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4- fragrant amido quinazoline derivatives and method of manufacturing the same and application in pharmacy thereof

A technology of aromatic aminoquinazoline and its derivatives, which is applied in antineoplastic drugs, drug combinations, and pharmaceutical formulations, and can solve problems such as difficult control and increased difficulty of specific inhibitors

Inactive Publication Date: 2008-01-23
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The ATP site in the tyrosine kinase region has long been considered a more difficult target to control because there are many protein kinases and other enzymes that use ATP as substrates that may be affected, which will increase the potential for designing specific inhibitors. difficulty

Method used

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  • 4- fragrant amido quinazoline derivatives and method of manufacturing the same and application in pharmacy thereof
  • 4- fragrant amido quinazoline derivatives and method of manufacturing the same and application in pharmacy thereof
  • 4- fragrant amido quinazoline derivatives and method of manufacturing the same and application in pharmacy thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] Example 1: Ethyl 3-(7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amino)-1H-pyrrole-2-carboxylate (GI-1)

[0138] 3-(6-(3-chloropropoxy)-7-methoxyquinazoline-4-amino)-1H-pyrrole-2-carboxylic acid ethyl ester (GI-Cl, 0.81g, 2mmol), morpholine 5ml, DMF (20ml), reacted at 70°C for 30 minutes, removed the remaining morpholine under reduced pressure, dissolved the residue with 60ml chloroform, washed twice with 20ml water, dried over anhydrous magnesium sulfate, 200-300 mesh silica gel column chromatography, ethyl acetate Ester:triethylamine=20:1 was eluted to obtain 0.78 g of white powder with a yield of 86%. mp: 181-183°C; 1 H-NMR (CDCl 3 )δ: 1.39(t, 3H), 2.04-2.18(m, 2H), 2.51(t, 4H), 2.63(t, 2H), 3.74(t, 4H), 4.00(s, 3H), 4.29(t , 2H), 4.40(q, 2H), 6.90(t, 1H), 7.20(s, 1H), 7.24(s, 1H), 7.45(t, 1H), 8.71(s, 1H), 9.10(b, 1H), 9.95(b, 1H); 13 C-NMR (CDCl 3 )δ: 14.68, 26.19, 53.76, 55.44, 56.10, 60.10, 66.98, 67.76, 101.38, 103.73, 107.92, 108.41, 109.35, 122.36, 147...

Embodiment 2

[0139] Example 2: 3-(7-methoxy-6-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline-4-amino)-1H-pyrrole-2-carboxylic acid Ethyl ester (GI-2)

[0140] Specific implementation method Referring to Example 1, N-methylpiperazine was used instead of morpholine to obtain 0.65 g of white powder with a yield of 71%. mp: 175-178°C; 1 H-NMR (CDCl 3 )δ: 1.43(t, 3H), 1.58(m, 2H), 2.15(t, 2H), 2.34(s, 3H), 2.62-2.69(m, 8H), 4.01(s, 3H), 4.27(t , 2H), 4.41(q, 2H), 6.69(t, 1H), 7.10(s, 1H), 7.24(s, 1H), 7.47(d, 1Hr), 8.58(b, 1H), 8.71(d, 1H), 9.54(b, 1H); 13 C-NMR (CDCl 3 )δ: 14.73, 26.53, 46.01, 53.21, 55.02, 55.20, 56.11, 60.11, 67.89, 101.33, 103.73, 107.95, 108.42, 109.36, 122.35, 147.20, 149.03, 153.87, 156.187 (cm -1 ): 2952, 2936, 2873, 2776, 1659, 1624, 1604, 1585, 1559, 1513, 1471, 1437, 1413, 1398, 1316, 1240, 1212, 1146, 1067, 1044, 987, 926, 844, 777, 617; M / z: 469.2 ([M+H] + , 100%). Elem. Anal. Calcd: C, 61.52; H, 6.88; N, 17.94. Found C, 61.83; H, 6.87; N, 17.32.

Embodiment 3

[0141] Example 3: Ethyl 3-(7-methoxy-6-(3-pyrrolepropoxy)quinazoline-4-amino)-1H-pyrrole-2-carboxylate (GI-3)

[0142] Specific implementation method Referring to Example 1, pyrrole was used instead of morpholine to obtain 0.48 g of yellow powder with a yield of 64%. mp: 192-194°C; 1 H-NMR (CDCl 3 )δ: 1.36(t, 3H), 1.79(b, 4H), 2.16(p, 2H), 2.57(b, 4H), 2.72(t, 2H), 4.00(s, 3H), 4.28(t, 2H ), 4.406(q, 2H), 6.86(t, 1H), 7.17(s, 1H), 7.22(s, 1H), 7, 41(t, 1H), 8.68(s, 1H), 9.10(b, 1H), 9.95(b, 1H); 13 C-NMR (CDCl 3 )δ: 14.69, 23.53, 28.56, 52.97, 54.21, 56.07, 60.05, 67.93, 101.20, 103.68, 107.88, 108.39, 109.34, 122.29, 147.13, 149.02, 153.79, 155.14, 155.27 -1 ): 3410, 3302, 3043, 2959, 2863, 1665, 1622, 1598, 1557, 1508, 1433, 1309, 1208, 1143, 1072, 1044, 896, 835, 774; M / z: 440.2 ([M+H ] + , 100%); Elem. Anal. Calcd: C, 62.85; H, 6.65; N, 15.93. Found C, 62.70; H, 6.62; N, 15.07.

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Abstract

The invention relates to a 4-aromatic aminoquinazoline compounds with general formula of (I) or a receivable salt pharmaceutically and the application in preparing the drugs for treating the tumour. Wherein, R1, R2 are hydrogen, halogen, nitryl, amino, alkyl of C1-6, alkylamino of C1-6 or alkoxy of C1-6, or the group replaced by the alkylamino on the terminal of the alkyl of C1-6, alkylamino and alkoxy; X is N,O or S; Ar is aromatic ring or heteroaromatic groups replaced by the ester of C5 to C8. The invention can inhibit the increase of the tumour cell obviously and has obvious inhibited effect on the tyrosine kinase of the cell, and has activity equal to that of the positive drugs Gefitinib and Erlotinib and even exceeds the positive control.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and relates to a tyrosine kinase inhibitor, namely 4-arylaminoquinazoline compound and its application in pharmacy. Background technique [0002] Mammalian cells have similar molecular regulatory mechanisms that regulate cell proliferation, differentiation, and death throughout the cell cycle. Among them, protein phosphorylation is the main mechanism of transmembrane or intracellular signal transduction, which has the function of regulating cell cycle, and phosphorylation is controlled by protein kinase and protein phosphatase. Protein kinase catalyzes the transfer of the phosphoryl group at the end of ATP to a specific amino acid residue, thereby changing the protein structure and ultimately affecting its binding and catalytic activity in vivo. [0003] In 1980, Hunter et al. first discovered and identified a gene product of RNA tumor virus (RSV)-infected cell transformation gene as Tyrosine Ki...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07D403/12C07D409/14C07D409/12A61K31/498A61P35/00
Inventor 吉民胡刚李铭东孙秀兰郑友广曾晓宁
Owner SOUTHEAST UNIV
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