Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Nucleosides analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the DNA polymerase of hepatitis B virus (HBV)

A technology of compounds and nucleosides, applied in the field of nucleoside analogs, can solve the problems of unreported bioavailability and low bioavailability

Inactive Publication Date: 2000-12-06
北京恩立诺医药科技发展有限公司
View PDF10 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The former compound FLG has good activity in vitro, but the inventors have detected that its bioavailability is very low, about 4%, so that the use of this compound in vivo is still limited to animal models of intraperitoneal or subcutaneous administration so far
[0003] US Patent 4,963,662 discloses a series of 3'-fluoronucleosides and the corresponding triphosphate compounds and specifically describes 5'-O-palmitoyl derivatives of FLT, but does not report any improvement in bioavailability

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Nucleosides analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the DNA polymerase of hepatitis B virus (HBV)
  • Nucleosides analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the DNA polymerase of hepatitis B virus (HBV)
  • Nucleosides analogues, such as antivirals including inhibitors of retroviral reverse transcriptase and the DNA polymerase of hepatitis B virus (HBV)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] 2-(Stearyloxymethyl)-2-(N-(fluorenylmethoxycarbonyl)-L-valyloxymethyl)-propionic acid

[0109] To a solution of 2,2-bis(hydroxymethyl)propionic acid (28.16 g, 210 mmol) in water (50 mL) was added potassium hydroxide (11.78 g, 210 mmol). After 5 minutes, the solution was evaporated in vacuo and the residue was co-evaporated three times with anhydrous DMF. The residue was then dissolved in DMF (500 mL), and to this solution was added benzoyl bromide (3.57 mL, 30 mL). After stirring for 30 minutes, the reaction mixture was filtered through Celite, poured into aqueous sodium bicarbonate and extracted with dichloromethane. The organic phases were collected and washed with an aqueous solution of sodium bicarbonate. Subsequent evaporation in vacuo gave benzyl 2,2-bis(hydroxymethyl)propionate (4.37 g), 1 H-NMR (CDCl 3 ): 7.35 (s, 5H), 5.20 (d, 2H), 3.91-3.71 (m, 4H), 1.10 (s, 3H).

[0110] To a solution of benzyl 2,2-bis(hydroxymethyl)propionate (4.37 g, 19.5 mmol) in pyri...

Embodiment 2

[0112] 2-(N-fluorenyl-methoxycarbonyl)-L-valyloxymethyl)-2-(stearyloxymethyl) in THF / methanol (16ml / 8ml) mixed solvent ) benzyl propionate (1.86 g, 3.8 mmol) was added ammonium formate (376 mg, 6 mmol), formic acid (1.87 ml) and palladium black (40 mg). The reaction was maintained at room temperature for 16 hours, then filtered through Celite. After evaporation, the product was isolated by silica gel column chromatography, yield 1.05 g. Example 21-O-stearyl-2-O-(N-CBz-L-valyl)glycerol a) Preparation of 1-O-stearylglycerol

[0113] To a mixture of glycerol (30 g, 326 mmol) and pyridine (25 mL) dissolved in DMF (300 mL) was added stearoyl chloride (10 g, 33 mmol) dissolved in DMF (100 mL) dropwise. The mixture was cooled on an ice bath until the addition was complete. Response to N 2 Keep overnight under atmosphere. CH was added after 15 hours 2 Cl 2 (300 ml) and saturated NaHCO 3 (aqueous solution). The phases were separated and the organic phase was washed with water ...

Embodiment 3

[0117] Removal of the pixyl group from the product of step d) by selective deprotection using the method described in Example 3 affords the title compound, 1 H-NMR (CDCl 3 ): δ7.35(m, 5H), 5.3-4.9(m, 4H), 4.35-4.25(m, 3H), 3.8-3.6(m, 2H), 2.31-2.25(m, 2H), 2.20-2.10 (m, 1H), 1.60 (m, 2H), 1.02-0.86 (m, 9H). Example 31-O-(N-CBz-L-valyl)-2-O-stearyl glycerol a) Preparation of 1-O-(N-CBz-L-valyl)glycerol

[0118] CBz-L-valine (4.35 g, 17.3 mmol), dicyclohexylcarbodiimide (4.29 g, 20.8 mmol) and 4-dimethylaminopyridine (0.212 g) were added together at room temperature into a five-fold excess of glycerol (8 mL, 86.9 mmol). After stirring overnight, the suspension was filtered and DMF was removed from the filtrate in vacuo. Dissolve the residue in CH 2 Cl 2 In continuous use of saturated NaHCO 3 , brine and water washes, then dried. The crude product was chromatographed on silica gel with 4 / 1 EtOAc-hexane as eluent, yield 2.465 g, Rf (4 / 1 EtOAc-hexane) 0.17, (20 / 1 CH 2 Cl ...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

A compound of the formula (I), wherein: nuc is the residue of a nucleoside analogue bonded through its single hydroxy group on the cyclic or acyclic saccharide moiety, R1 is hydroxy, amino or carboxy; optionally having esterified / amide bonded thereon; a C4-C22 saturated or unsaturated, optionally substituted fatty acid or alcohol, or an aliphatic L-amino acid; R2 is the residue of an aliphatic L-amino acid; L1 is a trifunctional linker group; L2 is absent or a difunctional linker group; and pharmaceutically acceptable salts thereof have favourable pharmacological properties and are antivirally active.

Description

technical field [0001] The present invention relates to nucleoside analogs which are antiviral agents which act as reverse transcriptase and DNA polymerase inhibitors of retroviruses including hepatitis B virus (HBV). The present invention provides novel compounds with favorable pharmacodynamic parameters, processes for their preparation, pharmaceutical compositions containing these compounds and methods of using them to inhibit viruses and tumors including HBV and HIV. Background of the invention [0002] International patent application WO88 / 00050 describes a series of 3'-fluoronucleosides, including the compounds 2',3'-dideoxy-3'-fluoroguanosine (FLG) and 3'-fluorothymidine (FLT) for antiretroviral Recording virus and anti-HBV activity. The latter compound was clinically identified as an anti-HIV agent, and despite its good antiviral activity and pharmacokinetics, it showed unexpected toxicity (Flexner et al., J Inf Dis 170 (6) 1394-403 (1994 )). The former compound FL...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18A61K31/00A61K31/52A61K31/522A61K31/70A61K31/7042A61K31/7052A61K31/7076A61K31/708A61P31/12A61P31/16A61P31/18A61P43/00C07B61/00C07D213/80C07D213/85C07D307/68C07D473/00C07D473/32C07D473/34C07D513/04C07H17/08C07H19/04C07H19/16C07H19/173
CPCC07D307/68C07D213/80C07H19/04C07D213/85C07D473/32C40B40/00C07D473/00C07D513/04C07H17/08C07H19/16C07D473/18A61P1/16A61P31/12A61P31/14A61P31/16A61P31/18A61P43/00C07D307/20
Inventor 周晓雄N·-G·约翰松H·瓦林
Owner 北京恩立诺医药科技发展有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com