(20S,24R) -ocotillol type ginsenoside amino acid derivative, preparation method and application

文档序号：1682418 发布日期：2020-01-03 浏览：36次中文

阅读说明：本技术 (20S,24R)-ocotillol型人参皂苷氨基酸衍生物及制备方法和用途 ((20S,24R) -ocotillol type ginsenoside amino acid derivative, preparation method and application ) 是由刘俊丽张莹王钟瑶刘云鹤焦玉凤司雨周柏松张晶李平亚刘金平于 2019-10-22 设计创作，主要内容包括：本发明提供一种(20S,24R)-ocotillol型人参皂苷氨基酸衍生物及制备方法和用途,属于医药领域。本发明提供一种(20S,24R)-ocotillol型人参皂苷衍生物在制备或预防慢性阻塞性肺部疾病药物中的应用。在(20S,24R)-ocotillol型人参皂苷类化合物作用下IL-6和IL-10表达水平的变化与COPD的相关性,有助于深入了解炎症因子的具体作用机制,从而为进一步研究预防或治疗慢性阻塞性肺疾病药物打下坚实基础。(The invention provides a (20S,24R) -ocotillol type ginsenoside amino acid derivative, a preparation method and application thereof, belonging to the field of medicines. The invention provides application of a (20S,24R) -ocotillol type ginsenoside derivative in preparation of a medicine for preventing chronic obstructive pulmonary diseases. The relevance of the change of the expression levels of IL-6 and IL-10 under the action of the (20S,24R) -ocotillol type ginsenoside compound and COPD is helpful for deeply understanding the specific action mechanism of inflammatory factors, thereby laying a solid foundation for further researching medicaments for preventing or treating chronic obstructive pulmonary diseases.)

1. A (20S,24R) -ocotillol type ginsenoside amino acid derivative characterized by the following formula:

wherein: r₁Selected from hydroxyl, amino acyloxy, Boc-X-amino acyloxy; r₂Selected from hydroxyl, amino acyloxy, Boc-X-amino acyloxy; r₃Selected from H, hydroxyl, amino acyloxy, Boc-X-amino acyloxy.

2. A ginsenoside amino acid derivative of the (20S,24R) -ocotillol type according to claim 1, wherein: r₁、R₂、R₃Not being hydroxyl at the same time; when R is₃When H, R₁、R₂Not simultaneously being hydroxyl.

3. A ginsenoside amino acid derivative of the (20S,24R) -ocotillol type according to claim 1, wherein: the amino acid acyloxy includes the following 19 types: alanyloxy, valyloxy, leuyloxy, isoleuyloxy, phenylalanyyloxy, threonyloxy, cysteinyloxy, glutamyloxy, asparaginyloxy, methionyloxy, serynyloxy, prolynyloxy, tyrynyloxy, tryptophanyloxy, aspartyloxy, glutamyloxy, lysyloxy, arginyloxy, histidyloxy.

4. A ginsenoside amino acid derivative of the (20S,24R) -ocotillol type according to claim 1, wherein: said Boc is t-butyloxycarbonyl; x represents D or L.

5. A ginsenoside amino acid derivative of the (20S,24R) -ocotillol type according to claim 1, wherein: contain one or more asymmetric centers, and exist as enantiomers or diastereomers.

6. A ginsenoside amino acid derivative of the (20S,24R) -ocotillol type according to claim 1, comprising:

(20S,24R) -epoxy-12 β, 25-dihydroxy- (3 β -O-alanyl) -dammarane;

(20S,24R) -epoxy-12 β, 25-dihydroxy- (3 β -O-leucinyl) -dammarane;

(20S,24R) -epoxy-12 β, 25-dihydroxy- (3 β -O-valyl) -dammarane;

(20S,24R) -epoxy-12 β, 25-dihydroxy- (3 β -O-phenylalanyl) -dammarane;

(20S,24R) -epoxy-12 β, 25-dihydroxy- (3 β -O-lysyl) -dammarane;

(20S,24R) -epoxy-12 β, 25-dihydroxy- (3 β -O-histidyl) -dammarane;

(20S,24R) -epoxy-25-hydroxy- (3 β,12 β -O-dipropionyl) -dammarane;

(20S,24R) -epoxy-25-hydroxy- (3 β,12 β -O-diisoleucyl) -dammarane;

(20S,24R) -epoxy-25-hydroxy- (3 β,12 β -O-di-methionyl) -dammarane;

(20S,24R) -epoxy-6 α,12 β, 25-trihydroxy- (3 β -O-alanyl) -dammarane;

(20S,24R) -epoxy-6 α,12 β, 25-trihydroxy- (3 β -O-seryl) -dammarane;

(20S,24R) -epoxy-6 α,12 β, 25-trihydroxy- (3 β -O-threonyl) -dammarane;

(20S,24R) -epoxy-3 β,12 β, 25-trihydroxy- (6 α -O-alanyl) -dammarane;

(20S,24R) -epoxy-3 β,12 β, 25-trihydroxy- (6 α -O-cysteinyl) -dammarane;

(20S,24R) -epoxy-6 α,12 β, 25-trihydroxy- (3 β -O-tyrosyl) -dammarane;

(20S,24R) -epoxy-6 α,12 β, 25-trihydroxy- (3 β -O-glutamyl) -dammarane.

7. A process for the preparation of a ginsenoside derivative of the (20S,24R) -ocotillol type according to claim 1, comprising the steps of:

boc-amino acid (0.19mmol), DMAP (16mg,0.13mmol) and EDCI (35mg,0.18mmol) were dissolved in anhydrous dichloromethane (7ml), stirred for 0.5h and added with (20S,24R) -ocotillol type ginsenoside (0.126mmol) and reacted overnight at room temperature; after the reaction is finished, washing with water and saturated salt solution, drying and concentrating to obtain a crude product; dissolving the crude product in anhydrous dichloromethane (15ml), adding trifluoroacetic acid (1ml,12.67mmol), and reacting at room temperature overnight; slowly adding saturated sodium bicarbonate solution until pH is neutral, extracting with dichloromethane for 3 times, washing with water and saturated saline solution, mixing organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (dichloro: methanol) to obtain the target compound.

8. A pharmaceutical composition characterized by: comprising at least a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. Use of a compound as claimed in any one of claims 1 to 6 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.

10. Use of a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel (20S,24R) -ocotillol type ginsenoside amino acid derivative, and a preparation method and a pharmaceutical effect thereof.

Background

The ocotillone type (Ocotillol type) ginsenoside is the first found in American ginseng, is an important marker component of the American ginseng different from the ginseng, has various physiological activities, has unique functions in the aspects of resisting tumors, myocardial ischemia, reducing blood sugar, resisting oxidation, preventing senile dementia and the like, and has wide development prospects in clinical application. The active ingredients of ginsenoside Rg3, Rh2 and protopanaxadiol all have the common defects of poor water solubility and low bioavailability. Hydrophilic groups such as amino acid and the like are introduced into the molecules of the chitosan hydrogel, so that the purposes of improving physicochemical properties and improving bioavailability can be achieved.

Chronic Obstructive Pulmonary Disease (COPD) is a common Disease characterized by persistent airflow limitation that is not fully reversible and progresses in a progressive manner, associated with an enhanced Chronic inflammatory response of the airways and lungs to toxic particles or gases. COPD shows symptoms such as cough, shortness of breath and chest distress in clinic, and complications such as respiratory failure and pulmonary encephalopathy can cause failure of other organs in severe cases, thereby having serious influence on life safety of patients. COPD prevalence is high, and the prevalence of people over 40 years old in China is about 8.2%, and is 9-10% abroad; COPD has a high mortality rate, currently residing at the 4 th cause of death worldwide.

At present, no effective means for treating COPD exists, and the clinical treatment of COPD has the following problems: simple smoking cessation does not prevent the continued development of chronic inflammation of COPD airways; simple inhaled glucocorticoids (ICS) have poor anti-inflammatory effects and do not prevent or reverse the progression of COPD; the mere use of bronchodilators (β -AR agonists) is very limited; combination therapy (ICS/β -AR agonists) may partially improve lung function but may not reduce mortality. It follows that the ability to control chronic airway inflammation is a key issue in the treatment of COPD.

COPD patients have chronic inflammation in both the airways and lung parenchyma, particularly during the acute exacerbation phase, where airway inflammation is in a highly reactive phase. Among them, inflammatory mediators and cytokines secreted from neutrophils, macrophages, lymphocytes, etc. are involved in the onset of COPD. Recent studies found that IL-6 and IL-10 are major inflammatory factors among many cytokines involved in the inflammation of COPD, and the expression levels of IL-6 and IL-10 can represent the severity of the disease. IL-6 is detected to be increased in induced sputum and serum of patients in the acute attack phase of COPD, and the IL-6 level is gradually increased along with the increase of the COPD series, which reflects the inflammatory severity of COPD; IL-10, a regulator of the immune response, has been found to be directly associated with decreased expression of IL-10 in COPD lung tissue and airway lesions.

Disclosure of Invention

The invention provides a (20S,24R) -ocotillol type ginsenoside amino acid derivative, a preparation method and application thereof.

The (20S,24R) -ocotillol type ginsenoside amino acid derivative is a compound shown as the following formula or a medicinal salt thereof:

further, R₁、R₂、R₃Not being hydroxyl at the same time; when R is₃When H, R₁、R₂Not being hydroxyl at the same time;

further, the above amino acid acyloxy groups include the following 19 types: alanyloxy, valyloxy, leuyloxy, isoleuyloxy, phenylalanyyloxy, threonyloxy, cysteinyloxy, glutamyloxy, asparaginoyloxy, methionyloxy, seryloxy, prolyloxy, tyrosinyloxy, tryptophanyloxy, aspartyloxy, glutamyloxy, lysyloxy, arginyloxy, histidyloxy;

further, Boc is tert-butoxycarbonyl; x represents D or L;

the compounds of the invention contain one or more asymmetric centers, and exist as enantiomers or diastereomers. It is to be understood that the present invention encompasses both mixtures and separate individual isomers of the compounds of formula (I). The structural formula I comprises a racemate or an optical isomer, and pharmaceutically acceptable salts and solvates thereof.

The compounds of the present invention include the following: