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Radioactive halogen-labeled phenyloxyaniline derivatives

A phenoxyaniline and radioactive technology, applied in the field of phenoxyaniline derivatives, can solve problems such as quantitative analysis problems

Inactive Publication Date: 2008-02-27
TAISHO PHARMACEUTICAL CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the minimal accumulation of this compound in the brain and problems in quantitative analysis, it is necessary to develop a PBR ligand that can give a very high signal

Method used

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  • Radioactive halogen-labeled phenyloxyaniline derivatives
  • Radioactive halogen-labeled phenyloxyaniline derivatives
  • Radioactive halogen-labeled phenyloxyaniline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] preparation[ 131 1]-N-(2,5-dimethoxybenzyl)-N-(5-iodo-2-phenoxyphenyl)acetamide (hereinafter referred to as [ 131 I]-1IDAA1106)

[0034] 1-1) Dissolve N-(2,5-dimethoxybenzyl)-N-(5-bromo-2-phenoxyphenyl)acetamide (510 mg, 1.12 mmol) in toluene, and wash with hexa Butylditin(IV) and dichlorobis(triphenylphosphine)palladium(0) were refluxed for 4 days. After removing toluene, the reaction product was purified by silica gel column chromatography (eluted by hexane:ethyl acetate=1:4) to obtain 320 mg (43%) of N-(2,5-dimethoxybenzyl)-N -(5-tributylstannyl-2-phenoxyphenyl)acetamide.

[0035] FABMS C 36 h 48 FNO 3 Sn(m / z)680.5(m + +1)

[0036] To a solution of N-(2,5-dimethoxybenzyl)-N-(5-tributylstannyl-2-phenoxyphenyl)acetamide (55 mg, 0.083 mmol) in chloroform was added 100 mg of solid iodine, the resulting reaction solution was stirred at room temperature for 1 hour, and then a saturated aqueous solution of sodium thiosulfate was added to the reaction solution until...

Embodiment 2

[0039] Preparation of N-(2-[ 131 I] iodo-methoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (hereinafter referred to as [ 131 I]-2IDAA1106)

[0040] Add 100 μL of acetic acid / 30% hydrogen peroxide (3 / 1) to N-(2-tributylstannyl-5-methoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl ) acetamide (0.1 mg) in ethyl acetate (100 μL) and mix. Add to it [ 131 I] NaI (0.1 mCi), let stand for 1 minute. After the reaction was completed, the reaction mixture was injected into a reverse-phase semi-preparative HPLC (YMC J'sphere ODS-H80 column, 10mmID x 250mm). Using CH at a flow rate of 4 mL / min 3 CN / H 2 O(9 / 1) was used as the mobile phase to obtain [ 131 I] Fraction of 1IDAA1106. The solvent was removed from this fraction by distillation under reduced pressure, and the residue was dissolved in physiological saline (1 mL), which was then passed through a 0.22 μm Millipore filter to successfully obtain [ 131 I] 2IDAA1106 (0.095 mCi).

[0041] (experimental example)

[0042] ex vivo autor...

Embodiment 3

[0060] N-(4-Chloro-2-phenoxyphenyl)-N-(2-[2- 11 C] isopropoxybenzyl) acetamide ([ 11 C]3)

[0061] Ultra-high-purity nitrogen (1.5 MPa) containing 0.01% oxygen is irradiated with 18.5 MeV protons from a cyclotron by 14 N(p,α) 11 The C nuclear reaction produces carrier-free [ 11 C]CO 2 .

[0062] After radiation, through N 2 (50mL / min) [ 11 C]CO 2 , and concentrated until liquid N 2 The radioactivity throughout the coil reaches a steady state in a stainless steel coil cooled to -150°C. The concentrated [ 11 C]CO 2 , so that dry N 2 (2mL / min) inflow containing CH at -5°C 3 In the loop of MgBr. When the transfer of radioactivity is complete, stop the N 2 flow, and then hold the loop at 25°C for 5 minutes to perform the Grignard reaction. Subsequently, LiAlH 4 A solution of THF (0.2M, 500 μL) was passed through the loop and the reaction mixture was moved to a heated reactor at 180° C. for 1 min. After the reactor was cooled at 50-60°C, an aqueous solution of HI (...

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Abstract

A radioactive halogen-labeled phenyoxyaniline derivative represented by the following formula: wherein R<1> represents a group such as an alkyl group; X<1>, X<2>, X<3> and X<4> represent each a hydrogen atom, an alkyl group, an alkoxy group, an alkoxy group carrying <11>C introduced thereinto or a radioactive halogen atom, provided that at least one of X<1>, X<2>, X<3> and X<4> represents an alkoxy group carrying <11>C introduced thereinto or a radioactive halogen atom; which is a compound useful as a PBR ligand having a high affinity and a high selectivity. In in vitro measurement of PBR, a PBR ligand having a high affinity and a high selectivity is labeled with a radioactive halogen nuclear species so as to enable the measurement of PBRin vivo with the use of means including not only PET but also SPECT. Thus, a compound which is useful in early diagnosing, preventing and treating diseases such as Alzheimer type dementia can be obtained.

Description

technical field [0001] The present invention relates to radioactive halogen-labeled phenoxyaniline derivatives with high affinity for peripheral benzodiazepine receptors. Background technique [0002] Benzodiazepine receptors (BZ) are divided into central and peripheral receptors. Benzodiazepine receptors (PBR) were first observed in peripheral tissues, but their presence has also been recognized in the central nervous system. Furthermore, it has been revealed that the density of PBR in the central nervous system is very high, almost as high or higher than the density of central benzodiazepine receptors (CBR) in the same region. Studies so far have reported that PBR is associated with a variety of diseases, such as Alzheimer's disease, front-temporal dementia, diffuse Lewy corpuscle disease , vascular lesions, Parkinson's disease (Parkinson's disease) related diseases, corticobasilardegeneration (corticobasilardegeneration), Parkinson's disease, Whittington's chorea (Hunti...

Claims

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Application Information

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IPC IPC(8): C07C233/25A61K51/00C07B59/00
CPCC07B59/001A61K51/04C07B2200/05C07C233/88C07C233/25C07C233/07
Inventor 铃木和年须原哲也H·克里斯塔尔张明荣中里笃郎
Owner TAISHO PHARMACEUTICAL CO LTD
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