CN114716366B - 3-羟基吡啶-4-酮类衍生物及在抑制肾细胞铁死亡中的应用 - Google Patents
3-羟基吡啶-4-酮类衍生物及在抑制肾细胞铁死亡中的应用 Download PDFInfo
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- CN114716366B CN114716366B CN202210389175.0A CN202210389175A CN114716366B CN 114716366 B CN114716366 B CN 114716366B CN 202210389175 A CN202210389175 A CN 202210389175A CN 114716366 B CN114716366 B CN 114716366B
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- hydrochloride
- hydroxy
- methyl
- phenyl
- pyridin
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- LQUSVSANJKHVTM-UHFFFAOYSA-N 3-hydroxy-3h-pyridin-4-one Chemical class OC1C=NC=CC1=O LQUSVSANJKHVTM-UHFFFAOYSA-N 0.000 title claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 title abstract description 47
- 229910052742 iron Inorganic materials 0.000 title abstract description 24
- 230000002401 inhibitory effect Effects 0.000 title abstract description 8
- -1 iron ions Chemical class 0.000 claims abstract description 72
- 208000009304 Acute Kidney Injury Diseases 0.000 claims abstract description 20
- 208000033626 Renal failure acute Diseases 0.000 claims abstract description 19
- 201000011040 acute kidney failure Diseases 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- ZCUUVWCJGRQCMZ-UHFFFAOYSA-N 3-hydroxypyridin-4-one Natural products OC1=CC=NC=C1O ZCUUVWCJGRQCMZ-UHFFFAOYSA-N 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 16
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 10
- 210000004369 blood Anatomy 0.000 abstract description 7
- 239000008280 blood Substances 0.000 abstract description 7
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 abstract description 5
- 229940109239 creatinine Drugs 0.000 abstract description 5
- 210000002966 serum Anatomy 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 210000003292 kidney cell Anatomy 0.000 abstract description 2
- 102000019034 Chemokines Human genes 0.000 abstract 1
- 108010012236 Chemokines Proteins 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000047 product Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 24
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 12
- 238000006264 debenzylation reaction Methods 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 9
- 210000005084 renal tissue Anatomy 0.000 description 8
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 7
- 238000010186 staining Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000003833 cell viability Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- 206010039020 Rhabdomyolysis Diseases 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000005779 cell damage Effects 0.000 description 4
- 208000037887 cell injury Diseases 0.000 description 4
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 description 4
- 230000003907 kidney function Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229960003351 prussian blue Drugs 0.000 description 4
- 239000013225 prussian blue Substances 0.000 description 4
- WOQHEDBJSCPOOY-UHFFFAOYSA-N 1-[2-(dimethylamino)ethyl]-2-methyl-3-phenylmethoxypyridin-4-one Chemical compound CN(C)CCN1C=CC(=O)C(OCC=2C=CC=CC=2)=C1C WOQHEDBJSCPOOY-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
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- 239000002504 physiological saline solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 101000780208 Homo sapiens Long-chain-fatty-acid-CoA ligase 4 Proteins 0.000 description 2
- 102100034319 Long-chain-fatty-acid-CoA ligase 4 Human genes 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 150000001924 cycloalkanes Chemical group 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JJJVMCZDRGQMJS-UHFFFAOYSA-N n-[2-(4-methylpiperazin-1-yl)ethyl]-4-nitroaniline Chemical compound C1CN(C)CCN1CCNC1=CC=C([N+]([O-])=O)C=C1 JJJVMCZDRGQMJS-UHFFFAOYSA-N 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 238000012959 renal replacement therapy Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 210000003699 striated muscle Anatomy 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- BHIHPFLLSGZAER-UHFFFAOYSA-N 1-N,2-N-dimethyl-1-N-(4-nitrophenyl)propane-1,2-diamine Chemical compound CC(CN(C1=CC=C(C=C1)[N+](=O)[O-])C)NC BHIHPFLLSGZAER-UHFFFAOYSA-N 0.000 description 1
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 1
- JCOQCIOOCBCHDU-UHFFFAOYSA-N 1-methyl-3-(4-nitrophenoxy)pyrrolidine Chemical compound C1N(C)CCC1OC1=CC=C([N+]([O-])=O)C=C1 JCOQCIOOCBCHDU-UHFFFAOYSA-N 0.000 description 1
- WGTASENVNYJZBK-UHFFFAOYSA-N 3,4,5-trimethoxyamphetamine Chemical compound COC1=CC(CC(C)N)=CC(OC)=C1OC WGTASENVNYJZBK-UHFFFAOYSA-N 0.000 description 1
- ICTGXNILNPWNLH-UHFFFAOYSA-N 4-(1-methylpyrrolidin-3-yl)oxyaniline Chemical compound C1N(C)CCC1OC1=CC=C(N)C=C1 ICTGXNILNPWNLH-UHFFFAOYSA-N 0.000 description 1
- KDHPQNXUMCNVCX-UHFFFAOYSA-N 4-(3-morpholin-4-ylpropoxy)aniline Chemical compound C1=CC(N)=CC=C1OCCCN1CCOCC1 KDHPQNXUMCNVCX-UHFFFAOYSA-N 0.000 description 1
- MOZNZNKHRXRLLF-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)aniline Chemical compound C1CN(C)CCN1C1=CC=C(N)C=C1 MOZNZNKHRXRLLF-UHFFFAOYSA-N 0.000 description 1
- FWXCMZOZLKWFHZ-UHFFFAOYSA-N 4-[3-(4-nitrophenoxy)propyl]morpholine Chemical compound C1=CC([N+](=O)[O-])=CC=C1OCCCN1CCOCC1 FWXCMZOZLKWFHZ-UHFFFAOYSA-N 0.000 description 1
- BXIJUQJYXZCOFB-UHFFFAOYSA-N 4-n-[2-(dimethylamino)ethyl]-4-n-methylbenzene-1,4-diamine Chemical compound CN(C)CCN(C)C1=CC=C(N)C=C1 BXIJUQJYXZCOFB-UHFFFAOYSA-N 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000008575 Iron Assay Methods 0.000 description 1
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 1
- OHSSVBNSOVDBKU-UHFFFAOYSA-N OC1=C(N(C=CC1=O)C1=CC=C(C=C1)OCCCN1CCOCC1)C Chemical compound OC1=C(N(C=CC1=O)C1=CC=C(C=C1)OCCCN1CCOCC1)C OHSSVBNSOVDBKU-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000035618 desquamation Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000028208 end stage renal disease Diseases 0.000 description 1
- 201000000523 end stage renal failure Diseases 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- NGGPLHHTRNJSDT-UHFFFAOYSA-N methylmaltol Natural products COC1=C(C)OC=CC1=O NGGPLHHTRNJSDT-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 230000003589 nefrotoxic effect Effects 0.000 description 1
- 231100000381 nephrotoxic Toxicity 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000276 potassium ferrocyanide Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种3‑羟基吡啶‑4‑酮类衍生物及在抑制肾细胞铁死亡中的应用,包含结构如通式(I)或(II)所示的化合物。细胞结果表明,该类化生物可以有效地抑制肾细胞铁死亡。小鼠急性肾损伤模型中也证实了该类化生物通过螯合铁离子,有效地降低血尿素氮和血清肌酐水平,缓解或减轻急性肾损伤,可在制备治疗急性肾损伤药物中应用;
Description
技术领域
本发明属于药物化学领域,涉及一种3-羟基吡啶-4-酮类化合物及在抑制肾细胞铁死亡中的应用,具体涉及在制备抑制肾细胞铁死亡药物中的应用,尤其在制备与急性肾损伤有关适应症治疗药物中的应用,包括所述化合物及其药学上可接受的盐。
背景技术
急性肾细胞损伤是一种常见的临床急危重症,表现为突发和持续的肾功能下降,而且急性肾损伤发生后易转归为慢性肾脏病和终末期肾脏病,每年持续影响超过1亿的患者,近年来已成为全球性的公共卫生问题。急性肾损伤患者个体差异性大,病情多样,目前尚无标准治疗方法。临床上只能在明确其诱因的前提下采取相应的支持性治疗,如恢复血容量、暂停使用肾毒性药物或接受肾脏替代治疗等。近期研究发现,急性肾损伤的发生与铁死亡高度相关。在大部分可诱发急性肾损伤的外因作用下,肾组织催化性Fe2+的含量会显著升高,这些催化性Fe2+可以通过Fenton反应产生大量的活性氧ROS来氧化膜脂质,导致脂质过氧化产物的生成增多,进而引起脂质过氧化物的累积,最终促进了肾细胞发生铁死亡。因此通过螯合催化性铁离子,减少脂质过氧化物的生成,抑制铁死亡,有望缓解或减轻急性肾损伤。
发明内容
本发明的目的在于提供一种3-羟基吡啶-4-酮类化合物,所述化合物包含如通式(I)或(II)所示的化合物及其在药学上可接受的盐:
所述的通式(I)化合物及其盐中:R1选自烷基;R2选自环烷基、芳基、R5R6N-烷基;具体为:
(1)所述烷基选自含C1~C3烷基,其中C1~C3烷基是指甲基、乙基、正丙基;
(2)所述环烷基选自具有3~7个原子的脂肪族环状结构,其中3~7个原子的脂肪族环状结构是指环己基;
(3)所述芳基选自苯基;
(4)所述R5R6N-烷基中的R5和R6相同或不同,选自氢原子或甲基;
(5)所述n=1~3。
所述的通式(II)化合物及其盐中:R1选自烷基;R3选自氢、卤素、烷氧基;R4选自杂环烷基、R7R8N-;X选自O、N;具体为:
(1)所述烷基选自含C1~C3烷基,其中C1~C3烷基是指甲基、乙基、正丙基;
(2)所述卤素选自F、Cl或Br;
(3)所述烷氧基选自含C1~C3烷氧基,其中C1~C3烷氧基是指甲氧基、乙氧基、正丙氧基、叔丁氧基;
(4)所述杂环烷基是具有3~8个原子的环状烷烃结构,其中至少有一个杂原子,杂原子选用O或N,3~8个原子的环状烷烃结构是指N-甲基哌嗪基、吗啉基、哌啶基、N-甲基哌啶基、N-甲基吡咯基;
(5)所述R7R8N-中的R7和R8相同或不同,选用氢原子或甲基;
(6)所述n=0~3。
本发明的另一个目的是提供所述3-羟基吡啶-4-酮类化合物及其药学上可接收的盐在制备抑制肾细胞铁死亡药物中的应用。
所述3-羟基吡啶-4-酮类化合物及其药学上可接收的盐在制备与急性肾细胞损伤有关适应症治疗药物中的应用。
本发明提供的3-羟基吡啶-4-酮类化合物具有的式(I)或(II)的化合物可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、氢溴酸盐。
本发明提供的3-羟基吡啶-4-酮类化合物及其盐可以通过螯合铁离子,抑制肾细胞铁死亡,降低血尿素氮和血清肌酐水平,对横纹肌溶解诱导的急性肾损伤具有较好的保护作用。
本发明有益效果:目前治疗急性肾损伤的仅为对症治疗。本发明提供一种3-羟基吡啶-4-酮类化合物,细胞实验说明该类化合物具有较好的抑制肾细胞铁死亡,小鼠急性肾损伤模型显示该类化合物可以有效地降低急性肾损伤小鼠血尿素氮和血清肌酐水平,缓解或减轻急性肾损伤的效果。
附图说明
图1是化合物CJ-B-05对横纹肌溶解小鼠急性肾细胞损伤的活性评价。
具体实施方式
本发明结合附图和实施例作进一步的说明。
实施例1.3-羟基-2-甲基-1-苯乙基吡啶-4(1H)-酮盐酸盐(编号CJ-B-01)的合成
将3-羟基-2-甲基-4H-吡喃酮126mg(1mmol)、苯硼酸122mg(1mmol)加入反应瓶中,加入5mL水,混合物加热至80度,加入苯乙胺132μL(1.05mmol),继续80度搅拌反应,TLC检测反应(二氯甲烷/甲醇=20:3的体积比)。反应结束后,反应液经旋转蒸发仪旋干后,加入浓盐酸5mL室温搅拌6h成盐,旋蒸浓缩,加入3mL乙腈,得到沉淀抽滤,滤饼用20mL乙醚打浆后再次抽滤得到盐酸盐产物252mg,收率95%。
白色固体,mp:245.9-246.8℃;1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),8.12(d,J=7.0Hz,1H),7.34–7.28(m,3H),7.25–7.20(m,3H),4.58(t,J=7.4Hz,2H),3.10(t,J=7.4Hz,2H),2.49(s,3H);13C NMR(125MHz,DMSO-d6)δ158.5,142.8,141.7,138.1,136.5,129.0,128.5,127.0,110.5,56.8,40.0,39.9,39.7,39.5,39.4,39.2,39.0,35.4,12.4;HRMS(ESI):m/z calcd for C14H16NO2[M+H]+:230.1176,found:230.1177。
实施例2.2-乙基-3-羟基-1-苯乙基吡啶-4(1H)-酮盐酸盐(编号CJ-B-02)的合成
以3-羟基-2-乙基-4H-吡喃酮代替3-羟基-2-甲基-4H-吡喃酮,摩尔量不变,其余同实施例1,得到产物257mg,收率92%。
白色固体,mp:201.7-202.3℃;1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),8.12(d,J=7.0Hz,1H),7.31–7.29(m,3H),7.26–7.23(m,1H),7.21–7.20(m,2H),4.56(t,J=7.4Hz,2H),3.11(t,J=7.3Hz,2H),2.86(q,J=7.4Hz,2H),1.14(t,J=7.5Hz,3H);13C NMR(125MHz,DMSO-d6)δ159.0,145.7,142.8,138.2,136.2,129.1,128.7,127.1,110.8,56.2,40.0,39.9,39.7,39.5,39.4,39.2,39.0,36.5,19.6,11.9;HRMS(ESI):m/z calcd forC15H18NO2[M+H]+:244.1332,found:244.1338。
实施例3.1-(环己基甲基)-3-羟基-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-03)的合成
以环己基甲胺代替苯乙胺,摩尔量不变,其余同实施例1,得到产物247mg,收率96%。
白色固体,mp:188.7-189.6℃;1H NMR(500MHz,DMSO-d6)δ10.54(s,1H),8.20(dd,J=8.0,3.0Hz,1H),7.40(d,J=6.9Hz,1H),4.20(d,J=7.5Hz,2H),2.53(s,3H),1.80–1.73(m,1H),1.67–1.60(dd,J=26.1,9.6Hz,3H),1.48–1.46(d,J=11.7Hz,2H),1.20–1.08(m,3H),1.05–0.98(m,2H);13C NMR(125MHz,DMSO-d6)δ158.5,143.0,141.5,138.6,110.3,61.2,40.0,39.9,39.7,39.5,39.4,39.2,39.0,37.2,29.3,25.7,25.0,12.8;HRMS(ESI):m/z calcd for C13H20NO2[M+H]+:222.1489,found:222.1485。
实施例4.1-(2-(二甲基氨基)乙基)-3-羟基-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-04)的合成
3-羟基-2-甲基-4H-吡喃-4-酮(编号4-b)
将3-羟基-2-甲基-4H-吡喃酮100g(800mmol)加至反应瓶中,加入80mL 95%乙醇成白色浊液,35.2g(880mmol)氢氧化钠溶于80mL水缓慢滴加入体系,加料完毕升温至60度,滴加氯化苄82.5mL(720mmol),60度搅拌反应,TLC检测反应(石油醚/乙酸乙酯=1:1的体积比)。反应结束后,反应液经旋转蒸发仪旋至无蒸出液后,加水120mL溶解,用3x150mL二氯甲烷萃取三次,合并有机层,有机层用3x100mL 5%氢氧化钠溶液洗涤三次,TLC检测无甲基麦芽酚原料残留,有机层用饱和食盐水洗涤三次,无水硫酸钠干燥,旋蒸浓缩至无蒸出液,冷却固化,碾碎风干得到产物3-(苄氧基)-2-甲基-4H-吡喃酮143.3g,收率83%。黄色固体,mp:46.7-47.2℃。1H NMR(500MHz,CDCl3)δ7.59(d,J=5.6Hz,1H),7.40–7.37(m,2H),7.36–7.30(m,3H),6.36(d,J=5.6Hz,1H),5.15(s,2H),2.08(s,3H);HRMS(ESI):m/z calcd forC13H12NaO3[M+Na]+:239.0679,found:239.0677。
3-(苄氧基)-1-(2-(二甲氨基)乙基)-2-甲基吡啶-4(1H)-酮(编号4-c)
将3-羟基-2-甲基-4H-吡喃-4-酮432mg(2mmol)、N,N-二甲基-1,2-乙二胺437μL(4mmol)加至反应瓶中,后加入水5.0mL,加料完毕后,80度搅拌反应7小时,TLC检测反应(二氯甲烷/甲醇=10:1的体积比)。反应结束后,反应液经旋转蒸发仪旋干后,柱层析(二氯甲烷/甲醇=20:1)得到产物3-(苄氧基)-1-(2-(二甲氨基)乙基)-2-甲基吡啶-4(1H)-酮483.4mg,收率84%。1H NMR(500MHz,CDCl3)δ7.39–7.37(m,2H),7.32–7.27(m,3H),7.20(d,J=7.5Hz,1H),6.38(d,J=7.5Hz,1H),5.19(s,2H),3.78(t,J=6.8Hz,2H),2.44(t,J=6.8Hz,2H),2.21(s,6H),2.06(s,3H);HRMS(ESI):m/z calcd for C17H23N2O2[M+H]+:287.1754,found:287.1761。
1-(2-(二甲基氨基)乙基)-3-羟基-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-04)
将3-(苄氧基)-1-(2-(二甲氨基)乙基)-2-甲基吡啶-4(1H)-酮1.92g溶于20mL乙醇中,加入催化量浓盐酸,然后在40%Pd/C催化条件下加氢脱苄基,40度搅拌反应,TLC检测反应(二氯甲烷/甲醇=6:1的体积比)。反应结束后,硅藻土抽滤,滤液经旋转蒸发仪旋干后,固体经盐酸乙醚溶液处理生成盐酸盐,乙腈重结晶后得盐酸盐产物1.11g,收率71%。白色固体,mp:247.2-248.7℃;1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),8.33(d,J=7.0Hz,1H),7.36(d,J=7.0Hz,1H),4.83–4.80(m,2H),3.53–3.50(m,2H),2.82(s,6H),2.58(s,3H);13C NMR(125MHz,DMSO-d6)δ160.4,143.4,140.7,138.6,111.0,53.9,49.6,42.3,40.0,39.9,39.7,39.5,39.4,39.2,39.0,12.8;HRMS(ESI):m/z calcd for C17H22N3O2[M+H]+:197.1285,found:197.1286。
实施例5.3-羟基-2-甲基-1-(4-(4-甲基哌嗪-1-基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-05)的合成
3-(苄氧基)-2-甲基-1-(4-(4-甲基哌嗪-1-基)苯基)吡啶-4(1H)-酮(编号5-a)
将3-羟基-2-甲基-4H-吡喃-4-酮950mg(4.4mmol)、4-(4-甲基哌嗪-1-基)苯胺765mg(4mmol)加入反应瓶中,后加入10.4mL乙醇、5.2mL水和686μL(12mmol)冰醋酸,125度搅拌反应,TLC检测反应(二氯甲烷/甲醇=30:1的体积比)。反应结束后,反应液经旋转蒸发仪旋干后,柱层析(二氯甲烷/甲醇=30:1)得到产物887mg,收率57%。微黄色固体,mp:157.7-159.6℃;1H NMR(500MHz,DMSO-d6)δ7.52(d,J=7.5Hz,1H),7.44–7.42(m,2H),7.38–7.35(m,2H),7.34–7.30(m,1H),7.20–7.17(m,2H),7.03–7.00(m,2H),6.20(d,J=7.5Hz,1H),5.07(s,2H),3.22–3.20(m,4H),2.46–2.44(m,4H),2.22(s,3H),1.85(s,3H);HRMS(ESI):m/z calcd for C24H28N3O2[M+H]+:390.2176,found:390.2176。
3-羟基-2-甲基-1-(4-(4-甲基哌嗪-1-基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-05)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐178mg,收率36%。
微粉色固体,mp:>250℃;1H NMR(500MHz,MeOD)δ8.06(d,J=6.9Hz,1H),7.39(d,J=9.0Hz,2H),7.23(d,J=9.0Hz,2H),7.17(d,J=6.9Hz,1H),4.03(d,J=12.8Hz,2H),3.64(d,J=11.5Hz,2H),3.31–3.19(m,4H),2.97(s,3H),2.30(s,3H).13C NMR(125MHz,MeOD)δ160.8,152.4,144.6,144.0,140.3,134.8,128.1,117.8,111.7,54.2,49.5,49.3,49.2,49.0,48.8,48.7,48.5,46.8,43.5,40.3,40.1,39.9,39.8,39.6,39.4,39.3,15.0;HRMS(ESI):m/z calcd for C17H22N3O2[M+H]+:300.1707,found:300.1701。
实施例6.3-羟基-2-甲基-1-(4-((2-(4-甲基哌嗪-1-基)乙基)氨基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-06)的合成
N-(2-(4-甲基哌嗪-1-基)乙基)-4-硝基苯胺(编号6-b)
将4-氟硝基苯282mg(2mmol)、碳酸钾304mg(2.2mmol)加入反应瓶中,加入1mL二甲基亚砜,室温下搅拌0.5h。随后,向反应体系中滴加2-(4-甲基哌嗪-1-基)乙二胺382mg(2mmol),室温搅拌反应,TLC检测反应(二氯甲烷/甲醇=15:1的体积比)。反应结束后,加水5mL,用3X10 mL二氯甲烷萃取3次,合并有机层,有机层用饱和食盐水洗涤,无水硫酸钠干燥后,旋蒸柱层析(二氯甲烷/甲醇=75:1)得到产物199mg,收率35%。黄色固体,,mp:98.1-102.7℃;1H NMR(500MHz,DMSO-d6)δ7.98(d,J=9.3Hz,2H),7.16(t,J=5.3Hz,1H),6.66(d,J=9.4Hz,2H),3.25(dd,J=12.3,6.5Hz,2H),2.51–2.27(m,10H),2.14(s,3H);HRMS(ESI):m/z calcd for C13H21N4O2[M+H]+:265.1659,found:265.1657。
N1-(2-(4-甲基哌嗪-1-基)乙基)苯-1,4-二胺(编号6-c)
将N-(2-(4-甲基哌嗪-1-基)乙基)-4-硝基苯胺1.92g(7.3mmol)、二水氯化亚锡9.8g(43.6mmol)加至反应瓶中,加入120mL乙醇,升温至78度反应6h,TLC检测反应(二氯甲烷/甲醇=15:2的体积比)。反应结束后,反应液经旋转蒸发仪旋至无蒸出液,饱和碳酸氢钠调pH=8,抽滤,滤液用3x150mL乙酸乙酯萃取三次,合并有机层,无水硫酸钠干燥后,旋干得得产物1.19g,收率70%。
3-(苄氧基)-2-甲基-1-(4-((2-(4-甲基哌嗪-1-基)乙基)氨基)苯基)吡啶-4(1H)-酮(编号6-d)
以5-a同样方法得到产物527mg,收率28%。黄色黏稠液体;1H NMR(500MHz,DMSO-d6)δ7.49(d,J=7.5Hz,1H),7.42(d,J=7.1Hz,2H),7.37(t,J=7.2Hz,2H),7.33–7.30(m,1H),7.03(d,J=8.6Hz,2H),6.63(d,J=8.7Hz,2H),6.19(d,J=7.5Hz,1H),5.87(t,J=5.1Hz,1H),5.06(s,1H),3.13(dd,J=12.2,6.2Hz,2H),2.48–2.36(m,8H),2.16(s,3H),1.85(s,3H),1.23(s,2H);HRMS(ESI):m/z calcd for C26H33N4O2[M+H]+:433.2598,found:433.2599。
3-羟基-2-甲基-1-(4-((2-(4-甲基哌嗪-1-基)乙基)氨基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-06)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐155mg,收率34%。
灰棕色固体,mp:204.9-207.7℃;1H NMR(500MHz,MeOD)δ8.04(d,J=6.9Hz,1H),7.24(d,J=8.7Hz,2H),7.17(d,J=6.9Hz,1H),6.91(d,J=8.7Hz,2H),3.96–3.70(m,11H),3.55(t,J=5.9Hz,2H),3.01(s,3H),2.30(s,3H);13C NMR(125MHz,MeOD)δ160.4,150.3,144.4,144.3,140.3,132.5,127.9,114.6,111.5,56.4,51.2,50.2,49.5,49.3,49.2,49.0,48.8,48.7,48.5,43.7,39.0,14.9;HRMS(ESI):m/z calcd for C19H27N4O2[M+H]+:343.2129,found:343.2126。
实施例7.3-羟基-2-甲基-1-(4-吗啉代苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-07)的合成
3-(苄氧基)-2-甲基-1-(4-吗啉代苯基)吡啶-4(1H)-酮(编号7-a)
以5-a同样方法得到产物239mg,收率75%。褐色固体,mp:163.2-164.7℃;1H NMR(500MHz,DMSO-d6)δ7.53(d,J=7.5Hz,1H),7.45–7.42(m,2H),7.39–7.36(m,2H),7.32(ddd,J=7.2,3.6,1.4Hz,1H),7.23–7.21(m,2H),7.04–7.03(m,2H),6.21(d,J=7.5Hz,1H),5.07(s,2H),3.75–3.73(m,4H),3.19–3.17(m,4H),1.86(s,3H);HRMS(ESI):m/z calcdfor C23H25N2O3[M+H]+:377.1860,found:377.1863。
3-羟基-2-甲基-1-(4-吗啉代苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-07)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐160mg,收率94%。白色固体,mp:217.5-221.9℃;1H NMR(500MHz,MeOD)δ8.10(d,J=6.9Hz,1H),7.41–7.38(m,2H),7.27–7.25(m,2H),7.19(d,J=6.9Hz,1H),3.90–3.89(m,4H),3.36–3.34(m,4H),2.34(s,3H);13C NMR(125MHz,MeOD)δ160.9,148.6,144.9,144.0,140.1,139.3,129.1,121.6,111.7,66.3,53.6,49.5,49.3,49.2,49.0,48.8,48.7,48.5,15.1;HRMS(ESI):m/z calcdfor C16H19N2O3[M+H]+:287.1390,found:287.1390。
实施例8.3-羟基-1-(4-(二甲氨基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-08)的合成
3-(苄氧基)-1-(4-(二甲氨基)苯基)-2-甲基吡啶-4(1H)-酮(编号8-a)
以5-a同样方法得到产物560mg,收率84%。棕色固体,mp:133.4-134.2℃;1H NMR(500MHz,DMSO-d6)δ7.51(d,J=7.5Hz,1H),7.44–7.42(m,2H),7.39–7.35(m,2H),7.32(ddd,J=7.2,3.6,1.4Hz,1H),7.17–7.14(m,2H),6.78–6.75(m,2H),6.20(d,J=7.5Hz,1H),5.07(s,2H),2.95(s,6H),1.85(s,3H);HRMS(ESI):m/z calcd for C21H23N2O2[M+H]+:335.1754,found:335.1750。
3-羟基-1-(4-(二甲氨基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-08)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐170mg,收率77%。白色固体,mp:225.7-229.2℃;1H NMR(500MHz,MeOD)δ8.12(d,J=6.9Hz,1H),7.71–7.69(m,2H),7.65–7.64(m,2H),7.21(d,J=6.9Hz,1H),3.27(s,6H),2.31(s,3H);13C NMR(125MHz,MeOD)δ161.1,146.6,145.0,143.9,142.0,139.9,129.7,123.3,111.7,49.5,49.3,49.2,49.0,48.8,48.7,48.5,46.6,15.0;HRMS(ESI):m/z calcd for C14H17N2O2[M+H]+:245.1285,found:245.1283。
实施例9.3-羟基-1-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-09)的合成
N1,N1,N2-三甲基-N2-(4-硝基苯基)乙烷-1,2-二胺(编号9-a)
以6-b同样方法得到产物1.4g,收率72%。黄色液体;1H NMR(500MHz,DMSO-d6)δ8.04–8.02(m,2H),6.76(d,J=9.5Hz,2H),3.56(t,J=6.9Hz,2H),3.06(s,3H),2.40(t,J=6.9Hz,2H),2.18(s,6H);HRMS(ESI):m/z calcd for C11H18N3O2[M+H]+:224.1394,found:224.1394。
N1-(2-(二甲氨基)乙基)-N1-甲基苯-1,4-二胺(编号9-b)
以例6-c同样方法得到产物369mg,收率96%。棕色液体;1H NMR(500MHz,DMSO-d6)δ6.50(dd,J=20.6,8.7Hz,4H),4.37(s,2H),3.18(t,J=7.2Hz,2H),2.71(s,3H),2.31–2.28(m,2H),2.13(s,6H);HRMS(ESI):m/z calcd for C11H20N3[M+H]+:194.1652,found:194.1652。
3-(苄氧基)-1-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-2-甲基吡啶-4(1H)-酮(编号9-c)
以5-a同样方法得到产物294mg,收率75%。棕色液体;1H NMR(500MHz,DMSO-d6)δ7.51(d,J=7.5Hz,1H),7.44–7.42(m,2H),7.38–7.35(m,2H),7.33–7.31(m,1H),7.14(d,J=9.0Hz,2H),6.73(d,J=9.0Hz,2H),6.19(d,J=7.5Hz,1H),5.06(s,2H),3.47(t,J=7.1Hz,2H),2.94(s,3H),2.43(t,J=6.3Hz,2H),2.22(s,6H),1.85(s,3H);HRMS(ESI):m/zcalcd for C24H30N3O2[M+H]+:392.2333,found:392.2330。
3-羟基-1-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-09)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐160mg,收率95%。
白色固体,mp:242.9-244.0℃;1H NMR(500MHz,MeOD)δ8.09(d,J=6.9Hz,1H),7.35(d,J=9.0Hz,2H),7.21(d,J=6.9Hz,1H),7.06(d,J=9.0Hz,2H),3.90–3.87(m,2H),3.42–3.40(m,2H),3.11(s,3H),2.98(s,6H),2.34(s,3H);13C NMR(125MHz,MeOD)δ160.4,151.2,144.7,144.5,140.3,132.6,128.0,114.5,111.5,54.7,49.5,49.3,49.2,49.0,48.8,48.7,48.5,48.4,44.0,39.3,14.9;HRMS(ESI):m/z calcd for C17H24N3O2[M+H]+:302.1863,found:302.1863。
实施例10.3-(苄氧基)-2-甲基-1-(4-(3-吗啉代丙氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-10)的合成
4-(3-(4-硝基苯氧基)丙基)吗啉(编号10-a)
以6-b同样方法得到产物954mg,收率37%。黄色固体,mp:79.3-80.1℃;1H NMR(500MHz,DMSO-d6)δ8.20(d,J=9.2Hz,2H),7.14(d,J=9.2Hz,2H),4.16(t,J=6.4Hz,2H),3.56(t,J=4.4Hz,4H),2.41(t,J=7.1Hz,2H),2.36(s,4H),1.91(p,J=6.6Hz,2H);HRMS(ESI):m/z calcd for C13H19N2O4[M+H]+:267.1339,found:267.1338。
4-(3-吗啉代丙氧基)苯胺(编号10-b)
以6-c同样方法得到产物236mg,收率50%。棕色液体;HRMS(ESI):m/z calcd forC13H21N2O2[M+H]+:237.1598,found:237.1599。
3-羟基-2-甲基-1-(4-(3-吗啉代丙氧基)苯基)吡啶-4(1H)-酮(编号10-c)
以5-a同样方法得到产物170mg,收率39%。黑色黏稠液体;1H NMR(500MHz,DMSO-d6)δ7.55(d,J=7.5Hz,1H),7.43(d,J=6.9Hz,2H),7.37(t,J=7.2Hz,2H),7.34–7.30(m,3H),7.06–7.04(m,2H),6.22(d,J=7.5Hz,1H),5.07(s,2H),4.06(t,J=6.3Hz,2H),3.57(t,J=4.2Hz,4H),2.42–2.36(m,6H),1.92–1.86(m,2H),1.85(s,3H);HRMS(ESI):m/zcalcd for C26H31N2O4[M+H]+:435.2278,found:435.2277。
3-(苄氧基)-2-甲基-1-(4-(3-吗啉代丙氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-10)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐92mg,收率83%。
灰黑色固体,mp:182.6-185.8℃;1H NMR(500MHz,MeOD)δ8.06(d,J=6.9Hz,1H),7.40(d,J=8.8Hz,2H),7.17–7.15(m,3H),4.19(t,J=5.7Hz,2H),4.03(dd,J=13.1,3.1Hz,2H),3.80(t,J=11.8Hz,2H),3.54(d,J=12.4Hz,2H),3.39–3.36(m,2H),3.17(td,J=12.2,3.2Hz,2H),2.32–2.28(m,2H),2.27(s,3H);13C NMR(125MHz,MeOD)δ161.4,160.6,144.8,144.3,140.2,135.7,128.6,116.9,111.5,66.7,65.1,56.0,53.4,49.5,49.3,49.2,49.0,48.8,48.7,48.5,24.8,15.0;HRMS(ESI):m/z calcd for C19H25N2O4[M+H]+:345.1809,found:345.1809。
实施例11.3-羟基-2-甲基-1-(4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-11)的合成
3-(苄氧基)-2-甲基-1-(4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-4(1H)-酮(编号11-a)
以5-a同样方法得到产物118mg,收率56%。棕色黏稠液体;1H NMR(500MHz,DMSO-d6)δ7.55(d,J=7.5Hz,1H),7.44–7.42(m,2H),7.39–7.36(m,2H),7.34–7.30(m,3H),7.10–7.03(m,2H),6.22(d,J=7.5Hz,1H),5.06(s,2H),4.11(t,J=5.8Hz,2H),2.67(s,2H),2.44(s,4H),1.85(s,3H),1.51–1.47(m,4H),1.37(s,2H);HRMS(ESI):m/z calcd for C26H31N2O3[M+H]+:419.2329,found:419.2323。
3-羟基-2-甲基-1-(4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-11)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐75mg,收率86%。
白色固体,mp:>250℃;1H NMR(500MHz,MeOD)δ8.12(d,J=6.9Hz,1H),7.52–7.49(m,2H),7.31–7.28(m,2H),7.22(d,J=6.9Hz,1H),4.52(t,J=5.0Hz,2H),3.68–3.61(m,4H),3.13(td,J=12.3,2.7Hz,2H),2.33(s,3H),2.00–1.97(m,2H),1.89–1.85(m,3H),1.60–1.56(m,1H);13C NMR(125MHz,MeOD)δ160.7,160.6,144.8,144.3,140.2,136.3,128.7,117.2,111.5,63.8,57.0,54.9,49.5,49.3,49.2,49.0,48.8,48.7,48.5,24.1,22.5,14.8;HRMS(ESI):m/z calcd for C19H25N2O3[M+H]+:329.1860,found:329.1860。
实施例12.3-羟基-2-甲基-1-(4-((1-甲基哌啶-4-基)甲氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-12)的合成
3-(苄氧基)-2-甲基-1-(4-((1-甲基哌啶-4-基)甲氧基)苯基)吡啶-4(1H)-酮(编号12-a)
以5-a同样方法得到产物40mg,收率10%。棕色液体;1H NMR(500MHz,DMSO-d6)δ7.54(d,J=7.5Hz,1H),7.44–7.42(m,2H),7.37(t,J=7.2Hz,2H),7.34–7.31(m,3H),7.06(d,J=8.9Hz,2H),6.22(d,J=7.5Hz,1H),5.07(s,2H),3.90(d,J=5.9Hz,2H),3.07(s,2H),2.42–2.36(m,5H),1.85–1.83(m,6H),1.45–1.43(m,2H);HRMS(ESI):m/z calcd forC26H31N2O3[M+H]+:419.2329,found:419.2322。
3-羟基-2-甲基-1-(4-((1-甲基哌啶-4-基)甲氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-12)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐27mg,收率93%。白色固体,mp:>250℃;1H NMR(500MHz,MeOD)δ8.11(d,J=6.9Hz,1H),7.47–7.43(m,2H),7.24–7.18(m,3H),4.03(d,J=5.8Hz,2H),3.61–3.58(m,2H),3.12–3.07(m,2H),2.89(s,3H),2.33(s,3H),2.21–2.14(m,3H),1.79–1.71(m,2H);13C NMR(125MHz,MeOD)δ161.7,160.8,144.8,144.2,140.2,135.5,128.5,116.8,111.5,72.8,55.3,49.0,44.0,34.4,27.5,14.8;HRMS(ESI):m/z calcd for C19H25N2O3[M+H]+:329.1860,found:329.1862。
实施例13.3-羟基-1-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-13)的合成
3-(苄氧基)-1-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮(编号13-a)
以5-a同样方法得到产物217mg,收率52%。微黄色固体,mp:152.4-153.3℃;1HNMR(500MHz,DMSO-d6)δ7.42–7.36(m,6H),7.10(d,J=8.7Hz,1H),6.66(d,J=2.4Hz,1H),6.56(dd,J=8.8,2.5Hz,1H),6.17(d,J=7.5Hz,1H),5.10(d,J=11.1Hz,1H),5.02(d,J=11.1Hz,1H),3.74(s,3H),3.25–3.23(m,4H),2.47–2.45(m,4H),2.23(s,3H),1.74(s,3H);HRMS(ESI):m/z calcd for C25H30N3O3[M+H]+:420.2282,found:420.2284。
3-羟基-1-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-13)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐124mg,收率79%。灰棕色固体,mp:>250℃;1H NMR(500MHz,MeOD)δ8.00(d,J=6.9Hz,1H),7.32(d,J=8.7Hz,1H),7.19(d,J=6.9Hz,1H),6.88(d,J=2.4Hz,1H),6.79(dd,J=8.8,2.4Hz,1H),4.08(d,J=12.3Hz,2H),3.86(s,3H),3.66(d,J=10.8Hz,2H),3.33–3.23(m,4H),3.00(s,3H),2.27(s,3H);13C NMR(125MHz,MeOD)δ160.8,155.4,154.5,145.2,144.6,141.0,128.7,123.6,111.7,109.3,101.7,56.8,54.4,49.5,49.3,49.2,49.0,48.8,48.7,48.5,47.1,43.6,13.9;HRMS(ESI):m/z calcd for C18H24N3O3[M+H]+:330.1812,found:330.1810。
实施例14.3-羟基-2-甲基-1-(4-((1-甲基吡咯烷-3-基)氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-16)的合成
1-甲基-3-(4-硝基苯氧基)吡咯烷(编号14-a)
以6-b同样方法得到产物500mg,收率34%。黄色液体;HRMS(ESI):m/z calcd forC11H15N2O3[M+H]+:223.1077,found:223.1075。
4-((1-甲基吡咯烷-3-基)氧基)苯胺(编号14-b)
以6-c同样方法得到产物180mg,收率42%。棕色液体;HRMS(ESI):m/z calcd forC11H17N2O1[M+H]+:193.1335,found:193.1333。
3-(苄氧基)-2-甲基-1-(4-((1-甲基吡咯烷-3-基)氧基)苯基)吡啶-4(1H)-酮(编号14-c)
以5-a同样方法得到产物100mg,收率27%。棕色液体;1H NMR(500MHz,DMSO-d6)δ7.55(d,J=7.5Hz,1H),7.44–7.42(m,2H),7.39–7.36(m,2H),7.34–7.29(m,3H),7.00(d,J=8.9Hz,2H),6.21(d,J=7.5Hz,1H),5.07(s,2H),4.95–4.92(m,1H),2.83(dd,J=10.5,5.9Hz,1H),2.72(dt,J=16.2,9.2Hz,2H),2.42(dd,J=15.1,7.8Hz,1H),2.36–2.29(m,4H),1.85–1.77(m,4H);HRMS(ESI):m/z calcd for C24H27N2O3[M+H]+:391.2016,found:391.2015。
3-羟基-2-甲基-1-(4-((1-甲基吡咯烷-3-基)氧基)苯基)吡啶-4(1H)-酮盐酸盐(编号CJ-B-16)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐60mg,收率70%。白色固体,mp:248.3-250.2℃;1H NMR(500MHz,MeOD)δ8.11(d,J=6.9Hz,1H),7.50(d,J=8.9Hz,2H),7.26–7.24(m,2H),7.21(d,J=6.9Hz,1H),5.37–5.33(m,1H),3.97–3.86(m,2H),3.51–3.42(m,1H),3.09–3.04(m,3H),2.80–2.73(m,1H),2.49–2.46(m,1H),2.33–2.28(m,4H);13C NMR(125MHz,MeOD)δ160.8,159.2,144.9,144.2,140.1,136.3,128.8,118.0,111.5,77.3,61.8,61.6,55.9,55.4,49.5,49.3,49.2,49.0,48.8,48.7,48.5,43.1,41.5,32.3,31.6,14.8;HRMS(ESI):m/z calcd for C17H21N2O3[M+H]+:301.1547,found:301.1546。
实施例15.3-羟基-1-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-18)的合成
3-(苄氧基)-1-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮(编号15-a)
以5-a同样方法得到产物120mg,收率29%。黄色固体,mp:188.3-190.3℃;1H NMR(500MHz,DMSO-d6)δ7.56(d,J=7.5Hz,1H),7.44–7.43(m,2H),7.39–7.36(m,3H),7.34–7.31(m,1H),7.17–7.11(m,2H),6.21(d,J=7.5Hz,1H),5.06(s,2H),3.08(s,4H),2.51–2.50(m,4H),2.25(s,3H),1.89(s,3H);HRMS(ESI):m/z calcd for C24H27N3O2F[M+H]+:408.2082,found:408.2083。
3-羟基-1-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐(编号CJ-B-18)
以CJ-B-04同样方法脱苄基,盐酸乙醚处理生成盐酸盐89mg,收率86%。
粉色固体,mp:238.3-239.8℃;1H NMR(500MHz,MeOD)δ8.13(d,J=6.9Hz,1H),7.47–7.45(m,1H),7.38–7.33(m,2H),7.22(d,J=6.9Hz,1H),3.76(d,J=13.1Hz,2H),3.66(d,J=11.9Hz,2H),3.38(td,J=12.0,2.2Hz,2H),3.29–3.27(m,2H),3.00(s,3H),2.35(s,3H);13C NMR(125MHz,MeOD)δ161.0,157.1,155.2,144.8,144.2,141.8(d,J=8.2Hz),140.1,136.8(d,J=9.9Hz),124.2,124.1,121.7,116.1(d,J=24.8Hz),111.6,54.6,49.5,49.3,49.2,49.0,48.8,48.7,48.5,43.7,14.8;HRMS(ESI):m/z calcd for C17H21N3O2F[M+H]+:318.1612,found:318.1610。
实施例16.体外抑制肾细胞铁死亡(细胞存活率)活性检测
将HK-2细胞接种于96孔细胞板培养。24h后,弃除培养基,加入含不同浓度药物和RSL-3的培养基,以含相应浓度溶剂(DMSO)的培养基为空白对照组。给药后培养48h进行SRB实验,使用sulforhodamine B(SRB,#S1402,Sigma-Aldrich,St.Louis,MO,USA)测定法评估细胞生长抑制。
在下表1中的化合物存在下,测定体外抑制肾细胞铁死亡情况,在2μM RSL-3,25μM化合物浓度下,细胞存活率结果展示于表1中。在表1中,A为存活率80%至100%;B为存活率50%至80%;C为存活率20%至50%。
从细胞水平来看,本发明提供的化合物均可以有效地恢复RSL-3诱导的肾细胞铁死亡,所有化合物的铁死亡抑制效果均相当或优于经典铁螯合剂DFP。
表1 3-羟基吡啶-4-酮系列化合物抑制肾细胞铁死亡(细胞存活率)
化合物编号 | 细胞存活率 | 化合物编号 | 细胞存活率 |
CJ-B-01 | B | CJ-B-10 | A |
CJ-B-02 | B | CJ-B-11 | B |
CJ-B-03 | C | CJ-B-12 | A |
CJ-B-04 | B | CJ-B-13 | B |
CJ-B-05 | B | CJ-B-16 | B |
CJ-B-06 | B | CJ-B-18 | B |
CJ-B-07 | A | DFP | C |
CJ-B-08 | B | ||
CJ-B-09 | B |
实施例17.横纹肌溶解诱导的急性肾损伤动物模型活性评价
横纹肌溶解诱导急性肾损伤小鼠模型建立:选取雄性9周龄20-25g C57BL/6小鼠,常规分笼适应性饲养1周,测尿蛋白均为阴性后采用完全随机分组方式分为3组:对照组、急性肾损伤组、给药组。将小鼠置于代谢笼中,观察并记录正常饮水量及尿量,实验前禁水24小时,体重减轻10%的大鼠入组。对照组大鼠给予双后肢肌肉注射生理盐水10mL/kg。急性肾损伤组给予双后肢肉注射50%甘油生理盐水10mL/kg。给药组给予灌胃给药后20min,双后肢肌肉注射50%甘油生理盐水10mL/kg。
急性肾损伤小鼠肾功能评价:于给药前及给药后72h,眼眶内眦静脉丛采血,取血清检测肾功能生化指标(包括血清肌酐和血尿素氮)。
急性肾损伤小鼠肾脏铁死亡相关基因的表达检测:给药72h后,剖杀取肾脏组织,以生理盐水洗去血液,滤纸吸干,使用TRIzol试剂从肾组织样品中提取总RNA。游离铁水平可以采用比色法检测完成(iron assay kit,Sigma,MaK025),并通过半定量RT-PCR测量PTGS2和ACSL4的mRNA表达水平。
肾组织苏木精-伊红染色和普鲁士蓝染色:采集新鲜肾组织,立即用福尔马林固定,然后包埋在4%PFA中,切成5μm厚的切片,用于苏木精-伊红染色和普鲁士蓝染色。使用新鲜制备的10%亚铁氰化钾和20%盐酸进行普鲁士蓝染色。在光学显微镜下评估肾脏的组织病理学变化。
实验结果发现,相比于甘油造模组和DFP给药组,化合物CJ-B-05可以显著地降低横纹肌溶解急性肾细胞损伤小鼠的尿素氮和肌酐水平,恢复肾损伤小鼠的肾功能。肾损伤小鼠肾组织中与铁死亡相关基因PTGS2和ACSL4的异常表达被逆转。普鲁士蓝染色结果显示CJ-B-05给药组肾组织的游离铁水平明显下降。H&E肾组织染色结果也显示CJ-B-05给药组小鼠的肾小管上皮细胞脱屑、空泡化以及肾小管扩张等组织病理学改变都得到明显的改善。
Claims (3)
1.一种3-羟基吡啶-4-酮类化合物,其特征在于,包含如通式(I)或(II)所示的化合物及其在药学上可接受的盐,
通式(I)中,R1选自烷基;R2选自环烷基、芳基,
(1)所述烷基选自甲基或乙基;
(2)所述环烷基选自环己基;
(3)所述芳基选自苯基;
(4)所述n=1~3;
通式(II)中,R1选自烷基;R3选自氢、卤素、烷氧基;R4选自杂环烷基、含杂原子烷基;X选自O、N,
(1)所述烷基选自甲基或乙基;
(2)所述卤素选自F、Cl或Br;
(3)所述烷氧基选自甲氧基;
(4)所述杂环烷基选用N-甲基哌嗪基、吗啉基、哌啶基、N-甲基哌啶基或N-甲基吡咯基;
(5)所述含杂原子烷基,选用N,N-二甲基;
(6)所述n=0~3。
2.根据权利要求1所述的一种3-羟基吡啶-4-酮类化合物,其特征在于,通式(I)选自下述化合物:
3-羟基-2-甲基-1-苯乙基吡啶-4(1H)-酮盐酸盐,
2-乙基-3-羟基-1-苯乙基吡啶-4(1H)-酮盐酸盐,
1-(环己基甲基)-3-羟基-2-甲基吡啶-4(1H)-酮盐酸盐,
1-(2-(二甲基氨基)乙基)-3-羟基-2-甲基吡啶-4(1H)-酮盐酸盐,
通式(II)选自下述化合物:
3-羟基-2-甲基-1-(4-(4-甲基哌嗪-1-基)苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-2-甲基-1-(4-((2-(4-甲基哌嗪-1-基)乙基)氨基)苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-2-甲基-1-(4-吗啉代苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-1-(4-(二甲氨基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐,
3-羟基-1-(4-((2-(二甲基氨基)乙基)(甲基)氨基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐,
3-羟基-2-甲基-1-(4-(3-吗啉代丙氧基)苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-2-甲基-1-(4-(2-(哌啶-1-基)乙氧基)苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-2-甲基-1-(4-((1-甲基哌啶-4-基)甲氧基)苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-1-(2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐,
3-羟基-2-甲基-1-(4-((1-甲基吡咯烷-3-基)氧基)苯基)吡啶-4(1H)-酮盐酸盐,
3-羟基-1-(3-氟-4-(4-甲基哌嗪-1-基)苯基)-2-甲基吡啶-4(1H)-酮盐酸盐。
3.权利要求1或2所述的3-羟基吡啶-4-酮类衍生物在制备与急性肾损伤有关适应症治疗药物中的应用。
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