CN117327068A - Iron death inhibitor based on multi-component reaction and preparation method and application thereof - Google Patents

Iron death inhibitor based on multi-component reaction and preparation method and application thereof Download PDF

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CN117327068A
CN117327068A CN202311096699.1A CN202311096699A CN117327068A CN 117327068 A CN117327068 A CN 117327068A CN 202311096699 A CN202311096699 A CN 202311096699A CN 117327068 A CN117327068 A CN 117327068A
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iron death
nmr
400mhz
chloroform
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王勇
王积磊
范雪静
张倩儿
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Ocean University of China
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses an iron death inhibitor based on a multi-component reaction, and a preparation method and application thereof. The invention is generalThe novel iron death inhibitor is synthesized by excessive component reaction, has a structural formula shown in a general formula I, and further enriches the variety of the iron death domain inhibitor. Experiments prove that the iron death inhibitor has better effect of inhibiting iron death, thereby protecting nerve cells from damage, improving survival rate of the nerve cells, and achieving the effect of recovering nervous system functions, so that the iron death inhibitor has good application value for treating iron death related diseases such as nervous system diseases.

Description

Iron death inhibitor based on multi-component reaction and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to an iron death inhibitor based on a multi-component reaction, and a preparation method and application thereof.
Technical Field
In 2012, the Brent R.Stockwell team reported that iron-dependent non-apoptotic cell death forms-iron death (ferroptosis), which is mainly characterized by the presence of extensive lipid peroxidation, mitochondrial shrinkage, intracellular Reactive Oxygen Species (ROS) accumulation, glutathione (GSH) depletion, etc., as opposed to apoptosis and cell death. Studies have demonstrated that iron death has a strong correlation with neurological diseases, and iron death has been found in neuronal cell death associated with various neurological diseases, such as Alzheimer's Disease (AD), hemorrhagic stroke, ischemic stroke, parkinson's disease, which is one of the major cell death pathways of neurological diseases, accompanied by lipid peroxidation, mitochondrial dysfunction and inactivation of glutathione peroxidase 4 (GPX 4), and studies have found that iron death inhibitors protect neurons and restore cognitive function, and thus inhibition of iron death is an effective strategy for drug development against neurological diseases.
At present, many reports are made on research on iron death inhibitors, most of the inhibitors mainly play a role in inhibiting iron death by capturing ROS generated by lipid peroxides and inhibiting antioxidant pathways such as lipoxygenase, but the research on the inhibitors is in a primary stage at present, and the inhibitor has the defects of short half-life, high toxicity, poor pharmacokinetics, low patentability and the like. Therefore, it is a real problem to develop an iron death inhibitor which has low toxicity, good BBB permeability and is easy to be used as a medicine.
The multicomponent reaction (Multicomponent Reactions, MCRs) has wide application in medicine research, and the reaction has the advantages of simple synthesis and purification steps, high atom economy, diversity of products, capability of quickly constructing a compound library and the like, and plays an important role in treating various diseases, such as nervous system diseases, cardiovascular system diseases, parasitic diseases, virus infection and the like. Imidazo [1,2-a ] pyridines are an important structural backbone in drug development, exerting a variety of biological activities, such as anti-tumor, antibacterial, anti-inflammatory, neurological diseases, metabolic diseases, etc. The study shows that imidazo [1,2-a ] pyridine compounds obtained by Groebke-Blackburn-Bienayme three-component reaction (Groebke-3 CR) have a certain antioxidation effect.
Therefore, in order to improve atomic aggressiveness and better exert pharmacological actions for treating neurological diseases, iron death inhibitors synthesized based on multicomponent reactions have great significance for the treatment of neurological diseases.
Disclosure of Invention
It is an object of the present invention to provide an iron death inhibitor based on a multicomponent reaction.
Another object of the present invention is to provide a method for preparing the above iron death inhibitor.
It is still another object of the present invention to provide the use of the above iron death inhibitors and pharmaceutical compositions thereof in the medical field, which can be used for the treatment of iron death-related diseases such as nervous system diseases.
In order to achieve the aim of the invention, the invention is realized by adopting the following technical scheme:
the invention provides an iron death inhibitor based on a multicomponent reaction, which has a structural formula shown in a general formula I:
wherein R is 1 Selected from hydrogen, C 1 -C 3 Alkyl, F, cl, br, aryl, C 1 -C 4 Heteroalkyl, or C containing 1 or more substituents 1 -C 4 A heteroalkyl group;
R 2 selected from C 1 -C 6 Alkyl aldehyde group, C 3 -C 8 Saturated heteroaryl, C 1 -C 6 Aryl, or C containing 1 or more substituents 1 -C 6 An aryl group;
R 3 selected from C 1 -C 6 Alkyl, C 1 -C 6 Ester group, adamantyl group, C 1 -C 3 Alkyl, C 3 -C 6 Saturated heteroaryl, C 1 -C 6 Aryl, or C containing 1 or more substituents 1 -C 6 An aryl group;
x is selected from any one of N, S;
wherein the substituents are selected from methyl, C 1 -C 6 Alkoxy, aryl, or halogen-containing aryl, halogen, -CF 3 Or hydroxy;
the hetero atom in the hetero alkyl and saturated heteroaryl is selected from any one of N, S and O.
Further, the iron death inhibitor has a structural formula as shown in a general formula I:
wherein R is 1 Selected from hydrogen, methyl, F, phenyl, 1-methylpiperazinyl, or (methoxy) methyl-3-chlorophenyl;
R 2 selected from cyclohexyl aldehyde groups, C 3 -C 8 Saturated heteroaryl, phenyl, or phenyl containing 1-2 substituents;
R 3 selected from tert-butyl, 2-methyl-3-butynyl, ethyl formate, adamantyl, 2-methylfuryl, phenyl/benzyl, or phenyl/benzyl containing 1-2 substituents;
x is selected from N;
wherein the substituents are selected from F, cl, -CF 3 Hydroxy, methoxy;
the heteroatom in the saturated heteroaryl is selected from any one of N, S and O.
Further, the iron death inhibitor is specifically compounds I-1 to I-45, and the structural formulas are as follows:
the invention also provides a preparation method of the iron death inhibitor, which is shown as follows:
primary amine 1 reacts with ethyl formate to obtain an intermediate 2, and the intermediate 2 is dehydrated to obtain an isonitrile intermediate 3; the intermediate 3 reacts with 2-aminopyridine 4 containing substituent and aldehyde 5 containing substituent through three components of Groebke-Blackburn-Bienayme to obtain compounds I-1, I-9-I-45;
or the isonitrile 3 reacts with 2-aminopyridine 4 containing substituent groups and aldehyde 5 containing substituent groups through three components of Groebke-Blackburn-Bienayme to obtain compounds I-2 to I-8;
wherein, a) is ethyl formate, and the reaction condition is reflux; b) For POCl 3 、DIPEA、N 2 The reaction temperature is-60 ℃; c) Is LaCl 3 EtOH and reaction temperature was 60 ℃.
The invention also provides a composition comprising at least one of the iron death inhibitor, an isomer thereof, and a pharmaceutically acceptable salt thereof.
The invention also provides the application of the iron death inhibitor or the composition in inhibiting cell iron death.
Further, the iron death inhibitor or composition is used at a concentration of not less than 0.01. Mu.M.
The invention also provides application of the iron death inhibitor or the composition in preparing medicines for treating nervous system diseases.
Further, the neurological diseases include Alzheimer's disease, hemorrhagic stroke, ischemic stroke, parkinson's disease.
Further, the medicine also comprises a pharmaceutically acceptable carrier or auxiliary agent.
Furthermore, the iron death inhibitor can protect nerve cells from damage by inhibiting iron death, improve survival rate of the nerve cells and achieve the effect of recovering nervous system functions.
Further, the iron death inhibitors can be used to treat neurological disorders that are refractory to treatment with one or more other chemotherapeutic agents; or treating a neurological disorder with drug resistance.
Compared with the prior art, the invention has the advantages and beneficial effects that:
the novel iron death inhibitor is synthesized through a multi-component reaction, and the variety of the iron death inhibitor is enriched. Experiments prove that the compound has better effect of inhibiting iron death, thereby protecting nerve cells from damage, improving survival rate and achieving the effect of recovering nervous system functions. Therefore, the composition has good application value for treating iron death related diseases such as nervous system diseases and the like.
Detailed Description
The technical scheme of the invention is further described in detail by combining the following specific examples.
In the following examples, unless otherwise specified, all experimental methods used are conventional and all materials, reagents, etc. are commercially available from biological or chemical reagent companies.
Example 1: preparation of iron death inhibitors based on multicomponent reactions
Of compounds 1 H-NMR、 13 C-NMR spectroscopic data measurements were performed on silica gel H (10-40. Mu.M) using VJEOL 400MHz or Bruker AVENCE NEO MHz nuclear magnetic resonance.
Preparation of Compound I-1: 2-methyl-3-butyn-2-amine (1000 mg,1.2029 mmol) in ethyl formate (9.68 mL,120.2935 mol), N 2 Protection, reflux reaction, reduced pressure evaporation after reaction, DCM/MeOH as eluent, silica gel column chromatography to obtain intermediate 2. Intermediate 2 (100 mg,0.8998 mmol), DIPEA (0.784 mL,4.4988 mmol) was dissolved in dichloromethane (5 mL), N 2 Protection, POCl 3 (0.168 mL,1.7995 mmol) was dissolved in dichloromethane (0.5 mL), slowly added dropwise to the reaction system, reacted overnight at-60℃and after the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution and dichloromethane and extracted, the organic phases were combined, dried and evaporated under reduced pressure to give intermediate 3. 2-aminopyridine (42.2 mg,0.4488 mmol), 3-chlorobenzaldehyde (0.051 mL,0.4488 mmol), intermediate 3 (38.0 mg,0.4080 mmol) were dissolved in ethanol and the catalyst LaCl was added 3 (20.0 mg,0.0816 mmol), reacted at 60℃and evaporated to dryness under reduced pressure, DCM/MeOH as eluent, by silica gel column chromatography to give compound I-1 as a white solid, yield: 39.7%.
1 H NMR(400MHz,Chloroform-d)δ8.44(d,J＝6.9Hz,1H),8.14(t,J＝1.8Hz,1H),7.97(dt,J＝7.7,1.2Hz,1H),7.53(d,J＝9.0Hz,1H),7.35-7.26(m,2H),7.18-7.13(m,1H),6.75(t,J＝6.8Hz,1H),3.47(s,1H),2.12(s,1H),1.39(s,6H). 13 C NMR(400MHz,Chloroform-d)δ142.54,138.46,136.66,134.35,129.67,128.17,127.68,126.21,125.18,124.51,122.81,117.56,111.59,89.86,71.04,52.67,30.45.
The preparation of compound I-2 was similar to the preparation of the same type of compound described above, white solid, yield: 87.0%.
1 H NMR(400MHz,Acetone-d 6 )δ9.85(d,J＝8.6Hz,1H),7.83(dd,J＝7.9,1.4Hz,1H),7.60(ddd,J＝8.7,7.1,1.6Hz,1H),7.49(d,J＝9.3Hz,1H),7.45-7.40(m,1H),7.35(d,J＝9.3Hz,1H),4.14(s,1H),1.79(dd,J＝33.8,10.0Hz,8H),1.30(s,1H),1.29(s,2H),1.21(s,9H). 13 C NMR(400MHz,Acetone-d 6 )δ141.01,136.13,129.40,128.38,127.50,125.83,125.80,125.36,124.77,118.76,117.99,55.91,36.41,34.03,32.64,29.70,27.52,26.89,23.33.
The preparation of compound I-3 was similar to the preparation of the same type of compound described above, yellow solid, yield: 42.0%.
1 H NMR(400MHz,Chloroform-d)δ7.99(t,J＝1.7Hz,1H),7.95-7.93(m,1H),7.83(dd,J＝7.7,1.5Hz,1H),7.43(d,J＝9.1Hz,1H),7.32(t,J＝7.8Hz,1H),7.25(ddd,J＝7.9,1.9,1.2Hz,1H),6.98(dd,J＝9.1,1.5Hz,1H),2.33(s,3H),1.06-1.04(m,9H). 13 C NMR(400MHz,Chloroform-d)δ142.03,141.16,137.60,136.94,134.36,129.70,128.21,127.54,126.26,123.71,121.68,121.31,116.72,56.71,30.63,18.67.
The preparation of compound I-4 was similar to the preparation of the same type of compound described above, yellow solid, yield: 26.3%.
1 H NMR(400MHz,Chloroform-d)δ8.21(d,J＝6.9Hz,1H),7.86-7.83(m,2H),7.55(d,J＝9.0Hz,1H),7.15-7.11(m,1H),6.97-6.94(m,2H),6.77(t,J＝6.8Hz,1H),3.84(s,3H),1.03(s,9H). 13 C NMR(400MHz,Chloroform-d)δ159.29,141.81,139.04,129.57,127.44,124.53,123.64,123.11,117.07,113.95,111.69,56.59,55.45,30.54.
Compound I-5 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 57.1%.
1 H NMR(400MHz,Chloroform-d)δ8.17(d,J＝6.9Hz,1H),7.98(s,1H),7.51-7.47(m,2H),7.13-7.09(m,1H),6.95(s,1H),6.74(t,J＝6.3Hz,1H),2.89(s,1H),1.16(s,9H). 13 C NMR(400MHz,Chloroform-d)δ143.08,142.40,140.80,133.12,124.54,123.53,123.26,120.27,117.07,111.64,110.00,56.66,30.81.
Compound I-6 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 35.9%.
1 H NMR(400MHz,Chloroform-d)δ8.24-8.22(m,1H),8.04-8.01(m,2H),7.55(d,J＝9.0Hz,1H),7.46-7.42(m,2H),7.34-7.29(m,1H),7.17-7.12(m,1H),6.82(dd,J＝6.8,1.0Hz,1H),4.18(t,J＝7.2Hz,2H),3.80(d,J＝5.5Hz,2H),3.74(s,1H),1.24(s,3H). 13 C NMR(400MHz,Chloroform-d)δ171.98,141.78,136.04,134.04,128.89,127.77,127.15,124.91,124.57,122.95,117.58,112.11,61.60,49.60,14.32.
Compound I-7 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 39.5%.
1 H NMR(400MHz,Chloroform-d)δ8.23(d,J＝6.8Hz,1H),7.98-7.95(m,2H),7.56(d,J＝9.0Hz,1H),7.17-7.12(m,1H),6.99-6.96(m,2H),6.81(t,J＝6.8Hz,1H),4.17(d,J＝7.2Hz,2H),3.84(s,3H),3.79(d,J＝3.8Hz,2H),3.71(s,1H),1.26-1.24(m,3H). 13 C NMR(400MHz,Chloroform-d))δ172.05,159.44,141.52,135.82,134.12,130.26,128.47,124.72,122.95,117.15,114.35,112.16,61.59,55.50,49.50,14.33.
Compound I-8 was prepared in a similar manner to the preparation of the same type of compound described above, red solid, yield: 71.5%.
1 H NMR(400MHz,Chloroform-d)δ8.24(d,J＝6.7Hz,1H),7.57(s,1H),7.41(d,J＝8.8Hz,1H),7.14(t,J＝7.5Hz,2H),6.83(t,J＝6.6Hz,1H),6.78(d,J＝7.9Hz,1H),4.14(q,J＝7.1Hz,2H),3.73(s,2H),1.36-1.26(m,3H).
The preparation of compound I-9 was similar to the preparation of the same type of compound described above, as a reddish brown solid, yield: 50.0%.
1 H NMR(400MHz,Chloroform-d)δ8.09(d,J＝6.9Hz,1H),7.99-7.95(m,2H),7.53(d,J＝9.1Hz,1H),7.13-7.08(m,1H),7.00-6.95(m,2H),6.78-6.74(m,1H),3.85(s,3H),3.08(s,1H),2.94(ddd,J＝14.0,8.3,3.7Hz,1H),1.79(d,J＝12.2Hz,2H),1.72-1.49(m,4H),1.22-1.12(m,4H). 13 C NMR(101MHz,CDCl 3 )δ159.24,141.26,136.11,128.53,126.60,124.45,124.30,122.93,116.99,114.16,111.96,57.01,55.46,34.34,25.92,25.01.
The preparation of compound I-10 was similar to the preparation of the same type of compound described above, a yellowish solid, yield: 91.6%.
1 H NMR(400MHz,Chloroform-d)δ8.04(dt,J＝3.0,1.5Hz,3H),7.52(d,J＝9.1Hz,1H),7.26(t,J＝1.9Hz,1H),7.17-7.13(m,1H),6.82-6.77(m,1H),3.04-2.88(m,2H),1.85-1.55(m,6H),1.29-1.23(m,4H). 13 C NMR(400MHz,Chloroform-d)δ141.91,137.59,135.24,134.19,127.16,125.79,125.34,124.87,122.85,117.82,112.30,57.28,34.49,25.84,25.01.
The preparation of compound I-11 was similar to the preparation of the same type of compound described above, white solid, yield: 45.9%.
1 H NMR(400MHz,Chloroform-d)δ9.27(d,J＝8.6Hz,1H),7.84(d,J＝1.9Hz,2H),7.75(dd,J＝7.8,1.5Hz,1H),7.59(ddd,J＝8.7,7.3,1.4Hz,1H),7.44(s,3H),7.29(t,J＝1.9Hz,1H),3.42(d,J＝5.7Hz,1H),2.91(tt,J＝10.8,5.4Hz,1H),1.81(d,J＝11.6Hz,2H),1.68-1.51(m,4H),1.18-1.10(m,4H). 13 C NMR(400MHz,Chloroform-d)δ141.12,137.94,135.90,135.29,132.31,129.02,128.08,127.88,127.11,126.88,126.37,125.81,125.78,124.86,124.81,117.71,117.11,57.56,33.63,29.91,25.86,25.11.
Compound I-12 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 50.7%.
1 H NMR(400MHz,Chloroform-d)δ9.39(d,J＝8.6Hz,1H),7.79(d,J＝7.8Hz,1H),7.76(dd,J＝7.9,1.4Hz,1H),7.62(d,J＝7.2Hz,1H),7.58-7.53(m,3H),7.44(dd,J＝9.6,6.5Hz,3H),3.31(d,J＝7.6Hz,1H),2.81-2.72(m,1H),1.74(d,J＝10.9Hz,2H),1.55-1.43(m,3H),0.99(dd,J＝24.2,10.1Hz,5H). 13 C NMR(400MHz,Chloroform-d)δ140.22,134.88,134.38,133.35,131.69,131.26,130.16,129.86,128.71,128.56,127.88,126.52,126.47,126.28,124.75,124.67,117.54,117.38,56.65,33.29,25.74,24.72.
The preparation of compound I-13 was similar to the preparation of the same type of compound described above, yellow solid, yield: 65.2%.
1 H NMR(400MHz,Chloroform-d)δ9.36(d,J＝8.6Hz,1H),7.73(dd,J＝7.8,1.4Hz,1H),7.69(dd,J＝2.7,1.1Hz,1H),7.65(dd,J＝4.9,1.0Hz,1H),7.57(ddd,J＝8.6,7.2,1.4Hz,1H),7.44-7.38(m,4H),3.41(d,J＝5.2Hz,1H),2.99(td,J＝10.4,9.8,5.3Hz,1H),1.85(d,J＝12.4Hz,2H),1.70-1.50(m,4H),1.22(d,J＝13.8Hz,2H),1.10(s,2H). 13 C NMR(400MHz,Chloroform-d)δ140.55,134.89,131.00,129.59,128.93,128.72,127.71,126.95,126.20,125.77,124.62,124.43,121.42,117.33,117.20,57.44,33.51,25.86,25.09.
Compound I-14 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 54.4%.
1 H NMR(400MHz,Chloroform-d)δ8.19(d,J＝6.9Hz,1H),7.47(d,J＝9.0Hz,1H),7.06-7.01(m,1H),6.68(t,J＝7.2Hz,1H),2.79-2.69(m,2H),1.89-1.73(m,8H),1.71(d,J＝2.6Hz,7H),1.64-1.52(m,7H),1.37(d,J＝6.9Hz,3H). 13 C NMR(400MHz,Chloroform-d)δ145.72,141.98,123.63,123.51,121.11,116.83,111.00,55.35,44.05,36.44,36.30,33.17,29.91,27.06,26.10.
Compound I-15 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 88.3%.
1 H NMR(400MHz,Chloroform-d)δ8.25(d,J＝6.9Hz,1H),7.87(d,J＝8.9Hz,2H),7.52(d,J＝9.0Hz,1H),7.13-7.08(m,1H),6.96(d,J＝8.8Hz,2H),6.75(t,J＝6.8Hz,1H),3.85(s,3H),1.60-1.41(m,15H). 13 C NMR(400MHz,Chloroform-d)δ159.14,141.96,139.34,129.52,127.80,124.13,123.70,122.05,117.12,113.87,111.39,56.77,55.43,44.07,36.36,29.87.
Compound I-16 was prepared in a similar manner to the preparation of the same type of compound described above, as a white solid, yield: 87.0%.
1 H NMR(400MHz,Chloroform-d)δ8.24(d,J＝6.9Hz,1H),8.05(t,J＝1.8Hz,1H),7.88(dt,J＝7.7,1.3Hz,1H),7.52(d,J＝9.0Hz,1H),7.34(t,J＝7.8Hz,1H),7.29-7.25(m,1H),7.16-7.11(m,1H),6.79-6.75(m,1H),2.99(s,1H),1.58(d,J＝2.5Hz,7H),1.56-1.43(m,8H). 13 C NMR(400MHz,Chloroform-d)δ142.27,138.22,137.22,134.35,129.65,128.29,127.52,126.28,124.57,123.75,122.94,117.56,111.72,56.95,44.19,36.32,29.88.
Compound I-17 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 41.3%.
1 H NMR(400MHz,Chloroform-d)δ8.24(d,J＝6.8Hz,1H),7.83(d,J＝2.2Hz,1H),7.72(d,J＝5.8Hz,1H),7.52(d,J＝9.0Hz,1H),7.36(dd,J＝5.0,3.0Hz,1H),7.15-7.10(m,1H),6.76(t,J＝6.7Hz,1H),1.64(d,J＝2.4Hz,7H),1.60-1.43(m,8H). 13 C NMR(400MHz,Chloroform-d)δ142.00,135.86,135.79,127.50,125.33,124.58,123.77,122.88,122.24,117.07,111.67,56.81,44.20,36.35,29.92.
Compound I-18 was prepared in a similar manner to the preparation of the same type of compound described above, as a white solid, yield: 53.0%.
1 H NMR(400MHz,Chloroform-d)δ8.84(d,J＝2.0Hz,1H),8.31(d,J＝6.9Hz,1H),7.92(d,J＝2.0Hz,1H),7.49(d,J＝9.1Hz,1H),7.13-7.08(m,1H),6.73(t,J＝6.8Hz,1H),4.64(s,1H),1.69(d,J＝2.4Hz,7H),1.53(q,J＝12.1Hz,8H). 13 C NMR(400MHz,Chloroform-d)δ152.26,142.21,132.35,126.12,124.51,124.42,117.10,114.50,111.41,57.50,43.54,36.45,29.96.
Compound I-19 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 59.2%.
1 H NMR(400MHz,Acetone-d6)δ8.30-8.23(m,2H),8.15(d,J＝7.4Hz,1H),7.43(q,J＝9.1,7.8Hz,3H),7.31-7.17(m,5H),6.84(t,J＝6.6Hz,1H),4.91(t,J＝6.3Hz,1H),4.26(d,J＝6.2Hz,2H). 13 C NMR(400MHz,Acetone-d6)δ143.13,142.32,134.74,134.62,130.88,130.80,129.30,128.12,127.79,127.63,127.55,127.35,126.09,125.15,124.04,118.21,112.52,52.06.
Compound I-20 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 61.0%.
1 H NMR(400MHz,Acetone-d6)δ9.44-9.41(m,1H),8.01(s,1H),7.94(d,J＝7.8Hz,1H),7.91(dd,J＝7.9,1.5Hz,1H),7.66(ddd,J＝8.7,7.2,1.6Hz,1H),7.60(d,J＝9.3Hz,1H),7.50(ddd,J＝8.0,7.2,1.1Hz,1H),7.45-7.34(m,3H),7.28(d,J＝9.1Hz,1H),7.24-7.19(m,3H),5.19(t,J＝6.3Hz,1H),4.27(d,J＝6.3Hz,2H). 13 C NMR(400MHz,Acetone-d6)δ142.03,141.56,137.77,136.24,135.75,134.68,134.60,131.99,130.79,130.71,129.85,129.48,129.11,128.18,127.91,127.59,127.21,126.40,125.57,125.49,118.43,117.69,52.90.
The preparation of compound I-21 was similar to the preparation of the same type of compound described above, brown solid, yield: 87.4%.
1 H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.90(d,J＝7.7Hz,1H),7.38-7.30(m,3H),7.27(s,1H),7.24(d,J＝8.8Hz,1H),7.17-7.10(m,2H),7.01(d,J＝7.1Hz,1H),6.92(d,J＝9.6Hz,1H),4.32(s,1H),4.10(s,2H),3.20(s,4H),2.98(s,4H),2.63(s,3H). 13 C NMR(400MHz,Chloroform-d)δ143.60,140.03,139.31,138.12,134.64,134.49,130.87,130.72,129.30,128.01,127.82,127.16,127.02,125.60,122.09,117.75,108.97,55.17,54.95,54.19,50.19,45.57,42.47.
Compound I-22 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 24.5%.
1 H NMR(400MHz,Chloroform-d)δ7.99(dt,J＝6.9,1.2Hz,1H),7.85(d,J＝1.9Hz,2H),7.56(dt,J＝9.1,1.0Hz,1H),7.29(t,J＝1.9Hz,1H),7.26(d,J＝1.9Hz,1H),7.21(ddd,J＝9.0,6.7,1.3Hz,1H),7.17(d,J＝1.9Hz,2H),6.84(td,J＝6.8,1.1Hz,1H),4.12(d,J＝6.2Hz,2H),3.45(t,J＝6.2Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ142.17,141.96,137.13,135.53,135.48,134.82,128.25,127.62,126.93,125.48,125.30,125.24,122.37,118.18,112.75,51.74.
Compound I-23 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 28.7%.
1 H NMR(400MHz,Chloroform-d)δ9.21(d,J＝8.6Hz,1H),7.83(dd,J＝7.9,1.5Hz,1H),7.67(ddd,J＝8.7,7.2,1.6Hz,1H),7.63(d,J＝1.9Hz,2H),7.54-7.47(m,3H),7.29(t,J＝1.9Hz,1H),7.25(t,J＝1.9Hz,1H),7.06(d,J＝1.9Hz,2H),4.13(d,J＝6.5Hz,2H),3.89(t,J＝6.4Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ141.35,140.89,136.95,135.49,135.45,134.80,134.69,130.34,129.36,128.76,128.30,128.07,128.02,127.56,127.36,127.14,126.27,126.12,125.65,125.22,124.81,117.65,116.43,52.70.
Compound I-24 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 15.7%.
1 H NMR(400MHz,Chloroform-d)δ9.28(d,J＝9.1Hz,1H),7.79(dd,J＝7.9,1.5Hz,1H),7.60(ddd,J＝8.7,7.2,1.6Hz,1H),7.52-7.44(m,3H),7.39(dd,J＝8.1,0.7Hz,2H),7.27(dd,J＝8.8,7.4Hz,1H),7.15(t,J＝1.9Hz,1H),6.97(d,J＝1.9Hz,2H),4.05(d,J＝6.6Hz,2H),3.61(t,J＝6.7Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ142.05,141.08,136.35,135.14,134.77,133.01,132.12,131.55,130.54,129.00,128.35,128.30,127.83,126.55,126.40,124.87,124.65,117.95,116.65,52.54.
Compound I-25 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 42.2%.
1 H NMR(400MHz,Chloroform-d)δ9.29(d,J＝8.6Hz,1H),7.78(dd,J＝7.9,1.4Hz,1H),7.60(ddd,J＝8.7,7.2,1.5Hz,1H),7.51-7.44(m,3H),7.27(dt,J＝8.1,5.8Hz,2H),7.11(t,J＝1.9Hz,1H),7.04(ddd,J＝9.3,7.4,2.1Hz,1H),6.90(d,J＝1.9Hz,2H),4.02(d,J＝6.8Hz,2H),3.75(t,J＝6.7Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ141.79,141.23,135.09,134.65,131.90,130.62,130.53,128.99,128.43,127.85,126.61,125.60,125.57,124.93,124.61,117.79,116.67,114.58,114.35,52.47.
Compound I-26 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 93.4%.
1 H NMR(400MHz,Chloroform-d)δ9.27(d,J＝8.1Hz,1H),7.81(dd,J＝7.9,1.4Hz,1H),7.63(ddd,J＝8.7,7.2,1.6Hz,1H),7.50(d,J＝6.0Hz,3H),7.40(s,2H),7.19(t,J＝1.9Hz,1H),6.97(d,J＝1.9Hz,2H),4.07(d,J＝6.6Hz,2H),3.63(t,J＝6.7Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ142.07,141.27,136.76,135.45,135.25,134.76,132.28,131.51,130.96,129.09,128.47,128.36,127.78,126.63,126.52,124.99,124.68,117.95,116.60,52.43.
Compound I-27 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 56.1%.
1 H NMR(400MHz,Chloroform-d)δ7.95-7.91(m,2H),7.54-7.51(m,2H),7.27(t,J＝1.9Hz,1H),7.24(d,J＝1.9Hz,2H),7.15(ddd,J＝9.0,6.7,1.3Hz,1H),6.89(dd,J＝1.8,0.8Hz,1H),6.77(td,J＝6.8,1.0Hz,1H),4.14(d,J＝6.2Hz,2H),3.35(t,J＝6.0Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ143.80,142.53,142.03,141.99,140.33,135.44,128.08,126.78,124.93,124.26,122.26,119.45,119.43,117.28,112.40,109.15,51.61.
Compound I-28 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 62.3%.
1 H NMR(400MHz,Chloroform-d)δ8.83(d,J＝2.1Hz,1H),7.99(d,J＝6.9Hz,1H),7.88(d,J＝2.1Hz,1H),7.53(d,J＝9.1Hz,1H),7.29(d,J＝1.8Hz,2H),7.22(t,J＝1.8Hz,1H),7.15(ddd,J＝9.0,6.7,1.2Hz,1H),6.80(td,J＝6.8,1.0Hz,1H),5.41(t,J＝7.4Hz,1H),4.13(d,J＝7.4Hz,2H). 13 C NMR(400MHz,Chloroform-d)δ153.16,151.56,142.69,141.74,135.13,129.23,128.37,127.72,126.76,124.60,122.63,117.63,113.86,112.45,51.28.
Compound I-29 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 72.1%.
1 H NMR(400MHz,Chloroform-d 6 )δ8.16(dt,J＝6.9,1.1Hz,1H),7.60(qd,J＝15.0,14.6,7.8Hz,2H),7.45-7.42(m,1H),7.40-7.37(m,1H),7.32-7.30(m,1H),7.25-7.19(m,4H),6.96(d,J＝6.9Hz,1H),6.88(td,J＝6.8,1.0Hz,1H),4.14(d,J＝6.9Hz,2H),3.83(t,J＝7.0Hz,1H). 13 C NMR(400MHz,Chloroform-d)δ161.09,136.57,132.51,132.42,131.94,131.07,130.89,129.99,129.59,127.91,127.15,126.23,126.18,126.12,122.89,116.84,113.60,48.61.
Compound I-30 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 51.1%.
1 H NMR(400MHz,Chloroform-d 6 )δ7.86(d,J＝6.8Hz,1H),7.84(dd,J＝2.9,1.1Hz,1H),7.65(d,J＝1.3Hz,1H),7.64(d,J＝1.2Hz,1H),7.59(d,J＝9.0Hz,1H),7.41-7.34(m,2H),7.31(dd,J＝5.0,3.0Hz,2H),7.17(ddd,J＝9.0,6.8,1.2Hz,1H),6.75(td,J＝6.8,1.0Hz,1H),4.36-4.32(m,2H),3.97(s,1H). 13 C NMR(400MHz,Chloroform-d 6 )δ140.50,137.33,132.34,131.18,127.94,126.38,126.26,126.20,126.03,124.52,122.93,122.60,116.20,112.95,48.74.
Compound I-31 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 63.0%.
1 H NMR(400MHz,Chloroform-d)δ7.76(d,J＝6.7Hz,1H),7.57(d,J＝9.0Hz,1H),7.18-7.13(m,1H),6.77-6.70(m,2H),6.61(d,J＝2.8Hz,1H),6.30(dd,J＝8.8,2.8Hz,1H),3.80(s,3H),2.74(t,J＝11.8Hz,1H),1.74(dt,J＝42.3,10.5Hz,8H),1.28(d,J＝8.1Hz,2H). 13 C NMR(400MHz,Chloroform-d)δ148.82,147.54,142.58,140.09,124.50,123.83,122.47,117.48,117.28,115.50,114.14,112.05,111.97,56.93,36.76,32.58,26.72,26.05.
The preparation of compound I-32 was similar to the preparation of the same type of compound described above, brown solid, yield: 56.1%.
1 H NMR(400MHz,Chloroform-d)δ7.70-7.68(m,1H),7.53(dd,J＝9.7,4.9Hz,1H),7.07(ddd,J＝10.1,8.0,2.4Hz,1H),6.77(d,J＝8.8Hz,1H),6.60(d,J＝2.8Hz,1H),6.31(dd,J＝8.8,2.8Hz,1H),5.39(s,1H),3.82(s,3H),2.73(ddd,J＝11.9,8.5,3.4Hz,1H),1.83-1.64(m,8H),1.29-1.26(m,2H). 13 C NMR(400MHz,Chloroform-d)δ154.74,149.15,139.97,139.53,124.00,118.92,117.98,117.89,115.67,114.22,112.13,109.53,109.13,56.99,36.84,32.58,26.71,26.05.
The preparation of compound I-33 was similar to the preparation of the same type of compound described above, brown solid, yield: 76.0%.
1 H NMR(400MHz,Chloroform-d)δ7.73(dd,J＝7.0,0.7Hz,1H),7.53(s,1H),7.35-7.32(m,1H),7.26-7.24(m,2H),7.23-7.18(m,1H),6.77-6.73(m,2H),6.61-6.59(m,1H),6.29(dd,J＝8.8,2.8Hz,1H),5.48(s,1H),4.55(s,2H),4.51(s,2H),3.79(s,3H),2.74(tt,J＝12.0,3.3Hz,1H),1.82-1.65(m,7H),1.32-1.26(m,3H). 13 C NMR(400MHz,Chloroform-d)δ148.77,142.11,139.99,134.46,129.85,127.99,127.71,125.72,123.76,122.52,117.50,115.47,115.17,114.08,111.96,71.53,71.34,56.87,36.65,32.47,26.63,25.97.
Compound I-34 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 28.0%.
1 H NMR(400MHz,Chloroform-d)δ7.91(d,J＝1.6Hz,2H),7.82(d,J＝6.8Hz,1H),7.63(d,J＝9.1Hz,1H),7.26(d,J＝7.2Hz,3H),6.84-6.78(m,2H),6.68(d,J＝2.7Hz,1H),6.42(dd,J＝8.8,2.7Hz,1H),5.50(s,1H),3.82(s,3H). 13 C NMR(400MHz,Chloroform-d)δ149.57,142.95,138.48,136.90,136.19,135.43,127.97,126.24,125.35,124.23,122.96,119.05,118.04,115.99,114.34,113.16,112.59,56.94.
The preparation of compound I-35 was similar to the preparation of the same type of compound described above, yellow solid, yield: 19.3%.
1 H NMR(400MHz,Chloroform-d)δ9.14(s,1H),7.91(s,3H),7.32(d,J＝17.2Hz,2H),6.81(d,J＝7.1Hz,2H),6.68(s,1H),6.40(d,J＝7.9Hz,1H),3.83(s,3H). 13 C NMR(400MHz,Chloroform-d)δ150.01,144.26,139.11,138.02,137.41,135.64,135.43,130.12,128.72,125.62,124.38,120.33,116.33,115.95,115.91,114.25,112.82,56.85.
The preparation of compound I-36 was similar to the preparation of the same type of compound described above, brown solid, yield: 38.3%.
1 H NMR(400MHz,Chloroform-d)δ7.80(s,2H),7.44(d,J＝10.3Hz,1H),7.15(s,1H),7.09(d,J＝7.0Hz,2H),6.77(d,J＝8.8Hz,1H),6.66(d,J＝2.2Hz,1H),6.37(dd,J＝8.8,2.2Hz,1H),5.98(s,1H),3.81(s,3H),3.00(s,4H),2.59(s,4H),2.36(s,3H). 13 C NMR(400MHz,Chloroform-d)δ149.19,140.20,139.78,138.65,136.43,135.13,127.31,124.85,124.00,122.42,119.76,117.68,115.81,114.23,112.38,107.51,56.83,54.70,49.79,45.89.
The preparation of compound I-37 was similar to the preparation of the same type of compound described above, brown solid, yield: 38.7%.
1 H NMR(400MHz,Chloroform-d)δ7.86(d,J＝1.9Hz,2H),7.72(d,J＝7.0Hz,1H),7.54(s,1H),7.38(s,1H),7.30-7.27(m,2H),7.26-7.23(m,1H),7.21(t,J＝1.9Hz,1H),6.79(s,1H),6.77(d,J＝2.9Hz,1H),6.64(d,J＝2.8Hz,1H),6.37(dd,J＝8.8,2.8Hz,1H),5.67(d,J＝1.8Hz,1H),4.58(s,2H),4.57(s,2H),3.81(s,3H). 13 C NMR(400MHz,Chloroform-d)δ149.42,139.80,138.34,135.29,134.59,129.97,128.18,127.84,127.81,125.81,125.07,124.08,122.87,119.27,115.88,115.04,114.21,112.78,112.53,71.97,71.08,56.83.
Compound I-38 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 93.7%.
1 H NMR(400MHz,Chloroform-d)δ8.78(dd,J＝8.3,1.3Hz,1H),7.78(dd,J＝7.7,1.7Hz,1H),7.57-7.51(m,3H),7.47-7.39(m,3H),7.28-7.23(m,3H),6.66-6.63(m,2H),6.31(dd,J＝8.8,2.8Hz,1H),5.88(s,1H),3.73(s,3H). 13 C NMR(400MHz,Chloroform-d)δ149.15,141.79,139.78,137.51,133.97,133.08,132.33,132.14,129.82,129.78,129.01,128.95,127.72,127.08,125.16,124.89,124.50,123.54,117.24,116.72,116.44,113.74,113.01,56.68.
Compound I-39 was prepared in a similar manner to the preparation of the same type of compound described above, as a white solid, yield: 22.2%.
1 H NMR(400MHz,Chloroform-d)δ8.76-8.73(m,1H),7.83-7.80(m,1H),7.58(s,2H),7.50-7.42(m,2H),7.38(s,2H),6.75(d,J＝2.8Hz,1H),6.70(d,J＝8.8Hz,1H),6.46(dd,J＝8.8,2.8Hz,1H),5.42(s,1H),3.78(s,3H). 13 C NMR(400MHz,Chloroform-d)δ149.60,138.85,136.83,133.74,129.53,129.30,128.44,125.80,125.76,124.61,123.68,116.81,116.76,113.68,113.33,56.72.
Compound I-40 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 54.5%.
1 H NMR(400MHz,Chloroform-d)δ7.86(t,J＝3.3Hz,2H),7.59(d,J＝9.0Hz,1H),7.39(s,1H),7.22(d,J＝7.8Hz,1H),6.87-6.85(m,1H),6.82-6.75(m,2H),6.67(d,J＝2.8Hz,1H),6.40(dd,J＝8.8,2.8Hz,1H),5.56(s,1H),3.80(s,3H). 13 C NMR(400MHz,Chloroform-d)δ149.28,143.60,143.28,140.92,139.25,134.67,125.40,124.14,122.55,119.28,117.61,117.58,115.75,114.35,112.60,112.30,109.13,56.99.
The preparation of compound I-41 was similar to the preparation of the same type of compound described above, brown solid, yield: 52.5%.
1 H NMR(400MHz,Chloroform-d)δ8.22(s,1H),7.78(s,1H),7.55(s,4H),7.43(d,J＝8.7Hz,1H),7.32-7.06(m,5H),6.93(s,1H),4.03(s,2H). 13 C NMR(400MHz,Chloroform-d)δ149.13,142.36,140.15,139.33,138.12,136.10,128.20,125.55,125.29,125.00,124.69,124.67,124.04,122.73,122.51,119.12,117.69,115.87,114.29,112.76,112.32,56.91.
The preparation of compound I-42 was similar to the preparation of the same type of compound described above, brown solid, yield: 25.1%.
1 H NMR(400MHz,Chloroform-d)δ7.86-7.84(m,1H),7.79-7.77(m,1H),7.64-7.61(m,2H),7.32(ddd,J＝4.9,3.0,1.2Hz,1H),7.24-7.21(m,1H),6.82-6.77(m,2H),6.71(dd,J＝2.8,1.0Hz,1H),6.41(ddd,J＝8.8,2.8,1.1Hz,1H),5.52(s,1H),3.81(d,J＝1.1Hz,3H). 13 C NMR(400MHz,Chloroform-d)δ149.28,138.85,126.42,126.23,124.04,122.93,115.83,114.22,112.40,56.88.
Compound I-43 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 57.6%.
1 H NMR(400MHz,Chloroform-d)δ8.04(d,J＝6.8Hz,1H),7.76(d,J＝7.5Hz,1H),7.53(dd,J＝12.9,7.8Hz,3H),7.35(d,J＝7.0Hz,1H),7.20-7.14(m,2H),6.81(t,J＝6.6Hz,1H),6.18(s,1H),5.95(d,J＝2.8Hz,1H),3.94(d,J＝5.4Hz,2H),3.51(s,1H). 13 C NMR(400MHz,Chloroform-d)δ152.34,142.44,140.93,133.13,132.38,131.68,130.15,128.78,126.54,126.50,126.44,126.39,124.96,122.87,117.61,112.54,110.53,108.02,45.10.
Compound I-44 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 43.7%.
1 H NMR(400MHz,Chloroform-d)δ8.83(d,J＝2.0Hz,1H),8.02(d,J＝6.9Hz,1H),7.90(d,J＝2.1Hz,1H),7.52(d,J＝9.1Hz,1H),7.31(dd,J＝1.7,0.7Hz,1H),7.13(ddd,J＝9.0,6.7,1.2Hz,1H),6.76(td,J＝6.8,0.9Hz,1H),6.22(dd,J＝3.1,1.9Hz,1H),6.12-6.10(m,1H),5.40(s,1H),4.17(s,2H). 13 C NMR(400MHz,Chloroform-d)δ152.93,152.72,151.40,142.24,141.51,128.99,128.53,124.66,122.89,117.15,113.71,112.17,110.46,107.97,44.91.
Compound I-45 was prepared in a similar manner to the preparation of the same type of compound described above, as a yellow solid, yield: 61.4%.
1 H NMR(400MHz,Chloroform-d)δ8.38(dd,J＝7.2,1.5Hz,1H),8.02(d,J＝6.9Hz,1H),7.89(dd,J＝7.1,1.3Hz,1H),7.60(d,J＝9.1Hz,1H),7.55(s,1H),7.40(ddd,J＝8.9,7.5,1.3Hz,2H),7.23(dd,J＝1.8,0.7Hz,1H),7.18-7.13(m,1H),6.80(td,J＝6.8,0.9Hz,1H),6.15(dd,J＝3.1,1.9Hz,1H),5.98(d,J＝3.1Hz,1H),4.08(s,2H),3.67(s,1H). 13 C NMR(400MHz,Chloroform-d)δ152.43,142.36,141.50,140.16,138.65,132.56,129.58,126.29,124.60,124.48,124.44,124.05,122.53,122.47,117.63,112.04,110.47,108.03,44.93.
Example 2: effect of iron death inhibitors on the growth of iron death-sensitive neural cell lines
Studies have shown that GPX4 inhibitors such as RSL-3 are able to induce cell-derived iron death, which can also be blocked by other small molecule substances such as the lipophilic antioxidants Ferrostatin-1 (fer-1), liproxstatin, etc. Thus, the ability of an iron death inhibitor to block iron death may be indicative of the reversal of cellular iron death induced by an iron death inducer.
Cell lines: the human neuroblastoma cell line SH-SY5Y is purchased from Shanghai cell bank of China academy of sciences.
The method comprises the following steps: the MTT method is to take SH-SY5Y cells in logarithmic growth phase, digest, collect and dilute the cells, seed the cells in 96-well plates with about 4000-5000 cells per well, and test the cells in 3 multiple wells with 80 mu L per well. Placing at 37deg.C and 5% CO 2 After overnight incubation in incubator, the observation under the mirror was confirmedCell adhesion was considered good. The experiments were performed in a DMSO control group and a drug administration group (9 dilution concentrations, 100. Mu.M, 30. Mu.M, 10. Mu.M, 2. Mu.M, 0.4. Mu.M, 0.08. Mu.M, 0.016. Mu.M, 0.0032. Mu.M, 0.00064. Mu.M) in this order. The dosing groups were dosed with different concentrations of compound, 10 μl per well, and DMSO control (same dilution as the highest concentration of compound) was set, 5% CO 2 Incubation was continued for 1h at 37℃in an incubator. Thereafter, iron death was induced by adding 5. Mu.M RSL-3 at a concentration of 10. Mu.L per well to each of the administration wells, and setting an RSL-3 control group and a DMSO control group, and 5% CO 2 Incubation was continued for 48h in an incubator at 37 ℃. After adding 5mg/mL of 20. Mu.L MTT solution per well and continuing to culture SH-SY5Y cells in an incubator at 37℃for 2 hours, the supernatant was discarded, and 100. Mu.L DMSO was added per well, and the mixture was stirred smoothly for 10 minutes and mixed well. Placing on an ELISA detector, detecting optical density value (OD value) of each hole at 570nm wavelength, and IC 50 Values were calculated using a nonlinear regression method and normalized dose response fitting was performed using Prism-Graph Pad software, and all experiments were performed at least three times independently.
Results: the compounds of the invention have protective activity on iron death sensitive SH-SY5Y nerve cells, show a certain iron death inhibition effect, and the specific data are shown in Table 1.
Compounds of table 1 activity against iron death
In the table: "A" indicates IC 50 Less than or equal to 0.1 mu M, and "B" indicates 0.5 mu M less than or equal to IC 50 >0.1. Mu.M, "C" indicates 2. Mu.M.ltoreq.IC 50 >0.5 mu M, with "D" indicating 10 mu M.ltoreq.IC 50 >2. Mu.M, "E" indicates IC 50 Value of>10μM。
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be apparent to one skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features thereof; such modifications and substitutions do not depart from the spirit and scope of the corresponding technical solutions.

Claims (10)

1. An iron death inhibitor based on a multicomponent reaction, characterized in that the iron death inhibitor has a structural formula as shown in formula I:
wherein R is 1 Selected from hydrogen, C 1 -C 3 Alkyl, F, cl, br, aryl, C 1 -C 4 Heteroalkyl, or C containing 1 or more substituents 1 -C 4 A heteroalkyl group;
R 2 selected from C 1 -C 6 Alkyl aldehyde group, C 3 -C 8 Saturated heteroaryl, C 1 -C 6 Aryl, or C containing 1 or more substituents 1 -C 6 An aryl group;
R 3 selected from C 1 -C 6 Alkyl, C 1 -C 6 Ester group, adamantyl group, C 1 -C 3 Alkyl, C 3 -C 6 Saturated heteroaryl, C 1 -C 6 Aryl, or C containing 1 or more substituents 1 -C 6 An aryl group;
x is selected from any one of N, S;
wherein the substituents are selected from methyl, C 1 -C 6 Alkoxy, aryl, or halogen-containing aryl, halogen, -CF 3 Or hydroxy;
the hetero atom in the hetero alkyl and saturated heteroaryl is selected from any one of N, S and O.
2. The iron death suppressing agent according to claim 1, wherein the iron death suppressing agent has a structural formula as shown in formula I:
wherein R is 1 Selected from hydrogen, methyl, F, phenyl, 1-methylpiperazinyl, or (methoxy) methyl-3-chlorophenyl;
R 2 selected from cyclohexyl aldehyde groups, C 3 -C 8 Saturated heteroaryl, phenyl, or phenyl containing 1-2 substituents;
R 3 selected from tert-butyl, 2-methyl-3-butynyl, ethyl formate, adamantyl, 2-methylfuryl, phenyl/benzyl, or phenyl/benzyl containing 1-2 substituents;
x is selected from N;
wherein the substituents are selected from F, cl, -CF 3 Hydroxy, methoxy;
the heteroatom in the saturated heteroaryl is selected from any one of N, S and O.
3. The iron death inhibitor according to claim 2, wherein the iron death inhibitor is specifically compounds I-1 to I-45, which have the following structural formulae:
4. a method of preparing an iron death suppressing agent according to any one of claims 1 to 3, wherein the method is as follows:
primary amine 1 reacts with ethyl formate to obtain an intermediate 2, and the intermediate 2 is dehydrated to obtain an isonitrile intermediate 3; the intermediate 3 reacts with 2-aminopyridine 4 containing substituent and aldehyde 5 containing substituent through three components of Groebke-Blackburn-Bienayme to obtain compounds I-1, I-9-I-45;
or the isonitrile 3 reacts with 2-aminopyridine 4 containing substituent groups and aldehyde 5 containing substituent groups through three components of Groebke-Blackburn-Bienayme to obtain compounds I-2 to I-8;
wherein, a) is ethyl formate, and the reaction condition is reflux; b) For POCl 3 、DIPEA、N 2 The reaction temperature is-60 ℃; c) Is LaCl 3 EtOH and reaction temperature was 60 ℃.
5. A composition comprising at least one of the iron death inhibitor according to claim 1, an isomer thereof, a pharmaceutically acceptable salt thereof.
6. Use of the iron death inhibitor according to claim 1 or the composition according to claim 5 for inhibiting cellular iron death.
7. The use according to claim 6, wherein the iron death inhibitor or composition is used in a concentration of not less than 0.01 μm.
8. Use of the iron death inhibitor according to claim 1 or the composition according to claim 5 for the manufacture of a medicament for the treatment of neurological disorders.
9. The use according to claim 8, wherein said neurological disorder comprises alzheimer's disease, hemorrhagic stroke, ischemic stroke, parkinson's disease.
10. The use according to claim 8, wherein the medicament further comprises a pharmaceutically acceptable carrier or adjuvant.
CN202311096699.1A 2023-08-29 2023-08-29 Iron death inhibitor based on multi-component reaction and preparation method and application thereof Pending CN117327068A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116514988A (en) * 2023-04-06 2023-08-01 中国海洋大学 Nanometer antibody targeting glutathione peroxidase 4 and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116514988A (en) * 2023-04-06 2023-08-01 中国海洋大学 Nanometer antibody targeting glutathione peroxidase 4 and application thereof
CN116514988B (en) * 2023-04-06 2024-05-17 中国海洋大学 Nanometer antibody targeting glutathione peroxidase 4 and application thereof

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