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Compounds

A compound and pharmaceutical technology, applied in the field of compounds, can solve problems such as affecting cell degradation of α-synuclein

Inactive Publication Date: 2016-09-14
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. 16 394-406)

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[2298] N-(1,3-Dimethyl-1H-pyrazol-4-yl)-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine (E1)

[2299]

[2300] N-(1,3-Dimethyl-1H-pyrazol-4-yl)-4-ethoxy-7-toluenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-2-amine A solution of (which can be prepared according to D3) (100 mg, 0.234 mmol) and sodium hydroxide (0.586 mL, 1.172 mmol) in isopropanol (10 mL) was stirred at 50 °C overnight. The reaction mixture was concentrated in vacuo. The residue was poured into water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by preparative HPLC to afford the title compound E1 (12 mg, 0.042 mmol, 18.12% yield) as a yellow solid.

[2301] LCMS: 273.1[M+H] + . t R = 1.10 min. (LCMS condition 2)

[2302] 1 H NMR (400MHz, chloroform-d): δ8.66-9.05(m, 1H), 7.80(s, 1H), 6.69(d, J=1.5Hz, 1H), 6.41(d, J=1.8Hz, 1H ), 6.24(s, 1H), 4.53(q, J=7.1Hz, 2H), 3.82(s, 3H), 2.27(s, 3H), 1.47(t,...

Embodiment 2 and 3

[2304] 1-(4-((4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-2- Methylpropan-2-ol (E2)

[2305] 1-(4-((4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-2- Methylpropan-2-ol (E3)

[2306]

[2307] 2-Chloro-4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine (which can be prepared according to D1) (200 mg, 1.012 mmol), 1-(4-amino-3-methyl-1H -pyrazol-1-yl)-2-methylpropan-2-ol and 1-(4-amino-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol Mixture (206mg, 1.214mmol), Pd 2 (dba) 3 (46.3mg, 0.051mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis-(diphenylphosphine) (58.6mg, 0.101mmol) and potassium carbonate (420mg, 3.04 mmol) in 2-butanol (2.0 mL) was microwave irradiated at 120° C. for 45 min. The reaction mixture was quenched with water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was purified by silica gel column chromatography (DCM:M...

Embodiment 4

[2313]N-(5-chloro-1-methyl-1H-pyrazol-4-yl)-4-ethoxy-7H-pyrrolo[2,3-d]-pyrimidin-2-amine (E4)

[2314]

[2315] N-(5-chloro-1-methyl-1H-pyrazol-4-yl)-4-ethoxy-7-tosyl-7H-pyrrolo[2,3-d]-pyrimidine-2 - A solution of the amine (which can be prepared according to D4) (50 mg, 0.112 mmol) and sodium hydroxide (1 mL, 2.0 mmol, 2M in water) in methanol (3 mL) was stirred at 50 °C for 2 hours. The mixture was extracted with ethyl acetate. The organic layer was dried and evaporated. The crude product was purified by preparative HPLC to afford the title compound E4 (19 mg, 0.065 mmol, 58.0% yield) as a white solid.

[2316] LCMS: 293[M+H] + . t R = 1.278 minutes. (LCMS condition 2)

[2317] 1 H NMR (400MHz, methanol-d 4 ): δ7.82-8.01 (m, 1H), 6.86 (d, J = 3.5Hz, 1H), 6.32 (d, J = 3.5Hz, 1H), 4.51 (q, J = 7.0Hz, 2H), 3.85 (s, 3H), 1.44 (t, J=7.2Hz, 3H).

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Abstract

he present invention relates to novel compounds that inhibit LRRK2 kinase activity, processes for their preparation, to compositions containing them and to 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 / 000139 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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IPC IPC(8): C07D487/04A61K31/519A61P25/16
CPCA61K31/519A61P25/16C07D487/04C07D403/12C07D405/14
Inventor 丁晓刘谦桑迎霞L.P.斯塔西万泽红赵保卫C.M.埃奇
Owner GLAXOSMITHKLINE INTPROP DEV LTD
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