Arylpyrrolopyridine derived compounds as LRRK2 inhibitors

a technology of arylpyrrolopyridine and derivatives, applied in the field of arylpyrrolopyridine derivatives, can solve problems such as adverse side effects

Inactive Publication Date: 2014-10-23
VERNALIS (R&D) LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these therapies provide significant symptomatic benefit to the patient, they are also associated with adverse side effects and often become ineffective after prolonged treatment.

Method used

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  • Arylpyrrolopyridine derived compounds as LRRK2 inhibitors
  • Arylpyrrolopyridine derived compounds as LRRK2 inhibitors
  • Arylpyrrolopyridine derived compounds as LRRK2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-(3-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0220]

[0221]A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.1 g, 0.56 mmol), 3-methoxyphenylboronic acid (0.094 g, 0.62 mmol), potassium fluoride (0.098 g, 1.6.9 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.003 g, 0.006 mmol), 1,4-dioxane (6 mL) and water (1 mL) was stirred at room temperature for 5 min under a stream of nitrogen. The stirred reaction mixture was then heated with microwaves at 150° C. for 30 min and cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (2×20 mL), followed by brine (20 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with dichloromethane, and the residue was dried in vacuo to afford a light yellow solid (0.061 g, 44%), identified as 4-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS (Method B) (m / z) 25...

example 2

4-(3-Methylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0223]

[0224]0.10 g prepared from 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.20 g, 1.13 mmol) and 3-methylphenylboronic acid (0.17 g, 1.24 mmol) as an off-white solid in 38% yield. LC-MS (Method A) (m / z) 234 (MH+); tR=2.18. 1H NMR (DMSO-d6, 400 MHz) δ: 13.05 (1H, s, br), 8.50 (1H, s), 8.43-8.42 (1H, d), 7.46-7.44 (1H, m), 7.43-7.40 (2H, m), 7.34-7.29 (1H, m), 7.25-7.24 (1H, d), 2.40 (3H, s).

example 3

4-(3-Ethylphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

[0225]

[0226]0.065 g prepared from 4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.10 g, 0.56 mmol) and 3-ethylphenylboronic acid (0.09 g, 0.62 mmol) as an off-white solid in 47% yield. LC-MS (Method A) (m / z) 248 (MH+); tR=2.37. 1H NMR (DMSO-d6, 400 MHz) δ: 12.96 (1H, s, br), 8.51 (1H, s), 8.44-8.42 (1H, d), 7.48-7.41 (3H, m), 7.36-7.33 (1H, m), 7.25-7.24 (1H, d), 2.73-2.67 (2H, q), 1.27-1.24 (3H, t).

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Abstract

The present invention is directed to arylpyrrolopyridine derivatives of formula (A)The compounds are considered useful for the treatment of diseases associated with LRRK2 such as Lewy body dementia, Parkinson's disease or cancer.

Description

FIELD OF THE INVENTION[0001]The present invention relates to arylpyrrolopyridine derivatives which are LRRK2 inhibitors and thus useful in therapy and to pharmaceutical composition comprising said compounds.BACKGROUND OF THE INVENTION[0002]Parkinson's disease is a neurodegenerative disease. It is the second most common neurodegenerative disease after Alzheimer's disease and affects more than 1% of the population above the age of 65. Parkinson's disease is clinically characterised by resting tremor, bradykinesia and muscular rigidity. Pathologically, the disease is characterised by loss of dopaminergic neurons with the consequent decrease in dopamine levels in the brain and by aggregation of the protein α-synuclein in the dopaminergic neurons. These aggregations called Lewy-bodies are composed of insoluble α-synuclein phosporylated at serine-129 and ubiquitin. Current Parkinson's disease therapeutic intervention strategies aim at increasing the dopamine levels in areas innervated by ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04
CPCC07D471/04A61P25/00A61P25/16A61P25/28A61P35/00A61P37/00A61K31/437A61K31/444A61K31/5377
Inventor BEDFORD, SIMON TIMOTHYCHEN, I-JENWANG, YIKANGWILLIAMSON, DOUGLAS STEWART
Owner VERNALIS (R&D) LTD
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