CN111615515B - 杂环化合物、制备方法及其在医药上的应用 - Google Patents
杂环化合物、制备方法及其在医药上的应用 Download PDFInfo
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- CN111615515B CN111615515B CN201980008657.3A CN201980008657A CN111615515B CN 111615515 B CN111615515 B CN 111615515B CN 201980008657 A CN201980008657 A CN 201980008657A CN 111615515 B CN111615515 B CN 111615515B
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- Prior art keywords
- mmol
- ethyl
- methanone
- pyrimidin
- solution
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- 239000003814 drug Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 201000005569 Gout Diseases 0.000 claims abstract description 19
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 14
- -1 cyano, hydroxy Chemical group 0.000 claims description 94
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052805 deuterium Inorganic materials 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052721 tungsten Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 218
- 239000000243 solution Substances 0.000 description 159
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 130
- 238000006243 chemical reaction Methods 0.000 description 107
- 238000003786 synthesis reaction Methods 0.000 description 105
- 230000015572 biosynthetic process Effects 0.000 description 103
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 89
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- 235000019439 ethyl acetate Nutrition 0.000 description 74
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
- 239000000203 mixture Substances 0.000 description 51
- 239000007787 solid Substances 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 34
- 239000003208 petroleum Substances 0.000 description 32
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 24
- 238000003818 flash chromatography Methods 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 19
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 18
- 229940116269 uric acid Drugs 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000002207 metabolite Substances 0.000 description 17
- 238000002953 preparative HPLC Methods 0.000 description 17
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 16
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical group N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 16
- 229960002529 benzbromarone Drugs 0.000 description 16
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- ZRSNZINYAWTAHE-UHFFFAOYSA-N Anisaldehyde Natural products COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 15
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 15
- 210000003494 hepatocyte Anatomy 0.000 description 15
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 14
- 239000002609 medium Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- 239000000523 sample Substances 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 13
- QRPUVEAHEMVOOG-UHFFFAOYSA-O (4-hydroxyphenyl)methanone Chemical compound OC1=CC=C([C+]=O)C=C1 QRPUVEAHEMVOOG-UHFFFAOYSA-O 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- FDGCNGPUZIIRQI-UHFFFAOYSA-N (4-methoxyphenyl)methanone Chemical compound O(C1=CC=C([C-]=O)C=C1)C FDGCNGPUZIIRQI-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- KLVOEDVKCPIDSW-UHFFFAOYSA-N 1-(4-methoxyphenyl)pentane-1,3-dione Chemical compound CCC(=O)CC(=O)C1=CC=C(OC)C=C1 KLVOEDVKCPIDSW-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- YDTWTLOLPFLZHX-UHFFFAOYSA-N 1-(3-iodo-4-methoxyphenyl)ethanone Chemical compound COC1=CC=C(C(C)=O)C=C1I YDTWTLOLPFLZHX-UHFFFAOYSA-N 0.000 description 7
- AXNULSKCYOZLIO-UHFFFAOYSA-N 1-(3-iodo-4-methoxyphenyl)pentane-1,3-dione Chemical compound CCC(=O)CC(=O)c1ccc(OC)c(I)c1 AXNULSKCYOZLIO-UHFFFAOYSA-N 0.000 description 7
- DUIBRMKJJKOTPL-UHFFFAOYSA-N 3-bromo-5-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidine-3-carbonyl)-2-hydroxybenzonitrile Chemical compound CCc1nc2ncc(F)cn2c1C(=O)c1cc(Br)c(O)c(c1)C#N DUIBRMKJJKOTPL-UHFFFAOYSA-N 0.000 description 7
- 102000002269 Cytochrome P-450 CYP2C9 Human genes 0.000 description 7
- 108010000543 Cytochrome P-450 CYP2C9 Proteins 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000012131 assay buffer Substances 0.000 description 7
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 238000012746 preparative thin layer chromatography Methods 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- UNUMEJFHRMWZRE-UHFFFAOYSA-N 1-[4-methoxy-3-(trifluoromethyl)phenyl]pentane-1,3-dione Chemical compound CCC(=O)CC(=O)c1ccc(OC)c(c1)C(F)(F)F UNUMEJFHRMWZRE-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000029142 excretion Effects 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- SXRHGLQCOLNZPT-UHFFFAOYSA-N 3,5-dibromo-4-hydroxybenzaldehyde Chemical compound OC1=C(Br)C=C(C=O)C=C1Br SXRHGLQCOLNZPT-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
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- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- DQDCGTUHSVXZIS-UHFFFAOYSA-N iodobenzene;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.IC1=CC=CC=C1 DQDCGTUHSVXZIS-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
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- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
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- 239000012224 working solution Substances 0.000 description 5
- RJOFJTISBRDKJW-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethylfuro[3,2-c]pyridin-3-yl)methanone Chemical compound CCc1oc2ccncc2c1C(=O)c1cc(Br)c(O)c(Br)c1 RJOFJTISBRDKJW-UHFFFAOYSA-N 0.000 description 4
- NYPFSCKXPMSAFK-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ncccn2c1C(=O)c1cc(Br)c(O)c(Br)c1 NYPFSCKXPMSAFK-UHFFFAOYSA-N 0.000 description 4
- ABUSWLOUSQWWLA-UHFFFAOYSA-N 1-[4-methoxy-3-(trifluoromethyl)phenyl]ethanone Chemical compound COC1=CC=C(C(C)=O)C=C1C(F)(F)F ABUSWLOUSQWWLA-UHFFFAOYSA-N 0.000 description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 4
- KNQVIRRXVOTGGT-UHFFFAOYSA-N 4-hydroxy-3-iodobenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1I KNQVIRRXVOTGGT-UHFFFAOYSA-N 0.000 description 4
- BZTDTCNHAFUJOG-UHFFFAOYSA-N 6-carboxyfluorescein Chemical compound C12=CC=C(O)C=C2OC2=CC(O)=CC=C2C11OC(=O)C2=CC=C(C(=O)O)C=C21 BZTDTCNHAFUJOG-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 231100000304 hepatotoxicity Toxicity 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000004533 oil dispersion Substances 0.000 description 4
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 4
- 229960003081 probenecid Drugs 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
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- NABFOUJEJCWQKY-UHFFFAOYSA-N (2-ethylimidazo[1,2-a]pyrimidin-3-yl)-(4-hydroxyphenyl)methanone Chemical compound CCc1nc2ncccn2c1C(=O)c1ccc(O)cc1 NABFOUJEJCWQKY-UHFFFAOYSA-N 0.000 description 3
- QDMPRAKKWVSMFX-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-5-fluoroindazol-3-yl)methanone Chemical compound CCn1nc2ccc(F)cc2c1C(=O)c1cc(Br)c(O)c(Br)c1 QDMPRAKKWVSMFX-UHFFFAOYSA-N 0.000 description 3
- ACXPMDYWZAUOJS-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ncc(F)cn2c1C(=O)c1cc(Br)c(O)c(Br)c1 ACXPMDYWZAUOJS-UHFFFAOYSA-N 0.000 description 3
- MVOCNSSATKNHBF-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethylpyrazolo[4,3-c]pyridin-3-yl)methanone Chemical compound CCn1nc2ccncc2c1C(=O)c1cc(Br)c(O)c(Br)c1 MVOCNSSATKNHBF-UHFFFAOYSA-N 0.000 description 3
- BUEIQLYAYLVKDZ-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-[2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methanone Chemical compound CCc1nc2ncc(cn2c1C(=O)c1cc(Br)c(O)c(Br)c1)C(F)(F)F BUEIQLYAYLVKDZ-UHFFFAOYSA-N 0.000 description 3
- IXPPCYSKRZWREU-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-[2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methanone Chemical compound CCc1nc2nc(ccn2c1C(=O)c1cc(Br)c(O)c(Br)c1)C(F)(F)F IXPPCYSKRZWREU-UHFFFAOYSA-N 0.000 description 3
- KMGJXUGOJOCEGR-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-[2-ethyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-3-yl]methanone Chemical compound CCc1nc2cc(ncn2c1C(=O)c1cc(Br)c(O)c(Br)c1)C(F)(F)F KMGJXUGOJOCEGR-UHFFFAOYSA-N 0.000 description 3
- YENUEVOIMJJTQW-UHFFFAOYSA-N (4,6-dibromo-5-hydroxypyridin-2-yl)-(2-ethyl-5-fluoroindazol-3-yl)methanone Chemical compound CCn1nc2ccc(F)cc2c1C(=O)c1cc(Br)c(O)c(Br)n1 YENUEVOIMJJTQW-UHFFFAOYSA-N 0.000 description 3
- IRPLBPWXHJNUCL-UHFFFAOYSA-N (6-bromo-2-ethylimidazo[1,2-a]pyrimidin-3-yl)-(3,5-dibromo-4-hydroxyphenyl)methanone Chemical compound CCc1nc2ncc(Br)cn2c1C(=O)c1cc(Br)c(O)c(Br)c1 IRPLBPWXHJNUCL-UHFFFAOYSA-N 0.000 description 3
- AKQYLYWRSIBQJI-UHFFFAOYSA-N (6-chloro-2-ethylimidazo[1,2-a]pyrimidin-3-yl)-(3,5-dibromo-4-hydroxyphenyl)methanone Chemical compound CCc1nc2ncc(Cl)cn2c1C(=O)c1cc(Br)c(O)c(Br)c1 AKQYLYWRSIBQJI-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- HIDVARGIOGXLNT-UHFFFAOYSA-N 2-ethyl-5-fluoroindazole Chemical compound C1=C(F)C=CC2=NN(CC)C=C21 HIDVARGIOGXLNT-UHFFFAOYSA-N 0.000 description 3
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- 239000005720 sucrose Substances 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
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- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
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- 238000010257 thawing Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
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- 238000005303 weighing Methods 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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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
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
Abstract
提供一种杂环化合物、制备方法及其在医药上的应用,特别是涉及一种预防和/或治疗高尿酸血症和痛风的杂环化合物、制备方法及其在医药上的应用。具体而言,提供一种如式(I)和/或式(II)所示的化合物或其互变异构体及其药学上可接受的盐、其制备方法及其治疗高尿酸血症和痛风的方法和用途。
Description
技术领域
本发明涉及一种预防和/或治疗高尿酸血症和痛风的药物。具体来讲,本发明涉及一种人体尿酸盐阴离子转运体(hURAT1)抑制剂及其制备方法,以及包含其的药物组合物及其用途。
背景技术
痛风是由于长期高尿酸血症导致尿酸盐沉积于关节和软组织而形成的一组异质性、代谢类疾病。正常男性血尿酸为150-380umol/L,女性更年期之前血尿酸为100-300umol/L,更年期后其值接近男性。37℃时血清尿酸的饱和浓度约为416umol/L,高于此值即为高尿酸血症。高尿酸血症是痛风病的生化基础。
痛风在普通人群中的发病率为1-2%。目前,全球的痛风患者有数千万之多。在我国,近年来随着人民生活水平的提高,饮食结构的改变,痛风的发病率逐年增加,到2008年我国痛风患病率在一般人群中达到了1.1%(The Journal of Foot and Ankle Surgery48(1):70-73)。
目前,治疗高尿酸血症和痛风的药物主要包括:用于痛风急性发作的关节肿胀、疼痛等症状的控制的消炎止痛药,如非甾体抗炎药(NSAID)等;用于抑制尿酸生成的药物,例如黄嘌呤氧化酶抑制剂非布索坦等;用于促尿酸排泄的药物,如丙磺舒和苯溴马隆等;用于急性痛风发作时快速境地血尿酸的尿酸分解药物,如尿酸酶等。其中,促尿酸排泄药在高尿酸血症和痛风的治疗中占有非常重要的地位,该类药物的作用机理主要是通过抑制位于肾脏近曲小管的上皮细胞的刷状缘上的尿酸盐阴离子转运体1(hURAT1),从而抑制尿酸盐在近曲小管的主动再吸收,增加尿液中尿酸盐的排泄,进而达到降低血中尿酸浓度和控制痛风发作的目的。该类药物主要包括丙磺舒和苯溴马隆等。但是,促尿酸排泄药具有比较严重的副作用,例如苯溴马隆具有肝毒性,存在引发爆发性肝炎的风险。文献(Chem.Res.Toxicol 2007,20(12):1833-1842)报道,苯溴马隆在体内经氧化代谢,生成两种具有邻苯二醌结构的代谢产物,这是导致苯溴马隆肝毒性的直接原因。具体来说,苯溴马隆在人体内被CYP2C9氧化首先生成6-羟基苯溴马隆,接着有两种代谢途径:一种是被CYP2C9连续氧化,首先生成5,6-二羟基苯溴马隆,再进一步氧化生成邻苯二醌样代谢产物;另一种是被CYP2C9氧化生成6,7-二羟基苯溴马隆(或4,6-二羟基苯溴马隆),其继续被其它P450s酶氧化,生成另一种邻苯二醌样代谢产物。
两种邻苯二醌样代谢产物化学性质均非常活泼,可以与蛋白质或多肽的半胱氨酸残基上的巯基进行共轭加成,使蛋白质或多肽的空间结构发生改变,导致蛋白质或多肽变性或失活。
此外,文献(Novel Bioactivation Pathway of Benzbromarone Mediated byCytochrome P450,Yumina Kitagawara et al.,Drug Metab Dispos 43:1303-1306,September 2015)还报道,苯溴马隆在体内经过ipso-取代代谢在肝脏中生成代谢物2,6-二溴对苯二酚(DBH)和2,6-二溴苯醌(DBBQ)。这两种代谢产物对肝脏具有较强的毒副作用,其也是导致苯溴马隆肝毒性的原因之一。
基于上述毒性机制,为了避免苯溴马隆的毒性代谢物导致的副作用同时还保留苯溴马隆的促尿酸排泄活性,人们尝试对苯溴马隆的结构进行改造,以干扰或减少其代谢产物的生成,从而开发出一系列高效低毒的促尿酸排泄剂,用于高尿酸血症和痛风的预防和治疗。参见,WO2012/048058A2、CN106432229A、WO2009/145456A2、CN106045898A、CN102718735B等。但是,截至目前,仍然没有获得令人满意的结果。因此,目前临床上对于疗效好,毒副作用小的促尿酸排泄药仍然存在着迫切的需求。
发明内容
本发明的目的在于提供一种人体尿酸盐阴离子转运体(hURAT1)抑制剂,其不仅具有高选择性的促尿酸排泄活性,而且对于肝脏具有显著降低的毒副作用。
为了实现上述目的,一方面,本发明提供如式(I)和/或式(II)所示的化合物或其互变异构体及其药学上可接受的盐,
其中,A环是六元芳环或杂芳环,B环是五元杂芳环,
W1选自N或O;
W2选自CR6或NR7;
W3和W4各自独立地选自C或N;
W5、W6和W7各自独立地选自CR8或N;
R1、R2、R3、R4、R5、R6、R7和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基;
条件是排除下列情况:
当W1选自O的时候,W2、W3、W4、W5、W6和W7同时为CR6;
当W1和W4选自N的时候,W2为CR6,W3为C,W5、W6和W7同时为CR8。
另一方面,本发明提供一种式(Ia)和/或式(Ib)所示的化合物或其互变异构体及其药学上可接受的盐的制备方法。
再一方面,本发明提供一种预防或治疗高尿酸血症和痛风的药物组合物,其包含式(Ia)和/或式(Ib)所示化合物或其互变异构体或其药学上可接受的盐。
再一方面,本发明提供一种治疗高尿酸血症和痛风的方法,其包括将本发明的式(Ia)和/或式(Ib)所示的化合物或其互变异构体及其药学上可接受的盐,或者包含式(Ia)和/或式(Ib)所示的化合物或其互变异构体及其药学上可接受的盐的药物组合物施用于患有高尿酸血症或痛风的个体。
具体实施方式
定义:
如本文所用,术语“烷基”是指直链的或支链的具有1-20个碳原子的饱和烃基。优选地,烷基是具有1至12个碳原子的烷基。更优选地,烷基是具有1-6个碳原子的烷基。最优选地,烷基是具有1-4个碳原子的烷基。烷基的实例包括,但不限于,甲基、乙基、1-丙基(正丙基)、2-丙基(异丙基)、1-丁基(正丁基)、2-甲基-1-丙基(异丁基)、2-丁基(仲丁基)、2-甲基-2-丙基(叔丁基)、1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基、1-辛基、1-壬基、1-癸基等。
如本文所用,术语“卤素”是指氟、氯、溴、碘。
如本文所用,术语“烷氧基”是指“-O-烷基”,其中烷基的定义如上所述。
如本文所用,术语“卤代烷基”是指被一个或多个卤素取代的烷基,其中卤素和烷基的定义如上所述。
如本文所用,术语“互变异构体”是指是指在质子位置和/或电子分布彼此不同的化合物的异构体。其描述了质子迁移互变异构体和价态互变异构体,并且应当理解,给定化合物可能存在两个以上的互变异构体。互变异构体的实例包括但不限于含有连接到环-NH-部分和环=N-部分的环原子的杂芳基的互变异构形式,环-NH-部分和环=N-部分例如存在于吡唑,咪唑,苯并咪唑,三唑和四唑中(参见例如Smith,March′s AdvancedOrganiCChemistry(第5版),第1218-1223页,Wiley-Interscience,2001;Katritzky A.和Elguero J,et al.,The Tautomerism of Heterocycles,AcademiCPress(1976))。
如本文所用,术语“药学上可接受的盐”是指药学上可接受的并且具有母体化合物的所需药理学活性(或可以转化为具有该活性的形式)的化合物的盐。这些盐包括与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐;或与有机酸如乙酸、三氟乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、乳酸、马来酸、丙二酸、扁桃酸、甲磺酸、2-萘磺酸、油酸、棕榈酸、丙酸、硬脂酸、琥珀酸、酒石酸、对甲苯磺酸、三甲基乙酸等形成的酸加成盐;以及当母体化合物中存在的酸性质子被金属离子例如碱金属离子(如钠或钾)、碱土金属离子(如钙或镁)或铝离子时形成的盐;或与有机碱诸如二乙醇胺、三乙醇胺、N-甲基葡糖胺等的配合物。该定义中还包括铵和取代的或季铵化铵盐。药学上可接受的盐的代表性非限制性列表可见于S.M.Berge et al.,J.Pharma Sci.,66(1),1-19(1977)和Remington:The Science and Practice of Pharmacy,R.Hendrickson,ed.,第21版,Lippincott,Williams&Wilkins,Philadelphia,PA,(2005)第732页,表38-5,两者特此通过引用并入本文。
如本文所用,“预防”是指防止疾病或紊乱发作的方案,使得疾病的临床症状不发展。因此,“预防”涉及在个体内检测到疾病迹象之前对个体施用治疗(例如,治疗性物质的施用)(例如,在个体中不存在可检测的疾病迹象的情况下向个体施用治疗性物质)。个体可以是处于疾病发展风险的个体,例如具有已知与疾病的发展或发作相关的一种或多种危险因素的个体。
如本文所用,术语“治疗”是指治疗性治疗和预防性或防范性或阻止性措施,其中目的是预防或减缓(减轻)不期望的病理变化或病症。对于本发明的目的,有益或期望的临床结果包括但不限于:症状的减轻,疾病程度的降低,延缓或减慢疾病进展,改善或缓和疾病状态,以及缓解(无论是部分还是全部),无论是可检测的还是不可检测的。
“个体”是指人、家畜(例如狗和猫)、农场动物(例如牛、马、绵羊、山羊和猪)、实验动物(例如小鼠、大鼠、仓鼠、豚鼠、猪、兔、狗和猴)等。
除非另有规定,本文所述给定式的化合物包括所公开的化合物和所有药学上可接受的盐、互变异构体和氘代形式。
在某些实施方案中,本发明公开了式(Ia)和/或式(IIa)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W2选自CR6;
W5、W6和W7各自独立地选自CR8或N;
R1、R2、R3、R4、R5、R6和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在某些优选的实施方案中,本发明提供如式(Ib)和/或(IIb)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W5和W7各自独立地选自CR8或N;
R1、R2、R3、R4、R5、R6和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在某些优选的实施方案中,本发明提供如式(Ic)和/或式(IIc)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W6和W7各自独立地选自CR6或N;
R1、R2、R3、R4、R5、R6和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在某些优选的实施方案中,本发明提供如式(Id)和/或(IId)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W7选自CR8或N;
R1、R2、R3、R4、R5、R6和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在某些优选的实施方案中,本发明提供如式(Ie)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W5、W6和W7各自独立地选自CR8或N;
R1、R2、R3、R4、R5、R7和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在某些优选的实施方案中,本发明提供如式(If)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W2选自CR6;
W5、W6和W7各自独立地选自CR8或N;
R1、R2、R3、R4、R5、R6和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在某些优选的实施方案中,本发明提供如式(Ig)所示的化合物或其互变异构体或其药学上可接受的盐,
其中,
W2选自CR6;
W5、W6和W7各自独立地选自CR8或N;
R1、R2、R3、R4、R5、R6和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1-20烷基、C1-20烷氧基、C1-20卤代烷基。
在最优选的实施方案中,本发明的化合物选自:
(3,5-二溴-4-羟基苯基)(2-乙基咪唑并[1,2-c]嘧啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基呋喃并[3,2-c]吡啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮;
(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮;
(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)甲酮;
(4,6-二溴-5-羟基吡啶-2-基)(2-乙基-5-氟-2H-吲唑-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基-5-氟-2H-吲唑-3-基)甲酮;
3-溴-5-(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈;
3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈;
3-溴-5-(3-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈;
5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基间苯二甲腈2,2,2-三氟乙酸盐;
(3,5-二溴-4-羟基苯基)(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)甲酮;
3-溴-5-(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈;
(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮;
(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-基)甲酮;
3-溴-5-(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈;
(3,5-二溴-4-羟基苯基)(2-乙基-7-氘代咪唑并[1,2-c]嘧啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基-2H-吲唑-3-基)甲酮;
(4,6-二溴-5-羟基吡啶-2-基)(2-乙基-5-氟-苯并呋喃-3-基)甲酮;
(4-溴-5-羟基-6-(三氟甲基)吡啶-2-基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮;
(4-溴-5-羟基-6-(三氟甲基)吡啶-2-基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮;
(7-乙基咪唑并[1,2-a][1,3,5]三嗪-6-基)(3,5-二溴-4-羟基苯基)甲酮;
(7-羟基-2-乙基咪唑并[1,2-f]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮;
(3-溴-4-羟基-5-(三氟甲基)苯基)(3-乙基-6-氟-咪唑并[1,2-a]嘧啶-2-基)甲酮;
(3-溴-4-羟基-5-(三氟甲基)苯基)(3-乙基-6-(三氟甲基)-咪唑并[1,2-a]嘧啶-2-基)甲酮;
(2,6-二氟-3,5-二溴-4-羟基苯基)(2-乙基-6-氟-咪唑并[1,2-a]嘧啶-3-基)甲酮;
(2,6-二氟-3,5-二溴-4-羟基苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基2H-吡唑并[3,4-d]嘧啶-3-基)甲酮;
3-溴-5-(2-乙基-2H-吡唑并[3,4-d]嘧啶-3-羰基)-2-羟基苯甲腈;
(3,5-二溴-4-羟基苯基)(2-乙基咪唑并[4,5-c]嘧啶-3-基)甲酮;
(3,5-二溴-4-羟基苯基)(2-乙基呋喃并[3,2-c]吡啶-3-基)甲酮;
2,6-二溴-4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚;
(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮;
3-溴-5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈;
(4-溴-5-羟基-6-(三氟甲基)吡啶-2-基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮;
(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮;
或其互变异构体或其药学上可接受的盐。
在某些实施方案中,本发明提供了制备本发明化合物的方法:
方案一:
步骤1:将杂芳胺化合物1与1,3-二酮化合物2进行环合反应得到苯甲醚中间体化合物3;其中,环合反应在催化剂存在的条件下进行,优选地,催化剂包含二乙酸碘苯、二(三氟乙酸)碘苯等与三氟化硼乙醚络合物的组合;
步骤2:将步骤1中生成的苯甲醚中间体化合物3在催化剂存在下脱除甲基得到苯酚化合物4;其中,催化剂为本领域常见的脱除羟基的甲基保护基时常用的催化剂,包括但不限于三溴化硼、乙硫醇钠等,Greene,T.W.和Wuts,P.G.M.,Greene’s Protective Groupsin Organic Synthesis,第4版,John Wiley and Sons中详细地描述了脱除羟基的甲基保护基时常用的催化剂以及操作方法;
步骤3:将步骤2中得到的苯酚化合物4进行卤代反应,得到苯酚化合物5(X表示卤素);其中,卤代试剂包含卤素单质(例如溴、碘)、氯代琥珀酰亚胺、溴代琥珀酰亚胺、碘代琥珀酰亚胺、三氯化磷、五氯化磷、三溴化磷、五溴化磷等;
此外,方案一还可以任选地包含下面的步骤:
步骤4:将步骤3得到的苯酚化合物5进一步进行氰基化反应,将其中的苯酚环上的一个或多个卤素置换为氰基。
方案二:
步骤1:将化合物6与酰卤化合物7在碱性条件下进行反应得到苯甲醚中间体化合物8;其中,所用碱可以是无机碱或有机碱,其中无机碱可以选自碱金属或碱土金属的氢氧化物(例如氢氧化钠、氢氧化钾、氢氧化钡、氢氧化锂、氢氧化钙、氢氧化镁)、碱金属或碱土金属的碳酸盐或碳酸氢盐(例如碳酸钾、碳酸钠、碳酸锂、碳酸钙、碳酸镁、碳酸氢钠)、碱金属或碱土金属的醇盐(例如甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾等)、碱金属或碱土金属的氨基化物(例如氨基钠、六甲基二硅氨基钠、LDA)、正丁基锂、仲丁基锂、叔丁基锂,有机碱可以选自本领域常见的有机胺,例如三乙胺、三甲胺、吡啶、哌啶、4-N,N-二甲基氨基吡啶、吗啉、N-甲基吗啉、四甲基乙二胺、DBU、DBN、DABCO等;
步骤2:将步骤1中生成的苯甲醚中间体化合物8在催化剂存在下脱除甲基得到苯酚化合物9;其中,催化剂为本领域常见的脱除羟基的甲基保护基时常用的催化剂,包括但不限于三溴化硼、乙硫醇钠等,Greene,T.W.和Wuts,P.G.M.,Greene’s Protective Groupsin Organic Synthesis,第4版,John Wiley and Sons中详细地描述了脱除羟基的甲基保护基时常用的催化剂以及操作方法;
步骤3:将步骤2中得到的苯酚化合物9进行卤代反应,得到苯酚化合物10(X表示卤素);其中,卤代试剂包含卤素单质(例如溴、碘)、氯代琥珀酰亚胺、溴代琥珀酰亚胺、碘代琥珀酰亚胺、三氯化磷、五氯化磷、三溴化磷、五溴化磷等;
此外,方案二还可以任选地包含下面的步骤:
步骤4:将步骤3得到的苯酚化合物5进一步进行氰基化反应,将其中的苯酚环上的一个或多个卤素置换为氰基。
在某些实施方案中,本发明还提供了一种预防和/或治疗高尿酸血症和痛风的药物组合物,其包含本发明的式(Ia)和/或式(Ib)所示的化合物或其互变异构体或其药学上可接受的盐以及药学上可接受的载体。本发明的药物组合物包含大约90重量%至大约80重量%,或者大约80重量%至大约70重量%,或者大约70重量%至大约60重量%,或者大约60重量%至大约50重量%,或者大约50重量%至大约40重量%,或者大约40重量%至大约30重量%,或者大约30重量%至大约20重量%,或者大约20重量%至大约10重量%,或者大约10重量%至大约1.0重量%,或者大约1.0重量%至大约0.1重量%,或者大约0.1重量%至大约0.01重量%的本发明的式(Ia)和/或式(Ib)所示的化合物或其互变异构体或其药学上可接受的盐。药学上可接受的载体可以是固体或液体。其中,固体载体可以是用作赋形剂、稀释剂、甜味剂、增溶剂、润滑剂、粘合剂、片剂崩解剂、稳定剂、防腐剂或包封材料的一种或多种物质。液体载体可以是溶剂或液体分散介质。合适的固体载体包括但不限于例如纤维素、葡萄糖、乳糖、甘露醇、硬脂酸镁、碳酸镁、碳酸钠、糖精钠、蔗糖、糊精、滑石、淀粉、果胶、明胶、黄芪胶、阿拉伯胶、藻酸钠、对羟基苯甲酸酯、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。合适的液体载体包括但不限于水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油(例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油)、甘油酯、琼脂、无热原水、等渗盐水、林格溶液及其混合物。
制备本发明的药物组合物的方法一般是已知的,例如在“Remington:the Scienceand Pratice of Pharmacy,第19版,1995年”中描述。以已知的方法制备本发明的药物组合物包括常规的混合、制粒、压片、包衣、溶解或冻干方法。
本发明所述的化合物或包含其的药物组合物的治疗有效量可以通过常规实验容易地测定,最有效和方便的给药途径可以通过常规实验测定。
本发明的药物组合物可以以任何合适的给药方式施用于需要治疗的患者或者受试者,包括口腔给药、肠胃外(包括皮下、肌内、静脉内、尿道内以及真皮内)给药、直肠给药、鼻腔给药、阴道给药或者经由植入型储器给药。优选地,本发明的药物组合物通过口腔给药。
本发明所用适于经口施用的组合物包括固体形式,例如丸剂、片剂、囊片剂、胶囊剂(分别包括立即释放制剂、定时释放制剂和持续释放制剂)、颗粒剂和粉剂;和液体形式例如溶液剂、糖浆剂、酏剂、乳剂和混悬剂。用于眼施用的形式包括无菌溶液或眼递送装置。可用于肠胃外施用的形式包括无菌溶液剂、乳剂和混悬剂。
本发明的药物组合物的施用剂量取决于各种因素,包括患者的年龄、体重和状态以及给药途径。施用的精确剂量基于治疗医生的判断确定。本发明的药物组合物中的活性成分的给予的实际剂量水平和时程可以变化,以便获得以下量的活性成分,该量对于具体患者、组合物和给药方式而言可有效地达到希望的治疗应答,而对该患者没有毒性。通常,以足以减少或消除与细菌感染相关的症状的量给予本发明的药剂或药物组合物。
本发明的药剂或药物组合物的优选剂量是患者可承受的并且不产生严重或不可接受的副作用的最大量。示例性剂量范围包括0.01mg至250mg/天、0.01mg至100mg/天、1mg至100mg/天、10mg至100mg/天、1mg至10mg/天以及0.01mg至10mg/天。药剂的优选剂量是患者可承受的并且不产生严重或不可接受的副作用的最大量。在实施例中,以约10微克至约100mg/千克体重/天、约0.1至约10mg/kg/天或约1.0mg至约10mg/kg体重/天的浓度给予该药剂。
在一个实施方案中,治疗有效剂量产生从约0.1ng/ml至约50-100mg/ml的药剂血清浓度。这些药物组合物典型地应该提供从约0.001mg至约2000mg的化合物/千克体重/天的剂量。例如,用于全身性给予人类患者的剂量的范围可以是1-10mg/kg、20-80mg/kg、5-50mg/kg、75-150mg/kg、100-500mg/kg、250-750mg/kg、500-1000mg/kg、1-10mg/kg、5-50mg/kg、25-75mg/kg、50-100mg/kg、100-250mg/kg、50-100mg/kg、250-500mg/kg、500-750mg/kg、750-1000mg/kg、1000-1500mg/kg、101500-2000mg/kg、5mg/kg、20mg/kg、50mg/kg、100mg/kg、500mg/kg、1000mg/kg、1500mg/kg、或2000mg/kg。制备药用单位剂型以提供每单位剂型从约1mg至约5000mg(例如从约100mg至约2500mg)的化合物或必要成分的组合。优选的单位剂量配制品是含有给予成分的如在此讨论的每日剂量或单位、每日亚剂量、或其适当部分的那些。
以下通过具体实施例的方式对本发明做进一步的说明,但这并非是对本发明的限制。本领域技术人员根据本发明的教导可以做出各种修改或调整,其并不背离本发明的精神和范围。
实施例
实施例1:(3,5-二溴-4-羟基苯基)(2-乙基呋喃并[3,2-c]吡啶-3-基)甲酮的合成
步骤1:2-戊炔酰氯的合成
向2-戊炔酸(2.45g,25mmol)的二氯甲烷(50mL)溶液中加入草酰氯(3.465g,27.5mmol)和1滴N,N-二甲基甲酰胺。反应液在室温下搅拌2小时,得2-戊炔酰氯(0.5M的二氯甲烷溶液,50mL,25mmol),不经纯化直接用于下一步反应。
步骤2:1-(4-羟基苯基)-2-戊炔-1-酮的合成
在0℃下,将苯酚(2.35g,25mmol)和三氯化铝(16.5g,125mmol)混合于二氯甲烷(100mL)中,并在此温度下搅拌2小时。加入2-戊炔酰氯(0.5M的二氯甲烷溶液,50mL,25mmol),将得到的混合液升至室温并搅拌过夜。将反应液倒入冰中,用饱和碳酸氢钠调节pH=8,然后用二氯甲烷萃取(50mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(1g,23%),为黄色固体。LCMS(ESI)[M+H]+=175.
步骤3:(2-乙基呋喃并[3,2-c]吡啶-3-基)(4-羟基苯基)甲酮的合成
向1-(4-羟基苯基)-2-戊炔-1-酮(1g,5.75mmol)的甲苯(30mL)溶液中加入4-氯吡啶-1-氧化物(742mg,5.75mmol),将反应液加热至130℃搅拌16小时。将反应液浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/4),得标题化合物(0.2g,13%),为黄色固体。LCMS(ESI)[M+H]+=268.0.
步骤4:(3,5-二溴-4-羟基苯基)(2-乙基呋喃并[3,2-c]吡啶-3-基)甲酮的合成
在0℃下,向(2-乙基呋喃并[3,2-c]吡啶-3-基)(4-羟基苯基)甲酮(0.19g,0.71mmol)的醋酸(2mL)溶液中滴加溴水(166mg,1.07mmol)。将反应液升至室温继续搅拌6小时然后浓缩。残余物用制备-TLC分离纯化(甲醇/二氯甲烷=1/20),得标题化合物(0.11g,37%)。LCMS(ESI)[M+H]+=424;1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.52(d,J=5.6Hz,1H),7.98(s,2H),7.79(dd,J=5.6Hz,1H),2.82(q,J=7.2Hz,2H),1.28(t,J=7.6Hz,3H).
实施例2:(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
步骤1:1-(4-甲氧基苯基)戊烷-1,3-二酮的合成
向氢化钠(11.2g,60%的油分散液,280mmol)的乙醚(250mL)溶液中加入乙醇(1mL),然后加入4-甲氧基苯乙酮(20g,133mmol)的乙醚(50mL)溶液,大约花费5分钟。向上述混合液中迅速加入丙酸乙酯(23.4g,266mmol)。将得到的混合物加热回流16小时。反应液冷却至室温,用水(400mL)稀释,收集生成的固体,用水和乙醚洗涤得粗产品(钠盐)。将粗产品用水溶解,用盐酸酸化,然后用乙酸乙酯萃取。将有机相浓缩,得标题化合物(25g,92%),为黄色油状物。LCMS(ESI)[M+H]+=207.
步骤2:(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
将1-(4-甲氧基苯基)戊烷-1,3-二酮(0.35g,1.69mmol),4-(三氟甲基)嘧啶-2-胺(0.332g,2.03mmol)和二乙酸碘苯(0.820g,2.53mmol)溶于四氢呋喃(15mL)中,在室温下搅拌2小时。加入三氟化硼乙醚络合物(0.14g,1.00mmol),将得到的混合物在室温下搅拌过夜。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(150mg,42%),为黄色油状物。LCMS(ESI)[M+H]+=350.
步骤3:(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮的合成
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向(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)-甲酮(200mg,0.571mmol)的二氯甲烷(2mL)溶液中加入三溴化硼(17%的二氯甲烷溶液,5mL)。反应液在室温下搅拌24小时,然后用水淬灭,用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩得标题化合物(110mg,55%),为棕色固体。LCMS(ESI)[M+H]+=336.
步骤4:(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
在0℃下,向(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)-甲酮(110mg,0.328mmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入N-溴代丁二酰亚胺(118.8mg,0.67mmol)。反应液升至室温后继续搅拌2小时,然后浓缩。残余物用制备-HPLC分离纯化,得标题化合物(66mg,44%)。LCMS(ESI)[M+H]+=492;1H NMR(400MHz,DMSO-d6)δ9.57-9.55(m,1H),7.92(s,2H),7.73-7.71(m,1H),2.60(q,2H),1.23(t,3H).
实施例3:(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮的合成
步骤1:(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
将1-(4-甲氧基苯基)戊烷-1,3-二酮(1.00g,4.85mmol),5-溴嘧啶-2-胺(1.01g,5.82mmol)和二乙酸碘苯(2.34g,7.28mmol)溶于四氢呋喃(15mL)中,在室温下搅拌2小时。加入三氟化硼乙醚络合物(0.14g,1.00mmol),得到的混合物在室温下搅拌过夜。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(750mg,75%),为黄色油状物。LCMS(ESI)[M+H]+=360.
步骤2:(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮的合成
向(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮(500mg,1.38mmol)的二氯甲烷(2mL)溶液中加入三溴化硼(17%的二氯甲烷溶液,5mL,8.5mmol)。反应液在室温下搅拌24小时,然后用水淬灭,用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,得标题化合物(380mg,76%),为棕色固体。LCMS(ESI)[M+H]+=346.
步骤3:(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮的合成
在0℃下,向(6-溴-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮(100mg,0.289mmol)的N,N-二甲基甲酰胺(5.0mL)溶液中加入N-溴代丁二酰亚胺(51mg,0.289mmol)。将反应液升至室温继续搅拌2小时,然后浓缩。残余物用制备-HPLC分离纯化,得标题化合物(22mg,22%)。LCMS(ESI)[M+H]+=492;1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.83(s,1H),7.85(s,2H),2.60(q,2H),1.20(t,3H).
实施例4:(3,5-二溴-4-羟基苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
步骤1:(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
将1-(4-甲氧基苯基)戊烷-1,3-二酮(20g,97mmol),二乙酸碘苯(30.8g,96mmol),三氟化硼乙醚络合物(1.2g,16mmol)和5-氟嘧啶-2-氨基(9.04g,80mmol)溶于四氢呋喃(300mL)中,在室温下搅拌过夜。将反应液倒入饱和碳酸氢钠溶液(300mL)中,用乙酸乙酯萃取(100mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(9g,38%),为黄色固体。LCMS(ESI)[M+H]+=300.1.
步骤2:(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮的合成
在0℃和氮气保护下,向(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮(9g,30.1mmol)的无水二氯甲烷(60mL)溶液中滴加三溴化硼(10mL),将反应液升至室温继续搅拌16小时。在0℃下将反应液缓慢倒入饱和碳酸氢钠(100mL)中,然后用乙酸乙酯萃取(150mL×3)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩,得标题化合物(5.5g,64%),为黄色固体,不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=286.0.
步骤3:(3,5-二溴-4-羟基苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
在0℃下,向(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮(5.5g,19.3mmol)的N,N-二甲基甲酰胺(50mL)溶液中加入N-溴代丁二酰亚胺(8.2g,46.3mmol),反应液升至室温并继续搅拌3小时。用水淬灭反应,有固体析出。将反应液过滤,滤饼用水洗涤,用乙腈重结晶,再用甲醇/二氯甲烷(1/10)的混合溶液洗涤,得标题化合物(4.5g,53%)。LCMS(ESI)[M+H]+=441.7;1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),9.51(s,1H),8.99(s,1H),7.91(s,2H),2.50(q,J=7.6Hz,2H),1.19(t,J=7.6Hz,3H).
实施例5:(3,5-二溴-4-羟基苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
步骤1:(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
将1-(4-甲氧基苯基)戊烷-1,3-二酮(4.50g,21.84mmol),5-(三氟甲基)嘧啶-2-胺(7.40g,45.39mmol)和二乙酸碘苯(13.30g,41.30mmol)溶于四氢呋喃(80mL)中,在室温下搅拌2小时。加入三氟化硼乙醚络合物(0.7g,5.00mmol),将得到的混合物在室温下搅拌过夜。反应液用水淬灭然后用乙酸乙酯萃取(40mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(2.20g,29%),为黄色油状物。LCMS(ESI)[M+H]+=350.
步骤2:(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮的合成
向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)-甲酮(4.90g,14.04mmol)的二氯甲烷(25mL)溶液中加入三溴化硼(27.0g,10mL,107.70mmol),在室温下搅拌过夜。将反应液倒入饱和碳酸氢钠溶液(100mL)中,黄色固体析出。过滤,滤饼用石油醚洗涤(30mL×3),干燥得标题化合物(3.50g,75%),为棕色固体。LCMS(ESI)[M+H]+=336.
步骤3:(3,5-二溴-4-羟基苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
在0℃下,向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮(6.40g,19.10mmol)的N,N-二甲基甲酰胺(60mL)溶液中缓慢加入N-溴代丁二酰亚胺(120mg,0.67mmol)。反应液升至室温继续搅拌2小时,然后用水淬灭,有固体析出。过滤,滤饼用水,乙腈和石油醚洗涤,干燥后得标题化合物(2.80g,30%)。LCMS(ESI)[M+H]+=492;1HNMR(400MHz,DMSO-d6)δ9.62(s,1H),9.14(s,1H),7.92(s,2H),2.53(q,2H),1.22(t,3H).
实施例6:(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮的合成
步骤1:(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
将1-(4-甲氧基苯基)戊烷-1,3-二酮(1.00g,4.85mmol),5-氯吡啶-2-胺(0.75g,5.82mmol)和二乙酸碘苯(2.30g,7.28mmol)溶于四氢呋喃(15mL)中,在室温下搅拌2小时。然后加入三氟化硼乙醚络合物(0.14g,1.00mmol),得到的混合物在室温下搅拌过夜。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(500mg,33%),为黄色油状物。LCMS(ESI)[M+H]+=316.
步骤2:(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)甲酮的合成
向(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基苯基)甲酮(250mg,0.79mmol)的二氯甲烷(2mL)溶液中加入三溴化硼(17%的二氯甲烷溶液,5mL,8.5mmol)。将反应液在室温下搅拌72小时,然后用水淬灭,用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,得标题化合物(230mg,96%),为深红色固体。LCMS(ESI)[M+H]+=302.
步骤3:(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(3,5-二溴-4-羟基苯基)-甲酮的合成
在0℃下,向(6-氯-2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-羟基苯基)-甲酮(50mg,0.17mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中缓慢加入N-溴代丁二酰亚胺(75mg,0.42mmol)。将反应液升至室温继续搅拌2小时,然后浓缩。残余物用制备-HPLC分离纯化得标题化合物(6.9mg,9%)。LCMS(ESI)[M+H]+=458;1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.83(s,1H),7.87(s,2H),2.52(q,2H),1.22(t,3H).
实施例7:(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)甲酮的合成
步骤1:(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
将1-(4-甲氧基苯基)戊烷-1,3-二酮(20g,97mmol),二乙酸碘苯(30.8g,96mmol),三氟化硼乙醚络合物(1.2g,16mmol)和6-(三氟甲基)嘧啶-4-胺(13g,80mmol)溶于四氢呋喃(300mL)中,在室温下搅拌过夜。将反应液倒入饱和碳酸氢钠溶液(300mL)中,用乙酸乙酯萃取(100mL×3)。将有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=2/1),得标题化合物(10g,35%)。LCMS(ESI)[M+H]+=350.0.
步骤2:(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)(4-羟基苯基)甲酮的合成
在0℃下,向(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)(4-甲氧基苯基)甲酮(10g,28.6mmol)的无水二氯甲烷(60mL)溶液中滴加三溴化硼(10mL),反应液升至室温继续搅拌16小时。在0℃下将反应液缓慢倒入饱和碳酸氢钠(100mL)中,然后用乙酸乙酯萃取(150mL×3)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩,得标题化合物(5.0g,52%),不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=336.0.
步骤3:(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)甲酮的合成
在0℃下,向(2-乙基-7-(三氟甲基)咪唑并[1,2-c]嘧啶-3-基)(4-羟基苯基)甲酮(5.0g,14.9mmol)的N,N-二甲基甲酰胺(50mL)溶液中加入N-溴代丁二酰亚胺(6.3g,35.8mmol),将反应液升至室温并继续搅拌3小时。用水淬灭反应,有固体析出。反应液过滤,滤饼用水洗涤,用乙腈重结晶,再用快速色谱法分离纯化(甲醇/二氯甲烷=1/20),得标题化合物(4.2g,57%)。LCMS(ESI)[M+H]+=492.7;1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.42(s,1H),7.95(s,2H),2.52(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H).
实施例8:(4,6-二溴-5-羟基吡啶-2-基)(2-乙基-5-氟-2H-吲唑-3-基)甲酮的合成
步骤1:2-乙基-5-氟-2H-吲唑的合成
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向5-氟-2H-吲唑(1.9g,13.9mmol)的乙酸乙酯(25mL)溶液中加入三乙基氧鎓四氟硼酸(4g,20.9mmol),在室温下搅拌16小时。反应液用水(20mL)稀释,然后用乙酸乙酯萃取(20mL×2)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=7/3),得标题化合物(2.29g,99%),为黄色油状物。LCMS(ESI)[M+H]+=165.
步骤2:(2-乙基-5-氟-2H-吲唑-3-基)(5-甲氧基吡啶-2-基)甲酮的合成
在-78℃和氩气保护下,向2-乙基-5-氟-2H-吲唑(164mg,1mmol)的无水四氢呋喃(5mL)溶液中滴加正丁基锂(0.8mL,2.5M的四氢呋喃溶液,2mmol)。反应液在-20℃下搅拌30分钟,然后冷却至-78℃,加入5-甲氧基吡啶-2-酰氯(342mg,2mmol),将得到的混合物在室温下搅拌1小时。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用制备型TLC分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(15mg,5%),为黄色固体。LCMS(ESI)[M+H]+=300.
步骤3:(2-乙基-5-氟-2H-吲唑-3-基)(5-羟基吡啶-2-基)甲酮的合成
在0℃和氮气保护下,向(2-乙基-5-氟-2H-吲唑-3-基)(5-甲氧基吡啶-2-基)甲酮(15mg,0.05mmol)的无水二氯甲烷(1mL)溶液中滴加三溴化硼(2mL,17%的二氯甲烷溶液)。反应液升至室温搅拌16小时。然后在0℃下将上述反应液缓慢加入到饱和碳酸氢钠水溶液(100mL)中,并用乙酸乙酯萃取(20mL×3)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩得标题化合物(14mg,98%),为黄色固体,不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=286.0.
步骤4:(4,6-二溴-5-羟基吡啶-2-基)(2-乙基-5-氟-2H-吲唑-3-基)甲酮的合成
在0℃下,向(2-乙基-5-氟-2H-吲唑-3-基)(5-羟基吡啶-2-基)甲酮(14mg,0.05mmol)的N,N-二甲基甲酰胺(1mL)溶液中加入N-溴代丁二酰亚胺(27mg,0.15mmol)。将反应液升至室温后继续搅拌2小时。将反应液用水(10mL)淬灭,然后用乙酸乙酯萃取(20mL×2)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用制备-HPLC分离纯化,得标题化合物(4.1mg,19%)。LCMS(ESI)[M+H]+=442;1H NMR(400MHz,CD3OD)δ8.26(s,1H),7.74-7.77(m,1H),7.11-7.22(m,2H),4.73(q,J=6.4Hz,2H),1.60(t,J=6.8Hz,3H).
实施例9:(3,5-二溴-4-羟基苯基)(2-乙基-5-氟-2H-吲唑-3-基)甲酮的合成
步骤1:(2-乙基-5-氟-2H-吲唑-3-基)(4-甲氧基苯基)甲酮的合成
在0℃和氩气保护下,向2-乙基-5-氟-2H-吲唑(1.64g,10mmol)的无水四氢呋喃(30mL)溶液中滴加二异丙基氨基锂(10mL,2M的四氢呋喃溶液,20mmol),反应液在0℃下搅拌30分钟然后冷却至-78℃,缓慢加入4-甲氧基苯甲醛(2.055g,15mmol),得到的反应液在室温下搅拌16小时。将反应液用水(100mL)淬灭,然后用乙酸乙酯萃取(50mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用制备-TLC分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(300mg,10%),为黄色油状物。LCMS(ESI)[M+H]+=299.
步骤2:(2-乙基-5-氟-2H-吲唑-3-基)(4-羟基苯基)甲酮的合成
在0℃和氮气保护下,向2-乙基-5-氟-2H-吲唑-3-基)(4-甲氧基苯基)甲酮(300mg,1mmol)的无水二氯甲烷(2mL)溶液中滴加三溴化硼(8mL,17%的二氯甲烷溶液)。将反应液升至室温后搅拌16小时。然后在0℃下将上述反应液缓慢加入到饱和碳酸氢钠水溶液(100mL)中,并用乙酸乙酯萃取(30mL×3)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩,得标题化合物(284mg,99%),为黄色油状物,不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=285.
步骤3:(3,5-二溴-4-羟基苯基)(2-乙基-5-氟-2H-吲唑-3-基)甲酮的合成
在0℃下,向2-乙基-5-氟-2H-吲唑-3-基)(4-羟基苯基)甲酮(100mg,0.35mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入N-溴代丁二酰亚胺(157mg,0.88mmol)。将反应液升至室温后继续搅拌2小时并浓缩。残余物用制备-HPLC分离纯化,得标题化合物(20mg,13%)。LCMS(ESI)[M+H]+=441;1H NMR(400MHz,DMSO-d6)δ7.90-7.93(m,3H),7.26-7.31(m,1H),6.78-6.82(m,1H),4.67(q,J=6.4Hz,2H),1.52(t,J=6.8Hz,3H).
实施例10:3-溴-5-(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
步骤1:1-(3-碘-4-甲氧基苯基)乙酮的合成
将1-(4-甲氧基苯基)乙酮(15g,100mmol)、二(三氟乙酸)碘苯(III)(47.3g,110mmol)和碘单质(25.2g,100mmol)溶于乙腈(300mL)中,在室温下搅拌16小时。将反应液用水(400mL)稀释,用亚硫酸钠水溶液(100mL×2)洗涤,然后用乙酸乙酯萃取(100mL×4)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1)得标题化合物(18g,65%),为黄色固体。LCMS(ESI)[M+H]+=277.
步骤2:1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮的合成
在0℃下,向氢化钠(5g,60%的油分散液,125mmol)的乙醚(200mL)溶液中滴加1-(3-碘-4-甲氧基苯基)乙酮(13.8g,50mmol)的乙醚溶液(50mL)。向上述混合液中迅速加入丙酸乙酯(10.2g,100mmol),将得到的混合物加热回流16小时。将反应液冷却至室温,用水(400mL)稀释,然后用浓盐酸调节pH=5。将反应液用乙酸乙酯萃取(50mL×4)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(13g,78%),为黄色固体。LCMS(ESI)[M+H]+=333.
步骤3:(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮的合成
将1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮(332mg,1mmol)、二乙酸碘苯(483mg,1.5mmol)和5-(三氟甲基)嘧啶-2-胺(163mg,1mmol)溶液四氢呋喃(5mL)溶液中,在7℃下搅拌1小时。缓慢加入三氟化硼乙醚络合物(28g,0.2mmol),将得到的混合物升至室温继续搅拌过夜。将反应液倒入饱和碳酸氢钠溶液(20mL)中,然后用乙酸乙酯萃取(20mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/2),得标题化合物(150mg,32%),为黄色固体。LCMS(ESI)[M+H]+=476.
步骤4:(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-羟基苯基)甲酮的合成
向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮(5g,10.53mmol)的二氯甲烷(25mL)溶液中加入三溴化硼(10mL,99%),在室温下搅拌24小时。然后在0℃下将上述反应液缓慢加入到饱和碳酸氢钠水溶液(100mL)中,并用二氯甲烷(150mL×3)萃取。有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤并浓缩.残余物用石油醚(50mL)和乙酸乙酯(10mL)洗涤,滤饼干燥后得标题化合物(4g,82%),为黄色固体,不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=462.
步骤5:5-(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-羟基苯基)甲酮(0.8g,1.73mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入氰化亚铜(312mg,3.47mmol),在氮气保护下加热至100℃搅拌过夜。反应液用饱和氯化铵水溶液(60mL)稀释,然后用二氯甲烷萃取(50mL×3)。有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=2/3)得标题化合物(80mg,12%),为黄色固体。LCMS(ESI)[M+H]+=361.
步骤6:3-溴-5-(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
向5-(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(80mg,0.22mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入N-溴代丁二酰亚胺(79mg,0.44mmol)。反应液在室温下搅拌1小时并浓缩。残余物用快速色谱法分离纯化(甲醇/二氯甲烷=1/10)得标题化合物(38.1mg,39%)。LCMS(ESI)[M+H]+=439;1H NMR(400MHz,CD3OD)δ9.67(s,1H),8.98(d,J=2.4Hz,1H),8.13(d,J=2.4Hz,1H),7.89(d,J=2.0Hz,1H),2.78(q,J=7.6Hz,2H),1.37(t,J=7.6Hz,3H).
实施例11:3-溴-5-(3-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈的合成
步骤1:5-(3-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈的合成
向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-羟基苯基)甲酮(0.8g,1.73mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入氰化亚铜(312mg,3.47mmol),在氮气保护下加热至100℃搅拌过夜。将反应液用饱和氯化铵水溶液(60mL)稀释,然后用二氯甲烷萃取(50mL×3)。有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=2/3),得标题化合物(150mg,24%),为黄色固体。LCMS(ESI)[M+H]+=361.
步骤2:3-溴-5-(3-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈的合成
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向5-(3-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈(150mg,0.417mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入N-溴代丁二酰亚胺(148mg,0.833mmol)。反应液在室温下搅拌1小时并浓缩。残余物用快速色谱法分离纯化(甲醇/二氯甲烷=1/10)得标题化合物(30mg,16%)。LCMS(ESI)[M+H]+=439;1H NMR(400MHz,CD3OD)δ9.41(s,1H),8.95(d,J=2.4Hz,1H),8.60(d,J=2.0Hz,1H),8.54(s,1H),3.33(q,J=7.2Hz,2H),1.33(t,J=7.6Hz,3H).
实施例12:3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈和5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基间苯二甲腈2,2,2-三氟乙酸盐的合成
步骤1:3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈和5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基间苯二甲腈2,2,2-三氟乙酸盐的合成
向(3,5-二溴-4-羟基苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮(66mg,0.15mmol)的1-甲基-2-吡咯烷酮(2mL)溶液中加入氰化亚铜(27mg,0.3mmol),微波加热至140℃搅拌3小时。反应液用饱和氯化铵溶液(20mL)稀释,然后用乙酸乙酯萃取(20mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用制备-TLC分离纯化(甲醇/二氯甲烷=1/9),得标题化合物的混合物,进一步用制备制备-HPLC分离纯化得3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(12mg,21%)。LCMS(ESI)[M+H]+=389;1H NMR(400MHz,CD3OD)δ9.22-9.24(m,1H),8.69(d,J=2.8Hz,1H),7.95(d,J=2.4Hz,1H),7.70(d,J=2.0Hz,1H),2.65(q,J=7.6Hz,2H),1.21(t,J=7.6Hz,3H).
和5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基间苯二甲腈2,2,2-三氟乙酸盐(1.6mg,2%)。LCMS(ESI)[M-TFA+H]+=336;1H NMR(400MHz,CD3OD)δ9.57-9.59(m,1H),8.95(d,J=2.8Hz,1H),8.20(s,2H),2.70(q,J=7.2Hz,2H),1.32(t,J=7.6Hz,3H).
实施例13:3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈和(3,5-二溴-4-羟基苯基)(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-基)甲酮的合成
步骤1:3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈和(3,5-溴-4-羟基苯基)(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-基)甲酮的合成
向(3,5-二溴-4-羟基苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮(220mg,0.5mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入氰化亚铜(40mg,0.45mmol),在氮气保护下加热至100℃搅拌16小时。反应液用饱和氯化铵水溶液(60mL)稀释,然后用二氯甲烷萃取(50mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用制备型HPLC分离纯化,得3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(10mg,5%)。LCMS(ESI)[M+H]+=389;1H NMR(400MHz,CD3OD)δ9.61(dd,J=4.4Hz,1H),8.91(d,J=3.2Hz,1H),8.20(d,J=2.4Hz,1H),8.01(d,J=2.0Hz,1H),2.60(q,J=7.6Hz,2H),1.27(t,J=7.2Hz,3H).
和(3,5-溴-4-羟基苯基)(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-基)甲酮(25mg,11%)。LCMS(ESI)[M+H]+=441;1H NMR(400MHz,DMSO-d6)δ11.01(bs,1H),9.38(dd,J=4.4Hz,1H),8.90(d,J=2.8Hz,1H),8.59(s,2H),3.24(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).
实施例14:3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
步骤1:1-(3-碘-4-甲氧基苯基)乙酮的合成
将1-(4-甲氧基苯基)乙酮(15g,100mmol),二(三氟乙酸)碘苯(III)(47.3g,110mmol)和碘单质(25.2g,100mmol)溶于乙腈(300mL)中,在室温下搅拌16小时。将反应液用水(400mL)稀释,用亚硫酸钠水溶液(100mL×2)洗涤,然后用乙酸乙酯萃取(100mL×4)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/1),得标题化合物(18g,65%),为黄色固体。LCMS(ESI)[M+H]+=277.
步骤2:1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮的合成
在0℃下,向氢化钠(5g,60%的油分散液,125mmol)的乙醚(200mL)溶液中滴加1-(3-碘-4-甲氧基苯基)乙酮(13.8g,50mmol)的乙醚溶液(50mL)。向上述混合液中迅速加入丙酸乙酯(10.2g,100mmol),将得到的混合物加热回流16小时。将反应液冷却至室温,用水(400mL)稀释,然后用浓盐酸调节pH=5。反应液用乙酸乙酯萃取(50mL×4)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(13g,78%),为黄色固体。LCMS(ESI)[M+H]+=333.
步骤3:(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮的合成
将1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮(6.2g,18.6mmol)、二乙酸碘苯(9g,27.9mmol)和5-氟嘧啶-2-胺(2.11g,18.6mmol)溶于四氢呋喃(100mL)中,在室温下搅拌1小时。缓慢加入三氟化硼乙醚络合物(0.53g,3.73mmol),将得到的混合物在室温下搅拌过夜然后浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/3)得标题化合物(2.5g,31%),为黄色固体。LCMS(ESI)[M+H]+=426.
步骤4:(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-碘苯基)甲酮的合成
在0℃下,向(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮(2g,4.7mmol)的二氯甲烷(3mL)溶液中缓慢加入三溴化硼(6mL,纯度99%)。将反应液升至室温搅拌16小时。将反应液缓慢倒入冰中,在0℃下用碳酸氢钠溶液(30mL)调节pH至9,将得到的混合物在室温下搅拌1小时,然后过滤。滤饼用水(50mL),乙酸乙酯(10mL)和石油醚(50mL)洗涤,干燥得标题化合物(1.4g,72%),为黄色固体,不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=412.
步骤5:5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
将(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-碘苯基)甲酮(1.4g,3.4mmol)、氰化锌(598mg,5.1mmol)、锌粉(44mg,0.68mmol)、三(二亚苄基丙酮)二钯(155mg,0.17mmol)和1,1′-双(二苯基膦)二茂铁(94mg,0.17mmol)混合于N,N-二甲基甲酰胺(10mL)中,在氮气保护下加热至75℃后搅拌16小时。反应液用饱和氯化铵水溶液(50mL)淬灭,用二氯甲烷(100mL)稀释,然后过滤。滤饼用二氯甲烷(50mL)和甲醇(10mL)洗涤,干燥得标题化合物(910mg,86%),为黄色固体。LCMS(ESI)[M+H]+=311.
步骤6:3-溴-5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
向5-(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(910mg,2.93mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入N-溴代丁二酰亚胺(627mg,3.5mmol)。反应液在室温下搅拌1小时,然后用水(25mL)淬灭。将反应液过滤,滤饼用水(30mL)和甲醇(10mL)洗涤。滤液用乙酸乙酯萃取(30mL×4),有机相浓缩。残余物与滤饼用甲醇(100mL)稀释,在室温下搅拌30分钟,过滤,滤饼用二氯甲烷(50mL),甲醇(10mL)和乙酸乙酯(100mL)洗涤。滤液浓缩,然后用制备型TLC分离纯化两次(甲醇/二氯甲烷=0-15%),得标题化合物(900mg,79%)。LCMS(ESI)[M+H]+=389;1H NMR(400MHz,CD3OD)δ9.35(dd,J=4.4Hz,1H),8.80(d,J=3.2Hz,1H),8.06(d,J=2.4Hz,1H),7.82(d,J=2.0Hz,1H),2.77(q,J=7.6Hz,2H),1.33(t,J=7.6Hz,3H).
实施例15:3-溴-5-(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈的合成
步骤1:5-(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈的合成
向(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-基)(4-羟基-3-碘苯基)甲酮(5g,12.1mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入氰化亚铜(2.19g,24.2mmol),在氮气保护下加热至100℃后搅拌16小时。反应液倒入甲醇(50mL)中,然后过滤,滤饼用甲醇洗涤(10mL)。收集滤液并浓缩,残余物用快速色谱法分离纯化(乙酸乙酯),得标题化合物(500mg,13%),为黄色固体。LCMS(ESI)[M+H]+=311.
步骤2:3-溴-5-(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈的合成
向5-(3-乙基-6-氟咪唑并[1,2-a]嘧啶-2-羰基)-2-羟基苯甲腈(500mg,1.61mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入N-溴代丁二酰亚胺(574mg,3.22mmol)。反应液在室温下搅拌1小时然后用水(20mL)淬灭。将反应液过滤,滤饼用制备-HPLC分离纯化,得标题化合物(175mg,28%)。LCMS(ESI)[M+H]+=389;1H NMR(400MHz,CD3OD)δ9.11(dd,J=4.0Hz,1H),8.80(d,J=2.4Hz,1H),8.74(d,J=2.0Hz,1H),8.64(d,J=2.0Hz,1H),3.33(q,J=7.6Hz,2H),1.33(t,J=7.6Hz,3H).
实施例16:(3,5-二溴-4-羟基苯基)(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)甲酮的合成
步骤1:4-叠氮-3-吡啶甲醛的合成
向4-氯-3-吡啶甲醛(1g,7.06mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入叠氮化钠(459mg,7.06mmol),在室温下搅拌16小时。反应液用乙酸乙酯(100mL)稀释,用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,得标题化合物(1g,95%),为黄色固体。不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=121.
步骤2:N-((4-叠氮吡啶-3-基)亚甲基)乙胺的合成
将4-叠氮-3-吡啶甲醛(1g,6.76mmol)、四氯化钛(4mL,1M的二氯甲烷溶液,4mmol)和乙胺盐酸盐(551mg,6.76mmol)混合于二氯甲烷(10mL)中,在室温下搅拌7小时。反应液浓缩,残余物用乙酸乙酯(100mL)稀释,用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,得标题化合物(1.2g,99%),为黄色固体。不经纯化直接用于下一步反应。LCMS(ESI)[M-28+H]+=148.
步骤3:2-乙基-2H-吡唑并[4,3-c]吡啶的合成
将N-((4-叠氮吡啶-3-基)亚甲基)乙胺(1.2g,6.76mmol)溶于甲苯(60mL),加热至105℃搅拌4小时。反应液浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/3),得标题化合物(0.55g,55%),为黄色油状物。LCMS(ESI)[M+H]+=148.0.
步骤4:(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)(4-甲氧基苯基)甲醇的合成
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在0℃和氩气保护下,向2-乙基-2H-吡唑并[4,3-c]吡啶(0.3g,2.04mmol)的无水四氢呋喃(30mL)溶液中滴加二异丙基氨基锂(1.23mL,2M,2.45mmol)。反应液在0℃下搅拌1小时,然后冷却至-78℃,将4-甲氧基苯甲醛(278mg,2.04mmol)滴加至上述反应液中。将得到的混合液升至室温继续搅拌1小时。反应液用水(100mL)淬灭,然后用乙酸乙酯萃取(50mL×3)。有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=1/3),得标题化合物(340mg,59%),无色油状物。LCMS(ESI)[M+H]+=284.
步骤5:(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)(4-甲氧基苯基)甲酮的合成
在0℃下,向(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)(4-甲氧基苯基)甲醇(0.34g,1.2mmol)的二氯甲烷(10mL)溶液中加入Dess-Martin氧化剂(1g,2.4mmol)。反应液升至室温搅拌16小时然后浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(180mg,31%),为白色固体。LCMS(ESI)[M+H]+=282.
步骤6:(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)(4-羟基苯基)甲酮的合成
在0℃和氮气保护下,向(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)(4-甲氧基苯基)甲酮(90mg,0.32mmol)的无水二氯甲烷(2mL)溶液中加入三溴化硼(2mL,17%的二氯甲烷溶液)。将反应液升至室温继续搅拌2天。然后在0℃下将上述反应液缓慢加入到饱和碳酸氢钠水溶液(100mL)中,并用乙酸乙酯萃取(30mL×3)。有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤并浓缩,得标题化合物(78mg,91%),为白色固体。不经纯化直接用于下一步反应。LCMS(ESI)[M+H]+=268.
步骤7:(3,5-二溴-4-羟基苯基)(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)甲酮的合成
在0℃下,向(2-乙基-2H-吡唑并[4,3-c]吡啶-3-基)(4-羟基苯基)甲酮(72mg,0.29mmol)的醋酸(2mL)溶液中加入溴水(186mg,1.17mmol)。将反应液升至室温继续搅拌2小时。反应液浓缩,残余物用制备-HPLC分离纯化,得标题化合物(80mg,64%)。LCMS(ESI)[M+H]+=424;1H NMR(400MHz,CD3OD)δ8.81(d,J=0.9Hz,1H),8.28(d,J=6.4Hz,1H),7.99(s,2H),7.76(dd,J=6.4Hz,1H),4.74(q,J=7.2Hz,2H),1.64(t,J=7.2Hz,3H).
实施例17:3-溴-5-(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
步骤1:3-溴-5-(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
向(3,5-二溴-4-羟基苯基)(2-乙基-7-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮(100mg,0.2mmol)的1-甲基-2-吡咯烷酮(5.0mL)溶液中缓慢加入氰化亚铜(36mg,0.40mmol)。反应液加热至110℃搅拌12小时然后浓缩。残余物用制备型HPLC分离纯化,得标题化合物(6mg,6%)。LCMS(ESI)[M+H]+=439;1H NMR(400MHz,DMSO-d6)δ9.75-9.74(m,1H),8.24-8.23(m,1H),8.05(s,1H),7.68-7.66(m,1H),2.67(q,2H),1.32(t,3H).
实施例18:(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
步骤1:1-(4-甲氧基-3-(三氟甲基)苯基)戊烷-1,3-二酮的合成
在0℃下,向1-(4-甲氧基-3-(三氟甲基)苯基)乙酮(4.00g,18.34mmol)的乙醚(200mL)溶液中加入氢化钠(60%油分散液,2.00g,180.34mmol),在0℃下继续搅拌30分钟。加入丙酸甲酯(2.422g,27.5mmol),得到的混合物加热至40℃搅拌12小时。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(3.9g,97%),为黄色油状物。LCMS(ESI)[M+H]+=275.
步骤2:(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基-3-(三氟甲基)苯基)甲酮的合成
将1-(4-甲氧基-3-(三氟甲基)苯基)戊烷-1,3-二酮(2.0g,5.3mmol)、5-氟嘧啶-2-胺(0.723g,6.4mmol)和二乙酸碘苯(2.55g,7.95mmol)溶于四氢呋喃(40mL)中,在7℃下搅拌2小时。将三氟化硼乙醚络合物(0.149g,1.00mmol)加入上述反应液中,得到的混合物在室温下搅拌过夜。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(640mg,32%),为黄色油状物。LCMS(ESI)[M+H]+=368.
步骤3:(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-(三氟甲基)苯基)甲酮的合成
向(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-(三氟甲基)苯基甲酮(610mg,1.66mmol)的二氯甲烷(2mL)溶液中加入三溴化硼(17%的二氯甲烷溶液,20mL)。反应液在室温下搅拌24小时。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,得标题化合物(150mg,24%),为棕色固体。LCMS(ESI)[M+H]+=354.
步骤4:(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
在0℃下,向(2-乙基-6-氟咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-(三氟甲基)苯基)甲酮(80mg,0.22mmol)的N,N-二甲基甲酰胺(4.5mL)溶液中缓慢加入N-溴代丁二酰亚胺(120mg,0.67mmol)。反应液升至室温搅拌2小时然后浓缩。残余物用制备-HPLC分离纯化,得标题化合物(60mg,63%)。LCMS(ESI)[M+H]+=432;1H NMR(400MHz,DMSO-d6)δ9.52-9.50(m,1H),8.99(s,1H),8.18-8.18(m,1H),7.91-7.90(m,1H),2.49(q,2H),1.18(t,3H).
实施例19:(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
步骤1:(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基-3-(三氟甲基)苯基)甲酮的合成
将1-(4-甲氧基-3-(三氟甲基)苯基)戊烷-1,3-二酮(1.5g,4.02mmol)、5-(三氟甲基)嘧啶-2-胺(0.78g,4.8mmol)和二乙酸碘苯(1.93g,6.0mmol)溶于四氢呋喃(40mL)中,在室温下搅拌2小时。将三氟化硼乙醚络合物(0.111g,1.00mmol)加入上述反应液中,得到的混合物在室温下搅拌过夜。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,残余物用快速色谱法分离纯化(石油醚/乙酸乙酯=3/1),得标题化合物(400mg,26%),为黄色油状物。LCMS(ESI)[M+H]+=418.
步骤2:(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-(三氟甲基)苯基)甲酮
向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基-3-(三氟甲基)苯基)甲酮(400mg,0.95mmol)的二氯甲烷(2mL)溶液中加入三溴化硼(17%的二氯甲烷溶液,20mL)。反应液在室温下搅拌24小时。反应液用水淬灭,然后用乙酸乙酯萃取(20mL×3)。有机相用水洗涤(20mL×2),无水硫酸钠干燥,过滤并浓缩,得标题化合物(100mg,25%),为棕色固体。LCMS(ESI)[M+H]+=404.
步骤3:(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
在0℃下,向(2-乙基-6-(三氟甲基)咪唑并[1,2-a]嘧啶-3-基)(4-羟基-3-(三氟甲基)苯基)甲酮(90mg,0.22mmol)的N,N-二甲基甲酰胺(4.5mL)溶液中缓慢加入N-溴代丁二酰亚胺(120mg,0.67mmol)。将反应液升至室温搅拌2小时,然后浓缩。残余物用制备型HPLC分离纯化,得标题化合物(8.1mg,9%)。LCMS(ESI)[M+H]+=482;1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),9.13(s,1H),8.16(s,1H),7.90(s,1H),2.55(q,2H),1.23(t,3H).
实施例20:2,6-二溴-4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚的合成
步骤1:2-乙基-3-[(4-甲氧基苯基)羰基]咪唑并[1,2-a]嘧啶的合成
在0℃下,将嘧啶-2-胺(950mg,9.99mmol,1.00eq)、1-(4-甲氧基苯基)戊烷-1,3-二酮(2.47g,11.98mmol,1.20eq)在THF(60mL)中的溶液置入250-mL圆底烧瓶中,添加碘苯二乙酯(3.86g,11.98mmol,1.20eq)和BF3.Et2O(280mg,2.00mmol,0.20eq)。将得到的溶液在室温下搅拌15h。然后通过加入30mL水淬灭反应。用NaHCO3(aq)调节混合物至pH约为7。用乙酸乙酯萃取得到的溶液(3x100mL),合并有机层,并用无水硫酸钠干燥。粗产物通过快速制备型HPLC纯化,条件是(CombiFlash-1):硅胶柱;流动相:PE/EA=100/1至PE/EA=10/1(30min内)。生成1.4g(50%)2-乙基-3-[(4-甲氧基苯基)羰基]咪唑并[1,2-a]嘧啶,为棕色固体。ESI-MS(EI+,m/z):282,0.954min
步骤2:4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚的合成
将化合物2(1300mg,4.26mmol,1.00eq)的DCM(20mL)溶液置于60-mL密封试管中,添加BBr3(18ml,18mmol,4.00eq)。将生成的溶液在50℃下搅拌6小时。然后通过加入30mL冰水淬灭反应。用NaHCO3将混合物调节至约7。用乙酸乙酯(3x100mL)萃取生成的溶液,合并有机层,并用无水硫酸钠干燥。得到1g(81%)4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚,为白色固体。ESI-MS(EI+,m/z):268,0.816min.
步骤3:2,6-二溴-4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚的合成
将4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚(130mg,0.49mmol,1.00eq)的DCM(10mL)溶液置于20-mL密封试管中,添加Br2(180mg,1.13mmol,2.20eq)。将得到的溶液在室温下搅拌120min。真空浓缩生成的溶液。通过制备型HPLC纯化粗产物,条件是:柱:XBridge Prep C18 OBD柱,5um,19*150mm;流动相A:水(0.1%FA),流动相B:CAN;流速:20mL/min;梯度:36%B至37%B(7min内);254,220nm;Rt:5.82min。得到22.8mg(11%)2,6-二溴-4-([2-乙基咪唑并[1,2-a]嘧啶-3-基]羰基)苯酚。ESI-MS(EI+,m/z):426,2.497min.δH(300MHz,DMSO-d6)1.20(3H,t),2.51(3H,d),7.31(1H,dd),7.90(2H,s),8.77(1H,dd),9.41(1H,dd).
实施例21:(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮的合成
步骤1:(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(4-甲氧基苯基)甲酮的合成
在氮气氛围下,在0℃下,将三氟化硼乙醚络合物(0.280g,1.94mmol)添加至碘苯二乙酸酯(3.74g,11.65mmol)、1-(4-甲氧基苯基)戊烷-1,3-二酮(2g,9.71mmol)和6-氯嘧啶-4-胺(1.5g,11.65mmol)的THF(4mL)溶液中。将生成的混合物在室温下搅拌过夜。将反应混合物蒸干,再次溶解于EtOAc(25mL)中,用饱和食盐水顺序洗涤(25mL×3)。有机层用Na2SO4干燥,过滤,蒸发得到粗产物。将剩余物通过制备型TLC纯化(EtOAc∶石油醚=1∶2),得到(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(4-甲氧基苯基)甲酮(0.350g,11.4%),为黄色固体。m/z(ES+),[M+H]+=316;碱,HPLC Rt=1.124min.1H NMR(300MHz,氯仿-d)δ10.67(s,1H),7.97(s,1H),7.74(d,J=7.4Hz,1H),7.31(s,1H),7.18-7.06(m,1H),6.34(d,J=17.0Hz,1H),6.12(dd,J=17.0,10.2Hz,1H),5.66(d,J=10.3Hz,1H),1.39(s,12H).
步骤2:(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(4-羟基苯基)甲酮的合成
在氮气氛围下,在0℃下,将三溴化硼的甲苯溶液(1.5mL,1mol/L)添加至(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(4-甲氧基苯基)甲酮(150mg,0.43mmol)的THF溶液(5mL)中。将反应混合物在50℃下搅拌14小时。将反应混合物蒸干,再次溶解于EtOAc(25mL)中,用饱和食盐水顺序洗涤(25mL×3)。有机层用Na2SO4干燥,过滤,蒸发得到粗产物。将剩余物通过制备型TLC纯化(EtOAc∶石油醚=1∶1),得到(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(4-羟基苯基)甲酮(120mg,83.3%),为黄色固体。m/z(ES+),[M+H]+=302;碱,HPLC Rt=1.286min.1H NMR(300MHz,氯仿-d)δ9.68(d,J=1.3Hz,1H),7.68-7.44(m,3H),6.85(dd,J=9.0,2.3Hz,2H),2.54(q,J=7.5Hz,2H),1.18-1.12(m,3H).
步骤3:(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮的合成
在氮气氛围下,将NBS(120mg,0.66mmol)添加至(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(4-羟基苯基)甲酮(100mg,0.33mmol)的MeCN溶液(10mL)中。将生成的混合物在室温下搅拌2小时。将粗产物通过制备型HPLC纯化,柱:Xselect CSH OBD柱30*150mm 5um n;流动相A:水(0.1%FA),流动相B:CAN;流速:60mL/min;梯度:47%B至57%B(7分钟内);254;220nm;Rt:7.12min。将包含期望化合物的级分蒸干得到(7-氯-2-乙基咪唑并[1,2-f]嘧啶-3-基)(3,5-二溴-4-羟基苯基)甲酮(25.2mg,16.4%)。m/z(ES+),[M+H]+=460;酸,HPLC Rt=1.548min.1H NMR(300MHz,DMSO-d6)δ11.06(d,J=1.3Hz,1H),δ9.61(d,J=1.3Hz,1H),8.02(d,J=1.3Hz,1H),7.89(s,2H),2.44(t,J=7.5Hz,2H),1.17(t,J=7.5Hz,3H).
实施例22:3-溴-5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
步骤1:1-(3-碘-4-甲氧基苯基)乙酮的合成
按照实施例10步骤1的方法合成得到1-(3-碘-4-甲氧基苯基)乙酮的合成。
步骤2:1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮的合成
将1-(3-碘-4-甲氧基苯基)乙酮(15g,100mmol,1eq)的DMF溶液(100mL)置于100mL密封试管中。将混合物在冰浴中搅拌。在0℃下添加NaH(7.87g,199.9mmol,2eq)。将生成的溶液在0℃下搅拌2小时,然后加入丙酸乙酯(10.2g,100mmol,1eq)。将反应混合物在室温下搅拌过夜。反应用水淬灭(50mL)并用EA萃取。将有机层干燥并浓缩得到粗产物,其经硅胶柱纯化(石油醚∶乙酸乙酯=5∶1,Rf=0.55)得到期望的产物1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮(3.44g,19%)。
步骤3:(2-乙基咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮的合成
在0℃下,向1-(3-碘-4-甲氧基苯基)戊烷-1,3-二酮(3.8g,16.4mmol,1eq)和嘧啶-2-胺(1.4g,14.8mmol,0.9eq)的THF溶液(30mL)中添加碘苯二乙酸酯(4.67g,16.4mmol,1eq),然后添加BF3.Et2O(465mg,3.28mmol,0.2eq)。反应在室温下搅拌过夜。用NaHCO3碱化混合物,并用EA萃取。干燥有机层,并浓缩得到粗产物。将粗产物用硅胶柱纯化(PE∶EA=2∶1,Rf=0.45)得到期望的产物(2-乙基咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮(1.66g,36%).1H NMR(300MHz,DMSO-d6)δ1.17(dt,J=9.9,7.5Hz,3H),2.49(d,J=7.7Hz,2H),3.83-4.01(m,3H),7.12(d,J=8.8Hz,1H),7.31(dt,J=6.9,4.0Hz,1H),8.21(d,J=4.8Hz,2H),8.76(tt,J=4.8,2.4Hz,1H),9.44(dd,J=6.9,1.9Hz,1H).ESI-MS(EI+,m/z):408,0.927min.
步骤4:5-(2-乙基咪唑并[1,2-a]嘧啶3-羰基)-2-甲氧基苯甲腈的合成
将(2-乙基咪唑并[1,2-a]嘧啶-3-基)(3-碘-4-甲氧基苯基)甲酮(1.66g,4mmol,1eq)和CuCN(0.725g,8mmol,2eq)的DMF溶液(10mL)在130℃下搅拌2小时。将反应混合物冷却,经硅藻土过滤。将滤液添加至水中形成绿色固体。将固体用水洗涤并在乙腈中结晶得到期望的产物5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-甲氧基苯甲腈(280mg,22.4%),其为黄色固体。ESI-MS(EI+,m/z):408,0.927min.
步骤5:5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
将5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-甲氧基苯甲腈(180mg,0.59mmol,1eq)和NaSEt(1.76mmol,3eq)的DMF溶液(5mL)在100℃下搅拌2小时。基于LCMS,反应完全。将混合物冷却至室温,并用H2O(5mL)处理。将混合物过滤,用水洗涤滤饼。干燥固体并在乙腈中结晶得到期望的产物5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(150mg,41%).1H NMR(400MHz,DMSO-d6)δ1.17(t,J=7.5Hz,3H),2.53-2.70(m,2H),7.27-7.43(m,2H),7.86(dd,J=8.8,2.2Hz,1H),7.93-8.12(m,1H),8.77(dd,J=4.2,2.0Hz,1H),9.41(dd,J=6.9,2.0Hz,1H).ESI-MS(EI+,m/z):293,0.794min.
步骤6:3-溴-5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈的合成
向5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(150mg,0.51mmol,1eq)的AcOH溶液(2mL)添加Br2(120mg,0.75mmol,1.5eq)的AcOH溶液(0.2mL)。将混合物在室温下搅拌1小时。基于LCMS,反应完全。将混合物浓缩,并在乙腈中结晶。固体通过制备型HPLC(柱:XSelect CSH Prep C18 OBD柱,19*250mm,5um;流动相A:水(0.1%FA),流动相B:CAN;流速:25mL/min;梯度:25%B至84%B(7分钟内),254/220nm;Rt:6.5min)纯化得到期望的产物3-溴-5-(2-乙基咪唑并[1,2-a]嘧啶-3-羰基)-2-羟基苯甲腈(16.3mg,8.57%)。1H NMR(300MHz,DMSO-d6)δ1.21(t,J=7.5Hz,3H),7.17-7.47(m,1H),8.02(s,1H),8.15(d,J=2.0Hz,1H),8.81(s,1H),9.41(d,J=7.0Hz,1H).ESI-MS(EI+,m/z):371/373,0.887min.
实施例23:(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
步骤1:1-(4-甲氧基-3-(三氟甲基)苯基)乙酮的合成:
在0℃下,向1-(4-氟-3-(三氟甲基)苯基)乙酮(10g,48.5mmol,1eq)的DMF溶液(100mL)添加NaOMe(3.14g,58.2mmol,1.2eq)。添加完毕后,将反应混合物在室温下搅拌1小时直至反应完全。用NH4Cl(aq)淬灭反应,并用乙酸乙酯萃取反应混合物。有机层用饱和食盐水洗涤,并用无水硫酸钠干燥。减压除去溶剂得到期望的产物1-(4-甲氧基-3-(三氟甲基)苯基)乙酮(15g,粗产物),其不经进一步纯化直接用于下一步。1H NMR(300MHz,氯仿-d)δ2.59(s,3H),3.98(s,3H),7.06(d,J=8.7Hz,1H),8.01(s,1H),8.14(dd,J=8.7,2.1Hz,1H).
步骤2:1-(4-甲氧基-3-(三氟甲基)苯基)戊烷-1,3-二酮的合成
将1-(4-甲氧基-3-(三氟甲基)苯基)乙酮(4g,18.3mmol,1eq)的DMF溶液(50mL)置于100mL密封试管中。将混合物在冰浴中搅拌。在0℃下加入NaH(1.46g,36.6mmol,2eq)。将生成的溶液在0℃下搅拌2小时,然后添加丙酸乙酯(1.86g,18.3mmol,1eq)。将反应混合物在室温下搅拌过夜。用NH4Cl(20mL)淬灭反应,并用乙酸乙酯萃取反应混合物。干燥有机层,并浓缩得到粗产物,其通过硅胶柱(石油醚∶乙酸乙酯=5∶1,Rf=0.5)纯化得到期望的产物1-(4-甲氧基-3-(三氟甲基)苯基)戊烷-1,3-二酮(3.4g)。
步骤3:(2-乙基咪唑并[1,2-a]嘧啶-3-基)(4-甲氧基-3-(三氟甲基)苯基)甲酮的合成
在0℃下,向1-(4-甲氧基-3-(三氟甲基)苯基)戊烷-1,3-二酮(3.4g,12.4mmol,1eq)和嘧啶-2-胺(1.0g,11.2mmol,0.9eq)的THF(30mL)溶液中添加碘苯二乙酸酯(3.53g,12.4mmol,1eq),然后添加BF3.Et2O(352mg,2.48mmol,0.2eq)。将反应混合物在室温下搅拌过夜。用NaHCO3(aq)碱化反应混合物,并用乙酸乙酯萃取得到的混合物。干燥有机层并浓缩得到粗产物。将粗产物用硅胶柱纯化(PE∶EA=2∶1,Rf=0.45)得到期望的产物(4-甲氧基-3-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮(420mg,9.8%)。1H NMR(400MHz,DMSO-d6)δ1.15(t,J=7.5Hz,3H),2.43(t,J=7.5Hz,2H),4.02(s,3H),7.32(dd,J=6.9,4.3Hz,1H),7.46(d,J=8.7Hz,1H),7.97(d,J=2.0Hz,1H),8.05(dd,J=8.7,2.1Hz,1H),8.69-8.85(m,1H),9.40-9.51(m,1H).ESI-MS(EI+,m/z):350,0.796min.
步骤4:(4-羟基-3-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
将(4-甲氧基-3-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮(400mg,1.15mmol,1eq)和NaSEt(3.43mmol,3eq)的DMF溶液(7mL)在100℃下搅拌2小时。基于LCMS,反应完全。将反应混合物冷却至室温,并用水(10mL)处理。将反应混合物过滤,用水洗涤滤饼。将固体用C18快速柱纯化得到期望的产物(4-羟基-3-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮(110mg,28.7%)。1H NMR(400MHz,DMSO-d6)δ1.14-1.31(m,3H),2.66(q,J=7.5Hz,2H),6.13(d,J=9.2Hz,1H),7.12(dd,J=6.8,4.2Hz,1H),7.48(dd,J=9.2,2.6Hz,1H),7.64(d,J=2.5Hz,1H),8.60(dd,J=4.2,2.0Hz,1H),9.02-9.10(m,1H).ESI-MS(EI+,m/z):336,0.927min.
步骤5:(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮的合成
将(4-羟基-3-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮(110mg,0.33mmol,1eq)的AcOH溶液(2mL)添加至Br2(78.8mg,0.49mmol,1.5eq)的AcOH溶液(0.2mL)中。将反应混合物室温下搅拌1小时。基于LCMS,反应完全。浓缩反应混合物,并通过制备型HPLC(柱:SunFire C18 OBD制备柱;5μm,19mm X 250mm;流动相A:水(0.1%FA),流动相B:乙腈;流速:25mL/min;梯度:50%B至50%B(7分钟内);254/220nm;Rt:6.3min)纯化得到期望的产物(3-溴-4-羟基-5-(三氟甲基)苯基)(2-乙基咪唑并[1,2-a]嘧啶-3-基)甲酮(3.2mg)。1H NMR(300MHz,DMSO-d6)δ1.20(t,J=7.5Hz,2H),2.47(d,J=7.4Hz,2H),7.29(dd,J=6.9,4.2Hz,1H),7.86(s,1H),8.13(d,J=4.7Hz,1H),8.76(dd,J=4.2,2.0Hz,1H),9.36(d,J=6.8Hz,1H).ESI-MS(EI+,m/z):416,1.151min.
实施例24:化合物对HEK293转染细胞株中的hURAT1的抑制试验
1.细胞培养及接种
1).培养稳定表达hURAT1的HEK-293T细胞株,培养基组成为:DMEM培养基+10%胎牛血清+500μg/ml G418+1%P/S。
2).待细胞长到80%满的时候,弃掉培养基,加PBS清洗细胞一次,之后加入胰酶-EDTA进行消化,待细胞脱壁时加入培养基,吹打使细胞脱落,离心收集细胞,加入培养基吹打成细胞悬液。
3).调整细胞密度为3×105/ml,然后按100微升/孔的量接种到96孔的壁白底透的细胞培养板中,培养12-24小时。
2.化合物配制
1)化合物用DMSO配成20mM浓度的母液,再用DMSO稀释成2mM的起始浓度。
2)在96孔板上,以2mM的起始浓度用DMSO进行4倍等比稀释,10个梯度,另分别设置质控化合物,此为100×化合物板。
3)在另一块96孔板上用Cl-free HBSS缓冲液缓冲液进行对应孔的10倍稀释,此为10×化合物板。
4)之后在一块新的96孔板上加入45μL/孔的含0.1μCi/mL14C-尿酸的缓冲液和5μL/孔的10×已稀释好的化合物,将此配制成1×的化合物板待用。所含DMSO的浓度为1%。
3.14C-尿酸在稳定表达hURAT1细胞中的吸收
1).待96孔板中细胞培养贴壁后可进行吸收试验。
2).用200微升/孔预热的缓冲液洗细胞1次。
3).吸干各孔,之后立即加入50微升/孔含有相对应的化合物和0.1μCi/ml14C-尿酸溶液。
4).将加完化合物的板子在37℃培养箱中孵育5分钟。
5).立即在每个孔中加入150微升冰冷的缓冲液液以终止吸收。用缓冲液清洗每孔三次。清洗过程中,尽量避免细胞脱落。
6).加入50微升/孔的裂解液到所有孔中,置于振荡器上以900rpm的速度振荡5分钟。
7).加入150微升/孔的闪烁液Microsint40到所有孔中,以900rpm的速度振荡5分钟。
8).最后,微孔板送至MicroBeta Trilux(PerkinElmer公司生产)仪器上测定放射活性。
4.数据处理
分析数据,用XL-fit软件计算板子的质控及各化合物的IC50。结果参见表1。
实验结果表明这些化合物对HEK293转染细胞中hURAT1转运尿酸均有较好的抑制效果,大部分化合物抑制效果优于苯溴马隆。
实施例25:化合物对HEK293转染细胞株中的oAT1/OAT3靶点的抑制试验
1.试剂和耗材
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2.培养基和溶液
复苏培养基:90%DMEM+10%FBS+1X Pen/Strep,4℃保存备用。
细胞培养基:90%DMEM+10%FBS+1X Pen/Strep+100μg/mL Hygromycin B,4℃保存备用。
5X Matrigel:将1瓶Matrigel放4℃过夜融化,用冷DMEM稀释至500mL,分装后4℃保存备用。
Uptake assay缓冲液:487.5mL HBSS缓冲液+12.5mL 1M HEPES,HEPES的终浓度为25mM,实验前配置。
30mM丙磺舒:2mg粉末溶于233.62μL 100%DMSO,分装后-20℃度保存备用。
30mM苯溴马隆:2mg粉末溶于157.20μL 100%DMSO,分装后-20℃保存备用。
1mM 6-羧基荧光素(分子量376.32):0.3763mg粉末溶于1mL Uptake assay缓冲液。分装后4℃保存,避光。
3.仪器
Envision多功能盘式分析仪(参数设置如下:)
要求的滤波器:
激发波长:485nm
发射波长:590nm
激发截止滤镜:505nm
4.实验流程
5.1细胞培养
1)细胞复苏
将需要复苏的细胞从液氮罐内迅速取出,37℃水浴中不停摇晃,直到全部融化。迅速将细胞悬液加入预热的培养基中,放入离心机,1000转/分钟,离心5分钟。将离心管取出,弃去上清液,向离心管内加入新鲜预热的培养基,重悬细胞,将细胞悬液加入100mm培养皿,37℃,5%CO2培养。
2)传代
当细胞长满培养皿80~90%,0.25%Trypsin-EDTA消化细胞,用新的培养基将细胞重悬,通常情况下,每2~3天按1∶3至1∶5传代。
5.2实验
第1天 细胞铺板
1)细胞板包被
消化处理细胞前,在384孔细胞板中加入5×Matrigel 5μL/well,37℃培养箱孵育30分钟。
2)铺板
消化收集细胞沉淀,计数,用培养基重悬至1×106细胞/mL,使用Multidrop Combi以每孔60μL加入包被好的细胞板中,使其细胞密度为6x104cell/孔,37℃,5%CO2孵育过夜。
第2天 反应检测
3)Uptake assay缓冲液配制
实验当天,按照实验需要的用量配制新鲜的缓冲液。
4)化合物的准备(使用ECHO)
按照PlateMap利用3个母液浓度制备曲线的11个浓度。3个浓度分别为为:30mM,0.3mM,0.003mM,3个浓度都用DMSO配置。ECHO的详细信息如下表:
5)6uM 6-羧基荧光素与化合物混合液的配制
按照实验用量,用Uptake assay缓冲液稀释1mM 6-羧基荧光素得到6μM 6-羧基荧光素稀释液,然后用Combi将6μM 6-羧基荧光素稀释液加入到ECHO准备好的化合物板,每孔30μL,得到6-羧基荧光素与化合物的混合液,放置于避光处待用。此时DMSO浓度为2%。
6)洗板
取出孵育过夜的细胞板,小心去除培养基,然后每孔加入室温的80μL Uptakeassay缓冲液清洗3次,清洗完后每孔加入20μL Uptake assay缓冲液。
7)加入化合物
用Bravo转移20μL/孔第5步配制好的6μM 6-CF与化合物的混合液到细胞板中,400RMP离心1分钟,然后避光室温反应10分钟。此时6-CF的浓度变为3μM,化合物的浓度变为终浓度,DMSO的浓度变为1%。
8)洗板
用预冷的Uptake assay缓冲液,80μL每孔清洗细胞板3次,去除游离未被吸收的6-CF。
9)读板
在Envision上读板,收集记录数据,处理计算IC50。
5.3数据分析
根据每块细胞板上HPE和ZPE的荧光信号值计算该细胞板上每孔中化合物的抑制率(%)。HPE含有高浓度的阳性化合物(400μM的丙磺舒),为100%抑制对照;ZPE不含任何化合物,只有作为化合物溶剂的DMSO(1%DMSO),为0%抑制对照。
抑制率计算公式如下:
抑制%=100-(I化合物-IHPE)/(IZPE-IHPE)×100
使用XLfit软件作图,计算化合物的IC50值。阳性化合物的IC50值亦是衡量每次实验质量的标准之一。结果参见表1。
结果表明,大部分化合物对OAT1/3的选择性都优于苯溴马隆。
表1
A:IC50<50nM;B:50<IC50<200nM;C:200<IC50<500nM
实施例26:化合物对人原代正常肝细胞的细胞毒性试验
试验材料名称及来源:
人原代肝细胞购自BioreclamationIVT.公司(lot:AKB/S1391);体外人原代细胞培养基组分和供应商如下:
实验方法
1.将冻存的人原代肝细胞复苏,重悬在含10%FBS的培养基中,按8×104/孔细胞数接种于96孔板中,置37℃、5%CO2孵箱培养过夜;
2.用含10%FBS的培养基配制不同浓度梯度的试验化合物或对照药物苯溴马隆,并按100μL/孔加入,做为试验化合物孔或对照药物孔;按100μL/孔加入含10%FBS的培养基,做为阴性对照孔。置37℃、5%CO2孵箱中培养48h。
3.人原代肝细胞分别用PBS(0.1M、pH=7.4)清洗2次,按100μL/孔加入CellTiter-Glo试剂;在无细胞的孔中加入100μL/孔CellTiter-Glo试剂,做为空白对照孔。将96孔板在plate shaker上振荡5分钟,然后在室温放置10分钟。。
4.用Victor X4(Perkin Elmer)读取化学发光数值。试验化合物孔的化学发光值以F(试验化合物)表示;空白对照孔的化学发光值以F(空白对照)表示;阴性对照孔的化学发光值以F(阴性对照)表示。按以下公式计算不同药物浓度下的细胞存活率,每个浓度重复测定3次,得出平均值和标准偏差。
5.利用Prism Graph软件分别计算出试验化合物对人原代肝细胞的半数抑制浓度(IC50)。
结果见表2。从结果可以看出所有化合物对人原代肝细胞的生长抑制都远小于苯溴马隆,说明其对肝脏的毒性远低于苯溴马隆。
表2
化合物 | IC50,μM |
苯溴马隆 | 6.65 |
实施例4 | 257.00 |
实施例5 | 77.78 |
实施例14 | 1000 |
实施例21 | 347.00 |
实施例27:评价化合物对CYP2C9酶抑制作用
实验在100mM磷酸盐缓冲液中进行,总体积200μL。反应体系中微粒体浓度为0.25mg/mL,待测化合物浓度为10、3.33、1.11、0.37、0.12、0.04、0μM,CYP2C9特异性探针底物及浓度为10μM双氯芬酸。孵育体系在37度恒温振荡器中预孵育5分钟,加入NADPH发生体系(含1.3mM NADP+、3.3mM葡萄糖6-磷酸、0.4U/L葡萄糖6-磷酸脱氢酶、3.3mM MgCl2)开始反应。孵育10min后加入等体积的乙腈终止反应,涡旋,13000rpm离心,取上清LC-MS-MS进样测定代谢产物生成量。双氯芬酸经过CYP2C9特异性代谢产物为对4-羟基双氯芬酸。CYP2C9特异性抑制剂选用磺胺苯吡唑。本实验最终在GraphPad Primsm 5.0中进行分析,计算半数抑制浓度IC50值。
按照上述的实验方法,本发明的实施例4、5、14、20、21的化合物对各种CYP酶均只有不强的抑制或无抑制,其IC50均高于苯溴马隆。
实施例28:化合物在人和大鼠肝细胞孵育体系中的代谢产物研究
1.储备液和工作液的制备
储备液:称取适量的供试品粉末,加入DMSO或其它合适溶剂,溶解后混合均匀,得浓度为10mM的储备溶液并保存于4℃冰箱备用。
工作液:将10mM的储备液用乙腈稀释至1mM的工作液,混匀,备用。
2.细胞解冻分离液(Thawing Medium I)的制备
将Williams’Medium E,谷氨酸盐,HEPES,胎牛血清蛋白,人体重组胰岛素,地塞米松和细胞分离液(PercollTM)以比例700∶10∶15∶50∶1∶0.1∶300混合备用。
3.终止液的制备
配制含有0.1%甲酸的乙腈溶液作为终止液,置于4℃冰箱中备用。
4.肝细胞悬浮液的分离与制备
取出冻存的肝细胞,37℃水浴解冻(约90s)后,迅速倒入已预热的细胞分离液中,并用细胞分离液洗涤残留肝细胞,合并后混匀,室温下以离心力100×g,离心5min。弃上清液,沉淀用已预热的William’Medium E重悬肝细胞。取20μL肝细胞悬液,加入100μL 0.4%台酚蓝染色,并对细胞计数,细胞存活率要求大于70%。采用William’Medium E调整肝细胞密度至1.25×106cells/mL。
5.样品孵育与处理
1)供试品工作液置37℃的恒温孵育箱中预孵育(预热)10分钟后,用移液枪移取2μL的工作液(1mM),加入到含有160μL浓度为1.25×106细胞/mL的肝细胞悬浮液的细胞培养板中混匀,再加入38μL Williams’Medium E,混匀后置培养箱中孵育并开始计时(孵育总体积为200μL)。空白对照样品中,用40μL Williams’Medium E替代工作液。对于0分钟的样品,加入400μL乙腈(含0.1%甲酸)后,加入工作液及Williams’Medium E。
2)孵育180分钟后,从恒温孵育箱中取出孵育样品,测定细胞存活率后,加入400μL乙腈(含0.1%甲酸)溶液终止反应。
3)反应终止后,置摇板机上以300转/分钟的速度震摇10分钟;之后以离心力至少为10000×g离心至少10分钟。离心后,移取全部上清液于离心管中,氮气吹干。
4)残留物用合适的溶液复溶,室温下以离心力至少为10000×g离心至少15分钟,移取上清液到样品分析板中进行LC-MS分析。
5)7-乙氧基香豆素(30μM)实验方法同供试品。只有当阳性对照样品检测到目标代谢产物时,供试品经孵育后的样品才能用于代谢产物分析鉴定。否则,上述实验须重新进行。
6.数据采集与分析
1)数据采集
在UPLC-PDA(Waters)-Q-E Plus(Thermo)或Waters UPLC-PDA-Q/TOF上建立了LC-MSn(n=1-2)分析方法,使用不同质谱扫描模式(MSE和MS2)和紫外全波长(190-500nm)扫描对样品进行数据采集。
2)数据分析
采用MetaboLynx或Compound Discoverer软件对采集得到的质谱数据进行处理。根据供试品的化学结构设置适当的参数筛选潜在的代谢产物。
对软件处理后的数据进一步筛选与供试品相关的代谢产物。
对各个种属肝微粒体产生的代谢产物进行综合分析,并给出各代谢产物的紫外积分峰面积的相对百分比。
通过比较分析供试品(母药)与代谢产物的碎片,推测代谢产物可能的结构。
通过大鼠和人的肝细胞代谢产物鉴定,测试的实施例4、5、14、20、21的化合物都没有检测到苯溴马隆通过体内代谢产生的有毒性的代谢产物。
实施例29:化合物体内药代动力学
化合物在大鼠体内的药物代谢动力学研究方法:
1.雄性SD大鼠买入后,在动物房适应性饲养7天。
2. 6只SD大鼠随机分为2组,每组3只,一组用于灌胃给药,另一组用于尾静脉注射给药。灌胃给药组的大鼠,给药前需过夜禁食。
3.大鼠给药后,采用眼眶静脉丛采血的方法取血,每个采血时间点采血量约为200μl。
4.采集的血样在4℃以12000rpm的转速离心5分钟,然后采集上层血浆样品,并于-20℃冰箱中保存待测。
5.实验操作总结见下:
6.使用LC-MS/MS(UPLC-MS/MS:液相Waters Acquity UPLC(USA)和质谱5500QTrap(Applied Biosystem/MDS SCIEX)或者HPLC-MS\MS:液相Agilent 1200series(USA)和质谱API 4000(Applied Biosystem/MDS SCIEX))检测血浆中的化合物浓度。
使用药代动力学专业软件WinNonlin【型号:PhoenixTM 6.1厂家:Pharsight Corporation】计算药代动力学参数。【Phoenix 1.1 User’s Guide:p251-p300】
按照上述的实验方法,本发明中已测定的实施例4、5、14、20、21的化合物均表现出较好的生物利用度(>30%)。
Claims (6)
1.一种通式I所示的化合物或其互变异构体或其药学上可接受的盐:
其中,A环是六元杂芳环,B环是五元杂芳环,
W1选自N;
W2选自CR6;R6选自乙基;
W3选自C且W4选自N;
W7选自CH;
W5和W6各自独立地选自CR8或N,条件是W5和W6中的一个选自N;
R2和R3独立地选自氢和氘;R4和R5各自独立地选自卤素、氰基、C1卤代烷基;
R1和R8各自独立地选自氢、氘、卤素、氰基、羟基、C1烷基、C1烷氧基、C1卤代烷基;
条件是排除下列化合物:
2.根据权利要求1所述的式(Ia)的化合物或其互变异构体或其药学上可接受的盐:
3.根据权利要求2所述的式(Ib)的化合物或其互变异构体或其药学上可接受的盐:
4.根据权利要求2所述的式(Ic)的化合物或其互变异构体或其药学上可接受的盐:
5.一种药物组合物,其包含权利要求1-4中任一项所述的化合物或其互变异构体或其药学上可接受的盐,和药学上可接受的载体。
6.根据权利要求1-4任一项所述的化合物或权利要求5所述的药物组合物在制备用于预防和/或治疗高尿酸血症和痛风的药物中的用途。
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Address after: 215028 unit 511, building B2, 218 Xing Hu Street, Suzhou Industrial Park, Suzhou, Jiangsu. Applicant after: Suzhou Sinoway Pharmaceutical Technology Co.,Ltd. Address before: Unit 511, B2 / F, 218 Xinghu street, Suzhou Industrial Park, Suzhou, Jiangsu, China 215028 Applicant before: SUZHOU SINOVENT PHARMA Co.,Ltd. |
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