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Group of geldanamycin derivative with nucleoside base

A geldanamycin and nucleoside base technology, applied in the field of geldanamycin derivatives, can solve problems such as no literature reports

Inactive Publication Date: 2006-08-16
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The introduction of nucleoside bases into the 17th position of geldanamycin to screen the synthesis of antiviral drugs has not been reported in the literature so far

Method used

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  • Group of geldanamycin derivative with nucleoside base
  • Group of geldanamycin derivative with nucleoside base
  • Group of geldanamycin derivative with nucleoside base

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: 17-(4'-((5"-(4-amino-2-oxopyrimidin-1(2H)-yl)-1",3"-oxathiolane-2" Preparation of -yl)methoxy)-4'-oxobutylamine)-17-desmethoxygeldanamycin (1)

[0040] With reference to the literature (Zhao Zhizhong, Protecting Groups in Organic Chemistry, Science Press, 1984: 41-49), use Boc 2 O is used as a raw material to protect the primary amino group of γ-aminobutyric acid to obtain γ-tert-butoxyamide-butyric acid.

[0041] Take 0.45g (2.22mmol) of γ-tert-butoxyamide-butyric acid, add 5mL CHCl 3 . After dissolving, 0.6 g (2.91 mmol) of dicyclohexylcarbodiimide (DCC) was added and stirred at room temperature, a large amount of white turbidity appeared. The reaction was carried out for 4 hours, the white precipitate was filtered off, and the filtrate containing γ-tert-butyroxyamide-butyric anhydride was set aside.

[0042] Take 0.6g (2.63mmol) of lamivudine and place it in a 250mL round-bottomed flask with a reflux condenser, add 50mL of N,N-dimethylformamide, and ...

Embodiment 2

[0047] Example 2: 17-(4'-((5"-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1",3"-oxathia Preparation of cyclopent-2"-yl)methoxy)-4'-oxobutylamine)-17-desmethoxygeldanamycin (2)

[0048] The nucleobase part uses 5-flulamivudine as the raw material, and the Linker part is γ-aminobutyric acid, which is synthesized by a method similar to Example 1 to obtain (2).

[0049] 1 H-NMR δ(ppm): 0.9~1.3(m, 6H, C 10 -CH 3 , C 14 -CH 3 ); 1.3~1.4(m, 5H, C 13 -H 2 , C 14 -H,C 15 -H 2 ); 1.5~1.7(m, 2H, C 17 -NH-CH 2 -CH 2 -CH 2 -COO); 1.983(s, 3H, C 8 -CH 3 ); 2.211(s, 3H, C 2 -CH 3 ); 2.3~2.4(m, 1H, C 10 -H); 2.632(s, 2H, CH 2 -COO); 2.8~3.0(m, 4H, C 17 -NH-CH 2 , oxathione 4-position 2H); 3.182(s, 3H, C 12 -OCH 3 ); 3.458(s, 3H, C 6 -OCH 3 ); 3.5~3.7(m, 4H, C 11 -H,C 12 -H); 4.2~4.3(m, 2H, COO-CH 2 -CH-S); 4.6~4.7(m, 1H, C 6 -H); 5.294(s, 1H, C 7 -H); 5.3~5.4(m, 1H, 2-position 1H of oxathione ring); 5.9~6.2(m, 2H, C 9 -H,C 5 -H); 6.427(s, 1H, 5-position 1H of...

Embodiment 3

[0051] Example 3: 17-(4'-(2"-((2-amino-6-oxygen-1,6-dihydro-4H-purin-9(5H)-yl)methoxy )ethoxy)-4'-oxobutylamine)-17-desmethoxy-geldanamycin (3)

[0052] Acyclovir is used as the raw material for the nucleoside base part, and gamma-aminobutyric acid is used for the Linker part, which is synthesized by a method similar to Example 1 to obtain (3).

[0053] 1 H-NMR δ(ppm): 0.7~1.1(m, 6H, C 10 -CH 3 , C 14 -CH 3 ); 1.2~1.5(m, 5H, C 13 -H 2 , C 14 -H,C 15 -H 2 ); 1.645(m, 2H, C 17 -NH-CH 2 -CH 2 -CH 2 -COO); 2.135(s, 3H, C 8 -CH 3 ); 2.261(s, 3H, C 2 -CH 3 ); 2.3~2.4(m, 1H, C 10 -H); 2.6~2.7(m, 2H, CH 2 -COO); 2.7~2.9(m, 2H, C 17 -NH-CH 2 ); 3.242(s, 3H, C 12 -OCH 3 ); 3.388(s, 3H, C 6 -OCH 3 ); 3.5~3.9(m, 6H, C 11 -H,C 12 -H, nucleoside side chain O-CH 2 -CH 2 OOC); 4.1~4.4(m, 2H, nucleoside side chain OCH 2 -CH 2 -OOC); 4.6~4.8(m, 1H, C 6 -H); 5.073(s, 1H, C 7 -H); 5.283(s, 2H, nucleoside side chain N-CH 2 -O); 6.0~6.3(m, 2H, C 9 -H,C 5 -H); ...

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Abstract

A geldanamycin derivate with nucleoside base is prepare by inducing soluble nucleoside by geldanamycin and obtaining the final product. Nucleoside base is connected with geldanamycin on Linker. It can keep or strengthen antiviral activity of geldanamycin and improve solubility and tissue distribution.

Description

Technical field: [0001] The present invention relates to a group of geldanamycin derivatives linked with nucleoside bases; the present invention also relates to the preparation method of said compound and its application in antiviral and antitumor aspects; the present invention also relates to the medicine of said compound combination. Background technique: [0002] Geldanamycin is a benzoquinone-ANSA antibiotic produced by the fermentation of Streptomyces hygroscopicus. It consists of a benzoquinone structure and a planar macrocyclic ANSA bridge. The target of geldanamycin is the heat shock protein Hsp90, which specifically inactivates Hsp90 and inhibits the replication of the virus. Geldanamycin interferes with the normal function of Hsp90, prevents the activation of Hsp90 substrate protein, induces cell cycle arrest and inhibits virus replication, thereby playing an antiviral or antitumor role. The unique mechanism of action makes geldanamycin have a wide anti-virus / tum...

Claims

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Application Information

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IPC IPC(8): C07D225/06A61K31/395A61P31/12A61P35/00
Inventor 李卓荣陶佩珍山广志李玉环
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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