Fluorinated benzoyl group-containing anthracycline structure derivative as well as preparation and application thereof

Abstract

The invention discloses a preparation method and application of a fluorinated benzoyl group-containing anthracycline structure derivative, and belongs to the technical field of medicines, the fluorinated benzoyl group-containing anthracycline structure derivative has a chemical formula of # imgabs0 #, R1 is-CH2OH,-O-CH3 and other groups, R2 is-H,-OH,-O-CH3 and other groups, and R3 is-H,-OH,-O-CH3 and other groups. And R3 is benzoyl substituted by trifluoromethyl or benzoyl substituted by trifluoromethyl phenyl. The anthracene ring structure derivative containing the fluorinated benzoyl group is obtained by deriving on an amino group of the anthracene ring structure derivative. The device is used as an ablation medium for chemical ablation of heart heterogeneous myocardium, effective damage of the heterogeneous myocardium is realized, and the device has the characteristics of targeted positioning and controllable damage.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical compounds, and specifically relates to anthracene ring structure derivatives containing fluorinated benzoyl groups, and their preparation and application. Background Art

[0002] In heart diseases, there is a group of pathological heterogeneous signs caused by abnormal development and / or dysfunction of the myocardium itself, which can be life-threatening in severe cases. These heterogeneous myocardiums show diversity in heart diseases. In the field of myocardial structure, hypertrophic cardiomyopathy (HCM) and severe left ventricular outflow tract stenosis (LVOTO) are representative, and patients suffer from cardiac circulation disorders until death. In the field of cardiac electrophysiology, patients often suffer from various arrhythmias, such as atrial fibrillation or rapid ventricular rhythm, which endanger the patient's life.

[0003] After more than 30 years of technological progress, clinicians have established a group of ablation techniques for heterogeneous myocardium, including chemical ablation, such as alcohol septal ablation (ASA); or physical ablation, such as catheter radiofrequency ablation for arrhythmias. Although ablation of these heterogeneous myocardium has been applied to disease treatment, there are still many unresolved clinical problems, such as fatal complications during or after ASA, the inability of cardiac catheter radiofrequency ablation to eliminate epicardial ectopic lesions, and the recurrence of persistent atrial fibrillation after ablation.

[0004] Take HCM as an example: it has been determined that LVOTO is closely related to cardiovascular death. In order to reduce cardiovascular events, clinicians have established alcohol ablation methods for hypertrophic myocardium, which has become the main procedure for ventricular septal volume reduction. Practice has shown that serious or even fatal complications occur during or after ASA, including complete heart block, early ventricular arrhythmia, coronary artery dissection, and sudden death and distant myocardial infarction caused by accidental alcohol spillage. In order to avoid malignant complications, clinicians continue to innovate technologies; for example, the use of polyvinyl alcohol particles, microspheres, absorbable gelatin sponges or septal coils to block blood vessels in order to achieve necrosis of hypertrophic myocardial tissue, as well as the recent attempts of catheter radiofrequency ablation and cryoablation; including surgeons are constantly trying to update surgical procedures. Unfortunately, the low clinical benefit / risk ratio has led to the fact that these technologies have not been widely used in clinical practice.

[0005] Establishing effective heterogeneous myocardial ablation therapy is of great significance to saving the lives of patients with heart disease, alleviating pain and improving their quality of life. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a fluorinated benzoyl-containing anthracene ring structure derivative, preparation and application thereof in view of the deficiencies of the prior art. The derivative can be used as an ablation medium for heterogeneous myocardial ablation to achieve effective damage to the heterogeneous myocardium, and has the characteristics of targeted positioning and controllable damage.

[0007] To achieve the above object, the present invention adopts the following technical solution:

[0008] The first aspect of the present invention provides a class of anthracene ring structure derivatives containing fluorinated benzoyl groups, wherein the anthracene ring structure derivatives containing fluorinated benzoyl groups have a structure as shown in the general formula (I):

[0009]

[0010] Among them, R 1 Selected from -CH 3 、-CH 2 OH, -O-CH 3 Group; R 2 Selected from -H, -OH, -O-CH 3 Group, R 3 It is a benzoyl group substituted with trifluoromethyl or a benzoyl group substituted with trifluoromethylphenyl.

[0011] R 3 When it is a trifluoromethyl-substituted benzoyl group, the structural formula of general formula (I) is: When R3 is a benzoyl group substituted with trifluoromethylphenyl, the structural formula of the general formula (I) is:

[0012] According to the above scheme, the trifluoromethyl-substituted benzoyl group includes a monosubstituted, disubstituted or trisubstituted trifluoromethyl group, and the structure is shown as follows:

[0013] The trifluoromethylphenyl-substituted benzoyl group includes a trifluoromethylphenyl mono-substituted, di-substituted or tri-substituted trifluoromethylphenyl group, and the structure is as follows:

[0014] According to the above scheme, the specific structure of the trifluoromethyl-substituted benzoyl group includes:

[0015]

[0016] According to the above scheme, the trifluoromethylphenyl substituted benzoyl group specifically includes:

[0017]

[0018] According to the above scheme, the anthracene ring structure derivatives containing fluorinated benzoyl groups include but are not limited to the following compounds:

[0019]

[0020] The second aspect of the present invention provides a method for preparing the anthracene ring structure derivative containing a fluorinated benzoyl group as described above, and the synthesis route is as follows: an anthracene ring structure compound represented by general formula 2 or its hydrochloride, and a trifluoromethyl-substituted benzoyl chloride represented by general formula 3 or a trifluoromethylphenyl-substituted benzoyl chloride represented by general formula 4 are reacted by amide to prepare the anthracene ring structure derivative containing a fluorinated benzoyl group,

[0021]

[0022] According to the above scheme, the specific steps of the method are: dissolving the compound represented by general formula 2 in an organic solvent such as acetonitrile, adding an acid binding agent such as triethylamine, and dropping the compound represented by general formula 3 or the compound represented by general formula 4 at low temperature to acylate the amino group to prepare an anthracene ring structure derivative containing a fluorinated benzoyl group.

[0023]

[0024] According to the above scheme, the synthesis route of the trifluoromethylphenyl substituted benzoyl chloride represented by general formula 4 is: using tetrakis triphenylphosphine palladium as a catalyst, sodium carbonate as a base, and a mixed system of 1,4-dioxane and water as a reaction solvent, 4-iodobenzoic acid and mono-, di- or tri-trifluoromethylphenylboric acid, i.e. trifluoromethyl mono-, di- or tri-substituted phenylboric acid, undergo SUZUKI coupling reaction to generate 4-mono-, di- or tri-trifluoromethylphenylbenzoic acid, and the product reacts with dithionyl chloride to generate 4-mono-, di- or tri-trifluoromethylphenylbenzoyl chloride.

[0025]

[0026] The third aspect of the present invention provides the use of the anthracene ring structure derivative containing a fluorinated benzoyl group as described above in the preparation of an ablation medium for chemical ablation of heterogeneous myocardium.

[0027] According to the above scheme, the heterogeneous myocardium mainly includes two categories:

[0028] 1) Abnormal myocardial hyperplasia, such as hypertrophic cardiomyopathy and severe left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, which require ventricular septal volume reduction therapy;

[0029] 2) Heterogeneous myocardium, which produces abnormal cardiac electrical activity. These heterogeneous myocardium can cause arrhythmias. Severe malignant arrhythmias can be life-threatening.

[0030] Ablation is performed using anthracene ring structure derivatives containing fluorinated benzoyl groups as ablation media, resulting in cell necrosis and / or functional loss in the heterogeneous myocardium, relief of left ventricular outflow tract obstruction or disappearance of malignant arrhythmias.

[0031] According to the above scheme, the application is the application in preparing an ablation medium for chemical ablation of hypertrophic cardiomyopathy.

[0032] Beneficial effects of the present invention:

[0033] The present invention constructs a class of anthracene ring structure derivatives containing fluorinated benzoyl groups by derivatizing the amino groups of anthracene ring structure derivatives containing fluorinated benzoyl groups, and constructs specific biochemical target effects, including efficient 'first-pass effect' and 'endothelial injury under self-controlled positioning'. The efficient "first-pass effect" is one of the foundations of the present invention. The anthracene ring structure derivatives containing fluorinated benzoyl groups complete the delivery of ablation media through catheter intervention. When the ablation media is distributed to the local arterial endothelium of the heart with the blood flow, the targeted distribution and efficient utilization of the media are formed due to the efficient "first-pass effect" of the drug; the synergistic ablation media interacts with the transmural artery endothelium, and the 'endothelial injury under self-controlled positioning' of the transmural artery of the heart is magically realized. Such damage only causes blood flow attenuation at the arteriolar level, resulting in myocardial tissue ischemia and necrosis under dual-target fusion and precise positioning.

[0034] Therefore, the anthracene ring structure derivative containing fluorinated benzoyl provided by the present invention can be used as an ablation medium in the treatment of heart diseases through interventional methods. Based on the above-mentioned dual target effect, the regional transmural arterial endothelium is conditionally damaged, causing the attenuation of arteriolar blood flow in the target area, and the ischemic heterogeneous myocardium is damaged or necrotic. The two technical paths respectively generate endothelial injury responses under biological targeting, and the dual spatial interactive guidance technology improves the benefit / risk ratio of heterogeneous myocardial ischemia ablation. For example: a new chemical ablation procedure under precise self-controlled positioning is constructed for left ventricular outflow tract stenosis in hypertrophic cardiomyopathy. Because the ablation medium has a clear therapeutic effect and has the characteristics of regional targeted positioning and precise tissue damage, the success rate is improved and the risks and complications of interventional ablation procedures are greatly reduced.

[0035] The synthesis method of the invention is simple, the raw materials are easily available, and it is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 is the mass spectrum of compound 1 of the present invention;

[0037] Figure 2 is the LCMS chart of compound 1 of the present invention;

[0038] Figure 3 is the HNMR diagram of compound 1 of the present invention;

[0039] Figure 4 is the FNMR diagram of compound 1 of the present invention;

[0040] Figure 5 is the mass spectrum of compound 2 of the present invention;

[0041] Figure 6 is the LCMS chart of compound 2 of the present invention;

[0042] Figure 7 is the HNMR diagram of compound 2 of the present invention;

[0043] Figure 8 is the FNMR diagram of compound 2 of the present invention;

[0044] Fig. 9 is the mass spectrum of compound 3 of the present invention;

[0045] Fig.10 is the LCMS chart of compound 3 of the present invention;

[0046] Fig.11 is the HNMR diagram of compound 3 of the present invention;

[0047] Fig.12 is the FNMR diagram of compound 3 of the present invention;

[0048] Fig.13 The effect of the anthracene ring structure derivative of the fluorinated benzoyl group of the present invention on the activity of endothelial cells;

[0049] Fig.14 The ability of the anthracene ring structure derivatives of the fluorinated benzoyl group of the present invention to promote endothelial cell apoptosis;

[0050] Fig.15 The fluorinated benzoyl anthracene ring structure derivative of the present invention targets the percutaneous arterial endothelium for damage: cardiac arterial endothelial apoptosis (A), PET evaluation of myocardial ischemia image (B), PET evaluation of myocardial uptake SUV value (C), cardiac ultrasound image (D) and cardiac ejection fraction EF value (E);

[0051] Fig.16 The directional distribution of the anthracene ring structure derivative of the fluorinated benzoyl ablation medium of the present invention in the porcine coronary artery through catheter intervention and its biological effect: determination of compound concentration in different target tissues (A), CFR determination of microcirculatory reserve (B), electrocardiogram (C) and detection of myocardial ischemia index cTnI (D). DETAILED DESCRIPTION

[0052] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0053] The present invention obtains a series of anthracene ring structure derivatives containing fluorinated benzoyl groups by deriving fluorinated benzoyl groups on the amino groups of anthracene ring structure derivatives. The derivatives can be used as ablative media with the characteristics of targeted positioning and controllable damage, and are effective and safe for chemical ablation of heterogeneous myocardium. Relying on this new ablative medium, the interventional procedure of ASA can be improved to damage the transmural arterial endothelium of cardiac regional tissue, cause ischemic necrosis of the target myocardium, achieve effective damage to the heterogeneous myocardium, and reduce ablation complications during and after the interventional surgery. The following is an example of anthracene ring structure derivatives containing fluorinated benzoyl groups substituted with 4-trifluoromethylbenzoyl, 3,5-trifluoromethylbenzoyl, and 2,4,6-trifluoromethylbenzoyl as examples for explanation in combination with specific experiments.

[0054] Example 1 Anthracene ring structure derivative containing fluorinated benzoyl group

[0055] Synthesis of compound 1:

[0056] Compound A (500 mg, 919 μmol, 1.00 eq) was dissolved in dichloromethane (20 mL) solution, and triethylamine (279 mg, 2.76 mmol, 384 μL, 3.00 eq) and compound a (287 mg, 1.38 mmol, 205 μL,, 1.50 eq) were added. Stir at 25 ° C for 2 hours. LC-MS (EC22858-1-P1A) showed that A was consumed and the required mass was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. Pre-HPLC column: CD01-Phenomenex luna C18 150*25*10um, mobile phase: [water (FA)-ACN], gradient: 36%-66% B, time 8min) was used for purification. Compound Target 1 (168 mg, 159 μmol, yield 17.32%, purity 95.0%). The product was confirmed to be a red solid by HPLC (EC22858-1-P1C6), LCMS (EC22858-1-P1E2), HNMR (EC22858-1-P1A1) and FNMR (EC22858-1-P1F1).

[0057]

[0058] Figure 1 shows the mass spectrum of compound 1, Figure 2 The LCMS chart of compound 1 is shown. Figure 3 The H-NMR of compound 1 is shown. Figure 4 The figure shows the FNMR diagram of compound 1, and the specific data are as follows:

[0059] LCMS: RT = 0.447 min, [M + Na]+ =738.2; HNMR: δ14.06(br s,1H),13.51-12.85(m,1H),

[0060] 8.26(d,J=7.6Hz,1H),8.02(d,J=8.1Hz,2H),7.95-7.88(m,2H),7.81(d,J=8.4Hz,2H),7.70-7.62(m,1H),5.50(s,1H),5.29(br d,J=3.2Hz,1H),5.04-4.95(m,1H),4.94-4.78(m,2H),4.60(d,J=6.0Hz,2H),4.33-4.16(m,2H),3.98(s,3H),3.59(br d,J=2.8Hz,1H),3.10-2.88(m,2H),2.33-2.03(m,3H),1.54(br dd,J=4.1,12.0Hz,1H),1.17(d,J=6.4Hz,3H).

[0061] Synthesis of compound 2:

[0062] Triethylamine (366 mg, 3.62 mmol, 504 μL, 2.10 eq) and compound b (525 mg, 1.90 mmol, 344 μL, 1.1 eq) were added to a solution of compound A (1.00 g, 1.72 mmol, 1.00 eq) in acetonitrile (300 mL). 2 Under protection, the mixture was stirred at 25°C for 2 hours. Thin layer chromatography monitoring (plate 1: dichloromethane: methanol = 2:1) showed that the residual compound A (R f =0.00), and detected 3 new major spots (R f =0.50,Rf=0.59,R f =0.71), product R f is 0.50. LC-MS (EC10154-49-P1C) showed that compound A remained at 36.42%. LC-MS showed a new peak, and the target compound was detected to account for 53.74%. The reaction mixture was quenched with 20 mL of water at 25°C and extracted with 150 mL (50 mL×3) of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the filtrate was concentrated to obtain a crude product. It was purified by preparative high performance liquid chromatography (trifluoroacetic acid conditions). The mixed solution was diluted with water (1000 ml) and extracted with 2000 ml (1000 ml×2) of dichloromethane. The organic layers were combined, washed with 1000 ml (500 ml×2) of water, and washed with NaHCO 31000ml (5%, 500ml × 2) washing, water 1000ml (500ml × 2) washing, Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain the product.

[0063]

[0064] Figure 5 shows the mass spectrum of compound 2, Figure 6 The LCMS chart of compound 2 is shown. Figure 7 The H-NMR of compound 2 is shown. Figure 8 The figure shows the FNMR diagram of compound 2, and the specific data of H-NMR are as follows:

[0065] δ=1.34(d,J=6.8Hz,3H)1.89(td,J=13.2,4.0Hz,1H)2.00-2.07(m,2H)2.18-2.2 4(m,1H)2.34-2.41(m,1H)2.99-3.08(m,2H)3.31(dd,J=18.8,1.2Hz,1H)3.77(br s,1H)4.05-4.08(m,3H)4.25(q,J=6.4Hz,14.35-4.43(m,1H)4.47 -4.57(m,1H)4.79(s,2H)5.28-5.31(m,1H)5.56(d,J=3.6Hz,1H)6..60(br d,J=8.4Hz,1H)7.39(d,,J=8.00Hz,1H)7.77-7.82(m,1H)7.96-7.99(m,1H )8.04(dd,J=7.6,0.8Hz,1H)8.12-8.18(m,2H)13.25(s,1H)14.01(s,1H).

[0066] LCMS(EC10154-49-P1F6_LCMS_WH,R t =2.530min) to confirm the structure.

[0067] Compound 3

[0068] Compound c (21.0 g, 84.6 mmol, 1.00 eq) and compound d (22.9 g, 88.9 mmol, 1.05 eq) were dissolved in dioxane (200 mL) and water (50 mL), and Na 2 CO 3(17.9 g, 169 mmol, 2.00 eq) and Pd(PPh3)4 (4.89 g, 4.23 mmol, 0.050 eq). Stir at 25 °C for 12 hours. LC-MS (EC16604-133-P1A) showed that the reactant d was completely consumed and the required mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The reaction solution was diluted with 500 mL of water and extracted three times with ethyl acetate (500 mL). The combined organic layers were concentrated in Na 2 SO 4 The product was dried on ice and concentrated under reduced pressure to remove the solvent. Purified; 35g Silica gel flash column, eluent: 0-30% ethyl acetate / petroleum ether gradient, TLC: petroleum ether: ethyl acetate = 3 / 1). Compound e (11.0 g, 59.8 mmol, yield 40.6%) was a white solid.

[0069] Compound e (2.00 g, 5.98 mmol, 1.00 eq) was added to toluene (20 mL). SOCl 2 (854 mg, 7.18 mmol, 521 μL, 1.20 eq) 20 mL. Stir at 80 ° C for 3 hours. Thin layer chromatography (polarity: petroleum ether: ethyl acetate = 5 / 1) shows that reactant 1 is completely consumed and a product spot (RF = 0.65) is formed. The reaction mixture is concentrated under reduced pressure to obtain a residue. The crude product is directly used in the next step to obtain compound f (2.00 g, crude product) as a white solid.

[0070] Compound A (1.50 g, 2.76 mmol, 1.00 eq) was dissolved in dichloromethane (38 mL), TEA (837 mg, 8.28 mmol, 1.15 mL, 3.00 eq) and compound f (973 mg, 2.76 mmol, 1.00 eq) were added, and stirred at 25 ° C for 2 hours. LC-MS (EC22858-10-P1A2) showed that reactant 1 was completely consumed and the desired mass was detected (retention time = 0.526 min). The reaction mixture was concentrated under reduced pressure to obtain a residue. Purification by column chromatography (SiO 2 , eluent: dichloromethane / methanol = 100 / 1 ~ 20 / 1, RF = 0.7). Pre-HPLC (column: CD05-Phenomenex lunaC18 150*40*10um, mobile phase: [water (FA)-ACN], gradient: 51% ~ 81% B, more than 10min) was used for purification. Compound 3 (239mg, 278μmol, yield 11.9%) was obtained.

[0071] LCMS (EC22858-13-P1C2) and HNMR (EC22858-13-P1A) confirmed the product to be a red solid.

[0072]

[0073] Fig. 9 shows the mass spectrum of compound 3, Fig.10 The LCMS chart of compound 3 is shown. Fig.11 The H-NMR of compound 3 is shown. Fig.12 The figure shows the FNMR chart of compound 3.

[0074] The specific data are as follows:

[0075] LC-MS: RT = 0.526 min, [M + Na] + =882.2; 1 HNMR: δ14.02(s,1H),13.27(s,1H),8.06(d,J=8.0Hz,1H),7.99(s,2H),7.93-7.74(m,4H),7.64(d,J=8.4Hz,2H),7.40(d,J=8.2Hz,1H),6.57(br d,J=8.4Hz,1H),5.58(d,J=3.6Hz,1H),5.33(br s,1H),4.80(s,2H),4.59(br s,1H),4.47-4.36(m,1H),4.27(q,J=6.4Hz,1H),4.08(s,3H),3.79(br s,1H),3.32(br d,J=18.8Hz,1H),3.12-2.92(m,2H),2.39(br d,J=14.8Hz,1H),2.22(dd,J=3.9,14.8Hz,1H),2.05(br dd, J=4.8, 13.2Hz, 1H), 1.91 (dt, J=4.2, 13.2Hz, 1H), 1.35 (d, J=6.4Hz, 3H).

[0076] Example 2 Observation of the effects of the anthracene ring structure derivatives containing fluorinated benzoyl groups on the viability and apoptosis of cardiac endothelial cells

[0077] Purpose of the experiment: To evaluate the interaction effect between the compound and the cardiac arterial endothelium, that is, the cardiac arterial endothelium is a special group of endothelial cells that bear the pulsating cycle of heart contraction. This experiment simulates the cardiac pulsating cycle and constructs a cell culture model under a bionic pulsating cycle, in order to study the effects of the compound of the present invention on endothelial cell viability and apoptosis under the bionic cycle.

[0078] Experimental method: Coronary endothelial cells were passaged to the third generation and inoculated into 96-well plates when the cell count reached the exponential growth phase. The experimental groups were as follows: control group (without the compound of the present invention), compound 1, compound 2, compound 3, cardiac bionic pulsation + control group (without the compound of the present invention), cardiac bionic pulsation + compound 1, cardiac bionic pulsation + compound 2, and cardiac bionic pulsation + compound 3. Accurately weigh 5 mg of the compound, add an appropriate amount of DMSO to obtain a 10 μmol / L stock solution, and the final concentration of the added compound is 1 μmol / L.

[0079] Experimental results: After 24h, 48h and 72h of cell culture, the absorbance values ​​of the above-mentioned groups of cells at 450nm were detected by CCK-8 method to evaluate the effect of the interaction between cardiac arterial endothelium and compounds on cell viability. Relative viability (%) = (OD value of experimental group - background OD value) / (mean OD value of control group - background OD value) × 100. The relative cell viability results are shown in Fig.13 As shown, the relative viability of the cells in the three groups of compound 1, compound 2 and compound 3 basically showed a downward trend with the extension of culture time. Under the interaction between cardiac arterial endothelium and compounds, the cell viability decreased significantly after 72 hours of culture, and the cell viability of compound 2 decreased the most.

[0080] Endothelial cells of the cardiac artery were inoculated in 24-well plates and cultured for 24 hours. After the cells were placed on the slides, they were washed with PBS three times, each time for 3 minutes. The cell slides were then fixed with 4% paraformaldehyde for 30 minutes, and then the slides were washed with PBS three times, each time for 3 minutes. Subsequently, 0.5% Triton X-100 was used to permeabilize the membrane at room temperature for 20 minutes, and the slides were washed with PBS three times, each time for 3 minutes. Finally, the apoptosis of coronary endothelial cells was determined using the Tunel kit. The results are shown in Fig.14 As shown, compound 1, compound 2 and compound 3 can induce mild apoptosis of arterial endothelial cells; in comparison, when loaded with cardiac bionic pressure, the cell apoptosis of compound 1, compound 2 and compound 3 increased significantly under the interaction of arterial endothelium and compounds. Relatively speaking, the promoting apoptosis effect of compound 2 and compound 3 is better.

[0081] Example 3 Effect of Compounds on Targeted Damage to Cardiac Transmural Arterial Endothelium

[0082] Purpose of the experiment: By intraperitoneally injecting the compound into mice, observe whether the compound targets and damages the arterioles in the myocardial domain of the heart, inducing myocardial ischemia

[0083] Methods and Results: C57BL / 6 mice, male, 8 weeks old, were intraperitoneally injected with 40 mg / kg of the scalar compound. Seven days later, cardiac function was measured, myocardial ischemia was assessed by PET-CT, and arterial endothelial damage was detected by immunofluorescence.

[0084] The experiment found that under the stimulation of compound 1, compound 2, and compound 3, apoptosis occurred in the endothelium of cardiac arterioles ( Fig.15 A, arrowhead); PET further indicated myocardial blood flow attenuation in mice ( Fig.15 B, Fig.15 C); Echocardiographic EF value ( Fig.15 D, Fig.15 E) showed that the cardiac function of mice was significantly downregulated under the action of compound 1, compound 2, and compound 3, and relatively speaking, the damage effect of compound 2 and compound 3 was higher than that of compound 1. The above results indicate that the compounds of the present invention interact with the endothelial cells of cardiac arterioles, damage the percutaneous arteries, and produce conditional myocardial ischemia.

[0085] Example 4 Directional distribution and biological effects of compounds in porcine coronary arteries under intervention

[0086] Experimental purpose: To determine the concentration of compounds in heart tissue of Bama miniature pigs and understand the targeted distribution and biological effects of compounds in local heart tissues under the "first-pass effect".

[0087] Methods and Results: 25-30 kg Bama miniature pigs were selected and anesthetized with 0.1 ml / kg of Shutai intramuscularly, followed by 0.5 mg of atropine intramuscularly. An experiment without the compound of the present invention was designed as a control group.

[0088] First, the Bama miniature pig was fixed in a supine position on a surgical wooden frame, the chest and groin were prepared and disinfected, and a twelve-lead electrocardiogram was measured before surgery. Then a 5F sheath was inserted into the femoral artery, and the catheter was sent to the left anterior descending coronary artery after coronary angiography. After measuring CFR, the compound of the present invention was injected into the catheter at 4 mg / kg, and the injection was completed in 30 minutes. The twelve-lead electrocardiogram was measured 3 hours after surgery, and coronary angiography was performed in parallel. CFR was detected again after surgery to obtain the above data. After the pig was euthanized, the heart was sampled, and the myocardial tissue of the left ventricular anterior descending branch (left anterior descending branch), the right ventricle (right coronary artery) and the posterior wall (circumflex branch) were taken for sample delivery, and the distribution of tissue compounds was detected by liquid mass spectrometry. The specific steps are as follows: Accurately weigh an appropriate amount of analyte standard, prepare a 2.00 mg / mL stock solution with methanol for standby use, and mark it as S01. S01 was diluted with methanol to a series of concentration gradients of 5000ng / mL, 2000ng / mL, 500ng / mL, 200ng / mL, 50ng / mL, and 20ng / mL to obtain a standard curve. The above myocardial tissue samples were weighed and added with 1mL of methanol solution, ground for 5min, centrifuged at 12000rpm for 10min, and the supernatant was filtered with a 0.22μm filter membrane before sampling and analysis. The results showed that the compound standard curve had a good linear relationship in the concentration range of 20 to 5000ng / mL, r 2 >0.99.

[0089] The above results show that: Fig.16 As shown, the compound of the present invention has a high "first-pass effect" in local cardiac tissues, and exhibits targeted distribution under catheter intervention, with the target concentration being 7 to 10 times that of non-targeted ( Fig.16 A). After targeted injection of Compound 1, Compound 2, and Compound 3 of the present invention, the coronary blood flow was significantly slowed down, and the CFR data of the heart examination was ≤2.0 ( Fig.16 B), which indicates that the coronary blood flow reserve is reduced and the microcirculatory blood supply is impaired; the surface electrocardiogram chest leads show that the anthracene ring structure derivatives containing fluorinated benzoyl groups of the present invention, especially compound 2 and compound 3, cause significant acute myocardial ischemia ( Fig.16 C). The blood cTnI increased significantly, confirming acute myocardial infarction ( Fig.16 D), and its effect is synchronized with the results of electrocardiogram. The above results further confirmed that the endothelial apoptosis and necrosis of micro-arteries in experimental pigs occurred, and microcirculatory ischemia occurred under the intervention of the compound of the present invention.

[0090] The above experimental results comprehensively show that: the present invention uses the anthracene ring structure derivative containing fluorinated benzoyl groups to derive the anthracene ring structure derivative containing fluorinated benzoyl groups as an ablation medium for heterogeneous myocardial chemical ablation, achieving endothelial injury of cardiac arterioles, that is, controllable endothelial injury under precise tissue positioning. When constructing endothelial injury of cardiac arterioles under precise tissue positioning, the present invention has a unique binary path; first, the anthracene ring structure derivative compound containing fluorinated benzoyl groups designed based on the lipophilic active group trifluoromethyl, with the help of interventional technology, produces an efficient "first-pass effect" on target cells under blood flow (the anthracene ring structure derivative containing fluorinated benzoyl groups is carried by arterial blood flow, and when the drug-loaded blood flows through the tissue for the first time, the endothelium achieves efficient uptake and "bioavailability"); research data show that the distribution concentration of the anthracene ring structure derivative containing fluorinated benzoyl groups in the target tissue of the present invention can reach 7 to 10 times that of the non-target tissue. Secondly, anthracene ring structure derivatives containing fluorinated benzoyl groups interact with the endothelium of cardiac arterioles, producing specific biochemical reactions, which target and damage the endothelial cells of transcutaneous arteries through cascade transduction of derived molecular signals. Endothelial injury of transmural arteries is a special self-controlled localized injury. It will cause arterial blood flow attenuation and conditional myocardial ischemia, thereby achieving the ablation medium at an effective concentration to induce severe apoptosis of the arteriole endothelium in the intervention target area, ultimately leading to myocardial ischemia and necrosis.

[0091] It should be understood that those skilled in the art can make improvements or changes based on the above description, and all these improvements and changes should fall within the scope of protection of the appended claims of the present invention.

Claims

1. A type of anthracene ring structure derivative containing a fluorinated benzoyl group, characterized in that: The anthracene ring structure derivative containing a fluorinated benzoyl group has a structure as shown in the general formula (I): Wherein, R1 is selected from -CH3, -CH2OH, -O-CH3 groups; R2 is selected from -H, -OH, -O-CH3 groups, and R3 is a benzoyl group substituted with trifluoromethyl or a benzoyl group substituted with trifluoromethylphenyl.

2. The anthracene ring structure derivative containing a fluorinated benzoyl group according to claim 1, characterized in that: The trifluoromethyl-substituted benzoyl group includes a monosubstituted, disubstituted or trisubstituted trifluoromethyl group, and the structure is shown below: The trifluoromethylphenyl-substituted benzoyl group includes a trifluoromethylphenyl mono-substituted, di-substituted or tri-substituted trifluoromethylphenyl group, and the structure is as follows:

3. The anthracene ring structure derivative containing a fluorinated benzoyl group according to claim 1, characterized in that: The specific structure of the trifluoromethyl-substituted benzoyl group includes: The trifluoromethylphenyl substituted benzoyl group specifically includes:

4. The anthracene ring structure derivative containing a fluorinated benzoyl group according to claim 1, characterized in that: The anthracene ring structure derivative containing a fluorinated benzoyl group is a compound represented by the following formula (II), formula (III) or formula (IV):

5. A method for preparing a trifluoromethylbenzoyl-containing anthracene ring structure derivative as claimed in claim 1, wherein the synthetic route is as follows: an anthracene ring structure compound represented by general formula 2 or its hydrochloride, and a trifluoromethyl-substituted benzoyl chloride represented by general formula 3 or a trifluoromethylphenyl-substituted benzoyl chloride represented by general formula 4 are reacted by amide to prepare an anthracene ring structure derivative containing a fluorinated benzoyl group, 6. The method according to claim 5, characterized in that: The compound of general formula 2 is dissolved in an organic solvent, triethylamine is added as an acid-binding agent, and the compound of general formula 3 or the compound of general formula 4 is added dropwise at low temperature to acylate the amino group to prepare a fluorinated benzoyl anthracene ring structure derivative.

7. The method according to claim 5, characterized in that: The synthesis route of the trifluoromethylphenyl substituted benzoyl represented by general formula 4 is: using tetrakistriphenylphosphine palladium as a catalyst, sodium carbonate as a base, a mixed system of 1,4-dioxane and water as a reaction solvent, 4-iodobenzoic acid and mono-, di- or tri-trifluoromethylphenylboronic acid undergo SUZUKI coupling to generate 4-mono-, di- or tri-trifluoromethylphenylbenzoic acid, and the product reacts with thionyl chloride to generate 4-mono-, di- or tri-trifluoromethylphenylbenzoyl chloride.

8. Use of the anthracene ring structure derivative containing a fluorinated benzoyl group according to any one of claims 1 to 4 in the preparation of a heterogeneous myocardial ablation medium.

9. The use according to claim 8, characterized in that: The heterogeneous myocardium is a heterogeneous myocardium with abnormal myocardial hyperplasia or a heterogeneous myocardium with abnormal cardiac electrical activity.

10. The use according to claim 8, wherein the use is for preparing an ablation medium for chemical ablation of hypertrophic cardiomyopathy and / or cardiac arrhythmia.

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