Adefovir Derivatives Of The Design, Synthesis And Preliminary In Vitro Stability Test

Recently, chronic hepatitis B and its accompaniment of liver cirrhosis, hepatocirrhosis and hepao-action prostration etc., have already become the most common diseases which caused serious damage to the human health. However, the researchs of medicine which cure chronic hepatitis B relatively has fall behind. Up to now, there are no a good special medicine that could completely eliminate cccDNA as well as that could alleviate hepatocellular injury, death and reproduction.Adefovir belongs to certain nucleoside analogue inhibitors of virus reverse transcriptase, it carries out the function of anti-virus by restraint hepatitis B virus (HBV)DNA replication. Adefovir has showed significant activities in animal tests, and its prodrug adefovir dipivoxil was satisfactory with treating chronic hepatitis B in the clinic. Its anti-HBV action restrains HBV DNA polymerase through the metabolites' competition with deoxyadenosine triphosphate(dATP), which is the natural substrate of viral enzyme. It can also directly integrate into viral DNA chain to terminate the synthesis of the viral DNA. Adefovir has displayed a perfect restraining function to wild HBV and variational HBV strains that resistant to Lamivudine, it has a vast market perspective as a kind of anti-HBV drug.Glycyrrhetic acid is the hydrolysate of glycyrrhizic acid——a pentacyclic triterpene compound which is produced by taking two glycuronic acid molecules off glycyrrhizae. The researches demonstrated that glycyrrhetic acid had various pharmacologic functions, the mechanism of treatment to hepatitis B mainly included:â‘ restrain the active ofβ-glucosiduronic acid enzyme.â‘¡hamper the transmissions of fos-related antigen in HBV, and improve the immune state to HBV.â‘¢enhance the organismic immunity.Some studies showed that the anti-HBV action of adefovir came from the metabolism products of phosphate group in its molecular extremity. Meantime, the relationship of structure-activity studies suggested that the anti-viral active group of glycyrrhetic acid was 3—OH of pentacyclic triterpene framework. In order to find new compounds which have high effective anti-HBV function, we took adefovir as the lead compound and designed new type target molecules by modifying glycyrrhetic acid, introduced glycyrrhetic acid using of the principle of hybridization.According to above ideas, we designed a concise route to synthesis a series of target compound as below:1. The synthesis of PMEA1-chloro-2-(chloromethoxy)ethane reacted with triisopropyl phosphate through Arbuzov reaction to gain the side chain named diisopropyl (2-chloroethoxy)methylphosphonate. The side chain reacted with adenine and K₂CO₃ in DMF solvent to produce diisopropyl (2-(6-amino-9H- purin-9-yl)ethoxy)methylphosphonate with condensation reaction. Then it hydrolyzed with trimethylbromosilane to give PMEA.2. The synthesis of diglycyrrhetic adefovir esterGalycyrrhetic acid was modified with 3-OH to induct benzoyl, ethanoyl etc. Then its 30-COOH through halogeno-reaction and chloromethylation obtained to its 1-chloropropan-2-one, chloromethyl acetate. Then it reacted with PMEA to give target molecules.Six compounds were designed and synthesized, there were no evidence that the target compounds and intermediates had been reported. The structure of the target compounds and intermediates were confirmed by spectra of IR, ¹H-NMR and ¹³C-NMR.The study of physiological activity of title compounds is in progress.