Thiadiazine compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a thiadiazine compound as well as a preparation method and application thereof. The structural formula of the thiadiazine compound is shown as a formula 1A or a formula 1B. In the formula 1A, the substitution site corresponding to R is any one or any two adjacent sites in the substitution sites on the benzene ring; r is selected from one or two of a hydroxyl group, a 4-hydroxyphenyl group, a 4-chlorphenyl group and a 3, 4-dimethoxy group; in the formula 1B, the number of R'is 1; r'is selected from any one of fluorine, chlorine, bromine, methyl and trifluoromethyl. A series of thiadiazine compounds are synthesized, the antioxidant activity of the thiadiazine compounds is researched, and two molecules with good antioxidant activity are found from the thiadiazine compounds. The antioxidants have important medicinal values in many disease fields, such as cancers, cardiovascular diseases, diabetes, nervous system 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 molecules that are naturally produced in organisms and are highly chemically active. Under normal circumstances, free radicals are involved in a variety of physiological processes, such as signal transduction, immune response, etc., and the body is able to balance the generation and removal of free radicals through the antioxidant system. However, when the generation of free radicals exceeds the body's ability to remove them, it will lead to oxidative stress, which will cause a series of negative effects on the body. Excessive accumulation of free radicals can cause a variety of pathological conditions, such as cell membrane damage, protein and gene damage, protein and gene damage, immune system problems and nervous system diseases. Therefore, it is very important to remove excess free radicals in the body. Antioxidants are a common substance that removes excess free radicals in the body and reduces the negative effects of free radicals.

[0003] Antioxidants refer to substances with antioxidant activity. They have the ability to inhibit or reduce the damage caused to organisms by free radicals and other oxidants such as reactive oxygen species. Antioxidant activity is very important for maintaining cell health. Common antioxidants include vitamin C, vitamin E, β-carotene, selenium, glutathione, etc. They can remove free radicals in the body and protect the body from damage. Antioxidants can exert their protective effects through various mechanisms, for example, directly reacting with free radicals and converting them into more stable molecules, thereby preventing the free radical chain reaction from continuing; inhibiting or slowing down the process of lipid peroxidation, protecting the integrity of cell membranes, and avoiding damage to cell membrane function; capturing metal ions through chelation to prevent them from catalyzing the generation of free radicals; promoting the repair of damaged molecules and helping to restore cell function; activating antioxidant enzymes in cells, such as glutathione peroxidase and superoxide dismutase, to remove ROS and reduce oxidative stress. Antioxidants can help improve the body's antioxidant activity, thereby maintaining the body's overall health level. Among them, the English name for reactive oxygen species is ROS.

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

[0005] In order to solve the problem that some thiadiazine compounds in the prior art are unstable in structure in the organism and easily decomposed during storage, the present invention provides a thiadiazine compound and a preparation method and application thereof. To achieve the above purpose, the present invention adopts the following technical solution:

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

[0007]

[0008] In Formula 1A, the substitution site corresponding to R is any one of the substitution sites on the benzene ring or any two adjacent sites; 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 as shown in Formula 1A and the thiadiazine compound as shown in Formula 1B is that the structures of the thiadiazine compound as shown in Formula 1A and the thiadiazine compound as shown in Formula 1B both contain the same mother core structure: the thiadiazine mother core structure.

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

[0012] The thiadiazine compounds provided by the present invention have the characteristics of using benzyl as a lipophilic group to replace hydrophilic groups such as phenolic hydroxyl groups on the benzene ring, having a stable structure in the body and not easily decomposed during storage, thus solving the problem that some existing thiadiazine compounds have an unstable structure 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 Formula 5 to Formula 18 provided by the present invention, except for the compounds shown in Formula 5 and Formula 6, all other compounds 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 into the para position of the benzene ring, in the structure of the compound shown in Formula 8, two lipophilic methoxy groups are introduced into the two positions of the benzene ring, and in the structures of the compounds shown in Formula 9 to Formula 18, a benzyl group containing a substituent is introduced into the ortho, meta, and para positions of the benzene ring as a lipophilic group. It is worth noting that the introduction of these lipophilic groups into the structures of the compounds shown in Formula 7 to Formula 18 greatly improves the stability of the thiadiazine compounds, and solves the problem that some existing thiadiazine compounds are unstable in structure in the organism and are easily decomposed 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 of the substitution sites on the benzene ring or any two adjacent sites; 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 a reaction solvent to obtain a thiadiazine compound shown in Formula 3' through a cyclization reaction.

[0021]

[0022] The compound shown in Formula 3' and the compound shown in Formula 4 are used as raw materials, potassium carbonate is used as a basic catalyst, and DMF is used as a reaction solvent to prepare a thiadiazine compound shown in Formula 1B through an 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. to 60° C. for 2 hours to 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 is carried out 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: any substitution site on the benzene ring substituted by R or any two adjacent substitution sites on the benzene ring are substituted by the 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: any substitution site on the benzene ring substituted by R 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.

[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: the substitution site 4 on the benzene ring substituted by R is substituted by a hydroxyl group, or the substitution sites 3 and 4 on the benzene ring are respectively substituted by a methoxy group, or the substitution sites 3 and 4 on the benzene ring are simultaneously substituted by a phenyl group substituted by 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: the substitution site on the benzene ring substituted by R' 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: 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 the use of the thiadiazine compound or its pharmaceutically acceptable salt or the pharmaceutical composition in the preparation of an antioxidant.

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

[0037] The present invention prepares o-aminobenzamide into a thiadiazine antioxidant by a chemical synthesis method. Compared with traditional antioxidants, the antioxidant prepared by the present invention using the thiadiazine compound or its pharmaceutically acceptable salt or the pharmaceutical composition as an active ingredient has the characteristics of 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 and a preparation method and application thereof. 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, has a stable structure in the body, and is not easy to decompose during storage, thus solving the problem that some existing thiadiazine compounds are unstable in structure in the body and are easy to decompose during storage.

[0040] 2. The present invention introduces the structure of benzyl phenyl ether into the thiadiazine structure by synthesizing the thiadiazine skeleton. Since the introduction of a phenyl group containing a phenolic hydroxyl group into the thiadiazine structure cannot well enhance its antioxidant activity, the introduction of a benzyl group is a common strategy in drug design. Due to the introduction of a benzyl ring, the benzyl group can provide additional electron density, which helps to improve the antioxidant properties of the molecule. The p electron cloud on the benzene ring can stabilize free radical intermediates, so compounds containing a benzyl group may exhibit better antioxidant activity. It has been proven that the introduction of the structure of benzyl phenyl ether into thiadiazine compounds improves the stability of the compound and enhances 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 in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 5; Figure 1 Figure B in the figure is the verification of the cell proliferation effect and cytotoxicity of compound 6; Figure 1 Figure C in the figure is the verification of the cell proliferation effect and cytotoxicity 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 in the figure is the verification of the cell proliferation effect and cytotoxicity 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 is described in detail below in conjunction with the accompanying drawings and specific examples, but 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, and 10 mL of anhydrous ethanol was added. 366 mg 3 mmol of 4-hydroxybenzaldehyde was further added to the reaction flask. The temperature was raised to 45 °C with stirring, and the reaction was carried out for 3 h. TLC detected that the reaction was complete, and the mixture was cooled to room temperature. 10 mL of petroleum ether was added with stirring, and 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 DMF, 149 mg 1.08 mmol of anhydrous potassium carbonate was added, and the reaction was stirred at room temperature for 5 min. Then 136 mg 0.72 mmol of 4-fluorobenzyl bromide was added and the reaction was continued for 2 h. The reaction was completed after TLC detection. The mixture was filtered, distilled water was added dropwise to the filtrate and stirred, and the precipitated solid was the crude product. The mixture was further eluted with ethyl acetate: petroleum ether = 1:2 to obtain the pure product: compound 14, 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 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 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 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 is 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, and 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is 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 is referred to, and 4-fluorobenzyl bromide in the reaction substrate in Example 2 is 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 is 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, and 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is 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 is referred to, and 4-fluorobenzyl bromide in the reaction substrate in Example 2 is 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 is 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, and 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is 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 is referred to, and 4-fluorobenzyl bromide in the reaction substrate in Example 2 is 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 is 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, and 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is 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 is referred to, and 4-fluorobenzyl bromide in the reaction substrate in Example 2 is 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 is 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, and 4-hydroxybenzaldehyde in the reaction substrate in Example 1 is 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 is referred to, and 4-fluorobenzyl bromide in the reaction substrate in Example 2 is 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 raw material for the reaction, and continue the 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 is 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] Embodiment 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), and use the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) as the reaction raw material to continue the reaction similar to Example 2: 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, and replace the 4-fluorobenzyl bromide in the reaction substrate 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 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 was replaced by 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), and use the compound (3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[e][1,2,4]-thiadiazine-1,1-dioxide) as the reaction raw material to continue the reaction similar to Example 2: 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, and replace the 4-fluorobenzyl bromide in the reaction substrate 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 inoculated in a 96-well plate containing 100 μL of culture medium, placed in a 5% CO2, 37°C constant temperature incubator for 12 hours to adhere to the wall, and different concentrations of thiadiazine compounds, compounds 5-compound 18 were added, incubated for 24 hours, washed 3 times with PBS, 4 minutes each time, and then added with 10% CCK-8 solution by mass, gently tapped the culture plate to mix, and incubated in the incubator for 1 hour. The 450nm light absorption value was measured using an ELISA instrument, and the inhibition rate of the drug on the cells was calculated according to the formula to determine its effect on the proliferation activity and cytotoxicity of cardiomyocytes.

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

[0129] The culture medium is Gibco domestic DMEM culture medium, which is supplemented with 10% fetal bovine serum and 1% double antibody.

[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 survival rate 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 obvious cytotoxicity under the experimental conditions. In addition, the cell survival rates of the above compounds were close to 100%, and only compound 6 and compound 14 were close to 120%, indicating that the above compounds had no obvious ability to promote proliferation. It is worth noting that compounds 9, 10, 15, and 17 have certain cytotoxicity at high doses. The concentration of subsequent functional verification of compound 9 was selected as 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 selected, 2×10 3 H9C2 cells were inoculated 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, each time for 4 min. Then, according to Figure 1 The results showed that a safe dose of thiadiazine compounds was added for treatment and incubated in the incubator for 24 hours. PBS was washed 3 times, 4 minutes each time, and then 100 μL of medium containing DCFH-DA diluted to 10 μmol / L with serum-free culture was added to each well, incubated in a 37°C cell culture incubator for 20 minutes, and the cells were washed three times with serum-free cell culture fluid to remove the medium of DCFH-DA that did not enter the cells. The microplate reader used an excitation wavelength of 488 nm and an emission wavelength of 525 nm to detect the fluorescence value of each well.

[0137] The formula composition of the culture medium containing DCFH-DA is DMEM culture medium containing 10 μmol / L DCFH-DA.

[0138] The results are as follows Figure 2 As shown in the figure, 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] From the above experimental results, it can be seen 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 which 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 compounds provided by the present invention have the characteristics of using benzyl as a lipophilic group to replace hydrophilic groups such as phenolic hydroxyl groups on the benzene ring, having a stable structure in the body and not easily decomposed during storage, thus solving the problem that some existing thiadiazine compounds have an unstable structure 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 the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. In order 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 they understand the basic inventive concepts, and all such changes and modifications fall within the scope of the present invention.

Claims

1. A thiadiazine compound, characterized in that: 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 of the substitution sites on the benzene ring or any two adjacent sites; 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 1; R' is selected from any one of fluorine, chlorine, bromine, methyl or trifluoromethyl.

2. The thiadiazine compound according to claim 1, characterized in that The thiadiazine compound is any one of the compounds shown in formula 5 to formula 18:

3. 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 a 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 of the substitution sites on the benzene ring or any two adjacent sites; 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 a reaction solvent, a thiadiazine compound shown in Formula 3' is prepared through a cyclization reaction; 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, a thiadiazine compound shown in 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.

4. The method for preparing thiadiazine compounds according to claim 3, characterized in that: 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.

5. The method for preparing thiadiazine compounds according to claim 3, characterized in that: The reaction conditions for the electrophilic substitution reaction are: potassium carbonate as a basic catalyst, DMF as a reaction solvent, and the reaction time at room temperature for 1 hour to 6 hours.

6. The method for preparing thiadiazine compounds according to claim 3, characterized in that: 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 benzene ring substituted by R 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.

7. A pharmaceutical composition, characterized in that Comprising the thiadiazine compound of claim 1 and a pharmaceutically acceptable carrier, or a pharmaceutically acceptable salt of the thiadiazine compound and a pharmaceutically acceptable carrier; The carrier is one or more of a diluent, a binder, a wetting agent, a disintegrant, a lubricant and a glidant.

8. Use of the thiadiazine compound or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 8 in the preparation of an antioxidant.

9. The use according to claim 8, characterized in that: The antioxidant takes a thiadiazine compound or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as an active ingredient.

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