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Piperidine amide derivative, and preparation method, pharmaceutical composition, single crystal culture method and application thereof

A technology of benzylpiperidine and phenylpropionamide, applied in the field of medicinal chemistry, can solve the problems of low response rate, strong side effects, no evaluation of in vivo analgesic activity, etc., and achieve the effect of good analgesic activity

Active Publication Date: 2021-08-06
江苏谛奇医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tricyclic antidepressants (such as amitriptyline, noramitriptyline, etc.) and serotonin and norepinephrine reuptake inhibitor antidepressants (such as venlafaxine, duloxetine, etc.) , such drugs have strong side effects and low response rates
In 1992, Carroll et al found that phenazocine and its derivatives had dual pharmacological activities of sigma-1 receptor and mu receptor through in vitro assay, but did not evaluate the analgesic activity in vivo

Method used

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  • Piperidine amide derivative, and preparation method, pharmaceutical composition, single crystal culture method and application thereof
  • Piperidine amide derivative, and preparation method, pharmaceutical composition, single crystal culture method and application thereof
  • Piperidine amide derivative, and preparation method, pharmaceutical composition, single crystal culture method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] Example 1: N-(2-(4-benzylpiperidin-1-yl)ethyl)-N-phenylacetamide (target compound 1)

[0102] Reaction 1

[0103]

[0104] general method of synthesis

[0105] 1) Synthesis of 2-chloro-N-phenylacetamide (intermediate 1):

[0106]

[0107] With 1g (10.74mmol) aniline, 2.969g (21.48mmol) K 2 CO 3 Dissolve in 10mL acetone, place in an ice bath and stir to 0°C. 1.456 g (12.89 mmol) of chloroacetyl chloride was slowly added dropwise, and stirred at room temperature for 4 hours. Add water to quench after the reaction, extract with EA, wash with dilute NaOH solution and saturated brine respectively, add anhydrous sodium sulfate to stir and dry, distill under reduced pressure to remove the solvent, add appropriate amount of absolute ethanol and petroleum ether to heat to dissolve, cool Crystallized, filtered and washed the filter cake with petroleum ether, and dried to obtain a white solid with a yield of about 54.7%.

[0108] 2) Synthesis of 2-(4-benzylpiperidin-...

Embodiment 2

[0118] Example 2: N-(2-(4-benzylpiperidin-1-yl)ethyl)-N-(4fluorophenyl)acetamide (target compound 2)

[0119] The difference from Example 1 is only that in the synthesis step 1), aniline is replaced by p-fluoroaniline, and other steps are basically the same, so they will not be repeated here.

[0120] 1 H NMR (400MHz, CDCl 3 )δ7.26(t,J=7.4Hz,2H),7.23–7.15(m,3H),7.15–7.04(m,4H),3.79(t,J=7.0Hz,2H),2.82(d,J =11.4Hz, 2H), 2.51(d, J=7.1Hz, 2H), 2.43(t, J=7.0Hz, 2H), 1.92–1.84(m, 2H), 1.81(s, 3H), 1.58(d ,J=13.1Hz,2H),1.48–1.43(m,1H),1.29–1.16(m,2H).MS(ESI)m / z=355.2([M+H] + )

Embodiment 3

[0121] Example 3: N-(2-(4-benzylpiperidin-1-yl)ethyl)-N-(4methylphenyl)acetamide (target compound 3)

[0122] The difference from Example 1 is only that in the synthesis step 1), the aniline is replaced by p-methylaniline, and the other steps are basically the same, and will not be repeated here.

[0123] 1 H NMR (400MHz, CDCl 3 )δ7.29–7.24(m,2H),7.20–7.15(m,3H),7.12(dd,J=5.1,3.1Hz,2H),7.09–7.05(m,2H),3.86–3.76(m, 2H), 2.85(d, J=11.3Hz, 2H), 2.51(d, J=7.1Hz, 2H), 2.47–2.42(m, 2H), 2.37(s, 3H), 1.90(t, J=11.1 Hz,2H),1.81(s,3H),1.58(d,J=13.1Hz,2H),1.53–1.42(m,1H),1.30–1.18(m,2H).MS(ESI)m / z= 351.2([M+H] + )

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Abstract

The invention provides N-(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide, a pharmaceutical composition thereof and application of the N-(2-(4-benzylpiperidin-1-yl) propyl)-N-phenylpropanamide in preventing or treating pain diseases. A result in a formalin induced pain model shows that the ED50 value of the above compound is lower than that of a positive drug pregabalin; and results in an acetic acid writhing body model show that the ED50 value of S-N-(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide is lower than that of R-configuration N-(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide and is superior to that of raceme N-(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide, and the N-(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide has better analgesic activity.

Description

[0001] This application claims the priority of a Chinese patent application with an application date of February 03, 2020, an application number of 202010078685.7, and an invention titled "piperidine amide derivatives, pharmaceutical compositions and applications thereof", all of which are approved by References are incorporated in this application. technical field [0002] The invention belongs to the field of medicinal chemistry, and specifically relates to a kind of N-(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide and its enantiomer compound, and its S configuration N -(2-(4-benzylpiperidin-1-yl)propyl)-N-phenylpropanamide preparation method, its single crystal culture method, biological activity evaluation, as well as the pharmaceutical composition containing the above-mentioned substances and its use Application in the prevention and treatment of pain diseases. Background technique [0003] Pain is an unpleasant subjective sensory and emotional experience assoc...

Claims

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Application Information

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IPC IPC(8): C07D211/14C07D211/58C07D211/46C07D211/32C07D211/22C07D401/12A61K31/4468A61K31/445A61P25/04A61P29/00
CPCC07D211/14C07D211/58C07D211/46C07D211/32C07D211/22C07D401/12A61P25/04A61P29/00
Inventor 张桂森熊家英陈寅刘笔锋刘欣
Owner 江苏谛奇医药科技有限公司
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