Isopropylphenol compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an isopropyl phenol compound as well as a preparation method and application thereof. The isopropyl phenol compound provided by the invention is a compound with a structure as shown in a formula I or a pharmaceutically acceptable salt thereof; the compound provided by the invention can significantly relieve cardiotoxicity of quinolone antibacterial drugs such as moxifloxacin, and provides a new thought for research and development of drugs for treating drug-induced cardiotoxicity. # imgabs0 #

Description

[0001] This application claims the following priority:

[0002] CN202311549184.2, application date 2023.11.20. Technical Field

[0003] The invention belongs to the field of medical technology, and specifically relates to isopropyl phenol compounds and preparation methods and uses thereof. Background Art

[0004] It is reported that the number of deaths caused by drug-induced diseases in my country is about 192,000 per year, among which drug-induced cardiovascular disease is one of the main causes of death. Drug-induced cardiotoxicity is one of the serious adverse reactions caused by drug use, which can cause acute, subacute or chronic myocardial cell damage, cardiac dysfunction and electrophysiological imbalance or cardiac structural damage, and even heart failure, cardiogenic shock, sudden death, etc. In clinical applications, anticoagulant anesthetics, tumor drugs, molecular targeted drugs, radiotherapy drugs, antibacterial drugs, antiarrhythmic drugs, and many traditional Chinese medicines such as toad venom and aconite have been reported to have cardiotoxicity.

[0005] Huang Yiran et al. reported in the article "Effects of Propofol on Central and Cardiac Toxicity of Ropivacaine" that propofol can alleviate the central and cardiac toxicity caused by ropivacaine. Since the mechanisms of cardiotoxicity caused by different drugs vary greatly, whether propofol can alleviate the cardiotoxicity of other drugs is still highly unpredictable, and the structural modification of propofol further increases the above unpredictability. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide an isopropylphenol compound and a preparation method and use thereof, wherein the compound can significantly alleviate the cardiotoxicity of quinolone antibacterial drugs such as moxifloxacin.

[0007] The technical solution of the present invention is:

[0008] An isopropylphenol compound, wherein the compound is a compound having a structure shown in Formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] In Formula I,

[0011] R1 is selected from one of isopropyl and prop-1-en-2-yl;

[0012] R2 is selected from one of bromine, chlorine and fluorine;

[0013] R3 is selected from hydrogen and a group having a structure as shown in Formula II:

[0014]

[0015] In formula II,

[0016] R4 is selected from one of isopropyl and prop-1-en-2-yl;

[0017] R5 is selected from one of bromine, chlorine and fluorine.

[0018] Further preferably, the compound is selected from one of the following compounds 1 to 4 or a pharmaceutically acceptable salt thereof:

[0019]

[0020] Another aspect of the present invention provides a method for preparing the aforementioned compound 1, wherein the preparation method is carried out according to the following reaction formula:

[0021]

[0022] Another aspect of the present invention provides a method for preparing the aforementioned compound 2, wherein the preparation method is carried out according to the following reaction formula:

[0023]

[0024] Another aspect of the present invention provides a method for preparing the compound 3 as described above, wherein the preparation method is carried out according to the following reaction formula:

[0025]

[0026] Another aspect of the present invention provides a method for preparing the compound 4 as described above, wherein the preparation method is carried out according to the following reaction formula:

[0027]

[0028] Another object of the present invention is to provide a composition comprising the above-mentioned isopropyl phenol compound and a pharmaceutically acceptable excipient.

[0029] Further preferably, the composition is sterile.

[0030] More preferably, the composition can be administered by injection.

[0031] Another object of the present invention is to provide the use of the isopropylphenol compound in the preparation of a drug for alleviating the cardiotoxicity caused by quinolone antibiotics.

[0032] More preferably, the quinolone antibiotic is selected from one of levofloxacin and moxifloxacin.

[0033] Drug-induced cardiotoxicity is one of the main safety issues in the clinical application of drugs and is also a hot topic of concern. However, drug-induced cardiotoxicity has many influencing factors and diverse toxic reactions. The mechanisms of action of different drugs inducing cardiotoxicity vary greatly, so it is highly unpredictable whether a compound can alleviate the cardiotoxicity of different drugs. The present invention obtains a novel isopropylphenol compound through a large number of creative experiments. The compound can significantly improve the cardiotoxicity caused by quinolone antibiotics moxifloxacin and levofloxacin, and can be used to prepare drugs for alleviating cardiotoxicity caused by quinolone antibiotics.

[0034] Compared with the prior art, the present invention has the following advantages:

[0035] (1) The isopropylphenol compounds provided by the present invention have novel structures, simple preparation methods, and are easy to implement industrially.

[0036] (2) In vitro experiments have shown that the isopropylphenol compounds synthesized by the present invention can significantly improve the cardiac toxicity caused by the quinolone antibiotics moxifloxacin and levofloxacin.

[0037] (3) The present invention provides a new idea for the development of drugs for treating drug-induced cardiotoxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 Compound 1 hydrochloride 1 H-NMR spectrum;

[0039] Figure 2 Compound 1 hydrochloride 13 C-NMR spectrum;

[0040] Figure 3 Compound 2 hydrochloride 1 H-NMR spectrum;

[0041] Figure 4 Compound 2 hydrochloride 13 C-NMR spectrum;

[0042] Figure 5 Compound 3 hydrochloride 1 H-NMR spectrum;

[0043] Figure 6 Compound 3 hydrochloride 13 C-NMR spectrum;

[0044] Figure 7 Compound 4 hydrochloride 1 H-NMR spectrum;

[0045] Figure 8 Compound 4 hydrochloride13 C-NMR spectrum. DETAILED DESCRIPTION

[0046] The present invention is further illustrated below through the description of specific implementation modes, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0047] Example 1: Preparation and structural confirmation of compound 1 hydrochloride

[0048] Reactive

[0049]

[0050] operate

[0051] Weigh 2.6g of (R)-4-(dimethylamino)-2-fluorobutyric acid hydrochloride in 20ml of dichlorothionyl, heat to 55℃ and dissolve until clear, react for 3h, and concentrate to dryness. Stir the concentrate in 26ml of dichloromethane, cool to -20℃, add 10mL of dichloromethane mixed solution containing 1.0g of 3,3',5,5'-tetraisopropyl-[1,1'-biphenyl]-4,4'-diol and 1.8g of 4-dimethylaminopyridine, and react at -20℃ for 1h. Add dilute hydrochloric acid solution, separate the liquids, wash the organic phase with 0.9% sodium chloride aqueous solution, and concentrate the dichloromethane phase. The concentrate is slurried and dried with ethyl acetate to obtain 0.86g, and the yield is 44.3% calculated based on 3,3',5,5'-tetraisopropyl-[1,1'-biphenyl]-4,4'-diol.

[0052] Structure confirmation:

[0053] Compound 1 hydrochloride 1 H-NMR spectrum and 13 C-NMR diagrams are shown in Figure 1 and Figure 2 . Figure 1 The attribution of each peak is shown in Table 1.

[0054] Table 1

[0055]

[0056] Example 2: Preparation and structure of compound 2 hydrochloride

[0057] Reactive

[0058]

[0059] operate

[0060] Weigh 1g of (S)-4-(dimethylamino)-2-fluorobutyric acid hydrochloride in 10ml of dichlorothionyl, heat to 55℃ and dissolve until clear, react for 3h, and concentrate to dryness. Stir the concentrate in 10ml of dichloromethane, cool to 0℃, add 10mL of dichloromethane mixed solution containing 6g of propofol and 5g of 4-dimethylaminopyridine, and react at 0℃ for 1h. Add dilute hydrochloric acid solution, separate the liquids, wash the organic phase with 0.9% sodium chloride aqueous solution, and concentrate the dichloromethane phase. The concentrate is slurried and dried with ethyl acetate to obtain 0.44g, with a yield of 23.75%.

[0061] Structural confirmation

[0062] Compound 2 hydrochloride 1 H-NMR spectrum and 13 C-NMR diagrams are shown in Figure 3 and Figure 4 . Figure 3 The attribution of each peak is shown in Table 2.

[0063] Table 2

[0064]

[0065] Example 3: Preparation and structural confirmation of compound 3 hydrochloride

[0066] Reactive

[0067]

[0068] operate

[0069] Weigh 1g of (R)-4-(dimethylamino)-2-fluorobutyric acid hydrochloride in 10ml of dichlorothionyl, heat to 55℃ and dissolve until clear, react for 3h, and concentrate to dryness. Stir the concentrate in 10ml of dichloromethane, cool to -10℃, add 10mL of dichloromethane mixed solution containing 0.5g of 2-isopropenyl-6-isopropylphenol and 1.8g of 4-dimethylaminopyridine, and react at -10℃ for 1h. Add dilute hydrochloric acid solution, separate the liquids, wash the organic phase with 0.9% sodium chloride aqueous solution, and concentrate the dichloromethane phase. The concentrate is slurried and dried with ethyl acetate to obtain 0.37g, with a yield of 20.4%.

[0070] Structural confirmation

[0071] Compound 3 hydrochloride 1 H-NMR spectrum and 13 C-NMR diagrams are shown in Figure 5 and Figure 6 . Figure 5 The attribution of each peak is shown in Table 3.

[0072] Table 3

[0073]

[0074] Example 4: Preparation and structural confirmation of compound 4 hydrochloride

[0075] Reactive

[0076]

[0077] operate

[0078] Weigh 1g of (R)-2-chloro-4-(dimethylamino)butyric acid hydrochloride in 10ml of thionyl chloride, heat to 55℃ and dissolve until clear, react for 3h, and concentrate to dryness. Stir the concentrate in 10ml of dichloromethane, cool to -10℃, add 10mL of dichloromethane mixed solution containing 0.68g of propofol and 0.52g of 4-dimethylaminopyridine, and react at -10℃ for 1h. Add dilute hydrochloric acid solution, separate the liquids, wash the organic phase with 0.9% sodium chloride aqueous solution, and concentrate the dichloromethane phase. The concentrate is slurried and dried with ethyl acetate to obtain 0.44g, with a yield of 41.8%.

[0079] Structural confirmation

[0080] Compound 4 hydrochloride 1 H-NMR spectrum and 13 C-NMR diagrams are shown in Figure 7 and Figure 8 . Figure 7 The attribution of each peak is shown in Table 4.

[0081] Table 4

[0082]

[0083] Example 5: Effect of isopropylphenol compounds on the alleviation of cardiotoxicity caused by quinolone antibiotics

[0084] The method disclosed in the article "Study on the Mechanism of Protective Effect of Sophora japonica glycosides on Doxorubicin-Induced Myocardial Cell Damage" was basically adopted to investigate the mitigating effect of the isopropyl phenol compounds described in the present invention on the cardiotoxicity caused by quinolone antibiotics.

[0085] 5.1 Materials Drugs tested:Solution I: a solution with a concentration of 1 mM prepared by dissolving moxifloxacin or levofloxacin in DMSO; Solution II: solution I mixed with an equal volume of DMSO; Solution III: one of the hydrochlorides of compounds 1 to 4 was diluted twice with DMSO, with the highest concentration being 10 μM; Solution IV: solution I and solution III were mixed in equal volumes.

[0086] Test cells: Rat myocardial H9c2 cells were donated by the Laboratory of Pharmacology and Toxicology, School of Pharmacy, Sun Yat-sen University.

[0087] 5.2 Methods

[0088] 80% of H9c2 cardiomyocytes were digested and diluted, and inoculated into 96-well plates, 6,000 cells / well, with 3 replicates per group. After they adhered to the wall, 100 μL of solution II and IV were added respectively. After 24 hours, MTT reagent was added, incubated at 37°C for 4 hours, the supernatant was discarded, 150 μL of DMSO was added to each well, and the cells were shaken on a horizontal shaker for 15 minutes. The absorbance value (OD) of each well was detected using an ELISA reader at a wavelength of 570 nm, and the inhibition rate of cell viability was calculated according to the following formula. The experiment was repeated 3 times.

[0089] Inhibition rate = 1-(OD of each treatment group-OD of blank group) / (OD of blank control group-OD of blank group) × 100%.

[0090] The remission rate (RR) of each test substance on quinolone-induced cardiotoxicity was calculated using the following formula: RR = (1-cell inhibition rate of solution IV / cell inhibition rate of test solution II) × 100%.

[0091] Calculate the average remission rate of three consecutive concentration points, select the concentration point corresponding to the remission rate with the lowest absolute value of the difference from 50% for linear fitting with the remission rate value, and calculate RC 50 , i.e. “half effective remission concentration”), the results are shown in Table 5 (quinolone is moxifloxacin) and Table 6 (quinolone is levofloxacin).

[0092] 5.3 Results

[0093] Table 5

[0094]

[0095]

[0096] Table 6

[0097]

[0098] Y

[0099] It can be seen from Tables 5 and 6 that the isopropylphenol compounds of the present invention can significantly alleviate the cardiotoxicity caused by moxifloxacin and levofloxacin.

[0100] The same method was used to measure the effect of propofol on the cardiotoxicity induced by moxifloxacin and levofloxacin. All >-2.

[0101] Example 6 Preparation of injection containing isopropylphenol compounds

[0102] Take 10 g of the hydrochloride salt of compound 1, add 200 mL of water for injection, stir to dissolve, then add water for injection to 1000 mL, sterilize at 121° C. for 30 min, and divide into packages to obtain the product.

Claims

1. An isopropylphenol compound, characterized in that: The compound is a compound having a structure shown in Formula I or a pharmaceutically acceptable salt thereof: In Formula I, R1 is selected from one of isopropyl and prop-1-en-2-yl; R2 is selected from one of bromine, chlorine and fluorine; R3 is selected from hydrogen and a group having a structure as shown in Formula II: In formula II, R4 is selected from one of isopropyl and prop-1-en-2-yl; R5 is selected from one of bromine, chlorine and fluorine.

2. The isopropyl phenol compound according to claim 1, characterized in that The compound is selected from one of the following compounds 1 to 4 or a pharmaceutically acceptable salt thereof:

3. The method for preparing isopropylphenol compounds according to claim 2, characterized in that: The preparation method of the compound 1 is carried out according to the following reaction formula:

4. The method for preparing isopropylphenol compounds according to claim 2, characterized in that: The preparation method of the compound 2 is carried out according to the following reaction formula:

5. The method for preparing isopropylphenol compounds according to claim 2, characterized in that: The preparation method of the compound 3 is carried out according to the following reaction formula:

6. The method for preparing isopropylphenol compounds according to claim 2, characterized in that: The preparation method of compound 4 is carried out according to the following reaction formula:

7. A composition, characterized in that It comprises the isopropylphenol compound according to claim 1 or 2 and pharmaceutically acceptable excipients.

8. The composition according to claim 7, characterized in that The composition can be administered by injection.

9. Use of the isopropylphenol compound according to claim 1 or 2 in the preparation of a medicament for alleviating the cardiotoxicity caused by quinolone antibiotics.

10. The use according to claim 9, characterized in that The quinolone antibiotic is selected from one of levofloxacin and moxifloxacin.

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