A thiadiazine compound and its preparation method and application

Abstract

The present invention belongs to the field of pharmaceutical technology and specifically relates to a thiadiazine compound, its preparation method, and its use. The structural formula of the thiadiazine compound is shown in Formula 1A or Formula 1B. In Formula 1A, the substitution site corresponding to R is any one or any two adjacent substitution sites on the benzene ring; R is selected from one or two of hydroxyl, 4-hydroxyphenyl, 4-chlorophenyl, and 3,4-dimethoxy. In Formula 1B, the number of R' is one; R' is selected from any one of fluorine, chlorine, bromine, methyl, and trifluoromethyl. The present invention synthesized a series of thiadiazine compounds and studied their antioxidant activity, discovering two molecules with excellent antioxidant activity. Antioxidants have important medicinal value in many disease areas, such as cancer, cardiovascular disease, diabetes, neurological diseases, and liver diseases. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a thiadiazine compound and a preparation method and application thereof. Background Art

[0002] Free radicals are a class of highly chemically active molecules naturally produced in organisms. Under normal circumstances, free radicals participate in various physiological processes, such as signal transduction and immune responses. The body is able to balance the generation and removal of free radicals through the antioxidant system. However, when free radical production exceeds the body's ability to remove them, it causes oxidative stress, which in turn has a range of negative effects on the body. Excessive accumulation of free radicals can trigger a variety of pathological conditions, such as cell membrane damage, protein and gene damage, immune system problems, and neurological diseases. Therefore, it is extremely important to eliminate excess free radicals in the body. Antioxidants are a common substance that can remove excess free radicals from the body and mitigate their negative effects.

[0003] Antioxidants are substances with antioxidant activity. They have the ability to inhibit or reduce the damage caused by free radicals and other oxidants, such as reactive oxygen species, to organisms. Antioxidant activity is crucial for maintaining cellular health. Common antioxidants include vitamin C, vitamin E, beta-carotene, selenium, and glutathione, which scavenge free radicals in the body and protect against damage. Antioxidants exert their protective effects through various mechanisms. For example, they directly react with free radicals, converting them into more stable molecules, thereby preventing the free radical chain reaction from continuing; inhibit or slow the process of lipid peroxidation, protecting cell membrane integrity and preventing damage to cell membrane function; capture metal ions through chelation, preventing them from catalyzing the formation of free radicals; promote the repair of damaged molecules, helping to restore cellular function; and activate intracellular antioxidant enzymes, such as glutathione peroxidase and superoxide dismutase, to scavenge ROS and reduce oxidative stress. Antioxidants can help enhance the body's antioxidant activity, thereby maintaining overall health. Reactive oxygen species, for example, are also known as ROS.

[0004] Although some thiadiazine compounds currently show certain antioxidant potential, these compounds are structurally unstable in the body and easily decompose during storage, which limits their potential use as drugs or food additives. Summary of the Invention

[0005] To address the problem in the prior art that some thiadiazine compounds are structurally unstable in vivo and easily decompose during storage, the present invention provides a thiadiazine compound, a preparation method, and applications thereof. To achieve the above objectives, the present invention employs the following technical solutions:

[0006] The present invention provides a thiadiazine compound, the structural formula of the thiadiazine compound is shown in Formula 1A or Formula 1B:

[0007]

[0008] In Formula 1A, the substitution site corresponding to R is any one or any two adjacent substitution sites on the benzene ring; R is selected from one or two of hydroxyl, 4-hydroxyphenyl, 4-chlorophenyl and 3,4-dimethoxy.

[0009] In Formula 1B, the number of R' is 1; R' is selected from any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

[0010] The common point of the structures of the thiadiazine compound shown in Formula 1A and the thiadiazine compound shown in Formula 1B is that both contain the same parent core structure: the thiadiazine parent core structure.

[0011] The main difference is that, in the structure of the thiadiazine compound shown in Formula 1A, R is a substituent other than a benzyl group; in the structure of the thiadiazine compound shown in Formula 1B, a hydrogen atom of a phenolic hydroxyl group on the benzene ring is replaced by a benzyl group, and the benzyl group has a substituent on the benzyl ring.

[0012] The thiadiazine compound provided by the present invention has the characteristics of using benzyl as a lipophilic group to replace hydrophilic groups such as phenolic hydroxyl groups on the benzene ring. It has a stable structure in the body and is not easily decomposed during storage, thus solving the problem that some existing thiadiazine compounds have unstable structures in the body and are easily decomposed during storage.

[0013] Preferably, the thiadiazine compound is any one of the compounds shown in Formula 5 to Formula 18:

[0014]

[0015] The compounds shown in Formulas 5 to 18 provided by the present invention, except for the compounds shown in Formulas 5 and 6, all have lipophilic groups introduced into their structures. For example, in the structure of the compound shown in Formula 7, a lipophilic 4-chlorophenyl group is introduced at the para position of the benzene ring, in the structure of the compound shown in Formula 8, two lipophilic methoxy groups are introduced at two positions of the benzene ring, and in the structures of the compounds shown in Formulas 9 to 18, a benzyl group containing a substituent is introduced as a lipophilic group at the ortho, meta, and para positions of the benzene ring, respectively. It is worth noting that the introduction of these lipophilic groups into the structures of the compounds shown in Formulas 7 to 18 greatly improves the stability of the thiadiazine compounds, solving the problem that some existing thiadiazine compounds are structurally unstable in the body and easily decompose during storage.

[0016] The present invention also provides a method for preparing the thiadiazine compound, comprising the following steps:

[0017] The compound shown in Formula 1 and the compound shown in Formula 2 are used as raw materials and ethanol is used as a reaction solvent to prepare a thiadiazine compound shown in Formula 1A through a cyclization reaction.

[0018]

[0019] In Formula 1A, the substitution site corresponding to R is any one or any two adjacent substitution sites on the benzene ring; R is selected from one or two of hydroxyl, 4-hydroxyphenyl, 4-chlorophenyl and 3,4-dimethoxy.

[0020] The compound shown in Formula 1 and the compound shown in Formula 2' are used as raw materials and ethanol is used as the reaction solvent to prepare the thiadiazine compound shown in Formula 3' through cyclization reaction.

[0021]

[0022] The thiadiazine compound shown in Formula 1B is prepared by using the compound shown in Formula 3' and the compound shown in Formula 4 as raw materials, potassium carbonate as a basic catalyst, and DMF as a reaction solvent through electrophilic substitution reaction.

[0023]

[0024] In Formula 1B, the number of R' is 1; R' is selected from any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

[0025] Preferably, the reaction conditions for the cyclization reaction are: using ethanol as the reaction solvent and reacting at 45° C.–60° C. for 2 hours–6 hours.

[0026] Preferably, the reaction conditions for the electrophilic substitution reaction are: potassium carbonate as the alkaline catalyst, DMF as the reaction solvent, and the reaction at room temperature for 1 hour to 6 hours.

[0027] Preferably, the structure of the thiadiazine compound shown in Formula 1A prepared using the compound shown in Formula 1 and the compound shown in Formula 2 as raw materials is as follows: any substitution site on the R-substituted benzene ring or any two adjacent substitution sites on the benzene ring are substituted with a substituent R.

[0028] The substituent R is one or two of hydroxyl, 4-hydroxyphenyl, 4-chlorophenyl and 3,4-dimethoxy.

[0029] More preferably, the structure of the thiadiazine compound shown in Formula 1A prepared using the compound shown in Formula 1 and the compound shown in Formula 2 as raw materials is as follows: any substitution site on the R-substituted benzene ring is substituted by a hydroxyl group, or any two adjacent substitution sites on the benzene ring are respectively substituted by a methoxy group, or any two adjacent substitution sites on the benzene ring are simultaneously substituted by a phenyl group substituted by a 4-hydroxy group.

[0030] Furthermore, the structure of the thiadiazine compound shown in Formula 1A prepared using the compound shown in Formula 1 and the compound shown in Formula 2 as raw materials is as follows: the substitution position 4 on the R-substituted benzene ring is substituted by a hydroxyl group, or the substitution positions 3 and 4 on the benzene ring are respectively substituted by a methoxy group, or the substitution positions 3 and 4 on the benzene ring are simultaneously substituted by a phenyl group substituted with a 4-hydroxyl group.

[0031] Preferably, the structure of the thiadiazine compound shown in Formula 1B prepared using the compound shown in Formula 3' and the compound shown in Formula 4 as raw materials is as follows: the substitution site on the R'-substituted benzene ring is substituted by any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

[0032] More preferably, the structure of the thiadiazine compound shown in Formula 1B prepared using the compound shown in Formula 3' and the compound shown in Formula 4 as raw materials is as follows: the substitution positions 2, 3, and 4 on the R'-substituted benzene ring are substituted by any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

[0033] The present invention also provides a pharmaceutical composition comprising the thiadiazine compound and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt of the thiadiazine compound and a pharmaceutically acceptable carrier.

[0034] The carrier is one or more of a diluent, a binder, a wetting agent, a disintegrant, a lubricant and a glidant.

[0035] The present invention also provides use of the thiadiazine compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing an antioxidant.

[0036] Preferably, the antioxidant comprises the thiadiazine compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as an active ingredient.

[0037] The present invention prepares anthranilamide into a thiadiazine antioxidant through a chemical synthesis method. Compared with traditional antioxidants, the antioxidant prepared in the present invention using the thiadiazine compound or its pharmaceutically acceptable salt or the pharmaceutical composition as the active ingredient has a relatively stable chemical structure.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. The present invention provides a thiadiazine compound, a preparation method, and an application thereof. The thiadiazine compound provided by the present invention has the characteristic of using a benzyl group as a lipophilic group to replace a hydrophilic group such as a phenolic hydroxyl group on a benzene ring. It has a stable structure in vivo and is not easily decomposed during storage. This solves the problem of some existing thiadiazine compounds having unstable structures in vivo and easily decomposed during storage.

[0040] 2. The present invention synthesizes a thiadiazine skeleton and introduces a benzyl phenyl ether structure into the thiadiazine structure. Since the introduction of a phenyl group containing a phenolic hydroxyl group into the thiadiazine structure does not significantly enhance its antioxidant activity, the introduction of a benzyl group is a common strategy in drug design. The benzyl group provides additional electron density, which helps improve the antioxidant properties of the molecule. The p electron cloud on the benzyl ring can stabilize free radical intermediates, so compounds containing benzyl groups may exhibit enhanced antioxidant activity. The introduction of a benzyl phenyl ether structure into thiadiazine compounds has been shown to improve the compound's stability and enhance its antioxidant activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The results are the cell proliferation effect and cytotoxicity verification results of thiadiazine compounds 5-18 in the present invention; wherein, Figure 1 Figure A shows the cell proliferation effect and cytotoxicity verification of compound 5; Figure 1 Figure B shows the cell proliferation effect and cytotoxicity verification of compound 6; Figure 1 Figure C shows the cell proliferation effect and cytotoxicity verification of compound 7; Figure 1 Figure D in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 8; Figure 1 Figure E in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 9; Figure 1 Figure F shows the cell proliferation effect and cytotoxicity verification of compound 10; Figure 1 Figure G in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 11; Figure 1 Figure H in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 12; Figure 1 Figure I in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 13; Figure 1 Figure J in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 14; Figure 1 The K diagram in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 15; Figure 1 Figure L in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 16; Figure 1 Figure M in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 17; Figure 1 Figure N in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 18.

[0042] Figure 2 is the antioxidant capacity of thiadiazine compounds 5 to 18 in the present invention. DETAILED DESCRIPTION

[0043] The present invention will be described in detail below with reference to the accompanying drawings and specific examples, but they should not be construed as limiting the present invention. Unless otherwise specified, the technical means used in the following examples are conventional means well known to those skilled in the art, and the materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0044] Example 1

[0045] Compound 5: Preparation of 3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0046]

[0047] 516 mg 3 mmol of o-aminobenzenesulfonamide was added to a reaction flask, followed by 10 mL of anhydrous ethanol. 366 mg 3 mmol of 4-hydroxybenzaldehyde was then added to the reaction flask. The temperature was raised to 45°C with stirring and the reaction was continued for 3 h. The reaction was complete after TLC detection. The reaction was cooled to room temperature, and 10 mL of petroleum ether was added with stirring. The solid was separated to obtain compound 5 as a white solid with a yield of 82%. 1 HNMR (600MHz, DMSO-d6) δ9.63 (s, 1H), 7.74 (d, J = 12.0Hz, 1H), 7.51 (d, J = 7.9Hz, 1H), 7.46 (d, J = 8.3Hz, 2H), 7 .35–7.22 (m, 2H), 6.90 (d, J = 8.4Hz, 1H), 6.82 (d, J = 8.4Hz, 2H), 6.75 (t, J = 7.5Hz, 1H), 5.66 (d, J = 11.9Hz, 1H). 13CNMR (150MHz, DMSO-d6) δ158.0, 144.0, 132.7, 128.9, 127.9, 123.7, 121.5, 116.5, 116.3, 115.1, 68.2; [MH] - :275.3.

[0048] Among them, the structural formula of compound 5 is shown above.

[0049] Example 2

[0050] Compound 14: Preparation of 3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0051]

[0052] 200 mg (0.72 mmol) of compound 5 obtained above was dissolved in 6 mL of DMF, and 149 mg (1.08 mmol) of anhydrous potassium carbonate was added. The mixture was stirred at room temperature for 5 min, and then 136 mg (0.72 mmol) of 4-fluorobenzyl bromide was added. The reaction was allowed to proceed for 2 h. The reaction was complete as determined by TLC. The mixture was filtered, and distilled water was added dropwise to the filtrate with stirring. The crude product precipitated as a solid. The product was then washed with ethyl acetate:petroleum ether in a ratio of 1:2 to obtain the pure product: compound 14 as a white solid with a yield of 54%. 1 HNMR (600MHz, DMSO-d6) δ7.81 (d, J=11.9Hz, 1H), 7.59 (d, J=8.6Hz, 2H), 7.52 (t, J=7.4Hz, 3H), 7.35–7.28 (m, 2H), 7.23 (t , J=8.8Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 6.91 (d, J=8.4Hz, 1H), 6.76 (t, J=7.5Hz, 1H), 5.73 (d, J=11.8Hz, 1H), 5.15 (s, 2H). 13 CNMR (150MHz, DMSO-d6) δ161.7 (d, J=241.5Hz), 158.7, 143.9, 133.2 (d, J=3Hz), 132.8, 129.8 ( d, J=7.5Hz), 129.8, 128.9, 123.7, 121.5, 116.6, 116.3, 115.3, 115.2, 114.7, 68.5, 67.9; [M+H] + :385.1.

[0053] Among them, the structural formula of compound 14 is shown above.

[0054] Example 3

[0055] Compound 6: Preparation of 3-(6-hydroxynaphthalen-2-yl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine 1,1-dioxide

[0056]

[0057] The preparation method of compound 6 refers to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that the 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is replaced by 6-hydroxy-2-naphthaldehyde.

[0058] NMR data of compound 6: 1 HNMR (600MHz, DMSO-d6) δ9.86 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 11.4Hz, 1H), 7.82 (d, J = 8.6Hz, 1H), 7.78 (d, J = 8.4Hz, 1H), 7.68 (d, J = 8.4Hz, 1H), 7 .55(d, J=7.7Hz, 1H), 7.45(s, 1H), 7.33(t, J=7.1Hz, 1H), 7.21–7.10(m, 2 H), 6.94 (d, J=8.2Hz, 1H), 6.78 (t, J=7.1Hz, 1H), 5.89 (d, J=11.2Hz, 1H). 13 CNMR (150MHz, DMSO-d6) δ156.0, 144.0, 134.9, 132.8, 131.5, 129.7, 127.1, 126.6, 126.4, 125.3, 123.7, 121.6, 119.2, 116.7, 116.4, 108.6, 68.6; [M+H] + :327.1.

[0059] Among them, the structural formula of compound 6 is shown above.

[0060] Example 4

[0061] Compound 7: Preparation of 3-(4'-chloro-[1,1'-biphenyl]-4-yl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0062]

[0063] The preparation method of compound 7 refers to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that the 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is replaced by 4'-chloro-[1,1'-biphenyl]-4-carboxaldehyde.

[0064] NMR data of compound 7: 1 HNMR (600MHz, DMSO-d6) δ7.96 (d, J=12.1Hz, 1H), 7.81–7.71 (m, 6H), 7.58–7.51 (m, 3H), 7.44 (s, 1H), 7.33 (t, J=7.7Hz, 1H), 6.94 (d, J=8.3Hz, 1H), 6.79 (t, J=7.5Hz, 1H), 5.86 (d, J=12.1Hz, 1H). 13 CNMR (150MHz, DMSO-d6) δ143.9, 139.6, 138.4, 136.8, 132.8, 132.6, 129.0, 128.5, 128.2, 126.7, 123.8, 121.7, 116.8, 116.4, 68.0; [M+H] + :371.0.

[0065] Among them, the structural formula of compound 7 is shown above.

[0066] Example 5

[0067] Compound 8: Preparation of 3-(3,4-dimethoxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0068]

[0069] The preparation method of compound 8 refers to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that the 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is replaced by 3,4-dihydroxybenzaldehyde.

[0070] NMR data of compound 8: 1HNMR (600MHz, DMSO-d6) δ7.80 (d, J=12.0Hz, 1H), 7.53 (d, J=7.3Hz, 1H), 7.40–7.25 (m, 3H), 7.17 (dd, J=8.2, 1.8Hz, 1H ), 7.00 (d, J=8.3Hz, 1H), 6.90 (d, J=8.3Hz, 1H), 6.76 (t, J=7.5Hz, 1H), 5.71 (d, J=12.0Hz, 1H), 3.79 (d, J=6.7Hz, 6H). 13 CNMR (150MHz, DMSO-d6) δ149.4, 148.7, 143.8, 132.8, 129.8, 123.7, 121.5, 120.0, 116.6, 116.3, 111.4, 111.1, 68.3, 55.6, 55.6; [M+H] + :321.1.

[0071] Among them, the structural formula of compound 8 is shown above.

[0072] Example 6

[0073] Compound 9: Preparation of 3-(2-((4-bromophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0074]

[0075] The preparation method of compound 9 was first referred to the synthesis method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that 4-hydroxybenzaldehyde in the reaction substrate in Example 1 was replaced with 2-hydroxybenzaldehyde. Then, the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2 was referred to, except that 4-fluorobenzyl bromide in the reaction substrate in Example 2 was replaced with 4-bromobenzyl bromide.

[0076] NMR data of compound 9: 1HNMR (600MHz, DMSO-d6) δ7.85 (d, J=12.2Hz, 1H), 7.74 (d, J=6.7Hz, 1H), 7.54 (dd, J=15.9, 8.1Hz, 3H), 7.46 (d, J=8.3Hz, 2H), 7.41 (t, J=7.2Hz, 1H), 7. 37–7.28 (m, 2H), 7.17 (d, J=8.2Hz, 1H), 7.08 (t, J=7.4Hz, 1H), 6.90 (d, J=8. 2Hz, 1H), 6.76 (t, J=7.3Hz, 1H), 6.25 (d, J=12.2Hz, 1H), 5.24–5.15 (m, 3H). 13 CNMR (150MHz, DMSO-d6) δ155.1, 144.2, 136.5, 132.9, 131.3, 130.4, 129.5, 128 .1, 125.4, 123.9, 121.6, 120.9, 120.9, 116.7, 116.3, 112.7, 68.8, 61.9; [M+H] + :445.0.

[0077] Among them, the structural formula of compound 9 is shown above.

[0078] Example 7

[0079] Compound 10: Preparation of 3-(2-((4-methylphenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0080]

[0081] The preparation method of compound 10 was first referred to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that 4-hydroxybenzaldehyde in the reaction substrate in Example 1 was replaced with 2-hydroxybenzaldehyde. Then, the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2 was referred to, except that 4-fluorobenzyl bromide in the reaction substrate in Example 2 was replaced with 4-methylbenzyl bromide.

[0082] NMR data of compound 10: 1HNMR (600MHz, DMSO-d6) δ7.80 (d, J=12.3Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.52 (d, J= 7.9Hz, 1H), 7.40 (dd, J=20.6, 8.1Hz, 3H), 7.31 (t, J=7.7Hz, 1H), 7.28 (s, 1H), 7.19 (d, J=8.3Hz, 1H), 7.16 (d, J=7.8Hz, 2H), 7.07 (t, J=7.5Hz, 1H), 6.90 (d, J=8.3Hz, 1 H), 6.76 (t, J=7.5Hz, 1H), 6.25 (d, J=12.3Hz, 1H), 5.23–5.10 (m, 2H), 2.29 (s, 3H). 13 CNMR (150MHz, DMSO-d6) δ144.2, 137.0, 133.8, 132.7, 130.3, 129.0, 128.1, 12 7.4, 125.4, 123.8, 121.6, 120.7, 116.5, 116.2, 112.7, 69.6, 61.8, 20.7; [M+H] + :381.1.

[0083] Among them, the structural formula of compound 10 is shown above.

[0084] Example 8

[0085] Compound 11: Preparation of 3-(3-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0086]

[0087] The preparation method of Compound 11 was first referred to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that 4-hydroxybenzaldehyde in the reaction substrate in Example 1 was replaced with 3-hydroxybenzaldehyde. Then, the synthesis method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2 was referred to, except that 4-fluorobenzyl bromide in the reaction substrate in Example 2 was replaced with 4-methylbenzyl bromide.

[0088] NMR data of compound 11: 1HNMR (600MHz, DMSO-d6) δ7.88 (d, J=12.1Hz, 1H), 7.53 (t, J=7.3Hz, 3H), 7.41 (s, 1H), 7.37 (t, 2H), 7.32 (t, J=7.7Hz, 1H), 7 .29–7.19 (m, 3H), 7.08 (d, J = 9.8Hz, 1H), 6.93 (d, J = 8.3Hz, 1H), 6.77 (t, J = 7.5Hz, 1H), 5.77 (d, J = 12.1Hz, 1H), 5.13 (s, 2H). 13 CNMR (150MHz, DMSO-d6) δ162.6, 161.0, 158.4, 143.8, 138.8, 133.2, 133.2, 132.8, 130.0, 129 .9, 129.7, 123.7, 121.6, 120.1, 116.7, 116.4, 115.5, 115.4, 115.2, 113.96, 68.6, 68.2; [M+H] + :385.1.

[0089] Among them, the structural formula of compound 11 is shown above.

[0090] Example 9

[0091] Compound 12: Preparation of 3-(3-((4-bromophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0092]

[0093] The preparation method of compound 12 was first referred to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that 4-hydroxybenzaldehyde in the reaction substrate in Example 1 was replaced with 3-hydroxybenzaldehyde. Then, the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2 was referred to, except that 4-fluorobenzyl bromide in the reaction substrate in Example 2 was replaced with 4-bromobenzyl bromide.

[0094] NMR data of compound 12: 1HNMR (600MHz, DMSO-d6) δ7.87 (d, J=12.1Hz, 1H), 7.61 (d, J=8.0Hz, 2H), 7.53 (d, J=7.9Hz, 1H), 7.44 (d, J=8.0Hz, 2H), 7.42–7.35 (m, 3H), 7.32 (t , J=7.7Hz, 1H), 7.25 (d, J=7.4Hz, 1H), 7.07 (d, J=9.4Hz, 1H), 6.92 (d, J=8.4Hz, 1H), 6.77 (t, J=7.5Hz, 1H), 5.77 (d, J=12.1Hz, 1H), 5.13 (s, 2H). 13 CNMR (150MHz, DMSO-d6) δ158.3, 143.8, 138.8, 136.4, 132.8, 131.4, 129.8, 129 .7, 123.7, 121.6, 121.0, 120.1, 116.7, 116.4, 115.5, 114.0, 68.5, 68.2; [M+H] + :445.0.

[0095] Among them, the structural formula of compound 12 is shown above.

[0096] Example 9

[0097] Compound 13: Preparation of 3-(3-((4-methylphenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0098]

[0099] The preparation method of compound 13 was first referred to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1, except that 4-hydroxybenzaldehyde in the reaction substrate in Example 1 was replaced with 3-hydroxybenzaldehyde. Then, the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2 was referred to, except that 4-fluorobenzyl bromide in the reaction substrate in Example 2 was replaced with 4-methylbenzyl bromide.

[0100] NMR data of compound 13: 1HNMR (600MHz, DMSO-d6) δ7.88 (d, J=12.1Hz, 1H), 7.54 (d, J=7.9Hz, 1H), 7.43–7.34 (m, 5H), 7.32 (t, J=7.7Hz, 1H), 7.23 (dd, J=12.4, 7.8Hz, 3H), 7.07 (d, J=10.0Hz, 1H), 6.93 (d, J=8.3Hz, 1H), 6.77 (t, J=7.5Hz, 1H), 5.77 (d, J=12.1Hz, 1H), 5.09 (s, 2H), 2.32 (s, 3H). 13 CNMR (150MHz, DMSO-d6) δ158.5, 143.8, 138.7, 137.1, 133.9, 132.8, 129.6, 129.0 , 127.8, 123.7, 121.6, 119.9, 116.7, 116.4, 115.5, 114.0, 69.3, 68.3, 20.8; [M+H] + :381.1.

[0101] Among them, the structural formula of compound 13 is shown above.

[0102] Example 10

[0103] Compound 15: Preparation of 3-(4-((4-chlorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0104]

[0105] Preparation method of compound 15: First, refer to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1 to obtain the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide). 2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) as the starting material for the reaction, and proceed with a reaction similar to that in Example 2: referring to the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2, the 4-fluorobenzyl bromide in the reaction substrate in Example 2 was replaced by 4-chlorobenzyl bromide.

[0106] NMR data of compound 13: 1HNMR (600MHz, DMSO-d6) δ7.88 (d, J=12.1Hz, 1H), 7.54 (d, J=7.9Hz, 1H), 7.43–7.34 (m, 5H), 7.32 (t, J=7.7Hz, 1H), 7.23 (dd, J=12.4, 7.8Hz, 3H), 7.07 (d, J=10.0Hz, 1H), 6.93 (d, J=8.3Hz, 1H), 6.77 (t, J=7.5Hz, 1H), 5.77 (d, J=12.1Hz, 1H), 5.09 (s, 2H), 2.32 (s, 3H). 13 CNMR (150MHz, DMSO-d6) δ158.5, 143.8, 138.7, 137.1, 133.9, 132.8, 129.6, 129.0 , 127.8, 123.7, 121.6, 119.9, 116.7, 116.4, 115.5, 114.0, 69.3, 68.3, 20.8; [M+H] + :381.1.

[0107] Among them, the structural formula of compound 10 is shown above.

[0108] Example 11

[0109] Compound 16: Preparation of 3-(4-((4-bromophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0110]

[0111] Preparation method of compound 16: First, refer to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1 to obtain the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide). Using the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) as the reaction raw material, a reaction similar to that in Example 2 was carried out: refer to the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2, except that 4-fluorobenzyl bromide in the reaction substrate was replaced with 4-bromobenzyl bromide.

[0112] NMR data of compound 16: 1HNMR (600MHz, DMSO-d6) δ7.81 (d, J=12.0Hz, 1H), 7.59 (t, J=8.9Hz, 4H), 7.52 (d, J=7.2Hz, 1H), 7.43 (d, J=8.3Hz, 2H), 7.3 6–7.26 (m, 2H), 7.08 (d, J=8.7Hz, 2H), 6.90 (d, J=8.2Hz, 1H), 6.76 (t, J=7.2Hz, 1H), 5.73 (d, J=12.0Hz, 1H), 5.16 (s, 2H). 13 CNMR (150MHz, DMSO-d6) δ158.5, 143.9, 136.5, 132.8, 131.4, 129.9, 129.7, 128.9, 123.7, 121.5, 120.9, 116.6, 116.3, 114.72, 68.4, 67.9.[M+H] + :445.1.

[0113] Among them, the structural formula of compound 16 is shown above.

[0114] Example 12

[0115] Compound 17: Preparation of 3-(4-((4-(trifluoromethyl)phenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0116]

[0117] Preparation method of compound 17: First, refer to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1 to obtain the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide). The reaction was carried out similarly to that in Example 2 by using 4-trifluoromethylbenzyl bromide as the starting material of the reaction: referring to the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2, and replacing the 4-fluorobenzyl bromide in the reaction substrate with 4-trifluoromethylbenzyl bromide.

[0118] NMR data of compound 17: 1HNMR (600MHz, DMSO-d6) δ7.81 (d, J=12.1Hz, 1H), 7.77 (d, J=8.2Hz, 2H), 7.69 (d, J=8.1Hz, 2H), 7.60 (d, J=8.7Hz, 2H), 7.52 (dd, J=7.9, 1 .3Hz, 1H), 7.35–7.26 (m, 2H), 7.10 (d, J=8.7Hz, 2H), 6.90 (d, J=8.3Hz, 1H), 6.76 (t, J=7.9Hz, 1H), 5.73 (d, J=12.0Hz, 1H), 5.30 (s, 2H). 13 CNMR (150MHz, DMSO-d6) δ158.5, 143.9, 141.9, 132.8, 130.0, 129.0, 127.9 , 125.3 (q, J=7.5Hz), 123.7, 121.5, 116.6, 116.3, 114.7, 68.3, 67.9; [M+H] + :435.1.

[0119] Among them, the structural formula of compound 17 is shown above.

[0120] Example 13

[0121] Compound 18: Preparation of 3-(4-((4-methylphenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide

[0122]

[0123] Preparation method of compound 18: First, refer to the preparation method of the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 1 to obtain the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide). Using the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) as the reaction raw material, a reaction similar to that in Example 2 was carried out: Referring to the preparation method of the compound (3-(4-((4-fluorophenylmethoxy)phenyl))-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) in Example 2, the 4-fluorobenzyl bromide in the reaction substrate was replaced with 4-methylbenzyl bromide.

[0124] NMR data of compound 18: 1HNMR (600MHz, DMSO-d6) δ7.83 (d, J=12.1Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 7.52 (d, J=7.9Hz, 1H), 7.35 (d, J=6.5Hz, 3H), 7.31 (t, J=7.8Hz, 1H), 7.20 (d, J=7.6Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 6.90 (d, J=8.4Hz, 1H), 6.75 (t, J=7.5Hz, 1H), 5.72 (d, J=12.0Hz, 1H), 5.12 (s, 2H), 2.31 (s, 3H). 13 C NMR (150MHz, DMSO-d6) δ158.8, 144.0, 137.1, 134.0, 132.8, 129.7, 129.1, 1 28.9, 127.8, 123.8, 121.5, 116.64, 116.33, 114.8, 69.1, 68.0, 20.8.[M+H] + :381.1.

[0125] Among them, the structural formula of compound 18 is shown above.

[0126] Example 14: In vitro drug toxicity testing

[0127] The cardiomyocyte cell line H9C2 was selected and 2×10 3 H9C2 cells were seeded in 96-well plates containing 100 μL of culture medium and cultured in a 5% CO2, 37°C incubator for 12 hours to allow attachment. Thiadiazines (compounds 5–18) were then added at varying concentrations and incubated for 24 hours. The cells were washed three times with PBS for 4 minutes each. A 10% by weight CCK-8 solution was then added, the plates gently tapped to mix, and the cells were incubated in the incubator for 1 hour. Absorbance at 450 nm was measured using a microplate reader, and the inhibitory rate of the drugs on the cells was calculated according to the formula to determine their effects on cardiomyocyte proliferation and cytotoxicity.

[0128] Here, different concentrations refer to 0, 1.25 μg / mL, 2.5 μg / mL, 5 μg / mL, 10 μg / mL, and 20 μg / mL.

[0129] The culture medium is Gibco's domestically produced DMEM culture medium, which is supplemented with 10% fetal bovine serum and 1% double-antibody by mass.

[0130] H9C2 cells are derived from rat cardiomyocytes.

[0131] PBS is a phosphate buffered saline solution with a concentration of 10 mM and a pH of 7.4.

[0132] The calculation formula is: (absorption value of the experimental group - absorption value of the blank control) / (absorption value of the control group - absorption value of the blank control)×100%.

[0133] The results are as follows Figure 1 As shown, the cell viability of compound 5, compound 6, compound 7, compound 8, compound 11, compound 12, compound 13, compound 14, compound 16, and compound 18 after incubation with H9C2 for 24 hours at different concentrations: 1.25μg / mL, 2.5μg / mL, 5μg / mL, 10μg / mL, and 20μg / mL was greater than 80%, indicating that the above compounds had no significant cytotoxicity under the experimental conditions. In addition, the cell viability of the above compounds was close to 100%, with only compound 6 and compound 14 close to 120%, indicating that the above compounds had no significant ability to promote proliferation. It is worth noting that compounds 9, 10, 15, and 17 had certain cytotoxicity at high doses. The concentration of subsequent functional verification of compound 9 was selected to be 5μg / mL, compound 10 was 1.25μg / mL, compound 15 was 10μg / mL, and compound 17 was 5μg / mL.

[0134] Depend on Figure 1 It can be seen that, except for compound 9, compound 10, compound 15, and compound 17, the synthesized thiadiazine compounds have no effect on the proliferation activity of cardiomyocytes and have low cytotoxicity, and can be further used for functional verification.

[0135] Example 15: In vitro pharmacological activity assay

[0136] The cardiomyocyte cell line H9C2 was used, 2×10 3 H9C2 cells were seeded into a 96-well plate containing 100 μL of culture medium and cultured in a 5% CO2, 37°C constant temperature incubator for 12 h to adhere to the wall. High glucose was induced for 48 h to construct a cell model (model group). Subsequently, the model group was randomly divided into two groups. One group was treated with PBS as a control, and the other group was washed with PBS three times for 4 min each time. Then, the cells were cultured according to the following formula: Figure 1 The cells were treated with a safe dose of a thiadiazide and incubated in a culture incubator for 24 hours. The cells were washed three times with PBS for 4 minutes each time. Then, 100 μL of culture medium containing DCFH-DA, diluted to 10 μmol / L in serum-free medium, was added to each well. The cells were incubated in a 37°C cell culture incubator for 20 minutes. The cells were washed three times with serum-free medium to remove any DCFH-DA that had not entered the cells. Fluorescence was measured in each well using a microplate reader with an excitation wavelength of 488 nm and an emission wavelength of 525 nm.

[0137] The DCFH-DA-containing culture medium comprises a DMEM culture medium containing 10 μmol / L DCFH-DA.

[0138] The results are as follows Figure 2 As shown in the results, compared with the model group, after treatment with compound 8, compound 11, compound 13, compound 14, compound 15, and compound 16, the fluorescence values ​​of the groups were significantly lower than those of the model group, indicating that the intracellular ROS content was significantly decreased compared with the model group, among which the decrease in the compound 13 and compound 16 groups was the most obvious.

[0139] Depend on Figure 2 It can be seen that compound 8, compound 11, compound 13, compound 14, compound 15, and compound 16 all have antioxidant activity, among which compound 13 and compound 16 have the strongest activity.

[0140] The above experimental results show that although compound 15 has good antioxidant activity, it has certain cytotoxicity at high concentrations. Compounds 8, 11, 13, 14, and 16 all have antioxidant activity and no obvious cytotoxicity. Among them, compounds 13 and 16 have the strongest activity and have the potential for clinical antioxidant application.

[0141] In summary, the thiadiazine compound provided by the present invention can be used as a stable antioxidant in clinical practice. Antioxidants have important medicinal value in many disease areas, such as cancer, cardiovascular disease, diabetes, nervous system diseases, and liver diseases.

[0142] The thiadiazine compound provided by the present invention has the characteristics of using benzyl as a lipophilic group to replace hydrophilic groups such as phenolic hydroxyl groups on the benzene ring. It has a stable structure in the body and is not easily decomposed during storage, thus solving the problem that some existing thiadiazine compounds have unstable structures in the body and are easily decomposed during storage.

[0143] It should be noted that when the present invention involves a numerical range, it should be understood that both endpoints of each numerical range and any value between the two endpoints can be selected. To avoid redundancy, the present invention describes a preferred embodiment.

[0144] Although preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once the basic inventive concepts become known, and all such changes and modifications fall within the scope of the present invention.

Claims

1. Use of a thiadiazine compound or a pharmaceutically acceptable salt thereof in the preparation of an antioxidant, characterized in that: The structural formula of the thiadiazine compound is shown in Formula 1A and / or Formula 1B: ； In Formula 1A, the substitution site corresponding to R is any one or any two adjacent substitution sites on the benzene ring; R is selected from one or two of hydroxyl, 4-hydroxyphenyl, and 4-chlorophenyl; In Formula 1B, the number of R' is 1; R' is selected from any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

2. The use according to claim 1, characterized in that The thiadiazine compound is at least one of the compounds shown in formulas 5 to 18: 。 3. The use according to claim 1, characterized in that The antioxidant takes a thiadiazine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

4. A method for preparing the thiadiazine compound according to claim 1, characterized in that: The steps include: Using the compound shown in Formula 1 and the compound shown in Formula 2 as raw materials and ethanol as the reaction solvent, a thiadiazine compound shown in Formula 1A is prepared through a cyclization reaction; ； In Formula 1A, the substitution site corresponding to R is any one or any two adjacent substitution sites on the benzene ring; R is selected from one or two of hydroxyl, 4-hydroxyphenyl, 4-chlorophenyl, and 3,4-dimethoxy; Using the compound shown in Formula 1 and the compound shown in Formula 2' as raw materials and ethanol as the reaction solvent, a thiadiazine compound shown in Formula 3' is prepared through a cyclization reaction; ； Using the compound represented by Formula 3' and the compound represented by Formula 4 as raw materials, potassium carbonate as a basic catalyst, and DMF as a reaction solvent, a thiadiazine compound represented by Formula 1B is prepared through an electrophilic substitution reaction; ； In Formula 1B, the number of R' is 1; R' is selected from any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

5. The method for preparing a thiadiazine compound according to claim 4, wherein: The reaction conditions for the cyclization reaction are: using ethanol as the reaction solvent and reacting at 45°C-60°C for 2 hours-6 hours.

6. The method for preparing a thiadiazine compound according to claim 4, wherein: The reaction conditions for the electrophilic substitution reaction are: potassium carbonate as a basic catalyst, DMF as a reaction solvent, and reaction time at room temperature for 1 hour to 6 hours.

7. The method for preparing a thiadiazine compound according to claim 4, wherein: The structure of the thiadiazine compound shown in Formula 1A prepared using the compound shown in Formula 1 and the compound shown in Formula 2 as raw materials is as follows: any substitution site on the R-substituted benzene ring is substituted by a hydroxyl group, or any two adjacent substitution sites on the benzene ring are respectively substituted by a methoxy group, or any two adjacent substitution sites on the benzene ring are simultaneously substituted by a phenyl group substituted by a 4-hydroxyl group.

Images