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A set of geldanamycin derivant and method for preparing the same

A technology of geldanamycin and derivatives, applied in the field of geldanamycin structure modification derivatives

Inactive Publication Date: 2008-07-16
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 geldanamycin structurally modified derivatives and their antiviral activity have so far not been reported at home and abroad.

Method used

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  • A set of geldanamycin derivant and method for preparing the same
  • A set of geldanamycin derivant and method for preparing the same
  • A set of geldanamycin derivant and method for preparing the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 >: Preparation of 17-(2'-(1",4"-oxazepinyl-1"-)ethylamino)-17-desmethoxygeldanamycin GM-APML):

[0044] Take geldanamycin 50mg (89.29μmol), add 5mL CHCl 3 , methanol 0.5ml, stirred until the geldanamycin was dissolved, and the reaction solution was orange-yellow. Add 21 mg (164 μmol) of 4-(2-aminoethyl)-1,4-oxazepine, react at room temperature for 4 days, evaporate the solvent to obtain a dark purple solid, and dissolve the solid residue in 10 mL of ethyl acetate , followed by deionized water, saturated NaHCO 3 , 1mol / L HCl solution, washed with saturated brine. Anhydrous Na was added to the organic phase 2 SO 4 Let dry overnight. The desiccant was filtered off, and the organic phase was concentrated under reduced pressure. Chromatographic separation was performed on a silica gel column to obtain 46.2 mg (61.2%) of the compound GM-APML.

[0045]1 H-NMR (400MHz, CDCl 3 )δ(ppm): 0.9~1.0(m, 6H, C10-CH3, C14-CH3), 1.28-1.38(m, 2H, C13-H2), 1.5(m, 1H, C14-H...

Embodiment 2

[0046] Example 2 >: Preparation of 17-(2'-(1"-azacyclohexyl-1"-)ethylamino)-17-desmethoxygeldanamycin (GM-AEPD):

[0047] When the side chain reactant is 2-(1'-azacyclohexyl)ethylamine, the compound GM-AEPD is synthesized according to the method similar to Example 1.

[0048] 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 0.82(1H, m, C14-H), 0.94~1.0(m, 6H, C10-CH3, C14-CH3), 1.24-1.3(m, 4H, C13-H2, C15-H2) , 1.4~1.5(m, 2H, C17-N(CH2-CH2) 2 CH2 )), 1.6(br, 4H, C17-N(CH2- CH2 ) 2 CH2), 1.76(br, 1H, C10-H), 1.78(s, 3H, C8-CH3), 2.03(s, 3H, C2-CH3), 2.3~2.4(br, 4H, C17-N-(C H2 -CH2) 2 CH2), 2.6~2.8(m, 4H, C17-NH- CH2-CH2 -N), 3.24(s, 3H, C12-OCH3), 3.38(s, 3H, C6-OCH3), 3.44(d, 1H, J=9.2Hz, C12-H), 3.58(d, 1H, J= 9.2Hz, C11-H), 3.7(br, 1H, C17-NH-), 4.31(d, 1H, J=10.0Hz, C6-H), 4.5(br, 1H, C11-OH), 4.80(br , 2H, -CO-NH2), 5.20 (s, 1H, C7-H), 5.83 (t, 1H, J=10.4, C5-H) 5.94 (d, 1H, J=9.6, C9-H), 6.59 (t, 1H, J=11.6Hz, C4-H), 6.96(d, 1H, J=11.6Hz, C3-H), 7.22(br, 1H, C20-NH-CO), 9...

Embodiment 3

[0049] Example 3 >: 1 Preparation of 7-(4'-benzyl-4'-azacyclohexylamino)-17-desmethoxygeldanamycin (GM-ABPD):

[0050] When the side chain reactant was 4-benzyl-4-azacyclohexylamine, the compound GM-ABPD was synthesized according to the method similar to Example 1.

[0051] 1 H-NMR (400MHz, CDCl 3 )δ(ppm): 0.94~1.0(dd, 6H, C10-CH3, C14-CH3), 1.5~1.6(m, 4H, C17-NH-CH( CH2 -CH2) 2 N-), 1.64(d, 2H, C15-H2), 1.7(m, 2H, C13-H2), 1.8(s, 3H, C8-CH3), 1.9(s, 2H, C17-NH-CH-( CH2-CH2) 2 -N- CH2 -Ph), 2.03(s, 3H, C2-CH3), 2.1-2.2(m, 2H, C17-NH-CH-(CH2- CH2 ) 2 -N-CH2-Ph), 2.7~2.8(m, 3H, C14-CH, C17-NH-CH-(CH2- CH2 ) 2 -N-CH2-Ph), 2.87(br, 1H, C17-NH-C H (CH2-CH2) 2 N-), 3.26(s, 3H, C12-OCH3), 3.38(s, 3H, C6-OCH3), 3.4(d, 1H, J=9.2Hz, C12-H), 3.58(d, 1H, J= 9.2Hz, C11-H), 3.6(s, 1H, C10-H), 3.9(br, 1H, C17-NH-), 4.2(br, 1H, C11-OH), 4.3(d, 1H, J= 10.0Hz, C6-H), 4.78(br, 2H, -CO-NH2), 5.17(s, 1H, C7-H), 5.8-5.9(m, 2H, C5-H, C9-H), 6.27( br, 1H, C20-NH-CO), 6.5 (t, 1H, J=...

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Abstract

The invention provides a set of new geldanamycin derivatives and the preparation method thereof, which also provides a drug combination using the compound as an active component. The experimental results prove that the derivatives have broad-spectrum antiviral activity, which have stronger inhibition on HIV-1 and HBV and have better inhibitory activity on herpesvirus. Owing to the inhibition on Hsp90, the compound is effective in antivirus and antitumor at the same time.

Description

Technical field: [0001] The invention relates to a group of geldanamycin structural modification derivatives; the invention also relates to the preparation method of the compound and its application in antiviral and antitumor aspects; the invention also relates to the pharmaceutical composition of the compound. 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 heat shock protein 90 (Hsp90), which specifically inactivates Hsp90 to inhibit tumor growth or inhibit virus replication. 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 the characteristics of broad-spectr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07D401/12C07F9/553A61K31/395A61K31/675A61K31/4427A61P31/12A61P35/00
CPCC07D401/14C07D401/12C07D405/14C07D409/12C07D405/12C07D403/14C07D225/06C07H19/067A61P31/12A61P35/00
Inventor 李卓荣彭宗根李艳萍朱建华陶佩珍樊博王宇萍山广志王淑琴章天蒋建东
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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