阅读说明：本技术 二氢青蒿素含羧基酚/酯基酚/酰胺基酚偶联物、合成方法及应用 (Dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate, synthetic method and application ) 是由 杨大成 潘建芳 范莉 刘建 唐雪梅 周福委 杨龙 于 2019-08-28 设计创作，主要内容包括：本发明公开了一种二氢青蒿素含羧基酚/酯基酚/酰胺基酚偶联物,该偶联物或其消旋体、立体异构体和互变异构体及其药学上可接受的盐具有式I的结构通式：<Image he="280" wi="700" file="DDA0002183202360000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>n＝2或3,X为烷氧基、羟基、胺基或-O(CH<Sub>2</Sub>)<Sub>b</Sub>-DHA,Y为-H或烷氧基,Z为烯基、烷基或无基团,b＝2或3,DHA代表二氢青蒿素。本发明还公开了其合成方法,以及所述偶联物在抗结核、抗糖尿病、降脂和抑制白细胞介素-17药物中的应用。(The invention discloses a dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate, wherein the conjugate or racemate, stereoisomer and tautomer thereof and pharmaceutically acceptable salt thereof have a structural general formula shown in a formula I: n is 2 or 3, X is alkoxy, hydroxy, amino or-O (CH) 2 ) b -DHA, Y is-H or alkoxy, Z is alkenyl, alkyl or nothing, b ═ 2 or 3, DHA represents dihydroartemisinin. The invention also discloses a synthetic method of the conjugate and application of the conjugate in anti-tuberculosis, anti-diabetes, lipid-lowering and interleukin-17 inhibition drugs.)

1. The dihydroartemisinin carboxyl/ester group phenol/amido phenol conjugate, or racemate, stereoisomer, tautomer and pharmaceutically acceptable salt thereof are characterized by having a structural general formula shown in formula I:

wherein n is 2 or 3, Y is H or alkoxy, Z is alkenyl, alkyl or nothing, and

when X is hydroxy or-O (CH)₂)_b-DHA, b-2 or 3, denoted by TM5,

when X is alkoxy or amino, represented by TM 6;

wherein the DHA is dihydroartemisinin.

2. A dihydroartemisinin carboxyl/ester/amido phenol conjugate as claimed in claim 1, wherein n is 2 or 3, Y is-H or-OMe and Z is- (CH)₂)-_mor-CH-, m-0, 1 or 2, X is-OH, -O (CH)₂)_b-DHA, -OMe or-NH₂And b is 2 or 3.

3. The method for synthesizing a dihydroartemisinin carboxyl-containing phenol/esterphenol/amidophenol conjugate as claimed in claim 2, wherein the synthesis of TM5 is carried out according to the following reaction equation, comprising the following steps:

wherein n is 2 or 3, Y is-H or-OMe, and Z is- (CH)₂)-_mor-CH ═ CH-, X is-OH or-O (CH)₂)_b-DHA, m ═ 0, 1 or 2, b ═ 2 or 3;

adding the raw materials of carboxyl-containing substituted phenol B1, IM1 and K₂CO₃And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-15 h, and after the reaction is finished, performing post-treatment to obtain TM 5.

4. The method for synthesizing a dihydroartemisinin carboxyl-containing phenol/esterphenol/amido phenol conjugate as claimed in claim 3, wherein the mass ratio of the material IM1 and the material carboxyl-containing phenol B1 is 1: 1-2, and the reaction temperature is 40-85 ℃.

5. The method for synthesizing a dihydroartemisinin carboxyl-containing phenol/esterphenol/amidophenol conjugate as claimed in claim 2, wherein the synthesis of TM6 is carried out according to the following reaction equation, comprising the following steps:

wherein n is 2 or 3, and X is-OMe or-NH₂Y is-H or-OMe, Z is- (CH)₂)-_mor-CH ═ CH-, m ═ 0, 1, or 2;

adding the raw materials of the phenol B2, IM1 and K which contain ester group or amido group substitution₂CO₃And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-10 h, and after the reaction is finished, carrying out post-treatment to obtain the dihydroartemisinin ester-containing or acylaminophenol conjugate, namely TM 6.

6. The method for synthesizing a dihydroartemisinin carboxyl-containing phenol/ester-group phenol/amido phenol conjugate as claimed in claim 5, wherein the mass ratio of the material IM1 and the material of the material ester-group-or amido-group-containing phenol B2 is 1: 1-2, and the reaction temperature is 40-85 ℃.

7. The application of the conjugate of dihydroartemisinin containing carboxyl phenol/ester phenol/amido phenol is characterized in that the conjugate of dihydroartemisinin containing carboxyl phenol/ester phenol/amido phenol or the racemate, stereoisomer, tautomer and pharmaceutically acceptable salt thereof in the drugs of tuberculosis resistance, diabetes resistance, lipid reduction and interleukin-17 inhibition are applied to the drugs of the claims 1 and 2.

8. The use of a dihydroartemisinin carboxyl/ester group-containing phenol/amido phenol conjugate as claimed in claim 7, wherein when n is 2, Y is-OMe, Z is-CH ═ CH-, X is-OH in antitubercular drugs;

n-3, Y is H, Z is nothing, X is-O (CH)₂)_b-DHA, b-3 for use in lipid lowering drugs;

n is 3, Y is H, Z is-CH₂CH₂-X is-OH for use in a medicament for inhibiting interleukin-17.

9. Use of a dihydroartemisinin carboxyl/ester/amido phenol conjugate according to claim 7, wherein n-2, X is-OMe, Y is-H, Z is-CH₂-, n ═ 2, X is-OMe, Y is-OMe, Z is-CH ═ CH-, n ═ 3, X is-OMe, Y is-OMe, Z is-CH ═ CH-, n ═ 2, X is-NH₂Y is-H, Z is-CH₂-use in antitubercular drugs;

n is 3 and X is-NH₂Y is-H, Z is-CH₂-use in an antidiabetic medicament;

n-2, X-OMe, Y-H, Z is unsubstituted, n-3, X-OMe, Y-H, Z is unsubstituted, n-3, X-OMe, Y-H, Z is-CH₂CH₂-, n ═ 3, X is-NH₂Y is-H, Z is-CH₂The use in medicaments for inhibiting interleukin-17.

Technical Field

The invention relates to the technical field of chemical medicines, in particular to a dihydroartemisinin carboxyl-containing phenol/ester group phenol/amido group phenol conjugate, a synthesis method and application.

Background

Artemisinin is a terpenoid found in the plant Artemisia annua, and is a colorless needle crystal. Dihydroartemisinin (DHA) is a first-generation derivative of artemisinin, has a unique structure, shows better pharmaceutical properties than artemisinin, and is an important clinical antimalarial drug. Based on the special structure and excellent activity of DHA, research on DHA is continuous, and at present, the research mainly focuses on the design and synthesis of novel derivatives of DHA and the exploration of new activity of old or new DHA molecules. To date, a number of novel derivatives of DHA have been synthesized, and some artemisinin derivatives have been used in clinical trials against breast cancer, colorectal cancer, non-small cell lung cancer, and the like. Researches also find that certain DHA derivatives show very good activity in diseases such as antivirus, antibacterial sensitization, anti-HIV, anti-cytomegalovirus, anti-tuberculosis and the like, show the potential of multi-target molecules, and are worthy of further research and development.

Salicylic acid is a plant willow bark extract, and is a natural anti-inflammatory drug. The common cold drug aspirin is salicylic acid derivative sodium acetylsalicylate; salicylic acid is commonly used in dermatology for the treatment of various chronic skin diseases such as acne, tinea, etc. Para-aminosalicylate is a commonly used clinical antituberculosis drug. The m-hydroxybenzoic acid is mainly used as a bactericide, a preservative, an ion exchanger, a plasticizer, a medical intermediate and the like. Para-hydroxybenzoic acid is an organic synthetic raw material with wide application, is widely used for antisepsis, mildew preventive, bactericide and the like of foods, cosmetics and medicines, and is also used as an intermediate of dyes and pesticides. P-hydroxyphenylacetic acid is an important organic synthesis intermediate and is used for synthesizing beta-receptor blocker atenolol and puerarin-4, 7-dihydroxyisoflavone serving as an effective component of daidzein. Ferulic acid is one of cinnamic acid derivatives, and its sodium salt has effects of resisting platelet aggregation, inhibiting release of platelet 5-hydroxytryptamine, inhibiting generation of platelet thromboxane A2, enhancing prostaglandin activity, relieving pain, and relieving vasospasm, and is a basic raw material for producing medicines for treating cardiovascular disease and cerebrovascular disease and leukopenia, such as XINXUEKANG, LIMAI Capsule, TAITAI oral liquid, etc., and it can be used for building body and protecting skin. Most of phenol containing carboxyl has wide biological activity, such as salicylic acid and ferulic acid which are directly used as medicines on the market for clinical application.

Carboxylic acid esters have a lower water solubility but a higher fat solubility than carboxylic acids. In this regard, the design of carboxylate esters as drug molecules is sometimes avoided in drug molecule design, but this is sometimes used to design prodrugs. Carboxylic acid esters are also important intermediates in organic synthesis, and target molecules such as amides and carboxylic acids can be obtained from carboxylic acid esters.

Numerous carboxylic acid esters containing phenolic hydroxyl groups, such as methyl salicylate, methyl paraben, methyl ferulate and the like, have important application in the fields of medicines, foods and chemical industry. The methyl salicylate has local stimulation effect, can promote local blood circulation, can generate stimulation reaction such as skin vasodilatation, red skin color and the like by external application or local inunction, reflectively affects skin, muscle, nerve and joints of corresponding parts, has the effects of detumescence, inflammation diminishing and pain easing, and also has the effect of relieving itching. Methylparaben is a phenolic preservative, is effective on various molds, yeasts and bacteria, and is used as a preservative bactericide of medicaments in the pharmaceutical industry; methyl paraben is also used as preservative additive for food, spices, films and the like. The ferulic acid methyl ester has effects of resisting oxidation, whitening skin, and relieving inflammation, and is mainly used in cosmetics. In addition, the ferulic acid methyl ester also has biological activities of resisting aging, regulating immunity, killing nematocide, resisting tumor and the like. Simple carboxylic ester containing phenolic hydroxyl group has wide biological activity, and the coexisting phenolic hydroxyl group can be used as a reaction site for further derivatization.

The amide compounds have wide biological activity, many polypeptide drugs with specific activity, beta-lactam antibiotics (penicillins, cephalosporins and the like), chloramphenicol antibiotics and some antitubercular drugs all contain amide bond structures, and more drug lead molecules or candidate drugs are attempted to be introduced into the amide structures.

Although it has been reported that a phenolic hydroxycarboxylic acid derivative and a carboxyl group-containing phenol structure are introduced into a DHA parent, the amount of the obtained compound is small and the system is insufficient. Therefore, the DHA phenolic hydroxyl carboxylic acid derivatives are synthesized, the biological activity and the structure-activity relationship are investigated, and the pharmaceutical significance is achieved. Based on the method, the carboxyl-containing phenol/ester-group phenol/amido phenol is connected with DHA through a simple Linker to form an aryl ether compound, namely a target molecule.

Disclosure of Invention

The invention provides a dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate, a synthesis method and application.

The invention provides a conjugate of dihydroartemisinin and carboxyl-containing phenol/ester-based phenol/amido phenol, or a racemate, a stereoisomer, a tautomer and pharmaceutically acceptable salts thereof, which has a structural general formula shown in a formula I:

wherein n is 2 or 3, Y is H or alkoxy, Z is alkenyl, alkyl or nothing, and when X is hydroxy or-O (CH)₂)_b-DHA, b ═ 2 or 3, denoted by TM5, and when X is an alkoxy or amine group, denoted by TM 6; wherein the DHA is dihydroartemisinin.

Preferably, n is 2 or 3, Y is-H or-OMe, and Z is- (CH)₂)-_mor-CH-, m-0,1 or 2, X is-OH, -O (CH)₂)_b-DHA, -OMe or-NH₂And b is 2 or 3.

The invention also provides a synthesis method of the derivative, wherein the synthesis of the TM5 is carried out according to the following reaction equation, and the synthesis method comprises the following steps:

wherein n is 2 or 3, Y is-H or-OMe, and Z is- (CH)₂)-_mor-CH ═ CH-, X is-OH or-O (CH)₂)_b-DHA, m ═ 0, 1 or 2, b ═ 2 or 3;

adding the raw materials of carboxyl-containing substituted phenol B1, IM1 and K₂CO₃And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-15 h, and after the reaction is finished, performing post-treatment to obtain a conjugate of dihydroartemisinin containing carboxyl phenol, namely TM 5.

Preferably, the mass ratio of the raw material IM1 to the raw material carboxyl-containing substituted phenol B1 is 1: 1-2, and the reaction temperature is 40-85 ℃.

The synthesis of TM6 was performed according to the following reaction equation, including the following steps:

wherein n is 2 or 3, Y is-H or-OMe, and X is-OMe or-NH₂Z is- (CH)₂)-_mor-CH ═ CH-, m ═ 0, 1, or 2;

adding the raw materials of the phenol B2, IM1 and K which contain ester group or amido group substitution₂CO₃And a solvent dimethylformamide, heating, stirring and dissolving, reacting for 1-10 h, and after the reaction is finished, carrying out post-treatment to obtain the dihydroartemisinin ester-containing or acylaminophenol conjugate, namely TM 6.

Preferably, the mass ratio of the raw material IM1 to the raw material containing the ester-group or amido-group substituted phenol B2 is 1: 1-2, and the reaction temperature is 40-85 ℃.

The invention also provides an application of the dihydroartemisinin carboxyl-containing phenol/ester-based phenol/amido phenol conjugate or racemate, stereoisomer, tautomer and pharmaceutically acceptable salt thereof in medicaments for resisting tuberculosis, resisting diabetes, reducing fat and inhibiting interleukin-17.

Preferably, when n is 2, Y is-OMe, Z is-CH, X is-OH (represented by TM5-5) for use in anti-tuberculosis drugs;

n-3, Y is H, Z is nothing, X is-O (CH)₂)_b-DHA, b-3 (denoted TM 5-6) for use in lipid lowering drugs;

n is 3, Y is H, Z is-CH₂CH₂Use of a compound of formula (I), wherein X is-OH (as indicated by TM 5-10) for the manufacture of a medicament for the inhibition of interleukin-17.

Preferably, when n is 2, X is-OMe, Y is-H, Z is-CH₂-, n ═ 2, X is-OMe, Y is-OMe, Z is-CH ═ CH-, n ═ 3, X is-OMe, Y is-OMe, Z is-CH ═ CH-, n ═ 2, X is-NH₂Y is-H, Z is-CH₂- (TM 6-3, TM6-5, TM6-11 and TM6-12, respectively) in antituberculosis drugs;

n is 3 and X is-NH₂Y is-H, Z is-CH₂- (TM 6-13) use in antidiabetic agents;

n-2, X-OMe, Y-H, Z (TM 6-2), n-3, X-OMe, Y-H, Z (ortho-para, TM6-6, TM6-8, respectively), n-3, X-OMe, Y-H, Z-CH₂CH₂- (TM 6-10), n ═ 3, and X is-NH₂Y is-H, Z is-CH₂- (TM 6-13) for use in a medicament for inhibiting interleukin-17.

Compared with the prior art, the invention has the beneficial effects that: the invention provides a conjugate of dihydroartemisinin and carboxyl-containing phenol/ester-based phenol/amido phenol, the derivatives connect pharmacophores of dihydroartemisinin and carboxyl-containing phenol/ester-based phenol/amido phenol medicaments with each other through a proper connecting structure, the synthetic method is simple, and the synthetic yield is high; biological activity tests show that the derivative has various biological activities of resisting tuberculosis, resisting diabetes, reducing blood fat, inhibiting interleukin-17 and the like, and has good application prospect.

Detailed Description

The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.