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4-(2-chloroaryl) quinazoline-2-amide derivative and application thereof

A technology of amide derivatives and derivatives, applied in the fields of radiopharmaceutical chemistry and nuclear medicine, can solve the problems of complex labeling conditions, short half-life of ER-176, and inability to transport long distances

Active Publication Date: 2021-09-14
首都医科大学脑重大疾病研究中心
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem solved by the present invention is to provide a kind of high-affinity TSPO 18 F-marked 4-(2-chloroaryl) quinazoline-2-amide derivatives and applications thereof, the derivatives can overcome [ 11 C] ER-176 has short half-life, complex labeling conditions, and incapable of long-distance transportation. It is a new compound for diagnosis and treatment of TSPO-related diseases

Method used

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  • 4-(2-chloroaryl) quinazoline-2-amide derivative and application thereof
  • 4-(2-chloroaryl) quinazoline-2-amide derivative and application thereof
  • 4-(2-chloroaryl) quinazoline-2-amide derivative and application thereof

Examples

Experimental program
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Effect test

example 1

[0029] The synthesis of example 1 (R)-4-(2-chlorophenyl)-N-(4-fluorobut-2-yl)-N-methylquinazoline-2-carboxamide, its structural formula is as follows:

[0030]

[0031] The synthetic route is as follows:

[0032]

[0033] (1) Preparation of (R)-4-(2-chlorophenyl)-N-(4-hydroxybut-2-yl)quinazoline-2-carboxamide

[0034] N 2 Under protection, 4-(2-chlorophenyl)quinazoline-2-carboxylic acid (0.31g, 1.07mmol) was dissolved in anhydrous dichloromethane (20mL), and EDCI (1.02g, 5.35mmol) was added successively , HOBt (0.04g, 0.22mmol) and TEA (0.54g, 5.35mmol), add (R)-3-aminobutyl-1-ol (0.12g, 1.29mmol), stir well, and react overnight at room temperature. After stopping the reaction, the reaction solution was washed with water and saturated brine successively, the organic layer was dried and rotary evaporated, and separated by a column (DCM / MeOH=95 / 5) to obtain 0.23 g of light yellow oil with a yield of 60.7%. 1 H NMR (300MHz, CDCl 3 )δ8.35(d, J=8.5Hz, 1H), 8.22(d, J=8.4Hz...

example 2

[0044] Example 2 (R)-4-(2-chlorophenyl)-N-(4-fluorobut-2-yl)-N-(methyl-d 3 ) the synthesis of quinazoline-2-carboxamide, its structural formula is as follows:

[0045]

[0046] The synthetic route is as follows:

[0047]

[0048] (1) Preparation of 4-(2-chlorophenyl)-N-(methyl-d 3 )-N-((2R)-4-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazoline-2-carboxamide

[0049] Under ice-cooling, the starting material (0.22g, 0.50mmol) was dissolved in anhydrous DMF (15mL), NaH (0.04mg, 1.50mmol) and deuteroiodomethane (0.22g, 1.50mmol) were added, and ice-bathed to Reaction at room temperature, the raw material disappeared after 0.5h. The reaction was quenched with ice water, and saturated brine (30mL x 5) was added to wash the DCM layer, the organic phase was dried and rotary evaporated, and column separation gave 0.21g of a colorless oil, with a yield of 92.2%. MS ES + (m / z):479.2220[M+Na] +

[0050] (2) Preparation of (R)-4-(2-chlorophenyl)-N-(4-hydroxybut-2-yl)-N-(meth...

example 3

[0056] Example 3 Synthesis of 4-(2-chlorophenyl)-N-((2R)-4-fluorobut-2-yl-4-d)-N-methylquinazoline-2-carboxamide, its structural formula as follows:

[0057]

[0058] The synthetic route is as follows:

[0059]

[0060] (1) Preparation of (R)-4-(2-chlorophenyl)-N-methyl-N-(4-oxobut-2-yl)quinazoline-2-carboxamide

[0061] The starting material (0.06 g, 0.17 mmol) was dissolved in anhydrous DCM (20 mL) in an ice bath, and Dess-Martin oxidant (0.22 g, 0.51 mmol) and NaHCO were added 3 (0.10g, 1.19mmol), reacted at 0°C, monitored by TLC, and the reaction was complete after 1.5h. After stopping the reaction, add anhydrous DCM (50mL), add sodium thiosulfate aqueous solution (20mL, 1mol / L) and saturated NaHCO 3 Aqueous solution (20 mL), stirred for 10 min, the organic layer was separated, dried and rotary evaporated to obtain 0.05 g of a colorless oily product with a yield of 79.4%. MS ES + (m / z):368.1150[M+H] +

[0062](2) Preparation of (R)-4-(2-chlorophenyl)-N-methyl-...

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Abstract

The invention discloses a 4-(2-chloroaryl) quinazoline-2-amide derivative, which has a structure as shown in a formula 1 in the specification, wherein X1 and X2 are independently selected from C or N, at least one of X1 and X2 is N, R is selected from substituted or unsubstituted alkyl, R1 is selected from substituted or unsubstituted alkylene, Ar is selected from fluorine atoms and substituted or unsubstituted leaving groups, and the substituent groups of R, R1 and Ar are respectively and independently selected from deuterium, sulfonate groups and halogen groups. According to the invention, a series of 4-(2-chloroaryl) quinazoline-2-amide derivatives designed and synthesized by the invention have the advantages of long half-life period, simple marking condition, high yield and convenience in long-distance transportation, and can be used for diagnosis and treatment of TSPO change related diseases. The invention belongs to the technical field of radiopharmaceutical chemistry and nuclear medicine.

Description

technical field [0001] The invention belongs to the technical field of radiopharmaceutical chemistry and nuclear medicine, and specifically relates to a 4-(2-chloroaryl)quinazoline-2-amide derivative and an application thereof. Background technique [0002] 18kDa translocation protein (TSPO) is an evolutionarily conserved nuclear gene-encoded membrane protein, which is mainly distributed in tissues related to steroid synthesis, such as: testis, ovary granule and luteal cells, placenta, bone marrow, liver, lung and adrenal cortex. TSPO is related to the activation of glial cells, mitochondrial respiration, the opening of mitochondrial permeability transduction pores, immune regulation, cell proliferation and apoptosis, and the transport of cholesterol from the outside of the mitochondrial membrane to the inside of the membrane. Therefore, TSPO is related to stroke , brain trauma, Alzheimer's disease, and the occurrence and development of glioma are closely related. For exam...

Claims

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Application Information

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IPC IPC(8): C07D239/74C07D401/04C07B59/00A61K51/04A61K101/02
CPCC07D239/74C07D401/04C07B59/002A61K51/0459A61K51/0455C07B2200/05
Inventor 吴泽辉吉训明陈华龙蒋增程雪波
Owner 首都医科大学脑重大疾病研究中心
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