CN105924436A - Tropinone derivative and drug composition thereof and preparation method and application thereof - Google Patents
Tropinone derivative and drug composition thereof and preparation method and application thereof Download PDFInfo
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- CN105924436A CN105924436A CN201610339818.5A CN201610339818A CN105924436A CN 105924436 A CN105924436 A CN 105924436A CN 201610339818 A CN201610339818 A CN 201610339818A CN 105924436 A CN105924436 A CN 105924436A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
Abstract
The invention belongs to the technical field of medicines and relates to a tropinone derivative shown by a structural formula 1-3, a drug composition thereof and application of the derivative and the drug composition in preparation of anti-tumor disease drugs, in particular to application of the same in preparation of drugs for treating or improving leukemia, lung cancers, liver cancers, breast cancers and colon cancers.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to tropinone derivative 1-3 and pharmaceutical composition thereof, their system
Preparation Method, and they application in the medicine of the disease relevant to malignant tumour is treated in preparation.
Background technology
The morbidity and the continuous of death toll that cause along with cancer are risen, and cancer brings heavy economy to society and bears
Load.Owing to pathogenesis of cancer mechanism is extremely complex, beat cancer still has extremely challenging.Along with to cancer pathology, physiology
The in-depth study learned, the result for the treatment of cancer is encouraging, but still needs effective new drug to help to control cancer.
Along with Natural products research is goed deep into by people, increasing natural small molecule is paid close attention to by medicine scholar.Henbane
Alkaloid is the alkaloid that a class has 8 azepines [3.2.1] octane mother nucleus structure, and it has interesting pyrrolo-piperidine ring
Structure, special twin nuclei, design and research and development for medicine provide the foundation；Its biologically active is extensive, such as, regulate monoamine
Neurotransmitter secretion and affect acetylcholinergic receptor effect etc..Tropane is carried out structural modification and obtains different types of derivative
Thing: 2 chromanone tropane analog derivative [WO 2004113334；WO 2007054531；WO 2008074798], benzothiazole
Tryasolyl tropane derivatives, benzothiazole 2 ketone Tryasolyl tropane derivatives [WO 2009034042] and novel compound phenylacetylene base Liang
Henbane alkane derivative [WO 2009098208] is as a kind of monoamine neurotransmitter (DA, NE, 5 HT) reuptaking inhibitor, permissible
Prevent and alleviate biological disease；Tryasolyl tropane derivatives can be as central nervous system 5 HT3Acceptor effective, high optionally
Antagonist [US 20100087364].Tropane or class Tryasolyl tropane derivatives are as muscarinic receptor antagonist, to other acceptors
Antagonistic activity is more weak, and respiratory tract can be suppressed to shrink [US 20080027094].Tropane or class Tryasolyl tropane derivatives as in
NAChR (nAChRs) in pivot nervous system (CNS) and Peripheral Nervous is in regulation central nervous system merit
Can play an important role, especially by regulation release various neurotransmitters [WO 2007137030].Tropane ethers chemical combination
Thing, as anti-melanin concentrating hormone acceptor-1 (MCHRl) receptor activators, utilizes I] MCHR binding test prove to MCHR1 have
Competitive, in MCHRl receptor activation is tested, series compound IC50Less than 10 μMs [WO 2006130075].Tropine alcohol ester
Compounds can treat amyloidosis, reduces the risk of amyloid beta deposition in mammalian brain or delays disease
Sick morbidity, the Alzheimer's disease [WO 2013019901] for the treatment of mammal.N Heterocyclylalkyl henbane alkanes chemical combination
Thing, as the antagonist of mu opioid receptor, utilizes radioligand GTP Eu guanylic acid exchange Competition binding assay to analyze method: its
PKi7.0 to 10.6 [WO 2009029253] at value.N Heterocyclylalkyl and 3 alkylation tropane compounds are as μ Ah
The antagonist of sheet acceptor, utilize radioligand GTP Eu guanylic acid exchange Competition binding assay analyze method: its PKiAt value 8.5
To 10.2 [WO 2009029257].
α, beta unsaturated ketone analog derivative Numerous, it is a very important organic synthesis intermediate of class, is widely used in
The fields such as medicine, chemical industry and spices, Recent study finds chalcone and α, beta unsaturated ketone (Coumarins, pyrimidine ring class, ammonia
Base Thiourea, imidazoles, piperidines etc.) there is antitumor activity.On this basis, it is contemplated that double α based on tropane skeleton, β
Beta-unsaturated ketone derivative is likely to be of good antitumor activity.At present, the tropinone derivative (1-3) that the present invention provides is used for
The medicine of anti-tumor disease active ingredient has no report, its derivative or its pharmaceutical composition as antineoplastic in preparation or
Treatment anti-tumor disease medicine has no report.
Summary of the invention
It is desirable to provide a kind of new tropinone derivative (1 3) with medical value, derive containing tropinone
Thing (1 3) or its pharmaceutical salts and pharmaceutical carrier or the pharmaceutical composition of excipient, their preparation method, and this compounds
Or the application that its pharmaceutical composition is in the medicine preparing anti-tumor disease.
In order to realize the above-mentioned purpose of the present invention, the invention provides following technical scheme:
Tropinone derivative 13 shown in following structural formula or its pharmaceutical salts,
Tropinone derivative or its pharmaceutical salts as mentioned, wherein said pharmaceutical salts refers to pharmaceutically acceptable salt,
With organic acid such as tartaric acid or citric acid or formic acid or ethanedioic acid, or formed with inorganic acid example hydrochloric acid or sulfuric acid or phosphoric acid
Salt.
Pharmaceutical composition, containing described tropinone derivative 13 or its pharmaceutical salts and pharmaceutically suitable carrier or excipient.
The method of the tropinone derivative 13 described in preparation, tropinone and benzaldehyde or 3 bromobenzaldehydes or 2 methoxyl groups
Benzaldehyde reacts to end under catalyst n aOH effect in ethanol solution, and reactant liquor regulates pH=with 5% watery hydrochloric acid
7, decompression is distilled off ethanol, the reactant liquor diluted ethyl acetate of 3 times of volumes, successively with saturated sodium bicarbonate aqueous solution with full
And brine It, organic phase anhydrous sodium sulfate is dried, and decompression and solvent recovery obtains crude product；Crude product, through silica gel column chromatography, uses diethyl
Amine ethyl acetate petroleum ether elutes to obtain tropinone derivative 13.
The method preparing tropinone derivative 13 as mentioned, tropinone 2 (mmol) and the 5mL10%NaOH aqueous solution are molten
In 15mL absolute ethyl alcohol, under condition of ice bath, slowly drip corresponding aldehyde benzaldehyde or 3 bromobenzaldehydes or 2 methoxybenzaldehydes 4.4
(mmol), TLC detection terminates to reaction, and decompression is distilled off ethanol, and reactant liquor is with 3 times of diluted ethyl acetate, successively with 5% dilute
Hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt aqueous solution wash, and organic phase anhydrous sodium sulfate is dried, and decompression distillation obtains
Crude product, crude product, through silica gel column chromatography, diethylamine ethyl acetate petroleum ether=2:20:78 wash-out, prepares tropinone and derives
Thing derivative 13.
Described tropinone derivative 13 or the application in the medicine of preparation treatment anti-tumor disease of its pharmaceutical salts.
Described tropinone derivative 13 or the application in the medicine of preparation treatment anti-tumor disease of its pharmaceutical salts.
Described pharmaceutical composition is treated in preparation or improves the application in the medicine of anti-tumor disease.
Described tropinone derivative 13 or its pharmaceutical salts in preparation treatment or improve anti-leukocythemia, lung cancer, liver cancer, breast
Gland cancer, colon cancer medicine in application.
The present invention, with tropinone as raw material, occurs Claisen Schimidt to react with corresponding aldehyde, obtains a series of couples of α, β
Beta-unsaturated ketone derivative, and complete tropinone derivative carries out leukaemia HL 60, lung cancer A 549, liver cancer SMMC 7721, breast
The antitumor activity test of gland cancer MCF 7 and colon cancer SW480.
Utilize tropinone derivative (1-3) to leukemia HL-60, lung cancer A-549, liver cancer SMMC-7721, breast cancer MCF-
7 and the cell anti-tumor active testing table of colon cancer SW480, it is the most anti-that this seminar tentatively finds that tropinone derivative has
Tumor disease effect.1,2 and 3 pair of leukemia HL-60 of compound, lung cancer A-549, liver cancer SMMC-7721, breast cancer MCF-7 and
The cell of colon cancer SW480 has preferable antitumor activity, the wherein IC of compound 1 correspondence50Value is respectively 13.62,
16.78,14.24,16.57 and 11.95 μMs；The IC of compound 2 correspondence50Value be respectively 3.39,13.59,6.65,13.09 and
12.38μM；The IC of compound 3 correspondence50Value is respectively 18.97,29.23,28.90,21.14 and 19.79 μMs.
When the compounds of this invention is used as medicine, can directly use, or use with the form of pharmaceutical composition.This medicine
Composition contains 0.1 99%, the compounds of this invention of preferably 0.5 90%, and remaining is the most acceptable, to people and
Nontoxic and the inert pharmaceutically suitable carrier of animal or excipient.
Described pharmaceutical carrier or excipient are one or more solids, semisolid and liquid diluent, filler and medicine
Tetramune assistant agent.The pharmaceutical composition of the present invention is used with the form of per weight dose.The medicine of the present invention can be through note
Penetrate (intravenous, intramuscular injection) and oral two kinds of forms are administered.
Accompanying drawing illustrates:
Fig. 13 is respectively the structural formula schematic diagram of tropinone derivative of the present invention (1 3).
Detailed description of the invention:
In order to be more fully understood that the essentiality content of the present invention, with embodiments of the invention, tropine of the present invention is described below
The preparation method of ketone derivatives (1 3) and pharmacological action result, but do not limit the present invention with this.
Embodiment 1:
High-resolution electrospray ionization mass spectrometry (HRESIMS) LCMS IT TOF mass spectrograph (Shimadzu, Kyoto,
Japan) upper mensuration, nuclear magnetic resoance spectrum (1H and13C NMR) Bruker AM 400 (1H/13C, 400M Hz/100M Hz) superconduction
Nuclear magnetic resonance chemical analyser (Bruker, Bremerhaven, Germany) measures, with TMS (tetramethylsilane) as internal standard.Column chromatography
Silica gel (200～300 mesh) and thin-layer chromatography silica GF254 are Qingdao Makall Group Co., Ltd. and produce.Reaction reagent is purchased from
Alfa Aesar, lark prestige and Acros company.
The preparation of compound (1 3):
Tropinone (2mmol) and the 5mL 10%NaOH aqueous solution are dissolved in 15mL absolute ethyl alcohol, under condition of ice bath, slowly drip
Corresponding benzaldehyde or 3 bromobenzaldehydes or 2 methoxybenzaldehydes (4.4mmol), TLC detection terminates to reaction.Decompression distillation removes
Remove ethanol, 3 times of diluted ethyl acetate, successively with watery hydrochloric acid, saturated sodium bicarbonate aqueous solution, the washing of the saturated common salt aqueous solution, have
Machine phase anhydrous sodium sulfate is dried, decompression distillation obtain crude product, crude product with silica gel column chromatography (diethylamine ethyl acetate petroleum ether=
2:20:78) wash-out, prepares tropinone derivative derivative (1 3):
Compound 13 structure determines data:
8 methyl 8 azepine 2,4 pairs benzylidene dicyclos [3,2,1] octane 3 ketone (1):
Unformed yellow powder, yield 82%,1H NMR(400MHz,CDCl3)δ:7.84(s,2H,H‐9,10),7.45‐
7.26(m,10H,Ar),4.40(m,2H,H‐1,5),2.62‐2.60(m,2H,H‐6,7),2.30(s,3H,H‐8),2.04‐
2.03(m,2H,H‐6,7).13C NMR(100MHz,CDCl3)δ:187.96,138.34,136.57,135.07,130.25,
128.85,128.54,60.85,35.78,30.28.IR(KBr)ν:3439.59,2950.01,1670.23,1608.43,
1584.51,1445.67,1237.37,1164.00,946.78,778.14,692.99cm‐1.ESIMS:m/z 317[M+H]+,
HRESIMS:C22H22NO[M+H]+Measured value 317.1669, calculated value is 317.1696.
8 methyl 8 azepine 2,4 pairs (3' bromobenzene methylene) dicyclo [3,2,1] octanes 3 ketone (2):
Unformed yellow powder, yield 84%,1H NMR(400MHz,CDCl3)δ:7.72(s,2H,H‐9,10),7.50‐
7.26(m,8H,Ar‐H'),4.32(m,2H,H‐1,5),2.62‐2.59(m,2H,H‐6,7),2.30(s,3H,H‐8),2.02‐
1.97(m,2H,H‐6,7).13C NMR(100MHz,CDCl3)δ:187.41,139.43,137.04,134.86,132.87,
131.75130.05,128.61,122.63,60.75,35.86,30.12.IR(KBr)ν:3435.22,2929.28,
1668.94,1608.57,1556.02,1470.37,1220.77,1058.10,944.71,787.31,681.41cm‐ 1.ESIMS:m/z 472[M+H]+,HRESIMS:C22H20NOBr2[M+H]+Measured value 472.9928, calculated value is 472.9906.
8 methyl 8 azepine 2,4 pairs (2' methoxybenzylidene) dicyclo [3,2,1] octanes 3 ketone (3):
Unformed yellow powder, yield 70%,1H NMR(400MHz,CDCl3)δ:8.02(s,2H,H‐9,10),7.35‐
6.90(m,8H,Ar‐H),4.27(m,2H,H‐1,5),3.82(s,6H,OMe),2.53‐2.51(m,2H,H‐6,7),2.30(s,
3H,H‐8),2.02‐1.99(m,2H,H‐6,7).13C NMR(100MHz,CDCl3)δ:188.51,158.39,138.19,
132.53,130.46 130.36,124.26,120.05,110.73,60.98,55.41,35.24,30.33.IR(KBr)ν:
3441.66,2944.42,1673.41,1598.62,1486.74,1462.73,1250.85,1058.22,757.06cm‐ 1.ESIMS:m/z 377[M+H]+,HRESIMS:C24H26NO3[M+H]+Measured value 377.1906, calculated value is 377.1907.
Following antitumor activity pharmacological action test example is used for illustrating the pharmacological action of the tropinone derivative of the present invention
Result:
Test example 1:
The above-mentioned compound of the present invention prepares tropinone derivative (1 3) that embodiment obtains in leukaemia HL 60, lung cancer
The cell of A 549, liver cancer SMMC 7721, breast cancer MCF 7 and colon cancer SW480 is tested.
1 material and method
1.1 materials:
The cell line that screening active ingredients uses is respectively to leukemia HL60, lung cancer A 549, liver cancer SMMC 7721, breast cancer
MCF 7 and colon cancer SW480；Cell culture medium (Dulbecco's Modified Eagle containing 10% hyclone
Medium,DMEM)。
1.2 instruments: CO2Constant incubator Thermo Forma 3310 (U.S.)；Inverted biologic microscope XD 101 type
(Nanjing)；Multi-functional ELIASA Multiskan FC (U.S.).
1.3 experimentation
It is made into individual cells suspension with the nutrient solution (DMEM) containing 10% hyclone, thin with every hole 3000～15000
Born of the same parents are inoculated into 96 orifice plates, every pore volume 100 μ L, and attached cell shifts to an earlier date 12～24 hours inoculated and cultured.Add derivative to be measured molten
Liquid: derivative DMSO dissolves, derivative with the concentration primary dcreening operation of 40 μMs, every hole final volume 200 μ L, every kind of process be all provided with 3 multiple
Hole.After 37 degrees Celsius are cultivated 48 hours, attached cell abandons nutrient solution in hole, and every hole adds MTS solution 20 μ L and nutrient solution 100 μ L；
100 μ L culture supernatant are abandoned in the every hole of suspension cell, and every hole adds MTS solution 20 μ L.Continue to hatch 2～4 hours, react fully into
Absorbance value is measured after row.Selecting 492nm wavelength, multi-functional ELIASA reads each hole absorbance value, records result, and data process
After with the numbered abscissa of derivative, cell inhibitory rate is the inhibiting rate figure that ordinate draws 5 strain cells.Exist with ELIASA
It is measured at 490nm, the number of living cells can be deduced according to optical density OD value.It is all provided with cis-platinum (DDP) and taxol every time
(Taxol) two positive control derivatives, positive derivative is with concentration as abscissa, and cell inhibitory rate is that ordinate draws song
Line, application two-point method (Reed and Muench method) calculates the IC of derivative50Value.As shown in Table 1 and Table 2:
During double benzylidene derivative unsubstituted, compound 1 is 68 92% to five strain inhibition rate of tumor cell.Chemical combination
Thing 2 is 68 95% to five strain cell inhibitory rates.Compound 3 is 57 88% to five strain inhibition rate of tumor cell.
Table 1 tropinone derivative is to inhibiting tumour cells activity
Use MTS method synthesized derivative has been carried out tumor cell in vitro (HL 60, A 549, SMMC 7721,
MCF 7 and W480) inhibitory activity test, when concentration is 40 μMs, major part derivative shows stronger pressing down to tumour cell
System activity, compound 1 is to HL 60, and A 549, SMMC 7721, MCF 7 and SW480 cell inhibitory activities are more significant, IC50Value point
Wei 13.62,16.78,14.24,16.57 and 11.95 μMs；Compound 2 to HL 60, A 549, SMMC 7721, MCF 7 He
SW480 cell inhibitory activity is notable, IC50Value is respectively 3.39,13.59,6.65,13.09 and 12.38 μMs, is better than positive control
Thing (cis-platinum)；Compound 3 to HL 60, A 549, SMMC 7721, MCF 7 and SW480 cell there is inhibitory activity, IC50Value point
It is not 18.97,29.23,28.90,21.14 and 19.79 μMs, has established good base for exploring new type antineoplastic medicine further
Plinth.
Table 2 tropinone derivative anti tumor activity in vitro (IC50,μM)
3. conclusion: under 40 μMs of concentration, compound 1 and compound 3 are more satisfactory to five strain cell inhibitory activities；Compound 2
More significant to five strain cell inhibitory activities, inhibitory activity is better than positive control (cis-platinum).
Example of formulations:
Example of formulations 1:
Obtain tropinone derivative 13 by what the method for preparation embodiment 1 prepared, after dissolving with a small amount of DMSO, press
Routine injects uses water, and essence filter, parenteral solution is made in embedding sterilizing.
Example of formulations 2:
First prepare the arbitrary compound of tropinone derivative 13 or two or three by the method for preparation embodiment 1 to mix
Close, after dissolving with a small amount of DMSO, be dissolved in sterile water for injection, be stirred to dissolve, filter with aseptic suction funnel, then
Aseptic essence filter, is sub-packed in ampoule, and after frozen drying, aseptic sealing by fusing obtains powder-injection.
Example of formulations 3:
First prepare the arbitrary compound of tropinone derivative 13 or two or three by the method for preparation embodiment 1 to mix
Close, add excipient with excipient weight than the ratio for 9:1 in it, make pulvis.
Example of formulations 4:
First prepare by the method for preparation embodiment 1 and obtain the arbitrary compound of tropinone derivative 13 or two kinds or three
Plant mixing, add excipient, pelletizing press sheet with excipient weight than the ratio for 5:1 in it.
Example of formulations 5:
The arbitrary compound of tropinone derivative 13 or two or three first prepared by the method for preparation embodiment 1
Mixing, oral liquid preparation method makes oral liquid routinely.
Example of formulations 6:
The arbitrary compound of tropinone derivative 13 or two or three first prepared by the method for preparation embodiment 1
Mixing, adds excipient with excipient weight than the ratio for 5:1 in it, makes capsule.
Example of formulations 7:
First prepare the arbitrary compound of tropinone derivative 13 or two or three mixing by the method for preparation embodiment 1, press
It adds excipient with excipient weight than the ratio for 3:1, makes capsule.
Example of formulations 8:
The arbitrary compound of tropinone derivative 13 or two or three first prepared by the method for preparation embodiment 1
Mixing, adds excipient with excipient weight than the ratio for 5:1 in it, makes granule.
Claims (9)
1. the tropinone derivative 13 shown in following structural formula or its pharmaceutical salts,
2. tropinone derivative 13 as claimed in claim 1 or its pharmaceutical salts, it is characterised in that wherein said pharmaceutical salts is
Refer to pharmaceutically acceptable salt, and organic acid such as tartaric acid or citric acid or formic acid or ethanedioic acid, or with inorganic acid example hydrochloric acid
Or the salt that sulfuric acid or phosphoric acid are formed.
3. pharmaceutical composition, containing the tropinone derivative 13 described in claim 1 or its pharmaceutical salts and pharmaceutically suitable carrier or tax
Shape agent.
4. the method for preparation tropinone derivative 13 described in claim 1, it is characterised in that tropinone and benzaldehyde or 3 bromines
Benzaldehyde or 2 methoxybenzaldehydes react to end under catalyst n aOH effect in ethanol solution, and reactant liquor is used
5% watery hydrochloric acid regulation pH=7, decompression is distilled off ethanol, with the diluted ethyl acetate of 3 times of volumes, uses unsaturated carbonate hydrogen successively
Sodium water solution and saturated aqueous common salt washing, organic phase anhydrous sodium sulfate is dried, and decompression and solvent recovery obtains crude product；Crude product is through silicagel column
Chromatography, elutes to obtain tropinone derivative 13 with diethylamine ethyl acetate petroleum ether.
5. the method preparing tropinone derivative 13 as claimed in claim 4, it is characterised in that tropinone 2mmol and 5mL
The 10%NaOH aqueous solution is dissolved in 15mL absolute ethyl alcohol, under condition of ice bath, slowly drips benzaldehyde or 3 bromobenzaldehydes or 2 methoxies
Benzaldehyde 4.4mmol, TLC detection terminates to reaction, and decompression is distilled off ethanol, and reactant liquor, with 3 times of diluted ethyl acetate, depends on
Secondary with 5% watery hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt aqueous solution washing, organic phase anhydrous sodium sulfate is dried, decompression
Distillation obtains crude product, and crude product, through silica gel column chromatography, diethylamine ethyl acetate petroleum ether=2:20:78 wash-out, prepares torr
Product ketone derivatives derivative 13.
6. tropinone derivative 13 described in claim 1 or its pharmaceutical salts are in the medicine of preparation treatment anti-tumor disease
Application.
7. tropinone derivative 13 described in claim 2 or its pharmaceutical salts are in the medicine of preparation treatment anti-tumor disease
Application.
8. the pharmaceutical composition described in claim 3 is treated in preparation or improves the application in the medicine of anti-tumor disease.
9. tropinone derivative 1-3 or its pharmaceutical salts described in claim 1 or 2 in preparation treatment or improve anti-leukocythemia, lung
Cancer, liver cancer, breast cancer, colon cancer medicine in application.
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| CN114748476A (en) * | 2021-01-08 | 2022-07-15 | 江苏九基生物科技有限公司 | Application of coumarin derivative containing piperidine in preparation of antitumor drugs |
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| CN1273973A (en) * | 1999-02-20 | 2000-11-22 | R·普弗雷格尔博士化学工厂股份有限公司 | Method of preparing endonortropine by using 9-benzyl-nortropine-3-one-perchlorate as intermediate and salt thereof |
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| CN108164529A (en) * | 2017-12-25 | 2018-06-15 | 三峡大学 | A kind of micromolecular inhibitor SLD9059 and its application in pharmacy |
| CN114748476A (en) * | 2021-01-08 | 2022-07-15 | 江苏九基生物科技有限公司 | Application of coumarin derivative containing piperidine in preparation of antitumor drugs |
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Application publication date: 20160907 |