CN110818636A - Compound or salt thereof, and application and synthesis method thereof - Google Patents

Compound or salt thereof, and application and synthesis method thereof Download PDF

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CN110818636A
CN110818636A CN201911200976.2A CN201911200976A CN110818636A CN 110818636 A CN110818636 A CN 110818636A CN 201911200976 A CN201911200976 A CN 201911200976A CN 110818636 A CN110818636 A CN 110818636A
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compound
curcumin
pharmaceutically acceptable
pyrazole
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徐志栋
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Hebei University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Abstract

The invention relates to the technical field of drug synthesis, and particularly discloses a compound or a salt thereof, and an application and a synthesis method thereof, wherein the compound or the salt thereof can be used for preparing an early diagnosis drug for Alzheimer's disease, has firm binding force with β -like starch protein (β -amyloid protein), has good stability under physiological conditions, is more suitable for stably existing in organisms, can smoothly cross a cerebral blood barrier after being absorbed to be combined with β -amyloid protein in brains of Alzheimer's disease patients, has better bioavailability, and provides a sensitive and specific targeted drug basis for early diagnosis of Alzheimer's disease, and the structure of the compound is as follows:
Figure DDA0002295859620000011

Description

Compound or salt thereof, and application and synthesis method thereof
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a compound or salt thereof, and application and a synthesis method thereof.
Background
Alzheimer disease is a neurodegenerative and lethal disease, patients gradually worsen after disease onset, daily life capacity declines, and various neuropsychiatric symptoms and behavior disorders are accompanied, so that the quality of life of the patients in the middle and late stages after disease onset is poor, nursing difficulty is high, the patients usually die within 7-10 years after diagnosis, and huge burden is caused to families and society. According to statistics, the total disease rate of people over 65 years old reaches 5.9%, the disease rate of old people over 85 years old reaches 30%, and the condition is more prominent in the near future along with the aggravation of the aging of the population in China.
Because the pathogenesis of the Alzheimer disease is complex, the brain of a patient has quite serious synapse loss, neuron loss and brain atrophy when clinical symptoms appear, dispute failure of clinical potential medicaments in human clinical tests in recent years highlights the necessity of early diagnosis and treatment research on the Alzheimer disease, pharmaceutical scientists and clinicians gradually realize that the treatment time of the Alzheimer disease plays a key role in preventing and relieving the disease, the American NIH-AD standard is generally adopted for clinical diagnosis of the Alzheimer disease at present, the diagnosis accuracy of patients in the middle and later stages is only 50 percent, so that the diagnosis of the Alzheimer disease by the clinical symptoms is unreliable, and finally the diagnosis can be confirmed only by the fact that whether amyloid protein can be found in autopsy, 97 percent of patients in patients with mild dementia cannot be diagnosed, so the development of the method can be used for carrying out early diagnosis in vivo, Techniques for non-invasive, specific examination and accurate diagnosis of alzheimer's disease have become of paramount importance.
The Positron Emission Computed Tomography (PET) technology is a relatively advanced clinical examination imaging technology in the nuclear medicine field, and the PET imaging technology utilizes drug molecules labeled with radioisotopes with short half-lives (such as 18F, 11C and the like) or special substances in life metabolism (such as glucose, proteins, nucleic acids, fatty acids) to specifically bind or selectively accumulate at diseased regions after entering a human body, reflects disease occurrence characteristics through a PET imaging technology, so that an excellent PET tracer is developed as a precondition for improving PET diagnostic quality.
Curcumin is an orange crystalline substance extracted from the rhizome of curcuma longa of the family zingiberaceae, is a natural diketone chemical component, and has a structural formula:
Figure BDA0002295859600000021
a large number of pharmacological studies prove that curcumin has wide physiological activity and low toxicity, has the functions of oxidation resistance, anti-inflammation, anti-tumor, heart and liver protection, anti-inflammation and the like, particularly has anti-tumor activity, and in recent years, the study finds that curcumin also has the characteristics of scavenging free radicals in the brain and specifically binding β -amyloid protein, the binding can improve the deposition of β -amyloid protein, further improve the occurrence and development of Alzheimer's disease, the effectiveness of the curcumin is proved by a large number of in vivo and in vitro experiments, and the binding provides a structural basis for developing a PET tracer diagnostic agent taking β -amyloid protein as a biomarker, but the curcumin has a 1, 3-diketone structure, so that the curcumin is unstable to light, heat and acid and alkali, is easy to degrade in intestinal tracts, has low oral bioavailability, and has low binding capacity with β -amyloid protein, so that the curcumin is not ideal as a PET tracer agent for the development and early diagnosis results of Alzheimer's disease.
Disclosure of Invention
Aiming at the problem that the early diagnosis result of the Alzheimer disease is not ideal because the existing PET imaging agent for diagnosing the Alzheimer disease has low capability of crossing the brain blood barrier and low binding capability with target protein, the invention provides a compound or salt thereof, and an application and a synthetic method thereof.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a compound, or a pharmaceutically acceptable salt thereof, having the structure:
Figure BDA0002295859600000031
wherein R is CH3Or CH2CH2F。
Compared with the prior art, the compound or the pharmaceutically acceptable salt thereof provided by the invention has firm binding force with β -like amyloid protein (β -amyloid protein), has good stability under physiological conditions, is more suitable for stably existing in organisms, is not degraded in gastrointestinal tracts after being orally taken, has good lipophilicity, can smoothly cross cerebral blood barriers after being absorbed to be combined with β -amyloid protein in brains of Alzheimer's disease patients, has better bioavailability, and provides sensitive and specific targeted drug basis for early diagnosis of Alzheimer's disease.
Preferably, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt of the compound.
The pharmaceutically acceptable salt (inorganic acid salt or organic acid salt) of the compound does not influence the structure of the compound and the properties such as the binding force of the compound with β -amyloid protein and the like, and has stable structural characteristics.
Preferably, the inorganic acid salt is carbonate, hydrochloride, sulfate, phosphate or phosphite, and the organic acid salt is formate, acetate, citrate, lactate, fumarate, tartrate or gluconate.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof as a β -amyloid detection reagent.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof in preparing an early diagnosis medicament for the Alzheimer's disease.
Preferably, the compound or the pharmaceutically acceptable salt thereof is isotopically labeled to serve as a PET tracer.
β -amyloid protein in the brain of an Alzheimer disease patient is used as a biological targeting marker, the isotopically labeled compound which has specific binding to β -amyloid protein or pharmaceutically acceptable salt thereof is used as a PET tracer agent for diagnosing the Alzheimer disease, and the specific and sensitive targeting binding of the compound or the pharmaceutically acceptable salt thereof to β -amyloid protein in the brain and a PET developing technology are utilized, so that the disease can be rapidly and accurately diagnosed at the early stage of the Alzheimer disease.
The PET tracer agent comprises an isotope-labeled compound or a pharmaceutically acceptable salt thereof and a solvent, wherein the solvent is a pharmaceutically acceptable, inert and nontoxic solvent such as water or ethanol, and the mass ratio of the isotope-labeled compound or the pharmaceutically acceptable salt thereof to the solvent is 1: 100-10000.
Preferably, the R group in the compound or a pharmaceutically acceptable salt thereof is isotopically labeled.
Preferably, the isotopically-labeled R group is11CH3Or CH2CH2 18F。
The isotope marks the position, the marking method is simple, and11c or18The half-life of F is long, which is beneficial to the effective diagnosis of diseases as a PET tracer.
The invention also provides a synthesis method of the compound, which comprises the following steps: performing cyclization reaction on curcumin and hydrazine hydrate to generate pyrazole curcumin, protecting phenolic hydroxyl of the pyrazole curcumin, introducing an R group on an N atom of a pyrazole ring, and then deprotecting the phenolic hydroxyl to obtain the compound.
Compared with the prior art, the synthesis method has the advantages of simple synthesis process, mild synthesis conditions and low cost, and is beneficial to large-scale production.
Preferably, the reaction condition for generating the pyrazole curcumin by the cyclization reaction of the curcumin and hydrazine hydrate is 80-85 ℃ for 8-10 h.
Preferably, tert-butyldimethylsilyl chloride is used as a protective agent to protect the phenolic hydroxyl group of the pyrazole curcumin.
The tertiary butyl dimethylchlorosilane is used as a protective agent to protect the phenolic hydroxyl of the pyrazole curcumin, so that an R group can be prevented from being introduced to the phenolic hydroxyl, and the synthesis efficiency of a product is ensured.
Drawings
FIG. 1 is a nuclear magnetic resonance of 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1H-pyrazole in example 1 of the present invention1H spectrum atlas;
FIG. 2 is a nuclear magnetic resonance of 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1H-pyrazole in example 1 of the present invention13C spectrum atlas;
FIG. 3 is a high resolution mass spectrum of 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1H-pyrazole in example 1 of the present invention;
FIG. 4 shows NMR of Compound 1 in example 1 of the present invention1H spectrum atlas;
FIG. 5 shows NMR of Compound 1 in example 1 of the present invention13C spectrum atlas;
FIG. 6 is a high resolution mass spectrum of Compound 1 of example 1 of the present invention;
FIG. 7 shows NMR of Compound 2 in example 2 of the present invention1H spectrum atlas;
FIG. 8 shows NMR of Compound 2 in example 2 of the present invention13C spectrum atlas;
FIG. 9 is a high resolution mass spectrum of Compound 2 of example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
4,4'- ((1E,1' E) - (1-methyl-1H-pyrazole-3, 5-diyl) bis (ethylene-2, 1-diyl)) bis (2-methoxyphenol) having the formula:
Figure BDA0002295859600000061
the pharmaceutically acceptable salt of the compound is carbonate, hydrochloride, sulfate, phosphate, phosphite, formate, acetate, citrate, lactate, fumarate, tartrate or gluconate;
the synthesis method of the compound 1 comprises the following steps: taking curcumin as a raw material, carrying out cyclization reaction on curcumin and hydrazine hydrate to generate pyrazole curcumin, protecting phenolic hydroxyl of the pyrazole curcumin, introducing an R group on an N atom of a pyrazole ring, and then carrying out deprotection on the protected phenolic hydroxyl to obtain the compound 1; the specific synthetic process is as follows:
1) performing cyclization reaction on curcumin and hydrazine hydrate to generate pyrazole curcumin: weighing 0.88g of curcumin, placing the curcumin in a 100mL round-bottom flask, adding 10mL of glacial acetic acid, dissolving the curcumin, enabling the dissolved solution to be yellow, stirring at room temperature for 30min, adding 0.15g of hydrazine hydrate, stirring in an oil bath stirrer at 85 ℃ for 8h, enabling the solution to be changed from yellow to orange red, stopping heating after the reaction is completed, suspending the reaction solution, adding 50mL of ethyl acetate, washing the organic phase with 50mL of saturated saline water, repeatedly washing for 3 times, drying the organic phase with anhydrous sodium sulfate, filtering and concentrating the organic phase, and then carrying out column chromatography (EA/PE is 1-50%) separation and purification to obtain faint yellow solid pyrazole curcumin, wherein the content of the pyrazole curcumin is 45%;
the reaction formula of the process is as follows:
using nuclear magnetic resonance1H spectrum and nuclear magnetic resonance13C spectrum detection determines the structure of the pyrazole curcumin, and the detection result is as follows: mp 222.6-224.1 deg.C; LC-MS (ESI, m/z) Calcd for C21H21N2O4([M+H]+):366.15,found:366.01；1H NMR(600MHz,DMSO-d6):δ9.42(s,1H),9.35(s,1H),7.30(d,J＝3.6Hz,2H),7.29(d,J＝1.2Hz,1H),7.27(d,J＝4.8Hz,1H),7.04-7.11(m,4H),6.86(s,1H),6.81(d,J＝4.8Hz,1H),6.81(d,J＝4.2Hz,1H),3.85(s,6H)。
2) Protecting the phenolic hydroxyl group of pyrazole curcumin: weighing 0.95g of pyrazole curcumin obtained in the step 1) into a 50mL round-bottom flask, adding 15mL of Dimethylformamide (DMF) for dissolving, adding 1.18g of TBDMS-Cl and 0.492g of imidazole into a reaction solution, reacting at room temperature for 12H, adding 20mL of water for quenching reaction after the reaction is finished, then extracting with 30mL of ethyl acetate, repeatedly extracting for 3 times, combining organic phases, washing with 30mL of water, repeatedly washing for 3 times, washing with 30mL of saturated saline water again, repeatedly washing for 3 times, drying the washed organic phase with anhydrous sodium sulfate, filtering and concentrating the organic phase, separating and purifying by column chromatography (EA/PE & lt 1-20%) to obtain a white solid 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1H-pyrazole, wherein the content of 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1H-pyrazole is 98%;
the reaction formula of the process is as follows:
Figure BDA0002295859600000071
respectively using nuclear magnetic resonance1H spectrum, nuclear magnetic resonance13C spectrum and high resolution mass spectrum detection to determine the structure of 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1H-pyrazole to obtain nuclear magnetic resonance1The spectrum of H spectrum is shown in FIG. 1, and the obtained nuclear magnetic resonance13The spectrum of the spectrum C is shown in figure 2, the spectrum of the obtained high-resolution mass spectrum is shown in figure 3, and the nuclear magnetic resonance detection result is as follows: mp 191.5-193.9 deg.C; HRMS (ESI, m/z): Calcd for C33H49N2O4Si2([M+H]+):593.3225,found:593.3221；1H NMR(600MHz,CDCl3):δ7.90(s,1H),6.87(s,1H),6.84(s,1H),6.82(s,2H),6.78(d,J＝1.2Hz,1H),6.76(d,J＝1.2Hz,2H),6.73(s,1H),6.65(s,1H),6.63(s,1H),6.42(s,1H),3.65(s,6H),0.83(s,18H),0.00(s,12H)；13C NMR(125MHz,CDCl3):δ151.1(Overlap,2C),145.75(Overlap,2C),131.10(Overlap,2C),130.86(Overlap,2C),121.30(Overlap,2C),120.19(Overlap,2C),116.18(Overlap,2C),110.12(Overlap,2C),99.95,56.67(Overlap,2C),25.98(Overlap,6C),18.72(Overlap,2C),4.35(Overlap,4C)；
The high resolution mass spectrometry detection result is as follows:
Figure BDA0002295859600000081
3) introducing an R group on the N atom of the pyrazole ring: weighing 1.24g of the white solid obtained in the step 2), adding 20mL of THF into a 50mL round-bottom flask for dissolving, stirring at 0 ℃ for 10min, adding 0.36g of potassium tert-butoxide, continuing stirring for 30min, dropwise adding 0.18mL of methyl iodide into the reaction solution, reacting at room temperature for 4H after dropwise adding, adding 20mL of water after the reaction is finished for quenching reaction, extracting with 30mL of ethyl acetate, repeatedly extracting for 3 times, combining organic phases, washing with 30mL of distilled water, repeatedly washing for 3 times, washing with 30mL of saturated saline water, repeatedly washing for 3 times, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase, separating and purifying by column chromatography (EA/PE is 1-10%) to obtain a white solid, and 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1-methyl-1H-pyrazole in the white solid The content of (A) is 56%;
the reaction formula of the process is as follows:
Figure BDA0002295859600000082
using nuclear magnetic resonance1H spectrum and nuclear magnetic resonance13C spectrum detection determines the structure of 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1-methyl-1H-pyrazole, and the detection result is as follows: mp 123.2-124.8 deg.C; HRMS (ESI, m/z): Calcd for C34H51N2O4Si2([M+H]+):607.3382,found:607.3376；1H NMR(600MHz,DMSO-d6):δ7.17(d,J＝1.2Hz,2H)，7.06(d,J＝1.8Hz,2H)，6.70(s,1H)，6.96(s,1H)，6.95-6.92(m,1H)，6.90(s,1H)，6.86-6.85(m,1H)，6.84-6.83(m,1H)，6.70-6.65(m,3H)，3.76(s,3H)，3.70(s,3H)，3.67(s,3H)，0.82(s,9H)，0.82(s,9H)，0.01(s,6H)，0.00(s,6H)；13C NMR(125MHz,DMSO-d6):δ150.71,150.67,148.75,144.63,144.03,142.07,131.45,131.15,130.69,128.65,120.48,120.29,119.46,119.15,113.20,110.18,109.70,98.95,55.47(Overlap,2C),36.38,25.53(Overlap,6C),18.12(Overlap,2C),-4.72(Overlap,4C)。
4) And (3) deprotection of phenolic hydroxyl group: weighing 1.27g of the white solid obtained in the step 3), dissolving the white solid in a 50mL round-bottom flask by adding 15mL of THF, dropwise adding 10.4mL of TBAF into the reaction solution while stirring at 0 ℃, stirring for 0.5H, after the reaction is finished, adding 20mL of water to carry out quenching reaction, extracting with 30mL of ethyl acetate, repeating the extraction process for 3 times, combining organic phases, washing the organic phases with 30mL of water, repeating the washing process for 3 times, washing with 30mL of saturated saline, repeating the washing process for 3 times, drying the washed organic phases with anhydrous sodium sulfate, filtering, concentrating the organic phases, separating and purifying by column chromatography (EA/PE is 1-50%) to obtain the white solid, wherein 4,4'- ((1E,1' E) - (1-methyl-1H-pyrazole-3, 5-diyl) bis (ethylene-2 in the white solid, 1-diyl)) bis (2-methoxyphenol) was contained in an amount of 98%;
the reaction formula of the process is as follows:
Figure BDA0002295859600000091
respectively using nuclear magnetic resonance1H spectrum, nuclear magnetic resonance13C spectrum and high resolution mass spectrum detection determine the structure of 4,4'- ((1E,1' E) - (1-methyl-1H-pyrazole-3, 5-diyl) bis (ethylene-2, 1-diyl)) bis (2-methoxyphenol), and the obtained nuclear magnetic resonance1The obtained NMR spectrum is shown in FIG. 413The spectrum of the spectrum C is shown in fig. 5, the spectrum of the obtained high-resolution mass spectrum is shown in fig. 6, and the nuclear magnetic resonance detection result is as follows: mp 227.6-229.1 deg.C; HRMS (ESI, M/z) Calcd for C22H23N2O4([ M + H)]+):379.1652,found:379.1649；1H NMR(600MHz,DMSO-d6):δ9.23(s,1H),9.90(s,1H),7.27(s,1H),7.16(s,1H),7.05(d,J＝3.6Hz,2H),7.03(s,1H),7.00(s,1H),6.95-6.93(m,1H),6.90(d,J＝16.2Hz,1H),6.79(d,J＝7.8Hz,2H),6.77-6.76(m,2H),3.98(s,3H),3.83(s,3H)；13C NMR(125MHz,DMSO-d6):δ148.89,147.86,147.83,147.17,146.53,142.21,131.80,128.98,128.60,128.11,120.70,119.85,117.92,115.54(Overlap,2C),111.90,110.09,109.55,98.52,55.73,55.57,36.32；
The high resolution mass spectrometry detection result is as follows:
the methyl group of the pyrazole ring of the compound is marked with an isotope to obtain a compound 1', the structural formula of which is as follows:
Figure BDA0002295859600000102
the synthesis process of compound 1' is:
bombardment by protons using Siemens cyclotron (RDS-111)14N, by nuclear reaction14N(p,α)11C production11CO2Isotopically labelled11CO2Reacting with hydrogen to obtain11CH4，11CH4With Br2Reaction to obtain11CH3Br, then11CH3With Br reacting with AgOTf to obtain the gaseous state11CH3OTf; 0.3mg of the white solid product synthesized in step 2) above was dissolved in 300. mu.L of CH3CN, 2 mu L of 2M NaOH aqueous solution is added, the obtained mixture is transferred into a small reaction bottle of an automatic reaction device, and then the mixture is introduced11CH3Obtained by OTf reaction11C]Labeled Compound 1', the reaction flask was heated at 80 ℃ for 3min, and 0.1M NaHCO was added3Diluting 1mL of the solution, adding TBAF at 0 ℃ with stirring, stirring for 0.5h, deprotecting the phenolic hydroxyl group, diluting with water, purifying the diluted reaction by semi-preparative HPLC, diluting the resulting product with 30mL of water, adsorbing the diluted solution on an SPE solid phase extraction column, washing with 30mL of water, washing with 0.4mL of EtOH, washing with 3 times of saturated saline, washing with 10mL of saturated saline, washing with 3 times of saturated saline, filtering the eluted product through a 0.2 μm Millex-FG membrane into a sterile vial, measuring the radioactivity of the resulting compound 1' and recording its concentration, and calculating the resulting compound 1The isotopic labeling efficiency of 1' was 65%.
The synthesis reaction formula of the compound 1' is as follows:
Figure BDA0002295859600000111
example 2
3, 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1- (2-fluoroethyl) having the formula:
the pharmaceutically acceptable salt of the compound 2 is carbonate, hydrochloride, sulfate, phosphate, phosphite, formate, acetate, citrate, lactate, fumarate, tartrate or gluconate;
the synthesis method of the compound 2 comprises the following steps:
introduction of fluoroethyl group on N atom of pyrazole ring: 1.09g of the white solid obtained in step 2) of example 1 was weighed, dissolved in a 50mL round-bottomed flask by adding 10mL of DMF, and then 0.081 g of NaH (60 wt%) was added to the reaction mixture, and after stirring at room temperature for 20min, 0.153mL of BrCH (basic chlorinated polyethylene) was added2CH2F, stirring at room temperature for 12H, after the reaction is finished, adding 10mL of water to carry out quenching reaction, extracting with 20mL of ethyl acetate again, repeatedly extracting for 3 times, combining organic phases, washing with 20mL of water again, repeatedly washing for 3 times, then washing with 20mL of saturated saline solution again, repeatedly washing for 3 times, drying the obtained organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase, and separating and purifying by column chromatography (EA/PE ═ 1-20%) to obtain 3, 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1- (2-fluoroethyl) -1H-pyrazole of which 3, 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1- (2-fluoroethyl) -1H-pyrazole as a white solid -a pyrazole content of 44%;
the reaction formula of the process is as follows:
Figure BDA0002295859600000121
using nuclear magnetic resonance1H spectrum and nuclear magnetic resonance13C spectrum detection determines the structure of the obtained 3, 5-bis ((E) -4- ((tert-butyldimethylsilyl) oxy) -3-methoxystyryl) -1- (2-fluoroethyl) -1H-pyrazole, and the detection result is that: mp is 77.9-81.1 deg.C; HRMS (ESI, m/z): calcd for C35H52FN2O4Si2([M+H]+):639.3444,found:639.3443；1H NMR(600MHz,CDCl3):δ6.88-6.76(m,7H),6.68-6.61(m,3H),6.46(s,1H),4.69-4.67(m,1H),4.61-4.59(m,1H),4.32-4.31(m,1H),4.28-4.27(m,1H),3.66(s,3H),0.83(s,9H),0.82(s,9H),0.01(s,6H),9.23(s,1H)；13C NMR(125MHz,CDCl3):δ151.21,151.10,150.74,145.87,145.13,143.35,133.06,131.14,130.39,130.11,121.18,120.98,120.04,119.93,118.65,112.36,110.24,109.48,99.35,1C(82.80,81.66),55.57,55.39,1C(49.59,49.44),25.72(Overlap,6C),18.49(Overlap,2C),-4.59(Overlap,2C)；
And (3) deprotection of phenolic hydroxyl group: weighing 1.27g (2.09mmol) of the white solid obtained above, adding 15mL of THF for dissolving, dropwise adding TBAF (10.4mL, 20.1mmol) into the reaction solution under stirring at 0 ℃, stirring at room temperature for 0.5H, adding water (20mL) to quench the reaction after the reaction is finished, extracting with 30mL of ethyl acetate, repeating for 3 times, combining the organic phases, washing with 30mL of water, repeating for 3 times, washing with 30mL of saturated saline water, repeating for 3 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase, separating and purifying the crude product by column chromatography (EA/PE is 1-50%) to obtain the white solid 4,4'- ((1E,1' E) - (1- (2-fluoroethyl) -1H-pyrazole-3, 5-diyl) bis (ethylene-2, 1-diyl)) bis (2-fluoroethyl), wherein the content of 4,4'- ((1E,1' E) - (1- (2-fluoroethyl) -1H-pyrazole-3, 5-diyl) bis (ethylene-2, 1-diyl)) bis (2-fluoroethyl) is 69.7%;
the reaction formula of the process is as follows:
Figure BDA0002295859600000131
respectively using nuclear magnetic resonance1H spectrum, nuclear magnetic resonance13C spectrum and high resolution mass spectrum detection determine the structure of 4,4'- ((1E,1' E) - (1- (2-fluoroethyl) -1H-pyrazole-3, 5-diyl) bis (ethylene-2, 1-diyl)) bis (2-fluoroethyl), and the obtained nuclear magnetic resonance1The spectrum of H spectrum is shown in FIG. 7, and the obtained NMR13The spectrum of the spectrum C is shown in fig. 8, the spectrum of the obtained high-resolution mass spectrum is shown in fig. 9, and the nuclear magnetic resonance detection result is as follows: mp 115.3-117.0 deg.C; HRMS (ESI, m/z): calcd for C23H24FN2O4([M+H]+):411.1715,found:411.1712；1H NMR(600MHz,DMSO-d6):δ9.24(s,1H),9.11(s,1H),7.25(s,1H),7.18(s,1H),7.07(d,J＝6.6Hz,1H),7.04(d,J＝6.0Hz,1H),7.03(s,1H),6.96(s,1H),6.94-6.93(m,1H),6.83(s,1H),6.79(d,J＝8.4Hz,1H),6.76(d,J＝7.8Hz,1H),4.82-4.81(m,1H),4.75-4.73(m,1H),4.61-4.59(m,1H),4.56-4.55(m,1H),3.85(s,3H),3.83(s,3H)；13C NMR(125MHz,DMSO-d6):δ149.78,147.28(Overlap,2C),147.21,146.61,143.01,132.07,129.51,128.51,128.09,120.69,119.95,117.86,115.55(Overlap,2C),111.71,110.25,109.55,98.51,1C(82.90,81.78),55.75,55.57,1C(48.74,48.61)；
The high resolution mass spectrometry detection result is as follows:
Figure BDA0002295859600000132
the methyl group of the pyrazole ring of the compound is marked with an isotope to obtain a compound 2', the structural formula of which is as follows:
Figure BDA0002295859600000141
the synthesis process of the compound 2' is as follows:
oriented angle18F]To an aqueous solution of fluoride (500MBq) was added kryptofix 2.2.2.(10mg,25mmol), 12.5mL potassium carbonate and 1mL acetonitrile, the mixture was dried under a stream of nitrogen at 80 ℃, and the drying step was repeated three times until the reaction mixture was completely dried. The dried Kryptofix 2.2.218F]The fluoride complex was dissolved in 1mL acetonitrile and 3mg of 1, 2-bis was addedBromoethane, the mixture was stirred at 701 ℃ reaction temperature for 3min, diluted with 20mL of water and passed through a LiChrolutesEN-column, the immobilized product was eluted with 1mL of acetonitrile and immediately passed through an column of aluminas b-into the receiving liquid, the total preparation time was 10min and the total radiochemical yield was 70%; the white solid (0.2mg) obtained in step 2) of example 1 was dissolved in CH3CN (300. mu.L), 2. mu.L of a 2M aqueous NaOH solution was added to the mixture, and the mixture was transferred into a small reaction flask of an automatic reaction apparatus18F]FCH2CH2Br nucleophilic substitution, heating the reaction flask at 80 ℃ for 3min, and reacting with 0.1M NaHCO3The solution (1mL) was diluted, TBAF was added with stirring at 0 ℃ to deprotect, and diluted with water. Purifying the diluted reaction by semi-preparative HPLC, adding water (30mL) to the obtained product for dilution, then adsorbing the diluted tracer solution by an SPE solid phase extraction column, washing with 30mL water, repeating for 3 times, washing with 0.4mL of E tOH, repeating for 3 times, finally washing with saline (10mL), finally filtering the eluted product into a sterile vial through a 0.2 μm Millex-FG membrane, measuring the radioactivity of the product 2 'and recording the concentration of the tracer, wherein the calculated isotopic labeling efficiency of the compound 2' is 46%;
the synthesis reaction formula of the compound 2' is as follows:
Figure BDA0002295859600000142
example 3
Log P and Clog P values were calculated by Chemdraw for Compounds 1 and 2 and for the carbonate, hydrochloride, formate and lactate salts of Compounds 1 and 2, compared to the four PET tracers for Alzheimer's disease diagnosis [11C ] PIB, [18F ] Amyvid, [11C ] PBB3 and [18F ] T807 that have entered clinical diagnostic use, with the results shown in the following table:
Compound Log P CLog P
compound
1 4.20 4.01
Compound 2 4.39 4.26
[11C]PIB 3.41 3.99
[18F]Amyvid 3.16 3.91
[11C]PBB3 4.09 4.05
[18F]T807 2.25 3.18
。
The results of comparative experiments show that compounds 1 and 2 have similar Log P values to the four existing PET tracers, and therefore, compounds 1 and 2 and the pharmaceutically acceptable salts thereof have better lipophilicity and better ability of crossing the brain blood barrier.
The binding capacity of compounds 1 and 2 to β -amyloid Protein was determined by the thioflavin T (ThT) competitive binding assay (Harry Levine, Protein Science (1993),2,404-410)Dissolving a test compound in water to a final concentration of 0, 0.3. mu.M, 1. mu.M, 3. mu.M and 10. mu.M, dissolving 5. mu.M of β -amyloid protein in 50mM Tris-HCl (pH7.6), measuring the initial fluorescence intensity E0 (Ex: 440-nm Em: 486-nm), adding the test compound to a final concentration of 0, 0.3. mu.M, 1. mu.M, 3. mu.M and 10. mu.M, incubating at 37 ℃ for 24 hours, adding 1/10 volumes of 30. mu.M thioflavin T (ThT) (final concentration 3. mu.M), measuring the fluorescence intensity Et (Ex: 440-nm Em: 486-nm), plotting the fluorescence intensity (Et-E0) and the concentration of the test sample, calculating the 50% inhibition concentration IC50The measurements were repeated three times, and the mean and standard deviation were calculated, and the results are shown in the following table:
Compound IC50μM
compound 1 1.2±0.2
Compound 2 1.7±0.3
Curcumin (curcumin) 6.8±0.5
。
The detection result shows that: IC of Compounds 1 and 250IC with both the μ M values being less than curcumin50The μ M value indicates that the compounds 1 and 2 and pharmaceutically acceptable salts thereof of the present invention have better binding ability to β -amyloid protein compared to curcumin.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (10)

1. A compound or a pharmaceutically acceptable salt thereof, characterized by: the structure of the compound is as follows:
Figure FDA0002295859590000011
wherein R is CH3Or CH2CH2F。
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt of the compound.
3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: the inorganic acid salt is carbonate, hydrochloride, sulfate, phosphate or phosphite, and the organic acid salt is formate, acetate, citrate, lactate, fumarate, tartrate or gluconate.
4. Use of a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, as a β -amyloid detection reagent.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the early diagnosis of alzheimer's disease.
6. Use according to claim 4 or 5, characterized in that: the compound or the pharmaceutically acceptable salt thereof is used as a PET tracer after being labeled by an isotope.
7. The use of claim 6, wherein: isotopically labeling the R groups in said compound or a pharmaceutically acceptable salt thereof.
8. The use of claim 7, wherein: the isotopically-labeled R group is11CH3Or CH2CH2 18F。
9. A method of synthesis of a compound according to any one of claims 1 to 3, characterized in that: performing cyclization reaction on curcumin and hydrazine hydrate to generate pyrazole curcumin, protecting phenolic hydroxyl of the pyrazole curcumin, introducing an R group on an N atom of a pyrazole ring, and then deprotecting the phenolic hydroxyl to obtain the compound.
10. The method of synthesis of claim 9, wherein: the reaction condition for generating pyrazole curcumin by cyclization reaction of curcumin and hydrazine hydrate is 80-85 ℃ for 8-10 h; and/or.
And (3) protecting the phenolic hydroxyl of the pyrazole curcumin by using tert-butyldimethylsilyl chloride as a protective agent.
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