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Application of evodiamine derivative in preparation of medicine for treating superficial fungal infection

A technology for evodial and fungal infection, which is applied in the field of medicine and can solve the problems of narrow antibacterial spectrum, inability to meet the needs of patients for medication, and large toxic and side effects.

Active Publication Date: 2021-12-10
NANHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The research on antifungal drugs is still slow. In recent years, allylamine and azoles are the main drugs for treating dermatophytes, but the drug resistance of dermatophytes to therapeutic drugs such as ketoconazole and fluconazole is gradually increasing. The drug mechanism involves changes in drug target enzymes, high expression of efflux pumps, and changes in drug permeability. There are few types, poor curative effect, large toxic and side effects, coupled with narrow antibacterial spectrum and continuous emergence of drug resistance, clinically limited antifungal drugs Drugs are far from meeting the medication needs of patients, seriously threatening human health and quality of life

Method used

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  • Application of evodiamine derivative in preparation of medicine for treating superficial fungal infection
  • Application of evodiamine derivative in preparation of medicine for treating superficial fungal infection
  • Application of evodiamine derivative in preparation of medicine for treating superficial fungal infection

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] 14-ethyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one (compound BT1)

[0029] The structural formula of compound BT1 is:

[0030] (1) At room temperature, dissolve methyl 2-(ethylamino)benzoate (compound 1-1, 1 mmol), tryptamine (1.5 mmol), and trimethylaluminum (3.0 mmol) in 10 ml of dichloromethane, in 0 ℃ for 6 hours, the product N-(2-(1 H -indol-3-yl)ethyl)-2-(ethylamino)benzamide (compound 1-2), the yield was 71%.

[0031] The structural formula of compound 1-1 is:

[0032] The structural formula of compound 1-2 is:

[0033] (2) N-(2-(1H-indol-3-yl)ethyl)-2-(ethylamino)benzamide (compound 1-2, 1 mmol), triethyl orthoformate (3 mmol) and boron trifluoride ether (0.5 mmol) was added to a 25 mL round bottom flask, and N,N-dimethylformamide was used as the solvent, replaced by argon, and reacted for 6 hours. After the completion of the reaction monitored by TLC, the N,N-dimethylformamide was extracted and washed with water and ethyl...

Embodiment 2

[0035] 14-isobutyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one (Compound BT2)

[0036] The structural formula of compound BT2 is:

[0037] The raw material methyl 2-(ethylamino)benzoate (compound 1-1) in step (1) of Example 1 was replaced with methyl 2-(isobutylamino)benzoate (compound 2-1), and the remaining steps were prepared in the same way as in Example 1. Yield 73%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.20 (s, 1H), 8.06 (dd, J = 7.8, 1.6 Hz,1H), 7.55 (d, J = 7.8 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.25 – 7.20 (m, 1H), 7.15(t, J = 7.5 Hz, 1H), 7.11 – 7.02 (m, 2H), 5.92 (s, 1H), 4.86 (m, J = 13.1,5.6, 1.9 Hz, 1H), 3.30 (m, 1H), 3.08 (m, 1H), 3.00 – 2.82 (m, 3H), 2.71 (dd, J = 13.5, 9.5 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H). 13 CNMR (101 MHz, CDCl 3 ) Δ 165.27, 148.73, 136.28, 132.72, 129.59, 129.07,126.57, 122.75, 122.65, 122.34, 120.59, 119.84, 118.72, 111.30, 70.54, 58.18, 27.23, 19.8.8, 19.8, 19.8, 19.8, 19...

Embodiment 3

[0040] 14-allyl-8,13,13b,14-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazolin-5(7H)-one (compound BT3)

[0041] The structural formula of compound BT3 is:

[0042] The raw material methyl 2-(ethylamino)benzoate (compound 1-1) in step (1) of Example 1 was replaced with methyl 2-(allylamino)benzoate (compound 3-1), and the remaining steps were prepared in the same way as in Example 1. The yield is 80%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.56 (s, 1H), 8.11 (dd, J = 7.8, 1.6 Hz,1H), 7.59 (dd, J = 7.8, 1.1 Hz, 1H), 7.47 – 7.38 (m, 2H), 7.28 – 7.24 (m,1H), 7.20 – 7.05 (m, 3H), 5.99 (t, J = 1.6 Hz, 1H), 5.82 (m, J = 16.9, 10.2,6.6, 5.3 Hz, 1H), 5.04 (m, J = 10.2, 1.4 Hz, 1H), 4.94 (m, J = 17.0, 1.5 Hz,1H), 4.87 (m, J = 12.9, 4.9, 2.3 Hz, 1H), 3.69 (m, J = 15.8, 5.4, 1.7 Hz,1H), 3.50 (m, J = 15.8, 6.6, 1.2 Hz, 1H), 3.26 (m, J = 12.9, 10.5, 5.2 Hz,1H), 3.05 – 2.89 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) Δ 165.06, 148.39, 136.44,134.84, 132.77, 128.84, 128.11, 12...

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Abstract

The invention provides application of an evodiamine derivative in preparation of a medicine for treating superficial fungal infection. The evodiamine derivative disclosed by the invention is prepared by taking a methyl anthranilate compound and tryptamine as initial raw materials through amine-ester exchange and a one-step ring closing reaction catalyzed by Lewis acid. The evodiamine derivative disclosed by the invention can show good antibacterial activity on three fungi, namely trichophyton rubrum, trichophyton mentagrophytes and candida albicans. Moreover, cell walls, cell membranes and organelles of fungal spores are destroyed to a certain extent, the hydrophobicity of fungal biomembranes can be influenced to a certain extent, phenomena of dark red erythema, skin hardening and generation of a large amount of scurf caused by errhysis spots of skin subjected to dermabrasion treatment can be obviously relieved, and phenomena of thickened epidermal layer of skin tissue, small-area epidermal layer necrosis, cuticle small-area parakeratosis and the like are avoided. The evodiamine derivative has low toxicity and low drug resistance and can be applied to preparation of drugs for treating the superficial fungal infection.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to the preparation of a series of evodiamine derivatives; the invention also relates to the application of the evodiamine derivatives in the preparation of anti-superficial fungal infection drugs. Background technique [0002] Fungal diseases are a public health problem of increasing public concern and in recent years are becoming a serious threat to humans, especially to immunocompromised individuals. The incidence of fungal diseases is increasing year by year, especially superficial mycosis, which is the highest incidence of fungal diseases and is caused by superficial fungal infections. Superficial mycosis is a common disease in dermatology, and it is also a stubborn disease that plagues patients. It mainly infects the skin, hair and nails by fungi, and only invades the stratum corneum and superficial skin. The common clinical superficial mycosis is mainly bran versic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P31/10C07D471/14
CPCA61K31/519A61P31/10C07D471/14Y02A50/30
Inventor 王震张红花邓杰丹梁妍石桃李俊芳
Owner NANHUA UNIV
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