та спосіб її одержання |
IT1318641B1 (it) | 2000-07-25 | 2003-08-27 | Novuspharma Spa | Ammidi di acidi 2-(1h-indol-3-il)-2-oxo-acetici ad attivita'antitumorale. |
DE10037310A1 (de) * | 2000-07-28 | 2002-02-07 | Asta Medica Ag | Neue Indolderivate und deren Verwendung als Arzneimittel |
EA013371B1 (ru) * | 2002-07-09 | 2010-04-30 | Фасджен, Ллс. | Новые соединения, содержащие их фармацевтические композиции и способы их применения |
AU2004270733B2 (en) | 2003-09-11 | 2011-05-19 | Itherx Pharma, Inc. | Cytokine inhibitors |
EP1740171B1 (en) * | 2004-03-11 | 2010-06-09 | Actelion Pharmaceuticals Ltd. | Indol-1-yl-acetic acid derivatives |
DK3091011T3 (en) | 2006-04-07 | 2018-02-26 | Vertex Pharma | MODULATORS OF ATP BINDING CASSETTE TRANSPORT |
US7645789B2 (en) | 2006-04-07 | 2010-01-12 | Vertex Pharmaceuticals Incorporated | Indole derivatives as CFTR modulators |
US10022352B2 (en) | 2006-04-07 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
EA018724B1 (ru) * | 2006-08-07 | 2013-10-30 | Айронвуд Фармасьютикалз, Инк. | Соединения индола |
US8563573B2 (en) | 2007-11-02 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Azaindole derivatives as CFTR modulators |
US8802868B2 (en) | 2010-03-25 | 2014-08-12 | Vertex Pharmaceuticals Incorporated | Solid forms of (R)-1(2,2-difluorobenzo[D][1,3]dioxo1-5-yl)-N-(1-(2,3-dihydroxypropyl-6-fluoro-2-(1-hydroxy-2-methylpropan2-yl)-1H-Indol-5-yl)-Cyclopropanecarboxamide |
SG184987A1 (en) | 2010-04-22 | 2012-11-29 | Vertex Pharma | Process of producing cycloalkylcarboxamido-indole compounds |
AR084433A1 (es) | 2010-12-22 | 2013-05-15 | Ironwood Pharmaceuticals Inc | Inhibidores de la faah y composiciones farmaceuticas que los contienen |
US9056851B2 (en) | 2011-03-25 | 2015-06-16 | The Research Foundation For The State University Of New York | Thiolactone antibiotics |
AU2013290444B2 (en) | 2012-07-16 | 2018-04-26 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of (R)-1-(2,2-diflurorbenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide and administration thereof |
PL3925607T3 (pl) | 2014-04-15 | 2023-10-30 | Vertex Pharmaceuticals Incorporated | Kompozycje farmaceutyczne do leczenia chorób, w których pośredniczy mukowiscydozowy przezbłonowy regulator przewodnictwa |
CN115785079B (zh) * | 2022-11-28 | 2024-02-13 | 沈阳药科大学 | 4-(1h-吲哚-5-基)氨基呋喃-2(5h)-酮类化合物及其制备和应用 |
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