New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions

A technology of compound and hydrogen atom, which is applied in the field of preparing the compound and can solve problems such as drug resistance

Pending Publication Date: 2021-07-23
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 tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions
  • New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions
  • New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions

Examples

Experimental program
Comparison scheme
Effect test

example

[0329] In the following examples, the preparation of two intermediate compounds as well as compounds according to the invention is disclosed.

[0330] Use the following abbreviations:

[0331] ACN: Acetonitrile

[0332] Aq: water-based

[0333] CH: Cyclohexane

[0334] DCM: dichloromethane

[0335] DIAD: Diisopropyl azodicarboxylate

[0336] DIBAL: diisobutylaluminum hydride

[0337] DIPEA: N,N-Diisopropylethylamine

[0338] DMA: N,N-Dimethylacetamide

[0339] EtOAc: ethyl acetate

[0340] EtOH: ethanol

[0341] Ex: example

[0342] h: hour / s

[0343] HPLC: High Performance Liquid Chromatography

[0344] MeOH: Methanol

[0345] MS: mass spectrometry

[0346] Min: minutes

[0347] PPh 3 :Triphenylphosphine

[0348] Ret: retention time

[0349] rt: room temperature

[0350] Sat: saturated

[0351] TBAF: Tetrabutylammonium fluoride

[0352] TBAI: Tetrabutylammonium iodide

[0353] TFA: Trifluoroacetic acid

[0354] THF: Tetrahydrofuran

[0355] The followin...

example 1

[0358] Example 1: (S)-1-methyl-4-(2-methyl-4-(3-(methylamino)-1-phenylpropoxy)benzyl)-1,2,3,4- Tetrahydro-5H-pyrido[4,3-e][1,4]diazepine-5-one.

[0359]

[0360] a) Methyl (S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-1-phenylpropoxy)-2-methylbenzoate. To tert-butyl(S)-(3-hydroxy-3-phenylpropyl)(methyl)carbamate (1.8g, 6.78mmol) and methyl 4-fluoro-2-methylbenzoate (2.28 g, 13.57 mmol) in DMA (36 mL) was added NaH (60% suspension in mineral oil, 407 mg, 10.18 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 (1.8 g, 65% yield).

[0361] HPLC (Method B): Ret, 7.0 min; ESI + - MS m / z, 436.2 (M+Na).

[0362] b) tert-butyl (S)-(3-(4-(hydroxymethyl)-3-methylphenoxy)-3-phenylpropyl)(methyl)carbamate. To a solution of the compound obtained in step a (2.7 g, 6.53 mmol) in toluene ...

example 8

[0371] Example 8: (S)-4-(2-fluoro-4-(3-(methylamino)-1-phenylpropoxy)benzyl)-1-methyl-1,2,3,4-tetra Hydrogen-5H-pyrido[4,3-e][1,4]diazepine-5-one.

[0372]

[0373] a) (S)-tert-butyl((4-(3-chloro-1-phenylpropoxy)-2-fluorobenzyl)oxy)dimethyl-silane. To a solution of (R)-3-chloro-1-phenylpropan-1-ol (850 mg, 4.98 mmol) in THF (25 mL) was added 4-(((tert-butyldimethylsilyl)oxy base) methyl)-3-fluorophenol (1.34g, 5.23mmol) in THF (12mL) and PPh 3 (1.57 g, 5.98 mmol). The reaction mixture was cooled at 0 °C, DIAD (1.25 mL, 5.98 mmol) was added dropwise, and the mixture was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum. Purification by flash silica gel chromatography (Gradient: CH to 100% EtOAc) gave the title product (1.30 g, 64% yield).

[0374] HPLC (Method B): Ret, 8.8 min; ESI + - MS m / z, 409.1 (M+H).

[0375] b) (S)-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenoxy)-N-methyl-3-phenylpropan- 1-amine. To a solution of the compo...

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Abstract

The present invention relates to new compounds of general formula (I) that show dual activity towards subunit alpha 2Delta of voltage-gated calcium channels (VGCC), especially alpha2Delta-1 subunit of voltage-gated calcium channels,and 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 showing dual activity on the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels, and the norepinephrine transporter (NET). 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, and insomn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D487/04A61P25/00A61K31/5513
CPCC07D471/04C07D487/04A61P25/00
Inventor 费利克斯·奎瓦斯-科多韦斯卡门·阿曼萨-罗萨勒斯
Owner ESTEVE PHARMA SA
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