CN102180780A - Indenone derivative and applications thereof as developing agent and aggregation inhibitor of amyloid protein deposit and neurofibrillary tangle - Google Patents

Abstract

The present invention relates to the use of a compound of general formula (1) or a pharmaceutically acceptable salt, ester, amide or prodrug thereof as an imaging agent and an aggregation inhibitor for amyloid deposits and neurofibrillary tangles, and for Methods for the preparation of marker compounds for imaging, and methods of delivering such compounds to amyloid deposits and neurofibrillary tangles. When such compounds are used as imaging agents for detecting amyloid deposits and neurofibrillary tangles in vivo or in tissues, they need to be labeled with appropriate radioactive isotopes or contrast agents suitable for magnetic resonance detection. The compounds are especially useful in the diagnosis and treatment of patients suffering from amyloid deposition and neurofibrillary tangle diseases, including Alzheimer's disease.

Description

Indanone derivatives and their use as imaging agents and aggregation inhibitors for amyloid deposits and neurofibrillary tangles

field of invention

The present invention relates to a new biologically active compound and its application, a method for diagnosis and treatment using a radioactive isotope or magnetic resonance contrast agent-labeled compound, and a preparation method for the labeled compound.

Background technique

Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset and progressive aggravation. The main clinical manifestations are cognitive decline, irreversible memory loss, disorientation and language dysfunction. Brain tissue autopsy confirmed a large number of senile plaques (Senile plaques, SPs) formed by amyloid-β (Aβ) peptide aggregation and many neurofibrillary tangles (neurofibrillary tangles) formed by filaments of hyperphosphorylated tau protein, NFTs), and the loss of neurons and synapses, etc., the amyloid deposits mentioned in the present invention include but are not limited to senile plaques.

Senile plaques and neurofibrillary tangles composed of amyloid deposits, as two markers of AD, are also the gold standard for diagnosis of AD by clinical autopsy or biopsy. Currently, methods for the detection of amyloid deposits and neurofibrillary tangles mainly include biopsy and histological analysis of autopsy material. These two methods have obvious defects: biopsy has greater trauma and risk, and autopsy can only be used for postmortem diagnosis. Therefore, a simple, effective and non-invasive method to detect and quantify amyloid deposits in patient brains would be useful for the diagnosis and treatment of related diseases, especially Alzheimer's disease.

Because amyloid deposits in the brain share many of the same physical properties (such as density and water content) with normal brain tissue, these deposits are difficult to directly image in vivo. Previous attempts to image amyloid deposits directly (without probes) using magnetic resonance imaging (MRI) and computed tomography (CT) have been unsatisfactory or only under certain favorable conditions to detect amyloid deposits.

Some classic fluorescent dyes in the past, such as Congo Red (CR), Thioflavin S (ThS), etc., can bind amyloid deposits (senile plaques) and neurofibrillary tangles with high specificity in vitro. If these high-affinity ligands are engineered and labeled with radioisotopes or magnetic resonance contrast agents, and if these labeled ligands can enter brain tissue smoothly, then positron emission tomography (PET), single photon Emission computed tomography (SPECT) or magnetic resonance imaging (MRI) technology can be used to visually detect the distribution and quantification of senile plaques in AD patients, so as to improve the accuracy of diagnosis, and it can also be used for the research and development of anti-Aβ drugs. Treatment provides intuitive evaluation, thereby laying the foundation for early diagnosis.

Ligands for detecting Aβ amyloid deposits in living brains must be able to pass through the blood-brain barrier (Blood-Brain-Barrier, BBB) smoothly. Congo red, Thioflavin S, and Thioflavin T are difficult to pass through the blood-brain barrier due to their large size or charge. Using a ligand with a relatively small molecular size (compared to Congo red) can enhance brain uptake and increase lipophilicity. At present, several potential ligands are mostly based on structural modification of Congo red, Thioflavin T, and Thioflavin S), such as [ ¹¹ C]PIB (Mathis, Wang et al.2003.46: 2740-54; Wang, Klunk et al.2004.24:55-62; Klunk, Lopresti et al.25:10598-606.), [ ¹²³ I]IBOX (Zhuang, Kung et al.28:887-94.), [ ¹²³ I]IMPY (Kung , Hou et al.2002.956:202-10; Zhuang, Kung et al.2003.46:237-43.; Cai, Chin et al.2004.47:2208-18.; Newberg, Wintering et al.2006.47:748-54.), [ ¹⁸ F]FDDNP (Agdeppa, Kepe et al.21: RC189.; Shoghi-Jadid, Small et al. 2002.10: 24-35.; Nordberg 2004.3: 519-27.), [ ¹¹ C]SB-13 (Verhoeff , Wilson et al.2004.12:584-595.; Ono, Wilson et al.2003.30:565-571.; Zhang, Oya et al.2005.48:5980-8.) [ ¹¹ C]-BF-227 (Okamura, Suemoto et al.2005.25:10857-62; Kudo, Okamura et al.2007.48:553-61.), where [ ¹⁸ F]FDDNP, [ ¹¹ C]PIB, [ ¹¹ C]SB-13, [ ¹¹ C]-BF -227, both have been studied clinically using positron emission tomography (PET) in AD patients and age-matched normal elderly. (Shoghi-Jadid, Small et al. 2002.10: 24-35.; Klunk, WE, H. Engler, et al. (2004). 55(3): 306-19.; Verhoeff, NPLG, AAWilson, et al. ( 2004). 12(6): 584-595.; Kudo, Okamura et al. 2007. 48: 553-61.; Nordberg, A. 2007. 20: 398-402.).

The existing targeting ligands are mainly divided into the following categories according to the different binding sites with Aβ amyloid deposits:

1. Analogs of Congo Red and Chrysamine G

Chrysamine G and its derivatives, such as X-34, ISB, BSB, IMSB, and FSB, which are similar in structure to Congo red, can also effectively bind Aβ. However, further studies have shown that although the hydrophobicity of Chrysamine G has increased, the brain absorption is also relatively low. X-34, BSB, ISB and IMSB were prepared by modifying the structure of Chrysamine G. The brain uptake of radioactive iodine-labeled ISB and IMSB is still lower than that of thioflavin-T derivatives, which may be due to the carboxyl group in its structure affecting the ability to pass through the blood-brain barrier.

2. Benzothiazoles (thioflavin T analogues) and stilbenes

In order to improve the brain permeability of Thioflavin T, its molecular structure was modified to obtain several derivatives, such as TZDM, IBOX, IMPY, and 6-OH-BTA-1. Among them, although [ ¹²⁵ I]TZDM and [ ¹²⁵ I]IBOX can bind amyloid, they are cleared slowly in the brain of normal mice, indicating that there may be a high degree of non-specific binding in vivo. [ ¹¹ C]6-OH-BTA-1 (PIB) is a very effective molecular probe material for AD. It has high brain uptake and rapid brain clearance for normal mouse brain. The human brain has a higher uptake than that of AD patients.

[ ¹¹ C]SB-13 of the stilbene class shows potential in detecting senile plaques, it has moderate lipophilicity, and has high initial brain uptake and rapid brain clearance for normal mouse cerebral cortex. Labeled with ¹⁸ F, a fluorine isotope with a longer half-life, studies have shown that this type of compound is also a potential age spot imaging agent.

3. FDDNP class

The non-steroidal anti-inflammatory drugs naproxen and ibuprofen were structurally modified to obtain a neutral lipophilic fluorescent dye DDNP, which was then labeled with fluorine as ¹⁸ FDDNP. The PET results of this radioligand show that it can bind to senile plaques and neurofibrillary tangles, and has high lipophilicity, which makes it easy to pass through the blood-brain barrier. Clinical studies have shown that the PET imaging of AD patients shows that the concentration of ¹⁸ FDDNP is consistent with the position of hypometabolism of ¹⁸ FDG, while the normal control group has no concentration. ¹⁸ FDDNP deficiency is slower to clear from normal brain regions.

Contents of the invention

The present invention provides the use of compounds in the general formula 1-33 of indanone derivatives as imaging agents and inhibitors of amyloid polymers and neurofibrillary tangles, as well as a preparation method of the labeled compound for imaging, It also relates to methods of delivering such compounds to amyloid deposits and neurofibrillary tangles. Such compounds are especially useful in the diagnosis, evaluation and treatment of patients suffering from amyloid aggregation and neurofibrillary tangle diseases, including Alzheimer's disease.

Novel compounds of general formula 1-33 or pharmaceutically acceptable salts, esters, amides or prodrugs thereof:

In the formula,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ independently represent hydrogen, tritium, halogen, -OH, -NH ₂ , NHR ^a , NR ^a R ^b , -COOH, COOR ^a , -NO ₂ , -OC ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl, -CF ₃ , -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl , -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl, -O(CH ₂ ) _m NR ^a R ^b , -CO-NR ^a R ^b or NHCO-R ^a , -Sn(alkyl) ₃ , ⁹⁹ mTc complex ^{, 123} I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, 18 F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino wherein R ^a and R ^b are independent Ground represents hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, m is 1-5;

n is 0-5;

X ₁ , X ₂ , X ₃ , X ₄ independently represent C, O, S, N;

中 

独立地表示为单键、双键或三键；

middle

independently represented as a single bond, double bond or triple bond;

X' represents hydrogen, tritium, halogen, ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br , ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino, Sn(alkyl) ₃ ;

Q represents a substituted or unsubstituted aromatic or heterocyclic ring;

B and D are independently expressed as C, N, O;

A means C, O, S, N;

Z ₁ represents hydrogen, tritium, halogen, -OH, -NH ₂ , -NHR ^a , -NR ^a R ^b , -COOH, -COOR ^a , -NO ₂ , -OC _1-12 alkyl, C _1-12 alkane -CF3, -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl group, -O(CH ₂ ) _m NR ^a R ^b , -CONR ^a R ^b or NHCOR ^a , Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N , ¹⁵ O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino; wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, and m is 1-5.

The present invention also provides a diagnostic composition comprising a compound of formula 1-33 as a radiolabel or magnetic resonance contrast agent and a pharmaceutically acceptable carrier, excipient or diluent.

The present invention also provides the use and method of using the diagnostic composition as an imaging agent for amyloid deposits and neurofibrillary tangles. Acceptable salts, esters, amides or prodrugs are introduced into mammals or patients, and after a certain period of time, they are combined with protein deposits and neurofibrillary tangles, and then imaged using corresponding instruments.

The present invention also provides the use and method of use of the compound of general formula 1-33 as an aggregation inhibitor of amyloid deposits and neurofibrillary tangles, the method of use comprising administering to a mammal or a patient an inhibitory amount of A compound of general formula 1-33 or a pharmaceutically acceptable salt, ester, amide or prodrug.

When the compound of the general formula 1-33 of the present invention is used as an in vivo imaging agent, it must be labeled with a suitable radioactive isotope or a contrast agent suitable for magnetic resonance detection.

For radiopharmaceutical imaging, the imaging moieties that can be labeled may be based on two classes of isotopes. Commonly used in single photon emission computed tomography (SPECT) such as ⁹⁹ mTc (T _1/2 = 6 hours; 140 KeV) and ¹²³ I (T _1/2 = 13 hours; 159 KeV), or commonly used in positron emitters For tomography (PET), for example, ¹¹ C (T _1/2 = 20 minutes; 511KeV) and ¹⁸ F (T _1/2 = 110 minutes; 511KeV) and the like.

A pharmaceutically acceptable marker compound of general formula 1-33 is usually part of a pharmaceutical composition and administered to a tissue or patient by methods well known to those skilled in the art. For example, the compound can be administered orally, intravenously, intramuscularly, subcutaneously, rectally, intracisternally, intravaginally, intraperitoneally, intravesically, topically (powder, ointment or drops), or as a buccal or nasal spray, etc. Drug administration.

Administration of a labeled compound to a patient may be by systemic or local routes of administration. For example, a labeled compound can be administered in a system that is delivered throughout the body of the patient. Labeled compounds may also be administered to specific organs or tissues of interest. For example, localizing and quantifying amyloid deposits in the brain to diagnose or track the progression of Alzheimer's disease.

Compounds of general formula 1-33, if they can form stable chelates with metals, and if the chelates thus formed are sufficiently stable as radiological or magnetic resonance imaging diagnostic agents, can be administered as such or stored until their use. The diagnostic agent may contain optional additives such as pH control agents (eg, acids, bases, buffers), stabilizers (eg, vitamin C) or isotonic agents (eg, sodium chloride), if necessary.

In addition to being a pathological feature in Alzheimer's disease, amyloid deposits are also associated with the following diseases: Scrapie, Creutzfeldt-Jakob disease (CJD Creutzfeldt-Jakob disease), Kuru disease disease), Down's syndrome, type II diabetic insulinoma, bone marrow carcinoma of the thyroid, idiopathic myeloma, Mediterranean fever, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloid disease, Muckle - Wells syndrome, hereditary cerebral hemorrhage with amyloidosis, isolated atrial amyloid, inclusion body myositis, and beta2-amyloid deposits in muscular dystrophy, among others.

In addition to being a pathological feature in Alzheimer's disease, neurofibrillary tangles have been associated with:

Pick's disease, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, chronic traumatic encephalopathy (dementia pugilistica), frontotemporal dementia, Lytico-Bodig disease, tangle predominance Dementia, ganglioglioma, gangliocytoma, meningeal angiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, etc.

The term "alkyl" as used herein by itself or as part of another group refers to straight and branched chain groups of up to 8 carbons, preferably 6 carbons, more preferably 1-4 carbons, such as methyl , ethyl, propyl.

The term "monoalkylamine" as used herein by itself or as part of another group refers to an amino group substituted with one alkyl group as defined above.

The term "dialkylamine" as used herein by itself or as part of another group refers to an amino group substituted with two or more defined alkyl groups.

The term "halo" or "halogen" as used herein by itself or as part of another group refers to fluorine, chlorine, bromine, or iodine.

The term "aromatic ring" as used herein by itself or as part of another group refers to a monocyclic or bicyclic aromatic group containing 6-12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, e.g. Phenyl, naphthyl or tetrahydronaphthyl.

The term heterocycle used in the present invention, unless otherwise specified, represents a stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized. Particularly useful are rings containing one nitrogen or two nitrogen heteroatoms bonded to an oxygen or sulfur. Examples of such heterocyclic groups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, iso Oxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, homopiperidinyl, homopiperazinyl, pyridazinyl, pyrazolyl and pyrazolidinyl, most preferably thiamorpholine group, piperazinyl and morpholinyl.

The term "heteroatom" as used herein means an oxygen atom ("O"), a sulfur atom ("S") or a nitrogen atom ("N"). It is recognized that when the heteroatom is nitrogen, it can form an NR ^a R ^b moiety, wherein R ^a and R ^b independently of each other are hydrogen or C _1-4 alkyl, C _2-4 aminoalkyl, C _1-4 Haloalkyl.

Description of drawings:

Figure 1. Indanone derivative D8L can bind to senile plaques on AD human brain slices. Four adjacent AD human brain sections (paraffin sections of 6 μm thick AD human brain) were stained separately: A. Positive control Congo red (CR), B. Positive control Thioflavin S (ThS), C. D8L, D. Negative blank Control (solvent blank control). The three solid arrows point to landmarks, and the hollow arrows point to senile plaques. A2 is the enlarged picture of the area inside the white box in A1. Bar = 100 μm.

Figure 2. Indanone derivative D8L can bind to neurofibrillary tangles on AD human brain slices. Four adjacent AD human brain sections (paraffin sections of 6 μm thick AD human brain) were stained separately: A. Positive control Congo red (CR), B. Positive control Thioflavin S (ThS), C. D8L, D. Negative blank Control (solvent blank control). The two solid arrows point to landmarks, and the hollow arrows point to neurofibrillary tangles. 3, 4, and 5 in each column are photos of the same slice excited under three fluorescent channels (DAPI, CY3, GFP), and A6, B6, C6, and D6 are the white squares in A4, B5, C5, and D5, respectively. A magnified image of the area inside the frame. Bar = 100 μm.

Figure 3. The results of in vitro autoradiography of radioactive ¹²⁵ I-labeled indanone derivatives [ ¹²⁵ I]D8j and [ ¹²⁵ I]D8L using paraffin sections of AD human brain. a1 and a1-2 are the same AD patient, c1 and c2 are two elderly normal controls. Horizontal rows A, B, and C represent the autoradiographic results of positive controls [ ¹²⁵ I]IMPY, [ ¹²⁵ I]D8j, and [ ¹²⁵ I]D8L, respectively. The solid white arrows show the wrinkled part of the tissue section and the abnormal signal caused by some paraffin residues. The four photos in row A show that there are many senile plaques (A-a1 and A-a1-2) on the brain slices of AD patients, but only a few sporadic ones on the brain slices of normal aged controls (A-c1 and A-c2) plaque. Like the positive control [ ¹²⁵ I]IMPY in row A, the data in rows B and C show that senile plaques that can be labeled by [ ¹²⁵ I]IMPY can also be labeled by [ ¹²⁵ I]D8j and [ ¹²⁵ I]D8L.

Table 1. Ki values after competitive binding of indanone derivatives D8e and D8f using AD human brain homogenate.

Detailed ways

Example 1: Example of labeling method of radioactive isotope

1. ¹¹ C labeling (shown in the following reaction formula):

In a 3 mL V-shaped flask, 1 mg (0.0036 mmol) of compound 2-(4-dimethylamino-benzylidene)-5-hydroxy-1-indanone was dissolved in 400 μL DMSO, 10 mg dry KOH was added, and vortexed for 5 min. [ ¹¹ C]CH ₃ I was bubbled through the solution at 30 mL/min, and the reaction was heated at 95° C. for 5 min. Then, the reaction product was purified by semi-preparative HPLC, Prodigy ODS column, the eluent was 70% acetonitrile/30% triethylamine phosphate buffer (pH7.2), and ^{the 11} C-labeled radioactive compound was collected.

2. ¹²⁵ I labeling (as shown in the following reaction formula):

Sequentially weigh the compound 2-(4-dimethylamino-benzylidene)-5-bromo-1-indanone 400mg (1.17mmol), bistributyltin 4.0g (7.02mmol) and tetrakistriphenylphosphine palladium Pd(PPh ₃ ) ₄ 135mg (0.12mmol), add 8mL dioxane and 2mL Et ₃ N, and heat to reflux reaction for 16h under the protection of nitrogen. Remove the solvent under reduced pressure, put on a silica gel column, pass through the column with petroleum ether: ethyl acetate 8/1, collect the corresponding components, and obtain the product 2-(4-dimethylamino-benzylidene)-5-tributyltin- 1-Indanone (26%). ¹ H NMR (CDCl ₃ ): δ7.82(d, 1H, J=7.5Hz), 7.68-7.64(m, 2H), 7.62-7.59(d, 2H, J=9.0Hz), 7.52(d, 1H , J=7.5Hz), 6.75-6.72(d, 2H, J=9.0Hz), 3.99(s, 2H), 3.04(s, 6H), 1.61-1.51(m, 6H), 1.41-1.29(m, 6H), 1.14-1.08 (m, 6H), 0.90 (t, 9H, J=7.2Hz). 5-SnBu3-G964 IR (cm ^-1 ): 2955, 2925, 1687, 1624, 1595, 1453, 1091, 882.ESI-MS: [M+H] ⁺ 528.28.

At room temperature, add 50 μL 3% H 2 O ₂ to a mixture containing tributyltin precursor compound in ethanol (100 μg/50 μL EtOH), 1.5 mCi [ ¹²⁵ I]NaI (activity 2200 Ci/mmol), 100 μL _1N HCl , react for 10min. The reaction was quenched by adding NaHSO ₃ . The reaction mixture was neutralized with sodium carbonate solution, and extracted with ethyl acetate. The extract was dried through anhydrous sodium sulfate column and blown dry under _N2 . The radioligand was purified by HPLC with a Cosmosil C18 column, the mobile phase was acetonitrile: water (2/3), and the flow rate was 1.0 mL/min. The purified radiolabel was stored at -20°C.

3. ¹⁸ F labeling (shown in the following reaction formula):

Add (E)-2-(4-methylamino-benzylidene)-5,6-dimethoxy-1-indanone 309 mg (1 mmol), 2-bromoethanol 137 mg (1.1 mmol), potassium carbonate 207mg (1.5mmol) and DMF10mL, reflux for 15h. The solvent was removed under reduced pressure and passed through a silica gel column, eluting with dichloromethane:methanol 10/1. Collect the corresponding components to obtain the product.

Weigh 177mg (0.5mmol) of (E)-2-(4-N-methyl, N-hydroxyethylamino-benzylidene)-5,6-dimethoxy-1-indanone and dissolve it in 15mL Anhydrous pyridine, cooled to 0°C, added 137 mg (0.72 mmol) p-toluenesulfonyl chloride under stirring, kept at 0°C for 2 hours, and then reacted at room temperature for 1 hour. Pyridine was removed under reduced pressure, 15 mL of water was added, extracted twice with 15 mL of dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate. Pass through a silica gel column and elute with chloroform:methanol 20/1. Collect the corresponding components to obtain the product.

Dissolve 4 mg of p-toluenesulfonyl precursor in 0.2 mL DMSO and add the dried ¹⁸ F active substance, and heat at 120°C for 4 min. Add 2 mL of water, extract twice with 1 mL of ethyl acetate, combine the organic phases, and dry over anhydrous sodium sulfate. The solvent was purged with argon and the residue was dissolved in acetonitrile and purified by HPLC. Chromatographic conditions: Hamilton PRP-1 column (7.0×305 mm, 10 μm); CH ₃ CN/dimethylglutarate buffer (5 mM, pH 7)=9/1; flow rate=2 mL/min).

Embodiment 2: Design example of complexes

1. Ligand example:

In the ligand structure shown in the above structural formula (1-4), a multi-dentate coordination site is constructed on the benzene ring. This coordination site can be located at other positions of the benzene ring, and can also be moved to the benzene ring connected to indanone superior. In this multidentate coordination region, single bonds can be replaced by carbon-carbon double bonds or triple bonds, and double bonds can also be reduced to single bonds. The heteroatoms therein can be O, N, S, P.

Design example of ferromagnetic complex (shown in the following reaction formula)

Taking the above ligand 1 as an example, prepare the Mn complex (as shown in the following reaction formula)

In 20mL DMF, add bromoethanol 375mg (3mmol), (E)-2-(4-dimethylamino-benzylidene)-5,6-diamino-1-indanone 293mg (1mmol) and carbonic acid Potassium 276mg (2mmol), reacted at 100°C for 4h. Then the solvent was removed under reduced pressure, washed with water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Silica gel column chromatography and eluting with chloroform/methanol (10:1) gave a brown-red solid.

In a solution containing 50 mg (0.13 mmol) of the above-mentioned ligand and 10 mL of methanol, 30 mg (0.14 mmol) of manganese acetate was added, and stirred at room temperature for 1 h. Then, 210 mg (5.2 mmol) of sodium hydroxide was added, followed by stirring overnight. Add 30 mL of water, extract 3 times with 25 mL of benzene, and combine the organic phases. The organic phase was washed with water and dried over anhydrous sodium sulfate. Filter, remove the solvent, concentrate and pass through the column. The target complex was obtained by eluting with petroleum ether/ethyl acetate (3:2), and collecting the corresponding components.

Embodiment three:

A method for synthesizing a series of derivatives using indanone as a raw material, wherein D8a-c, D8e-h, D8l and D8m can be easily obtained by base catalysis, and the operation is simple and the yield is high. D8d can be obtained by reducing D8c under the catalysis of SnCl2 2H2O, and D8h and D8j can be refluxed with (Bu3Sn)2 under the catalysis of Pd(PPh3)4 in triethylamine to obtain tributyltin substituted products D8i and D8k. D8i reacts with iodine in THF to obtain iodo product D8j. The reaction process is shown in the following reaction formula:

(E)-2-苯亚甲基-5，6-二甲氧基-1-茚酮(D8a)。称取5，6-二甲氧基-1-茚酮192mg(1mmol)和苯甲醛106mg(1mmol)溶于10mL乙醇，在搅拌下滴加10％NaOH水溶液2.2mL，室温搅拌过夜，析出大量黄色沉淀。抽滤，滤饼以乙醇重结晶(产率86％)。(E)-2-苯亚甲基-5，6-二甲氧基-1-茚酮(E)-2-benzylidene-5，6-dimethoxy-1-indanone(D8a).¹H NMR(CDCl₃)：δ7.66-7.64(m，2H)，7.59(s，1H)，7.46-7.43(m，2H)，7.40-7.37(m，1H)，7.33(s，1H)，6.98(s，1H)，4.00(s，3H)，3.96(s，2H)，3.95(s，3H).¹³CNMR(CDCl₃)：δ193.3，155.6，149.8，145.1，135.7，135.6，132.6，131.2，130.7，129.5，129.2，129.1，129.0，107.3，105.2，56.5，56.3，32.3.HRMS：calcd for C₁₈H₁₆O₃ 280.1099，found 280.1092([M]⁺).IR(cm^-1)：3002，2938， 2835，1688，1631，1587，1501，1305，1255，1223，1128，1095，774。

(E)-2-Benzylidene-5,6-dimethoxy-1-indanone (D8a). Weigh 192 mg (1 mmol) of 5,6-dimethoxy-1-indanone and 106 mg (1 mmol) of benzaldehyde in 10 mL of ethanol, add 2.2 mL of 10% NaOH aqueous solution dropwise under stirring, stir overnight at room temperature, and precipitate a large amount of yellow precipitation. After suction filtration, the filter cake was recrystallized from ethanol (yield 86%). (E)-2-benzylidene-5,6-dimethoxy-1-indanone (E)-2-benzylidene-5,6-dimethoxy-1-indanone (D8a). ¹ H NMR (CDCl ₃ ): δ7.66-7.64(m, 2H), 7.59(s, 1H), 7.46-7.43(m, 2H), 7.40-7.37(m, 1H), 7.33(s, 1H), 6.98(s, 1H), 4.00(s, 3H), 3.96(s, 2H), 3.95(s, 3H). ¹³ CNMR(CDCl ₃ ): δ193.3, 155.6, 149.8, 145.1, 135.7, 135.6, 132.6, 131.2, 130.7 , 129.5, 129.2, 129.1, 129.0, 107.3, 105.2, 56.5, 56.3, 32.3. HRMS: calcd for C ₁₈ H ₁₆ O ₃ 280.1099, found 280.1092([M] ⁺ ).IR(cm ^-1 ): 3002, 2938 , 2835, 1688, 1631, 1587, 1501, 1305, 1255, 1223, 1128, 1095, 774.

Embodiment four:

(E)-2-(4-溴-苯亚甲基)-5，6-二甲氧基-1-茚酮(D8b，产率82％)。用和D8a类似的方法，合成了D8b。¹H NMR(CDCl₃)：δ7.57-7.55(m，2H)，7.49-7.47(m，3H)，7.30(s，1H)，6.96(s，1H)，3.99(s，3H)，3.94(s，3H)，3.89(s，2H).¹³C NMR(CDCl₃)：δ193.0，155.7，149.8，144.9，136.2，134.6，132.3，132.2，132.0，131.9，131.8，131.1，123.9，107.2，105.2，56.5，56.3，32.3.HRMS：calcd for C₁₈H₁₅ ⁷⁹BrO₃ 358.0205，found 358.0203([M]⁺)，calcd for C₁₈H₁₅ ⁸¹BrO₃ 360.0184，found 360.0175([M+2]⁺).IR(cm^-1)：3003，2938，2834，1690，1632，1585，1500，1309，1128，1090，1007，796。

(E)-2-(4-Bromo-benzylidene)-5,6-dimethoxy-1-indanone (D8b, 82% yield). In a similar manner to D8a, D8b was synthesized. ¹ H NMR (CDCl ₃ ): δ7.57-7.55 (m, 2H), 7.49-7.47 (m, 3H), 7.30 (s, 1H), 6.96 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.89 (s, 2H). ¹³ C NMR (CDCl ₃ ): δ193.0, 155.7, 149.8, 144.9, 136.2, 134.6, 132.3, 132.2, 132.0, 131.9, 131.8, 131.1, 123.9, 107.2 , 105.2, 56.5, 56.3, 32.3. HRMS: calcd for C ₁₈ H ₁₅ ⁷⁹ BrO ₃ 358.0205, found 358.0203 ([M] ⁺ ), calcd for C ₁₈ H ₁₅ ⁸¹ BrO ₃ 360.0184, found 360.0175 ([M+2] ⁺ ).IR(cm ⁻¹ ): 3003, 2938, 2834, 1690, 1632, 1585, 1500, 1309, 1128, 1090, 1007, 796.

Embodiment five:

(E)-2-(4-硝基-苯亚甲基)-5，6-二甲氧基-1-茚酮(D8c，产率89％)。用和D8a类似的方法，合成了D8c。¹H-NMR(CDCl₃)：δ8.31(d，2H，J＝8.7Hz)，7.79(d，2H，J＝8.7Hz)，7.61(s，1H)，7.36(s，1H)，7.00(s，1H)，4.02(s，3H)，4.01(s，2H)，3.96(s，3H).¹³C NMR(CDCl₃)：δ192.3，156.1，150.0，147.6，144.8，141.9，139.3，130.8，129.4，124.1，107.2，105.3，56.4，56.2，32.1.HRMS：calcd for C₁₈H₁₅NO₅ 325.0950，found 325.0947([M]⁺).IR(cm^-1)：3077，2944，2866，1682，1631，1516，1502，1341，1310，1095，1002，850。

(E)-2-(4-Nitro-benzylidene)-5,6-dimethoxy-1-indanone (D8c, 89% yield). In a similar manner to D8a, D8c was synthesized. ¹ H-NMR (CDCl ₃ ): δ8.31(d, 2H, J=8.7Hz), 7.79(d, 2H, J=8.7Hz), 7.61(s, 1H), 7.36(s, 1H), 7.00 (s, 1H), 4.02 (s, 3H), 4.01 (s, 2H), 3.96 (s, 3H). ¹³ C NMR (CDCl ₃ ): δ192.3, 156.1, 150.0, 147.6, 144.8, 141.9, 139.3 , 130.8, 129.4, 124.1, 107.2, 105.3, 56.4, 56.2, 32.1. HRMS: calcd for C ₁₈ H ₁₅ NO ₅ 325.0950, found 325.0947 ([M] ⁺ ).IR(cm ^-1 ): 3077, 2944, 2866 , 1682, 1631, 1516, 1502, 1341, 1310, 1095, 1002, 850.

Embodiment six:

(E)-2-(4-Dimethylamino-benzylidene)-5,6-dimethoxy-1-indanone (D8e, 80%). In a similar manner to D8a, D8e was synthesized. ¹ H NMR (CDCl ₃ ): δ7.59-7.57 (m, 3H), 7.34 (s, 1H), 6.98 (s, 1H), 6.75-6.73 (m, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 3.92 (s, 2H), 3.05 (s, 6H). IR (cm-1): 2923, 1676, 1596, 1524, 1303, 1122, 1001, 817. ¹³ C NMR (CDCl ₃ ) : δ32.3, 40.1, 56.1, 56.2, 104.9, 107.1, 111.9, 123.3, 130.5, 131.6, 132.4, 133.4, 144.3, 149.3, 150.9, 154.6, 193.4. HRMS: cacldfor C ₂₀ H ₂₁ NO ₃ 323f.15 ([M] ⁺ ).

Embodiment seven:

(E)-2-(4-甲氧基-苯亚甲基)-5，6-二甲氧基-1-茚酮(D8f，78％)。用和D8a类似的方法，合成了D8f。¹H NMR(CDCl₃)：δ7.63-7.62(m，2H)，7.57(s，1H)，7.35(s，1H)，6.99-6.97(m，3H)，3.99(s，3H)，3.95-3.94(m，5H)，3.87(s，3H).¹³C NMR(CDCl₃)：δ32.2，55.4，56.2，56.3，105.0，107.2，114.4，128.3，131.2，132.3，133.1，144.7，149.5，155.2，160.6，193.3.HRMS：cacld for C₁₉H₁₈O₄ 310.1205，found 310.1202([M]⁺).IR(cm^-1)：2941，2834，1685，1605，1504，1299，1258，1091，820。

(E)-2-(4-Methoxy-benzylidene)-5,6-dimethoxy-1-indanone (D8f, 78%). In a similar manner to D8a, D8f was synthesized. ¹ H NMR (CDCl ₃ ): δ7.63-7.62 (m, 2H), 7.57 (s, 1H), 7.35 (s, 1H), 6.99-6.97 (m, 3H), 3.99 (s, 3H), 3.95 -3.94 (m, 5H), 3.87 (s, 3H). ¹³ C NMR (CDCl ₃ ): δ32.2, 55.4, 56.2, 56.3, 105.0, 107.2, 114.4, 128.3, 131.2, 132.3, 133.1, 144.7, 149.5 , 155.2, 160.6, 193.3. HRMS: cacld for C ₁₉ H ₁₈ O ₄ 310.1205, found 310.1202 ([M] ⁺ ). IR (cm ^-1 ): 2941, 2834, 1685, 1605, 1504, 1299, 1258, 1091 , 820.

Embodiment eight:

(E)-2-(4-二甲氨基-苯亚甲基)-5-溴-1-茚酮(D8g，产率75％)。用和D8a类似的方法，合成了D8g。¹H NMR(CDCl₃)：δ7.75-7.64(m，3H)，7.58-7.53(m，3H)，6.74-6.71(m，2H)，3.95(s，2H)，3.05(s，6H). ¹³C NMR(CDCl₃)：δ193.0，151.3，151.0，137.7，135.7，132.9，130.9，129.2，128.9，128.6，125.2，122.8，111.9，40.0，32.4.HRMS：calcd for C₁₈H₁₆ ⁷⁹BrNO341.0415，found 341.0417([M]⁺)，calcd for C₁₈H₁₆ ⁸¹BrNO 343.0395，found343.0392([M+2]⁺).IR(cm^-1)：2919，1683，1592，1526，1444，1316，1113，960，882。

(E)-2-(4-Dimethylamino-benzylidene)-5-bromo-1-indanone (D8g, 75% yield). In a similar manner to D8a, D8g was synthesized. ¹ H NMR (CDCl ₃ ): δ7.75-7.64(m, 3H), 7.58-7.53(m, 3H), 6.74-6.71(m, 2H), 3.95(s, 2H), 3.05(s, 6H) . ¹³ C NMR (CDCl ₃ ): δ193.0, 151.3, 151.0, 137.7, 135.7, 132.9, 130.9, 129.2, 128.9, 128.6, 125.2, 122.8, 111.9, 40.0, 32.4. HRMS: calcd for C ₁₈ H ₁₆ ⁷⁹ BrNO341.0415, found 341.0417([M] ⁺ ), calcd for C ₁₈ H ₁₆ ⁸¹ BrNO 343.0395, found343.0392([M+2] ⁺ ).IR(cm ^-1 ): 2919, 1683, 1592, 1526, 1444, 1316, 1113, 960, 882.

Embodiment nine:

(E)-2-(4-二甲氨基-苯亚甲基)-6-溴-1-茚酮(D8h，产率81％)。用和D8a类似的方法，合成了D8h。¹H NMR(CDCl₃)：δ8.00(s，1H)，7.67-7.64(m，2H)，7.57(d，2H，J＝8.8Hz)，7.41(d，1H，J＝8.0Hz)，6.72(d，2H，J＝8.8Hz)，3.91(s，2H)，3.06(s，6H).¹³C NMR(CDCl₃)：δ193.0，151.5，148.0，140.9，136.6，136.2，133.2，129.4，127.7，127.2，123.0，121.8，112.0，40.3，32.6.HRMS：calcd for C₁₈H₁₆ ⁷⁹BrNO 341.0415，found341.0409([M]⁺)，calcd for C₁₈H₁₆ ⁸¹BrNO 343.0395，found 343.0387([M+2]⁺).IR(cm^-1)：2893，1681，1589，1523，1462，1363，1188，1169，1115，810。

(E)-2-(4-Dimethylamino-benzylidene)-6-bromo-1-indanone (D8h, 81% yield). In a similar manner to D8a, D8h was synthesized. ¹ H NMR (CDCl ₃ ): δ8.00 (s, 1H), 7.67-7.64 (m, 2H), 7.57 (d, 2H, J=8.8Hz), 7.41 (d, 1H, J=8.0Hz), 6.72 (d, 2H, J=8.8Hz), 3.91 (s, 2H), 3.06 (s, 6H). ¹³ C NMR (CDCl ₃ ): δ193.0, 151.5, 148.0, 140.9, 136.6, 136.2, 133.2, 129.4, 127.7, 127.2, 123.0, 121.8, 112.0, 40.3, 32.6. HRMS: calcd for C ₁₈ H ₁₆ ⁷⁹ BrNO 341.0415, found 341.0409 ([M] ⁺ ), calcd for C ₁₈ H ₁₆ ⁸¹ BrNO 343.03743, found 3 ([M+2] ⁺ ).IR(cm ⁻¹ ): 2893, 1681, 1589, 1523, 1462, 1363, 1188, 1169, 1115, 810.

Embodiment ten:

(E)-2-(4-二甲氨基-苯亚甲基)-6-碘-1-茚酮(D8L，产率76％)。用和D8a类似的方法，合成了D8L。¹H NMR(CDCl₃)：δ8.20(s，1H)，7.85-7.83(m，1H)，7.63(s，1H)，7.55(d，2H，J＝8.8Hz)，7.30-7.26(m，1H)，6.71(d，2H，J＝8.8Hz)，3.88(s，2H)，3.05(s，6H).¹³C NMR(CDCl₃)：δ192.9，151.5，148.7，142.3，141.1，136.1，133.3，133.1，129.1，128.0，123.0，112.1，92.9，40.3，32.6.HRMS：calcd for C₁₈H₁₆INO 389.0277，found389.0279([M]⁺).IR(cm^-1)：2851，1678，1585，1522，1362，1308，1263，1187，1116，809。

(E)-2-(4-Dimethylamino-benzylidene)-6-iodo-1-indanone (D8L, 76% yield). In a similar manner to D8a, D8L was synthesized. ¹ H NMR (CDCl ₃ ): δ8.20(s, 1H), 7.85-7.83(m, 1H), 7.63(s, 1H), 7.55(d, 2H, J=8.8Hz), 7.30-7.26(m , 1H), 6.71(d, 2H, J=8.8Hz), 3.88(s, 2H), 3.05(s, 6H). ¹³ C NMR(CDCl ₃ ): δ192.9, 151.5, 148.7, 142.3, 141.1, 136.1, 133.3, 133.1, 129.1, 128.0, 123.0, 112.1, 92.9, 40.3, 32.6. HRMS: calcd for C ₁₈ H ₁₆ INO 389.0277, found 389.0279([M] ⁺ ).IR(cm ^-1 ): 2851, 1678, 1585, 1522, 1362, 1308, 1263, 1187, 1116, 809.

Embodiment eleven:

(E)-2-(4-二甲氨基-苯亚甲基)-5-甲氧基-1-茚酮(D8m， 产率85％)。用和D8a类似的方法，合成了D8m。¹H NMR(CDCl₃)：δ7.83(d，1H，J＝8.4Hz)，7.59-7.56(m，3H)，6.99(s，1H)，6.96-6.92(dd，1H，J＝8.4Hz，1.8Hz)，6.74(d，2H，J＝8.7Hz)，3.95(s，2H)，3.90(s，3H)，3.05(s，6H).¹³C NMR(CDCl₃)：δ193.0，164.7，152.2，151.0，133.7，132.5，132.1，130.4，125.7，123.3，114.8，111.9，109.7，55.6，40.1，32.8。

(E)-2-(4-Dimethylamino-benzylidene)-5-methoxy-1-indanone (D8m, 85% yield). In a similar manner to D8a, D8m was synthesized. ¹ H NMR (CDCl ₃ ): δ7.83(d, 1H, J=8.4Hz), 7.59-7.56(m, 3H), 6.99(s, 1H), 6.96-6.92(dd, 1H, J=8.4Hz , 1.8Hz), 6.74(d, 2H, J=8.7Hz), 3.95(s, 2H), 3.90(s, 3H), 3.05(s, 6H). ¹³ C NMR (CDCl ₃ ): δ193.0, 164.7, 152.2, 151.0, 133.7, 132.5, 132.1, 130.4, 125.7, 123.3, 114.8, 111.9, 109.7, 55.6, 40.1, 32.8.

Embodiment 12:

(E)-2-(4-氨基-苯亚甲基)-5，6-二甲氧基-1-茚酮(D8d)的合成：称取200mg(0.61mmol)2-(4-硝基苯亚甲基)-5，6-二甲氧基-1-茚酮(D8c)溶于25mL乙醇，在氮气保护下，加入695mg SnCl₂·2H₂O(3.08mmol)，加热回流反应4h。冷至室温，加入1MNaOH调节pH至弱碱性。以50mL乙酸乙酯萃取，水相再以乙酸乙酯萃取二次，合并有机相，有机相水洗后，无水硫酸钠干燥。过滤，减压除去溶剂，得粗品。过硅胶柱，以石油醚∶乙酸乙酯2/1洗脱，收集相应组分，得目标产物(产率56％)。¹H NMR(CDCl₃)：δ7.52-7.48(m，3H)，7.34(s，1H)，6.97(s，1H)，6.74-6.71(m，2H)，3.99(s，3H)，3.94(s，3H)，3.91(s，2H).¹³C NMR(CDCl₃)：δ193.6，149.6，147.8，144.7，133.2，132.7，115.3，107.3，105.1，56.4，56.3，32.5.HRMS：calcd for C18H17NO3295.1208，found 295.1201([M]⁺).IR(cm^-1)：3427，3348，2929，1671，1578，1499，1304，1130，1099，1004，819。

Synthesis of (E)-2-(4-amino-benzylidene)-5,6-dimethoxy-1-indanone (D8d): Weigh 200mg (0.61mmol) 2-(4-nitro Benzylidene)-5,6-dimethoxy-1-indanone (D8c) was dissolved in 25mL of ethanol, under the protection of nitrogen, 695mg of SnCl ₂ ·2H ₂ O (3.08mmol) was added, and heated to reflux for 4h. After cooling to room temperature, 1M NaOH was added to adjust the pH to slightly alkaline. Extract with 50 mL of ethyl acetate, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phase with water, and dry over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to obtain a crude product. After passing through a silica gel column and eluting with petroleum ether: ethyl acetate 2/1, the corresponding components were collected to obtain the target product (yield 56%). ¹ H NMR (CDCl ₃ ): δ7.52-7.48(m, 3H), 7.34(s, 1H), 6.97(s, 1H), 6.74-6.71(m, 2H), 3.99(s, 3H), 3.94 (s, 3H), 3.91 (s, 2H). ¹³ C NMR (CDCl ₃ ): δ193.6, 149.6, 147.8, 144.7, 133.2, 132.7, 115.3, 107.3, 105.1, 56.4, 56.3, 32.5. HRMS: calcd for C18H17NO3295.1208, found 295.1201([M] ⁺ ).IR(cm ^-1 ): 3427, 3348, 2929, 1671, 1578, 1499, 1304, 1130, 1099, 1004, 819.

Embodiment thirteen:

(E)-2-(4-二甲氨基-苯亚甲基)-5-三丁基锡基-1-茚酮(D8i).依次称取化合物D8g 400mg(1.17mmol)、双三丁基锡4.0g(7.02mmol)和四三苯基膦合钯Pd(PPh₃)₄135mg(0.12mmol)，加入10mLEt₃N，在氮气保护下加热回流反应16h。减压除去溶剂，上硅胶柱，以石油醚∶乙酸乙酯8/1过柱，收集相应组分，得产物D8i 176mg(产率26％)。

(E)-2-(4-dimethylamino-benzylidene)-5-tributyltin base-1-indanone (D8i). Weigh compound D8g 400mg (1.17mmol), bistributyltin 4.0g ( 7.02mmol) and tetrakistriphenylphosphine palladium Pd(PPh ₃ ) ₄ 135mg (0.12mmol), add 10mL Et ₃ N, and heat to reflux for 16h under the protection of nitrogen. The solvent was removed under reduced pressure, put on a silica gel column, passed through the column with petroleum ether: ethyl acetate 8/1, and collected the corresponding components to obtain 176 mg of product D8i (yield 26%).

¹ H NMR (CDCl ₃ ): δ7.82(d, 1H, J=7.5Hz), 7.68-7.64(m, 2H), 7.62-7.59(d, 2H, J=9.0Hz), 7.52(d, 1H , J=7.5Hz), 6.75-6.72(d, 2H, J=9.0Hz), 3.99(s, 2H), 3.04(s, 6H), 1.61-1.51(m, 6H), 1.41-1.29(m, 6H), 1.14-1.08(m, 6H), 0.90(t, 9H, J=7.2Hz).5-SnBu3-G964IR(cm ^-1 ): 2955, 2925, 1687, 1624, 1595, 1453, 1091, 882 .ESI-MS: [M+H] ⁺ 528.28.

Embodiment 14:

用和D8i类似的方法合成化合物(E)-2-(4-二甲氨基-苯亚甲基)-6-三丁基锡基-1-茚酮(D8k).¹H-NMR(CDCl₃)：δ8.01(s，1H)，7.66-7.58(m，4H)，7.53-7.50(m，1H)，6.75-6.72(m，2H)，3.97(s，2H)，3.04(s，6H)，1.58-1.49(m，6H)，1.37-1.30(m，6H)，1.13-1.07(m，6H)，0.89(t，9H，J＝7.2Hz).IR(cm^-1)：2925，1735，1686，1596，1524，1458，1109，882。

Compound (E)-2-(4-dimethylamino-benzylidene)-6-tributyltinyl-1-indanone (D8k) was synthesized by a method similar to D8i. ¹ H-NMR (CDCl ₃ ): δ8.01(s, 1H), 7.66-7.58(m, 4H), 7.53-7.50(m, 1H), 6.75-6.72(m, 2H), 3.97(s, 2H), 3.04(s, 6H), 1.58-1.49(m, 6H), 1.37-1.30(m, 6H), 1.13-1.07(m, 6H), 0.89(t, 9H, J=7.2Hz).IR(cm ^-1 ): 2925, 1735, 1686, 1596, 1524, 1458, 1109, 882.

Embodiment fifteen:

(E)-2-(4-dimethylamino-benzylidene)-5-iodo-1-indanone (D8j). Weigh compound D8i 75mg (0.14mmol) and dissolve in 3mL THF, ice bath, 53mg I ₂ (0.20mmol) dissolved in 2mL THF was added dropwise to the above system. After the dropwise addition, the system continued to react at 0°C for 1h, and then 5mL saturated NaHSO ₃ solution was added to quench the reaction. After adding 5 mL of saturated Na ₂ CO ₃ solution for neutralization, 10 mL of ethyl acetate was used to extract three times, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure, passed through a silica gel column, and eluted with petroleum ether: ethyl acetate 6/1, the corresponding components were collected and spin-dried to obtain D8j as a brown solid (42 mg, yield 52%).

¹ H NMR (CDCl ₃ ): δ7.95(s, 1H), 7.77(m, 1H), 7.66(s, 1H), 7.62-7.58(m, 3H), 6.78(d, 2H, J=7.8Hz ), 3.96(s, 2H), 3.07(s, 6H). ¹³ C NMR (CDCl ₃ ): δ193.6, 151.1, 138.4, 137.0, 135.9, 135.5, 133.1, 125.5, 112.4, 101.9, 40.5, 32.4. HRMS: calcd for C ₁₈ H ₁₆ INO 389.0277, found 389.0271 ([M] ⁺ ). IR (cm ⁻¹ ): 2898, 1682, 1590, 1525, 1312, 1111, 959, 810.

Embodiment sixteen:

(E)-2-(4-二甲氨基-苯亚甲基)-5-羟基-1-茚酮(D8n).如示意图8所示，在10mL圆底烧瓶中，依次加入5-羟基-1-茚酮200mg(1.35mmol)、冰醋酸2.2mL、浓盐酸0.38mL，室温搅拌10min后，加入4-二甲氨基苯甲醛201mg(1.35mmol)，室温搅拌2h，放置2天。加入饱和碳酸钠溶液中和至碱性，析出大量沉淀，过滤得棕色固体。粗品经硅胶柱色谱纯化，以二氯甲烷∶甲醇20/1洗脱，得产物D8n(产率65％).¹H NMR(DMSO-d₆)δ7.58-7.53(m，3H)，7.29(s，1H)，6.87(s，1H)，6.80-6.75(m，4H)，3.88(s，2H)，3.0(s，6H)。

(E)-2-(4-Dimethylamino-benzylidene)-5-hydroxy-1-indanone (D8n). As shown in Scheme 8, in a 10mL round bottom flask, add 5-hydroxy- 200 mg (1.35 mmol) of 1-indanone, 2.2 mL of glacial acetic acid, and 0.38 mL of concentrated hydrochloric acid were stirred at room temperature for 10 minutes, then 201 mg (1.35 mmol) of 4-dimethylaminobenzaldehyde was added, stirred at room temperature for 2 hours, and left for 2 days. Add saturated sodium carbonate solution to neutralize to alkaline, precipitate a large amount of precipitate, and filter to obtain a brown solid. The crude product was purified by silica gel column chromatography, eluting with dichloromethane:methanol 20/1, to obtain the product D8n (65% yield). ¹ H NMR (DMSO-d ₆ ) δ7.58-7.53 (m, 3H), 7.29 (s, 1H), 6.87 (s, 1H), 6.80-6.75 (m, 4H), 3.88 (s, 2H), 3.0 (s, 6H).

Synthesis of (E)-2-(4-dimethylamino-benzylidene)-5-hydroxy-1-indanone

Example 17: Contrastive staining of AD human brain paraffin sections of indenone derivatives D8L

Using the classical method in this field, carry out comparative staining to the consecutive paraffin sections of AD human brain, the steps are as follows:

1. Dewaxing to water

2. Potassium permanganate (0.25%, prepared in PBS) solution was treated for 20 minutes (until the section appeared brown), and a mixed solution of potassium metabisulfite (1.0%, prepared in PBS) and oxalic acid (1.0%, prepared in PBS) was used to treat the section until Brown fading (approximately 1-6 minutes, after the browning of the slices fades, it can be processed for 30 seconds) 3.0.3% Trioton X-100 treats the slices for 20 minutes.

4. Histochemical pen drawing, staining the slices corresponding to D8L, one of the indanone derivatives, and the slices corresponding to ThioflavinS and Congo red, respectively, and the steps are as follows:

Staining of indanone derivatives D8L: (continued from step 4)

5. D8L working liquid drop dyeing, 1h in 37 degree humidity box.

6. 70% ethanol for 15 minutes, PBS for 10 minutes twice.

7. 70% glycerol for sealing and storage at 4 degrees.

Steps for Thioflavin S staining: (continued from Step 4)

5. Thioflavin S (ThioflavinS, 0.5g% in PBS), staining for 20 minutes.

6. Differentiate in 70% ethanol for 10 minutes, PBS for 5 minutes.

7. 80% glycerol for mounting.

Congo red staining steps: (continued from step 4)

5. Congo Red (Congo Red, 0.5g%, 50% ethanol preparation), staining for 10 minutes.

6. 0.2% KOH (80% ethanol preparation) differentiation, about 15 seconds.

7. 80% glycerol for mounting.

Embodiment 18: Use AD brain homogenate to do competition binding test (Ki determination, the results are shown in Table 1 below). Using the classic method in this field, use postmortem brain tissue homogenate of AD patients to do competition binding test, and BSA ( prepared in PBS), the known positive control radioactive ligand ( ¹²⁵ IMPY), AD and control brain tissue homogenate, the ligand to be tested (prepared 10 gradient concentrations) were aliquoted and mixed, and then added to borosilicate glass In the test tube, incubate at a constant temperature of 37 degrees for 2 hours, and then vacuum filter the bound and free radioligands through Whatman GF/B filter paper (soaked in 1% polyethyleneimine solution) with a ZT-II multi-head cell sample collector Separate and wash with 50mM PBS solution for 3 times, then measure the count on the membrane with a gamma counter, use Graphpad5.0 software for the test results, and perform nonlinear regression analysis to calculate the Ki value. Values are the mean ± SEM of 3 independent experiments, with each experiment repeated once.

Table 1

Example 19: Autoradiography using AD human brain slices

Autoradiography experiments were performed using serial AD human brain tissue sections using classical methods in the field. First dewax paraffin human brain slices with a thickness of 6 μm to water, prepare [ ¹²⁵ I]D8j and [ ¹²⁵ I]D8L ⁽ radioactive ligands) of 125 I-labeled indanone derivatives, and add 500ul of the prepared ¹²⁵ I-labeled radioligand working solution, incubated in a 37-degree water bath for 2 hours. The hot ligand solution on the tissue slices was sucked off, and treated with 0.01M PBS twice, each for 5 minutes. Then choose different differentiation conditions according to the properties of different compounds to be tested. Taking ¹²⁵ IMPY as an example, the differentiation conditions are saturated Li ₂ CO ₃ dissolved in 40% ethanol for 2 minutes, 40% ethanol for 2 minutes, then washed with 0.01M PBS, and rinsed with ddH2O 30 seconds, placed in a fume hood for 30 minutes to dry. The dried tissue sections were placed in a cassette in a darkroom and exposed to X-ray film. After exposure for a certain period of time, the X-ray film is taken out in the darkroom for development and fixing, and the processed film is scanned with a scanner.

Claims (17)

1. A novel compound of general formula (1) or a pharmaceutically acceptable salt thereof: (1) In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , and R ₈ independently represent hydrogen, tritium, halogen, -OH, -NH ₂ , NHR ^a , NR ^a R ^b , -COOH, COOR ^a , -NO ₂ , -OC ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl, -CF ₃ , -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl , -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl, -O(CH ₂ ) _m NR ^a R ^b , -CO-NR ^a R ^b or NHCO-R ^a , -Sn(alkyl) ₃ , ⁹⁹ mTc complex ^{, 123} I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, 18 F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino wherein R ^a and R ^b are independent Ground represents hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, m is 1-5; n is 0-5; X _1, X _2, X _3, X ₄ independently represent C, O, S, N; , are independently represented as a single bond, a double bond or a triple bond; X' represents hydrogen, tritium, halogen, ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, 15 O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ^{76 Br} , ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino, Sn(alkyl) ₃ ; Q represents a substituted or unsubstituted aromatic or heterocyclic ring; B and D are independently expressed as C, N, O; A means C, O, S, N; Z ₁ represents hydrogen, tritium, halogen, -OH, -NH ₂ , -NHR ^a , -NR ^a R ^b , -COOH, -COOR ^a , -NO ₂ , -OC _1-12 alkyl, C _1-12 alkane -CF3, -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl group, -O(CH ₂ ) _m NR ^a R ^b , -CONR ^a R ^b or NHCOR ^a , Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N , ¹⁵ O, ¹⁸ F , ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino; wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, and m is 1-5. 2. The compound of claim 1, characterized in that it is a novel compound of general formula (2)-(9) or a pharmaceutically acceptable salt thereof: (2)

(3)

(4) (5)

(6) (7) (8) (9) in: X ₁ and X ₃ represent C; X ₂ and X ₄ represent C or N; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ independently represent hydrogen, tritium, halogen, -OH, -NH ₂ , NHR ^a , NR ^a R ^b , -COOH, COOR ^a , -NO ₂ , -OC ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl, -CF ₃ , -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted benzene -CH=CH-phenyl, -CH=CH-substituted phenyl, -O(CH ₂ ) _m NR ^a R ^b , -CO-NR ^a R ^b or NHCO-R ^a , -Sn(alkyl) ₃ , ⁹⁹ mTc complex , ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F , 22 Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ^{82 Rb} , ¹⁸ F( C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino wherein R ^a and R ^b independently represent hydrogen, C _{1 -6} alkyl or -(CH ₂ ) _m -phenyl, m is 1-5; n is 0-5; , are independently represented as a single bond, a double bond or a triple bond; X' represents hydrogen, tritium, halogen, ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, 15 O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ^{76 Br} , ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino, Sn(alkyl) ₃ ; Z ₁ represents hydrogen, tritium, halogen, -OH, -NH ₂ , -NHR ^a , -NR ^a R ^b , -COOH, -COOR ^a , -NO ₂ , -OC _1-12 alkyl, C _1-12 alkane -CF3, -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl group, -O(CH ₂ ) _m NR ^a R ^b , -CONR ^a R ^b or NHCOR ^a , Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N , ¹⁵ O, ¹⁸ F , ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino; wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, and m is 1-5. 3. The compound of claim 1, characterized in that it is a novel compound of general formula (10)-(17) or a pharmaceutically acceptable salt thereof:

(10) (11) (12) (13) (14) (15) (16) (17) in: X ₁ and X ₃ represent C; X ₂ and X ₄ represent C or N; R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ independently represent hydrogen, tritium, halogen, -OH, -NH ₂ , NHR ^a , NR ^a R ^b , -COOH, COOR ^a , -NO ₂ , -OC ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl, -CF ₃ , -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, - CH=CH-phenyl, -CH=CH-substituted phenyl, -O(CH ₂ ) _m NR ^a R ^b , -CO-NR ^a R ^b or NHCO-R ^a , -Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F , ²² Na, 52 Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ^{82 Rb} , ¹⁸ F(C _{1- 5} ) Alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkane Base or -(CH ₂ ) _m -phenyl, m is 1-5; n is 0-5; ,

middle

independently represented as a single bond, double bond or triple bond; X' represents hydrogen, tritium, halogen, ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, 15 O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ^{76 Br} , ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino, Sn(alkyl) ₃ ; Z ₁ represents hydrogen, tritium, halogen, -OH, -NH ₂ , -NHR ^a , -NR ^a R ^b , -COOH, -COOR ^a , -NO ₂ , -OC _1-12 alkyl, C _1-12 alkane -CF3, -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl group, -O(CH ₂ ) _m NR ^a R ^b , -CONR ^a R ^b or NHCOR ^a , Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N , ¹⁵ O, ¹⁸ F , ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino; wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, and m is 1-5. 4. The compound of claim 1, characterized in that it is a novel compound of general formula (18)-(25) or a pharmaceutically acceptable salt thereof:

(18) (19)

(20) (21) (22) (23) (24) (25) in: X ₁ and X ₃ represent C; X ₂ and X ₄ represent C or N; R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ independently represent hydrogen, tritium, halogen, -OH, -NH ₂ , NHR ^a , NR ^a R ^b , -COOH, COOR ^a , -NO ₂ , -OC ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl, -CF ₃ , -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, - CH=CH-phenyl, -CH=CH-substituted phenyl, -O(CH ₂ ) _m NR ^a R ^b , -CO-NR ^a R ^b or NHCO-R ^a , -Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F , ²² Na, 52 Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ^{82 Rb} , ¹⁸ F(C _{1- 5} ) Alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkane Base or -(CH ₂ ) _m -phenyl, m is 1-5; n is 0-5; ,

independently represented as a single bond, a double bond or a triple bond; X' represents hydrogen, tritium, halogen, ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br , ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino, Sn(alkyl) ₃ ; Z ₁ represents hydrogen, tritium, halogen, -OH, -NH ₂ , -NHR ^a , -NR ^a R ^b , -COOH, -COOR ^a , -NO ₂ , -OC _1-12 alkyl, C _1-12 alkane -CF3, -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl group, -O(CH ₂ ) _m NR ^a R ^b , -CONR ^a R ^b or NHCOR ^a , Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N , ¹⁵ O, ¹⁸ F , ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino; wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, and m is 1-5. 5. The compound of claim 1, characterized in that it is a novel compound of general formula (26)-(33) or a pharmaceutically acceptable salt thereof: (26) (27) (28) (29) (30) (31) (32) (33) in: X ₁ and X ₃ represent C; X ₂ and X ₄ represent C or N; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₆ independently represent hydrogen, tritium, halogen, -OH, -NH ₂ , NHR ^a , NR ^a R ^b , -COOH, COOR ^a , -NO ₂ , -OC ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl, -CF ₃ , -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted benzene -CH=CH-phenyl, -CH=CH-substituted phenyl, -O(CH ₂ ) _m NR ^a R ^b , -CO-NR ^a R ^b or NHCO-R ^a , -Sn(alkyl) ₃ , ⁹⁹ mTc complex , ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F , 22 Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ^{82 Rb} , ¹⁸ F( C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino wherein R ^a and R ^b independently represent hydrogen, C _{1 -6} alkyl or -(CH ₂ ) _m -phenyl, m is 1-5; n is 0-5;

, are independently represented as a single bond, a double bond or a triple bond; X' represents hydrogen, tritium, halogen, ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br , ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino, Sn(alkyl) ₃ ; Z ₁ represents hydrogen, tritium, halogen, -OH, -NH ₂ , -NHR ^a , -NR ^a R ^b , -COOH, -COOR ^a , -NO ₂ , -OC _1-12 alkyl, C _1-12 alkane -CF3, -CN, -OCH ₂ -phenyl, -OCH ₂ substituted phenyl, -O-phenyl, -O-substituted phenyl, -CH=CH-phenyl, -CH=CH-substituted phenyl group, -O(CH ₂ ) _m NR ^a R ^b , -CONR ^a R ^b or NHCOR ^a , Sn(alkyl) ₃ , ⁹⁹ mTc complex, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, ¹³ N , ¹⁵ O, ¹⁸ F , ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ⁸² Rb, ¹⁸ F(C _1-5 )alkyl, [ ¹⁸ F(C _1-5 )alkyl]amino, [ ¹⁸ F(C _1-5 )alkyl]alkylamino; wherein R ^a and R ^b independently represent hydrogen, C _1-6 alkyl or -(CH ₂ ) _m -phenyl, and m is 1-5. 6. The compound of claim 1, wherein the compound is a novel compound or a pharmaceutically acceptable salt thereof in the following compounds: ( E )-2-benzylidene-5,6-dimethoxy-1-indanone; ( E )-2-(4-bromo-benzylidene)-5,6-dimethoxy-1-indanone; ( E )-2-(4-nitro-benzylidene)-5,6-dimethoxy-1-indanone; ( E )-2-(4-dimethylamino-benzylidene)-5,6-dimethoxy-1-indanone; ( E )-2-(4-methoxy-benzylidene)-5,6-dimethoxy-1-indanone; ( E )-2-(4-dimethylamino-benzylidene)-5-bromo-1-indanone; ( E )-2-(4-dimethylamino-benzylidene)-6-bromo-1-indanone; ( E )-2-(4-dimethylamino-benzylidene)-6-iodo-1-indanone; (E)-2-(4-Dimethylamino-benzylidene)-5-methoxy-1-indanone; (E)-2-(4-amino-benzylidene)-5,6-dimethoxy-1-indanone; (E)-2-(4-Dimethylamino-benzylidene)-5-tributyltinyl-1-indanone; (E)-2-(4-Dimethylamino-benzylidene)-6-tributyltinyl-1-indanone; (E)-2-(4-Dimethylamino-benzylidene)-5-iodo-1-indanone; (E)-2-(4-Dimethylamino-benzylidene)-5-hydroxy-1-indanone. 7. A diagnostic composition for imaging amyloid deposits and neurofibrillary tangles, characterized in that it comprises a novel compound according to any one of claims 1-6 labeled with a radioisotope or a magnetic resonance contrast agent, or A pharmaceutically acceptable salt, ester, amide, prodrug, excipient or diluent thereof. 8. Use of the diagnostic composition of claim 7 as an imaging agent for amyloid deposits and neurofibrillary tangles. 9. the use method of imaging agent when diagnostic composition is used as imaging agent in claim 8, the method comprises: a. introducing the labeled diagnostic composition of claim 7 into a patient; b. allowing the labeled diagnostic composition to bind to the amyloid deposits and neurofibrillary tangles for sufficient time; c. A diagnostic composition for detecting a marker associated with amyloid deposits and neurofibrillary tangles. 10. Use as claimed in claim 8, when said diagnostic composition is labeled with a radioactive isotope suitable for PET (Positron Emission Tomography) or SPECT (Single Photon Emission Computed Tomography) detection, it can be labeled The radioactive isotopes include ⁹⁹ mTc, ¹²³ I, ¹²⁵ I, ¹³¹ I, ¹¹ C, 13 N, ¹⁵ O, ¹⁸ F, ²² Na, ⁵² Fe, ⁶⁴ Cu, ⁶⁸ Ga, ⁷⁶ Br, ^{82 Rb} . 11. The use as claimed in claim 10, when the radioactive isotope commonly used in clinical practice is labeled on the benzene ring of the novel compound, it is characterized in that (as shown in the following structural formula):

, , , ,

, The use according to claim 8, when the diagnostic composition is labeled with a magnetic resonance contrast agent suitable for MRI (magnetic resonance imaging) detection, the magnetic resonance contrast agent for imaging that can be labeled mainly includes: ¹⁹ F, ¹³ C, ¹⁵ N, Mn ²⁺ , Gd ³⁺ , Dy ³⁺ , Fe ²⁺ , Fe ³⁺ elements or nano iron, Gd-DTPA, Gd-DOPA, Mn-DPDP, iron oxide particles, transferrin, porphyrin compounds or metal chelates. 12. The purposes described in claim 12, it is characterized in that: metal chelate has diethylene amino alcohol or diethylene triamine, diethylene tetramine site, ethylenediaminetetraacetic acid site . 13. A pharmaceutical composition for inhibitors of amyloid deposits and neurofibrillary tangle aggregation, characterized in that it comprises a novel compound or a pharmaceutically acceptable salt or ester thereof according to any one of claims 1-6 , amide, prodrug, excipient or diluent. 14. Use of the pharmaceutical composition as claimed in claim 14 as an aggregation inhibitor of amyloid or neurofibrillary tangles in mammals or humans. 15. The use method of the inhibitor during the use as the aggregation inhibitor of amyloid protein or neurofibrillary tangles in claim 15, the method comprises the drug combination of amyloid protein and neurofibrillary tangle aggregation inhibitory amount in claim 14 The drug or a pharmaceutically acceptable salt thereof is administered to a mammal or a patient in need of inhibiting aggregation of amyloid and neurofibrillary tangles. 16. purposes as described in claim 8 or 15, patient suffers from or is suspected of suffering from the disease that comprises Alzheimer's disease etc. with amyloid deposit and neurofibrillary tangle, these diseases comprise: Alzheimer's disease, Scrapie, Creutzfeldt-Jakob disease (CJD Creutzfeldt-Jakob disease), Kuru disease, Down's syndrome, type II diabetic insulinoma, bone marrow cancer of the thyroid, Idiopathic myeloma, Mediterranean fever, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, Muckle-Wells syndrome, hereditary cerebral hemorrhage with amyloidosis, isolated atrial Amyloid, β2-amyloid deposits in inclusion body myositis and muscular dystrophy, Pick's disease, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, chronic trauma Encephalopathy (dementia pugilistica), frontotemporal dementia, Lytico-Bodig disease, tangle-predominant dementia, ganglioglioma, ganglioneuroma, meningeal angiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, etc. 17. Use as claimed in claim 8 or 15, the diagnostic composition or the pharmaceutical composition can be applied to the tissue or the patient by methods known to those skilled in the art, for example, the compound can be administered orally, intravenously, intramuscularly, Subcutaneous, rectal, intracisternal, intravaginal, intraperitoneal, intravesical, topically (powder, ointment or drops) or as a buccal or nasal spray; administration of the labeled compound to the patient may be Using systemic or topical routes of administration, for example, the labeled compound can be administered in a manner that is delivered throughout the body of the patient, or the labeled compound can be administered to a specific organ or tissue of interest, for example, to localize amyloid deposits in the brain and quantification to diagnose or track the progression of Alzheimer's disease.

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