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Carbamate TRPV1 antagonism/FAAH inhibition double-target drug, and preparation method and application of carbamate TRPV1 antagonism/FAAH inhibition double-target drug

A technology of carbamates and carbamates, applied in the fields of carbamate TRPV1 antagonistic/FAAH inhibitory dual-target drugs and their preparation and application, can solve problems such as elevated body temperature, eliminate side effects and reduce adverse reactions , the effect of increasing the therapeutic window

Pending Publication Date: 2022-05-13
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, subsequent studies have found that TRPV1 antagonists of different chemical structure types can cause different degrees of body temperature rise

Method used

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  • Carbamate TRPV1 antagonism/FAAH inhibition double-target drug, and preparation method and application of carbamate TRPV1 antagonism/FAAH inhibition double-target drug
  • Carbamate TRPV1 antagonism/FAAH inhibition double-target drug, and preparation method and application of carbamate TRPV1 antagonism/FAAH inhibition double-target drug
  • Carbamate TRPV1 antagonism/FAAH inhibition double-target drug, and preparation method and application of carbamate TRPV1 antagonism/FAAH inhibition double-target drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: Synthesis of phenyl (4-(4-(2-(4-methylpiperidin-1-yl) benzyl) piperazin-1-yl)-4-oxobutyl) carbamate

[0049]

[0050] (1) Synthesis of tert-butyl (4-(4-(2-(4-methylpiperidin-1-yl) benzyl) piperazin-1-yl)-4-oxobutyl) carbamate

[0051] At room temperature, Boc-4-aminobutyric acid (2.50 mmol), 1-hydroxybenzotriazole monohydrate (HOBt·H 2 O) (3.125mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (3.125mmol), triethylamine (7.50mmol), then add 10mL di Chloromethane was used as a solvent, and after stirring at room temperature for 0.5h, 1-(2-(4-methylpiperidin-1-yl)benzyl)piperazine (2.50mmol) was added, and the reaction was continued for 8h at room temperature. After the reaction was completed, the reaction solution was successively washed with 10% citric acid solution (10mL×3), saturated saline solution (10mL×3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl (4-(4-(2...

Embodiment 2

[0057] Example 2: Synthesis of phenyl-(3-oxo-3-(2-(4-phenylthiazol-2-yl)pyrrolidin-1-yl)propyl)carbamate

[0058]

[0059] Replace 1-(2-(4-methylpiperidin-1-yl) benzyl) piperazine in Example 1 with (S)-4-phenyl-2-(pyrrolidin-2-yl)thiazole, Boc-4-aminobutyric acid in Example 1 was replaced with Boc-β-alanine, and other references were made to the preparation method in Example 1 to obtain Compound 2, a pale yellow oil with a yield of 76.6%. The experimental data are as follows:

[0060] C 23 h 23 N 3 o 3 S, light yellow oil, (76.6%, yield), 1 H NMR (CDCl 3 ,300MHz)δppm7.92(m,2H,Ar-H),7.48-7.33(m,7H,Ar-H and thiazole),7.24-7.13(m,3H,Ar-H andNH),5.69-5.24(m ,1H,pyrrolidine),3.90-3.65(m,2H,pyrrolidine),3.63-3.46(m,2H,CH 2 ),2.77-2.59(m,2H,CH 2 ), 2.51-2.31 (m, 2H, pyrrolidine), 2.29 (s, 2H, pyrrolidine).

Embodiment 3

[0061] Example 3: Synthesis of phenyl (4-(4-chloropyrimidin-2-yl) piperazin-1-yl)-4-oxobutyl) carbamate

[0062]

[0063] Replace 1-(2-(4-methylpiperidin-1-yl)benzyl)piperazine in Example 1 with 4-chloro-2-(piperazin-1-yl)pyrimidine to obtain compound 3, white Paste, yield 63.3%. The experimental data are as follows:

[0064] C 17 h 18 ClN 5 o 3 ,white paste,(63.3%,yield), 1 H NMR (DMSO, 300MHz) δppm 8.11 (d, J = 6.2Hz, 1H, Ar-H), 7.83-7.73 (t, 1H, NH), 7.37 (t, J = 7.8Hz, 2H, Ar-H) ,7.19(t,J=7.4Hz,1H,Ar-H),7.14-7.06(m,2H,Ar-H),6.85(d,J=6.2Hz,1H,Ar-H),3.70-3.51( m,8H,piperazine),3.11(q,J=6.6Hz,2H,CH 2 ),2.41(q,J=8.2,7.8Hz,2H,CH 2 ), 1.73(t, J=7.2Hz, 2H, CH 2 ).

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Abstract

The invention discloses a carbamic acid ester TRPV1 antagonism / FAAH inhibition double-target medicine as well as a preparation method and application of the carbamic acid ester TRPV1 antagonism / FAAH inhibition double-target medicine. Particularly relates to compounds shown in the general formula (I) and the general formula (II) and pharmaceutically acceptable salts thereof, and can be used for treating diseases related to TRPV1 and / or FAAH activity, such as chronic pain, neurodegenerative diseases and the like. The compounds represented by the general formula (I) and the general formula (II) respectively show relatively strong antagonism / inhibition effects and animal analgesic activity on TRPV1 and FAAH.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of carbamate TRPV1 antagonist / FAAH inhibitory dual-target drugs. TRPV1 antagonist / FAAH inhibitor or its application in the preparation of analgesic drugs to treat clinical pain. Background technique [0002] Chronic pain greatly reduces people's quality of life, and it is a major clinical problem that needs to be solved urgently. At present, the clinical treatment of chronic pain is mainly antipyretic analgesics and narcotic analgesics represented by non-steroidal anti-inflammatory drugs. Although they can relieve pain temporarily, long-term use is often accompanied by gastrointestinal irritation and dependence. Obvious side effects. In recent years, research on chronic pain has mainly focused on peripheral nociceptors and spinal cord levels. However, practice has shown that there are very few analgesic drugs that only target peripheral and / or spi...

Claims

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Application Information

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IPC IPC(8): C07D211/14C07D417/04C07D239/42C07D209/14C07D471/04C07D401/04A61P29/00A61K31/496A61K31/427A61K31/506A61K31/4045A61K31/437A61K31/4545
CPCC07D211/14C07D417/04C07D239/42C07D209/14C07D471/04C07D401/04A61P29/00
Inventor 严琳陈英达王国豪宋德朴郭宁邵芦莲
Owner HENAN UNIVERSITY
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