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Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5- phenylimidazolone compounds as ss-secretase inhibitors

A technology of difluoromethoxyl compounds applied to amino-5-[substituted-4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds as beta-secretase inhibitors field, it can solve the problems that cannot be predicted a priori, blocking hERG channels, etc.

Inactive Publication Date: 2010-02-03
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Disappointingly, it is currently impossible to predict a priori whether a particular class of compound will block hERG channels

Method used

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  • Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5- phenylimidazolone compounds as ss-secretase inhibitors
  • Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5- phenylimidazolone compounds as ss-secretase inhibitors
  • Amino-5-[substituted-4-(difluoromethoxy)phenyl]-5- phenylimidazolone compounds as ss-secretase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0348] Preparation of 2-amino-5-[4-(difluoromethoxy)-3-methylphenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one

[0349]

[0350] Step 1: 1-(Difluoromethoxy)-4-iodo-2-methylbenzene

[0351] A mixture of 4-iodo-2-methylphenol (10 g, 42.7 mmol) in DMF and water was treated with 2-chloro-2,2-difluoroacetic acid (3.61 ml, 42.7 mmol) and potassium carbonate (23.62 g, 171 mmol) Worked up, heated to 120 °C for 12 hours, cooled to room temperature and diluted with EtOAc and water. The organic phase was separated, washed successively with water and brine, washed with Na 2 SO 4 Dry and concentrate in vacuo. The resulting residue was purified by flash chromatography (0-10% EtOAc / hexanes) to give 1-(difluoromethoxy)-4-iodo-2-methylbenzene (3 g, 10.56 mmol, 24.72 %Yield). 1 H NMR (400MHz, DMSO-d 6 )δ7.66(d, J=1.5Hz, 1H), 7.56(dd, J=8.47 and 2.09Hz, 1H), 7.15(t, J H-F =74Hz, 1H), 6.92(d, J=8.47Hz, 1H), 2.15(s, 3H).

[0352] Step 2: 1-(Difluoromethoxy)-2-methyl-4-(phenylethyn...

example 2

[0359] Preparation of (5S)-2-amino-5-[4-(difluoromethoxy)-3-methylphenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazole -4-keto[A] and (5R)-2-amino-5-[4-(difluoromethoxy)-3-methylphenyl]-3-methyl-5-phenyl-3,5 -Dihydro-4H-imidazol-4-one[B]

[0360]

[0361] 2-amino-5-[4-(difluoromethoxy)-3-methylphenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one (1.8 g, 5.21 mmol) of the racemic mixture was separated by chiral chromatography (Chiral Cel OJ (Chiral Cel OJ) 5 x 50 cm, mobile phase 15% 2-butanol (0.1% DEA) in hexane) , the title product A (S-enantiomer) peak 1 was obtained as a white solid, RT = 8.5 min, (0.9 g, 2.61 mmol, 50.0% yield), MS m / e (M+H) + 346.10, [α] D 25 =+11.2 (c=1% in MeOH); and the title product B (R-enantiomer) peak 2 as a white solid, RT=11.8 min, (0.84 g, 2.432 mmol, 46.7% yield ), MS m / e(M+H) + 346.10, [α] D 25 = -9.2 (c = 1% in MeOH).

example 3

[0363] Preparation of 2-amino-4-(4-(difluoromethoxy)-3-methylphenyl)-4-(4-fluorophenyl)-1-methyl-1H-imidazole-5(4H)- ketone

[0364]

[0365] Step 1: {[4-(Difluoromethoxy)-3-methylphenyl]ethynyl}trimethylsilane

[0366] 4-Bromo-1-(difluoromethoxy)-2-methylbenzene (5.3g, 22.36mmol), ethynyltrimethylsilane (4.74ml, 33.5mmol) and triethylamine (15.58ml, 112mmol ) in DMF by adding N 2 Degas by bubbling for 30 min under constant N 2 Treat with bis(triphenylphosphine)dichloropalladium (0.785 g, 1.118 mmol) with bubbling, copper(I) iodide (0.426 g, 2.236 mmol), warm to 65°C for 12 hours, cool to room temperature , partitioned between ether and 2M HCl and filtered through Celite. The filtrate was separated and the organic phase was washed successively with 2M HCl and brine, washed with Na 2 SO 4 Dry and concentrate in vacuo. The resulting residue was purified by flash chromatography (100% hexanes) to give ((4-(difluoromethoxy)-3-methylphenyl)ethynyl)trimethylsilane (5.49 g, ...

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Abstract

The present invention provides a 2-amino-5-[substituted-4-(difluoromethoxy)phenyl]-5-phenylimidazolone compound of formula (I) The present invention also provides methods for the use thereof to inhibit ss-secretase (BACE) and treat ss-amyloid deposits and neurofibrillary tangles.

Description

technical field [0001] The present invention relates to amino-5-[substituted-4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds as beta-secretase inhibitors, compositions and reagents containing said derivatives Boxes, methods of making the same and methods of using the same to prevent and treat diseases or disorders associated with beta-amyloid deposition and neurofibrillary tangles, including Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary Hemorrhagic Amyloidosis of the Dutch Type (HCHWA-D) and other neurodegenerative disorders. Background technique [0002] β-Amyloid deposition and neurofibrillary tangles are two major pathological features associated with Alzheimer's disease (AD). AD is clinically manifested as loss of memory, cognition, reasoning, judgment and sense of orientation. As the disease progresses, motor, sensory, and language abilities are also affected, until global impairment of multiple cognitive functions occurs. These cognitive los...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/88
CPCC07D233/88A61P25/00A61P25/28A61P43/00A61K31/4168
Inventor 迈克尔·索蒂里奥斯·马拉马斯艾伯特·琼·罗比肖亚历山大·迈克尔·波特威廉·罗纳德·索尔维比莱盖·米谢勒·莫里斯斯凯勒·亚当·安塔内金智寅罗伯特·埃米特·麦克德维特
Owner WYETH LLC
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