CN117045647A - 4-羟基吡唑类化合物及其衍生物和盐在制备抑制铁死亡药物中的应用 - Google Patents
4-羟基吡唑类化合物及其衍生物和盐在制备抑制铁死亡药物中的应用 Download PDFInfo
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- CN117045647A CN117045647A CN202310968611.4A CN202310968611A CN117045647A CN 117045647 A CN117045647 A CN 117045647A CN 202310968611 A CN202310968611 A CN 202310968611A CN 117045647 A CN117045647 A CN 117045647A
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- CN
- China
- Prior art keywords
- hydroxy
- pyrazole
- chlorophenyl
- phenyl
- nmr
- Prior art date
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229910052742 iron Inorganic materials 0.000 title claims abstract description 34
- 230000034994 death Effects 0.000 title claims abstract description 33
- 239000003814 drug Substances 0.000 title claims abstract description 15
- 150000003839 salts Chemical class 0.000 title claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title claims description 11
- KAUABWYBFARJAF-UHFFFAOYSA-N 1h-pyrazol-4-ol Chemical class OC=1C=NNC=1 KAUABWYBFARJAF-UHFFFAOYSA-N 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title description 12
- -1 4-hydroxy pyrazole compound Chemical class 0.000 claims abstract description 172
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- MCWGALOBIOENGQ-UHFFFAOYSA-N 3-(4-chlorophenyl)-1-methyl-5-phenylpyrazol-4-ol Chemical compound CN1N=C(C=2C=CC(Cl)=CC=2)C(O)=C1C1=CC=CC=C1 MCWGALOBIOENGQ-UHFFFAOYSA-N 0.000 claims description 4
- WUDYUEUMBVOTSY-UHFFFAOYSA-N C1=CC=C(C=C1)C2=NNC(=C2O)C3=CC=C(C=C3)Br Chemical compound C1=CC=C(C=C1)C2=NNC(=C2O)C3=CC=C(C=C3)Br WUDYUEUMBVOTSY-UHFFFAOYSA-N 0.000 claims description 4
- KCEQOUUPAPQVNJ-UHFFFAOYSA-N CN1C(=C(C(=N1)C2=CC=CC=C2)O)C3=CC=C(C=C3)Br Chemical compound CN1C(=C(C(=N1)C2=CC=CC=C2)O)C3=CC=C(C=C3)Br KCEQOUUPAPQVNJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- AWAVVFCXLWOCMD-UHFFFAOYSA-N 3,5-diphenyl-1h-pyrazol-4-ol Chemical compound OC=1C(C=2C=CC=CC=2)=NNC=1C1=CC=CC=C1 AWAVVFCXLWOCMD-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- UJHBVMHOBZBWMX-UHFFFAOYSA-N ferrostatin-1 Chemical compound NC1=CC(C(=O)OCC)=CC=C1NC1CCCCC1 UJHBVMHOBZBWMX-UHFFFAOYSA-N 0.000 abstract description 13
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 22
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- 101100173542 Caenorhabditis elegans fer-1 gene Proteins 0.000 description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 7
- WCBPJVKVIMMEQC-UHFFFAOYSA-N 1,1-diphenyl-2-(2,4,6-trinitrophenyl)hydrazine Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1NN(C=1C=CC=CC=1)C1=CC=CC=C1 WCBPJVKVIMMEQC-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 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 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 229940125851 compound 27 Drugs 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 230000003859 lipid peroxidation Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 229940045835 RSL3 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 4
- 230000007760 free radical scavenging Effects 0.000 description 4
- 239000000411 inducer Substances 0.000 description 4
- TXJZRSRTYPUYRW-NQIIRXRSSA-N methyl (1s,3r)-2-(2-chloroacetyl)-1-(4-methoxycarbonylphenyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate Chemical compound C1([C@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](N2C(=O)CCl)C(=O)OC)=CC=C(C(=O)OC)C=C1 TXJZRSRTYPUYRW-NQIIRXRSSA-N 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- 230000002292 Radical scavenging effect Effects 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- MGJZITXUQXWAKY-UHFFFAOYSA-N diphenyl-(2,4,6-trinitrophenyl)iminoazanium Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1N=[N+](C=1C=CC=CC=1)C1=CC=CC=C1 MGJZITXUQXWAKY-UHFFFAOYSA-N 0.000 description 2
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- HSYSVXKJIVUNBR-UHFFFAOYSA-N 3-(benzylamino)-4-(cyclohexylamino)-N-(2-piperazin-1-ylethyl)benzenesulfonamide Chemical compound C(C1=CC=CC=C1)NC=1C=C(C=CC=1NC1CCCCC1)S(=O)(=O)NCCN1CCNCC1 HSYSVXKJIVUNBR-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZOCSXAVNDGMNBV-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile Chemical compound NC1=C(S(=O)C(F)(F)F)C(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl ZOCSXAVNDGMNBV-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000005899 Fipronil Substances 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
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- 238000003782 apoptosis assay Methods 0.000 description 1
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- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
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- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- 229940013764 fipronil Drugs 0.000 description 1
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- 239000012530 fluid Substances 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
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- 239000001963 growth medium Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- KJDJPXUIZYHXEZ-UHFFFAOYSA-N hydrogen sulfate;methylaminoazanium Chemical compound CN[NH3+].OS([O-])(=O)=O KJDJPXUIZYHXEZ-UHFFFAOYSA-N 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
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- 101150077696 lip-1 gene Proteins 0.000 description 1
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- YAFQFNOUYXZVPZ-UHFFFAOYSA-N liproxstatin-1 Chemical compound ClC1=CC=CC(CNC=2C3(CCNCC3)NC3=CC=CC=C3N=2)=C1 YAFQFNOUYXZVPZ-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- NGGPLHHTRNJSDT-UHFFFAOYSA-N methylmaltol Natural products COC1=C(C)OC=CC1=O NGGPLHHTRNJSDT-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
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- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- NLXXVSKHVGDQAT-UHFFFAOYSA-N o-(oxan-2-yl)hydroxylamine Chemical compound NOC1CCCCO1 NLXXVSKHVGDQAT-UHFFFAOYSA-N 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
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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
-
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Abstract
本发明属于药物化学领域,具体涉及一种4‑羟基吡唑类化合物及其衍生物和盐在制备抑制铁死亡药物中的应用。本发明的4‑羟基吡唑类化合物及其衍生物和在药学上可接受的盐,在多种细胞系中铁死亡抑制活性优于经典的铁死亡抑制剂Ferrostatin‑1。
Description
技术领域
本发明属于药物化学领域,具体涉及一种4-羟基吡唑类化合物及其衍生物和盐在制备抑制铁死亡药物中的应用。
背景技术
铁死亡(Ferroptosis)是近年发现的一种铁依赖的新型程序性细胞死亡方式,与传统的凋亡、坏死或自噬等细胞死亡模式不同,其典型特征为细胞内脂质过氧化物和活性氧簇的过量积蓄。大量研究表明,铁死亡与心脑血管疾病、肝病、肾病、神经退行性疾病等多种重大慢性疾病的发生和发展密切相关,因此,铁死亡抑制剂已成为防治相关疾病的热点靶标药物。
目前现有的铁死亡抑制剂包括:Ferrostatin-1(Fer-1)(Cell,2012,149,1060–1072)、Liprostatin-1(Lip-1)(Nat.Cell Biol.,2014,16,1180–1191)和UAMC-3203(J.Med.Chem.,2018,61,10126-10140)等。
CN201410540869.5的发明公开了一种多取代4-羟基吡唑类衍生物的制备方法,4-羟基吡唑类衍生物据报道具有较好的药效学性质和重要的生理活性,比如抗菌、抗病毒以及抗血栓。吡唑类衍生物特别是多取代的吡唑环已报道在一些上市药物结构中,如塞来昔布(治疗骨关节炎和风湿性关节炎)、氟虫腈(杀虫剂)。
发明内容
本发明要解决的技术问题是提供一种4-羟基吡唑类化合物及其及其衍生物和盐在制备抑制铁死亡药物中的应用。
为解决上述技术问题,本发明提供4-羟基吡唑类化合物及其衍生物和盐在制备抑制铁死亡药物中的应用,4-羟基吡唑类化合物的通式如下:
作为本发明的应用的改进,通式中:
R1为氢、烷基,苯基;R2,R3为烷基、芳基,
烷基为以下任一:甲基、乙基、正丙基、正丁基,
芳基为以下任一苯基、取代苯基、萘基、吡啶基、呋喃基、咪唑基;
取代苯基的取代基为以下任一:氟、氯、溴、甲基、甲氧基、羟基、3,4-亚甲二氧基、三氟甲基、苯基、硝基、甲氧羰基、羧基、
作为本发明的应用的进一步改进,4-羟基吡唑类化合物的盐为药学上可接受的盐,优选4-羟基吡唑类化合物的盐酸盐。
作为本发明的应用的进一步改进:
4-羟基吡唑类化合物为以下任一:
3,5-二苯基-4-羟基-1H-吡唑、3-(4-甲氧基苯基)-5-苯基-4-羟基-1H-吡唑、3-(4-氟苯基)-5-苯基-4-羟基-1H-吡唑、3-(4-氯苯基)-5-苯基-4-羟基-1H-吡唑、3-(3-氯苯基)-5-苯基-4-羟基-1H-吡唑、3-(2-氯苯基)-5-苯基-4-羟基-1H-吡唑、3-(2,4-二氯苯基)-5-苯基-4-羟基-1H-吡唑、5-苯基-3-(间甲苯基)-4-羟基-1H-吡唑、5-苯基-3-(4-(三氟甲基)苯基)-4-羟基-1H-吡唑、3-(苯并[d][1,3]二氧代醇-5-基)-5-苯基-4-羟基-1H-吡唑、3-([1,1'-联苯]-4-基)-5-苯基-4-羟基-1H-吡唑、3-(4-氯苯基)-1,5-二苯基-4-羟基-1H-吡唑、3-(4-氯苯基)-1-甲基-5-苯基-4-羟基-1H-吡唑、5-(4-溴苯基)-1-甲基-3-苯基-4-羟基-1H-吡唑、5-(4-溴苯基)-3-苯基-4-羟基-1H-吡唑、5-(4-甲氧基苯基)-3-苯基-4-羟基-1H-吡唑、5-(4-氟苯基)-3-苯基-4-羟基-1H-吡唑、5-(4-氯苯基)-3-苯基-4-羟基-1H-吡唑、5-(2-呋喃)-3-苯基-4-羟基-1H-吡唑、5-正丁基-3-苯基-4-羟基-1H-吡唑、5-(4-氯苯基)-3-(2-甲氧基苯基)-4-羟基-1H-吡唑、5-(4-氯苯基)-3-(2-羟基苯基)-4-羟基-1H-吡唑、3-(4-硝基苯基)-5-(对甲苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-氟苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-(三氟甲基)苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-甲氧基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-羟基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(3,4-二甲氧基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(3,4-二羟基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(1-萘基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(1H-咪唑4-基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(吡啶-2-基)-4-羟基-1H-吡唑;
4-羟基吡唑类化合物的衍生物为以下任一:4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸甲酯、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-乙基苯甲酰胺、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-(3-(二甲氨基)丙基)苯甲酰胺、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-(2-(3-羟基-2-甲基-4-氧代吡啶-1(4H)基)乙基)苯甲酰胺;
4-羟基吡唑类化合物的盐酸盐为以下任一:4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸盐酸盐、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-羟基苯甲酰胺盐酸盐。
即,本发明提供的通式(I)化合物含有足以形成盐的碱性官能团,代表性的药用无机酸盐选用盐酸盐。
作为本发明的应用的进一步改进:在多种细胞系中能有效抑制细胞铁死亡。所述细胞为HT-1080、786-O、H9C2、BJ。
本发明发现:4-羟基吡唑类衍生物具有抑制细胞铁死亡的生物活性。细胞结果表明,该类化合物在多种细胞系中均能有效抑制细胞铁死亡。进一步研究表明,该类化合物能有效清除自由基,降低细胞内脂质过氧化水平。
本发明有益效果:所述4-羟基吡唑类化合物及其衍生物和在药学上可接受的盐,在多种细胞系中铁死亡抑制活性优于经典的铁死亡抑制剂Ferrostatin-1。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细说明。
图1为二苯基苦基苯肼(DPPH)法检测评估铁死亡特异抑制剂Ferrostatin-1(Fer-1)及化合物4、26、27的自由基清除能力;
图2为Fer-1及化合物27在四种细胞中抑制RSL3诱导铁死亡的量效曲线;
图3为C11-BODIPY法检测评估化合物Fer-1及27抗脂质过氧化能力。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实施例1、3,5-二苯基-4-羟基-1H-吡唑(1)
制备方法同CN201410540869.5的实施例1。
实施例2、3-(4-甲氧基苯基)-5-苯基-4-羟基-1H-吡唑(2)
制备方法同CN201410540869.5的实施例7。
实施例3、3-(4-氟苯基)-5-苯基-4-羟基-1H-吡唑(3)
将2mmol的2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮与0.24ml(4mmol)水合肼加至反应瓶中,加入5ml N,N-二甲基甲酰胺,再加入0.598ml(4mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯,室温反应12h,待TLC板检测原料消失。减压蒸出溶剂,粗产品经柱层析纯化(石油醚:乙酸乙酯=5:1),收集所有的洗脱液,而后脱除石油醚和乙酸乙酯的混合液,得到白色固体,收率64%。
白色固体,mp:236-237℃.1H NMR(500MHz,DMSO-d6)δ12.89(s,1H),8.34(s,1H),7.93(d,J=31.7Hz,4H),7.45(m,J=7.6Hz,2H),7.35-7.21(m,3H).13C NMR(125MHz,Acetone-d6)δ135.31,128.52,127.87,127.81,127.19,125.81,115.22,115.05.HRMS(ESI)m/z calcd for C15H11FN2O[M+H]+:255.0928.Found:255.0931。
实施例4、3-(4-氯苯基)-5-苯基-4-羟基-1H-吡唑(4)
制备方法同CN201410540869.5的实施例6。
实施例5、3-(3-氯苯基)-5-苯基-4-羟基-1H-吡唑(5)
以2-叠氮-1-(3-氯苯基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率69%。
白色固体,mp:208-209℃.1H NMR(500MHz,DMSO-d6)δ13.02(s,1H),8.51(s,1H),8.08-7.76(m,4H),7.47(m,J=7.8Hz,3H),7.39-7.28(m,2H).13C NMR(125MHz,Acetone-d6)δ135.84,133.90,130.12,128.58,127.34,126.77,125.86,125.51,124.12.HRMS(ESI)m/zcalcd for C16H11ClN2O[M+H]+:271.0633.Found:271.0633.
实施例6、3-(2-氯苯基)-5-苯基-4-羟基-1H-吡唑(6)
以2-叠氮-1-(2-氯苯基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率96%。
白色固体,mp:154-155℃.1H NMR(500MHz,DMSO-d6)δ12.86(d,J=169.5Hz,1H),8.41(s,1H),7.92(d,J=29.1Hz,2H),7.72(s,1H),7.58-7.48(m,2H),7.44(s,2H),7.28(t,J=7.2Hz,1H).13C NMR(125MHz,Acetone-d6)δ136.79,134.56,134.08,133.33,129.23,128.48,127.10,126.95,125.41.HRMS(ESI)m/z calcd for C16H11ClN2O[M+H]+:271.0633.Found:271.0636.
实施例7、3-(2,4-二氯苯基)-5-苯基-4-羟基-1H-吡唑(7)
以2-叠氮-1-(2,4-二氯苯基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率96%。
白色固体,mp:184-185℃.1H NMR(500MHz,DMSO-d6)δ12.86(d,J=169.5Hz,1H),8.41(s,1H),7.92(d,J=29.1Hz,2H),7.72(s,1H),7.58-7.48(m,2H),7.44(s,2H),7.28(t,J=7.2Hz,1H).13C NMR(125MHz,Acetone-d6)δ136.79,134.56,134.08,133.33,129.23,128.48,127.10,126.95,125.41.HRMS(ESI)m/z calcd for C15H10Cl2N2O[M+H]+:305.0243.Found:305.0250.
实施例8、5-苯基-3-(间甲苯基)-4-羟基-1H-吡唑(8)
以2-叠氮基-3-苯基-1-(间甲苯基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率74%。
淡黄色固体,mp:244-245℃.1H NMR(500MHz,DMSO-d6)δ12.84(s,1H),8.28(s,1H),7.92(d,J=7.5Hz,2H),7.76–7.69(m,2H),7.44(t,J=7.7Hz,2H),7.31(dt,J=14.9,7.5Hz,2H),7.12(d,J=7.5Hz,1H),2.36(s,3H).13C NMR(125MHz,DMSO-d6)δ137.92,135.74,128.95,128.88,128.07,127.37,126.48,125.92,123.13,21.73.HRMS(ESI)m/zcalcd for C16H14N2O[M+H]+:251.1179.Found:251.1180.
实施例9、5-苯基-3-(4-(三氟甲基)苯基)-4-羟基-1H-吡唑(9)
以2-叠氮-3-苯基-1-(4-(三氟甲基)苯基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率38%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ13.13(s,1H),8.59(s,1H),8.17(d,J=34.9Hz,2H),7.99-7.74(m,4H),7.47(d,J=7.8Hz,2H),7.33(m,J=7.4Hz,1H).13CNMR(125MHz,Acetone-d6)δ136.24,128.62,127.43,126.11,125.89,125.30,125.27.HRMS(ESI)m/z calcd for C16H11F3N2O[M+H]+:305.0896.Found:305.0899.
实施例10、3-(苯并[d][1,3]二氧代醇-5-基)-5-苯基-4-羟基-1H-吡唑(10)
以2-叠氮-1-(苯并[d][1,3]二氧基-5-基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率59%。
白色固体,mp:211-212℃.1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),8.24(s,1H),7.90(s,2H),7.44(s,4H),7.29(m,1H),7.01(d,J=7.8Hz,1H),6.05(s,2H).13C NMR(125MHz,Acetone-d6)δ147.88,146.81,135.00,128.43,127.04,125.83,119.60,108.24,106.35,101.12.HRMS(ESI)m/z calcd for C16H12N2O3[M+H]+:281.0921.Found:281.0921.
实施例11、3-([1,1'-联苯]-4-基)-5-苯基-4-羟基-1H-吡唑(11)
以1-([1,1'-联苯]-4-基)-2-叠氮-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率52%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ12.94(s,1H),8.40(s,1H),7.99(d,J=48.5Hz,4H),7.75(m,4H),7.47(m,4H),7.34(m,2H).13C NMR(125MHz,DMSO-d6)δ135.98,129.46,129.02,128.92,127.90,127.43,127.20,127.19,126.97.HRMS(ESI)m/zcalcd for C21H16N2O[M+H]+:313.1335.Found:313.1328.
实施例12、3-(4-氯苯基)-1,5-二苯基-4-羟基-吡唑(12)
以2-叠氮-1-(4-氯苯基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;以苯肼代替水合肼,摩尔用量保持不变;其余同实施例3,收率45%。
淡黄色固体,mp:181-182℃.1H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.06(d,J=8.6Hz,2H),7.52(d,J=8.6Hz,2H),7.42–7.24(m,10H).13C NMR(125MHz,DMSO-d6)δ140.53,140.42,138.12,132.32,131.97,131.88,129.95,129.41,129.33,129.01,128.95,128.53,128.14,127.63,125.00.HRMS(ESI)m/z calcd for C21H15ClN2O[M+H]+:347.0946.Found:347.0950.
实施例13、3-(4-氯苯基)-1-甲基-5-苯基-4-羟基-吡唑(13)
以2-叠氮-1-(4-氯苯基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;以甲基肼硫酸盐代替水合肼,摩尔用量保持不变;其余同实施例3,收率38%。
黄色固体,mp:172-173℃.1H NMR(500MHz,DMSO-d6)δ8.33(s,1H),7.98(d,J=8.1Hz,2H),7.54(d,J=7.8Hz,4H),7.47(d,J=8.5Hz,3H),3.76(s,3H).13C NMR(125MHz,Acetone-d6)δ136.87,136.37,132.62,131.64,129.65,129.23,128.69,128.30,128.24,127.31,37.47.HRMS(ESI)m/z calcd for C16H13ClN2O[M+H]+:285.0789.Found:285.0795.
实施例14、5-(4-溴苯基)-1-甲基-3-苯基-4-羟基-吡唑(14)
制备方法同CN201410540869.5的实施例10。
实施例15、5-(4-溴苯基)-3-苯基-4-羟基-1H-吡唑(15)
制备方法同CN201410540869.5的实施例2。
实施例16、5-(4-甲氧基苯基)-3-苯基-4-羟基-1H-吡唑(16)
制备方法同CN201410540869.5的实施例3。
实施例17、5-(4-氟苯基)-3-苯基-4-羟基-1H-吡唑(17)
以2-叠氮-3-(4-氟苯基)-1-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变,其余同实施例3,收率54%。
淡黄色固体,mp:231-232℃.1H NMR(500MHz,DMSO-d6)δ12.90(s,1H),8.36(s,1H),7.94(d,J=31.2Hz,4H),7.45(m,2H),7.30(m,3H).13C NMR(125MHz,Acetone-d6)δ135.32,128.51,127.89,127.82,127.19,125.83,115.22,115.05.HRMS(ESI)m/z calcd forC15H11FN2O[M+H]+:255.0928.Found:255.0930.
实施例18、5-(4-氯苯基)-3-苯基-4-羟基-1H-吡唑(18)
以2-叠氮-3-(4-氯苯基)-1-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率79%。
黄色固体,mp:240-241℃.1H NMR(400MHz,DMSO-d6)δ12.95(s,1H),8.41(s,1H),7.93(d,J=26.6Hz,4H),7.48(d,J=21.0Hz,4H),7.32(d,J=6.5Hz,1H).13C NMR(125MHz,Acetone-d6)δ135.59,132.13,131.11,128.52,128.45,127.37,127.24,125.83.HRMS(ESI)m/zcalcd for C15H11ClN2O[M+H]+:271.0633.Found:271.0635.
实施例19、5-(2-呋喃)-3-苯基-4-羟基-1H-吡唑(19)
制备方法同CN201410540869.5的实施例4。
实施例20、5-正丁基-3-苯基-4-羟基-1H-吡唑(20)
以2-叠氮-1-苯基庚-2-烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率47%。
淡黄色固体,mp:211-212℃.1H NMR(500MHz,DMSO-d6)δ12.73(s,1H),8.17(s,1H),7.87(s,4H),7.43(s,2H),7.29(t,J=7.1Hz,1H),7.02(s,2H),3.79(s,3H).13C NMR(125MHz,Acetone-d6)δ205.36,159.02,128.37,127.19,126.92,125.81,113.84,54.67.HRMS(ESI)m/zcalcd for C13H16N2O[M+H]+:217.1335.Found:217.1344.
实施例21、5-(4-氯苯基)-3-(2-甲氧基苯基)-4-羟基-1H-吡唑(21)
以-2-叠氮-3-(4-氯苯基)-1-(2-甲氧基苯基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率74%。
白色固体,mp:167-168℃.1H NMR(500MHz,DMSO-d6)δ12.53(s,1H),8.13(s,1H),8.07–7.93(m,2H),7.72(s,1H),7.48(d,J=8.3Hz,2H),7.38–7.33(m,1H),7.12(d,J=8.2Hz,1H),7.05(t,J=7.4Hz,1H),3.85(s,3H).13C NMR(125MHz,DMSO-d6)δ161.11,136.12,134.30,133.61,132.27,125.72,116.73,60.73.HRMS(ESI)m/z calcd forC16H13ClN2O2[M+H]+:301.0738.Found:301.0736.
实施例22、5-(4-氯苯基)-3-(2-羟基苯基)-4-羟基-1H-吡唑(22)
将300mg(1mmol)5-(4-氯苯基)-3-(2-甲氧基苯基)-4-羟基-1H-吡唑(21)溶于5ml无水二氯甲烷中,0℃下缓慢滴加0.48ml(5mmol)三溴化硼,滴加时间约为5分钟;滴加完毕后,移至室温反应直至TLC板检测原料消失(反应时间约为3小时),降温至0℃,缓慢滴加甲醇淬灭,然后加饱和碳酸氢钠溶液20ml,用二氯甲烷20ml萃取一次,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压旋干,粗产品经柱层析纯化(石油醚:乙酸乙酯=5:1-2:1),得到白色固体,收率为85%。
白色固体,mp:195-196℃.1H NMR(500MHz,DMSO-d6)δ12.86(d,J=331.2Hz,1H),7.74(m,5H),7.13(t,J=7.4Hz,1H),6.87(m,2H).13C NMR(125MHz,DMSO-d6)δ136.08,129.36,129.13,129.07,128.99,128.77,127.46,119.83,116.63.HRMS(ESI)m/z calcdfor C15H11ClN2O2[M+H]+:287.0582.Found:287.0585.
实施例23、3-(4-硝基苯基)-5-(对甲苯基)-4-羟基-1H-吡唑(23)
制备方法同CN201410540869.5的实施例9。
实施例24、3-(4-氯苯基)-5-(4-氟苯基)-4-羟基-1H-吡唑(24)
以2-叠氮-1-(4-氯苯基)-3-(4-氟苯基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率67%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ12.97(s,1H),8.45(s,1H),7.94(s,4H),7.52(s,2H),7.30(s,2H).13C NMR(125MHz,Acetone-d6)δ135.43,132.28,128.55,127.91,127.84,127.34,115.36,115.18.HRMS(ESI)m/z calcd for C15H10ClFN2O[M+H]+:289.0538.Found:289.0541.
实施例25、3-(4-氯苯基)-5-(4-(三氟甲基)苯基)-4-羟基-1H-吡唑(25)
以2-叠氮-1-(4-三氟甲基)-3-苯基丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率57%。
白色固体,mp:247-248℃.1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),8.70(s,1H),8.23-7.77(m,6H),7.54(d,J=20.8Hz,2H).13C NMR(125MHz,Acetone-d6)δ136.40,132.55,128.64,127.44,126.13,125.37,125.34.HRMS(ESI)m/z calcd for C16H10ClF3N2O[M+H]+:339.0507.Found:339.0506.
实施例26、3-(4-氯苯基)-5-(4-甲氧基苯基)-4-羟基-1H-吡唑(26)
以2-叠氮-1-(4-氯苯基)-3-(4-甲氧基苯基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率54%。
白色固体,mp:239-240℃.1H NMR(500MHz,DMSO-d6)δ12.78(s,1H),8.24(s,1H),7.89(d,J=70.6Hz,4H),7.49(d,J=7.2Hz,2H),7.02(d,J=8.0Hz,2H),3.79(s,3H).13CNMR(125MHz,DMSO-d6)δ163.67,136.45,132.44,132.27,132.09,131.91,60.38.HRMS(ESI)m/z calcd for C16H13ClN2O2[M+H]+:301.0738.Found:301.0738.
实施例27、3-(4-氯苯基)-5-(4-羟基苯基)-4-羟基-1H-吡唑(27)
以3-(4-氯苯基)-5-(4-甲氧基苯基)-4-羟基-1H-吡唑(26)代替5-(4-氯苯基)-3-(2-甲氧基苯基)-4-羟基-1H-吡唑(21),其余同实施例22,收率65%。
白色固体,mp:240-241℃.1H NMR(500MHz,DMSO-d6)δ12.73(s,1H),9.57(s,1H),8.20(s,1H),7.95(s,2H),7.69(s,2H),7.49(d,J=7.8Hz,2H),6.84(d,J=8.4Hz,2H).13CNMR(125MHz,DMSO-d6)δ157.14,131.61,128.91,127.59,127.52,127.47,127.35,115.82.HRMS(ESI)m/z calcd for C15H11ClN2O2[M+H]+:287.0582.Found:287.0588.
实施例28、3-(4-氯苯基)-5-(3,4-二甲氧基苯基)-4-羟基-1H-吡唑(28)
以2-叠氮-1-(4-氯苯基)-3-(3,4-二甲氧基苯基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率65%。
淡绿色固体,mp:221-222℃.1H NMR(500MHz,DMSO-d6)δ12.84(s,1H),8.35(s,1H),7.98(s,2H),7.49(s,4H),7.04(d,J=7.7Hz,1H),3.80(d,J=12.9Hz,6H).13C NMR(125MHz,Acetone-d6)δ149.49,148.98,135.04,132.03,128.42,127.37,118.48,111.91,109.74,55.22,55.16.HRMS(ESI)m/z calcd for C17H15ClN2O3[M+H]+:331.0844.Found:331.0846.
实施例29、3-(4-氯苯基)-5-(3,4-二羟基苯基)-4-羟基-1H-吡唑(29)
以3-(4-氯苯基)-5-(3,4-二甲氧基苯基)-4-羟基-1H-吡唑(28)代替5-(4-氯苯基)-3-(2-甲氧基苯基)-4-羟基-1H-吡唑(21),其余同实施例22,收率62%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ12.65(s,1H),8.97(s,2H),8.15(s,1H),7.94(s,2H),7.48(d,J=7.7Hz,2H),7.32(s,1H),7.11(s,1H),6.83–6.75(m,1H).13CNMR(125MHz,DMSO-d6)δ145.69,145.31,134.87,131.58,128.90,117.46,116.13,113.84.HRMS(ESI)m/z calcd for C15H11ClN2O3[M+H]+:303.0531.Found:303.0529.
实施例30、3-(4-氯苯基)-5-(1-萘基)-4-羟基-1H-吡唑(30)
以2-叠氮-1-(4-氯苯基)-3-(4-萘基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率62%。
淡黄色固体,mp:180-181℃.1H NMR(500MHz,DMSO-d6)δ12.98(d,J=132.0Hz,1H),8.42(s,1H),8.03(d,J=29.3Hz,5H),7.70–7.42(m,6H).13C NMR(125MHz,Acetone-d6)δ137.07,133.93,131.94,131.85,128.74,128.46,128.22,128.16,127.14,126.38,126.20,126.07,125.42.HRMS(ESI)m/z calcd for C19H13ClN2O[M+H]+:321.0789.Found:321.0788.
实施例31、3-(4-氯苯基)-5-(1H-咪唑4-基)-4-羟基-1H-吡唑(31)
以2-叠氮-1-(4-氯苯基)-3-(1H-咪唑4-基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率45%。
黄色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ12.56(d,J=195.6Hz,2H),8.01–7.90(m,2H),7.84(s,1H),7.48(d,J=8.0Hz,2H),7.41(s,1H).13C NMR(125MHz,DMSO-d6)δ140.50,140.43,136.12,131.79,131.75,131.66,131.60.HRMS(ESI)m/z calcd forC12H9ClN4O[M+H]+:261.0538.Found:261.0528.
实施例32、3-(4-氯苯基)-5-(吡啶-2-基)-4-羟基-1H-吡唑(32)
以2-叠氮基-1-(4-氯苯基)-3-(吡啶-2-基)丙烯酮代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率41%。
淡黄色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ13.07(s,1H),8.33(s,1H),7.73–7.81(m,4H),7.47–7.41(m,3H),7.31–7.26(m,1H).13C NMR(125MHz,Acetone-d6)δ135.11,131.25,128.35,126.37,125.58,124.11,123.21,123.03.HRMS(ESI)m/z calcdfor C14H10ClN3O[M+H]+:272.0585.Found:272.0591.
实施例33、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸甲酯(33)
以4-[2-叠氮基-3-(4-氯苯基)-3-氧代-1-丙烯基]苯甲酸甲酯代替2-叠氮-1-(4-氟苯基)-3-苯基丙烯酮,摩尔用量保持不变;其余同实施例3,收率65%。
白色固体,mp:237-238℃.1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),8.69(s,1H),8.01(m,6H),7.53(s,2H),3.87(s,3H).13C NMR(125MHz,DMSO-d6)δ141.63,136.82,134.75,133.87,132.97,132.61,132.48,132.08,130.34,130.10,57.27.HRMS(ESI)m/z calcd forC17H13ClN2O3[M+H]+:329.0687.Found:329.0682.
实施例34、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸盐酸盐(34)
将1.64g(5mmol)4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸甲酯(33)置于三颈瓶中,加入20ml浓盐酸回流反应,LC-MS检测反应完全后(约为24小时),旋干溶剂,粗产品用丙酮打浆纯化,得到白色固体,收率90%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ13.06(s,2H),8.66(s,1H),8.03(m,4H),7.94(d,J=8.1Hz,2H),7.53(d,J=8.2Hz,2H).13C NMR(125MHz,DMSO-d6)δ167.77,136.75,132.00,130.13,129.71,129.09,127.55,125.56.HRMS(ESI)m/z calcd forC16H11ClN2O3[M+H]+:315.0531.Found:315.0533.
实施例35、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-乙基苯甲酰胺(35)
将351mg(1mmol)4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸盐酸盐(34)与351mg(1mmol)HATU溶于5ml无水DMF中,加入0.28ml(2mmol)三乙胺,冰盐浴冷却至0℃,加入122mg(1.5mmol)乙胺盐酸盐,然后移至室温反应。TLC板检测反应(反应时间约为2小时),完毕后加入饱和碳酸氢钠溶液30ml,乙酸乙酯(30ml)萃取两次,合并有机层后用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压旋干后,粗品经柱层析纯化(石油醚:乙酸乙酯=2:1),得到淡黄色固体,收率71%。
淡黄色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ13.08(s,1H),8.53(d,J=48.9Hz,2H),7.95(m,6H),7.52(s,2H),3.34–3.26(m,2H),1.15(t,J=7.2Hz,3H).13C NMR(125MHz,DMSO-d6)δ168.21,136.46,133.35,131.88,129.16,128.98,127.90,127.05,125.71,124.93,34.52,15.34.HRMS(ESI)m/z calcd for C18H16ClN3O2[M+H]+:342.1004.Found:342.1000.
实施例36、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-(3-(二甲氨基)丙基)苯甲酰胺(36)
以N,N-二甲基丙二胺代替乙胺盐酸盐,摩尔用量保持不变;其余同实施例35,收率67%。
黄色固体,mp:240-241℃.1H NMR(500MHz,DMSO-d6)δ8.51(t,J=5.3Hz,1H),7.99(dd,J=22.7,8.2Hz,4H),7.89(d,J=8.3Hz,2H),7.47(d,J=8.3Hz,2H),3.29(m,2H),2.27(t,J=7.0Hz,2H),2.14(s,6H),1.70–1.63(m,2H).13C NMR(125MHz,DMSO-d6)δ166.24,133.06,131.64,128.93,127.81,127.40,125.18,57.47,45.69,38.27,27.62.HRMS(ESI)m/z calcd for C21H23ClN4O2[M+H]+:399.1582.Found:399.1584.
实施例37、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-羟基苯甲酰胺盐酸盐(37)
37-A:以O-(四氢-2H-吡喃-2-基)羟基胺代替乙胺盐酸盐,摩尔用量保持不变;其余同实施例35,得到37-A,收率65%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ11.34(s,1H),8.01(d,J=8.2Hz,2H),7.99–7.94(m,2H),7.82(d,J=8.4Hz,2H),7.47(d,J=8.3Hz,2H),5.01(s,1H),4.10–4.00(m,1H),3.53(m,2H),1.73(m,3H),1.56(m,3H).13C NMR(125MHz,DMSO-d6)δ128.86,127.81,127.30,125.01,101.41,61.98,28.59,25.29,19.06.HRMS(ESI)m/z calcdfor C21H20ClN3O4[M+H]+:414.1215.Found:414.1208.
37:将37-A于30%盐酸甲醇溶液(PH=1)中搅拌过夜后减压旋干得白色固体,收率88%。
白色固体,mp:>250℃.1H NMR(500MHz,DMSO-d6)δ11.37(s,1H),8.81(s,4H),8.04–7.97(m,4H),7.85(d,J=8.5Hz,2H),7.54–7.50(m,2H).13C NMR(125MHz,DMSO-d6)δ164.32,136.44,132.03,131.47,129.03,127.70,127.66,125.61.HRMS(ESI)m/z calcdfor C16H12ClN3O3[M+H]+:330.0640.Found:330.0645.
实施例38、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-(2-(3-羟基-2-甲基-4-氧代吡啶-1(4H)基)乙基)苯甲酰胺(38)
38-A:将100g甲基麦芽酚溶于80mL 95%乙醇,再加入83mL苄氯和116mL 30%氢氧化钠水溶液,将混合物在60℃下反应6-10小时,TLC板检测反应(石油醚:乙酸乙酯=2:1)。反应完成后,45℃减压蒸馏除去乙醇,加二氯甲烷300mL萃取,分液所得的二氯甲烷层用30mL 4%氢氧化钠溶液洗涤5次,再加30mL饱和食盐水洗涤2次,45℃减压蒸干得粗产品,再用60mL乙酸乙酯和120mL石油醚重结晶,抽滤得淡黄色固体,收率84%。
38-B:将2.16g 38-A与600mg的1,2-乙二胺溶于25mL乙醇和25mL水,加入400mgNaOH固体,升温至75℃反应3小时。反应完全后,冷却至室温,用2M盐酸调节使pH=1,减压蒸干。加入水使其溶解,用10M NaOH溶液调节pH=12,二氯甲烷萃取3次,减压蒸干得黄色液体,收率87%。
38-C:以38-B代替乙胺盐酸盐,其余同实施例35,收率78%。
白色固体,mp:>250.1H NMR(500MHz,DMSO-d6)δ13.13(s,1H),8.68(d,J=25.2Hz,2H),8.08–7.84(m,6H),7.53(d,J=7.5Hz,3H),7.43–7.38(m,2H),7.37–7.28(m,3H),6.13(d,J=7.5Hz,1H),4.99(s,2H),4.07(t,J=6.1Hz,2H),3.53(q,J=5.9Hz,2H),2.24(s,3H).13CNMR(125MHz,DMSO-d6)δ172.48,145.86,141.25,140.25,138.32,136.56,128.82,128.70,128.27,116.40,72.32,52.21,12.48.HRMS(ESI)m/z calcd for C31H27ClN4O4[M+H]+:555.1794.Found:555.1785.
38:将100mg 38-C溶于2ml甲醇与2ml乙酸乙酯混合溶液中,加入20mg 10% Pd/C。抽真空,通入氢气(置换3次),于室温搅拌反应(反应时间约为12小时)。TLC板检测,反应完全后,用硅藻土抽滤,甲醇淋洗3次,滤液旋干过柱,得白色固体,收率92%。
白色固体,mp:>250.1H NMR(500MHz,DMSO-d6)δ13.01(s,1H),8.70(s,1H),7.97(dd,J=21.5,8.1Hz,4H),7.86(d,J=8.3Hz,2H),7.52(t,J=7.3Hz,3H),6.14(d,J=7.2Hz,1H),4.15(t,J=5.8Hz,2H),3.57(q,J=5.4Hz,2H),2.35(s,3H).13C NMR(125MHz,DMSO-d6)δ168.91,166.84,145.72,138.53,136.54,132.68,131.96,129.94,129.07,127.93,127.54,125.49,110.97,52.49,11.98.HRMS(ESI)m/z calcd for C24H21ClN4O4[M+H]+:465.1324.Found:465.1333.
实施例39、体外抑制HT-1080细胞铁死亡(细胞存活率)活性检测
下文中所用的完全培养基配置比例为:MEM培养基90%(v/v),胎牛血清10%(v/v)。其中MEM培养基购自赛默飞世尔科技公司的Gibco细胞培养基,胎牛血清均为购自翌圣生物科技(上海)股份有限公司的Fetal Bovine Serum(Gold)-原装进口特级胎牛血清。
在96孔细胞板中每孔接种100μl的含约5000个HT-1080细胞的悬液,于37℃、5%CO2环境的孵箱中培养。24h后显微镜观察96孔板中细胞是否完全贴壁以及每孔细胞数目是否一致。
根据待测药物或化合物的效力,用含铁死亡诱导剂RSL3的完全培养基等比或等差稀释配置药物浓度梯度溶液,制成含RSL3和不同浓度待测药物的工作液。每孔加入100μl不同浓度的工作液,孔内RSL3终浓度始终为1μM,每个待测药物浓度设置3个平行重复,同时设置铁死亡诱导剂处理对照、溶剂对照和不含细胞的空白对照。37℃,5%CO2环境下培养细胞24h,采用CellTiter-Glo化学发光法检测每孔吸光度值。参照下述公式计算细胞活力:
细胞活力%=[(A溶剂对照-A空白对照)-(A待测药物-A空白对照)]/[(A溶剂对照-A空白对照)-(A铁死亡诱导剂-A空白对照)]×100%
将计算好的细胞活力值输入GraphPad Prism软件中,选用非线性回归分析计算出化合物的EC50。
化合物1~38以及Fer-1的EC50值结果展示于表1中。
结果表明,所述4-羟基吡唑类化合物在HT-1080细胞中能有效抑制铁死亡。
表1、4-羟基吡唑类化合物抑制HT-1080细胞铁死亡的EC50值
化合物编号 | EC50(nM) | 化合物编号 | EC50(nM) |
Fer-1 | 23.1 | 20 | 150.0 |
1 | 69.1 | 21 | 37.9 |
2 | 32.1 | 22 | 300.1 |
3 | 42.4 | 23 | 120.1 |
4 | 18.9 | 24 | 52.7 |
5 | 187.2 | 25 | 187.2 |
6 | 94.9 | 26 | 23.1 |
7 | 56.6 | 27 | 8.6 |
8 | 37.3 | 28 | 31.7 |
9 | 79.6 | 29 | 26.1 |
10 | 27.4 | 30 | 44.8 |
11 | 39.5 | 31 | 25.9 |
12 | 24.6 | 32 | 76.1 |
13 | 22.0 | 33 | 51.1 |
14 | 28.2 | 34 | 1035.6 |
15 | 22.6 | 35 | 81.9 |
16 | 24.8 | 36 | 44.8 |
17 | 79.6 | 37 | 80.2 |
18 | 30.8 | 38 | 267.1 |
19 | 525.3 |
实施例40、DPPH法检测化合物自由基清除活性
制备40.2μM的DPPH甲醇溶液,并吸取498μl DPPH甲醇溶液至1.5ml离心管中,分别加入2μl各个浓度的待测化合物DMSO溶液,使得DPPH的最终浓度为40μM,待测化合物的最终浓度分别为0.16μM、0.625μM、2.5μM、10μM、40μM,作为实验组(待测化合物)。并同时设置DMSO对照和甲醇空白对照。
说明:DMSO对照,即,取消待测化合物的使用,其余参照实验组;甲醇空白对照,即,仅仅为甲醇。
混匀后室温孵育1小时,在517nm测定溶液吸光度。计算化合物的DPPH自由基清除率,计算公式如下:
DPPH自由基清除率%=[A(DMSO对照)-A(待测化合物)]/[A(DMSO对照)-A(甲醇对照)]×100%
将计算好的DPPH自由基清除率值输入GraphPad Prism软件中,选用柱状图分析。据实施例39中的检测到的化合物对铁死亡的抑制效果,选取抑制效果最佳的4、26、27化合物进行实验,并与Fer-1对比自由基清除活性,结果如图1所示。
结果表明,四种化合物在20μM和40μM下都表现出显著的自由基清除效果。与经典铁死亡抑制剂Fer-1相比,化合物27在各个浓度下的自由基清除能力均优于Fer-1。
实施例41、多细胞系测定化合物抑制铁死亡浓度-活性曲线
将实施例39中的HT-1080细胞分别改成HT-1080、786-O、H9C2、BJ,仅仅取化合物27进行实验,实验方法参照实施例39。结果如图2所示,在所选的四种细胞系中,化合物27均展现出优于Fer-1的铁死亡抑制活性。
实施例42、C11-BODIPY法检测化合物脂质过氧化清除能力
以4*105个HT1080细胞密度于6孔板铺板,培养12h使细胞贴壁,用0.5μM铁死亡诱导剂RSL3和不同浓度的待测铁死亡抑制剂药物共同处理HT-1080细胞8h。弃去细胞培养液,PBS洗涤两次,避光加入200μl预先用PBS配置的BODIPY 581/591C11探针溶液,终浓度为5μM,使溶液均匀覆盖孔底。在37℃,5%CO2培养箱孵育1h,用PBS洗涤掉多余的荧光探针,胰酶消化收集细胞,采用流式细胞术检测细胞中脂质过氧化水平,选用FITC通道,以溶剂对照组为阴性对照,设置参数并应用到所有实验组样本,每个样本收集记录10000个细胞。按照阴性对照脂质过氧化<5%圈门,记录每个实验样本的脂质过氧化水平。
如图3所示,与阳性药物Fer-1相比,化合物27具有更强的抗脂质过氧化能力。
最后,还需要注意的是,以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (7)
1.4-羟基吡唑类化合物及其衍生物和盐在制备抑制铁死亡药物中的应用。
2.根据权利要求1所述的应用,其特征在于,4-羟基吡唑类化合物的通式如下:
3.根据权利要求2所述的应用,其特征在于通式中:
R1为氢、烷基,苯基;R2,R3为烷基、芳基,
烷基为以下任一:甲基、乙基、正丙基、正丁基,
芳基为以下任一苯基、取代苯基、萘基、吡啶基、呋喃基、咪唑基;
取代苯基的取代基为以下任一:氟、氯、溴、甲基、甲氧基、羟基、3,4-亚甲二氧基、三氟甲基、苯基、硝基、甲氧羰基、羧基、
4.根据权利要求3所述的应用,其特征在于:4-羟基吡唑类化合物的盐为药学上可接受的盐,优选4-羟基吡唑类化合物的盐酸盐。
5.根据权利要求4所述的应用,其特征在于:
4-羟基吡唑类化合物为以下任一:
3,5-二苯基-4-羟基-1H-吡唑、3-(4-甲氧基苯基)-5-苯基-4-羟基-1H-吡唑、3-(4-氟苯基)-5-苯基-4-羟基-1H-吡唑、3-(4-氯苯基)-5-苯基-4-羟基-1H-吡唑、3-(3-氯苯基)-5-苯基-4-羟基-1H-吡唑、3-(2-氯苯基)-5-苯基-4-羟基-1H-吡唑、3-(2,4-二氯苯基)-5-苯基-4-羟基-1H-吡唑、5-苯基-3-(间甲苯基)-4-羟基-1H-吡唑、5-苯基-3-(4-(三氟甲基)苯基)-4-羟基-1H-吡唑、3-(苯并[d][1,3]二氧代醇-5-基)-5-苯基-4-羟基-1H-吡唑、3-([1,1'-联苯]-4-基)-5-苯基-4-羟基-1H-吡唑、3-(4-氯苯基)-1,5-二苯基-4-羟基-1H-吡唑、3-(4-氯苯基)-1-甲基-5-苯基-4-羟基-1H-吡唑、5-(4-溴苯基)-1-甲基-3-苯基-4-羟基-1H-吡唑、5-(4-溴苯基)-3-苯基-4-羟基-1H-吡唑、5-(4-甲氧基苯基)-3-苯基-4-羟基-1H-吡唑、5-(4-氟苯基)-3-苯基-4-羟基-1H-吡唑、5-(4-氯苯基)-3-苯基-4-羟基-1H-吡唑、5-(2-呋喃)-3-苯基-4-羟基-1H-吡唑、5-正丁基-3-苯基-4-羟基-1H-吡唑、5-(4-氯苯基)-3-(2-甲氧基苯基)-4-羟基-1H-吡唑、5-(4-氯苯基)-3-(2-羟基苯基)-4-羟基-1H-吡唑、3-(4-硝基苯基)-5-(对甲苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-氟苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-(三氟甲基)苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-甲氧基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(4-羟基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(3,4-二甲氧基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(3,4-二羟基苯基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(1-萘基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(1H-咪唑4-基)-4-羟基-1H-吡唑、3-(4-氯苯基)-5-(吡啶-2-基)-4-羟基-1H-吡唑;
4-羟基吡唑类化合物的衍生物为以下任一:4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸甲酯、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-乙基苯甲酰胺、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-(3-(二甲氨基)丙基)苯甲酰胺、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-(2-(3-羟基-2-甲基-4-氧代吡啶-1(4H)基)乙基)苯甲酰胺;
4-羟基吡唑类化合物的盐酸盐为以下任一:4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)苯甲酸盐酸盐、4-(3-(4-氯苯基)-4-羟基-1H-吡唑-5-基)-N-羟基苯甲酰胺盐酸盐。
6.根据权利要求5所述的应用,其特征在于:在多种细胞系中能有效抑制细胞铁死亡。
7.根据权利要求6所述的应用,其特征在于:所述细胞为HT-1080、786-O、H9C2、BJ。
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