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Inhibitors of leucine rich repeat kinase 2

A compound, selected technology, applied in the direction of medical preparations containing active ingredients, drug combinations, organic chemistry, etc., can solve the problems of reduced axon length and branching, defects in cell proliferation and migration, etc.

Inactive Publication Date: 2020-03-17
GLAXOSMITHKLINE INTPROP DEV LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Other studies have also shown that overexpression of the G2019S mutant form of LRRK2 results in defects in cell proliferation and migration of subventricular zone (SVZ) neural progenitor cells in a transgenic mouse model (see Winner et al., 2011 Neurobiol. Dis. 41:706- 716) and a cell culture model of reduced axon length and branching (see Dachsel et al., 2010 Parkinsonism & Related Disorders 16:650-655)

Method used

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  • Inhibitors of leucine rich repeat kinase 2
  • Inhibitors of leucine rich repeat kinase 2
  • Inhibitors of leucine rich repeat kinase 2

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0748] General Experimental Methods

[0749] The following description and examples illustrate the invention. These examples are not intended to limit the scope of the invention, but to provide guidance to those skilled in the art in making and using the compounds, compositions and methods of the invention. While specific embodiments of the invention have been described, it will be understood by chemists in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

[0750] The chemical names of the compounds described in this application follow the IUPAC nomenclature.

[0751] Heating of the reaction mixture by microwave irradiation was accomplished on a Smith Creator (purchased from Personal Chemistry, Forboro / MA, now owned by Biotage), Emrys Optimizer (commercially available from Personal Chemistry), or Explorer (courtesy of CEM Discover, Matthews / NC) microwaves.

[0752] Conventional techniques can be used h...

Embodiment E1

[1669] 14-Chloro-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatricyclo[11.3.1.0 3,7 ]Heptadeca-1(16),3,6,13(17),14-pentaene(E1)

[1670]

[1671] To a solution of D9 (121 mg, 0.30 mmol) in i-PrOH (5 mL) was added HCl (0.03 mL, 0.3 mmol). The reaction was stirred at 100°C for 16 hours. The reaction mixture was concentrated and the residue was diluted with EtOAc (20 mL) and washed with saturated NaHCO 3 Wash with aqueous solution (20 mL). The organic layer was then concentrated and the residue was purified by prep-HPLC to give the title compound as a white solid (29 mg, 26.4% yield). LC-MS: 367.5[M+H] + . 1 H NMR (400MHz, CDCl 3 ): δ7.81(s, 1H), 6.26(s, 1H), 5.55(s, 1H), 4.40(br, 2H), 4.12~4.10(m, 3H), 3.48~3.36(m, 4H), 2.29-2.21 (m, 5H), 1.92 (br, 2H), 1.80-1.74 (m, 2H).

Embodiment E2

[1673] 14-Chloro-10-methoxy-4-methyl-5-(oxan-4-yl)-8-oxa-2,5,6,12,16,17-hexaazatri ring [11.3.1.0 3,7 ]Heptadeca-1(16),3,6,13(17),14-pentaene(E2)

[1674]

[1675] To a solution of D16 (120 mg, 0.26 mmol) in EtOH (20 mL) was added Fe (72 mg). Then add NH 4 Cl (68.9mg) in H 2 solution in O (2 mL). The reaction was stirred overnight at 100 °C. The mixture was filtered and the filter cake was washed with EtOH (2 x 50 mL). The combined filtrates were concentrated to give the title compound as a white solid (40 mg, 38.9% yield). LC-MS: 395.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 ): δ7.85(s, 1H), 6.07(s, 1H), 5.68(br, 1H), 4.50(d, J=7.6Hz, 1H), 4.34~4.29(m, 1H), 4.12~4.06( m, 3H), 3.90(d, J=2.0Hz, 1H), 3.52(t, J=11.6Hz, 2H), 3.40(s, 3H), 3.36~3.27(m, 2H), 2.32~2.20(m , 5H), 1.81 ~ 1.75 (m, 2H).

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Abstract

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

Description

technical field [0001] The present invention relates to novel compounds that inhibit LRRK2 kinase activity, methods for their preparation, compositions containing them and their use in the treatment of diseases associated with or characterized by LRRK2 kinase activity, e.g. Parkinson's disease, Alzheimer's Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Background technique [0002] Parkinson's disease (PD) is a neurodegenerative disorder characterized by selective degeneration and cell death of dopaminergic neurons in a large portion of the substantia nigra region of the brain. Parkinson's disease is generally considered to be sporadic and of unknown etiology, however, the past 15 years have seen important developments in the understanding of the genetic basis of the disease and the associated pathogenic mechanisms. One area of ​​this research and development is understanding the leucine-rich repeat kinase 2 (LRRK2) protein. In familial studies, many missense...

Claims

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Application Information

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IPC IPC(8): C07D487/08A61P25/16A61P25/28A61K31/529
CPCC07D487/08A61P25/16A61P25/28C07D498/18C07D519/00
Inventor 丁晓M-H.霍任峰H.于湛洋
Owner GLAXOSMITHKLINE INTPROP DEV LTD
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