Design, Synthesis And Skin Permeability Of Adenosine Prodrugs And Penetration Enhancer DDAK Derivatives In A PAMPA Model Study

Painful diabetic peripheral neuropathy is one of common complications of diabetes,which is a chronic neuropathic pain with high incidence and low remission rates.In recent years,studies have shown that adenosine is an endogenous analgesic in the nervous system,has a promising to be a new candidate in the field of treatment of chronic neuropathic pain.However,adenosine has a short half-life in vivo and many side effects,and then can not be systemically delivery.Transdermal and topical delivery may have better analgesic effect and avoid adverse reactions.DDAK is a highly effective and non-toxicity transdermal permeation enhancer,may enhance skin permea-bility of adenosine.In this thesis,6 adenosine ester prodrugs were prepared by esterification of hydroxy groups of ribose to reduce the hydrophilicity and enhance the skin permeability.In addition,DDAK was selected as a leading,and a hydrophobic chain was added to synthesize a series of new highly effective DDAK analogs to further enhance the transdermal effect of adenosine prodrug,which expected to achieve the needs for the treatment of chronic neuropathic pain.The thesis have 35 compounds,30 were new,including 2 adenosine ester prodrugs and 28 DDAK analogs,the structures of all compounds were indentified by Mass Spectrometry,1H-NMR,13C-NMR and infrared spectrum.The aim of this experiment was to evaluate effective permeability coefficients of adenosine prodrugs and the effect of permeation enhancer DDAK analogs with the ultraviolet spectrophotometric and PAMPA method,a membrane consisting of 30%isopropyl myristate and 70%silicone oil,simulating human stratum comeum.The results showed that:1.The skin permeability of adenosine ester prodrugs were stronger than adenosine,which the permeability of compound HYC-1 was the best;and in all monoesterification adenosine prodrugs,with the increasing of carbon chain,the effective permeability were decreased;after adding DDAK,the effective permeability of adenosine prodrugs were improved.2.In DDAK analogs,15 compounds have stronger penetration enhancing effect than DDAK,the compound HYC-21 is the best,the effective permeability coefficient was 1.955 times of DDAK;HYC-10,11 and 20 also have greater penetration effect,the effective permeability coefficient were 1.773,1.688,1.747 times of DDAK.