CN101386604A - 抑制黄嘌呤氧化酶活性的芳腈基噻唑衍生物及制备方法和用途 - Google Patents
抑制黄嘌呤氧化酶活性的芳腈基噻唑衍生物及制备方法和用途 Download PDFInfo
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- CN101386604A CN101386604A CNA2008101216544A CN200810121654A CN101386604A CN 101386604 A CN101386604 A CN 101386604A CN A2008101216544 A CNA2008101216544 A CN A2008101216544A CN 200810121654 A CN200810121654 A CN 200810121654A CN 101386604 A CN101386604 A CN 101386604A
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 34
- 230000000694 effects Effects 0.000 title claims abstract description 23
- 108010093894 Xanthine oxidase Proteins 0.000 title claims abstract description 21
- 102100033220 Xanthine oxidase Human genes 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims description 61
- 150000007979 thiazole derivatives Chemical class 0.000 title claims description 31
- 230000002401 inhibitory effect Effects 0.000 title abstract 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 104
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 59
- 235000019253 formic acid Nutrition 0.000 claims abstract description 52
- -1 aryl nitrile group thiazole derivative Chemical class 0.000 claims abstract description 47
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims abstract description 18
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Chemical group CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical group [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims abstract description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- XKPJKVVZOOEMPK-UHFFFAOYSA-M lithium;formate Chemical group [Li+].[O-]C=O XKPJKVVZOOEMPK-UHFFFAOYSA-M 0.000 claims abstract description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical group [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 52
- 229940013688 formic acid Drugs 0.000 claims description 51
- 239000002585 base Substances 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 201000005569 Gout Diseases 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 12
- 239000012141 concentrate Substances 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- RTLVVMJJVHVUEI-UHFFFAOYSA-N C(=S)N.C1=CC=CC=C1 Chemical compound C(=S)N.C1=CC=CC=C1 RTLVVMJJVHVUEI-UHFFFAOYSA-N 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 8
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical group BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 6
- 229910000037 hydrogen sulfide Inorganic materials 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000001347 alkyl bromides Chemical class 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- 230000001012 protector Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- YXZFFTJAHVMMLF-UHFFFAOYSA-N 1-bromo-3-methylbutane Chemical compound CC(C)CCBr YXZFFTJAHVMMLF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- SDZZCOGODKGKBW-UHFFFAOYSA-N bromomethane;cyclopropane Chemical compound BrC.C1CC1 SDZZCOGODKGKBW-UHFFFAOYSA-N 0.000 claims description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 claims description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims description 2
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims description 2
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- 229910018894 PSCl3 Inorganic materials 0.000 claims description 2
- 206010039361 Sacroiliitis Diseases 0.000 claims description 2
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims description 2
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 2
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000005987 sulfurization reaction Methods 0.000 claims description 2
- WQYSXVGEZYESBR-UHFFFAOYSA-N thiophosphoryl chloride Chemical compound ClP(Cl)(Cl)=S WQYSXVGEZYESBR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 10
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 241001465754 Metazoa Species 0.000 abstract description 3
- 229960002708 antigout preparations Drugs 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 abstract 2
- BDJAEZRIGNCQBZ-UHFFFAOYSA-N methylcyclobutane Chemical group CC1CCC1 BDJAEZRIGNCQBZ-UHFFFAOYSA-N 0.000 abstract 2
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical group CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 abstract 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical group CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 abstract 2
- 239000004280 Sodium formate Chemical group 0.000 abstract 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Chemical group CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 abstract 1
- VNXBKJFUJUWOCW-UHFFFAOYSA-N methylcyclopropane Chemical group CC1CC1 VNXBKJFUJUWOCW-UHFFFAOYSA-N 0.000 abstract 1
- 125000002560 nitrile group Chemical group 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 235000019254 sodium formate Nutrition 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 57
- 229910052739 hydrogen Inorganic materials 0.000 description 55
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 29
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 25
- 241000287828 Gallus gallus Species 0.000 description 18
- 235000013330 chicken meat Nutrition 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 10
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 10
- 229940116269 uric acid Drugs 0.000 description 10
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 9
- 238000003810 ethyl acetate extraction Methods 0.000 description 9
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- 239000008280 blood Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 8
- 210000002784 stomach Anatomy 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 6
- YBTJNZFGUXNZMQ-UHFFFAOYSA-N FC(F)(F)[Na] Chemical compound FC(F)(F)[Na] YBTJNZFGUXNZMQ-UHFFFAOYSA-N 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
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- OUOXWNNWFUCGHL-UHFFFAOYSA-N ethyl 3-cyano-4-(3-methylbutoxy)benzoate Chemical compound C(C)OC(C1=CC(=C(C=C1)OCCC(C)C)C#N)=O OUOXWNNWFUCGHL-UHFFFAOYSA-N 0.000 description 3
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- 238000010438 heat treatment Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- YOJAHJGBFDPSDI-UHFFFAOYSA-N methyl 4-nitrobenzoate Chemical class COC(=O)C1=CC=C([N+]([O-])=O)C=C1 YOJAHJGBFDPSDI-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
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- JNDIDDMPBOLGER-UHFFFAOYSA-N 2-methylpropyl 2,2,2-trifluoroacetate Chemical compound CC(C)COC(=O)C(F)(F)F JNDIDDMPBOLGER-UHFFFAOYSA-N 0.000 description 1
- UOUKEYVAKRKVQA-UHFFFAOYSA-N 3-methylbutyl 2,2,2-trifluoroacetate Chemical compound CC(C)CCOC(=O)C(F)(F)F UOUKEYVAKRKVQA-UHFFFAOYSA-N 0.000 description 1
- MHPUGCYGQWGLJL-UHFFFAOYSA-N 5-methyl-hexanoic acid Chemical compound CC(C)CCCC(O)=O MHPUGCYGQWGLJL-UHFFFAOYSA-N 0.000 description 1
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- KJGPAEUTPOVBIL-UHFFFAOYSA-N CC(C)CC[K] Chemical compound CC(C)CC[K] KJGPAEUTPOVBIL-UHFFFAOYSA-N 0.000 description 1
- XLJYGTUUQWFFGT-UHFFFAOYSA-N CC(C)CC[Na] Chemical compound CC(C)CC[Na] XLJYGTUUQWFFGT-UHFFFAOYSA-N 0.000 description 1
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
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- MOLRJCRTZIEBKH-UHFFFAOYSA-N cyclopropane propanoic acid Chemical compound C(CC)(=O)O.C1CC1 MOLRJCRTZIEBKH-UHFFFAOYSA-N 0.000 description 1
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- 206010016256 fatigue Diseases 0.000 description 1
- 229960005101 febuxostat Drugs 0.000 description 1
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 description 1
- 231100000771 fixed dose procedure Toxicity 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-N isocaproic acid Chemical compound CC(C)CCC(O)=O FGKJLKRYENPLQH-UHFFFAOYSA-N 0.000 description 1
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
Description
编号 | R1 | R2 | R3 | 对XOD的半数抑制浓度IC50(ng/ml) |
5a | 异丁基 | 三氟甲基 | 甲酸 | 0.13 |
5b | 环丙烷甲基 | 三氟甲基 | 甲酸 | 0.21 |
5c | 环丁烷甲基 | 三氟甲基 | 甲酸 | 0.39 |
5d | 异戊基 | 三氟甲基 | 甲酸 | 0.19 |
5e | 环戊烷甲基 | 三氟甲基 | 甲酸 | 0.51 |
5f | 环己烷甲基 | 三氟甲基 | 甲酸 | 0.48 |
5g | 环丙烷甲基 | 甲基 | 甲酸 | 0.82 |
5h | 环丁烷甲基 | 甲基 | 甲酸 | 0.86 |
5i | 异戊基 | 甲基 | 甲酸 | 0.92 |
5j | 环戊烷甲基 | 甲基 | 甲酸 | 0.97 |
5k | 环己烷甲基 | 甲基 | 甲酸 | 1.24 |
51 | 异丁基 | 甲基 | 甲酸 | 0.29 |
6a | 异丁基 | 三氟甲基 | 甲酸钠 | 0.10 |
6b | 环丙烷甲基 | 三氟甲基 | 甲酸钠 | 0.17 |
6c | 环丁烷甲基 | 三氟甲基 | 甲酸钠 | 0.28 |
6d | 异戊基 | 三氟甲基 | 甲酸钠 | 0.19 |
6e | 环戊烷甲基 | 三氟甲基 | 甲酸钠 | 0.38 |
6f | 环己烷甲基 | 三氟甲基 | 甲酸钠 | 0.41 |
6g | 环丙烷甲基 | 甲基 | 甲酸钠 | 0.56 |
6h | 环丁烷甲基 | 甲基 | 甲酸钠 | 0.64 |
6i | 异戊基 | 甲基 | 甲酸钠 | 0.98 |
6j | 环戊烷甲基 | 甲基 | 甲酸钠 | 0.71 |
6k | 环己烷甲基 | 甲基 | 甲酸钠 | 0.82 |
61 | 异丁基 | 甲基 | 甲酸钠 | 0.22 |
6m | 异丁基 | 甲基 | 甲酸钾 | 0.21 |
6n | 异丁基 | 甲基 | 甲酸锂 | 0.25 |
化合物 | 给药方式 | LD50 |
5a | 灌胃 | 200mg/kg<LD50<2000mg/kg |
6a | 灌胃 | 200mg/kg<LD50<2000mg/kg |
6l | 灌胃 | 200mg/kg<LD50<2000mg/kg |
5b | 灌胃 | 200mg/kg<LD50<2000mg/kg |
5d | 灌胃 | 200mg/kg<LD50<2000mg/kg |
6b | 灌胃 | 200mg/kg<LD50<2000mg/kg |
6d | 灌胃 | 200mg/kg<LD50<2000mg/kg |
6m | 灌胃 | 200mg/kg<LD50<2000mg/kg |
Claims (8)
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ITMI20091670A1 (it) * | 2009-09-29 | 2011-03-30 | Dipharma Francis Srl | Sali di febuxostat |
WO2011101867A2 (en) | 2010-02-19 | 2011-08-25 | Cadila Healthcare Limited | Substantially pure salts of febuxostat and processes for preparation thereof |
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