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3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative and application thereof

A technology of diarylpyrazoles and diarylpyrazoles is applied in the field of 3,5-diarylpyrazole and 3,4-diarylpyrazole derivatives and their preparation, and can solve the problem of drug resistance Serious problems such as good reversal of antibacterial drug resistance, good antifungal infection activity, and good economic effects

Inactive Publication Date: 2018-05-04
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is worth noting that the drug resistance of the first-line antifungal drug fluconazole has become increasingly serious, which has brought great pressure to clinical medication

Method used

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  • 3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative and application thereof
  • 3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative and application thereof
  • 3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of compound I-1 and II-1

[0031]

[0032] Get genistein (I) 400mg and place round bottom flask, then add 1.8g K 2 CO 3 , add 50 mL of anhydrous acetone to dissolve, then add 800 μL of iodomethane, and reflux at 60°C overnight. After the reaction was completed, acetone was removed by rotary evaporation, water-ethyl acetate was added for extraction, and the organic phase was evaporated to dryness under pressure to obtain compound II as a yellow solid (yield 95%).

[0033] Take 100 mg of compound II in a round bottom flask, add 10 mL of ethanol to dissolve, then add 300 μL of phenylhydrazine, and heat at 90°C for 48 hours. After the reaction was completed, the solvent was removed under reduced pressure and passed through a silica gel column to obtain yellow compounds I-1 (22 mg, yield 22%) and II-1 (77 mg, yield 77%).

[0034] Ⅰ-1: MS m / z 403 (M+1); 1H NMR (400MHz, CDCl3) δ = 7.99 (s, 1H), 7.26 (m, 7H), 6.82 (d, J = 8.8, 2H), 6.12 (d,J...

Embodiment 2

[0036] Embodiment 2: the preparation of compound III-4

[0037]

[0038] Take 400mg of 7,8-dihydroxyflavone (Ⅲ) and place it in a round bottom flask, then add 1.5g K 2 CO 3 , add 50mL of anhydrous acetone to dissolve, then add 500μL of iodomethane, and reflux at 60°C overnight. After the reaction was completed, acetone was removed by rotary evaporation, water-ethyl acetate was added for extraction, and the organic phase was evaporated to dryness under pressure to obtain compound IV as a yellow solid (yield 90%).

[0039] Take 100 mg of compound IV in a round bottom flask, add 10 mL of ethanol to dissolve, then add 100 μL of hydrazine hydrate, and heat at 100 ° C for 24 h. After the reaction was completed, the solvent was removed under reduced pressure, and extracted with water-ethyl acetate to obtain 92 mg of tan solid V (92% yield).

[0040] Take 50 mg of compound V in a round bottom flask, dissolve it in 6 mL of anhydrous DCM, cool down to -78°C, add 2 mL of 1M boron tri...

Embodiment 3

[0042] Embodiment 3: the preparation of compound I-2 and II-2

[0043]

[0044] Take 100mg of formononetin VI, dissolve it in 6mL of absolute ethanol, add 200mg of ethylhydrazine maleic acid, stir at 100°C for 12h to complete the reaction, evaporate the solvent to dryness under reduced pressure, and pass through a silica gel column. 35 mg of I-2 (yield 35%) and 50 mg of II-2 (yield 50%) were obtained.

[0045] Ⅰ-2: MS m / z 311 (M+1); 1H NMR (400MHz, MeOD) δ = 7.60 (d, J = 2.7, 1H), 7.19 (d, J = 7.8, 2H), 6.97 (d, J=8.5,1H),6.86(d,J=7.9,2H),6.36(d,J=1.6,1H),6.12(dd,J=8.5,2.4,1H),4.17(dd,J=7.3, 1.6, 2H), 3.77 (d, J = 0.9, 3H), 1.55–1.41 (m, 3H).

[0046] Ⅱ-5: MS m / z 310 (M+1); 1H NMR (400MHz, MeOD) δ = 7.70 (s, 1H), 7.15 (d, J = 8.8, 2H), 6.80 (d, J = 8.3, 1H), 6.76(d, J=8.8, 2H), 6.45(d, J=2.2, 1H), 6.35(dd, J=8.3, 2.3, 1H), 3.96(q, J=7.2, 2H), 3.80 -3.56 (m, 3H), 1.30 (t, J = 7.2, 3H).

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Abstract

The invention discloses 3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative and application thereof. The 3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative is prepared from compound which is shown in a formula (I), a formula (II), a formula (III) or a formula (IV) or pharmaceutical-acceptable salt of the compound. A formula of the 3,5-diaryl pyrazole or 3,4-diaryl pyrazole derivative is shownin a following image, wherein R1, R2, R3, R4 and R5 are respectively and independently chosen from hydrogen atom, hydroxy, nitro, amino, alkoxy or ester group with a C1 to C10 alkyl substituent group; alkyl in the alkoxy is a C1 to C10 alkyl; R is independently chosen from hydrogen atom, 2-ethoxy, acetyl, phenyl, benzoyl, p-methoxyphenyl, 4-trifluoromethoxy, 2-cyanoethyl or C1 to C10 alkyl. The 3,5-diaryl pyrazole derivative or the 3,4-diaryl pyrazole derivative can be applied to preventing and treating fungal infection; especially, application in treating candida albicans infection and reversing fluconazole drug resistance has good development value.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to 3,5-diarylpyrazole and 3,4-diarylpyrazole derivatives and their preparation methods and their anti-Candida albicans and reversing fluconazole resistance Applications. Background technique [0002] Candida albicans is an opportunistic pathogenic fungus that inhabits the mouth, skin, digestive tract, respiratory tract, and reproductive tract of normal people. In recent years, with the wide application of broad-spectrum antibiotics, hormones, immunosuppressants, and cytotoxic drugs, as well as the continuous development of repair devices and the continuous improvement of life-sustaining technology, immunocompromised patients, especially AIDS patients, organ transplant patients, The increasing number of cancer patients receiving radiation and chemotherapy has resulted in increasing morbidity and mortality from fungal infections. According to statistics, deep ...

Claims

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Application Information

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IPC IPC(8): C07D231/12C07D405/10A61K31/415A61K31/4155A61P31/10
CPCC07D231/12C07D405/10
Inventor 娄红祥崔昌义孙斌
Owner SHANDONG UNIV
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