Application of dihydrotanshinone I derivative in preparation of medicine for treating cerebral cavernous malformation
By using dihydrotanshinone I derivative as an active ingredient of anti-brain sponge vascular malformation drugs, combined with pharmaceutical excipients and carriers, it was prepared into a drug dosage form suitable for treatment, and its efficacy was verified in a mouse model, the brain sponge was solved. The lack of effective drug treatment for vascular malformations has achieved the effect of significantly reducing the number of lesions and improving endothelial structure.
Patent Information
- Application Number
- CN202411431855.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-14
- Publication Date
- 2024-12-13
AI Technical Summary
Currently, there is a lack of effective drug treatments to treat spongy vascular malformations in the brain. Current treatments mainly rely on surgery, and there is a lack of progress in drug development for the disease.
Dihydrotanshinone I derivative (DPDH) is used as the active ingredient of anti-cerebrosponic vascular malformation drugs, and is prepared in a preparation form suitable for oral or injection in Ccm1ECKO mice The efficacy of the model was studied, and the efficacy of the brain tissue asana, H&E staining, CT imaging and scanning electron microscopy were used to investigate its efficacy.
DPDH significantly reduces the number and volume of lesions in the brain of spongy vascular malformations, improves the endothelial structure, and provides an effective drug treatment plan for the brain of spongy vascular malformations.
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Figure CN119112911A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to application of a dihydrotanshinone I derivative in preparing an anti-cerebral cavernous malformation drug, and belongs to the field of traditional Chinese medicine pharmacy. Background Art
[0002] Cerebral cavernous malformations (CCMs) are a common cerebrovascular disease with an incidence of about 0.5%. Clinical manifestations of CCMs patients include intracranial hemorrhage, stroke, epilepsy and even sudden death. Pathological features include lumen dilation, thinning of vessel wall, destruction of endothelial cell connections, lack of mature vascular wall components such as smooth muscle cells and thrombosis. Currently, CCMs disease relies on surgical treatment and lacks effective drug treatment.
[0003] Endothelial cell-specific knockout of the cerebral cavernous malformation 1 gene (Ccm1) in mice ECKO ) will show obvious symptoms of CCMs disease damage, which can provide a reliable animal model for drug development. As one of the commonly used clinical drugs, Danshen has the effects of promoting blood circulation and removing blood stasis, cooling blood and reducing inflammation and carbuncle, and has significant effects in the treatment of cardiovascular diseases. The effective ingredients of Danshen can be divided into fat-soluble components such as tanshinone, tanshinol, and tanshinol, and water-based components such as tanshinone and tanshinol polyphenolic acid. The effective ingredients have multiple pharmacological effects such as anti-platelet aggregation, reducing blood viscosity, reducing inflammatory response, dilating coronary arteries, and anti-fibrosis. Our animal experiments showed that dihydrotanshinone I derivatives ((R)-1,6-dimethyl-11-phenyl-1,10-dihydro-2H-furo[2',3':1,2]phenanthro[3,4-d]imidazole, DPDH) have a good effect on improving CCMs diseases, and the research on using DPDH to fight CCMs diseases has not been reported. Summary of the invention
[0004] The purpose of the present invention is to provide the use of dihydrotanshinone I derivatives in the preparation of anti-cerebral cavernous malformation drugs.
[0005] The anti-cerebral cavernous malformation drug involved in the present invention is a dihydrotanshinone I derivative, and its chemical name is:
[0006] (R)-1,6-dimethyl-11-phenyl-1,10-dihydro-2H-furo[2',3':1,2]phenanthro[3,4-d]imidazole, molecular formula C 25 H 20 ON2, its structural formula is as follows:
[0007]
[0008] The dihydrotanshinone I derivative is used in the preparation of a drug for treating cerebral cavernous malformations. The dihydrotanshinone I derivative is prepared with pharmaceutically acceptable excipients into one of an oral preparation and an injection.
[0009] The dihydrotanshinone I derivative is used in the preparation of a drug for treating cerebral cavernous malformations, and the oral preparation is one of a tablet, a hard capsule, a soft capsule, and a granule.
[0010] The technical solution of the present invention is to use Ccm1 ECKO Mouse model, with the help of brain tissue type, H&E staining, CT imaging and scanning electron microscopy, investigated the pharmacological effects of DPDH in mice as a whole, providing important experimental basis for the preparation of drugs against cerebral cavernous malformations.
[0011] The experimental results of the present invention show that DPDH has a good effect on improving cerebral cavernous malformations in vivo, whether in reducing the number and volume of lesions or relieving endothelial structure.
[0012] The Chinese medicine monomer dihydrotanshinone I derivative of the present invention can be used as an active ingredient and can be prepared with its pharmaceutically acceptable carrier and / or excipient into any dosage form of anti-CCMs drug suitable for humans or animals, such as oral pharmaceutical preparations, injections, tablets, etc. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Figure 1 For DPDH 1 H NMR spectrum;
[0014] Figure 2 For DPDH 13 C NMR spectrum;
[0015] Figure 3 DPDH to Ccm1 ECKO Effects of cavernous malformation lesions on brain in mice, where Figure a is the result of body type and Figure b is the result of H&E staining;
[0016] Figure 4 DPDH to Ccm1 ECKO Effects of lesion number and lesion volume on cerebral cavernous malformation in mice, where Figure a is the CT imaging result, Figure b is the quantification of lesion number, and Figure c is the quantification of lesion volume;
[0017] Figure 5 DPDH to Ccm1 ECKO Effects of vascular architecture on cerebral cavernous malformations in mice. DETAILED DESCRIPTION
[0018] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art can make various changes or modifications to the present invention, but these equivalent forms fall within the scope limited by the appended claims of the application equally.
[0019] The present invention provides a potential anti-cerebral cavernous malformation drug for the treatment of cerebral cavernous malformation, which is further described in detail below in conjunction with the specific embodiments of the present invention. Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.
[0020] Example 1: Take 10 g of dihydrotanshinone I derivative, add starch, granulate and prepare tablets.
[0021] Preparation of dihydrotanshinone I derivatives: Dihydrotanshinone I derivatives are obtained by a one-step reaction using dihydrotanshinone I (Shanghai Yuanye Biotechnology Co., Ltd., B20357), benzaldehyde (McLean, B802738) and ammonium acetate (McLean, A800996) as reactants. 1 H NMR spectrum Figure 1 As shown, 13 C NMR spectrum Figure 2 shown.
[0022] References: Li, MM;
[0023] Example 2: Take 10 g of dihydrotanshinone I derivative, add starch, granulate and prepare granules.
[0024] Example 3: Take 10 g of dihydrotanshinone I derivative, add dextrin, fill the capsules, and prepare capsules.
[0025] Example 4: Take 10 g of dihydrotanshinone I derivative, add DMSO, TWEEN80 and physiological saline (8%:4%:88%) to prepare an injection.
[0026] Example 5: Investigation of the pharmacodynamic effects of dihydrotanshinone I derivatives on cerebral cavernous malformations in mice 1. Animals
[0027] Cerebral cavernous malformation 1, referred to as CCM1. SPF level Ccm1 fl / fl 10 mice, Ccm1 ECKO 30 mice, donated by Peter Choi of Centennial Research Institute, Australia.
[0028] 2. Dihydrotanshinone I derivatives: prepared according to the method of Example 1 above.
[0029] 3. Main Reagents
[0030] Tamoxifen (Sigma-Aldrich, H7904), 4% paraformaldehyde (Biosharp, 70071800), hematoxylin and eosin (HE) staining kit (Beyotime, C0105S), iodine solution (Sigma Aldrich, L6146).
[0031] 4. Main instruments
[0032] Stereo microscope (Leica), pathology imager (PerkinElmer), CT imaging system (PerkinElmer).
[0033] 5. Animal Grouping
[0034] 10 Ccm1 fl / fl Mice were used as normal controls, and 30 Ccm1 ECKO The mice were randomly divided into the model group (n=10), dihydrotanshinone I derivative (5 mg / kg; n=10), and dihydrotanshinone I derivative (10 mg / kg; n=10).
[0035] 6. Animal Model Establishment
[0036] The mouse model of cerebral cavernous malformation was established by intragastric injection of tamoxifen. The specific steps are as follows: On the first day of birth (D1) of the young mice, 50 μL of tamoxifen (0.5 mg / mL) was injected intragastricly. On D19, brain tissues of the mice were collected and pharmacodynamics was evaluated.
[0037] 7. Treatment Methods
[0038] Drug treatment group: The young mice were intraperitoneally administered DPDH 5mg / kg or 10mg / kg starting on the 11th day of birth (D11), and then once every 2 days, namely D13, D15, and D17; the normal control group and the model group were intraperitoneally injected with the same volume of drug solvent for a total of 4 times.
[0039] 8.Indicator detection
[0040] The overall lesion of CCMs was observed by stereomicroscope; HE staining was used to examine the lesion area of brain tissue; the CT imaging system was able to quantify the number and volume of lesions; and the scanning electron microscope was used to detect the vascular structure at the lesion site.
[0041] 9. Statistical methods
[0042] All data were expressed as Mean±SD. GraphPad Prism 9 software was used to analyze the differences among the groups. P<0.05 indicated a significant difference.
[0043] 10. Results and Conclusions
[0044] The results showed that DPDH (10 mg / kg) could improve Ccm1 ECKO Mouse cerebral cavernous malformation (see Figure 3 ), specifically a reduction in the number and volume of lesions (see Figure 4 ), while reducing Ccm1 ECKO Vascular structure of cavernous malformations in mice (see Figure 5 ).
[0045] Conclusion: DPDH can play an anti-cerebral cavernous malformation role.
[0046] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. The use of a dihydrotanshinone I derivative in the preparation of a drug for treating cerebral cavernous malformations, characterized in that: Its chemical name is (R)-1,6-dimethyl-11-phenyl-1,10-dihydro-2H-furo[2',3':1,2]phenanthro[3,4-d]imidazole, molecular formula C 25 H 20 ON2, the structural formula is as follows:
2. The use of the dihydrotanshinone I derivative according to claim 1 in the preparation of a drug for treating cerebral cavernous malformations, characterized in that: The dihydrotanshinone I derivative is prepared with pharmaceutically acceptable excipients into one of an oral preparation and an injection.
3. The use of the dihydrotanshinone I derivative according to claim 2 in the preparation of a drug for treating cerebral cavernous malformations, characterized in that: The oral preparation is one of tablets, hard capsules, soft capsules and granules.