CN116120337A - Dihydroartemisinin derivative, medicine and application thereof in preparation of medicine for preventing and treating cerebrovascular diseases - Google Patents
Dihydroartemisinin derivative, medicine and application thereof in preparation of medicine for preventing and treating cerebrovascular diseases Download PDFInfo
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Abstract
The invention provides a novel dihydroartemisinin derivative, which can be used as an active ingredient to prepare a medicine for preventing and treating ischemic cerebral apoplexy, and the medicine can pass through a blood brain barrier more easily and has higher brain tissue medicine concentration.
Description
Technical Field
The invention relates to a dihydroartemisinin derivative and a pharmaceutical application thereof.
Background
With the aging process of China, cerebrovascular diseases become the first cause of death disability. The main cause is that the nerve cells die from ischemia and hypoxia due to the interruption of blood flow caused by cerebral vascular embolism or thrombosis, and the severity of the illness is closely related to the infarct volume of brain tissues.
Neural stem cells (Neural Stem Cells, NSCs), which are mainly present in the subtubular region of the lateral ventricle wall and the dentate gyrus region of the hippocampus, are a group of special cells that can self-renew, stem maintain and differentiate into functional neurons. Since neurons are terminally differentiated cells and cannot self-renew, the neurons can only repair functions through proliferation and differentiation of neural stem cells after ischemic death, and how to activate rapid proliferation of endogenous neural stem cells to repair infarcted brain tissues in the research of cerebrovascular diseases is always a hot spot field.
The subject group is directed towards artemisinin and its use in the treatment of neurological related disorders.
CN104523679a provides the use of dihydroartemisinin in the treatment of cerebrovascular diseases. Although dihydroartemisinin is found to have a promoting effect on neural stem cell proliferation, neural stem cell proliferation can be induced in vitro, and ischemic sites of cerebral infarction can be reduced in vivo. However, studies have shown that long-term low doses of dihydroartemisinin may lead to side effects such as bone marrow suppression, peripheral red blood cell depletion and extramedullary hematopoiesis of the spleen, while reduced doses may effectively avoid the occurrence of related side effects [ Yin Jiye. Toxicology reevaluation of two artemisinin derivatives and its cardiotoxicity mechanism study [ D ]. National discharge military medical sciences, 2014 ]. In addition, as the research is in progress, dihydroartemisinin belongs to a water-soluble drug, and can pass through the blood brain barrier, but has limited transmittance, and higher blood drug concentration is required to reach the brain tissue concentration required by neuroprotection [ Yepu He et al, synergistic integration of dihydro-artemsinin with gamma-aminobutyric acid results in a more potential anti-depressant. Bioorg chem.2021.110:104769 ]. In conclusion, the search of the dihydroartemisinin derivative can achieve higher blood brain barrier permeability, and has important clinical significance in reducing side reactions generated in the treatment of cerebrovascular diseases.
Disclosure of Invention
Based on the problem, through intensive research, the invention aims to provide a novel dihydroartemisinin derivative which has the function of treating and preventing cerebrovascular diseases, improves the problem of low permeability of dihydroartemisinin blood brain barrier and improves the drug concentration in brain tissues.
The aim of the invention is achieved by the following measures:
a dihydroartemisinin derivative, which has the structural formula:
the invention also provides a medicine.
A medicament comprising a dihydroartemisinin derivative as described above. The medicament may also comprise one or more pharmacologically acceptable auxiliary materials including diluents, excipients, fillers, wetting agents, absorption enhancers, surfactants, lubricants or stabilizers and the like which are conventional in the pharmaceutical arts. The medicine is preferably prepared into aqueous solution or powder and other medicine forms suitable for injection; more preferably an aqueous solution, the drug concentration is 150mg/kg. The medicine can be used by intravenous drip or intramuscular injection, and is generally applied for 1 time in 1 day, 40mg each time, and 14 days are a course of treatment. The dosage is reduced by 30% compared with the conventional dosage of dihydroartemisinin (60 mg).
It is another object of the present invention to provide the use of the above dihydroartemisinin derivatives.
The application of the dihydroartemisinin derivative in the medicaments for treating and preventing the cerebrovascular diseases. Furthermore, the dihydroartemisinin derivative is applied to the preparation of medicines for treating and preventing ischemic cerebral apoplexy. Furthermore, the dihydroartemisinin derivative is applied to the preparation of medicines for relieving or eliminating cerebral infarction and ischemia.
The application of the dihydroartemisinin derivative in preparing medicines for promoting proliferation of neural stem cells. Further, the use of said dihydroartemisinin derivatives to promote proliferation of brain subventricular zone (Subventricular Zone, SVZ) neural stem cells (Neural Stem Cells, NSCs).
The dihydroartemisinin derivative has a promoting effect on the proliferation of the neural stem cells; in vitro, neural stem cell proliferation can be induced; can effectively reduce ischemic focus of cerebral infarction and improve neurological deficit caused by cerebral apoplexy. The dihydroartemisinin derivative can be used as an active ingredient to prepare a medicine for treating ischemic cerebral apoplexy, and the medicine can pass through the blood brain barrier more easily, so that the medicine has higher brain tissue medicine concentration.
Advantageous effects
1. After cerebral ischemia, a large number of functional nerve cells die in a short period of time due to the special tolerance of neurons to blood oxygen, which has an extremely adverse effect on prognosis. The dihydroartemisinin derivative provided by the invention maintains the related functions of dihydroartemisinin in treating the related diseases, and particularly can promote endogenous NSCs to activate, proliferate and differentiate into nerve precursor cells (neurobalasts) and migrate to lesion sites after the nerve cells in an ischemic area are damaged, and the dihydroartemisinin derivative is re-integrated in a damaged nerve network system, restores a damaged nerve network structure and can replace necrotic neurons to play corresponding nerve functions. The dihydroartemisinin derivative functions by early activation (figure 2) of proliferation of NSCs endogenous to neural stem cells instead of periischemic necrotic neurons, and can be used for treating cerebral infarction.
2. The dihydroartemisinin derivative provided by the invention not only has the efficacy, but also has better blood brain barrier transmittance (figure 4) than dihydroartemisinin, can have higher drug concentration for central nervous system diseases, can effectively reduce the drug dosage, improve the drug curative effect, and further reduce the toxic and side effects.
Drawings
FIG. 1 chemical structural Change in the preparation of Dihydroartemisinin derivatives (Dihydroartemisinin derivatives, DD) in example 1
FIG. 2 example 2 immunofluorescence results show: the NSC proliferation number (Nestin/Ki 67 double-dyeing) of the DD group is obviously increased compared with that of the control group;
FIG. 3 MRI photograph of the MCAO animal of example 3 after 72 hours of surgery, it can be seen that the cerebral infarction focus of the DD group animal is significantly reduced compared with the control group and the Dihydroartemsinin (DHA) group
FIG. 4 high performance liquid chromatography of MCAO animals of example 4 after 72h of surgery to determine plasma and brain tissue drug concentrations; A. determining a chromatogram of DHA in plasma; B. DD determination chromatogram in brain tissue; C. no significant difference in plasma concentration versus the two groups; D. the concentration in brain tissue is significantly higher than in DHA.
Detailed Description
The invention will be described in further detail with reference to the drawings and examples. The following examples are merely illustrative of the present invention and are not intended to limit the scope of the invention.
Throughout the specification, unless specifically indicated otherwise, the terms used herein should be understood as meaning as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification will control.
Embodiments of the present invention will be described in detail with reference to examples, in which specific conditions are not noted, according to conventional conditions or conditions suggested by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's knowledge.
EXAMPLE 1 preparation of Dihydroartemisinin derivative (Dihydroartemisinin derivatives, DD)
1.10 preparation of beta- (2-bromoethoxy) dihydroartemisinin
3.103g (24 mmol) of 2-bromoethyl alcohol and 100mL of tetrahydrofuran are introduced into a 250mL round bottom flask, followed by 4mL of BF3.Et2O (C) under ice-bath conditions 4 H 10 BF 3 O, boron trifluoride etherate, commercially available) and 5.690g (20 mmol) of dihydroartemisinin (C) 15 H 24 O 5 ). The mixture was stirred in an ice bath for 1.5 hours. The reaction progress was monitored by TLC. The reaction is completed, saturated NaHCO is added respectively 3 Solution and 50mL EtOAc (CH) 3 COOC 2 H 5 ) After extraction of the layers, the aqueous layer was extracted with EtOAc (30 ml×2) and the organic layers were combined. The organic layer was washed with 40mL of saturated brine solution, anhydrous solid Na 2 SO 4 After drying and filtration, the organic solvent was distilled under reduced pressure. The crude product obtained was recrystallized (petroleum ether was added dropwise to EtOAc dissolved in sample), left to stand, filtered, and dried in vacuo to give white crystals.
2. Preparation of dihydroartemisinin derivatives
10 beta- (2-bromoethoxy) dihydroartemisinin, CH 3 CN，KI，K 2 CO 3 And furbenamine%
Sigma-Aldrich company) was added to a 100mL round bottom flask, and the mixture was reacted by heating at a controlled temperature (50 ℃). The reaction progress was monitored by TLC. Then 15mL of methylene chloride and 20mL of saturated NaCl solution were added. After the separation by extraction, the aqueous layer was extracted with dichloromethane (10 ml×2) and the organic layers were combined. The organic layer was washed with 20mL of saturated brine solution, anhydrous solid Na 2 SO 4 Drying; after filtration, dichloromethane was distilled under reduced pressure. After silica gel column chromatography (petroleum ether mixed EtOAc) the pure product was obtained. The structure change process of the compound is shown in figure 1.
Respectively obtaining under the conditions of 600MHz and 151MHz of an Agilent nuclear magnetic resonance apparatus 1 H spectrum 13 C spectrum, the compound is measured by high resolution mass spectrum using a Waters SYNPAT G2 instrument, and the spectrum information is as follows: 1H NMR (600 MHz, DMSO) d 7.75 (s, 1H), 6.57 (s, 1H), 6.52 (s, 1H), 5.40 (s, 1H), 4.71 (s, 1H), 4.20 (s, 2H), 3.89 (s, 1H), 3.55 (s, 1H), 3.08 (s, 2H), 2.42 (s, 1H), 2.18 (s, 1H), 2.01 (s, 1H), 1.80 (s, 1H), 1.66 (M, 2H), 1.54 (s, 1H), 1.32 (M, 6H), 1.14 (s, 1H), 0.88 (M, 7H) 13C NMR (MHz, DMSO) d 146.84,143.96,111.41,110.87,103.43,101.06,86.89,80.34,63.65,51.90,45.75,43.83,42.83,36.46,36.01,34.09,30.27,25.62,24.22,23.95,20.11,12.62.HRMS M/z [ M+H 151]+:408.2375(Calcd for C22H33NO6:407.230788)。
EXAMPLE 2 Effect of Dihydroartemisinin Derivative (DD) on proliferation of neural Stem cells under ex vivo conditions
Pregnant 14.5d SD rats were selected, 5% chloral hydrate was anesthetized intraperitoneally, the peritoneum was opened, embryos were removed, scalp, skull and dura were removed, and the rat brain was stripped. Under a dissecting microscope, longitudinal cutting is carried out by taking the olfactory bulb as a central sagittal position, and materials are obtained in the subventricular zone. Proliferation medium (DMEM/F12, bFGF 20ng/mL, EGF 20ng/mL,2% B27) was added, and after filtration through a 200 mesh screen, trypan blue staining was performed, and the cell count was adjusted to 1X 10 6 Transfer to a culture flask, put into a 5% CO2 incubator at a constant temperature of 37 ℃ for culture, and passaged once in three days.
Taking NSCs grown in logarithmic phase, digesting with 0.25% EDTA trypsin for 2min, adjusting cell number to 8000/100 μl after stopping digestion with 10% DMEM/F12, inoculating into 96-well plate, and placing into 5% CO 2 And placing the mixture in a constant temperature incubator at 37 ℃. After 24 hours, the wall-attached growth is carried out, the supernatant is discarded, and a blank control group and an 800nmol/L DD group are arranged. Each group had 6 duplicate wells and were removed after 72h incubation. PBS buffer was washed 3 times, 75% ethanol was fixed for 30min, PBS buffer was washed 3 times, 0.5% Triton X-100 was added, and the mixture was allowed to stand for 20min, buffer was washed 3 times, BSA was blocked for 20min, and Ki67 primary antibody (cell proliferation marker) and Nestin primary antibody (NSC marker) were added, respectively. Washing 3 times at 4 ℃ overnight with buffer solution, adding corresponding fluorescent secondary antibody, reacting for lh at 37 ℃, washing 3 times with buffer solution, counterstaining DAPI, and sealing with glycerol. Ki67 and Nestin biscationic cells were observed under a phase contrast inverted microscope and counted in photographs. Dihydroartemisinin Derivative (DD) group Ki67 and Nestin double cationsThe rate is significantly higher than that of the control group (p < 0.05).
Example 3 Effect of Dihydroartemisinin derivatives on ischemic foci in rats with middle cerebral artery occlusion model
Rat middle cerebral artery thrombosis establishes a rat MCAO model. The experimental animal is injected with chloral hydrate 5% into abdominal cavity, and the general anesthesia is cut through the front middle of neck, the right common carotid artery and carotid bifurcation are exposed and separated, a small opening is cut on the common carotid artery under the direct vision of ophthalmic scissors, a bolt wire is placed into the common carotid artery through the small opening to advance to the bifurcation of the middle cerebral artery, and the middle cerebral artery blood flow is obstructed. A negative Control group (postoperative daily intraperitoneal injection of 150mg/kg of physiological saline, control group), a positive Control group (postoperative daily intraperitoneal injection of aqueous solution of dihydroartemisinin (Dihydro artemisinin, DHA), 150mg/kg, DHA group) and an experimental group (postoperative daily intraperitoneal injection of aqueous solution of Dihydroartemisinin Derivative (DD) 150mg/kg, DD group) were set. Six animals per group. The animals were 7.0T cranium MR-examined 72h later and the examination results are shown in FIG. 4. And performing histogram analysis to find that: the volume of the cerebral infarction of the animals in the DD group is obviously lower than that of the Control group (p is less than 0.05), and the volume of the cerebral infarction of the animals in the DD group is obviously lower than that of the DHA group, but no statistical difference exists (p is more than 0.05). It is shown that the same dose of the Dihydroartemisinin Derivative (DD) has better effect than the dihydroartemisinin in treating cerebral infarction.
After the three groups of animals are injected with the medicine, the animals move normally, no obvious toxicity appears, no death occurs after 14 days of continuous observation, and no obvious toxicity difference exists among the three groups.
EXAMPLE 4 comparative study of Dihydroartemisinin derivatives across the blood brain barrier
The rat middle cerebral artery occlusion model is established by the rat middle cerebral artery line embolism method. The experimental animal is injected with chloral hydrate 5% into abdominal cavity, and the general anesthesia is cut through the front middle of neck, the right common carotid artery and carotid bifurcation are exposed and separated, a small opening is cut on the common carotid artery under the direct vision of ophthalmic scissors, a bolt wire is placed into the common carotid artery through the small opening to advance to the bifurcation of the middle cerebral artery, and the middle cerebral artery blood flow is obstructed. A negative control group (daily intra-abdominal injection of physiological saline 150mg/kg after the operation), a positive control group (daily intra-abdominal injection of dihydroarteannuin aqueous solution (DHA) 150mg/kg after the operation) and an experimental group (daily intra-abdominal injection of dihydroarteannuin derivative aqueous solution (DD) 150mg/kg after the operation) were set, six animals per group. And taking a mouse brain tissue homogenate and a plasma sample after 72 hours, and detecting the concentration of the injection medicine respectively contained in the homogenate brain tissue and the plasma sample by using a high performance liquid chromatography. The plasma concentration of the dihydroartemisinin derivative group is not significantly different from that of the dihydroartemisinin group (p is more than 0.05). The brain tissue drug concentration of the dihydroartemisinin derivative group is obviously higher than that of the equivalent dose dihydroartemisinin group (p is less than 0.05). The blood brain barrier permeability of the same dose DD is increased by 40% compared with DHA, and according to the measurement, compared with DHA and DD, the same neuroprotective effect is achieved, and the dosage can be reduced by 30%.
Claims (10)
1. A dihydroartemisinin derivative, which has the structural formula:
2. a medicament comprising a dihydroartemisinin derivative of claim 1.
3. The medicament of claim 2, further comprising one or more pharmacologically acceptable excipients including diluents, excipients, fillers, wetting agents, absorption promoters, surfactants, lubricants or stabilizers and the like conventional in the pharmaceutical arts.
4. The medicament of claim 2, which is an injection.
5. The medicament of claim 4, wherein the injection is an aqueous solution with a medicament concentration of 150mg/kg.
6. Use of a dihydroartemisinin derivative according to claim 1 or a medicament according to any one of claims 2 to 5 in the treatment of, or prophylaxis of, cerebrovascular disease.
7. Use of a dihydroartemisinin derivative according to claim 1 or a medicament according to any one of claims 2 to 5 for the preparation of a medicament for the treatment and prevention of ischemic stroke.
8. Use of a dihydroartemisinin derivative according to claim 1 or a medicament according to any one of claims 2 to 5 for the preparation of a medicament for the alleviation or elimination of cerebral infarction ischemic events.
9. Use of a dihydroartemisinin derivative according to claim 1 or a medicament according to any one of claims 2 to 5 for the preparation of a medicament for promoting proliferation of neural stem cells.
10. Use of a dihydroartemisinin derivative according to claim 1 or a medicament according to any one of claims 2 to 5 for the preparation of a medicament for promoting proliferation of neural stem cells in the subventricular zone of the ventricle.
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| CN105732654A (en) * | 2016-01-29 | 2016-07-06 | 暨南大学 | Dihydroarteannuin-memantine diad compounds, and synthesis method and application thereof |
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| CN113264946A (en) * | 2021-05-11 | 2021-08-17 | 中国人民解放军陆军军医大学第一附属医院 | Dihydroartemisinin derivative and application thereof in preparation of drugs for treating and preventing cerebrovascular diseases |
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| WO2019104247A1 (en) * | 2017-11-21 | 2019-05-31 | Ming Zhao | Artemisinin-derived trimers and tetramers and their use thereof |
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