Application of benzoxazine-2, 2-dioxide derivative in preparation of antitumor drugs

Abstract

The invention discloses an application of a benzoxazine-2, 2-dioxide derivative in preparation of antitumor drugs, and belongs to the technical field of biological medicines. The benzoxazine-2, 2-dioxide is used for preparing an anti-tumor drug; the structural formula of the benzoxazine-2, 2-dioxide derivative, such as # imgabs0 #, has a relatively good inhibition effect on human choroidal melanoma cells MUM-2B (human choroidal melanoma) and human non-small cell lung cancer cells (A549), and can be used for preparing antitumor drugs.

Description

Technical Field

[0001] The present invention relates to a new use of a benzothiazine-2,2-dioxide derivative, and in particular to the use of a 4-alkylbenzo[e][1,2,3]thiazine-2,2-dioxide derivative in the preparation of anti-tumor drugs, belonging to the field of medical technology. Background Art

[0002] Choroidal melanoma is the most common intraocular malignant tumor in adults. Choroidal melanoma is a malignant tumor with a high mortality rate. About 40% of patients have liver metastasis at the beginning of diagnosis, and the survival rate of patients with liver metastasis of choroidal melanoma is only 50% to 80%. At present, choroidal melanoma is usually treated with a comprehensive treatment plan, hoping to preserve the eyeball and maintain partial vision without reducing the patient's survival rate. For patients with small tumors, good visual function, and strong patient requirements to preserve the eyeball, transpupillary thermotherapy, local radiotherapy, or local tumor resection can be used; if the tumor is large, the visual function is severely damaged, or the patient strongly requires the removal of the eyeball, eye removal combined with artificial orbital implantation can be performed. If the tumor cells have metastasized from the eye to the orbit, orbital enucleation can be performed. Transpupillary thermotherapy and radiotherapy can only reduce or maintain the volume of intraocular tumors to a limited extent. Surgery can locally remove the tumor but cannot prevent micrometastasis.

[0003] Currently, various chemotherapy, immunotherapy and combination of the two can be used clinically for patients with choroidal melanoma that has metastasized to the whole body. Unfortunately, most of these treatments have not been proven to be effective in treating primary human choroidal melanoma or systemic metastatic choroidal melanoma. Therefore, research and development of anti-choroidal melanoma drugs is urgent.

[0004] Benzo[e][1,2,3]thiazine-2,2-dioxide is an important class of heterocyclic compounds with biological activities such as antiviral, anticancer, anticonvulsant and anti-osteoporosis. The literature (Wang Jingjing, Liu Xue, Wu Ziyan, Li Feng, Qin Tingting, Zhang Siyuan, Kong Weiguang, Liu Lantao, Silver-catalyzed decarboxylative CH functionalization of cyclic aldimines with aliphaticcarboxylic acids, Chin. Chem. Lett., 2021, 32, 2777-2781) first publicly synthesized 4-alkylbenzo[e][1,2,3]thiazine-2,2-dioxide, but did not specifically disclose the specific use of 4-alkylbenzo[e][1,2,3]thiazine-2,2-dioxide, let alone mention its use in anti-tumor drugs. Summary of the invention

[0005] In view of the defects of the prior art, the purpose of the present invention is to provide a new use of benzothiazine-2,2-dioxide derivatives. The benzothiazine-2,2-dioxide derivatives have good inhibitory effects on human choroidal melanoma cells MUM-2B and human non-small cell lung cancer cells, and can be used to prepare anti-tumor drugs.

[0006] In order to achieve the above technical objectives, the present invention provides an application of a benzothiazine-2,2-dioxide derivative for preparing an anti-tumor drug; the benzothiazine-2,2-dioxide derivative has the following chemical structure:

[0007]

[0008] The benzothiazine-2,2-dioxide derivatives of the present invention are based on benzothiazine-2,2-dioxide as the parent structure. Such parent structure compounds are currently reported to have biological activities such as antiviral, anticancer, anticonvulsant and anti-osteoporosis, but such parent structure compounds have almost no inhibitory effect on human choroidal melanoma cells MUM-2B and human non-small cell lung cancer cells. The present invention unexpectedly discovered that introducing a relatively large molecular weight aliphatic hydrocarbon group, amine group or ether group on the 4-carbon of benzothiazine-2,2-dioxide can significantly improve its inhibitory effect on human choroidal melanoma cells MUM-2B, but most of them 4-Alkylbenzothiazine-2,2-dioxide derivatives have poor inhibitory effects on the activity of human choroidal melanoma cells MUM-2B and human non-small cell lung cancer cells. The present invention further optimizes the types of substituents at the 4th position on the benzothiazine-2,2-dioxide parent structure and the substituents at the 5th, 6th, 7th and 8th carbons on the benzene ring. A large number of experimental studies have shown that five benzothiazine-2,2-dioxide derivatives are selected, which have better inhibitory effects on the activity of human choroidal melanoma cells MUM-2B and human non-small cell lung cancer cells than the commercial broad-spectrum anticancer drug 5-fluorouracil on the market, and have clinical application and commercial value.

[0009] As a preferred embodiment, the anti-tumor drug has an inhibitory effect on human choroidal melanoma cells and human non-small cell lung cancer cells.

[0010] Compared with the prior art, the technical solution of the present invention has the following beneficial technical effects:

[0011] The present invention firstly finds that benzothiazine-2,2-dioxide has good inhibitory effects on human choroidal melanoma cells MUM-2B and human non-small cell lung cancer cells, and can be used for preparing anti-tumor drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 4-cyclohexyl-6-fluorobenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound A) 1 H NMR spectrum.

[0013] Figure 2 4-cyclohexyl-6-fluorobenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound A) 13 C NMR spectrum.

[0014] Figure 3 4-cyclohexyl-6-fluorobenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound A) 19 F NMR spectrum.

[0015] Figure 4 4-cyclohexyl-6-trifluoromethylbenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound B) 1 HNMR spectrum.

[0016] Figure 5 4-cyclohexyl-6-trifluoromethylbenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound B) 13 CNMR spectrum.

[0017] Figure 6 4-cyclohexyl-6-trifluoromethylbenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound B) 19 FNMR spectrum.

[0018] Figure 7 The antitumor activity of 4-cyclohexyl-6-fluorobenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound A) was investigated.

[0019] Figure 8 The antitumor activity of 4-cyclohexyl-6-trifluoromethylbenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound B) was investigated.

[0020] Fig. 9 The antitumor activity of 4-cyclohexyl-7-chlorobenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound C) was investigated.

[0021] Fig.10 The antitumor activity of 4-(hexane-2-yl)-benzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound D) was investigated.

[0022] Fig.11 The antitumor activity of 4-(1-butoxy)-butylbenzo[e][1,2,3]oxathiazine-2,2-dioxide (Compound E) was investigated.

[0023] Fig.12 The antitumor activity of 5-fluorouracil (5-FU). DETAILED DESCRIPTION

[0024] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. The following specific embodiments do not limit the protection scope of the claims.

[0025] Example 1

[0026] The synthetic route of the benzothiazine-2,2-dioxide derivative in the following specific examples is as follows:

[0027]

[0028] The specific synthesis steps are as follows: benzo[e][1,2,3]oxathiazine-2,2-dioxide (0.2 mmol), alkane (2 mmol), 6% Nd@C 3 N 4 Photocatalyst (10 mg), tetrabutylammonium chloride (0.4 mmol), acetonitrile (2 mL), 10 W purple LED (390 nm) irradiation, the reaction mixture was stirred at room temperature in a nitrogen atmosphere for about 24 hours, and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, the target product 4-alkylbenzo[e][1,2,3]thiazine-2,2-dioxide was separated by silica gel column chromatography.

[0029] Referring to the above preparation method, according to the different types of benzo[e][1,2,3]thiazine-2,2-dioxide and alkane, the following 4-alkylbenzo[e][1,2,3]thiazine-2,2-dioxide target products were synthesized:

[0030]

[0031]

[0032] Structural characterization of 4-alkylbenzo[e][1,2,3]oxathiazine-2,2-dioxide:

[0033]

[0034] 4-cyclohexylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:83%,yellow oil. 1 HNMR (400MHz, CDCl 3 )δ7.88(d,J=8.0Hz,1H),7.77–7.69(m,1H),7.43(t,J=7.7Hz,1H),7.35–7.28(m,1H),3.29–3.16(m,1H ),2.02–1.92(m,4H),1.82(d,J=13.2Hz,1H),1.72–1.61(m,2H),1.51–1.41(m,2H),1.37–1.29(m,1H); 13 C NMR (101 MHz, CDCl 3)δ183.9,154.1,136.8,127.9,125.9,119.6,115.6,43.4,30.9,26.0,25.7.

[0035]

[0036] 4-cyclohexyl-6-methylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:81%,yellow oil. 1 HNMR(500 MHz,CDCl 3 )δ7.61(d,J=2.1 Hz,1H),7.51(dd,J=8.4,2.1 Hz,1H),7.19(d,J=8.3 Hz,1H),3.23-3.17(m,1H),2.47(s,3H),2.01–1.90(m,4H),1.84–1.78(m,1H),1.68–1.60(m,2H),1.51–1.41(m,2H),1.35–1.27(m,1H); 13 C NMR(126MHz,CDCl 3 )δ183.9,151.9,137.5,135.8,127.6,119.2,115.3,43.1,30.8,25.9,25.7,21.1.

[0037]

[0038] 6-(tert-butyl)-4-cyclohexylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:78%,yellow oil. 1 H NMR(400 MHz,CDCl 3 )δ7.76(d,J=2.4 Hz,1H),7.72(dd,J=8.7,2.3Hz,1H),7.20(d,J=8.6 Hz,1H),3.23–3.17(m,1H),1.95–1.88(m,4H),1.78(d,J=13.1Hz,1H),1.66–1.56(m,2H),1.51–1.42(m,2H),1.35(s,9H),1.29–1.22(m,1H); 13 CNMR(101MHz,CDCl 3)δ184.2,151.8,149.1,134.3,124.0,119.0,114.9,43.3,34.9,31.2,30.9,25.9.

[0039]

[0040] 4-cyclohexyl-6-fluorobenzo[e][1,2,3]oxathiazine 2,2-dioxide:79%,yellow oil. 1 HNMR(400 MHz,CDCl 3 )δ7.50(d,J=8.2 Hz,1H),7.45–7.38(m,1H),7.30(dd,J=8.8,4.2 Hz,1H),3.12–3.05(m,1H),1.98–1.89(m,4H),1.80(d,J=13.6 Hz,1H),1.64(dd,J=14.2,10.8 Hz,2H),1.48–1.39(m,2H),1.34–1.27(m,1H); 13 C NMR(101 MHz,CDCl 3 )δ182.9,160.4,158.0,150.0,124.0(d,J=24 Hz),121.4(d,J=8Hz),116.4(d,J=7 Hz),114.0(d,J=24 Hz),43.6,30.8,25.9,25.7; 19 F NMR(376MHz,CDCl 3 )δ-113.54.

[0041]

[0042] 6-chloro-4-cyclohexylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:80%,yellow oil. 1 HNMR(400 MHz,CDCl 3 )δ7.81(d,J=2.4 Hz,1H),7.68(dd,J=8.8,2.4 Hz,1H),7.29(d,J=8.8 Hz,1H),3.19–3.12(m,1H),2.00–1.93(m,4H),1.87–1.80(m,1H),1.71–1.60(m,2H),1.53–1.43(m,2H),1.38–1.29(m,1H); 13C NMR(101 MHz,CDCl 3 )δ182.8,152.4,136.5,131.4,127.4,121.1,116.6,43.4,30.8,25.9,25.7.

[0043]

[0044] 6-bromo-4-cyclohexylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:77%,yellow oil. 1 HNMR(500 MHz,CDCl 3 )δ7.84(d,J=2.3 Hz,1H),7.72(dd,J=8.8,2.4 Hz,1H),7.14(d,J=8.8 Hz,1H),3.08–3.02(m,1H),1.90–1.83(m,4H),1.76–1.72(m,1H),1.60–1.52(m,2H),1.43–1.33(m,2H),1.27–1.18(m,1H); 13 C NMR(126 MHz,CDCl 3 )δ182.6,152.9,139.3,130.2,121.3,118.5,116.9,43.3,30.7,25.8,25.5.

[0045]

[0046] 4-cyclohexyl-6-iodobenzo[e][1,2,3]oxathiazine 2,2-dioxide:74%,yellowoil.1H NMR(400 MHz,CDCl 3 )δ8.15–8.13(m,1H),8.05–8.01(m,1H),7.33(d,J=5.0 Hz,1H),7.14(dd,J=8.8,4.9 Hz,1H),3.21–3.14(m,1H),2.05–1.96(m,4H),1.87(d,J=13.0Hz,1H),1.71(s,2H),1.58–1.47(m,2H),1.41–1.36(m,1H); 13 C NMR(101MHz,CDCl 3 )δ182.6,153.8,145.2,136.3,121.6,117.5,88.8,43.4,30.9,25.9,25.7.

[0047]

[0048] 4-cyclohexyl-6-(trifluoromethyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:78%,yellowoil. 1 H NMR(400 MHz,CDCl 3 )δ8.05(s,1H),7.98–7.88(m,1H),7.44(d,J=8.7Hz,1H),3.26–3.14(m,1H),1.99–1.91(m,4H),1.81(d,J=13.3 Hz,1H),1.68–1.60(m,2H),1.47(d,J=13.2 Hz,2H),1.35–1.29(m,1H); 13 C NMR(101 MHz,CDCl 3 )δ182.9,156.2,133.3(d,J=3 Hz),130.5,128.5(d,J=34 Hz),126.8,125.2(d,J=4 Hz),124.2,121.7,120.7,115.6,43.5,30.9,25.8,25.6; 19 F NMR(376 MHz,CDCl 3 )δ-62.41.

[0049]

[0050] 4-cyclohexyl-5-methylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:73%,yellow oil.

[0051] 1H NMR(500 MHz,CDCl 3 )δ7.64–7.56(m,1H),7.47–7.45(m,1H),7.22–7.18(m,2H),3.14–3.08(m,1H),2.33(s,3H),1.90–1.82(m,4H),1.75–1.69(m,1H),1.61–1.54(m,2H),1.40–1.30(m,2H),1.27–1.23(m,1H); 13 C NMR(126 MHz,CDCl 3)δ183.8,154.1,149.1,127.7,126.9,119.7,113.3,43.3,30.9,26.0,25.7,22.1.

[0052]

[0053] 7-chloro-4-cyclohexylbenzo[e][1,2,3]oxathiazine 2,2-dioxide):75%,yellow oil. 1 HNMR(400 MHz,CDCl 3 )δ7.81(d,J=2.4 Hz,1H),7.68(dd,J=8.8,2.4 Hz,1H),7.32–7.29(m,1H),3.21–3.09(m,1H),2.00–1.94(m,4H),1.84(d,J=13.2 Hz,1H),1.67–1.62(m,2H),1.54–1.45(m,2H),1.37–1.31(m,1H); 13 C NMR(101 MHz,CDCl 3 )δ182.8,152.5,136.5,131.4,127.4,121.2,116.6,43.5,30.8,25.9,25.7.

[0054]

[0055] 4-cyclohexyl-8-methylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:76%,yellow oil. 1 HNMR(500 MHz,CDCl 3 )δ7.66(d,J=8.0 Hz,1H),7.53(d,J=7.5 Hz,1H),7.26(d,J=15.5 Hz,1H),3.18(tt,J=11.7,3.1 Hz,1H),2.39(s,3H),1.99–1.88(m,4H),1.78(m,1H),1.67–1.58(m,2H),1.41(m,2H),1.29(t,J=3.6 Hz,1H); 13 C NMR(126MHz,CDCl 3 )δ184.3,152.5,138.1,129.4,125.4,125.1,115.6,43.5,31.0,26.1,25.8,15.2.

[0056]

[0057] 6-allyl-4-cyclohexylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:73%,yellow oil. 1 H NMR(400 MHz,CDCl 3 )δ7.70(d,J=7.9 Hz,1H),7.55(d,J=7.6 Hz,1H),7.31(t,J=7.8Hz,1H),5.99–5.89(m,1H),5.19–5.06(m,2H),3.52(d,J=6.6 Hz,2H),3.18(m,1H),1.98–1.88(m,4H),1.78(d,J=13.3 Hz,1H),1.67–1.58(m,2H),1.47–1.37(m,2H),1.24–1.25(m,1H); 13 C NMR(101 MHz,CDCl 3 )δ184.2,152.1,137.4,134.4,131.4,125.9,125.4,117.8,115.7,43.5,33.1,31.0,26.0,25.8.

[0058]

[0059] 4-cyclopentylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:77%,yellowoil. 1 H NMR(400MHz,CDCl 3 )δ7.96–7.82(m,1H),7.78–7.64(m,1H),7.45–7.31(m,2H),3.75–3.66(m,1H),2.07(m,4H),1.87(dd,J=13.3,6.5 Hz,2H),1.80–1.73(m,2H); 13 CNMR(101MHz,CDCl 3 )δ185.0,153.9,136.6,128.3,125.7,119.3,115.5,44.5,31.5,26.1.

[0060]

[0061] 4-cycloheptylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:74%,yellowoil. 1 H NMR(400MHz,CDCl 3 )δ7.87(dd,J=8.0,1.5 Hz,1H),7.74–7.70(m,1H),7.42(t,J=7.7 Hz,1H),7.31(d,J=8.0 Hz,1H),3.30–3.17(m,1H),2.00–1.89(m,5H),1.83–1.73(m,2H),1.67–1.62(m,1H),1.50–1.40(m,2H),1.35–1.28(m,2H); 13 C NMR(101MHz,CDCl 3 )δ183.9,154.0,136.8,127.9,125.9,119.5,115.6,43.3,35.6,30.8,25.9.

[0062]

[0063] 4-cyclooctylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:74%,yellow oil. 1 HNMR(400MHz,CDCl 3 )δ7.87(dd,J=8.2,4.3 Hz,1H),7.74–7.69(m,1H),7.44–7.39(m,1H),7.30(dd,J=8.4,3.7 Hz,1H),3.25–3.19(m,1H),1.99–1.88(m,5H),1.82–1.73(m,2H),1.62(dd,J=14.4,10.9 Hz,2H),1.50–1.41(m,2H),1.32–1.26(m,4H); 13 C NMR(101 MHz,CDCl 3 )δ183.9,154.0,136.8,127.9,125.9,119.5,115.5,43.3,35.6,30.8,25.9,25.7.

[0064]

[0065] <h2 style=";text-align:left;direction:ltr">4-cyclododecylbenzo[e][1,2,3]oxathiazine 2,2-dioxide:72%,yellowoil.<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR(500 MHz,CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> )δ7.77(dd,J=8.1,1.6 Hz,1H),7.65-7.62(m,1H),7.35-7.32(m,1H),7.24(dd,J=8.3,1.2 Hz,1H),3.43-3.38(m,1H),1.75(m,4H),1.45(m,2H),1.39–1.29(m,16H);<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR (126 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> )δ184.4,154.0,138.1,136.8,127.8,126.0,119.7,40.1,31.0,27.9,26.0,24.2,23.4,22.3.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0066] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0067] <h2 style=";text-align:left;direction:ltr"> 4-((1r,3R,5S)-adamantan-1-yl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:71%,yellowoil.<h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H NMR(500 MHz,CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> )δ7.74–7.59(m,1H),7.46–7.29(m,2H),7.16(d,J=6.5 Hz,1H),2.19(s,3H),2.07–1.64(m,12H);<h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> C NMR (126 MHz, CDCl<h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> )δ185.8,182.6,154.0,151.8,136.3,135.9,129.4,129.1,128.1,1 27.3,126.0,125.8,125.0,124.9,120.3,119.9,119.2,115.8,58.4, 49.2,45.2,45.0,40.6,39.4,38.7,38.4,38.2,38.1,37.4,36.5,36.4,32.2,31.9,31.8,31.4,29.0,28.4,28.0,27.8,27.8,27.7,27.4.<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0068] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0069] 4-(hexan-2-yl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:75%,yellowoil. 1 H NMR(400 MHz,CDCl 3 )δ7.83(dd,J=8.1,1.7 Hz,1H),7.72–7.68(m,1H),7.41–7.37(m,1H),7.31(dd,J=8.3,1.2 Hz,1H),3.42–3.37(m,1H),2.06–1.62(m,3H),1.38–1.30(m,6H),0.91–0.87(m,3H); 13 C NMR(101 MHz,CDCl 3 )δ184.7,154.1,136.9,127.8,125.9,119.7,116.1,38.6,34.7,29.6,22.8,18.5,14.0.

[0070]

[0071] 4-(1-butoxybutyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:74%,yellowoil. 1 H NMR(400 MHz,CDCl 3 )δ8.47–8.38(m,1H),7.78–7.65(m,1H),7.41–7.35(m,1H),7.34–7.30(m,1H),5.30(d,J=5.3 Hz,1H),4.38(dd,J=8.8,5.3 Hz,1H),3.48–3.44(m,2H),2.02–1.94(m,1H),1.85–1.78(m,1H),1.34–1.27(m,5H),0.98–0.95(m,3H),0.88–0.86(m,3H); 13 C NMR(101 MHz,CDCl 3 )δ180.8,154.4,137.1,129.5,125.7,119.4,114.6,70.6,37.3,31.9,29.9,19.4,19.3,13.9,13.8.

[0072]

[0073] 4-(tetrahydro-2H-pyran-2-yl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:76%,yellow oil. 1 H NMR(400 MHz,CDCl 3 )δ7.7–7.6(m,2H),7.39–7.35(m,1H),7.23(t,J=7.2Hz,1H),3.92–3.85(m,1H),3.61–3.52(m,1H),3.44–3.42(m,1H),1.94–1.73(m,3H),1.70–1.40(m,3H). 13 C NMR(100 MHz,CDCl 3 )δ180.6,167.86,137.76,130.94,126.30,118.72,115.46,79.45,65.39,28.33,25.22,22.63.

[0074]

[0075] 4-(1,4-dioxan-2-yl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:73%,yellowoil. 1 H NMR(400 MHz,CDCl 3 )δ7.96(d,J=7.8 Hz,1H),7.66(t,J=8.0 Hz,1H),7.34(t,J=7.8Hz,1H),7.24(d,J=8.2 Hz,1H),4.93(dd,J=9.3,2.7 Hz,1H),4.07(dd,J=12.0,2.8Hz,1H),3.97–3.75(m,5H); 13 C NMR(100 MHz,CDCl 3 )δ174.7,154.2,137.5,129.3,126.1,119.3,114.8,74.9,68.2,67.4,66.4.

[0076]

[0077] 4-((methyl(phenyl)amino)methyl)benzo[e][1,2,3]oxathiazine 2,2-dioxide:81%,yellow oil. 1 H NMR(400MHz,CDCl3 )δ7.42–7.26(m,5H),7.13–7.06(m,1H),6.86(dd,J=8.0,3.3Hz,3H),4.00(d,J=6.5Hz,2H),3.05(s,3H); 13 C NMR (101 MHz, CDCl 3 )δ151.2,148.9,129.8,129.7,126.9,125.6,120.5,119.4,118.0,113.0,111.1,77.5,77.2,76.8,55.7,40.1.

[0078] Example 2

[0079] The anticancer activity of the above benzothiazine-2,2-dioxide derivatives was tested:

[0080] Test methods and effect standards:

[0081] Test method: CCK-8 cell proliferation detection reagent (Dojindo Cell Counting Kit-8 CCK-8) was used to evaluate the in vitro anti-tumor activity against human choroidal melanoma cells (MUM-2B) and lung cancer cells (A549). MUM-2B cells and A549 cells were cultured at 5×10 3 Cells were seeded into the wells of a 96-well microplate at a density of 100 μL of growth medium. The cells were incubated at 37°C and 5% CO. 2 Then, 100 μL of 0.1% DMSO medium solution containing the test compound at a final concentration of 0 μM to 32 μM was added to the wells. For the control group, 100 μL of 0.1% dimethyl sulfoxide was added to the medium. The cells were incubated at 37°C and 5% CO 2 Incubate for 72 hours at 37°C. Then add 10 μL CCK8 to each well. The plate is incubated at 37°C for 1 hour and then recorded using EnVision Multilabel Reader (PerkinElmer) by measuring at 450 nm (with a reference wavelength of 630 nm for absorbance). 50 The values ​​were calculated using GraphPad Prism 6.0 software.

[0082] Efficacy criteria:

[0083] Using the commercial broad-spectrum anticancer drug 5-fluorouracil as a reference:

[0084] Table 1 Anticancer activity effect

[0085]

[0086]

[0087] As can be seen from Table 1, as a parent structure compound, benzo[e][1,2,3]oxathiazine-2,2-dioxide has a relatively low inhibitory activity against MUM-2B cells and A549 cells, and has little application value compared to the existing commercial 5-FU. However, after modifying and modifying the parent structure, several benzooxathiazine-2,2-dioxide derivatives obtained have good inhibitory effects on human choroidal melanoma cells MUM-2B and human non-small cell lung cancer cells (A549), which are better than the existing commercial 5-FU, and can be used to prepare anti-tumor drugs.

[0088] It should be understood by those skilled in the art that the discussion of any of the above embodiments is exemplary only and is not intended to imply that the scope of the present disclosure (including claims) is limited to these examples. Under the thinking of the present invention, the technical features in the above embodiments or different embodiments may also be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for simplicity. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. An application of a benzothiazine-2,2-dioxide derivative, characterized in that: For the preparation of anti-tumor drugs; The benzothiazine-2,2-dioxide derivative has the following chemical structure:

2. The use of a benzothiazine-2,2-dioxide derivative according to claim 1, characterized in that: The anti-tumor drug has an inhibitory effect on human choroidal melanoma cells and human non-small cell lung cancer cells.

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