TWI434836B - 苯基-異噁唑衍生物及其製備方法 - Google Patents
苯基-異噁唑衍生物及其製備方法 Download PDFInfo
- Publication number
- TWI434836B TWI434836B TW101111335A TW101111335A TWI434836B TW I434836 B TWI434836 B TW I434836B TW 101111335 A TW101111335 A TW 101111335A TW 101111335 A TW101111335 A TW 101111335A TW I434836 B TWI434836 B TW I434836B
- Authority
- TW
- Taiwan
- Prior art keywords
- piperazin
- phenyl
- methanone
- isoxazol
- amino
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 87
- ZBRDJMFLJXFIGJ-UHFFFAOYSA-N 3-phenyl-1,2-oxazole Chemical class O1C=CC(C=2C=CC=CC=2)=N1 ZBRDJMFLJXFIGJ-UHFFFAOYSA-N 0.000 title description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 291
- 150000001875 compounds Chemical class 0.000 claims description 275
- -1 hydroxy, Methoxy Chemical group 0.000 claims description 237
- 238000000034 method Methods 0.000 claims description 153
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 120
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 110
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 83
- 241000700605 Viruses Species 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 150000002367 halogens Chemical group 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 150000001412 amines Chemical class 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000012453 solvate Substances 0.000 claims description 17
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 16
- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000004498 isoxazol-4-yl group Chemical group O1N=CC(=C1)* 0.000 claims description 12
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 10
- 229960003752 oseltamivir Drugs 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 230000009385 viral infection Effects 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 208000036142 Viral infection Diseases 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
- 229960001028 zanamivir Drugs 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- SRJOCJYGOFTFLH-UHFFFAOYSA-M piperidine-4-carboxylate Chemical compound [O-]C(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-M 0.000 claims description 6
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 claims description 5
- 229960003805 amantadine Drugs 0.000 claims description 5
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 229960000888 rimantadine Drugs 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MTIJFSAHYRILPM-UHFFFAOYSA-N [5-amino-3-(3-fluorophenyl)-1,2-oxazol-4-yl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone Chemical compound NC=1ON=C(C=2C=C(F)C=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1F MTIJFSAHYRILPM-UHFFFAOYSA-N 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- SPWXGRKSGUICBQ-UHFFFAOYSA-N [4-(3,4-dichlorophenyl)piperazin-1-yl]-[5-methyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C(=CC=CC=2)OC(F)(F)F)C=1C(=O)N(CC1)CCN1C1=CC=C(Cl)C(Cl)=C1 SPWXGRKSGUICBQ-UHFFFAOYSA-N 0.000 claims description 3
- DBKANSUTJUIPDE-UHFFFAOYSA-N [4-(3,4-dichlorophenyl)piperazin-1-yl]-[5-methyl-3-[3-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C=C(C=CC=2)C(F)(F)F)C=1C(=O)N(CC1)CCN1C1=CC=C(Cl)C(Cl)=C1 DBKANSUTJUIPDE-UHFFFAOYSA-N 0.000 claims description 3
- GJLMGWMEORQEGE-UHFFFAOYSA-N [5-amino-3-(2-chlorophenyl)-1,2-oxazol-4-yl]-[4-(2-methoxyphenyl)piperazin-1-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(C(=O)C=2C(=NOC=2N)C=2C(=CC=CC=2)Cl)CC1 GJLMGWMEORQEGE-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- XTRWLBZTZBNRTP-UHFFFAOYSA-N ethyl 1-[5-amino-3-(2-chlorophenyl)-1,2-oxazole-4-carbonyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1C(=O)C1=C(N)ON=C1C1=CC=CC=C1Cl XTRWLBZTZBNRTP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RMATZYQNGMLMLR-UHFFFAOYSA-N CC(C1(C=O)N(CC2)C(CCCCl)CN2Cl)ON=C1C1=C(C(F)(F)F)C=CC=C1 Chemical compound CC(C1(C=O)N(CC2)C(CCCCl)CN2Cl)ON=C1C1=C(C(F)(F)F)C=CC=C1 RMATZYQNGMLMLR-UHFFFAOYSA-N 0.000 claims description 2
- CZLPWEBWQCCMCN-UHFFFAOYSA-N ClC=1C=C(C=CC1Cl)N1CCN(CC1)C(=O)C=1C(=NOC1C)C1=C(C=CC=C1)Cl Chemical compound ClC=1C=C(C=CC1Cl)N1CCN(CC1)C(=O)C=1C(=NOC1C)C1=C(C=CC=C1)Cl CZLPWEBWQCCMCN-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- BRUBZXPHABUDKG-UHFFFAOYSA-N [3-(2-chlorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(3-methoxyphenyl)piperazin-1-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C(=CC=CC=2)Cl)=C1 BRUBZXPHABUDKG-UHFFFAOYSA-N 0.000 claims description 2
- GLQABFMWZCVWGQ-UHFFFAOYSA-N [3-(2-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(2-fluorophenyl)piperazin-1-yl]methanone Chemical compound CC=1ON=C(C=2C(=CC=CC=2)F)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1F GLQABFMWZCVWGQ-UHFFFAOYSA-N 0.000 claims description 2
- UFIYAHZKMNYVPR-UHFFFAOYSA-N [3-(2-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(2-methoxyphenyl)piperazin-1-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(C(=O)C=2C(=NOC=2C)C=2C(=CC=CC=2)F)CC1 UFIYAHZKMNYVPR-UHFFFAOYSA-N 0.000 claims description 2
- JUQCZZNYGHAGLP-UHFFFAOYSA-N [3-(2-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(4-fluorophenyl)piperazin-1-yl]methanone Chemical compound CC=1ON=C(C=2C(=CC=CC=2)F)C=1C(=O)N(CC1)CCN1C1=CC=C(F)C=C1 JUQCZZNYGHAGLP-UHFFFAOYSA-N 0.000 claims description 2
- MNQXUVOKDYHVQR-UHFFFAOYSA-N [3-(2-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methanone Chemical compound CC=1ON=C(C=2C(=CC=CC=2)F)C=1C(=O)N(CC1)CCN1C1=CC=CC(C(F)(F)F)=C1 MNQXUVOKDYHVQR-UHFFFAOYSA-N 0.000 claims description 2
- JLSSLUGYEMZPLI-UHFFFAOYSA-N [3-(3-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(2-methoxyphenyl)piperazin-1-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(C(=O)C=2C(=NOC=2C)C=2C=C(F)C=CC=2)CC1 JLSSLUGYEMZPLI-UHFFFAOYSA-N 0.000 claims description 2
- DHVNIWMFFJZQCL-UHFFFAOYSA-N [3-(3-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(3-methoxyphenyl)piperazin-1-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C=C(F)C=CC=2)=C1 DHVNIWMFFJZQCL-UHFFFAOYSA-N 0.000 claims description 2
- YFBAEFDESWBBNK-UHFFFAOYSA-N [3-(3-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-(4-fluorophenyl)piperazin-1-yl]methanone Chemical compound CC=1ON=C(C=2C=C(F)C=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=C(F)C=C1 YFBAEFDESWBBNK-UHFFFAOYSA-N 0.000 claims description 2
- PWOHUXYIYWPVCX-UHFFFAOYSA-N [3-(3-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]methanone Chemical compound CC=1ON=C(C=2C=C(F)C=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=CC(C(F)(F)F)=C1 PWOHUXYIYWPVCX-UHFFFAOYSA-N 0.000 claims description 2
- CJSBOZUKQKLRGR-UHFFFAOYSA-N [4-(2-fluorophenyl)piperazin-1-yl]-[5-methyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C(=CC=CC=2)OC(F)(F)F)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1F CJSBOZUKQKLRGR-UHFFFAOYSA-N 0.000 claims description 2
- CSNQBUCBRBPAHT-UHFFFAOYSA-N [4-(2-fluorophenyl)piperazin-1-yl]-[5-methyl-3-[3-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C=C(C=CC=2)C(F)(F)F)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1F CSNQBUCBRBPAHT-UHFFFAOYSA-N 0.000 claims description 2
- HUHUVBMPUAWLPS-UHFFFAOYSA-N [4-(2-fluorophenyl)piperazin-1-yl]-[5-methyl-3-[4-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(OC(F)(F)F)=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1F HUHUVBMPUAWLPS-UHFFFAOYSA-N 0.000 claims description 2
- GRPANRHGVGNIOC-UHFFFAOYSA-N [4-(2-hydroxyphenyl)piperazin-1-yl]-[5-methyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C(=CC=CC=2)C(F)(F)F)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1O GRPANRHGVGNIOC-UHFFFAOYSA-N 0.000 claims description 2
- VGGATZWEMNMOOE-UHFFFAOYSA-N [4-(2-hydroxyphenyl)piperazin-1-yl]-[5-methyl-3-[3-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C=C(OC(F)(F)F)C=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1O VGGATZWEMNMOOE-UHFFFAOYSA-N 0.000 claims description 2
- OCVXDZZBSJZMCE-UHFFFAOYSA-N [4-(2-hydroxyphenyl)piperazin-1-yl]-[5-methyl-3-[4-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(OC(F)(F)F)=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=CC=C1O OCVXDZZBSJZMCE-UHFFFAOYSA-N 0.000 claims description 2
- INHBWGIXHWYVHB-UHFFFAOYSA-N [4-(2-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(C(=O)C=2C(=NOC=2C)C=2C(=CC=CC=2)OC(F)(F)F)CC1 INHBWGIXHWYVHB-UHFFFAOYSA-N 0.000 claims description 2
- UTCRPLCGHYUEHI-UHFFFAOYSA-N [4-(2-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[3-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC=C1N1CCN(C(=O)C=2C(=NOC=2C)C=2C=C(OC(F)(F)F)C=CC=2)CC1 UTCRPLCGHYUEHI-UHFFFAOYSA-N 0.000 claims description 2
- CSUPYNGBUBVHBU-UHFFFAOYSA-N [4-(3,4-dichlorophenyl)piperazin-1-yl]-[3-(3-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methanone Chemical compound CC=1ON=C(C=2C=C(F)C=CC=2)C=1C(=O)N(CC1)CCN1C1=CC=C(Cl)C(Cl)=C1 CSUPYNGBUBVHBU-UHFFFAOYSA-N 0.000 claims description 2
- MYHZPJLYWFDLFV-UHFFFAOYSA-N [4-(3,4-difluorophenyl)piperazin-1-yl]-[5-methyl-3-[4-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound FC=1C=C(C=CC1F)N1CCN(CC1)C(=O)C=1C(=NOC1C)C1=CC=C(C=C1)OC(F)(F)F MYHZPJLYWFDLFV-UHFFFAOYSA-N 0.000 claims description 2
- KDSKZFWNGITMED-UHFFFAOYSA-N [4-(3-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C(=CC=CC=2)OC(F)(F)F)=C1 KDSKZFWNGITMED-UHFFFAOYSA-N 0.000 claims description 2
- MCCUETIRZBSXBU-UHFFFAOYSA-N [4-(3-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[2-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C(=CC=CC=2)C(F)(F)F)=C1 MCCUETIRZBSXBU-UHFFFAOYSA-N 0.000 claims description 2
- AFKUKDVWKIPZKE-UHFFFAOYSA-N [4-(3-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[3-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C=C(OC(F)(F)F)C=CC=2)=C1 AFKUKDVWKIPZKE-UHFFFAOYSA-N 0.000 claims description 2
- BKNOHXFLORJWSS-UHFFFAOYSA-N [4-(3-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[3-(trifluoromethyl)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C=C(C=CC=2)C(F)(F)F)=C1 BKNOHXFLORJWSS-UHFFFAOYSA-N 0.000 claims description 2
- KCQYXROQNFUDMP-UHFFFAOYSA-N [4-(3-methoxyphenyl)piperazin-1-yl]-[5-methyl-3-[4-(trifluoromethoxy)phenyl]-1,2-oxazol-4-yl]methanone Chemical compound COC1=CC=CC(N2CCN(CC2)C(=O)C=2C(=NOC=2C)C=2C=CC(OC(F)(F)F)=CC=2)=C1 KCQYXROQNFUDMP-UHFFFAOYSA-N 0.000 claims description 2
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本發明係關於對流感病毒及其他類似病毒具有抗病毒活性的新的苯基一異噁唑衍生物,其可用來治療並預防病毒之感染。本發明也關於使用化合物來治療或預防流感病毒及其他類似病毒之感染的方法,含有該化合物之藥物組成,該化合物之製備方法,及用於該製備方法中的合成中間體。
流感病毒會使宿主引發傳染的嚴重的發熱性呼吸系統疾病。當流感病毒流行時,由於其強大的感染力,使其極容易跨國傳播。而且,它可能會有不可預期的各種不同的突變,因而引起異種間的傳染。因此,有必要提供全世界共同的對策及監督系統。
流感病毒在分類學上是屬於正粘病毒的一員,其有A、B、C三種類型,尤其是A及B型會流行傳播。A型流感病毒有很高的變異性,會感染鳥類、豬、馬及人。依據表面抗原(HA及NA)之組合,A型流感包括有各種不同的亞型。不同於A型流感,B型流感引起較輕的症狀,且只感染人類及海豹。尤其對於人類,它只引起兒童的生病。C型流感會感染人類及豬,已知其對人類的致病性較低。在這些病毒的表面上,有二種表面抗原(即血凝素(HA)及神經氨酸酶(NA)的醣蛋白)。而且,在病毒內有八種不完整的RNA。血凝素具
有包括頭及莖的三聚體結構。頭部有關於大多數抗原的變異,其利用終端的唾液酸殘基結合到宿主細胞的表面而使病毒黏附到宿主細胞上,進而使病毒穿入宿主細胞內。神經氨酸酶形狀如蘑菇,係具有頭及莖的四聚體。在頭的表面上有活性區域,其可使終端神經氨酸殘基連接到細胞表面寡糖基的α-酮苷鍵結分裂。當感染細胞內的被複製傳播的病毒由宿主細胞出來且穿入呼吸器官黏膜細胞時,此種分裂扮演一個重要的角色。病毒的表面抗原在同一亞型內會變異,且每年都會出現新的抗原突變體。尤其在流感病毒中,最近造成問題的禽流感經由抗原轉變及迅速蔓延而會感染各種不同的禽類,如雞、火雞、鴨及野鳥等。
當雞感染病毒時,死亡率是80%或更多。因此,病毒引起的嚴重損害而威脅了全球的家禽養殖業。甚者,有報告指出其漣漪效應並不侷限於家禽養殖業。換句話說,病毒經由感染人體而可傳播給人類。因此,病毒防治之研究可包括吸附到上皮細胞之抑制、穿入細胞之抑制、基因轉錄及複製之抑制、蛋白質合成上之抑制、由細胞釋出之抑制等等。這些都是研發新的抗病毒藥物之目的。
用於治療流感病毒的常規發展的代表性治療藥物有四種,如金剛烷胺、金剛乙胺、扎那米韋及奧司他韋,它們已得到美國食品及藥物管理局(FDA)之批准(參看圖1到圖4)。金剛烷胺或金剛乙胺是M2離子通道阻滯劑,其只對Hamagglutinin病毒株(一種流感病毒)有效,可中斷引入宿主細胞之病毒粒子的複製。這些藥物僅對A型流感病毒A有效,而且已被使用了40年,因而產生了抗藥物的病毒。此外,藥物會引起神經系統及胃方面的嚴重副作用。同時,奧司他韋(韓國專利10-1998-0703600)或是扎那米韋(韓國註冊專利0169496)是一種神經氨酸酶抑制劑,只對神經氨酸酶病毒株(流感病毒)有效,其可中斷複製的病毒逃離宿主細胞。這二種治療藥物可干擾流感病毒傳染之過程並中斷其過程,因而可抑制病毒之傳播。雖然扎那米韋有較高的抗病毒效果,但其具有低生物利用度及快速由腎臟排出等之缺點。而且,奧司他韋有抗藥病毒之產生,及極嚴重的嘔吐等之副作用。
追蹤這些抗病毒治療藥物,發現最近已迅速出現突變病毒,其具有嚴重的副作用、耐受性、及強大的抗藥性等。因
此,它們的使用上要更小心。而且,在疫苗發展方面會產生一個問題,當流行病毒類型與疫苗病毒不符時,治療效果很小。因此特別需要發展改良的藥物,其對於流感病毒之治療與預防具有高度之效果,且有高度之穩定性。
經由研究,本發明之發明人揭露出新的苯基-異噁唑化合物,其抗病毒性優於傳統的藥物,其具有高的流感病毒抑制活性,及高的病毒複製的預防效果,其可治療及預防流感病毒引起的疾病。
本發明可解決上面所提之傳統藥物的缺點。本發明之發明人發現了分子式1所表示之化合物,其結構不同於傳統發展出來的化合物結構。依此發現遂完成了此發明。
依據本發明之特徵,提供了由下面分子式1所表示之苯基-異噁唑衍生物,或是其藥學上可接受的鹽、水合物、溶劑化物、前藥、或是複合物。
在上面分子式中,R1
,R2
及R3
各自表示氫,可選擇性以鹵素取代的低烷基,可選擇性以鹵素取代的低烷氧基,或是鹵素,R4
表示甲基或胺,及,R8
可被下面分子式2取代,或是被下面分子式3取代
其中,R5
,R6
及R7
各自表示氫,可選擇性以鹵素取代之低烷基、羥基、低烷氧基、或是鹵素,及R9
表示低烷基,依據本發明之另一特徵,本發明提供一藥物組成,其含有本發明的化合物,或是其藥物上可接受的鹽、水合物、溶劑化物、前藥、或複合物,以及藥物上可接受的載體或賦形劑。
依據本發明之再另一特徵,本發明提供用來治療或預防病毒感染的藥物組成,其含有本發明的化合物,或其藥物上可接受的鹽、水合物、溶劑化物、前藥、或複合物,以及藥物上可接受的載體或賦形劑。
依據本發明之再另一特徵,本發明提供發明的化合物,或其藥物上可接受的鹽、水合物、溶劑化物、前藥、或複合物之利用,用來製備治療或預防病毒感染之藥物組成。
依據本發明之再另一特徵,本發明提供一用來治療或預防病毒感染之方法,該方法包括將一藥理上有效量之發明的化合物或其藥物上可接受的鹽、水合物、溶劑化物、前藥、
或複合物給需要病毒感染治療或預防的包括人類的哺乳動物服用。
以下將詳細說明本發明。
由流感病毒引起的流感病毒感染對於人類及動物經常是種致命的疾病。流感病毒會使宿主發生感染性急性發熱的呼吸器官疾病。當流感病毒流行時,由於其具有強大的感染性,極容易跨國散佈。而且,其具有不可預期的各種不同的突變,能引起異種間的感染。因此,有必要提供世界性的共同對策及監測系統。
然而,不同於一般的抗菌藥物,目前只有有限的幾種藥物可應用於流感。例如,目前以神經氨酸苷酶抑制劑使用的代表性治療藥劑包括奧司他韋及扎那米韋。這些治療藥劑有抑制流感病毒傳播之作用。然而,雖然扎那米韋有高度的抗病毒作用,但其也有缺點,例如,低的生物利用度,且會迅速由腎臟排掉。而且,據報導奧司他韋具有一些副作用,例如抗藥性病毒之產生,及嚴重的嘔吐症狀等。
本發明之發明人發現了下面分子式1所表示的化合物,苯基-異噁唑衍生物,與對應的奧司他韋磷酸鹽相比較,其具有較高的抗流感病毒活性,及對抑制病毒之複製有較高的敏感性。
因此,本發明提供由下面分子式1所表示的化合物,及其藥物上可接受的衍生物。
在分子式1中,R1
,R2
,R3
,R4
及R8
相同於上面所界定者。
在本發明中,應了解到,除非有明確的說明,否則分子式1所表示的化合物(或是發明的化合物)均包括其水合物、溶劑化物、藥理上可接受的鹽、前藥、複合物、及藥理上可接受的包括非對映異構物或是對映結構體的衍生物。
在本發明中,「低烷基」一詞表示直鏈或支鏈的飽和脂肪烴基,其較佳地包括1到12個碳原子,或是1到8個碳原子,或是1到6個碳原子。烷基的例子有甲基、乙基、正-丙基、異丙基、正-丁基、異丁基、二級-丁基、三級-丁基、戊基、異戊基、正己基等等,但本發明並不侷限於這些。在本發明中,烷基可選擇性地被取代。
而「烷氧基」一詞表示氧被加入烷基取代物。在本發明中,烷氧基可以選擇性地具有取代物。
而「低鹵烷基」一詞表示直鏈或支鏈的飽和脂肪烴基,其較佳地包括1到12個碳原子,或是1到8個碳原子,或是1到6個碳原子,其中氫被鹵素元素取代。
而「鹵族元素」表示氟、氯、溴或碘之原子,其較佳地表示氟或氯。在本發明中,鹵族元素可以選擇性地被取代。
本發明的化合物也包括在本發明之範疇中之鹽。應了解
到,除非有明確的說明,本發明的化合物,即分子式1表示之化合物,包括其鹽。
在本發明中,「鹽」一詞表示由無機及/或有機酸及鹼所形成的酸及/或鹼鹽。本發明的化合物的鹽可以是,例如,以本發明的化合物與酸或鹼反應來形成,其中,本發明的化合物的量相同於在可以沉析該鹽的媒介或水溶液中化合物的量。
非限定的鹽的例子可包括下面的鹽。化合物可以下列之酸反應來形成酸加成鹽:醋酸、己二酸、苯磺酸、苯甲酸、樟腦酸、檸檬酸、甜蜜素、乙烷-1,2-二磺酸、乙磺酸、2-羥基乙磺酸、甲酸、富馬酸、溴乙酸、氫氯酸、硫酸、硝酸、磷酸、蘋果酸、馬來酸、甲磺酸、萘-1,5-二磺酸、尼古丁酸、三氟乙酸、草酸、對甲苯磺酸、丙酸、乙醇酸、琥珀酸、酒石酸、草酸、氨基酸(例如賴氨酸)、水楊酸、2,2-氯乙酸、L-天冬氨酸、(+)-(1S)-樟腦-10-磺酸、4-2酰氨基苯甲酸、己酸、肉桂酸、龍膽酸、戊二酸、丙二酸、扁桃酸、乳清酸、撲酸鹽、氨基水楊酸等等。當許多鹼基存在時,可形成單或多酸加成鹽。
而,由分子式1所表示之化合物也可以乙酯做為其官能基,故可形成羧基。在酸性或鹼性條件下,例如,在pH 11-12(像氫氧化鈉、氫氧化鉀、碳酸鈉;碳酸氫鈉、或氫氧化銨等鹼),或是在pH 2-3(例如鹽酸或硫酸等之酸),分子式1所表示之化合物的乙酯可被水解。水解的分子式1所表示
的化合物包括羧基,從而形成陽離子及鹽。只要藥理上可接受,這樣的鹽並沒特別的限制。這種鹽的例子有:像鈉、鉀、及鋰等之鹼金屬鹽,像鈣及鎂等之鹼土金屬鹽,像鋁、鐵、鋅、銅、鎳、及鈷等其它金屬鹽,像銨等之其它無機鹽,及胺鹽,像t-辛胺、二苄胺、嗎啉、葡萄糖胺、苯烷基酯、乙二胺、甲葡糖胺、胍、二乙胺、三乙胺、二環己胺、N,N-二苯乙二胺、氯普魯卡因、普魯卡因、二乙胺、芐基苯乙胺、哌嗪、四乙基銨及三(羥甲基)氨基甲烷鹽。
在本發明中,「藥理上可接受的衍生物」一詞表示本發明的化合物的水合物、溶劑化物、藥理上可接受的鹽、前藥或複合物,它們保有所要的化合物的生物上的活性,而沒有不想要的毒性作用。
本發明也包括本發明的化合物的前藥。「前藥」一詞表示共價結合載體之化合物。當生病的哺乳動物服用藥物時,前藥可釋出有效的成份。活性成份的釋出可發生於活體內,而前藥可以本領域之專業人士所知之技術來製備。在此種技術中,化合物之合適官能基可被修改。然而,修改過的官能基可經由一般的操作或在活體內重新產生原來的官能基。前藥的非限定例子包括酯(如,醋酸鹽、甲酸鹽、及苯甲酸鹽衍生物)等。
本發明的化合物具有對抗流感病毒株的抑制活性,可高度有效治療及預防對病毒複製抑制劑敏感的流感之感染。
依據本發明之一實施例,當分子式2取代R8
時,在分子
式1所表示的化合物中,R1
,R2
及R3
中的二個表示氫,而剩下的一個表示可選擇性被鹵素取代的烷基,可選擇性被鹵素取代的低烷氧基,或是鹵素、較佳為氟或氯。R4
表示甲基或胺,且R5
,R6
及R7
中的一個或二個各自獨立表示氫,可選擇性以鹵素取代的低烷基、羥基、低烷氧基、或鹵素;或是R1
表示鹵素,較佳為氯,R4
表示甲基或胺,R2
,R3
,R5
,及R7
各表示鹵素,而R6
表示烷氧基,較佳為甲氧基。當分子式3取代R8
時,R1
,R2
及R3
中之二個表示氫,而剩下的一個表示可選擇性以鹵素取代之低烷基,可選擇性以鹵素取代之烷氧基,或鹵素,R4
表示胺,而R9
表示低烷基。
在本發明之另一實施例中,由分子式1所表示的化合物,更佳地,當分子式2取代R8
時,R1
,R2
及R3
中之二個表示氫、而剩下的一個表示三氧甲基、氟、或三氟甲基,R4
表示甲基或胺,R5
,R6
及R7
中的一個或二個各自表示氫、甲氧基、氯、氟、三氟甲基、或羥基;或者,R1
表示鹵素,較佳為氯,R4
表示甲基或胺,R2
,R3
,R5
,及R7
各自表示氫,而R6
表示烷氧基,較佳為甲氧基,當分子式3取代R8
時,R4
表示胺,R1
,R2
及R3
中之二個表示氫、而剩下的一個表示三氧甲基、氟、或三氟甲基,而R9
表示甲基或乙基。考慮流感病毒之抑制,尤其是當分子式2取代R8
時,R1
表示三氟甲基或三氟甲氧基,R2
及R3
表示氫,R4
表示甲基,而R5
,R6
及R7
中之一個或二個各自表示氫、羥基、甲氧基、或氯。R1
表示氯,R4
表示甲基,R2
,R3
,R5
及R7
表示氫,而R6
表示甲氧基。或是R2
表示氟、三氟甲基或三氟甲氧基,R1
及R3
表示氫,R4
表示甲基或胺,而R5
,R6
及R7
中的一個或二個各自表示氫、羥基、甲氧基、三氟甲基或氯。同時,當分子式3取代R8
時,R1
表示三氟甲氧基,R2
及R3
表示氫,R4
表示胺,而R9
表示乙基。
由分子式1所表示之本發明的化合物可依下面之合成步驟來製備。分子式1所表示之化合物的同分異構物及溶劑化物(例如水合物)也包含在本發明之範疇內。溶劑化之方法一般在本技藝領域係屬已知。因此,本發明的化合物可以藥理上有用的水合物或鹽類之形式來使用,其可以下面所述之反應計畫來製備。
分子式1之本發明的化合物的製備步驟為:將下面分子式4所表示的化合物與羥基氯化銨在鹼之參與下起反應,以製得下面分子式5所表示之化合物;將分子式5所表示之化合物加以氯化以產生下面分子式6所表示之化合物;將分子式6所表示之化合物加以環化以製得下面分子式7所表示之化合物,而做為異噁唑化合物;將做為分子式7之保護基的
R10
去除以製得分子式8所表示之化合物;並且將分子式8所表示之化合物與分子式2或分子式3所表示之化合物起反應以製得分子式9a或分子式9b所表示之化合物。
在上面之分子式中R1
到R9
與前面所界定者相同,而R10
表示低烷基,較佳是甲基、乙基、或是異丙基。
在上面反應設計中,R1
到R10
相同於前面所界定者。
苯環上R1
,R2
及R3
被取代的苯醛化合物(I)可以購買
到。苯醛化合物(I)與羥基氯化銨或其等效物在鹼之參與下起反應而合成苯甲醛胺(II)之化合物。之後,經由氯化反應可得到亞氨苄基氯化鹽化合物(III)。經由一般所用的合成方法(環化反應),利用烷基乙酰乙酸或烷基氰乙酸可得到其R4
被甲基或胺取代的異噁唑化合物(V)。利用1-乙基-3-(3'-二甲氨丙基)碳二亞胺氯化氫(EDCl)或羥苯基三唑(HOBt)在鹼之參與下,可由苯基-異噁唑衍生物化合物(V,R4
=甲基)或包含羧基及胺基之化合物(V,R4
=胺),製得苯基-異噁唑衍生物化合物(VIa or VIb)。
本發明的製備方法較佳地在鹼或酸的溶劑中實施。於此,除非對反應有不利的效果,否則對於溶劑、酸及鹼並無特別的限定。例如,溶劑可選自下列中至少之一種:四氫呋喃、二氯甲烷、乙醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙酸乙酯、叔丁酶、甲苯及二噁烷。鹼可選自下列中至少之一種:吡啶、三乙胺、二乙胺、碳酸鈉、碳酸鉀、氫氧化鈉、氫氧化鉀、氫化納、甲醇鈉、乙醇鈉、叔丁醇鈉、叔丁醇鉀、氫化鋁鋰、硼氫化鋰、硝酸鈉、及碳酸銫。酸可選自下列中至少之一種:三氟乙酸、鹽酸、硝酸、硫酸、溴酸及乙酸。
本發明的化合物在依據方法製備時所用的起始原料市面上可取得,或可容易地買到。反應一般在冷卻或加熱條件下實施。反應後,經由一般的後處理過程,例如柱層析、再結晶等,最後的化合物可被純化。
同時,本發明關係到用來治療或預防病毒感染的藥物組成,其中,由分子式1所表示的化合物或其藥理上可接受的衍生物以一有效量給包括人類的哺乳動物服用。尤其,藥物組成對抑制流感感染是有效的,故其可有效地用來治療這種疾病。
在服用對疾病抑制有效的本發明的化合物時,一般單劑或多劑的量的範圍為每天0.01到750mg/kg,較佳是由0.1到100mg,最佳是由0.5到25mg。然而,依據特定的化合物,病患的體重、性別、飲食、服藥時間、服藥方法、釋出率、藥物混合比率、病患狀態、及年齡等,可改變個別病患的特定劑量。
在治療時,本發明的化合物不需處理就可以服用。然而,活性成份較佳係以藥劑配方提供。
因此,本發明提供藥劑配方,其係將分子式1所表示之化合物或其藥理上可接受的衍生物與藥理上可接受的載體及/或賦形劑混合而得。
此外,本發明化合物可以任何合適的方法來服用。然而,較佳是以注射或口服來服用化合物。
注射劑之製備,例如無菌注射之水性或油性懸浮液,可利用合適之材料像分散劑、潤濕劑、或懸浮劑等依據已知技藝來製備。水、林格氏液或等滲壓NaCl溶液可被用做溶劑。而無菌的固定的油一般也可做為溶劑或懸浮媒介。任何無刺激性的固定的油,包括單-甘油酯或雙-甘油酯也可被用於
此。此外,像油酸之脂肪酸可用於注射劑之製備。
固態的口服藥劑的形式包括膠囊、片、丸、粉末、和微粒之形式。尤其,膠囊與片之形式較佳。片與丸之形式較佳是以腸道藥劑來製備。
固態的口服劑形式之製備可將分子式1所表示之本發明的活性化合物與至少一種惰性稀釋劑(像蔗糖、乳糖、澱粉)、潤滑劑(像硬脂酸鎂)及載體(像碎裂劑、結合劑等)等混合而成。
本發明化合物對流感病毒株有抑制之活性,可以被用來治療及預防流感及其它類似之病毒的感染,這些流感對神經氨酸酶抑制劑或病毒複製抑制劑有敏感性。於此,其可與第二種對相同病毒有效之治療劑結合使用。本化合物,例如,可與扎那米韋、奧司他韋、金剛烷胺、金剛乙胺等結合使用。與單獨化合物使用之劑量比較,各化合物之劑量可以相同或不同。
下面將以製備例及範例來詳細說明本發明。然而,下面所述之製備例與範例僅做為說明用,並不用來限定本發明。
製備例1
2-(三氟甲基)苯甲醛肟之合成
2-(三氟甲基)苯甲醛(34.82g,200.0mmol)溶解在乙醇(200mL)中,填加入溶在純水(50mL)中之氫氯酸羥胺(16.68g,240mmol),攪拌三小時,完成反應後,將冰加入所得產物,
所得固體加以過濾,以純水(600mL)洗淨、乾燥,可得所要的白色固體化合物(32.15g,171mmol,85%)。
1
H-NMR(400 MHz,CDCl3
,δ)=7.23(dd,1H),7.59(dd,1H),7.76(m,2H),8.39(s,1H),11.63(s,1H)
製備例2
2-氯苯甲醛肟之合成
依製備例1所述之相似方法,使用2-氯苯甲醛(29.14g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.68g,240mmol),可得所要的白色固體化合物(29.73g,189mmol,95%)。
1
H-NMR(400 MHz,CDCl3
,δ)=7.37(m,2H),7.48(dd,1H),7.82(dd,1H),8.37(s,1H),11.28(s,1H)
製備例3
3-氟苯甲醛肟之合成
依製備例1所述之相似方法,使用3-氟苯甲醛24.82g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.68g,240mmol),可製得所要的白色固體化合物(22.48g,162mmol,81%)。
1
H-NMR(400 MHz,CDCl3
,δ)=7.32(m,1H),7.56(m,3H),8.20(s,1H)
製備例4
2-氟苯甲醛肟之合成
依製備例1所述之相似方法,使用2-氟苯甲醛24.82g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.68g,240mmol),可製得所要的白色固體化合物(25.96g,186mmol,93%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.22(m,1H),7.45(m,1H),7.65(m,2H),8.15(s,1H)
製備例5
4-(三氟甲氧)苯甲醛肟之合成
依製備例1所述之相似方法,使用4-(三氟甲氧)苯甲醛(38.02g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.68g,240mmol),可製得所要的白色固體化合物(38.68g,1881mmol,94%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.38(d,2H),7.72(tt,2H),8.20(s,1H),11.43(s,1H)
製備例6
2-(三氟甲氧)苯甲醛肟之合成
依製備例1所述之相似方法,使用2-(三氟甲氧)苯甲醛(38.02g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.6g,240mmol),可製得所要的白色固體化合物
(38.67g,188mmol,94%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.43(m,2H),7.54(m,1H),7.89(m,1H),8.24(s,1H),11.76(s,1H)
製備例7
3-(三氟甲基)苯甲醛肟之合成
依製備例1所述之相似方法,使用3-(三氟甲基)苯甲醛(34.82g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.68g,240mmol),可製得所要的白色固體化合物(35.33g,187mmol,93%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.33(m,1H),7.72(m,3H),8.44(s,1H),11.62(s,1H)
製備例8
3-(三氟甲氧)苯甲醛肟之合成
依製備例1所述之相似方法,使用3-(三氟甲氧)苯甲醛(38.03g,200.0mmol)、氫氧化鈉(12.00g,300.0mmol)、及氫氯酸羥胺(16.68g,240mmol),可製得所要的白色固體化合物(39.74g,193mmol,97%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.53(m,1H),7.69(m,3H),8.31(s,1H),11.71(s,1H)
製備例9
N-羥基-2-(三氟甲基)亞氨苄基氯化物之合成
2-(三氟甲基)苯甲醛肟(30.0g,158.60mmol)被溶解入二甲基甲酰胺(300mL),加入N-氯代琥珀酰亞胺(23.31g,174.46mmol),接著攪拌15小時,反應完成之後,所得溶液以真空蒸發,加入乙酸乙酯(1,500mL),分別以飽和氯化鈉水溶液(1,000mL)及純水(1,000mL)洗淨,以無水的硫酸納乾燥,再真空蒸發,得到所要的淡黃固體化合物(32.81g,146.70mmol,93%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.73(m,2H),7.80(t,1H),7.86(d,1H),12.61(s,1H)
製備例10
2-氯-N-羥亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用二甲基甲酰胺(240mL)、2-氯苯甲醛肟(19.97g,128.32mmol)、及N-氯琥珀酰亞胺(18.85g,141.14mmol),可製得所要的淡黃固體化合物(20.04g,105.21mmol,82%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.46(m,1H),7.54(m.1H),7.58(m,2H),12.54(s,1H)
製備例11
3-氟-N-羥亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用二甲基甲酰胺
(240mL)、3-氯苯甲醛肟(20.0g,143.77mmol)、及N-氯琥珀酰亞胺(21.12g,158.12mmol),可製得所要的淡黃固體化合物(22.52g,129.79mmol,90%)。
1
H-NMR(400 MHz,CDCl3
,δ)=7.37(m,1H),7.60(m,3H)
製備例12
2-氟-N-羥亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用二甲基甲酰胺(240mL)、4-氯苯甲醛肟(20.0g,143.76mmol)、及N-氯琥珀酰亞胺(21.12g,158.12mmol),可製得所要的淡黃固體化合物(23.32g,134.40mmol,94%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.29(m,1H),7.47(m,1H),7.62(m,2H)
製備例13
N-羥基-4-(三氟甲氧)亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用二甲基甲酰胺(240mL)、4-(三氟甲氧)苯甲醛肟(20.0g,97.51mmol)、及N-氯琥珀酰亞胺(14.31g,107.26mmol),可製得所要的淡黃固體化合物(21.10g,88.04mmol,90%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.47(dd,1H),7.72(tt,2H),12.60(s,1H)
製備例14
N-羥基-2-(三氟甲氧)亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用二甲基甲酰胺(240mL)、4-(三氟甲氧)苯甲醛肟(20.0g,97.50mmol)、及N-氯琥珀酰亞胺(14.32g,107.26mmol),可製得所要的淡黃固體化合物(19.48g,81.30mmol,83%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.49(m,1H),7.62(m,1H),7.68(dd,1H),12.67(s,1H)
製備例15
N-羥基-3-(三氟甲基)亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用3-(三氟甲基)苯甲醛肟(30.0g,158.60mmol)、二甲基甲酰胺(300mL)、及N-氯琥珀酰亞胺((23.31g,174.46mmol),可製得所要的淡黃固體化合物(33.81g,151.22mmol,95%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.79(m,3H),7.83(m,1H),12.64(s,1H)
製備例16
N-羥基-3-(三氟甲氧)亞氨苄基氯化物之合成
依製備例9所述之類似方法,使用二甲基甲酰胺(240mL)、3-(三氟甲氧)苯甲醛肟(20.0g,97.50mmol)、及N-氯琥珀酰亞氨(14.32g,107.26mmol),可製得所要的淡黃固體
化合物(19.43g,81.10mmol,82%)
1
H-NMR(400 MHz,CDCl3
,δ)=7.56(m,1H),7.64(m,3H),12.61(s,1H)
製備例17
甲基-5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸鹽之合成
N-羥基-2-(三氟甲基)亞氨苄基氯化物(8.0g,35.78mmol)及乙酰乙酸甲酯(8.30g,71.56mmol)被溶解入甲醇(160mL)。所得溶液攪拌30分鐘,同時反應器被冷卻到-10℃。之後,甲醇鈉(5.80g,107.34mmol)被慢慢地加入其中,所得生成物加溫到室溫,攪拌3小時,並真空蒸發去除甲醇。然後把乙酸乙酯(200mL)加入其中。所得生成物分別以純水(200mL)及飽和的氯化鈉水溶液(200mL)洗淨,再以無水的硫酸鈉乾燥,並以真空蒸發。經由柱層析,可製得純化的所要的白色固體化合物(5.79g,20.31mmol,57%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.75(s,3H),3.58(s,3H),7.56(m,1H),7.78(m,1H),7.90(m,1H)
製備例18
甲基-3-(2-氯苯基)-5-甲基異噁唑-4-羧酸鹽
依製備例17所述之類似方法,使用甲醇(160mL)、2-氯-N-羥亞氨苄基氯化物(8.0g,42.10mmol)、乙酰乙酸甲酯
(9.78g,84.20mmol)、及甲醇鈉(6.83g,126.30mmol)、可製得所要的白色固體化合物(6.32g,25.11mmol,60%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.59(s,3H),3.86(s,3H),7.62(m,3H)
製備例19
甲基-3-(3-氟苯基)-5-甲基異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(160mL)、3-氟-N-羥亞氨苄基氯化物(8.00g,46.09mmol)、乙酰乙酸甲酯(10.07g,92.18mmol)、及甲醇鈉(7.47g,138.27mmol),可製得所要的白色固體化合物(7.60g,32.14mmol,70%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.58(s,3H),3.91(s,3H),7.21(m,1H),7.42(m,3H)
製備例20
甲基-3-(2-氟苯基)-5-甲基異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(160mL)、2-氟-N-羥亞氨苄基氯化物(8.00g,46.09mmol)、乙酰乙酸甲酯(10.07g,92.18mmol)、及甲醇鈉(7.47g,138.27mmol),可製得所要的白色固體化合物(7.84g,33.33mmol,72%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.59(s,3H),3.92(s,3H),7.22(m,1H),7.43(m,1H),7.55(m,2H)
製備例21
甲基-5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(160mL)、N-羥基-4-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、乙酰乙酸甲酯(7.76g,66.78mmol)、及甲醇鈉(5.41g,100.17mmol),可製得所要的白色固體化合物(6.74g,22.36mmol,67%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.71(s,3H),3.73(s,3H),7.48(d,2H),7.76(d,2H)
製備例22
甲基-5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(160mL)、N-羥基-4-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、乙酰乙酸甲酯(7.76g,66.78mmol)、及甲醇鈉(5.41g,100.17mmol),可製得所要的白色固體化合物(7.04g,23.37mmol,70%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.73(s,3H),3.64(s,3H),7.53(m,1H),7.61(m,1H),7.69(m,1H)
製備例23
甲基-5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(160mL)、N-羥基-3-(三氟甲基)亞氨苄基氯化物(8.0g,35.78mmol)、乙酰乙酸甲酯(8.30g,71.56mmol)、及甲醇鈉(5.80g,107.34mmol),可製得所要的白色固體化合物(5.82g,20.41mmol,57%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.73(s,3H),3.56(s,3H),7.58(m,1H),7.97(m,3H)
製備例24
甲基-5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(160mL)、N-羥基-3-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、乙酰乙酸甲酯(7.76g,66.78mmol)、及甲醇鈉(5.41g,100.17mmol),可製得所要的白色固體化合物(6.82g,22.64mmol,68%)
1
H-NMR(400 MHz,CDCl3
,δ)=2.76(s,3H),3.62(s,3H),7.54(m,1H),7.61(m,3H)
製備例25
5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸之合成
將5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸鹽(6.0g,21.03mmol)溶解在甲醇(60mL)中,加入3%氫氧化鈉水溶液(60mL),在30℃攪拌7小時,以真空蒸發去除甲醇,剩下溶液再以乙酸乙酯(20mL)沖洗,所得水溶液層以鹽酸水溶液中
和,然後過濾生成之晶體,以純水(50mL)洗淨並乾燥,則可製得所要之白色固體化合物(5.48g,20.12mmol,96%)。
1
H-NMR(400 MHz,DMSO,δ)=2.69(s,3H),7.49(m,1H),7.72(m,1H),7.83(m,1H),13.12(brs,1H)
製備例26
3-(2-氯苯基)-5-甲基異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-3-(2-氯苯基)-5-甲基異噁唑-4-羧酸鹽(6.0g,23.84mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(5.10g,21.44mmol,90%)。
H-NMR(400 MHz,DMSO,δ)=2.75(s,3H),7.46(m,2H),7.53(m,1H),7.59(m,1H),13.00(brs,1H)
製備例27
3-(3-氟苯基)-5-甲基異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-3-(3-氟苯基)-5-甲基異噁唑-4-羧酸鹽(6.0g,25.51mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(5.51g,24.92mmol,98%)。
1
H-NMR(400 MHz,DMSO,δ)=2.58(s,3H),7.21(m,1H),7.42(m,3H),13.04(brs,1H)
製備例28
3-(3-氟苯基)-5-甲基異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-3-(3-氟苯基)-5-甲基異噁唑-4-羧酸鹽(6.0g,25.51mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(5.21g,23.44mmol,92%)。
1
H-NMR(400 MHz,DMSO,δ)=2.60(s,3H),7.21(m,1H),7.43(m,1H),7.54(m,2H)
製備例29
5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-羧酸鹽(6.0g,19.91mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(5.55g,19.32mmol,97%)。
1
H-NMR(400 MHz,DMSO,δ)=2.71(s,3H),7.48(d,2H),7.76(d,2H),13.15(brs,1H)
製備例30
5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸鹽(6.0g,19.91mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物
(5.34g,18.59mmol,93%)。
1
H-NMR(400 MHz,DMSO,δ)=2.72(s,3H),7.50(m,2H),7.58(m,1H),7.67(m,1H),13.62(brs,1H)
製備例31
5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸鹽(6.0g,21.03mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(5.37g,19.80mmol,94%)。
1
H-NMR(400 MHz,DMSO,δ)=2.67(s,3H),7.48(m,1H),7.80(m,3H),13.11(brs,1H)
製備例32
5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸鹽(6.0g,19.91mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(5.47g,19.04mmol,96%)。
1
H-NMR(400 MHz,DMSO,δ)=2.71(s,3H),7.48(m,2H),7.64(m,2H),13.57(brs,1H)
製備例33
甲基-5-氨基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、N-羥基-2-(三氟甲基)亞氨苄基氯化物(8.00g,33.39mmol)、氰乙酸甲酯(4.14g,41.74mmol)、及甲醇納(3.61g,66.78mmol)、可製得所要之白色固體化合物(8.13g,28.42mmol,85%)。
1
H-NMR(400 MHz,DMSO,δ)=3.59(s,3H),6.12(brs,2H),7.36(m,1H),7.57(m,2H),7.69(m,1H)
製備例34
甲基-5-氨基-3-(2-氯苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、2-氯-N-羥亞氨苄基氯化物(8.00g,42.10mmol)、氰乙酸甲酯(5.22g,52.63mmol)、及甲醇納(4.55g,84.20mmol),可製得所要之白色固體化合物(9.40g,37.21mmol,88%)。
1
H-NMR(400 MHz,DMSO,δ)=3.65(s,3H),6.20(brs,2H),7.41(m,4H)
製備例35
甲基-5-氨基-3-(3-氟苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、3-氟-N-羥亞氨苄基氯化物(8.00g,46.09mmol)、氰乙酸甲酯(5.94g,59.92mmol)、及甲醇納(4.98g,92.18mmol),可製得所要之白
色固體化合物(8.42g,35.64mmol,77%)。
1
H-NMR(400 MHz,CDCl3,δ)=3.92(s,3H),6.30(brs,2H),7.21(m,1H),7.42(m,3H)
製備例36
甲基-5-氨基-3-(2-氟苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、2-氟-N-羥亞氨苄基氯化物8.00g,46.09mmol)、氰乙酸甲酯(5.94g,59.92mmol)、及甲醇納(4.98g,92.18mmol),可製得所要之白色固體化合物(8.23g,34.82mmol,76%)。
1
H-NMR(400 MHz,CDCl3,δ)=3.89(s,3H),6.31(brs,2H),7.22(m,1H),7.41(m,1H),7.55(m,2H)
製備例37
甲基-5-氨基-3-(4-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、N-羥基-4-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、氰乙酸甲酯(4.31g,43.41mmol)、及甲醇鈉(3.61g,66.78mmol),可製得所要之白色固體化合物(8.27g,27.35mmol,82%)。
1
H-NMR(400 MHz,DMSO,δ)=3.51(s,3H),6.21(brs,2H),7.26(d,2H),7.77(d,2H)
製備例38
甲基-5-氨基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、N-羥基-2-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、氰乙酸甲酯(4.31g,43.41mmol)、及甲醇鈉(3.61g,66.78mmol),可製得所要之白色固體化合物(9.07g,30.02mmol,90%)。
1
H-NMR(400 MHz,DMSO,δ)=3.38(s,3H),6.18(brs,2H),7.41(m,2H),7.42(m,1H),7.47(m,1H)
製備例39
甲基-5-氨基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、N-羥基-3-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、氰乙酸甲酯(4.14g,41.74mmol)、及甲醇鈉(3.61g,66.78mmol),可製得所要之白色固體化合物(7.46g,26.06mmol,78%)。
1
H-NMR(400 MHz,DMSO,δ)=3.61(s,3H),6.11(brs,2H),7.32(m,1H),7.62(m,3H)
製備例40
甲基-5-氨基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸鹽之合成
依製備例17所述之類似方法,使用甲醇(60mL)、N-羥基-3-(三氟甲氧)亞氨苄基氯化物(8.00g,33.39mmol)、氰乙酸甲酯(4.31g,43.41mmol)、及甲醇鈉(3.61g,66.78mmol),可製得所要之白色固體化合物(8.42g,27.87mmol,83%)。
1
H-NMR(400 MHz,DMSO,δ)=3.42(s,3H),6.22(brs,2H),7.46(m,2H),7.53(m,2H)
製備例41
5-氨基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、5-氨基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸鹽(6.0g,20.96mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(4.06g,14.92mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=7.40(m,1H),7.70(m,2H),7.76(m,1H),7.81(brs,2H),12.18(brs,1H)
製備例42
5-氨基-3-(2-氯苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-氨基-3-(2-氯苯基)異噁唑-4-羧酸鹽(6.0g,23.75mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(3.66g,15.33mmol,65%)。
1
H-NMR(400 MHz,DMSO,δ)=7.45(m,3H),7.54(m,1H),7.85
(brs,2H),12.04(brs,1H)
製備例43
5-氨基-3-(3-氟苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-氨基-3-(3-氟苯基)異噁唑-4-羧酸鹽(6.0g,25.40mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(3.08g,13.86mmol,55%)。
1
H-NMR(400 MHz,DMSO,δ)=6.28(brs,2H),7.20(m,1H),7.44(m,3H)
製備例44
5-氨基-3-(2-氟苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-氨基-3-(2-氟苯基)異噁唑-4-羧酸鹽(6.0g,25.40mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(3.18g,14.33mmol,56%)。
1
H-NMR(400 MHz,DMSO,δ)=6.22(brs,2H),7.25(m,1H),7.45(m,1H),7.59(m,2H),12.13(brs,1H)
製備例45
5-氨基-3-(4-(三氟甲氧)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-
氨基-3-(4-(三氟甲氧)苯基)異噁唑-4-羧酸鹽(6.0g,19.85mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(4.32g,15.02mmol,76%)。1
H-NMR(400 MHz,
DMSO,δ)=7.31(d,2H),7.83(d,2H),7.85(brs,2H),12.01(brs,1H)
製備例46
5-氨基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-氨基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸鹽(6.0g,19.85mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(4.00g,13.89mmol,70%)。
1
H-NMR(400 MHz,DMSO,δ)=7.45(m,3H),7.59(m,1H),7.82(brs,2H),12.04(brs,1H)
製備例47
5-氨基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、5-氨基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸鹽(6.0g,20.96mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(4.14g,15.21mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=7.34(m,1H),7.68(m,3H),7.87(brs,2H),12.31(brs,1H)
製備例48
5-氨基-3-.(3-(三氟甲氧)苯基)異噁唑-4-羧酸之合成
依製備例25所述之類似方法,使用甲醇(60mL)、甲基-5-氨基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸鹽(6.0g,19.85mmol)、及3%氫氧化鈉水溶液(60mL),可製得所要之白色固體化合物(4.16g,14.43mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=7.43(m,3H),7.63(m,1H),7.84(brs,2H),12.04(brs,1H)
例1
4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
將5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、與1-(2-氟丙基)哌嗪(332mg,1.84mmol)溶解在二氯甲烷(30mL)中,於室溫下攪拌8小時。所得溶液分別以飽和碳酸鈉水溶液(30mL)、純水(30mL)、及飽和氯化鈉水溶液(30mL)沖洗。之後以無水硫酸鈉乾燥有機層、濃縮、並以柱層析純化,而得到所要的白色固體化合物(528mg,1.34mmol,73%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.56(s,3H),2.73(brs,2H),3.01(brs,2H),3.41(brs,2H),3.72(brs,2H),6.04(m,3H),6.81(t,
1H),7.49(m,1H),7.72(m,1H),7.83(m,1H)
例2
(4-(3,4-二氯丙基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物644mg,1.33mmol,72%)。
1
H-NMR(400 MHz,CDCl3,δ)=2.58(s,3H),2.75(brs,2H),3.03(brs,2H),3.42(brs,2H),3.74(brs,2H),6.69(dd,1H),6.89(d,1H),7.28(m,1H),7.55(d,1H),7.64(m,2H),7.82(d,2H)
例3
(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol)、可製得所要的膠狀化合物(602mg,1.35mmol,73%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.64(brs,2H),2.67(s,3H),3.13
(brs,2H),3.38(brs,2H),4.06(brs,2H),6.43(brs,1H),6.53(m,2H),7.39(dd,1H),7.49(m,1H),7.70(m,1H),7.80(dd,1H),7.81(m,1H)
例4
(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol)、可製得所要的膠狀化合物(504mg,1.13mmol,62%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.59(S,3H),2.75(brs,2H),3.06(brs,2H),3.42(brs,2H),3.76(brs,2H),3.82(s,3H),6.49(brs,1H),6.49(m,2H),7.19(t,1H),7.55(d,1H),7.67(m,2H),7.82(d,1H)
例5
(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、
及1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的膠狀化合物(593mg,1.23mmol,67%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.63(brs,2H),2.69(s,3H),3.15(brs,2H),3.37(brs,2H),3.39(brs,2H),4.02(brs,2H),6.91(m,2H),7.03(m,1H),7.26(m,1H),7.51(m,1H),7.70(m,2H),7.82(m,1H)
例6
(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(467mg,1.08mmol,59%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.64(brs,H),2.69(s,3H),3.91(brs,4H),6.78(m,4H),7.49(m,2H),7.72(m,1H),7.83(m,1H)
例7
(4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(451mg,1.05mmol,57%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.49(brs,2H),2.61(s,3H),2.78(brs,2H),3.50(brs,2H),3.80(brs,2H),6.93(m,3H),7.13(m,1H),7.58(m,1H),7.70(m,2H),7.86(m,1H)
例8
(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(548mg,1.26mmol,69%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.68(s,3H),2.91(brs,4H),3.42(brs,4H),6.91(m,2H),7.05(m,2H),7.45(m,1H),7.71(m,1H),7.82(m,1H)
例9
(3-(2-氯苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氯苯基)-5-甲基異噁唑-4-羧酸(437mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(576mg,1.40mmol,76%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.61(s,3H),3.10(brs,2H),3.33(brs,2H),3.74(brs,4H),3.79(s,3H),6.36(t,1H),6.46(m,2H),7.18(t,1H),7.41(m,2H),7.50(m,1H),7.56(dd,1H)
例10
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(562mg,1.41mmol,76%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.70(brs,2H),3.14(brs,2H),3.28(brs,2H),3.96(brs,2H),6.70(m,2H),7.02(m,2H),7.17(m,1H),7.45(m,3H)
例11
(4-(3,4-二氯苯基)哌嗪-1-基)(3-(3-氟苯基)-5-甲基異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(619mg,1.43mmol,78%)。
1
H-NMR(CDCl3
,400MHz,δ)=2.56(s,3H),2.66(brs,2H),3.16(brs,2H),3.27(brs,2H),3.91(brs,2H),6.67(dd,1H),6.88(d,1H),7.19(m,1H),7.29(m,1H),7.44(m,3H)
例12
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-二氯苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(612mg,1.55mmol,84%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.73(brs,2H),3.19(brs,2H),3.30(brs,2H),3.80(s,3H),3.93(brs,2H),6.41(m,1H),6.49(m,2H),7.18(m,2H),7.46(m,3H)
例13
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-二氯苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(586mg,1.48mmol,81%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.61(brs,2H),3.07(brs,2H),3.34(brs,2H),3.86(s,3H),3.97(brs,2H),6.53(m,1H),6.90(m,2H),7.18(m,1H),7.05(m,1H),7.46(m,3H)
例14
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(506mg,1.17mmol,64%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.59(brs,2H),3.03(brs,2H),3.32(brs,2H),3.88(brs,2H),6.99(m,1H),7.21
(m,4H),7.42(m,3H)
例15
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(424mg,1.84mmol),可製得所要的白色固體化合物(486mg,1.27mmol,69%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.61(brs,2H),3.07(brs,2H),3.32(brs,2H),3.95(brs,2H),6.78(m,4H),7.19(m,1H),7.45(m,3H)
例16
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(424mg,1.84mmol),可製得所要的白色固體化合物(462mg,1.21mmol,
66%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.58(s,3H),2.63(brs,2H),3.00(brs,2H),3.39(brs,2H),4.02(brs,2H),6.89(m,1H),7.01(m,2H),7.17(m,1H),7.24(m,1H),7.45(m,1H),7.51(m,2H)
例17
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(3-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(511mg,1.33mmol,72%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.55(s,3H),2.66(brs,2H),2.99(brs,2H),3.44(brs,2H),3.88(brs,2H),6.74(m,2H),7.03(m,2H),7.17(m,1H),7.45(m,3H)
例18
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、氫氯化物
(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(578mg,1.51mmol,82%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.71(brs,2H),3.06(brs,2H),3.38(brs,2H),3.75(brs,2H),6.10(m,3H),6.79(t,1H),7.19(m,1H),7.40(m,1H),7.57(m,2H)
例19
(4-(3,4-二氯苯基)哌嗪-1-基)(3-(2-氯苯基)-5-甲基異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(587mg,1.35mmol,74%)。
1
H-NMR(CDCl3
,400MHz,δ)=2.57(s,3H),2.79(brs,2H),3.01(brs,2H),3.40(brs,2H),3.73(brs,2H),6.65(dd,1H),6.87(d,1H),7.16(m,1H),7.27(m,1H),7.40(m,1H),7.54(m,2H)
例20
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(3-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(622mg,1.57mmol,86%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.57(s,3H),2.63(brs,2H),3.11(brs,2H),3.32(brs,2H),3.83(brs,2H),3.82(s,3H),6.43(brs,1H),6.48(m,2H),7.19(m,1H),7.42(m,1H),7.46(dd,1H),7.54(m,1H),7.78(dd,2H)
例21
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(532mg,1.35mmol,73%)。
1
H-NMR(400MHHz,CDCl3
,δ)=2.56(s,3H),2.61(brs,2H),2.99(brs,2H),3.31(brs,2H),3.79(brs,2H),3.83(s,3H),6.78(brs,1H),6.84(t,1H),6.91(t,1H),7.19(m,1H),7.42(m,1H),7.59(m,2H),7.69(dd,1H)
例22
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(501mg,1.15mmol,63%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.55(s,3H),2.62(brs,2H),3.03(brs,2H),3.38(brs,2H),7.02(m,2H),7.19(m,1H),7.23(m,1H),7.42(m,1H),7.54(m,2H)
例23
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(424mg,1.84mmol),可製得所要的白色固體化合物(542mg,1.42mmol,77%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.56(s,3H),2.61(brs,2H),3.07(brs,2H),3.32(brs,2H),3.95(brs,2H),6.78(m,4H),7.19
(m,1H),7.40(m,1H),7.57(m,2H)
例24
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚424mg,1.84mmol),可製得所要的白色固體化合物(433mg,1.13mmol,62%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.57(s,3H),2.61(brs,2H),3.04(brs,2H),3.35(brs,2H),4.01(brs,2H),6.91(m,1H),7.03(m,2H),7.17(m,1H),7.20(m,1H),7.43(m,1H),7.58(m,2H)
例25
(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、3-(2-氟苯基)-5-甲基異噁唑-4-羧酸(407mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物
(538mg,1.40mmol,76%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.55(s,3H),2.87(brs,4H),3.05(brs,4.H),6.91(m,2H),7.04(m,2H),7.19(m,1H),7.43(m,1H),7.59(m,2H)
例26
(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(536mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.56(s,3H),2.63(brs,2H),3.06(brs,2H),3.33(brs,2H),3.94(brs,2H),6.80(t,1H),6.04(m,3H),7.32(d,2H),7.76(d,2H)
例27
(4-(3,4-二氟苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及
1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的膠狀化合物(589mg,1.17mmol,64%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.55(s,3H),2.68(brs,2H),3.15(brs,2H),3.28(brs,2H),3.89(brs,2H),6.65(dd,1H),6.87(d,1H),7.28(t,1H),7.32(dd,2H),7.74(dd,2H)
例28
(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(353mg,1.84mmol),可製得所要的白色固體化合物(622mg,1.35mmol,73%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.59(s,3H),2.64(brs,2H),3.17(brs,2H),3.29(brs,2H),3.75(brs,2H),3.80(s,3H),6.42(brs,1H),6.52(m,2H),7.43(dd,1H),7.47(d,2H),7.75(d,2H),7.78(dd,1H)
例29
(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基
-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(353mg,1.84mmol),可製得所要的白色固體化合物(604mg,1.33mmol,72%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.60(brs,5H),2.98(brs,2H),3.31(brs,2H),3.85(s,3H),6.76(s,1H),6.87(t,1H),6.91(t,1H),7.65(dd,1H),7.43(d,2H),7.73(d,2H),7.78(brs,2H)
例30
(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的膠狀化合物(574mg,1.15mmol,63%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.61(s,3H),2.65(brs,2H),3.13(brs,2H),3.32(brs,2H),7.10(m,2H),7.14(d,1H),7.41(m,1H),7.46(d,2H),7.77(d,2H)
例31
(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯摒三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(502mg,1.12mmol,61%)。
1
H-NMR(400 MHz,DMSO,δ)=2.60(brs,2H),2.62(s,3H),3.08(brs,2H),3.29(brs,2H),3.91(brs,2H),6.74(m,2H),6.74(m,2H),7.46(d,2H),7.78(d,2H)
例32
(4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(538mg,1.02mmol,65%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(s,3H),2.63(brs,2H),3.01(brs,2H),3.38(brs,2H),4.02(brs,2H),6.87(m,1H),7.08(m,2H),7.25(m,1H),7.43(d,2H),7.73(d,2H)
例33
(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(4-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(610mg,1.35mmol,74%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.62(s,3H),2.91(brs,4H),4.47(brs,4H),6.96(m,2H),7.07(m,2H),7.44(d,2H),7.75(d,2H)
例34
(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(593mg,1.32mmol,72%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.56(brs,2H),2.61(s,3H),3.01(brs,2H),3.31(brs,2H),3.81(brs,2H),6.80(t,1H),6.99(m,2H),7.05(m,1H),7.40(m,1H),7.44(dd,1H),7.55(m,1H),7.77(dd,1H)
例35
(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(381mg,1.84mmol),可製得所要的白色固體化合物(652mg,1.30mmol,71%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.60(s,3H),2.61(brs,2H),3.09(brs,2H),3.27(brs,2H),3.70(brs,2H),6.66(dd,1H),6.86(d,1H),7.29(t,1H),7.39(d,1H),7.43(t,1H),7.55(t,1H),7.66(dd,1H)
例36
(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-二氯苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(564mg,1.22mmol,66%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.60(s,3H),2.65(brs,2H),3.12
(brs,2H),3.31(brs,2H),3.79(brs,2H),3.81(s,3H),6.40(brs,1H),6.50(m,2H),7.19(t,1H),7.39(m,1H),7.44(dd,1H),7.54(m,1H),7.77(dd,1H)
例37
(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-二氯苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(570mg,1.24mmol,67%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.60(brs,2H),2.61(S,3H),2.99(brs,2H),3.33(brs,2H),3.78(brs,2H),3.85(s,3H),6.77(brs,1H),6.89(t,1H),6.92(t,1H),7.05(t,1H),7.42(m,2H),7.55(t,1H),7.66(dd,1H)
例38
(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及
1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(486mg,0.97mmol,53%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.61(s,3H),2.69(brs,2H),3.17(brs,2H),3.32(brs,2H),3.82(brs,2H),7.01(d,1H),7.02(s,1H),7.16(d,1H),7.40(m,2H),7.45(t,1H),7.55(t,1H),7.68(dd,1H)
例39
(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(502mg,1.12mmol,61%)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),2.64(s,3H),3.04(brs,2H),3.29(brs,2H),3.91(brs,2H),6.76(m,4H),7.53(m,2H),7.60(m,1H),7.69(m,1H)
例40
4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(2-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(536mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.39(brs,2H),2.63(s,3H),2.89(brs,2H),3.36(brs,2H),3.86(brs,2H),6.89(m,1H),6.98(m,2H),7.15(m,1H),7.47(m,2H),7.76(m,1H),7.68(dd,1H)
例41
4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(536mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.63(s,3H),2.91(brs,4H),3.51(brs,4H),6.94(m,2H),7.07(m,2H),7.53(m,2H),7.63(m,1H),7.74(m,1H)
例42
4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(536mg,1.24mmol,67%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.68(s,3H),2.73(brs,2H),3.01(brs,2H),3.41(brs,2H),3.72(brs,2H),6.09(m,3H),6.83(t,1H),7.34(m,1H),7.72(m,1H),7.86(m,2H)
例43
(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(644mg,1.24mmol,68%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.62(s,3H),2.73(brs,2H),3.12(brs,2H),3.48(brs,2H),3.76(brs,2H),6.70(dd,1H),6.84(d,1H),7.31(m,1H),7.54(d,1H),7.72(m,1H),7.82(m,2H)
例44
(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的膠狀化合物(602mg,1.37mmol,75%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.61(brs,2H),2.69(s,3H),3.15(brs,2H),3.46(brs,2H),4.12(brs,2H),6.48(brs,1H),6.6.50(m,2H),7.31(dd,1H),7.37(m,1H),7.75(m,1H),7.85(m,2H)
例45
(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(524mg,1.18mmol,64%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.59(S,3H),2.73(brs,2H),2.08(brs,2H),3.4.1(brs,2H),3.73(brs,2H),3.84(s,3H),6.47(brs,
1H),6.52(m,2H),7.13(t,1H),7.32(m,1H),7.76(m,1H),7.83(m,2H)
例46
(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲氧)丙基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的膠狀化合物(501mg,1.04mmol,56%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.60(brs,2H),2.62(s,3H),3.28(brs,2H),3.42(brs,2H),3.54(brs,2H),4.03(brs,2H),6.92(m,2H),7.04(m,1H),7.32(m,1H),7.76(m,2H),7.85(m,2H)
例47
(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物
(438mg,1.02mmol,55%)。
1H-NMR(400 MHz,CDCl3,δ)=2.67(s,3H),2.71(brs,4H),3.89(brs,4H),6.81(m,4H),7.36(m,1H),7.72(m,1H),7.86(m,2H)
例48
(4-(2-羥甲苯)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(466mg,1.08mmol,59%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.48(brs,2H),2.64(s,3H),2.77(brs,2H),3.53(brs,2H),3.87(brs,2H),6.92(m,3H),7.19(m,1H),7.36(m,1H),7.72(m,1H),7.84(m,2H)
例49
(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-
乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-甲氧苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(566mg,1.31mmol,71%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.68(s,3H),2.94(brs,4H),3.38(brs,4H),6.94(m,2H),7.06(m,2H),7.39(m,1H),7.75(m,1H),7.84(m,2H)
例50
(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(542mg,1.21mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.53(brs,2H),2.41(s,3H),3.03(brs,2H),3.48(brs,2H),3.79(brs,2H),6.84(t,1H),7.02(m,2H),7.06(m,2H),7.42(m,2H),7.61(m,2H)
例51
(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基
-3-(3-(三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(381mg,1.84mmol),可製得所要的白色固體化合物(602mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.59(brs,2H),2.72(s,3H),3.12(brs,2H),3.28(brs,2H),3.70(brs,2H),6.69(dd,1H),6.82(d,1H),7.20(t,1H),7.44(m,2H),7.58(m,2H)
例52
(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的膠狀化合物(564mg,1.22mmol,66%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.69(s,3H),2.72(brs,2H),3.16(brs,2H),3.33(brs,2H),3.82(brs,2H),3.83(s,3H),6.42(brs,1H),6.58(m,2H),7.22(t,1H),7.44(m,2H),7.59(m,2H)
例53
(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(633mg,1.37mmol,75%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.68(brs,2H),2.70(S,3H),2.98(brs,2H),3.43(brs,2H),3.87(brs,2H),3.82(s,3H),6.76(brs,1H),6.91(t,1H),6.96(t,1H),7.04(t,1H),7.41(m,2H),7.65(m,2H)
例54
(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲氧)丙基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的膠狀化合物(501mg,1.00mmol,55%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.64(s,3H),2.70(brs,2H),3.21(brs,2H),3.30(brs,2H),3.84(brs,2H),7.02(d,1H),7.08(s,1H),7.18(d,1H),7.40(m,1H),7.43(m,2H),7.68(m,2H)
例55
(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(502mg,1.12mmol,61%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,4H),2.69(s,3H),3.49(brs,4H),6.74(m,4H),7.47(m,2H),7.69(m,2H)
例56
(4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(536mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.34(brs,2H),2.63(s,3H),2.85(brs,2H),3.35(brs,2H),3.84(brs,2H),6.85(m,1H),6.97(m,2H),7.20(m,1H),7.45(m,2H),7.69(m,2H)
例57
(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-甲基-3-(3-(三氟甲氧)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(536mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.64(s,3H),2.94(brs,4H),3.58(brs,4H),6.90(m,2H),7.21(m,2H),7.50(m,2H),7.63(m,H)
例58
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-(氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氯苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(532mg,1.33mmol,72%)。
1
H-NMR(400 MHz,DMSO,δ)=2.73(brs,2H),3.04(brs,2H),3.45(brs,2H),3.73(brs,2H),6.09(m,3H),6.86(m,1H),7.41(s,2H),7.44(m,3H),7.54(m,1H)
例59
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3,4-二氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(577mg,1.35mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=2.98(brs,4H),3.43(brs,4H),6.86(t,1H),7.10(d,1H),7.40(s,2H),7.50(m,5H)
例60
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(516mg,1.25mmol,68%)。
1
H-NMR(400 MHz,DMSO,δ)=2.88(brs,4H),3.43(brs,4H),3.71(s,3H),6.38(m,2H),6.46(dd,1H),7.10(m,1H),7.38(s,2H),7.51(m,4H)
例61
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(523mg,1.27mmol,69%)。
1
H-NMR(400 MHz,DMSO,δ)=2.66(brs,4H),3.40(brs,4H),3.76(s,3H),6.76(d,1H),6.85(t,1H),6.95(m,2H),7.38(s,2H),7.50(m,3H),7.57(m,1H)
例62
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-(三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(633mg,1.40mmol,76%)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),3.14(brs,2H),3.35(brs,2H),7.15(m,2H),7.17(d,1H),7.46(m,1H),7.39(s,
2H),7.54(m,3H),7.59(m,1H)
例63
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰銨(15mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(504mg,1.26mmol,69%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,2H),3.09(brs,2H),3.31(brs,2H),3.95(brs,2H),6.80(m,4H),7.31(s,2H),7.50(m,3H),7.53(m,1H)
例64
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰銨(15mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(518mg,1.30mmol,
71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.60(brs,2H),3.04(brs,2H),3.32(brs,2H),3.99(brs,2H),6.87(m,1H),7.00(m,2H),7.19(m,1H),7.41(s,2H),7.54(m,3H),7.56(m,1H)
例65
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(440mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(561mg,1.40mmol,76%)。
1
H-NMR(400 MHz,DMSO,δ)=2.84(brs,4H),3.45(brs,4H),6.91(m,2H),7.03(m,2H),7.36(s,2H),7.52(m,3H),7.59(m,1H)
例66
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟
苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物((508mg,1.32mmol,72%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.72(brs,2H),3.04(brs,2H),3.39(brs,2H),3.69(brs,2H),6.05(m,3H),6.83(t,1H),7.26(m,1H),7.35(brs,2H),7.45(m,3H)
例67
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(596mg,1.37mmol,74%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.73(brs,2H),3.02(brs,2H),3.39(brs,2H),3.69(brs,2H),6.65(dd,1H),6.87(d,1H),7.20(m,1H),7.21(m,1H),7.36(brs,2H),7.43(m,3H)
例68
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二
甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(601mg,1.52mmol,82%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.61(brs,2H),3.14(brs,2H),3.30(brs,2H),3.78(brs,2H),3.80(s,3H),6.42(brs,1H),6.53(m,2H),7.19(m,1H),7.37(brs,2H),7.43(m,3H),7.46(dd,1H),7.76(dd,1H)
例69
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(482mg,1.21mmol,66%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.63(brs,2H),3.02(brs,2H),3.36(brs,2H),3.76(brs,2H),3.89(brs,2H),6.75(brs,1H),6.89(m,1H),6.90(m,1H),7.24(m,1H),7.33(brs,2H),7.45(m,3H),7.65(dd,1H)
例70
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)
哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(639mg,1.47mmol,80%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.61(brs,2H),3.17(brs,2H),3.35(brs,2H),7.01(m,2H),7.15(d,1H),7.21(m,1H),7.39(brs,2H),7.42(m,3H),7.45(m,1H)
例71
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(483mg,1.26mmol,68%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.60(brs,2H),3.14(brs,2H),3.36(brs,2H),3.99(brs,2H),6.83(m,4H),7.20(m,1H),7.39(brs,2H),7.45(m,3H)
例72
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(312mg,1.84mmol),可製得所要的白色固體化合物(381mg,0.81mmol,44%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.61(brs,2H),3.06(brs,2H),3.42(brs,2H),4.02(brs,2H),6.89(m,1H),7.06(m,1H),7.24(m,2H),7.41(brs,2H),7.48(m,3H)
例73
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(576mg,1.50mmol,81%)。
1
H-NMR(400MHz,DMSO,δ)=2.91(brs,4H),3.50(brs,4H),6.97(m,2H),7.10(m,2H),7.28(m,1H),7.37(brs,2H),
7.46(m,3H)
例74
(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(533mg,1.39mmol,75%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.69(brs,2H),2.92(brs,2H),3.40(brs,2H),3.85(brs,2H),6.62(m,1H),6.78(m,1H),7.06(m,2H),7.27(m,1H),7.37(brs,2H),7.47(m,1H),7.56(m,2H)
例75
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(613mg,1.49mmol,81%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.63(brs,2H),3.09(brs,2H),3.22(brs,2H),3.87(brs,2H),6.66(dd,1H),6.87(d,1H),7.28(m,1H),7.36(s,2H),7.37(m,1H),7.48(m,1H),7.57(m,2H)
例76
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(558mg,1.41mmol,77%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.64(brs,2H),3.19(brs,2H),3.30(brs,2H),3.80(s,3H),3.93(brs,2H),6.42(m,1H),6.48(m,2H),7.13(m,1H),7.26(m,1H),7.36(brs,2H),7.47(m,1H),7.61(m,2H)
例77
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲
氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(464mg,1.170.64mmol,77%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.57(brs,2H),3.03(brs,2H),3.32(brs,2H),3.83(s,3H),3.95(brs,2H),6.55(m,1H),6.90(m,2H),7.04(m,1H),7.25(m,1H),7.37(brs,2H),7.45(m,1H),7.59(m,2H)
例78
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(596mg,1.37mmol,75%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.62(brs,2H),3.07(brs,2H),3.33(brs,2H),3.90(brs,2H),7.00(m,1H),7.24(m,4H),7.32(brs,2H),7.44(m,1H),7.59(m,2H)
例79
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-
氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(412mg,1.08mmol,59%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.61(brs,2H),3.07(brs,2H),3.32(brs,2H),3.95(brs,2H),6.77(m,4H),7.22(m,1H),7.33(brs,2H),7.50(m,1H),7.63(m,2H)
例80
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(439mg,1.15mmol,62%)。
1
H-NMR(400MHz,CDCl3
,δ)=2.62(brs,2H),3.02(brs,2H),3.38(brs,2H),4.01(brs,2H),6.60(m,1H),6.83(m,3H),7.25(m,1H),7.33(brs,2H),7.47(m,1H),7.63(m,2H)
例81
(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氟苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(538mg,1.40mmol,76%)。
1
H-NMR(400MHz,DMSO,δ)=2.89(brs,4H),3.49(brs,4H),6.92(m,2H),7.06(m,2H),7.31(m,2H),7.33(brs,2H),7.54(m,2H)
例82
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(576mg,1.28mmol,70%)。
1
H-NMR(400 MHz,DMSO,δ)=2.71(brs,2H),3.04(brs,2H),3.43(brs,2H),3.69(brs,2H),6.07(m,3H),6.79(t,1H),7.31(brs,2H),7.41(m,3H),7.54(m,1H)
例83
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(3,4-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(713mg,1.42mmol,77%)。
1
H-NMR(400 MHz,DMSO,δ)=2.73(brs,2H),3.03(brs,2H),3.45(brs,2H),3.71(brs,2H),6.65(dd,1H),6.87(d,1H),7.29(m,1H),7.31(brs,2H),7.41(m,3H),7.54(m,1H)
例84
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(592mg,1.28mmol,70%)。
1
H-NMR(400 MHz,DMSO,δ)=2.65(brs,2H),3.12(brs,2H),3.31(brs,2H),3.79(brs,2H),3.81(s,3H),6.40(brs,1H),6.50(m,2H),7.32(brs,2H),7.45(m,3H),7.44(dd,1H),7.59(m,
1H),7.77(dd,1H)
例85
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(559mg,1.21mmol,66%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,2H),2.95(brs,2H),3.31(brs,2H),3.75(brs,2H),3.89(s,3H),6.78(brs,1H),6.86(t,1H),6.91(t,1H),7.32(brs,2H),7.41(m,3H),7.54(m,1H),7.69(dd,1H)
例86
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(633mg,1.27mmol,69%)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),3.13(brs,2H)3.35(brs,2H),7.01(m,2H),7.15(d,1H),7.31(brs,2H),7.45(m,4H),7.58(m,1H)
例87
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(608mg,1.36mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=2.60(brs,2H),3.34(brs,2H),3.29(brs,2H),3.98(brs,2H),6.71(m,4H),7.31(brs,2H),7.45(m,3H),7.55(m,1H)
例88
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,
2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(551mg,1.23mmol,67%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.04(brs,2H),3.33(brs,2H),4.03(brs,2H),6.85(m,1H),7.04(m,2H),7.20(m,1H),7.30(brs,2H),7.47(m,3H),7.61(m,1H)
例89
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(607mg,1.35mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=2.87(brs,4H),3.47(brs,4H),6.91(m,2H),7.05(m,2H),7.31(brs,2H),7.44(m,3H),7.62(m,1H)
例90
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基
-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(573mg,1.32mmol,72%)。
1
H-NMR(400 MHz,DMSO,δ)=2.72(brs,2H),3.06(brs,2H),3.39(brs,2H),3.69(brs,2H),6.04(m,3H),6.83(m,1H),7.42(brs,2H),7.40(m,1H),7.75(m,2H),7.79(m,1H)
例91
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(633mg,1.30mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.72(brs,2H),3.09(brs(brs,2H),3.38(brs,2H),3.76(brs,2H),6.66(dd,1H),6.84(d,1H),7.28(m,1H),7.41(brs,2H),7.40(m,1H),7.73(m,2H),7.78(m,1H)
例92
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3-甲氧苯基)
哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(549mg,1.23mmol,67%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,2H),3.15(brs,2H),3.33(brs,2H),3.81(brs,2H),3.87(s,3H),6.43(s,1H),6.51(m,2H),7.40(m,1H),7.43(brs,2H),7.44(dd,1H),7.73(m,2H),7.79(dd,1H)
例93
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(473mg,1.06mmol,58%)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),3.02(brs,2H),3.34(brs,2H),3.75(brs,2H),3.83(s,3H),6.72(brs,1H),6.89(t,1H),6.92(t,1H),7.43(brs,2H),7.44(m,1H),7.65(dd,1H),7.72(m,2H),7.75(m,1H)
例94
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(631mg,1.30mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.65(brs,2H),3.15(brs,4H),3.37(brs,2H),7.03(m,2H),7.16(d,1H),7.40(m,1H),7.43(brs,2H),7.44(m,1H),7.70(m,2H),7.76(m,1H)
例95
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(434mg,1.00mmol,55%)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),3.04(brs,2H),
3.32(brs,2H),3.89(brs,2H),6.79(m,4H),7.38(m,1H),7.46(brs,2H),7.70(m,2H),7.76(m,1H)
例96
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(471mg,1.09mmol,59%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.01(brs,2H),3.35(brs,2H),4.09(brs,2H),6.81(m,1H),7.06(m,2H),7.19(m,1H),7.42(brs,2H),7.48(m,1H),7.73(m,2H),7.78(m,1H)
例97
(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及
1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(603mg,1.39mmol,75%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.86(brs,4H),3.47(brs,4H),6.90(m,2H),7.04(m,2H),7.43(brs,2H),7.49(m,1H),7.70(m,2H),7.76(m,1H)
例98
(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(533mg,1.18mmol,64%)。
1
H-NMR(400 MHz,DMSO,δ)=2.72(brs,2H),3.03(brs,2H),3.43(brs,2H),3.70(brs,2H),6.08(m,3H),6.79(t,1H),7.31(brs,2H),7.38(d,2H),7.44(d,2H)
例99
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙
基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(688mg,1.37mmol,75%)。
1
H-NMR(400 MHz,DMSO,δ)=2.72(brs,2H),3.03(brs,2H),3.47(brs,2H),3.71(brs,2H),6.64(dd,1H),6.86(d,1H),7.32(brs,2H),7.33(d,2H),7.45(d,2H),7.54(m,1H)
例子100
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(588mg,1.27mmol,69%)。
1
H-NMR(400 MHz,DMSO,δ)=2.65(brs,2H),3.12(brs,2H),3.31(brs,2H),3.79(brs,2H),3.81(s,3H),6.40(brs,1H),6.50(m,2H),7.30(brs,2H),7.36(d,2H),7.44(dd,1H),7.49(d,2H),7.77(dd,1H)
例子101
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(603mg,1.30mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,2H),2.95(brs,2H),3.31(brs,2H),3.75(brs,2H),3.89(s,3H),6.78(brs,1H),6.86(t,1H),6.91(t,1H),7.32(brs,2H),7.36(d,2H),7.45(d,2H),7.69(dd,1H)
例子102
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(597mg,1.19mmol,65%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.12(brs,2H),3.33(brs,2H),7.02(m,2H),7.14(d,1H),7.33(brs,2H),7.38(d,2H),7.45(m,1H),7.46(d,2H),7.58(m,1H)
例子103
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(566mg,1.26mmol,69%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,2H),3.29(brs,2H),3.34(brs,2H),3.94(brs,2H),6.71(m,4H),7.33(brs,2H),7.37(d,2H),7.42(d,2H)
例子104
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(591mg,1.32mmol,72%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.04(brs,2H),3.33(brs,2H),4.03(brs,2H),6.85(m,1H),7.03(m,2H),7.22
(m,1H),7.31(brs,2H),7.38(d,2H),7.46(d,2H)
例子105
(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(621mg,1.38mmol,75%)。
1
H-NMR(400 MHz,DMSO,δ)=2.83(brs,4H),3.47(brs,4H),6.91(m,2H),7.05(m,2H),7.31(brs,2H),7.36(d,2H),7.46(d,2H)
例子106
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(566mg,1.31mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.73(brs,2H),3.02(brs,2H),
3.31(brs,2H),3.72(brs,2H),6.14(m,3H),6.87(m,1H),7.29(m,1H),7.49(brs,2H),7.63(m,1H),7.71(m,2H)
例子107
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(500mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(633mg,1.30mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.73(brs,2H),3.08(brs(brs,2H),3.35(brs,2H),3.72(brs,2H),6.62(dd,1H),6.84(d,1H),7.24(m,1H),7.31(m,1H),7.44(brs,2H),7.61(m,1H),7.71(m,2H)
例子108
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固
體化合物(549mg,1.23mmol,67%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.18(brs,2H),3.30(brs,2H),3.82(brs,2H),3.85(s,3H),6.39(s,1H),6.48(m,2H),7.29(m,1H),7.37(m,1H),7.40(brs,2H),7.60(m,1H),7.69(m,2H)
例子109
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(473mg,1.06mmol,58%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.12(brs,2H),3.37(brs,2H),3.79(brs,2H),3.81(s,3H),6.74(brs,1H),6.82(t,1H),6.91(t,1H),7.29(m,1H),7.46(m,3H),7.65(m,1H),7.70(m,2H)
例子110
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基
-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(631mg,1.30mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.69(brs,2H),3.14(brs,4H),3.35(brs,2H),7.01(m,2H),7.21(d,1H),7.33(m,1H),7.41(m,1H),7.45(brs,2H),7.63(m,1H),7.70(m,2H)
例子111
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(460mg,106mmol,58%)。
1
H-NMR(400 MHz,DMSO,δ)=2.69(brs,4H),3.82(brs,4H),6.72(m,4H),7.32(m,1H),7.46(brs,2H),7.64(m,1H),7.73(m,1H)
例子112
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-羥苯基)
哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(492mg,1.14mmol,62%)。
1
H-NMR(400 MHz,DMSO,δ)=2.62(brs,2H),3.02(brs,2H),3.32(brs,2H),4.09(brs,2H),6.85(m,1H),7.12(m,2H),7.17(m,1H),7.29(m,1H),7.46(brs,2H),7.63(m,1H),7.71(m,2H)
例子113
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(603mg,1.39mmol,75%)。
1
H-NMR(400 MHz,CDCl3
,δ)=2.89(brs,4H),3.46(brs,4H),6.91(m,2H),7.05(m,2H),7.31(m,1H),7.47(brs,2H),7.60(m,1H),7.76(m,2H)
例子114
(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(538mg,1.19mmol,65%)。
1
H-NMR(400 MHz,DMSO,δ)=2.74(brs,2H),3.06(brs,2H),3.41(brs,2H),3.69(brs,2H),6.12(m,3H),6.78(t,1H),7.33(brs,2H),7.36(m,2H),7.53(m,1H),7.69(m,1H)
例子115
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3,4-二氯苯基)哌嗪(425mg,1.84mmol),可製得所要的白色固體化合物(652mg,1.31mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.75(brs,2H),3.09(brs,2H),3.51(brs,2H),3.78(brs,2H),6.60(dd,1H),6.89(d,1H),7.36
(m,1H),7.37(brs,2H),7.53(m,3H),7.69(m,1H)
例子116
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(562mg,1.22mmol,66%)。
1
H-NMR(400 MHz,DMSO,δ)=2.63(brs,2H),3.15(brs,2H),3.29(brs,2H),3.82(brs,2H),3.82(s,3H),6.43(brs,1H),6.52(m,2H),7.31(brs,2H),7.36(m,2H),7.51(m,1H),7.70(m,1H),7.77(dd,1H)
例子117
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(2-甲氧苯基)哌嗪(354mg,1.84mmol),可製得所要的白色固體化合物(622mg,1.35mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=2.60(brs,2H),2.99(brs,2H),3.29(brs,2H),3.74(brs,2H),3.85(s,3H),6.71(brs,1H),6.85(t,1H),6.93(t,1H),7.31(brs,2H),7.36(m,2H),7.53(m,1H),7.65(m,1H),7.69(dd,1H)
例子118
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(3-三氟甲基)苯基)哌嗪(424mg,1.84mmol),可製得所要的白色固體化合物(542mg,1.19mmol,59%)。
1
H-NMR(400 MHz,DMSO,δ)=2.60(brs,2H),3.10(brs,2H),3.35(brs,2H),7.01(m,2H),7.15(d,1H),7.31(brs,2H),7.36(m,2H),7.43(m,1H),7.51(m,1H),7.53(m,1H),7.65(m,1H)
例子119
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,
2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及4-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(328mg,1.84mmol)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),3.31(brs,2H),3.32(brs,2H),3.95(brs,2H),6.69(m,4H),7.31(brs,2H),7.38(m,2H),7.52(m,1H),7.72(m,1H)
例子120
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二甲基甲酰胺(15mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、羥苯并三唑(299mg,2.21mmol)、及2-(哌嗪-1-基)苯酚(328mg,1.84mmol),可製得所要的白色固體化合物(588mg,1.31mmol,71%)。
1
H-NMR(400 MHz,DMSO,δ)=2.61(brs,2H),3.06(brs,2H),3.31(brs,2H),4.02(brs,2H),6.84(m,1H),7.01(m,2H),7.23(m,1H),7.31(brs,2H),7.38(m,2H),7.54(m,1H),7.66(m,1H)
例子121
(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(4-氟苯基)
哌嗪-1-基)甲酮之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及1-(4-氟苯基)哌嗪(332mg,1.84mmol),可製得所要的白色固體化合物(609mg,1.35mmol,73%)。
1
H-NMR(400 MHz,DMSO,δ)=2.81(brs,4H),3.45(brs,4H),6.92(m,2H),7.09(m,2H),7.34(brs,2H),7.39(m,2H),7.51(m,1H),7.68(m,1H)
例子122
乙基-1-(5-氨基-3-(2-氯苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(439mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及乙基 哌嗪-4-羧酸鹽(289mg,1.84mmol),可製得所要的白色固體化合物(422mg,1.12mmol,60%)。
1
H-NMR(400 MHz,CDCl3
,δ)=1.14(m,5H),1.66(m,2H),2.51(m,1H),2.81(q,2H),3.76(d,2H),4.05(q,2H),7.25(s,2H),7.46(m,3H),7.57(m,1H)
例子123
甲基-1-(5-氨基-3-(2-氯苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-氯苯基)異噁唑-4-羧酸(409mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及甲基 哌嗪-4-羧酸鹽(263mg,1.84mmol),可製得所要的白色固體化合物(463mg,1.33mmol,72%)。
1
H-NMR(400MHz,CDCl3
,δ)=1.58(m,2H),1.81(m,2H),2.03(m,2H),2.29(m,1H),7.76(m,2H),3.71(s,3H),7.26(m,1H),7.45(m,1H),7.64(m,2H)
例子124
乙基-1-(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(530mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及乙基 哌嗪-4-羧酸鹽(289mg,1.84mmol),可製得所要的白色固體化合物(429mg,1.00mmol,55%)。
1
H-NMR(400 MHz,CDCl3
,δ)=1.16(m,5H),1.65(m,2H),2.54(m,1H),2.83(q,2H),3.74(d,2H),4.06(q,2H),7.41,(brs,2H),7.45(m,3H),7.59(m,1H)
例子125
乙基-1-(5-氨基-3-(2-三氟甲氧)苯基)異噁唑)哌啶-4-羧酸鹽之合成
依例1所述之類似方法,使用二氯甲烷(30mL)、5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羧酸(501mg,1.84mmol)、1-乙基-3-(二甲氨丙基)碳二亞胺氫氯化物(388mg,2.02mmol)、及乙基 哌嗪-4-羧酸鹽(289mg,1.84mmol),可製得所要的白色固體化合物(495mg,1.20mmol,65%)。
1
H-NMR(400 MHz,CDCl3
,δ)=1.13(m,5H),1.62(m,2H),2.49(m,1H),2.76(q,2H),3.74(d,2H),4.09(q,2H),7.41(m,1H),7.43(brs,2H),7.78(m,2H),7.81(m,1H)
例子126
(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮 氫氯酸之合成
將(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮(100mg,0.20mmol)溶解於丙酮(10mL),冷卻到0℃,緩慢添加氫氯乙醇(10%,73mg,0.20mmol),所得生成物於室溫攪拌8小時,再過濾及乾燥,則可製得所要的白色固體化合物(84mg,1.20mmol,78%)。
1
H-NMR(400 MHz,DMSO,δ)=2.55(s,3H),2.78(brs,2H),3.14(brs,2H),3.28(brs,2H),3.58(brs,2H),6.88(dd,1H),7.10(d,1H),7.40(d,1H),7.56(m,2H),7.68(m,2H)
例子127
(3-(2-氯苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮 氫氯酸之合成
依例126所述之類似方法,使用丙酮(10mL),3-(2-氯苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮(82mg,0.20mmol)、及氫氯乙醇(10%,73mg,0.20mmol),可製得所要的白色固體化合物(58mg,0.13,65%)。
1
H-NMR(400 MHz,DMSO,δ)=2.56(s,3H),2.74(brs,2H),3.06(brs,2H),3.53(brs,2H),3.72(brs,2H),3.74(s,3H),6.66(m,1H),7.12(m,2H),7.52(m,4H),7.66(m,1H)
例子128
乙基-1-(5-甲基-3-(2-三氟甲氧)苯基)異噁唑-4-羰基)哌嗪-4-羧酸鹽 氫氯酸之合成
依例126所述之類似方法,使用丙酮(10mL),乙基-1-(5-甲基-3-(2-三氟甲氧)苯基)異噁唑-4-羰基)哌嗪-4-羧酸鹽(85mg,0.20mmol)、及氫氯乙醇(10%,73mg,0.20mmol),可製得所要的白色固體化合物(64mg,0.14mmol,69%)。
1
H-NMR(400 MHz,DMSO,δ)=1.18(m,5H),1.70(m,2H),2.53(m,1H),2.82(q,2H),3.70(d,2H),4.18(q,2H),7.42(m,3H),7.63(brs,2H),7.72(m,1H)
例子129
(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮 氫氯酸之合成
依例126所述之類似方法,使用丙酮(10mL),(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮(90mg,0.20mmol)、及氫氯乙醇(10%,73mg,0.20mmol),可製得所要的白色固體化合物(53mg,0.11mmol,55%)。
1
H-NMR(400 MHz,DMSO,δ)=2.36(brs,2H),2.57(s,3H),2.87(brs,2H),3.31(brs,2H),3.74(brs,2H),3.82(s,3H),6.39(m,2H),7.12(m,2H),7.71(m,2H),7.87(m,1H)
例子130
(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮 氫氯酸之合成
依例126所述之類似方法,使用丙酮(10mL),3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮(76mg,0.20mmol)、及氫氯乙醇(10%,73mg,0.20mmol),可製得所要的白色固體化合物(48mg,0.12mmol,57%)。
1
H-NMR(400 MHz,DMSO,δ)=2.48(brs,2H),2.53(s,3H),2.86(brs,2H),3.17(brs,2H),3.84(brs,2H),7.24(m,3H),7.42(m,3H),7.56(m,2H)
例子131
(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮 氫氯酸之合成
依例126所述之類似方法,使用丙酮(10mL),5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮(83mg,0.20mmol)、及氫氯乙醇(10%,73mg,0.20mmol),可製得所要的白色固體化合物(63mg,0.14mmol,70%)。
1
H-NMR(400 MHz,DMSO,δ)=2.58(brs,4H),3.29(brs,2H),3.53(brs,2H),3.66(s,3H),6.49(m,2H),6.58(m,1H),7.24(m,1H),7.62(s,2H),7.66(m,4H)
細胞(MDCK)利用以GFP(綠色螢光蛋白)表示之流感病毒感染一小時,並在添加不同濃度之化合物的媒介中培養,經過24到72小時之後,利用螢光顯微鏡來觀察GFP信號。之後利用完全不經病毒及化合物處理之細胞,及僅受流感病毒感染之細胞做為對照組。若化合物有抗病毒之功效,則可觀察到GFP信號會隨化合物濃度之增加而減少。
在此實驗中,細胞被病毒感染之前,病毒直接以化合物處理,以決定化合物對抑制流感病毒之細胞滲透是否有功效。為此,首先將不同濃度之化合物在室溫下與流感病毒起反應1小時。之後,MDCK細胞以病毒感染1小時,再以
PBS洗淨,並在2%之oxoid agar的介質中培養。經過72小時後,以結晶紫對細胞染色,然後觀察是否有菌斑形成。
在此實驗中,細胞以病毒來感染,而後病毒以化合物直接處理,以決定病毒感染的細胞是否具有毒性。為此,細胞(MDCK)以流感病毒(K09)感染1小時,並以不同濃度之化合物處理24小時。然後細胞以MTT試劑處理1小時,1小時後MTT試劑所產生的甲贊晶體被溶解在DMSO中,並以ELISA讀取器來量測吸光度,以便決定CC50。
經由實驗例1到實驗例3來測定本說明書所述之例子的化合物的抗病毒的功效。結果發現到本發明化合物具有抗病毒活性之分子式結構。
在本說明書所述之例子的化合物中大約有30種化合物經由減少測定顯示出在病毒之胞內感染後具有抗病毒活性。
這些化合物受到MTT測定及減少測定,並量測其EC50、CC50、及SI(選擇指數)數值,其結果列於下面之表1中。
1)EC50(有效之濃度50%):由減少測定來量測,其表示化合物之最小濃度,於此值時,與對照組相比較,菌斑之數目減少到一半或更多。
2)CC50(細胞毒性濃度50%):由MTT測定來量測,其表示化合物之最大濃度,於此值時,與對照組相比較,細胞之數目減少到一半或更多。
3)SI(選擇指數):其係CC50/EC50之值。
在本說明書之例子中,例3、例4、例9、例11、例12、例16、例35、例60、及例124,經由新的流感病毒(K09及B/Field)、H1N1流感病毒(solomon)及奧司他韋抗株病毒依照實驗例2及3之方法的抗病毒藥物功效之測定,顯示出具有高的抗病毒活性之效果。其結果列於下面之表2中。
如表1所示,由其結果可以了解到,例11、例35、及例60之化合物有最高的SI值(由EC50及CC50獲得)。尤其是本發明書之例子的化合物,大部分顯示出對抑制胞內感染病毒的傳播具有高度的效果。
目前被用做流感病毒治療藥劑的奧司他韋(tamiflu)及扎那米韋(relenza)係可抑制有關於流感病毒釋放之神經氨酸酶的藥物,藉此抑制病毒移動到未感染之細胞。此外,做為其它的治療藥物像金剛烷胺及金剛乙胺被用來做為流感病毒之M2離子通道抑制劑。然而目前由一些研究結果,已發現
到對奧司他韋具有抗藥性的突變流感病毒。此係因為流感病毒是種RNA病毒,其比DNA病毒更容易突變。因此當對奧司他韋有抗藥性之病毒及其副作用越來越多時,急迫需要發展有效的新的流感病毒治療藥劑。
因此,例3、例4、例9、例11、例12、例16、例35、例60、及例124之化合物及其衍生物,對於對奧司他韋(tamiflu)具有抗藥性之病毒株,具有高的抗病毒活性之作用,故它們非常有用於有效的新的流感病毒治療藥劑之發展。
藥物經由大鼠口服的急性毒性試驗
本發明化合物之急性毒性經由大鼠口服來測定。因為希望化合物於臨床情況下服用,故選擇口服給藥途徑。一隻6週大的雄性大鼠(SD-Rat,220±30g)先受檢疫後再馴化一週,馴化條件為照光12小時(08:00~20:00),亮度在22±3℃為150~300勒克斯,相對溼度為50±20%,可自由餵飼料及水。各對照組及實驗組均有8隻大鼠。對照組口服給藥0.5% HPMC,而實驗組口服給藥為懸浮在0.5% HPMC中的不同濃度的藥物,其量與各別重量成比例。
實驗組之口服藥物濃度設定為2000mg/kg(非臨床測試之單服藥物的最高濃度),及1000mg/kg及500mg/kg(共同比例)。口服藥物14天,觀察臨床症狀,同時量測體重之變化。
測試時死亡之動物受解剖驗屍,觀察並記錄主要器官(心、肝、肺、脾、腎及大腸)之異常。測試之最後一天(即口服藥物第14天),所有大鼠均受解剖檢驗,觀察測試藥物引起的器官變化,並與對照組的結果作比較。對照組中沒有大鼠死亡,且由解剖檢驗看不到任何異常。
各組口服給藥之濃度是500mg/kg,1000mg/kg,及2000mg/kg。口服給藥14天中,依照測試方法來觀察臨床症狀。測試最後一天(即給藥的第14天),經由解剖以肉眼觀察器官之變化。對照組及口服給藥500mg/kg,1000mg/kg,及2000mg/kg之實驗組在口服給藥後均無任何的前驅症狀。而且口服各種不同量的組別,均無個體死亡。此外所有口服給藥組別均顯示不論觀察期間的藥量如何都有相似的體重增加比率。此外沒有觀察到任何異常的反應,且解剖結果也沒有觀察到任何特殊的地方。這些實驗結果列於表3中,可以看出本說明書之例子中的化合物在2000mg/kg或更多的口服給藥時具有LD50之值。由這些結果可以下結論説,本發明化合物在急性毒性方面是安全的。
產業應用性
雖然,為了說明,本發明之幾個具體實施例已被詳細說明如上,但本領域之專業人士應了解到,在不違背隨附之專利範圍所揭露的本發明之範疇與精神下,有可能對這些例子做各種不同的修正、填加及取代。
Claims (14)
- 一種由下面分子式1所表示之化合物,或其藥理上可接受的鹽、水合物或溶劑化物:
- 如申請專利範圍第1項所述之化合物或其藥理上可接受的鹽、水合物或溶劑化物,其中當分子式2之根團取代R8 時, R1 表示三氟甲基,或三氟甲氧基,R2 及R3 表示氫,R4 表示甲基或胺,而R5 ,R6 及R7 各自獨立表示氫,及R6 表示甲氧基;或是R2 表示氟、三氟甲基、或三氟甲氧基,R1 及R3 各自獨立表示氫,R4 表示甲基或胺,而R5 ,R6 及R7 中的一個或二個各自獨立表示氫、羥基、甲氧基、三氟甲基或氯。
- 如申請專利範圍第1項所述之化合物或其藥理上可接受的鹽、水合物或溶劑化物,其中當分子式3之根團取代R8 時,R1 表示三氟甲氧基,R2 及R3 各自獨立表示氫,R4 表示胺,而R9 表示乙基。
- 如申請專利範圍第1項所述之化合物或其藥理上可接受的鹽、水合物或溶劑化物,其中化合物包括:(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(3,4-二氯丙基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁 唑-4-基)甲酮;(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-三氟甲基)苯基)異噁唑-4-基)甲酮;(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮;(3-(2-氯苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(3-(3-氟苯基)-5-甲基異噁唑-4-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮; (3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(3-(2-氯苯基)-5-甲基異噁唑-4-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(3-氟苯基)哌嗪-1-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪 -1-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3,4-二氟苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮; (4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑 -4-基)甲酮;4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(2-羥甲苯)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(2-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮; (4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(4-(4-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(4-氟苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-(氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3,4-二氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基) 甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-(三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮; (5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲 酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮; (5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪 -1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(4-三氟甲氧)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮; (5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-氟苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌 嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3-三氟甲基)苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(4-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(4-氟苯基)哌嗪-1-基)甲酮;乙基-1-(5-氨基-3-(2-氯苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽;甲基-1-(5-氨基-3-(2-氯苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽;乙基-1-(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽;乙基-1-(5-氨基-3-(2-三氟甲氧)苯基)異噁唑)哌啶-4-羧酸鹽。
- 如申請專利範圍第1至3項中任一項所述之化合物或其藥理上可接受的鹽、水合物或溶劑化物,其中化合物包括:(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(2-甲氧苯基)哌嗪-1-基)(5-甲基-3-(2-三氟甲基)苯基)異噁 唑-4-基)甲酮;(3-(2-氯苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(3-(3-氟苯基)-5-甲基異噁唑-4-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(3-(3-氟苯基)-5-甲基異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(3-(2-氟苯基)-5-甲基異噁唑-4-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(4-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(2-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(3-(2-氟苯基)-5-甲基異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮; (4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(2-羥苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲基)苯基)異噁唑-4-基)甲酮;(4-(3,4-二氯苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(4-(3-甲氧苯基)哌嗪-1-基)(5-甲基-3-(3-(三氟甲氧)苯基)異噁唑-4-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氯苯基)異噁唑-4-基)(4-(2-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-氟苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-氟苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基) 甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(2-三氟甲基)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲基)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3,4-二氯苯基)哌嗪-1-基)甲酮;(5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(3-甲氧苯基)哌嗪-1-基)甲酮; (5-氨基-3-(3-三氟甲氧)苯基)異噁唑-4-基)(4-(2-羥苯基)哌嗪-1-基)甲酮;乙基-1-(5-氨基-3-(2-氯苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽;或乙基-1-(5-氨基-3-(2-三氟甲氧)苯基)異噁唑-4-羰基)哌啶-4-羧酸鹽。
- 一種用來製備如申請專利範圍第1項所述之由分子式1所表示的化合物的方法,該方法包括下列之步驟:將下面分子式4所表示的化合物與羥胺氯化物,在鹼的參與下,反應生成下面分子式5所表示的化合物;將分子式5所表示之化合物加以氯化以產生下面分子式6所表示之化合物;將分子式6所表示的化合物加予環化,而生成下面分子式7所表示的異噁唑化合物;將分子式7中之烷基R10 移除,而生成下面分子式8所表示的化合物;以及將分子式8所表示的化合物與分子式2或分子式3所表示的化合物起反應,而生成下面分子式9a或9b所表示的化 合物:
- 如申請專利範圍第6項所述之方法,其中該方法係於一般之溶劑及/或酸或鹼之參與下實施,其中該溶劑、酸或鹼對於反應沒有不利的作用。
- 如申請專利範圍第7項所述之方法,其中溶劑係選自下列化學物中之至少一種:四氫呋喃、二氯甲烷、乙醇、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙酸乙酯、叔-丁醇、甲苯,及二噁烷。
- 如申請專利範圍第7項所述之方法,其中鹼係選自下列化學物中之至少一種:吡啶、三乙胺、二乙胺、碳酸鈉、碳酸鉀、氫氧化鈉、氫氧化鉀、氫化鈉、甲醇鈉、乙醇鈉、t-丁醇鈉、t-丁醇鉀、氫化鋁鋰、硼氫化鋰、硝酸鈉、及碳酸銫。
- 如申請專利範圍第7項所述之方法,其中酸係選自下列化學物中之至少一種:三氟乙酸、氫氯酸、硝酸、硫酸、溴乙酸、溴化鋅、及醋酸。
- 一種組成,其包含如申請專利範圍第1至4項中任一項所述之化合物,或其藥理上可接受的鹽、水合物或溶劑化物,及其藥理上可接受的載體或賦形劑。
- 一種藥物組成,其用來治療或預防病毒之感染,該藥物組成包含如申請專利範圍第1至4項中任一項所述之化合物,或其藥理上可接受的鹽、水合物或溶劑化物,及其藥理上可接受的載體或賦形劑。
- 一種組合,其包含如申請專利範圍第1至4項中任一項所述之化合物,或其藥理上可接受的鹽、水合物或溶劑化物,以及其它的病毒感染治療或預防的藥劑,像扎那米韋、奧司他韋、金剛烷胺、或金剛乙胺等。
- 如申請專利範圍第1至4項中任一項所述之化合物,或 其藥理上可接受的鹽、水合物或溶劑化物之利用,其用來製備治療或預防病毒感染之藥物組成。
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KR20120118665A (ko) | 2012-10-29 |
EP2699566B1 (en) | 2017-02-22 |
EP2699566A1 (en) | 2014-02-26 |
SA112330457B1 (ar) | 2015-08-19 |
EA022336B1 (ru) | 2015-12-30 |
HK1188998A1 (zh) | 2014-05-23 |
CA2824757A1 (en) | 2012-10-26 |
JP2014503601A (ja) | 2014-02-13 |
EP2699566A4 (en) | 2014-09-03 |
ZA201305277B (en) | 2014-09-25 |
KR101369584B1 (ko) | 2014-03-06 |
NZ613314A (en) | 2015-09-25 |
PE20140629A1 (es) | 2014-05-22 |
IL227711A0 (en) | 2013-09-30 |
CN103313982B (zh) | 2016-02-03 |
UY34023A (es) | 2012-06-29 |
TW201309658A (zh) | 2013-03-01 |
JP5833143B2 (ja) | 2015-12-16 |
US20140031364A1 (en) | 2014-01-30 |
AU2012246914A1 (en) | 2013-08-15 |
CN103313982A (zh) | 2013-09-18 |
WO2012144752A1 (en) | 2012-10-26 |
CL2013001910A1 (es) | 2014-04-21 |
AU2012246914B2 (en) | 2015-09-24 |
EA201300805A1 (ru) | 2013-11-29 |
SG192134A1 (en) | 2013-08-30 |
AR086029A1 (es) | 2013-11-13 |
MX340098B (es) | 2016-06-27 |
MX2013007661A (es) | 2013-08-12 |
US9132126B2 (en) | 2015-09-15 |
CO6771432A2 (es) | 2013-10-15 |
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