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A precursor of brain histamine H3 receptor radioligand and its preparation method

A technology of radioactivity and brain histamine, applied in the direction of organic chemistry, can solve the problems of multiple reaction steps, high non-specific binding, and low radiochemical yield, and achieve the goal of less harsh reaction conditions, improved binding force, and easy separation and purification Effect

Inactive Publication Date: 2015-11-04
NANJING UNIV OF SCI & TECH
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Problems solved by technology

[0004] year 2006, 11 The C-labeled non-imidazole compound JNJ-10181457 (Chart1) was reported as a selective H 3 Receptor radioligand, in vitro experiments showed very good results, but in vivo experiments showed unsatisfactory results due to high non-specific binding
[0005] In 2008, Merck Laboratories reported non-imidazole compounds merck1b and merck2b, and the results showed good high-specificity binding in vivo. The results of PET experiments in monkeys in vivo showed that they can be used to measure H 3 density distribution of inverse agonists, but these 18 The radiochemical yield of F-labeled formamide analogs is very low, the reaction steps are many, and it contains distilled radioactive intermediates, which is not conducive to the final automated synthesis
However, the compound has a furan ring structure, which has certain limitations when it binds to receptors

Method used

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  • A precursor of brain histamine H3 receptor radioligand and its preparation method
  • A precursor of brain histamine H3 receptor radioligand and its preparation method
  • A precursor of brain histamine H3 receptor radioligand and its preparation method

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preparation example Construction

[0032] A kind of brain histamine H of the present invention 3 The preparation method of the precursor of receptor radioligand, concrete steps are as follows:

[0033] Step 1, adding fluoro or nitrophenoxyphenol and 1-bromo-3-chloropropane or 1-bromo-2-chloroethane into the acetonitrile organic solvent, stirring to dissolve, then adding anhydrous potassium carbonate, Heating to 85-90°C, reflux for 24-48 hours, cooling, extraction, drying, concentration, and flash column chromatography to obtain the product of the first step; wherein, fluoro or nitrophenoxyphenol and 1-bromo-3- The molar ratio of chloropropane or 1-bromo-2-chloroethane is 1:1~2; the molar ratio of fluoro or nitrophenoxyphenol to potassium carbonate is 1:2~5; fluoro or nitrobenzene The molar ratio of oxyphenol to acetonitrile is 1:0.22~0.44; the nitro or fluorine of the fluorinated or nitrophenoxyphenol is the 2nd or 4th position, and the preferred scheme is that R is the 2nd nitro Or the 4th nitro group or the...

Embodiment 1

[0038] 1. At room temperature, add 4-(2-nitrophenoxy)phenol (500mg, 2.16mmol), potassium carbonate (597mg, 4.32mmol) and 25ml of acetonitrile into a 50mL round bottom flask, and slowly add 1-Bromo-3-chloropropane (0.427 mL, 4.32 mmol). The reaction mixture was heated to 85° C., condensed and refluxed and stirred for 38 h (TLC thin layer chromatography followed the reaction progress). Cooling, acetonitrile was removed by distillation under reduced pressure, potassium carbonate was extracted, the solution was concentrated, and flash column chromatography gave product 1-(4-(3-chloropropoxy)phenoxy)-2-nitrobenzene 573mg, the yield It was 86.1%, and the product was a yellow oily substance.

[0039] The product is identified by hydrogen spectrum and carbon spectrum, and the detection results are as follows:

[0040] 1 HNMR (500MHz, CDCl 3 ):δ7.94(1H,dd,J 1 =1.50Hz,J 1 =8.15Hz),7.46(1H,m),7.14(1H,m),7.03(2H,m),6.93(3H,d,J=8.85Hz),4.12(2H,t,J=5.80Hz), 3.77(2H,t,J=6.30Hz),2.26(2...

Embodiment 2

[0048] 1. At room temperature, add 4-(2-nitrophenoxy)phenol (1g, 4.32mmol), potassium carbonate (4.48g, 21.6mmol) and 30ml of acetonitrile in a 50mL round bottom flask, then slowly drop Add 1-bromo-2-chloroethane (0.358 mL, 4.32 mmol). The reaction mixture was heated to 85° C., condensed and stirred under reflux for 33 h (TLC thin layer chromatography followed the reaction progress). Cooling, acetonitrile was removed by distillation under reduced pressure, potassium carbonate was extracted, the solution was concentrated, and flash column chromatography gave product 1-(4-(2-chloroethoxy)phenoxy)-2-nitrobenzene 555mg, the yield was 43.8%, and the product was a pale yellow oily substance.

[0049] The product is identified by hydrogen spectrum and carbon spectrum, and the detection results are as follows:

[0050] 1 HNMR (CDCl 3 ):δ7.92(1H,dd,J 1 =1.60Hz,J 2 =8.15Hz),7.45(1H,m),7.13(1H,m),7.02(2H,m),6.92(3H,m),4.22(2H,t,J=5.80Hz),3.82(2H,t ,J=5.85Hz)ppm.

[0051] 13 CNMR...

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Abstract

The invention provides a precursor compound of a novel histamine H3 receptor PET (Positron Emission Tomography) ligand and a preparation method of the precursor compound. The precursor compound is mainly used for radiosynthesis of a PET radioligand of a histamine H3 receptor in a later period and is applied to PET detection of animal brains. The precursor compound has the advantages that a carbon chain structure of the precursor compound of the histamine H3 receptor PET ligand can flexibly rotate, and in addition, the energy of a rotation energy barrier of ether bonds is small, so that when the precursor compound is combined with the receptor, the self structure of the precursor compound can be adjusted so as to better coincide with a bonding joint of the receptor, and further, the bonding force is enhanced; and synthetic reaction conditions are mild, the reaction yield is high, and products are easy to separate and purify.

Description

a technical field [0001] The present invention relates to a kind of histamine H 3 The precursor compound of receptor PET radioligand and its preparation method, especially a kind of carbon chain connected by fluorinated or nitrophenoxyphenol, and then reacted with (R)-2-methylpyrrolidine to synthesize a new type Amine H 3 Method for Precursor Compounds of Receptor PET Radioligands. Two background technology [0002] Histamine receptors are a class of GPCR receptors, and four histamine receptor subtypes (H 1 , H 2 , H 3 , H 4 ), where histamine H 3 Receptors not only participate in the synthesis, release and metabolism of histamine in the brain, but also participate in the regulation of various neurotransmitters in the brain. Histamine H 3 Receptors can regulate a variety of neurobehavioral functions of the central nervous system, and play an important role in learning and memory, epilepsy, wakefulness and sleep. Histamine H 3 Receptors are widely distributed in the...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/06
Inventor 包晓峰金艳艳刘晓露刘督亮曹小伟
Owner NANJING UNIV OF SCI & TECH
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