Piperazinyl and piperidinyl quinazolin-4(3H)-one derivatives having activity against pain

An alkyl and alkynyl technology, applied in the field of pain treatment, can solve problems such as drug resistance

Pending Publication Date: 2021-08-13
塔拉森斯调节公司
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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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  • Piperazinyl and piperidinyl quinazolin-4(3H)-one derivatives having activity against pain
  • Piperazinyl and piperidinyl quinazolin-4(3H)-one derivatives having activity against pain
  • Piperazinyl and piperidinyl quinazolin-4(3H)-one derivatives having activity against pain

Examples

Experimental program
Comparison scheme
Effect test

example

[1179] The following abbreviations are used in the examples:

[1180] ACN: Acetonitrile

[1181] Aq: water-based

[1182] Anh: anhydrous

[1183] Chx: Cyclohexane

[1184] DCM: dichloromethane

[1185] DIPEA: N,N-Diisopropylethylamine

[1186] DME: Dimethoxyethane

[1187] DMF: Dimethylformamide

[1188] Eq: Equivalent

[1189] Et 2 O: diethyl ether

[1190] EtOAc: ethyl acetate

[1191] h: hours

[1192] HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[1193] HMDS: Hexamethyldisilazane

[1194] HPLC: High Performance Liquid Chromatography

[1195] LiHMDS: lithium bis(trimethylsilyl)amide

[1196] MeOH: Methanol

[1197] MS: mass spectrometry

[1198] Min: minutes

[1199] Pd(dppf)FeCl 2 : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[1200] PdCl 2 (bpy): (2,2'-bipyridyl)dichloropalladium(II)

[1201] Quant: quantitative

[1202] Rt.: retention time

[1203] r.t.: room temperature

[...

Synthetic example

[1232]

example 1

[1233] Example 1. 6-bromo-2-(1-((3S,5R)-3,5-dimethylpiperazin-1-yl)butyl)-3-ethylquinazoline-4(3H)- ketone.

[1234] Step a. 2-Amino-5-bromo-N-ethylbenzamide.

[1235] To a solution of 2-amino-5-bromobenzoic acid (10 g, 46.3 mmol) in anhydrous DMF (200 mL) was added TEA (13 mL, 92.6 mmol) and HATU (21.1 g, 55 mmol) under argon atmosphere, And the reaction mixture was stirred at 0 °C for 10 min. Then, ethylamine (2M in THF, 35 mL, 69.4 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 (300mL, 1:1) diluted with NaHCO 3 Wash with saturated aqueous solution. The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate to dryness to give the title compound (10.8 g, yield: 85%).

[1236] Step b. 5-Bromo-N-ethyl-2-pentaneaminobenzamide.

[1237] To a solution of the compound obtained in step a (10.7 g, 44.1 mmol) in anhydrous DCM (200 mL) was added TEA (9.23 mL, 6...

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Abstract

The present invention relates to piperazinyl and piperidinyl quinazolin-4(3H)-one derivatives having pharmacological activity towards the (formula (I)) subunit, in particular the (formula (2)) subunit, of the voltage-gated calcium channel, in particular having dual pharmacological activity towards both the (formula (I)) subunit, in particular the (formula (2)) subunit, of the voltage-gated calcium channel and the [mu]-opioid receptor. The present invention also relates to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. Formula I is [alpha]2[delta]; Formula II is [alpha]2[delta]-1.

Description

technical field [0001] The present invention relates to the alpha of voltage-gated calcium channels 2 Compounds in which the delta subunit has pharmacological activity. In particular, the present invention relates to the alpha 2 Compounds that have dual pharmacological activity at both the delta subunit and the mu-opioid receptor (MOR or M-opioid receptor). More particularly, the present invention relates to piperazinyl and piperidinylquinazolin-4(3H)-one derivatives having such pharmacological activity, to processes for the preparation of such compounds, to pharmaceutical compositions containing them, It also relates to its 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 conditions, leaving many patients without relief (Turk, D.C., Wilson, H.D., Cahana, A.; 2011; Lancet[ The Lancet]; 377; 2226-2235). Pain affects...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D403/06C07D403/14A61P25/00A61K31/517
CPCC07D401/14C07D403/06C07D403/14A61P25/00C07D239/90C07D405/14C07D471/04C07D471/18C07D498/10
Inventor 阿里亚德娜·费尔南德斯-多尼斯约瑟·路易斯·迪亚斯-费尔南德斯卡门·阿尔曼萨-罗萨莱斯阿德里亚娜·洛伦特-克里维尔
Owner 塔拉森斯调节公司
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