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PEGylated benzyltriazolyl pyridazinone compounds, and preparation method and application thereof

A technology for compounding benzyltriazolyl and pyridazinone, which is applied in the field of pyridazinone compounds containing PEGylated benzyltriazolyl and its preparation, can solve the problems of slow metabolism, fast clearance, poor stability, etc., and achieve Wide range of sources, favorable yield, and improved stability

Active Publication Date: 2013-05-22
BEIJING SINOTAU INT PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • PEGylated benzyltriazolyl pyridazinone compounds, and preparation method and application thereof
  • PEGylated benzyltriazolyl pyridazinone compounds, and preparation method and application thereof
  • PEGylated benzyltriazolyl pyridazinone compounds, 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 minutes, slowly inject 1.98g of 80% 3-bromopropyne in toluene and stir for 2 hours. 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...

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 minutes, slowly inject 1.98g of 80% 3-bromopropyne in toluene and stir for 2 hours. 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...

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Abstract

The invention provides PEGylated benzyltriazolyl pyridazinone compounds of which the molecular formula is Fmppn. The structure of the pyridazinone compounds is disclosed as Formula (1), wherein n is a whole number ranging from 1 to 8; and F is 19F or 18F. The compounds provided by the invention have the characteristics of simple preparation process, low use cost, high radiochemical yield, high radiochemical purity, high stability, favorable biological properties, high target to non-target ratio, high myocardial uptake ratio and the like, and can be applied to the technical fields of radiopharmaceutical chemistry and clinical nuclear medicine as a novel fluorine-18 labeled myocardial perfusion developer.

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 BEIJING SINOTAU INT PHARMA TECH CO LTD
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