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Amine Derivatives as Potassium Channel Blockers

a potassium channel and derivative technology, applied in the field of compounds useful in the modulation of the potassium channel activity in cells, can solve the problems of immune synapse formation, blockade of the channel, high blood sugar and other metabolic abnormalities,

Inactive Publication Date: 2015-10-22
BONOMICS LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively modulate Kv1.3 channel activity, providing therapeutic benefits for autoimmune and inflammatory diseases with minimal impact on beneficial immune responses, thus offering a more effective and safer treatment option.

Problems solved by technology

However, blockade of the channel does not prevent immune synapse formation (Panyi G. et al, Proc. Natl. Acad. Sci. U.S.A., 101(5):1285-90; Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A., 103(46): 17414-9).
Symptoms include muscle weakness and paralysis, and the disease can progress rapidly and unpredictably and may eventually lead to death.
Type 1 diabetes mellitus is a disease caused by autoimmune destruction of insulin-producing cells in the pancreas, resulting in high blood sugar and other metabolic abnormalities.
Its long-term consequences may include blindness, nerve damage and kidney failure, and left untreated is rapidly fatal.
Treatment involves life-long administration of insulin or pancreas transplantation, both of which may entail serious side effects (Beeton C. et al, Proc. Natl. Acad. Sci. U.S.A.
At present there exist a number of non-selective K channels that will inhibit lymphocyte proliferation, but have adverse side effects.
Other K channels exist in a wide range of tissues including the heart and brain, and generally blocking these channels is undesirable.
However the use of this compound is limited by its potent toxicity.

Method used

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  • Amine Derivatives as Potassium Channel Blockers
  • Amine Derivatives as Potassium Channel Blockers
  • Amine Derivatives as Potassium Channel Blockers

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-[cyclopropyl(4-methoxyphenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

[0494]

[0495]Intermediate a (25 mg, 0.09 mmol) was reacted with Intermediate nn (46.7 mg, 0.23 mmol) in presence of triethylamine (26 μl, 0.19 mmol) according to General Procedure C to afford the title compound (34 mg, 84%) as clear oil. 1H NMR (CDCl3) δ 8.52-8.37 (m, 1H), 7.65-7.43 (m, 1H), 7.30-6.70 (m, 10H), 5.19-4.96 (m, 1H), 4.55-4.12 (m, 2H), 3.81-3.77 (m, 3H), 3.57-3.47 (m, 1H), 2.79-2.35 (m, 2H), 1.33-1.23 (m, 4H), 1.20-0.15 (m, 4H). 1H NMR (d6-DMSO, 110° C.) δ 8.42 (br s, 1H), 7.61-7.56 (m, 1H), 7.27-6.99 (m, 8H), 6.84-6.81 (m, 2H), 4.72-4.67 (m, 2H), 4.34 (t, J=17.7 Hz, 1H), 3.75 (s, 3H), 3.42-3.32 (m, 1H), 2.80-2.43 (m, 2H), 1.28-1.12 (m, 4H), 0.68-0.61 (m, 1H), 0.32-0.12 (m, 3H). LCMS (Method 2) Rt 2.346 min (98.2% purity), m / z 433.3 (M+H)+.

example 2

N-[cyclopropyl(4-methoxyphenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)propanamide

[0496]

[0497]Intermediate a (30 mg, 0.11 mmol) was reacted with 3-(4-fluorophenyl)propanoyl chloride (41.7 mg, 0.22 mmol) in presence of triethylamine (31.2 μl, 0.22 mmol) according to General Procedure C to afford the title compound (32 mg, 68%) as clear oil. 1H NMR (CDCl3) δ 8.49-8.41 (m, 1H), 7.56-7.50 (m, 1H), 7.26-7.05 (m, 6H), 6.99-6.89 (m, 2H), 6.84-6.78 (m, 2H), 5.20-5.11 (m, 1H), 4.51-4.09 (m, 2H), 3.79 (br s, 3H), 3.06-2.90 (m, 2H), 2.75-2.47 (m, 2H), 1.04-0.95 (m, 1H), 0.79-0.66 (m, 1H), 0.39-0.28 (m, 2H), 0.12-0.04 (m, 1H). LCMS (Method 2) Rt 2.192 min (96.6% purity), m / z 419.2 (M+H)+.

example 3

(3R)—N-[cyclopropyl(4-chlorophenyl)methyl]-3-(4-fluorophenyl)-N-(pyridin-2-ylmethyl)butanamide

[0498]

[0499]Intermediate b (30 mg, 0.11 mmol) was reacted with Intermediate ei (44 mg, 0.22 mmol) in presence of triethylamine (31 μl, 0.22 mmol) according to General Procedure C to afford the title compound (42 mg, 88%) as clear oil. 1H NMR (CDCl3) δ 8.53-8.36 (m, 1H), 7.65-7.44 (m, 1H), 7.33-6.82 (m, 10H) 5.21-4.96 (m, 1H), 4.57-4.06 (m, 2H), 3.58-3.42 (m, 1H), 2.74-2.28 (m, 2H), 1.33-1.24 (m, 4H), 0.98-0.82 (m, 1H), 0.76-0.56 (m, 1H), 0.40-0.18 (m, 2H). HPLC (Method 2) Rt 2.831 min (100% purity). MS (ES+) m / z 437.3 (M+H+).

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Abstract

The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.

Description

FIELD OF INVENTION[0001]The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of Kv1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.BACKGROUND[0002]Potassium channels represent a complex class of voltage-gated ion channels from both functional and structural standpoints. Their functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. In general, four sequence-related potassium channel genes—shaker, shaw, shab, and shal—have been identified in Drosophila, and each has been shown to have human homolog(s). KCNA3 encodes the voltage-gated KV1.3 potassium ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D451/04C07D405/12C07D237/08C07D213/64C07D411/12C07D401/12C07D213/40C07D241/12
CPCC07D451/04C07D213/40C07D405/12C07D237/08C07D213/64C07D411/12C07D401/12C07D241/12C07C317/32C07D211/16C07D211/38C07D213/89C07D231/12C07D233/64C07D239/26C07D241/18C07D309/14C07D413/12C07C2601/02C07D233/56C07D239/24C07C217/90C07D209/52C07D211/26C07D213/16C07D213/61C07D213/70C07D239/34A61P1/02A61P13/12A61P17/00A61P17/06A61P25/00A61P29/00A61P3/04A61P31/08A61P35/00A61P37/02A61P37/06A61P43/00A61P9/00
Inventor HARVEY, ANDREWBOMBRUN, AGNESCOOKE, RACHELJEANCLAUDE-ETTER, ISABELLEKUCHEL, NATHANMOLETTE, JEROMEMOULD, JORGENPAUL, DHARAMSINGH, RAJINDERDONINI, CRISTINACOLOVRAY, VERONIQUEAVERY, THOMASCROSSMAN, JULIARIPPER, JUSTIN
Owner BONOMICS LTD
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