New quinoline and isoquinoline derivatives for treating pain and pain related conditions

A technology for isoquinoline and compounds, applied in the field of preparing said compounds, capable of solving problems such as drug resistance

Inactive Publication Date: 2019-09-17
ACANTICIO NANOMENT TARASONS
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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 quinoline and isoquinoline derivatives for treating pain and pain related conditions
  • New quinoline and isoquinoline derivatives for treating pain and pain related conditions
  • New quinoline and isoquinoline derivatives for treating pain and pain related conditions

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0287] The preparation of compounds of general formula IV can be carried out according to several methods described in the literature. As an example, two synthetic routes are described in Scheme 2:

[0288] Scenario 2

[0289]

[0290] where R 1 , R 2 and R 3 has the meaning defined above for the compound of formula (I).

[0291] Following Route A, a compound of formula (VIII) is treated with a strong base such as butyllithium to generate the corresponding organometallic reagent, followed by condensation with the Weinreb amide of formula (VII) in a suitable solvent such as tetrahydrofuran, Compounds of formula (IV) are obtained.

[0292] Alternatively, compounds of formula (IV) can be prepared by Mannich reaction of acetyl compounds of formula (IX) with amines of formula (VI) and a source of formaldehyde such as paraformaldehyde, preferably in The condensation is carried out in the presence of an acid such as hydrochloric acid in a suitable solvent such as ethanol o...

example

[0347] In the following preparation examples, the synthesis of two intermediate derivatives and compounds according to the invention is disclosed.

[0348] The following abbreviations are used in the examples:

[0349] ACN: Acetonitrile

[0350] ADDP: 1,1′-(Azodicarbonyl)dipiperidine

[0351] Boc: tert-butoxycarbonyl

[0352] BuLi: Butyl Lithium

[0353] Conc: concentrated

[0354] DCM: dichloromethane

[0355] DEA: Diethylamine

[0356] DIAD: Diisopropyl azodicarboxylate

[0357] DMA: N,N-Dimethylacetamide

[0358] Eq: Equivalent

[0359] Et 2 O: Ether

[0360] EtOAc: ethyl acetate

[0361] EtOH: ethanol

[0362] EX: Example

[0363] h: hours

[0364] HPLC: High Performance Liquid Chromatography

[0365] 2-Me-CBS-oxazoborin: 5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazoborin (Corey-Bakshi-Shibata oxazaborin catalyst)

[0366] MeOH: Methanol

[0367] MS: mass spectrometry

[0368] min minutes

[0369] PPh 3 :Triphenylphosphine

[0370] Quant: quantitativ...

example 1

[0446] Example 1: N-methyl-3-(quinolin-8-yloxy)-3-(thiophen-2-yl)propan-1-amine

[0447]

[0448] Step 1.8-(3-Chloro-1-(thiophen-2-yl)propoxy)quinoline: To 3-chloro-1-(thiophen-2-yl)propan-1-ol (0.2 g, 1.13 mmol) , tributylphosphine (0.34mL, 1.36mmol) and quinolin-8-ol (0.164g, 1.13mmol) in toluene (6mL) was added ADDP (0.343g, 1.36mmol), and the reaction mixture was heated at 100 °C overnight. Then it was allowed to cool, the suspension was filtered and the collected solid was washed with toluene. The filtrate containing the desired product was concentrated in vacuo. The crude product was purified by flash silica gel chromatography (gradient: DCM to MeOH:DCM (1:4)) to afford the title compound (74 mg, 21% yield).

[0449] Step 2. The title compound: In a sealed tube, the product obtained in Step 1 (74mg, 0.244mmol), NaI (7.3mg, 0.049mmol) and methylamine (33wt% in EtOH, 0.152mL, 1.22mmol) were mixed in The mixture in EtOH (28 mL) was heated at 100 °C overnight. Then, ...

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Abstract

The present invention relates to new compounds of formula (I): showing great affinity and activity towards the subunit [alpha]2[delta] of voltage-gated calcium channels (VGCC), especially the [alpha]2[delta]-1subunit of voltage-gated calcium channels or dual activity towards subunit [alpha]2[delta] of voltage-gated calcium channels (VGCC), especially the [alpha]2[delta]-1subunit of voltage-gated calcium channels, and the noradrenaline transporter (NET).

Description

technical field [0001] The present invention relates to the subunit α2δ of the voltage-gated calcium channel (VGCC), especially the α2δ-1 subunit of the voltage-gated calcium channel, showing great affinity and activity, or to the subunit of the voltage-gated calcium channel (VGCC). Novel compounds showing dual activities of the α2δ-based α2δ, especially the α2δ-1 subunit of the voltage-gated calcium channel and the norepinephrine transporter (NET). The invention also relates to processes for the preparation of said compounds and compositions comprising said compounds and their use 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 portion of the population, with an estimated prevalence of 20%, and its incidence, esp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D405/12C07D409/02C07D409/06C07D417/12A61K31/47A61K31/4725
CPCC07D401/12C07D405/12C07D409/02C07D409/06C07D417/12A61P25/02A61P25/04A61P25/06A61P25/22A61P25/24A61P25/28A61P43/00C07D407/12C07D409/12
Inventor 卡门·阿曼萨-罗萨勒斯S·叶尼斯-敏谷兹玛丽娜·威吉里-贝纳德欧莫妮卡·阿隆索-哈尔马
Owner ACANTICIO NANOMENT TARASONS
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