New alcoxyaminopyridine derivatives for treating pain and pain related conditions

A technology of alkoxy group and halogenated alkoxy group, applied in the field of preparing the compound, can solve problems such as drug resistance

Pending Publication Date: 2021-07-30
ESTEVE PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Indeed, due to incompatible pharmacokinetics between components of combination therapy, troughs in drug exposure may create low-dose windows of opportunity in which reduced selection pressure may lead to drug resistance

Method used

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  • New alcoxyaminopyridine derivatives for treating pain and pain related conditions
  • New alcoxyaminopyridine derivatives for treating pain and pain related conditions
  • New alcoxyaminopyridine derivatives for treating pain and pain related conditions

Examples

Experimental program
Comparison scheme
Effect test

example

[0237] In the preparation examples that follow, the preparation of two intermediate compounds as well as compounds according to the invention is disclosed.

[0238] Use the following abbreviations:

[0239] example

[0240] The preparation of examples according to the invention is disclosed.

[0241] Use the following abbreviations:

[0242] Acetonitrile: ACN

[0243] Aq: water-based

[0244] CH: Cyclohexane

[0245] DCM: dichloromethane

[0246] DIPEA: N,N-Diisopropylethylamine

[0247] DMA: N,N-Dimethylacetamide

[0248] EtOAc: ethyl acetate

[0249] h: hour / s

[0250] HPLC: High Performance Liquid Chromatography

[0251] MS: mass spectrometry

[0252] Min: minutes

[0253] Ret: retention time

[0254] rt: room temperature

[0255] Sat: saturated

[0256] TBAI: Tetrabutylammonium iodide

[0257] TFA: Trifluoroacetic acid

[0258] THF: Tetrahydrofuran

[0259] The following methods were used to generate HPLC-MS data:

[0260] Method A: column Eclipse XDB-C1...

example 1

[0262] Example 1: (S)-4-((3-fluoro-5-(3-(methylamino)-1-phenylpropoxy)pyridin-2-yl)methyl)-1-methyl-1, 2,3,4-Tetrahydro-5H-pyrido[2,3-e][1,4]diazepine-5-one.

[0263]

[0264] a) Methyl (S)-5-(3-((tert-butoxycarbonyl)(methyl)amino)-1-phenylpropoxy)-3-fluoropicolinate. To tert-butyl(S)-(3-hydroxy-3-phenylpropyl)(methyl)carbamate (650mg, 2.45mmol) and methyl 3,5-difluoropicolinate (848mg, 4.90 mmol) in DMA (13.6 mL) was added NaH (60% suspension in mineral oil, 147 mg, 3.67 mmol) and the mixture was stirred at rt for 2.5 h. Water was added, extracted with EtOAc, with Na 2 SO 4 Dry, filter and concentrate under vacuum. Purification by flash silica gel chromatography (Gradient: CH to 100% EtOAc) gave the title product (509 mg, 50% yield) as a mixture of two positional isomers (7:3).

[0265] HPLC (Method B): Ret, 5.3 min; ESI + - MS m / z, 419.2 (M+H).

[0266] b) tert-butyl (S)-(3-((5-fluoro-6-(hydroxymethyl)pyridin-3-yl)oxy)-3-phenylpropyl)(methyl)carbamate . To a solu...

example 8

[0276] Example 8: (S)-4-((3-fluoro-5-(3-(methylamino)-1-(thiophen-2-yl)propoxy)pyridin-2-yl)methyl)-1- Methyl-1,2,3,4-tetrahydro-5H-pyrido[2,3-e][1,4]diazepan-5-one.

[0277]

[0278]a) 4-((3,5-difluoropyridin-2-yl)methyl)-1-methyl-1,2,3,4-tetrahydro-5H-pyrido[2,3-e][ 1,4] Diazepan-5-one. To 1-methyl-1,2,3,4-tetrahydro-5H-pyrido[2,3-e][1,4]diazepine-5-one (260mg, 1.46mmol) To a solution in DMF (6 mL) at 0 °C was added NaH (60% suspension in mineral oil, 88 mg, 2.20 mmol), and the mixture was stirred at rt for 30 min. The reaction mixture was cooled at 0 °C, a solution of 2-(chloromethyl)-3,5-difluoropyridine (288 mg, 1.76 mmol) in DMF (5.5 mL) and TBAI (54 mg, 0.147 mmol) were added, and The mixture was warmed to rt and stirred for 20 h. Water was added and extracted with EtOAc. The organic layer was washed with Na 2 SO 4 Dry, filter and concentrate. Purification by flash chromatography (Gradient: CH to 100% EtOAc) gave the title product (395 mg, 88% yield).

[027...

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Abstract

The present invention relates to new compounds of formula (I) that show dual activity towards the subunit [alpha]2[delta] of voltage-gated calcium channels (VGCC), especially the [alpha]2[delta]-1 subunit of voltage-gated calcium channels, and the noradrenaline transporter (NET). The invention is also related to the process for the preparation of said compounds as well as to compositions comprising them, and to their use as medicaments.

Description

technical field [0001] The present invention relates to a novel compound, which shows the subunit α2δ of the voltage-gated calcium channel (VGCC), especially the α2δ-1 subunit of the voltage-gated calcium channel, and the norepinephrine transporter (NET) dual activity. The invention also relates to processes for the preparation of said compounds and to compositions comprising these compounds, and to the use of these compounds as medicaments. Background technique [0002] Adequate control of pain is a significant challenge as currently available treatments provide only modest improvement in many conditions, leaving many patients without relief (Turk, D.C., Wilson, H.D., Cahana, A.; 2011; Lancet; 377; 2226-2235). Pain affects a large proportion of the population, with an estimated prevalence of 20%, and its incidence, especially of chronic pain, is increasing due to an aging population. Furthermore, pain is clearly associated with comorbidities such as depression, anxiety, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P25/00A61P29/00A61K31/551
CPCC07D471/04A61P25/00A61P29/00
Inventor 卡门·阿曼萨-罗萨勒斯费利克斯·奎瓦斯-科多韦斯
Owner ESTEVE PHARMA SA
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