Novel compound that specifically binds to ampa receptor

一种化合物、溶剂合物的技术，应用在新颖化合物领域，能够解决探针脑移行性低、AMPA受体特异性结合不充分等问题，达到高产率、容易合成的效果

Active Publication Date: 2018-04-17
PUBLIC UNIV CORP YOKOHAMA CITY UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, conventional molecular probes are difficult to use for in vivo imaging of AMPA receptors due to insufficient specific binding to AMPA receptors or low brain migration of the probes.

Method used

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  • Novel compound that specifically binds to ampa receptor
  • Novel compound that specifically binds to ampa receptor
  • Novel compound that specifically binds to ampa receptor

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example 1

[0082] R 2 A compound of formula (I) or a pharmaceutically acceptable salt or a solvate thereof, which is an alkyl, alkenyl or alkynyl group, can be obtained, for example, by making a compound of the following formula (II) or a pharmaceutically acceptable salt or a solvent thereof compound:

[0083] [chemical 4]

[0084]

[0085] (where A, X, Y, Z, R 1 , R 3 , R 4 , R 5 , and n are the same as defined in the compound of formula (I)) and X 1 -R 2 (where, R 2 is alkyl, alkenyl or alkynyl, X 1 It is produced by reaction of halogen). In one embodiment, R in formula (I) and formula (II) 3 and R 4 Both are hydrogen. In one embodiment, R 2 for[ 11 C] alkyl, [ 11 C] alkenyl, or [ 11 C] alkynyl, preferably R 2 for[ 11 C] alkyl especially 11 CH 3 . In one embodiment, X 1 for I. If the specific example of the compound of formula (II) is listed, there are 2-[2,6-difluoro-4-({2-[(benzenesulfonyl)amino]ethyl}thio)phenoxy]acetamide (PEPA).

[0086] The reaction ca...

Synthetic example 2

[0091] R 1 A compound of formula (I) that is an alkyl, alkenyl, or alkynyl group, or a pharmaceutically acceptable salt or solvate thereof, can be obtained by making a compound of the following formula (III), or a pharmaceutically acceptable salt thereof Salt or solvate:

[0092] [chemical 5]

[0093]

[0094] (where A, X, Y, Z, R 2 , R 3 , R 4 , R 5 , and n are the same as defined above, R a independently, are alkyl, alkenyl, or alkynyl) and X 1 -R 1 (where, R 1 Same as defined above, X 1 It is produced by reaction of halogen). In one embodiment, R a All are n-butyl. In one embodiment, R 1 for[ 11 C] alkyl, [ 11 C] alkenyl, or [ 11 C] alkynyl, preferably R 1 for[ 11 C] alkyl especially 11 CH 3 . In one embodiment, X 1 for I.

[0095] Specific examples of the compound of formula (III) are as follows.

[0096] [table 3]

[0097]

[0098] The reaction can be carried out in the presence of palladium catalysts, phosphine ligands, carbonates and coppe...

Embodiment 1

[0115] (Synthesis of K-1 and K-2)

[0116] According to the following scheme, 2-[2,6-difluoro-4-({2-[(benzenesulfonyl)amino]ethyl}thio)phenoxy]acetamide (K-1, PEPA) was synthesized and {4-[2-(phenylsulfonyl-methyl-amino)-ethylthio]-2,6-difluoro-phenoxy}-acetamide (K-2).

[0117] about each compound 1 H NMR spectrum, using TMS (tetramethylsilane, tetramethylsilane) as an internal standard, and recorded with Bruker Avance III 400MHz or Varian Mercury plus-300MHz.

[0118] [chemical 6]

[0119]

[0120] Step (i): Synthesis of (2,6-difluoro-phenoxy)-methyl acetate (2)

[0121] [chemical 7]

[0122]

[0123] To a solution of 2,6-difluoro-phenol (1) (5.00 g, 38.5 mmol) in acetone (75 mL) was added K 2 CO 3 (8.40 g, 60.7 mmol), and methyl bromoacetate (5.80 g, 38.5 mmol) was added to the reaction solution after 10 minutes. The reaction solution was stirred overnight at room temperature. After the reaction, the reaction mixture was poured into a mixture of concentrated h...

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PUM

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Abstract

The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof. This compound is capable of specifically binding to an AMPA receptor, and shows extremely high brain uptake. (In the formula, each of A and Z independently represents CO, SO or SO2; each of X and Y independently represents S or O; each of R1-R4 independently represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group or a halogen group; each R5 independently represents an alkyl group, an alkenyl group, an alkynyl group or a halogen group; andn represents an integer of 0-4.)

Description

technical field [0001] The present invention relates to a novel compound specifically binding to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor, its pharmaceutically acceptable salt, and Solvates thereof, compositions comprising the compounds, methods for producing the compounds, and intermediates for producing the compounds. Background technique [0002] Regarding AMPA receptors, it is known that they are widely distributed in the central nervous system and are involved in learning, memory, neurodegeneration, and cell death. In recent years, studies on the treatment of psychiatric and neurological diseases targeting AMPA receptors have been advanced (Patent Documents 1 to 3). In order to investigate the relationship between AMPA receptors and these diseases, it is possible to evaluate the expression amount and distribution of AMPA receptors in the brain. However, in order to investigate the amount of expression of such AMPA receptors, there are vari...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/49A61K51/00C07C319/20C07F7/22C07B59/00
CPCC07C323/49C07F7/2208A61K51/04C07B59/001C07B2200/05A61K51/00A61K51/0474C07B59/004C07C319/20C07F7/22
Inventor 高桥琢哉宫崎智之须原哲也樋口真人张明栄
Owner PUBLIC UNIV CORP YOKOHAMA CITY UNIV
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