Benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof

A benzylpiperazine, dual-target technology, used in drug combinations, pharmaceutical formulations, antipyretics, etc., can solve problems such as nausea and vomiting, addiction, adverse reactions, etc., to reduce side effects and have broad analgesic applications Effects of Prospects and Practical Values

Pending Publication Date: 2021-08-24
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite the satisfactory effect of opioids in pain relief, continuous opioid use is also associated with a plethora of adverse effects, including respiratory depression, tolerance, addiction, constipation, nausea and vomiting, etc.

Method used

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  • Benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof
  • Benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof
  • Benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: N-(4-(tert-butyl)phenyl)-4-(2-(4-(N-phenylpropionamido)piperidin-1-yl)benzyl)piperazine-1- Preparation of formamide (compound (1))

[0048]

[0049] The preparation method comprises the following steps:

[0050] (a) Preparation of 4-(phenylamino)piperidine-1-carboxylic acid tert-butyl ester

[0051] Dissolve 4.582mL (0.0502mol) of aniline in 200mL of dichloromethane, add 10g (0.0502mol) of 1-Boc-4-piperidone, 2.870mL (0.0502mol) of glacial acetic acid, sodium triacetoxyborohydride 31.911g (0.151mol), stirred at room temperature for 14h, added 100mL of saturated aqueous sodium bicarbonate solution to quench the reaction, extracted 3 times with dichloromethane, 100mL each time, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 4-(phenylamino ) tert-butyl piperidine-1-carboxylate is dark yellow solid.

[0052] (b) Preparation of N-phenylpiperidin-4-amine

[0053] Dissolve 11.322 g (0.0409 mol) of tert-butyl 4-(phenylamino)pi...

Embodiment 2

[0065] Example 2: N-(3-isopropylphenyl)-4-(2-(4-(N-phenylpropanylamino)piperidin-1-yl)benzyl)piperazine-1-carboxamide (Compound (2)) preparation

[0066]

[0067] Replace the 4-tert-butyl-aniline in step (g) of Example 1 with 104 μL (0.737 mmol) of 3-isopropyl-aniline, and refer to the preparation method in Example 1 for other steps to obtain compound (2) , to obtain a white solid, yield: 63%. The experimental data are as follows:

[0068] C 35 h 45 N 5 o 2 ;yield: 63%, mp=142.9-143.6°C; 1 H NMR (400MHz, CDCl 3 )δppm 7.50-7.31(m, 4H, Ar-H), 7.29-6.99(m, 8H, Ar-H), 6.90(d, J=7.3Hz, 1H, Ar-H), 6.42(d, J= 8.2Hz, 1H, NH), 4.75(ddd, J=12.1, 8.4, 3.9Hz, 1H, Piperidine), 3.41(dd, J=12.9, 8.2Hz, 6H, Ar-CH 2 ,Piperazine), 3.12(d,J=11.7Hz,2H,Piperidine),2.93-2.74(m,3H,CH,Piperidine),2.49-2.29(m,4H,Piperazine),1.94(q,J=7.4Hz ,2H,CH 2 ), 1.86 (d, J = 10.2Hz, 2H, Piperidine), 1.49 (qd, J = 11.9, 3.5Hz, 2H, Piperidine), 1.25 (dd, J = 12.4, 7.0Hz, 6H, CH 3 ), 1.03(t, J=7.4Hz, ...

Embodiment 3

[0069] Example 3: N-(2-methoxyphenyl)-4-(2-(4-(N-phenylpropionamido)piperidin-1-yl)benzyl)piperazine-1-carboxamide (Compound (3)) preparation

[0070]

[0071] Replace the 4-tert-butyl-aniline in step (g) of Example 1 with 83 μL (0.737 mmol) of 2-methoxy-aniline, and refer to the preparation method in Example 1 for other steps to obtain compound (3) , to obtain a white solid, yield: 61%. The experimental data are as follows:

[0072] C 33 h 41 N 5 o 3;yield: 61%, mp=161.9-163.3°C; 1 H NMR (400MHz, CDCl 3 )δppm 8.18-8.12 (m, 1H, NH), 7.44 (tdd, J = 6.8, 4.6, 2.2Hz, 3H, Ar-H), 7.40-7.33 (m, 1H, Ar-H), 7.25-7.17 ( m,1H,Ar-H),7.17-7.10(m,2H,Ar-H),7.11-6.99(m,3H,Ar-H),6.99-6.90(m,2H,Ar-H),6.85( dt,J=4.2,3.5Hz,1H,Ar-H),4.76(tt,J=12.0,3.7Hz,1H,Piperidine),3.86(s,3H,Ar-OCH 3 ), 3.43 (dd, J=11.9, 7.1Hz, 6H, Ar-CH 2 ,Piperazine), 3.13(d,J=11.8Hz,2H,Piperidine),2.82(t,J=11.2Hz,2H,Piperidine),2.48-2.33(m,4H,Piperazine),1.95(q,J=7.4 Hz, 2H, CH 2 ), 1.87(d, J=10.0Hz, 2H, Pip...

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Abstract

The invention belongs to the technical field of pharmacy, particularly discloses a benzylpiperazine urea TRPV1 antagonistic and MOR agonistic double-target drug as well as a preparation method and application thereof, and particularly relates to a compound in a general formula (I) and pharmaceutically acceptable salts thereof, and the drug can be used for preventing and/or treating diseases related to TRPV1 and/or MOR activity, such as pain, inflammation, immune dysfunction, neurological and psychiatric disorders, respiratory diseases, urinary and reproductive disorders. the invention also relates to a preparation method of the compounds and a pharmaceutical preparation containing the compounds.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, and specifically relates to a benzylpiperazine urea TRPV1 antagonistic and MOR agonist dual-target drug and its preparation method and application. The dual-target drug uses benzylpiperazine urea compounds as active ingredients . Background technique [0002] Transient receptor potential vanilloid-1 (TRPV1) was the first identified member of the mammalian thermo-tryptophan protein family and is by far the most thoroughly characterized. TRPV1 is a Ca-preferring 2+ The non-selective cation channel of serotonin is a multi-channel receptor that can be detected by naturally occurring substances (such as capsaicin, camphor, resintoxin), preparations (such as 2-APB), acids (pH<5.9), endogenous Sexual lipids (such as pepperamine, N-arachidoyl dopamine, leukotriene B4) activation. Activation of TRPV1 triggers influx of calcium and sodium ions, initiating a cascade of events leading to membrane depo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/58C07D211/14A61P29/00A61P37/02A61P25/00A61P25/18A61P11/00A61P15/00A61P13/00A61K31/496
CPCC07D211/58C07D211/14A61P29/00A61P37/02A61P25/00A61P25/18A61P11/00A61P15/00A61P13/00
Inventor 严琳高梦康王玉睢乔振蕊宋德朴陈英达王国豪
Owner HENAN UNIVERSITY
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