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Medical application of benzothiazine derivative

A kind of use and pharmaceutical technology, applied in the field of medicine, can solve the problems of not enough to curb tumors, and the anti-tumor effect has not been reported in the literature.

Active Publication Date: 2013-09-04
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, tumor signal transduction is a complex, multi-factor protein network system, and inhibition of a single signal transduction is often not enough to curb tumor progression. Drug resistance to imatinib, gefitinib, and erlotinib has been clinically recognized Therefore, it is of great significance to find and study new targeted anti-tumor drugs
[0003] Patent literature reports that 2-methyl-4-hydroxyl-N-(aryl)-2H-1,2 benzothiazine-3-carboxamide-1,1-dioxide compounds have anti-inflammatory properties [see Lombardino J G.Benzothiazine dioxides[P].US3591584(1971-07-06)] and anti-platelet aggregation activity [see Lombardino J G, Wiseman E A.Benzothiazine dioxides as anti-thromobotic agents[P].US3862319(1975-06-21) ], its antitumor effect has not been reported in the literature

Method used

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  • Medical application of benzothiazine derivative
  • Medical application of benzothiazine derivative
  • Medical application of benzothiazine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Synthesis of 4-hydroxy-2-methyl-N-(3-methylphenyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 dioxide

[0014] 1.1 Synthesis of ethyl 1,1-dioxide of 1,3-oxo-1,2-benzisothiazole-2-acetate

[0015] Reaction formula

[0016]

[0017] reaction steps

[0018] Sodium saccharin (40.0 g, 0.17 mol), ethyl chloroacetate (21.0 g, 0.17 mol), and DMF 100 mL were sequentially added into the three-necked flask. The reaction temperature was raised slowly to 120°C for 3 hours. TLC [V (petroleum ether): V (ethyl acetate) = 1: 1 as developing solvent] showed that the reaction was almost complete. After cooling to room temperature, the reaction mixture was added to cold water (300 mL) with stirring, and a white solid precipitated immediately, which was filtered with suction, and the filter cake was washed three times with 50 mL of water. Recrystallize with 80% ethanol (100mL), cool, filter, and vacuum dry (60°C) to obtain 3-oxo-1,2-benzisothiazole-2-acetate ethyl 1,1-dioxide as white cr...

Embodiment 2

[0035] Synthesis of 4-Hydroxy-2-methyl-N-(4-methoxyphenyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (HP1)

[0036] Reaction formula

[0037]

[0038] reaction steps

[0039] According to the operating method of 1.4 in Example 1, 4-hydroxyl-2-methyl-N-(4-methoxyphenyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 - Dioxide light green solid, yield: 67.5%, m.p.253.2-255.1°C. 1H NMR (400MHz, DMSO-d6) δ: 14.23(s, 1H, NH), 10.24(s, 1H, OH), 8.04(d, J=8.0Hz, 1H, ArH), 7.95~7.86(m, 3H , ArH), 7.65(d, J=9.2Hz, 2H, ArH), 6.98(d, J=9.2Hz, 2H, ArH), 3.77(s, 3H, OCH 3 ), 2.86 (s, 3H, NCH 3 ); 13 C-NMR (100MHz, DMSO-d 6 )δ166.7, 156.9, 156.6, 134.0, 133.6, 133.0, 129.6, 127.8, 126.1, 124.1, 123.9, 113.7, 114.4, 55.2, 39.7; IR (KBr, cm -1 )υ: 3336.8, 2933.5, 1621.9, 1538.8, 1510.5, 1447.9, 1415.4, 1342.0, 1249.7, 1182.7, 1154.1, 1121.5, 1066.7, 1033.2, 933.7, 869.6, 830.6, 760.0 for CI-MS / ES, 7 17 h 16 N 2 o 5 S: 359.15 (M + -H).

Embodiment 3

[0041] Synthesis of 2-methyl-4-hydroxy-N-(3-bromophenyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (HP2)

[0042] Reaction formula

[0043]

[0044] reaction steps

[0045] According to the operation method of 1.4 in Example 1, 2-methyl-4-hydroxy-N-(3-bromophenyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-di Oxide white solid, yield 59.6%, m.p.271.1-273.3°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 13.82(s, 1H, NH), 10.42(s, 1H, OH), 8.06(d, 2H, J=8.0Hz, ArH), 7.96~7.89(m, 3H, ArH), 7.83(d, J=8.0Hz, 1H, ArH), 7.40~7.34(m, 2H, ArH), 2.87(s, 3H, NCH 3 ); 13 C-NMR (100MHz, DMSO-d 6 )δ: 167.3, 157.5, 138.6, 134.3, 133.6, 133.1, 132.8, 130.3, 127.7, 126.3, 124.6, 124.2, 121.5, 120.3, 111.4, 39.4; IR (KBr, cm -1 )υ: 3344.6, 3068.2, 2939.6, 1631.4, 1585.8, 1531.9, 1476.5, 1409.8, 1340.2, 1294.6, 1264.3, 1218.9, 1176.2, 1065.1, 865.9, 828.6, 770.5, 735.8 for I C-MS / z; 16 h 13 BrN 2 o 4 S: 408.04 (M + -H).

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Abstract

The invention relates to the field of medicine, in particular to a medical application of a benzothiazine derivative, namely an application of a 2-methyl-4-hydroxy-N-(aryl)-2H-1,2 benzothiazine-3-formamide-1,1-dioxide compound in an antitumor drug. A pharmacodynamic test proves that the compound with a general formula (I) has a certain anti-tumor curative effect.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to the medical use of a benzothiazine derivative, namely 2-methyl-4-hydroxy-N-(aryl)-2H-1,2-benzothiazine-3-methanol Application of amide-1,1-dioxide compounds in antineoplastic drugs. Background technique [0002] Tumor is one of the major diseases that seriously threaten human health. Although the research and development of anticancer drugs has made significant progress in the past ten years, the incidence of malignant tumors is still increasing year by year. The marketing of targeted therapy drugs such as imatinib, gefitinib, lapatinib, sorafenib, erlotinib and other signaling pathway inhibitors has brought new hope to the research and development of anti-tumor drugs. Compared with traditional chemotherapeutic drugs (alkylating agents, anti-metabolite drugs), anti-tumor drugs designed for key kinases or proteins in signaling pathways not only have the potential to reduce drug t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5415A61P35/00
Inventor 李家明何广卫许勤龙胡敏华王杰储昭兴
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE