The Studies On The Synthesis And Pharmacokinetics Of Borneol Derivates

Borneol is a simple monoterpene, which has the extensive pharmacological action, such as analgesia, anti-inflammatory, anti-bacterial, penetrating easily the blood brain barrier and helping other drugs enter into the brain, so that enhancing the pharmacological effect of other drugs in the brain. Nowadays, it is widely used in coronary heart disease, angina pectoris and apoplexy caused by cerebral disease. However, the shortcoming of borneol has been gradually exposed in clinical practice. It possesses not so strong analgesic effect, little stimulation on the membrane and chemical instability. These shortcomings are the factor to limit its usage. In order to find out the less low-toxic & higher effective borneol derivatives and to enhance the usage of natural resource, in the present study, the modifying of natural borneol and the relative pharmacological research on natural borneol has been performed. The results are summarized as follow.1. The synthesis of borneol derivativesModifications at hydroxyl group of borneol were carried out and obtained 5 borneol derivatives. They were all bornyl benzoate. The molecular structures of 5 borneol derivatives were comfirmed by UV、MS、IR and NMR. There has been no any record for the bornyl benzoate on the Chemistry Abstract (CA). Moreover, there is few published information of bornylb benzoate on synthetic technology, pharmacological effect.2. The synthetic methods of bornyl benzoateThree major factors, including of the ratio of raw material, the temperature and the times of the reaction for the synthesis of bornyl benzoate were considered。We moderate all of them by designing experimental conditions in orthogonal test. The best condition in synthesis was decided with the statistic analysis. 3. The determination of physical constant of some borneol derivativesIn our research, the melting point of bornyl benzoate was determined by melting point apparatus and the optical rotation of bornyl benzoate was observed by polar meter. The results showed that the melting point of bornyl benzoate was narrow. There areπ-πconjugate in their molecular structure. Hence bornyl benzoate emerge the ultra-absorption。The solubility and Oil-water Partition Coefficient can be measured with ultra-violet absorption spectrophotometer. The results showed that bornyl benzoate was soluble in oil, The pury was quite high, the chiary of borneol was kept during the reaction.4. The acute toxicity of bornyl benzoateThe acute toxicity of bornyl benzoate was investigated on mice, No any adverse effect appeared after the oral dose of bornyl, The mice did not show any phenomena of acute toxicity after oral administration. Furthermore, bornyl had no effect on normal growth period of mice. It suggested that bornyl benzoate is rather safe.The acute toxicity reaction and mortality in mice were observed after oral administration of the (+)-4-Methoxy bornyl benzoate. The oral half lethal dose(LD50) of the (+)-4-Methoxy bornyl benzoate in mice was calculated by Bliss method, and 95% confidence intervals of LD50 were computed. The results showed that the half lethal dose(LD5o) of (+)-4-Methoxy bornyl benzoate in mice by oral administration was 3.6606g/kg, and 95%confidence intervals of LD50 were 3.1895g/kg-4.2376g/kg. The acute toxicity reaction and mortality in mice were showed that the oral administration of (+)-4-Methoxy bornyl benzoate was wide for the medicine margin for safety, conforms to the low poisonous standard.5. Some pharmacodynamic effect of bornyl benzoateThe effect of opening the blood-brain barrier has been evaluated with ultra-violet spectrophotometer on half-quantitative methods. It was found that bornyl benzoate possesses the same analgesic effect as bornyl and outstanding effect of opening the blood-brain barrier. 6. The pharmacokinetics study of bornyl benzoate in ratsIn order to elucidate the pharmacokinetic profile of bornyl benzoate, a rapid, sensitive, and reliable analytical HPLC-UV method was developed and fully validated to determine bornyl benzoate in biological samples. The mobile phase consisted of methanol-water(90:10, v/v)was run at flow rate of 0.5mL/min for different biological matrix. Ultraviolet detection wavelength was set at 258 nm. The chromatographic system used provided good separation of the compound without interfering peaks from endogenous substances. The intra- and inter-day precision (relative standard deviation) was generally good (<10%) at low, medium and high concentrations. With its high selectivity, acceptable accuracy, precision and sensitivity, this validated HPLC-UV method was successfully used to support the pharmacokinetics study of bornyl benzoate. The assay was then used to determine the pharmacokinetic and absolute bioavailability of bornyl benzoate in rats.When the lmmol/kg dose of drug was given by oral administration to rats, the boold samples were collected at different time points after dosing. All the collected boold samples were centrifuged to obtain plasma and the concentration of bornyl benzoate in plasma were determined by HPLC-UV method described as above. The pharmacokinetic parameter calculations and pharmacokinetic modeling were carried out with the PK Solution 2.0(Summit Research Services, USA) pharmacokinetics software. The results showed that the concentration-time curve was best fitted to an open two-compartment model in rats after oral administration of bornyl benzoate.For the first time, a simple and reliable HPLC-UV method to determine bornyl benzoate levels in rat plasma was established and validated, which had been successfully applied to the pharmacokinetics studies. To the best of our knowledge, this method meets the request need in the present pharmacokinetic. studies of bornyl benzoate.7. The metabolism of bornyl benzoate in vitroThe in vitro metabolism of bornyl benzoate was studied by rat hepatic microsomes.The major metabolites included acid, borneol and camphor, the detailed biotransformation of bornyl benzoate was to be studied in the future.In order to find out whether the borneol derivatives possess the similar and other effect of pharmacology, bornyl benzoate was synthesized without any references., it is apparent that the substitute introduced to borneol significantly affects toxicity and pharmacokinetics. bornyl benzoate possesses lower toxicity than borneol. Its water solubility and some pharmacodynamic effect still remain similar to borneol.In conclusion, this study will not only offer testimony for further research and development of bornyl benzoate, but also offer experimental platform and reference model of other borneol derivatives.