CN111615515A - 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
- Publication number
- CN111615515A CN111615515A CN201980008657.3A CN201980008657A CN111615515A CN 111615515 A CN111615515 A CN 111615515A CN 201980008657 A CN201980008657 A CN 201980008657A CN 111615515 A CN111615515 A CN 111615515A
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- CN
- China
- Prior art keywords
- methanone
- ethyl
- pyrimidin
- compound
- dibromo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- 239000003814 drug Substances 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 201000005569 Gout Diseases 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 13
- -1 cyano, hydroxy Chemical group 0.000 claims description 87
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 239000000126 substance Substances 0.000 claims description 23
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 16
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 16
- 229910052805 deuterium Inorganic materials 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 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 claims description 8
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 8
- SXRHGLQCOLNZPT-UHFFFAOYSA-N 3,5-dibromo-4-hydroxybenzaldehyde Chemical compound OC1=C(Br)C=C(C=O)C=C1Br SXRHGLQCOLNZPT-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 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 claims description 5
- HJUQTFPZDNRYLD-UHFFFAOYSA-N 3-bromo-5-(2-ethylimidazo[1,2-a]pyrimidine-3-carbonyl)-2-hydroxybenzonitrile Chemical compound CCc1nc2ncccn2c1C(=O)c1cc(Br)c(O)c(c1)C#N HJUQTFPZDNRYLD-UHFFFAOYSA-N 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- 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 claims description 4
- YNKZVRQUZMTLBT-UHFFFAOYSA-N 3-bromo-5-(3-ethyl-6-fluoroimidazo[1,2-a]pyrimidine-2-carbonyl)-2-hydroxybenzonitrile Chemical compound CCc1c(nc2ncc(F)cn12)C(=O)c1cc(Br)c(O)c(c1)C#N YNKZVRQUZMTLBT-UHFFFAOYSA-N 0.000 claims description 4
- CXTZMNYIARMSEG-UHFFFAOYSA-N 3-bromo-5-[2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidine-3-carbonyl]-2-hydroxybenzonitrile Chemical compound CCc1nc2ncc(cn2c1C(=O)c1cc(Br)c(O)c(c1)C#N)C(F)(F)F CXTZMNYIARMSEG-UHFFFAOYSA-N 0.000 claims description 4
- HAEVIJAXGIEUOL-UHFFFAOYSA-N 3-bromo-5-[2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidine-3-carbonyl]-2-hydroxybenzonitrile Chemical compound CCc1nc2nc(ccn2c1C(=O)c1cc(Br)c(O)c(c1)C#N)C(F)(F)F HAEVIJAXGIEUOL-UHFFFAOYSA-N 0.000 claims description 4
- NOYWUNMVOPVLGQ-UHFFFAOYSA-N 3-bromo-5-[3-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidine-2-carbonyl]-2-hydroxybenzonitrile Chemical compound CCc1c(nc2ncc(cn12)C(F)(F)F)C(=O)c1cc(Br)c(O)c(c1)C#N NOYWUNMVOPVLGQ-UHFFFAOYSA-N 0.000 claims description 4
- VPOKXHQSXCAZSH-UHFFFAOYSA-N 5-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidine-3-carbonyl)-2-hydroxybenzene-1,3-dicarbonitrile 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCc1nc2ncc(F)cn2c1C(=O)c1cc(C#N)c(O)c(c1)C#N VPOKXHQSXCAZSH-UHFFFAOYSA-N 0.000 claims description 4
- MHRVHVQIHONKHP-UHFFFAOYSA-N [3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl]-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ncc(F)cn2c1C(=O)c1cc(Br)c(O)c(c1)C(F)(F)F MHRVHVQIHONKHP-UHFFFAOYSA-N 0.000 claims description 4
- DNCBBUHWDVUCBW-UHFFFAOYSA-N [3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl]-(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ncccn2c1C(=O)c1cc(Br)c(O)c(c1)C(F)(F)F DNCBBUHWDVUCBW-UHFFFAOYSA-N 0.000 claims description 4
- OCJOCDQACNBEFC-UHFFFAOYSA-N [3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl]-[2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methanone Chemical compound CCc1nc2ncc(cn2c1C(=O)c1cc(Br)c(O)c(c1)C(F)(F)F)C(F)(F)F OCJOCDQACNBEFC-UHFFFAOYSA-N 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000007333 cyanation reaction Methods 0.000 claims description 4
- GUPSLHBLWJMSRY-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(3-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)methanone Chemical compound CCc1c(nc2ncc(F)cn12)C(=O)c1cc(Br)c(O)c(Br)c1 GUPSLHBLWJMSRY-UHFFFAOYSA-N 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- QMADNBTZTWETKE-UHFFFAOYSA-N (3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound FC1=C(C(=C(C(=C1Br)O)Br)F)C(=O)C1=C(N=C2N1C=C(C=N2)F)CC QMADNBTZTWETKE-UHFFFAOYSA-N 0.000 claims description 2
- DCMZXXCSNDLHDF-UHFFFAOYSA-N (3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-[2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methanone Chemical compound FC1=C(C(=C(C(=C1Br)O)Br)F)C(=O)C1=C(N=C2N1C=C(C=N2)C(F)(F)F)CC DCMZXXCSNDLHDF-UHFFFAOYSA-N 0.000 claims description 2
- KRXGTIRDNFGXQP-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethylimidazo[1,2-c]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ccncn2c1C(=O)c1cc(Br)c(O)c(Br)c1 KRXGTIRDNFGXQP-UHFFFAOYSA-N 0.000 claims description 2
- NGLUHDPPLSTAKG-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethylindazol-3-yl)methanone Chemical compound BrC=1C=C(C=C(C=1O)Br)C(=O)C=1N(N=C2C=CC=CC=12)CC NGLUHDPPLSTAKG-UHFFFAOYSA-N 0.000 claims description 2
- RYWJAPKWLBFPAI-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(7-ethylimidazo[1,2-a][1,3,5]triazin-6-yl)methanone Chemical compound C(C)C=1N=C2N(C=NC=N2)C=1C(=O)C1=CC(=C(C(=C1)Br)O)Br RYWJAPKWLBFPAI-UHFFFAOYSA-N 0.000 claims description 2
- GKERMRWQXLPDSM-UHFFFAOYSA-N (4,6-dibromo-5-hydroxypyridin-2-yl)-(2-ethyl-5-fluoro-1-benzofuran-3-yl)methanone Chemical compound CCc1oc2ccc(F)cc2c1C(=O)c1cc(Br)c(O)c(Br)n1 GKERMRWQXLPDSM-UHFFFAOYSA-N 0.000 claims description 2
- GFUAWCHWCODIEZ-UHFFFAOYSA-N 3-bromo-5-(2-ethylpyrazolo[3,4-d]pyrimidine-3-carbonyl)-2-hydroxybenzonitrile Chemical compound CCn1nc2ncncc2c1C(=O)c1cc(Br)c(O)c(c1)C#N GFUAWCHWCODIEZ-UHFFFAOYSA-N 0.000 claims description 2
- BYRNUNSFWJKPLU-UHFFFAOYSA-N [3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl]-(3-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)methanone Chemical compound BrC=1C=C(C=C(C=1O)C(F)(F)F)C(=O)C=1N=C2N(C=C(C=N2)F)C=1CC BYRNUNSFWJKPLU-UHFFFAOYSA-N 0.000 claims description 2
- RRQBERVXXUSXMR-UHFFFAOYSA-N [3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl]-[3-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-yl]methanone Chemical compound BrC=1C=C(C=C(C=1O)C(F)(F)F)C(=O)C=1N=C2N(C=C(C=N2)C(F)(F)F)C=1CC RRQBERVXXUSXMR-UHFFFAOYSA-N 0.000 claims description 2
- WFSMHMDMPNLBMX-UHFFFAOYSA-N [4-bromo-5-hydroxy-6-(trifluoromethyl)pyridin-2-yl]-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ncc(F)cn2c1C(=O)c1cc(Br)c(O)c(n1)C(F)(F)F WFSMHMDMPNLBMX-UHFFFAOYSA-N 0.000 claims description 2
- OJVPPEVAUJMLBP-UHFFFAOYSA-N [4-bromo-5-hydroxy-6-(trifluoromethyl)pyridin-2-yl]-(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone Chemical compound CCc1nc2ncccn2c1C(=O)c1cc(Br)c(O)c(n1)C(F)(F)F OJVPPEVAUJMLBP-UHFFFAOYSA-N 0.000 claims description 2
- QCLKEOXQQHASGC-UHFFFAOYSA-N [4-bromo-5-hydroxy-6-(trifluoromethyl)pyridin-2-yl]-[2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl]methanone Chemical compound CCc1nc2ncc(cn2c1C(=O)c1cc(Br)c(O)c(n1)C(F)(F)F)C(F)(F)F QCLKEOXQQHASGC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 229940125773 compound 10 Drugs 0.000 claims description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 206
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 133
- 238000006243 chemical reaction Methods 0.000 description 106
- 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 87
- 239000000243 solution Substances 0.000 description 83
- 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 70
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- 239000007787 solid Substances 0.000 description 45
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 44
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- 210000004027 cell Anatomy 0.000 description 42
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 41
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 239000012074 organic phase Substances 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 30
- 238000005160 1H NMR spectroscopy Methods 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 26
- 238000003818 flash chromatography Methods 0.000 description 25
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 24
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- 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 22
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 18
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- 238000002953 preparative HPLC Methods 0.000 description 17
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 16
- 239000002207 metabolite Substances 0.000 description 16
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- ZRSNZINYAWTAHE-UHFFFAOYSA-N Anisaldehyde Natural products COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 15
- 210000003494 hepatocyte Anatomy 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
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- 238000002474 experimental method Methods 0.000 description 13
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- 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 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- QRPUVEAHEMVOOG-UHFFFAOYSA-O (4-hydroxyphenyl)methanone Chemical compound OC1=CC=C([C+]=O)C=C1 QRPUVEAHEMVOOG-UHFFFAOYSA-O 0.000 description 11
- 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
- 125000000217 alkyl group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000012065 filter cake Substances 0.000 description 11
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- 229940116269 uric acid Drugs 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
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- MINRDQDGBLQBGD-UHFFFAOYSA-N pent-2-ynoic acid Chemical compound CCC#CC(O)=O MINRDQDGBLQBGD-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical group C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 description 1
- 229960004818 sulfaphenazole Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 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
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000004797 therapeutic response Effects 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
- 238000012546 transfer Methods 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
- 239000003383 uricosuric agent Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 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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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4353—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C—CHEMISTRY; METALLURGY
- 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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- 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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- 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
- C07D471/04—Ortho-condensed systems
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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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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
PCT国内申请,说明书已公开。
Claims (15)
- PCT国内申请,权利要求书已公开。
Priority Applications (2)
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CN202311394666.5A CN117586272A (zh) | 2018-01-19 | 2019-01-18 | 杂环化合物、制备方法及其在医药上的应用 |
CN202110248844.8A CN112979661B (zh) | 2018-01-19 | 2019-01-18 | 杂环化合物、制备方法及其在医药上的应用 |
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CN2018073493 | 2018-01-19 | ||
CNPCT/CN2018/073493 | 2018-01-19 | ||
PCT/CN2019/072419 WO2019141259A1 (zh) | 2018-01-19 | 2019-01-18 | 杂环化合物、制备方法及其在医药上的应用 |
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CN202110248844.8A Division CN112979661B (zh) | 2018-01-19 | 2019-01-18 | 杂环化合物、制备方法及其在医药上的应用 |
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CN202110248844.8A Active CN112979661B (zh) | 2018-01-19 | 2019-01-18 | 杂环化合物、制备方法及其在医药上的应用 |
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US (1) | US11453674B2 (zh) |
EP (1) | EP3741759B1 (zh) |
JP (1) | JP7266901B2 (zh) |
KR (1) | KR20200112908A (zh) |
CN (3) | CN117586272A (zh) |
AU (1) | AU2019208785B2 (zh) |
CA (1) | CA3088932A1 (zh) |
WO (1) | WO2019141259A1 (zh) |
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JP7266901B2 (ja) | 2018-01-19 | 2023-05-01 | エボポイント、バイオサイエンシズ、カンパニー、リミテッド | 複素環式化合物、調製方法及びその医薬的な応用 |
CN113527236B (zh) * | 2021-08-20 | 2022-12-23 | 苏州弘森药业股份有限公司 | 一种制备盐酸胺碘酮的方法 |
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FR2502622A1 (fr) * | 1981-03-25 | 1982-10-01 | Synthelabo | Derives d'imidazo (1,2-a) pyrimidines, leur preparation et leur application en therapeutique |
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KR20200112908A (ko) | 2020-10-05 |
CA3088932A1 (en) | 2019-07-25 |
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CN117586272A (zh) | 2024-02-23 |
CN112979661A (zh) | 2021-06-18 |
US20200347070A1 (en) | 2020-11-05 |
US11453674B2 (en) | 2022-09-27 |
WO2019141259A1 (zh) | 2019-07-25 |
JP7266901B2 (ja) | 2023-05-01 |
CN111615515B (zh) | 2023-11-24 |
AU2019208785A1 (en) | 2020-09-03 |
EP3741759A1 (en) | 2020-11-25 |
JP2021510719A (ja) | 2021-04-30 |
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AU2019208785B2 (en) | 2023-10-26 |
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