Description
Aricept was launched in Canada, Germany, the UK and the US for treatment
of mild to moderate Alzheimer’s disease and dementia. It was prepared in three steps
beginning with the condensation of 5,6-dimethoxy-1-indanone with 1-benzylpiperidine-
4-carboxaldehyde. Aricept is a reversible, non-competitive inhibitor of
acetylcholinesterase. It is 570-1250 times more selective for acetylcholinesterase than
for butylcholinesterase. It has a greater affinity for brain over peripheral
acetylcholinesterase with no inhibition in cardiac and smooth muscle, but with slight
effects in striated muscle. Aricept inhibited all three isozymes (type A, G2 and G4) of
acetylcholinesterase thereby delaying the decline of cholinergics found in the AD brain
and slowing the loss of cognitive abilities. It has a 60-70 hr half-life, readily penetrates
the CNS, and is 100% bioavailable through the gut with no hepatotoxicity.
Chemical Properties
Donepezil hydrochloride is known chemically as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride[1]. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in n-hexane.
Uses
A labelled nootropic. An inhibitor of acetylcholinesterase.
Uses
A nootropic. An inhibitor of acetylcholinesterase
Uses
Labeled Donepezil, intended for use as an internal standard for the quantification of Donepezilby GC- or LC-mass spectrometry.
Application
Donepezil hydrochloride is a reversible，non-competitiveChEl with highly selective central action,approved for thetreatment of mild, moderate and advanced AD. Donepezil is unrelated to other ChEIs and has greaterselectivity for cerebral acetylcholinesterase (AChE) than forbutirylcholinesterase (BuChE).
Definition
ChEBI: Donepezil hydrochloride is a centrally acting reversible acetyl cholinesterase inhibitor. Its main therapeutic use is in the treatment of Alzheimer's disease where it is used to increase cortical acetylcholine.
Preparation
Donepezil Hydrochloride is being synthesized from alkylidene or arylidene-2-indanone formed by Aldol condensation chemistry as key intermediates (Sugimoto and co-workers)) followed by catalytic reduction affording donepezil hydrochloride with an overall yield of 27%.
Benzyl chloride (1.92 g, 0.0156 mol), potassium carbonate (2.28 g, 0.0165 mol) and PEG-200 (80 mg, 2% by weight) were added to a clear biphasic solution of 2-[(4-piperidyl)methyl]-5,6-dimethoxyindan-1-one 6 (4 g, 0.0138 mol) in 9 : 1 EtOAc–H2O (40 ml). The reaction mixture was heated to 50—55 °C and monitored on TLC. After completion of reaction (14 h), the solid was filtered and the filtrate was washed with water (4 ml). The EtOAc layer was separated, added water (8 ml) and acidified with conc. HCl till a pH 2. EtOAc layer was discarded and the acidic aqueous layer was extracted with CH2Cl2 (2*16 ml). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and evaporated under vacuum to yield the crude salt as a residue. The residue was dissolved in methanol (20 ml) followed by the addition of isopropyl ether (40 ml) and stirred for a further 1 h. The precipitated solid was filtered and dried under vacuum to yield pure donepezil hydrochloride.
A New Commercially Viable Synthetic Route for Donepezil Hydrochloride
Manufacturing Process
This reaction was conducted in an argon atmosphere. 2.05 ml of
diisopropylamine was added to 10 ml of anhydrous THF, followed by addition
of 9.12 ml of a 1.6 M solution of n-butyl lithium in hexane at 0°C. The
mixture was stirred at 0°C for 10 min and then cooled to -78°C, and a
solution of 2.55 g of 5,6-dimethoxy-1-indanone in 30 ml of anhydrous THF
and 2.31 ml of hexamethyl-phosphoric amide were added thereto. The
mixture was stirred at -78°C for 15 min, and a solution of 2.70 g of 1-benzyl-
4-piperidinecarboaldehyde in 30 ml of anhydrous THF was added thereto. The
temperature of the mixture was gradually raised to room temperature,
followed by stirring for 2 hr. An aqueous 1% ammonium chloride solution was
added thereto, and the organic phase was separated. The water phase was
extracted with ethyl acetate, and the organic phases were combined with each
other. The combined organic phase was washed with a saturated saline
solution, dried over magnesium sulfate, and concentrated in vacuo. The
resulting residue was purified by making use of a silica gel column (methylene
chloride:methanol=500:1-100:1). The eluate was concentrated in vacuo, and
the residue was dissolved in methylene chloride. A 10% solution of
hydrochloric acid in ethyl acetate was added to the resulting solution, followed
by concentration in vacuo to obtain a crystal, which was recrystallized from
methanol/IPE to obtain 3.40 g (yield: 62%) 1-benzyl-4-[(5,6-dimethoxy-1-
indanon)-2-ylidenyl]methylpiperidine HCl; melting point 237°-238°C.
4 g of 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-ylidenyl]methylpiperidine was
dissolved in 16 ml of THF, followed by addition of 0.04 g of 10% palladiumcarbon. The mixture was hydrogenated at room temperature under
atmospheric pressure for 6 hr. The catalyst was filtered off, and the filtrate
was concentrated in vacuo. The residue was purified by making use of a silica
gel column (methylene chloride:methanol=50:1). The eluate was concentrated
in vacuo, and the residue was dissolved in methylene chloride. A 10% solution
of hydrochloric acid in ethyl acetate was added to the resulting solution,
followed by concentration in vacuo to obtain a crystal, which was
recrystallized from methanol/IPE to obtain 0.36 g (yield: 82%) of the 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl-methylpiperidine]-hydrochloride
(donepezil HCl) having the melting point: 211°C-212°C (dec.).
Later it was described the synthesis of the donepezil HCl from 5,6-dimethoxy-
2-(pyridin-4-yl)methylene-indan-1-one by the reaction with H2 over platinum
dioxide at room temperature in acetic acid-methanol mixture to give 4-[(5,6-
dimethoxy-1-indanon)-2-yl]methylpiperidine. The last one yielded donepesyl
HCl by refluxing with benzyl bromide and triethylamine for 4 hours with the
following addition of methanolic HCl (10%).
Brand name
Aricept (Eisai Medical Research).
Therapeutic Function
Anti-Alzheimer's disease
General Description
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
Donepezil Hydrochloride is known as a selective, reversible inhibitor of acetylcholinesterase enzyme. It exhibits therapeutic effect by raising the acetylcholine concentrations and improving the cholinergic function. It can be used in the treatment of mild to moderate dementia of the Alzheimer′s type.
Biological Activity
donepezil hydrochloride (donepezil hcl) is a novel, potent and selective inhibitor of acetylcholinesterase (ache), an enzyme possibly involved in cognitive dysfunction of patients suffering alzheimer’s disease (ad), with the half maximal inhibition concentration ic50 value of 6.7 nm [1].donepezil hcl is a piperidine-class ache inhibitor containing an n-benzylpiperdine and an indanone moiety, which confers it a longer and more selective action against ache as compared to buche (ic50: 7.4 μm) [1].donepezil hcl has been approved by fda for the treatment of ad, in which it has improved cognitive function of mild to severe moderate ad patients and exhibited excellent tolerability without hepatotoxicity [1].
Biochem/physiol Actions
Donepezil hydrochloride is a piperidine containing an organic compound and a non-competitive inhibitor. It is useful in treating Alzheimer′s disease, in which dementia is a prominent symptom. Donepezil is shown to induce cognitive ability and overall body function. It has a half-life of 70 hours.
Clinical Use
Treatment of dementia in mild to moderate Alzheimer’s
disease
Side effects
Donepezil was generally well tolerated, although more adverse effects were reported in the 10 mg/day group than assessed as mild to moderate and transient, and were typi-cally diarrhoea，nausea，arthralgia，leg cramps，anorexia and headache. Donepezil (5-10 mg/day) had no effecton V-ADAS-cog but had significant effect on two measuresof executive function: EXIT25 and TMT-B. These subjectswere younger than most VaD patients and most (75%) hadno clinically significant memory dysfunction. The positive effect of donepezil on executive function, however, indicatessome cholinergic deficit in executive dysfunction.
Drug interactions
Potentially hazardous interactions with other drugs
None known
Metabolism
Donepezil hydrochloride is both excreted in the urine
intact and metabolised by the cytochrome P450
system to multiple metabolites, not all of which have
been identified. Following administration of a single
5 mg dose of [14C]-labelled donepezil hydrochloride,
plasma radioactivity, expressed as a percentage of the
administered dose, was present primarily as intact
donepezil hydrochloride (30%), 6-O-desmethyl donepezil
(11% - only metabolite that exhibits activity similar to
donepezil hydrochloride), donepezil-cis-N-oxide (9%),
5-O-desmethyl donepezil (7%) and the glucuronide
conjugate of 5-O-desmethyl donepezil (3%).
Approximately 57% of the total administered
radioactivity was recovered from the urine, and 14.5% was
recovered from the faeces, suggesting biotransformation
and urinary excretion as the primary routes of
elimination. There is no evidence to suggest enterohepatic
