CN114380687A - Preparation and application of novel lignanoid compounds in angelica sinensis - Google Patents
Preparation and application of novel lignanoid compounds in angelica sinensis Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered
Abstract
The invention belongs to the technical field of medicines, discloses preparation of neolignanoid in angelica sinensis and application thereof, and particularly relates to a remarkable sedative hypnotic effect of a novel neolignanoid compound. The results of animal experiments prove that: the compounds (+) -1 and (-) -1 have obvious sedative-hypnotic effect and are expected to become therapeutic drugs for mental diseases related to insomnia, convulsion, epilepsy/anxiety and depression.
Description
Technical Field
The invention relates to a new 2,7 '-epoxy-8, 9' -neolignan enantiomer obtained by extracting, separating and purifying Chinese medicine angelica, and application of derivatives and medicinal salts thereof in preparing medicines for preventing and treating diseases such as insomnia, convulsion, epilepsy and the like. Belongs to the technical field of medicine.
Background
Currently, sedative hypnotic drugs mainly include GABAa receptor agonists represented by diazepam (diazepam), oxazepam (oxazepam), zolpidem (zolpidem), eszopiclone (eszopiclone), zopiclone (zopiclone), melatonin receptor agonists represented by ramelteon (ramelteon) and teslameton (tasimelteon), orexin receptor antagonists represented by suvorexant (vorexant), which was developed by Merck and marketed in the united states in 2014, and antidepressant drugs having sedative hypnotic effects. However, most of the currently used drugs in clinical application have certain side effects, such as benzodiazepine
The drugs are easy to cause tolerance, dependence, withdrawal symptoms and the like, so that effective sedative hypnotic drugs with little side effect are lacked, and the market demand is urgent.
The diversity of the structure and the biological activity of natural products and the biological adaptability thereof are important and hot points of research of subjects such as medicinal chemistry, biology, organic chemistry and the like for a long time, and especially the research of active ingredients in traditional Chinese herbal medicines and folk medicinal biological resources is emphasized. In recent years, researches show that a plurality of natural products have potential sedative-hypnotic effects, for example, matrine and oxymatrine can play the sedative effect by increasing transmitters in brain, uncarine can enhance the sedative-hypnotic effect of pentobarbital sodium, scopolamine can enhance the hypnotic effect of ketamine hydrochloride, volatile oil in grassleaf sweelflag rhizome is the main active ingredient of the sedative-hypnotic effect, paeoniflorin can prolong the slow wave sleep time of normal rats and can restore the normal state of caffeine-induced insomnia rats, and the like [1 ]. The discovery of the sedative-hypnotic active ingredients with natural sources provides a lead compound for the research and development of clinical drugs for treating insomnia. The compound in the application is a novel natural product with hypnotic effect, which is separated and obtained from the traditional Chinese medicine angelica.
The traditional Chinese medicine Angelica is the dry root of Angelica sinensis (Oliv.) Diels of Umbelliferae, and has the efficacies of enriching and activating blood, regulating menstruation and relieving pain, relaxing bowel and the like [2 ]. The whole body of Dang Gui is also called "whole returning", the root head is called "returning to the head", the main root is called "returning to the body", the branch root and the tip of the branch root are called "returning to the tail", and different parts have different functions [2 ]. In China, "whole Chinese herbs" are often eaten as tonic herbs together with meat or as soup; is commonly used as a food additive in europe and north america [3,4 ]. Angelica sinensis is Gansu in China, and is a local industrial crop besides meeting the application of food, medicinal materials and the like.
Pharmacological research shows that the angelica extract and its chemical components have several pharmacological activities including antiphlogistic, antispasmodic, antioxidant, antifibrosis, neuroprotection, preventing and treating cardiac and cerebral vascular diseases, etc. [2-4 ]. At present, 100 chemical components including phthalide, phenylpropanoid, lignan, coumarin, alkyne, terpene, steroid, alkaloid, fatty acid and polysaccharide are probably identified from angelica extract [3-11 ]. The main ingredients, ligustilide, ferulic acid and polysaccharide, are considered as their main functional ingredients, however, the contents of these ingredients are significantly affected by the processing and extraction methods [3-5 ]. Currently, there are few studies on "homing" in the literature, and the studies on chemical components are mainly focused on ethanol or methanol extracts, which is not consistent with the way traditional chinese medicines are administered by water decoction [6-13 ]. Therefore, the project group develops the chemical component research of the 'head-in' water extract and obtains the neolignan compound with the obvious sedative and hypnotic effects in the application by matching with the pharmacological activity tracking evaluation.
Reference documents:
[1] glittering and translucent; 1, Maruvian; steel king; comparative chemistry 2018,2, 54-79.
[2] China pharmacopoeia Committee, China people's republic of China pharmacopoeia 2020 edition one [ M ]. Beijing, China pharmaceutical science and technology Press, 2020:139.
[3]I.L.I.Hook,J Ethnopharm,2014,152,1-13.
[4]W.L.Wei,R.Zeng,C.M.Gu,Y.Qu,L.F.Hunag,J Ethnopharm,2016,190,116-141.
[5]J.P.Ma,Z.B.Guo,L.Jin,Y.D.Li,Chin J Nat Med,2015,13,241-149.
[6]L.B.Zhang,J.L.Lv,J.W.Liu,J Nat Prod,2016,79,1857-1861.
[7]W.Gong,Y.Zhou,X.Li,et al.,Molecules,2016,21,549.
[8]L.Zhang,J.Lv,Chem Nat Comp,2018,54,13-17.
[9]J.L.Lv,L.B.Zhang,L.M.Gao,Fitoterapia,2018,129,102-107.
[10]J.Zou,G.D.Chen,H.Zhao,et al.,Org Lett,2018,20,884-887.
[11]J.Zou,G.D.Chen,H.Zhao,et al.,Chem Commun,2019,55,6221-6224.
[12]B.Sheng,Y.Vo,P.Lan,et al.,Org Lett,2019,21,6295-6299.
[13]K.Duric,Y.Liu,S.N.Chen,J Nat Prod,2019,82,2400-2408.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel medicament with sedative-hypnotic effect.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides neolignan shown as a general formula (I) and a derivative thereof.
Specifically, compounds represented by general formula (I) and pharmaceutically acceptable salts thereof are provided:
wherein, the chiral bond of the compound
Either R or S or racemic,
R1selected from H, OH, OCH3、OCH2CH3、NH2、NHCH3；
R2Selected from H, CH3、CH2CH3；
R3Selected from H, CH3、CH2CH3。
Further preferred compounds of the invention are selected from the group consisting of:
in a second aspect of the present invention, there is provided a process for the preparation of a compound according to the first aspect.
Drying 97kg of radix Angelicae sinensis, pulverizing, extracting with distilled water, 300L of water each time, boiling, heating for 30min, extracting for three times, mixing filtrates, recovering solvent under reduced pressure to obtain extract, separating with macroporous resin column chromatography, sequentially adding water: gradient elution is carried out on ethanol in a ratio of 1: 0-0: 1, TLC or HPLC monitoring is carried out, a solvent is recovered under reduced pressure to obtain a corresponding elution part, wherein a 50% ethanol part is separated by MCI resin, and water: eluting with ethanol at a gradient of 1: 0-0: 1, and combining the same components by TLC or HPLC; performing silica gel column chromatography, gradient elution TLC (thin layer chromatography) or HPLC (high performance liquid chromatography) monitoring on a 95% ethanol elution part of MCI (methanol-ethanol) column chromatography by using petroleum ether-ethyl acetate 1: 0-0: 1, and mixing the same components to obtain a component C1-C20; eluting subfraction C18 with Sephadex LH-20, petroleum ether-chloroform-methanol at 5:5:1 isocratic, and separating with reverse phase HPLC and 45% methanol-water to obtain compound 1; the compound 1 is separated by chiral HPLC, IG chiral column and n-hexane-ethanol 3:1 to obtain (+) -1 and (-) -1.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising neolignan represented by formula (I) as an active ingredient, and a carrier commonly used in the pharmaceutical field.
Typically, the pharmaceutical compositions of the present invention contain 0.1 to 95% by weight of a compound of the present invention.
Pharmaceutical compositions of the compounds of the invention may be prepared according to methods well known in the art. For this purpose, the compounds of the invention can, if desired, be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants, in a suitable administration form or dosage form for use as human or veterinary medicine.
The compound of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the administration route can be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum, etc., preferably oral.
The route of administration of the compounds of the invention or the pharmaceutical compositions containing them may be by injection. Injections include intravenous, intramuscular, subcutaneous, intradermal, and the like.
The administration dosage form can be liquid dosage form or solid dosage form. For example, the liquid dosage form can be true solution, colloid, microparticle, emulsion, or suspension. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, etc.
The extract or the compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various microparticle drug delivery systems.
In order to prepare the unit dosage form into tablets, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example, talc, silica, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
For example, to form the administration units into pills, various carriers well known in the art are widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talc and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc.
For example, in order to encapsulate the administration unit, the active ingredient of the extract or compound of the present invention is mixed with the above-mentioned various carriers, and the thus-obtained mixture is placed in a hard gelatin capsule or soft capsule. The effective component of the compound can also be prepared into microcapsules, and the microcapsules can be suspended in an aqueous medium to form a suspension, and can also be filled into hard capsules or prepared into injections for application.
For example, the extract or compound of the present invention may be formulated into injectable preparations such as solutions, suspensions, emulsions, lyophilized powders, which may be aqueous or non-aqueous, and may contain one or more pharmaceutically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. These adjuvants are commonly used in the art.
In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The dose of the compound, pharmaceutical composition of the present invention to be administered depends on many factors such as the nature and severity of the disease to be prevented or treated, sex, age, body weight, character and individual response of the patient or animal, administration route, administration frequency, therapeutic purpose, and thus the therapeutic dose of the present invention can be widely varied. Generally, the dosage of the pharmaceutical ingredients of the present invention used is well known to those skilled in the art. The prophylactic or therapeutic objectives of the present invention can be accomplished by appropriate adjustment of the actual amount of drug contained in the final formulation of the compound composition of the present invention to achieve the desired therapeutically effective amount. A suitable daily dosage range of the compound of the invention is 0.001-150mg/kg body weight, preferably 0.01-100mg/kg body weight, more preferably 0.01-60mg/kg body weight, most preferably 0.1-10mg/kg body weight. The above-mentioned dosage may be administered in a single dosage form or divided into several, e.g., two, three or four dosage forms which is limited by the clinical experience of the administering physician and by dosage regimens which include the use of other therapeutic means.
The total dose required for each treatment can be divided into multiple doses or administered as a single dose. The compound and the composition of the invention can be taken alone or combined with other therapeutic drugs or symptomatic drugs and the dosage is adjusted.
The fourth aspect of the technical scheme of the invention provides the application of the neolignan compound shown in the general formula (I) in preparing medicines for treating insomnia, convulsion, epilepsy and other diseases.
The invention also relates to the application of the angelica extract in preparing medicines for preventing or treating mental diseases such as insomnia, convulsion, epilepsy, anxiety, depression and the like.
The inventor finds that the compound (I) and the pharmaceutically acceptable salt have certain sedative and hypnotic effects. Therefore, the compound (I) and the pharmaceutically acceptable salt of the invention relate to a method for treating and improving sleep-related diseases in another aspect. The method comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
The invention shows that the compound (I) has good sedative-hypnotic effect at the level of whole animals. The compound (I) or a pharmaceutically acceptable salt thereof has not been reported in the public.
Advantageous technical effects
In the process of researching the active ingredients of the traditional Chinese medicine angelica, the inventor separates new neolignan compounds 1, (+) -1 and (-) -1 from angelica by an activity tracking method, wherein the compound 1 is a racemate of (+) -1 and (-) -1. The activity evaluation of the compound is carried out by combining a subthreshold dose pentobarbital sodium induced mouse sleep experiment, and the result shows that the compounds (+) -1 and (-) -1 have obvious sedative-hypnotic effect at the whole animal level. Belongs to a novel lead compound with value in the development process of sedative hypnotic drugs.
Drawings
FIG. 1, scheme for isolation of compounds 1, (+) -1 and (-) -1
FIG. 2 is a structural formula diagram of positive drug YZG-331
Detailed Description
The following experimental examples further illustrate the invention but do not limit it in any way.
Example 1, (+) -1 and (-) -1 are neolignans extracted from Angelica sinensis and purified as follows:
drying Angelica sinensis Diels, pulverizing 97kg, extracting with distilled water, each time with 300L water, boiling, heating for 30min, extracting for three times, mixing filtrates, recovering solvent under reduced pressure to obtain extract, separating with HP20 macroporous resin column chromatography, eluting with water (650L), 50% ethanol (500L) and 95% ethanol (250L), and recovering solvent under reduced pressure to obtain corresponding eluted fractions (A-C). Wherein, the component B (1.6kg) is suspended by water, treated by MCI resin of CHP 20 type, and eluted by water, 30% ethanol, 50% ethanol and 95% ethanol in sequence to obtain subfractions B1-B4. And mixing the B4(10g) and the C (135g), performing normal phase silica gel column chromatography, performing gradient elution with petroleum ether-ethyl acetate at a ratio of 1: 0-0: 1, and monitoring by TLC or HPLC to combine the same components to obtain a component C1-C20. And (3) eluting the subfraction C18 (2.4g) with Sephadex LH-20, petroleum ether-chloroform-methanol 5:5:1 isocratic elution, monitoring and combining the same components by TLC or HPLC to obtain a subfraction C18-1-C18-7, and preparing the subfraction C18-7-1-C18-7-2 by using reversed phase HPLC and 45% methanol-water as a mobile phase for C18-7(114 mg). Wherein C18-7-2(25.6mg) was further prepared by reverse phase HPLC with 30% acetonitrile-water as the mobile phase to give compound 1(20.3 mg). The compound 1 is prepared by using chiral HPLC, IG chiral column and n-hexane-ethanol 3:1 as a mobile phase to obtain (+) -1(7.8mg) and (-) -1(7.8mg)
Compound 1: a white amorphous powder;
IRνmax 3348,2931,2850, 1673,1611,1575,1514,1449,1427,1374,1328,1276,1126,1034,933,876,853,822, 775,678,600,570cm-1；(+)-HR-ESIMS m/z 355.1182[M–H]–(calcd.for C20H19O6, 355.1187)。
compound (+) -1:
CD(CH3OH)λmax(Δε)213.0(–0.52), 222.5(–1.74),235.0(+1.06),251.5(–2.01),293.5(+2.85),300.0(+2.70),321.5(+4.93) nm。
the compound (-) -1:
CD(CH3OH)λmax(Δε)206.0(+6.31), 216.0(+3.50),222.0(+3.85),235.5(–0.40),251.0(+3.00),293.0(–3.33),300.5(–3.04), 321.5(–6.00)nm.
experimental example 1 sedative-hypnotic Effect, Effect of Compounds (+) -1 and (-) -1 on the synergistic sodium pentobarbital Induction of sleep in mice
Test animals: ICR mice, male, weight 18-22 g, purchased from the Experimental animals center of Chinese academy of medical sciences. Animals were acclimatized for at least 3 days prior to the experiment, maintained at 25 + -1 deg.C at room temperature, and were fed freely and watered. All treatments for animals were in compliance with the requirements of the ethical committee of the international society for pain research.
Test compounds: the test substances are compounds (+) -1 and (-) -1, and the positive drug is YZG-331.
The method comprises the following steps: mice were gavaged or injected intraperitoneally with test substance or solvent control, and after 15min, pentobarbital sodium (32mg/kg) was injected intraperitoneally and timing was started, and the disappearance time of the righting reflex and the recovery time of the righting reflex of the mice were observed and recorded. In the experiment, the disappearance of righting reflex is more than 1min as the standard of falling asleep, and N is 8.
The experimental results are as follows: YZG-331(10mg/kg, ig) can obviously increase the sleep rate of mice induced by the sodium pentobarbital with subthreshold dose, and the experimental system is reliable. Both compounds (+) -1 and (-) -1 significantly increased the rate of sleep in mice induced by sodium pentobarbital (87.5% of the rate of sleep). Specific results are shown in table 1.
TABLE 1 evaluation results of the Compounds (+) -1 and (-) -1
Fisher's exact test (compared to solvent control).
Claims (7)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein, the chiral bond of the compound
Either R or S or racemic,
R1selected from H, OH, OCH3、OCH2CH3、NH2、NHCH3；
R2Selected from H, CH3、CH2CH3；
R3Selected from H, CH3、CH2CH3。
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from salts of the compound of the general formula (I) with organic acids or inorganic acids.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
4. a pharmaceutical composition comprising a compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the prevention or treatment of insomnia, sleep disorders and sleep-related disorders.
6. The use according to claim 5, wherein the medicament for preventing or treating insomnia, sleep disorder-related diseases is effective in ameliorating or aiding sleep disorder-related diseases.
7. The use as set forth in claim 5, wherein the agent for preventing or treating sleep-related diseases has potent sedative-hypnotic effects.
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