CN114276370B - Indole alkaloid compound, preparation method thereof, pharmaceutical composition and application thereof - Google Patents
Indole alkaloid compound, preparation method thereof, pharmaceutical composition and application thereof Download PDFInfo
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Abstract
The invention provides indole alkaloid, a preparation method thereof, a pharmaceutical composition and application thereof, and belongs to the technical field of medicines. The indole alkaloid or the pharmaceutically acceptable salt thereof provided by the invention has more remarkable inhibitory activity on CDK kinase (CDK 4/6 and CDK 5), and is a candidate drug with development potential and capable of being used for treating various cyclin dependent kinase related diseases (tumors and neurodegenerative diseases). The compound and the pharmaceutical composition thereof can be used for preparing medicines for treating various diseases related to cyclin dependent kinase, medicines for treating breast cancer, non-small cell lung cancer, liver cancer, intestinal cancer and pancreatic cancer, medicines for treating neurodegenerative diseases, medicines for treating AD, PD, huntington disease and amyotrophic lateral sclerosis, and CDK kinase inhibitors.
Description
Technical field:
the invention relates to the technical field of medicines, in particular to indole alkaloid or pharmaceutically acceptable salt thereof, a preparation method and application thereof, an indole alkaloid pharmaceutical composition and application thereof.
The background technology is as follows:
cyclin-dependent kinases (CDKs) are a class of serine/threonine (threonine) kinases that are involved in cell growth, proliferation, and apoptosis as important intracellular signaling molecules. Dysregulation of CDKs can trigger the onset of a variety of diseases (tumors, neurodegenerative diseases, etc.), and thus, CDKs have become effective and important targets in drug development. Wherein CDK4/6 is a key protein kinase for most malignant tumors, and the inhibitor can inhibit the continuous proliferation of tumor cells by inhibiting the transition of the cell cycle from the G1 phase to the S phase. In addition, another member of the CDK family, CDK5, plays a key role in neuronal physiology and in the pathological process of neurodegenerative diseases, CDK5 has become a potential target for the treatment of Alzheimer's Disease (AD) and Parkinson's Disease (PD). Therefore, the search for Cdk5 inhibitors has become a possible effective drug for treating neurodegenerative diseases such as AD, PD, etc.
Drugs that target CDK kinases have now entered a different phase of clinical research, for example CDK4/6 inhibitors Palbociclib, abemaciclib, ribociclib have been approved by the united states food and drug administration (Food and Drug Administration, FDA) for marketing as first-line drugs for the treatment of ER-positive, HER 2-negative breast cancers. The above studies have shown that the research and development of CDK kinase inhibitors with high activity and selectivity is of great clinical value.
At present, no indole alkaloid shown in a formula (I) is reported in the prior art, and no related activity is reported.
The invention comprises the following steps:
the invention aims to provide indole alkaloids compounds shown in formula (I) and formula (II) or pharmaceutically acceptable salts thereof, a preparation method and application thereof, a pharmaceutical composition containing active indole alkaloids and application thereof, and the indole alkaloids, pharmaceutically acceptable salts thereof and indole alkaloid pharmaceutical composition provided by the invention have excellent CDK-4,5,6 inhibiting activity (IC) 50 ＝0.1-2.0μM)。
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an indole alkaloid, which has a structure shown in a formula I:
in the formula I, R 1 Comprising hydrogen, hydroxy, halogen, or C 1-10 Alkoxy preferably includes hydrogen, hydroxy, fluoro, chloro, bromo, iodo, methyloxycarbonyl, ethyloxycarbonyl or propyloxycarbonyl, more preferably hydrogen. R is R 2 Or R is 3 Comprises C 1-10 Aldehyde or C 1-10 Acyl or C 1-10 Alkoxy ester groups, more preferably methyl formate.
In the present invention, indole alkaloids 1,2 and 3 having formula II are preferred:
in the present invention, the pharmaceutically acceptable salt includes an organic acid salt or an inorganic acid salt, i.e., the pharmaceutically acceptable salt of the indole alkaloid includes an organic acid salt of the indole alkaloid or an inorganic acid salt of the indole alkaloid; the organic acid salt of the indole alkaloid preferably comprises tartrate of the indole alkaloid, citrate of the indole alkaloid, formate of the indole alkaloid, acetate of the indole alkaloid or oxalate of the indole alkaloid; the inorganic acid salt of indole alkaloid preferably comprises hydrochloride, hydrobromide, nitrate or sulfate of indole alkaloid.
The invention provides a preparation method of indole alkaloid, which comprises the following steps:
mixing the core wood seeds with an extracting agent, extracting and concentrating to obtain an extract;
sequentially performing pH value adjustment to acidity, first extraction, pH value adjustment to alkalinity, second extraction, silica gel column chromatography, reversed phase chromatographic separation and Sephadex LH-20 separation on the extract to obtain indole alkaloid;
the silica gel column chromatography adopts a gradient elution mode, and the adopted eluent is a mixed solution of petroleum ether and acetone, wherein the volume ratio of the petroleum ether to the acetone is 10:1-1:1;
the eluent adopted by the reversed phase chromatographic separation is methanol and water, and the volume ratio of the methanol to the water is 30:70-70:30;
the solvent adopted in the Sephadex LH-20 separation is methanol.
The invention mixes the core wood seeds with the extractant, and extracts and concentrates the mixture to obtain extractum.
The invention preferably extracts the pistacia seed. In the present invention, the extraction is preferably further preceded by drying the seed of the pistacia chinensis. The temperature and time of the drying are not particularly limited in the present invention, and the drying temperature and time well known in the art may be used.
In the present invention, the solvent used for the extraction preferably includes an alcohol solvent, a ketone solvent, an ester solvent, an ether solvent, or an alkyl halide solvent; the alcohol solvent preferably includes a C1-6 alcohol, more preferably includes methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, isopentanol, cyclopentanol, n-hexanol, or cyclohexanol; the ketone solvent preferably includes a C3-6 ketone, more preferably acetone, methyl ethyl ketone or methyl isobutyl ketone; the ester solvent preferably comprises a C3-6 ester, more preferably ethyl formate, ethyl acetate or ethyl propionate; the ether solvent preferably comprises a C2-6 ether, more preferably comprises methyl ether or ethyl ether; the halogenated alkane solvent preferably comprises a C1-6 halogenated alkane, more preferably comprises methylene chloride, chloroform or tetrachloroethane. The invention preferably uses methanol or ethanol for extraction. In the present invention, the amount of the core wood seed and the extractant is preferably 1g: (20-30) mL, more preferably 1g: (20-25) mL.
In the present invention, the temperature of the extraction is preferably 60 to 70 ℃, more preferably 65 to 70 ℃; the extraction time is preferably 3 to 4 hours, more preferably 3 hours; the number of times of the extraction is preferably 3 to 4 times, more preferably 3 times.
The concentration of the present invention is not particularly limited, and any concentration means known in the art may be used, such as distillation under reduced pressure.
After the extract is obtained, the invention sequentially carries out pH value adjustment to be acidic, first extraction, pH value adjustment to be alkaline, second extraction and purification on the extract to obtain indole alkaloid.
In the present invention, the pH is adjusted to be acidic, preferably the pH of the system is adjusted to 2 to 3, more preferably 2.5 to 3. The acid used for adjusting the pH value to be acidic is not particularly limited, and acids well known in the art, such as hydrochloric acid, sulfuric acid or nitric acid, more preferably hydrochloric acid, are used in the present invention; the concentration of the hydrochloric acid is preferably 5 to 10wt%, more preferably 5wt%.
In the present invention, the organic solvents used for the first extraction and the second extraction independently preferably include an ester solvent, an ether solvent, or an alkyl halide solvent; the ester solvent preferably comprises a C3-6 ester, more preferably ethyl formate, ethyl acetate or ethyl propionate; the ether solvent preferably comprises a C2-6 ether, more preferably comprises methyl ether or ethyl ether; the halogenated alkane solvent preferably comprises a C1-6 halogenated alkane, more preferably comprises methylene chloride, chloroform or tetrachloroethane. The invention preferably adopts petroleum ether and ethyl acetate for the first extraction. In the present invention, the first extraction is preferably performed by using petroleum ether and ethyl acetate for 3 to 4 times. In the present invention, the solvent used for the second extraction is more preferably chloroform. In the present invention, the ratio of the extract to the organic solvent used for the first extraction is preferably 1g: (20-30) mL, more preferably 1g: (20-25) mL. In the present invention, the ratio of the extract to the organic solvent used for the second extraction is preferably 1g: (20-30) mL, more preferably 1g: (20-25) mL.
In the present invention, the pH is adjusted to be alkaline, preferably the pH of the system is adjusted to 9 to 10, more preferably 9.5 to 10. The alkali used for adjusting the pH to the alkaline is not particularly limited, and alkali solutions well known in the art, such as sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution, more preferably sodium carbonate solution, may be used.
In the present invention, the reversed phase chromatography is carried out by a chromatographic column, preferably a C-18 column.
The operation of the silica gel column chromatography, the reversed phase chromatography C-18 separation and the Sephadex LH-20 separation is not particularly limited, and the operation modes of the silica gel column chromatography, the reversed phase chromatography C-18 separation and the Sephadex LH-20 separation which are well known in the art can be adopted.
In the present invention, the preparation method of the pharmaceutically acceptable salt of indole alkaloid preferably comprises the following steps: reacting the indole alkaloid with an acid to obtain a pharmaceutically acceptable salt of the indole alkaloid; the acid is an organic acid or an inorganic acid. In the present invention, the organic acid preferably includes tartaric acid, citric acid, formic acid, acetic acid or oxalic acid; the mineral acid preferably comprises hydrochloric acid, hydrobromic acid, nitric acid or sulfuric acid.
A process for the preparation of indole alkaloids 1,2 and 3, comprising the steps of: drying the seed of the pistacia, heating and reflux-extracting for three times with methanol for 3 hours each time, combining the extracting solutions, recovering the methanol under reduced pressure, kneading the concentrated extract with 10% hydrochloric acid aqueous solution, regulating the pH value to 2-3, extracting with petroleum ether for three times, regulating the pH value to 9-10 with 10% NaOH solution, and using CH 2 Cl 2 Extracting to obtain total alkali part, subjecting the total alkali part to silica gel column chromatography, subjecting Fr C to petroleum ether-acetone gradient elution to obtain five parts of Fr.A-E, subjecting Fr C to silica gel column chromatography, subjecting petroleum ether/acetone (10:1→5:1, v/v), and subjecting C-18 (acetonitrile/water, 30:70→80:20) and Sephadex LH-20 (methanol) to separation to obtain indole alkaloids 1,2 and 3 with structure shown in formula II.
The invention also provides an indole alkaloid pharmaceutical composition, which comprises the indole alkaloid and/or pharmaceutically acceptable salts thereof.
In addition, the invention also provides the application of the indole alkaloid or the pharmaceutically acceptable salt thereof or the indole alkaloid pharmaceutical composition in preparing medicines for treating various diseases related to cyclin dependent kinase,
and the application in preparing medicines for treating breast cancer, non-small cell lung cancer, liver cancer, intestinal cancer and pancreatic cancer.
And the application in preparing medicines for treating neurodegenerative diseases.
And the application in preparing medicines for treating AD, PD, huntington's disease and amyotrophic lateral sclerosis.
And, the use in the preparation of a CDK kinase inhibitor.
In the invention, the mass percentage of the traditional Chinese medicine carrier and/or excipient in the indole alkaloid pharmaceutical composition is preferably 0.5-10%, more preferably 0.9-1%.
In the present invention, the indole alkaloid pharmaceutical composition preferably includes an indole alkaloid and/or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and/or an excipient. In the invention, the mass percentage of the indole alkaloid and/or the pharmaceutically acceptable salt thereof in the indole alkaloid pharmaceutical composition is preferably 0.1-99%, more preferably 0.5-90%; the total mass percentage of the traditional Chinese medicine carrier and/or excipient in the indole alkaloid pharmaceutical composition is preferably 1-99.9%, more preferably 10-99.5%.
The present invention is not particularly limited as to the pharmaceutically acceptable carrier or excipient, and may employ any pharmaceutically acceptable carrier or excipient known in the art, such as, in particular, one or more of a solid, semi-solid, or liquid diluent, filler, or pharmaceutical formulation adjuvant. In the present invention, the formulation types of the indole alkaloid pharmaceutical composition preferably include liquid formulations, solid formulations, sprays or mists; the liquid preparation preferably comprises injection, suspension, emulsion, solution or syrup; the solid preparation preferably comprises a tablet, a capsule, a granule or a electuary. The preparation method of the indole alkaloid pharmaceutical composition is not particularly limited, and the preparation method well known in the art can be adopted.
In the present invention, the indole alkaloid pharmaceutical composition is preferably administered by injection, orally, sublingually or by mucosal dialysis; the injection preferably comprises intravenous injection, intravenous drip, intramuscular injection, intraperitoneal injection or subcutaneous injection.
In the present invention, the indole alkaloid pharmaceutical composition is preferably used in the form of a unit weight dose. In the present invention, the indole alkaloid pharmaceutical composition is preferably used in the form of a unit weight dose. In the present invention, the administration amount per unit weight is preferably 0.5 to 20mg/kg.
The indole alkaloid or the pharmaceutically acceptable salt thereof provided by the invention has obvious inhibitory activity (IC) on CDK-4,5,6 50 =0.1-2.0 μm), indicating that the indole alkaloids or pharmaceutically acceptable salts thereof provided by the invention are candidate drugs with development potential for treating various cyclin-dependent kinase related diseases (tumors, neurodegenerative diseases).
In the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise.
Compared with the prior art, the invention has the following advantages:
1. the invention provides a new indole alkaloid compound.
2. The preparation method of the indole alkaloid provided by the invention does not need chemical synthesis, is obtained by extracting the core wood seeds as raw materials, has wide raw material sources and low cost, avoids using a large amount of organic raw materials and complex preparation process, is environment-friendly, is simple to operate, and has high yield.
3. The indole alkaloid or the pharmaceutically acceptable salt thereof has obvious inhibitory activity (IC) on CDK-4,5,6 50 =0.1-2.0 μm), is a candidate drug for the treatment of various cyclin-dependent kinase-related diseases (tumor, neurodegenerative diseases) with development potential.
4. The invention also provides application of the indole alkaloid or pharmaceutically acceptable salt thereof or indole alkaloid pharmaceutical composition in preparing medicines for treating various cyclin dependent kinase related diseases; and the application in preparing medicines for treating breast cancer, non-small cell lung cancer, liver cancer, intestinal cancer and pancreatic cancer; and the application in preparing medicines for treating neurodegenerative diseases; and the use in the manufacture of a medicament for the treatment of AD, PD, huntington's disease, amyotrophic lateral sclerosis, and the use in the manufacture of a CDK kinase inhibitor.
Drawings
FIG. 1 is a schematic diagram of the structural formula of an indole alkaloid compound of the invention;
FIG. 2 is a schematic diagram of the structural formula of a preferred indole alkaloid compound of the invention.
Detailed Description
The technical scheme of the present invention will be clearly and completely described with reference to the accompanying drawings. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1:
extracting 1.2kg of dry seed of herba Thesii (Kopsia carborea) with methanol under reflux for 3 hr for three times, mixing the extractive solutions, recovering methanol under reduced pressure, kneading the concentrated extract with 10% hydrochloric acid aqueous solution, adjusting pH to 2-3, extracting with petroleum ether for three times, adjusting pH to 9-10 with 10% NaOH solution, and adding CH 2 Cl 2 The total alkali fraction was extracted to 154g, the total alkali fraction was subjected to silica gel column chromatography, petroleum ether-acetone gradient elution to obtain five fractions (Fr.A-E), fr C (38 g) was subjected to silica gel column chromatography, petroleum ether/acetone (10:1. Fwdarw.5:1, v/v), reversed phase chromatography C-18 (acetonitrile/water, 30:70. Fwdarw.80:20) and Sephadex LH-20 (methanol) were separated to obtain indole alkaloid 1 (6.5 mg, yield 0.004%, purity 98%, colorless crystals) of the structure shown in formula II, 2 (12 mg, yield 0.008%, purity 98%, pale yellow oil) and 3 (8.7 mg, yield 0.006%, purity 98%, pale yellow oil).
Structural evidence data for indole alkaloids having the structure shown in formula II:
coloreless crystals;UV(MeOH)λ max (logε)299(3.24),249(3.67)nm；ECD(0.0004M,MeOH)λ max (Δε)212(-8.2)nm；IR(KBr)v max 3434,2926,2855,1731,1660,1475,1199cm –1 ；ESIMS 645[M+H] + ；HRESIMS m/z 645.3807(calcd for C 41 H 48 N 4 O 3 [M+H] + ,645.3799).
compound (2) colorless oil;UV(MeOH)λ max (logε)293(3.25),250(3.76)nm；ECD(0.0005M,MeOH)λ max (Δε)309(-3.7),264(+1.8),227(-7.5)nm；IR(KBr)v max 3429,2926,2858,1739,1665,1459,and 1236cm –1 ；ESIMS 613[M+H] + ；HRESIMS m/z 613.3539(calcd for C 40 H 44 N 4 O 2 [M+H] + ,613.3537).
compound (3) colorless oil;UV(MeOH)λ max (logε)296(2.82),227(3.35)nm；ECD(0.0003M,MeOH)λ max (Δε)239(-3.0),220(+17.1)nm；IR(KBr)v max 3428,2926,2855,1731,1483,1467,and 1347cm –1 ；ESIMS 633[M+H] + ；HRESIMS m/z 633.4153(calcd for C 41 H 52 N 4 O 2 [M+H] + ,633.4163).
TABLE 1 Compounds 1-3 1 H NMR data
a Measured in CDCl 3 at 500MHz.
b Measured in Methanol-d 4 at 500MHz.
c Overlapped.
TABLE 2 Compounds 1-3 13 C NMR data
As can be seen from Table 1, the indole alkaloids with the structure shown in the formula II are successfully prepared.
Example 2
The indole alkaloid prepared in the example 1 and water for injection are uniformly mixed, and subjected to fine filtration, encapsulation and sterilization in sequence to obtain the indole alkaloid injection.
Example 3
Preparation of pharmaceutically acceptable salts of indole alkaloids:
the indole alkaloids prepared in example 1 are respectively reacted with 4% of tartaric acid, citric acid, formic acid, acetic acid, oxalic acid, hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid to respectively obtain tartrate, citrate, formate of indole alkaloids, acetate of indole alkaloids, oxalate of indole alkaloids, hydrochloride of indole alkaloids, hydrobromide of indole alkaloids, nitrate of indole alkaloids and sulfate of indole alkaloids.
Example 4
Dissolving the indole alkaloid prepared in the example 1 in sterile water for injection, stirring until the indole alkaloid is dissolved, filtering by a sterile suction filter funnel, performing sterile fine filtration, packaging in an ampoule, and performing low-temperature freeze-drying and sterile sealing to obtain the indole alkaloid pharmaceutical composition powder injection.
Example 5
The indole alkaloid prepared in the example 1 and the excipient are uniformly mixed according to the mass ratio of 9:1, and the mixture is subjected to low-temperature freeze drying and sterilization to obtain indole alkaloid pharmaceutical composition powder.
Example 6
The indole alkaloid and the excipient prepared in the example 1 are uniformly mixed according to the mass ratio of 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 and 1:10 respectively, and the indole alkaloid pharmaceutical composition tablets are obtained by granulating and tabletting.
Example 7
The indole alkaloid prepared in the example 1 is prepared into an indole alkaloid pharmaceutical composition oral liquid by adopting a conventional preparation method of oral liquid.
Example 8
The indole alkaloid and the excipient prepared in the example 1 are uniformly mixed according to the mass ratio of 5:1, and the indole alkaloid pharmaceutical composition capsules, the indole alkaloid pharmaceutical composition granules and the indole alkaloid pharmaceutical composition granules are prepared by adopting the conventional preparation methods of capsules, granules and granules respectively.
Example 9
The indole alkaloid and the excipient prepared in the example 1 are uniformly mixed according to the mass ratio of 3:1, and the indole alkaloid pharmaceutical composition capsules, the indole alkaloid pharmaceutical composition granules and the indole alkaloid pharmaceutical composition granules are prepared by adopting the conventional preparation methods of capsules, granules and granules respectively.
Example 10
1. Compound solution (a): the 5mM compound stock was diluted 1/2log with DMSO to the desired concentration point, 3. Mu.l of the compound dilution and a blank (DMSO) were pipetted into 997. Mu.l of the reaction solution to give 3-fold 15. Mu.M compound solution A.
2. Enzyme solution (B): the kinase mother liquor of 100 ng/. Mu.l was diluted with the kinase diluent to 3 times the desired final concentration of enzyme reaction solution B.
3. ATP and substrate mixed solution (C): 10mM ATP mother liquor and substrate mother liquor are diluted into solutions with the required final concentration of 6 times respectively, and then mixed with the same volume to obtain the mixed solution C of ATP and substrate with the concentration of 3 times. Mu.l of each of solution A and solution B was added to the well plate and mixed and incubated at room temperature for 15 minutes, then 2. Mu.l of mixed solution C was added to each well and incubation was continued at room temperature for 45 minutes; after one hour of incubation, 6 μl of ADP-Glo reagent returned to room temperature was added to each well to terminate ADP production and consume the remaining ATP, and incubated at room temperature for 40 minutes; after 40 minutes, 12. Mu.l of ADP detection reagent was added to each well, and after 30 minutes of equilibration at room temperature in the absence of light, the fluorescent signal was read within a further half hour. The inhibition ratio of the compound = [1- (Δa assay/Max) ]×100% based on DMSO blank control without compound as maximum value Max of enzyme activity is shown in table 3.
TABLE 3 inhibitory Activity of Compounds 1-3 on CDK-4,5,6 (IC 50 in nM) a .
a IC 50 :50％inhibitory concentration.
b Positive control.
As can be seen from Table 3, the indole alkaloids have a significant inhibitory activity against CDK-4,5, 6.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. Indole alkaloids 1,2 and 3 shown in the following structural formula or pharmaceutically acceptable salts thereof,
2. the indole alkaloid or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an organic acid salt or an inorganic acid salt, the organic acid salt being a tartrate, citrate, formate, acetate or oxalate salt of the indole alkaloid; the inorganic acid salt of the indole alkaloid is hydrochloride, hydrobromide, nitrate or sulfate of the indole alkaloid.
3. A process for the preparation of indole alkaloids 1,2 and 3 according to claim 1, characterized in that it comprises the following steps: extracting dry seed of pistacia with methanol under reflux for three times (each for 3 hr), mixing extractive solutions, recovering methanol under reduced pressure, kneading the concentrated extract with 10% hydrochloric acid aqueous solution, adjusting pH to 2-3, extracting with petroleum ether for three times, adjusting pH to 9-10 with 10% NaOH solution, and adding CH 2 Cl 2 Extracting to obtain total alkali part, subjecting the total alkali part to silica gel column chromatography, subjecting the total alkali part to petroleum ether-acetone gradient elution to obtain five parts of Fr.A-E, subjecting Fr C to silica gel column chromatography at petroleum ether/acetone weight ratio of 10:1 to 5:1, and subjecting Fr C-18 to reversed phase chromatography: separating acetonitrile/water 30:70- & gt 80:20 and Sephadex LH-20 methanol to obtain indole alkaloids 1,2 and 3 shown in the structural formula.
4. An indole alkaloid pharmaceutical composition comprising an indole alkaloid of any of claims 1-2 and/or a pharmaceutically acceptable salt thereof.
5. The indole alkaloid pharmaceutical composition of claim 4 further comprising a pharmaceutically acceptable carrier and/or excipient.
6. Use of an indole alkaloid of any of claims 1-2 or a pharmaceutically acceptable salt thereof or an indole alkaloid pharmaceutical composition of any of claims 4-5 in the manufacture of a medicament for the treatment of CDK4, CDK5, CDK6 related disorders.
7. Use of an indole alkaloid as defined in any one of claims 1-2 or a pharmaceutically acceptable salt thereof or an indole alkaloid pharmaceutical composition as defined in any one of claims 4-5 in the manufacture of a medicament for the treatment of breast cancer, non-small cell lung cancer, liver cancer, intestinal cancer, pancreatic cancer.
8. Use of an indole alkaloid as defined in any one of claims 1-2 or a pharmaceutically acceptable salt thereof or an indole alkaloid pharmaceutical composition as defined in any one of claims 4-5 in the manufacture of a medicament for the treatment of a neurodegenerative disease.
9. Use of an indole alkaloid of any of claims 1-2 or a pharmaceutically acceptable salt thereof or an indole alkaloid pharmaceutical composition of any of claims 4-5 in the manufacture of a medicament for the treatment of AD, PD, huntington's disease, amyotrophic lateral sclerosis.
10. Use of an indole alkaloid of any of claims 1-2 or a pharmaceutically acceptable salt thereof or an indole alkaloid pharmaceutical composition of any of claims 4-5 in the preparation of a CDK4, CDK5, CDK6 kinase inhibitor.
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| 云南蕊木生物碱成分的研究;赵长朓;《海南师范大学学报（自然科学版）》;第33卷(第01期);5-8 * |
| 云南蕊木茎中的抗炎吲哚生物碱;解天珍;《有机化学》;第33卷(第01期);5-8 * |
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