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p2x3 receptor antagonists for the treatment of pain

A technology of CH2 and medicinal salts, applied in the field of regulators, can solve the problems of complication, hindrance and lack of susceptibility

Active Publication Date: 2011-12-07
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, in mammalian physiology, the availability of purinergic ligands to evaluate the effects of individual P2 receptor subtypes is complicated by the susceptibility of P2 receptor agonists to undergo enzymatic degradation
Likewise, studies of the roles of individual P2X receptors have been hampered by the lack of receptor subtype-specific agonists and antagonists

Method used

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  • p2x3 receptor antagonists for the treatment of pain

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 132

[0305]

[0306] 2-(2-fluoro-4-methylphenyl)-6-morpholin-4-yl-N-[(1S)-1-(4H-1,2,4-triazol-3-yl) Ethyl]isonicotinamide

[0307] Step A: Methyl 2-chloro-6-(2-fluoro-4-methylphenyl)isonicotinate

[0308] To a solution of methyl 2,6-dichloroisonicotinate (3.34 g, 16.2 mmol) in toluene (100 mL) was added (2-fluoro-4-methylphenyl)boronic acid (1.4 g, 9.09 mmol), tetrakis( Triphenylphosphine) palladium(0) (0.94 g, 0.81 mmol) and sodium carbonate (2.0 M in water; 8.1 g, 16.2 mmol). The mixture was degassed with nitrogen (3x) and heated to 80°C. After 42 h, the mixture was cooled to ambient temperature and saturated NaHCO was added 3 . The mixture was extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase chromatography (C-18, 85% water / acetonitrile → 5% water / acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (1.07 g). MS 280.0(M+1).

...

Embodiment 162

[0316]

[0317] 2-(2,4-difluorophenyl)-6-(1-hydroxyl-1-methylethyl)-N-{(1R)-1-[1-oxidation-6-(three Fluoromethyl)pyridin-3-yl]ethyl}isonicotinamide

[0318] Step A: Methyl 2-(2,4-difluorophenyl)-6-isopropenylisonicotinate

[0319] Methyl 2,6-dichloroisonicotinate (0.1g, 0.49mmol), tripotassium phosphate (0.16g, 0.73mmol), palladium(II) acetate (8.72mg, 0.04mmol) and tris(2-methyl A degassed solution of oxyphenyl)phosphine (27.4 mg, 0.08 mmol) in THF (1 mL) and water (0.25 mL) was added to 2-isopropenyl-4,4,5,5-tetramethyl-1, 3,2-Dioxaborolane (0.11 mL, 0.61 mmol)). The mixture was heated to 65°C. After 4 h, a solution of (2,4-difluorophenyl)boronic acid (0.12 g, 0.73 mmol) in THF (0.5 mL) was added. The mixture was continuously stirred at 65°C. After 18 h, the mixture was cooled to ambient temperature. Add saturated NaHCO 3aqueous solution and the mixture was extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over mag...

Embodiment 163

[0325]

[0326] 2-(2-Hydroxypropan-2-yl)-6-(4-methylphenyl)-N-[(1S)-1-(4H-1,2,4-triazole-3- Base) ethyl] pyridine-4-carboxamide

[0327] Step A: Methyl 2-(4-methylphenyl)-6-(prop-1-en-2-yl)pyridine-4-carboxylate

[0328] To a degassed solution of palladium(II) acetate (21.8 mg, 0.10 mmol) and tris(2-methoxyphenyl)phosphine (68.4 mg, 0.19 mmol) in THF (1 mL) was added methyl 2,6-dichloroiso Nicotinate (250mg, 1.21mmol), tripotassium phosphate (386mg, 1.82mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborol A degassed mixture of alkanes (0.285 mL, 1.52 mmol) in THF (1.5 mL) and water (0.625 mL). The mixture was heated to 63°C. After 4 h, a degassed solution of 4-methylphenylboronic acid (247 mg, 1.82 mmol) in THF (1.25 mL) was added. The resulting mixture was heated to 63°C. After 18 h, 4-methylphenylboronic acid (247 mg, 1.82 mmol), palladium(II) acetate (21.8 mg, 0.10 mmol) and tris(2-methoxyphenyl)phosphine (68.4 mg, 0.19 mmol) were added. The resulting ...

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Abstract

The present invention relates to novel P2X3 receptor antagonists, which play an important role in the treatment of pain-related disease states, especially peripheral pain, inflammatory pain or tissue injury pain that can be treated with P2X3 receptor subunit modulators.

Description

field of invention [0001] The present invention generally relates to acting as a P2X 3 Compounds that are modulators of receptors, such as antagonists, compositions and therapeutic uses thereof. Background of the invention [0002] Purines acting through extracellular purinoceptors have been implicated in a variety of physiological and pathological roles (see, Burnstock (1993) Drug Dev. Res. 28: 195-206.). Purinergic receptors (P2) have been broadly classified as metabotropic nucleotide receptors or ionotropic receptors for extracellular nucleotides. Metabotropic nucleotide receptors (often called P2Y or P2Y (n) , where "n" is an integer subscript indicating a subtype) is distinct from ionotropic receptors (commonly referred to as P2X or P2X (n) , the difference being that they are based on different fundamental modes of transmembrane signal transduction: P2Y receptors act through a G protein-coupled system, whereas P2X receptors are ligand-gated ion channels. [0003] A...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/505C07D239/02
CPCC07D413/12C07D413/14C07D401/14C07D401/12A61P25/02A61P25/04A61P25/08A61P25/20
Inventor C·S·伯盖Z·J·邓D·N·阮D·V·保恩A·W·肖
Owner MERCK SHARP & DOHME BV
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