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Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines containing thioether structure and their applications

A compound, the technology of tetrahydrobenzene, applied in the field of medicine, can solve the problems of prolongation of cardiac QT interval and reduction of bioavailability

Active Publication Date: 2017-06-30
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[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.

Method used

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  • Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines containing thioether structure and their applications
  • Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines containing thioether structure and their applications
  • Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines containing thioether structure and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: 7-(4-ethoxyphenyl)-4-phenylthio-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine ( Compound No. 01) Preparation

[0025] Step A: Preparation of 4-(4-ethoxyphenyl)cyclohexanone

[0026] 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.

[0027] Step B: Preparation of 2-amino-6-(4-ethoxyphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide

[0028] Add 2.0g (9.2mmol) of 4-(4-ethoxyphenyl)cyclohexanone, 0.8g (9.2mmol) of cyanoacetamide, and 0.3g (9.2mmol) of sulfur powder (sublimation) int...

Embodiment 2

[0035] Example 2: 7-(4-ethoxyphenyl)-4-(2-methoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2 ,3-d] the preparation of pyrimidine (compound number 02)

[0036] With reference to the method of Example 1, 7-(4-ethoxyphenyl)-4-(2-methoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5] was obtained Thieno[2,3-d]pyrimidine (Compound No. 02) 0.4g, yield 58.5%. m.p.:140-142℃;IR:(KBr,cm -1 )3452(m),2921(s),2851(s),1612(m),1512(s),1495(s),1383(s),1246(s),1115(m),828(s) ,752(s),620(s); 1 H-NMR (400MHz, CDCl 3 ):δ1.42(t,3H,CH 3 ),1.99-2.09(m,1H,CH 2 ),2.25-2.30(m,1H,CH 2 ),2.94-3.01(m,1H,CH 2 ),3.06-3.26(m,3H,CH 2 ),3.50-3.56(m,1H,CH),3.80(s,3H,CH 3 ),4.04(m,2H,CH 2 ), 6.89 (d, 2H, Ar-H, J=8.4Hz), 7.02-7.07 (m, 2H, Ar-H), 7.21 (d, 2H, Ar-H, J=8.4Hz), 7.47-7.51 (m,1H,Ar-H),7.56(dd,1H,J 1 =7.2Hz,J 2 =2.0Hz), 8.53 (s, 1H, Ar-H); ESI-MS (m / z): 449.2 ([M+H] + ).

Embodiment 3

[0037] Example 3: 7-(4-ethoxyphenyl)-4-(3-methoxyphenylthio)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2 ,3-d] the preparation of pyrimidine (compound number 03)

[0038] With reference to the method of Example 1, 7-(4-ethoxyphenyl)-4-(3-methoxyphenylsulfanyl)-5,6,7,8-tetrahydrobenzo[4,5] was obtained Thieno[2,3-d]pyrimidine (Compound No. 03) 0.4g, yield 58.5%. m.p.:146-148℃;IR:(KBr,cm -1 )3450(m),2921(s),2851(s),1641(m),1512(s),1492(s),1411(s),1383(s),1246(s),1114(s) ,828(s),779(s),620(s); 1 H-NMR (400MHz, CDCl 3 ):δ1.42(t,3H,CH 3 ),1.99-2.09(m,1H,CH 2 ),2.26-2.31(m,1H,CH 2 ),2.95-3.01(m,1H,CH 2 ),3.06-3.21(m,3H,CH 2 ),3.44-3.49(m,1H,CH),3.83(s,3H,CH 3 -O),4.04(m,2H,CH 2 ), 6.89(d,2H,Ar-H,J=8.8Hz),7.01(dd,1H,Ar-H,J 1 =8.4Hz,J 2 =2.4Hz),7.14(t,1H,Ar-H),7.17-7.22(m,3H,Ar-H),7.38(t,1H,Ar-H),8.58(s,1H,Ar-H) ;ESI-MS(m / z):449.3([M+H] + ).

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Abstract

The invention belongs to the technical field of medicines and relates to a tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine compound containing a thioether structure and application of the tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine compound as an epidermal growth factor receptor tyrosine kinase inhibitor and a preparation method the tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine compound. The tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine compound containing the thioether structure, pharmaceutically acceptable salt, and a pharmaceutically compatibility acceptable carrier or a diluent are used as the epidermal growth factor receptor tyrosine kinase inhibitor. The structural general formula of the compound is shown in the description, wherein R1 and R2 are shown in the claim and description. The compound provided by the invention is simple and convenient in synthesis method, and suitable for industrial production, and a biological activity test result shows that the compound has the effect of restraining activity of epidermal growth factors, activity of human lung cancer cell line A549, activity of human ovarian cancer cell line SKOV3 and activity of human osteosarcoma cell U2OS-EGFP-4A12G, and is the epidermal growth factor receptor tyrosine kinase inhibitor with an anti-tumor effect.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine compound containing a sulfide structure and a preparation method thereof, and also relates to its use as an epidermal growth factor receptor tyrosine Use of acid kinase inhibitors. 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 sma...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D495/04A61K31/519A61P35/00A61P11/06
CPCC07D495/04
Inventor 胡春孙冰徐越张富荣黄钰淑金辄刘晓平黄二芳王金辉
Owner SHENYANG PHARMA UNIVERSITY
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