New propanamine derivatives for treating pain and pain related conditions

A compound, selected technology, applied in the direction of drug combination, neurological diseases, non-central analgesics, etc., can solve drug resistance and other problems

Inactive Publication Date: 2020-05-05
ESTEVE PHARMA SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Indeed, troughs in drug exposure due to pharmacokinetic incompatibilities between components of combination therapies may create low-dose windows of opportunity where reduced selection pressure may lead to drug resistance

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0585] Example 1: 3-(indol-1-yl)-N-methyl-3-(thiophen-2-yl)propan-1-amine

[0586]

[0587] Step 1 1-(3-Chloro-(thiophen-2-yl)propyl)indoline: To a solution of indoline (92 mg, 0.77 mmol) in ACN (0.5 mL) was added K 2 CO 3 (53 mg, 0.38 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, a solution of Intermediate 6 (50 mg, 0.26 mmol) in ACN (0.5 mL) was added dropwise, and the mixture was heated at 70 °C overnight. It was then allowed to cool and diluted with saturated ammonium chloride solution and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, MgSO 4 Dry and concentrate to dryness. The crude product was purified by flash chromatography, silica gel, a gradient of CH / EtOAc 100:0 to CH / EtOAc 50:50 to afford the title compound (34 mg, 47% yield).

[0588] Step 2 Title compound: In a sealed tube, a solution of the product obtained in Step 1 (34 mg, 0.12 mmol) an...

Embodiment 2

[0590] Example 2: 3-(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-N-methyl-3-(thiophen-2-yl)propan-1- amine

[0591]

[0592]Step 1 3-(2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)-3-(thiophen-2-yl)propionic acid ethyl ester: at -78°C To a cooled solution of 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (157 mg, 1.31 mmol) in anhydrous THF (4 mL), LDA solution (1.5 M in THF / ethylbenzene / heptane, 1 mL, 1.5 mmol), and the mixture was stirred at -78°C for 30 minutes. Then, a solution of ethyl (E)-3-(thiophen-2-yl)acrylate (216 mg, 1.19 mmol) in anhydrous THF (4 mL) was added slowly, and the reaction mixture was stirred at -78°C for 1.5 hours. Join NH 4 Sat. aq. Cl and EtOAc, the phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, MgSO 4 Dry and concentrate to dryness. The crude product was purified by flash chromatography, silica gel, gradient of CH / EtOAc 100:0 to CH / EtOAc 0:100 to afford the title compound (153 m...

preparation Embodiment 3-14

[0597]

[0598]

[0599] (1) Use ethylamine solution instead of methylamine in step 2

[0600] (2) Use ammonia instead of methylamine in step 2

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Abstract

The present invention relates to new compounds of general formula (I) that show dual activity towards alpha 2 delta subunit of voltage-gated calcium channels (VGCC), especially the alpha 2 delta-1 subunit, and to 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 novel compounds exhibiting great affinity and dual activity for 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). compound. The invention also relates to processes for the preparation of said compounds and compositions comprising them, and to their use as medicaments. Background technique [0002] Adequate pain control is an important 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 portion of the population, with an estimated prevalence of 20%, and its incidence, especially in the context of chronic pain, increases due to population aging. Furthermore, pain is clearly associated with co-morbidities, such as depression, anxiety ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/06A61K31/4045A61K31/437A61P25/04C07D471/04
CPCC07D409/06C07D471/04A61K31/4045A61K31/437A61P29/00A61P25/02A61P25/24A61P25/22
Inventor 玛丽娜·比尔希利-贝尔纳多·玛丽娜卡梅·阿尔曼萨-罗萨莱斯莫妮卡·阿隆索-哈尔马劳拉·奥索里奥-普拉内斯
Owner ESTEVE PHARMA SA
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