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Pyrroloquinoline quinone derivative or medicinal salt thereof, preparation method and application

A technology of pyrroloquinoline quinone and its derivatives, which is applied in the field of biomedicine, can solve problems affecting drugability, etc., and achieve excellent solubility and ideal drug efficacy

Pending Publication Date: 2022-07-29
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, PQQ-TME is almost insoluble in water, affecting its druggability

Method used

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  • Pyrroloquinoline quinone derivative or medicinal salt thereof, preparation method and application
  • Pyrroloquinoline quinone derivative or medicinal salt thereof, preparation method and application
  • Pyrroloquinoline quinone derivative or medicinal salt thereof, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Synthesis of PQQ trimethyl ester: Take a single-neck flask, dissolve PQQ (3.3 g, 10 mmol) in DMF (200 mL), then add potassium carbonate (6.9 g, 50 mmol) in small portions and stir for 1 hour. Dimethyl sulfate (25 g) was dropped into the reaction suspension at room temperature, and the reaction was continued at room temperature for 5 days after the drop was completed. After DMF was evaporated with an oil pump, water (200 mL) was added to the residue and the residue was made acidic with 4N hydrochloric acid. The reaction solution was stirred at room temperature for 6 hours, and suction filtered to obtain an orange solid PQQ trimethyl ester (3.17 g, yield 85%).

[0039] Reduction of PQQ trimethyl ester: Take a single-neck flask, suspend PQQ trimethyl ester (1.86 g, 5 mmol) in acetonitrile (100 mL), add 1M sodium hydrosulfite solution (100 mL), and stir at room temperature overnight. The reaction solution was directly suction filtered, and the filter cake was dried to obtai...

Embodiment 2

[0042] Referring to the method of Example 1, the acetyl chloride in Example 1 was replaced with palmitoyl chloride to obtain compound 2 (319 mg, 75%). 1 H NMR (300MHz, Chloroform-d) δ 12.67(s, 1H), 8.94(s, 1H), 7.32(s, 1H), 4.20(s, 3H), 4.06(s, 3H), 4.03(s, 3H), 2.83 (t, J=7.6Hz, 2H), 2.75 (t, J=7.5Hz, 2H), 1.91 (dt, J=14.3, 7.2Hz, 4H), 1.30 (d, J=8.3Hz, 54H), 0.90(t, J=6.3Hz, 6H).

Embodiment 3

[0044]Referring to the method of Example 1, acetyl chloride in Example 1 was replaced with benzoyl chloride to obtain compound 3 (230 mg, 79%). 1 H NMR (300MHz, Chloroform-d) δ 12.74 (s, 1H), 8.96 (s, 1H), 8.47-8.11 (m, 4H), 7.95-6.91 (m, 7H), 4.21 (s, 3H), 4.01(s, 3H), 3.82(s, 3H).

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PUM

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Abstract

The invention discloses a pyrroloquinoline quinone derivative with a structure as shown in a formula (I) or a medicinal salt thereof, a preparation method and application of the pyrroloquinoline quinone derivative. The derivative has excellent solubility and / or permeability, is obviously superior to PQQ and PQQ salt (commercially available disodium salt), shows an ideal drug effect in anti-inflammatory, anti-diabetes and anti-metabolic disease models, and is superior to PQQ and PQQ salt (commercially available disodium salt). The invention also provides a preparation method of the derivative and an intermediate thereof, a pharmaceutical composition and medical application thereof.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a pyrroloquinoline quinone derivative or a pharmaceutically acceptable salt thereof, a preparation method and use thereof. Background technique [0002] Pyrroloquinoline quinone (PQQ) has been proven to be an important nutrient for mammals with a wide range of physiological and pharmacological activities, including growth-promoting, antioxidant, anti-diabetic, and neuroprotective effects. However, there are three carboxylic acid groups in the molecular structure of PQQ, resulting in unsatisfactory solubility and permeability. Carboxylic acid compounds can solve the solubility problem by forming salts, but the salt types of PQQ are diverse and complex, such as monosodium salt, disodium salt, trisodium salt and tetrasodium salt. Among them, only the disodium salt exists in various hydrated forms, such as trihydrate and pentahydrate; the solubility of trihydrate in water is about...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P29/00A61P3/00A61P3/10
CPCC07D471/04A61P29/00A61P3/00A61P3/10
Inventor 王广基甄乐许亚文王健鲲
Owner CHINA PHARM UNIV
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