WO2023208108A1 - 可用于降尿酸的化合物 - Google Patents
可用于降尿酸的化合物 Download PDFInfo
- Publication number
- WO2023208108A1 WO2023208108A1 PCT/CN2023/091140 CN2023091140W WO2023208108A1 WO 2023208108 A1 WO2023208108 A1 WO 2023208108A1 CN 2023091140 W CN2023091140 W CN 2023091140W WO 2023208108 A1 WO2023208108 A1 WO 2023208108A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- substituted
- compound
- cyano
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 69
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 title abstract description 33
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 title abstract description 30
- 229940116269 uric acid Drugs 0.000 title abstract description 30
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 229960002708 antigout preparations Drugs 0.000 claims abstract description 4
- -1 nitrooxy, carboxyl Chemical group 0.000 claims description 101
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 229940079593 drug Drugs 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 33
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 22
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 20
- 229910052805 deuterium Inorganic materials 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 125000004185 ester group Chemical group 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 7
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical group O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 claims description 6
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 150000003235 pyrrolidines Chemical class 0.000 claims description 2
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical class C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 2
- 150000003572 thiolanes Chemical class 0.000 claims description 2
- 210000002966 serum Anatomy 0.000 abstract description 17
- 238000002560 therapeutic procedure Methods 0.000 abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- 238000003786 synthesis reaction Methods 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 230000015572 biosynthetic process Effects 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000203 mixture Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 23
- 241000700159 Rattus Species 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 239000002994 raw material Substances 0.000 description 19
- 230000002194 synthesizing effect Effects 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 17
- 229910002027 silica gel Inorganic materials 0.000 description 17
- 201000005569 Gout Diseases 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229940125810 compound 20 Drugs 0.000 description 14
- 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 14
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- 229960003459 allopurinol Drugs 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- 238000010828 elution Methods 0.000 description 13
- 108010093894 Xanthine oxidase Proteins 0.000 description 12
- 102100033220 Xanthine oxidase Human genes 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 229960005101 febuxostat Drugs 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IAPCTXZQXAVYNG-UHFFFAOYSA-M Potassium 2,6-dihydroxytriazinecarboxylate Chemical compound [K+].[O-]C(=O)C1=NC(=O)NC(=O)N1 IAPCTXZQXAVYNG-UHFFFAOYSA-M 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 229950000193 oteracil Drugs 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- LPFAZORIHIYBNC-UHFFFAOYSA-N CC(C)N(C(C1=C2)=CC=C2C2=NC=CC(C(O)=O)=C2)N=C1C#N Chemical compound CC(C)N(C(C1=C2)=CC=C2C2=NC=CC(C(O)=O)=C2)N=C1C#N LPFAZORIHIYBNC-UHFFFAOYSA-N 0.000 description 7
- FAUVUUMRZYCBCH-UHFFFAOYSA-N CC(C)N(C(C1=C2)=CC=C2N2N=CC(C(O)=O)=C2)N=C1C#N Chemical compound CC(C)N(C(C1=C2)=CC=C2N2N=CC(C(O)=O)=C2)N=C1C#N FAUVUUMRZYCBCH-UHFFFAOYSA-N 0.000 description 7
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 7
- 229940126208 compound 22 Drugs 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 6
- CQZBGDRKNGLQAR-UHFFFAOYSA-N CC(C)N(C(C1=C2)=CC=C2Br)N=C1C#N Chemical compound CC(C)N(C(C1=C2)=CC=C2Br)N=C1C#N CQZBGDRKNGLQAR-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229960002529 benzbromarone Drugs 0.000 description 6
- 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 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000002526 effect on cardiovascular system Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- OOCCDEMITAIZTP-QPJJXVBHSA-N (E)-cinnamyl alcohol Chemical compound OC\C=C\C1=CC=CC=C1 OOCCDEMITAIZTP-QPJJXVBHSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 108010092464 Urate Oxidase Proteins 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229940126585 therapeutic drug Drugs 0.000 description 3
- 229940075420 xanthine Drugs 0.000 description 3
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- GCKBVYBCFQGKGP-UHFFFAOYSA-N (3-hydroxyphenyl)methyl nitrate Chemical compound OC1=CC=CC(CO[N+]([O-])=O)=C1 GCKBVYBCFQGKGP-UHFFFAOYSA-N 0.000 description 2
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 2
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- HGBDENWEGVXBJB-UHFFFAOYSA-N 1-chloroethyl 2-methylpropanoate Chemical compound CC(C)C(=O)OC(C)Cl HGBDENWEGVXBJB-UHFFFAOYSA-N 0.000 description 2
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-Hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- HXDLWJWIAHWIKI-UHFFFAOYSA-N 2-hydroxyethyl acetate Chemical compound CC(=O)OCCO HXDLWJWIAHWIKI-UHFFFAOYSA-N 0.000 description 2
- QCLFSYYUWPUWQR-UHFFFAOYSA-N 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1CCl QCLFSYYUWPUWQR-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- FBOGSWRRYABFKU-UHFFFAOYSA-N 4-hydroxybutyl nitrate Chemical compound OCCCCO[N+]([O-])=O FBOGSWRRYABFKU-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920001304 Solutol HS 15 Polymers 0.000 description 2
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 description 2
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- OOCCDEMITAIZTP-UHFFFAOYSA-N allylic benzylic alcohol Natural products OCC=CC1=CC=CC=C1 OOCCDEMITAIZTP-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 230000003749 cleanliness Effects 0.000 description 2
- 229940125807 compound 37 Drugs 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 229940126540 compound 41 Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003651 drinking water Substances 0.000 description 2
- 235000020188 drinking water Nutrition 0.000 description 2
- 208000009743 drug hypersensitivity syndrome Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 229920000669 heparin Polymers 0.000 description 2
- 231100000304 hepatotoxicity Toxicity 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229960003838 lesinurad Drugs 0.000 description 2
- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007056 liver toxicity Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000010197 meta-analysis Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229960003081 probenecid Drugs 0.000 description 2
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910001961 silver nitrate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 229910021642 ultra pure water Inorganic materials 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940005267 urate oxidase Drugs 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- SSJXIUAHEKJCMH-WDSKDSINSA-N (1s,2s)-cyclohexane-1,2-diamine Chemical compound N[C@H]1CCCC[C@@H]1N SSJXIUAHEKJCMH-WDSKDSINSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- YVRGKFXJZCTTRB-UHFFFAOYSA-N 1-chloroethyl ethyl carbonate Chemical compound CCOC(=O)OC(C)Cl YVRGKFXJZCTTRB-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JHQONOCFAYZOEQ-UHFFFAOYSA-N 3-(bromomethyl)phenol Chemical compound OC1=CC=CC(CBr)=C1 JHQONOCFAYZOEQ-UHFFFAOYSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UOABIRUEGSGTSA-UHFFFAOYSA-N 4-bromobutyl acetate Chemical compound CC(=O)OCCCCBr UOABIRUEGSGTSA-UHFFFAOYSA-N 0.000 description 1
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- QIULWQLXNFSZJG-UHFFFAOYSA-N 5-bromo-1h-indazole-3-carbonitrile Chemical compound BrC1=CC=C2NN=C(C#N)C2=C1 QIULWQLXNFSZJG-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 101000796092 Arabidopsis thaliana Sodium-dependent phosphate transport protein 1, chloroplastic Proteins 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010073508 Drug reaction with eosinophilia and systemic symptoms Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 101001094043 Homo sapiens Solute carrier family 26 member 6 Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KFNNIILCVOLYIR-UHFFFAOYSA-N Propyl formate Chemical compound CCCOC=O KFNNIILCVOLYIR-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010037127 Pseudolymphoma Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102100030935 Solute carrier family 2, facilitated glucose transporter member 9 Human genes 0.000 description 1
- 102100035281 Solute carrier family 26 member 6 Human genes 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010044223 Toxic epidermal necrolysis Diseases 0.000 description 1
- 231100000087 Toxic epidermal necrolysis Toxicity 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 229940083914 URAT1 inhibitor Drugs 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 231100000060 cardiovascular toxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 1
- 230000001587 cholestatic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000003870 depth resolved spectroscopy Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 208000022143 drug rash with eosinophilia and systemic symptoms Diseases 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- KACZQOKEFKFNDB-UHFFFAOYSA-N ethyl 1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1 KACZQOKEFKFNDB-UHFFFAOYSA-N 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 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 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 231100001022 leukopenia Toxicity 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- MZMWAPNVRMDIPS-RQJHMYQMSA-N methyl (2s,3r)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoate Chemical compound COC(=O)[C@H]([C@@H](C)O)NC(=O)OC(C)(C)C MZMWAPNVRMDIPS-RQJHMYQMSA-N 0.000 description 1
- OLXYLDUSSBULGU-UHFFFAOYSA-N methyl pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1 OLXYLDUSSBULGU-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- DGOURJVMLMKIPE-UHFFFAOYSA-N propan-2-yl 1h-pyrazole-4-carboxylate Chemical compound CC(C)OC(=O)C=1C=NNC=1 DGOURJVMLMKIPE-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 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
- 206010037844 rash Diseases 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 208000016261 weight loss Diseases 0.000 description 1
- 150000003952 β-lactams Chemical class 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
- A61K31/41—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
- A61K31/4155—1,2-Diazoles non condensed and containing further 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
- A61K31/41—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
- A61K31/4192—1,2,3-Triazoles
-
- 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
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
-
- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention belongs to the field of medical technology, and specifically relates to a class of compounds that can be used to lower uric acid.
- Xanthine oxidase is an important target for drug treatment of hyperuricemia and gout. Hypoxanthine in the human body will be metabolized into xanthine, and xanthine is further metabolized into uric acid. In the process of uric acid formation, XO plays a decisive role. When the activity of XO is inhibited, hypoxanthine, xanthine and uric acid will The conversion between them will be inhibited, thereby reducing the concentration of uric acid in human serum. Therefore, inhibiting the activity of XO has become the key to inhibiting uric acid production.
- hyperuricemia blood uric acid levels exceeding 420 ⁇ mol/L in men and 360 ⁇ mol/L in women are called hyperuricemia.
- hyperuricemia has become the second largest metabolic disease after diabetes, seriously threatening human health.
- Hyperuricemia is not only an important biochemical basis for gout, but is also closely related to the occurrence of hypertension, hyperlipidemia, atherosclerosis, obesity, and insulin resistance.
- the prevalence of gout among adults in the United States was 3.9% (approximately 8.3 million people) from 2007 to 2008 (Zhu Y, Pandya BJ, Choi HK.
- urate anion transporter 1 URAT1
- xanthine oxidase inhibitors urate oxidase
- URAT1 inhibitors mainly act on the urate transporter in the renal proximal tubule, inhibiting the reabsorption of uric acid and increasing its excretion, thereby reducing the concentration of uric acid in the body.
- Drugs in this class include benzbromarone, lesinurad, and probenecid.
- Benzbromarone is an effective uricosuric drug that has been approved for marketing in many countries, but has not been approved in the United States. Benzbromarone was withdrawn from the market in some European countries in 2003 due to severe liver toxicity.
- benzbromarone As a first-line uric acid-lowering drug. Lesinurad was approved for marketing in the United States in 2015. Its drug instructions include a black box warning that it may cause acute renal failure and cardiovascular disease risks (possibly fatal), and its efficacy is far inferior to benzbromarone, and it needs to be combined with allopurinol. use.
- Probenecid is recommended as a single drug for reducing urinary symptoms in the US guidelines
- Uric acid excretion drugs are the first choice in acid treatment, but their application is limited due to multiple significant interactions with some commonly used drugs (such as nonsteroidal anti-inflammatory drugs, ⁇ -lactam drugs, heparin, etc.) .
- Xanthine oxidase inhibitors mainly include allopurinol and febuxostat. Allopurinol has been widely used clinically since it was approved by the US FDA in 1966. Currently, this drug is still recommended as the first-line drug for the treatment of gout in most countries’ gout guidelines. However, allopurinol has poor efficacy. It only inhibits XO in the reduced state and has no effect on XO in the oxidized state. Relevant studies have shown that even if allopurinol is used at the maximum dose, the rate of subjects reaching the treatment endpoint is less than 50%. (Robert M, Douglas CA, Scott B.
- allopurinol induces acute liver damage , allopurinol should be used with caution when treating patients with hyperuricemia combined with liver disease (Imai H, Kamei H, Onishi Y, et al. Successful living-donor liver transplantation for cholestatic liver failure induced by allopurinol:case report[J] .Transplantation Proceedings, 2015,47(9):2778-2781).
- Other side effects of allopurinol include stomach discomfort, nausea, abdominal pain, diarrhea, leukopenia and thrombocytopenia, headache, fever, loss of appetite, weight loss, and urination Pain, hematuria, itching, and drowsiness.
- Febuxostat is a non-purine XO inhibitor developed by Teijin Company of Japan. It can inhibit the oxidation and reduction states of XO, and its activity is significantly higher than that of allopurinol. It was launched in Europe in 2008 and in the United States in 2009. With the continuous expansion of clinical application of febuxostat, its cardiovascular adverse reactions in the treatment of hyperuricemia are increasingly reported, and due to its cardiovascular toxicity (such as the risk of sudden death), the United States The Food and Drug Administration requires the addition of a black box risk warning to its drug inserts, and will adjust the prescription information in 2019 from first-line drugs to second-line drugs.
- Polyethylene glycol recombinant uricase is the main urate oxidase drug currently on the market and is administered via intravenous injection.
- the FDA has multiple black box warnings for this drug, and severe immune allergic side effects occur in 20%-40% of patients. Its efficacy is average, with only 47% of patients reaching the treatment endpoint of less than 0.36mmol/L.
- the object of the present invention is to provide a compound with xanthine oxidase inhibitory activity based on the existing technology.
- Another object of the present invention is to provide the use of the above compounds in the medical field.
- the object of the present invention can be achieved by the following measures:
- R is C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 heterocycloalkyl or substituted C 3- 6 heterocycloalkyl; wherein the substituents in each group involved in R are selected from deuterium, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring One or more types of alkyl or C 3-6 heterocycloalkyl;
- Ar is a substituted or unsubstituted following group:
- the substituent in the Ar group is selected from one or more of deuterium, hydroxyl, halogen, C 1-4 alkyl or C 1-4 alkoxy;
- Y is O or NR 3 ,
- R 1 is a connecting bond or a substituted or unsubstituted C 1-6 alkylene group or a substituted or unsubstituted C 2-12 alkenylene group.
- the substituent in the R 1 group is selected from deuterium, hydroxyl, amino, and cyano. , one or more of halogen, C 1-4 alkyl or C 1-4 alkoxy;
- R 2 is hydrogen, nitrooxy, carboxyl or the following substituted or unsubstituted groups: dioxole-2-one group, C 4-12 condensed heteroaromatic ring group, C 4-16 condensed hetero group Arylpyrazolylcarbonyloxy, C 4-16 fused heteroaromatic pyridylcarbonyloxy, C 4-16 fused heteroaromatic triazolylcarbonyloxy, C 2-6 ester group, pyridine base, phenyl, C 1-6 alkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 2-8 alkylcarbonyloxy or C 2-8 alkoxycarbonyloxy, R 2 The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, halo-substituted C 1-6 alkyl, nitrooxy-substituted C 1-6 alkyl or C 1 -6 One or more alkoxy groups;
- R 3 is hydrogen or C 1-6 alkyl.
- the compound of the present invention is selected from the group consisting of compounds represented by the general formula (II), (III) or (IV),
- Y is O or NH.
- R is C 3-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 heterocycloalkyl group or substituted C 3-6 heterocycloalkyl; wherein the substituents in each group involved in R are selected from deuterium, cyano, nitro, halogen, C 1-5 alkyl, C 1-5 alkoxy One or more of C 3-6 cycloalkyl groups.
- R is C 3-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrofuran Hydrothiophene, substituted tetrahydrothiophene, tetrahydropyrrole or substituted tetrahydropyrrole; wherein the substituents in each group involved in R are selected from deuterium, cyano, nitro, halogen, C 1-5 alkyl, One or more of C 1-5 alkoxy or C 3-6 cycloalkyl.
- R is C 3-6 alkyl, substituted C 1-3 alkyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl, and the substituents in the R group Selected from deuterium, halogen or C 3-6 cycloalkyl.
- R is C 3-6 alkyl or C 3-6 cycloalkyl.
- R is n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.
- R 1 is a connecting bond or a substituted or unsubstituted C 1-4 alkylene group or a substituted or unsubstituted C 4-12 alkenylene group, and the substituent in the R 1 group is selected from deuterium , one or more of amino, cyano, halogen or C 1-4 alkoxy.
- R 2 is hydrogen, nitrooxy, carboxyl or the following substituted or unsubstituted groups: dioxol-2-one, indazolyl, quinolyl, iso Quinolyl, indolyl, benzofuranyl, purinyl, indazolylpyrazolylcarbonyloxy, quinolylpyrazolylcarbonyloxy, isoquinolylpyrazolylcarbonyloxy, indole Pyrazolylcarbonyloxy, benzofurylpyrazolylcarbonyloxy, purinylpyrazolylcarbonyloxy, indazolylpyridylcarbonyloxy, quinolylpyridylcarbonyloxy, isoquinolylpyridine Carbonyloxy, indolypyridylcarbonyloxy, benzofurylpyridylcarbonyloxy, purinylpyridylcarbonyloxy, indazolyltriazolylcarbonyloxy
- R 2 is hydrogen, nitrooxy, carboxyl, or the following substituted or unsubstituted groups: dioxol-2-one, indazolylpyrazolylcarbonyloxy , Indazolylpyridylcarbonyloxy, indazolyltriazolylcarbonyloxy, indolylpyrazolylcarbonyloxy, indolylpyridylcarbonyloxy, indolyltriazolylcarbonyloxy , C 2-6 ester group, pyridyl group, phenyl group, C 1-6 alkoxy group, C 6-20 alkenyl group, C 2-8 alkylcarbonyloxy group or C 2-8 alkoxycarbonyloxy group,
- the substituents in the R 2 group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, nitrooxy substituted C 1-6 alkyl or C 1-6 alkoxy. one or more.
- R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl or butyl.
- the compound of the present invention can be selected from:
- the present invention also includes a pharmaceutical composition, which uses the compound involved in the present application or a pharmaceutically acceptable salt thereof as an active substance, supplemented by pharmaceutically acceptable excipients.
- the compound of the present invention or its pharmaceutically acceptable salt can be used in the preparation of xanthine oxidase inhibitor drugs, especially in the preparation of anti-gout drugs or anti-hyperuricemia drugs.
- H or hydrogen, refers to protium (1H), which is the main stable isotope of hydrogen.
- D or “deuterium” refers to a stable isotope of hydrogen, also known as heavy hydrogen, and its element symbol is D.
- Halogen refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- Amino refers to the -NH 2 group.
- Alkyl refers to a saturated aliphatic hydrocarbon group containing 1-10 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as “1-10", refers to the group The group, in this case an alkyl group, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). Alkyl groups containing 1-4 carbon atoms are called lower alkyl groups. When the lower alkyl group has no substituent, it is called unsubstituted lower alkyl group.
- the alkyl group can be C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-3 alkyl , C 2-4 Alkyl etc.
- Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc.
- Alkyl groups may be substituted or unsubstituted.
- the alkenyl group can be C 2-20 alkenyl, C 2-18 alkenyl, C 2-16 alkenyl, C 2-14 alkenyl, C 2-12 alkenyl, C 4-14 alkenyl, C 4-12 Alkenyl etc.
- Specific alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutenyl, tert-butenyl, wait.
- Alkoxy means -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl) groups, which further means -O- (unsubstituted alkyl).
- the alkyl group can be C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, C 2-3 alkyl, C 2 -4 alkyl etc. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, and the like.
- Triazolyl includes 1,2,3-triazolyl, where "1,2,3-triazolyl” means
- Condensed heteroaromatic ring group refers to an aromatic group containing two or more fused rings and heteroatoms, including but not limited to indazolyl, quinolyl, isoquinolyl, indolyl, benzoyl, etc. Furyl, purinyl, acridinyl, etc.
- Carboxy refers to the -COOH group.
- a substituted ester group means that the hydrogen in the ester group is replaced by one substituent, or that multiple hydrogens in the ester group are replaced by the same or different substituents.
- Heterocycloalkyl refers to a saturated cyclic group containing 3-10 ring atoms, and its ring atoms contain one or more heteroatoms selected from N, O, and S.
- the numerical range mentioned in this application, such as “3-6" refers to the heterocycloalkyl group at this time, which can contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., until Includes 6 carbon atoms as ring atoms.
- the heterocycloalkyl group can be C 3-8 heterocycloalkyl, C 3-6 heterocycloalkyl, C 3-5 heterocycloalkyl, C 3-4 heterocycloalkyl, or C 3-9 heterocycloalkyl.
- alkyl groups include, but are not limited to, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, 1,4-dioxane, oxospiro[3,3]heptyl, oxospiro[4,4]nonanyl , oxospiro[5,5]undecyl, oxospiro[6,6]tridecyl, oxobicyclo[1,1,1]pentyl, oxobicyclo[2,2 ,2]octyl, oxobicyl[3,2,1]octyl, azospiro[3,3]heptyl, azospiro[4,4]nonyl, azospiro[ 5,5]undecyl, azospiro[6,6]tridecyl, azobicyclo[1,1,1
- Connecting bond means that the groups at both ends are directly connected by covalent bonds. Take the group fragment YR 1 -R 2 as an example. When R 1 is a connecting bond, the group fragment is YR 2 .
- Nirooxy refers to the -ONO 2 group.
- “Pharmaceutically acceptable salts” are salts comprising compounds of general formula (I) formed with organic or inorganic acids, meaning those salts which retain the biological effectiveness and properties of the parent compound. Such salts include, but are not limited to:
- inorganic acid such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid, etc.
- organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid , Methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, Mandelic acid, succinic acid or malonic acid,
- “Pharmaceutical composition” refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients .
- the purpose of pharmaceutical compositions is to facilitate the administration of compounds to an organism.
- the present invention further claims a pharmaceutical composition
- a pharmaceutical composition comprising any of the above-mentioned compounds, pharmaceutically acceptable salts thereof or readily hydrolyzable prodrugs thereof and other pharmaceutically active ingredients.
- the present invention also includes any of the above compounds and their pharmaceutically acceptable salts, which can be formulated into any clinically or pharmaceutically acceptable dosage form in a manner known in the art.
- oral administration it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc.
- oral preparations appropriate fillers, binders, disintegrants, lubricants, etc. can be added.
- parenteral administration it can be made into injections, including injection liquid, sterile powder for injection and concentrated solution for injection.
- injections conventional methods in the existing pharmaceutical field can be used.
- no additives may be added, or appropriate additives may be added according to the properties of the drug.
- the compound provided by the invention can significantly reduce the serum uric acid level in a hyperuricemia rat model, and has potential application value in anti-gout drugs, anti-hyperuricemia drugs, and the like. Because febuxostat is associated with severe sudden cardiac death, severe kidney toxicity and liver toxicity, the compounds provided by the present invention may have certain advantages in reducing drug toxicity and have good drug development prospects.
- Step A Combine 5-bromo-1H-indazole-3-carbonitrile (3.0g, 13.5mmol), isopropane iodide (9.19g, 54.1mmol), and cesium carbonate. A mixture of (8.80 g, 27.0 mmol) and DMF (50 mL) was stirred at 80°C for 1.5 hours. Cool to room temperature and filter to remove insoluble matter. Water (200 mL) was added, extracted with ethyl acetate (80 mL ⁇ 3), the combined organic phases were washed with water (50 mL ⁇ 2) and saturated brine (50 mL), and dried over anhydrous sodium sulfate.
- Step B Mix the mixture containing 1H-pyrazole-4-carboxylic acid ethyl ester (1.06g, 7.56mmol), compound 1 (1.0g, 3.79mmol), potassium carbonate (833mg, 6.04mmol), copper iodide (1.05g, A mixture of 5.51 mmol), (1S,2S)-1,2-diaminocyclohexane (432 mg, 3.78 mmol) and DMF (20 mL) was stirred at 110°C overnight under nitrogen.
- Step A A mixture containing compound 2 (500 mg, 1.55 mmol), lithium hydroxide hydrate (623 mg, 14.8 mmol), water (1.5 mL), methanol (1.5 mL) and THF (1.5 mL) was stirred at 20°C for 2 hours. . Part of the solvent was evaporated under reduced pressure, water (8 mL) was added, and the pH value was adjusted to 1-2 with 6M hydrochloric acid. Filter, and the filter cake is recrystallized with acetonitrile to obtain 1-(3-carbamoyl-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (3) (300 mg). The yield is 61.8%. MS (ESI, m/z): 313.9[M+H] + .
- Step B Add trifluoroacetic anhydride (906 mg, 4.31 mmol) and triethylamine (873 mg, 8.63 mmol) to a solution of compound 3 (300 mg, 0.958 mmol) in dichloromethane (5 mL) under an ice-water bath, and complete the addition. Afterwards, the resulting mixture was stirred at room temperature overnight. Add saturated brine (20 mL), extract with dichloromethane (20 mL ⁇ 2), wash the combined organic phases with saturated brine (20 mL ⁇ 2), and dry over anhydrous sodium sulfate.
- the filter cake was purified by column chromatography (200-300 mesh silica gel, eluent with dichloromethane) to obtain 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole -4-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (6).
- Step A A mixture containing compound 4 (200 mg, 0.677 mmol), Boc-L-threonine methyl ester (189 mg, 0.810 mmol), DCC (210 mg, 1.02 mmol) and dichloromethane (5 mL) was stirred at room temperature. overnight. Insoluble matter was removed by filtration, and the filter cake was rinsed with dichloromethane (5 mL).
- Step B A solution of compound 10 (340 mg, 0.666 mmol) and trifluoroacetic acid (0.3 mL) in dichloromethane (5 mL) was stirred at room temperature overnight. Add water (20 mL) and adjust the pH to 7-8 with saturated sodium bicarbonate solution. Extract with dichloromethane (20 mL ⁇ 2), wash the combined organic phases with saturated brine (10 mL ⁇ 2), and dry over anhydrous sodium sulfate.
- Step A To a solution containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indazole (8.40g, 34.4mmol), [1,1'- After the addition of bis(diphenylphosphine)ferrocene]palladium dichloride (1.20 g, 1.47 mmol), the resulting mixture was stirred at 80°C under nitrogen for 3 hours. Cool to room temperature, filter, and rinse the filter cake with a small amount of ethyl acetate.
- Step B To a solution of compound 16 (2.75g, 10.9mmol) in DMF (30mL), add cesium carbonate (7.08g, 21.7mmol) and iodine (5.50g, 21.7mmol). After the addition is completed, the resulting mixture is stirred at room temperature. 2 hours. Water (120 mL) and 2M sodium thiosulfate solution (20 mL) were added. Filter, dissolve the filter cake with ethyl acetate (300 mL), filter to remove insoluble matter, and then dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 2-(3-iodo-1H-indazol-5-yl)isonicotinate (17) (3.90g). The yield is 94.5%.
- Step C Add a solution containing compound 17 (3.90g, 10.3mmol), potassium carbonate (1.70g, 12.3mmol), isopropane bromide (1.90g, 15.4mmol), potassium iodide (340mg, 2.05mmol) and DMF (40mL) The mixture was stirred at 60°C overnight. Cool to room temperature, add water (160 mL), extract with ethyl acetate (100 mL ⁇ 2), wash the combined organic phases with water (40 mL ⁇ 2) and saturated brine (40 mL), and dry over anhydrous sodium sulfate.
- Step D A mixture containing compound 18 (3.81 g, 9.04 mmol), copper cyanide (1.14 g, 12.7 mmol) and DMF (30 mL) was stirred at 120°C overnight. Cool to room temperature, add ethyl acetate (100 mL) and water (100 mL), and filter to remove insoluble matter. The layers were separated, and the aqueous layer was extracted with ethyl acetate (100 mL ⁇ 2). The combined organic phases were washed with water (40 mL ⁇ 2) and saturated brine (40 mL) in sequence, and dried over anhydrous sodium sulfate.
- Step A A mixture containing compound 19 (1.0 g, 3.12 mmol), 2M sodium hydroxide solution (15 mL), methanol (5 mL) and THF (5 mL) was stirred at room temperature for 30 minutes. Water (20 mL) was added, extracted with ethyl acetate (50 mL), and the product was in the aqueous phase. Use 2M citric acid solution to adjust the pH value of the aqueous phase to 5-6. Filter to obtain 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (20) (688 mg). The yield is 72.0%.
- step B For the experimental operation of step B, refer to Example 4 to obtain 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid isopropyl ester (21).
- MS ESI, m/z: 349.1[M+H] + .
- Example 22 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (2-methoxy)ethyl ester (30) and 2-(3-cyano) Synthesis of -1-isopropyl-1H-indazol-5-yl)isonicotinic acid (2-methoxy)ethyl ester hydrobromide (31)
- Step A Using compound 20 and ethylene glycol monomethyl ether as raw materials, refer to Example 8 for the experimental operation of synthesizing compound 30.
- Step B Pour hydrogen bromide into a solution of compound 30 (48 mg, 0.132 mmol) in dichloromethane (10 mL) to make the solution strongly acidic, then evaporate the dichloromethane and recrystallize with ethyl acetate/petroleum ether. 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (2-methoxy)ethyl ester hydrobromide (31) was obtained.
- Step A The mixture containing 4-bromobutylacetate (1.0g, 5.13mmol), silver nitrate (1.30g, 7.65mmol) and acetonitrile (15mL) was stirred under reflux overnight in the dark. Cool to room temperature and filter to remove insoluble matter. Water (60 mL) was added, extracted with ethyl acetate (30 mL ⁇ 3), the combined organic phases were washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then 2M sodium hydroxide solution (2.5 mL) and methanol (5 mL) were added to the residue. After the addition was complete, the resulting mixture was stirred at room temperature for 2 hours.
- Step B A mixture containing compound 4 (80 mg, 0.272 mmol), compound 37 (40 mg, 0.296 mmol), DCC (84 mg, 0.407 mmol), DMAP (4 mg, 0.0327 mmol) and dichloromethane (5 mL) was added to room temperature. Stir overnight. Filter to remove insoluble matter.
- Step A Combine m-hydroxybenzyl bromide (500 mg, 2.67 mmol), silver nitrate (500 mg, 2.94 mmol) and acetonitrile (5 mL). The mixture was stirred in an ice-water bath in the dark for 5 hours. Filter to remove insoluble matter. Water (20 mL) was added, extracted with ethyl acetate (20 mL ⁇ 2), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate.
- step B For the experimental operation of step B, refer to step B in Example 28 to obtain 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid [3- (Nitrooxy)methyl]phenyl ester (42).
- Example 34 Experimental study on the treatment of hyperuricemia in rats by compound 22
- Compound 22 is a light yellow powder. Before use, it is ground with 0.5% CMC-Na and prepared into a suspension of corresponding concentration for intragastric administration.
- Febuxostat purchased from Sigma, was ground with 0.5% CMC-Na before use and prepared into a suspension of corresponding concentration for intragastric administration.
- Rats are kept in independent air-supply cages with air cleanliness level 10000, laboratory temperature 26 ⁇ 2°C; relative humidity 60% ⁇ 80%; number of air exchanges per hour: 10-15 times/hour; light cycle: 12 (day)/12 (night) hours, 3 animals per cage.
- Rat full-price pellet feed was purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd., and its quality complied with GB14924.1-2001 "General Quality Standard for Compound Feed for Experimental Animals".
- Bedding material sterilized granular bedding material, purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd.
- Drinking water Drink purified water, drink it freely after acidification.
- Varioskan LUX multifunctional microplate reader was purchased from Thermo, USA; BS210S precision electronic balance (0.1mg ⁇ 10g) was purchased from Sartorius, Germany; FEJ-200 electronic balance (0.1 ⁇ 200g) was purchased from Fuzhou Furi Hengzhibao Electronics Co., Ltd.; Pacific TII+Genpure XCAD PLUS UV/TOC/UF pure water ultrapure water system was purchased from Thermo in the United States.
- Uric acid detection kit (phosphotungstic acid reduction method), batch number: 20220305, purchased from Nanjing Jiancheng Bioengineering Research Institute; potassium oxacinate, product number 00164, batch number GR4VI-RK, purchased from Tokyo Chemical Industry Co., Ltd. (TCI), Japan; Sodium carboxymethylcellulose (CMC-Na), batch number 20170810, chemically pure, purchased from Sinopharm Chemical Reagent Co., Ltd.
- Rats in each group were purchased and adapted to be raised, fasted for 12 hours, and modeled with potassium oxonate at a dose of 300 mg/kg ip, and each test drug group was administered intragastrically once 0.5 h after modeling. Blood was collected from the retroorbital venous plexus before the injection of potassium oxonate and 1, 3, and 5 hours after the injection of potassium oxonate, and centrifuged at 3500 rpm for 10 min. 30 ⁇ L of serum was taken to measure the uric acid level at each time point.
- the measurement data of each test are expressed as (mean) ⁇ s standard deviation).
- the comparison between groups uses ANOVA-Dunnett T test to examine the significance. P ⁇ 0.05 is used as the significance index, and P ⁇ 0.01 is used as the extremely significant index.
- Example 35 Experimental study on the treatment of hyperuricemia in rats by compounds 13, 38 and 41
- Compound 13 is a light yellow powder, and compounds 38 and 41 are off-white powders. Before use, they are ground with 0.5% CMC-Na and prepared into a 0.4 mg/mL suspension for intragastric administration.
- Febuxostat purchased from Sigma, was ground with 0.5% CMC-Na before use and prepared into a 0.4 mg/mL suspension for intragastric administration.
- Rats are kept in independent air-supply cages with air cleanliness level 10000, laboratory temperature 26 ⁇ 2°C; relative humidity 60% ⁇ 80%; number of air exchanges per hour: 10-15 times/hour; light cycle: 12 (day)/12 (night) hours, 3 animals per cage.
- Rat full-price pellet feed was purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd., and its quality complied with GB14924.1-2001 "General Quality Standard for Compound Feed for Experimental Animals".
- Bedding material sterilized granular bedding material, purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd.
- Drinking water Drink purified water, drink it freely after acidification.
- Varioskan LUX multifunctional microplate reader was purchased from Thermo, USA; BS210S precision electronic balance (0.1mg ⁇ 10g) was purchased from Sartorius, Germany; FEJ-200 electronic balance (0.1 ⁇ 200g) was purchased from Fuzhou Furi Hengzhibao Electronics Co., Ltd.; Pacific TII+Genpure XCAD PLUS UV/TOC/UF pure water ultrapure water system was purchased from Thermo in the United States.
- Uric acid detection kit (phosphotungstic acid reduction method), batch number: 20230224, purchased from Nanjing Jiancheng Bioengineering Research Institute; potassium oxonate, product number 00164, batch number T6GKM-TA, purchased from Tokyo Chemical Industry Co., Ltd. (TCI), Japan; Sodium carboxymethylcellulose (CMC-Na), batch number 20170810, chemically pure, purchased from Sinopharm Chemical Reagent Co., Ltd.
- Rats in each group were purchased and adapted to be raised, fasted for 12 hours, and modeled with potassium oxonate at a dose of 300 mg/kg ip, and each test drug group was administered intragastrically once 0.5 h after modeling. The administration was continued for 3 days. On the third day, blood was collected from the retroorbital venous plexus before the injection of potassium oxonate and 1, 3, and 5 hours after the injection of potassium oxonate. The blood was centrifuged at 3500 rpm for 10 min. 30 ⁇ L of serum was taken to measure the uric acid level at each time point.
- the measurement data of each test are expressed as (mean) ⁇ s standard deviation).
- the comparison between groups uses ANOVA-Dunnett T test to examine the significance. P ⁇ 0.05 is used as the significance index, and P ⁇ 0.01 is used as the extremely significant index.
- Example 36 In vivo pharmacokinetic experiment of compounds in SD rats
- Preparation of compound stock solution Weigh an appropriate amount of compound solid powder, add a certain amount of DMSO, and vortex and sonicate to obtain a 10 mg/mL stock solution.
- test compounds for intragastric administration Pipette appropriate amounts of compound stock solutions, add a certain amount of Solutol HS15 solution, vortex for 1 minute, then add a certain amount of normal saline, and mix thoroughly to obtain a 1 mg/mL solution.
- test compounds for intravenous injection Pipette appropriate amounts of compound stock solutions, add a certain amount of Solutol HS15 solution, vortex for 1 minute, then add a certain amount of normal saline, and mix thoroughly to obtain a 0.5 mg/mL solution.
- test animals were fasted overnight before intragastric administration and were given food 4 hours after administration. During this period, the animals had free access to water.
- Each test compound is divided into two groups, namely intravenous administration and oral administration groups.
- the specific dosage and method of administration are shown in Table 3 below.
- Jugular vein blood samples (150 ⁇ L/ sample), and placed in a centrifuge tube containing the anticoagulant heparin sodium, centrifuged at 2000 g for 5 minutes at 4°C to separate the plasma.
- Plasma samples were analyzed using LC/MS/MS to detect the concentration of each test compound in the plasma samples.
- the pharmacokinetic parameters of SD rats for each test compound obtained according to the above method are shown in Table 4.
- Each compound of the present invention has good pharmacokinetic parameters and high bioavailability.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了一类可用于降尿酸的化合物,它为通式(I)所示的化合物或其药学上可接受的盐,它能够显著降低高尿酸血症大鼠模型的血清尿酸水平,在抗痛风药物、抗高尿酸血症药物等方面具有潜在的应用价值。
Description
本发明属于医药技术领域,具体涉及一类可用于降尿酸的化合物。
黄嘌呤氧化酶(XO)是药物治疗高尿酸血症和痛风的重要靶点。人体内的次黄嘌呤会代谢成黄嘌呤,黄嘌呤再进一步代谢生成尿酸,在尿酸形成的过程中,XO起了决定性的作用,当XO的活性被抑制,次黄嘌呤、黄嘌呤及尿酸之间的转化就会被抑制,进而降低人体血清中尿酸的浓度。因此,抑制XO的活性成了抑制尿酸生成的关键。
一般情况下将男性血尿酸水平超过420μmol/L,女性超过360μmol/L称之为高尿酸血症。目前,高尿酸血症成为仅次于糖尿病的第二大代谢性疾病,严重威胁人类的健康。高尿酸血症不仅是引起痛风的重要生化基础,而且与高血压、高脂血症、动脉粥样硬化、肥胖、胰岛素抵抗的发生密切相关。根据美国国家健康与营养调查的数据,2007~2008年间,美国成年人群中痛风患病率为3.9%(约830万人)(Zhu Y,Pandya BJ,Choi HK.Prevalence of Gout and Hyperuricemia in the US General Population:The National Health and Nutrition Examination Survey 2007-2008[J].Arthritis Rheum,2011,63(10):3136-3141);Meta分析显示,中国高尿酸血症的总体患病率为13.3%,痛风为1.1%(Liu R,Han C,Wu D,et al.Prevalence of hyperuricemia and gout in mainland China from 2000to 2014:A systematic review and meta-analysis[J].Biomed Research International,2015:1-12)。在过去数十年内,由于可促进高尿酸血症的合并疾病(如高血压、肥胖、代谢综合征、2型糖尿病、慢性肾脏病)的流行,痛风的发病率也逐渐上升(Khanna D,Fitzgerald JD,Khanna PP,et al.American College of Rheumatology Guidelines for Management of Gout.Part 1:Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia[J].Arthritis Care&Research,2012,64(10):1432-1446)。
高尿酸血症和痛风发病率的日益升高严重危害着人类健康,应及早干预和治疗。但目前上市的降尿酸药物非常有限,而且毒副作用明显、患者的依从性较差。目前,用于高尿酸血症和痛风的治疗药物主要有三大类:尿酸盐阴离子转运蛋白1(URAT1)抑制剂、黄嘌呤氧化酶抑制剂和尿酸氧化酶。
URAT1抑制剂主要作用于肾近曲小管的尿酸盐转运体,抑制尿酸的重吸收,增加其排泄,从而降低体内的尿酸浓度。该类药物包括苯溴马隆、Lesinurad和丙磺舒。苯溴马隆是一种有效的促尿酸排泄药,已在多国获批上市,但美国未批准。由于严重肝毒性,2003年苯溴马隆从欧洲一些国家撤市。由于苯溴马隆相关的肝脏相关不良事件存在种族差异,中国高尿酸血症与痛风诊疗指南(2019)推荐苯溴马隆为一线降尿酸药物。Lesinurad于2015年在美国获批上市,其药品说明书中以黑框警示其可能引发急性肾衰竭和心血管疾病的风险(可能致死),且疗效远不如苯溴马隆,需与别嘌醇联用。丙磺舒在美国指南中是单药降尿
酸治疗中促尿酸排泄药的首选,但由于其与部分常用药物(如非甾体抗炎药、β-内酰胺类药、肝素等)之间存在多重显著的相互作用,使其应用受到限制。
黄嘌呤氧化酶抑制剂主要包括别嘌醇和非布司他。别嘌醇于1966年被美国FDA批准上市以来被广泛用于临床。目前,该药仍然是大多数国家痛风指南中推荐的治疗痛风的一线用药。但是别嘌醇疗效差,只对还原态的XO有抑制作用,对氧化态的XO不起作用,有关研究表明别嘌醇即使使用到最大剂量,受试者达到治疗终点率也低于50%(Robert M,Douglas CA,Scott B.Less than half of patients treated with high-Dose allopurinol reach serum uric acid target[J].ACR/ARHP Annual Meeting,2017,Abstract Number:1120)。另外它还会引起皮疹和其它罕见但致命的副反应,包括Stevens-Johnson综合征,中毒性表皮坏死松解症,致死率约10%~30%(Bocquet H,Bagot M,Roujeau JC.Drug-induced pseudolymphoma and drug hypersensitivity syndrome(drug rash with eosinophilia and systemic symptoms:DRESS[J].Seminars in Cutaneous Medicine and Surgery,1996,15(4):250-257)。临床上曾经报道别嘌醇致急性肝损害,别嘌醇在治疗合并肝脏疾病高尿酸血症患者时应慎用(Imai H,Kamei H,Onishi Y,et al.Successful living-donor liver transplantation for cholestatic liver failure induced by allopurinol:case report[J].Transplantation Proceedings,2015,47(9):2778-2781)。别嘌醇的其他副反应包括胃部不适、恶心、腹痛、腹泻、白细胞及血小板减少、头痛、发热、食欲不振、体重下降、排尿疼痛、血尿、瘙痒和嗜睡。
非布司他为日本Teijin公司研制的非嘌呤类XO抑制剂,能抑制XO的氧化态和还原态,活性明显高于别嘌醇。2008年于欧洲上市,2009年于美国上市。随着非布司他在临床上应用的不断扩展,其治疗高尿酸血症时出现的心血管不良反应越来越多地被报道出来,并且由于其心血管毒性(如猝死的风险)导致美国食品药品监督管理局要求在其药品说明书上增加黑框风险警示,并在2019年调整处方信息,由一线用药改为二线用药。2018年3月新英格兰医学杂志发表一项6190例痛风患者的研究结果公布:研究人员发现平均治疗32个月后,非布司他和别嘌醇治疗组总体的不良心血管事件发生风险相似(HR 1.03,95%CI,0.87-1.23),但是非布司他组的全因死亡率和心血管死亡率高于别嘌呤醇组。非布司他组患者心血管死亡率增加34%(HR 1.34,95%CI,1.03-1.73),全因死亡率增加22%(HR 1.22,95%CI,1.01-1.47)。心血管死亡原因中心脏性猝死最常见,其中非布司他组83例(2.7%),别嘌醇组56例(1.8%)(William B,Kenneth G,Michael A,et al.Cardiovascular safety of febuxostat or allopurinol in patients with gout[J].The New England Journal of Medicine,2018,378:1200-1210)。此外,非布司他也可能会导致严重的胃肠道毒副作用、肾脏毒副作用、肝功能异常等。
聚乙二醇重组尿酸酶为目前主要上市的尿酸氧化酶类药物,通过静脉注射给药。FDA对此药物有多条黑框警告,在20%-40%的患者中有严重的免疫过敏性副反应。其疗效一般,只有47%的病人达到低于0.36mmol/L的治疗终点。
在过去的几十年里,高尿酸血症和痛风的治疗药物开发进度缓慢,但随着发病率的逐渐增高,治疗药
物的开发引起越来越多研究人员的关注。以黄嘌呤氧化酶为作用靶点的新药设计也已经得到广泛重视,多种化合物已经进入临床试验,但仍面临毒副作用较大等诸多问题,有待更深入的研究。因此,高效低毒的XO抑制剂具有巨大开发潜力和应用价值。
发明内容
本发明的目的是在现有技术的基础上,提供一种具有黄嘌呤氧化酶抑制活性的化合物。
本发明的另一目的是提供上述化合物在医药领域的用途。
本发明的目的可以通过以下措施达到:
通式(I)所示的化合物或其药学上可接受的盐,
其中,
R为C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基或C3-6杂环烷基中的一种或多种;
Ar为取代或非取代的以下基团:Ar基团中的取代基选自氘、羟基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;
Y为O或NR3,
R1为连接键或者取代或非取代的C1-6亚烷基或者取代或非取代的C2-12亚烯基,R1基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;
R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、C4-12稠杂芳环基、C4-16稠杂芳环基吡唑基羰基氧基、C4-16稠杂芳环基吡啶基羰基氧基、C4-16稠杂芳环基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C2-20烯基、C2-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-6烷基、卤代C1-6烷基、硝基氧基取代的C1-6烷基或C1-6烷氧基中的一种或多种;
R3为氢或C1-6烷基。
在一种优选方案中,Ar为取代或非取代的以下基团:其中“*”为与C=O的连接位点。
在一种优选方案中,本发明的化合物选自通式化合物选自通式(II)、(III)或(IV)所示的化合物,
在一种优选方案中,Y为O或NH。
在一种优选方案中,R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
在一种优选方案中,R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、四氢呋喃、取代的四氢呋喃、四氢噻吩、取代的四氢噻吩、四氢吡咯或取代的四氢吡咯;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
在一种优选方案中,R为C3-6烷基、取代的C1-3烷基、C3-6环烷基或者取代的C3-6环烷基,R基团中的取代基选自氘、卤素或C3-6环烷基。
在一种优选方案中,R为C3-6烷基或者C3-6环烷基。
在一种优选方案中,R为正丙基、异丙基、正丁基、异丁基、环丙基、环丁基或环戊基。
在一种优选方案中,R1为连接键或者取代或非取代的C1-4亚烷基或者取代或非取代的C4-12亚烯基,R1基团中的取代基选自氘、氨基、氰基、卤素或C1-4烷氧基中的一种或多种。
在一种优选方案中,R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、嘌呤基、吲唑基吡唑基羰基氧基、喹啉基吡唑基羰基氧基、异喹啉基吡唑基羰基氧基、吲哚基吡唑基羰基氧基、苯并呋喃基吡唑基羰基氧基、嘌呤基吡唑基羰基氧基、吲唑基吡啶基羰基氧基、喹啉基吡啶基羰基氧基、异喹啉基吡啶基羰基氧基、吲哚基吡啶基羰基氧基、苯并呋喃基吡啶基羰基氧基、嘌呤基吡啶基羰基氧基、吲唑基三氮唑基羰基氧基、喹啉基三氮唑基羰基氧基、异喹啉基三氮唑基羰基氧基、吲哚基三氮唑基羰基氧基、苯并呋喃基三氮唑基羰基氧基、嘌呤基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C6-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-6烷基、卤代C1-6烷基、硝基氧基取代的C1-6烷基或C1-6烷氧基中的一种或多种。
在一种优选方案中,R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲唑基吡唑基羰基氧基、吲唑基吡啶基羰基氧基、吲唑基三氮唑基羰基氧基、吲哚基吡唑基羰基氧基、吲哚基吡啶基羰基氧基、吲哚基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-6烷基、硝基氧基取代的C1-6烷基或C1-6烷氧基中的一种或多种。
在一种优选方案中,R3为氢、甲基、乙基、正丙基、异丙基或丁基。在一种优选方案中,本发明的化合物可选自:
本发明还包括一种药物组合物,它以本申请中所涉及的化合物或其药学上可接受的盐为活性物质,辅以药学上可接受的辅料。
本发明的化合物或其药学上可接受的盐可以应用在制备黄嘌呤氧化酶抑制剂药物方面,特别是应用在制备抗痛风药物或抗高尿酸血症药物方面。
本发明中所指出的各基团,如无其他明确限定,均具有以下含义:
“H”,即氢,是指氕(1H),它是氢元素的主要稳定同位素。
“D”,或“氘”,是指氢的一种稳定形态同位素,也被称为重氢,其元素符号为D。
“卤素”,是指氟原子,氯原子,溴原子或碘原子。
“羟基”,是指-OH基团。
“氨基”,是指-NH2基团。
“烷基”,是指含有1-10个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-10”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括10个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时,称其为未取代的低级烷基。烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。具体的烷基包括但不限于甲基、乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烯基”,是指含有2-30个碳原子的具有一个或多个“C=C”的烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“2-10”,是指该基团,此时为烯基,可以含2个碳原子、3个碳原子等,直至包括10个碳原子)。烯基可以选用C2-20烯基、C2-18烯基、C2-16烯基、C2-14烯基、C2-12烯基、C4-14烯基、C4-12烯基等。具体的烯基包括但不限于乙烯基、丙烯基、烯丙基、丁烯基、异丁烯基、叔丁烯基、等。
“烷氧基”表示-O-(未取代的烷基)和-O-(未取代的环烷基)基团,其进一步表示-O-(未取代的烷基)。其中的烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。代表性实施例包括但不限于甲氧基、乙氧基、丙氧基、环丙氧基等。
“二氧杂环戊烯-2-酮基”为基团。
“吡唑基”,是指中的任意一种。
“三氮唑基”,包括1,2,3-三氮唑基,其中“1,2,3-三氮唑基”,是指
“吡啶基”,是指中的任意一种。
“稠杂芳环基”,是指含有两个或多个稠和环以及杂原子的芳香基团,包括但不限于吲唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、嘌呤基、吖啶基等。
“羧基”,是指-COOH基团。
“酯基”,是指“-C(=O)-O-烷基”基团,其中的烷基可以选用C1-6烷基、C1-5烷基、C1-4烷基、C1-3烷基、C1-2烷基、C2-3烷基、C2-4烷基等。代表性实施例包括但不限于甲酸甲酯基、甲酸乙酯基、甲酸正丙酯基、甲酸异丙酯基等。取代的酯基是指酯基中的氢被一个取代基所取代,或者酯基中的多个氢分别被相同或不同的取代基所取代。
“杂环烷基”,是指含有3-10个环原子的饱和的环状基团,它的环原子中含有一个或多个选自N、O、S的杂原子。本申请书中提到的数字范围,例如“3-6”,是指此时为杂环烷基的该基团,可以含3个碳原子、4个碳原子、5个碳原子等,直至包括6个碳原子作为环原子。杂环烷基可以选用C3-8杂环烷基、C3-6杂环烷基、C3-5杂环烷基、C3-4杂环烷基、C3-9杂环烷基、C4-6杂环烷基等。具体的烷基包括但不限于四氢呋喃、四氢吡咯、四氢噻吩、1,4-二氧六环、氧代螺[3,3]庚烷基、氧代螺[4,4]壬烷基、氧代螺[5,5]十一烷基、氧代螺[6,6]十三烷基、氧代二环[1,1,1]戊烷基、氧代二环[2,2,2]辛烷基、氧代二环[3,2,1]辛烷基、氮代螺[3,3]庚烷基、氮代螺[4,4]壬烷基、氮代螺[5,5]十一烷基、氮代螺[6,6]十三烷基、氮代二环[1,1,1]戊烷基、氮代二环[2,2,2]辛烷基或氮代二环[3,2,1]辛烷基等。杂环烷基可以是取代的或未取代的。
“C4-16稠杂芳环基吡唑基羰基氧基”,是指含有4-16个碳原子的-O-C(=O)-吡唑基-稠杂芳环基基团,一种具体的例子包括但不限于:吲唑基吡唑基羰基氧基吲哚基吡唑基羰基氧基
“C2-8烷氧基羰基氧基”,是指含有2-8个碳原子的-O-C(=O)-O-烷基基团。
“C2-8烷基羰基氧基”,是指含有2-8个碳原子的-O-C(=O)-烷基基团。
“C4-16稠杂芳环基吡啶基羰基氧基”,是指含有4-16个碳原子的-O-C(=O)-吡啶基-稠杂芳环基基团,一种具体的例子包括但不限于:吲唑基吡啶基羰基氧基吲哚基吡啶基羰基氧基
“C4-16稠杂芳环基三氮唑基羰基氧基”是指含有4-16个碳原子的-O-C(=O)-三氮唑基-稠杂芳环基基团,一种具体的例子包括但不限于:吲唑基三氮唑基羰基氧基吲哚基三氮唑基羰基氧基
“连接键”,是指其两端的基团直接通过共价键相连。以基团片段Y-R1-R2为例,当R1为连接键时,该基团片段即为Y-R2。
“硝基氧基”,是指-ONO2基团。
“药学上可接受的盐”是包含通式(I)的化合物与有机酸或无机酸形成的盐,表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括但不限于:
(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应而得,无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等,有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐,金属离子例如碱金属离子、碱土金属离子或铝离子,有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药用组合物”指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐和前药与其它的化学成分,例如药学上可接受的载体和赋形剂的混合物。药用组合物的目的是促进化合物对生物体的给药。
本发明进一步要求保护包括上面所述的任一化合物、其药学上可接受的盐或其易水解的前药与其它药用活性成分的药物组合物。
本发明也包括上述任一化合物、其药学上可接受的盐,可以用本领域已知的方式配制成临床上或药学上可接受的任一剂型。用于口服给药时,可制成常规的固体制剂,如片剂、胶囊剂、丸剂、颗粒剂等;也可制成口服液体制剂,如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时,可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时,可以制成注射剂,包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时,可采用现有制药领域中常规方法生产,配制注射剂时,可以不加入附加剂,也可以根据药物的性质加入适宜的附加剂。
本发明提供的化合物能够显著降低高尿酸血症大鼠模型的血清尿酸水平,在抗痛风药物、抗高尿酸血症药物等方面具有潜在的应用价值。因为非布司他存在严重的心脏猝死、严重的肾脏毒性和肝脏毒性,本发明提供的化合物可能在降低药物毒性方面具有一定的优势,拥有良好的药物开发前景。
以下结合实施例对本发明做进一步说明,但是本发明的保护范围并不局限于以下各实施例。
实施例1:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸乙酯(2)的合成
步骤A:将含有5-溴-1H-吲唑-3-甲腈(3.0g,13.5mmol)、碘代异丙烷(9.19g,54.1mmol)、碳酸铯
(8.80g,27.0mmol)和DMF(50mL)的混合物在80℃搅拌1.5小时。冷却到室温,过滤除去不溶物。加入水(200mL),用乙酸乙酯(80mL×3)萃取,合并的有机相依次用水(50mL×2)和饱和食盐水(50mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:50~1:30洗脱),得5-溴-1-异丙基-1H-吲唑-3-甲腈(1)(2.10g)。收率为58.9%。1H NMR(CDCl3,400MHz)δ7.95(d,J=1.2Hz,1H),7.55(dd,J=1.2,8.8Hz,1H),7.45(d,J=8.8Hz,1H),4.93-4.87(m,1H),1.61(d,J=6.4Hz,6H)。
步骤B:将含有1H-吡唑-4-甲酸乙酯(1.06g,7.56mmol)、化合物1(1.0g,3.79mmol)、碳酸钾(833mg,6.04mmol)、碘化亚铜(1.05g,5.51mmol)、(1S,2S)-1,2-二氨基环己烷(432mg,3.78mmol)和DMF(20mL)的混合物在氮气下110℃搅拌过夜。冷却到室温,加入水(80mL),用乙酸乙酯(40mL×3)萃取,合并的有机相用饱和食盐水(30mL×3)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:15~1:4洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸乙酯(2)(500mg)。收率为40.8%。1H NMR(DMSO-d6,400MHz)δ9.31(s,1H),8.47(d,J=1.2Hz,1H),8.23-8.16(m,3H),5.29-5.22(m,1H),4.29(q,J=7.2Hz,2H),1.54(d,J=7.2Hz,6H),1.33(t,J=7.2Hz,3H)。MS(ESI,m/z):324.1[M+H]+。
实施例2:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸甲酯(5)的合成
步骤A:将含有化合物2(500mg,1.55mmol)、水合氢氧化锂(623mg,14.8mmol)、水(1.5mL)、甲醇(1.5mL)和THF(1.5mL)的混合物在20℃搅拌2小时。减压蒸除部分溶剂,加入水(8mL),用6M盐酸调节pH值至1~2。过滤,滤饼用乙腈重结晶,得1-(3-氨基甲酰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(3)(300mg)。收率为61.8%。MS(ESI,m/z):313.9[M+H]+。
步骤B:在冰水浴下,向化合物3(300mg,0.958mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸酐(906mg,4.31mmol)和三乙胺(873mg,8.63mmol),加完后,所得混合物在室温下搅拌过夜。加入饱和食盐水(20mL),用二氯甲烷(20mL×2)萃取,合并的有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,然后用制备HPLC纯化,得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(4)。1H NMR(DMSO-d6,400MHz)δ9.10(s,1H),8.39(d,J=1.6Hz,1H),8.21-8.12(m,2H),
8.05(s,1H),5.22(q,J=6.4Hz,1H),1.53(d,J=6.4Hz,6H)。MS(ESI,m/z):296.2[M+H]+。
步骤C:将含有化合物4(250mg,0.847mmol)、碘甲烷(192mg,1.35mmol)、碳酸钾(235mg,1.70mmol)和DMF(5mL)的混合物在室温下搅拌过夜。加入水(20mL),过滤。滤饼经柱层析纯化(200~300目硅胶,二氯甲烷:石油醚=1:1洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸甲酯(5)。1H NMR(DMSO-d6,400MHz)δ9.34(s,1H),8.46(d,J=1.6Hz,1H),8.23-8.16(m,3H),5.28-5.22(m,1H),3.83(s,3H),1.54(d,J=7.2Hz,6H)。MS(ESI,m/z):310.1[M+H]+。
实施例3:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(6)的合成
将含有化合物4(150mg,0.508mmol)、4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(91mg,0.613mmol)、碳酸钾(140mg,1.01mmol)、碘化钾(110mg,0.663mmol)和DMF(5mL)的混合物在室温下搅拌3小时。加入水(20mL),过滤。滤饼经柱层析纯化(200~300目硅胶,二氯甲烷洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(6)。1H NMR(DMSO-d6,400MHz)δ9.47(s,1H),8.58(d,J=1.2Hz,1H),8.34-8.25(m,3H),5.38-5.31(m,1H),5.29(s,2H),2.33(s,3H),1.63(d,J=6.8Hz,6H)。MS(ESI,m/z):408.1[M+H]+。
实施例4:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸异丙酯(7)的合成
将含有化合物4(250mg,0.847mmol)、溴代异丙烷(325mg,2.64mmol)、碳酸钾(235mg,1.70mmol)、碘化钾(190mg,1.14mmol)和DMF(5mL)的混合物在30℃搅拌48小时。加入水(20mL),过滤。滤饼经柱层析纯化(200~300目硅胶,二氯甲烷:石油醚=1:1洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸异丙酯(7)(190mg)。收率为66.5%。1H NMR(DMSO-d6,400MHz)δ9.28(s,1H),8.47(d,J=1.2Hz,1H),8.24-8.16(m,3H),5.29-5.22(m,1H),5.16-5.10(m,1H),1.54(d,J=6.4Hz,6H),1.32(d,J=6.4Hz,6H)。MS(ESI,m/z):338.1[M+H]+。
实施例5:双[1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸]丙-1,3-二酯(8)的合成
将含有化合物4(200mg,0.677mmol)、1,3-二溴丙烷(68mg,0.337mmol)、碳酸钾(187mg,1.35mmol)、碘化钾(146mg,0.880mmol)和DMF(5mL)的混合物在30℃搅拌48小时。加入水(20mL),过滤。滤饼经柱层析纯化(200~300目硅胶,二氯甲烷:石油醚=1:1洗脱),得双[1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸]丙-1,3-二酯(8)(146mg)。收率为68.4%。1H NMR(DMSO-d6,400MHz)δ9.20(s,2H),8.24(s,2H),8.12-8.05(m,6H),5.23-5.16(m,2H),4.45(t,J=6.0Hz,4H),2.18(t,J=6.0Hz,2H),1.53(d,J=6.4Hz,12H)。MS(ESI,m/z):631.1[M+H]+。
实施例6:[1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-羰基]-L-缬氨酸甲酯(9)的合成
将含有化合物4(200mg,0.677mmol)、L-缬氨酸甲酯盐酸盐(136mg,0.811mmol)、二异丙基乙基胺(219mg,1.69mmol)、HBTU(385mg,1.02mmol)和DMF(5mL)的混合物在室温下搅拌过夜。加入水(20mL),用乙酸乙酯(30mL×2)萃取,合并的有机相用饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯:三乙胺=100:10:1洗脱),得[1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-羰基]-L-缬氨酸甲酯(9)(268mg)。收率为96.9%。1H NMR(DMSO-d6,400MHz)δ9.23(s,1H),8.34-8.29(m,3H),8.20-8.14(m,2H),5.27-5.24(m,1H),4.38-4.34(m,1H),3.67(s,3H),2.18-2.13(m,1H),1.55(d,J=6.8Hz,6H),0.99(d,J=6.8Hz,3H),0.94(d,J=6.4Hz,3H)。MS(ESI,m/z):409.2[M+H]+。
实施例7:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[(2R,3S)-3-氨基-4-甲氧基-4-氧代丁-2-基]酯(11)的合成
步骤A:将含有化合物4(200mg,0.677mmol)、Boc-L-苏氨酸甲酯(189mg,0.810mmol)、DCC(210mg,1.02mmol)和二氯甲烷(5mL)的混合物在室温下搅拌过夜。过滤除去不溶物,滤饼用二氯甲烷(5mL)淋洗。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯:三乙胺=100:4:1洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[(2R,3S)-3-(Boc-氨基)-4-甲氧基-4-氧代丁-2-基]酯(10)(340mg)。收率为99.8%。
步骤B:将化合物10(340mg,0.666mmol)和三氟乙酸(0.3mL)的二氯甲烷(5mL)溶液在室温下搅拌过夜。加入水(20mL),用饱和碳酸氢钠溶液调节pH值至7~8。用二氯甲烷(20mL×2)萃取,合并的有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,所得产物用乙酸乙酯/石油醚重结晶,得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[(2R,3S)-3-氨基-4-甲氧基-4-氧代丁-2-基]酯(11)。1H NMR(DMSO-d6,400MHz)δ9.32(s,1H),8.44(s,1H),8.23-8.18(m,3H),5.32-5.23(m,2H),3.61(s,3H),3.55(s,1H),2.06(s,2H),1.54(d,J=6.4Hz,6H),1.35(d,J=6.4Hz,3H)。MS(ESI,m/z):411.1[M+H]+。
实施例8:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(吡啶-2-基)甲酯(12)的合成
将含有化合物4(190mg,0.643mmol)、吡啶-2-甲醇(84mg,0.770mmol)、DCC(210mg,0.969mmol)、DMAP(2mg,0.0163mmol)和二氯甲烷(5mL)的混合物在室温下搅拌过夜。过滤除去不溶物,滤饼用二氯甲烷(5mL)淋洗。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,二氯甲烷:三乙胺=100:1洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(吡啶-2-基)甲酯(12)(75mg)。收率为30.2%。1H NMR(DMSO-d6,400MHz)δ9.42(s,1H),8.58(d,J=4.4Hz,1H),8.50(d,J=1.6Hz,1H),8.30(s,1H),8.23(d,J=1.6Hz,1H),8.20(s,1H),7.88-7.85(m,1H),7.56(d,J=8.0Hz,1H),7.39-7.36(m,1H),5.40(s,2H),5.29-5.23(m,1H),1.54(d,J=6.4Hz,6H)。MS(ESI,m/z):387.1[M+H]+。
实施例9:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(3,7,11-三甲基十二烷基-2,6,10-三烯-1-基)酯
(13)的合成
以化合物4和3,7,11-三甲基十二烷基-2,6,10-三烯-1-醇为原料,合成化合物13的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ9.29(s,1H),8.47(s,1H),8.23-8.15(m,3H),5.44-5.40(m,1H),5.29-5.22(m,1H),5.10-5.00(m,2H),4.79-4.74(m,2H),2.11-1.89(m,8H),1.83-1.74(m,6H),1.58-1.52(m,12H)。MS(ESI,m/z):500.3[M+H]+。
实施例10:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(3,7-二甲基辛烷-2,6-二烯-1-基)酯(14)的合成
以化合物4和3,7-二甲基辛烷-2,6-二烯-1-醇为原料,合成化合物14的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ9.31(s,1H),8.47(d,J=1.6Hz,1H),8.23-8.16(m,3H),5.44-5.41(m,1H),5.28-5.23(m,1H),5.22-5.07(m,1H),4.78(d,J=6.8Hz,2H),2.10-2.03(m,4H),1.74(s,3H),1.63(s,3H),1.57(s,3H),1.55(s,3H),1.53(s,3H)。MS(ESI,m/z):432.2[M+H]+。
实施例11:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(新戊酰氧基)甲酯(15)的合成
将含有化合物4(120mg,0.406mmol)、新戊酸氯甲酯(74mg,0.491mmol)、碳酸钾(113mg,0.818mmol)、碘化钾(88mg,0.530mmol)和DMF(5mL)的混合物在室温下搅拌48小时。加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并的有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,二氯甲烷:石油醚=1:1洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(新戊酰氧基)甲酯(15)。1H NMR(DMSO-d6,400MHz)δ9.41(s,1H),8.50(d,J=1.2Hz,1H),8.26-8.17(m,3H),5.94(s,2H),5.29-5.22(m,1H),1.54(d,J=6.4Hz,6H),1.17(s,9H)。MS(ESI,m/z):410.1[M+H]+。
实施例12:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸甲酯(19)的合成
步骤A:向含有5-(4,4,5,5-四甲基-1,3,2-二杂氧戊硼烷-2-基)-1H-吲唑(8.40g,34.4mmol)、2-溴吡啶-4-甲酸甲酯(9.0g,41.7mmol)、碳酸钾(12.0g,87.0mmol)、二氧六环(100mL)和水(20mL)的混合物中加入[1,1’-双(二苯基膦)茂铁]二氯化钯(1.20g,1.47mmol),加完后,所得混合物在氮气下80℃搅拌3小时。冷却到室温,过滤,滤饼用少量乙酸乙酯淋洗。减压蒸除大部分溶剂,加入乙酸乙酯(500mL),用饱和食盐水(100mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:二氯甲烷=1:15洗脱),得2-(1H-吲唑-5-基)异烟酸甲酯(16)。1H NMR(DMSO-d6,400MHz)δ13.25(s,1H),8.90(d,J=4.8Hz,1H),8.61(s,1H),8.40(s,1H),8.23-8.19(m,2H),7.79(dd,J=1.2,4.8Hz,1H),7.69(d,J=8.8Hz,1H),3.99(s,3H)。MS(ESI,m/z):254.1[M+H]+。
步骤B:向化合物16(2.75g,10.9mmol)的DMF(30mL)溶液中加入碳酸铯(7.08g,21.7mmol)和碘(5.50g,21.7mmol),加完后,所得混合物在室温下搅拌2小时。加入水(120mL)和2M硫代硫酸钠溶液(20mL)。过滤,滤饼用乙酸乙酯(300mL)溶解,过滤除去不溶物,然后用无水硫酸钠干燥。减压蒸除溶剂,得2-(3-碘-1H-吲唑-5-基)异烟酸甲酯(17)(3.90g)。收率为94.5%。
步骤C:将含有化合物17(3.90g,10.3mmol)、碳酸钾(1.70g,12.3mmol)、溴代异丙烷(1.90g,15.4mmol)、碘化钾(340mg,2.05mmol)和DMF(40mL)的混合物在60℃搅拌过夜。冷却到室温,加入水(160mL),用乙酸乙酯(100mL×2)萃取,合并的有机相依次用水(40mL×2)和饱和食盐水(40mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:10洗脱),得2-(3-碘-1-异丙基-1H-吲唑-5-基)异烟酸甲酯(18)(3.81g)。收率为87.8%。
步骤D:将含有化合物18(3.81g,9.04mmol)、氰化亚铜(1.14g,12.7mmol)和DMF(30mL)的混合物在120℃搅拌过夜。冷却到室温,加入乙酸乙酯(100mL)和水(100mL),过滤除去不溶物。分层,水层用乙酸乙酯(100mL×2)萃取,合并的有机相依次用水(40mL×2)和饱和食盐水(40mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:12~1:2洗脱),得2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸甲酯(19)(1.0g)。收率为34.5%。1H NMR(DMSO-d6,400MHz)δ8.92(d,J=4.8Hz,1H),8.67(s,1H),8.53(s,1H),8.41(d,J=8.8Hz,1H),
8.12(d,J=8.8Hz,1H),7.83(d,J=4.8Hz,1H),5.29-5.22(m,1H),3.97(s,3H),1.55(d,J=6.8Hz,6H)。MS(ESI,m/z):321.1[M+H]+。
实施例13:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸异丙酯(21)的合成
步骤A:将含有化合物19(1.0g,3.12mmol)、2M氢氧化钠溶液(15mL)、甲醇(5mL)和THF(5mL)的混合物在室温下搅拌30分钟。加入水(20mL),用乙酸乙酯(50mL)萃取,产物在水相。水相用2M柠檬酸溶液调节pH值至5~6。过滤,得2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(20)(688mg)。收率为72.0%。1H NMR(DMSO-d6,400MHz)δ8.88(d,J=4.8Hz,1H),8.65(s,1H),8.50(s,1H),8.40(dd,J=1.6,9.2Hz,1H),8.13(d,J=8.8Hz,1H),7.82(d,J=8.8Hz,1H),5.30-5.23(m,1H),1.58(d,J=6.8Hz,6H)。MS(ESI,m/z):307.3[M+H]+。
步骤B的实验操作参见实施例4,得2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸异丙酯(21)。1H NMR(DMSO-d6,400MHz)δ8.91(dd,J=0.8,4.8Hz,1H),8.64(d,J=0.8Hz,1H),8.48(s,1H),8.41(dd,J=1.6,8.8Hz,1H),8.12(d,J=8.8Hz,1H),7.81(dd,J=1.6,4.8Hz,1H),5.29-5.20(m,2H),1.56(d,J=6.4Hz,6H),1.39(d,J=6.4Hz,6H)。MS(ESI,m/z):349.1[M+H]+。
实施例14:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲酯(22)的合成
以化合物20和4-氯甲基-5-甲基-1,3-二氧杂环戊烯-2-酮为原料,合成化合物22的实验操作参见实施例3。1H NMR(DMSO-d6,400MHz)δ8.93(d,J=5.2Hz,1H),8.67(s,1H),8.53(s,1H),8.40(dd,J=1.6,9.2Hz,1H),8.12(d,J=9.2Hz,1H),7.85(dd,J=1.6,9.2Hz,1H),5.33(s,2H),5.29-5.22(m,1H),2.26(s,3H),1.55(d,J=6.8Hz,6H)。MS(ESI,m/z):419.1[M+H]+。
实施例15:[2-(3-氰基-1-异丙基-1H-吲唑-5-基)吡啶-4-羰基]-L-缬氨酸甲酯(23)的合成
以化合物20和L-缬氨酸甲酯盐酸盐为原料,合成化合物23的实验操作参见实施例6。1H NMR
(DMSO-d6,400MHz)δ9.10(d,J=7.6Hz,1H),8.85(d,J=4.8Hz,1H),8.65(s,1H),8.48(s,1H),8.42(d,J=8.8Hz,1H),8.15(d,J=8.8Hz,1H),7.77(d,J=5.2Hz,1H),5.28-5.23(m,1H),4.42-4.38(m,1H),3.70(s,3H),2.26-2.21(m,1H),1.56(d,J=6.8Hz,6H),1.03(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H)。MS(ESI,m/z):539.0[M+DMSO+ACN+H]+。
实施例16:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(3,7,11-三甲基十二烷基-2,6,10-三烯-1-基)酯(24)的合成
以化合物20和3,7,11-三甲基十二烷基-2,6,10-三烯-1-醇为原料,合成化合物24的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ8.90(d,J=4.8Hz,1H),8.63(s,1H),8.48(s,1H),8.38(dd,J=1.6,9.2Hz,1H),8.11(d,J=9.2Hz,1H),7.80(dd,J=1.6,5.2Hz,1H),5.49-5.46(m,1H),5.29-5.22(m,1H),5.11-5.07(m,2H),4.92-4.87(m,2H),2.12-1.88(m,8H),1.89-1.77(m,6H),1.64-1.52(m,12H)。MS(ESI,m/z):511.3[M+H]+。
实施例17:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(3,7-二甲基辛烷-2,6-二烯-1-基)酯(25)的合成
以化合物20和3,7-二甲基辛烷-2,6-二烯-1-醇为原料,合成化合物25的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ8.90(d,J=4.8Hz,1H),8.64(s,1H),8.48(s,1H),8.38(dd,J=1.6,9.2Hz,1H),8.11(d,J=9.2Hz,1H),7.81(dd,J=1.6,5.2Hz,1H),5.49-5.47(m,1H),5.26-5.24(m,1H),5.08-5.07(m,1H),4.92-4.90(m,2H),2.09-2.04(m,4H),1.77-1.57(m,15H)。MS(ESI,m/z):443.2[M+H]+。
实施例18:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸{1-[(乙氧基羰基)氧基]}乙酯(26)的合成
将含有化合物20(100mg,0.326mmol)、碳酸钾(90mg,0.651mmol)、1-氯乙基乙基碳酸酯(75mg,0.492mmol)、碘化钾(70mg,0.422mmol)和DMF(3mL)的混合物在40℃搅拌过夜。加入水(20mL),用乙酸乙酯(20mL×3)萃取,合并的有机相依次用水(15mL×2)和饱和食盐水(15mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:二氯甲烷:三乙胺=400:100:1洗
脱),得2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸{1-[(乙氧基羰基)氧基]}乙酯(26)。1H NMR(DMSO-d6,400MHz)δ8.94(d,J=5.2Hz,1H),8.67(s,1H),8.52(s,1H),8.40(dd,J=1.6,8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.84(dd,J=1.6,5.2Hz,1H),6.96(q,J=5.2Hz,1H),5.29-5.22(m,1H),4.19(q,J=6.8Hz,2H),1.65(d,J=5.2Hz,3H),1.56(d,J=6.8Hz,6H),1.24(d,J=6.8Hz,3H)。MS(ESI,m/z):423.1[M+H]+。
实施例19:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(2-乙酰氧基)乙酯(27)的合成
以化合物4和乙二醇单乙酸酯为原料,合成化合物27的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ9.34(s,1H),8.48(d,J=1.6Hz,1H),8.24-8.16(m,3H),5.29-5.23(m,1H),4.47-4.45(m,2H),4.35-4.33(m,2H),2.06(s,3H),1.55(d,J=6.4Hz,6H)。MS(ESI,m/z):382.5[M+H]+。
实施例20:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(2-乙酰氧基)乙酯(28)的合成
以化合物20和乙二醇单乙酸酯为原料,合成化合物28的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ8.93(d,J=5.2Hz,1H),8.64(s,1H),8.50(s,1H),8.38(dd,J=1.6,8.8Hz,1H),8.13(d,J=8.8Hz,1H),7.83(dd,J=1.6,5.2Hz,1H),5.29-5.22(m,1H),4.59-4.56(m,2H),4.44-4.41(m,2H),2.07(s,3H),1.56(d,J=6.8Hz,6H)。MS(ESI,m/z):393.1[M+H]+。
实施例21:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(2-甲氧基)乙酯(29)的合成
以化合物4和乙二醇单甲醚为原料,合成化合物29的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ9.33(s,1H),8.49(d,J=1.6Hz,1H),8.24-8.16(m,3H),5.29-5.22(m,1H),4.38(t,J=4.4Hz,2H),3.65(t,J=4.4Hz,2H),3.32(s,3H),1.54(d,J=6.8Hz,6H)。MS(ESI,m/z):354.1[M+H]+。
实施例22:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(2-甲氧基)乙酯(30)和2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(2-甲氧基)乙酯氢溴酸盐(31)的合成
步骤A:以化合物20和乙二醇单甲醚为原料,合成化合物30的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ8.93(d,J=4.8Hz,1H),8.66(s,1H),8.51(s,1H),8.39(dd,J=1.6,9.2Hz,1H),8.13(d,J=9.2Hz,1H),7.83(dd,J=1.6,5.2Hz,1H),5.29-5.23(m,1H),4.51(t,J=4.4Hz,2H),3.72(t,J=4.4Hz,2H),3.33(s,3H),1.55(d,J=6.4Hz,6H)。MS(ESI,m/z):365.1[M+H]+。
步骤B:将溴化氢通入到化合物30(48mg,0.132mmol)的二氯甲烷(10mL)溶液中使溶液呈强酸性,然后蒸除二氯甲烷,用乙酸乙酯/石油醚重结晶,得2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(2-甲氧基)乙酯氢溴酸盐(31)。1H NMR(DMSO-d6,400MHz)δ8.93(d,J=4.8Hz,1H),8.65(s,1H),8.51(s,1H),8.39(dd,J=1.6,8.8Hz,1H),8.13(d,J=8.8Hz,1H),7.83(dd,J=1.6,5.2Hz,1H),5.29-5.23(m,1H),4.52-4.50(m,2H),3.74-3.71(m,2H),3.33(s,3H),1.55(d,J=6.4Hz,6H)。MS(ESI,m/z):365.1[M+H]+。
实施例23:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸肉桂酯(32)的合成
以化合物4和肉桂醇为原料,合成化合物32的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ9.38(s,1H),8.49(d,J=1.6Hz,1H),8.26-8.17(m,3H),7.52-7.50(m,2H),7.39-7.29(m,3H),6.81(d,J=16.0Hz,1H),6.54-6.46(m,1H),5.29-5.22(m,1H),4.95(d,J=5.6Hz,2H),1.54(d,J=6.8Hz,6H)。MS(ESI,m/z):412.1[M+H]+。
实施例24:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸肉桂酯(33)的合成
以化合物20和肉桂醇为原料,合成化合物33的实验操作参见实施例8。1H NMR(DMSO-d6,400MHz)δ8.93(d,J=4.8Hz,1H),8.68(s,1H),8.56(s,1H),8.39(dd,J=1.6,8.8Hz,1H),8.12(d,J=8.8Hz,1H),7.84(dd,J=1.6,4.8Hz,1H),7.54-7.52(m,2H),7.39-7.30(m,3H),6.86(d,J=16.4Hz,1H),6.60-6.52(m,1H),5.29-5.22(m,1H),5.08(d,J=5.6Hz,2H),1.55(d,J=6.8Hz,6H)。MS(ESI,m/z):423.1[M+H]+。
实施例25:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸(1-异丁酰氧基)乙酯(34)的合成
以化合物4和1-氯乙基异丁酸酯为原料,合成化合物34的实验操作参见实施例18。1H NMR(DMSO-d6,400MHz)δ9.36(s,1H),8.48(s,1H),8.23-8.16(m,3H),6.98(q,J=5.6Hz,1H),5.29-5.22(m,1H),2.62-2.55(m,1H),1.57-1.54(m,9H),1.12-1.10(m,6H)。MS(ESI,m/z):410.1[M+H]+。
实施例26:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸(1-异丁酰氧基)乙酯(35)的合成
以化合物20和1-氯乙基异丁酸酯为原料,合成化合物35的实验操作参见实施例18。1H NMR(DMSO-d6,400MHz)δ8.94(d,J=4.8Hz,1H),8.66(s,1H),8.50(s,1H),8.39(dd,J=1.6,9.2Hz,1H),8.12(d,J=9.2Hz,1H),7.83(dd,J=1.2,4.8Hz,1H),7.04(q,J=5.2Hz,1H),5.29-5.22(m,1H),2.65-2.58(m,1H),1.63(d,J=5.2Hz,3H),1.56(d,J=6.4Hz,6H),1.12(d,J=6.8Hz,6H)。MS(ESI,m/z):421.2[M+H]+。
实施例27:双[2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸]丙-1,3-二酯(36)的合成
以化合物20和1,3-二溴丙烷为原料,合成化合物36的实验操作参见实施例5。1H NMR(DMSO-d6,400MHz)δ8.72(d,J=4.8Hz,2H),8.32-8.31(m,4H),8.17(dd,J=1.2,8.8Hz,2H),7.98(d,J=8.8Hz,2H),7.71(d,J=4.8Hz,2H),5.22-5.15(m,2H),4.62(t,J=6.0Hz,4H),2.33(t,J=6.0Hz,2H),1.53(d,J=6.4Hz,12H)。MS(ESI,m/z):653.2[M+H]+。
实施例28:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[4-(硝基氧基)]丁酯(38)的合成
步骤A:将含有4-溴丁基乙酸酯(1.0g,5.13mmol)、硝酸银(1.30g,7.65mmol)和乙腈(15mL)的混合物在避光下回流搅拌过夜。冷却到室温,过滤除去不溶物。加入水(60mL),用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,然后向剩余物中加入2M氢氧化钠溶液(2.5mL)和甲醇(5mL)。加完后,所得混合物在室温下搅拌2小时。加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并的有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯=5:1洗脱),得4-羟基丁基硝酸酯(37)(400mg)。收率为57.5%。
步骤B:将含有化合物4(80mg,0.272mmol)、化合物37(40mg,0.296mmol)、DCC(84mg,0.407mmol)、DMAP(4mg,0.0327mmol)和二氯甲烷(5mL)的混合物在室温下搅拌过夜。过滤除去不溶物。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯=10:1~10:3洗脱),得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[4-(硝基氧基)]丁酯(38)。1H NMR(DMSO-d6,400MHz)δ9.31(s,1H),8.46(s,1H),8.23-8.16(m,3H),5.29-5.22(m,1H),4.61(t,J=6.0Hz,2H),4.29(t,J=6.0Hz,2H),1.87-1.80(m,4H),1.54(d,J=6.4Hz,6H)。MS(ESI,m/z):413.3[M+H]+。
实施例29:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸[4-(硝基氧基)]丁酯(39)的合成
以化合物20和化合物37为原料,合成化合物39的实验操作参见实施例28中的步骤B。1H NMR(DMSO-d6,400MHz)δ8.91(d,J=4.8Hz,1H),8.63(s,1H),8.49(s,1H),8.38(dd,J=1.6,9.2Hz,1H),8.11(d,J=9.2Hz,1H),7.83(dd,J=1.2,4.8Hz,1H),5.29-5.22(m,1H),4.62(t,J=6.0Hz,2H),4.42(t,J=6.0Hz,2H),1.89-1.86(m,4H),1.56(d,J=6.4Hz,6H)。MS(ESI,m/z):424.0[M+H]+。
实施例30:1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[3-(硝基氧基)甲基]苯酯(41)的合成
步骤A:将含有间羟基苄基溴(500mg,2.67mmol)、硝酸银(500mg,2.94mmol)和乙腈(5mL)
的混合物在冰水浴下避光搅拌5小时。过滤除去不溶物。加入水(20mL),用乙酸乙酯(20mL×2)萃取,合并的有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,石油醚:乙酸乙酯=35:1洗脱),得3-羟基苄基硝酸酯(40)(230mg)。收率为50.9%。
步骤B的实验操作参见实施例28中的步骤B,得1-(3-氰基-1-异丙基-1H-吲唑-5-基)-1H-吡唑-4-甲酸[3-(硝基氧基)甲基]苯酯(42)。1H NMR(DMSO-d6,400MHz)δ9.58(s,1H),8.53(d,J=1.6Hz,1H),8.40(s,1H),8.28-8.19(m,2H),7.57-7.53(m,1H),7.44-7.42(m,2H),7.37-7.35(m,1H),5.64(s,2H),5.30-5.23(m,1H),1.55(d,J=6.4Hz,6H)。MS(ESI,m/z):447.0[M+H]+。
实施例31:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸[3-(硝基氧基)甲基]苯酯(42)的合成
以化合物20和化合物40为原料,合成化合物42的实验操作参见实施例28中的步骤B。1H NMR(DMSO-d6,400MHz)δ9.00(d,J=5.2Hz,1H),8.73(s,2H),8.46(dd,J=1.6,8.8Hz,1H),8.14(d,J=8.8Hz,1H),8.01(dd,J=1.6,5.2Hz,1H),7.61-7.57(m,1H),7.53-7.52(m,1H),7.48-7.45(m,2H),5.66(s,2H),5.30-5.23(m,1H),1.56(d,J=6.8Hz,6H)。MS(ESI,m/z):457.9[M+H]+。
实施例32:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸[2-(硝基氧基)]乙酯(44)的合成
以2-碘乙醇和化合物20为原料,合成化合物44的实验操作参见实施例28。1H NMR(DMSO-d6,400MHz)δ8.91(d,J=4.8Hz,1H),8.63(s,1H),8.50(s,1H),8.37(dd,J=1.6,8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.81(dd,J=1.2,4.8Hz,1H),5.27-5.20(m,1H),4.94-4.92(m,2H),4.69-4.67(m,2H),1.53(d,J=6.8Hz,6H)。MS(ESI,m/z):396.0[M+H]+。
实施例33:2-(3-氰基-1-异丙基-1H-吲唑-5-基)异烟酸[3-(硝基氧基)]丙酯(46)的合成
以3-溴-1-丙醇和化合物20为原料,合成化合物46的实验操作参见实施例28。1H NMR(DMSO-d6,400MHz)δ8.91(d,J=5.2Hz,1H),8.63(s,1H),8.49(s,1H),8.38(dd,J=1.6,8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.83(dd,J=1.2,4.8Hz,1H),5.28-5.18(m,1H),4.56(t,J=6.4Hz,2H),4.43(t,J
=6.4Hz,2H),1.91-1.87(m,2H),1.54(d,J=6.8Hz,6H)。MS(ESI,m/z):468.5[M+ACN+Na]+。
实施例34:化合物22对治疗大鼠高尿酸血症的实验研究
1.实验材料
(1)受试药物
化合物22为浅黄色粉末,临用前采用0.5%CMC-Na研磨,配成相应浓度的混悬液供灌胃。
非布司他,购自Sigma,临用前采用0.5%CMC-Na研磨,配成相应浓度的混悬液供灌胃。
(2)动物及饲养
a.动物种属和来源
SD大鼠,SPF级,36只,雄性,体重180-200g,购自上海斯莱克实验动物有限责任公司,生产许可证号:SCXK(京)2019-0010,质量合格证号:110324221100913432。
b.饲养条件
大鼠均饲养于独立送风笼具中,空气洁净度10000级,实验室温度26±2℃;相对湿度60%~80%;每小时空气交换次数:10-15次/小时;光照周期:12(日)/12(夜)小时,每笼3只。
饲料:鼠全价颗粒饲料,购自江苏省协同医药生物工程有限责任公司,其质量符合GB14924.1-2001《实验动物配合饲料通用质量标准》。
垫料:灭菌颗粒垫料,购自江苏省协同医药生物工程有限责任公司。
饮水:饮用纯化水,经酸化后自由饮用。
(3)主要仪器设备
Varioskan LUX多功能微孔板读数仪购自美国Thermo;BS210S精密电子天平(0.1mg~10g)购自德国赛多利斯;FEJ-200电子天平(0.1~200g)购自福州富日衡之宝电子有限公司;Pacific TII+Genpure XCAD PLUS UV/TOC/UF纯水超纯水系统购自美国Thermo。
(4)主要试剂
尿酸检测试剂盒(磷钨酸还原法),批号:20220305,购自南京建成生物工程研究所;氧嗪酸钾,货号00164,批号GR4VI-RK,购自日本东京化成工业株式会社(TCI);羧甲基纤维素钠(CMC-Na),批号20170810,化学纯,购自国药集团化学试剂有限公司。
2.实验方法
(1)分组
SD大鼠36只,雄性,适应一周后,体重约为200-230g。按体重分层随机分为6组,每组6只,分别为:(1)正常组(0.5%CMC-Na),(2)模型组(0.5%CMC-Na),(3)非布司他1mg/kg,(4)非布司他2mg/kg,(5)化合物22,1.45mg/kg,(6)化合物22,2.9mg/kg。各组药物配成相应浓度混悬液,给药体积均为0.5mL/100g。
(2)模型建立、给药方案与及检测指标
各组大鼠购入适应饲养完毕,禁食12h,分别用氧嗪酸钾按300mg/kg剂量ip造模,造模后0.5h各受试药物组分别灌胃给药1次。分别于氧嗪酸钾注射前以及氧嗪酸钾注射后1、3、5h经眼眶后静脉丛采血,3500rpm离心10min,取血清30μL测定各时间点尿酸水平。
(3)数据处理与统计方法
各试验计量数据均以(平均数)±s标准差)表示,组间比较采用ANOVA-Dunnett T检验考察显著性,以P<0.05作为显著性指标,P<0.01作为极显著性指标。
3.实验结果
结果见表1。与溶剂组相比,氧嗪酸钾模型组在造模后1、3、5h血清尿酸水平显著升高(P<0.05)。与同时间点模型组相比,非布司他1mg/kg及2mg/kg均可显著降低造模后1、3、5h的血清尿酸水平(P<0.01)。与相同时间点模型组相比,化合物22的1.45mg/kg组可显著降低造模后1h的血清尿酸水平(P<0.05)。化合物22的2.9mg/kg组可显著降低造模后1、5h的血清尿酸水平(P<0.05)。
表1.给药后对氧嗪酸钾诱发的高尿酸血症大鼠血清尿酸水平的影响
注:#P<0.05、##P<0.01,与同时间点溶剂组比较;*P<0.05、**P<0.01,与同时间点模型组比较。
实施例35:化合物13、38和41对治疗大鼠高尿酸血症的实验研究
1.实验材料
(1)受试药物
化合物13为浅黄色粉末,化合物38和41为类白色粉末,临用前采用0.5%CMC-Na研磨,配成0.4mg/mL的混悬液供灌胃。
非布司他,购自Sigma,临用前采用0.5%CMC-Na研磨,配成0.4mg/mL的混悬液供灌胃。
(2)动物及饲养
a.动物种属和来源
SD大鼠,SPF级,36只,雄性,体重180-200g,购自上海斯莱克实验动物有限责任公司,生产许可证号:SCXK(京)2019-0010,质量合格证号:110324221100913432。
b.饲养条件
大鼠均饲养于独立送风笼具中,空气洁净度10000级,实验室温度26±2℃;相对湿度60%~80%;每小时空气交换次数:10-15次/小时;光照周期:12(日)/12(夜)小时,每笼3只。
饲料:鼠全价颗粒饲料,购自江苏省协同医药生物工程有限责任公司,其质量符合GB14924.1-2001《实验动物配合饲料通用质量标准》。
垫料:灭菌颗粒垫料,购自江苏省协同医药生物工程有限责任公司。
饮水:饮用纯化水,经酸化后自由饮用。
(3)主要仪器设备
Varioskan LUX多功能微孔板读数仪购自美国Thermo;BS210S精密电子天平(0.1mg~10g)购自德国赛多利斯;FEJ-200电子天平(0.1~200g)购自福州富日衡之宝电子有限公司;Pacific TII+Genpure XCAD PLUS UV/TOC/UF纯水超纯水系统购自美国Thermo。
(4)主要试剂
尿酸检测试剂盒(磷钨酸还原法),批号:20230224,购自南京建成生物工程研究所;氧嗪酸钾,货号00164,批号T6GKM-TA,购自日本东京化成工业株式会社(TCI);羧甲基纤维素钠(CMC-Na),批号20170810,化学纯,购自国药集团化学试剂有限公司。
2.实验方法
(1)分组
SD大鼠36只,雄性,适应一周后,体重约为220-240g。按体重分层随机分为6组,每组6只,分别为:(1)正常组(0.5%CMC-Na),(2)模型组(0.5%CMC-Na),(3)非布司他2mg/kg,(4)化合物13,2mg/kg,(5)化合物38,2mg/kg(6)化合物41,2mg/kg。各组药物配成相应浓度混悬液,给药体积均为0.5mL/100g。
(2)模型建立、给药方案与及检测指标
各组大鼠购入适应饲养完毕,禁食12h,分别用氧嗪酸钾按300mg/kg剂量ip造模,造模后0.5h各受试药物组分别灌胃给药1次。连续给药3天,第3天分别于氧嗪酸钾注射前以及氧嗪酸钾注射后1、3、5h经眼眶后静脉丛采血,3500rpm离心10min,取血清30μL测定各时间点尿酸水平。
(3)数据处理与统计方法
各试验计量数据均以(平均数)±s标准差)表示,组间比较采用ANOVA-Dunnett T检验考察显著性,以P<0.05作为显著性指标,P<0.01作为极显著性指标。
3.实验结果
结果见表2。与溶剂组相比,氧嗪酸钾模型组在造模后1、3、5h血清尿酸水平显著升高(P<0.05)。与同时间点模型组相比,非布司他组可显著降低造模后1、3、5h的血清尿酸水平(P<0.01)。与相同时间点模型组相比,化合物13可显著降低造模后1、3和5h的血清尿酸水平(P<0.01或P<0.05)。化合物38可显著降低造模后1、3、5h的血清尿酸水平(P<0.01或P<0.05)。化合物41可显著降低造模后3、5h的血清尿酸水平(P<0.01)。
表2.给药后对氧嗪酸钾诱发的高尿酸血症大鼠血清尿酸水平的影响
注:##P<0.01,与同时间点溶剂组比较;*P<0.05、**P<0.01,与同时间点模型组比较。
实施例36:化合物的SD大鼠体内药物代谢动力学实验
1.实验材料
(1)受试药物
化合物储备液配制:分别称取适量化合物固体粉末,加入一定量的DMSO,涡旋超声,得10mg/mL的储备液。
用于灌胃的试验化合物配制:分别移取适量化合物储备液,加入一定量Solutol HS15溶液,涡旋1分钟,再加入一定量生理盐水,充分混合均匀,得1mg/mL的溶液。
用于静脉注射的试验化合物配制:分别移取适量化合物储备液,加入一定量Solutol HS15溶液,涡旋1分钟,再加入一定量生理盐水,充分混合均匀,得0.5mg/mL的溶液。
(2)实验动物
SD大鼠,雄性,SPF级,6-8周龄。购自JH Laboratory Animal Co.LTD。许可证号:SCXK(SH)2017-0012、SCXK(SH)2022-0009,合格证编号:20170012022154、20220009005149。
2.实验方法
(1)给药剂量及方式
试验动物在灌胃给药前禁食过夜,给药4小时后再给予食物,期间自由饮水。每个试验化合物均设2个组别,分别为静脉给药组合口服给药组,具体给药剂量及方式见下表3。
表3.化合物对SD大鼠的给药剂量和方式
(2)实验操作
分别于给药前和给药后5分钟(仅静脉给药组)、15分钟、30分钟、1小时、2小时、4小时、8小时和24小时,采集SD大鼠颈静脉血样(150μL/样本),并置于含有抗凝剂肝素钠的离心管中,4℃,2000g离心5分钟分离血浆。采用LC/MS/MS对血浆样品进行分析,检测血浆样本中各受试化合物的浓度。
(3)药物代谢动力学分析
非房室模型相关参数由Professional软件计算获得。
3.实验结果
依据上述方法获得的各受试化合物的SD大鼠药物代谢动力学参数如表4所示。本发明的各化合物的药物代谢动力学相关参数良好,生物利用度高。
表4.口服或静脉注射给予各化合物的SD大鼠药物代谢动力学参数
Claims (10)
- 通式(I)所示的化合物或其药学上可接受的盐,
其中,R为C1-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-6烷基、C1-6烷氧基、C3-6环烷基或C3-6杂环烷基中的一种或多种;Ar为取代或非取代的以下基团:Ar基团中的取代基选自氘、羟基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;Y为O或NR3,R1为连接键或者取代或非取代的C1-6亚烷基或者取代或非取代的C2-12亚烯基,R1基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-4烷基或C1-4烷氧基中的一种或多种;R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、C4-12稠杂芳环基、C4-16稠杂芳环基吡唑基羰基氧基、C4-16稠杂芳环基吡啶基羰基氧基、C4-16稠杂芳环基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C2-20烯基、C2-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-6烷基、卤代C1-6烷基、硝基氧基取代的C1-6烷基或C1-6烷氧基中的一种或多种;R3为氢或C1-6烷基。 - 根据权利要求1所述的化合物或其药学上可接受的盐,其中化合物选自通式(II)、(III)或(IV)所示的化合物,
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中Y为O或NH,R为C3-6烷基、取代的C1-6烷基、C3-6环烷基、取代的C3-6环烷基、C3-6杂环烷基或取代的C3-6杂环烷基;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中R为C3-6烷基、取代的C1-6烷基、C3-6环烷 基、取代的C3-6环烷基、四氢呋喃、取代的四氢呋喃、四氢噻吩、取代的四氢噻吩、四氢吡咯或取代的四氢吡咯;其中R所涉及的各基团中的取代基选自氘、氰基、硝基、卤素、C1-5烷基、C1-5烷氧基或C3-6环烷基中的一种或多种。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中R1为连接键或者取代或非取代的C1-4亚烷基或者取代或非取代的C4-12亚烯基,R1基团中的取代基选自氘、氨基、氰基、卤素或C1-4烷氧基中的一种或多种。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲唑基、喹啉基、异喹啉基、吲哚基、苯并呋喃基、嘌呤基、吲唑基吡唑基羰基氧基、喹啉基吡唑基羰基氧基、异喹啉基吡唑基羰基氧基、吲哚基吡唑基羰基氧基、苯并呋喃基吡唑基羰基氧基、嘌呤基吡唑基羰基氧基、吲唑基吡啶基羰基氧基、喹啉基吡啶基羰基氧基、异喹啉基吡啶基羰基氧基、吲哚基吡啶基羰基氧基、苯并呋喃基吡啶基羰基氧基、嘌呤基吡啶基羰基氧基、吲唑基三氮唑基羰基氧基、喹啉基三氮唑基羰基氧基、异喹啉基三氮唑基羰基氧基、吲哚基三氮唑基羰基氧基、苯并呋喃基三氮唑基羰基氧基、嘌呤基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C6-20炔基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-6烷基、卤代C1-6烷基、硝基氧基取代的C1-6烷基或C1-6烷氧基中的一种或多种。
- 根据权利要求5所述的化合物或其药学上可接受的盐,其中R2为氢、硝基氧基、羧基或者取代或非取代的下述基团:二氧杂环戊烯-2-酮基、吲唑基吡唑基羰基氧基、吲唑基吡啶基羰基氧基、吲唑基三氮唑基羰基氧基、吲哚基吡唑基羰基氧基、吲哚基吡啶基羰基氧基、吲哚基三氮唑基羰基氧基、C2-6酯基、吡啶基、苯基、C1-6烷氧基、C6-20烯基、C2-8烷基羰基氧基或C2-8烷氧基羰基氧基,R2基团中的取代基选自氘、羟基、氨基、氰基、卤素、C1-6烷基、硝基氧基取代的C1-6烷基或C1-6烷氧基中的一种或多种。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中化合物选自:
- 一种药物组合物,它以权利要求1所述的化合物或其药学上可接受的盐为活性物质,辅以药学上可接受的辅料。
- 权利要求1所述的化合物或其药学上可接受的盐在制备抗痛风药物或抗高尿酸血症药物方面的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210456939.3 | 2022-04-27 | ||
CN202210456939 | 2022-04-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023208108A1 true WO2023208108A1 (zh) | 2023-11-02 |
Family
ID=87872273
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2023/091140 WO2023208108A1 (zh) | 2022-04-27 | 2023-04-27 | 可用于降尿酸的化合物 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN116715633A (zh) |
TW (1) | TW202342456A (zh) |
WO (1) | WO2023208108A1 (zh) |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101282936A (zh) * | 2005-10-07 | 2008-10-08 | 橘生药品工业株式会社 | 氮化杂环化合物及包含其的药物组合物 |
WO2010093191A2 (en) * | 2009-02-13 | 2010-08-19 | Lg Life Sciences Ltd. | Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same |
EP2338887A1 (en) * | 2008-10-15 | 2011-06-29 | Kissei Pharmaceutical Co., Ltd. | Fused heterocyclic derivative and use thereof for medical purposes |
CN102574839A (zh) * | 2009-10-07 | 2012-07-11 | 株式会社Lg生命科学 | 有效作为黄嘌呤氧化酶抑制剂的新化合物、该化合物的制备方法和含有该化合物的药物组合物 |
CN103459381A (zh) * | 2011-04-06 | 2013-12-18 | 株式会社Lg生命科学 | 1-(3-氰基-1-异丙基-吲哚-5-基)吡唑-4-甲酸晶型及其生产方法 |
US20140005221A1 (en) * | 2011-01-28 | 2014-01-02 | Sato Pharmaceutical Co., Ltd. | Ring-fused compound |
CN105439946A (zh) * | 2014-08-13 | 2016-03-30 | 上海页岩科技有限公司 | 羧酸化合物及其制备方法和用途 |
CN106432229A (zh) * | 2015-09-10 | 2017-02-22 | 江苏新元素医药科技有限公司 | 一类用于治疗或预防高尿酸血症或痛风的化合物 |
CN107759588A (zh) * | 2016-08-19 | 2018-03-06 | 江苏新元素医药科技有限公司 | 一类苯基‑(吡唑并[1,5‑a]吡啶‑3‑基)甲酮衍生物 |
CN115160299A (zh) * | 2021-04-29 | 2022-10-11 | 江苏新元素医药科技有限公司 | 一类黄嘌呤氧化酶抑制剂 |
-
2023
- 2023-04-27 WO PCT/CN2023/091140 patent/WO2023208108A1/zh unknown
- 2023-04-27 TW TW112115878A patent/TW202342456A/zh unknown
- 2023-04-27 CN CN202310469300.3A patent/CN116715633A/zh active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101282936A (zh) * | 2005-10-07 | 2008-10-08 | 橘生药品工业株式会社 | 氮化杂环化合物及包含其的药物组合物 |
EP2338887A1 (en) * | 2008-10-15 | 2011-06-29 | Kissei Pharmaceutical Co., Ltd. | Fused heterocyclic derivative and use thereof for medical purposes |
WO2010093191A2 (en) * | 2009-02-13 | 2010-08-19 | Lg Life Sciences Ltd. | Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same |
CN102574839A (zh) * | 2009-10-07 | 2012-07-11 | 株式会社Lg生命科学 | 有效作为黄嘌呤氧化酶抑制剂的新化合物、该化合物的制备方法和含有该化合物的药物组合物 |
US20140005221A1 (en) * | 2011-01-28 | 2014-01-02 | Sato Pharmaceutical Co., Ltd. | Ring-fused compound |
CN103459381A (zh) * | 2011-04-06 | 2013-12-18 | 株式会社Lg生命科学 | 1-(3-氰基-1-异丙基-吲哚-5-基)吡唑-4-甲酸晶型及其生产方法 |
CN105439946A (zh) * | 2014-08-13 | 2016-03-30 | 上海页岩科技有限公司 | 羧酸化合物及其制备方法和用途 |
CN106432229A (zh) * | 2015-09-10 | 2017-02-22 | 江苏新元素医药科技有限公司 | 一类用于治疗或预防高尿酸血症或痛风的化合物 |
CN107759588A (zh) * | 2016-08-19 | 2018-03-06 | 江苏新元素医药科技有限公司 | 一类苯基‑(吡唑并[1,5‑a]吡啶‑3‑基)甲酮衍生物 |
CN115160299A (zh) * | 2021-04-29 | 2022-10-11 | 江苏新元素医药科技有限公司 | 一类黄嘌呤氧化酶抑制剂 |
Also Published As
Publication number | Publication date |
---|---|
TW202342456A (zh) | 2023-11-01 |
CN116715633A (zh) | 2023-09-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2021078301A1 (zh) | 蛋白降解剂及其在疾病治疗中的应用 | |
Wang et al. | Design and synthesis of 3-(4-pyridyl)-5-(4-sulfamido-phenyl)-1, 2, 4-oxadiazole derivatives as novel GSK-3β inhibitors and evaluation of their potential as multifunctional anti-Alzheimer agents | |
CN105102453B (zh) | 作为布罗莫结构域抑制剂的苯并咪唑酮衍生物 | |
CN105732640B (zh) | 醛糖还原酶抑制剂及其用途 | |
CN106478500A (zh) | 羧酸取代的(杂)芳环类衍生物及其制备方法和用途 | |
JP2022022368A (ja) | がんおよび糖尿病の治療に有用な6-アリール-4-モルホリン-1-イルピリドン化合物 | |
TWI844849B (zh) | 一類黃嘌呤氧化酶抑制劑 | |
WO2012031563A1 (zh) | 杂环氨基小檗胺衍生物、其制备方法和应用 | |
WO2020043173A1 (zh) | 作为受体相互作用蛋白1(rip1)激酶抑制剂的杂环化合物 | |
WO2023116835A9 (zh) | 一种具有酰亚胺骨架的多蛋白降解剂 | |
WO2016000568A1 (zh) | 一种治疗痛风的化合物 | |
CN110240587B (zh) | 一类芳基二氟苄基醚类化合物、制备方法及用途 | |
RU2670088C1 (ru) | Соль мангиферин-6-о-берберина, способ ее получения и применение | |
CA3030232A1 (en) | Pyrimidinone derivatives and uses thereof to neutralize the biological activity of chemokines | |
BR112021005086A2 (pt) | tratamento para doença hepática gordurosa não alcoólica | |
WO2018157801A1 (zh) | 氰基取代的稠合双环衍生物及其制备方法和用途 | |
CN106478619B (zh) | 一类黄嘌呤氧化酶抑制剂及其应用 | |
WO2023208108A1 (zh) | 可用于降尿酸的化合物 | |
CN106146533A (zh) | 含硫杂环羧酸类衍生物、其制备方法和应用 | |
JP2020506965A (ja) | プロテインキナーゼ活性を阻害するための(ヘテロ)アリールアミド系化合物 | |
ES2970120T3 (es) | Sal de potasio monohidratada de un derivado de tienopiridona y su proceso de preparación | |
WO2023208103A1 (zh) | 可用于痛风的化合物 | |
TWI831325B (zh) | 作為atr抑制劑的萘啶衍生物及其製備方法 | |
WO2020177752A1 (zh) | 1,2,4-三唑类化合物及其制法和药物用途 | |
US20210380586A1 (en) | 2-indolyl imidazo[4,5-d]phenanthroline polymorphs and compositions regarding the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23795540 Country of ref document: EP Kind code of ref document: A1 |