Homopiperazinyl and homopiperidinyl quinazolin-4 (3h)-one derivatives with multi-modal activity against pain

An alkylaryl, alkyl-based technology applied in the field of homopiperazinyl and homopiperidinylquinazolin-4(3H)-one derivatives with multimodal activity against pain, which can solve drug resistance And other issues

Pending Publication Date: 2022-05-13
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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  • Homopiperazinyl and homopiperidinyl quinazolin-4 (3h)-one derivatives with multi-modal activity against pain
  • Homopiperazinyl and homopiperidinyl quinazolin-4 (3h)-one derivatives with multi-modal activity against pain
  • Homopiperazinyl and homopiperidinyl quinazolin-4 (3h)-one derivatives with multi-modal activity against pain

Examples

Experimental program
Comparison scheme
Effect test

example

[1105] The following abbreviations are used in the examples:

[1106] ACN: Acetonitrile

[1107] AIBN: Azobisisobutyronitrile

[1108] Aq: water-based

[1109] Anh: anhydrous

[1110] Chx: Cyclohexane

[1111] DavePhos: 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl

[1112] DCM: dichloromethane

[1113] DME: Dimethoxyethane

[1114] DMF: Dimethylformamide

[1115] Eq: Equivalent

[1116] Et 2 O: diethyl ether

[1117] EtOAc: ethyl acetate

[1118] EtOH: ethanol

[1119] h: hours

[1120] HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[1121] HMDS: Hexamethyldisilazane

[1122] HPLC: High Performance Liquid Chromatography

[1123] KOAc: potassium acetate

[1124] LiHMDS: lithium bis(trimethylsilyl)amide

[1125] MeOH: Methanol

[1126] MS: mass spectrometry

[1127] Min: minutes

[1128] NaOAc: sodium acetate

[1129] NaOtBu: sodium tert-butoxide

[1130] NBS: N-Bromosuccinimide

[1131] PD ...

Synthetic example

[1161]

example 1

[1162] Example 1. 6-Bromo-3-ethyl-2-(1-(4-methyl-1,4-diazepan-1-yl)butyl)quinazoline-4(3H)- ketone.

[1163] Step a. 2-Amino-5-bromo-N-ethylbenzamide.

[1164] To a solution of 2-amino-5-bromobenzoic acid (6 g, 28 mmol) in anhydrous DMF (75 mL) was added TEA (8 mL, 57 mmol) and HATU (13.0 g, 33 mmol) under argon atmosphere, and the reaction The mixture was stirred at 0 °C for 10 min. Then, ethylamine (2M in THF, 31 mL, 42 mmol) was added dropwise and the reaction mixture was brought to r.t. and stirred overnight. The reaction crude was washed with EtOAc:Et 2 O(1:1) diluted with aqueous NaHCO 3 Wash with saturated solution. The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound (7.0 g, yield: 99%).

[1165] Step b. 5-Bromo-N-ethyl-2-pentaneaminobenzamide.

[1166] To a solution of the compound obtained in step a (7.0 g, 29 mmol) in anhydrous DCM (120 mL) was added TEA (6 mL, 43 mmol) dropwise under argon ...

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Abstract

The present invention relates to homopiperazinyl and homopiperidinyl quinazoline-4 (3H)-one derivatives having dual pharmacological activity on both the alpha2delta subunit of the voltage-gated calcium channel and the Scima-1 (sigma1) receptor, to processes for the preparation of such compounds, to pharmaceutical compositions comprising the same, and to pharmaceutical compositions comprising the same. And to the use thereof in therapy, in particular for the treatment of pain.

Description

technical field [0001] The present invention relates to the alpha of voltage-gated calcium channels 2 Compounds that have dual pharmacological activity at both the delta subunit and the sigma-1 (σ1) receptor. More specifically, the present invention relates to homopiperazinyl and homopiperidinylquinazolin-4(3H)-one derivatives having such pharmacological activity, to processes for the preparation of such compounds, to pharmaceutical combinations comprising them substances, and to their use in therapy, in particular for the treatment of pain. Background technique [0002] Adequate control of pain is a major challenge as currently available treatments provide only modest improvement in many cases, leaving many patients without relief (Turk DC, Wilson HD, Cahana A. Lancet [The Lancet]; 2011 , 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 pop...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D405/14C07D401/14C07D471/04C07D471/08A61K31/551A61P25/04A61P25/06A61P29/00
CPCC07D403/06C07D471/04C07D471/08C07D401/14C07D405/14A61K31/551A61P25/04A61P29/00A61P25/06C07B2200/07C07D403/04
Inventor 卡门·阿尔曼萨-罗萨莱斯亚力那·费南德斯-唐尼斯乔思-路易斯·迪亚兹-费南德斯摩尼卡·贾西亚-罗培兹萨吉欧·罗德利古兹-艾斯克里奇乌特·克里斯特曼
Owner ESTEVE PHARMA SA
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