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Benzimidazolone compounds, and use thereof in antitussive and antiasthmatic drugs

A technology of benzimidazolone and compound, applied in the field of benzimidazolone compounds

Inactive Publication Date: 2019-11-12
王兴理
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the development of new TRPV 1 Antagonist antitussives have very important research significance and development value, but the research on benzimidazolone compounds mentioned in the present invention has not been reported so far in terms of antitussive and antiasthmatic

Method used

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  • Benzimidazolone compounds, and use thereof in antitussive and antiasthmatic drugs
  • Benzimidazolone compounds, and use thereof in antitussive and antiasthmatic drugs
  • Benzimidazolone compounds, and use thereof in antitussive and antiasthmatic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Embodiment 1: the synthesis of intermediate 1

[0019]

[0020] Add methyl 3-(phenylamino)propionate (1 equivalent), palladium acetate (2mol%), silver carbonate (2 equivalents) and dichloroethane (4mL) into a round bottom flask, stir well and then add 4- Fluorophenylisocyanate (1.5 equivalents). The reaction solution was heated at 120° C., and filtered through diatomaceous earth after the completion of the reaction was monitored by TLC. The filtrate was concentrated by rotary evaporation, and the residue was purified by column chromatography (PE / EA=1 / 2) to obtain Intermediate 1 with a yield of 75%. 1 H-NMR (CDCl 3 ,400MHz)δ7.50(dd,J=8.6,4.6Hz,2H),7.21(t,J=8.6Hz,2H),7.17(t,J=7.6Hz,1H),7.08(t,J=7.6 Hz,1H),7.05(d,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),4.26(t,J=7.0Hz,2H),3.69(s,3H),2.87( t,J=7.0Hz,2H).HRMS(EI)[M+Na] + m / z calcd for C 17 h 15 FN 2 o 3 314.1067,found 314.1066.

Embodiment 2

[0021] Embodiment 2: the synthesis of intermediate 2

[0022]

[0023] Add intermediate 1 (0.1mmoL) to the round bottom flask, add the acetonitrile after dissolving A26(OH - )(1.34mmol / g(wet), 0.2mmoL OH - ). The reaction solution was stirred at room temperature for 16 h and filtered. After washing the resin with acetonitrile, add 20% formic acid solution, stir, and filter. The resin was washed with acetonitrile to obtain the pure intermediate 2 with a yield of 89%. 1 H-NMR (CDCl 3 ,400MHz)δ7.51(dd,J=8.6,4.6Hz,2H),7.21(t,J=8.6Hz,2H),7.18(t,J=7.6Hz,1H),7.08(t,J=7.6 Hz,1H),7.05(d,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),4.56(t,J=7.0Hz,2H),3.17(t,J=7.0Hz, 2H).HRMS(EI)[M+Na] + m / z calcd for C 16 h 13 FN 2 o 3 300.0910, found 300.0910.

Embodiment 3

[0024] Embodiment 3: the synthesis of compound 1

[0025]

[0026] Add intermediate 2 (1mmoL) and dry THF (1mL) into the round bottom flask, stir to dissolve, add CDI (2.2mmoL) at room temperature, stir the mixture at room temperature for 30min, then heat and stir at 55°C for 1h. After the reaction solution was cooled to room temperature, benzenesulfonamide (2mmoL) was added, and after stirring for 10min, DBU (2mmoL) was added. The reaction solution was stirred at room temperature for 5 h. After the reaction was complete as monitored by TLC, 1.0M HCl (7 mL) was added. The mixture was extracted with water and EA, the combined organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated by rotary evaporation, and the residue was purified by column chromatography (PE / EA=2 / 3) to obtain compound 1 with a yield of 72%. 1 H-NMR (CDCl 3 ,400MHz)δ7.79-7.69(m,2H),7.71(dd,J=8.6,4.6Hz,2H),7.51(t,J=8.6Hz,2H),7.42-7.34(m,3H),7.38 (t, J=7.6Hz, 1H),...

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Abstract

The present invention discloses benzimidazolone compounds represented by formula I, or pharmaceutically acceptable salts thereof. Results of citric acid-induced guinea pig cough model effect test, capsaicin-induced mouse cough inhibition test, influences of the benzimidazolone compounds on guinea pig allergic asthma and calcium influx test of vanilloid receptors show that the compounds exhibit good antitussive and antiasthmatic effects by inhibiting vanilloid receptor 1.

Description

technical field [0001] The invention relates to the field of medicine, in particular to the use of benzimidazolone compounds in antitussive and antiasthmatic drugs. Background technique [0002] Cough and asthma are the most common symptoms of respiratory diseases. After the sensory nerve endings are stimulated, the nerve impulses are transmitted along the vagus nerve to the cough center of the brainstem, and after the signal is integrated, it is transmitted to the effector through the efferent nerve, and finally leads to coughing action. The airway afferent nerves related to cough reflex mainly have myelinated Aδ fibers and unmyelinated C fibers, among which the myelinated Aδ fibers are sensitive to various mechanical stimuli; the unmyelinated C fiber endings are sensitive to various types of chemical stimuli . C fiber nerve endings contain the transient receptor potential vanilloid receptor 1 (TRPV 1 ), a variety of physical and chemical stimuli can directly or indirect...

Claims

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Application Information

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IPC IPC(8): C07D235/26C07D401/12C07D409/12A61P11/14A61P11/06
CPCA61P11/06A61P11/14C07D235/26C07D401/12C07D409/12
Inventor 王兴理
Owner 王兴理
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