Synthesis, anti-human immunodeficiency virus and anti-hepatitis B virus activities of 1-3-oxaselenolane nucleosides

A technology of oxyselenosides and oxyselenosides, which is applied in the field of synthesizing nucleosides and can solve problems such as difficulties

Inactive Publication Date: 2005-04-13
EMORY UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although their structures are similar to nucleosides with 3′-heteroatoms substituted, it is difficult to synthesize 1,3-oxyselenolane nucleosides due to the difficulty of synthesizing the oxyselenolane structure
Because of this, there is no report of 1,3-oxoselenopentanucleoside

Method used

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  • Synthesis, anti-human immunodeficiency virus and anti-hepatitis B virus activities of 1-3-oxaselenolane nucleosides
  • Synthesis, anti-human immunodeficiency virus and anti-hepatitis B virus activities of 1-3-oxaselenolane nucleosides
  • Synthesis, anti-human immunodeficiency virus and anti-hepatitis B virus activities of 1-3-oxaselenolane nucleosides

Examples

Experimental program
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preparation example Construction

[0073] Preparation of II Active Compounds

[0074] Hitherto, 1,3-oxoselenolane nucleosides have not been produced due to the difficulty in synthesizing the ring structure of 1,3-oxoselenolane. A method of producing this ring is provided herein. Figure 1 shows an embodiment of the method. Also provided herein are methods of producing isolated β-D (ie, 2S,5R) and β-L 1,3-oxoselenane (ie, 2R,5S) nucleosides. Figure 2 shows an embodiment of the method. Figure 1 also provides the numbering of the compounds used in the following examples.

Embodiment 1

[0075] Example 1 Preparation of 1,3-oxoselenolane

[0076] Application of Kirby's method to the preparation of selenocyanates gave very high yields. In the first step, ethyl bromoacetate (BrCH 2 CO 2 Et) reacts with potassium selenocyanate to form selenocyanate 2.

[0077] For the synthesis of lactone 5, an initial attempt was made to use NaBH 4 Reduction of selenocyanate 2 followed by hydrolysis of the resulting ester with NaOH yields selenolacetic acid, which can be used in the structure of the oxyselenolane system 5. However, during acidification to pH 2 with HCl, selenolacetic acid was degraded. It has been reported that selenol is easily oxidized by oxygen in air to form a stable dimer, which can be 3 PO 2 And reduced to selenol. It has been found that the reduction of bis(selenoacetic acid) to selenol and the cyclization reaction can be carried out in one reaction vessel without isolation of intermediate products. Therefore, 1 and KSeCN were refluxed in ethanol f...

Embodiment 2

[0081] Example 2 Resolution of 2-hydroxymethyl-4-(n-5'-cytosine-1'-yl)-1,3-oxyselenolane and 2-hydroxymethyl-4-( β-D and β-L enantiomers of n-5′-fluorocytosine-1′-yl)-1,3-oxoselenolane

[0082]2-Hydroxymethyl-4-(N-5′-cytosine-1′-yl)-1,3-oxoselenane and 2-hydroxymethyl-4-(N-5 '-fluorocytosine-1'-yl)-1,3-oxyselenolane. The compound (racemic, about 2 mg) was dissolved in a minimal amount (about 400 [mu]l) of methanol (HPLC grade). The conditions used for resolution are as follows: Waters HPLC system; column: Chiralpak AS 4.6×250mm; mobile phase: 2-propanol, flow rate: 0.80 ml / min; detector: UV-260nm; injection gas: helium; injection speed: 25 ml / min / solvent tank; injection volume: 20μl solution each time; retention time: (-)-(2S,5R)-β-L-2′,3′-dideoxy-3′-seleno-cytosine nucleus Glycoside, 5.50 minutes; (+)-(2R,5S)-β-D-2′,3′-dideoxy-3′-seleno-cytidine, 6.92 minutes; (-)-(2S,5R )-β-L-2′,3′-dideoxy-5-fluoro-3′-seleno-cytidine, 5.97 minutes; (+)-(2R,5S)-β-D-2′, 3'-dideoxy-5-fluor...

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Abstract

A method and composition for the treatment of HIV infection, HBV infection, or abnormal cellular proliferation in humans and other host animals is disclosed that includes the administration of an effective amount of a 1,3-oxaselenolane nucleoside or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

Description

Background of the invention [0001] The National Institute of Allergy and Infectious Disease and the Department of Veterans Affairs funded research in part on this invention, which arose out of the U.S. Public Health Funded by the U.S. Public Health Service Research Fund, the U.S. government has a patent right on the invention. [0002] The invention belongs to the field of synthetic nucleosides, and specifically relates to 1,3-oxaselenolane nucleosides, pharmaceutical applications, compositions and preparation methods thereof. [0003] In 1981, Acquired Immune Deficiency Syndrome (AIDS) was recognized as a disease that seriously compromises the human immune system, causing almost all deaths. In 1983, the cause of AIDS was identified as human immunodeficiency virus (HIV). [0004] In 1985, it was reported that the synthetic nucleoside 3'-azido-3'-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus. Since then, many other synthetic nucleosides, inclu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D421/04C07D473/30A61K31/505A61K31/02C07D473/00C07D473/18C07F9/6558C07F9/6561
CPCC07D421/04C07D473/00C07D473/18C07F9/65586C07F9/65616A61P1/16A61P31/12A61P31/18
Inventor R·F·施纳兹C·K·楚J·-F·杜
Owner EMORY UNIVERSITY
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