(S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof

A technology of phenylthiazole and pyrrolidine, which is applied in the field of preparing analgesic drugs to treat pain, and can solve problems such as gastrointestinal side effects and hematopoietic system adverse reactions

Active Publication Date: 2020-07-17
HENAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Non-steroidal anti-inflammatory drugs exert analgesic and anti-inflammatory effects by inhibiting cyclooxygenase (COX) to reduce arachidonic acid to synthesi

Method used

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  • (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof
  • (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof
  • (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: Preparation of (S)-N-(2-bromophenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide (1)

[0074]

[0075] (a) Preparation of (S)-tert-butyl-2-(2-oxo-2-phenylethylcarbamoyl)pyrrolidine-1-carboxylate

[0076] Accurately weigh 1.88g (8.74mmol) of Boc-L-proline into a 100mL eggplant-shaped bottle, dissolve with 30mL dichloromethane, 1.18g (8.74mmol) of 1-hydroxybenzotriazole, 1-(3- Add 1.68g (8.74mmol) of dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) into the reaction flask in turn, stir at room temperature, and after half an hour of reaction, add 2-aminoacetophenone salt Acetate 1.00g (5.80mmol) and triethylamine 2mL, continue to react at room temperature for 18 hours, after the reaction, the reaction solution is washed with 10% citric acid solution (30mL × 3) and saturated saline solution (30mL × 3) successively , dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain (S)-tert-butyl-2-(2-oxo-2-phenyl...

Embodiment 2

[0084] Example 2: Preparation of (S)-N-(3-chlorophenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide (2)

[0085]

[0086] During the preparation process, 2-bromoaniline in Example 1 was replaced with 3-chloro-aniline, and other references were made to the preparation method in Example 1 to obtain compound 2 as a brownish-yellow solid with a yield of 35%. The experimental data are as follows:

[0087] C 20 h 18 ClN 3 OS, 35% yield, dark brown solid, m.p = 140.9-1403.9°C; 1 H NMR (CDCl 3 ,400MHz): δppm 7.90(s,1H,Ar-H),7.56(t,1H,J=4.0Hz,Ar-H),7.53(d,2H,J=8.0Hz,Ar-H),7.40( t,2H,J=12.0Hz,Ar-H),7.32-7.28(m,2H,Ar-H),7.17(t,1H,J=16.0Hz,Ar-H),6.97(d,1H,J =8.0Hz, Ar-H), 5.40(dd, 1H, J=12.0, 4.0Hz, pyrrolidine-H), 3.79(t, 1H, J=8.0Hz, CH 2 ),3.68(q,1H,J=8.0Hz,CH 2 ),2.48-2.37(m,2H,CH 2 ),2.32-2.10(m,2H,CH 2 ); HRMS m / z: [M+H] + 384.0859 (calcd. 384.0931).

Embodiment 3

[0088] Example 3: Preparation of (S)-N-(4-fluorophenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide (3)

[0089]

[0090] During the preparation process, 2-bromoaniline in Example 1 was replaced with 4-fluoro-aniline, and other references were made to the preparation method in Example 1 to obtain compound 3 as a brownish-yellow solid with a yield of 17.4%. The experimental data are as follows:

[0091] C 20 h 18 FN 3 OS, 17.4% yield, brown yellow solid, m.p = 127.7-128.7°C; 1 H NMR (CDCl 3 ,300MHz): δppm 7.88(s,1H,Ar-H),7.50(d,2H,J=6.0Hz,Ar-H),7.41-7.33(m,5H,Ar-H),6.95(t,2H , J=9.0Hz, Ar-H), 5.27(dd, 1H, J=12.0, 3.0Hz, pyrrolidine-H), 3.70-3.65(m, 2H, CH 2 ),2.54-2.36(m,2H,CH 2 ),2.30-2.06(m,2H,CH 2 ); HRMS m / z: [M+H] + 368.1155 (calcd. 368.1226).

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Abstract

The invention discloses (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole novel TRPV1 antagonists as well as a preparation method and application thereof, and particularly relates to compounds represented bya general formula (I) or a general formula (II) and a pharmaceutically acceptable salt thereof. The compound 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 the invention further relates to a preparation method of the compounds and pharmaceutical preparationscontaining the compounds.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a class of (S)-4 / 5-phenyl-2-(pyrrolidin-2-yl)thiazole novel TRPV1 antagonists. The invention also discloses its preparation method, The pharmaceutical preparations in which the compounds are active ingredients, and their use as TRPV1 antagonists or in the preparation of analgesics for treating pain. Background technique [0002] Pain sensation plays a protective role in the physiological state, forewarning the coming of injury, and prompting the body to avoid the injury; but in the pathological state, pain is one of the main symptoms of most diseases, and chronic pain itself is a disease and a worldwide phenomenon. major health problems. According to statistics, 22% of primary care patients between the ages of 18 and 65 suffer from chronic pain. In developed countries, about half of all people seek medical help for pain at some point in their lives, so ef...

Claims

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Application Information

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IPC IPC(8): C07D417/04A61K31/427A61P29/00A61K9/20A61K47/36A61K47/26
CPCC07D417/04A61P29/00A61K9/2059A61K9/2018C07B2200/07
Inventor 严琳乔玥胡静王玉睢高梦康乔振蕊
Owner HENAN UNIVERSITY
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