Pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl and preparation method and application thereof

A technology for synthesizing benzyl triazolyl and pyridazinone, which is applied in the field of pyridazinone compounds containing PEGylated benzyl triazolyl and its preparation, can solve the problems of poor stability, excessive clearance, slow metabolism and the like, and achieves the Improved stability, favorable yields, wide-ranging effects

Inactive Publication Date: 2013-01-30
张现忠 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the above imaging agents have disadvantages such as poor stability in aqueous solution, rapid clearance in the myocardium, or slow metabolism in the liver.

Method used

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  • Pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl and preparation method and application thereof
  • Pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl and preparation method and application thereof
  • Pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] (1) Synthesis of ligand mpp-nOTs (n=1):

[0056] a. Synthesis of furochloric acid (DCA)

[0057] Under ice bath, add 480mL of concentrated hydrochloric acid into a 1L four-neck flask. At 0-10°C, add 80g MnO in batches 2 , stirred, and slowly added dropwise 24g furfural. After stirring at room temperature for 30 min, the temperature was slowly raised to 60°C. At 60-80°C, add 42g MnO in batches 2 , heated up to 100°C. After the reaction until the liquid turned into an orange transparent solution, the reaction was continued for 30 min, cooled, and suction filtered. The precipitate was dissolved with 40 mL of ether and filtered. The filtrate was evaporated to remove the solvent, and recrystallized with 40 mL of water to obtain 31 g of furochloric acid as light pink flaky crystals. NMR spectrum: ( 1 HNMR, CDCl 3 )δ:6.085(s,1H,HO-C-H);( 13 CNMR, CDCl 3 ) δ: 98.56, 123.87, 151.25, 165.15. Infrared Spectrum: (IR) / cm -1 : vOH:3407, vC=O:1770, vC=C:1638.

[0058] b....

Embodiment 2

[0078] (1) Synthesis of ligand mpp-nOTs (n=2):

[0079] a. Synthesis of furochloric acid (DCA): same as Example 1.

[0080] b. Synthesis of 2-tert-butyl-4,5-dichloropyridazinone (DCP): Same as Example 1.

[0081] c. Synthesis of mIP-OH: Same as Example 1.

[0082] d. Synthesis of mIP-OTs: Same as Example 1.

[0083] e.mIP-N 3 Synthesis: with embodiment 1.

[0084] f. Synthesis of P-nOH (n=2)

[0085] Under nitrogen protection at 0°C, 20 mmol of diethylene glycol was dissolved in redistilled THF, and 0.31 g (13 mmol) of NaH was slowly added. After stirring for 30 min, slowly inject 1.98 g of 80% 3-bromopropyne in toluene, and stir for 2 h. Stir at room temperature for 20 h, pour the reaction solution into water, extract with 100 mL of dichloromethane, and wash the organic phase with anhydrous Na 2 SO 4 Dry and spin dry to obtain P-nOH (n=2). NMR spectrum: ( 1 HNMR, CDCl 3 )δ:2.164(s,1H,O-H),2.452(t,1H,C≡CH),3.612-3.764(m,8H,(OCH 2 CH 2 )2),4.221(d,2H,C≡CCH 2 ). I...

Embodiment 3

[0096] (1) Synthesis of ligand mpp-nOTs (n=3):

[0097] a. Synthesis of furochloric acid (DCA): same as Example 1.

[0098] b. Synthesis of 2-tert-butyl-4,5-dichloropyridazinone (DCP): Same as Example 1.

[0099] c. Synthesis of mIP-OH: Same as Example 1.

[0100] d. Synthesis of mIP-OTs: Same as Example 1.

[0101] e.mIP-N 3 Synthesis: with embodiment 1.

[0102] f. Synthesis of P-nOH (n=3)

[0103] Under nitrogen protection at 0°C, 20 mmol of triethylene glycol was dissolved in redistilled THF, and 0.31 g (13 mmol) of NaH was slowly added. After stirring for 30 min, slowly inject 1.98 g of 80% 3-bromopropyne in toluene, and stir for 2 h. Stir at room temperature for 20 h, pour the reaction solution into water, extract with 100 mL of dichloromethane, and wash the organic phase with anhydrous Na 2 SO 4 Dried and spin-dried to obtain P-nOH (n=3). NMR spectrum: ( 1 HNMR, CDCl 3 )δ:2.357(s,1H,O-H),2.442(t,1H,C≡CH),3.609-3.749(m,12H,(OCH 2 CH 2 ) 3 ),4.215(d,2H,C≡CCH...

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Abstract

The invention provides a pyridazinone compound containing polyethyleneglycol (PEG) modified benzyl triazolyl. According to the pyridazinone compound, a molecular formula is Fmppn, and a structure is shown as a formula (1), wherein n is an integral number of 1 to 8; and F is 19F or 18F. The pyridazinone compound has the characteristics of simplicity in preparation, low using cost, high radiochemical yield and radiochemical purity, high stability and biological properties, high target-to-nontarget ratio, high myocardial intake value and the like, and is used as a novel fluorine-18 marked myocardial perfusion photographic developer to be applied to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine.

Description

technical field [0001] The invention relates to a class of pyridazinone compounds, in particular to a pyridazinone compound containing PEGylated benzyltriazolyl groups, a preparation method and application thereof. Background technique [0002] Although the diagnosis and treatment of coronary heart disease continue to develop, in the world, coronary heart disease is still the most serious disease threatening human health. In my country, the morbidity and mortality of coronary heart disease are on the rise. According to the 2008 Statistical Bulletin on the Development of Health Care in my country, the death rate (1 / 100,000) of heart disease among urban and rural residents in China is 121.00 and 87.10 respectively, accounting for 19.65% and 14.11% of the death causes of urban and rural residents respectively. , becoming the second cause of death among urban and rural populations in my country. According to the estimates of the World Health Organization (WHO), around 2020, my ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K51/04A61K101/02
Inventor 张现忠方纬牟甜甜
Owner 张现忠
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