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Inhibitors of trpc6

A CH2, -CH3 technology, applied in the field of TRPC6 inhibitors, can solve problems such as unclear mechanism

Pending Publication Date: 2021-11-19
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This inhibitor reduces the proliferation of PASMCs, but the mechanism by which this occurs is unknown

Method used

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  • Inhibitors of trpc6
  • Inhibitors of trpc6
  • Inhibitors of trpc6

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0456] 6-[(2S,4S)-1-{4-[(6-methoxypyridin-3-yl)oxy]benzoyl}-2-methylpiperidin-4-yl]-5-methyl pyridazin-3-amine trifluoroacetate

[0457]

[0458] 4-[(6-Methoxypyridin-3-yl)oxy]benzoic acid (23.8 mg; 0.10 mmol), 5-methyl-6-[(2S,4S)- 2-Methylpiperidin-4-yl]pyridazin-3-amine (20.0 mg; 0.10 mmol) and DIPEA (68.4 μL; 0.40 mmol) were stirred at room temperature and HATU (36.9 mg; 0.10 mmol) was added. After stirring overnight, the reaction mixture was purified by RP-HPLC (ACN / water+TFA).

[0459] Yield: 33.8 mg (64%) ESI-MS: m / z=434 [M+H] + R t (HPLC): 0.58 (Method 11)

Embodiment 2

[0461] 6-[(2S,4S)-1-{3-methoxy-4-[(6-methoxypyridin-3-yl)oxy]benzoyl}-2-methylpiperidine-4- yl]-5-methylpyridazin-3-amine

[0462]

[0463] 3-Methoxy-4-[(6-methoxypyridin-3-yl)oxy]benzoic acid (20.0 mg; 0.07 mmol), HATU (30.0 mg; 0.08 mmol) in DMF (2 mL) and DIPEA (60.0 μL; 0.35 mmol) were stirred at room temperature for 30 minutes. 5-Methyl-6-[(2S,4S)-2-methylpiperidin-4-yl]pyridazin-3-amine (15.0 mg; 0.07 mmol) was added. After stirring for 3 hours, the reaction mixture was passed through RP-HPLC (ACN / water+NH 3 )purification.

[0464] Yield: 6.4 mg (19%) ESI-MS: m / z=464 [M+H] + R t (HPLC): 0.81 (Method 1)

Embodiment 3

[0466] 6-[(2S,4S)-1-{4-methoxy-5-[(6-methoxypyridin-3-yl)oxy]pyridine-2-carbonyl}-2-methylpiperidine- 4-yl]-5-methylpyridazin-3-amine

[0467]

[0468] 4-Methoxy-5-[(6-methoxypyridin-3-yl)oxy]pyridine-2-carboxylic acid (20.0 mg; 0.07 mmol), HATU (30.0 mg; 0.08 mmol) and DIPEA (60.0 [mu]L; 0.35 mmol) were stirred at room temperature for 30 minutes. 5-Methyl-6-[(2S,4S)-2-methylpiperidin-4-yl]pyridazin-3-amine (15.0 mg; 0.07 mmol) was added. After stirring overnight at room temperature, the reaction mixture was passed through RP-HPLC (ACN / water+NH 3 )purification.

[0469] Yield: 2.0 mg (6%) ESI-MS: m / z=465 [M+H] + R t (HPLC): 0.76 (Method 1)

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Abstract

The present invention relates to compounds of formula (I), wherein A, X, R1, R2, R3, R4 and R5 are as defined herein, and pharmaceutically acceptable salts thereof. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, such as hypertension, preeclampsia, restenosis, a cardiac or respiratory condition, renal disease, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia or ischemic reperfusion injury, and cancer.

Description

technical field [0001] The present invention relates to inhibition of transient receptor potential C6 ion channel (TRPC6) for the treatment of cardiac and respiratory disorders, renal disease, liver disease, muscular dystrophy, fibrotic disorders, pain, ischemia or ischemia-reperfusion injury and cancer pharmaceutical compounds, compositions and methods. Background technique [0002] Various ion channel proteins exist to mediate ion flux across cell membranes. Correct expression and function of ion channel proteins are essential for maintaining cellular function, intracellular communication, and the like. An important aspect of achieving cellular homeostasis is maintaining appropriate ion concentrations in various cell types during development and in response to numerous stimuli. A number of different types of ion channels maintain cellular homeostasis by moving ions in and out of cells across the plasma membrane, and by moving ions across intracellular organelles includin...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61P9/12A61P13/12A61P25/00A61P35/00A61P37/00A61K31/501
CPCC07D401/14A61P35/00A61P37/00A61P25/00A61P13/12A61P9/12A61K31/501
Inventor D·格特施灵T·布伊索N·海涅
Owner BOEHRINGER INGELHEIM INT GMBH
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