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Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines and their applications
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A compound and 3-d technology, applied in the field of medicine, can solve the problems of decreased bioavailability, prolongation of cardiac QT interval, etc., and achieve the effect of obvious drug effect, novel structure type, and good development and application prospects
Active Publication Date: 2021-07-09
SHENYANG PHARMA UNIVERSITY
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[0004] Existing epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, erlotinib, lapatinib, etc., all have skin reactions such as diarrhea, rash, itching, and possible headache, heart attack, etc. Prolonged QT interval and decreased bioavailability, etc.
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Embodiment 1
[0041] Example 1: 7-[4-(4-methoxybenzoyl)methoxyphenyl]-4-(4-phenylpiperazin-1-yl)-5,6,7,8-tetra Preparation of Hydrobenzo[4,5]thieno[2,3-d]pyrimidine (W01)
[0042] Step A: Preparation of 4-(4-ethoxyphenyl)cyclohexanone
[0043] Put 15.0g (79.0mmol) of 4-(4-hydroxyphenyl)cyclohexanone, 109.0g (789.5mmol) of anhydrous potassium carbonate, 200mL of acetone, and 24.4g (157.9mmol) of diethyl sulfate into a 500mL eggplant type In the bottle, heated to reflux and stirred for 6 hours, evaporated the solvent to dryness under reduced pressure, added 500 mL of water to the residue, stirred at room temperature for 2 hours, filtered with suction, washed twice with water, and dried to obtain 16.6 g of a white solid with a yield of 96.5%, m.p. : 70-72°C.
[0044] Step B: Preparation of 2-amino-6-(4-ethoxyphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide
[0045] Add 2.0g (9.2mmol) of 4-(4-ethoxyphenyl)cyclohexanone, 0.8g (9.2mmol) of cyanoacetamide, and 0.3g (9.2mmol) of sulfur ...
Embodiment 2
[0056] Example 2: 7-[4-(4-methoxybenzoyl)methoxyphenyl]-4-[4-(4-fluorophenyl)piperazin-1-yl]-5,6, Preparation of 7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (W02)
[0057] Referring to the method of Example 1, a white solid was obtained with a yield of 36.7%. m.p.:142-144℃;IR(KBr,cm -1 ):3452,2919,2849,1694,1601,1510,1439,1384,1233,1172,981,830,715,618; 1 H-NMR (400MHz, CDCl 3 ):δ1.84-1.92(m,1H),2.14-2.16(m,1H),2.92-2.99(m,2H),3.11-3.25(m,5H),3.32-3.35(m,2H),3.48 -3.52(m,2H),3.61-3.66(m,2H),3.88(s,3H),5.22(s,2H),6.86-7.01(m,8H),7.19(d,J=8.8Hz,2H ), 8.01 (d, J=8.8Hz, 2H), 8.58 (s, 1H); ESI-MS (m / z): 609.3 ([M+H] + ).
Embodiment 3
[0058] Example 3: 7-[4-(4-methoxybenzoyl)methoxyphenyl]-4-[4-(4-methoxyphenyl)piperazin-1-yl]-5, Preparation of 6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine (W03)
[0059] Referring to the method of Example 1, a white solid was obtained with a yield of 42.1%. m.p.:138-140℃;IR(KBr,cm -1 ):3450,2918,2850,1695,1600,1520,1439,1384,1233,1170,976,830,720,600; 1 H-NMR (400MHz, CDCl 3 ):δ1.84-1.92(m,1H),2.12-2.16(m,1H),2.91-2.98(m,2H),3.10-3.18(m,3H),3.30-3.36(m,2H),3.40 -3.44(m,2H),3.48-3.55(m,2H),3.61-3.67(m,2H),3.89(s,3H),3.92(s,3H),5.23(s,2H),6.87-7.02 (m,8H),7.20(d,J=8.8Hz,2H),8.02(d,J=8.8Hz,2H),8.58(s,1H); ESI-MS(m / z):621.2([M +H] + ).
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Abstract
The invention belongs to the technical field of medicine, and relates to a tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compound, a preparation method thereof and an application as an epidermal growth factor receptor tyrosine kinase inhibitor. The general structural formulas of the tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines, their prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts are as follows: wherein R is independently selected from hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, halogen; R' is independently selected from hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, halogen. The synthesis method of this type of compound of the present invention is simple and convenient, and is suitable for industrial production. Biological activity tests show that this type of compound has the activity of inhibiting epidermal growth factor, human lung cancer cell line A549, and human ovarian cancer cell line SKOV3. Inhibitor of epidermal growth factor receptor tyrosine kinase.
Description
technical field [0001] The invention belongs to the technical field of medicine, relates to tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compounds and their preparation methods, and also relates to their use as epidermal growth factor receptor tyrosine kinase inhibitors Applications. Background technique [0002] According to the degree of differentiation and morphological characteristics of cancer cells, lung cancer can be divided into non-small cell lung cancer and small cell lung cancer. Studies have found that there is a large number of dysregulation of epidermal growth factor signal transduction and overexpression of epidermal growth factor receptor tyrosine kinase in lung cancer patients. [0003] Epidermal growth factor receptor (EGFR) is a transmembrane protein with an extramembrane ligand receptor binding domain and an intracellular tyrosine kinase activity domain. EGFR has four types: HER-1, HER-2, HER-3 and HER-4. When a small molecule ligand binds to EGFR, EGFR ...
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