Preparation method and medical application of daphnetin derivative
阅读说明：本技术 瑞香素衍生物制备方法及其医药用途 (Preparation method and medical application of daphnetin derivative ) 是由 蒋建勤 陶冶 于 2020-07-16 设计创作，主要内容包括：本发明属于医药技术领域。本发明公开了一种瑞香素衍生物制备方法及其医药用途,涉及结构通式(I)所示的8-OH位取代的瑞香素衍生物,该衍生物通过瑞香素与2-溴乙醇发生醚化反应得到中间体II,中间体II再与非甾体类抗炎药发生酯化反应制备得到。经活性筛选试验证明,本发明的化合物具备COX-2酶抑制作用,且瑞香素衍生物的抗炎活性优于原料瑞香素,具有开发成治疗炎症药物的前景,且本发明提供的瑞香素衍生物的制备方法步骤简单,条件温和,可操作性和可控性较强。现有技术没有公开过本发明衍生物及其制备方法和医药用途。<Image he="577" wi="443" file="DSA0000213450330000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the technical field of medicines. The invention discloses a preparation method of daphnetin derivatives and medical application thereof, and relates to daphnetin derivatives substituted at 8-OH position shown in a structural general formula (I), wherein the derivatives are prepared by performing etherification reaction on daphnetin and 2-bromoethanol to obtain an intermediate II, and performing esterification reaction on the intermediate II and non-steroidal anti-inflammatory drugs. The activity screening test proves that the compound has COX-2 enzyme inhibition effect, the anti-inflammatory activity of the daphnetin derivative is superior to that of daphnetin serving as a raw material, and the daphnetin derivative has a prospect of being developed into a medicament for treating inflammation. The prior art does not disclose the derivative, the preparation method and the medical application thereof.)
1. A daphnetin 8-OH derivative has the following structural formula:
in the general formula (I), R is selected from non-steroidal anti-inflammatory drugs with anti-inflammatory and analgesic effects, such as ibuprofen, diclofenac, flurbiprofen, indomethacin, naproxen, ketoprofen, and the like.
2. The process for the preparation of daphnetin 8-OH derivatives according to claim 1, comprising the steps of:
step a, performing etherification reaction on daphnetin and 2-bromoethanol to obtain an intermediate II shown in the following structural formula;
and step b, the intermediate II and the non-steroidal anti-inflammatory drug are subjected to esterification reaction to prepare the compound with the general structural formula (I).
3. The method according to claim 2, wherein the etherification reaction conditions in step a include: potassium iodide is used as a catalyst, potassium carbonate is used as an alkali, and the reaction temperature is 85-90 ℃.
4. The method of claim 3, wherein step a comprises: firstly, dissolving daphnetin, potassium carbonate and potassium iodide in anhydrous DMF (dimethyl formamide), uniformly stirring, adding 2-bromoethanol, carrying out reflux reaction at 85-90 ℃, and detecting the reaction process by TLC (thin layer chromatography); after the reaction is finished, adding a proper amount of diluted hydrochloric acid, stirring and neutralizing until the mixture is acidic, extracting for three times by using ethyl acetate, and combining organic layers; the organic layer was washed with distilled water and saturated brine three times, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to give intermediate II.
5. The method according to claim 2, wherein the esterification reaction in step b comprises reacting 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) as a condensing agent and 4-Dimethylaminopyridine (DMAP) as a catalyst at room temperature.
6. The method of claim 5, wherein step b comprises: firstly, dissolving the non-steroidal anti-inflammatory drug and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 4-Dimethylaminopyridine (DMAP) in dichloromethane, stirring and mixing uniformly, dissolving an intermediate II in dichloromethane, stirring and reacting at normal temperature, and detecting the reaction process by TLC; after the reaction was completed, the organic layer was washed three times with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to obtain the objective compound.
7. The medical use of the daphnetin 8-OH derivative of claim 1 for the preparation of an anti-inflammatory medicament.
Technical Field
The invention belongs to the field of natural medicinal chemistry, relates to a novel natural compound derivative, and particularly relates to a daphnetin derivative, and a preparation method and medical application thereof.
Background
Inflammation is a common clinical disease worldwide, and seriously threatens human health. Having become a major challenge for the public health system, while many scientists have been working on developing new treatments for treating various inflammations, it remains a clinical hotspot and difficulty of global concern. In recent years, a large number of anti-inflammatory drugs have been developed, most of which are natural products or derivatives thereof.
Daphnetin, also known as daphnetin A, is an effective component extracted from daphne giraldii nitsche, mainly exists in daphne plants, and has pharmacological effects of diminishing inflammation and relieving pain. However, daphnetin has the limitations of poor water solubility, low bioavailability, poor stability and the like, so that the application of daphnetin in medicines is limited. Therefore, the invention determines to use the effective components in natural plants as leads to carry out structural modification, and carries out structural modification on daphnetin so as to obtain the compound with stronger anti-inflammatory activity and higher bioavailability.
The daphnetin is structurally modified to obtain a series of derivatives. The purpose is basically achieved through preliminary pharmacological experiments, and the compound is expected to become a candidate drug for treating inflammation and has good application prospect.
Disclosure of Invention
One of the purposes of the invention is to provide a daphnetin derivative.
The invention also aims to provide a preparation method of the daphnetin derivative.
Still another object of the present invention is to provide a medical use of the aforementioned daphnetin derivative.
In order to realize the purpose, the invention provides a daphnetin derivative with 8-OH substituted position shown in a structural general formula (I), and screening of COX-2 enzyme inhibitory activity shows that most compounds have good in vitro activity and can be used as precursor compounds for further development into COX-2 enzyme inhibitors.
The 8-OH substituted daphnetin derivative provided by the invention is represented by a structural general formula (I):
in the general formula (I), R is selected from non-steroidal anti-inflammatory drugs with anti-inflammatory and analgesic effects, such as ibuprofen, diclofenac, flurbiprofen, indomethacin, naproxen, ketoprofen, and the like.
Wherein R is preferably flurbiprofen, indomethacin, naproxen and ketoprofen.
The compounds of the invention are preferably the following:
compound 1:
compound 3:compound 4:
the preparation method of the 8-OH substituted daphnetin derivative comprises the following steps: etherification reaction and esterification reaction.
The invention also provides a preparation method of the daphnetin 8-OH derivative, which comprises the following operation steps:
step a, performing etherification reaction on daphnetin and 2-bromoethanol to obtain an intermediate II shown in the following structural formula;
and step b, the intermediate II and the non-steroidal anti-inflammatory drug are subjected to esterification reaction to prepare the compound with the general structural formula (I).
Preferably, the etherification reaction conditions in step a include: potassium iodide is used as a catalyst, potassium carbonate is used as an alkali, and the reaction temperature is 85-90 ℃.
More preferably, step a comprises: firstly, dissolving daphnetin (1eq), potassium carbonate (3eq) and potassium iodide (0.1eq) in anhydrous DMF, uniformly stirring, adding 2-bromoethanol (2eq) into the solution, carrying out reflux reaction at 85-90 ℃, and detecting the reaction process by TLC (thin layer chromatography); after the reaction is finished, adding a proper amount of diluted hydrochloric acid, stirring and neutralizing until the mixture is acidic, extracting for three times by using ethyl acetate, and combining organic layers; the organic layer was washed with distilled water and saturated brine three times, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to give intermediate II.
Preferably, the esterification reaction conditions in step b comprise: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) is used as a condensing agent, 4-Dimethylaminopyridine (DMAP) is used as a catalyst, and the reaction is carried out at normal temperature.
More preferably, step b comprises: firstly, dissolving the non-steroidal anti-inflammatory drug (1.5eq) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI) (2eq) and 4-Dimethylaminopyridine (DMAP) (0.4eq) in dichloromethane, stirring and mixing uniformly, adding the intermediate II (1eq) into a reaction system, stirring and reacting at normal temperature, and detecting the reaction progress by TLC; after the reaction was completed, the organic layer was washed three times with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to obtain the objective compound.
The daphnetin derivative substituted at the 8-OH position prepared by the invention is developed into a COX-2 enzyme inhibitor and used for preventing and treating diseases such as inflammation, and the anti-inflammatory activity of the compound is evaluated by taking screening of COX-2 enzyme inhibitory activity as a carrier.
Screening for COX-2 enzyme inhibitory Activity of Compounds COX-2 inhibitor screening kit (purchased from Biyuntian Biotech Co., Ltd.) was used.
The daphnetin derivative substituted at the 8-OH position prepared by the invention still shows more obvious inhibitory activity under the concentration of 20 mu mol/L by COX-2 enzyme activity screening.
According to the present invention, other various modifications, substitutions and alterations can be made without departing from the technical spirit of the present invention in accordance with the common technical knowledge and conventional means in the field.
The above-mentioned contents are further explained by way of examples, but it should not be construed that the scope of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The invention is better illustrated by the following examples. However, the present invention is not limited to the following examples.
The process flow is as follows, and the room temperature or the rt in the preparation method are both referred to as the normal temperature: