TWI532499B - Compound of Radiocontrast Agent Using Tau-Protein - Google Patents

Description

Tau protein contrast drug compound

The present invention relates to a Tau protein contrast drug compound, and more particularly to a compound which selectively and strongly binds to a β -amyloid plaque, in particular, relates to Alzheimer's disease. A nuclear medicine diagnostic drug for PET imaging of β -amyloid plaques, or a cranial nerve therapeutic drug for treating the inhibition of the formation of the β -amyloid plaque and stopping the progression of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degenerative brain disease, also known as degenerative dementia, a most common and incurable dementia due to Alzheimer's disease. The disease is very common in the elderly, so the older the disease, the higher the chance of getting sick. The attack rate of 85 years old and above can reach 30~35%. The main clinical manifestations of this progressive disease include the degradation of cognition, behavior and mental state. It has a special change in neuropathology, and the appearance of the cerebral cortex is atrophy, the sulcus of the brain is widened, and the ventricle is enlarged. The most important pathological indicators for diagnosis of Alzheimer's disease are Neurofibrillary Tangles (NFT) and Senile Plaque (SP), which are widely distributed in the neocortex. The neurofibrillary tangles are caused by the entanglement of the abnormally phosphorylated Tau protein (Helical Filament), which causes the formation of neurofibrillary tangles in the interior of the nerve cells; and the senile plaques are made of starch-like composition, β - amyloid fibril amyloid deposits (β -amyloid protein, A β protein ) formed outside of the nerve cells.

Many small, rounded deposits or plaques are currently found in the brains of Alzheimer's patients. These spider-like tangled proteins are beta -amyloid proteins, which have become the focus of the mechanism of Alzheimer's disease and the treatment of Alzheimer's disease.

The biomarkers for Alzheimer's disease in the past studies can be divided into three categories, namely X-34, ISB, BSB, SB13 and IMSB of styrlbenzenes; FDDNP and FENE of Aminonaphthalene; And 6-OH-BTA-1, TZDM and IMPY of the tissue of Thioflavin S (Thioflavin-S, TF-S). Among them, the FDDNP of the aminonaphthalene type is a radioactive isotope fluorine-18 which can be used as a fluorine-18-FDDNP, and can be used as one of the contrast agents for Positron Emission Tomography (PET).

In recent years, more and more radiopharmaceuticals for positron tomography of β -amyloid plaques have been developed and proven to be useful in human angiography. Tracking with radiopharmaceuticals for beta -amyloid plaques can help diagnose Alzheimer's disease and can be used to evaluate the efficacy of therapeutics that reduce beta -amyloid plaque buildup in the brain. Therefore, it is necessary for the average practitioner to develop a compound that selectively and strongly binds to a β -amyloid plaque, and develops it into a set of β -related to Alzheimer's disease. A nuclear medicine diagnostic drug for PET imaging of amyloid plaques, or a cranial nerve therapeutic drug for treating the inhibition of the formation of the β -amyloid plaque and stopping the progression of Alzheimer's disease.

The main object of the present invention is to overcome the above problems encountered in the prior art and to provide a method for synthesizing a Tau protein contrast drug which is selective and strongly binds to a β -amyloid plaque. Its use.

A secondary object of the present invention is to provide a nuclear medicine diagnostic drug for PET imaging suitable for Alzheimer's disease-related β -amyloid plaques.

Another object of the present invention is to provide a cranial nerve therapeutic drug for treating a process of inhibiting the formation of plaques of beta -amyloid plaques and stopping Alzheimer's disease.

For the purposes of the above, the present invention is a Tau protein contrast drug compound having the structural formula:

Wherein F is a radioactive element containing a detection mark or a non-radioactive element without a radioactive label.

In the above specific embodiment, the radioactive element containing the detection label is F-18, which can be selected from the group consisting of Alzheimer's disease, neurodegenerative disorder or with Tau protein and β -type starch. A nuclear diagnostic drug for PET imaging of a disease or condition associated with a protein.

The above-described Tau protein contrast drug compound is in a specific embodiment, the non-radioactive non-radioactive element is F-19, and can be selected as a treatment selected from Alzheimer's disease, neurodegenerative disorder or with Tau protein and β - a cranial nerve drug of a fluoride standard for amyloid-related diseases or conditions.

1‧‧‧2-Acetyl-6-methoxynaphthalene

2‧‧‧2-Acetyl-6-hydroxynaphthalene

3‧‧‧2-Acetyl-6-[(2-hydroxyethyl)methylamino]naphthalene

4‧‧‧2-(1,1-Dicyanopropen-2-yl)-6-[(2-hydroxyethyl)methylamino]naphtha-lene

5‧‧‧2-(1,1-Dicyanopropen-2-yl)-6-{[2-(2-hydroxy-ethoxy)-ethyl]methylamino}naphthalene

6‧‧‧Tau protein contrast drug compound

Fig. 1 is a schematic view showing the production process of the Tau protein contrast drug compound of the present invention.

Please refer to FIG. 1 , which is a schematic diagram showing the preparation process of the Tau protein contrast drug compound of the present invention. As shown in the figure: The present invention is a Tau protein contrast drug compound, and its structural formula is:

For diagnostic purposes, the compound of the above formula preferably comprises or contains a radioactive element of a detectable label, such as a F-18 radiolabel, for development into a contrast agent for PET contrast, selected from Alzheimer's disease (as selected). nuclear medicine diagnostic agent PET contrast or the like associated a disease or condition of the amyloid protein (β -amyloid protein, A β protein ) - alzheimer's disease, AD), a neurodegenerative disorder or a T au protein (T au protein) and beta] .

For therapeutic purposes, the compounds of the above formula are preferably non-radioactive elements without radiolabeling, such as F-19 non-radioactive labels, for development into non-radioactive fluorine standards, as treatments selected from Alzheimer's disease A neurodegenerative disorder or a cranial nerve drug that is associated with a disease or condition associated with Tau protein and β -amyloid.

The present invention also provides a method of preparing a Tau protein contrast drug compound represented by the above structural formula. In particular, the methods of the invention for synthesizing and labeling such compounds as nuclear diagnostic drugs or cranial nerve drugs are more fully explained in the following examples, as shown in Figure 1. The examples illustrate certain aspects and advantageous results of the above methods and are shown by way of illustration and not limitation.

[Implementation Scheme 1] Preparation of 2-Acetyl-6-hydroxynaphthalene 2

First, 2-ethyl fluorenyl-6-methoxynaphthalene 1 (hereinafter referred to as compound 1) was used as a starting reactant, and 1.48 g (7.3 mmol) of compound 1 was taken. It was placed under reflux of 500 mL of concentrated hydrochloric acid for 2 hours, filtered while hot, and the filtrate was cooled, extracted with dichloromethane (2×200 mL), and hydrochloric acid was discarded. The organic phase is washed with 200 mL of water, and the organic phase is dried over anhydrous sodium sulfate, and evaporated to dryness to dryness to give 2-Acetyl-6-hydroxynaphthalene 2 (hereinafter referred to as compound 2) as an off-white solid. 1:3g and 95.7%.

[Implementation Scheme 2] Preparation of 2-Acetyl-6-[(2-hydroxyethyl)methylamino]naphthalene 3

0.4 g (2.1 mmol) of the compound 2, 1.8 g (24.0 mmol) of 2-methylaminoethanol (CH ₃ NHCH ₂ CH ₂ OH), 2.0 g (19.2 mmol) of sodium hydrogen sulfite ( In a mixture of Na ₂ O ₅ S ₂ ) and 4 mL of water, the mixture was heated to 140 ° C under vigorous stirring and refluxed for 76 hours. After cooling, 50 mL of dichloromethane was added, and after thorough stirring, the two phases were separated, wherein the organic phase was dried. 2-Acetyl- 6-hydroxynaphthalene 2 ( 3 SiO 2, EtOAc:: CH 2 Cl 2 = 1), recovery 0.15g (0.81mmol) of, i.e., dried over sodium sulfate, and concentrated under reduced pressure, separated and purified using liquid chromatography The solid product 2-Acetyl-6-[(2-hydroxyethyl)methylamino]naphthalene 3 (hereinafter referred to as Compound 3) was obtained, and its weight and yield were 0.276 g and 88.0%, respectively.

[Implementation Scheme 3] Preparation of 2-(1,1-Dicyanopropen-2-yl)-6-[(2-hydroxyethyl)methylamino]naphtha-lene 4

0.51 g (2.1 mmol) of compound 3 was taken, dissolved in 3 mL of anhydrous pyridine, and 0.63 g (8.3 mmol) of malononitrile (CH ₂ (CN) ₂ ) was added and reacted under nitrogen. The mixture was stirred under heating at 70 ° C for 4 hours. After cooling, 50 mL of diethyl ether was added and stirred well, and the ether was insoluble. To 50mL aqueous solution was washed with diethyl ether, the organic phase is dried over anhydrous sodium sulfate, and concentrated under reduced pressure, separated and purified using liquid chromatography _{(SiO 2, CHCl 3: EtOAc} = 1: 1), to give a red solid product 2- ( 1,1-Dicyanopropen-2-yl)-6-[(2-hydroxyethyl)methylamino]naphtha-lene 4 (hereinafter referred to as Compound 4), having a weight and a yield of 0.46 g and 75.3%, respectively.

[Implementation Scheme 4] Preparation of 2-(1,1-Dicyanopropen-2-yl)-6-{[2-(2-hydroxy-ethoxy)-ethyl]methylamino}naphthalene 5

0.40 g (1.4 mmol) of Compound 4 was dissolved in 8 mL of anhydrous acetonitrile, and 0.35 g (4.3 mmol) of 2-chloro-ethanol (2-Chloro-ethanol) was added thereto, and the mixture was stirred under heating at 80 ° C for 17 hours, and after cooling, The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified using liquid chromatography (SiO ₂ , CHCl ₃ :EtOAc = 1:1) to give the product 2-(1, 1-Dicyanopropen-2-yl)-6-{[2-(2-hydroxy-ethoxy)-ethyl]methylamino}naphthalene 5 (hereinafter referred to as compound 5) having a weight and a yield of 0.29 g and 60.0%, respectively.

[Implementation Scheme 5] Preparation of 2-(1,1-Dicyanopropen-2-yl)-6-{[2-(2-Fluoro-ethoxy)-ethyl]methylamino}naphthalene (Tau Protein Contrast Drug Compound) 6

0.20 g (0.6 mmol) of compound 5 was taken, dissolved in 10 mL of anhydrous dichloromethane, and 0.16 mL (1.2 mmol) of diethylaminosulfur trifluoride (DAST) was added at 0 °C. Then, it was reacted at room temperature for 16 hours. After the reaction is completed, the mixture is extracted with water and dichloromethane, and the organic layer is collected. The organic layer is separated by sodium sulfate, concentrated under reduced pressure, and purified by liquid chromatography to obtain product Tau protein contrast compound 6 in weight and yield. They were 0.12 g and 60.0%, respectively. As such, a novel Tau protein contrast drug compound is constructed by the above disclosed procedure.

In summary, the present invention is a Tau protein contrast drug compound, which can effectively improve various disadvantages of the conventional use, and develop a Tau protein contrast drug compound which selectively and strongly binds to β -amyloid plaque. It can be developed into a set of nuclear medicine diagnostic drugs for PET imaging for Alzheimer's disease-related β -amyloid plaques, or for the treatment of inhibition of the β -amyloid plaque formation. And stop the brain neurotherapy drugs in the process of Alzheimer's disease, so that the invention can be made more progressive, more practical, and more in line with the needs of the user. It has indeed met the requirements of the invention patent application, and has patented according to law. Application.

However, the above description is only a preferred embodiment of the present invention, and cannot be limited thereto. The scope of the present invention is intended to be within the scope of the invention as defined by the appended claims.

1‧‧‧2-Acetyl-6-methoxynaphthalene

2‧‧‧2-Acetyl-6-hydroxynaphthalene

3‧‧‧2-Acetyl-6-[(2-hydroxyethyl)methylamino]naphthalene

4‧‧‧2-(1,1-Dicyanopropen-2-yl)-6-[(2-hydroxyethyl)methylamino]naphtha-lene

5‧‧‧2-(1,1-Dicyanopropen-2-yl)-6-{[2-(2-hydroxy-ethoxy)-ethyl]methy1amino}naphthalene

6‧‧‧Tau protein contrast drug compound

Claims (5)

A Tau protein contrast drug compound having the structural formula: Wherein F is a radioactive element containing a detection mark or a non-radioactive element without a radioactive label. The Tau protein contrast drug compound according to claim 1, wherein the radioactive element containing the detection mark is F-18. The Tau protein contrast drug compound according to Item 2 of the patent application is selected from Alzheimer's Disease (AD), neurodegenerative disorder or Tau protein and β -type starch. A nuclear diagnostic drug for PET imaging of a disease or condition associated with β- amyloid Protein (A β Protein). The Tau protein contrast drug compound according to claim 1, wherein the non-radioactive element without radiolabel is F-19. The Tau protein contrast drug compound according to item 4 of the patent application scope is for treating a fluorine selected from the group consisting of Alzheimer's disease, a neurodegenerative disorder or a disease or condition associated with Tau protein and β -amyloid-like protein. Standard neuropeptide drugs.