CN110437255A - A kind of indole alkaloid or its pharmaceutically acceptable salt and preparation method and application, indole alkaloid pharmaceutical composition and its application - Google Patents
A kind of indole alkaloid or its pharmaceutically acceptable salt and preparation method and application, indole alkaloid pharmaceutical composition and its application Download PDFInfo
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Abstract
The present invention provides a kind of indole alkaloid or its pharmaceutically acceptable salt and preparation method and application, indole alkaloid pharmaceutical composition and its application, belong to technical field of pharmaceuticals.Indole alkaloid provided by the invention or its pharmaceutically acceptable salt are for the strain of Candida albicans fluconazole resistant without obvious inhibitory activity, but when Fluconazole and indole alkaloid collective effect Yu Bainian fluconazole resistant strain, dialogue reads the inhibiting rate of fluconazole resistant strain 99.2% or more, show, indole alkaloid dialogue provided by the invention, which reads fluconazole resistant strain, has very strong drug resistance inversion activity, be it is a kind of have a development potentiality the white drug candidate for reading fluconazole resistant strain drug resistance can be reversed.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, and in particular to a kind of indole alkaloid or its pharmaceutically acceptable salt and system
Preparation Method and application, indole alkaloid pharmaceutical composition and its application.
Background technique
Candida albicans is the principal causative fungi of nosocomial infection, with being widely used for antifungal, candida albicans sense
Deep fungal case caused by dye increases year by year.Fluconazole is facing as the line antimicrobial currently used for treating deep fungal
Achieve good therapeutic effect on bed, but recently as the extensive use of Fluconazole, the drug resistance of Candida albicans just by
Year rises, and causes heavy financial burden to patient and society.In view of the complexity of Candida albicans fluconazole resistant mechanism
With the sternness of drug resistance form, it is very urgent to research and develop efficient, less toxic, selective stronger antifungal.
Summary of the invention
The purpose of the present invention is to provide a kind of indole alkaloid or its pharmaceutically acceptable salt and preparation method and answer
With, indole alkaloid pharmaceutical composition and its application, indole alkaloid and its pharmaceutically acceptable salt provided by the invention with
And indole alkaloid pharmaceutical composition has the excellent white drug resistance sexual function for reading fluconazole resistant strain of reverse.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of indole alkaloids, have structure shown in Formulas I:
In Formulas I, R1Including hydrogen, C1-10Alkyl, C1-10Aldehyde radical or C1-10Acyl group；
R2Including hydrogen, hydroxyl, halogen or C1-10Alkoxy carbonyl；
The integer that n is 0~4.
Preferably, the indole alkaloid has structure shown in Formula II:
Preferably, the medically acceptable salt includes acylate or inorganic acid salt.
The present invention provides the preparation methods of indole alkaloid described in above-mentioned technical proposal, comprising the following steps:
Dog tartar and extractant are mixed, extracts and is concentrated, obtain medicinal extract；
PH value is successively adjusted to acid, the first extraction, adjusting pH value to alkalinity, the second extraction, silicon in the medicinal extract
Plastic column chromatography, reversed phase chromatography separation and Sephadex LH-20 separation, obtain indole alkaloid；
The silica gel column chromatography use gradient elution mode, the eluent used for the mixed solution of petroleum ether and acetone,
The volume ratio of the petroleum ether and acetone is 10:1~1:1；
The eluent that the reversed phase chromatography separation uses for first alcohol and water, the volume ratio of the first alcohol and water be 30:70~
70:30；
The solvent that the Sephadex LH-20 separation uses is methanol.
Preferably, the solvent used that extracts includes alcohol solvent, ketone solvent, esters solvent, ether solvent or halogen
For alkanes solvent.
Preferably, it includes esters solvent, ether that first extraction organic solvent used with second extraction is independent
Class solvent or halogenated alkanes solvent.
Preferably, the adjusting pH value to acidity is that the pH value of system is adjusted to 2~3；
The adjusting pH value to alkalinity is that the pH value of system is adjusted to 9~10.
The present invention provides a kind of indole alkaloid pharmaceutical compositions, including indole alkaloid described in above-mentioned technical proposal
And/or its pharmaceutically acceptable salt.
Preferably, the indole alkaloid pharmaceutical composition further includes pharmaceutical acceptable carrier and/or excipient.
The present invention also provides indole alkaloid described in above-mentioned technical proposal or its pharmaceutically acceptable salt or above-mentioned skills
Indole alkaloid pharmaceutical composition described in art scheme reverses the white application read in fluconazole resistant strain drug resistance drug in preparation.
Indole alkaloid provided by the invention is (referred to as white to read fluconazole resistant for the strain of Candida albicans fluconazole resistant
Strain) without obvious inhibitory activity, but when Fluconazole and indole alkaloid collective effect Yu Bainian fluconazole resistant strain, dialogue is read
For the inhibiting rate of fluconazole resistant strain 99.2% or more, this illustrates that indole alkaloid dialogue provided by the invention reads fluconazole resistant
Strain has very strong drug resistance inversion activity, be it is a kind of have a development potentiality the white candidate medicine for reading fluconazole resistant strain drug resistance can be reversed
Object.
The preparation method of indole alkaloid provided by the invention does not need chemical synthesis, avoids using a large amount of Organic Ingredients
And complicated preparation process, environmentally protective, easy to operate, dog tartar is that raw material extracts to obtain, raw material sources extensively, at
This is low.
Contain indole alkaloid or its pharmaceutically acceptable salt in indole alkaloid pharmaceutical composition provided by the invention,
Dialogue reads fluconazole resistant strain also and has very strong drug resistance inversion activity, and can be reversed with development potentiality is white that read Fluconazole resistance to
The drug candidate of medicine strain drug resistance.
Specific embodiment
The present invention provides a kind of indole alkaloids, have structure shown in Formulas I:
In Formulas I, R1Including hydrogen, C1-10Alkyl, C1-10Aldehyde radical or C1-10Acyl group, preferably include hydrogen, methyl, ethyl, propyl,
Isopropyl, butyl, carboxaldehyde radicals, aldehyde-base, propionic aldehyde base, formoxyl, acetyl group or propiono, more preferably hydrogen；
R2Including hydrogen, hydroxyl, halogen or C1-10Alkoxy carbonyl preferably includes hydrogen, hydroxyl, fluorine, chlorine, bromine, iodine, first
Base Epoxide carbonyl, ethyloxycarbonyl or propyloxycarbonyl group, more preferably hydrogen.
The integer that n is 0~4, preferably 0 or 1.
In the present invention, the indole alkaloid preferably has structure shown in Formula II:
In the present invention, the pharmaceutically acceptable salt preferably includes organic hydrochlorate or inorganic acid salt, i.e., the described indoles
The pharmaceutically acceptable salt of alkaloid includes the acylate of indole alkaloid or the inorganic acid salt of indole alkaloid；The Yin
The acylate of diindyl alkaloid preferably includes the tartrate of indole alkaloid, the citrate of indole alkaloid, indoles biology
The oxalate of the formates of alkali, the acetate of indole alkaloid or indole alkaloid；The inorganic acid salt of the indole alkaloid
Preferably include the hydrochloride of indole alkaloid, the hydrobromate of indole alkaloid, the nitrate of indole alkaloid or indoles biology
The sulfate of alkali.
Indole alkaloid provided by the invention or its pharmaceutically acceptable salt read fluconazole resistant strain without obvious for white
Inhibitory activity, but when Fluconazole and indole alkaloid or its pharmaceutically acceptable salt collective effect Yu Bainian fluconazole resistant
When strain, dialogue reads the inhibiting rate of fluconazole resistant strain 99.2% or more, shows indole alkaloid provided by the invention or its medicine
Acceptable salt dialogue, which reads fluconazole resistant strain drug resistance, on has very strong drug resistance inversion activity, is that one kind has development potentiality
The white drug candidate for reading fluconazole resistant strain drug resistance can be reversed.
In the present invention, if without specified otherwise, all raw material components are commercially available quotient well known to those skilled in the art
Product.
The present invention provides the preparation methods of indole alkaloid described in above-mentioned technical proposal, comprising the following steps:
Dog tartar and extractant are mixed, extracts and is concentrated, obtain medicinal extract；
PH value is successively adjusted to acid, the first extraction, adjusting pH value to alkalinity, the second extraction, silicon in the medicinal extract
Plastic column chromatography, reversed phase chromatography separation and Sephadex LH-20 separation, obtain indole alkaloid；
The silica gel column chromatography use gradient elution mode, the eluent used for the mixed solution of petroleum ether and acetone,
The volume ratio of the petroleum ether and acetone is 10:1~1:1；
The eluent that the reversed phase chromatography separation uses for first alcohol and water, the volume ratio of the first alcohol and water be 30:70~
70:30；
The solvent that the Sephadex LH-20 separation uses is methanol.
The present invention mixes dog tartar and extractant, extracts and is concentrated, obtains medicinal extract.
The present invention preferably extracts the branches and leaves of dog tartar.In the present invention, it is preferably also wrapped before carrying out the extraction
It includes and the branches and leaves of the dog tartar is dried.The present invention is not particularly limited the temperature and time of the drying, uses
Drying temperature well known in the art and time.
In the present invention, the solvent used that extracts preferably includes alcohol solvent, ketone solvent, esters solvent, ethers
Solvent or halogenated alkanes solvent；The alcohols solvent preferably includes C1~6Alcohol more preferably includes methanol, ethyl alcohol, normal propyl alcohol, isopropyl
Alcohol, n-butanol, isobutanol, the tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, cyclopentanol, n-hexyl alcohol or cyclohexanol；The ketones solvent is preferred
Including C3~6Ketone more preferably includes acetone, methyl ethyl ketone or methylisobutylketone；The esters solvent preferably includes C3~6Ester, more preferably
Including Ethyl formate, ethyl acetate or ethyl propionate；The ether solvent preferably includes C2~6Ether more preferably includes methyl ether or second
Ether；The halogenated alkanes solvent preferably includes C1~6Alkyl halide more preferably includes methylene chloride, chloroform or tetrachloroethanes.The present invention
It is preferred that being extracted using methanol or ethyl alcohol.In the present invention, the dosage of the dog tartar and extractant be preferably 1g:(20~
30) mL, more preferably 1g:(20~25) mL.
In the present invention, the temperature of the extraction is preferably 60~70 DEG C, and more preferably 65~70 DEG C；The extraction when
Between preferably 3~4h, more preferably 3h；The number of the extraction is preferably 3~4 times, and more preferably 3 times.
The present invention is not particularly limited the concentration, using condensing mode well known in the art, specifically such as subtracts
Pressure distillation.
After obtaining medicinal extract, the present invention by the medicinal extract be successively adjusted pH value to acid, the first extraction, adjust pH value to
Alkalinity, the second extraction and purification, obtain indole alkaloid.
In the present invention, the pH value of system is preferably adjusted to 2~3, more preferably 2.5 to acidity by the adjusting pH value
~3.The present invention for it is described adjusting pH value to acidity use acid be not particularly limited, using it is well known in the art acid,
Specific such as hydrochloric acid, sulfuric acid or nitric acid, more preferably hydrochloric acid；The concentration of the hydrochloric acid is preferably 5~10wt%, more preferably
5wt%.
In the present invention, independent to preferably include esters molten for first extraction and the used organic solvent of the second extraction
Agent, ether solvent or halogenated alkanes solvent；The esters solvent preferably includes C3~6Ester more preferably includes Ethyl formate, acetic acid second
Ester or ethyl propionate；The ether solvent preferably includes C2~6Ether more preferably includes methyl ether or ether；The halogenated alkanes solvent
Preferably include C1~6Alkyl halide more preferably includes methylene chloride, chloroform or tetrachloroethanes.Present invention preferably employs petroleum ethers, acetic acid
Ethyl ester carries out the first extraction.In the present invention, the mode of first extraction preferably uses petroleum ether and ethyl acetate to distinguish
Extraction 3~4 times.In the present invention, second extraction solvent used is more preferably chloroform.In the present invention, the medicinal extract
The amount ratio of the organic solvent used with the first extraction is preferably 1g:(20~30) mL, more preferably 1g:(20~25) mL.In
In the present invention, the amount ratio of the organic solvent of the medicinal extract and the second extraction use is preferably 1g:(20~30) mL, more preferably
1g:(20~25) mL.
In the present invention, the pH value of system is preferably adjusted to 9~10 to alkalinity by the adjusting pH value, more preferably
9.5~10.The present invention is not particularly limited the adjusting pH value to the alkali that alkalinity uses, using alkali soluble well known in the art
Liquid, it is specific such as sodium carbonate liquor, solution of potassium carbonate, sodium hydroxide solution or potassium hydroxide solution, more preferably sodium carbonate
Solution.
In the present invention, the reversed phase chromatography separation is preferably C-18 column using chromatographic column.
The present invention does not have the operation of the silica gel column chromatography, reverse-phase chromatography C-18 separation and Sephadex LH-20 separation
There is particular determination, using silica gel column chromatography well known in the art, reverse-phase chromatography C-18 separation and Sephadex LH-20 separation
Mode of operation.
The preparation method of indole alkaloid provided by the invention does not need chemical synthesis, extracts using dog tartar as raw material
It obtains, raw material sources are extensive, at low cost, and avoid the preparation process using a large amount of Organic Ingredients and complexity, green ring
It protects, it is easy to operate.
In the present invention, the preparation method of the pharmaceutically acceptable salt of the indole alkaloid preferably includes following step
It is rapid: indole alkaloid and acid being reacted, the pharmaceutically acceptable salt of indole alkaloid is obtained；The acid is organic acid or inorganic
Acid.In the present invention, the organic acid preferably includes tartaric acid, citric acid, formic acid, acetic acid or ethanedioic acid；The inorganic acid is excellent
Choosing includes hydrochloric acid, hydrobromic acid, nitric acid or sulfuric acid.
Indole alkaloid provided by the invention or its pharmaceutically acceptable salt dialogue are read fluconazole resistant strain also and are had very
Strong drug resistance inversion activity, and the white drug candidate for reading fluconazole resistant strain drug resistance can be reversed with development potentiality.
The present invention provides a kind of indole alkaloid pharmaceutical compositions, including indole alkaloid described in above-mentioned technical proposal
And/or its pharmaceutically acceptable salt.
In the present invention, the indole alkaloid pharmaceutical composition further includes pharmaceutical acceptable carrier and/or excipient.In this hair
In bright, in the indole alkaloid pharmaceutical composition mass percentage of pharmaceutical carrier and/or excipient be preferably 0.5~
10%, more preferably 0.9~1%.
In the present invention, the indole alkaloid pharmaceutical composition preferably includes indole alkaloid and/or it pharmaceutically may be used
Salt, pharmaceutical carrier and/or the excipient of receiving.In the present invention, indole alkaloid in the indole alkaloid pharmaceutical composition
And/or the mass percentage of its pharmaceutically acceptable salt is preferably 0.1~99%, more preferably 0.5~90%；The Yin
The gross mass percentage composition of diindyl alkaloidal drug combination of traditional Chinese medicine carrier and/or excipient is preferably 1~99.9%, more preferably
It is 10~99.5%.
The present invention is not particularly limited the pharmaceutical carrier or the excipient, using medicinal load well known in the art
Body or excipient, it is specific such as solid, semisolid or liquid diluent, one of filler or pharmaceutical preparation adjuvant or more
Kind.In the present invention, the type of preparation of the indole alkaloid pharmaceutical composition preferably includes liquid preparation, solid pharmaceutical preparation, spray
Agent or mist agent；The liquid preparation preferably includes injection, suspension, emulsion, solution or syrup；The solid pharmaceutical preparation is excellent
Choosing includes tablet, capsule, granule or electuary.For the preparation method of the indole alkaloid pharmaceutical composition in the present invention
It is not particularly limited, using preparation method well known in the art.
In the present invention, the administration mode of the indole alkaloid pharmaceutical composition is preferably injected, is taken orally, sublingual administration
Or mucous membrane dialysis；The injection preferably includes intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.
In the present invention, the indole alkaloid pharmaceutical composition uses preferably in the form of per weight dose.In
In the present invention, the indole alkaloid pharmaceutical composition uses preferably in the form of per weight dose.In the present invention, institute
Stating per weight dose is preferably 5~20mg/kg.
The present invention also provides indole alkaloid described in above-mentioned technical proposal or its pharmaceutically acceptable salt or above-mentioned skills
Indole alkaloid pharmaceutical composition described in art scheme reverses the white application read in fluconazole resistant strain drug resistance drug in preparation.In
In the present invention, the indole alkaloid or its pharmaceutically acceptable salt or indole alkaloid pharmaceutical composition are white as reversing
Fluconazole resistant strain drug resistance drug is read in use, it is preferred that being used cooperatively with Fluconazole.
Below in conjunction with the embodiment in the present invention, the technical solution in the present invention is clearly and completely described.It is aobvious
So, described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.Based on the reality in the present invention
Example is applied, every other embodiment obtained by those of ordinary skill in the art without making creative efforts all belongs to
In the scope of protection of the invention.
Embodiment 1
Dog tartar dries branches and leaves 10kg, is heated to 68 DEG C of refluxing extractions 3 times with 50L methanol, extracts 3h every time, merges and extracts
Liquid, vacuum distillation recycling methanol, obtains medicinal extract；
By the medicinal extract combined of 2000mL 5%, and pH value is adjusted to 2, use 2000mL petroleum respectively
Ether, 2000mL ethyl acetate respectively extract 3 times, then adjust pH value to 9 with saturated sodium carbonate solution, extracted, obtained total with chloroform
Alkali (70g)；The total alkali is carried out using silica gel column chromatography, petroleum ether-acetone gradient elution (petroleum ether/acetone=30:1~
10:1, v/v), then reverse-phase chromatography C-18 separates (methanol/water=30:70~80:20, v/v) and Sephadex LH-20 (first
Alcohol) separation, obtain indole alkaloid (0.04g, yield 0.0004%, purity 98%, the colorless oil with structure shown in Formula II
Shape).
The structural characterization data of indole alkaloid with structure shown in Formula II:
:75.1(c 0.06,MeOH)；
UV(MeOH)λmax(logε):284(3.10),220(3.26)nm；
IR(KBr)vmax:3380,2927,2856,1726,1630,1461,1254cm–1；
ESIMS:367[M+H]+；
HRESIMS m/z:367.2024(calcd for C22H26N2O3[M+H]+,367.2016)；
1H NMR(CDCl3, 600MHz) and13C NMR(CDCl3150 MHz) data are as shown in table 1.
Table 11H NMR(CDCl3, 600MHz) and13C NMR(CDCl3, 150MHz) and data
As shown in Table 1, the indole alkaloid with structure shown in Formula II is successfully prepared in the present invention.
Embodiment 2
Indole alkaloid and water for injection prepared by embodiment 1 are uniformly mixed, refined filtration, encapsulating sterilizing is successively carried out, obtains
To indole alkaloid injection.
Embodiment 3
The medically acceptable salt of indole alkaloid:
Indole alkaloid prepared by embodiment 1 respectively with mass concentration be 4% tartaric acid, citric acid, formic acid, second
Acid, ethanedioic acid, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid reaction respectively obtain the tartrate, citrate, Yin of indole alkaloid
The formates of diindyl alkaloid, the acetate of indole alkaloid, the oxalate of indole alkaloid, indole alkaloid hydrochloride,
The hydrobromate of indole alkaloid, the nitrate of indole alkaloid, indole alkaloid sulfate.
Embodiment 4
Indole alkaloid prepared by embodiment 1 is dissolved in sterile water for injection, stirring to indole alkaloid is dissolved, through nothing
It is sub-packed in ampoule after the filtering of bacterium suction funnel and sterile refined filtration, then sterile sealing after frozen drying, it is raw to obtain indoles
Alkaloids pharmaceutical composition powder-injection.
Embodiment 5
Indole alkaloid prepared by embodiment 1 is uniformly mixed with excipient according to mass ratio for 9:1, cryogenic freezing is carried out
Dry and sterilizing, obtains indole alkaloid pharmaceutical composition medicinal powder.
Embodiment 6
By indole alkaloid prepared by embodiment 1 and excipient according to mass ratio be respectively 1:5,1:5.5,1:6,1:6.5,
1:7,1:7.5,1:8,1:8.5,1:9,1:9.5,1:10 are uniformly mixed, and pelletizing press sheet obtains indole alkaloid pharmaceutical composition
Tablet.
Embodiment 7
Indole alkaloid prepared by embodiment 1 uses the preparation method of traditional oral liquid, and indole alkaloid is prepared
Drug composition oral liquid.
Embodiment 8
Indole alkaloid and excipient prepared by embodiment 1 are uniformly mixed according to mass ratio for 5:1, routine is respectively adopted
Capsule, granule and electuary preparation method, indole alkaloid medicament composition capsule, indole alkaloid medicine is prepared
Compositions granule and indole alkaloid pharmaceutical composition electuary.
Embodiment 9
Indole alkaloid and excipient prepared by embodiment 1 are uniformly mixed according to mass ratio for 3:1, routine is respectively adopted
Capsule, granule and electuary preparation method, indole alkaloid medicament composition capsule, indole alkaloid medicine is prepared
Compositions granule and indole alkaloid pharmaceutical composition electuary.
Test case
Indole alkaloid prepared by embodiment 1 is dissolved in DMSO, the indole alkaloid that concentration is 128 μ g/mL is obtained
Indole alkaloid solution is added in 96 well culture plates by solution, be added it is white reads fluconazole resistant strain bacterium solution, make white to read Fluconazole
Final concentration of the 1 × 10 of persister bacterium solution5CFU/mL, experiment while being arranged culture medium blank control group (D1), white reading Fluconazole
Persister control group and amphotericin B control group, are cultivated for 24 hours under the conditions of 37 DEG C, measure each sample under 625nm with microplate reader
OD value, calculate the inhibiting rate of each sample, inhibiting rate (%)=(1-sample OD value/white read fluconazole resistant strain control group OD value)
× 100%, the results are shown in Table 2 for inhibiting rate.
2 dialogue of table reads the inhibiting effect of fluconazole resistant strain
As shown in Table 2, indole alkaloid reads fluconazole resistant strain without obvious inhibitory activity for white.
The indole alkaloid solution of 128 μ g/mL is uniformly mixed with the Fluconazole of 5 μ g/mL, is added to 96 well culture plates
In, to each hole be added it is white read fluconazole resistant strain bacterium solution, it is white to read final concentration of the 1 × 10 of fluconazole resistant strain bacterium solution5CFU/mL,
Experiment while culture medium blank control group is set, white reads fluconazole resistant strain control group, amphotericin B control group and Fluconazole pair
According to group, is cultivated under the conditions of 37 DEG C for 24 hours, the OD value of each sample under 625nm is measured with microplate reader, calculates the inhibiting rate of each sample,
Inhibiting rate (%)=(1-sample OD value/white read fluconazole resistant strain control group OD value) × 100%, inhibiting rate result such as 3 institute of table
Show.
3 Fluconazole of table and indole alkaloid mixture dialogue read the inhibiting effect of fluconazole resistant strain
As shown in Table 3, resistance to the indole alkaloid collective effect Yu Bainian Fluconazole of 5 μ g/mL Fluconazoles and 128 μ g/mL
When medicine strain, dialogue reads the inhibiting rate of fluconazole resistant strain 99.2% or more, shows indole alkaloid dialogue provided by the invention
Reading fluconazole resistant strain drug resistance has very strong drug resistance inversion activity, be it is a kind of have a development potentiality can be reversed that white to read Fluconazole resistance to
The drug candidate of medicine strain drug resistance.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of indole alkaloid or its medically acceptable salt, which is characterized in that the indole alkaloid has shown in Formulas I
Structure:
In Formulas I, R1Including hydrogen, C1-10Alkyl, C1-10Aldehyde radical or C1-10Acyl group；
R2Including hydrogen, hydroxyl, halogen or C1-10Alkoxy carbonyl；
The integer that n is 0~4.
2. indole alkaloid according to claim 1 or its medically acceptable salt, which is characterized in that the indoles is raw
Alkaloids have structure shown in Formula II:
3. indole alkaloid according to claim 1 or 2 or its medically acceptable salt, which is characterized in that the doctor
Acceptable salt includes acylate or inorganic acid salt on.
4. the preparation method of any one of claims 1 to 3 indole alkaloid, which comprises the following steps:
Dog tartar and extractant are mixed, successively extracts and is concentrated, obtain medicinal extract；
PH value is successively adjusted to acid, the first extraction, adjusting pH value to alkalinity, the second extraction, silicagel column in the medicinal extract
Chromatography, reversed phase chromatography separation and Sephadex LH-20 separation, obtain indole alkaloid；
The silica gel column chromatography uses gradient elution mode, and the eluent used is described for the mixed solution of petroleum ether and acetone
The volume ratio of petroleum ether and acetone is 10:1~1:1；
For the eluent that the reversed phase chromatography separation uses for first alcohol and water, the volume ratio of the first alcohol and water is 30:70~70:
30；
The solvent that the Sephadex LH-20 separation uses is methanol.
5. the preparation method according to claim 4, which is characterized in that it is described extract use solvent include alcohols solvent,
Ketones solvent, esters solvent, ether solvent or halogenated alkanes solvent.
6. the preparation method according to claim 4, which is characterized in that used in first extraction and second extraction
Independent organic solvent includes esters solvent, ether solvent or halogenated alkanes solvent.
7. the preparation method according to claim 4, which is characterized in that the adjusting pH value to acidity is by the pH value of system
It is adjusted to 2~3；
The adjusting pH value to alkalinity is that the pH value of system is adjusted to 9~10.
8. a kind of indole alkaloid pharmaceutical composition, which is characterized in that raw including the described in any item indoles of claims 1 to 3
Alkaloids and/or its pharmaceutically acceptable salt.
9. indole alkaloid pharmaceutical composition according to claim 8, which is characterized in that further include pharmaceutical acceptable carrier and/
Or excipient.
10. any one of claims 1 to 3 indole alkaloid or its pharmaceutically acceptable salt or claim 8~9 are any
The item indole alkaloid pharmaceutical composition reverses the white application read in fluconazole resistant strain drug resistance drug in preparation.
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| CN114276370A (en) * | 2022-01-04 | 2022-04-05 | 中国科学院昆明植物研究所 | Indole alkaloid compound, preparation method thereof, pharmaceutical composition thereof and application thereof |
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| CN1915993A (en) * | 2006-09-12 | 2007-02-21 | 中国人民解放军第二军医大学 | Indole group alkaloid of Hainan Gouyahua, and application for preparing drug-breaking medicine |
| WO2013112673A1 (en) * | 2012-01-25 | 2013-08-01 | Demerx, Inc. | Synthetic voacangine |
| WO2017184531A1 (en) * | 2016-04-18 | 2017-10-26 | Demerx, Inc. | Treatment of movement-related disorders using noribogaine |
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2019
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| CN1915993A (en) * | 2006-09-12 | 2007-02-21 | 中国人民解放军第二军医大学 | Indole group alkaloid of Hainan Gouyahua, and application for preparing drug-breaking medicine |
| WO2013112673A1 (en) * | 2012-01-25 | 2013-08-01 | Demerx, Inc. | Synthetic voacangine |
| WO2017184531A1 (en) * | 2016-04-18 | 2017-10-26 | Demerx, Inc. | Treatment of movement-related disorders using noribogaine |
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| GUO LING-LI ET AL.: "A new monoterpenoid indole alkaloid from Ervatamia chinensis", 《CHINESE JOURNAL OF NATURAL MEDICINES》 * |
| TERIS A.VAN BEEK ET AL.: "ANTIMICROBIALLY ACTIVE ALKALOIDS FROM TABERNAEMONTANA CHIPPII", 《JOURNAL OF NATURAL PRODUCTS》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114276370A (en) * | 2022-01-04 | 2022-04-05 | 中国科学院昆明植物研究所 | Indole alkaloid compound, preparation method thereof, pharmaceutical composition thereof and application thereof |
| CN114276370B (en) * | 2022-01-04 | 2023-07-21 | 中国科学院昆明植物研究所 | Indole alkaloid compound, preparation method thereof, pharmaceutical composition and application thereof |
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| CN110437255B (en) | 2020-08-21 |
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