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WO2022135072A1 - Composé de coumarine, son procédé de préparation, utilisation et composition pharmaceutique associées - Google Patents

Composé de coumarine, son procédé de préparation, utilisation et composition pharmaceutique associées Download PDF

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WO2022135072A1
WO2022135072A1 PCT/CN2021/134014 CN2021134014W WO2022135072A1 WO 2022135072 A1 WO2022135072 A1 WO 2022135072A1 CN 2021134014 W CN2021134014 W CN 2021134014W WO 2022135072 A1 WO2022135072 A1 WO 2022135072A1
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compound
reaction
synuclein
present
organic solvent
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程妍
蔡继鸣
葛强
李向晖
柳芳
陈华西
勾家磊
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Chengdu New Radiomedicine Technology Co Ltd
Sichuan University
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Chengdu New Radiomedicine Technology Co Ltd
Sichuan University
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Definitions

  • the present invention relates to the technical field of medicine, in particular to a coumarin compound, a preparation method and application thereof, and a pharmaceutical composition.
  • ⁇ -synuclein ( ⁇ -syn) disease is a class of neurodegenerative diseases characterized by ⁇ -synuclein deposition as the main pathological hallmark, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy and Pure autonomic failure.
  • ⁇ -synuclein polymers can exhibit properties similar to Ruan virus, induce abnormal ⁇ -folding of normal ⁇ -synuclein, form ⁇ -synuclein-positive inclusion bodies, and spread from one cell to another. Another cell, suggesting deposition and diffusion of ⁇ -synuclein polymers in the nervous system, a core pathological mechanism common to ⁇ -synucleinopathies. Therefore, the development of detection reagents targeting ⁇ -synuclein polymers is of great significance for the early diagnosis of ⁇ -synucleinopathy, disease course monitoring, and research on therapeutic drugs.
  • small molecule compounds with high affinity and selectivity for ⁇ -synuclein polymers are developed and directly applied to the preparation of in vitro diagnostic reagents for the detection of ⁇ -synuclein polymers in body fluids (such as blood, cerebrospinal fluid, etc.). And the preparation of diagnostic drugs for imaging ⁇ -synuclein polymers in vivo in ⁇ -synuclein disease will have very important scientific significance and practical value.
  • small-molecule compounds with affinity and selectivity for ⁇ -synuclein polymers and it is difficult to effectively distinguish ⁇ -synuclein polymers from other protein polymers with a ⁇ -sheet structure.
  • how small molecule compounds release specific ⁇ -synuclein polymers to detect signals is also a key problem to be solved at present. .
  • the object of the present invention is to provide a coumarin compound, its preparation method, application, and pharmaceutical composition.
  • the coumarin compound provided by the present invention has high affinity with ⁇ -synuclein polymer, and can release specific
  • the detection signal of ⁇ -synuclein polymer can effectively distinguish ⁇ -synuclein polymer from other protein polymers with ⁇ -sheet structure, and can be used to prepare diagnostic reagents for the detection of ⁇ -synuclein polymer , in particular, it can be used to prepare a diagnostic reagent for fluorescently detecting ⁇ -synuclein polymers or a fluorescent developer for imaging ⁇ -synuclein polymers, when the coumarin compounds are labeled with radionuclides, It can also be used to prepare radiodiagnostic drugs for nuclear medicine imaging ⁇ -synuclein polymers.
  • the invention provides a kind of coumarin compound, has the structure shown in formula I:
  • n 0, 1, 2 or 3
  • Y is -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , - 19 F, -OCH 2 CH 2 19 F. -OCH 2 CH 2 18 F, - 127 I, - 125 I, - 123 I or - 131 I;
  • n 1, 2 or 3
  • X is , Y is -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 or -N(CH 2 CH 2 CH 3 ) 2 .
  • n is 0 or 1
  • X is
  • Y is -OCH 2 CH 2 19 F, -OCH 2 CH 2 18 F, - 127 I, - 125 I, - 123 I or - 131 I.
  • the present invention provides the preparation method of the coumarin compound described in the above technical scheme,
  • the preparation method comprises the following steps:
  • the first aldehyde compound has the structure shown in formula a:
  • the preparation method comprises the following steps:
  • the second aldehyde compound has the structure shown in formula b:
  • the chloride is ClCH 2 CH 2 OH, ClCH 2 CH 2 -O-CH 2 CH2OH or ClCH2CH2 - O - CH2CH2 - O - CH2CH2OH ;
  • Kryptofix 222/K 2 CO 3 mixed solution and [ 18 F] KF solution were mixed, the obtained residue was mixed with the third intermediate and an organic solvent after removing the solvent, and the labeling reaction was carried out under anhydrous conditions to obtain a compound having the formula of formula I.
  • Coumarin compounds showing the structure; the Kryptofix 222/K 2 CO 3 mixture consists of 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8] twenty Hexane, K 2 CO 3 and organic solvent are mixed to obtain;
  • the preparation method comprises the following steps:
  • the third aldehyde compound has the structure shown in formula c:
  • the fourth intermediate, hexa-n-butyl ditin, tetrakistriphenylphosphine palladium and an organic solvent are mixed and reacted to obtain the fifth intermediate;
  • the fifth intermediate, hydrogen peroxide solution, iodine label solution, hydrochloric acid and organic solvent are mixed, and the first-stage reaction and the second-stage reaction are carried out successively to obtain the coumarin compound having the structure shown in formula I;
  • the iodine label solution contains 125 I - , 123 I - or 131 I - .
  • the present invention provides the application of the coumarin compound having the structure shown in formula I according to the above technical solution in the preparation of a diagnostic reagent for detecting ⁇ -synuclein polymers.
  • n 1, 2 or 3 in the formula I
  • X is
  • Y is -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 or -N(CH 2 CH 2 CH 3 ) 2
  • the present invention provides the coumarin compounds in the preparation of fluorescence detection ⁇ - Use of synuclein polymers in diagnostic reagents.
  • the diagnostic reagent for fluorescently detecting ⁇ -synuclein polymers comprises a fluorescent imaging agent for imaging ⁇ -synuclein polymers.
  • the present invention when n is 0 or 1 in the formula I, X is Y is -OCH 2 CH 2 19 F, -OCH 2 CH 2 18 F, When - 127 I, - 125 I, - 123 I or - 131 I, the present invention provides the application of the coumarin compounds in the preparation of radiodiagnostic drugs for nuclear medicine imaging ⁇ -synuclein polymers,
  • the nuclear medicine imaging mode is positron emission tomography imaging or single photon emission tomography imaging.
  • the present invention provides a pharmaceutical composition, comprising the coumarin compound having the structure shown in formula I described in the above technical solution and a pharmaceutically acceptable carrier.
  • the invention provides a coumarin compound.
  • the coumarin compound provided by the invention has a flat flexible structure, and the coumarin side chain nitrogen atom in the structure can selectively affinity ⁇ -synuclein polymer C-terminal acidic protein, and the coumarin compounds provided by the present invention are integrated into the ⁇ -sheet space structure of the ⁇ -synuclein polymer, so that it has a high level with the ⁇ -synuclein polymer.
  • a diagnostic reagent for polymers when the coumarin compound is labeled with a radionuclide, it can also be used to prepare a radiodiagnostic drug for imaging ⁇ -synuclein polymers, specifically, it can detect ⁇ -synuclein in body fluids. Nuclein aggregates or imaging alpha-synuclein aggregates in the brain of alpha-synucleinopathies.
  • Fig. 2 is a graph showing the staining results of intracellular ⁇ -synuclein polymer by compound NBC-2 in Test Example 4;
  • Fig. 3 is the intracerebral fluorescence imaging diagram 30min after injection of compound NBC-2 in normal mice in Test Example 5;
  • Fig. 4 is the intracerebral fluorescence image of Parkinson's disease (PD) transgenic aged mice and normal aged mice injected with compound NBC-2 60 min in Test Example 6;
  • PD Parkinson's disease
  • FIG. 5 is a radiolabeling diagram of the brain sections of PD transgenic aged mice in Test Example 7.
  • FIG. 5 is a radiolabeling diagram of the brain sections of PD transgenic aged mice in Test Example 7.
  • the invention provides a kind of coumarin compound, has the structure shown in formula I:
  • n 0, 1, 2 or 3
  • Y is -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 2 CH 2 CH 3 ) 2 , - 19 F, -OCH 2 CH 2 19 F. -OCH 2 CH 2 18 F, - 127 I, - 125 I, - 123 I or - 131 I;
  • Y is preferably -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 or -N(CH 2 CH 2 CH 3 ) 2 .
  • n is 0 or 1
  • X is
  • Y is preferably -OCH 2 CH 2 19 F, -OCH 2 CH 2 18 F, - 127 I, - 125 I, - 123 I or - 131 I.
  • the coumarin compound can specifically be any one of the following compounds:
  • the present invention provides the preparation method of the coumarin compound described in the above technical solution, and specifically selects the corresponding preparation method according to the type of Y in the formula I, which will be described in detail below.
  • the preparation method of coumarin compound comprises the following steps:
  • the first aldehyde compound has the structure shown in formula a:
  • reaction scheme of the above-mentioned reaction of the present invention is:
  • the source of the 6-aminocoumarin is not particularly limited in the present invention, and it can be a commercial product or can be prepared by a method well known to those skilled in the art; in the present invention, the source of the 6-aminocoumarin is The preparation method preferably comprises the following steps:
  • the solvent for the reduction reaction is preferably an alcohol compound-water mixed solution
  • the alcohol compound is preferably methanol or ethanol
  • the volume ratio of the alcohol compound to water is preferably 1:(1-5 ), more preferably 1:3
  • the dosage ratio of the solvent to 6-nitrocoumarin is preferably (180-220) mL: 7 mmol, more preferably 200 mL: 7 mmol.
  • the reducing agent is preferably reducing iron powder
  • the molar ratio of the reducing agent to 6-nitrocoumarin is preferably (20-24):7, more preferably 22:7.
  • the concentration of the hydrochloric acid is preferably 31-32 mol/L
  • the dosage ratio of the hydrochloric acid to 6-nitrocoumarin is preferably (1.3-1.5) mL: 7 mmol, more preferably 1.4 mL: 7 mmol .
  • 6-nitrocoumarin is preferably dissolved in a solvent, and the obtained mixed solution is heated to a reflux state under agitation, then a reducing agent is added to the system, and then hydrochloric acid is added dropwise to carry out a reduction reaction.
  • the reduction reaction is preferably carried out under reflux conditions, and the time for the reduction reaction is preferably 8 to 10 hours, more preferably 9 hours.
  • the present invention preferably filters the obtained reaction solution while hot to remove the reducing agent (specifically, reducing iron powder), extracts the obtained filtrate with dichloromethane, separates the dichloromethane layer, and adds anhydrous sodium sulfate for drying. , then filtered, and the obtained filtrate was spin-dried to obtain 6-aminocoumarin; the alcohol compound is preferably methanol or ethanol.
  • the reducing agent specifically, reducing iron powder
  • the present invention mixes the 6-aminocoumarin, the first aldehyde compound and the organic solvent, and carries out the first Schiff base reaction to obtain the coumarin compound having the structure shown in formula I .
  • the molar ratio of 6-aminocoumarin and the first aldehyde compound is preferably 1:(1-1.2), more preferably 1:1.1.
  • the organic solvent for the first Schiff base reaction is preferably ethanol, acetonitrile or tetrahydrofuran, more preferably absolute ethanol, and the dosage ratio of the organic solvent to 6-aminocoumarin is preferably (3.5 ⁇ 4.5) mL: 1 mmol, more preferably 4 mL: 1 mmol.
  • the present invention does not specifically limit the mixing method of 6-aminocoumarin, the first aldehyde compound and the organic solvent, as long as it is sufficient to ensure that the components are mixed uniformly.
  • the first Schiff base reaction is preferably carried out under reflux conditions, and the time of the first Schiff base reaction is preferably 1-6 hours, more preferably 3-6 hours.
  • the present invention preferably cools the obtained reaction solution to room temperature, and then uses ethanol for recrystallization to obtain the coumarin compound having the structure shown in formula I.
  • the preparation method of the coumarin compound comprises the following steps:
  • the second aldehyde compound has the structure shown in formula b:
  • the chlorinated compound is Cl-CH 2 CH 2 -OH, ClCH 2 CH 2 -O -CH2CH2OH or ClCH2CH2 - O - CH2CH2 - O - CH2CH2OH ;
  • Kryptofix 222/K 2 CO 3 mixed solution and [ 18 F] KF solution were mixed, the obtained residue was mixed with the third intermediate and an organic solvent after removing the solvent, and the labeling reaction was carried out under anhydrous conditions to obtain a compound having the formula of formula I.
  • Coumarin compounds showing the structure; the Kryptofix 222/K 2 CO 3 mixture consists of 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8] twenty Hexane, K 2 CO 3 and organic solvent are mixed to obtain.
  • reaction scheme of the above-mentioned reaction of the present invention is:
  • the chlorinated compound is Cl-CH 2 CH 2 -OH, ClCH 2 CH 2 -O-CH 2 CH 2 OH or ClCH 2 CH 2 -O-CH 2 CH 2 -O-CH 2 CH 2 OH, m is 1, 2 or 3;
  • the 6-aminocoumarin, the second aldehyde compound and the organic solvent are mixed, and the second Schiff base reaction is carried out to obtain the first intermediate.
  • the molar ratio of 6-aminocoumarin and the second aldehyde compound is preferably 1:(1-1.2), more preferably 1:1.1.
  • the organic solvent used for the second Schiff base reaction is preferably ethanol, acetonitrile or tetrahydrofuran, more preferably absolute ethanol, and the dosage ratio of the organic solvent to 6-aminocoumarin is preferably (4.5 ⁇ 5.5) mL: 1 mmol, more preferably 5 mL: 1 mmol.
  • the present invention has no special limitation on the mixing mode of 6-aminocoumarin, the second aldehyde compound and the organic solvent, and it is sufficient to ensure that the components are mixed uniformly.
  • the second Schiff base reaction is preferably carried out under reflux conditions, and the time for the second Schiff base reaction is preferably 1-6 hours, more preferably 3-5 hours.
  • the present invention preferably cools the obtained reaction solution to room temperature, and then uses ethanol for recrystallization or column chromatography purification to obtain the first intermediate.
  • the column chromatography purification reagent is preferably a dichloromethane-methanol mixed solution, and the volume ratio of the dichloromethane and methanol is preferably (8-12):1, more preferably 10:1.
  • the present invention mixes the first intermediate, a chloride compound, an organic solvent and potassium carbonate, and performs a first substitution reaction to obtain a second intermediate.
  • the molar ratio of the first intermediate, chloride and potassium carbonate is preferably 1:(1-1.2):(0.9-1.1), more preferably 1:1.1:1.
  • the organic solvent for the first substitution reaction is preferably dimethylformamide (DMF), and the dosage ratio of the organic solvent to the first intermediate is preferably (2.5-3.5) mL: 1 mmol, more preferably 3 mL: 1 mmol.
  • the present invention does not specifically limit the mixing method of the first intermediate, the chlorinated compound, the organic solvent and the potassium carbonate, and it is sufficient to ensure that the components are mixed uniformly.
  • the temperature of the first substitution reaction is preferably 95-105°C, more preferably 100°C; the time is preferably 8-24h, more preferably 10-15h.
  • the present invention preferably cools the obtained reaction solution to room temperature, then mixes it with water, extracts the obtained mixture with chloroform, separates the chloroform layer, adds anhydrous sodium sulfate for drying, then filters, and spin-dry the resulting mixture.
  • the filtrate and the residue are purified by column chromatography to obtain the second intermediate;
  • the column chromatography purification reagent is preferably an ethyl acetate-petroleum ether mixed solution, and the volume ratio of the ethyl acetate to the petroleum ether is preferably 4: 1.
  • the present invention mixes the second intermediate, 4-toluenesulfonyl chloride and an organic solvent, and performs a second substitution reaction to obtain the third intermediate.
  • the molar ratio of the second intermediate and 4-toluenesulfonyl chloride is preferably 1:(1-1.2), more preferably 1:1.1.
  • the organic solvent for the second substitution reaction is preferably pyridine, and the molar ratio of the organic solvent to the second intermediate is preferably 1:(0.45-0.55), more preferably 1:0.5.
  • the present invention has no special limitation on the mixing mode of the second intermediate, 4-toluenesulfonyl chloride and the organic solvent, and it is ensured that each component is mixed evenly.
  • the temperature of the second substitution reaction is preferably room temperature, and the time of the second substitution reaction is preferably 1.5-2.5 h, more preferably 2 h.
  • the present invention preferably extracts the obtained reaction solution with chloroform, separates the chloroform layer, adds anhydrous sodium sulfate for drying, then filters and spins the obtained filtrate, and the residue is purified by column chromatography to obtain the third.
  • the column chromatography purification reagent is preferably an ethyl acetate-petroleum ether mixed solution, and the volume ratio of the ethyl acetate to the petroleum ether is preferably 1:2.
  • Kryptofix 222 4,7,13,16,21,24-hexaoxo-1,10-diazabicyclo[8.8.8]hexadecane (Kryptofix 222), K 2 CO 3 and organic solvent are mixed to obtain Kryptofix 222 /K 2 CO 3 mixed solution; the concentration of Kryptofix 222 in the Kryptofix 222/K 2 CO 3 mixed solution is preferably 9.5 mg/mL, and the concentration of K 2 CO 3 is preferably 1.7 mg/mL.
  • the present invention provides [ 18 F]KF solution; the present invention has no special limitation on the source of the [ 18 F]KF solution, and can be prepared by a method well known to those skilled in the art; the present invention preferably prepares [ 18 F] through an accelerator KF solution.
  • the present invention mixes the Kryptofix 222/K 2 CO 3 mixed solution and the [ 18 F]KF solution, and after removing the solvent, the obtained residue is mixed with a third
  • the intermediate and organic solvent are mixed, and the labeling reaction is carried out under anhydrous conditions to obtain the coumarin compound having the structure shown in formula I.
  • the 18 F]KF solution is placed in a reaction flask, 1.0 mL of Kryptofix 222/K 2 CO 3 mixed solution is added to the reaction flask, and after mixing uniformly, the solvent is removed by heating to obtain the first residue ; Add 1 mL of anhydrous acetonitrile to the first residue, remove the solvent by heating, and obtain the second residue to ensure that the water in the system is fully removed, and the temperature of the heating is preferably 115 ⁇ 125 °C, more preferably 120 °C ; Then, the second residue is mixed with the third intermediate and an organic solvent, and the labeling reaction is carried out under anhydrous conditions.
  • the amount of the third intermediate is preferably 0.9-1.1 mg, more preferably 1 mg.
  • the organic solvent for the labeling reaction is preferably acetonitrile, and the dosage ratio of the organic solvent to the third intermediate is preferably (190-210) ⁇ L:1 mg, more preferably 200 ⁇ L:1 mg.
  • the temperature of the labeling reaction is preferably 95-105°C, more preferably 110°C; the time of the labeling reaction is preferably 8-12 min, more preferably 10 min; the present invention preferably terminates the labeling by adding water reaction.
  • the present invention preferably injects the obtained reaction solution into a solid-phase extraction column (Oasis HLB solid-phase extraction column, the specification is preferably 3cm 3 ), first washes with water to remove unreacted 18 F ⁇ , and then elutes with acetonitrile , to obtain an eluate containing the 18 F marker; the eluate is separated by HPLC to obtain a coumarin compound with the structure shown in formula I; the conditions for the HPLC separation preferably include: YMC-Pack Pro C18 column, the size is 20mm ⁇ 150mm; the mobile phase is acetonitrile and water, and the volume ratio of acetonitrile and water is 95:5; the flow rate is 2.0mL/min.
  • a solid-phase extraction column the specification is preferably 3cm 3
  • the preparation method of the coumarin compound comprises the following steps:
  • the third aldehyde compound has the structure shown in formula c:
  • the fifth intermediate, hydrogen peroxide solution, iodine label solution, hydrochloric acid and organic solvent are mixed, and the first-stage reaction and the second-stage reaction are carried out successively to obtain a coumarin compound having the structure shown in formula I;
  • the iodine label solution contains 125 I - , 123 I - or 131 I - .
  • reaction scheme of the above-mentioned reaction of the present invention is:
  • the 6-aminocoumarin, the third aldehyde compound and the organic solvent are mixed, and the third Schiff base reaction is carried out to obtain the fourth intermediate.
  • the molar ratio of 6-aminocoumarin and the third aldehyde compound is preferably 1:(1-1.2), more preferably 1:1.1.
  • the organic solvent for the third Schiff base reaction is preferably ethanol, acetonitrile or tetrahydrofuran, more preferably absolute ethanol, and the dosage ratio of the organic solvent to 6-aminocoumarin is preferably (4.5 ⁇ 5.5) mL: 1 mmol, more preferably 5 mL: 1 mmol.
  • the present invention does not specifically limit the mixing method of the 6-aminocoumarin, the third aldehyde compound and the organic solvent, as long as it is ensured that the components are mixed uniformly.
  • the third Schiff base reaction is preferably carried out under reflux conditions, and the time of the third Schiff base reaction is preferably 1-6 hours, more preferably 3-5 hours.
  • the present invention preferably cools the obtained reaction solution to room temperature, and then uses ethanol for recrystallization or column chromatography purification to obtain the fourth intermediate.
  • the column chromatography purification reagent is preferably a dichloromethane-methanol mixed solution, and the volume ratio of the dichloromethane and methanol is preferably (8-12):1, more preferably 10:1.
  • the present invention mixes the fourth intermediate, hexa-n-butyl ditin, tetrakistriphenylphosphine palladium and an organic solvent and reacts to obtain the fifth intermediate.
  • the molar ratio of the fourth intermediate, hexa-n-butylditin and tetrakistriphenylphosphine palladium is preferably 1:(0.9-1.1):(0.9-1.1), more preferably 1:1 :1.
  • the organic solvent for the reaction is preferably a dioxane-triethylamine mixed solution, and the volume ratio of dioxane and triethylamine in the dioxane-triethylamine mixed solution is preferably (2.5 to 3.5): 1, more preferably 3:1.
  • the present invention does not specifically limit the mixing method of the fourth intermediate, hexa-n-butylditin, tetrakistriphenylphosphine palladium and the organic solvent, as long as it is sufficient to ensure that the components are mixed uniformly.
  • the reaction is preferably carried out under reflux conditions, and the reaction time is preferably 10-24 h, more preferably 12-15 h.
  • the present invention preferably cools the obtained reaction solution to room temperature, filters, and purifies the filtrate by column chromatography to obtain the fifth intermediate;
  • the column chromatography purification reagent is preferably an ethyl acetate-petroleum ether mixture, so The volume ratio of ethyl acetate and petroleum ether is preferably (0.8-1.2):1, more preferably 1:1.
  • the present invention mixes the fifth intermediate, the hydrogen peroxide solution, the iodine label solution, the hydrochloric acid and the organic solvent, and successively carries out the first-stage reaction and the second-stage reaction to obtain the compound having the formula I.
  • Coumarin compounds showing the structure In the present invention, the concentration of the hydrogen peroxide solution is preferably 3wt%; the dosage ratio of the fifth intermediate and the hydrogen peroxide solution is preferably 0.5mg:(95-105) ⁇ L, more preferably 0.5mg: 100 ⁇ L.
  • the iodine label solution is preferably [ 125 I]NaI solution, [ 123 I]NaI solution or [ 131 I]NaI solution; the radioactive intensity of the iodine label solution is preferably 0.74MBq.
  • the concentration of the hydrochloric acid is preferably 1 mol/L, and the dosage of the hydrochloric acid and the fifth intermediate is preferably (95-105) ⁇ L: 0.5 mg, more preferably 100 ⁇ L: 0.5 mg.
  • the organic solvent for the first-stage reaction and the second-stage reaction is preferably ethanol, and the amount of the organic solvent and the fifth intermediate is preferably (95-105) ⁇ L: 0.5 mg, more preferably 100 ⁇ L : 0.5mg.
  • the fifth intermediate is preferably dissolved in an organic solvent, and the obtained solution is placed in a reaction flask, followed by adding hydrogen peroxide solution, iodine marker solution and hydrochloric acid in sequence, and immediately sealing the reaction flask to carry out the first-stage reaction.
  • the first-stage reaction is preferably carried out at room temperature, and the time of the first-stage reaction is preferably 8-12 min, more preferably 10 min; the present invention preferably terminates the first-stage reaction by adding NaHSO 3 to the system stage reaction.
  • the obtained system does not need to carry out other post-treatments, and directly carries out the second-stage reaction;
  • the temperature of the second-stage reaction is preferably 95-105 °C, more preferably 100 °C, so
  • the time of the second-stage reaction is preferably 8-12 min, more preferably 10 min.
  • the second-stage reaction is preferably terminated by adding water to the system.
  • the present invention preferably neutralizes the obtained reaction solution with sodium bicarbonate to a pH value of 7, extracts with ethyl acetate, separates the ethyl acetate layer, and removes the ethyl acetate layer with nitrogen.
  • the obtained residue is separated by HPLC to obtain the coumarin compounds with the structure shown in formula I;
  • the conditions of the HPLC separation preferably include: YMC-Pack Pro C18 column, the specification is 5mm ⁇ 150mm; the mobile phase is Acetonitrile and water, the volume ratio of acetonitrile and water is 60:40; the flow rate is 1.0 mL/min.
  • the present invention provides the application of the coumarin compound having the structure shown in formula I in the preparation of a diagnostic reagent for detecting ⁇ -synuclein polymer.
  • the diagnostic reagent for detecting ⁇ -synuclein polymers can be used to detect ⁇ -synuclein polymers in living animals, human bodies or isolated tissues.
  • the present invention does not specifically limit the application method of the diagnostic reagent for detecting ⁇ -synuclein polymers, and methods well known to those skilled in the art can be used; in the embodiments of the present invention, the following three methods can be specifically adopted Either of:
  • Method 1 Introduce a detectable amount of coumarin into the body, and after a time sufficient to bind the coumarin to the ⁇ -synuclein polymer, non-invasively detect the coumarin in the body compound; in the present invention, the method of introducing the coumarin compound into the body is preferably injection, eye drop or oral administration; the time for the coumarin compound to bind to the ⁇ -synuclein polymer is preferably 0.5-3h
  • the non-invasive way of detecting the coumarin compounds in the body is preferably to directly use the in vivo imaging device to image the brain or the fundus of the eyes after administration.
  • Method 2 Introduce a detectable amount of coumarin compounds into the body, after a time sufficient to bind the coumarin compounds to the ⁇ -synuclein polymer, take a tissue sample and remove it from the in vivo detection tissue sample
  • the method of introducing the coumarin into the body is preferably injection, eye drops or oral administration; the time for the coumarin to bind to the ⁇ -synuclein polymer Preferably, the time is 0.5 to 3 hours; the tissue sample is preferably an animal brain or an animal eyeball.
  • Method 3 Take a tissue sample from the body, introduce a detectable amount of the coumarin-based compound into the tissue sample, and detect the tissue sample after a time sufficient to bind the coumarin-based compound to the ⁇ -synuclein polymer
  • the tissue sample is preferably the brain, cerebrospinal fluid or eyeball of an animal or patient; the method of introducing the coumarin compound into the tissue sample is preferably the coumarin
  • the coumarin-based compound is directly mixed with the tissue sample; the time for the coumarin-based compound to bind to the ⁇ -synuclein polymer is preferably 5 min to 1 h.
  • the present invention when n is 1, 2 or 3 in the formula I, X is When Y is -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 or -N(CH 2 CH 2 CH 3 ) 2 , the present invention provides the coumarin compounds in the preparation of fluorescence detection ⁇ - Use of synuclein polymers in diagnostic reagents.
  • the present invention does not specifically limit the application method of the diagnostic reagent for detecting ⁇ -synuclein polymer by fluorescence, and a method well known to those skilled in the art may be used, and specifically, any one of the above three methods may be used.
  • the diagnostic reagent for fluorescently detecting ⁇ -synuclein polymers in the present invention can be used for fluorescently detecting ⁇ -synuclein polymers in vitro, and specifically can be used for fluorescently detecting ⁇ -synuclein polymers in body fluids (such as blood, cerebrospinal fluid or urine). Synuclein polymer.
  • body fluids such as blood, cerebrospinal fluid or urine.
  • Synuclein polymer Synuclein polymer.
  • a detectable amount of the coumarin-based compound is added to the body fluid, and the time (preferably 0.5 ⁇ After 3h), the fluorescence intensity is detected at certain excitation and emission wavelengths.
  • the diagnostic reagent for fluorescently detecting ⁇ -synuclein polymers preferably includes a fluorescent imaging agent for imaging ⁇ -synuclein polymers.
  • the application method of the polymer fluorescent developer is not particularly limited, and a method well known to those skilled in the art may be used, and any one of the above three methods may be specifically adopted.
  • the fluorescent imaging agent for imaging ⁇ -synuclein polymers in the present invention can be used for imaging ⁇ -synuclein polymers, and specifically can be used for imaging ⁇ -synapses in living animals, human bodies or isolated tissues nucleoprotein polymers.
  • the present invention when n is 0 or 1 in the formula I, X is Y is -OCH 2 CH 2 19 F, -OCH 2 CH 2 18 F, When - 127 I, - 125 I, - 123 I or - 131 I, the present invention provides the application of the coumarin compounds in the preparation of radiodiagnostic drugs for nuclear medicine imaging ⁇ -synuclein polymers,
  • the nuclear medicine imaging mode is positron emission tomography imaging or single photon emission tomography imaging.
  • a radiolabeled nuclide is introduced into the para-side chain of the benzene ring or the pyridine ring of the coumarin compound, and the radiolabeled coumarin compound can be directly applied to the preparation of nuclear medicine imaging ⁇ -synuclein polymer
  • the radiodiagnostic drug can be used to image the ⁇ -synuclein polymer in living animal, human body or isolated tissue.
  • the present invention does not specifically limit the application method of the radiodiagnostic drug for nuclear medicine imaging ⁇ -synuclein polymer, and a method well known to those skilled in the art can be used; any of the three methods above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a coumarin compound having the structure shown in formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be, for example, physiological saline, glycerol or ethanol.
  • the preparation of 6-aminocoumarin intermediates includes the following steps:
  • the preparation of compound NBC-2 includes the following steps:
  • the preparation of compound NBC-3 includes the following steps:
  • the preparation of compound NBC-4 includes the following steps:
  • the preparation of compound NBC-5 includes the following steps:
  • the preparation of compound NBC-6 includes the following steps:
  • the preparation of compound NBC-8 includes the following steps:
  • the preparation of compound NBC-9 includes the following steps:
  • the structure of the first intermediate is as follows:
  • the structure of the second intermediate is as follows:
  • the structure of the third intermediate is as follows:
  • Kryptofix 222 4,7,13,16,21,24-hexaoxo-1,10 - diazabicyclo[8.8.8]hexadecane (Kryptofix 222) and K2CO3 were dissolved in acetonitrile to give Kryptofix 222/ K 2 CO 3 mixed solution, the concentration of Kryptofix 222 in the Kryptofix 222/K 2 CO 3 mixed solution is 9.5 mg/mL, and the concentration of K 2 CO 3 is 1.7 mg/mL;
  • the [ 18 F]KF solution was prepared by an accelerator, the [ 18 F]KF solution was placed in a reaction flask, 1.0 mL of Kryptofix 222/K 2 CO 3 mixed solution was added to the reaction flask, and after vortex mixing, the solution was added to the reaction flask at 120 Remove the solvent by heating at °C to obtain the first residue; add 1 mL of anhydrous acetonitrile to the first residue, and remove the solvent by heating at 120°C to obtain the second residue;
  • the second residue was mixed with 200 ⁇ L of the acetonitrile solution of the third intermediate (the mass of the third intermediate was 1.0 mg), reacted at 100° C. for 10 min, and then 5 mL of water was added to terminate the reaction; the resulting reaction solution was injected into the solid phase In the extraction column (Oasis HLB solid-phase extraction column, the specification is 3cm 3 ), first wash with 10 mL of water to remove unreacted 18 F ⁇ , and then eluate with 2 mL of acetonitrile to obtain an eluent containing the 18 F marker; The eluent was separated by HPLC (YMC-Pack Pro C18 column, the specification was 20mm ⁇ 150mm; the mobile phase was acetonitrile and water, and the volume ratio of acetonitrile and water was 95:5; the flow rate was 2.0 mL/min) to obtain compound NBC -9.
  • HPLC YMC-Pack Pro C18 column, the specification was 20mm ⁇
  • the compound NBC-9 and the compound NBC-8 have the same spectral retention time.
  • the preparation of compound NBC-10 includes the following steps:
  • the structure of the fourth intermediate is as follows:
  • the structure of the fifth intermediate is as follows:
  • 100 ⁇ L of the ethanol solution of the fifth intermediate (the mass of the fifth intermediate is 0.5 mg) was placed in a reaction flask, and 100 ⁇ L of hydrogen peroxide solution (concentration of 3wt%) and 0.74MBq [ 125 I]NaI solution were added in sequence, and then Add 100 ⁇ L of hydrochloric acid with a concentration of 1 mol/L, seal the reaction flask immediately, react at room temperature for 10 min, and then add 100 mg of NaHSO 3 to terminate the reaction; react the resulting reaction solution at 100 ° C for 10 min, and then add 5 mL of water to terminate the reaction; The obtained reaction solution was neutralized to pH 7 with sodium bicarbonate, extracted with ethyl acetate, the ethyl acetate layer was separated, and the acetic acid in the ethyl acetate layer was removed with nitrogen to obtain 125 I labeled substance.
  • the compound NBC-10 and the compound NBC-7 have the same spectral retention time.
  • the fluorescence changes before and after mixing the coumarin-based compounds with ⁇ -synuclein monomers and other protein monomers and polymers with similar structures in Examples 2 to 5 were investigated.
  • the test results are shown in Table 2. It can be seen from Table 2 that the coumarin compounds provided by the present invention have specific and selective fluorescence enhancement properties for ⁇ -synuclein polymers.
  • the ⁇ -synuclein polymers can be effectively distinguished from other polymers with ⁇ -sheets by directly reading the detection signal. Structure of protein polymers and protein monomers.
  • the coumarin compounds provided by the present invention have specific fluorescence enhancement properties for ⁇ -synuclein polymers in brain homogenate. Through the selective fluorescence enhancement of ⁇ -synuclein polymers in biological samples by the coumarin compounds provided in the present invention, the ⁇ -synuclein polymers can be effectively distinguished from other polymers with ⁇ -sheet structure of protein polymers and protein monomers.
  • the coumarin compound (NBC-2) in Example 2 was mixed with DMSO and PBS buffer, the content of compound NBC-2 in the obtained mixed solution was 1.0 mg/kg, and the volume ratio of DMSO and PBS buffer was 1: 9.
  • the mixture was injected into normal mice through the tail vein, 10 mL of PBS buffer was perfused 30 minutes after the injection, and the brain was decapitated; the brain tissue was observed in a small animal in vivo imager, and the results are shown in Figure 3. It can be seen from FIG. 3 that the coumarin compounds provided by the present invention can effectively cross the blood-brain barrier and have good brain uptake.
  • the coumarin compound (NBC-2) in Example 2 was mixed with DMSO and PBS buffer, the content of compound NBC-2 in the obtained mixed solution was 1.0 mg/kg, and the volume ratio of DMSO and PBS buffer was 1: 9.
  • the mixture was injected into PD transgenic aged (12-month-old) mice and normal aged (12-month-old) mice through the tail vein, and 10 mL of PBS buffer was perfused 60 min after the injection, and the brain was removed by decapitation; The tissue was observed in a small animal in vivo imager, and the results are shown in Figure 4.
  • PD transgenic aged mice showed strong fluorescent signals in the brains, indicating that the coumarin compounds provided by the present invention can effectively pass through the blood-brain barrier and the ⁇ -synapses in the brain.
  • the nuclein polymer binds and releases a specific detection signal to efficiently image ⁇ -synuclein polymers in the brains of PD transgenic aged mice.
  • the coumarin compound (NBC-9) in Example 9 was dissolved in the PBS solution, and the content of the compound NBC-9 in the obtained mixed solution was 5 ⁇ mol/L; 100-500 ⁇ L of the mixed solution was added dropwise with a pipette gun to cover
  • the brain slices (15 ⁇ m) of PD transgenic aged (12-month-old) mice were incubated at room temperature for 60 min; after that, the 40% ethanol aqueous solution (1 min), 40% ethanol aqueous solution (1 min), and pure water (30 s) were sequentially analyzed in the order
  • the slices were rinsed, air-dried, covered with a transparent film, placed on the surface of the phosphor screen, stored in the dark, and scanned and observed with a phosphor screen autograph.
  • the results are shown in Figure 5. It can be seen from FIG. 5 that the radiolabel provided by the present invention can clearly and effectively label the ⁇ -synuclein polymer in brain slices.

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Abstract

La présente invention concerne un composé de coumarine, son procédé de préparation, une utilisation et une composition pharmaceutique associées, se rapportant au domaine technique des médicaments. Le composé de coumarine selon la présente invention a une grande affinité et une sélectivité élevée pour un polymère d'alpha-synucléine, peut distinguer de manière efficace le polymère d'alpha-synucléine à partir d'autres polymères protéiques avec la structure de pliage β, et peut être utilisé pour préparer un réactif de diagnostic pour détecter le polymère d'alpha-synucléine, et en particulier peut être utilisé pour préparer un réactif de diagnostic pour la détection de fluorescence du polymère d'alpha-synucléine ou d'un développeur fluorescent pour le développement du polymère d'alpha-synucléine. Le composé de coumarine marqué avec un radionucléide peut être utilisé également pour préparer un médicament de radiodiagnostic pour le développement du polymère d'alpha-synucléine dans un médicament nucléaire.
PCT/CN2021/134014 2020-12-22 2021-11-29 Composé de coumarine, son procédé de préparation, utilisation et composition pharmaceutique associées Ceased WO2022135072A1 (fr)

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