Vesicle monoamine transporter target bound drug and preparation method thereof

A targeted binding and transporter technology, which is applied in pharmaceutical formulations, preparations for in vivo experiments, radioactive carriers, etc., can solve problems such as unfavorable transportation and long-term storage, high liver background, and affecting the imaging effect of the pancreas

Inactive Publication Date: 2011-03-23
BEIJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them, F-18-labeled AV-133 has completed the first phase of clinical research in the United States, and the imaging effect is very good, but because the chemical stability of the F-18-labeled precursor of AV-133 is not high, it is not conducive to transportation and long-term storage ; At the same time, as a β-cell targeting drug, its liver background is high, which affects the imaging effect of the pancreas

Method used

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  • Vesicle monoamine transporter target bound drug and preparation method thereof
  • Vesicle monoamine transporter target bound drug and preparation method thereof
  • Vesicle monoamine transporter target bound drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 1. Synthesis of 2-(2-fluoroethylamino)tetrabenazine (A-1)

[0039] (1) The structure of the compound

[0040]

[0041] (2) Synthesis method

[0042] Method 1: Add 1mmol tetrabenazine and 5ml absolute ethanol into a two-necked round-bottomed flask, then add 1.5mmol 2-fluoroethylamine hydrochloride and 2mmol triethylamine, under nitrogen protection, heat at 100°C for 12 hours . After cooling to room temperature, 6 mmol of sodium borohydride was added, and the reaction was stirred at room temperature for 6 hours. Stop the reaction, add 50ml of water to dissolve, extract with dichloromethane (3×20ml), combine the organic phases, wash with saturated sodium chloride solution, and add anhydrous sodium sulfate to dry. The solvent was evaporated by filtration and separated by column chromatography. The solvent ratio was ethyl acetate:n-hexane:triethylamine=1:9:0.5. A white solid was obtained with a product yield of 42%.

[0043] Method 2: Dissolve 1mmol 2-aminotetrabenaz...

Embodiment 2

[0049] 1. Synthesis of 2-(3-fluoropropylamino) tetrabenazine (A-2)

[0050] (1) The structure of the compound

[0051]

[0052] (2) Synthesis method

[0053] Take 1mmol of 2-aminotetrabenazine and dissolve it in 5ml of DMF, then add 1.3mol of 2-fluoroethyl p-toluenesulfonate and 1.5mmol of anhydrous potassium carbonate, heat and stir at 80°C for 6 hours to stop the reaction. Add 150ml of ethyl acetate to dilute the reaction solution and wash with H 2 After washing with O (4×15ml) and saturated sodium chloride solution, it was dried by adding anhydrous sodium sulfate. The solvent was evaporated by filtration and separated by column chromatography. The solvent ratio was: ethyl acetate:n-hexane:triethylamine=2:8:0.5. A yellow oily solid was obtained in a yield of 43.6%.

[0054] (3) Confirmation of A-2

[0055] h 1 -NMR (CDCl 3 , 200MHz): δ (ppm) 0.87-0.97 (m, 6H), 1.0-1.34 (m, 4H), 1.37-1.72 (m, 3H), 1.75-2.16 (m, 2H), 2.32-2.8 (m, 6H), 2.88-3.2(m, 3H), 3.42-3.52(m, 1...

Embodiment 3

[0059] 1. Synthesis of 2-(4-fluorobutylamino)tetrabenazine (A-3)

[0060] (1) The structure of the compound

[0061]

[0062] (2) Synthesis method

[0063] Dissolve 1.5mmol of 2-aminotetrabenazine in 6ml of DMF, add 1.3mol of 4-fluoro-n-butyl bromide and 1.5mmol of anhydrous potassium carbonate, heat and stir at 80°C for 8 hours, and stop the reaction. Add 150ml of ethyl acetate to dilute the reaction solution and wash with H 2 After washing with O (4×15ml) and saturated sodium chloride solution, it was dried by adding anhydrous sodium sulfate. The solvent was evaporated by filtration and separated by column chromatography. The solvent ratio was: ethyl acetate:n-hexane:dichloromethane:triethylamine=1:9:1:0.5. A yellow oily solid was obtained in 23.4% yield.

[0064] (3) Confirmation of A-3

[0065] h 1 -NMR (CDCl 3 , 200MHz): δ (ppm) 0.88-0.98 (m, 6H), 1.0-1.34 (m, 3H), 1.38-1.80 (m, 7H), 1.98-2.14 (m, 1H), 2.30-2.7 (m, 6H), 2.80-3.2(m, 3H), 3.4-3.52(d, 1H), 3.82-3....

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Abstract

The invention relates to a vesicle monoamine transporter target bound drug and a preparation method thereof; wherein the structure of a contained developing agent is shown as right; wherein R1=H, -CH3, -CH2CH3; R2=-(CH2)n-F, n=1-4, -(CH2CH2O)nCH2CH2-F, n=1-3. The invention adopts TBZ as lead compound, replaces 2-carbonyl group of TBZ with amino group and designs to synthetize a series of new TBZ-NH2 derivatives containing F; the series of TBZ-NH2 derivatives not only has higher targeting property and can be combined the specificity of VMAT2, but also can be used for PET development research when using F-18 to replace F-19, and is a developing agent which is used for PD diagnosis and diabetes diagnosis and has a good application prospect.

Description

technical field [0001] The invention relates to a vesicle monoamine transporter (VMAT2) targeting binding drug and a preparation method thereof. Background technique [0002] The vesicular monoamine transporter (VMAT) gene has two isoforms through different splicing. VMAT1 is mainly located in the peripheral nervous system and developing monoaminergic neurons, while VMAT2 is mainly located in the monoaminergic neurons and their nerve endings in the central nervous system. In the nigro-striatal projection system, 95% of VMAT2-positive fibers are dopaminergic. VMAT2 determines the storage site of monoamine transmitters in cells, and is related to the regulation of central monoamine transmitters and related neuropsychological diseases. [0003] Parkinson's disease (PD) is a neurodegenerative disease caused by the degeneration and necrosis of dopaminergic neurons, resulting in a decrease in the content of dopamine in the nigro-striatal system. The main symptoms are: tremor, sh...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K51/04A61K49/00C07D455/08A61K101/02
Inventor 朱霖刘晶莹
Owner BEIJING NORMAL UNIVERSITY
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