Nitrogen-containing five-membered aromatic heterocyclic compound, preparation method and application thereof

A technology for aromatic heterocycles and compounds, which is applied in the field of nitrogen-containing five-membered aromatic heterocycles and derivatives thereof and their preparation fields, can solve the problem of increasing serious adverse mental reactions, increasing the risk of suicide for users, and the nervous system being prone to side effects, etc. question

Active Publication Date: 2022-07-26
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] However, many clinical-stage compounds targeting cannabinoid receptors are not CB1 and CB2 selective
Since CB1 receptors are mainly located in the brain, spinal cord and peripheral nervous system, drugs targeting CB1 are prone to side effects on the human nervous system, which largely limits the development of drugs targeting cannabinoid receptors
Rimonabant, as a CB1 antagonist, was launched in Europe in 2006, but subsequent studies have shown that rimonabant will increase serious adverse reactions in the spirit, namely depression and anxiety
FDA statistics show that taking rimonabant can increase the risk of suicide for users, so rimonabant was withdrawn from the market two years after it was launched

Method used

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  • Nitrogen-containing five-membered aromatic heterocyclic compound, preparation method and application thereof
  • Nitrogen-containing five-membered aromatic heterocyclic compound, preparation method and application thereof
  • Nitrogen-containing five-membered aromatic heterocyclic compound, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0181] 1 H-NMR was measured with a Bruker 500MHz instrument; MS was measured with a Bruker MicroTOF-Q LCMS instrument, all ESI methods unless otherwise noted; all solvents were redistilled before use, and the anhydrous solvents used were standard The method was obtained by drying; all reactions were carried out under the protection of argon and tracked by TLC unless otherwise stated, and were washed with saturated brine and dried over anhydrous magnesium sulfate during post-treatment; silica gel (200 ℃) was used for purification of the product unless stated otherwise. -300 mesh) column chromatography; silica gel used, including 200-300 mesh and GF 254 Produced for Qingdao Ocean Chemical Factory or Yantai Yuanbo Silicone Company. Example 1-1, compound N-(2-(1-hydroxy-2-methyl)propyl)-3-tert-butyl-1-n-pentyl-1H-pyrazole-5-carboxamide (BE001) preparation

[0182]

[0183] Take pinacolone (1002mg, 11.0mmol) in tetrahydrofuran (100ml), cool the reaction system with an ice-water...

Embodiment 1-2 to 1-91

[0187] Preparations of BE series compounds shown in Examples 1-2 to 1-91 and Table 1 (see the following reference for the specific process)

[0188] Table 1

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

Embodiment 1-92

[0202] Example 1-92, compound N-(2-(1-hydroxy-2-methyl)propyl)-5-tert-butyl-1-(4-fluorophenyl)-1H-pyrazole-3-methyl Amide (BE092)

[0203]

[0204] Take pinacolone (200mg, 2.2mmol) in tetrahydrofuran (15ml), cool the reaction system with ice water bath, add potassium tert-butoxide (292mg, 2.9mmol), react at room temperature for 10min, then add diethyl oxalate The ester (292 mg, 2.4 mmol) was reacted overnight at room temperature. Continue to 4-fluorophenylhydrazine hydrochloride (393 mg, 2.4 mmol) in the reaction system, and reflux at 70 °C for 3 h. After cooling the reaction to room temperature, the solvent was evaporated to dryness, and extracted with ethyl acetate and water, respectively.

[0205] The organic phase was evaporated to dryness, and the intermediate compound 5-tert-butyl-1-(4-fluorophenyl)-pyrazole-3-carboxylic acid ethyl ester (435 mg, 1.5 mmol) was obtained by column chromatography.

[0206] 5-tert-Butyl-1-(4-fluorophenyl)-pyrazole-3-carboxylic acid eth...

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PUM

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Abstract

The invention discloses a nitrogen-containing five-membered aromatic heterocyclic compound represented by structural formula (I) and formula (II), and a medicinal derivative, a hydrate, and a combination containing the nitrogen-containing five-membered aromatic heterocyclic compound substances, and methods for their preparation. The present invention also discloses that the compounds of the present invention can be used as medicines, and can be used as cannabinoid receptor modulators to prevent and treat pain, inflammation, immune diseases and central nervous system diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a nitrogen-containing five-membered aromatic heterocyclic compound with the activity of regulating cannabinoid receptors and derivatives thereof, and a preparation method and application thereof. Background technique [0002] The currently recognized cannabinoid receptors are: CB1 and CB2 receptors. In the early 1990s, the CB1 and CB2 receptors that bind to cannabinoids in vivo were cloned respectively. The CB1 receptor is composed of 473 amino acids and 7 transmembrane domains, and the CB2 receptor is composed of 360 amino acids and 7 transmembrane domains, and both belong to G protein-coupled receptors. Gene cloning studies found that these two receptors have 44% amino acid sequence homology. Human cannabinoid receptors have high amino acid sequence homology with rat cannabinoid receptors. Therefore, adult rats can be used as ideal experimental animals to study the distribution and fu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/14C07D413/12C07D413/06C07D403/06C07D403/12C07D405/12C07D405/06C07D405/04C07D401/04C07D403/04C07D409/04A61K31/5377A61K31/415A61K31/422A61K31/496A61K31/4196A61K31/4155A61K31/506A61K31/454A61K31/4439A61P29/00A61P25/00A61P11/06A61P19/10A61P25/18A61P35/00A61P33/06A61P37/08A61P37/02A61P19/02A61P1/00A61P1/16
CPCC07D231/14C07D401/04C07D403/04C07D403/06C07D403/12C07D405/04C07D405/06C07D405/12C07D409/04C07D413/06C07D413/12Y02A50/30
Inventor 章涵堃卢伟强刘明耀胡龙龙蒋蓓尔姜兴武梁秋雯邱子粱
Owner EAST CHINA NORMAL UNIV
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