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Condensed aminodihydrothiazine derivative

An amino, thiazide technology, applied in Alzheimer's type dementia, fused aminodihydrothiazine derivatives and their drug applications, the field of Down syndrome, can solve the problem that basic drugs have not yet been developed and so on

Active Publication Date: 2013-08-21
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, Alzheimer's disease is only treated with symptomatic treatment using symptom-improving agents such as acetylcholinesterase inhibitors, and basic drugs that inhibit the progression of the disease have not yet been developed

Method used

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  • Condensed aminodihydrothiazine derivative
  • Condensed aminodihydrothiazine derivative
  • Condensed aminodihydrothiazine derivative

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0524] ( ± )-[(4aR ＊ , 8aS ＊ )-8a-(5-amino-2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl] Synthesis of tert-butyl carbamate

[0525] [Formula 20]

[0526]

[0527] (1) Synthesis of Ethyl 2-Trifluoromethanesulfonyloxycyclohex-1-enecarboxylate

[0528] Diisopropylethylamine (38.0 mL) was added to a solution of ethyl 2-oxocyclohexanecarboxylate (8.00 g) in dichloromethane (100 mL) at -78°C under nitrogen atmosphere. After stirring at the same temperature for 10 minutes, trifluoromethanesulfonic anhydride (8.80 mL) was added. The mixture was stirred overnight while gradually warming to room temperature. The mixture was washed with water and twice with 5% aqueous citric acid (150 mL). The organic layer was dried with anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound as a crude product (15.5 g). The crude product was used in the next r...

preparation example 2

[0552] [(4aR ＊ , 8aS ＊ )-8a-(5-amino-2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl] Synthesis of tert-butyl carbamate

[0553] [Formula 21]

[0554]

[0555] (1)( +)-[(4aR ＊ , 8aS ＊ )-8a-(2-Fluoro-5-nitrophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl ] Synthesis of tert-butyl carbamate

[0556] CHIRALPAK prepared with Daicel Chemical Industries, Ltd. TM OJ-H optical resolution of the compound (80.0 mg) obtained in Preparation Example 1-(7) (2 cm×25 cm, mobile phase: hexane:ethanol=8:2, flow rate: 20 mL / min). Fractions with retention times of 9.38-18.3 minutes were collected to give the title compound. The same operation was repeated to obtain the title compound (433 mg; >99% ee) from the racemate (1.00 g).

[0557] (2) [(4aR ＊ , 8aS ＊ )-8a-(5-amino-2-fluorophenyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl] Synthesis of tert-butyl carbamate

[0558] A solution of sodium hydrosulfite (923 mg) ...

preparation example 3

[0561] (-)-[(4aR ＊ , 7aS ＊ )-7a-(5-amino-2-fluorophenyl)-4,4a,5,6,7,7a-hexahydrocyclopentadieno[d][1,3]thiazin-2-yl] Synthesis of tert-butyl carbamate

[0562] [Formula 22]

[0563]

[0564] (1) Synthesis of Ethyl 2-Trifluoromethanesulfonyloxycyclopent-1-enecarboxylate

[0565] N,N-Diisopropylethylamine (27.2 mL) was added to a solution of ethyl 2-oxo-cyclopentanecarboxylate (5.00 g) in dichloromethane (100 mL) at -78°C for 10 minutes. Trifluoromethanesulfonic anhydride (5.92 mL) was added dropwise to the reaction solution at the same temperature. The reaction solution was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, which was then washed twice with 5% aqueous citric acid (150 mL). The organic layer was dried with anhydrous magnesium sulfate. The drying agent was removed by filtration and toluene (200 mL) was added to the filtrate. Dichloromethane was evaporated under reduced pressure at room tem...

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Abstract

A compound represented by the general formula: or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C 6-14 aryl group or the like, L is -NR e CO- or the like (wherein R e is a hydrogen atom or the like), Ring B is a C 6-14 aryl group or the like, X is a C 1-3 alkylene group or the like, Y is a single bond or the like, Z is a C 1-3 alkylene group or the like, R 1 and R 2 are each independently a hydrogen atom or the like, and R 3 , R 4 , R 5 and R 6 are independently a hydrogen atom, a halogen atom or the like, has an A² production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by A² and typified by Alzheimer-type dementia.

Description

technical field [0001] The present invention relates to fused aminodihydrothiazine derivatives and their pharmaceutical applications. More specifically, the present invention relates to fused aminodihydrothiazine derivatives having amyloid-beta (hereinafter referred to as Abeta) protein production inhibition or beta-site amyloid-beta precursor protein cleavage Enzyme 1 (hereinafter referred to as BACE1 or β-secretase) inhibits and effectively treats neurodegenerative diseases caused by Aβ protein, especially Alzheimer's dementia, Down's syndrome, etc.; A pharmaceutical composition of an aminodihydrothiazine derivative as an active ingredient. Background technique [0002] Alzheimer's disease is a disease characterized by neuronal degeneration and loss and the formation of senile plaques and neurofibrillary degeneration. At present, Alzheimer's disease is only treated with symptomatic treatment with typical symptom improving agents, such as acetylcholinesterase inhibitors, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D279/08A61K31/4439A61K31/5415A61K31/542A61P25/28A61P43/00C07D417/10C07D417/12C07D513/04
CPCC07D471/04A61K31/542C07D417/14C07D513/04C07D417/12C07D417/10C07D279/08A61P25/00A61P25/28A61P43/00
Inventor 鈴木裕一元木贵史金子敏彦高石守石田祐武田邦稔北陽一山本昇A·卡恩P·季莫普洛斯
Owner EISIA R&D MANAGEMENT CO LTD
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