Of -vincamine

DOS 2 337 202 (Centre d Etudes pour I lndustrie Pharmaceutique appl. 21.7.1973 F-prior. 24.7.1972). 5 bromonicotinate of vincamine ... 

Scheme 21. Structures of vincamine (79) and heteroyohimbines (81a-d) and their metabolites.

Maincent P, Le Verge R, Sado P, Couvreur P, Devissaguet JP (1986) Disposition kinetics and oral bioavailability of vincamine-loaded polyalkyl cyanoacrylate nanoparticles. J Pharm Sci 75 955-958. 

A formal total synthesis of vincamine (144) was achieved, once again by capitalizing upon the ability to affect oxidation... 

The latter served as a key-coupling partner with tryptophyl bromide (142) en route to the assembly of vincamine (144). 

Oipe HR, Steinmann MW. (1982). The effect of vincamine, Hydergine, and piracetam on the firing rate of iocus coeruieus neurons. J Neural Transm. 55(2) 101-9. 

Trifluorinated analogues of monomorin, an indolizidin-type alkaloid that is an ant pheromone,and of vincamine derivatives have been described (Figure 4.54). ... 

The c.d. spectra of vincamine and a number of close relatives have been discussed.89... 

In the eburnamine-vincamine sub-group, Takano etal. have given details99" of their synthesis of ( )-eburnamine.99i Other synthetic work reported includes further preparations of ( )-vincamone (eburnamonine)100" and ethyl apovin-caminate,100 and a modification of Szantay s route to vincamine which was intended to result in an asymmetric synthesis of vincamine-5-carboxylic acid, since L-tryptophan was used as starting material. Unfortunately, racemization of C-5 occurred during the synthesis, so the final product was an ester of ( )-vincamine-5-carboxylic acid.101... 

Details of the synthesis of cylindrocarine, cylindrocarpidine, and cylindro-carpine have now been published,125 as have details of an earlier synthesis of vincamine.126... 

Appropriate modification of Szantay s synthesis of vincamine has enabled the synthesis of 10-methoxyvincamine (isovincine) to be completed.129 Although it is not yet known as a natural product, it was clearly of interest to prepare isovincine in order to be able to examine the relationship between structure and pharmacological activity. 

The oxidation of vincamine by means of trifluoroperacetic acid simply gives the keto-lactam that results from oxidative fission of the indole 2,7 bond.71... 

Figure 7. Separation of (+)-vincamine (2 mg) and (+)-apovincamine (3 mg) on 6-cyclodextrin polymer (1.6x90 cm, pH 5 citrate buffer, flow rate 80 ml/h, 20 °C).

Methoxyvincamine (vincine, XXXV R = OMe), whose ring A methoxyl is so placed because of its UV-spectrum and a color reaction specific for that position, had properties (Chart III) that paralleled those of vincamine (21). This conclusion was reached independently on the basis of mass spectral comparisons (18). The stereochemistry of both alkaloids is regarded as being the same (21). Tetradehydro compounds (XXXVII) were formed by lead tetraacetate oxidation, and XXXVII... 

Z-Eburnamonine (XXXVI) has been produced by other reactions of vincamine. Oxidation of vincaminic acid (XL R = H) by means of ammoniacal silver nitrate was one way, and periodic acid fission of vincaminol was another (16). A different group of workers, who had probably attempted to prepare vincaminol by lithium aluminum hydride reduction of vincamine, obtained instead Z-ebumamonine in excellent yield (18). This has been rationalized as illustrated (partial formulas) by analogy with the base-induced decomposition of formic esters to carbon monoxide and alkoxide ion ... 

Perivincine (37) and isovincamine (38) were shown (36) to be mixtures of vincamine and vincine. c Suggested structures based on the present summary (proved, see footnote in Reference 46). 

Crude extracts of V. minor have shown a hypotensive effect in experimental animals (76) which is believed to be owing almost entirely to its vincamine content (77), and success has been claimed for clinical studies in middle Europe of purified alkaloid extracts (78). Besides this property, vincamine also has a curare-like property (79) and is known to induce strychnine-like convulsions in rabbits (80). The ability of vincamine to reduce blood sugar in an acute test in rats is apparently not because of the inhibition of hepatic glycogenolysis (81). The medicinal uses of V. minor have recently been reviewed (82). 

Most of the applications of Mannich base chemistry arc undoubtedly devoted to the synthesis of alkaloids, although some other studies, such as those dealing with the racemization of intermediates in the synthesis of vincamines or the production of derivatives for pharmacological purposes, arc also reported in the literature. 

Through a biomimetic approach, tabersonine is also the semisynthetic precursor of vincamine, a Eburna alkaloid isolated from Vinca minor, and is used for cerebral insufficiency in Europe. Tabemanthe iboga has a long history of use as a stimulant in tropical Africa its main active principle is ibogaine, a controlled substance in many countries (Fig. 40). It is being actively investigated in the United States for its potential to induce opium addiction withdrawal. 

Vincamine is an alkaloid extracted from the plant Vinca minor. Ethyl apovincaminate is a related synthetic ethyl ester of vincaminic acid. These drugs have spasmolytic effects similar to those of reserpine, but also have metabolic effects, including, in high doses, inhibition of phosphodiesterase. Although increased cerebral blood flow has been reported after the intravenous administration of vincamine, there have been no reliable studies of blood flow after oral medication. Improvement in scores on some psychometric tests have been obtained in some patients with cerebrovascular disease, but no clear-cut practical benefit has been demonstrated. 

Ban and coworkers completed a formal total synthesis of vincamine (101) by capitalizing upon the electrochemical oxidation of the piperidine carboxylic acid ester 96 [24]. Thus, when oxidized at a constant current (CCE 30 mA) in methanol at room temperature (Et4NC104 8.2F/mol), 96 was converted to 97, a material that, when treated with formic acid, afforded lactone 98 in a 76% yield after chromatography. Hydrogenation, hydro-... 

Schultz, A. G., Malachowski, W. P., Pan, Y. Asymmetric Total Synthesis of (+)-Apovincamine and a Formal Synthesis of (+)-Vincamine. Demonstration of a Practical "Asymmetric Linkage" between Aromatic Carboxylic Acids and Chiral Acyclic Substrates. J. Org. Chem. 1997, 62, 1223-1229. 

Hoppen et al. used a packed SE-30 column for the assay of vincamine in plasma. The molecular ion (m/e 426) and the parent peak (m/e 367) of the trimethyl silyl derivatives were assayed simultaneously by selected ion monitoring.Down to 30 pg/ml plasma could be assayed. The method is suitable for pharmacokinetic studies. Plasma samples of EDTA-anticoaaulated blood (1-2 ml) were extracted with hexane after addition of tris(hydroxymethyl)aminomethane. The aqueous phase was frozen out and the hexane phase decanted into a conical glass tube. 

Dubruc et al. reported the analysis of vincamine in plasma. Analysis was performed on an octadecyl bonded stationary phase. Large volumes (0.5 ml) of the sample in a non-eluting solvent (0.02 M aqueous potassium phosphate) were used for automatic operation of the analysis. 

Szepesi et al. reported an ion-pair separation of eburnane alkaloids on a chemically bonded cyanopropyl stationary phase. As counter-ion, di-(2-ethyl hexyl)phosphoric acid or (+)-10-camphorsulfonic acid were used in a mobile phase consisting of hexane - chloroform -acetonitrile mixtures (Table 8.8, 8.9). Because of the poor solubility of the latter pairing ion, diethylamine (Table 8.9) was added to the mobile phase. Addition of diethylamine considerably reduced the k1 of the alkaloids, due to suppression of the ionization of the alkaloids. However, due to the strong acidic character of the pairing ion, ion-pairs were still formed under these conditions. The camphorsulfonic acid containing mobile phases were found to be very useful for the separation of optical isomers (Table 8.10, 8.11, Fig.8.8) 6. It was also found that the selectivity of the system could be altered by choosing different medium-polarity solvents (moderator solvents) as dioxane, chloroform or tetrahydrofuran. The polar component of the solvent system affected peak shape. Based on these observations, a method was developed to analyze the optical purity of vincamine and vinpocetine. For the ana-... 

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