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Hydroxyphenyl benzyl ether derivative as well as preparation method and application thereof

A technology of phenylbenzyl ether and its derivatives, applied in the field of pharmaceutical compounds, can solve the problems of high fat solubility, poor stability in vivo, slow brain clearance, etc.

Active Publication Date: 2014-04-16
BEIJING ZHIBO BIO MEDICAL TECH +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, Aβ plaque imaging agents for SPECT imaging have not yet achieved breakthroughs, among which 123 I-labeled 2-phenylimidazopyridine derivatives [ 123 I]IMPY is the first SPECT imaging agent to enter the clinical stage (Newberg, A B et al.J.Nucl.Med.2006,47:748-754), but it was quickly eliminated due to its poor stability in vivo
Other radioactive iodine-labeled Aβ plaque imaging agents also generally have the disadvantages of high fat solubility, slow brain clearance, and deradioactive iodine in vivo

Method used

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  • Hydroxyphenyl benzyl ether derivative as well as preparation method and application thereof
  • Hydroxyphenyl benzyl ether derivative as well as preparation method and application thereof
  • Hydroxyphenyl benzyl ether derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Embodiment 1: the synthesis of iodo compound

[0126] The synthetic reaction scheme is as follows figure 1 As shown, the compound numbers in this example are all consistent with the numbers in the reaction scheme of this figure.

[0127] exist figure 1 In the synthetic route shown, reagent and condition are as follows: (a) K 2 CO 3 , DMF, 90℃; (b) SnCl 2 2H 2 O, EtOH, HCl, reflux; (c) 1: NaOMe, (CH 2 O) n , MeOH, reflux; 2: NaBH 4 , reflux; (d) (CH 2 O) n ,NaBH 3 CN, HAc, r.t.; (e) 1-bromo-2-fluoroethane, KOH, ethanol, reflux; (f) 10%Pd / C, 1atm H 2 ,50℃;(g)NaBH 4 ,MeOH,0℃;(h)PBr 3 ,CH 2 Cl 2 , r.t.; (i) (Bu 3 Sn) 2 ,(PPh 3 ) 4 Pd, toluene, Et 3 N, reflow; (j)[ 125 I]NaI,HCl(1M),H 2 o 2 (3%).

[0128] 1) Synthesis of 1-iodo-4-((4-nitrobenzyloxy)methyl)benzene (1-iodo-4-((4-nitrophenoxy)methyl)benzene, compound 1)

[0129] Dissolve 4-nitrophenol (2.78g, 20mmol), 4-iodobenzyl bromide (5.00g, 20mmol) in 5mL of anhydrous DMF, add K 2 CO 3 (5.53 g, ...

Embodiment 2

[0212] Embodiment 2: the synthesis of fluorinated compound

[0213] The synthetic reaction scheme is as follows figure 2 As shown, the compound numbers in this example are all consistent with the numbers in the reaction scheme of this figure.

[0214] exist figure 2 In the synthetic route shown, reagent and condition are as follows:

[0215] (a) 1-bromo-2-fluoroethane (1-bromo-2-fluoroethane) or1,2-dibromoethane (1,2-dibromoethane), K 2 CO 3 ,DMF,90℃;(b)NaBH 4 , MeOH, 0°C; (c) PBr 3 ,CH 2 Cl 2 , r.t.; (d) 4-methoxyphenol (4-methoxyphenol) or4-nitrophenol (4-nitrophenol), K 2 CO 3 , DMF, 90℃; (e) SnCl 2 2H 2 O, EtOH, HCl, reflux; (f) 1: NaOMe, (CH 2 O) n , MeOH, reflux; 2: NaBH 4 , reflux; (g) (CH 2 O) n ,NaBH 3 CN, HAc, r.t.; (h) AgOTs, MeCN, reflux; (i) 18 f - , K 2 CO3, Kryptofix-2.2.2 (ie K 222 , amino polyether), acetonitrile, 100 ° C; Ethoxy)ethanol instead of 2-chloroethanol), KOH, EtOH, reflux; (k) 10%Pd / C, 1atm H 2 ,50°C; (l) 1-(chloromethyl)-4...

Embodiment 3

[0256] Embodiment 3: the synthesis of pyridine derivatives

[0257] The synthetic reaction scheme is as follows image 3 As shown, the compound numbers in this example are all consistent with the numbers in the reaction scheme of this figure.

[0258] exist image 3 In the synthetic route shown, reagent and condition are as follows: (a) K 2 CO 3 , DMF, 90℃; (b) SnCl 2 2H 2 O, EtOH, HCl, reflux; (c) CH 3 I,K 2 CO 3 , r.t.

[0259] 1) Synthesis of 2-(4-iodobenzyloxy)pyridine (2-((4-iodobenzyl)oxy)pyridine, compound 54)

[0260] It was prepared according to the method of compound 1 (2-hydroxypyridine was used instead of 4-nitrophenol) to obtain white solid 54 (187.5 mg, 60.3%). 1 H NMR (400MHz, CDCl 3 )δ7.67(d,J=8.2Hz,2H),7.34(ddd,J=8.8,6.7,1.8Hz,1H),7.26–7.24(m,1H),7.06(d,J=8.2Hz,3H ),6.66(d,J=9.1Hz,1H),6.19(t,J=6.7Hz,1H),5.09(s,2H).

[0261] 2) Synthesis of 2-chloro-5-(4-iodobenzyloxy)pyridine (2-chloro-5-((4-iodobenzyl)oxy)pyridine, compound 55)

[0262] It was p...

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Abstract

The invention relates to hydroxyphenyl benzyl ether derivative as well as a preparation method and an application thereof. Part of a compound is marked by radionuclide and is used as an Abeta plaque imaging agent, and the hydroxyphenyl benzyl ether derivative is applied to the preparation of a drug for diagnosis and treatment of the allzheimer's disease. The structural formula of the hydroxyphenyl benzyl ether derivative is described in a formula (I). The chemical structure of the class of bran-new hydroxyphenyl benzyl ether derivatives with the high affinity with Abeta plaques inside an AD disease brain is different from a compound disclosed by the prior art, and the hydroxyphenyl benzyl ether derivative belongs a bran-new compound for the diagnosis and the treatment of the allzheimer's disease. The obtained Abeta plaque imaging agent is good in in-vivo stability, low in lipid solubility, and high in brain cleaning speed, does not generate the problem of the radionuclide removed in an in-vivo manner, and has great application values and market values.

Description

technical field [0001] The present invention relates to the field of pharmaceutical compounds, in particular to phenylbenzyl ether derivatives and a preparation method thereof, some compounds of which are labeled with radionuclides as Aβ plaque imaging agents, and the phenylbenzyl ether derivatives The application of the derivative in the preparation of medicines for diagnosing and treating Alzheimer's disease. Background technique [0002] Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disease, clinically manifested as cognitive and memory function decline, daily life ability decline, and various neuropsychiatric symptoms and behavioral disorders. AD mainly occurs in the elderly. Statistics show that the average prevalence of AD in my country is 6.6% among people over 65 years old. It has become one of the major diseases that seriously threaten the physical and mental health of the elderly after tumors, heart disease and stroke. At present, my count...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C205/37C07C201/12C07C43/225C07C43/23C07C41/16C07C217/86C07C213/06C07C323/20C07C319/14C07D213/64C07D213/65C07C211/53C07C209/78A61K31/085A61K31/09A61K31/136A61K31/10A61K31/44A61K31/137A61P25/28A61K49/00A61K51/04A61K101/02
CPCA61K51/04A61K51/0406A61P25/28C07B2200/05C07C43/225C07C43/23C07C205/37C07C211/53C07C217/86C07C323/20C07D213/64C07D213/65C07F7/2208C07C41/18C07C43/2055C07C201/12C07C213/02C07C319/20
Inventor 崔孟超林春平刘伯里国毓智张志勇
Owner BEIJING ZHIBO BIO MEDICAL TECH
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