Tenofovir, adefovir and intelligent polymer conjugates and preparation and use thereof

A smart polymer, tenofovir technology, which can be used in medical preparations with non-active ingredients, medical preparations containing active ingredients, and drug combinations, etc. It can solve the problems of low bioavailability and limited disease treatment effects. Achieve the effect of inhibiting virus replication, reducing renal clearance, and reducing adverse reactions

Inactive Publication Date: 2008-08-13
华林 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the incidence of nephrotoxicity of adifovir dipivoxil is low at the dose of 10mg / d, this limits its therapeutic effect on the disease to a certain extent
The nephrotoxicity of tenofovir dipivoxil is less than that of adifovir dipivoxil, but the oral dose needs to be 150-300 mg, and the bioavailability is low

Method used

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  • Tenofovir, adefovir and intelligent polymer conjugates and preparation and use thereof
  • Tenofovir, adefovir and intelligent polymer conjugates and preparation and use thereof
  • Tenofovir, adefovir and intelligent polymer conjugates and preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Synthetic example

[0041] In the following examples, the starting materials tenofovir and adifovir were synthesized with reference to the literature (Antonin Holy, et al, Collect. Czech. Chem. Commun., 1989, 5: pp. 2190-2195, US Patent 4,808,716).

[0042] Poly-N-isopropylacrylamide and poly-N,N-dimethylaminoethyl methacrylate were synthesized by conventional methods.

Embodiment 1

[0043] Example 1: Preparation of tenofovir-bispoly N-isopropylacrylamide conjugate

[0044] Add 40g (10mmol) of monohydroxypoly N-isopropylacrylamide with an average molecular weight of 4000 to 400ml of dichloromethane for dissolution, add tenofovir 1.45g (5mmol) and dicyclohexylcarbodiimide (DCC) 4.12 g (20mmol), heated to 60°C, and reacted at this temperature for 4 hours, cooled to room temperature, filtered, stirred after adding diethyl ether to the filtrate, heated to 35°C for centrifugation, and dried the precipitate for 24 hours to obtain Tenofo 25.3 g (61%) of Wei-dipoly N-isopropylacrylamide conjugate contains 3.3% tenofovir.

Embodiment 2

[0045] Example 2: Preparation of adifovir-bispoly N-isopropylacrylamide conjugate

[0046] Add 40g (10mmol) of monohydroxypoly N-isopropylacrylamide with an average molecular weight of 4000 to 400ml of dichloromethane to dissolve, add 1.38g (5mmol) of adifovir (5mmol) and 4.12g (20mmol) of DCC, and heat to 60°C. And react at this temperature for 4 hours, cool to room temperature, filter, add diethyl ether to the filtrate and stir, heat to 35°C for centrifugal sedimentation, and dry the precipitate for 24 hours to obtain Adifovir-bispoly N-isopropylacrylamide Conjugate 15.3g (37%), containing adefovir 3.1%.

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Abstract

The present invention provides a conjugate of tenofovir, addy adefovir and intelligent polymers, a method for preparing the same, and an usage. The invention relates to the technical field that antiviral medicinal molecular tenofovir and addy adefovir are chemical modified, namely, phosphate group of tenofovir or addy adefovir is linked with X group, then X group is linked with intelligent polymers R, or phosphate group of tenofovir or addy adefovir is linked with intelligent polymers R with X function group, and a conjugate of tenofovir, addy adefovir and intelligent polymers with A-X-R-Y formula is formed. The modified tenofovir and addy adefovir forms efficient screen for raw medicine, and improves obviously medicine absorption of intestinal and absorption of cell, improves bioavailability of medicine, at the same time, reduces the kidney cleaning of medicine, and reduces the toxic for kidney, improves security.

Description

technical field [0001] The present invention relates to the chemical modification of antiviral drug molecules tenofovir (tenofovir, PMPA) and adifovir (adefovir, PMEA), specifically combining them with intelligent polymers, especially poly-N-isopropylacrylamide (PNIPAM) ), polymethacrylic acid-N, N-dimethylaminoethyl ester (PDMAEMA), polymethylvinyl ether (PMVE) and poly-N-vinyl caprolactam (PVCa) and derivatives thereof, also relate to their preparation method and applications in antiviral drugs. Background technique [0002] Tenofovir (tenofovir, PMPA) and adefovir (adefovir, PMEA) are acyclic nucleoside antiviral drugs used to treat HIV-1 infection and HBV infection respectively, which were first launched by GileadSciences in the United States and have been launched in Listed on the market in the United States, Europe and other places. The role of tenofovir in the treatment of HBV infection is in clinical phase III trials. Due to the strong hydrophilicity at physiologi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K31/675A61P31/18A61P31/20A61P1/16A61K47/58
Inventor 华林张扬李明成
Owner 华林
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