Scheme 1. Trost 2005 Galanthamine total synthesis:a bromine, sodium acetate, acetic acid, iron, rt b potassium carbonate, 2days c Troc-Cl, DMAP, Pyridine, dichloromethane d palladium,Trost ligand, triethylamine, dichloromethane e 1.5 mol % TsOH, CH(OMe)3, methanol f DIBAL-H, toluene, -78 °C, 1 hr g triphenylphosphine, acetonecyanohydrin, DIAD, diethyl ether h 2.20 mol % TsOH, THF, water i 15 mol % Palladium(II) acetate, 15 mol% dppp, 3 eq. Ag2CO3, toluene, 107 °C j selenium dioxide disodium hydrogen phosphate dioxane, 150 °C 3 hrs k methylamine ,methanol l 4 eq. DIBAL-H, m aqueous NaH2PO4 n NaCNBH3

Find information on thousands of medical conditions and prescription drugs.

Galantamine

Galantamine (trade name Razadyne®, Reminyl®) is a medication used in the treatment of Alzheimer's disease. more...

Home

Gamma-hydroxybutyrate

Gemzar

Geodon

Gleevec

Gliadel

Galantamine is mostly used as hydrobromide salt. It is a centrally acting reversible cholinesterase inhibitor in the same class as donepezil. Galantamine has a much shorter half life than donepezil (there is a newer prolonged release version available in 2004) and it also has more nicotinic receptor activity and is potentially more stimulating but also probably because of this activity tends to cause worse gastrointestinal side effects.

Total synthesis

The natural source of galantamine are certain species of daffodil and because these species are scarce and because the isolation of galanthamine from daffodil is expensive (a 1996 figure specifies 50,000 US dollar per kilogram) alternative synthetic sources are under development by means of total synthesis. One recent publication details the enantioselective organic synthesis of galanthamine and also that of morphine from a single precursor .

The total synthesis of galanthamine (Trost 2005) is described as follows (see scheme 1): the sequence starts by bromination by electrophilic aromatic substitution of isovanillin 1 to bromophenol 2, then by synthesis of the second intermediate 5 by reacting dialdehyde 3 in a coupled aldol reaction and Horner-Wadsworth-Emmons reaction with trimethyl phosphonoacetate 4. The hydroxyl group is activated as a leaving group by acetylation with trichloroethyl carbonate (Troc) to 6. Next an enantioselective Trost AAA reaction takes place between bromophenol 2 and carbonate 6 to the allyl ether 7. Next the aldehyde group is protected as an acetal in 8 and this step enables the to organic reduction of the ester group to the alcohol 9 with DIBAH and subsequent conversion of this alcohol to a nitrile by nucleophilic displacement to 10 followed by aldehyde deprotection to 11. The intramolecular Heck reaction to 12 creates the dihydrofuran ring. Allylic oxidation by selenium dioxide provides allylic alcohol 13 with the correct stereochemistry. The aldehyde reacts with methylamine to the imine 14 and reduction of the imine and nitrile by DIBAL-H leading to ring-closure to the hemi-aminal 15 (not isolated) followed by acid quenching gives the alcohol 16. In the final step this alcohol group is reduced to give Galanthamine 17 together with 6% of the epi isomer 18.

Read more at Wikipedia.org

• [List your site here Free!]

Effect of galantamine on patients with dementia
From American Family Physician, 6/1/05 by Caroline Wellbery

Galantamine is an acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease. Considerable emphasis has been placed on the study of cognitive abilities in response to dementia treatment. Functional assessment, however, also is important in determining whether and to what extent patients with dementia can perform activities of daily living (ADL). Galasko and colleagues examined the effect of galantamine on ADL in patients with dementia.

The analysis draws on a double-blind, placebo-controlled trial of galantamine, targeting outpatients with a history of cognitive decline. After a run-in period, patients were randomized to treatment with placebo or galantamine in increasingly higher dosages over the study period. Because the lowest dosage (8 mg per day) of galantamine was suboptimal, it was not included in the current analysis. The authors focused on 659 patients who completed the five-month trial of galantamine in a dosage of 16 or 24 mg per day or placebo. The primary outcome measure was performance on the AD Cooperative Study ADL Inventory. A subsidiary analysis focused on patients' ability to maintain independence in ADL. Three other inventories also were used, in part to stratify patients according to dementia severity.

Patients taking galantamine had better overall ADL scores than the placebo group at the end of the study period. Patients with more severe dementia at baseline had greater improvement with galantamine, whereas there were no statistically significant differences among groups in patients with milder dementia. All patients taking galantamine were able to maintain their level of ADL, whereas patients taking placebo declined from their baseline ADL. Galantamine had a beneficial effect on ADL and instrumental ADL.

Patients receiving galantamine were able to preserve independence in approximately one ADL over the five-month study compared with those receiving placebo. Patients receiving galantamine over five months were able to maintain or improve their ADL, whereas patients receiving placebo declined. Patients with severe dementia showed statistically significant differences in preservation of ADL, as opposed to the merely numerical differences that held for all cognitive levels. This greater benefit of galantamine in the severely demented can be explained by the fact that patients with more severe dementia tend to have more rapid declines than patients with mild disease. ADL are a useful measure of caregiver burden and loss of basic ADL predict institutionalization. ADL are likely to represent a different domain of skills than cognitive function, and may have greater real-world relevance.

Galasko D, et al. Galantamine maintains ability to perform activities of daily living in patients with Alzheimer's disease. J Am Geriatr Soc July 2004;52:1070-6.

Return to Galantamine

Home

Contact

Resources

Exchange Links

ebay