A trifluoromethylseleno naphthoquinone derivative, preparation and application thereof
The photochemical synthesis of trifluoromethylselenoquinone derivatives has solved the problem of limited efficacy of existing anti-liver fibrosis drugs. It achieves efficient activation of vitamin D receptors, inhibits the activation and proliferation of liver myofibroblasts, and reduces extracellular matrix deposition, showing significant potential as an anti-liver fibrosis drug.
Patent Information
- Application Number
- CN202610390147.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-03-27
- Publication Date
- 2026-06-23
AI Technical Summary
Existing anti-liver fibrosis drugs have limited efficacy, and there is a lack of compounds that can efficiently activate vitamin D receptors and specifically inhibit the activation and proliferation of liver myofibroblasts.
Trifluoromethylselenoquinone derivatives were synthesized by photochemical synthesis. Using visible light as the driving force and ruthenium trichloride catalyst, the derivatives were synthesized in an oxygen atmosphere and purified by column chromatography to obtain the target compound.
This compound can efficiently activate vitamin D receptors, inhibit the proliferation and activation of hepatic myofibroblasts, and reduce extracellular matrix deposition, showing significant potential as an anti-hepatic fibrosis drug.
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Figure CN122255045A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a naphthoquinone derivative and its preparation method, and more particularly to a trifluoromethylselenoquinone derivative, its preparation, and its pharmaceutical uses. Background Technology
[0002] Liver fibrosis is a common pathological process in the progression of various chronic liver diseases (such as viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and autoimmune liver disease) to cirrhosis and liver cancer. Its core pathological feature lies in the transdifferentiation of hepatic stellate cells (HSCs) from a resting state into myofibroblasts, which possess the ability to proliferate, contract, and secrete large amounts of extracellular matrix (ECM), under the stimulation of various pathogenic factors. The continuous activation and proliferation of these myofibroblasts leads to excessive ECM deposition in the liver, damaging the normal liver structure and ultimately causing liver failure and even liver cancer. Therefore, inhibiting the proliferation and activation of hepatic myofibroblasts and reducing ECM deposition are key strategies for treating liver fibrosis.
[0003] The vitamin D receptor (VDR) is a nuclear receptor transcription factor. Recent studies have shown that VDR plays a crucial role in maintaining liver homeostasis and combating fibrosis. Activating the VDR signaling pathway can intervene in the pathological process of liver fibrosis in multiple dimensions: on the one hand, VDR activation can directly inhibit the activation and proliferation of hepatic stellate cells, inducing their reversal to a resting state; on the other hand, the VDR signaling pathway can block downstream signal transduction of pro-fibrotic factors such as transforming growth factor-β (TGF-β), thereby reducing the synthesis and secretion of ECM components such as collagen. In addition, VDR also participates in regulating inflammatory responses, immune responses, and autophagy, making VDR a highly promising multi-target intervention in the treatment of liver fibrosis.
[0004] Currently, there is a relative lack of commonly used anti-hepatic fibrosis drugs in clinical practice. While some drugs (such as ursodeoxycholic acid and silymarin) have certain hepatoprotective effects, their anti-fibrotic efficacy is limited or their mechanisms of action are singular, making it difficult to meet clinical needs. Therefore, developing novel compounds that can efficiently activate VDR, specifically inhibit the activation and proliferation of hepatic myofibroblasts, and reduce ECM deposition is of great significance for the treatment of liver fibrosis.
[0005] Trifluoromethylselenoyl (SeCF3), as a selenium- and fluorine-containing functional group, has attracted widespread attention in the field of medicinal chemistry in recent years due to its unique lipophilicity, metabolic stability, and biological activity. Introducing trifluoromethylselenoyl groups into the backbone of active molecules can often significantly improve the pharmacokinetic properties and enhance their pharmacological activity. Naphthoquinones are a class of natural products and drug backbones with broad biological activities; for example, vitamin K compounds contain naphthoquinone structures and exhibit excellent activities in anti-inflammatory and anti-tumor effects. However, methods for constructing such compounds by combining trifluoromethylselenoyl groups with naphthoquinone backbones using photochemical synthesis strategies have not yet been reported, and their medicinal applications in the field of anti-liver fibrosis are still lacking.
[0006] Based on this, the present invention provides a method for photochemical synthesis of trifluoromethylselenoquinone derivatives, and for the first time discovers that this type of compound can efficiently activate vitamin D receptors, significantly inhibit the proliferation and activation of hepatic myofibroblasts through a multi-target mechanism, and reduce extracellular matrix deposition, thereby providing a novel candidate molecule and a new strategy for the preparation of anti-hepatic fibrosis drugs. Summary of the Invention
[0007] Objectives of this invention: The objective of this invention is to provide a trifluoromethylselenonaphthoquinone derivative or a pharmaceutically acceptable salt thereof capable of efficiently activating vitamin D receptors. A second objective is to provide a method for preparing trifluoromethylselenonaphthoquinone derivatives, addressing the problem of how to prepare trifluoromethylselenonaphthoquinone derivatives via photochemical reactions. A third objective is to propose the application of trifluoromethylselenonaphthoquinone derivatives in the preparation of vitamin D receptor agonists or anti-liver fibrosis drugs, addressing the problem of how to prepare vitamin D receptor agonists or anti-liver fibrosis drugs.
[0008] Technical solution: A trifluoromethylselenoquinone derivative of formula (I) or a pharmaceutically acceptable salt thereof, as described in this invention:
[0009] (I) Among them, the R1 group is selected from H, halogen, C 1-5 Alkyl, C 1-5 One of alkoxy and acetyl groups, and the R2 group is selected from one of monosubstituted or unsubstituted phenyl and thiophene groups.
[0010] Preferably, the substituent group of the phenyl group is selected from C 1-4 Alkyl, C 1-4 One of the alkoxy groups or halogens.
[0011] Preferably, the trifluoromethylselenoquinone derivative includes any of the following compounds: , , , , , , , , .
[0012] The second aspect of this invention discloses a method for preparing the above-mentioned trifluoromethylselenoquinone derivative, comprising the following steps:
[0013] Among them, the R1 group is selected from H, halogen, C 1-5 Alkyl, C 1-5 One of alkoxy and acetyl groups, and the R2 group is selected from one of monosubstituted or unsubstituted phenyl and thiophene groups.
[0014] Preferably, the catalyst is ruthenium trichloride, and the reaction temperature is room temperature.
[0015] Preferably, the illumination conditions are white, blue, or purple visible light irradiation for 12-30 hours.
[0016] In some embodiments, the photoreaction is carried out with stirring in a Schlenk tube under an oxygen atmosphere.
[0017] Preferably, the molar ratio of compound II to bis(trifluoromethyl)diselenoether is 1:0.5-1.
[0018] Preferably, the above preparation method further includes the following post-processing steps: The reaction product was distilled under reduced pressure to remove the reaction solvent, and the crude product was then purified by column chromatography to obtain a trifluoromethylselenoquinone derivative.
[0019] In some embodiments, column chromatography purification is performed using silica gel column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 50-1:1.
[0020] Preferably, the solvent for the reaction includes at least one of methanol, ethanol, tert-butanol, and hexafluoroisopropanol.
[0021] The third aspect of this invention discloses the use of the above-mentioned trifluoromethylselenoquinone derivative in the preparation of vitamin D receptor agonists or anti-hepatic fibrosis drugs.
[0022] The trifluoromethylselenoquinone derivative can activate vitamin D receptor (VDR), inhibit the proliferation and activation of hepatic myofibroblasts, and reduce extracellular matrix deposition, showing promise as a drug for treating liver fibrosis.
[0023] Furthermore, the trifluoromethylselenoquinone derivative of this invention can be formulated alone or in combination with one or more pharmaceutically acceptable carriers to deliver the drug. For example, solvents, diluents, etc., can be used for oral dosage forms such as tablets, capsules, dispersible powders, granules, etc.
[0024] Various dosage forms of the pharmaceutical compositions of the present invention can be prepared according to methods well known in the pharmaceutical field. These pharmaceutical preparations may contain, for example, 0.05-90% by weight of the active ingredient in combination with a carrier, more commonly between about 15% and 50% by weight of the active ingredient.
[0025] The dosage of the compound of the present invention can be 0.005-5000 mg / kg / day, and the dosage may exceed this range depending on the severity of the disease or the dosage form.
[0026] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: This invention presents the first photochemical synthesis method for trifluoromethylselenoquinone derivatives. This method utilizes visible light as a clean driving force and offers advantages such as mild conditions and environmental friendliness, providing a new pathway for the efficient construction of trifluoromethylselenoquinone functional molecules.
[0027] This invention successfully introduced trifluoromethylselenoyl group into the naphthoquinone core, constructing a novel functional molecule that integrates the triple structural advantages of naphthoquinone skeleton, fluorine atom and chalcogenide, enriching the library of fluorine-containing chalcogenide heterocyclic compounds and providing a new structural unit for innovative drug development.
[0028] The compounds synthesized in this invention exhibit excellent VDR agonist activity and can reduce the activation of hepatic myofibroblasts and extracellular matrix deposition, showing promise for development into innovative drugs against liver fibrosis. Detailed Implementation
[0029] The technical solution of the present invention will be further described below.
[0030] Example 1: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0031] Under an oxygen atmosphere, 0.2 mmol of 2-hydroxymethylphenylacetylenol ketone, 0.12 mmol of bis(trifluoromethyl)diselenoether, 0.01 mmol of RuCl3·3H2O, and 2 mL of ethanol were added sequentially to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 20:1) to obtain the target compound 1a in a yield of 67%.
[0032] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.99 (t, J = 7.8 Hz, 1H), 7.85-7.84 (m, 2H), 7.64-7.53 (m, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.35 (d, J =7.8 Hz, 1H), 7.22 (t, J = 1.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 186.6, 184.3,150.4, 144.9, 139.5, 137.6, 136.9, 135.2, 133.1, 130.9, 129.7, 127.3, 127.0,126.2, 120.3. Example 2: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0033] Under an oxygen atmosphere, 0.2 mmol of 2-hydroxymethylphenyl-4-methylphenylethynyl ketone, 0.12 mmol of diselenoether (trifluoromethyl)diselenoether, 0.01 mmol of RuCl3·3H2O, and 2 mL of ethanol were added sequentially to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 10:1) to obtain the target compound 1b in 70% yield.
[0034] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 7.8 Hz, 1H), 8.10-8.02 (m, 1H), 7.70-7.62 (m, 2H), 7.21 (d, J = 7.8 Hz, 2H), 7.12 (d, J =7.8 Hz, 2H), 2.50(s, 3H); 13 C NMR (100 MHz, CDCl3) δ 187.6, 185.3, 149.6,142.1, 136.6, 135.4, 134.5, 133.9, 132.4, 129.5, 128.0, 127.7, 126.5, 125.1,119.3, 20.9. Example 3: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0035] Under an oxygen atmosphere, 5-fluoro-2-(3-(4-tert-butylphenyl)propynyl)benzyl alcohol (0.2 mmol), diselenoether (0.12 mmol), RuCl3·3H2O (0.01 mmol), and ethanol (2 mL) were sequentially added to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 20:1) to obtain the target compound 1c in 74% yield.
[0036] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.15 (dd, J = 8.8, 5.2Hz, 1H), 8.10 (dd, J = 8.0, 2.4 Hz, 1H), 7.75-7.70 (m, 2H), 7.36 (d, J = 8.4Hz, 2H), 7.16(s, 2H); 1.45 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 186.0, 179.7,155.0, 152.5, 136.6, 135.7, 133.9, 132.9, 132.0, 129.3, 129.0, 128.3, 127.6,126.6, 122.4, 35.5, 32.0. Example 4: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0037] Under an oxygen atmosphere, 0.2 mmol of 2-hydroxymethylphenyl-4-methoxyphenylethynyl ketone, 0.12 mmol of di(trifluoromethyl)diselenoether, 0.01 mmol of RuCl3·3H2O, and 2 mL of ethanol were sequentially added to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 1d, with a yield of 60%.
[0038] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.20 (dd, J = 7.8, 1.2Hz, 1H), 8.10 (dd, J = 7.2, 1.2 Hz, 1H), 7.86-7.74 (m, 2H), 7.20 (d, J = 9.0Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 3.78 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ184.3, 183.3, 159.1, 148.2, 135.1, 134.0, 131.9, 130.3, 130.0, 129.6, 127.0,126.6, 124.0, 122.3, 114.0, 56.5. Example 5: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0039] Under an oxygen atmosphere, 0.2 mmol of 2-hydroxymethylphenyl-4-fluorophenylethynyl ketone, 0.12 mmol of di(trifluoromethyl)diselenoether, 0.01 mmol of RuCl3·3H2O, and 2 mL of ethanol were added sequentially to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 1e in 57% yield.
[0040] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 7.6, 1.6Hz, 1H), 8.25 (dd, J = 6.8, 2.0 Hz, 1H), 7.98-7.87 (m, 2H), 7.58-7.43 (m,2H), 7.29-7.21 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 187.9, 186.8, 165.4, 149.9,134.2, 137.8, 136.5, 134.6, 134.3, 133.6, 128.5, 127.8, 125.2, 117.6, 113.2. Example 6: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0041] Under an oxygen atmosphere, 2-(3-thiophene-2-ylprop-2-ynyl)benzyl alcohol (0.2 mmol), diselenoether (0.12 mmol), RuCl3·3H2O (0.01 mmol), and ethanol (2 mL) were sequentially added to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target compound 1f in 42% yield.
[0042] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.22 (dd, J = 7.8, 1.2Hz, 1H), 8.20 (dd, J = 7.2, 1.8 Hz, 1H), 7.74-7.68 (m, 3H), 7.40 (d, J = 4.2Hz, 1H), 7.25-7.20 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 182.4, 179.9, 176.5,173.3, 163.9, 153.6, 153.5, 147.7, 140.2, 139.5, 133.5, 131.2, 128.5, 128.0,125.9. Example 7: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0043] Under an oxygen atmosphere, 5-chloro-2-(3-(2-methylphenyl)propynyl)benzyl alcohol (0.2 mmol), diselenoyl ether (0.12 mmol), RuCl3·3H2O (0.01 mmol), and ethanol (2 mL) were sequentially added to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 5:1) to obtain 1 g of the target compound, with a yield of 70%.
[0044] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.38 (dt, J = 7.8, 1.8Hz, 2H), 7.29-7.01 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 182.0, 181.1, 154.3,150.9, 142.8, 135.3, 133.6, 133.9, 132.1, 128.7, 128.0, 127.2, 126.7, 126.1,122.4 Example 8: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0045] Under an oxygen atmosphere, 5-chloro-2-hydroxymethylphenyl-4-methoxyphenylethynyl ketone (0.2 mmol), di(trifluoromethyl)diselenoether (0.12 mmol), RuCl3·3H2O (0.01 mmol), and ethanol (2 mL) were sequentially added to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 15:1) to obtain the target compound in 1 h, with a yield of 52%.
[0046] The NMR data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.94 (dd, J= 8.4, 2.0 Hz, 1H), 7.53-7.32 (m, 4H), 3.76 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 187.5, 178.6, 166.5, 149.4, 141.8,133.8, 132.6, 132.3, 131.9, 131.5, 126.5, 126.4, 124.2, 121.7, 115.5, 58.6. Example 9: A method for preparing a trifluoromethylselenoquinone derivative is as follows:
[0047] Under an oxygen atmosphere, 0.2 mmol of 2-hydroxymethyl-5-trifluoromethylphenylphenylethynyl ketone, 0.12 mmol of di(trifluoromethyl)diselenoether, 0.01 mmol of RuCl3·3H2O, and 2 mL of ethanol were added sequentially to a Schlenk tube equipped with a magnetic stirrer. After the addition was complete, a blue LED light was placed 2 cm away from the test tube, and the reaction was carried out at room temperature for 30 hours. After the reaction was completed, the organic phase was purified by removing the solvent using a rotary evaporator. The residue was purified by silica gel column chromatography (silica gel size 200-300 mesh, eluent: petroleum ether: ethyl acetate = 25:1) to obtain the target compound 1i in 57% yield.
[0048] The NMR data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.39 (d, J= 8.4 Hz, 1H), 8.01 (d, J= 7.8 Hz, 1H), 7.31-7.20 (m, 3H), 7.19 (d, J = 7.8Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 184.7, 183.5, 155.6, 146.2, 140.3, 137.0,136.3, 134.6, 133.7, 132.0, 130.1, 129.8, 129.6, 126.7, 125.7, 123.8, 122.4,121.9. Comparative Example 1: Everything else is the same as in Example 1, except that:
[0049] Replace 2-hydroxymethylphenylacetynyl ketone with:
[0050] The yield of compound 1a was 1.8%.
[0051] Comparative Example 2: Everything else is the same as in Example 1, except that: Replace 2-hydroxymethylphenylacetynyl ketone with:
[0052] The yield of compound 1a was 3.4%.
[0053] Comparative Example 3: The rest is the same as Example 1, except that:
[0054] The catalyst was replaced with copper acetate instead of ruthenium trichloride.
[0055] The yield of compound 1a was 7.1%.
[0056] Comparative Example 4: The rest are the same as in Example 1, except that:
[0057] The reaction was carried out in complete darkness without any blue light exposure.
[0058] The formation of compound 1a was not detected.
[0059] As can be seen from Comparative Examples 1 and 2, when the raw materials are changed, it is difficult to obtain the target product under room temperature photocatalytic conditions, and the reaction is quite difficult. Comparative Example 3 shows that under room temperature photocatalytic conditions, a ruthenium catalyst is required for the reaction, while a copper catalyst, due to its dependence on heating conditions, is difficult to catalyze under room temperature photocatalytic conditions, resulting in a low yield of the target product. Comparative Example 4 shows that the reaction depends on visible light irradiation, and the reaction hardly occurs under no light conditions.
[0060] Comparative Example 5: Everything else is the same as in Example 1, except that: Replace bis(trifluoromethyl)diselenoether with diphenyldiselenoether.
[0061] The final product obtained is:
[0062] The yield was 64%.
[0063] Comparative Example 6: Everything else is the same as in Example 1, except that: Replace bis(trifluoromethyl)diselenoether with dimethyldiselenoether.
[0064] The final product obtained is:
[0065] The yield was 71%.
[0066] Comparative Example 7: Everything else is the same as in Example 1, except that: Replace 2-hydroxymethylphenylacetynyl ketone with:
[0067] The final product obtained is:
[0068] The yield was 68%.
[0069] Comparative Example 8: The following compounds were used as test samples: .
[0070] Comparative Example 9: Everything else is the same as in Example 1, except that: Replace 2-hydroxymethylphenylacetynyl ketone with:
[0071] The final product obtained is:
[0072] The yield was 83%.
[0073] The trifluoromethylselenoquinone derivatives prepared in Examples 1-9 and Comparative Examples 5-9 were subjected to VDR affinity determination: As a key member of the nuclear receptor superfamily, VDR plays a central role in regulating the process of liver fibrosis, body metabolism, and inflammatory response. Its activation can block fibrosis-related signaling pathways and inhibit the activation of hepatic stellate cells, thereby alleviating liver fibrosis lesions. Therefore, it can be regarded as a novel drug candidate molecule for the treatment of liver fibrosis and related metabolic diseases.
[0074] The specific steps are as follows: Take the trifluoromethylselenoquinone derivative of the present invention and dilute it to 1 μM with the solvent specified in the kit as the test solution; mix the solution thoroughly with the fluorescently labeled VDR ligand and recombinant VDR protein, and add it to a 384-well black opaque detection plate; incubate at room temperature and in the dark for 3 hours to allow the compound in the system to competitively bind with the fluorescent ligand.
[0075] After incubation, the fluorescence polarization intensity of each well was measured using a multi-functional microplate reader under excitation wavelength of 535 nm and emission wavelength of 590 nm. Each batch of experiments included a positive control (calcipotriol) and a blank control (solvent group without the analyte). The VDR affinity of the samples was calculated using the following formula: Affinity rate (%) = (Blank group - Drug-treated group) / (Blank group - Positive control group) × 100% Detailed experimental results are shown in the table below:
[0076] The test results show that the trifluoromethylselenoquinone derivative of the present invention exhibits good VDR affinity overall. Among them, the 1d and 1h values show high activity and a relative VDR affinity greater than 100%, which exceeds that of the positive control Calcipotriol. The above results indicate that the compound provided by the present invention exhibits strong receptor affinity in the VDR competitive binding experiment and has the potential to be further developed into a vitamin D receptor modulator.
[0077] In Comparative Examples 5 and 6, when the trifluoromethyl group on the selenium group was replaced with a phenyl or straight-chain alkyl group, the VDR affinity of the compound decreased significantly, indicating that the substituents on the selenium group have a direct impact on the improvement of the VDR affinity of the compound.
[0078] In Comparative Examples 7 and 9, the VDR affinity of the compounds was significantly reduced after the ortho-substituent of the trifluoromethylselenoyl group was replaced by piperidinyl or methyl. This indicates that the type of substituent at this site on the naphthoquinone core also has a significant impact on the overall VDR affinity of the compound. Substitution with nitrogen-containing heterocycles or straight-chain alkyl groups not only fails to improve VDR affinity, but also further reduces the compound's affinity for VDR.
[0079] In Comparative Example 8, the lack of trifluoromethylselenoyl group resulted in the compound almost losing its VDR affinity, indicating that trifluoromethylselenoyl group is a necessary group for enhancing VDR affinity.
[0080] In summary, this invention develops a novel photochemical synthesis method for trifluoromethylselenoquinone derivatives. The method uses 2-(arylynylacetylenol)benzyl alcohol and bis(trifluoromethyl)diselenoether as reactants, ruthenium trichloride as a catalyst, and reacts under conditions of room temperature, oxygen atmosphere, and visible light irradiation. The target compound is then purified by column chromatography. This synthetic strategy uses visible light as a clean and green driving force, offering advantages such as mild conditions and environmental friendliness, and opening up a completely new pathway for constructing trifluoromethylselenoquinone functional molecules. Further bioactivity evaluation shows that these compounds possess vitamin D receptor (VDR) activating activity; VDR activating can inhibit the proliferation and activation of hepatic myofibroblasts, reduce the deposition of extracellular matrix such as collagen, and thus exert a pharmacological effect against liver fibrosis. Therefore, this invention provides a novel drug candidate molecule with development potential for clinical drug development in liver fibrosis and related metabolic diseases.
Claims
1. A trifluoromethylselenoquinone derivative of formula (I) or a pharmaceutically acceptable salt thereof: （I） in, The R1 group is selected from H, halogens, C. 1-5 Alkyl, C 1-5 One of alkoxy and acetyl groups, and the R2 group is selected from one of monosubstituted or unsubstituted phenyl and thiophene groups.
2. The trifluoromethylselenoquinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, The substituents of the phenyl group are selected from C 1-4 Alkyl, C 1-4 One of the alkoxy groups or halogens.
3. The trifluoromethylselenoquinone derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, Including any of the following compounds: 、 、 、 、 、 、 、 、 。 4. The method for preparing the trifluoromethylselenoquinone derivative according to claim 1, characterized in that, Includes the following steps: Among them, the R1 group is selected from H, halogen, C 1-5 Alkyl, C 1-5 One of alkoxy and acetyl groups, and the R2 group is selected from one of monosubstituted or unsubstituted phenyl and thiophene groups.
5. The method for preparing the trifluoromethylselenoquinone derivative according to claim 4, characterized in that, The catalyst is ruthenium trichloride, and the reaction temperature is room temperature.
6. The method for preparing the trifluoromethylselenoquinone derivative according to claim 4, characterized in that, The illumination conditions are white, blue, or purple visible light irradiation for 12-30 h.
7. The method for preparing the trifluoromethylselenoquinone derivative according to claim 4, characterized in that, The molar ratio of compound II to bis(trifluoromethyl)diselenoether is 1:0.5-1.
8. The method for preparing the trifluoromethylselenoquinone derivative according to claim 4, characterized in that, It also includes the following post-processing steps: The reaction product was distilled under reduced pressure to remove the reaction solvent, and the crude product was then purified by column chromatography to obtain a trifluoromethylselenoquinone derivative.
9. The method for preparing the trifluoromethylselenoquinone derivative according to claim 4, characterized in that, The solvent for the reaction includes at least one of methanol, ethanol, tert-butanol, and hexafluoroisopropanol.
10. The use of the trifluoromethylselenoquinone derivative according to any one of claims 1-3 in the preparation of vitamin D receptor agonists or anti-hepatic fibrosis drugs.