The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).
New methods for asymmetric reactions developed by the author's group are outlined. They include asymmetric nitroolefination through an addition-elimination process, asymmetric synthesis utilizing 2, 2'-disubstituted and 8, 8'-disubstituted binaphthyl derivatives, and enantioselective α-alkylation of carbonyl compounds under conditions with absolutely no external chiral environmental factors.
Several novel reactions utilizing the latent feature of sulfur atoms have been developed. We found that chiral p-toluenesulfinyl groups on olefines control the stereochemistry in highly diastereoselective manners as show in the following three types of reactions : 1) intramolecular Michael addition reactions, 2) Pummerer-type reactions, and 3) cyclopropanation reactions. These chiral auxiliary groups are also very efficient for the asymmetric desymmetrization of σ-symmetric diols via diastereoselective acetal fission. In addition, it was revealed that an aryl sulfide group on the cyclopropyl ring triggers single electron transfer reactions via cation radical species, resulting in the following reactions : 1) tandem oxidative ring cleavage-cyclization reactions and 2) intramolecular [3+2] cycloaddition reactions. These reactions have been applied to the syntheses of natural products.
New types of diclofenac sodium suppositories known to control a drug release function for hospital preparations were developed based on a concept of the drug delivery system. Hard fat (Witepsol[○!R]) used as a base of the suppository consists of a mixture of triglycerides, diglycerides and monoglycerides, and each Witepsol[○!R] is characterized by its physicochemical properties. Authors disclosed that the amount of drug release measured in the commercially available diclofenac sodium suppositories decreased at a low temperature (36°C). Mixed types of diclofenac sodium suppositories consisting of Witepsol W35[○!R] and Witepsol E85[○!R] as a base were also prepared and their drug release functions investigated in vitro and in vivo. The in vitro drug release properties changed with the mixing ratios of the two bases and with the temperature of the fluid tested. The amount of released diclofenac sodium increased with increases of both the ratio of Witepsol W35[○!R] in the suppository and the temperature of the test fluid. Moreover, several processes causing these phenomena were evidenced by the image analysis. The in vivo absorption of diclofenac sodium was found to be also influenced by these factors. Consequently, it is predicted that such factors as the ratio of Witepsol W35[○!R] in the suppository and the temperature will influence the drug absorption and the pharmacological effect of diclofenac sodium suppositories.
Cervi Parvum Cornu has been widely used as an agent in commercially available tonic medicines. The establishment of the method for the identification of each agent, especially crude drugs in formulations, is very important from the viewpoint of the quality control of drugs. In this paper, we reported the examination on the extraction method of DNA from the formulations, and also on the PCR method using four sets of primers, amplifying the DNA fragments of the regions of 12S rRNA and/or cytochrome b genes. The same size of DNA fragments as in the Cervi Parvum Cornu reference sample were found in all PCR products obtained from four commercial tonic medicines investigated. Therefore, it was confirmed that Cervi Parvum Cornu was contained in all the tonic medicines used. The PCR method was found to be a useful method for the identification of Cervi Parvum Cornu in tonic medicines and the DNA fragments amplified by the PCR method was clarified to be also helpful materials as index constituents for Cervi Parvum Cornu.