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Amide derivative containing benzoheterocycle structure, and composition and application thereof

A technology of amide derivatives and heterocycles, applied in the field of medicine, can solve the problems of toxic side effects, no neuropathic pain, etc., and achieve the effect of strong analgesic activity

Pending Publication Date: 2020-06-02
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Currently there is no clinically specific drug for neuropathic pain, and clinically available analgesics are ineffective in 30–50% of patients with neuropathic pain and often cause toxic side effects

Method used

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  • Amide derivative containing benzoheterocycle structure, and composition and application thereof
  • Amide derivative containing benzoheterocycle structure, and composition and application thereof
  • Amide derivative containing benzoheterocycle structure, and composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0140] Embodiment 1 (S)-2-(4-((benzofuran-4-)oxymethyl) benzylamino) propanamide (Ia-1) synthetic

[0141]

[0142] 1.1 Synthesis of p-hydroxymethylbenzaldehyde (2a-1) and m-hydroxymethylbenzaldehyde (2a-2)

[0143]

[0144] Take a 250mL eggplant-shaped bottle, add 10.00g (74.55mmol) of terephthalaldehyde 1a-1 or isophthalaldehyde 1a-2, and then add 50mL of ethanol and 80mL of tetrahydrofuran to dissolve it. Under stirring in an ice bath, 0.85 g (22.46 mmol) of sodium borohydride was added three times. After the injection was completed, the reaction was continued for more than 6 h under ice bath conditions. Monitor the reaction process with thin-layer chromatography until point 1a-1 or 1a-2 disappears completely, stop the reaction, quench the reaction solution with 3mol / L hydrochloric acid, adjust the pH to 4–5, filter, and distill the filtrate to remove the solvent under reduced pressure, leaving The substance is a brownish yellow oil, the residue is dissolved with 50 ...

Embodiment 2

[0154] Synthesis of Example 2 (S)-2-(3-((benzofuran-4-)oxymethyl)benzylamino)propanamide (Ia-2)

[0155]

[0156] Take one 100mL eggplant-shaped bottle, add 0.59g (4.70mmol) L-alaninamide hydrochloride, 0.95g (9.40mmol) triethylamine and 30mL methanol, stir at room temperature for 1h, and dissolve 0.79g (3.13mmol) 4a -2 Add the reaction solution, continue the reaction at room temperature for 2 hours, add 1.01g (18.80mmol) potassium borohydride to the reaction solution three times, and react for 3 hours under reflux after throwing, monitor the reaction process with thin-layer chromatography until point 4a-2 completely disappears, and depressurize The solvent was distilled off, and the residue was a light yellow solid. The residue was mixed with 100-200 mesh silica gel and separated by column chromatography (gradient elution: MeOH / DCM, 0-5%) to obtain a light yellow oil (Ia-2 , 0.93g, yield 91.18%). ESIMS m / z 325.15[M+H] + ;1H NMR(400MHz,DMSO-d6):7.91(d,1H),7.21–7.48(m,7H),...

Embodiment 3

[0157] Synthesis of Example 3 (S)-2-(4-((benzofuran-5-)oxymethyl)benzylamino)propanamide (Ia-3)

[0158]

[0159] 3.1 Synthesis of 4-((benzofuran-5-)oxymethyl)benzaldehyde (4a-3) and 3-((benzofuran-5-)oxymethyl)benzaldehyde (4a-4)

[0160]

[0161] Take a 100mL eggplant-shaped bottle, add 0.69g (5.15mmol) 5-hydroxybenzofuran, 1.74g (5.35mmol) Cs 2 CO 3 and 30mL of absolute ethanol, stirred at room temperature for 1h, 1.02g (5.15mmol) 3a-1 or 3a-2 and 0.13g (0.77mmol) KI were put into the reaction solution, and the reaction was refluxed at 80°C for more than 4h after the throwing was completed. Monitor the reaction process by layer chromatography until the 5-hydroxybenzofuran point completely disappears, filter, and distill the filtrate to remove the solvent under reduced pressure. The residue is a yellow solid. Dissolve the residue with 20 mL each of water and ethyl acetate. Extract twice with ethyl acetate, 10 mL each time, combine the organic phases, wash with satura...

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PUM

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Abstract

The invention belongs to the technical field of medicines, and discloses an amide derivative containing a benzoheterocycle structure, and a composition and an application thereof. The amide derivativecontaining the benzoheterocycle structure is a compound represented by structural formula I and a nontoxic pharmaceutically acceptable salt thereof, or the amide derivative containing the benzoheterocycle structure is a compound represented by structural formula II or a nontoxic pharmaceutically acceptable salt thereof. The amide derivative containing the benzoheterocycle structure has good analgesic activity and good inhibition effect on a target sodium ion channel Nav1.7.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to an amide derivative containing a benzoheterocyclic structure, a composition and an application. Background technique [0002] The description of the background technology of the present invention belongs to the relevant technology related to the present invention, and is only used to illustrate and facilitate the understanding of the content of the present invention. prior art on the filing date. [0003] Neuropathic pain is a kind of chronic pain, which refers to pain caused by peripheral or central nervous system, primary or secondary damage, dysfunction or transient disorder, which is characterized by persistent and recurrent attacks. Epidemiological studies indicate a prevalence of neuropathic pain of 6.9–10%. [0004] Currently, there is no clinically specific drug for neuropathic pain, and clinically available analgesics are ineffective in 30–50% of patients with neuropa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79C07D307/86C07D235/08C07D215/20C07D215/26C07D209/08C07D333/54C07D319/18A61K31/343A61K31/4184A61K31/47A61K31/404A61K31/357A61K31/381A61P25/04
CPCA61P25/04C07D209/08C07D215/20C07D215/26C07D235/08C07D307/79C07D307/86C07D319/18C07D333/54
Inventor 王丽韫童坤史卫国程京超于子兴任凤霞周琥熊颖
Owner ACADEMY OF MILITARY MEDICAL SCI
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