21-subunit digoxin derivative and preparation method thereof

A derivative and base technology, applied in the field of a series of digoxin derivatives and their preparation, can solve the problems of low content of natural cardiac glycoside compounds, many steps and high synthesis cost

Inactive Publication Date: 2007-09-26
ZHENGZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

One of the reasons may be that the content of natural cardiac glycoside compounds is low, and all current modification methods have many steps and high synthesis costs

Method used

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  • 21-subunit digoxin derivative and preparation method thereof
  • 21-subunit digoxin derivative and preparation method thereof
  • 21-subunit digoxin derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1 prepares R shown in general formula 1 1 = H, R 2 = Derivatives when furyl

[0018] 100 mg of digoxin and 60 mg of furfural were dissolved in 10 mL of acetonitrile, refluxed for 6 h under the catalysis of triethylamine (5 mg), and the reaction was detected to be complete. After concentration, 101 mg of red solid was isolated with a yield of 88%.

[0019] mp 172.8~173.8℃; IR 3462, 2933, 2880, 1742, 1645, 1472, 1449, 1405, 1380, 1274, 1163, 1128, 1068, 1015, 953, 869cm- 1 ; 1 H NMR (400MHz, CDCl 3 , TMS): 7.74 (1H, d, J = 1.3Hz), 7.01 (1H, d, J = 3.2Hz), 6.64 (1H, s), 6.51 (1H, dd, J = 1.6, 3.2Hz), 6.17 (1H, s), 4.87~4.92(3H, om), 4.2(2H, t, J=3.7Hz), 4.1(2H, m), 4.03(1, s), 3.75~3.78(4H, om), 3.48(1H, m), 3.75(1H, m), 3.2~3.3(4H, m), 2.25~1.65(20H, om), 1.27(6H, om), 1.23(9H, om), 0.91(3H, s), 0.77(3H,om); 13 C NMR (100.6MHz, CDCl 3 , TMS): δ170.2, 164.4, 149.5, 148.4, 143.8, 115.6, 114.9, 112.9, 100.1, 98.4, 98.3, 95.5, 86.5, 82.6, 28.2, 75.7, 72.7, 72....

Embodiment 2

[0020] Embodiment 2 prepares general formula R 1 = H, R 2 = Derivatives of p-methoxyphenyl

[0021] 100 mg of digoxin and 60 mg of anisaldehyde were dissolved in 15 mL of tetrahydrofuran, refluxed for 5 h under the catalysis of pyridine (5 mg), and the reaction was detected to be complete. After concentration, 88 mg of light yellow solid was isolated with a yield of 80%.

[0022] mp 156.5~157.8℃; IR3455, 2932, 2880, 1737, 1604, 1511, 1449, 1406, 1379, 1302, 1255, 1175, 1128, 1061, 1014, 954, 868, 829cm- 1 ; 1 H NMR (400MHz, CDCl 3 , TMS): 7.75 (1H, d, J = 8.4Hz), 6.89 (1H, d, J = 8.6Hz), 6.6 (1H, s), 6.15 (1H, s), 4.85 ~ 4.92 (); 13 C NMR (100.6MHz, CDCl 3 , TMS): δ170.2, 164.4, 149.5, 148.4, 143.8, 13H, m1, 4.2 (2H, m), 4.1 (1H, m), 4.02 (1H, s), 3.82 (3H, s), 3.84~ 3.75(4H, m), 3.50(2H, m), 3.19~3.27(4H, m), 2.25~1.45(20H, om), 1.27(6H, om), 1.23(9H, om), 0.91(3H, s), 0.77(3H, s); 13 C NMR (100.6MHz, CDCl 3 , TMS): δ170.8, 165.2, 160.1, 148.7, 132.5, 126.2, 114.6, 1...

Embodiment 3

[0023] Embodiment 3: preparation general formula R 1 = H, R 2 =CHCCH 3 CH 2 CH 2 CHC (CH 3 ) 2 time derivative

[0024] 100 mg of digoxin and 60 mg of citral were dissolved in 15 mL of ethanol, under the catalysis of potassium carbonate (5 mg), the reflux reaction was carried out for 7 hours, and the reaction was detected to be complete. After concentration, 76 mg of light yellow solid was isolated with a yield of 65%.

[0025] mp 159.7~160.4℃; IR3453, 2966, 2933, 2880, 1734, 1635, 1578, 1449, 1405, 1378, 1316, 1273, 1164, 1128, 1068, 955, 869cm- 1 ; 1 H NMR (400MHz, CDCl 3, TMS): 6.63(1H, d, J=12.0Hz), 6.40(1H, d, J=11Hz), 6.08(1H, s), 5.01(1H, s), 4.90~4.75(4H, om), 4.25(2H, br), 4.11(1H, s), 4.02(1H, s), 3.73~3.77(6H, om), 3.44~3.47(2H, m), 3.22~3.29(5H, m), 3.1( 2H, br), 2.16~1.47(33H, om), 1.27(6H, om), 1.23(9H, om), 0.92(3H, s), 0.75(3H, s); 13 CNMR (100.6MHz, CDCl 3 , TMS): δ170.5, 163.7, 149.1, 147.8, 123.7, 118.6, 115.0, 109.3, 98.3, 98.2, 95.4, 86.5, 82.5...

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Abstract

The invention discloses a 21-subunit cardoxin derivant and preparing method, which contains gamma-subunit butane lactone as structural unit as formula. The making method is convenient without protecting, which possesses potential drug using value.

Description

technical field [0001] The invention belongs to organic compounds and their preparation methods, in particular to a series of digoxin derivatives and their preparation methods. Background technique [0002] Cardiac glycosides are steroidal glycosides that exist in plants and have cardiotonic effects. At present, there are 20 or 30 kinds of cardiac glycosides in clinical use, mainly for the treatment of congestive mental failure and rhythm disorders. Their main problems It is due to the convex effect of the heart, which shows a low therapeutic index, and digoxin is the most widely used one. In order to develop safer cardiotonic drugs, medicinal chemists have invested a lot of money and energy in the synthesis and structural modification of digoxin analogues for many years. [0003] [0004] The selectivity of digoxin therapy mainly depends on the stereo configuration of 5β, 14β-sterane, besides, its lactone ring and glycogen are also its important pharmacophore. Therefor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J19/00A61K31/585A61P9/04
Inventor 刘宏民徐海伟黄利华高远刘改芝察雪湘聂亚莉
Owner ZHENGZHOU UNIV
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