CN111171016A - Pharmaceutical use of indole alkaloids and derivatives thereof - Google Patents
Pharmaceutical use of indole alkaloids and derivatives thereof Download PDFInfo
- Publication number
- CN111171016A CN111171016A CN202010012271.4A CN202010012271A CN111171016A CN 111171016 A CN111171016 A CN 111171016A CN 202010012271 A CN202010012271 A CN 202010012271A CN 111171016 A CN111171016 A CN 111171016A
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- China
- Prior art keywords
- vinpocetine
- composition
- preparation
- derivative
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- 150000002475 indoles Chemical class 0.000 title abstract description 5
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- 238000002360 preparation method Methods 0.000 claims abstract description 26
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- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000003322 phosphorimaging Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical class C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960002726 vincamine Drugs 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
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Abstract
Pharmaceutical use of indole alkaloids and derivatives thereof. The invention belongs to the fields of pharmaceutical chemistry, pharmacology and preparations, and relates to the application of vinpocetine derivatives in treating or preventing diseases caused by ischemic cerebrovascular diseases, cerebral arteriosclerosis, hypertension, hemorrhagic stroke sequelae, hyperviscosity and cerebral ischemia; relates to a vinpocetine derivative used for preparing a cerebral vasodilator, a composition for improving ischemic cerebrovascular disease focus parts and peripheral blood supply and a composition for improving cerebral blood oxygen utilization rate.
Description
The technical field is as follows:
the invention belongs to the fields of medicinal chemistry, pharmacology and preparations, relates to pharmaceutical application of indole alkaloids and derivatives thereof, in particular to preparation, pharmacological action mechanism research, application and preparation of a vinpocetine derivative, and relates to treatment and prevention of diseases caused by ischemic cerebrovascular diseases by the vinpocetine derivative.
Background art:
cerebrovascular disease (CVD) refers to a disease in which a cerebral artery or a neck artery that governs a brain is diseased, thereby causing intracranial blood circulation disorder and brain tissue damage, and is a common disease and frequently encountered disease that endangers human health at present. Due to the characteristics of high morbidity, high disability rate and high recurrence rate, the traditional Chinese medicine is a main disease causing death and disability of the middle-aged and the elderly. In the ranking of human death causes, cerebrovascular diseases are always listed in the first three, and become one of the main causes of human death.
Currently, the clinical treatments for ischemic cerebrovascular diseases include etiological treatment, conventional internal treatment (involving drugs), drug therapy, nerve intervention therapy, and stem cell transplantation, but the most common treatment methods are still drug therapy. There are two main mechanisms of action for drug therapy: one is mainly to improve cerebral circulation, such as dilating cerebral vessels in ischemic areas, improving blood rheological property and microcirculation; the other is mainly to improve brain metabolism, such as activating brain metabolism and nourishing brain tissue. In the 80 s, some medicines which improve cerebral circulation and cerebral metabolism are discovered, the effects of the medicines are different, and the clinical application range of the medicines is also different. The domestic commonly used medicines include Vinpocetine (vinpocetin, kalan), Idebenone (Idebenone, yaban Avan), Xinnaoshutong, sodium alginate diester (PSS), and the like. The vinpocetine is used as a drug for dilating cerebral vessels, is widely applied to treating and preventing ischemic cerebrovascular diseases, has comprehensive treatment effect and wide application prospect, and is well valued by domestic scholars.
Vinpocetine (Vinpocetine) is a semisynthetic derivative of vinblastine (Vincamine), an indole alkaloid extracted from vinca minor (Vincominor) of apocynaceae, also known as apovincamin ethyl ester, and has a chemical name of (3 α,16 α) -eburnine-14-carboxylic acid ethyl ester, developed by the Gedeon Richter pharmaceutical company of Hungary, and marketed in 1978, the Vinpocetine has a good lipid solubility and is easy to penetrate through the blood brain barrier to enter brain tissues, since marketed, the Vinpocetine has become a conventional drug for treating cerebrovascular diseases, is clinically used for treating and preventing diseases caused by ischemic cerebrovascular diseases, is a cerebral vasodilator, marketed in Japan, has a commercial name of Kalan (Calan), other foreign commercial names of Kashitong (Cavinton), and the commercial names of northwest origin of northeast China are Changchun tablets, and the Vinpocetine tablet developed by the northeast pharmaceutical general pharmaceutical factories of the east China has been approved in 1993 and brought into the countries and has been used as a pharmaceutical for improving cerebral ischemia and cerebral hemorrhage sequelae of brain regions, and can be used as a drug for improving cerebral ischemia and cerebral ischemia sequelae.
The invention mainly carries out structural modification on the ester group part of the vinpocetine, and finds that the activity of the derivative is superior to that of the vinpocetine derivative through in vitro molecular level, cell level and in vivo animal level researches.
Technical scheme
The invention relates to pharmaceutical applications of indole alkaloids and derivatives thereof.
The invention particularly relates to preparation, pharmacological action mechanism research, application and preparation of a vinpocetine derivative.
The invention relates to a composition of vinpocetine derivatives for treating and preventing diseases caused by ischemic cerebrovascular diseases.
The invention relates to a vinpocetine derivative, which has a structural general formula as follows:
r is selected from A type
Type B
Type C
Type D
Type E
Type F
Type G
H type
Any one of them.
The invention relates to a vinpocetine derivative, which has the following structure:
the vinpocetine derivative is used for preparing a composition for treating or preventing and treating diseases caused by ischemic cerebrovascular diseases.
The vinpocetine derivative is used for preparing the cerebral vasodilator.
The vinpocetine derivative is used for preparing the composition for improving ischemic cerebrovascular disease focus positions and peripheral blood supply.
The vinpocetine derivative is used for preparing a composition for treating or preventing cerebral arteriosclerosis.
The vinpocetine derivative is used for preparing a composition for treating or preventing hypertension.
The vinpocetine derivative is used for preparing a composition for treating or preventing hemorrhagic stroke sequelae.
The vinpocetine derivative is used for preparing a composition for treating or preventing the hyperviscosity.
The vinpocetine derivative is used for preparing a composition for treating or preventing cerebral ischemia.
The vinpocetine derivative is used for preparing the composition for improving the cerebral blood oxygen utilization rate.
The composition of the vinpocetine derivative comprises 0.01-500mg of the vinpocetine derivative.
The composition of the vinpocetine derivative comprises 0.1-200mg of the vinpocetine derivative per preparation unit.
The invention relates to a composition of vinpocetine derivative, which contains 1-100mg of vinpocetine derivative per preparation unit.
The vinpocetine derivative of the invention: the method is characterized in that: the auxiliary materials in the field are adopted to prepare the medicine and the health care product.
The composition of the vinpocetine derivative comprises capsules, tablets, granules, pellets, sustained-release capsules, freeze-dried powder, injection and the like.
Pharmacodynamic experiment of the present invention the pharmacodynamic experiment of the present invention:
pharmacodynamic experiment I: in vitro research on PDE1A enzyme inhibition effect of compound I, experimental instrument and reagent material
(1) Instrument for measuring the position of a moving object
A FORMA 700 model ultra-low temperature refrigerator, Thermo corporation; YC-300L type medicine storage cabinet, Mitsubishi low temperature science and technology, Inc., of China; Direct-Q with pump type ultrapure water instrument, Millopore corporation; SW-CJ-2FD type superclean bench: suzhou clarification plant, Inc.;
f200 PRO filter type multifunctional microplate reader, Tecan corporation; phosphorimaging, Bio-rad, USA.
(2) Reagent material
BMS-345541(Sigma, St.Louis, MO, USA), MOPS, Proclin 200 and DL-Dithioprimer (DTT) (Sigma, St.Louis, MO, USA), Fluorescein (FAM) -cycle-3 ',5' -AMPand Enzyme-IMAP Assays Kit (Molecular Devices Inc, CA, USA), PDE1A (BPSBioscience Inc, San Diego, CA), [ gamma-32P ] ATP (MP Biomedicals, Irvine, CA, USA), PMSF (Sigma, St.Louis, MO, USA), GST-Ikappa B α (Cell Signaling Technology Inc, Beverly, MA, USA).
Second, Experimental methods
PDE1A enzyme activity assay: preparing a phosphodiesterase reaction system: the reagent in the Enzyme-IMAP Assays kit was formulated as a solution containing 40mM MOPS, pH 7.5,0.5mM EDTA, 15mM MgCl2, 0.15mg/mL BSA, 1mM DTT, 0.05% Proclin 200,15ng/mL PDE1A and 100nM FAM-cyclic-3',5' -AMP, in a final volume of 50. mu.L. Preparing a tested medicine: after dissolving the test compound in 10% DMSO, it was diluted to the desired working concentration, and 5. mu.L of the dilution was added to 50. mu.L of the reaction mixture, so that the drug concentration in all reactions was 0.1. mu.M, 1. mu.M, 10. mu.M, 50. mu.M, 100. mu.M, and the DMSO content in the final reaction solution was 1%. As a kinase control well, 5. mu.L of distilled water containing 1% DMSO was added to the kinase reaction system. Meanwhile, the reaction system of the blank control hole does not contain PDE 1A. After incubating the reaction mixture at 25 ℃ for 1 hour, 100. mu.L of diluted binding agent was added to each well, followed by incubation at 25 ℃ for 1 hour with slow shaking. The polarized Fluorescence (FP) of the sample was measured using an excitation filter at 360nm and an emission filter at 480 nm. Percent inhibition was calculated using the following formula: the inhibition rate [1- (FP drug-FP control)/(FP enzyme-FP control) ] × 100%. IC50 values were calculated using GraphPad Prism software to fit a nonlinear regression curve.
Table, experimental results
Note:*P<0.05,**P<0.01vs Vinpocetine
the experimental results show that: the invention evaluates the inhibitory activity of PDE1A in vitro on a series of vinpocetine derivatives, and the result shows that the compounds 1-13 have obvious inhibitory activity to PDE1A, and the inhibitory activity of the derivative 13 with the best inhibitory activity is 11 times that of the vinpocetine.
And a second pharmacodynamic experiment: effect of vinpocetine derivatives on OGD/R model-mediated endothelial cell tubule formation
First, experimental instrument and reagent material
(1) Laboratory apparatus
SB-5200DT ultrasonic cleaning apparatus (Ningbo Xinzhi Biotechnology GmbH); YC-300L type drug storage cabinet (Mike Mitsubishi, Tegaku, Ltd.); GZX-9140MBE type forced air drying cabinet (Shanghai Boxun practice Co., Ltd.) medical equipment factory; a three gas incubator (Thermo corporation); SHZ-III type circulating water pump (tokyo kol instruments ltd); Direct-Q with pump type ultrapure water meter (Millopore Corp.); BS224 type electronic balance (beijing seudolis instruments systems limited); model 78-1 magnetic stirrers (Changzhou Guohua appliances Co., Ltd.); low temperature high speed centrifuge model 3K15 (Sigma company); TCL-16G-A type high speed refrigerated centrifuge (Shanghai' an Tint scientific Instrument factory); forma 3111 type water jacketed CO2 incubator (Thermo Electron company); model SW-CJ-2FD ultra-clean bench (suzhou clean-up facilities ltd); YXQ-LS-50 SII model vertical pressure steam sterilizer (Shanghai Boxun Industrial medical facility).
(2) Experimental reagent
Vinpocetine (Vinpocetine) (Sigma-Aldrich, st. louis, MO, USA); endothelial Cell Growth Supplements (ECGS), heparin and sodium dithionite (Sigma-Aldrich, st. louis, MO, USA); glucose (Glu) (national drug group chemical agents limited); penicillin (Sigma-Aldrich, st. louis, MO, USA); streptomycin (Sigma-Aldrich, st. louis, MO, USA); trypsin (Gibco, Grand Island, NY, USA); matrigel (Sigma-Aldrich, st. louis, MO, USA); ECM medium (ScienCell,1001, CA, USA); fetal Bovine Serum (FBS) (Hyclone, Logan, UT, USA).
(3) Experimental cell lines
HUVEC cell line was purchased from American Tissue Culture Collection (ATCC, Rockville, Md., USA).
Second, Experimental methods
(1) Human Umbilical Vein Endothelial Cells (HUVECs) culture
The cells are subcultured for 3-8 passages under the condition of ECM culture medium containing penicillin (final concentration of 100U/mL), streptomycin (final concentration of 100. mu.g/mL), heparin (final concentration of 0.1mg/mL), ESGS (final concentration of 0.05mg/mL) and 10% FBS, when the cells are fused to 90%, the old culture medium is discarded, the cells are washed with 2mL of PBS for 2 times, the PBS is discarded, 2mL of 0.25% trypsin-0.02% EDTA mixed digestion solution is added, the cells are observed under a microscope for about 30s, when the cells are rounded, 2mL of complete culture medium is rapidly added to stop digestion, the cells are lightly blown and collected. Centrifuging at 800rpm and 4 deg.C for 5min, discarding supernatant, suspending cells with complete culture medium, culturing in bottles, and changing the culture medium every other day.
(2) Vascular endothelial cell tubule formation experiment
The effect of compounds on the ability of HUVECs to form microvascular lumens was studied using a tubule formation experiment, which was essentially performed as follows:
1. melting glue: before the experiment, the Matrigel stock solution is transferred from a refrigerator at the temperature of-20 ℃ to a refrigerator at the temperature of 4 ℃ for melting overnight, meanwhile, the gun head is placed in the refrigerator at the temperature of-20 ℃ for precooling, and is taken out and placed on ice 30min before the experiment.
2. Spreading glue: adding 50 mu L of melted Matrigel glue into each hole of a 96-hole plate, gently operating to avoid the generation of bubbles, gently shaking the 96-hole plate to be flattened by the glue, and then standing the 96-hole plate in an incubator at 37 ℃ to incubate for 30-60min to fully solidify the Matrigel glue.
3. Cell pretreatment: HUVEC cells at 3X 10 per well5And (4) inoculating the number of the cells in a 6-well plate, removing the culture medium when the cell density in the well reaches 80% -90%, and starting to prepare the OGD/R model. The medium was first changed to ECM medium without glucose and serum, while the cells were placed in 5% CO2、95％N2Culturing in a three-air culture box for 2h to complete the anoxic process; the cell culture medium was then replaced with ECM medium containing heparin (final concentration of 0.1mg/ml), ESGS (final concentration of 0.05mg/ml), 5% FBS, while the cells were placed in an ECM medium containing 5% CO2、20％O2Culturing in an incubator for 24h to complete the reoxygenation process, and simultaneously adding complete culture medium containing vinpocetine derivatives (with concentration of 0, 2, 10 and 50 μ M) respectively.
4. Implanting cells: digesting and centrifuging the pretreated HUVEC cells by the method under 3.3 items, collecting, re-suspending with serum-free medium, counting, and adjusting the cell density in the serum-free medium to be 2 × 105Per mL; pipette 100. mu.L of single cell suspension gently into the wells of a 96-well plate without touching the gel surface, set three wells per well, and then place the 96-well plate in an incubator for incubation at 37 ℃ for 6 h.
5. Shooting: after incubation for 2h, the tube cavity forming state of the tubule is closely observed, and after the tube cavity is completely formed after culture for 6h, the 96-well plate is taken out and photographed under a microscope.
6. And (3) analysis: the length of the lumen branches formed by each group of cells was analyzed by Image PRO PLUS software, and the experiment was repeated three times.
7. And (3) data statistics: results are expressed in mean ± SD format. Statistical differences between data groups using the two-way anova and Sidak's test, P values less than 0.05 were considered significant differences.
Third, experimental results
Vinpocetine and its derivatives were chosen to see if they could effectively promote the OGD/R model-mediated tubule formation of vascular endothelial cells. The Matrigel cell tube forming experiment is a common experiment for observing the capability of external stimulation influencing vascular endothelial cells to form a tubular structure, is a rapid and quantifiable method for measuring angiogenesis in vitro, and can carry out quantitative analysis on a tubule forming result through software. Therefore, to confirm whether the vinpocetine derivative can effectively promote the small tube formation of the vascular endothelial cells mediated by the OGD/R model, a Matrigel stromal cell tube forming experiment is selected, and the influence of the vinpocetine derivative on the lumen forming capability of Human Umbilical Vein Endothelial Cells (HUVEC) mediated by the OGD/R model is observed through an in vitro cytology experiment, and the results are as follows.
Table: effect of vinpocetine derivatives on human umbilical vein endothelial cell tubule formation
Note:**P<0.01vs OGD/R group,##P<0.01vs Vinpocetine group.
in the tubule forming experiment, the length of tubules of different experimental groups takes OGD/R group as 1, and the length of tubules of each experimental group is expressed as a multiple of the OGD/R group, namely relative length. The number of small tube formation in the OGD/R group is obviously reduced compared with that in the normal control group, and the small tube formation in the OGD/R group is aggregated into a mass. Studies have shown that vinpocetine and its derivatives are able to promote vascular endothelial cell tubule formation in each dose group, and are dose-dependent with statistical significance for the differences between groups (P <0.01), surprisingly compared to the OGD/R group. Compared with the vinpocetine group, the different derivatives have stronger tubule forming ability at each dose than the vinpocetine group, wherein the effects of the derivatives 13, 8 and 3 are most obvious, and the tubule forming ability at each dose is remarkably different from that of the vinpocetine group (P < 0.01). When the concentration of derivative 13 reached 50. mu.M, the relative length of tubule formation was comparable to that of the normal group.
Description of the drawings:
FIG. 1: effect of vinpocetine derivatives on the ability of Human Umbilical Vein Endothelial Cell (HUVEC) microvascular lumen formation mediated by the OGD/R model
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Preparation of Compound 1
a.N2H4·H2O,EtOH,reflux；b.isothiocyanates,THF,rt；
c.BrCH2CO2C2H5,AcONa,EtOH,reflux.
Vinpocetine 3.15g (9mmol) was dissolved in 50mL of absolute ethanol, 5.46mL (90mmol) of hydrazine hydrate (80%) was added, the reaction was heated under reflux for 6 hours, and the reaction was monitored by TLC. And (3) after the reaction is complete, cooling, evaporating half of the solvent, adding saturated saline (20mL), separating out a precipitate, filtering, collecting a crude product SW-1, extracting the filtrate by using ethyl acetate to obtain all target products, drying an organic layer, concentrating, combining the concentrated filtrate with the precipitate obtained by filtering, and recrystallizing by using petroleum ether/ethyl acetate to obtain the target product F-1 with the yield of 91%.
F-1(0.6mmol) and p-fluorobenzene isothiocyanate (0.66mmol) were added sequentially to tetrahydrofuran solution (5mL) and reacted at room temperature for 5h, monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, distilled water (15mL) was added, ethyl acetate (15 mL. times.3) was added for extraction, the organic layers were combined, washed with saturated NaCl (45mL), and anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure, and separating by column chromatography (dichloromethane/methanol/ammonia 16/1/0.17) (v/v) to give F-2 as a yellow solid in 85% yield.
F-2(0.3mmol) was added to a solution of anhydrous ethanol (5mL) in succession with ethyl bromoacetate (33. mu.L, 0.3mmol) and sodium acetate (98mg,1.2 mmol), and the mixture was heated under reflux for 5h and monitored by TLC. After the reaction was complete, the solvent was evaporated to dryness, distilled water (10mL) was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic layers were combined, back washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering to remove desiccant, and concentrating the solution under reduced pressure. Column chromatography (dichloromethane/methanol 35/1) (v/v) gave compound 1 as a yellow solid in 71% yield.1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.1Hz,1H), 7.44(m,1H),7.37(m,1H),7.20(t,J＝8.4Hz,1H),7.13–7.06(m,2H),7.00(d,J＝ 8.0Hz,2H),5.99(s,1H),4.17(s,1H),3.88(br s,2H),3.35(dd,J＝13.7,5.8Hz,1H), 3.25(td,J＝11.2,5.2Hz,1H),3.04–2.99(m,1H),2.63–2.60(m,2H),2.49(ddd,J ＝16.3,5.1,2.2Hz,1H),1.90(q,J＝7.3Hz,2H),1.69(m,1H),1.48(d,J＝13.6Hz, 1H),1.38–1.32(m,1H),1.05–0.93(m,1H),0.98(t,J＝7.4Hz,3H).13C NMR (100MHz,CDCl3)δ167.92,162.17,160.32(d,JCF＝242.5Hz),142.98,133.81, 130.55,129.80,129.03(d,JCF＝7.0Hz),124.58,123.44,122.50(d,JCF＝8.3Hz), 120.67,118.32,116.72(d,JCF＝23.3Hz),116.28(d,JCF＝22.5Hz),112.84,109.22, 55.92,51.62,45.09,37.79,30.36,29.21,27.24,20.38,16.45,8.84.HRMS calculated for C29H28FN5O2S:529.1948,found 530.2020[M+H]+.
Preparation of Compound 2
a.NH2OH·HCl,Et3N,EtOH,reflux；b.C2H5ONa,EtOH,reflux.。
3-cyanopyridine (2mmol), hydroxylamine hydrochloride (153mg,2.2mmol) and triethylamine (305. mu.L, 2.2mmol) were added sequentially to anhydrous ethanol (10mL), heated under reflux for 3h and monitored by TLC. After the reaction was complete, the solvent was evaporated to dryness, distilled water (20mL) was added, ethyl acetate (20 mL. times.3) was extracted, the organic layers were combined, back washed with saturated NaCl (60mL), anhydrous Na2SO4Drying, filtering to remove a drying agent, and concentrating the solution under reduced pressure to obtain F-3 which is directly used for the next reaction.
Vinpocetine (105mg,0.3mmol), F-3(0.36mmol) and sodium ethoxide (41mg,0.6 mmol) were added sequentially to anhydrous ethanol (4mL), heated at reflux for 10h and monitored by TLC. After the reaction was complete, the solvent was evaporated to dryness, distilled water (10mL) was added, ethyl acetate (10 mL. times.3) was extracted, the organic layers were combined, back washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol 45/1) (v/v) gave compound 2 as a yellow solid in 72% yield.1H NMR(400MHz,Chloroform-d)δ9.40(dd,J＝2.2,0.8Hz,1H),8.78(dd, J＝4.9,1.7Hz,1H),8.43(dt,J＝8.0,1.9Hz,1H),7.51–7.44(m,2H),7.17–7.08 (m,2H),6.87(m,1H),6.24(s,1H),4.28(s,1H),3.42–3.27(m,2H),3.07(m,1H), 2.70–2.66(m,2H),2.57(ddd,J＝16.4,4.9,2.2Hz,1H),2.04–1.92(m,2H),1.79 (m,1H),1.64(dt,J＝13.6,3.2Hz,1H),1.47(m,1H),1.17(td,J＝13.6,3.7Hz,1H), 1.05(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ172.47,167.07, 152.45,148.88,134.98,133.99,130.80,129.30,128.79,123.86,122.91,122.56, 122.41,120.84,118.66,112.16,109.75,55.76,51.45,44.95,38.46,28.84,27.36, 20.38,16.49,8.89.HRMS calculated for C26H25N5O:423.2059,found 424.2132 [M+H]+.
Preparation of Compound 3
a.N2H4·H2O,EtOH,reflux；b.isothiocyanates,THF,rt；c.2N NaOH(aq),reflux.
F-1(0.6mmol) and methyl isothiocyanate (0.66mmol) were added sequentially to a tetrahydrofuran solution (5mL) and reacted at room temperature for 5h, monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, distilled water (15mL) was added, ethyl acetate (15 mL. times.3) was added for extraction, the organic layers were combined, washed with saturated NaCl (45mL), and anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol/ammonia ═ 16/1/0.17) (v/v) to give F-4 as a yellow solid in 81% yield.
F-4(0.2mmol) was added to 2N aqueous NaOH (3mL) and the reaction was heated at reflux for 5h and monitored by TLC. After the reaction was complete, dilute hydrochloric acid was added to neutralize to neutrality, extraction was performed with ethyl acetate (10 mL. times.3), the organic layers were combined, back washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol-35/1) (v/v) gave compound 3 as a yellow solid in 83% yield.1H NMR(400MHz,DMSO-d6)δ7.45(m,1H),7.07–6.99(m,2H),6.11(m,1H),5.69(s,1H),4.25(s,1H),3.36(br s,1H),3.26–3.14(m,2H), 3.18(s,3H),2.93(m,1H),2.58–2.42(m,3H),1.89–1.75(m,2H),1.65–1.53(m, 2H),1.37(m,1H),1.03(td,J＝13.6,3.6Hz,1H),0.94(t,J＝7.4Hz,3H).13C NMR (100MHz,DMSO-d6)δ167.53,146.49,132.69,130.66,128.63,124.69,122.27, 120.73,120.34,118.79,108.91,108.54,54.89,50.83,44.62,37.34,30.49,29.27, 26.52,19.98,15.84,8.51.HRMS calculated for C22H25N5S:391.1831,found 392.1914[M+H]+.
Preparation of Compounds 4-7
a.LiAlH4,dry THF,rt；b.isothiocyanates,NaH(60％),dry THF,rt.
Vinpocetine (700mg,2mmol) was dissolved in anhydrous THF (15mL) and LiAlH was added slowly at 0 deg.C4(152mg,4mmol), reaction at room temperature for 10 hours, and reaction monitored by TLC. Adding ethyl acetate to quench the reaction when the reaction is complete, adding 15% NaOH aqueous solution (10mL), adding diatomite into a suction filter funnel, filtering, adding distilled water (10mL) into the filtrate, extracting with ethyl acetate (20mL multiplied by 3), combining organic layers, backwashing with saturated NaCl (60mL), and adding anhydrous Na2SO4Drying and recrystallization from ethyl acetate gave intermediate F-5 in 93% yield.
F-5(62mg,0.2mmol) was dissolved in anhydrous THF (2mL), NaH (60%) (9mg,0.22mmol) was added slowly at 0 deg.C, stirring was continued for 20min, and after addition of isothiocyanate (0.22mmol), the reaction was allowed to proceed at room temperature for 6h, monitored by TLC. When the reaction was complete, the reaction was quenched with distilled water (10mL), extracted with ethyl acetate (10 mL. times.3), the organic layers were combined, back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering to remove desiccant, and concentrating the solution under reduced pressure. And (5) performing column chromatography separation (dichloromethane/methanol) (v/v) to obtain the compounds 4-7 which are all yellow solids. Compound 4:1H NMR (400MHz,Chloroform-d)δ12.34(br s,1H),7.58(t,J＝7.8Hz,1H),7.39(d,J＝8.4 Hz,1H),7.35(d,J＝7.7Hz,1H),7.30–7.26(m,1H),7.23–7.18(m,2H),7.16– 7.10(m,2H),6.04(d,J＝12.8Hz,1H),5.23(s,1H),4.89(d,J＝12.8Hz,1H),3.92(s, 1H),2.40–2.37(m,3H),2.20–2.16(m,1H),1.90–1.76(m,3H),1.39–1.27(m, 2H),1.23–1.16(m,2H),1.05–0.97(m,1H),1.03(t,J＝7.4Hz,3H).13C NMR (100MHz,Chloroform-d)δ189.65,156.96(d,JCF＝247.1Hz),133.98,130.89, 129.76,128.91,128.45(d,JCF＝7.9Hz),126.86,126.74,124.44(d,JCF＝3.8Hz),122.93,120.27,119.86,118.36,116.34(d,JCF＝19.7Hz),112.22,108.46,69.94, 55.55,49.18,44.71,37.12,28.51,26.96,19.91,15.65,8.64.HRMS calculated for C27H28FN3OS:461.1937,found 462.2012[M+H]+compound 5:1H NMR(400MHz, Chloroform-d)δ12.09(br s,1H),7.46–7.42(m,2H),7.36(t,J＝8.0Hz,2H),7.21(t, J＝7.0Hz,1H),7.10(m,3H),6.04(d,J＝12.8Hz,1H),5.21(s,1H),4.86(d,J＝12.8Hz,1H),3.92(s,1H),2.48–2.32(m,3H),2.24–2.20(m,1H),1.88–1.72(m, 3H),1.42–1.18(m,4H),1.04–0.96(m,1H),1.02(t,J＝7.4Hz,3H).13C NMR (100MHz,Chloroform-d)δ188.59,160.75(d,JCF＝244.5Hz),134.95(d,JCF＝3.0 Hz),133.93,130.96,129.75,128.94,126.56(d,JCF＝8.2Hz),122.86,120.28,119.67, 118.41,115.93(d,JCF＝22.6Hz),112.19,108.45,69.60,55.41,49.41,45.03,37.12, 28.69,27.09,20.14,15.65,8.70.HRMS calculated for C27H28FN3OS:461.1937, found 462.2010[M+H]+compound 6:1H NMR(400MHz,Chloroform-d)δ12.04(br s,1H),7.48(m,1H),7.37–7.32(m,3H),7.25–7.18(m,2H),7.12(t,J＝7.0Hz, 1H),6.95(t,J＝7.6Hz,1H),6.05(d,J＝12.9Hz,1H),5.23(s,1H),4.86(d,J＝12.9 Hz,1H),3.95(s,1H),2.49(t,J＝12.1Hz,1H),2.39–2.30(m,3H),1.90(m,1H), 1.82–1.74(m,2H),1.41(d,J＝13.2Hz,2H),1.29(m,1H),1.15(m,1H),1.04– 0.98(m,1H),1.02(t,J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ187.77, 162.87(d,JCF＝244.2Hz),140.55(d,JCF＝10.6Hz),133.90,130.81,130.08(d,JCF＝9.2Hz),129.80,129.00,122.88,120.29,119.77,119.44(d,JCF＝1.3Hz),118.45, 112.92(d,JCF＝20.8Hz),112.13,111.50(d,JCF＝24.6Hz),108.51,69.62,55.41, 49.44,45.09,37.18,28.85,27.08,20.18,15.65,8.71.HRMScalculated for C27H28FN3OS:461.1937,found462.2007[M+H]+compound 7:1H NMR(400MHz,Chloroform-d)δ9.45(br s,1H),7.30(d,J＝7.6Hz,1H),7.24(d,J＝8.4Hz,1H), 7.13(td,J＝8.4,1.4Hz,1H),7.06(t,J＝7.0Hz,1H),5.95(d,J＝11.7Hz,1H),5.11 (s,1H),4.72(d,J＝11.7Hz,1H),4.10(m,1H),3.83(s,1H),2.44(td,J＝12.2,3.0 Hz,1H),2.39–2.28(m,3H),2.16(d,J＝11.8Hz,1H),2.08(d,J＝11.8Hz,1H), 1.81–1.76(m,2H),1.72–1.66(m,3H),1.54–1.42(m,2H),1.41–1.35(m,2H), 1.32–1.26(m,2H),1.14–1.05(m,3H),1.03–0.99(m,1H),0.97–0.97(m,1H), 0.94(t,J＝7.5Hz,3H).13C NMR(100MHz,Chloroform-d)δ187.41,133.78, 130.88,130.13,129.00,122.50,119.96,119.32,118.22,112.29,108.31,69.31,55.15, 54.76,49.59,44.69,36.96,32.58,32.51,29.15,26.98,25.79,25.45,20.28,15.62, 8.60.HRMS calculated for C27H35N3OS:449.2501,found 450.2578[M+H]+.
preparation of Compound 8
Compound F-1(0.6mmol) and m-methylbenzene isothiocyanate (0.66mmol) were added sequentially to a tetrahydrofuran solution (5mL) and reacted at room temperature for 5h, monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, distilled water (15mL) was added, ethyl acetate (15 mL. times.3) was added for extraction, the organic layers were combined, washed with saturated NaCl (45mL), and anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol/ammonia 15/1/0.17) (v/v) gave compound 8 as a yellow solid in 88% yield.1H NMR(400MHz,Acetone-d6)δ9.44(s,1H),7.48–7.39(m,4H), 7.22(t,J＝7.8Hz,1H),7.05–6.97(m,3H),6.04(s,1H),4.17(s,1H),3.30–3.19 (m,2H),2.98(m,1H),2.61–2.59(m,2H),2.43(ddd,J＝15.9,4.8,2.3Hz,1H),2.31 (s,3H),1.88(q,J＝7.4Hz,2H),1.64(m,1H),1.53(dt,J＝13.8,3.2Hz,1H),1.38– 1.33(m,1H),1.03–0.95(m,1H),0.98(t,J＝7.3Hz,3H).13C NMR(100MHz, Acetone-d6)δ183.02,163.91,139.77,139.10,134.78,131.32,131.23,130.80,129.80, 129.24,126.86,125.82,123.23,122.45,120.84,118.73,114.07,109.07,56.65,52.14, 45.76,38.08,30.07,27.91,21.42,20.94,16.88,8.96.HRMS calculated for C28H31N5OS:485.2249,found 486.2319[M+H]+.
Preparation of Compound 9
a.N2H4·H2O,EtOH,reflux；b.isothiocyanates,THF,rt；c.IBX,Et3N,DCM,0℃.
Compound F-1(0.6mmol) and hydrogen furfuryl isothiocyanate (0.66mmol) were added sequentially to a tetrahydrofuran solution (5mL) and reacted at room temperature for 5h, monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, distilled water (15mL) was added, ethyl acetate (15 mL. times.3) was added for extraction, the organic layers were combined, washed with saturated NaCl (45mL), and anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure, and separating by column chromatography (dichloromethane/methanol/ammonia 15/1/0.17) (v/v) to give F-6 as a yellow solid in 92% yield.
F-6(0.2mmol) was added to dichloromethane (3mL) sequentially with 2-iodoxybenzoic acid (56mg,0.2mmol) and triethylamine (55. mu.L, 0.4mmol) and reacted at 0 ℃ for 10 min with TLC monitoring. When the reaction was complete, the reaction was quenched by addition of saturated sodium bicarbonate, extracted with dichloromethane (10 mL. times.3), the combined organic layers were back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol 45/1) (v/v) gave compound 9 as a brown solid in 81% yield.1H NMR(400MHz,Chloroform-d)δ7.45(dd,J＝6.2,1.5 Hz,1H),7.26–7.05(m,2H),6.79(m,1H),5.80(s,1H),5.64(br s,1H),4.20(s,1H), 4.10(m,1H),3.85(m,1H),3.75(m,1H),3.60(m,1H),3.38–3.22(m,3H),3.02(m, 1H),2.64–2.58(m,2H),2.49(ddd,J＝16.5,5.1,2.3Hz,1H),2.02–1.96(m,1H), 1.95–1.85(m,4H),1.72(m,1H),1.62–1.52(m,2H),1.41(dt,J＝13.4,3.2Hz,1H), 1.12(td,J＝13.7,2.3Hz,1H),1.00(t,J＝7.4Hz,3H).13C NMR(100MHz, Chloroform-d)δ164.02,154.74,133.79,133.77,130.89,129.05,124.50,122.19, 122.14,121.68,121.64,120.42,118.49,118.47,111.65,111.57,108.96,68.32,68.29, 56.05,56.03,51.58,47.51,47.41,47.41,45.06,37.93,28.90,28.67,28.64,27.39, 25.96,25.93,20.47,16.48,8.77.HRMS calculated for C26H31N5O2:445.2478,found 446.2552[M+H]+.
Preparation of Compound 10
Compound F-1(0.6mmol) and p-bromobenzene isothiocyanate (0.66mmol) were added to tetrahydrofuran solution (5mL) in this order, reacted at room temperature for 5h, and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, distilled water (15mL) was added, ethyl acetate (15 mL. times.3) was added for extraction, the organic layers were combined, washed with saturated NaCl (45mL), and anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol/ammonia 15/1/0.17) (v/v) to give F-7 as a yellow solid in 94% yield.
F-7(0.2mmol) was added to dichloromethane (3mL) sequentially with 2-iodoxybenzoic acid (56mg,0.2mmol) and triethylamine (55. mu.L, 0.4mmol) and reacted at 0 ℃ for 10 min with TLC monitoring. When the reaction was complete, the reaction was quenched by addition of saturated sodium bicarbonate, extracted with dichloromethane (10 mL. times.3), the combined organic layers were back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol 40/1) (v/v) gave compound F-8 as a light brown solid in 91% yield.
Compound F-8(0.2mmol) was dissolved in anhydrous THF (2mL), NaH (60%) (9mg,0.22mmol) was added slowly at 0 deg.C, stirring was continued for 20min, iodomethane (12. mu.L, 0.2mmol) was added, and the reaction was allowed to proceed at room temperature for 3h, monitored by TLC. When the reaction was complete, the reaction was quenched with distilled water (10mL), extracted with ethyl acetate (10 mL. times.3), the organic layers were combined, back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering to remove desiccant, and concentrating the solution under reduced pressure. Column chromatography (dichloromethane/methanol 50/1) (v/v) gave compound 10 as a pale yellow solid in 85% yield.1H NMR(400 MHz,Chloroform-d)δ7.47(m,1H),7.39(d,J＝8.8Hz,2H),7.24(d,J＝8.9Hz, 2H),7.15–7.08(m,2H),6.76(m,1H),5.81(s,1H),4.24(s,1H),3.55(s,3H),3.37 (dd,J＝13.7,6.0Hz,1H),3.28(td,J＝12.0,5.2Hz 1H),3.03(m,1H),2.68–2.60 (m,2H),2.53(ddd,J＝16.4,5.0,2.2Hz,1H),1.98–1.85(m,2H),1.74(m,1H),1.56 (dt,J＝13.8,3.3Hz,1H),1.46–1.41(m,1H),1.15(td,J＝13.7,3.7Hz,1H),0.99(t, J＝7.4Hz,3H).13C NMR(100MHz,Chloroform-d)δ163.12,155.48,141.35, 133.69,132.45,130.68,129.06,124.88,124.55,122.20,121.43,120.60,118.97, 118.70,111.31,109.05,55.85,51.47,44.95,38.87,38.10,28.92,27.35,20.36,16.48, 8.82.HRMS calculated for C28H28BrN5O:529.1477,found530.1552[M+H]+.
Preparation of Compound 11
Compound F-1(0.6mmol) and o-bromobenzene isothiocyanate (0.66mmol) were added to tetrahydrofuran solution (5mL) in sequence, reacted at room temperature for 5h, and monitored by TLC. After the reaction was completed, the solvent was evaporated under reduced pressure, distilled water (15mL) was added, ethyl acetate (15 mL. times.3) was added for extraction, the organic layers were combined, washed with saturated NaCl (45mL), and anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure, and separating by column chromatography (dichloromethane/methanol/ammonia 15/1/0.17) (v/v) to give F-9 as a yellow solid in 97% yield.
F-9(0.2mmol) was added to dichloromethane (3mL) sequentially with 2-iodoxybenzoic acid (56mg,0.2mmol) and triethylamine (55. mu.L, 0.4mmol) and reacted at 0 ℃ for 10 min with TLC monitoring. When the reaction was complete, the reaction was quenched by addition of saturated sodium bicarbonate, extracted with dichloromethane (10 mL. times.3), the combined organic layers were back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering off the drying agent, concentrating the solution under reduced pressure and separating by column chromatography (dichloromethane/methanol 40/1) (v/v) gave compound F-10 as a light brown solid in 86% yield.
Compound F-10(0.2mmol) was dissolved in anhydrous THF (2mL), NaH (60%) (9mg,0.22mmol) was added slowly at 0 deg.C, stirring was continued for 20min, iodomethane (12. mu.L, 0.2mmol) was added, and the reaction was allowed to proceed at room temperature for 3h, monitored by TLC. When the reaction was complete, the reaction was quenched with distilled water (10mL), extracted with ethyl acetate (10 mL. times.3), the organic layers were combined, back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering to remove desiccant, and concentrating the solution under reduced pressure. Column chromatography (dichloromethane/methanol 50/1) (v/v) afforded compound 11 as a yellow solid in 80% yield.1H NMR(400 MHz,Chloroform-d)δ7.61(dd,J＝8.1,1.4Hz,1H),7.42(m,1H),7.36(dd,J＝7.9, 1.7Hz,1H),7.29(td,J＝7.7,1.5Hz,1H),7.16(td,J＝7.8,1.7Hz,1H),7.11–7.07 (m,2H),6.77(m,1H),5.77(s,1H),4.21(s,1H),3.49(s,3H),3.36(dd,J＝13.7,5.9 Hz,1H),3.25(td,J＝12.3,5.2Hz,1H),3.01(m,1H),2.66–2.60(m,2H),2.49(dd, J＝16.1,3.2Hz,1H),1.97–1.85(m,2H),1.73(m,1H),1.55(dt,J＝13.4,3.2Hz, 1H),1.44–1.39(m,1H),1.13(td,J＝13.7,3.7Hz,1H),0.99(t,J＝7.5Hz,3H).13C NMR(100MHz,Chloroform-d)δ163.67,155.70,141.07,134.17,133.72,130.65, 129.99,129.65,129.08,128.89,124.62,122.83,122.24,121.51,120.45,118.36, 111.71,108.88,56.05,51.66,45.10,39.42,38.00,28.93,27.40,20.44,16.51,8.80. HRMS calculated for C28H28BrN5O:529.1477,found 530.1553[M+H]+.
Preparation of Compound 12
a.LiAlH4,dry THF,rt；b.isothiocyanates,NaH(60％),dry THF,rt；
c.dry pyridine,R5COCl,rt.
Compound F-5(0.2mmol) was dissolved in anhydrous THF (2mL), NaH (60%) (9mg,0.22mmol) was slowly added at 0 deg.C, stirring was continued for 20min, then benzeneisothiocyanate (26. mu.L, 0.22mmol) was added and the reaction was continued for 2h at room temperature, followed by addition of pyridine (32. mu.L, 0.4mmol) and 4-morpholinecarbonyl chloride (0.22mmol) in that order and continued for 5h at room temperature, monitored by TLC. When the reaction was complete, distilled water (10mL) was added, extraction was performed with ethyl acetate (10 mL. times.3), the organic layers were combined, back-washed with saturated NaCl (30mL), anhydrous Na2SO4Drying, filtering to remove desiccant, and concentrating the solution under reduced pressure. Column chromatography (dichloromethane/methanol 40/1) (v/v) afforded compound 12 as a yellow solid in 75% yield.1H NMR (400MHz,Chloroform-d)δ7.73(d,J＝8.2Hz,1H),7.46(dd,J＝7.8,1.3Hz,1H), 7.40–7.33(m,5H),7.25–7.23(m,1H),7.17(t,J＝7.4Hz,1H),5.22(s,1H),4.91 (s,1H),4.57(s,1H),3.74(t,J＝5.8Hz,4H),3.71(s,1H),3.63(t,J＝4.8Hz,4H), 3.25(dd,J＝13.8,6.7Hz,1H),3.18(td,J＝11.3,5.9Hz,1H),2.89(m,1H),2.58– 2.39(m,3H),2.29(dq,J＝15.1,7.5Hz,1H),1.76–1.63(m,2H),1.54(d,J＝13.9 Hz,1H),1.40(m,1H),1.09(td,J＝14.6,3.0Hz,1H),0.88(t,J＝7.5Hz,3H).13C NMR(100MHz,Chloroform-d)δ168.13,153.38,141.57,136.40,134.97,133.72, 131.11,130.19,129.62,129.42,129.34,122.32,121.14,118.63,113.91,107.79, 94.67,66.55,59.26,55.25,50.82,44.68,39.68,24.23,24.02,21.30,16.87,7.00. HRMS calculatedfor C32H36N4O3S:556.2508,found 557.2585[M+H]+.
Preparation of Compound 13
a.N2H4·H2O,EtOH,reflux；b.CS2,KOH,EtOH,reflux.
Compound F-1(0.4mmol), KOH (34mg,0.6mmol) were added sequentially to absolute ethanol (4mL), carbon disulfide (48. mu.L, 0.8mmol) was added dropwise with stirring, and the reaction mixture was heated under reflux for 8 hours and monitored by TLC. After the reaction was complete, the reaction was cooled to room temperature and the solvent was evaporated off under reduced pressure. Adding 10mL of water, neutralizing with dilute hydrochloric acid to neutrality, extracting with ethyl acetate (10 mL. times.3), backwashing with saturated saline, and adding anhydrous Na to the organic layer2SO4Drying, filtering to remove desiccant, and concentrating the solution under reduced pressure. Column chromatography (dichloromethane/methanol/ammonia 14/1/0.15) (v/v) afforded compound 13 as a yellow solid in 88% yield.1H NMR(400MHz,DMSO-d6)δ7.55(m,1H),7.15–7.10(m,2H),6.98(m, 1H),5.76(s,1H),4.89(s,1H),3.69–3.58(m,2H),3.11–3.02(m,2H),2.94–2.87 (m,2H),1.92(dq,J＝14.7,7.3Hz,1H),1.82(dq,J＝14.7,7.3Hz,1H),1.71(m,1H), 1.62–1.54(m,2H),1.08(td,J＝12.5,4.0Hz,1H),0.98(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ179.99,155.70,133.94,127.69,126.53,122.67, 122.45,121.30,120.62,118.82,112.32,108.03,55.45,50.63,44.51,37.41,27.76, 26.11,18.23,15.55,8.42.HRMS calculated for C21H22N4OS:378.1514,found 379.1586[M+H]+。
Claims (10)
1. The vinpocetine derivative has a structural general formula as follows:
r is selected from A type
Type B
Type C
Type D
Type E
Type F
Type G
H type
Any one of them.
2. The structure of the vinpocetine derivative is any one of the following structures:
3. use of a vinpocetine derivative according to claims 1-2 for the preparation of a composition for the treatment or prevention of diseases caused by ischemic cerebrovascular pathologies.
4. Use of vinpocetine derivatives according to claims 1-2 for the preparation of cerebral vasodilators.
5. Vinpocetine derivatives according to claims 1-2 for the preparation of a composition for improving ischemic cerebrovascular lesion sites and peripheral blood supply.
6. Use of a vinpocetine derivative according to claims 1-2 for the preparation of a composition for the treatment or prevention of cerebral arteriosclerosis.
7. Use of a vinpocetine derivative according to claims 1-2 for the preparation of a composition for the treatment or prevention of hypertension.
8. Use of a vinpocetine derivative according to claims 1-2 for the preparation of a composition for the treatment or prevention of hemorrhagic stroke sequelae.
9. Use of a vinpocetine derivative according to claims 1-2 for the preparation of a composition for the treatment or prevention of hyperviscosity.
10. Use of a vinpocetine derivative according to claims 1-2 for the preparation of a composition for the treatment or prevention of cerebral ischemia; or; can be used for preparing composition for improving oxygen utilization rate of cerebral blood.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103121998A (en) * | 2013-02-06 | 2013-05-29 | 罗军 | Vinpocetine compound and drug composition thereof |
| CN105985334A (en) * | 2015-02-04 | 2016-10-05 | 哈药集团技术中心 | Diaza-benzofluoranthene alkene type compounds |
| CN105985333A (en) * | 2015-02-04 | 2016-10-05 | 哈药集团技术中心 | Diaza-benzofluoranthene type compounds |
| CN109336879A (en) * | 2018-11-07 | 2019-02-15 | 青岛科技大学 | A kind of 3- pyridyl group -1,2,4- furodiazole compound and its application |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103121998A (en) * | 2013-02-06 | 2013-05-29 | 罗军 | Vinpocetine compound and drug composition thereof |
| CN105985334A (en) * | 2015-02-04 | 2016-10-05 | 哈药集团技术中心 | Diaza-benzofluoranthene alkene type compounds |
| CN105985333A (en) * | 2015-02-04 | 2016-10-05 | 哈药集团技术中心 | Diaza-benzofluoranthene type compounds |
| CN109336879A (en) * | 2018-11-07 | 2019-02-15 | 青岛科技大学 | A kind of 3- pyridyl group -1,2,4- furodiazole compound and its application |
Non-Patent Citations (2)
| Title |
|---|
| BO-WEN PAN 等: "Synthesis and biological evaluation of Vinpocetine derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| KIRILL GEYL 等: "Convenient entry to N-pyridinylureas with pharmaceutically privileged oxadiazole substituents via the acid-catalyzed C-H activation of N-oxide", 《TETRAHEDRON LETTERS》 * |
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