Physostigmine derivatives

Eserine blue (250), formed from a reaction of rubreserine with ammonia (315), was reported to exhibit very low potency in a horse serum butyrylcholinesterase assay (314). A later communication (316)suggests total inactivity of these latter two physostigmine derivatives. 

Carbamate Insecticides. These are stmcturaUy optimi2ed derivatives of the unique plant alkaloid physostigmine [57-47-6] a cholinergic dmg isolated in 1864 from Phjsostigma venenosum (see Alkaloids) (17,24,35—39). The carbamates maybe considered synthetic derivatives of the synaptic neurotransmitter acetylcholine, with very low turnover numbers. The A/,A/-dimethylcarbamates of heterocycHc enols (36) and the Ai-methylcarbamates of a variety of substituted phenols (35) with a wide range of insecticidal activity were described in 1954 (35). The latter are the most widely used carbamate insecticides, and the A/-methylcatbamates of oximes have subsequentiy been found to be effective systemic insecticides. 

Physostigmine (36) is actually a complex fused heterocycle iMther than a simple derivative of aniline. The drug is men-... 

The relative inaccessibility of physostigmine led to molecular dissection studies to define the parts of the molecule necessary for activity. A surprisingly simple derivative of m-hydroxy-aniline, neostigmine (40), proved to have the same activity as the complex heterocyclic molecule. In addition, this drug has found use as a cholinsterase inhibitor in pathologic conditions such as myasthenia gravis, marked by insufficient muscle tone. Reaction of m-dimethylaminophenol (37) witn pnosgene affords tne... 

Materials required The cholinesterase preparation (biotests or simple extracts from biological tissues), the reagents for a reaction medium choosen (see section 3.2.), alkaloid physostigmine salycilate and its derivative neostigmine ("Sigma"). 

Catalysis of the C-alkylation of 5-methyoxy-l,3-dimethyloxindole with chloroacetonitrile by A-(3,4-dichlorobenzyl)cinchoninium or quininium chloride leads in good yield to the (5)-3-alkylatcd derivative (78% ee), which provides an efficient stereospecific route to the anticholinesterase agent, (-)-physostigmine [9]. Other analogous alkylation reactions have been reported [10]. 

Traditionally, plants are a rich source of AChE inhibitors. People from the Caucasus used bulbs of snowdrops Galanthus sp.) to treat forgetfulness [25]. The active compound in this plant has been isolated and called galanthamine. Other plant-derived AChE inhibitors used for treatment of Alzheimer s disease include Huperzine A from Huperzia serrata and Rivastigmine (Excelon). The latter is a derivative from physostigmine isolated from the calabar bean, Physos-tigma vmmosum. 

The discovery of insecticidal carbamates arose independently from studies on the naturally occurring toxin physostigmine (86), and from research on insect repellants. The latter produced some pyrazoles of which isolan was an example (87) (68MI10701), derived from 3-methyl-5-pyrazolone which is made by condensation of hydrazine with ethyl acetoacetate. 

Although the annelated octahydropyrrolo[2,3-b ]pyrrole unit occurs in the physostigmine-type alkaloids, simple systems were reported only in 1978. DIBAL reduction of the pyrrolidones (348) furnished the octahydropyrrolo[2,3-b jpyrrole derivatives (349 Scheme 120). It is interesting to note that LAH failed to bring about ring closure (78JOC4276). 

A series of tricyclic indole alkaloids (physostigmine alkaloids) has been obtained from the cheilostome bryozoan Flustrafoliacea (90). In addition, flustramide B (83) and flustrarine B (84) were isolated from this bryozoan (91). Flustrarine B (84) was prepared from previously known fiustramine B (85) (92) via oxidation with hydrogen peroxide. Five fiustramine derivatives, dihydroflustramine C (86) and its N-oxide (87), fiustramine D (88) and its N-oxide (89), and isoflustramine D (90), were isolated from the methylene chloride fraction of the aqueous methanol extract of a Canadian F. foliacea, and these alkaloids were found to be responsible for the antimicrobial activity of the extract (93). Oxidation of dihydroflustramine C (86) and fiustramine D (88) with m-chloroperbenzoic acid afforded the corresponding A-oxides (87 and 88, respectively). 

Azomethine ylids derived from amidines undergo internal [3 + 2]cyclization reactions with a styrenic double bond present in the starting amidine. This strategy has been applied to the synthesis of physostigmine and erythramine. 

In the following sections we will discuss the development of carbamates as AD drugs. A full list of these can be found elsewhere [31], but in the following section we will describe only some of the close derivatives of physostigmine, with special focus on rivastigmine. 

In rivastigmine (see Fig. 12.5), which was modeled in miotin s skeleton, the tricyclic eseroline of physostigmine is simplified into a benzylamine system. As detailed above, Stedman found that the m-Me2N-CH(CH3)-aryl derivative (miotin ... 

Derivatives. A table listing physical constants of derivatives and transformation products of physostigmine is given in Volume II of this series (page 462 ff.). 

The proof of structure of dehydroesermetholemethine gave considerable further support to the 3a-methylpyrrolo[2,3-6]indole structure for physostigmine proposed by Robinson. The Robinson structure for the alkaloid also was derived easily from tryptophan, thus offering an obvious biogenetic route of synthesis by the plant (this will be discussed in more detail later). 

---