N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethylbenzenesulfonamide, analogues, preparation method, application and pharmaceutical composition of N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethylbenzenesulfonamide and analogues

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method and application of N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzenesulfonamide and analogues thereof, and a medicinal composition of the N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzenesulfonamide and the analogues thereof. The method comprises the following steps: dissolving a compound 1 and a compound 2 in an organic solvent, adding an acid-binding agent, carrying out a stirring reaction at 20-100 DEG C, and carrying out TLC detection until raw material fluorescence disappears so as to complete the reaction; and carrying out spin-drying on the reaction liquid, and carrying out crystallization or column chromatography separation on a crude product to obtain N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzenesulfonamide and the analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethyl benzenesulfonamide. N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethylbenzenesulfonamide and analogues thereof are used for recovering the physiological level of TERT in senescent tissues, and N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethylbenzenesulfonamide and analogues thereof are used for preparing oral pharmaceutical compositions. The N-(3-chloro-4-fluorophenyl)-4-fluoro-3, 5-dimethylbenzenesulfonamide and the analogue thereof can be used for recovering the physiological level of TERT (telomerase reverse transcriptase) of the whole aging tissue and relieving various aging characteristics.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and relates to a preparation method, use and pharmaceutical composition of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide and its analogs. Specifically, it includes a preparation method of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide and its analogs, a pharmaceutical composition, and the application through the oral administration route in treating and restoring the physiological level of TERT in aging tissues, and alleviating various aging characteristics. Alleviating aging characteristics; mainly manifested in alleviating cellular senescence and systemic inflammation, promoting the formation of new neurons, improving cognitive ability, and enhancing neuromuscular function. Background Art

[0002] Telomeres are closely related to aging. When telomeres become very short or are modified, they trigger a persistent DNA damage response, leading to cellular senescence. Telomerase is a ribonucleoprotein complex responsible for extending telomeres, and TERT (telomerase reverse transcriptase) is the core catalytic subunit of telomerase. TERT also affects the expression of many genes as a transcription factor, and these genes direct neurogenesis, learning and memory, cellular senescence, and inflammation. The expression level of TERT continuously decreases with age. (Chakravarti, D.; LaBella, K. A.; DePinho, R. A., Telomeres: history, health, and hallmarks of aging. Cell 2021, 184(2), 306 - 322.)

[0003] The research team led by Professor Ronald DePinho at The University of Texas MD Anderson Cancer Center discovered a small molecule compound through high-throughput screening. This compound can enhance the transcription of TERT in adult somatic cells of humans and mice, restoring its physiological expression level in young cells, promoting telomere synthesis, reducing DNA damage signals at telomeres, and thus reversing cellular senescence. It is called the TERT Activator Compound (TAC). A typical TAC molecule is N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide. N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide can upregulate the hypermethylation of the p16INK4A promoter mediated by DNMT3B to silence the expression of p16INK4A, and p16INK4A is a very important senescence-related factor. Shim, H.S.; Iaconelli, J.; Shang, X.; Li, J.; Lan, Z.D.; Jiang, S.; Nutsch, K.; Beyer, B.A.; Lairson, L.L.; Boutin, A.T.; Bollong, M.J.; Schultz, P.G.; DePinho, R.A., TERT activation targets DNA methylation and multiple aging hallmarks. Cell 2024, 187(15), 4030-4042.e13.

[0004] However, there is currently no reported efficient synthesis method for N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, and the oral administration effect is not yet clear. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a preparation method, use, and pharmaceutical composition of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide and its analogs for application in the treatment and prevention of senescence. The preparation method provided by the present invention has mild reaction conditions and simple operation.

[0006] To solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0007] Compounds of the first aspect:

[0008] An N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, and the compound shown in the general formula (I) is:

[0009]

[0010] Wherein X, X1 , X 2 are the same or different F, Cl, Br halogens respectively.

[0011] The chemical reaction formula of the compound shown in general formula (I) is:

[0012]

[0013] where X, X 1 , X 2 are the same or different F, Cl, Br halogens respectively, 1 is compound 1, and 2 is compound 2.

[0014] A preparation method of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, comprising the following steps:

[0015] Dissolve compound 1 and compound 2 in an organic solvent, stir and react at 20 - 100 °C, and when the fluorescence of the raw materials disappears detected by TLC, the reaction is completed; spin-dry the reaction solution, and crystallize and filter the crude product to obtain the white solid compound I.

[0016] Preferably, the organic solvent is one of dichloromethane, acetonitrile and tetrahydrofuran;

[0017] Dissolve compound 1 and compound 2 in an organic solvent, and also add an acid-binding agent, and the acid-binding agent is one of triethylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate, ammonium bicarbonate and sodium carbonate;

[0018] The molar ratio of compound 1: compound 2: organic solvent: acid-binding agent is 1:1:40:0 - 4;

[0019] The TLC detection is carried out with a developing agent, and the developing agent includes petroleum ether and ethyl acetate, and the volume ratio of petroleum ether: ethyl acetate is 4:1;

[0020] The temperature for spin-drying the reaction solution is 46 °C;

[0021] The solvent for crystallizing the crude product is a mixed solution of n-hexane and dichloromethane, the volume ratio of n-hexane: dichloromethane is 9:1, and the mass ratio of the solvent to the crude product is 10:1. The crystallization temperature is room temperature, generally 0 - 40 °C.

[0022] Compounds of the second aspect:

[0023] An analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, and the compound shown in general formula (II) is:

[0024]

[0025] where X, X 1 , X2 are the same or different F, Cl, Br halogens respectively.

[0026] A method for preparing an analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, and the reaction formula of the compound shown in general formula (Ⅱ) is:

[0027]

[0028] wherein X, X 1 , X 2 are the same or different F, Cl, Br halogens respectively, 1 is compound 1, and 2 is compound 2.

[0029] Preferably, it includes the following steps:

[0030] Dissolve compound 1 and compound 2 in an organic solvent, stir at 20 - 100 °C, and after detecting by TLC until the fluorescence of the raw materials disappears, the reaction is completed; spin-dry the reaction solution, and separate the crude product by column chromatography to obtain the white solid compound Ⅱ.

[0031] Preferably, the organic solvent is one of dichloromethane, acetonitrile and tetrahydrofuran;

[0032] Dissolve compound 1 and compound 2 in an organic solvent, and also add an acid-binding agent, and the acid-binding agent is one of triethylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate, ammonium bicarbonate and sodium carbonate;

[0033] The molar ratio of compound 1:compound 2:organic solvent:acid-binding agent is 1:2:40:0 - 4;

[0034] The TLC detection is carried out with a developing agent, and the developing agent includes petroleum ether and ethyl acetate, and the volume ratio of petroleum ether:ethyl acetate is 4:1;

[0035] The temperature for spin-drying the reaction solution is 46 °C;

[0036] The eluent used for column chromatography separation of the crude product is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether:ethyl acetate is 10:1; the stationary phase used for column chromatography separation of the crude product is 200 - 300 mesh column chromatography silica gel.

[0037] The use of an analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide and N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide is for restoring the physiological level of TERT in senescent tissues.

[0038] Any compound of the present invention can be administered orally to treat and restore the physiological level of TERT in aging tissues and alleviate various aging characteristics. This is mainly manifested in alleviating cellular senescence and systemic inflammation, promoting the formation of new neurons, improving cognitive ability, and enhancing neuromuscular function. It can be formulated into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be formulated into oral liquid preparations, such as oral solution preparations, oral suspensions, syrups, etc. When formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. The compounds described in the present invention can be formulated into common pharmaceutical preparations by adding pharmaceutically acceptable carriers, such as tablets, capsules, powders, syrups, liquids, suspensions, injections, and common pharmaceutical excipients such as flavors, sweeteners, liquid or solid fillers or diluents can be added.

[0039] A pharmaceutical composition or a pharmaceutical composition of one or more pharmaceutical carriers and / or diluents, excipients contains N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide or a pharmaceutical composition of an analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, and the dosage forms include tablets, capsules, powders, syrups, liquids, suspensions, and injections; oral preparations include tablets, capsules, and oral liquids; the oral dosage is 6 - 60 mg / Kg / day.

[0040] The pharmaceutical composition of the compound described in the first aspect and the second aspect and the pharmaceutical composition of one or more pharmaceutical carriers and / or diluents are any pharmaceutically acceptable dosage form clinically or pharmaceutically, preferably an oral preparation or an injection. It contains a physiologically effective amount of compound I or compound II, etc., 6 mg to 2000 mg of the compound, which can be 6 mg, 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 100 mg, 200 mg, 300 mg, 500 mg, 600 mg, 1000 mg, 1500 mg, 2000 mg, etc.

[0041] Advantageous technical effects of the present invention:

[0042] The compounds and their analogues of the present invention can restore the physiological level of TERT in the entire aging tissue and alleviate various aging characteristics. The alleviation of aging phenomena in the present invention includes alleviating cellular senescence and systemic inflammation, promoting the formation of new neurons, improving cognitive ability, and enhancing neuromuscular function. The preparation method provided by the present invention has the characteristics of mild reaction conditions and simple operation. Detailed implementation mode

[0043] Preparation method of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide and its analogues.

[0044] Experimental example 1: N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide (I-1):

[0045]

[0046] Dissolve compound 1-1 (222.66 mg, 1 mmol, 1 equiv) and compound 2-1 (145.56 mg, 1 mmol, 1 equiv) in acetonitrile (2.08 ml), add sodium carbonate (423.96 mg, 4 mmol, 4 equiv), stir at 40 °C for about 2 h. When the fluorescence of the raw materials disappears by TLC detection (the volume ratio of petroleum ether to ethyl acetate in the developing agent = 4:1), the reaction is completed. Rotate the reaction solution to dryness (46 °C), and crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (the volume ratio of n-hexane to dichloromethane = 9:1, the mass ratio of the crude product to the mixed solvent = 1:10) at room temperature, then filter to obtain the white solid compound I-1 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 6.4 Hz, 2H), 7.20 (dd, J = 6.4, 2.7 Hz, 1H), 7.07 (t, J = 8.6 Hz, 1H), 6.98 (dt, J = 8.8, 3.4 Hz, 1H), 6.72 (s, 1H), 2.30 (d, J = 2.3 Hz, 6H)], and the yield is 85 - 95%.

[0047] Experimental Example 2: Synthesis method of N-(3-chloro-4-fluorophenyl)-N,N-bis(4-fluoro-3,5-dimethylphenyl)sulfonamide (II-1):

[0048]

[0049] Dissolve compound 1-1 (222.66 mg, 1 mmol, 1 equiv) and compound 2-1 (291.12 mg, 2 mmol, 2 equiv) in dichloromethane (2.56 ml), stir at room temperature for about 12 h. When the fluorescence of the raw materials disappears by TLC detection (the developing agent: the volume ratio of petroleum ether to ethyl acetate = 4:1), the reaction is completed. Rotate the reaction solution to dryness, and separate the crude product by column chromatography (eluent: petroleum ether:ethyl acetate = 10:1; stationary phase: silica gel for column chromatography, 200 - 300 mesh) to obtain the white solid compound II-1, and the yield is 75 - 85%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (d, J = 6.4 Hz, 4H), 7.15 (d, J = 8.6 Hz, 1H), 7.11 (dd, J = 6.5, 2.6 Hz, 1H), 6.93 (ddd, J = 8.7, 4.2, 2.6 Hz, 1H), 2.35 (d, J = 2.2 Hz, 12H).

[0050] Experimental Example 3: Synthesis method of N-(3-chloro-4-fluorophenyl)-3-fluoro-2,4-dimethylbenzenesulfonamide (I-2):

[0051]

[0052] Dissolve compound 1-2 (222.66 mg, 1 mmol, 1 equiv) and compound 2-1 (145.56 mg, 1 mmol, 1 equiv) in tetrahydrofuran (3.24 ml), add triethylamine (404.76 mg, 4 mmol, 4 equiv), and stir at room temperature for about 12 h. After detecting by TLC (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappears, the reaction is completed. Rotate the reaction solution to dryness (46 °C), and crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature, then filter to obtain the white solid compound I-2 with a yield of 75-85%. 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J = 8.1 Hz, 1H), 7.15 (dd, J = 6.3, 2.6 Hz, 2H), 7.04 (t, J = 8.6 Hz, 1H), 6.93 (dq, J = 9.0, 3.0 Hz, 1H), 6.58 (s, 1H), 2.57 (d, J = 2.5 Hz, 3H), 2.35 (d, J = 2.3 Hz, 3H).

[0053] Experimental Example 4: Synthesis of N-(3,4-dichlorophenyl)-4-chloro-3,5-dimethylbenzenesulfonamide (I-3)

[0054]

[0055] Dissolve compound 1-3 (239.11 mg, 1 mmol, 1 equiv) and compound 2-2 (162.01 mg, 1 mmol, 1 equiv) in chloroform (3.23 ml), add potassium carbonate (552.82 mg, 4 mmol, 4 equiv), and stir at room temperature for about 12 h. After detecting by TLC (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappears, the reaction is completed. Rotate the reaction solution to dryness (46 °C), and crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature, then filter to obtain the white solid compound I-3 with a yield of 75-85%.

[0056] Experimental Example 5: Synthesis of N-(3-chloro-4-bromophenyl)-4-bromo-3,5-dimethylbenzenesulfonamide (I-4)

[0057]

[0058] Dissolve Compound 1-4 (283.56 mg, 1 mmol, 1 equiv) and Compound 2-3 (206.47 mg, 1 mmol, 1 equiv) in acetonitrile (2.08 ml), add sodium bicarbonate (336.04 mg, 4 mmol, 4 equiv), stir at room temperature for about 12 h. After detecting by TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappears, the reaction is completed. Rotate the reaction solution to dryness (46 °C), crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature, and filter to obtain a white solid compound with a yield of 75-85%.

[0059] Experimental Example 6: Synthesis of N-(3-chloro-4-fluorophenyl)-bis-4-chloro-3,5-dimethylbenzenesulfonamide (II-2)

[0060]

[0061] Dissolve Compound 1-5 (239.11 mg, 1 mmol, 1 equiv) and Compound 2-1 (291.12 mg, 2 mmol, 2 equiv) in acetonitrile (2.08 ml), add ammonium bicarbonate (316.22 mg, 4 mmol, 4 equiv), stir at room temperature for about 12 h. After detecting by TLC (developing solvent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappears, the reaction is completed. Rotate the reaction solution to dryness (46 °C), and separate the crude product by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1; stationary phase: column chromatography silica gel 200-300 mesh) to obtain a white solid compound II-2 with a yield of 75-85%.

[0062] Experimental Example 7: Synthesis of N-(3,4-difluorophenyl)-4-bromo-3,5-dimethylbenzenesulfonamide (I-5)

[0063]

[0064] Compound 1-6 (283.56 mg, 1 mmol, 1 equiv) and Compound 2-4 (129.11 mg, 1 mmol, 1 equiv) were dissolved in acetonitrile (2.08 ml), and sodium bicarbonate (336.04 mg, 4 mmol, 4 equiv) was added. The mixture was stirred at 40 °C for about 2 h. After TLC detection (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappeared, the reaction was completed. The reaction solution was concentrated by rotary evaporation (46 °C), and the crude product was crystallized with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature and filtered to obtain the white solid Compound I-5 with a yield of 75-85%.

[0065] Experimental Example 8: Synthesis of N-(3,4-difluorophenyl)-4-bromo-3,5-dimethylbenzenesulfonamide (I-5)

[0066]

[0067] Compound 1-6 (283.56 mg, 1 mmol, 1 equiv) and Compound 2-4 (129.11 mg, 1 mmol, 1 equiv) were dissolved in acetonitrile (2.08 ml), and ammonium bicarbonate (316.22 mg, 4 mmol, 4 equiv) was added. The mixture was stirred at 40 °C for about 2 h. After TLC detection (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappeared, the reaction was completed. The reaction solution was concentrated by rotary evaporation (46 °C), and the crude product was crystallized with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature and filtered to obtain the white solid Compound I-5 with a yield of 75-85%.

[0068] Experimental Example 9: Synthesis of N-(3,4-difluorophenyl)-4-bromo-3,5-dimethylbenzenesulfonamide (I-5)

[0069]

[0070] Dissolve Compound 1-6 (283.56 mg, 1 mmol, 1 equiv) and Compound 2-4 (129.11 mg, 1 mmol, 1 equiv) in acetonitrile (2.08 ml), add sodium carbonate (423.96 mg, 4 mmol, 4 equiv), stir at 40 °C for about 2 h. After detecting by TLC (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappears, the reaction is completed. Rotate the reaction solution to dryness (46 °C), crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature, and filter to obtain the white solid Compound I-5 with a yield of 75-85%.

[0071] Experimental Example 10: Synthesis of N-(3,4-difluorophenyl)-4-bromo-3,5-dimethylbenzenesulfonamide (I-5)

[0072]

[0073] Dissolve Compound 1-6 (283.56 mg, 1 mmol, 1 equiv) and Compound 2-4 (129.11 mg, 1 mmol, 1 equiv) in acetonitrile (2.08 ml), add triethylamine (101.19 mg, 1 mmol, 1 equiv), stir at 40 °C for about 2 h. After detecting by TLC (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1) until the fluorescence of the raw materials disappears, the reaction is completed. Rotate the reaction solution to dryness (46 °C), crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature, and filter to obtain the white solid Compound I-5 with a yield of 75-85%.

[0074] Experimental Example 11: Synthesis of N-(2-chloro-3-fluorophenyl)-4-bromo-3,5-dimethylbenzenesulfonamide (I-6)

[0075]

[0076] Dissolve Compound 1-6 (283.56 mg, 1 mmol, 1 equiv) and Compound 2-5 (145.56 mg, 1 mmol, 1 equiv) in acetonitrile (2.08 ml), add triethylamine (101.19 mg, 1 mmol, 1 equiv), stir at 40 °C for about 2 h. When the fluorescence of the raw materials disappears by TLC detection (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1), the reaction is completed. Rotate the reaction solution to dryness (46 °C), crystallize the crude product with a mixed solvent of n-hexane and dichloromethane (n-hexane: dichloromethane volume = 9:1, crude product: mixed solvent mass ratio = 1:10) at room temperature, and filter to obtain white solid Compound I-6 with a yield of 20-30%.

[0077] Experimental Example 12: Synthesis of N-(2-chloro-3-fluorophenyl)-bis-4-chloro-3,5-dimethylbenzenesulfonamide (II-3)

[0078]

[0079] Dissolve Compound 1-6 (239.11 mg, 1 mmol, 1 equiv) and Compound 2-5 (291.12 mg, 2 mmol, 2 equiv) in acetonitrile (2.08 ml), stir at room temperature for about 12 h. When the fluorescence of the raw materials disappears by TLC detection (developing agent: petroleum ether: ethyl acetate volume ratio = 4:1), the reaction is completed. Rotate the reaction solution to dryness (46 °C), and separate the crude product by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1; stationary phase: column chromatography silica gel 200-300 mesh) to obtain white solid Compound II-3 with a yield of 75-85%.

[0080] Experimental Example 13: Oral administration to explore dose optimization and dosing regimens and determine the efficacy results.

[0081] To investigate the efficacy and pharmacokinetics of each of Compound I and Compound II in the present invention in mice. Using senescent mice as experimental animals, divide the mice into 30 groups with 5 mice in each group. Except for the blank group, each of Compound I and Compound II is administered to the mice by gavage three times (dosing doses: 6 mg / kg / day, 30 mg / kg / day, 60 mg / kg / day). Take blood from the mouse eye sockets at 0.1 h, 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 16 h, and 24 h respectively to detect the blood drug concentration. Half-life: 0.589 h.

[0082] Blood drug concentration results of Compound I-1, I-2, and II-1:

[0083] Note: Blood drug concentration (ng / ml)

[0084] ①Gavage administration at 6 mg / Kg / day

[0085]

[0086]

[0087] ②Gavage administration at 30 mg / Kg / day

[0088]

[0089] ③Gavage administration at 60 mg / Kg / day

[0090]

[0091]

[0092] Drug effect: mainly reflected in the comparison of the expression level of hTERT-mRNA compared with the blank group.

[0093]

[0094] Note: "=" indicates little difference from the blank group; "+" indicates the anti-aging effect.

[0095] From the above results, it can be seen that Compounds I-1, I-2, and II-1 have good half-lives and good bioavailability in mice. Both Compound I and Compound II have certain anti-aging effects, and among them, Compound I-1 has the best effect.

[0096] Experimental Example 14: Pharmaceutical composition.

[0097] The mass composition of the pharmaceutical composition, in addition to the active Compound I or Compound II, includes:

[0098] Granules: Filling agents (such as lactose, starch): 50-80%; Binders (such as hydroxypropyl methylcellulose): 2-10%; Sweeteners (such as sucrose, aspartame): 5-20%; Glidants (such as silica): 0.1-0.5%.

[0099] Oral liquid: Solvents (such as water, ethanol): 80-95%; Sweeteners (such as sucrose, sorbitol): 5-20%; Preservatives (such as sodium benzoate, parabens): 0.01-0.5%; Thickening agents (such as sodium carboxymethylcellulose): 0.1-1%.

[0100] Tablet: Filler (such as lactose, microcrystalline cellulose): 30 - 70%; Binder (such as hydroxypropyl methylcellulose, polyvinylpyrrolidone): 2 - 10%; Disintegrant (such as sodium carboxymethyl starch, crospovidone): 2 - 10%; Lubricant (such as magnesium stearate, talc): 0.5 - 2%; Glidant (such as silica): 0.1 - 0.5%.

[0101] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide, characterized in that: The compound represented by general formula (I) is: Wherein X, X1, and X2 are the same or different F, Cl, and Br halogens; The chemical reaction formula of the compound represented by general formula (I) is: Wherein X, X1, X2 are the same or different F, Cl, Br halogens, 1 is compound 1, and 2 is compound 2.

2. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 1, characterized in that: The steps include: Compound 1 and compound 2 are dissolved in an organic solvent, and reacted by stirring at 20-100° C. The reaction is completed when the fluorescence of the raw material disappears as detected by TLC. The reaction solution is spin-dried, and the crude product is crystallized and filtered to obtain a white solid compound I.

3. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 2, characterized in that: The organic solvent is one of dichloromethane, acetonitrile and tetrahydrofuran; Dissolving compound 1 and compound 2 in an organic solvent, and adding an acid binding agent, wherein the acid binding agent is one of triethylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate, ammonium bicarbonate and sodium carbonate; The molar ratio of compound 1: compound 2: organic solvent: acid binding agent is 1: 1: 40: 0-4; TLC detection was performed with a developing agent, the developing agent included petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 4:1; The temperature of the reaction solution when it was spin dried was 46°C.

4. The method for preparing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 2, characterized in that: The solvent used for the crystallization of the crude product was a mixed solution of n-hexane and dichloromethane, the volume ratio of n-hexane: dichloromethane was 9:1, and the mass ratio of the solvent to the crude product was 10:

1.

5. The analog of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 1, characterized in that The compound represented by general formula (II) is: Wherein X, X1, X2 are the same or different F, Cl, Br halogens respectively.

6. The method for preparing the analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 5, characterized in that: The reaction formula of the compound represented by general formula (II) is: Wherein X, X1, X2 are the same or different F, Cl, Br halogens, 1 is compound 1, and 2 is compound 2.

7. The method for preparing the analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 6, characterized in that: The steps include: Compound 1 and compound 2 are dissolved in an organic solvent, stirred at 20-100° C., and the reaction is completed when the fluorescence of the raw material disappears as detected by TLC. The reaction solution is spin-dried, and the crude product is separated by column chromatography to obtain a white solid compound II.

8. The method for preparing the analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 7, characterized in that: The organic solvent is one of dichloromethane, acetonitrile and tetrahydrofuran; Dissolving compound 1 and compound 2 in an organic solvent, and adding an acid binding agent, wherein the acid binding agent is one of triethylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate, ammonium bicarbonate and sodium carbonate; The molar ratio of compound 1: compound 2: organic solvent: acid binding agent is 1: 2: 40: 0-4; TLC detection was performed with a developing agent, the developing agent included petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 4:1; The temperature of the reaction solution when it was spin-dried was 46°C; The eluent used for column chromatography separation of the crude product is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether:ethyl acetate is 10:1; the stationary phase used for column chromatography separation of the crude product is 200-300 mesh column chromatography silica gel.

9. Use of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide and its analogs according to claim 1 or 5, characterized in that: Used to restore physiological levels of TERT in aged tissues.

10. A pharmaceutical composition or a pharmaceutical composition of a plurality of pharmaceutical carriers and / or diluents, excipients containing N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide or an analogue of N-(3-chloro-4-fluorophenyl)-4-fluoro-3,5-dimethylbenzenesulfonamide according to claim 1 or 5, characterized in that: Dosage forms include tablets, capsules, powders, syrups, liquids, suspensions and injections; oral preparations include tablets, capsules and oral liquids; the oral dosage is 6-60 mg / Kg / day.

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