WO2022156404A1 - Composé de benzimidazole, son procédé de préparation et son application dans la préparation d'un inhibiteur de la ferroptose - Google Patents

Composé de benzimidazole, son procédé de préparation et son application dans la préparation d'un inhibiteur de la ferroptose Download PDF

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WO2022156404A1
WO2022156404A1 PCT/CN2021/136185 CN2021136185W WO2022156404A1 WO 2022156404 A1 WO2022156404 A1 WO 2022156404A1 CN 2021136185 W CN2021136185 W CN 2021136185W WO 2022156404 A1 WO2022156404 A1 WO 2022156404A1
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ferroptosis
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顾琼
徐峻
房玉影
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中山大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a benzimidazole compound, a preparation method thereof, and an application in the preparation of a ferroptosis inhibitor.
  • Ferroptosis is a new type of non-apoptotic and regulated cell death discovered in recent years, characterized by iron-dependent accumulation of lipid ROS.
  • Glutathione peroxidase 4 GPX4
  • GPX4 Glutathione peroxidase 4
  • GPX4 is a key ferroptosis inhibitory protein in the ferroptosis pathway, which uses reduced glutathione as a cofactor to convert toxic lipid hydroperoxides. Reduced to non-toxic lipid alcohols. But when GPX4 is inactivated, intracellular lipid hydroperoxides accumulate in large quantities, thereby inducing ferroptosis.
  • Cysteine is a key raw material for the synthesis of reduced glutathione, and the source of intracellular cysteine depends on the glutamate/cystine antiporter system x c - .
  • the extracellular cystine is taken up by cells into the cell under the mediation of system x c - and then reduced to cysteine.
  • Inhibition of system x c - causes cysteine depletion, inhibits glutathione synthesis, and thus indirectly inhibits GPX4 enzymatic activity, ultimately inducing ferroptosis. Therefore, direct inhibition of GPX4 enzymatic activity, GPX4 knockdown, or inhibition of system x c- can induce ferroptosis.
  • ferroptosis is closely related to the occurrence and development of various neurological diseases (such as neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease, etc.) and stroke, etc.)
  • Ferroptosis is expected to be an effective strategy to prevent or treat these diseases; and ferroptosis inhibitors have been reported to significantly inhibit Parkinson's disease, Huntington's disease, ischemic stroke and hemorrhagic stroke in pathological models such as Cell damage and death.
  • ferroptosis inhibitors only radical-trapping antioxidants (RTAs), lipoxygenase inhibitors, and acyl-CoA synthase long-chain family members 4 (acyl- CoA synthetase long chain family member 4, ACSL4) inhibitors, iron chelators and deuterated polyunsaturated fatty acids. Therefore, the development of novel ferroptosis inhibitors is urgently needed.
  • the object of the present invention is to overcome the defects or deficiencies that the existing ferroptosis inhibitors have less types and poor activity, and provide a benzimidazole compound.
  • the benzimidazole compounds provided by the present invention have good ferroptosis inhibitory activity by introducing a lipophilic group at the R 1 position and a specific group at the R 2 position, and can be used for preventing and treating nervous system diseases such as A lead compound in stroke.
  • Another object of the present invention is to provide a method for preparing the above-mentioned benzimidazole compounds.
  • Another object of the present invention is to provide the application of the above-mentioned benzimidazole compounds in the preparation of ferroptosis inhibitors.
  • the present invention provides the following technical solutions:
  • R is halogen, methyl, alkoxy, alkynyloxy or hydroxy
  • X is C or N.
  • the present invention synthesized a series of benzimidazole compounds (formula (I)) by introducing a lipophilic group at the R1 position.
  • the lipophilic group at the R 1 position includes the following four different cyclic aliphatic amine side chains: N-methylpiperazine, methylpiperidine, piperidine and morpholine, and the middle aromatic ring is a benzene ring or pyridine ;
  • Determination of the inhibitory activity of this series of benzimidazole compounds on ferroptosis shows that R 1 is When X is C, the inhibitory activity is the best; therefore, based on this, different groups are introduced at the R 2 position to obtain a series of benzimidazole compounds (such as formula (II)).
  • the benzimidazole compounds provided by the invention have good ferroptosis inhibitory activity, and can be used as a leading compound for preventing and treating nervous system diseases such as stroke.
  • the halogen is F or Cl.
  • the alkoxy group is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 or -OCH(CH 3 ) 2 .
  • the alkynyloxy group is -OCH 2 C ⁇ CH.
  • R is substituted at one or both of the 6, 7 or 8 positions.
  • R when R is substituted at the 6-position, R is -F, -Cl, -OCH 3 , -OH, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 or - OCH 2 C ⁇ CH;
  • R is -CH 3 when R is substituted at the 7 position
  • R is -OCH 3 or -OH
  • R is substituted at the 6- and 7-positions, R is -OH or -OCH 3 .
  • R is -OH or -OCH 3 .
  • the present invention also provides a method for preparing the above-mentioned benzimidazole compounds.
  • the preparation method of above-mentioned benzimidazole compound comprises the steps:
  • the conditions of the coupling reaction in S11 are: basic conditions, and the reaction is carried out at 110° C. for 16 hours.
  • the reduction temperature in S12 is 60° C. and the time is 2 h.
  • the amide reaction in S13 is stirring at room temperature for 6 hours, and the subsequent ring-closing reaction is refluxing overnight under glacial acetic acid.
  • a mixture of dichloromethane and methanesulfonic acid is used as a solvent.
  • lithium aluminum hydride is used for reduction in S22.
  • the reaction is carried out at 80° C. for 24 hours.
  • the conditions of the amide reaction and the ring closure reaction in S25 are the same as those in S13.
  • the conditions of the coupling reaction in S31 are as follows: in an inert atmosphere, the reaction is carried out at 80° C. for 24 h or 16 h.
  • the conditions of the amide reaction and the ring closure reaction in S33 are the same as those in S13.
  • the use of the benzimidazole compounds in the preparation of ischemic stroke medicines is preferred.
  • the compounds provided by the present invention are tested for the activity of inhibiting ferroptosis by using Erastin to induce ferroptosis on HT22 cells, and it is found that the activity of compound 9a is the best.
  • 9a has significant inhibitory activity against ferroptosis induced by different types of ferroptosis inducers, and has inhibitory effects on two hallmark features of ferroptosis (lipid peroxidation and up-regulation of PTGS2 mRNA).
  • the present invention has the following advantages and effects:
  • the benzimidazole compounds provided by the invention have significant ferroptosis inhibitory activity, and the benzimidazole ferroptosis inhibitors have great application prospects in the prevention and treatment of nervous system diseases such as stroke;
  • the preparation method of the present invention has easily available raw materials and simple preparation.
  • Figure 1 shows the inhibitory effect of compound 9a on two features of ferroptosis (RSL3-induced lipid peroxidation and PTGS2 mRNA up-regulation);
  • FIG. 1 shows the TTC detection results.
  • the present invention is further explained below with reference to the embodiments and the accompanying drawings, but the embodiments do not limit the present invention in any form.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • reaction formula 1 (a) potassium carbonate, N,N-dimethylformamide, 110°C, 16h; (b) nickel, hydrazine hydrate, methanol, 60°C, 2h; (c) 1.O-benzo Triazole-N,N,N',N'-tetramethylurea tetrafluoroborate, N,N-diisopropylethylamine, N,N-dimethylformamide, room temperature, 6h; 2 . Glacial acetic acid, reflux, overnight.
  • Triazole-N,N,N',N'-tetramethylurea tetrafluoroborate (385mg, 1.2mmol)
  • o-phenylenediamine derivatives 2a-2d (1.1mmol) were added , at room temperature for 6 hours.
  • the reaction was quenched with ice water, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and spin-dried under reduced pressure; the solid obtained by spin-drying was dissolved in 10 mL of glacial acetic acid, and the reaction was refluxed overnight.
  • intermediates 7a-7i are hydrolyzed under alkaline conditions to obtain the intermediates 8a-8i, which are then reacted with the intermediate o-phenylenediamine derivative 2a through amide reaction and ring closure reaction, and finally the final products 9a-9k are obtained.
  • intermediates 5a-5b, 6a-6b, 7a and 7c were synthesized according to the conditions in our previous work.
  • reaction formula 2 (a) methanesulfonic acid, sodium azide, dichloromethane, room temperature, overnight; (b) lithium aluminum hydride, tetrahydrofuran, reflux, 4h; (c) potassium carbonate, cuprous iodide, L-proline, dimethyl sulfoxide, 80°C, 24h, nitrogen protection; (d) lithium hydroxide, tetrahydrofuran, 90°C, 3h; (e) 1.O-benzotriazole-N,N ,N',N'-tetramethylurea tetrafluoroborate, N,N-diisopropylethylamine, N,N-dimethylformamide, room temperature, 6h; 2. Glacial acetic acid, reflux, overnight . Compounds 9j and 9k were obtained by demethylation of compounds 9h and 9i under boron tribromide, respectively.
  • intermediate 7b was synthesized from 6-chloro-1,2,3,4-tetrahydroisoquinoline (5.03g, 30mmol) and ethyl 3-iodobenzoate (5.52g, 20mmol) according to the above method to obtain a white oil material (3.72 g, 59%).
  • intermediate 7d was synthesized from 1,2,3,4-tetrahydroisoquinolin-6-ol (4.48g, 30mmol) and ethyl 3-iodobenzoate (5.52g, 20mmol) according to the above method to obtain a white oil material (3.33 g, 56%).
  • intermediate 7g was synthesized from 1,2,3,4-tetrahydroisoquinolin-8-ol (4.48g, 30mmol) and ethyl 3-iodobenzoate (5.52g, 20mmol) according to the above method to obtain a white oil material (3.98 g, 67%).
  • reaction formula 3 (a) di-tert-butyl dicarbonate, 4-dimethylaminopyridine, tetrahydrofuran, room temperature, 0.5h; (b) sodium hydride, acetonitrile, 60°C, 24h; (c) 1. hydrochloric acid, 1 ,4-dioxane, room temperature, 3h; 2.
  • Potassium carbonate cuprous iodide, L-proline, dimethyl sulfoxide, 80°C, 24h, nitrogen protection;
  • reaction formula 4 (a) potassium carbonate, cuprous iodide, L-proline, dimethyl sulfoxide, 80°C, 24h; or sodium carbonate, tetrakistriphenylphosphonium palladium, 1,4-dioxane Hexacyclic/water, 80°C, 16h, nitrogen protection; (b) lithium hydroxide, tetrahydrofuran, 90°C, 3h; (c) 1.O-benzotriazole-N,N,N',N'- Tetramethylurea tetrafluoroborate, N,N-diisopropylethylamine, N,N-dimethylformamide, room temperature, 6h; 2. Glacial acetic acid, reflux, overnight.
  • 17b was synthesized from 16b and 2a as above as a white solid (40%).
  • 1 H NMR 400MHz, CD 3 OD
  • 17c was synthesized from 16c and 2a as above as a tan solid (44%).
  • 1 H NMR 400MHz, CD 3 OD
  • ⁇ 8.24 s, 1H
  • 7.54-7.49 m, 2H
  • 7.19 s, 1H
  • 7.18-7.16 m, 1H
  • 7.04(dd, J 8.8, 2.0Hz, 1H)
  • Example 2 Test of ferroptosis inhibitory activity of the compounds obtained in Example 1
  • HT22 cells mouse hippocampal neuron cells
  • DMEM high-glucose medium containing 10% fetal bovine serum and 1% double antibody at 37°C and 5% carbon dioxide concentration.
  • HT22 cells were seeded in a 96-well plate at 3000 cells/well, and after culturing for 24 hours, the original culture medium was removed by suction, 1 ⁇ M RSL3 ⁇ compound was added for 24 hours, and 10 ⁇ l CCK-8 solution was added to each well, and incubated at 37°C for 4 hours. , and the absorbance OD value was detected at a wavelength of 450 nm.
  • HT1080 cells human fibrosarcoma cells
  • MEM medium containing 10% fetal bovine serum and 1% double antibody at 37°C and 5% carbon dioxide concentration.
  • 50nM siRNA scramble and siRNA GPX4 were transferred into HT1080 cells with Lipofectamine TM 3000 reagent, respectively. Compounds were added after 12 hours, and the cells were harvested after incubation for 36 hours for qPCR and CCK-8 experiments.
  • the specific steps of the qPCR experiment are as follows: the cells to be treated were washed twice with PBS, the total RNA was extracted with RNAiso plus reagent, 1 ⁇ g of total RNA was reverse transcribed into cDNA using ReverTra Ace qPCR RT Master Mix, and then PCR was performed using SYBR Green Realtime PCR Master Mix. Amplification.
  • HT22 cells were seeded in 6-well plates at 3 ⁇ 10 4 cells/well for 24 hours, then 1 ⁇ M RSL3 ⁇ compound was added for 3 hours, and then incubated with 5 ⁇ M BODIPY-C11 probe at 37°C for half an hour. After cells were washed once with PBS, trypsinized, centrifuged and collected in 1 ml of PBS, the fluorescence intensity of the FL1 channel was detected by flow cytometry at 488 nm. At least 10,000 cells were detected per sample.
  • HT22 cells were seeded at 3000 cells/well in a 96-well plate and cultured for 24 hours, then 1 ⁇ M RSL3 ⁇ compound was added for 3 hours, and then 5 ⁇ M BODIPY-C11 probe and Hoechst 33342 (1 ⁇ g/ml) were used at 37°C After co-incubating for half an hour, the cells were washed once with PBS, and then photographed with a FV3000 laser confocal microscope (60 ⁇ ).
  • HT22 cells were seeded at 3 ⁇ 10 4 cells/well in 6-well plates and cultured for 24 hours, then added 1 ⁇ M RSL3 ⁇ compound for 12 hours, washed twice with PBS, extracted total RNA with RNAiso plus reagent, and used ReverTra Ace qPCR RT Master Mix 1 ⁇ g of total RNA was reverse transcribed into cDNA, and then used SYBR Green Realtime PCR Master Mix for PCR amplification.
  • compound 9a inhibited RSL3-induced ferroptosis in HT22 cells in a dose-dependent manner; compound 9a also inhibited the ferroptosis induced by GPX4 in HT1080 cells in a dose-dependent manner.
  • Activity live cell imaging results showed that compound 9a could significantly inhibit the increase of RSL3-induced lipid ROS, which was consistent with the results of flow cytometry.
  • compound 9a also had inhibitory activity on the increase of RSL3-induced cytoplasmic ROS; finally, compound 9a also had inhibitory activity. Concentration-dependently inhibited RSL3-induced upregulation of PTGS2 mRNA.
  • Example 4 Relief effect of compound 9a obtained in Example 1 on ischemia-reperfusion injury in vivo
  • Ischemic stroke is the most common form of stroke and one of the leading causes of death and permanent disability. So far, there is no effective treatment.
  • ferroptosis is involved in neuronal damage and death in the pathological process of ischemic stroke, and inhibition of ferroptosis can alleviate brain damage in vivo.
  • compound 9a has significant ferroptosis inhibitory activity on HT22 cells, we investigated whether this compound can protect SD rats from ischemia/reperfusion in the Middle Cerebral Artery Occlusion (MCAO) model nerve damage caused.
  • MCAO Middle Cerebral Artery Occlusion
  • the animals were randomly divided into 4 groups, namely blank control group, model control group, positive control group, and test sample 9a group, with 12 animals in each group.
  • Dosage test sample 9a 10 mg/kg, positive control drug edaravone 10 mg/kg; blank control group and model control group were given normal saline in the same way.
  • Dosing frequency once half an hour before the operation, once 2 hours after the operation; administration route: intraperitoneal injection, the volume is 5ml/kg.
  • the rats were anesthetized by intraperitoneal injection of 7% chloral hydrate 5ml/kg, the median neck incision was made, the left common carotid artery and external carotid artery were isolated and ligated, and the pterygofrontal artery was isolated.
  • the proximal end of the internal carotid artery is prepared, and the distal end is placed with an arterial clip.
  • An incision is made at the bifurcation of the common carotid artery, and a 4-0 nylon thread is inserted with a depth of 17 to 20 mm. , block all blood flow sources in the middle cerebral artery, let it be ischemia for 1.5h and then pull out the suture for about 1cm to achieve reperfusion.
  • the wound was disinfected with iodophor, and the skin was sutured. Then return to the cage.
  • the rest of the steps were the same as above, except that the line was not plugged in.
  • the results of TTC staining showed that compared with the model group, the cerebral infarct volume was significantly reduced and the behavior was more normal after 9a treatment, indicating that compound 9a can significantly alleviate ischemia/reperfusion-induced brain injury in vivo, and is expected to develop into a Lead compounds for the treatment of ischemic stroke.

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Abstract

Sont divulgués dans la présente invention un composé de benzimidazole, son procédé de préparation et son application dans la préparation d'un inhibiteur de la ferroptose. Le composé de benzimidazole a une structure telle que représentée dans la formule (I) ou la formule (II). Selon le composé de benzimidazole fourni par la présente invention, un groupe lipophile est introduit dans une position R1, et un groupe spécifique est introduit dans une position R2, de telle sorte que le composé obtenu présente une activité inhibitrice de la ferroptose relativement bonne et peut être utilisé en tant que composé principal pour la prévention et le traitement de maladies du système nerveux telles que l'accident vasculaire cérébral.
PCT/CN2021/136185 2021-01-25 2021-12-07 Composé de benzimidazole, son procédé de préparation et son application dans la préparation d'un inhibiteur de la ferroptose WO2022156404A1 (fr)

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CN115232074A (zh) * 2022-08-22 2022-10-25 湖南复瑞生物医药技术有限责任公司 一种1-烷基取代-2-甲基-5-溴苯并咪唑的合成方法

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