4-(2-(pyrrolidine/piperidine-1-yl)benzyl)-piperazine urea TRPV1 antagonist and preparation method and application thereof

A technology of pyrrolidine and pyrrolidine, which is used in the preparation of analgesic drugs to treat pain, in the field of 4-benzyl)-piperazine urea novel TRPV1 antagonists, which can solve problems such as elevated body temperature and achieve strong effects , No side effects of elevated body temperature, analgesic effect

Active Publication Date: 2020-07-28
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, however, many TRPV1 antagonists have the side effect of causing body temperature to rise. Therefore, it is of great research significance to develop TRPV1 antagonists that do not cause hyperthermia.

Method used

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  • 4-(2-(pyrrolidine/piperidine-1-yl)benzyl)-piperazine urea TRPV1 antagonist and preparation method and application thereof
  • 4-(2-(pyrrolidine/piperidine-1-yl)benzyl)-piperazine urea TRPV1 antagonist and preparation method and application thereof
  • 4-(2-(pyrrolidine/piperidine-1-yl)benzyl)-piperazine urea TRPV1 antagonist and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: Preparation of N-(4-methyl-2-nitrophenyl)-4-(2-(pyrrolidinyl-1-yl)benzyl)piperazine-1-carboxamide (1)

[0060]

[0061] (a) Preparation of 2-(pyrrolidin-1-yl) benzaldehyde

[0062] Accurately weigh anhydrous potassium carbonate (2.7840g, 20.143mmol), put it into a 100mL eggplant-shaped bottle, stir and dissolve 10mL dimethyl sulfoxide, add 2-fluorobenzaldehyde (1.0g, 8.057mmol) and tetrahydro Pyrrole (0.859 g, 12.085 mmol). Reacted overnight in an oil bath at 85°C. After the reaction was detected by TLC, extracted with ethyl acetate (30mL×2), combined the organic phases and washed with water (30mL×3), evaporated the solvent under reduced pressure to obtain 2-(pyrrolidine-1 -yl) benzaldehyde.

[0063] (b) Preparation of 4-(2-(pyrrolidin-1-yl) benzyl) piperazine-1 carboxylic acid tert-butyl ester

[0064] At room temperature, add 2-(pyrrolidin-1-yl)benzaldehyde (1.3697g, 7.8165mmol) and 20mL dichloromethane into a 100mL one-necked flask and stir to dissol...

Embodiment 2

[0070] Example 2: Preparation of N-(4-chloro-2-nitrophenyl)-4-(2-(pyrrolidin-1-yl)benzyl)piperazine-1-carboxamide (2)

[0071]

[0072] During the preparation process, the 4-methyl-2-nitroaniline in Example 1 was replaced with 4-chloro-2-nitroaniline, and other references were made to the preparation method in Example 1 to obtain compound 2 and obtain a red solid. Yield 13.9%. The experimental data are as follows:

[0073] C 22 h 26 ClN 5 o 3 ; yield: 13.9%; red solid; m.p=54.8-55.8°C; 1 H NMR (CDCl 3 ,300MHz): δppm10.15(s,1H,NH),8.66(d,1H,J=9.0Hz,Ar-H),8.19(d,1H,J=2.7Hz,Ar-H),7.55(dd ,1H,J=3.0,9.0Hz,Ar-H),7.41(dd,1H,J=3.0,9.0Hz,Ar-H),7.19(t,1H,J=9.0Hz,Ar-H),6.96 -6.91(m,2H,Ar-H),3.59(t,5H,J=4.5Hz,Ar-CH 2 ,pyrrolidine), 3.19(t,3H,J=3.0Hz,piperazine),2.54(t,3H,J=6.0Hz,piperazine),1.94-1.90(m,3H,pyrrolidine),1.49-1.33(m,2H ,pyrrolidine),1.28-1.22(m,2H,pyrrolidine); HRMS m / z:[M+H] + 444.1805 (calcd 444.1797).

Embodiment 3

[0074] Example 3: Preparation of 4-(2-(pyrrolidinyl-1-yl)benzyl)-N-(2-(trifluoromethyl)phenyl)piperazine-1-carboxamide (3)

[0075]

[0076] During the preparation process, the 4-methyl-2-nitroaniline in Example 1 was replaced with 2-trifluoromethylaniline, and other references were made to the preparation method in Example 1 to obtain compound 3 to obtain a reddish-brown solid, producing rate of 50.4%. The experimental data are as follows:

[0077] C 23 h 27 f3 N 4 O; yield: 50.4%; refous solid; m.p=102.2-103.2°C; 1 H NMR (CDCl 3 ,300MHz): δppm8.11(d,1H,J=9.0Hz,Ar-H),7.53(q,2H,J=9.0Hz,Ar-H),7.42(dd,1H,J=9.0,3.0Hz ,Ar-H),7.21-7.10(m,2H,Ar-H),6.91(q,2H,J=9.0Hz,Ar-H),6.80(s,1H,NH),3.58(s,2H, Ar-CH2), 3.51(t, 4H, J=4.5Hz, pyrrolidine), 3.20(t, 4H, J=6.0Hz, piperazine), 2.52(t, 4H, J=4.5Hz, piperazine), 1.94-1.88 (m,4H,pyrrolidine); HRMSm / z:[M+H] + 433.2207 (calcd. 433.2210).

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Abstract

The invention discloses a novel 4-(2-(pyrrolidine/piperidine-1-yl)benzyl)-piperazine urea type TRPV1 antagonist and a preparation method and application thereof. The invention relates to a compound ina general formula (I) and a pharmaceutically acceptable salt thereof, in the formula, n is equal to 1 or 2, R is H, F, Cl, Br, I, CF3, CH3 or OH, and Ar is phenyl or aromatic heterocyclic group. Thecompounds have a strong analgesic effect, the activity of part of the compounds is far higher than that of a TRPV1 receptor antagonist BCTC, almost no body temperature rise side effect exists, and theinvention further relates to the preparation method of the compounds and pharmaceutical preparations containing the compounds.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of 4-(2-(pyrrolidin / piperidin-1-yl) benzyl)-piperazine urea novel TRPV1 antagonists. The invention also discloses its preparation method, Pharmaceutical preparations with the compounds as active ingredients, and their use as TRPV1 antagonists or in the preparation of analgesics for pain treatment. Background technique [0002] Pain is closely related to people's lives, and is one of the most common diseases in life. Severe pain can even endanger people's lives. The analgesic drugs currently used clinically mainly include opioids and non-steroidal anti-inflammatory drugs (NSAIDs), but both types of drugs have some side effects. The common adverse reactions of opioids are addiction, withdrawal and respiratory depression, which limit their application in pain treatment; non-steroidal anti-inflammatory drugs have serious gastrointestinal side effects, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/195C07D217/02C07D213/75C07D211/14C07D401/12C07D211/46A61K31/496A61P25/04
CPCC07D295/195C07D217/02C07D213/75C07D211/14C07D401/12C07D211/46A61P25/04
Inventor 严琳胡静乔玥高梦康王玉睢乔振蕊
Owner HENAN UNIVERSITY
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