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Novel harringtonlne derivative, method for making same and its pharmaceutical composition and use thereof

A compound, C1-C4 technology, applied in the field of anti-tumor drugs, can solve the problems of high harringtonine content, low ester base content, and no obvious therapeutic effect

Inactive Publication Date: 2008-11-26
北京协和制药二厂有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Harringtonine and homoharringtonine are clinically effective in the treatment of acute non-lymphatic leukemia, but have no obvious therapeutic effect on solid tumors such as liver cancer; these drugs also have the myelosuppressive and anticancer effects of general anticancer drugs. Gastrointestinal side effects
Harringtonine and homoharringtonine have the highest content in Hainan Torreya (C.Hainanensis) and Xishuangbanna Torreya (C.Mannii Hookt.), most of which exist in the bark, and these two plants are only distributed in Hainan And in some areas of Yunnan, the quantity is limited, so that the wide use of ester-alkali is subject to certain restrictions
Other plants of the genus Cedarwood, such as C.Fortunei Hook.f, C.Sinenisis Li, etc., are widely distributed and have a large number, but their ester alkali content is extremely low, and their branches and leaves High content of harringtonine (5) is not utilized

Method used

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  • Novel harringtonlne derivative, method for making same and its pharmaceutical composition and use thereof
  • Novel harringtonlne derivative, method for making same and its pharmaceutical composition and use thereof
  • Novel harringtonlne derivative, method for making same and its pharmaceutical composition and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1 3-O-{(4'S,5'R)-2',4'-Diphenyl-1',3'-Azaxolane-5'-Formyl}-Oxytricine Cetine (II 1 ) preparation:

[0086] Dissolve 160mg (0.49mmol) oxyharringtonine 1, 30mg (0.49mmol) 8a, 202mg (0.98mmol) DCC and 4mg (0.03mmol) PP in anhydrous chloroform under nitrogen protection, and stir at room temperature for 1 day. The reaction is complete. Concentration gave a yellow oil, which was separated by silica gel column to give 0.165 g of the title compound as a white foamy solid.

[0087] Yield: 58.5%, melting point: 94-96°C, [α] D 17 =-37.2(c 0.41 CHCl 3 ).

[0088] 1 H-NMR, 90MHz (CDCl 3 δppm): 3.46 (s, 3H, OCH 3 ), 3.80 (d, 1H, J=9Hz, H 4 ), 4.32(d, 1H, J=5.4Hz, H 2’ ), 4.66(d, 1H, J=5.4Hz, H 3’ ), 4.96 (d, 1H, J=9Hz, H 3 ), 4.96 (m, 1H, H 11 ), 5.64, 5.80 (2d, 2H, J=1Hz, OCH 2 O), 6.50, 6.64 (2s, 2H, H 14，17 ), 7.2-8.0 (m, 10H, aromatic hydrogen).

[0089] EI-MS, m / e (%): 580 (M + , 10), 563(5), 314(100), 284(5), 254(10), 222(12), 173(15), 119(25), 91(45)...

Embodiment 2

[0090] Example 2 3-O-{(4'R,5'S)-2',4'-Diphenyl-1',3'-Azaxolane-5'-Formyl}-Oxytricine Cetine (II 2 ) preparation:

[0091] With the method of embodiment 1, difference is that raw material (8 a ) to (8 b ), 150 mg (0.56 mmol) of 8b yielded 195 mg of the title compound as a white foamy solid.

[0092] Yield: 59.8%, melting point: 87-89°C, [α] D 17 =+9.75(c 0.4 CHCl 3 ).

[0093] 1 H-NMR, 90MHz (CDCl 3 δppm): 3.44 (s, 3H, OCH 3 ), 3.74(d, 1H, J=9.36HzH 5’ ), 4.48(d, 1H, J=6.48Hz, H 4 ), 4.72 (m, 1H, H 11 ), 4.97(d, 1H, J=6.48Hz, H 3 ), 5.04 (d, 1H, J=9.36Hz, C-H 4’ ), 5.68, 5.8 (dd, 2H, J=2.16Hz, OCH 2 O), 6.2, 6.45 (2s, 2H, H 14，17 ), 7.4-8.04 (m, 10H, aromatic hydrogen).

[0094] EI-MS, m / e (%): 580 (M + , 4), 563(3), 330(3), 314(100), 282(2), 254(3), 222(10), 173(15), 119(20), 91(50).

Embodiment 3

[0095] Example 3 3-O-{(4'S,5'R)-2',4'-diphenyl-1',3'-azoxolane-5'-formyl}-harringtonine (II 3 ) preparation:

[0096] With the method of Example 1, the difference is that the raw material ox harringtonine is changed to harringtonine. 100 mg (0.32 mmol) of harringtonine and 170 mg (0.64 mmol) of 8a were reacted to give 165 mg of the title compound as a white foamy solid.

[0097] Yield: 91.0%, melting point 80.4-82.6°C, [α] D 17 =-1 36.4 (c 0.47 CHCl 3 ).

[0098] 1 H-NMR, 90MHz (CDCl 3 δppm): 3.68 (s, 3H, OCH 3 ), 3.80 (d, 1H, J=10Hz, H 4 ), 4.56(d, 1H, J=6Hz, H 5’ ), 4.66(d, 1H, J=6Hz, H 4’ ), 5.08(s, 1H, H 1), 5.78 (dd, 2H, J=1Hz, OCH 2 O), 5.98(d, 1H, J=10Hz, H 3 )6.48, 6.57 (2s, 2H, H 14，17 ), 7.22-8.0 (m, 10H, aromatic hydrogen).

[0099] EI-MS, m / e (%): 564 (M + , 18), 533(4), 314(12), 298(100), 266(25), 222(18), 193(30), 173(16), 150(32), 105(20), 91 (50), 71(60).

[0100] Step 2:

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Abstract

The present invention relates to one new series of ester alkaloid derivatives including cephalotaxine, 11-hydroxy cephalotaxine, drupacine and relevant derivatives, their preparation, their medicine composition and their use as antitumor medicine.

Description

technical field [0001] The present invention relates to a series of novel compounds including Cephalotaxine (Cephalotaxine), 11-hydroxy Cephalotaxine (11-hydroxy Cephalotaxine), Drupacine (Drupacine) and related derivatives thereof as the mother core Neoester base derivatives, their preparation methods, pharmaceutical compositions containing them, and their use as antitumor drugs. Background of the invention [0002] Cancer is a major disease that plagues human beings. The mortality rate caused by malignant tumors ranks second among all causes in my country, and the incidence rate is on the rise. [0003] Drug therapy is an important means of cancer treatment, especially for patients with advanced tumors. Although tumor chemotherapy has made great progress in recent years, some cancer patients have been cured or remitted, their quality of life has improved, and their survival time has been significantly prolonged, but it is the most serious threat to human life and health, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/14C07D491/22C07D498/22A61K31/55A61P35/00C07D209/00C07D223/00C07D317/00
CPCY02P20/582
Inventor 吴克美籍秀娟叶仙蓉黄量柴永海李行南
Owner 北京协和制药二厂有限公司