Nitrogen-containing five-membered heteroaromatic compound and preparation method and application thereof

A technology of aromatic heterocycles and compounds, which is applied in the field of nitrogen-containing five-membered aromatic heterocycles and their derivatives and their preparation, can solve the problem of lack of CB1 and CB2 selectivity, increase the risk of suicide for users, and limit cannabinoids. Problems such as drug development in the body, to achieve good curative effect

Active Publication Date: 2019-03-26
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FDA statistics show that taking rimonabant can increase the risk of suicide for users, so rimonabant was withdrawn from the market two years after it was launched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 heteroaromatic compound and preparation method and application thereof
  • Nitrogen-containing five-membered heteroaromatic compound and preparation method and application thereof
  • Nitrogen-containing five-membered heteroaromatic compound and 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, and all were ESI methods unless specified; all solvents were re-distilled before use, and the anhydrous solvents used were all according to the standard method obtained by drying; except for the instructions, all reactions were carried out under the protection of argon and followed by TLC, and the post-treatment was washed with saturated brine and dried with anhydrous magnesium sulfate; the purification of the product was performed using silica gel (200 -300 mesh) column chromatography; the 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 of

[0182]

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

Embodiment 1-2 to 1-91

[0187] Preparation of BE series compounds shown in Examples 1-2 to 1-91 and Table 1 (see references below 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-methan Amide (BE092)

[0203]

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

[0205] After the organic phase was evaporated to dryness, 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] Dissolve ethyl 5-tert-butyl-1-(4-fluorophenyl)-pyrazole-3-carboxylate (435m...

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Abstract

The invention discloses a nitrogen-containing five-membered heteroaromatic compound as shown in structural formulae (I) and (II), a medicinal derivative, a hydrate, a composition containing the nitrogen-containing five-membered heteroaromatic compound and a preparation method thereof. The invention also disclose an application of the compound as a drug and as a cannabinoid acceptor adjustor for preventing and treating ache, inflammation, immune diseases and central nervous system diseases and the like.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a class of nitrogen-containing five-membered aromatic heterocyclic compounds capable of regulating the activity of cannabinoid receptors and derivatives thereof, as well as preparation methods and applications 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 respectively cloned. The CB1 receptor consists of 473 amino acids and 7 transmembrane domains, and the CB2 receptor consists of 360 amino acids and 7 transmembrane domains, both of which belong to G protein-coupled receptors. Gene cloning studies found that the 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...

Claims

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Application Information

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Patent Type & Authority Applications(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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