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Benzothiazole formamide compound and application thereof

A compound, formamide technology, applied in the field of medicine, can solve serious problems such as drug resistance

Active Publication Date: 2017-08-08
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the research and development of this type of drug is also facing many challenges: the problem of drug resistance caused by tumor cell gene mutation is becoming more and more serious; a balance should be sought between multi-target inhibitory effects and highly selective inhibitory effects; preclinical experiments Accurately predict compound toxicity, pharmacokinetic characteristics, etc.

Method used

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  • Benzothiazole formamide compound and application thereof
  • Benzothiazole formamide compound and application thereof
  • Benzothiazole formamide compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Synthesis of N-benzyl-6-(2-diethylamino-2-oxoethoxy)benzo[d]thiazole-2-carboxamide (compound ZL01)

[0035] Step A: Synthesis of L-cysteine ​​ethyl ester hydrochloride

[0036] Put L-cysteine ​​(24.20g, 0.20mol) and 300mL of ethanol in a 500mL eggplant-shaped flask, and slowly add thionyl chloride (22mL, 0.30mol) dropwise in an ice-water bath. Continue to react for 3h, and heat to reflux for 12h. The reaction solution was cooled to room temperature, and the solvent was evaporated to obtain 36.42 g of white powder, with a yield of 98.1%.

[0037] Step B: Synthesis of S-(2,5-dihydroxyphenyl)cysteine ​​ethyl ester

[0038] Put L-cysteine ​​ethyl ester hydrochloride (22.28g, 0.12mol) and methanol 60mL in a 1000mL eggplant-shaped flask, stir to dissolve it. A solution prepared by p-benzoquinone (6.48 g, 0.060 mol) and 150 mL of methanol was added dropwise in an ice-water bath. After the addition was completed, the reaction was continued at room temperature for 3...

Embodiment 2

[0057] Example 2: Synthesis of N-benzyl-6-[2-(1-piperidinyl)-2-oxoethoxy]benzo[d]thiazole-2-carboxamide (compound ZL02)

[0058] Referring to the synthesis method of Example 1, 0.92 g of pink solid was obtained, yield: 74.8%. M.p.: 198-199℃; IR: (KBr,cm -1 ):υ3429.8, 2921.8, 2852.9, 1649.8, 1521.6, 1495.8, 1384.4, 1249.8, 1216.9, 1122.7, 1085.8, 956.0, 829.1, 730.0, 694.4; ESI-MS, m / z: calcd.409.15(M + ); found 410.1([M+H] + ); 1 H NMR (400MHz, CDCl 3 ): δ7.91(d, J=9.0Hz, 1H), 7.45(d, J=2.5Hz, 1H), 7.40–7.34(m, 5H), 7.21(dd, J=9.0, 2.5Hz, 1H) ,4.78(s,2H),4.68(d,J=6.0Hz,2H),3.59(t,J=5.1Hz,2H),3.48(t,J=5.1Hz,2H),1.68–1.55(m, 6H).

Embodiment 3

[0059] Example 3: Synthesis of N-benzyl-6-[2-(4-morpholinyl)-2-oxoethoxy]benzo[d]thiazole-2-carboxamide (compound ZL03)

[0060] Referring to the synthesis method of Example 1, 0.77 g of white solid was obtained, yield: 62.6%. M.p.:186-188℃;IR:(KBr,cm -1 ):υ3421.4, 3277.0, 2923.5, 2845.7, 1666.0, 1637.9, 1496.5, 1436.6, 1359.1, 1253.8, 1210.2, 1114.7, 1001.5, 838.4, 827.6, 697.5; ESI-MS, m / z1: calcd.13 ( + ); found 412.1([M+H] + ); 1 H NMR (400MHz, CDCl 3 ): δ7.92(d,J=9.0Hz,1H),7.45(d,J=2.3Hz,1H),7.38–7.34(m,5H),7.19(dd,J=9.0,2.4Hz,1H) , 4.79 (s, 2H), 4.68 (d, J=6.0Hz, 2H), 3.67–3.65 (m, 8H).

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Abstract

The invention belongs to the technical field of medicines and relates to a benzothiazole formamide compound and application thereof. The benzothiazole formamide compound comprises a derivative of the benzothiazole formamide compound and pharmaceutically applicable salt; a general molecular formula is shown in the description, wherein R1, R2 and Ar are described as claims and the description. The benzothiazole formamide compound and addition salt of the pharmaceutically applicable acid of the compound can be combined with an existing medicine or can be independently utilized as an epidermal growth factor tyrosine kinase inhibitor for treating related diseases of epidermal growth factor acceptor signal transduction disorder, such as small cell lung cancer, squamous cancer, glandular cancer, large cell lung cancer, colorectal cancer, breast cancer, ovarian cancer and renal cell carcinoma. A formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a benzothiazole carboxamide compound and its application and preparation method as an epidermal growth factor receptor tyrosine kinase inhibitor. Background technique [0002] For a long time, tumor treatment, which is a worldwide problem, has always been an important challenge in the field of medical research. In recent years, with the further elucidation of tumor pathogenesis and the continuous discovery of anti-tumor targets, protein tyrosine kinase (PTK) has become one of the most effective and promising anti-tumor drug targets. [0003] Epidermal growth factor receptor (EGFR) is a transmembrane protein with both an extramembrane ligand receptor binding domain and an intracellular tyrosine kinase activity domain. The EGFR family mainly includes four types of members: EGFR / ErbB-1, HER-2 / ErbB-2, HER-3 / ErbB-3 and HER-4 / ErbB-4. EGFR is widely distributed in the epithelial cell m...

Claims

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Application Information

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IPC IPC(8): C07D277/68C07D417/12A61K31/428A61K31/5377A61K31/454A61P35/00
CPCC07D277/68C07D417/12
Inventor 胡春张兰徐赫男金辄柯佳路奇
Owner SHENYANG PHARMA UNIVERSITY
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