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Pyrimidyl piperazine urea TRPV1 antagonistic/MOR agonistic double-target compound as well as preparation method and application thereof

A technology of pyrimidinylpiperazine urea and pyrimidinylpiperazine, which is applied in the field of medicinal chemistry, can solve problems such as loss of thermal perception and hinder development, and achieve the effects of blocking pain transmission, reducing side effects, and having good application prospects.

Active Publication Date: 2021-08-27
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, a large number of TRPV1 antagonists have been designed and developed, but their further development has been hindered by side effects such as increased body temperature and loss of noxious heat perception during clinical research.

Method used

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  • Pyrimidyl piperazine urea TRPV1 antagonistic/MOR agonistic double-target compound as well as preparation method and application thereof
  • Pyrimidyl piperazine urea TRPV1 antagonistic/MOR agonistic double-target compound as well as preparation method and application thereof
  • Pyrimidyl piperazine urea TRPV1 antagonistic/MOR agonistic double-target compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of N-(4-bromophenyl)-4-(4-(pyrrolidin-1-yl)pyrimidin-2-yl)piperazine-1-carboxamide (compound 1) according to synthetic route A:

[0046] (1) At 0°C, triethylamine (3.84mL) was added dropwise to 2,4-dichloropyrimidine (2.05g, 13.8mmol) in dichloromethane solution (30mL) and stirred, then pyrrolidine (0.985g , 13.8mmol) of dichloromethane (20mL) was added dropwise to the above reaction system, heated to room temperature, reacted for 4h, and detected by TLC. After the reaction was completed, it was washed with saturated brine (30mL×3), and the organic phase was washed with anhydrous MgSO 4 Dry, filter, concentrate under reduced pressure, and separate and purify by column chromatography (PE:EA=50:1) to obtain 2-chloro-4-(pyrrolidin-1-yl)pyrimidine (compound a).

[0047] (2) Weigh the 2-chloro-4-(pyrrolidin-1-yl)pyrimidine (1.50g, 8.194mmol) prepared in step (1), anhydrous piperazine (0.705g, 8.194mmol), sodium hydroxide (0.492g, 12.291mmol), were added to a 100...

Embodiment 2

[0051] Prepare N-(3,4-dichlorophenyl)-4-(4-(4-methylpiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carboxamide (compound 2):

[0052]

[0053] The difference between Example 2 and Example 1 is: 4-methylpiperidine and 3,4-dichloroaniline are used to replace the pyrrolidine in the step (1) of Example 1 and the 4-bromo Aniline, all the other are identical with embodiment 1. This affords N-(3,4-dichlorophenyl)-4-(4-(4-methylpiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carboxamide (compound 2), yielding Rate 46.5%.

[0054] C 21 h 26 Cl 2 N 6 O; 46.5% yield, white solid; 1 H NMR (300MHz, CDCl 3 )δppm 7.93(d, J=6.1Hz, 1H, Pyrimidine), 7.63(d, J=2.4Hz, 1H, Ar-H), 7.34(d, J=8.7Hz, 1H, Ar-H), 7.25( dd,J=8.8,2.5Hz,1H,Ar-H),6.91(s,1H,NH),5.95(d,J=6.1Hz,1H,Pyrimidine),4.35(d,J=13.2Hz,2H, Piperidine), 3.96-3.78 (m, 4H, piperazine), 3.67-3.54 (m, 4H, piperazine), 2.85 (td, J=12.8, 2.5Hz, 2H, piperidine), 1.82-1.59 (m, 3H, piperidine ),1.26-1.10(m,2H,Piperidine),1.00(d,J=6.1Hz,3H,CH ...

Embodiment 3

[0056] Prepare N-(3,4-dichlorophenyl)-4-(4-(4-phenylpiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carboxamide (compound 3):

[0057]

[0058] The difference between Example 3 and Example 1 is: 4-phenylpiperidine and 3,4-dichloroaniline are used to replace the pyrrolidine in the step (1) of Example 1 and the 4-bromo Aniline, all the other are identical with embodiment 1. This affords N-(3,4-dichlorophenyl)-4-(4-(4-phenylpiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carboxamide (compound 3), yielding rate 42%.

[0059] C 26 h 28 Cl 2 N 6 O; 42% yield, white solid; 1 H NMR (300MHz, CDCl 3 )δppm 7.98(d, J=6.1Hz, 1H, Pyrimidine), 7.63(d, J=2.4Hz, 1H, Ar-H), 7.41-7.31(m, 3H, Ar-H), 7.31-7.22(m ,4H,Ar-H),7.00(s,1H,NH),6.01(d,J=6.1Hz,1H,Pyrimidine),4.55(d,J=13.1Hz,2H,Piperidine),3.87(dd,J =6.7, 3.8Hz, 4H, piperazine), 3.60 (dd, J = 6.5, 3.9Hz, 4H, piperazine), 2.98 (td, J = 12.9, 2.6Hz, 2H, piperidine), 2.83 (tt, J = 12.2 ,3.6Hz,1H,Piperidine),2.07-1.90(m,2H,Piperidine),1.73(q...

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Abstract

The invention discloses a pyrimidinyl piperazine urea TRPV1 antagonistic / MOR agonistic double-target compound or a pharmaceutically acceptable salt thereof, the compound has a structural general formula I, and a drug taking the compound as an active component not only shows obvious inhibitory activity on TRPV1, but also can show obvious agonistic activity on MOR. The invention also discloses a preparation method of the compound or the pharmaceutically acceptable salt thereof. The preparation method has the characteristic of mild reaction conditions. The invention also discloses application of the compound or the pharmaceutically acceptable salt thereof in preparation of a medicine for treating and / or preventing TRPV1 and / or MOR mediated diseases, the medicine not only can block pain transmission of peripheral and central nervous systems, but also can reduce side effects related to single targeting, such as nausea, sleepiness and respiratory depression caused by an MOR agonist and nociceptive thermal inductance weakening and obvious body temperature rise caused by a TRPV1 antagonist, and has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a pyrimidinyl piperazine urea TRPV1 antagonistic / MOR activating dual-target compound and a preparation method and application thereof. Background technique [0002] Pain is the result of complex interactions between the nervous system, and the forms of pain are divided into acute pain and chronic pain. Among them, chronic pain often lasts for more than one month, which is very harmful to human health; relevant data show that the incidence of chronic pain among adults worldwide is 30%. World Pain Relief Day. [0003] Most of the potent analgesics currently in use act through opioid receptors, which are G protein-coupled receptors and are generally divided into four subtypes: μ opioid receptors (MOR), delta opioid receptors ( DOR), kappa opioid receptor (KOR) and sigma opioid receptor (SOR), which are mainly involved in physiological functions such as analgesia and immu...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/506A61P29/00A61P1/10
CPCC07D401/04A61P29/00A61P1/10
Inventor 严琳王玉睢高梦康乔振蕊王国豪宋德朴陈英达
Owner HENAN UNIVERSITY
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