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Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist

A technology of phyllophyllin and prodrugs, which is applied in the field of medicine, can solve the problems of low inhibitory activity, poor membrane penetration ability, poor oral bioavailability, etc., and achieve good safety and high safety effects

Inactive Publication Date: 2016-02-10
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, the commercially available COMT enzyme inhibitors (such as tolcapone and entocapone) have low inhibitory activity in the body, short metabolic half-life, continuous use can easily cause many defects such as liver and kidney toxicity, and long-term use can cause serious complications. Adverse reactions【Neurology2004;62:39-46】
[0004] The inventors found in previous studies that catechol flavonoids have good COMT enzyme inhibitory activity, but their membrane penetration ability is poor, resulting in poor oral bioavailability

Method used

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  • Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist
  • Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist
  • Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of kelplin A-7-acetyl ester

[0027]

[0028] Weigh 2.0g of phyllophyllin A and place it in a 100ml three-neck flask, add 20ml of dichloromethane to dissolve, add 2ml of pyridine and 1.5ml of acetic anhydride under stirring, react at 25°C for 8h, and detect the end of the reaction by TLC. Add 30ml of water to quench the reaction, extract with 50mlx3 dichloromethane, combine the dichloromethane phases, wash 30mlx2 with water, dry over anhydrous sodium sulfate, filter, evaporate the solvent to dryness under reduced pressure, and separate the residue by silica gel column chromatography to obtain the compound Melaleuca paper Preparation of Vetin A-7-Acetyl Ester 1.6g, pale yellow solid.

[0029] 1 HNMR (400MHz, d-DMSO) δ: 2.31 (s, 3H), 3.93 (s, 3H), 7.09 (d, J = 4Hz, 2H), 7.58-7.64 (m, 3H), 8.13 (d, J = 8Hz, 2H), 12.87(s, 1H);

[0030] 13 CNMR (100MHz, d-DMSO) δ: 20.48, 57.36, 92.26, 105.56, 105.67, 123.01, 127.01, 129.65, 131.01, 132.76, 151.94, 154.92, ...

Embodiment 2

[0032] Preparation of kelplin A-7-butyryl ester

[0033]

[0034] Weigh 1.0g of phyllophyllin A and place it in a 50ml three-necked bottle, add 10ml of dichloromethane to dissolve, add 1.5ml of triethylamine under stirring, slowly add 0.6ml of butyryl chloride dropwise in an ice-water bath, and react at 5-10°C After 6 h, TLC detected that the reaction was complete. Add 20ml of ice water to quench the reaction, extract with 30mlx3 dichloromethane, combine the dichloromethane phases, wash 20mlx2 with water, dry over anhydrous sodium sulfate, filter, evaporate the solvent to dryness under reduced pressure, and separate the residue by silica gel column chromatography to obtain compound Melaleuca Preparation of paperin A-7-butyryl ester 780mg, pale yellow solid.

[0035] 1 HNMR (400MHz, d-DMSO) δ: 0.96(t, J=7.2Hz, 3H), 1.64(q, J=7.6Hz, 2H), 2.37(t, J=7.2Hz, 2H), 3.91(s, 3H), 7.10(d, J=4Hz, 2H), 7.59-7.66(m, 3H), 8.12(d, J=8Hz, 2H), 12.91(s, 1H);

[0036] 13 CNMR (100MHz, d-...

Embodiment 3

[0038] Preparation of kelplin A-7-glucuronic acid

[0039]

[0040] Melaleucain A-7-glucuronic acid is a metabolite of glucuronidation metabolism of Melaleucain A. For this, the use of human liver microsomes as the enzyme source combined with biological preparation and fast chromatography technology A-7-glucuronic acid is prepared, and the specific experimental process is as follows:

[0041] (1) Add the following solutions to a 1.5ml EP tube: 815μl of Tris-HCl (50mM), 100μl of MgCl2 (150mM), 25μl of HLM (20mg / ml), 10μl of Melaleucain A (100mM), shake and mix;

[0042] (2) Pre-incubate the EP tube at 37°C for 3 minutes, add 50 μl of UDPGA (40mM), shake and mix, and react at 37°C;

[0043] (3) After reacting for 4 hours, add 500 μl of acetonitrile to the reaction system to terminate the reaction;

[0044] (4) Centrifuge at 20000g / min for 20min at 4°C, and collect the supernatant in a 50ml centrifuge tube;

[0045] (5) Load the sample on the SPE column, wash with water, wash...

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Abstract

An application of oroxylin A and a pro-drug thereof as a catechol-type medicine synergist belongs to the technical field of medicines. The compound is used as the catechol-type medicine synergist and has the following structure general formula (I), wherein R is hydrogen, carboxylic ester, glucuronic acid and the like substitutive groups. One or more compounds of the oroxylin A and the pro-drug thereof can be mixed with levodopa according to a certain ratio to prepare a drug composition for treatment of Parkinson's disease. The oroxylin A and the pro-drug prepared through modification thereof are improved in both solubility and transmembrane capability and are significantly prolonged in in-vivo metabolic half life period, which is longer than the in-vivo metabolic half life periods of majority of catechol-type medicines, so that the compounds have excellent medicine preparation prospect. In addition, the compounds also can be combined with a catechol-type medicine to form a compound medicine. The compound medicine can be prepared into an oral-taking slow-release preparation to further improve oral-taking bioavailability and treatment effects of the catechol-type medicines.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to the application of phyllothin A and its prodrug as a synergist of catechol drugs. Background technique [0002] Catechol compounds have a variety of pharmacological activities and play an important role in the treatment of various diseases such as inflammation, cancer, neurotransmitter conduction, hypertension and diabetes. For example, the catechol drug levodopa is used as a prodrug of dopamine to supplement the deficiency of dopamine in the brain of patients with Parkinson's disease (PD), and dopamine replacement therapy is the most effective means for treating Parkinson's disease [EurNeurol.2009; 62:1- 8】. It is worth noting that levodopa can only play a role if it reaches the brain, but because it is easily absorbed by catechol-O-methyltransferase (COMT), uridine diphosphate glucuronosyltransferase (UGT) in peripheral tissues ), and phase II enzymes such as su...

Claims

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Application Information

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IPC IPC(8): C07D311/30C07H17/07C07H1/00A61K31/7048A61K31/352A61P9/12A61P11/06A61P25/16A61K31/198
Inventor 杨凌王平葛广波宁静夏杨柳
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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