CN115160160A - Rupestonic acid ephedrine derivative and preparation method and application thereof - Google Patents

Rupestonic acid ephedrine derivative and preparation method and application thereof Download PDF

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CN115160160A
CN115160160A CN202210135516.1A CN202210135516A CN115160160A CN 115160160 A CN115160160 A CN 115160160A CN 202210135516 A CN202210135516 A CN 202210135516A CN 115160160 A CN115160160 A CN 115160160A
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ephedrine
rupestonic acid
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pharmaceutical composition
rupestonic
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雍建平
卢灿忠
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Xiamen Institute of Rare Earth Materials
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Abstract

The invention relates to a compound of the formulaI) The derivatives of the esters of the rupestonic acid ephedrine or the complex salts of the rupestonic acid ephedrine shown in the formula (II), the preparation methods of the derivatives and the complex salts and the application of the derivatives and the complex salts in the aspect of resisting influenza viruses. The inventor finds that the inhibitory activity of the two substances on influenza viruses, particularly influenza A viruses (such as H1N 1) is far higher than that of raw materials of ephedrine and rupestonic acid, and the two substances have great development and research potential.
Figure DDA0003504353660000011

Description

Rupestonic acid ephedrine derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a rupestonic acid ephedrine ester derivative, a rupestonic acid ephedrine double salt, preparation methods of the rupestonic acid ephedrine ester derivative and the rupestonic acid ephedrine double salt, and application of the rupestonic acid ephedrine ester derivative and the rupestonic acid ephedrine double salt in the aspect of resisting influenza viruses.
Background
Ephedra (Ephedrae Herba) is mainly distributed in Xinjiang, inner Mongolia, hebei, shanxi, etc. The Chinese ephedra is the most valuable medicine material in the application history of Chinese traditional medicine, has medicinal history for thousands of years, and has the functions of promoting blood circulation, reducing blood pressure, inducing diuresis, reducing edema, inducing perspiration, relieving asthma, promoting blood circulation, resisting oxidation and resisting virus (Li Jianing, research progress of chemical components and pharmacological activity of the Chinese ephedra, this day is healthy, 2016,15 (9): 310). Ephedrine is one of the core components in the ephedra herb, has wide pharmacological activity, and specifically comprises the following components: (1) effects on the heart: ephedrine can dilate blood vessels of coronary artery, brain and muscle, enhance myocardial contraction force, increase cardiac output, increase systolic pressure and diastolic pressure, increase pulse pressure, and reduce blood viscosity. (2) The ephedrine has the effects of exciting respiratory center, expanding bronchial smooth muscle, and treating asthma. (3) effects on the central nervous system: ephedrine can excite cerebral cortex and subcortical center, and make people feel mental excitation, even insomnia, etc. (4) sweating and antipyretic effects: ephedrine has antipyretic effect on fever patients, and the main reasons are as follows: ephedra herb hinders reabsorption of sodium by sweat gland ducts to cause increased sweat gland secretion. (5) antibacterial and antiviral effects: the related data report that the ephedra decoction has antibacterial and antiviral effects on candida albicans, typhoid bacillus, escherichia coli, dysentery bacillus, pseudomonas aeruginosa, diphtheria bacillus, haemophilus influenzae, bacillus anthracis, streptococcus B, streptococcus A, staphylococcus aureus and the like. However, ephedrine is inactive against influenza virus, particularly influenza a virus.
Artemisia Rupestris L is mainly distributed in Xinjiang, zhongya and Europe. The history of medication in Xinjiang is long. It can be used for treating dyspepsia, abdominal distention and pain, hepatitis, snake bite, common cold, and fever. Wherein the compound preparation 'Compound Yizhihao granule' taking Xinjiang Yizhihao as the main component has the approval document No.: the Chinese medicine quasi-character Z200226711 is clinically used for relieving exterior syndrome, dispelling wind, treating diseases such as viral cold and sore throat. Rupestonic acid (rupestonic acid) is one of the characteristic compounds in artemisia rupestris, and is a sesquiterpene compound containing multiple functional groups.
However, the medicinal use of both is still to be further expanded.
Disclosure of Invention
In order to solve the above technical problems, the present invention first provides a rupestonic acid ephedrine ester derivative shown in formula (I) below, or a rupestonic acid ephedrine double salt shown in formula (II),
Figure BDA0003504353640000021
。
the invention also provides a preparation method of the rupestonic acid ephedrine ester derivative shown in the formula (I), which comprises the following steps:
Figure BDA0003504353640000022
condensation reaction is carried out on rupestonic acid and ephedrine to obtain the rupestonic acid ephedrine ester derivative shown in the formula (I).
According to an embodiment of the invention, the molar ratio of rupestonic acid to ephedrine is 1: (1-1.5), for example, they are mixed at a molar ratio of 1:1 to react.
According to an embodiment of the invention, the condensation reaction is carried out in the presence of DCC and DMAP.
According to an embodiment of the invention, the condensation reaction is carried out in the presence of an organic solvent; wherein the organic solvent is selected from chloroform, acetone, toluene, dichloromethane, ethyl acetate, tetrahydrofuran, etc. and can dissolve two compounds.
The invention also provides a preparation method of the rupestonic acid ephedrine hydrochloride compound salt shown in the formula (II), which comprises the following steps:
Figure BDA0003504353640000031
mixing rupestonic acid and ephedrine according to the molar ratio of 1:1, and stirring or ultrasonic reacting.
According to an embodiment of the invention, the stirring reaction is carried out at 0 to 40 degrees for a reaction time of 5min to 2h, e.g. 30min.
According to an embodiment of the invention, the ultrasound reaction time is between 5min and 2h, for example 10min.
According to an embodiment of the present invention, the stirring reaction or the ultrasonic reaction is carried out in the presence of an organic solvent; wherein the organic solvent is selected from methanol, ethanol, chloroform, acetone, toluene, dichloromethane, ethyl acetate, etc. which can dissolve two compounds.
The invention also provides the application of the rupestonic acid ephedrine ester derivative and/or the rupestonic acid ephedrine double salt in preparing the anti-influenza virus drugs.
According to an embodiment of the invention, the influenza virus is an influenza A virus, e.g. H1N1, such as influenza virus strains A/PR/8/34 and A/FM/1/47.
The invention also provides an anti-influenza virus pharmaceutical composition, which comprises a therapeutically effective amount of the derivates of the esters of the rupestonic acid ephedrine and/or the double salts of the rupestonic acid ephedrine.
According to an embodiment of the invention, the influenza virus is an influenza A virus, e.g. H1N1, such as influenza virus strains A/PR/8/34 and A/FM/1/47.
According to an embodiment of the present invention, the pharmaceutical composition may be a solid oral formulation or an injectable formulation.
According to an embodiment of the present invention, the solid oral preparation may be a capsule, a tablet, a granule, a sustained-release agent, or the like.
According to an embodiment of the present invention, the injection may be a small needle injection, a lyophilized injection.
According to an embodiment of the invention, the pharmaceutical composition further optionally comprises one or more pharmaceutically acceptable excipients; the auxiliary materials comprise one or a mixture of more of a filling agent, a binding agent, a disintegrating agent, a lubricating agent, a flavoring agent, an enteric coating or a slow-release material.
According to an embodiment of the invention, the filler comprises: one or more of lactose, sucrose, dextrin, starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium carbonate and microcrystalline cellulose;
according to the embodiment of the invention, the adhesive comprises one or a mixture of several of sucrose, starch, sodium carboxymethyl cellulose, methyl cellulose, polyethylene glycol and water;
according to the embodiment of the invention, the disintegrating agent comprises one or a mixture of more of starch, cross-linked polyketone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl cellulose;
according to the embodiment of the invention, the lubricant comprises one or a mixture of more of talcum powder, magnesium stearate, stearic acid, superfine silica powder, polyethylene glycol-4000 and polyethylene glycol-6000;
according to an embodiment of the invention, the flavoring agent comprises one or a mixture of sucrose, sorbitol, saccharin sodium, maltitol, stevioside and aspartame;
according to the embodiment of the invention, the slow release material comprises one or a mixture of several of hypromellose and guar gum with different specification viscosities.
According to an embodiment of the invention, when the pharmaceutical composition is a solid oral preparation, the pharmaceutical composition comprises the following components in parts by weight: 0.01-0.5 part of rupestonic acid ephedrine ester derivatives and/or rupestonic acid ephedrine double salt, 2-20 parts of lactose, 1-10 parts of pregelatinized starch, 1-5 parts of microcrystalline cellulose, 0.1-5 parts of carboxymethyl starch sodium, 2-10 parts of 10% povidone solution, 1-5 parts of magnesium stearate and 1-5 parts of talcum powder.
According to a preferred embodiment of the present invention, when the pharmaceutical composition is a solid oral preparation, the pharmaceutical composition comprises the following components in parts by weight: 0.078 parts of rupestonic acid ephedrine ester derivatives and/or rupestonic acid ephedrine double salt, 13 parts of lactose, 3.5 parts of pregelatinized starch, 2.5 parts of microcrystalline cellulose, 0.8 part of carboxymethyl starch sodium, 5 parts of 10% povidone solution, 1.5 parts of magnesium stearate and 1.5 parts of talcum powder.
According to an embodiment of the present invention, when the pharmaceutical composition is a solid oral preparation, the preparation method thereof comprises: mixing the auxiliary materials, sieving by a 40-100 mesh sieve, adding the rupestonic acid ephedrine ester derivative and/or the rupestonic acid ephedrine double salt into 10% povidone solution, mixing, adding into the sieved auxiliary materials, grinding, mixing, drying at 50-60 ℃ for 2-3 hours, and tabletting to obtain the solid oral preparation of the pharmaceutical composition.
Advantageous effects
The invention provides a rupestonic acid ephedrine ester derivative and a rupestonic acid ephedrine double salt, both are synthesized from natural substances of ephedrine and rupestonic acid, and the preparation process is simple. Furthermore, the inventor surprisingly finds that the inhibitory activity of the two substances on influenza viruses, particularly influenza A viruses (such as H1N 1) is far higher than that of the raw materials of ephedrine and rupestonic acid, and the two substances have greater development and research potential.
Drawings
FIG. 1 shows the HPLC analysis result of the raw ephedrine in example 2 (chromatographic conditions: C) 18 A column; mobile phase: v Methanol :V Water (containing 0.3% phosphoric acid) 7:3; detection wavelength: 254nm; retention time: 4.707 min).
FIG. 2 shows the HPLC analysis result of the raw material rupestonic acid in example 2 (chromatographic condition: C) 18 A column; mobile phase: v Methanol :V Water (containing 0.3% phosphoric acid) 7:3; detection wavelength: 254nm; retention time: 13.440 min).
FIG. 3 shows the HPLC analysis result of the ephedrine double salt of rupestonic acid (chromatographic condition: C) obtained in example 2 18 A column; mobile phase: v Methanol :V Water (containing 0.3% phosphoric acid) 7:3; detection wavelength: 254nm; retention time: 13.447 min).
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Instruments and reagents:
rupestonic acid (purity 98%, provided by a Ji Aike bayer pizza researcher, sinkiang, china); l-ephedrine is a commercially available analytical reagent; LC3000N type high performance liquid chromatograph (Beijing Innovation Heng chromatography technology Co., ltd.); hitachi L2000 high performance liquid chromatograph (Hitachi ).
Example 1: preparation of rupestonic acid ephedrine ester derivatives
Figure BDA0003504353640000061
Adding 0.124g (0.5 mmol) of rupestonic acid, 0.103g (0.5 mmol) of DCC and 0.012g (0.5 mmol) of DMAP into a 50mL round-bottom flask, adding 8mL of THF, stirring in ice bath for 5min, slowly dripping THF solution containing 0.083g (0.5 mmol) of L-ephedrine into the reaction system through a syringe, reacting in ice bath for 10min, naturally heating to room temperature for reaction, after TLC detection reaction is finished, concentrating the reaction solution under reduced pressure, and separating the residue through silica gel column to obtain rupestonic acid ephedrine ester (V) Petroleum ether ：V Ethyl acetate 1:0-1:1), white solid, melting point: at the temperature of between 187 and 188 ℃, 1 H NMR(CDCl 3 ,400MHz):0.66(d,3H,CH 3 ,J＝5.6Hz),0.97(d,1H,J＝5.2Hz),1.26(d,3H,CH 3 ,J＝3.6Hz),1.27-1.28(m,1H),1.51-1.57(m,1H),1.65(s,3H,CH 3 ),1.71-1.88(m,4H),2.02-2.12(m,4H),2.87(d,3H,CH 3 ,J＝8.8Hz),3.11(s,1H),4.26-4.38(m,1H,NH),4.71(dd,1H,J＝6.0,7.6Hz),4.98(s,1H),5.26(s,1H),7.32-7.39(m,5H). 13 C NMR(CDCl 3 ,100MHz):8.03,12.03,14.15,26.39,30.16,35.26,36.59,37.61,40.45,41.34,45.89,59.43,76.03,113.50,126.12,126.93,127.65,128.36,128.55,128.82,137.91,142.39,149.81,173.98,208.09.
example 2: preparation of rupestonic acid ephedrine double salt
Figure BDA0003504353640000062
Adding 0.124g (0.5 mmol) of rupestonic acid and 0.083g (0.5 mmol) of L-ephedrine into a 10mL round-bottom flask, adding 5mL of dry methanol, stirring at room temperature for 30min, concentrating under reduced pressure to obtain crude product of rupestonic acid ephedrine double salt, and separating and purifying the crude product by preparative HPLC to obtain pure double salt (chromatographic condition: C) 18 A column; mobile phase: v Methanol :V Water (containing 0.3% phosphoric acid) 7:3; detection wavelength: 254 nm) (chromatogram in FIG. 3), HPLC purity: 98.5 percent. In addition, HPLC detection was performed on L-ephedrine and rupestonic acid, which are starting materials, respectively (FIGS. 1 and 2). Tests show that the retention time of the product chromatogram after the reaction of the two is different from that of the raw material (the three are tested under the same chromatographic conditions), and the HPLC analysis is carried out after the reaction, and the ephedrine chromatographic peak disappears, so that the two can be conjectured to generate a new substance, namely the rupestonic acid ephedrine double salt.
Example 3: in vitro anti-influenza virus Activity assay
The in vitro anti-influenza virus activity is determined by the virus chamber of the institute of medical and biotechnology of Chinese academy of medical sciences.
The test principle is as follows: the sample compounds prepared in examples 1 and 2 were tested for their ability to inhibit virus-induced cytopathic extent (CPE) using MDCK (dog kidney) cells as the viral host.
Test materials and methods:
1. virus strain: influenza virus A/PR/8/34 (H1N 1), subcultured in allantoic cavity of chick embryo (2018.3), and stored at-80 deg.C.
2. Sample treatment: the samples were prepared into stock solutions with DMSO just before use, and then diluted 3-fold with culture medium, 8 dilutions each.
3. Positive control drug: ribavirin (RBV), hubei Tian Yao pharmaceutical industry Co., ltd. (batch No. 31712252). Oseltamivir phosphate, shanghai luo pharmaceutical limited (batch No. SH 0071).
4. The test method comprises the following steps: inoculation of MDCK cells into 96-well plates placed at 5% CO 2 And cultured at 37 ℃. Infection with influenza virus 10 after 24 hours -4 Adsorbing for 2 hr, discarding virus solution, adding maintenance solution containing samples with different dilutions and positive control drug, setting cell control well and virus control well simultaneously, and 5% CO 2 And cultured at 37 ℃. Observing the pathological change degree (CPE) of each group when the pathological change degree (CPE) of the virus control group reaches more than 4 hours, and respectively calculating the half Toxic Concentration (TC) of the sample to the cells by a Reed-Muench method 50 ) And half maximal Inhibitory Concentration (IC) against virus 50 ). The results of the activity test are shown in Table 1.
TABLE 1 results of anti-influenza Virus Activity of samples
Figure BDA0003504353640000081
Note: TC (tungsten carbide) 50 : half toxic concentration of drug; IC (integrated circuit) 50 : the median inhibitory concentration of the drug on the virus; and (3) SI: selection index, SI = TC 50 /IC 50 。
"_ a" indicates that it is not a fixed value.
"_ b": no testing was done.
From the above results, it can be seen that the derivatives of the esters of ephedrine of rupestonic acid and the double salts of ephedrine of rupestonic acid prepared in examples 1 and 2 have good inhibitory effects on influenza a virus strains a/PR/8/34 (H1N 1) and a/FM/1/47 (H1N 1), and both can be used as anti-influenza virus drugs. Moreover, the rupestonic acid ephedrine ester derivative and the rupestonic acid ephedrine double salt both show obviously stronger inhibitory activity to A/PR/8/34 (H1N 1) virus strain than the rupestonic acid and the ephedrine which are used as raw materials, namely, the combination of the two produces unexpected effect.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A rupestonic acid ephedrine ester derivative shown in formula (I) or rupestonic acid ephedrine double salt shown in formula (II),
Figure FDA0003504353630000011
。
2. the method for preparing the derivatives of the esters of rupestonic acid ephedrine shown in the formula (I) in claim 1, is characterized by comprising the following steps:
Figure FDA0003504353630000012
condensation reaction is carried out on rupestonic acid and ephedrine to obtain the rupestonic acid ephedrine ester derivative shown in the formula (I).
3. The method for preparing the rupestonic acid ephedrine double salt shown in the formula (II) in claim 1, which is characterized by comprising the following steps:
Figure FDA0003504353630000013
mixing rupestonic acid and ephedrine according to the molar ratio of 1:1, stirring for reaction or ultrasonic reaction.
4. The use of the derivatives of the esters of rupestonic acid ephedrine shown in the formula (I) and/or the complex salts of rupestonic acid ephedrine shown in the formula (II) in the preparation of drugs for resisting influenza virus in claim 1.
5. Use according to claim 4, wherein the influenza virus is an influenza A virus.
6. Use according to claim 5, wherein the influenza virus is H1N1.
7. A pharmaceutical composition against influenza virus, which comprises a therapeutically effective amount of the derivatives of the ephedrine rupestonic acid ester of the formula (I) and/or the double salts of the ephedrine rupestonic acid of the formula (II) of claim 1.
8. The pharmaceutical composition of claim 7, wherein the influenza virus is an influenza a virus.
9. The pharmaceutical composition according to claim 7 or 8, wherein the pharmaceutical composition is a solid oral formulation or an injectable formulation.
10. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition further optionally comprises one or more pharmaceutically acceptable excipients; the auxiliary materials comprise one or a mixture of more of a filling agent, a binding agent, a disintegrating agent, a lubricating agent, a flavoring agent, an enteric coating or a slow-release material.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101148418A (en) * 2007-11-05 2008-03-26 中国科学院新疆理化技术研究所 Alpine yarrow herb ketoacid derivatives and applications thereof
CN101721400A (en) * 2008-10-13 2010-06-09 青岛启元生物技术有限公司 Action of ferulic acid on enhancing drug effect of some medicaments and purpose thereof
CN101898966A (en) * 2010-07-15 2010-12-01 中国科学院新疆理化技术研究所 Bromine and piperazine ring-containing Artemisia rupestris L. keto ester derivative as well as preparation method and application thereof
CN102040511A (en) * 2010-09-27 2011-05-04 南京泽朗医药科技有限公司 Method for preparing rupestonic aid
CN102351811A (en) * 2011-07-28 2012-02-15 中国科学院新疆理化技术研究所 Ester derivative of rupestonic acid, and preparation method and purpose thereof
CN103073514A (en) * 2013-01-31 2013-05-01 中国科学院新疆理化技术研究所 Rupestonic acid heterocyclic amide derivative, and preparation method and application of derivative
CN109369436A (en) * 2018-11-12 2019-02-22 中国科学院新疆理化技术研究所 A kind of amide replaces alpine yarrow herb ketoacid derivatives and preparation method and purposes

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101148418A (en) * 2007-11-05 2008-03-26 中国科学院新疆理化技术研究所 Alpine yarrow herb ketoacid derivatives and applications thereof
CN101721400A (en) * 2008-10-13 2010-06-09 青岛启元生物技术有限公司 Action of ferulic acid on enhancing drug effect of some medicaments and purpose thereof
CN101898966A (en) * 2010-07-15 2010-12-01 中国科学院新疆理化技术研究所 Bromine and piperazine ring-containing Artemisia rupestris L. keto ester derivative as well as preparation method and application thereof
CN102040511A (en) * 2010-09-27 2011-05-04 南京泽朗医药科技有限公司 Method for preparing rupestonic aid
CN102351811A (en) * 2011-07-28 2012-02-15 中国科学院新疆理化技术研究所 Ester derivative of rupestonic acid, and preparation method and purpose thereof
CN103073514A (en) * 2013-01-31 2013-05-01 中国科学院新疆理化技术研究所 Rupestonic acid heterocyclic amide derivative, and preparation method and application of derivative
CN109369436A (en) * 2018-11-12 2019-02-22 中国科学院新疆理化技术研究所 A kind of amide replaces alpine yarrow herb ketoacid derivatives and preparation method and purposes

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