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HA improved the condition of the patients from Week 6. In comparison with the
baseline data, the HA group improved significantly the cognitive function, activity
of daily life (ADL), noncognitive disorders, and overall clinical efficacy. Mild and
transient adverse events (edema of bilateral ankles and insomnia) were observed in
3% of HA-treated patients.
Chang et al. surveyed the effect of HA on promoting verbal recall in middle-
aged and elderly patients with dysmnesia of varying severities and disclosed that
HA has a fair effect on improving the ability of verbal recall, retention, and repeti-
tion in patients with mild and moderate dysmnesia.
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The randomized double-blind
crossing medication method was used for 50 middle-aged and elderly patients with
dysmnesia. They were given each placebo or HA 100 mg p.o., b.i.d., for 2 weeks.
Multiple selective verbal reminding tests were conducted before and after the
medication. In patients with mild and moderate dysmnesia, values of recall
(R), long-term retrievel (LTR), random LTR, presentation, reminded recall and
pass number, long-term storage, consistent LTR, and unreminded recall of HA
group were markedly increased in contrast to those of the placebo group. Further-
more, HA was found to have no evident effect on most patients with severe
dysmnesia. No severe adverse reactions and inhibition of blood ChE activity
were encountered during the treatment with HA.
4.6
SYNTHESIS OF HA AND ITS ANALOGS
The multifaceted bioactivities of HA and its scarcity in nature have provided the
impetus for renewed interests in the synthesis of this target molecule. Moreover,
the structure activity relationship (SAR) of HA has been extensively studied.
4.6.1
Synthesis of Racemic HA
Total synthesis of racemic HA was first accomplished independently by both Qian
and Ji
96
and Xia and Kozikowski
96
in 1989 (Schemes 4-1 and 4-2). Almost the
same synthetic strategy was adopted starting from the b-keto ester 2 or 2a. Qian
and Ji prepared 2a using traditional methods with 17.1% yield from ethyl aceto-
acetate. The three-carbon bridge ring was constructed through tandem Michael-
adlol reaction with methacrolein. Hereinafter, a MsOH elimination reaction to
form an endocyclic double bond, a Wittig reaction for exocyclic double bond,
and a Curtius rearrangement and deprotection reaction were successively con-
ducted. The low yield of E-product of Wittig reaction is the important deficiency.
Xia and Kozikowski synthesized 2a using another route. In contrast to Qian and
Ji's, it is longer and required expensive reagents such as PhSeCl and Pd(OH)
2
.
The remaining steps to rac-HA is similar to that of Qian and Ji's, with the exception
of using PhSH/AIBN to enhance the E/Z product ratio from 10:90 to 90:10.
In 1990, Xia and Kozikowski improved the preparation of key intermediate
4 from 3 (Scheme 4-3).
97
They used an efficient one-pot, three-component process
to prepare 2-pyridone 6 from a carbonyl compound, ammonia, and methyl propio-
late, which enhanced the yield of 2a and avoided those expensive reagents. In 1993,
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