Compounds

A chemical compound and pharmaceutical technology, applied in the field of chemical compounds, can solve problems affecting cells to degrade α-synuclein

Inactive Publication Date: 2016-09-28
GLAXOSMITHKLINE INTPROP DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The LRRK2 protein causes a defect in chaperone-mediated autophagy, which negatively affects the cell's ability to degrade α-synuclein (Orenstein et al., 2013 Nature Neurosci. 16394-406)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0560] (4-((4-ethoxy-7H-pyrrolo-[2,3-d]-pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone (E1 )

[0561]

[0562] The title compound E1 was prepared according to general procedure 5 of the Buchwald reaction starting from 2-chloro-4-ethoxy-7H-pyrrolo-[2,3-d]pyrimidine (which can be prepared according to D1) and ( 4-Amino-3-methoxyphenyl)(morpholino)methanone (which can be prepared according to the procedure described in PCT International Application WO2012097682) as 810 mg of off-white solid. Yield: 35.4%.

[0563] LCMS:398[M+H] + . t R = 3.420 minutes. (LCMS condition 1)

[0564] 1 H NMR (400MHz, DMSO-d 6 ): δ8.62(d, J=8.0Hz, 1H), 7.63(s, 1H), 6.93-7.15(m, 3H), 6.34(d, J=3.5Hz, 1H), 4.52(q, J= 7.0Hz, 2H), 3.94(s, 3H), 3.45-3.70(m, 8H), 1.41(t, J=7.0Hz, 3H).

Embodiment 2

[0566](4-((4-ethoxy-7H-pyrrolo-[2,3-d]-pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino) Methyl ketone (E2)

[0567]

[0568] The title compound E2 was prepared according to general procedure 5 of the Buchwald reaction starting from 2-chloro-4-ethoxy-7H-pyrrolo-[2,3-d]pyrimidine (which can be prepared according to D1) and ( 4-amino-2-fluoro-5-methoxyphenyl)(morpholino)methanone (which can be prepared according to the procedure described in Journal of Medicinal Chemistry, 55(22), 9416-9433; 2012), It was 125 mg of an off-white solid. Yield: 47.1%.

[0569] LCMS:416[M+H] + . t R = 2.999 minutes. (LCMS condition 1)

[0570] 1 H NMR (400MHz, DMSO-d 6 ): δ11.50-11.83 (m, 1H), 8.59 (d, J=12.5Hz, 1H), 7.72 (s, 1H), 7.10 (broad singlet, 1H), 7.01 (d, J=6.1Hz, 1H), 6.36 (broad singlet, 1H), 4.52 (q, J=7.1Hz, 2H), 3.93 (s, 3H), 3.50-3.70 (m, 6H), 3.37-3.43 (m, 2H), 1.41 (t, J = 7.0 Hz, 3H).

Embodiment 3

[0572] (4-((4-ethoxy-7H-pyrrolo-[2,3-d]-pyrimidin-2-yl)amino)-3-methoxyphenyl)(4-methylpiperazine-1 -yl)-methanone (E3)

[0573]

[0574] (4-((4-ethoxy-7-tosyl-7H-pyrrolo-[2,3-d]-pyrimidin-2-yl)amino)-3-methoxyphenyl)(4 A solution of -methylpiperazin-1-yl)-methanone (which can be prepared according to D137) (100 mg, 0.177 mmol) and sodium hydroxide (2 mL, 4.00 mmol, 2M in water) in isopropanol (5 mL) Stir overnight at 60°C. The mixture was evaporated and 2N HCl was added until pH=7. The mixture was extracted with EA. The organic layer was washed with MgSO 4 Dry and evaporate. The residue was purified by prep-HPLC to afford the title compound E3 (25 mg, 0.061 mmol, 34.4% yield) as a white solid.

[0575] LCMS:411[M+H] + . t R = 1.259. (LCMS condition 2)

[0576] 1 H NMR (400MHz, DMSO-d 6 ): δ11.58 (broad singlet, 1H), 8.60 (d, J=8.3Hz, 1H), 7.63 (s, 1H), 6.93-7.13 (m, 3H), 6.33 (broad singlet, 1H), 4.51(d, J=7.0Hz, 2H), 3.93(s, 3H), 3.52(broad singlet, 4H), 2.3...

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Abstract

Provided are novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of or prevention of diseases characterized by LRRK2 kinase activity, for example Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

Description

[0001] related application [0002] This application claims to protect the priority rights and interests of PCT International Application No. PCT / CN2014 / 000140 filed with the State Intellectual Property Office of the People's Republic of China on January 29, 2014, the entire contents of which are incorporated herein by reference. field of invention [0003] The present invention relates to novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, compositions containing them and their use in the treatment of diseases characterized by LRRK2 kinase activity, e.g. Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Background technique [0004] Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective degeneration and cell death of dopaminergic neurons in the substantia nigra region of the brain. Parkinson's disease is generally considered to be sporadic and of unknown etiology, however, the pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D487/00C07D403/00C07D403/02A61K31/437A61K31/4375A61P25/16
CPCA61P25/16A61K31/437A61K31/4375C07D487/04C07D519/00
Inventor 丁晓刘谦龙凯桑迎霞L.P.斯塔西万泽红徐琼峰C.M.埃奇
Owner GLAXOSMITHKLINE INTPROP DEV LTD
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