Acyclic nucleotide analogs as well as preparation method and application thereof

A technology of acyclic nucleotides and analogues, which is applied in the field of chemical synthesis of drugs and can solve problems such as drug resistance and side effects

Active Publication Date: 2013-01-23
SICHUAN GOODDOCTOR PANXI PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In summary, although open-ring nucleoside drugs have been greatly developed, there are still problems such as drug resistance and high toxicity. Therefore, exploring and developing new antiviral drugs is still an urgent research topic

Method used

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  • Acyclic nucleotide analogs as well as preparation method and application thereof
  • Acyclic nucleotide analogs as well as preparation method and application thereof
  • Acyclic nucleotide analogs as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] The preparation of embodiment 1 (R)-1-(2-hydroxypropyl)-4-aminopyrazolo[3,4-d]pyrimidine

[0090]

[0091] Add 5.26g of 4-aminopyrazolo[3,4-d]pyrimidine to a 250mL round bottom flask, then add 200mL of DMF and 83mg of sodium hydroxide, heat the reaction solution to 140°C, slowly add 3.90mL of R-carbonic acid Acrylate, react at 140°C for 16 hours after addition. TLC (DCM:MeOH=8:1) detected that the reaction was complete. The solvent was distilled off under reduced pressure and separated by silica gel column chromatography to obtain 5.55 g of a white solid with a yield of 74.7%.

[0092] 1 H NMR (DMSO-d 6 ,400Hz)δ8.16(s,1H),8.08(s,1H),7.63(s,2H),4.28-4.22(m,1H),4.13(d,2H,J=5.6Hz),3.37(s ,1H), 1.03(d,3H,J=5.6Hz).

Embodiment 2

[0093] Example 2 (R)-N 4 - Preparation of dimethylaminomethylene-1-(2-hydroxypropyl)-pyrazolo[3,4-d]pyrimidine

[0094]

[0095] In a 100mL flask, add 11.24g (R)-1-(2-hydroxypropyl)-4-aminopyrazolo[3,4-d]pyrimidine, 23.5mLN,N-dimethylformamide dimethyl acetal (DMF-DMA), and then add 50 mL of chloroform. Under nitrogen protection, stir overnight at room temperature. TLC detection (DCM:MeOH=9:1) until the reaction is complete. The solvent was distilled off under reduced pressure to obtain a pale yellow oil, which was separated by silica gel column chromatography to obtain 11.4 g of a white solid with a yield of 78.9%.

Embodiment 3

[0096] Example 3 (R)-N 4 - Preparation of dimethylaminomethylene-1-[2-bis(ethylphosphonomethoxy)propyl]-pyrazolo[3,4-d]pyrimidine

[0097]

[0098] In a 500mL flask, add 11.4g (R)-N 4 -Dimethylaminomethylene-1-(2-hydroxypropyl)-pyrazolo[3,4-d]pyrimidine and 14.1 mL of diethyl p-toluenesulfonyloxymethylphosphonate, then 300 mL of toluene was added, Add 5.51gNaH under ice-salt bath. Under nitrogen protection, stir overnight at room temperature. TLC detection (DCM:MeOH=10:1) until the reaction was complete. The solvent was distilled off under reduced pressure, the solid was dissolved in 100ml of dichloromethane, and glacial acetic acid was added drop by drop under stirring to adjust the pH to 8-9. It was extracted three times with dichloromethane, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to obtain a yellow oil. Separated by silica gel column chromatography, 11.01 g of a white solid was obtained with a yield of 60.2%. 1 HNMR (CDCl 3 ,400...

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Abstract

The invention belongs to the technical field of chemical synthetic drugs, and particularly relates to acyclic nucleotide analogs as well as a preparation method and an application of the acyclic nucleotide analogs in antiviral drugs. The technical problem to be solved by the invention is to provide a new class of acyclic nucleotide analogs which has the structure shown as the formula I. The acyclic nucleotide analogs provided by the invention has an antiviral pesticide effect, and provides a new choice for the development of antiviral drugs.

Description

technical field [0001] The invention belongs to the technical field of chemically synthesized drugs, and in particular relates to an acyclic nucleotide analogue, a preparation method thereof and an application in antiviral drugs. Background technique [0002] Diseases caused by viral infections such as viral hepatitis and AIDS are major diseases that seriously threaten human health. International research on antiviral drugs has made important progress, and some clinically effective antiviral drugs have been found, such as interferon, lamivudine, telbivudine, clavudine, entecavir, adefovir dipivoxil, Nofovir dipivoxil, zidovudine, stavudine, nevirapine, indinavir and valacyclovir, etc. As an important family of nucleoside antiviral drugs, ring-opening nucleoside compounds have low toxicity, good tolerance and broad-spectrum anti-DNA virus activity, and have a strong killing effect on drug-resistant strains, and play an important role in the field of antiviral therapy. Among...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07F9/6512C07F9/6571C07F9/6574C07F9/6584A61K31/675A61P31/14A61P31/18A61P31/20
CPCC07F9/141C07F9/65515C07D487/04C07F9/653A61P31/14A61P31/18A61P31/20C07F9/6561C07F9/657181C07F9/65846
Inventor 谢永美魏于全李炯
Owner SICHUAN GOODDOCTOR PANXI PHARMA
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