WO2019141259A1 - 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
- WO2019141259A1 WO2019141259A1 PCT/CN2019/072419 CN2019072419W WO2019141259A1 WO 2019141259 A1 WO2019141259 A1 WO 2019141259A1 CN 2019072419 W CN2019072419 W CN 2019072419W WO 2019141259 A1 WO2019141259 A1 WO 2019141259A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrimidin
- ethyl
- methanone
- dibromo
- hydroxyphenyl
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 201000005569 Gout Diseases 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 14
- -1 cyano, hydroxy Chemical group 0.000 claims description 89
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 22
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000001188 haloalkyl group Chemical group 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-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
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 12
- 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 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 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 6
- 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
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 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
- 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 5
- 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 5
- 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 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
- 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 5
- 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 5
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- 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
- 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
- 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
- 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
- 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
- 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
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 238000007333 cyanation reaction Methods 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 238000005658 halogenation reaction Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 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 3
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- 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
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- 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
- 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 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
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000004533 oil dispersion Substances 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
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 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
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid group Chemical group C(C=1C(C(=O)O)=CC=CC1)(=O)O XNGIFLGASWRNHJ-UHFFFAOYSA-N 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
- 239000013641 positive control Substances 0.000 description 1
- 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
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 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
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response 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
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 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
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 230000010473 stable expression Effects 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
- 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
- 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
- 238000010257 thawing Methods 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
- 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
- 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
-
- 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
- A61K31/495—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
-
- 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
-
- 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
-
- 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
- A61K31/4439—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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- 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
-
- 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
-
- 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
-
- 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
Definitions
- the present invention relates to a medicament for preventing and/or treating hyperuricemia and gout.
- the present invention relates to a human urate anion transporter (hURAT1) inhibitor, a process for the preparation thereof, and a pharmaceutical composition comprising the same and use thereof.
- hURAT1 human urate anion transporter
- Gout is a group of heterogeneous, metabolic diseases caused by long-term hyperuricemia leading to deposition of urate in joints and soft tissues.
- the normal male blood uric acid is 150-380umol/L, and the female uric acid is 100-300umol/L before menopause. After menopause, the value is close to that of male.
- the saturation concentration of serum uric acid at 37 ° C is about 416 umol / L, above which is hyperuricemia.
- Hyperuricemia is the biochemical basis of gout.
- the drugs for treating hyperuricemia and gout mainly include: anti-inflammatory analgesics for controlling joint swelling and pain such as acute gout, such as non-steroidal anti-inflammatory drugs (NSAID); for inhibiting uric acid production Drugs, such as xanthine oxidase inhibitor febuxostat; drugs for uric acid excretion, such as probenecid and benzbromarone; uric acid decomposition drugs for rapid blood uric acid in acute gout attacks, Such as uric acid enzymes.
- uric acid excretion drugs play an important role in the treatment of hyperuricemia and gout.
- the mechanism of action of this class of drugs is mainly through inhibition of the urate anion on the brush border of epithelial cells located in the proximal convoluted tubules of the kidney.
- Transporter 1 hURAT1
- hURAT1 Transporter 1
- uric acid excretion drugs have more serious side effects.
- benzbromarone has hepatotoxicity and there is a risk of causing fulminant hepatitis.
- benzbromarone is oxidatively metabolized in the body to form two metabolites with an phthalic acid structure, which leads to benzbromarone.
- the direct cause of liver toxicity Specifically, benzbromarone is first oxidized by CYP2C9 in the human body to produce 6-hydroxy benzbromarone, followed by two metabolic pathways: one is continuous oxidation by CYP2C9, and the first is 5,6-dihydroxyphenyl bromide.
- Both phthalate-like metabolites are very chemically active and can be conjugated with a thiol group on a cysteine residue of a protein or polypeptide to alter the spatial structure of the protein or polypeptide, resulting in a protein or polypeptide. Denatured or inactivated.
- hURAT1 human urate anion transporter
- the present invention provides a compound represented by formula (I) and/or formula (II) or a tautomer thereof, and a pharmaceutically acceptable salt thereof,
- ring A is a six-membered aromatic ring or a heteroaryl ring
- ring B is a five-membered heteroaryl ring.
- W 1 is selected from N or O;
- W 2 is selected from CR 6 or NR 7 ;
- W 3 and W 4 are each independently selected from C or N;
- W 5 , W 6 and W 7 are each independently selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 Alkoxy, C 1-20 haloalkyl;
- the condition is to exclude the following:
- W 1 is selected from O
- W 2 , W 3 , W 4 , W 5 , W 6 and W 7 are simultaneously CR 6 ;
- W 1 and W 4 are selected from N
- W 2 is CR 6
- W 3 is C
- W 5 , W 6 and W 7 are simultaneously CR 8 .
- the present invention provides a process for the preparation of a compound of the formula (Ia) and/or formula (Ib) or a tautomer thereof and a pharmaceutically acceptable salt thereof.
- the present invention provides a pharmaceutical composition for preventing or treating hyperuricemia and gout comprising a compound of the formula (Ia) and/or formula (Ib) or a tautomer thereof or a pharmaceutically thereof thereof Acceptable salt.
- the present invention provides a method for treating hyperuricemia and gout comprising the compound of the formula (Ia) and/or formula (Ib) of the present invention or a tautomer thereof and a pharmaceutically acceptable thereof An acceptable salt, or a pharmaceutical composition comprising a compound of the formula (Ia) and/or formula (Ib) or a tautomer thereof and a pharmaceutically acceptable salt thereof, for administration to hyperuricemia Or an individual with gout.
- alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 20 carbon atoms.
- the alkyl group is an alkyl group having from 1 to 12 carbon atoms. More preferably, the alkyl group is an alkyl group having 1 to 6 carbon atoms. Most preferably, the alkyl group is an alkyl group having from 1 to 4 carbon atoms.
- alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl 1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl , 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2- Methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl
- halogen refers to fluoro, chloro, bromo, iodo.
- alkoxy refers to "-O-alkyl", wherein alkyl is as defined above.
- haloalkyl refers to an alkyl group substituted with one or more halogens, wherein halo and alkyl are as defined above.
- tautomer refers to an isomer of a compound that differs from each other at a proton position and/or an electron distribution. It describes proton-transporting tautomers and valency tautomers, and it should be understood that there may be more than two tautomers for a given compound.
- pyrazole, imidazole, benzimidazole, triazole and tetrazole see for example Smith, March's Advanced Organi C Chemistry (5th edition), pages 1218-1223, Wiley-Interscience, 2001; Katritzky A. and Elguero J, et a1., The Tautomerism of Heterocycles, Academi CPress (1976)).
- salts refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound (or can be converted to a form having such activity).
- These salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, trifluoroacetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid , ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, An acid addition salt formed by stearic acid, succinic acid, tartaric acid,
- ammonium and substituted or quaternized ammonium salts are also included in this definition.
- a representative, non-limiting list of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005) at page 732, Table 38-5, both of which are hereby incorporated by reference.
- prevention refers to a regimen that prevents the onset of a disease or disorder such that the clinical symptoms of the disease do not develop.
- "preventing” involves administering a treatment (eg, administration of a therapeutic substance) to an individual prior to detecting an indication of the disease within the individual (eg, administering a therapeutic substance to the individual in the absence of a detectable indication of the disease in the individual) .
- a treatment eg, administration of a therapeutic substance
- An individual can be an individual at risk of developing a disease, such as an individual having one or more risk factors known to be associated with the development or onset of the disease.
- beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in disease severity, delay or slowing of disease progression, improvement or mitigation of disease states, and relief (either in part or in whole), regardless of Is detectable or undetectable.
- “Individual” means humans, livestock (such as dogs and cats), farm animals (such as cattle, horses, sheep, goats, and pigs), experimental animals (such as mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and Monkey) and so on.
- the compounds of the formulae described herein include the disclosed compounds and all pharmaceutically acceptable salts, tautomers, and deuterated forms.
- the present invention discloses a compound of Formula (Ia) and/or Formula (IIa) or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 2 is selected from CR 6 ;
- W 5 , W 6 and W 7 are each independently selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the invention provides a compound of formula (Ib) and/or (IIb), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 5 and W 7 are each independently selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the invention provides a compound of formula (Ic) and/or formula (IIc), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 6 and W 7 are each independently selected from CR 6 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the invention provides a compound of formula (Id) and/or (IId), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 7 is selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the invention provides a compound of formula (Ie) or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 5 , W 6 and W 7 are each independently selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the invention provides a compound of formula (If) or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 2 is selected from CR 6 ;
- W 5 , W 6 and W 7 are each independently selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the invention provides a compound of formula (Ig), or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
- W 2 is selected from CR 6 ;
- W 5 , W 6 and W 7 are each independently selected from CR 8 or N;
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxy, C 1-20 alkyl, C 1-20 alkoxy. , C 1-20 haloalkyl.
- the compound of the invention is selected from the group consisting of
- the invention provides methods of preparing the compounds of the invention:
- Step 1 cyclizing the heteroarylamine compound 1 with the 1,3-diketone compound 2 to obtain an anisole intermediate compound 3; wherein the cyclization reaction is carried out in the presence of a catalyst, preferably, the catalyst comprises two a combination of iodobenzene acetate, bis(trifluoroacetic acid) iodobenzene, and the like; and a boron trifluoride diethyl ether complex;
- Step 2 removing the methyl ether intermediate compound 3 formed in the step 1 in the presence of a catalyst to obtain a phenol compound 4;
- the catalyst is a catalyst commonly used in the field for removing a methyl group from a hydroxyl group, Removal of hydroxyl group-protected methyl groups is described in detail in, but not limited to, boron tribromide, sodium ethoxide, and the like, Greene, TW and Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons. Commonly used catalysts and methods of operation;
- Step 3 The phenol compound 4 obtained in the step 2 is subjected to a halogenation reaction to obtain a phenol compound 5 (X represents a halogen); wherein the halogenating agent contains a halogen element (for example, bromine, iodine), chlorosuccinimide, bromine Substituted succinimide, iodosuccinimide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, etc.;
- a halogen element for example, bromine, iodine
- the first solution may optionally include the following steps:
- Step 4 The phenol compound 5 obtained in the step 3 is further subjected to a cyanation reaction, and one or more halogens on the phenol ring are replaced with a cyano group.
- Step 1 The compound 6 is reacted with the acid halide compound 7 under basic conditions to obtain an anisole intermediate compound 8; wherein the base used may be an inorganic base or an organic base, wherein the inorganic base may be selected from an alkali metal or an alkaline earth metal.
- the base used may be an inorganic base or an organic base, wherein the inorganic base may be selected from an alkali metal or an alkaline earth metal.
- Hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide
- alkali metal or alkaline earth metal carbonate or hydrogencarbonate such as potassium carbonate, carbonic acid
- alkali metal or alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, etc.
- Amino compounds eg sodium amide, sodium hexamethyldisilazide, LDA), n-butyllithium, sec-butyllithium, tert-butyllithium, organic bases may be selected from organic amines commonly found in the art, such as triethylamine, Trimethylamine, pyridine, piperidine, 4-N,N-dimethylaminopyridine, morpholine, N
- Step 2 removing the methyl ether intermediate compound 8 formed in the step 1 in the presence of a catalyst to obtain a phenol compound 9;
- the catalyst is a catalyst commonly used in the field for removing a methyl group from a hydroxyl group, Removal of hydroxyl group-protected methyl groups is described in detail in, but not limited to, boron tribromide, sodium ethoxide, and the like, Greene, TW and Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons. Commonly used catalysts and methods of operation;
- Step 3 The phenol compound 9 obtained in the step 2 is subjected to a halogenation reaction to obtain a phenol compound 10 (X represents a halogen); wherein the halogenating agent contains a halogen element (for example, bromine, iodine), chlorosuccinimide, bromine Substituted succinimide, iodosuccinimide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, etc.;
- a halogen element for example, bromine, iodine
- Option 2 may optionally include the following steps:
- Step 4 The phenol compound 5 obtained in the step 3 is further subjected to a cyanation reaction, and one or more halogens on the phenol ring are replaced with a cyano group.
- the present invention also provides a pharmaceutical composition for preventing and/or treating hyperuricemia and gout comprising a compound of the formula (Ia) and/or formula (Ib) of the present invention Or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the pharmaceutical composition of the present invention comprises from about 90% to about 80% by weight, or from about 80% to about 70% by weight, or from about 70% to about 60% by weight, or from about 60% to about 50% by weight, Or from about 50% to about 40% by weight, or from about 40% to about 30% by weight, or from about 30% to about 20% by weight, or from about 20% to about 10% by weight, or about 10% by weight to About 1.0% by weight, or about 1.0% by weight to about 0.1% by weight, or about 0.1% by weight to about 0.01% by weight of the compound of the formula (Ia) and/or formula (Ib) of the present invention or a mutual mutation thereof
- the pharmaceutically acceptable carrier can be either solid or liquid.
- the solid carrier can be one or more of those used as excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives or encapsulating materials. substance.
- the liquid carrier can be a solvent or a liquid dispersion medium.
- Suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, Acacia gum, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils (eg, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil). ), glycerides, agar, pyrogen-free water, isotonic saline, Ringer's solution, and mixtures thereof.
- polyols eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like
- vegetable oils eg, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil.
- glycerides eg, agar, pyrogen-free water, isotonic saline, Ringer's solution, and mixtures thereof.
- compositions of the invention are generally known, for example, in "Remington: the Science and Pratice of Pharmacy, 19th edition, 1995".
- the preparation of the pharmaceutical compositions of the present invention in a known manner includes conventional methods of mixing, granulating, tableting, coating, dissolving or lyophilizing.
- the therapeutically effective amount of the compound of the present invention or a pharmaceutical composition comprising the same can be easily determined by routine experimentation, and the most effective and convenient route of administration can be determined by routine experimentation.
- compositions of this invention may be administered to a patient or subject in need of treatment in any suitable mode of administration, including buccal administration, parenteral (including subcutaneous, intramuscular, intravenous, intraurethral, and intradermal) administration.
- parenteral including subcutaneous, intramuscular, intravenous, intraurethral, and intradermal
- nasal administration vaginal administration or administration via an implantable reservoir.
- the pharmaceutical composition of the invention is administered orally.
- compositions suitable for oral administration for use in the present invention include solid forms such as pills, tablets, caplets, capsules (including immediate release formulations, time release formulations and sustained release formulations, respectively), granules and powders; and liquids Forms such as solutions, syrups, elixirs, emulsions and suspensions.
- forms for ocular administration include sterile solutions or ocular delivery devices.
- Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
- the dosage of the pharmaceutical composition of the present invention to be administered depends on various factors including the age, weight and condition of the patient and the route of administration. The precise dose administered is determined based on the judgment of the treating physician.
- the actual dosage level and time course of administration of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve the following amounts of active ingredient which are effective to achieve the desired condition for the particular patient, composition and mode of administration.
- the response is treated without toxicity to the patient.
- the agents or pharmaceutical compositions of the invention are administered in an amount sufficient to reduce or eliminate the symptoms associated with bacterial infection.
- the preferred dosage of the agent or pharmaceutical composition of the invention is the maximum amount that the patient can withstand and does not produce serious or unacceptable side effects.
- Exemplary dosage ranges include 0.01 mg to 250 mg/day, 0.01 mg to 100 mg/day, 1 mg to 100 mg/day, 10 mg to 100 mg/day, 1 mg to 10 mg/day, and 0.01 mg to 10 mg/day.
- the preferred dosage of the agent is the maximum amount that the patient can withstand and does not produce serious or unacceptable side effects.
- the agent is administered at a concentration of from about 10 micrograms to about 100 mg/kg body weight per day, from about 0.1 to about 10 mg/kg/day, or from about 1.0 mg to about 10 mg/kg body weight per day.
- the therapeutically effective dose produces a serum concentration of the agent from about 0.1 ng/ml to about 50-100 mg/ml.
- These pharmaceutical compositions should typically provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
- the dose for systemic administration to a human patient may range from 1-10 mg/kg, 20-80 mg/kg, 5-50 mg/kg, 75-150 mg/kg, 100-500 mg/kg, 250-750 mg/kg.
- the pharmaceutical unit dosage form is prepared to provide a compound or combination of essential ingredients from about 1 mg to about 5000 mg (e.g., from about 100 mg to about 2500 mg) per unit dosage form.
- Preferred unit dosage formulations are those containing the daily dose or unit, daily sub-dose, or suitable fraction thereof as discussed herein.
- Step 4 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethylfuro[3,2-c]pyridin-3-yl)methanone
- Step 2 Synthesis of (2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 3 Synthesis of (2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(4-hydroxyphenyl)methanone
- Step 4 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)methanone
- Step 1 Synthesis of (6-bromo-2-ethylimidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 3 Synthesis of (6-bromo-2-ethylimidazo[1,2-a]pyrimidin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone
- N-N-(6-bromo-2-ethylimidazo[1,2-a]pyrimidin-3-yl)(4-hydroxyphenyl)methanone 100 mg, 0.289 mmol
- N-Bromosuccinimide 51 mg, 0.289 mmol
- the reaction solution was warmed to room temperature and stirred for 2 hr then concentrated.
- Step 1 Synthesis of (2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 3 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)methanone
- Step 1 Synthesis of (2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 2 Synthesis of (2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(4-hydroxyphenyl)methanone
- Step 3 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)methanone
- Step 1 Synthesis of (6-chloro-2-ethylimidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 3 Synthesis of (6-chloro-2-ethylimidazo[1,2-a]pyrimidin-3-yl)(3,5-dibromo-4-hydroxyphenyl)-methanone
- N,N (6-chloro-2-ethylimidazo[1,2-a]pyrimidin-3-yl)(4-hydroxyphenyl)-methanone (50 mg, 0.17 mmol) at 0 °C N-Bromosuccinimide (75 mg, 0.42 mmol) was slowly added to a solution of dimethylformamide (3.0 mL). The reaction solution was warmed to room temperature and stirred for 2 hr then concentrated.
- Step 1 Synthesis of (2-ethyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 3 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-3-yl)methanone
- Step 2 Synthesis of (2-ethyl-5-fluoro-2H-indazol-3-yl)(5-methoxypyridin-2-yl)methanone
- Step 4 Synthesis of (4,6-dibromo-5-hydroxypyridin-2-yl)(2-ethyl-5-fluoro-2H-indazol-3-yl)methanone
- Step 3 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-5-fluoro-2H-indazol-3-yl)methanone
- Step 3 Synthesis of (2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(3-iodo-4-methoxyphenyl)methanone
- Step 4 Synthesis of (2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(3-iodo-4-hydroxyphenyl)methanone
- Step 6 Synthesis of 3-bromo-5-(2-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-carbonyl)-2-hydroxybenzonitrile
- Step 1 Synthesis of 5-(3-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-carbonyl)-2-hydroxybenzonitrile
- Step 2 Synthesis of 3-bromo-5-(3-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-carbonyl)-2-hydroxybenzonitrile
- N-N-N-N-N-N-N-6-(3-ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-2-carbonyl)-2-hydroxybenzonitrile 150 mg, 0.417 mmol
- N-Bromosuccinimide 148 mg, 0.833 mmol
- the reaction solution was stirred at room temperature for 1 hour and concentrated.
- Step 1 3-bromo-5-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-carbonyl)-2-hydroxybenzonitrile and 5-(2-ethyl-6 Synthesis of fluoroimidazo[1,2-a]pyrimidin-3-carbonyl)-2-hydroxyisophthalonitrile 2,2,2-trifluoroacetate
- Step 1 3-bromo-5-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-carbonyl)-2-hydroxybenzonitrile and (3,5-bromo-4- Synthesis of hydroxyphenyl)(3-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-2-yl)methanone
- Step 3 Synthesis of (2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)(3-iodo-4-methoxyphenyl)methanone
- Step 4 Synthesis of (2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)(4-hydroxy-3-iodophenyl)methanone
- N-N-dimethylformamide 5-(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-carbonyl)-2-hydroxybenzonitrile 910 mg, 2.93 mmol
- N-bromosuccinimide 627 mg, 3.5 mmol
- the reaction was stirred at room temperature for 1 h then quenched with water (25 mL).
- the reaction was filtered and the filter cake was washed with water (30 mL)
- the filtrate was extracted with ethyl acetate (30 mL ⁇ 4) and then evaporated.
- the residue was diluted with EtOAc (EtOAc) (EtOAc)EtOAc.
- N-N-dimethylformamide 5-(3-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-2-carbonyl)-2-hydroxybenzonitrile (500 mg, 1.61 mmol) N-bromosuccinimide (574 mg, 3.22 mmol) was added to the (3 mL) solution. The reaction was stirred at room temperature for 1 h then quenched with water (20 mL).
- Step 5 Synthesis of (2-ethyl-2H-pyrazolo[4,3-c]pyridin-3-yl)(4-methoxyphenyl)methanone
- Step 7 Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-2H-pyrazolo[4,3-c]pyridin-3-yl)methanone
- Step 1 Synthesis of 3-bromo-5-(2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-carbonyl)-2-hydroxybenzonitrile
- Step 2 Synthesis of (2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)(4-methoxy-3-(trifluoromethyl)phenyl)methanone
- Step 3 Synthesis of (2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)(4-hydroxy-3-(trifluoromethyl)phenyl)methanone
- Step 4 (3-Bromo-4-hydroxy-5-(trifluoromethyl)phenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyrimidin-3-yl)methanone synthesis
- Step 2 (2-Ethyl-6-(trifluoromethyl)imidazo[1,2-a]pyrimidin-3-yl)(4-hydroxy-3-(trifluoromethyl)phenyl)methanone
- N-Bromosuccinimide 120 mg, 0.67 mmol was slowly added to a solution of ketone (90 mg, 0.22 mmol) in N,N-dimethylformamide (4.5 mL). The reaction solution was stirred at room temperature for 2 hr then concentrated.
- Step 1 Synthesis of (7-chloro-2-ethylimidazo[1,2-f]pyrimidin-3-yl)(4-methoxyphenyl)methanone
- Step 3 Synthesis of (7-chloro-2-ethylimidazo[1,2-f]pyrimidin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone
- NBS (120 mg, 0.66 mmol) was added to (7-chloro-2-ethylimidazo[1,2-f]pyrimidin-3-yl)(4-hydroxyphenyl)methanone (100 mg) under a nitrogen atmosphere. , 0.33 mmol) in a MeCN solution (10 mL). The resulting mixture was stirred at room temperature for 2 hours.
- the crude product was purified by preparative HPLC, column: X-select CSH OBD column 30*150mm 5 um n; mobile phase A: water (0.1% FA), mobile phase B: CAN; flow rate: 60 mL/min; gradient: 47% B to 57% B (within 7 minutes); 254; 220 nm; Rt: 7.12 min.
- Step 3 Synthesis of (2-ethylimidazo[1,2-a]pyrimidin-3-yl)(3-iodo-4-methoxyphenyl)methanone
- Step 3 Synthesis of (2-ethylimidazo[1,2-a]pyrimidin-3-yl)(4-methoxy-3-(trifluoromethyl)phenyl)methanone
- Step 4 Synthesis of (4-hydroxy-3-(trifluoromethyl)phenyl)(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone
- Step 5 Synthesis of (3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl)(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone
- reaction mixture was concentrated and passed through preparative HPLC (column: SunFire C18 OBD preparative column; 5 ⁇ m, 19 mm X 250 mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL/min; gradient: 50% B to 50% B (within 7 minutes); 254/220 nm; Rt: Purification afforded the desired product (3-bromo-4-hydroxy-5-(trifluoromethyl)phenyl)(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone (3.2 mg).
- Example 24 Inhibition test of compound on hURAT1 in HEK293 transfected cell line
- HEK-293T cell line stably expressing hURAT1 was cultured, and the medium composition was: DMEM medium + 10% fetal bovine serum + 500 ⁇ g/ml G418 + 1% P/S.
- microplate was sent to a MicroBeta Trilux (manufactured by PerkinElmer) instrument for measuring radioactivity.
- Example 25 Inhibition test of compound on OAT1/OAT3 target in HEK293 transfected cell line
- Resuscitation medium 90% DMEM + 10% FBS + 1X Pen / Strep, stored at 4 ° C for use.
- Cell culture medium 90% DMEM + 10% FBS + 1X Pen / Strep + 100 ⁇ g / mL Hygromycin B, stored at 4 ° C for use.
- 5X Matrigel One bottle of Matrigel was thawed at 4 ° C overnight, diluted to 500 mL with cold DMEM, and stored at 4 ° C after dispensing.
- Uptake assay buffer 487.5 mL HBSS buffer + 12.5 mL 1 M HEPES, final concentration of HEPES 25 mM, pre-experimental configuration.
- the cells requiring resuscitation were quickly removed from the liquid nitrogen tank and shaken continuously in a 37 ° C water bath until they were all melted.
- the cell suspension was quickly added to the preheated medium, placed in a centrifuge, centrifuged at 1000 rpm for 5 minutes. The centrifuge tube was taken out, the supernatant was discarded, fresh pre-warmed medium was added to the tube, the cells were resuspended, the cell suspension was added to a 100 mm dish, and cultured at 37 ° C, 5% CO 2 .
- Trypsin-EDTA digests the cells, and the cells are resuspended in a new medium. Typically, they are passaged 1:3 to 1:5 every 2 to 3 days.
- 5 ⁇ Matrigel 5 ⁇ L/well was added to a 384-well cell plate, and incubated at 37° C. for 30 minutes.
- the cell pellet was collected by digestion, counted, resuspended to 1 ⁇ 10 6 cells/mL with medium, and added to the coated cell plate at 60 ⁇ L per well using Multidrop Combi to a cell density of 6 ⁇ 10 4 cells/well, 37°C. Incubate overnight with 5% CO 2 .
- the cell plates were washed 3 times with 80 ⁇ L per well using pre-cooled Uptake assay buffer to remove free unabsorbed 6-CF.
- the board is read on Envision, the recorded data is collected, and the calculation IC50 is processed.
- the inhibition rate (%) of the compound in each well on the cell plate was calculated from the fluorescence signal values of HPE and ZPE on each cell plate.
- HPE contained a high concentration of positive compound (400 ⁇ M of probenecid) as a 100% inhibition control;
- ZPE did not contain any compound, only DMSO (1% DMSO) as a solvent for the compound, a 0% inhibition control.
- the inhibition rate is calculated as follows:
- Inhibition % 100-(I compound -I HPE )/(I ZPE -I HPE ) ⁇ 100
- IC 50 values of the compounds are also one of the criteria for measuring the quality of each experiment. See Table 1 for the results.
- Test material name and source are Test material name and source:
- Human primary hepatocytes were purchased from Bioreclamation IVT. (lot: AKB/S1391); in vitro human primary cell culture media components and suppliers are as follows:
- test compound or control drug benzbromarone with different concentration gradients in medium containing 10% FBS, and add as 100 ⁇ L/well as test compound well or control drug well; add 10% at 100 ⁇ L/well The medium of FBS was used as a negative control well. Incubate for 48 h at 37 ° C in a 5% CO 2 incubator.
- the chemiluminescence values of the test compound wells are represented by F (test compound); the chemiluminescence values of the blank control wells are represented by F (blank control); the chemiluminescence values of the negative control wells are represented by F (negative control).
- F test compound
- F blank control
- F negative control
- the cell viability at different drug concentrations was calculated according to the following formula, and each concentration was repeatedly measured 3 times to obtain an average value and a standard deviation.
- Example 27 Evaluation of the inhibitory effect of compounds on CYP2C9 enzyme
- the experiment was carried out in 100 mM phosphate buffer for a total volume of 200 ⁇ L.
- the concentration of the microsomes in the reaction system was 0.25 mg/mL, and the concentration of the test compound was 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0 ⁇ M, and the CYP2C9-specific probe substrate and the concentration of 10 ⁇ M diclofenac.
- the incubation system was pre-incubated for 5 minutes in a 37-degree constant temperature shaker, and the reaction was started by adding a NADPH-producing system (containing 1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 0.4 U/L glucose 6-phosphate dehydrogenase, 3.3 mM MgCl 2 ).
- the compounds of Examples 4, 5, 14, 20, and 21 of the present invention have only strong inhibition or no inhibition on various CYP enzymes, and their IC50 is higher than that of benzbromarone.
- Example 28 Metabolites of Compounds in Human and Rat Hepatocyte Incubation Systems
- Stock solution Weigh the appropriate amount of test powder, add DMSO or other suitable solvent, dissolve and mix evenly to obtain a stock solution with a concentration of 10 mM and store in a refrigerator at 4 °C for use.
- Working solution Dilute 10 mM stock solution with acetonitrile to 1 mM working solution, mix and set aside.
- An acetonitrile solution containing 0.1% formic acid was prepared as a stop solution and placed in a refrigerator at 4 ° C for use.
- the frozen hepatocytes were taken out, thawed in a 37 ° C water bath (about 90 s), and then quickly poured into the pre-warmed cell separation solution, and the residual hepatocytes were washed with the cell separation solution, combined and mixed, and centrifuged at room temperature for 100 ⁇ g. , centrifuge for 5 min. The supernatant was discarded and the pellet was resuspended with pre-warmed William'Medium E. 20 ⁇ L of hepatocyte suspension was added, stained with 100 ⁇ L of 0.4% phenol blue, and the cells were counted, and the cell survival rate was required to be greater than 70%. Hepatocyte density was adjusted to 1.25 x 106 cells/mL using William'Medium E.
- the residue is reconstituted with a suitable solution, centrifuged at least 10,000 x g for at least 15 minutes at room temperature, and the supernatant is removed to a sample analysis plate for LC-MS analysis.
- the acquired mass spectrometry data was processed using MetaboLynx or Compound Discoverer software. Potential metabolites are screened according to the appropriate parameters of the chemical structure of the test article.
- the software-processed data is further screened for metabolites associated with the test article.
- the possible structure of the metabolite is presumed by comparing and analyzing the fragments of the test article (parent drug) and metabolites.
- the collected blood samples were centrifuged at 12000 rpm for 5 minutes at 4 ° C, then the upper plasma samples were collected and stored in a refrigerator at -20 ° C for testing.
- LC-MS/MS liquid phase Waters Acquity UPLC (USA) and mass spectrometry 5500Q Trap (Applied Biosystem/MDS SCIEX) or HPLC-MS ⁇ MS: liquid phase Agilent 1200 series (USA) and mass spectrometry API 4000 (Applied Biosystem/MDS SCIEX) detects the concentration of compounds in plasma.
- the compounds of Examples 4, 5, 14, 20, 21 which have been determined in the present invention all exhibit good bioavailability (>30%).
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Abstract
Description
化合物 | IC 50,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 |
Claims (15)
- 一种通式I和/或II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环是六元芳环或杂芳环,B环是五元杂芳环,W 1选自N或O;W 2选自CR 6或NR 7;W 3和W 4各自独立地选自C或N;W 5、W 6和W 7各自独立地选自CR 8或N;R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8各自独立地选自氢、氘、卤素、氰基、羟基、C 1-20烷基、C 1-20烷氧基、C 1-20卤代烷基;条件是排除下列情况:当W 1选自O的时候,W 2、W 3、W 4、W 5、W 6和W 7同时为CR 6;当W 1和W 4选自N的时候,W 2为CR 6,W 3为C,W 5、W 6和W 7同时为CR 8。
- 根据权利要求1所述的化合物或其互变异构体或其药学上可接受的盐:(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。
- 根据权利要求8所述通式(Ia)和/或(Ib)所示的化合物的制备方法,其中,所述方法进一步包括: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。
- 根据权利要求10所述通式(Ia)和/或(Ib)所示的化合物的制备方法,其中,所述方法进一步包括: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。
- 一种药物组合物,其包含权利要求1-8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。
- 根据权利要求1-8任一项所述的化合物和权利要求12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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