阅读说明：本技术 一种番石榴混源萜类新化合物及其制备方法和在制备抗炎药物中的应用 (New guava mixed source terpenoid compound, preparation method thereof and application thereof in preparation of anti-inflammatory drugs ) 是由 谢志翔 刘珍玲 宁帅 于 2019-07-22 设计创作，主要内容包括：本发明涉及有机合成和药物化学技术领域,其目的在于提供了一种番石榴混源萜类新化合物及其制备方法和在制备抗炎药物中的应用,所述的混源萜类化合物具有如下所示的结构：<Image he="483" wi="700" file="DDA0002138419530000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to the technical field of organic synthesis and pharmaceutical chemistry, and aims to provide a guava mixed source terpenoid compound, a preparation method thereof and application thereof in preparing anti-inflammatory drugs, wherein the mixed source terpenoid compound has the following structure:)

1. A guava mixed source terpenoid new compound is characterized in that: the mixed source terpenoid has the following structure:

2. the guava mixed source terpenoid of claim 1, which is characterized in that: the first formula also has the structure shown as follows:

3. the guava mixed source terpenoid of claim 1, which is characterized in that: the second formula also has the following structure:

4. the guava mixed source terpenoid of claim 1, which is characterized in that: the third formula also has the following structure:

5. the preparation method of the guava mixed source terpenoid as claimed in any one of claims 1to 4, wherein the preparation method comprises the following steps: the synthetic route is shown as the following formula:

the reaction in the step i is based on a biomimetic synthesis strategy, and the phloroglucinol derivative (1), paraformaldehyde (2) and beta-caryophyllene (3) are used as raw materials to prepare a mixture containing the compounds (4) and (5) in one step through tandem Novogel (knoevenagel) condensation/Hetero-Diels-Alder reaction (heter-Diels-Alder reaction), wherein a catalyst is required for the reaction, and the catalyst is selected from silica gel-supported perchloric acid and silica gel-supported iron trichloride (FeCl)₃) Various solid acid catalysts or sodium acetate (NaOAc), and the solvent can be selected from acetonitrile, toluene or acetic acid;

step ii is a reduction reaction, and requires the use of a reducing agent, which may be selected from NaBH₄Or NaBH₃CN, which is used for reducing the compounds (4) and (5) under an acidic condition to obtain a mixture of a compound shown as a formula I and a compound shown as a formula II, wherein the operation steps of separating the mixture are as follows: the crude product can be divided into two parts by silica gel column, one part contains the compound shown as the formula I,the other part contains a compound shown as a formula II (wherein an eluant is required to be utilized, the component ratio of the eluant is 50:1, and the compound I, the compound II, the compound III and the compound IV are obtained by preparative high performance liquid separation;

step iii is an oxidation reaction, such as the compounds (I and II) shown in formula I can be in basic CH₃Oxidizing OH-DCM solution (volume ratio is 1:1), wherein the alkali can be selected from KOH or NaOH, the oxygen can be selected from air or gas containing oxygen in different proportions, and oxidizing to generate a compound shown as a formula III;

step iv is an oxidative coupling reaction, which requires the use of a one-electron oxidizing agent selected from AgOAc, Ag₂CO₃Or Ag₂O, the oxidant can initiate compound II to generate psigujdianone (VII) through free radical dimerization, and the solvent can be selected from dichloromethane or acetonitrile.

6. The guava mixed-source terpenoid of any one of claims 1-4, wherein: the mixed source terpenoids are all obtained from the leaves of guava.

7. Use of the guava mixed source terpenoid or the pharmaceutically acceptable salt thereof according to any one of claims 1to 4, alone or in a mixture, for the preparation of an anti-inflammatory agent.

8. An anti-inflammatory agent characterized by: comprises an effective amount of the mixed source terpenoid or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Technical Field

The invention relates to the technical field of organic synthesis and pharmaceutical chemistry, in particular to a guava mixed source terpenoid new compound, a preparation method thereof and application thereof in preparing anti-inflammatory drugs.

Background

Guava (Psidium guajava Linn.) is a tropical tree with medicinal value and is planted in southern China. Its fruit can be eaten, and its leaf has great medicinal value, so that it has a long history of using as medicine in africa and Chinese folks. The leaf extract is believed to have antibacterial, antidiabetic, hypoglycemic, hypotensive, anticancer, anti-inflammatory, antiplaque, antiallergic, cardiovascular protective, antioxidant, and antimutagenic effects.

Guava mixed terpenes are natural metabolites found in guava leaf extracts from 2007, are considered to have good biological activity and novel framework structures, and reports indicate that many of the more than forty guava mixed terpenes found at present have tumor cell inhibitory activity (org.lett.,2010,12, 5040; nature.prod. & bioprosp.,2013,3, 14; sci.748 rep.,2016,6, 32323240). Some guava heteroterpenes also showed inhibitory activity (org.lett.,2010,12,656) and hepatoprotective activity on PTP1B, with effects approximately comparable to that of the hepatoprotective drug Bicycol (org.lett.,2016,18, 168-171). In 2017, Yi Sheng et al, university of Zhongshan reported that of 28 guava mixed terpenes isolated therefrom, all compounds had good inhibitory activity against the inflammatory factor PDE4 except for (±) -guajadial B and guadial B, with a half inhibitory concentration of psigujadial G of only 1.37 μ M (Sci. Rep.,2017,7,1047), suggesting that the guava mixed terpenes may have anti-inflammatory activity.

The novel structure and good biological activity of guava mixed source terpenes have stimulated interest of chemists and pharmacologists. The synthesis of such compounds has also become a hotspot. Until now, 5 groups have completed the total synthesis of 13 of mixed-source terpenes, which are the total synthesis of Psidial a and Guajadial by Thompson project group (org.lett.,2010,12, 1676); total synthesis of (+ -) -Guajadial B by the liuji opening topic group (org. lett.,2012,14, 5936); cramer project group total synthesis of Psiguadial a, C and D (chem. eur.j.,2014,20,10654) and Psiguadial B (angelw. chem. int.ed.2017,56,13776); total synthesis of (+) -psiguadadial B (j.am. chem. soc.,2016,138,9803) by Reisman group and total synthesis of guadadial B, guadadial C, guapdial a and Psiguajadial D by dete group (org.biomol. chem.,2018,16,4793) in 2018.

However, it is noteworthy that: the Dethe project group tried the synthesis of Guapsidial A and Psiguajaidial D by the series reaction of formaldehyde, beta-caryophyllene and phloroglucinol derivatives, which resulted in failure of the reaction due to the use of 30% formaldehyde aqueous solution as a reactant, and then increased the number of synthesis steps and decreased the yield by using other reaction raw materials. According to the invention, serial reaction of phloroglucinol derivatives, paraformaldehyde and beta-caryophyllene is realized to synthesize the guava mixed source terpene through a series of condition optimization experiments and reactant screening experiments, and the synthesis yield is greatly improved. Finally, the total synthesis of the guava mixed source terpene newly separated from the guava leaves is realized by the overall three-step or four-step synthesis steps, so that the further intensive research on the pharmaceutical aspects of the several guava mixed source terpenes becomes possible.

Disclosure of Invention

The invention aims to provide a guava mixed source terpenoid new compound, and also provides a preparation method of the compound and application of the compound in preparing anti-inflammatory drugs.

A guava mixed source terpenoid new compound is characterized in that: the mixed source terpenoid has the following structure:

the first formula also has the structure shown as follows:

the second formula also has the following structure:

the third formula also has the following structure:

the preparation method of the mixed source terpenoid new compound is characterized by comprising the following steps: the synthetic route is shown as the following formula:

the reaction in the step i is based on a biomimetic synthesis strategy, takes phloroglucinol derivative (1), paraformaldehyde (2) and beta-caryophyllene (3) as raw materials, and is condensed/mixed-Di by connecting Novoguel (Knoevnagel) in series(iii) a one-step preparation of a mixture comprising the compounds (4) and (5) by a Hetero-Diels-Alder reaction (Hetero-Diels-Alder reaction) using a catalyst selected from the group consisting of perchloric acid on silica gel, iron trichloride on silica gel (FeCl)₃) Solid acid catalysts (such as amberlyst 15, amberlyst A-21, amberlyst IR120) and sodium acetate (NaOAc), and solvent can be selected from acetonitrile, toluene or acetic acid, and the yield can reach 61%;

step ii is a reduction reaction, and requires the use of a reducing agent, which may be selected from NaBH₄Or NaBH₃CN, which is used for reducing the compounds (4) and (5) under the acidic condition (pH value is about 4) to obtain a mixture of the compound shown as the formula I and the compound shown as the formula II, and the operation steps of separating the mixture are as follows: the crude product can be firstly divided into two parts by a silica gel column, wherein one part contains a compound shown as a formula I, the other part contains a compound shown as a formula II (an eluant of 50:1 petroleum ether and ethyl acetate is required), and then the pure products of the compounds I, II, III and IV can be obtained by preparative high performance liquid separation;

step iii is an oxidation reaction, such as the compounds (I and II) shown in formula I can be in basic CH₃Oxidizing OH-DCM solution (volume ratio is 1:1) with oxygen, wherein the alkali can be selected from KOH or NaOH, the oxygen can be selected from air or gas containing oxygen in different proportions, and generating a compound shown as a formula III;

step iv is an oxidative coupling reaction, which requires the use of a one-electron oxidizing agent selected from AgOAc, Ag₂CO₃Or Ag₂O, the oxidant can initiate compound II to generate psigujdianone (VII) through free radical dimerization, and the solvent can be selected from dichloromethane or acetonitrile.

The mixed source terpenoids are all obtained from the leaves of guava.

After the safe administration concentration is tested, the influence of guava mixed source terpenoid new compounds shown in formula I or formula II or formula III or formula IV on the secretion of NO, TNF-alpha and PGE2 by RAW264.7 cells induced by LPS is tested by adopting an enzyme-linked immunosorbent assay. Anti-inflammatory action (IC) of these compounds₅₀≤12.57μM) are all stronger than the positive control drug celecoxib, and the anti-inflammatory effect of some compounds is nearly ten times or more than ten times of that of the celecoxib.

The invention has the characteristics that the preparation method of the compound is simple and feasible, the structure of the compound is novel, and related experiments show that most of the compounds of the invention have stronger anti-inflammatory action than positive drugs, and the action is not realized by inhibiting cell proliferation or toxicity and can be applied to the preparation of anti-inflammatory drugs.

In summary, the present invention provides a medicament comprising the structure represented by formula one or formula two or formula three or formula four or a pharmaceutically acceptable salt thereof, the medicament comprising a pharmaceutically acceptable adjuvant; the medicament can be injection, tablet, pill, capsule, suspending agent or emulsion.

The mixed source terpenoid or the pharmaceutically acceptable salt thereof can be used for preparing anti-inflammatory drugs singly or in the form of a mixture.

The invention provides an anti-inflammatory drug, which is characterized in that: comprises an effective amount of the mixed source terpenoid or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compound of the formula I or the formula II or the formula III or the formula IV can be prepared into anti-inflammatory medicaments by being matched with various pharmaceutically acceptable carriers, excipients or auxiliary materials, and is used for treating inflammatory diseases.

The compounds of the present invention may be administered alone or in the form of a pharmaceutical composition. The route of administration may be oral, parenteral or topical. The pharmaceutical composition can be formulated into various suitable dosage forms according to the administration route.

Pharmaceutical compositions of the compounds of the present invention may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, buccal, topical, parenteral, such as: subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an ex-situ reservoir. Among them, oral, intraperitoneal or intravenous administration is preferable.

When administered orally, the compounds of the present invention may be formulated in any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions or suspensions. Among these, carriers for tablets generally include lactose and corn starch, and additionally, lubricants such as: magnesium stearate. Diluents for use in capsules typically include lactose and dried corn starch. Aqueous suspension formulations are generally prepared by mixing the active ingredient with suitable emulsifiers. Optionally, some sweetener, aromatic or colorant may be added into the above oral preparation.

When applied topically to the skin, the present invention may be formulated in a suitable ointment, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers for use in ointments include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxypropylene, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl 2-octyldodecanol, benzyl alcohol and water.

The compounds of the present invention may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions or solutions. Among the carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oils may also be employed as a solvent or suspending medium. Such as: a monoglyceride or diglyceride.

It is further noted that the dosage and method of administration of the compounds of the present invention will depend on a variety of factors. Including the age, weight, sex, physical health, nutritional status, activity intensity of the compound, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician.

The invention provides the anti-inflammatory activity of the compound shown in the formula I or the formula II or the formula III or the formula IV, and provides a lead compound for developing novel anti-inflammatory drugs.

Detailed Description

The present invention will be described in further detail with reference to specific examples. Unless otherwise specified, the reagents mentioned in the examples of the present invention are those conventionally used in the art.

Preparation of the compound: