Triazole compound as well as preparation method and application thereof

Abstract

The invention specifically discloses a triazole compound as well as a preparation method and application thereof, and relates to the technical field of specific biological medicines. The invention provides a triazole compound, and the triazole compound has a structure as shown in a formula (I): # imgabs0 #, in which R1 represents OCH3, N (CH3) 2; and R2 represents F. The triazole compound provided by the invention has high affinity with the A beta plaque in the brain and is subjected to < 18 > F labeling, and the labeled probe can accurately identify a tissue sample containing the A beta plaque.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technologies, and in particular, to a triazole compound, a preparation method thereof, and uses thereof. Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease mainly characterized by dementia. In 2020, approximately 5.8 million Americans aged 65 and older had AD. The issues of early diagnosis and early intervention of AD are among the problems that cannot be ignored. In 2018, the National Institute on Aging and the Alzheimer's Association (NIA-AA) in the United States completed the standardized assessment of the pathological process of AD through the ATN framework that can be demonstrated by specific biomarkers: A refers to amyloid deposition; T refers to neurofibrillary tangles composed of abnormally hyperphosphorylated Tau protein; N refers to neurodegeneration.

[0003] The cerebral accumulation of β-amyloid (Aβ) peptide is considered the initial event in the process of AD. The deposition of Aβ plaques begins in the neocortex and then spreads layer by layer to other regions of the brain. The extracellular senile plaques (SPs) formed by the overproduction, aggregation, and precipitation of Aβ in the brain promote the generation of neurofibrillary tangles (NFTs), which can ultimately lead to neuronal death. Currently, through the use of 11 C and 18 F-labeled amyloid-binding ligands and PET, in vivo detection of amyloid pathology in the human brain has become possible. A variety of Aβ molecular probes for PET imaging have been developed, such as 11 C-PIB, 18 F-flutemetamol (abbreviation: 18 F-GE067), 18 F-AV-45, 18 F-florbetaben (abbreviation: 18 F-FBB), etc.

[0004] The deposition of Aβ is crucial in the pathogenesis of AD. The application of Aβ PET imaging agents is increasing in basic research and clinical trials of AD. This phenomenon drives researchers to strive to standardize their application methods. An Aβ imaging agent with excellent in vivo imaging characteristics can evaluate the disease progression and therapeutic efficacy of AD based on PET, helping with the clinical diagnosis of AD. However, since the pathogenesis of AD is still unclear and there are still some deficiencies in existing drugs: poor selectivity for different subtypes of Aβ deposition, lack of an ideal ligand that can specifically bind to the pathological changes of AD brain tissue, etc. Therefore, it is still necessary to develop Aβ imaging agents with more excellent properties, which are expected to solve the problems faced in the early diagnosis of AD. Summary of the Invention

[0005] (1) Technical problem to be solved

[0006] In view of this, one of the main objects of the present invention is to provide a triazole compound having the structure shown in formula (I):

[0007]

[0008] wherein, R1 represents OCH3, N(CH3)2; R2 represents F. The triazole compound provided by the present invention has a high affinity for Aβ plaques in the brain and 18 is F-labeled, and the obtained probe can accurately identify tissue samples containing Aβ plaques.

[0009] (2) Technical solution

[0010] To achieve the above object, the present invention provides a triazole compound having the structure shown in formula (I):

[0011]

[0012] wherein, R1 represents OCH3, N(CH3)2; R2 represents F.

[0013] In one embodiment, R1 further includes NHCH3, F or I.

[0014] In one embodiment, R2 further includes OCH3, N(CH3)2, NHCH3 or I.

[0015] In one embodiment, the triazole compound further includes one or a combination of its pharmaceutically acceptable salts, esters, hydrates, solvates, metabolites, prodrugs, stereoisomers, tautomers, polymorphs and isotope derivatives.

[0016] In one embodiment, the triazole compound is

[0017] In one embodiment, the triazole compound is

[0018] In one embodiment, the triazole compound is

[0019] In one embodiment, the triazole compound is

[0020] In one embodiment, the triazole compound is

[0021] In one embodiment, the triazole compound is

[0022] In one embodiment, the triazole compound is

[0023] In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is In one embodiment, the triazole compound is On the other hand, the present invention also provides a method for preparing the above triazole compound, which includes: S1: Dissolve in an organic solvent to prepare a mixture A;

[0024] S2: Add a reducing agent solution and a chelating agent solution to the mixture A to obtain a mixture B;

[0025] S3: Add solution to the mixture B to carry out a reaction;

[0026] S4: Purify the reaction product in S3 to obtain the above triazole compound.

[0027] In one embodiment, R1 is OCH3, N(CH3)2 or NHCH3, and R2 is I or F.

[0028] In one embodiment, the R2 is OCH3, N(CH3)2 or NHCH3, and R2 is I or F.

[0029] In one embodiment, in S1 and in S2 The molar ratio is 1:3 - 3:1.

[0030] In one embodiment, in S1 and in S2 The molar ratio is 1:1.

[0031] In one embodiment, the dosage of in S1 is 1 - 3 mmol.

[0032] In one embodiment, the The dosage of

[0033] In one embodiment, the organic solvent in S1 includes one or a combination of benzene, toluene, cyclohexane, methanol, ethanol, isopropanol, acetone, and butanone.

[0034] In one embodiment, the organic solvent is ethanol.

[0035] In one embodiment, the concentration of mixture A in S1 is 0.2 - 0.6 mmol / mL.

[0036] In one embodiment, the concentration of mixture A is 0.2 mmol / mL.

[0037] In one embodiment, the reducing agent in S2 is selected from one or a combination of bisulfites, formamidine sulfinic acid, diaminodisulfonates, or suitable metal reducing agents such as Sn(II), Fe(II), Cu(I), Ti(III), or Sb(III).

[0038] In one embodiment, the reducing agent is anhydrous copper sulfate.

[0039] In one embodiment, the chelating agent is selected from one or a combination of oxalic acid, malonic acid, succinic acid, maleic acid, phthalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, or pyrophosphates and other phosphorus compounds of these acids; or enolates.

[0040] In one embodiment, the chelating agent is ascorbic acid.

[0041] In one embodiment, S2 further includes stirring at room temperature for 10 min.

[0042] In one embodiment, in S3 The dosage of

[0043] In one embodiment, the The dosage of

[0044] In one embodiment, the The solvent of the solution includes one or a combination of benzene, toluene, cyclohexane, methanol, ethanol, isopropanol, acetone, and butanone.

[0045] In one embodiment, the solvent is ethanol.

[0046] In one embodiment, the The concentration of the solution is 0.2 - 0.6 mmol / mL.

[0047] In one embodiment, the The concentration of the solution is 0.2 mmol / mL.

[0048] In one embodiment, the solution is added under the stirring condition of mixture B in S2.

[0049] In one embodiment, the reaction conditions in S3 are as follows: reaction time is 10 min, reaction temperature is 25 °C, and reaction pressure is 101.325 kPa.

[0050] In one embodiment, the purification in S4 includes vacuum distillation and suction filtration washing.

[0051] In one embodiment, the detergent is deionized water.

[0052] In one embodiment, the F is 18 F; and / or the I is 125 I.

[0053] In one embodiment, the triazole compound is

[0054] In one embodiment, the triazole compound is

[0055] In one embodiment, the triazole compound is

[0056] In one embodiment, the triazole compound is

[0057] On the other hand, the present invention also provides a pharmaceutical composition, which comprises:

[0058] (1) The above-mentioned triazole compound;

[0059] (2) A pharmaceutically or immunologically acceptable carrier or excipient.

[0060] On the other hand, the present invention also provides a pharmaceutical preparation, which comprises the above-mentioned pharmaceutical composition.

[0061] On the other hand, the present invention also provides a diagnostic composition for amyloid deposit imaging, which comprises the above-mentioned triazole compound.

[0062] On the other hand, the present invention also provides a diagnostic preparation, which comprises the above-mentioned diagnostic composition.

[0063] On the other hand, the present invention also provides a method for imaging amyloid protein deposits, which comprises:

[0064] a. Introduce a detectable amount of the above-mentioned diagnostic composition and / or diagnostic preparation into the subject;

[0065] b. Bind the labeled compound to amyloid deposits;

[0066] c. Detect the labeled compound associated with one or more amyloid deposits.

[0067] In another aspect, the present invention also provides the use of the above-mentioned triazole compound, pharmaceutical composition and / or pharmaceutical preparation in the preparation of a drug for inhibiting amyloid plaque aggregation.

[0068] (III) Beneficial effects

[0069] The present invention provides a triazole compound having the structure shown in formula (I):

[0070]

[0071] Wherein, R1 represents OCH3, N(CH3)2; R2 represents F.

[0072] Compared with the prior art, the following beneficial effects are achieved:

[0073] 1. The provided preparation method is simple to operate, the reaction is rapid, there are fewer by-products, and it is easy to separate and purify.

[0074] 2. In vitro competitive binding experiments show that this type of molecule has a very high affinity for Aβ 1-42 aggregates; in vitro autoradiography experiments show that 125 the I-labeled product and 18 the F-labeled product can specifically bind to Aβ plaques in AD human brain slices and the brains of AD transgenic mice; in vivo biodistribution experiments in normal mice show that 18 F]-1.6 and 18 F]-1.21 have the advantages of high initial brain uptake and fast clearance.

[0075] (IV) Terms and definitions

[0076] As used herein, the term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound having one or more (e.g., one, two, three, or four) asymmetric centers, it can give rise to a racemic mixture, a single enantiomer, a mixture of diastereoisomers, and individual diastereoisomers. A particular individual molecule can also exist as a geometric isomer (cis / trans).

[0077] The pharmaceutically acceptable salts of the compounds disclosed in the present invention include their acid addition salts and base addition salts.

[0078] The compounds disclosed in the present invention form pharmaceutically acceptable acid or base addition salts with a variety of organic and inorganic acids and bases, and include physiologically acceptable salts commonly used in medicinal chemistry. Such salts are also part of the present invention. Typical inorganic acids used to form such salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphoric acid, etc. Salts derived from aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids of organic acids can also be used. Therefore, such pharmaceutically acceptable salts include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, β-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, maleate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate, etc. Preferred salts are hydrochloride, hydrobromide, citrate and oxalate.

[0079] Typical bases used to form pharmaceutically acceptable addition salts can be inorganic bases, such as bases of sodium, potassium, lithium, calcium, aluminum, ammonium, barium, zinc, magnesium, etc. Additionally, organic bases can be used to form salts, such as N,N'-dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, triethylamine, dimethylamine, procaine salts, etc. Salts of amino acids, such as arginine salts, etc. are also included.

[0080] Pharmaceutically acceptable acid or base salts are generally formed by reacting the compound of formula (I) with an equimolar or excess amount of acid or base in a neat solvent or in a suitable inert solvent. The salts formed are further processed and purified by known methods.

[0081] As used herein, the term "ester" means an ester derived from the compounds of each general formula in the present application, which includes physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acids or alcohols). The compounds disclosed in the present invention themselves can also be esters.

[0082] The compounds disclosed by the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly water, methanol or ethanol for example, as a structural element of the crystal lattice of the compound. The amount of the polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio.

[0083] Also included within the scope of the present invention are metabolites of the compounds disclosed by the present invention, i.e., substances formed in vivo when the compounds disclosed by the present invention are administered. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, de-esterification, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by a method of contacting a compound of the present invention with a mammal for a time sufficient to produce its metabolite.

[0084] The compounds disclosed by the present invention may be in the form of prodrugs. Prodrugs are generally pharmacologically inactive derivatives of the parent drug molecule, which require spontaneous or enzymatic conversion in vivo to release the active drug and which have superior pharmacokinetic properties compared to the parent drug molecule. Accordingly, prodrugs of the compounds of general formula (I) have groups that are chemically or metabolically cleavable and that are readily subject to chemical change under physiological conditions to provide the compounds of formula (I) in vivo. Prodrugs include conjugates obtained by binding a compound of formula (I) and a sugar moiety with an appropriate spacer, alkyl esters obtained by reacting a parent acidic compound with an appropriate alcohol, or amides obtained by reacting a parent acidic compound with an appropriate amine.

[0085] The labeled compound may be administered to a patient by a general or local route of administration. For example, the compound may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), intracisternally, vaginally, intraperitoneally, intravesically, locally (powder, ointment or drops) or as an oral or nasal spray. The labeled compound may be administered to a patient to effect its delivery throughout the body. Alternatively, the labeled compound may be administered to a particular organ or tissue of interest. For example, it is desirable to localize and quantify amyloid deposits in the brain to diagnose or track the progression of Alzheimer's disease in a patient. One of the most desirable properties of a brain in vivo imaging agent is the ability to cross the intact blood-brain barrier following intravenous bolus injection.

[0086] As used herein, the term "derivative" may include any salt, hydrate and solvate prepared by the methods customarily applied.

[0087] As used herein, the term "isotope derivative" means a compound that is identical to the compounds disclosed by the present invention, except that one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D,2 H), tritium (T, 3 H)); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g., 36 Cl); isotopes of fluorine (e.g., 18 F); isotopes of iodine (e.g., 123 I and 125 I); isotopes of nitrogen (e.g., 13 N and 15 N); isotopes of oxygen (e.g., 15 O, 17 O, and 18 O); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g., 35 S). Certain isotopically labeled compounds disclosed herein can be used in drug and / or substrate tissue distribution studies (e.g., assays).

[0088] As used herein, the term "tissue" refers to a part of a patient's body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries. A detectable amount is the amount of the labeled compound necessary to be detected by the selected detection method. The amount of the labeled compound introduced into the patient's body for detection can be readily determined by one of ordinary skill in the art. For example, the amount of the labeled compound can be increased in the patient until the compound is detected by the selected detection method. A label is introduced into the compound to provide for detection of the compound.

[0089] As used herein, the term "patient" refers to humans and other animals. One of ordinary skill in the art is also familiar with determining the amount of time sufficient for the compound to bind to amyloid deposits. By introducing a detectable amount of 125 I]-1.7, 125 I]-1.8, 18 F]-1.6, and 18 F]-1.21 into the patient's body and then detecting the labeled compound at different times after administration, the amount of time required can be readily determined.

[0090] As used herein, the term "binding" refers to the chemical interaction between the labeled compound and the amyloid deposit. Examples of binding include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complexes.

[0091] One of ordinary skill in the art is familiar with various methods for detecting labeled compounds. For example, magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT) can be used to detect radiolabeled compounds. The label introduced into the compound will depend on the detection method desired. Brief Description of the Drawings

[0092] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0093] Figure 1 It is a synthetic route diagram of triazole compounds 1.6 - 1.12, 1.19 - 1.21.

[0094] Figure 2 It is a triazole compound 125 Preparation diagram of I - labeled precursor 1.22 - 1.23.

[0095] Figure 3 It is a triazole compound 18 Preparation diagram of F - labeled precursor 1.24 - 1.25.

[0096] Figure 4 It is 125 Preparation diagram of I - labeled triazole compound.

[0097] Figure 5 It is 18 Preparation diagram of F - labeled triazole compound.

[0098] Figure 6 It is the affinity constant of the compound with Aβ 1-42 aggregates.

[0099] Figure 7 It is 125 Autoradiography results of [I] - 1.7 with brain sections of AD patients and AD transgenic mice.

[0100] Figure 8 It is 125 Autoradiography results of [I] - 1.8 with brain sections of AD patients and AD transgenic mice.

[0101] Figure 9 It is 18 Autoradiography results of [F] - 1.6 with brain sections of AD patients and AD transgenic mice.

[0102] Figure 10 It is 18 Autoradiography results of [F] - 1.21 with brain sections of AD patients and AD transgenic mice.

[0103] In the figure:

[0104] A is a brain slice of an AD patient; B is a brain slice of a transgenic AD mouse; C is a brain slice of a normal human; D is a brain slice of a normal mouse. Detailed implementation manners

[0105] To make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Apparently, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0106] As used herein, "comprising", "having" or "including" include "containing", "consisting essentially of", "consisting substantially of", and "consisting of"; "consisting essentially of", "consisting substantially of" and "consisting of" are subordinate concepts of "comprising", "having" or "including".

[0107] The experimental methods used in the following embodiments are all conventional methods unless otherwise specified, and the reagents, methods and equipment used are all conventional reagents, methods and equipment in the technical field of the present invention unless otherwise specified.

[0108] Example 1

[0109] Synthesize intermediate 1.1:

[0110] Add p-methoxyaniline (372.2 mg, 3 mmol) and 10 mL of water to a 250 mL round-bottom flask to obtain a reaction mixture. Add HCl (522 μL, 6.3 mmol) to the reaction mixture that is vigorously stirred in an ice-water bath for reaction. After 30 minutes, add a freshly prepared 5 mL aqueous solution of NaNO2 (216 mg, 0.10 mmol) dropwise while maintaining the internal temperature at 0 - 5 °C, and stir for 10 minutes to obtain a reaction solution. Dissolve freshly prepared sodium azide (300 mg, 4.5 mmol) in 10 mL of water, slowly add it dropwise to the reaction solution, then stir at 0 °C for 30 minutes, and then stir at room temperature for 3 hours for reaction. After the reaction is completed, extract with ethyl acetate (3 × 15 mL). The combined organic phases are dried over anhydrous magnesium sulfate, the desiccant is filtered off, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to obtain 282.0 mg of a brown oily product with a yield of 63.1%.

[0111] Characterization is as follows:

[0112] 11H NMR (600 MHz, DMSO-d6) δ 7.06 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H).

[0113] The structural formula of Intermediate 1.1 is:

[0114] Example 2

[0115] Synthesize Intermediate 1.2:

[0116] Intermediate 1.2 was prepared according to the method of Intermediate 1.1 (using 4-aminophenol instead of methoxyaniline as the reaction raw material), and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to obtain 1069.2 mg of a yellow solid product with a yield of 72.3%.

[0117] Characterization is as follows:

[0118] 1H NMR (600 MHz, Chloroform-d) δ 8.25 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H).

[0119] The structural formula of Intermediate 1.2 is:

[0120] Example 3

[0121] Synthesize Intermediate 1.3:

[0122] Intermediate 1.3 was prepared according to the method of Intermediate 1.1 (using N,N-dimethyl-p-phenylenediamine instead of methoxyaniline as the reaction raw material), and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to obtain 73.7 mg of a brown solid product with a yield of 45.4%.

[0123] Characterization is as follows:

[0124] 1H NMR (400 MHz, Chloroform-d) δ 6.92 (d, J = 2.9 Hz, 2H), 6.75 (s, 2H), 2.94 (q, J = 2.8 Hz, 6H).

[0125] The structural formula of Intermediate 1.3 is:

[0126] Example 4

[0127] Synthesize Intermediate 1.4:

[0128] Intermediate 1.4 was prepared according to the method of Intermediate 1.1 (using 4-fluoroaniline instead of methoxyaniline as the reaction raw material), and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to obtain 589.1 mg of a brown oily product with a yield of 71.6%.

[0129] Characterization is as follows:

[0130] 1H NMR (600 MHz, Chloroform-d) δ 7.05 (t, J = 8.6 Hz, 2H), 6.98 (dd, J = 9.1, 4.5 Hz, 2H).

[0131] The structural formula of Intermediate 1.4 is:

[0132] Example 5

[0133] Synthesize Intermediate 1.5:

[0134] Intermediate 1.5 was prepared according to the method of Intermediate 1.1 (using 4-iodoaniline instead of methoxyaniline as the reaction raw material), and purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to obtain 6 18 .0 mg of a brown oily product with a yield of 84.0%.

[0135] Characterization is as follows:

[0136] 1H NMR (600 MHz, Chloroform-d) δ 7.63 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H).

[0137] The structural formula of Intermediate 1.5 is:

[0138] Example 6

[0139] Synthesize Compound 1.6:

[0140] Add 4-fluorophenylacetylene (122.6 mg, 1 mmol) and 5 mL of ethanol to a 100 mL round-bottom flask, dropwise add a freshly prepared aqueous solution of 3 mL of anhydrous copper sulfate (101.1 mg, 0.4 mmol) and an aqueous solution of 5 mL of sodium ascorbate (403.0 mg, 2 mmol), and stir at room temperature for 10 minutes. While stirring, add Compound 1.1 (150.7 mg, 1 mmol) dissolved in ethanol to the reaction solution. After 10 minutes, the reaction is complete. After removing ethanol by rotary evaporation under reduced pressure, filter by suction and wash with 200 mL of deionized water. Dry the obtained compound to obtain 196.9 mg of a yellow solid product with a yield of 73.1%.

[0141] Characterization is as follows:

[0142] 1H NMR (400 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.88 (dd, J = 8.8, 5.3 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H).

[0143] HRMS: m / z calcd for [C 15 H 12 FN3O] + 269.0964, found 270.1035.

[0144] The structural formula of Compound 1.6 is:

[0145] Example 7

[0146] Synthesize Compound 1.7:

[0147] Compound 1.7 was prepared according to the method of Compound 1.6 (using 4-iodophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and 635.7 mg of yellow solid product was obtained with a yield of 48.4%.

[0148] Characterization is as follows:

[0149] 1H NMR (600 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.67 (dd, J = 13.3, 8.7 Hz, 4H), 7.05 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H).

[0150] HRMS: m / z calcd for [C 15 H 12 IN3O] + 377.0025, found 378.0093.

[0151] The structural formula of Compound 1.7 is:

[0152] Example 8

[0153] Synthesize Compound 1.8:

[0154] Compound 1.8 was prepared according to the method of Compound 1.6 (using 4-iodophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and 102.6 mg of yellow solid product was obtained with a yield of 52.6%.

[0155] Characterization is as follows:

[0156] 1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.72 (dd, J = 16.0, 8.8 Hz, 4H), 6.88 (d, J = 9.1 Hz, 2H), 2.99 (s, 6H).

[0157] HRMS: m / z calcd for [C 16 H 15 IN4] + 390.0341, found 391.0406.

[0158] The structural formula of Compound 1.8 is:

[0159] Example 9

[0160] Synthesize Compound 1.9:

[0161] Compound 1.9 was prepared according to the method of Compound 1.6 (using 4-methoxyphenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and 46.9 mg of a white solid product was obtained with a yield of 17.4%.

[0162] Characterization is as follows:

[0163] 1H NMR (600 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.99 (dd, J = 8.0, 4.5 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.50 (s, 2H), 7.07 (d, J = 8.0 Hz, 2H), 3.81 (s, 3H).

[0164] HRMS: m / z calcd for [C 15 H 12 FN3O] + 269.0964, found 270.1037.

[0165] The structural formula of Compound 1.9 is:

[0166] Example 10

[0167] Synthesize Compound 1.10:

[0168] Compound 1.10 was prepared according to the method of Compound 1.6 (using 4-dimethylaminophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and 4.8 mg of a white solid product was obtained with a yield of 85.0%.

[0169] Characterization is as follows:

[0170] 1H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 7.98 (dd, J = 8.9, 4.7 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 8.7 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 2.96 (s, 6H).

[0171] HRMS: m / z calcd for [C 16 H 15 FN4] + 282.1281, found 283.1350.

[0172] The structural formula of compound 1.10 is:

[0173] Example 11

[0174] Synthesize compound 1.11:

[0175] Compound 1.11 was prepared according to the method of compound 1.6 (using 4-methoxyphenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and 330.2 mg of yellow solid product was obtained with a yield of 87.5%.

[0176] Characterization is as follows:

[0177] 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 7.99 (d, J = 8.6 Hz, 3H), 7.86 (d, J = 8.6 Hz, 3H), 7.77 (d, J = 8.2 Hz, 3H), 7.07 (d, J = 8.7 Hz, 3H), 3.81 (s, 4H).

[0178] HRMS: m / z calcd for [C 15 H 12 IN3O] + 377.0025, found 378.0091.

[0179] The structural formula of compound 1.11 is:

[0180] Example 12

[0181] Synthesize compound 1.12:

[0182] Compound 1.12 was prepared according to the method of compound 1.6 (using 4-dimethylaminophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and 303.8 mg of yellow solid product was obtained with a yield of 77.9%.

[0183] Characterization is as follows:

[0184] 1H NMR (400 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.6 Hz, 2H), 6.85 (s, 2H), 3.03 (s, 6H).

[0185] HRMS: m / z calcd for [C 16 H 15 IN4] + 390.0341, found 391.0406.

[0186] The structural formula of Compound 1.12 is:

[0187] Example 13

[0188] Synthesize Compound 1.13:

[0189] Compound 1.13 was prepared according to the method of Compound 1.6 (using 4-bromophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material) and was used directly in the next reaction without further purification.

[0190] The structural formula of Compound 1.13 is:

[0191] Example 14

[0192] Synthesize Compound 1.14:

[0193] Compound 1.14 was prepared according to the method of Compound 1.6 (using 4-bromophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material) and was used directly in the next reaction without further purification.

[0194] The structural formula of Compound 1.14 is:

[0195] Example 15

[0196] Synthesize Compound 1.15:

[0197] Compound 1.15 was prepared according to the method of Compound 1.6 (using Intermediate 1.2 instead of Intermediate 1.1 as the reaction raw material) and was used directly in the next reaction without further purification.

[0198] The structural formula of Compound 1.15 is:

[0199] Example 16

[0200] Synthesize Compound 1.16:

[0201] Compound 1.16 was prepared according to the method of Compound 1.6 (using 4-nitrophenylacetylene instead of 4-fluorophenylacetylene as the reaction raw material), and was directly used in the next reaction without further purification.

[0202] The structural formula of Compound 1.16 is:

[0203] Example 17

[0204] Synthesize Compound 1.17:

[0205] Weigh Compound 1.15 (51.2 g, 0.18 mmol) into a 250 mL round-bottom flask, add an appropriate amount of anhydrous methanol to dissolve it, stir, add palladium on carbon (10% Pd, 15.0 mg) and 1.5 mL of hydrazine hydrate solution (concentration 85%, W / W), heat under reflux for 1 hour, cool, filter off the palladium on carbon by suction, collect the filtrate, and evaporate the solvent by rotary evaporation to obtain 40.3 mg of the amino intermediate with a yield of 87.9%. Compound 1.17 has a greater polarity and lower lipophilicity compared to Compound 1.15.

[0206] Characterization is as follows:

[0207] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.95 (d, J = 3.1 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.33 (t, J = 8.9 Hz, 2H), 6.71 (d, J = 8.8 Hz, 2H), 5.54 (s, 2H).

[0208] The structural formula of Compound 1.17 is:

[0209] Example 18

[0210] Synthesize Compound 1.18:

[0211] Compound 1.18 was prepared according to the method of Compound 1.17 to obtain 25.0 mg of the amino intermediate with a yield of 92.8%.

[0212] Characterization is as follows:

[0213] 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.95 (dd, J = 8.6, 5.6 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.32 (t, J = 8.9 Hz, 2H), 6.71 (d, J = 8.7 Hz, 2H), 5.53 (s, 2H).

[0214] The structural formula of Compound 1.18 is:

[0215] Example 19

[0216] Synthesize compound 1.19:

[0217] Dissolve amino intermediate 1.17 (40.5 mg, 0.16 mmol) in 10 mL of methanol, and then add paraformaldehyde (57.6 g, 0.64 mmol) and sodium methoxide (400 μL, 0.32 mmol) in sequence. Heat under reflux in an oil bath at 90 °C for 1 hour. After the reaction solution cools down, slowly add sodium borohydride (80.6 mg, 0.64 mmol), and continue to heat under reflux at 90 °C overnight. After the reaction is completed, adjust the pH of the reaction solution to neutral with 1 M HCl. After removing methanol by reduced pressure distillation, add 100 mL of deionized water to the round-bottom flask, sonicate for half an hour, filter by suction and wash with 200 mL of deionized water. Dry the obtained compound to obtain 33.1 mg of yellow solid product with a yield of 77.1%.

[0218] Characterization is as follows:

[0219] 1H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 1.2 Hz, 1H), 7.96 (dd, J = 8.5, 5.5 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 8.8 Hz, 2H), 6.69 (d, J = 8.9 Hz, 2H), 6.13 (d, J = 5.1 Hz, 1H), 2.74 (d, J = 4.9 Hz, 3H).

[0220] HRMS: m / z calcd for [C 15 H 13 FN4] + 268.2954, found 269.1192.

[0221] The structural formula of compound 1.19 is:

[0222] Example 20

[0223] Synthesize compound 1.20:

[0224] Prepare compound 1.20 according to the method of compound 1.19 to obtain 31.7 mg of yellow solid product with a yield of 74.7%.

[0225] Characterization is as follows:

[0226] 1H NMR (400 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.77 (d, J = 4.6 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.24 (s, 2H), 6.71 (d, J = 8.4 Hz, 2H), 2.90 (s, 3H).

[0227] HRMS: m / z calcd for [C 15 H 13 FN4] + 268.2954, found 269.1192.

[0228] The structural formula of Compound 1.20 is:

[0229] Example 21

[0230] Synthesize Compound 1.21:

[0231] Weigh the amino intermediate 1.17 (39.6 mg, 0.26 mmol) and paraformaldehyde (144 mg, 1.6 mmol) into a 100 mL round-bottom flask, dissolve them with an appropriate amount of glacial acetic acid, stir in an ice-water bath, slowly add sodium cyanoborohydride (92.2 mg, 1.6 mmol), and react overnight at room temperature. After the reaction is completed, slowly add ammonia water to neutralize while stirring in an ice bath, filter by suction, wash with deionized water, and dry to obtain 32.2 mg of a yellow solid product with a yield of 71.3%.

[0232] Characterization is as follows:

[0233] 1H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.87 (dd, J = 8.5, 5.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.14 (t, J = 8.7 Hz, 2H), 6.85 (s, 2H), 3.05 (s, 6H).

[0234] HRMS: m / z calcd for [C 16 H 15 FN4] + 282.1281, found 283.1352.

[0235] The structural formula of Compound 1.21 is:

[0236] Example 22

[0237] Synthesize the labeled precursor 1.22:

[0238] Compound 1.13 (40.4 mg, 0.1 mmol), hexabutylditin (253 μL, 0.4 mmol) and tetrakis(triphenylphosphine)palladium (15 mg, 0.01 mmol) were dissolved in 10 mL of 1,4-dioxane (containing 1 mL of triethylamine), and the mixture was stirred at 110 °C overnight. Palladium carbon was removed by filtration, the filtrate was collected, the solvent was removed by rotary evaporation, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 12 / 1) to obtain 8.4 mg of colorless oily compound 1.22 with a yield of 15.6%.

[0239] Characterization is as follows:

[0240] 1H NMR (600 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.84 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 1.59 (d, J = 14.8 Hz, 4H), 1.54 (ddt, J = 10.4, 8.1, 3.6 Hz, 6H), 1.27 (s, 2H), 1.26–1.20 (m, 5H), 0.88 (t, J = 7.3 Hz, 10H).

[0241] HRMS: m / z calcd for [C 27 H 39 N3OSn] + 540.3390, found 542.2177.

[0242] The structural formula of labeled precursor 1.22 is:

[0243] Example 23

[0244] Synthesis of labeled precursor 1.23:

[0245] Compound 1.23 was prepared according to the method of compound 1.22 to obtain 10.2 mg of yellow solid product with a yield of 18 .4%.

[0246] Characterization is as follows:

[0247] 1H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J = 7.8 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 7.7 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.03 (s, 6H), 1.32 (s, 5H), 1.28–1.20 (m, 11H), 0.92–0.84 (m, 11H).

[0248] HRMS: m / z calculated for + [C28H42N4Sn]

[0249] The structural formula of labeled precursor 1.23 is:

[0250] Example 24

[0251] Synthesize labeled precursor 1.24:

[0252] Dissolve compound 1.13 (99.6 mg, 0.3 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (15.3 mg, 0.03 mmol), bis(pinacolato)diboron (200.4 mg, 0.66 mmol) and potassium acetate (200.2 mg, 1.82 mmol) in 10 mL of 1,4-dioxane, stir and react at 110 °C overnight. Add diatomaceous earth and filter by suction, collect the filtrate, evaporate the solvent by rotary evaporation, and separate by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 12 / 1 / 12) to obtain 103.1 mg of a colorless oily compound 1.22, with a yield of 91.2%.

[0253] Characterization is as follows:

[0254] 1H NMR (600 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.87 (d, J = 5.0 Hz, 4H), 7.60 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 1.33 (s, 12H).

[0255] HRMS: m / z calculated for 21 [C 24 H + [BN3O3]

[0256] The structural formula of labeled precursor 1.24 is:

[0257] Example 25

[0258] Synthesize labeled precursor 1.25:

[0259] Prepare compound 1.25 according to the method of compound 1.24 to obtain 17.2 mg of a yellow solid product, with a yield of 14.5%.

[0260] Characterization is as follows:

[0261] 1H NMR (600 MHz, Chloroform-d) δ 7.89 (q, J = 7.7 Hz, 4H), 6.77 (d, J = 8.6 Hz, 2H), 3.01 (s, 6H), 1.22 (s, 12H).

[0262] HRMS: m / z calcd for [C 22 H 27 BN4O2] + 390.2940, found 391.2296.

[0263] The structural formula of labeled precursor 1.25 is:

[0264] Example 26

[0265] Synthesis of labeled compound 125 I]-1.7:

[0266] Weigh 0.1 mg of labeled precursor 1.22 into a reaction flask and dissolve it in 100 μL of ethanol. Then, successively add 1 μL of 125 I] NaI solution (200 μCi, 2200 Ci / mmol), 1 M hydrochloric acid, and 50 μL of H2O2 aqueous solution (3%). After sealing, react at room temperature for 15 min, add 20 μL of saturated sodium bicarbonate solution to terminate the reaction, and adjust to neutral with an appropriate amount of sodium bicarbonate. The reaction solution is separated by Radio-HPLC to obtain a labeled compound 125 I]-1.7 with a radiochemical purity greater than 98%. The uncorrected radiochemical yield is approximately 86%. The HPLC separation conditions are: Venusil MP C 18 reverse-phase column (4.6 × 250 mm, 5 μm); mobile phase: acetonitrile: water = 70%: 30%; flow rate 1.0 mL / min. The retention time is 10.6 min.

[0267] The structural formula of labeled compound 125 I]-1.7 is:

[0268] Example 27

[0269] Synthesis of labeled compound 125 I]-1.8:

[0270] According to the preparation method of labeled compound 125 I]-1.7, prepare labeled compound 125 I]-1.8 (using labeled precursor 1.23 instead of labeled precursor 1.22). The uncorrected radiochemical yield is approximately 64%. The HPLC separation conditions are: Venusil MP C 18Reverse phase column (4.6×250 mm, 5 μm); Mobile phase: Acetonitrile:Water = 75%:25%; Flow rate 1.0 mL / min. Retention time is 8.6 min.

[0271] Labeled compound 125 The structural formula of

[0272] Example 28

[0273] Synthesis of labeled compound 18

[0274] Weigh 3 mg of labeled precursor 1.24 and dissolve it in 300 μL of n-butanol. Weigh 7 mg of tetrakis(pyridine)copper(II) trifluoromethanesulfonate and dissolve it in N,N-dimethylacetamide. Add it to a water-free reaction tube containing a certain activity of TEAB 18 containing 18 18 18 and perform enrichment of the 18 18 F-labeled product, wash away salts and remaining

[0275] Labeled compound 18 The structural formula of

[0276] Example 29

[0277] Synthesis of labeled compound 18

[0278] According to the preparation method of labeled compound 18 18 prepare labeled compound 18 ​​​​​​​

[0279] Labeled compound 18 The structural formula of [¹⁸F]-1.21 is:

[0280] Example 30

[0281] Competitive binding experiment:

[0282] Prepare 4 L of PBS (0.2 M) buffer solution with pH = 7.4; the radioligand 125 [¹²⁵I]IMPY is prepared according to the existing method. Add 125 [¹²⁵I]IMPY to prepare an aqueous solution of 2 μCi / 3 mL; prepare a series of ethanol solutions of the test compound with concentrations from 10 -3 to 10 -9 mol / L; the receptor Aβ 1-42 protein is prepared according to the existing method and diluted into an aqueous solution of about 60 nM; soak the glass fiber filter membrane in PBS solution containing 0.1% (volume fraction) polyethyleneimine for 0.5 h; add 100 μL of test compound solutions with different concentrations, 100 μL of 125 [¹²⁵I]IMPY solution, 700 μL of PBS and 100 μL of Aβ 1-42 solution into 12×75 mm borosilicate glass tubes respectively. Seal with a sealing film and vortex; incubate with shaking in a constant temperature water bath at 37 °C for 2 h; collect the reaction solution with a multiple cell harvester and wash it three times with PBS, 3 mL each time.

[0283] Measure the counts with a γ counter; analyze and process the data using GraphPad Prism 8.3.0, obtain the IC50 value from the counts corresponding to the gradient concentrations, and calculate the affinity constant Ki using the Cheng-Prusoff equation (equation 1);

[0284] K i = IC50 / (1 + [L] / K d )(equation 1)

[0285] Where [L] and Kd are respectively 125 the concentration of [¹²⁵I]IMPY and the dissociation constant of IMPY.

[0286] The half-inhibition constant (IC50) obtained from the competitive binding experiment and the further calculated inhibition constant results are as Figure 6 shown, 1.7 and 1.8 with Aβ 1-42The aggregates have a high affinity. Considering the inhibitory activity of the compounds, through comparative analysis, the half-maximal inhibitory concentration (IC50) value of compound 1.10 is 72.9 nM, while the IC50 values of compounds 1.6 and 1.21 reach 63.4 nM and 45.3 nM respectively, indicating that compounds 1.6 and 1.21 have more advantages in terms of inhibitory activity. At the same time, considering various factors such as the inhibition constants of the corresponding iodine compounds, compounds 1.6 and 1.21 were finally selected for the synthesis of the corresponding precursors.

[0287] Example 31

[0288] Autoradiography experiment:

[0289] Immerse the brain slices of AD transgenic mice and human AD brain slices in xylene for 2 minutes for dewaxing, and then continue to immerse them in absolute ethanol for 1 minute; cover 100 μL of 125 I]-1.7, 125 I]-1.8, 18 F]-1.6 and 18 F]-1.21 solution on the brain slices of AD transgenic mice or human AD brain slices respectively, and incubate at room temperature for 60 minutes. Rinse with 40% ethanol solution for 5 minutes and rinse with running water for 5 minutes; after drying, wrap with plastic wrap and expose to a phosphor screen for 120 minutes, and collect and analyze the images with a storage phosphor screen system.

[0290] The experimental results are as Figures 7 - 10 shown, fully demonstrating that the compounds of the present invention can be used as imaging agents for Aβ plaques after being labeled with radionuclides and applied in clinical diagnosis.

[0291] Example 32

[0292] In vivo distribution experiment:

[0293] Inject 5 - 10 μCi of labeled compound (100 μL of normal saline solution containing 5% ethanol) into the tail vein of normal mice (ICR, male, 20 - 22 g, 5 weeks old) (n = 5). Decapitate and sacrifice them at 2 minutes and 60 minutes after injection respectively, dissect and take out the relevant organs, and measure the wet weight and radioactivity count. The data are expressed as the percentage of radioactive dose in the organ (%ID / organ) and the percentage of radioactive dose per gram of organ (%ID / g).

[0294] The experimental results are shown in Table 1 - 2. The 125 I]-1.7, 125 I]-1.8, 18 F]-1.6 and 18 F]-1.21 provided by the present invention can all cross the blood - brain barrier. Especially 18The initial brain uptake of F]-1.21 was relatively high, reaching 7.62% ID / g, 18 The clearance of F]-1.6 in the brains of normal mice was rapid, and the brain uptake ratio at 2 minutes to 60 minutes was 14.84.

[0295] Table 1. 125 I]-1.7 and 125 The biodistribution experiment of I]-1.8 in normal mice

[0296]

[0297]

[0298] Where a represents the radioactive uptake value of each organ, with the unit of % ID / g, mean ± SD, n = 5; b represents the radioactive uptake values of the stomach and small intestine, with the unit of % ID.

[0299] Table 2. 18 F]-1.6 and 18 The biodistribution experiment of F]-1.21 in normal mice

[0300]

[0301]

[0302] Where a represents the radioactive uptake value of each organ, with the unit of % ID / g, mean ± SD, n = 5; b represents the radioactive uptake values of the stomach and small intestine, with the unit of % ID.

[0303] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or also includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising a..." does not exclude the existence of additional identical elements in the process, method, article or device comprising the said element.

[0304] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A triazole compound, characterized in that The triazole compound has a structure shown in formula (I); Wherein, R1 represents OCH3, N(CH3)2; R2 represents F.

2. The triazole compound according to claim 1, characterized in that The R1 also includes NHCH3, F or I.

3. The triazole compound according to claim 1, characterized in that The R2 also includes OCH3, N(CH3)2, NHCH3 or I.

4. The triazole compound according to any one of claims 1 to 3, characterized in that The triazole compound also includes one or a combination of pharmaceutically acceptable salts, esters, hydrates, solvates, metabolites, prodrugs, stereoisomers, tautomers, polymorphs and isotopic derivatives thereof.

5. The triazole compound according to claim 4, characterized in that The F is 18 F; and / or said I is 125 I.

6. The triazole compound according to claim 5, characterized in that The triazole compound comprises: One or a combination of the following.

7. A pharmaceutical composition, characterized in that It includes: (1) The triazole compound according to any one of claims 1 to 6; (2) A pharmaceutically or immunologically acceptable carrier or excipient.

8. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the above-mentioned pharmaceutical composition.

9. A diagnostic composition for imaging amyloid deposits, characterized in that It comprises the triazole compound according to any one of claims 1 to 6.

10. Use of the triazole compound according to any one of claims 1 to 6, the pharmaceutical composition according to claim 7 or the pharmaceutical preparation according to claim 8 in the preparation of a drug for inhibiting the aggregation of amyloid plaques.

Images